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RE49782 | DETAILED DESCRIPTION The technical solutions of the embodiments will be described in a clearly and fully understandable way in connection with the drawings related to the embodiments of the disclosure. Apparently, the described embodiments are just a part but not all of the embodiments of the disclosure. Based on the described embodiments herein, those skilled in the art can obtain other embodiment(s), without any inventive work, which should be within the scope of the disclosure. The transistors used in all the embodiments of the present disclosure can be thin film transistors or field effect transistors, or other devices with the same characteristics. In the present embodiment, the drain electrode and source electrode of each transistor can be interchanged. Therefore, the drain electrode and the source electrode of each transistor in the embodiments of the present disclosure are no difference in practice. Here, just to distinguish between the two electrodes of a transistor other than its gate electrode, one of them is referred to as a drain electrode while the other is referred to as a source electrode. The present disclosure provides a shift register, which can reduce the noise at the output terminal of the shift register and improve the driving ability of the shift register. FIG.1shows a block diagram of a shift register according to an embodiment of the present disclosure. As illustrated inFIG.1, in an embodiment, the shift register includes an input unit11, a pull-up unit12, a pull-up control unit13, a pull-down unit14, a pull-down control unit15, a first noise reduction unit16, and a second noise reduction unit17. A first terminal of the input unit11is connected with an input terminal INPUT of the shift register to receive an input signal from the input terminal INPUT, a second terminal of the input unit11is connected with a first clock signal terminal CK1, and a third terminal of the input unit11is connected with a first node N1. The input unit11is configured to provide the input signal to the first node N1under control of a first clock signal from the first clock signal terminal CK1. A first terminal of the pull-up unit12is connected with a first supply voltage terminal VGH, a second terminal of the pull-up unit12is connected with a second node N2, and a third terminal of the pull-up unit12is connected with an output terminal OUTPUT of the shift register. The pull-up unit12is configured to provide a voltage of the first supply voltage terminal VGH to the output terminal OUTPUT under control of a voltage of the second node N2. A first terminal of the pull-up control unit13is connected with a second clock signal terminal CK2, a second terminal of the pull-up control unit13is connected with the first supply voltage terminal VGH, a third terminal of the pull-up control unit13is connected with the second node N2, a fourth terminal of the pull-up control unit13is connected with the input terminal INPUT, and a fifth terminal of the pull-up control unit13is connected with a second supply voltage terminal VGL. The pull-up control unit13is configured to provide the voltage of the first supply voltage terminal VGH to the second node N2under control of the input signal, or to provide a voltage of the second supply voltage terminal VGL to the second node N2under control of a second clock signal from the second clock signal terminal CK2. A first terminal of the pull-down unit14is connected with the first node N1, a second terminal of the pull-down unit14is connected with a third clock signal terminal CK3, and a third terminal of the pull-down unit14is connected with the output terminal OUTPUT. The pull-down unit14is configured to provide a third clock signal from the third clock signal terminal CK3to the output terminal OUTPUT under control of a voltage of the first node N1. A first terminal of the pull-down control unit15is connected with the first supply voltage terminal VGH, a second terminal of the pull-down control unit15is connected with the first node N1, and a third terminal of the pull-down control unit15is connected with the second node N2. The pull-down control unit15is configured to provide the voltage of the first supply voltage terminal VGH to the first node N1under control of a voltage of the second node N2. A first terminal of the first noise reduction unit16is connected with the third clock signal terminal CK3, a second terminal of the first noise reduction unit16is connected with the output terminal OUTPUT, and a third terminal of the first noise reduction unit16is connected with the third node N3. The first noise reduction unit16is configured to reduce the electrical leakage of the input unit11to the first node N1by adjusting a voltage of the third node N3. A first terminal of the second noise reduction unit17is connected with a fourth node N4, a second terminal of the second noise reduction unit17is connected with the first node N1, and a third terminal of the second noise reduction unit17is connected with the second supply voltage terminal VGL. The second noise reduction unit17is configured to reduce the electrical leakage of the pull-down control unit15to the first node N1by adjusting a voltage of the fourth node N4. The third node N3is a connection node between the first noise reduction unit16and the input unit11, and the fourth node N4is a connection node between the second noise reduction unit17and the pull-down control unit15. The first noise reduction unit16and the second noise reduction unit17maintain the level of the first node N1by reducing the electrical leakage of the input unit11and the pull-down control unit15to the first node N1, so as to reduce the noise at the output terminal of the shift register. The duty cycles of the first, second and third clock signal from the above-described first, second and third clock signal terminal are 33%. The first supply voltage terminal VGH is a high supply voltage terminal while the second supply voltage terminal VGL is a low supply voltage terminal. FIG.2shows an exemplary circuit structural diagram of a shift register according to an embodiment of the present disclosure. Hereinafter, description is given with respect to a case where the transistors inFIG.2are all p-type transistors which are respectively turned on when low levels are inputted to their gate electrodes respectively. As illustrated inFIG.2, in an embodiment, for example, the input unit11includes a first transistor M1and a second transistor M2. A gate electrode of the first transistor M1is connected with the first clock signal terminal CK1, a first electrode of the first transistor M1is connected with the input terminal INPUT, and a second electrode of the first transistor M1is connected with the third node N3. A gate electrode of the second transistor M2is connected with the first clock signal terminal CK1, a first electrode of the second transistor M2is connected with the third node N3and a second electrode of the second transistor M2is connected with the first node N1. When the first clock signal from the first clock signal terminal CK1is at a low level, the first transistor M1and the second transistor M2are both turned on, and the input signal from the input terminal INPUT is transmitted to the first node N1. In an embodiment, for example, the pull-up unit12includes a third transistor M3and a first capacitor C1. A gate electrode of the third transistor M3is connected with the second node N2, a first electrode of the third transistor M3is connected with the first supply voltage terminal VGH and a second electrode of the third transistor M3is connected with the output terminal OUTPUT. A first end of the first capacitor C1is connected with the second node N2and a second end of the first capacitor C1is connected with the first supply voltage terminal VGH. When the voltage of the second node N2is at a low level, the third transistor M3is turned on, and the voltage of the first supply voltage terminal VGH is provided to the output terminal OUTPUT. In an embodiment, for example, the pull-up control unit13includes a fourth transistor M4and a fifth transistor M5. A gate electrode of the fourth transistor M4is connected with the input terminal INPUT, a first electrode of the fourth transistor M4is connected with the first supply voltage terminal VGH and a second electrode of the fourth transistor M4is connected with the second node N2. A gate electrode of the fifth transistor M5is connected with the second clock signal terminal CK2, a first electrode of the fifth transistor M5is connected with the second node N2and a second electrode of the fifth transistor M5is connected with the second supply voltage terminal VGL. For example, when the second clock signal from the second clock signal terminal VGL is at a low level, the fifth transistor M5is turned on, and the voltage of the second supply voltage terminal VGL is provided to the second node N2; when the input signal from the input terminal INPUT is at a low level, the fourth transistor M4is turned on, and the voltage of the first supply voltage terminal VGH is provided to the second node N2. In an embodiment, for example, the pull-down unit14includes a sixth transistor M6and a second capacitor C2. A gate electrode of the sixth transistor M6is connected with the first node N1, a first electrode of the sixth transistor M6is connected with the output terminal OUTPUT and a second electrode of the sixth transistor M6is connected with the third clock signal terminal CK3. A first end of the second capacitor C2is connected with the first node N1and a second end of the second capacitor C2is connected with the output terminal OUTPUT. When the voltage of the first node N1is at a low level, the sixth transistor M6is turned on, and the third clock signal from the third clock signal terminal CK3is provided to the output terminal OUTPUT. In an embodiment, for example, the pull-down control unit15includes a seventh transistor M7and a eighth transistor M8. A gate electrode of the seventh transistor M7is connected with the second node N2, a first electrode of the seventh transistor M7is connected with the first supply voltage terminal VGH and a second electrode of the seventh transistor M7is connected with the fourth node N4. A gate electrode of the eighth transistor M8is connected with the second node N2, a first electrode of the eighth transistor M8is connected with the fourth node N4and a second electrode of the eighth transistor M8is connected with the first node N1. When the voltage of the second node N2is at a low level, the seventh transistor M7and the eighth transistor M8are respectively turned on, and the voltage of the first supply voltage terminal VGH is provided to the first node N1. In an embodiment, for example, the first noise reduction unit16includes a ninth transistor M9, with a gate electrode of the ninth transistor M9is connected with the output terminal OUTPUT, a first electrode of the ninth transistor M9is connected with the third clock signal terminal CK3and a second electrode of the ninth transistor M9is connected with the third node N3. When the output signal of the output terminal OUTPUT is at a low level and the third clock signal from the third clock signal terminal CK3is at a low level, the ninth transistor M9is turned on, so that the voltage of the third node N3is pulled down to reduce the electrical leakage of the above-described second transistor M2to the first node N1and reduce the influence on the level of the first node N1, which reduces the influence on the level of a gate electrode of the driving transistor, that is, the sixth transistor M6, reducing noise at the output terminal of the shift register and improve the driving ability of the driving transistor. In an embodiment, for example, the second noise reduction unit17includes a tenth transistor M10, with a gate electrode of the tenth transistor M10is connected with the first node N1, a first electrode of the tenth transistor M10is connected with the fourth node N4and a second electrode of the tenth transistor M10is connected with the second supply voltage terminal VGL. When the voltage of the first node N1is at a low level, the tenth transistor M10is turned on, so that the voltage of the fourth node N4is pulled down to reduce electrical leakage of the above-described eighth transistor M8to the first node N1and reduce the influence on the level of the first node N1, so that the level of the first node N1can be continuously maintained at a low level, which reduces the influence on the level of a gate electrode of the driving transistor, that is, the sixth transistor M6, reducing noise at the output terminal and improve the driving ability of the driving transistor. It can be understood that the specific circuits structures of the input unit11, the pull-up unit12, the pull-up control unit13, the pull-down unit14, the pull-down control unit15, the first noise reduction unit16and the second noise reduction unit17as illustrated inFIG.2are only exemplary. Any other appropriate circuit structure can be adopted for each unit as long as the respective functions can be implemented, which is not limited in the present disclosure. FIG.3shows a timing chart of respective signals when the shift register inFIG.2is scanning. In the following, the specific working process of the shift register according to an embodiment of the present disclosure during scanning will be described with reference toFIG.2andFIG.3. In the present embodiment, the first supply voltage terminal VGH is a high supply voltage terminal while the second supply voltage terminal VGL is a low supply voltage terminal. During the first phase t1(the input phase), the signal input from the input terminal INPUT and the first clock signal of the first clock signal terminal CK1are at a low level VL (which also represents the level of the second supply voltage terminal VGL in the present embodiment), and the third clock signal of the third clock signal terminal CK3is at a high level VH (which also represents the level of the first supply voltage terminal VGH in the present embodiment). The first transistor M1and the second transistor M2are turned on, and the low level signal of the input terminal INPUT is transmitted to the first node N1, and at this time, the first node N1is at a low level. Because there is produced a threshold loss when the p-type transistor transmits a low level, the level of the first node N1is VL+|vthp|, where vthp represents the threshold voltage of the transistor (in this embodiment, it is assumed that all the transistors have the same threshold voltage). Because the first node N1is at a low level, the driving transistor, that is, the sixth transistor M6, is turned on. Because the third clock signal of the third clock signal terminal CK3is at a high level VH, the output terminal OUTPUT outputs a high-level output signal. At the same time, because the signal input from the input terminal INPUT is at a low level, the fourth transistor M4is turned on, the level of the second node N2is pulled to a high level of the first supply voltage terminal VGH and the third transistor M3is turned off. During the second phase t2(the pull-down phase), the signal input from the input terminal INPUT and the first clock signal of the first clock signal terminal CK1are at a high level VH, and the third clock signal of the third clock signal terminal CK3is at a low level VL. Because the sixth transistor M6is turned on in the phase t1and the third clock signal of the third clock signal terminal CK3is at a low level, the output terminal OUTPUT outputs a low-level output signal. Because the first clock signal of the first clock signal terminal CK1is at a high level, the first transistor M1and the second transistor M2are turned off. The level of the second node N2is pulled to a high level in the phase t1, so the seventh transistor M7and the eighth transistor M8are turned off, and the gate electrode of the sixth transistor M6is in a floating state. Because a capacitor has the function of keeping the voltage difference across both ends thereof constant, the voltage difference (VL+|Vthp|−VH) across the two ends of the second capacitor C2remains constant. Therefore, the level of the first node N1decreases as the level of the output terminal OUTPUT decreases, and finally stabilizes at 2VL+|Vthp|−VH. The sixth transistor M6operates in a linear region, the third clock signal of the third clock signal terminal CK3is transmitted to the output terminal OUTPUT without a threshold loss, and the level of the output signal from the output terminal OUTPUT is the level VL. In this process, the output signal at a low level from the output terminal OUTPUT turns on the ninth transistor M9, the level of the third node N3is pulled down, the leakage current of the second transistor M2is reduced, and the influence on the level of the first node N1is reduced, that is, the influence on the level of a gate electrode of the driving transistor (that is the sixth transistor M6) is reduced, reducing the noise at the output terminal of the shift register. At the same time, the level of the first node N1is at a low level, the tenth transistor M10is turned on and the level of the fourth node N4is pulled down, so as to reduce the leakage current of the eighth transistor M8and reduce the influence on the level of the first node N1. So the level of the first node N1can be continuously maintained at a low level, which reduces the influence on the level of a gate electrode of the driving transistor (that is the sixth transistor M6), reduces the noise at the output terminal and improves the driving ability of the driving transistor. During the third phase t3(the pull-up phase), this phase is divided into two sub-phases. In the first sub-phase, the third clock signal of the third clock signal terminal CK3jumps to the high level VH, and the second capacitor C2has a function of keeping the voltage difference across both ends constant. Therefore, the level of the first node N1also jumps to VL+|Vthp|. The sixth transistor M6is still in an on-state and pulls up the level of the output signal from the output terminal OUTPUT to the high level VH of the third clock signal from the third clock signal terminal CK3. In the second sub-phase, the second clock signal of the second clock signal terminal CK2jumps to the low level, the fifth transistor M5is turned on, the level of the second node N2is pulled down, the third transistor M3is turned on, and the level of the output signal from the output terminal OUTPUT remains at high level VH. At the same time, the seventh transistor M7and the eighth transistor M8are turned on, the level of the first node N1is pulled to the high level VH, and the sixth transistor M6is turned off. During the fourth phase t4(the maintaining phase), the second clock signal of the second clock signal terminal CK2periodically jumps to a low level and the level of the second node N2remains at a low level, so that the third transistor M3remains to turn on and the level of the output signal from the output terminal OUTPUT is stable at the high level VH. The first clock signal of the first clock signal terminal CK1periodically jumps to a low level which turns on the first transistor M1and the second transistor M2and stabilizes the level of the first node N1to be the high level VH, therefore ensuring a stable output of the output terminal OUTPUT, and reducing the noise. Then, until the next frame arrives, after the shift register receives the low level signal of the input terminal INPUT, the above-described phases is re-executed. The duty cycles of the first, second and third clock signal from the above-described first, second and third clock signal terminal are 33%. The shift register according to the embodiments of the present disclosure adopts a series-connection transistor structure (for example, transistors M1and M2are connected in series, and transistors M7and M8are connected in series) and, by means of a timing control, connects a corresponding level to the connection points (for example, nodes N3and N4) of the series-connection transistors to reduce the leakage current (for example, the leakage current of the second transistor M2and the leakage current of the eighth transistor M8are reduced), which reduces the influence of the pull-down phase (that is, the output phase) on the level of the gate electrode (that is, the level of the first node N1) of the driving transistor, and thereby eliminating the noise at the output terminal and improving the driving ability of the shift register. The present disclosure further provides a driving method for the above-described shift register. Hereinafter, the method will be described in conjunction withFIG.1andFIG.3. In an embodiment, for example, as illustrated inFIG.1, the shift register includes an input unit11, a pull-up unit12, a pull-up control unit13, a pull-down unit14, a pull-down control unit15, a first noise reduction unit16, and a second noise reduction unit17. The driving method for the shift register includes the following operations: providing the input signal to the first node N1by the input unit11; providing the voltage of the first supply voltage terminal VGH to the output terminal OUTPUT of the shift register by the pull-up unit12; providing the voltage of the first supply voltage terminal VGH or the voltage of a second supply voltage terminal VGL to the second node N2by the pull-up control unit13; providing the third clock signal from the third clock signal terminal CK3to the output terminal OUTPUT by the pull-down unit14; providing the voltage of the first supply voltage terminal VGH to the first node N1by the pull-down control unit15; reducing electrical leakage of the input unit11to the first node N1by adjusting the voltage of the third node N3by the first noise reduction unit16; and reducing electrical leakage of the pull-down control unit15to the first node N1by adjusting the voltage of the fourth node N4by the second noise reduction unit17. Here the first node N1is a connection node among the input unit11, the pull-down unit14, the pull-down control unit15and the second noise reduction unit17, the second node N2is a connection node among the pull-up unit12, the pull-up control unit13, and the pull-down control unit15, the third node N3is a connection node between the first noise reduction unit16and the input unit11, and fourth node N4is a connection node between the second noise reduction unit17and the pull-down control unit15. In the present embodiment, the first supply voltage terminal VGH is a high supply voltage terminal while the second supply voltage terminal VGL is a low supply voltage terminal, and a duty cycle of the third clock signal from the above third clock signal terminal CK3is 33%. FIG.4shows a circuit structural diagram of a known shift register.FIG.5andFIG.6respectively show a comparison diagram between the gate level and the output level of the driving transistors in the shift register inFIG.2and the shift register inFIG.4with the same circuit parameters. As illustrated inFIG.5andFIG.6, the driving ability of the shift register in an embodiment of the present disclosure and a known shift register as shown inFIG.4are compared under the same conditions regarding device size, device model, driving pulse width and load (10 Ω, 60 pF). It can be seen that, in the output phase, the gate level of the driving transistor in the shift register according to the embodiments of the present disclosure is better in the low potential holding effect than the gate level of the driving transistor of the known shift register. Therefore, the delay of the output level of the driving transistor in the shift register according to the embodiments of the present disclosure is correspondingly smaller than the delay of the output level of the driving transistor of the known shift register. The shift register according to an embodiment of the present disclosure adopts a series-connection transistor structure and, by means of a timing control, connect a corresponding level at the connection points of the series-connection transistors to reduce the leakage current, which reduces the influence of the pull-down phase (that is, output phase) on the level of a gate electrode of the driving transistor, thereby eliminating the noise at the output terminal and improving the driving ability of the shift register. An embodiment of the disclosure further provides a gate driving circuit, which includes the shift register in the above-described embodiments. The shift register in the gate driving circuit has the same advantages as the shift register in the above-described embodiments, and the redundant description will be omitted here. An embodiment of the disclosure further provides a display apparatus, which includes the gate driving circuit in the above-described embodiments. Exemplarity, the display apparatus can be any products or components with display functions, such as organic light emitting diode display panels, electronic papers, mobile telephones, tablet computers, TVs, displays, notebook computers, digital picture frames, navigators or the like. According to embodiments of the present disclosure, in the shift register and the driving method thereof, the gate driving circuit and the display apparatus including the shift register, the corresponding level is connected to the connection point of the series-connection transistors to reduce the leakage current at the output phase of the gate level of the driving transistor by the way of adopting a series-connection transistor structure and a timing control, thereby reducing the noise at the output terminal of the shift register and improving the driving ability of the shift register. What have been described above are only specific implementations of the present disclosure, the protection scope of the present disclosure is not limited thereto. Any modifications or substitutions easily occur to those skilled in the art within the technical scope of the present disclosure should be within the protection scope of the present disclosure. Therefore, the protection scope of the present disclosure should be based on the protection scope of the claims. | 26,348 |
RE49783 | DETAILED DESCRIPTION Certain embodiments provide a nonvolatile semiconductor memory device and a memory system capable of improving processing performance. In general, according to an embodiment, a memory device includes a nonvolatile semiconductor memory cell array, a plurality of terminals through which control signals are received to control the memory device, an on-die termination circuit connected to at least one of the terminals and having a variable resistor, and a control circuit. The control circuit is configured to enable the on-die termination circuit in response to an enabling signal to enable the on-die termination circuit, with a resistance of the variable resistor at different values depending on whether a control signal is asserted or deasserted when the enabling signal is received. Hereinafter, embodiments will be described with reference to the drawings. Throughout the drawings, common parts will be assigned common reference numerals in the following description. 1. First Embodiment A nonvolatile semiconductor memory device and a memory system according to a first embodiment will be described. In the following description, it will be described that a NAND flash memory is used as an example of the nonvolatile semiconductor memory device. 1.1 Configuration 1.1.1 Entire Configuration of Memory System Initially, the entire configuration of a memory system according to the present embodiment will be described with reference toFIG.1. As shown inFIG.1, a memory system1includes, for example, a plurality of NAND flash memories10(10_0,10_1,10_2, . . . ), and one controller100. The plurality of memories10is connected to the controller100via a NAND bus. The memory10is a nonvolatile semiconductor memory device, and is, for example, a NAND flash memory. Each of the memories10may include a plurality of memory chips. Here, the memory10may use an arbitrary memory chip, and more specifically, the memory may use, for example, various types of NAND flash memory chips. InFIG.1, three memories10are arranged. However, the number of memories is not limited to three, and may be arbitrarily set. In the present embodiment, the NAND flash memory is used as the nonvolatile semiconductor memory device, but the nonvolatile semiconductor memory device is not necessarily limited thereto. The controller100is connected to a host device200. For example, the controller100controls the respective memories10, or transmits and receives data based on a command from the host device200. 1.1.2 Configuration of Memory Hereinafter, the configuration of the memory10will be described with reference toFIGS.2and3. Although the memory10_0will be described in the following description, the other memories10(10_1,10_2, . . . ) have the same configuration. Initially, a sectional configuration of the memory10_0will be described. As shown inFIG.2, the memory10_0includes a package substrate40, an interface chip20, and a plurality (for example, 8) of memory chips30(30a to30h). For example, the interface chip20and the plurality of memory chips30are sealed on the package substrate40by a mold resin (not shown). The package substrate40mounts the interface chip20and the memory chips30. The package substrate40supplies, for example, a power supply voltage VCC and a ground voltage VSS to the memory chips30and the interface chip20. The package substrate40transmits data between the controller100and the interface chip20. The interface chip20transmits data between the package substrate40and each memory chip30. The memory chip30stores data from the controller100. InFIG.2, the eight memory chips30(30a to30h) are layered. However, the number of memory chips is not limited to eight, and may be arbitrarily set. Hereinafter, the cross-sectional configuration of the memory10_0will be described in more detail. Bumps41are formed on a bottom surface of the package substrate (semiconductor substrate)40. When the nonvolatile semiconductor memory device is a ball grid array (BGA) package, the bump41is a solder ball. The package substrate40is electrically connected to the controller100with the bumps41disposed therebetween. The interface chip (semiconductor chip)20is provided on a top surface of the package substrate40. The eight memory chips30(30a to30h) are provided above the interface chip20and the package substrate40. The eight memory chips30a to30h are sequentially layered from the bottom. Through silicon vias (TSV)31which arrive at the bottom surface from the top surface are formed in each of the memory chips30a to30g except for the topmost memory chip30h. Bumps32for electrically connecting the TSVs31of the memory chips30are formed between two adjacent memory chips30. The topmost memory chip30h may include the TSVs31. A wiring33is formed on a bottom surface of the bottommost memory chip30a. Bumps21are formed between the wiring33and the interface chip20. Bumps42are formed between the wiring33and the package substrate40. Hereinafter, the configurations of the interface chip20and the memory chip30will be described. As shown inFIG.3, the interface chip20and each memory chip30are connected through the TSVs31. Each memory chip30transmits and receives data to and from the controller100via the interface chip20. The memory chip30includes a memory cell array53which stores data. For example, the memory chip30may be a plane NAND flash memory including the memory cell array53in which memory cells are two-dimensionally arranged on the semiconductor substrate, or may a three-dimensional stacked NAND flash memory including the memory cell array53in which memory cells are three-dimensionally arranged on the semiconductor substrate. For example, the configuration of the memory cell array53of the three-dimensional layered NAND flash memory is described in U.S. patent application Ser. No. 12/407,403 which is entitled “THREE DIMENSIONAL STACKED NONVOLATILE SEMICONDUCTOR MEMORY” and is filed on Mar. 19, 2009. The configuration of the memory cell array of the three-dimensional stacked NAND flash memory is described in U.S. patent application Ser. No. 12/406,524 which is entitled “THREE DIMENSIONAL STACKED NONVOLATILE SEMICONDUCTOR MEMORY” and is filed on Mar. 18, 2009, U.S. patent application Ser. No. 12/679,991 which is entitled “NON-VOLATILE SEMICONDUCTOR STORAGE DEVICE AND METHOD OF MANUFACTURING THE SAME” and is filed on Mar. 25, 2010, and U.S. patent application Ser. No. 12/532,030 which is entitled “SEMICONDUCTOR MEMORY AND METHOD FOR MANUFACTURING SAME” and is filed on Mar. 21, 2009. All of these patent applications are herein incorporated by reference in their entirety. The interface clip20includes an input and output control circuit50, a logic circuit51, and an on-die termination (ODT) control circuit52. In order to transmit and receive signals including data to and from the outside (controller100), the interface chip20includes a plurality of terminals corresponding to 8-bit data line DQ[7:0], clock signals DQS and DQSn, read enable signals RE and REn, a chip enable signal CEn, a command latch enable signal CLE, an address latch enable signal ALE, a write enable signal WEn, a write protect signal WPn, and an ODT enable signal ODTEN. The logic circuit51receives control signals, for example, the read enable signals RE and REn, the chip enable signal CEn, the command latch enable signal CLE, the address latch enable signal ALE, the write enable signal WEn, the write protect signal WPn, and the ODT enable signal ODTEN from the controller100. The logic circuit51is connected to a plurality of terminals corresponding to the plurality of control signals. The logic circuit51includes a non-shown ODT circuit that is connected a terminal which receives the read enable signals RE and REn. The ODT circuit is a circuit that terminates signal reflection occurring between the outside (controller100) and the memory in the input and output of the signal. The logic circuit51transmits the received signal to the ODT control circuit52. The chip enable signal CEn is a signal for enabling the memory10, and is asserted at a low (“L”) level. The command latch enable signal CLE is a signal indicating that an input and output signal I/O is a command, and is asserted at a high (“H”) level. The address latch enable signal ALE is a signal indicating that the input and output signal I/O is an address, and is asserted at an “H” level. The write enable signal WEn is a signal for acquiring the received signal into the memory10, and is asserted at an “L” level each time the command, address and data are received by the controller100. Thus, each time the signal WEn is toggled, the signal is acquired into the memory10. The rend enable signals RE and REn are signals for allowing the controller100to read data from the memory10. The read enable signal REn is an inverted signal of the signal RE. For example, the read enable signal REn is asserted at an “L” level. The write protect signal WPn is a signal for commanding the prohibition of a write operation, and is asserted at an “L” level. The ODT enable signal ODTEN is a signal which controls an ON/OFF state of the ODT circuit within the memory10, and is asserted at an “H” level. The input and output control circuit50is connected to terminals corresponding to the data line DQ[7:0] and the clock signals DQS and DQSn. The input and output control circuit50includes an ODT circuit (not shown inFIG.3) that is connected to terminals corresponding to the data line DQ[7:0] and the clock signals DQS and DQSn. The input and output control circuit50controls the input and output of an 8-bit input and output data signal IO[7:0] and the clock signals DQS and DQSn transmitted and received between the controller100and the memory10through the data line DQ[7:0]. The input and output data signal IO[7:0] is an 8-bit data signal, and includes various commands, addresses, and data. The input and output data signal IO is not limited to the 8-bit signal, and may be arbitrarily set. The clock signals DQS and DQSn are signals used in the input and output of data, and the clock signal DQSn is an inverted signal of the clock signal DQS. Hereinafter, various signals are transmitted and received through a signal line (hereinafter, referred to as a “common signal line”) that connects the controller100and the memories10in common unless particularly limited. In the present embodiment, the chip enable signal CEn, the command latch enable signal CLE, the address latch enable signal ALE, the write enable signal Wen, and the ODT enable signal ODTEN may be transmitted using the common signal line, or may be transmitted using signal lines (hereinafter, referred to as “individual signal lines”) that individually connect the controller100and the memories10. The ODT control circuit52includes a parameter storage unit54. The ODT control circuit52controls the ODT circuits included in the input and output circuit50and the logic circuit51based on the setting of the parameter stored in the parameter storage unit54and the ODT enable signal and other signals transmitted from the logic circuit51. The parameter storage unit54stores parameters regarding the ODT circuits. The ODT control circuit52may not include a memory region, or may retain the parameters in another memory region. 1.1.3 Configuration of ODT Circuit Hereinafter, the configuration of the ODT circuit will be described with reference toFIGS.4and5. Initially, the ODT circuit included in the input and output control circuit50will be described. As shown inFIG.4, the input and output control circuit50includes an ODT circuit60, an input receiver64, and an output driver65for each corresponding terminal. The input receiver64functions as, for example, a buffer, converts an input signal from the controller100into, for example, an appropriate voltage level for processing the signal within the memory10, and transmits the converted signal to other circuits within the interface chip20and the memory chip30. The output driver65functions as, for example, a buffer, converts a signal transmitted from the memory chip30into an appropriate voltage level, and outputs the converted signal to the controller100. The ODT circuit60is provided between the terminal and the input receiver64. The ODT circuit60includes a p-channel MOS transistor61, an n-channel MOS transistor62, and variable resistance elements63a and63b. A signal ODTSn is input to a gate of the p-channel MOS transistor61, a poster supply voltage VCC is applied to a source thereof, and a drain thereof is connected to one end of the variable resistance element63a. The p-channel MOS transistor61functions as a first switch element for connecting the variable resistance element63a to a voltage line (power supply voltage line) to which the power supply voltage VCC is applied. The other end of the variable resistance element63a is connected to one end of the variable resistance element63b and a wiring that connects the terminal and the input receiver64. The ODT control circuit52sets resistance values of the variable resistance elements63a and63b according to a parameter written during a process of Set Feature (described below). A signal ODTS is applied to a gate of the n-channel MOS transistor62, a drain thereof is connected to the other end of the variable resistance element63b, and a ground voltage VSS is applied to a source thereof. The n-channel MOS transistor62functions as a second switch element for connecting the variable resistance element63b to a voltage line (ground voltage line) to which the ground voltage VSS is applied. The signal ODTS and the signal ODTSn are signals applied from the ODT control circuit52in order to control the ODT circuit60. The signal ODTSn is an inverted signal of the signal ODTS. When the ODT circuit60is turned on, the ODT control circuit52sets the signal ODTS to an “H” level, and sets the signal ODTSn to an “L” level. Hereinafter, the ODT circuit60included in the logic circuit51will be described. As shown inFIG.5, the logic circuit51includes an input receiver64for each corresponding terminal (reference numeral “PAD” ofFIG.5). The ODT circuit60is provided between the input receiver64and the terminals corresponding to the read enable signals REn and RE. The ODT circuit60connected to the terminals corresponding to the read enable signals REn and RE may not be provided, or the ODT circuit60connected to other terminals may be provided. The ODT circuit may be arbitrarily set. 1.2 Operation of ODT circuit Hereinafter, the operation of the ODT circuit60will be described. The ODT control circuit52has two control modes called a “DIN mode” and a “DOUT mode”. The ODT control circuit52selects one or more ODT circuits60to be turned on depending on the control modes. The DIN mode is a mode selected when the controller100outputs the data and a write operation is performed in a memory10. Meanwhile, the DOUT mode is a mode selected when a read operation is performed in a memory10and the memory10outputs data. Hereinafter, in the present embodiment, a case where the ODT circuit60corresponding to the data line DQ[7:0] and the clock signals DQS and DQSn is turned on in the DIN mode and the ODT circuit60corresponding to the data line DQ[7:0], the clock signals DQS and DQSn and the read enable signals REn and RE is turned on in the DOUT mode will be described. 1.2.1 Control Flow of ODT Circuit Initially, the control flow of the ODT circuit60will be described with reference toFIG.6. As shown inFIG.6, as the control of the ODT circuit60, there are broadly two operations. In the first operation, the controller100sets the parameter of the ODT circuit60(step S1). Hereinafter, the write operation of the parameter is referred to as “Set Feature”. During the Set Feature, various parameters other than the parameter of the ODT circuit60are written. More specifically, for example, after power is supplied, the controller100performs the Set Feature and sets various parameters during a first operation. In this case, the controller100determines setting of whether or not to use the ODT circuit60in the interface chip20of the memory10. For example, the controller100determines setting such that only the interface chip20of the memory10that is connected through the longest signal line (NAND bus) to the controller100uses the ODT circuit60and the interface chip20of the other memory10does not use the ODT circuit60. The controller100sets the resistance values of the variable resistance elements63a and63b in the DIN mode and the DOUT mode to the interface chip20that can use the ODT circuit60. The ODT control circuit52of the interface chip20retains setting of whether or not to use the ODT circuit60and parameter information regarding the resistance values of the variable resistance elements63a and63b in the parameter storage unit54. Subsequently, the controller100transmits the ODT enable signal ODTEN in a second operation. The ODT control circuit52of the interface chip20of the memory10controls the ON/OFF of the ODT circuit60depending on the parameter information set in the first operation and the ODT enable signal ODTEN. More specifically, initially, the controller100sets the ODT enable signal ODTEN to an “H” level, and transmits the signal to the memory10(step S2). When the ODT circuit60is usable in step S1(step S3Yes), the ODT control circuit52of the memory10which receives the ODT enable signal selects the control mode of the ODT circuit60. Meanwhile, when the ODT circuit60is not usable (Step S3_No), the control operations of the ODT circuit60subsequent to step S3are omitted. When the write operation is performed in any one of the memories10(step S4_Yes), the ODT control circuit52selects the DIN mode. Subsequently, the ODT control circuit52turns on the ODT circuit60corresponding to the data line DQ[7:0] and the clock signals DQS and DQSn (step S5). More specifically, the ODT control circuit52sets the signal ODTS of the corresponding ODT circuit60to an “H” level, and sets the signal ODTSn to an “L” level. Thus, the transistors61and62are turned on, and the ODT circuit60is turned on. Meanwhile, when the write operation is not performed in any one of the memories10, that is, when the read operation is performed, the ODT control circuit52selects the DOUT mode, and turns on the ODT circuit60corresponding to the data line DQ[7:0], the clock signals DQS and DQSn and the read enable signals REn and RE (step S6). Subsequently, the controller100sets the ODT enable signal ODTEN to an “L” level. Accordingly, the ODT control circuit52turns off the ODT circuit60(step S7). When it is not necessary to change the parameter, the controller100controls the ODT circuit60by repeatedly performing the second operation according to the write and read operations. 1.2.2 Control Mode Selection of ODT Circuit Hereinafter, the control mode selection of the ODT circuit60will be described with reference toFIG.7. As shown inFIG.7, the memory10(ODT control circuit52) latches the read enable signal REn at a timing when the ODT enable signal ODTEN is switched from the “L” level to the “H” level. When the read enable signal REn is at the “H” level, the memory10selects the DIN mode, and turns on the corresponding ODT circuit60. Meanwhile, when the read enable signal REn is at the “L” level, the memory10selects the DOUT mode, and turns on the corresponding ODT circuit60. That is, in the write operation, the controller100sets the read enable signal REn to an “H” level, and switches the ODT enable signal ODTEN from an “L” level to an “H” level. In the read operation, the controller sets the read enable signal REn to an “L” level, and switches the ODT enable signal ODTEN from an “L” level to an “H” level. The memory10turns off the ODT circuit60for a period during which the ODT enable signal ODTEN is at an “L” level. 1.2.3 Set Feature Hereinafter, transmission and reception of signals between the controller100and the memory10during the Set Feature will be described with reference toFIG.8. As shown inFIG.8, the controller100initially asserts the chip enable signal CEn (to an “L” level). Subsequently, the controller100issues a command, for example, “D5h” for notifying that the Set Feature is performed, and asserts the command latch enable signal CLE (to an “H” level). Subsequently, the controller100issues address data items “xxh” and “yyh”, and asserts the address latch enable signal ALE (to an “H” level). For example, the address data “xxh” is address data regarding the setting of the Set Feature, and the address data “yyh” is address data indicating the corresponding memory10. The details of the address data and the number of cycles are not particularly limited. These commands and addresses are respectively stored in the corresponding memories10each time the write enable signal WEn is toggled. Subsequently, the controller100transmits the clock signals DQS and DQSn, and issues data “W-B0” to “W-B3”. For example, the data “W-B0” indicate data regarding whether or not the ODT circuit60is usable and the setting of the variable resistance elements63a and63b, and the data “W-B1” to “W-B3” indicate data regarding other parameters. The number of cycles of the data may be arbitrarily set depending on a parameter required to be set. The memory10starts to write the parameter, and turns into a busy state. The memory10sets a ready/busy signal R/Bn for notifying that various signals are not received during the busy state to an “L” level, and transmits the signal to the controller100. When the memory10completes the write operation, the ready/busy signal R/Bn is returned to an “H” level. 1.2.4 Control of ODT Circuit in Write Operation Hereinafter, the transmission and reception of the signal between the controller100and the memory10in the write operation will be described with reference toFIG.9by especially focusing on the control of the ODT circuit60in the non-selected memory10. InFIG.9, the command latch enable signal CLE and the address latch enable signal ALE are omitted. As shown inFIG.9, the controller100initially asserts the chip enable signal CEn (to an “L” level). The controller100maintains the read enable signal REn at an “H” level in the write operation. Subsequently, the controller100issues a command, for example, “80h” for notifying that the write operation is performed, and address data items “AD1”, “AD2”, “AD3”, “AD4” and “AD5”. For example, the address data items “AD1” and “AD2” indicate column addresses of the memory chip30, and the address data items “AD3”, “AD4” and “AD5” indicate row addresses. In the selected memory10, the command and the address data are retained within the memory10each time the write enable signal WEn is toggled. The number of cycles of the address data is not limited to five cycles, and may be arbitrarily set. The address data may include an address for designating the memory10, and a chip address (CADD) for designating the memory chip30within the memory10. The row address may include a block address, and a page address. The page address may include, for example, word lines WL, odd/even-numbered bit lines (E/O), string addresses, or information regarding lower page/intermediate page/upper page (L/M/U). The configuration of the page address is described in U.S. patent application Ser. No. 13/784,753 which is titled “NONVOLATILE SEMICONDUCTOR MEMORY DEVICE AND CONTROL METHOD THEREOF” and is filed on Mar. 4, 2013. The present patent application is herein incorporated by reference in its entirely. Subsequently, the controller100sets the ODT enable signal ODTEN to an “H” level. In this case, in the non-selected memory10in which the GDT circuit60is usable, that is, to which the parameter of the ODT circuit60in the first operation (Set Feature) is set, since the read enable signal REn is at an “H” level, the ODT control circuit52selects the DIN mode, and turns on the corresponding OUT circuit60. Meanwhile, in the non-selected memory10which does not use the ODT circuit60, that is, to which the parameter of the ODT circuit60is not set in the first operation (Set Feature), the ODT control circuit52does not turn on the ODT circuit60irrespective of the ODT enable signal ODTEN. Subsequently, the controller100transmits the clock DQS and DQSn, and issues the write data “WD”. When the write operation in the selected memory10is completed, the controller100sets the chip enable signal CEn to an “H” level, and sets the ODT enable signal ODTEN to an “L” level. When the ODT enable signal ODTEN is at an “L” level, the non-selected memory10in which the ODT circuit60is usable turns off the ODT circuit60. 1.2.5 Control of ODT Circuit in Read Operation Hereinafter, transmission and reception of signals between the controller100and the memory10in the read operation will be described with reference toFIG.10by especially focusing on the control of the ODT circuit60in the non-selected memory10. InFIG.10, the command latch enable signal CLE and the address latch enable signal ALE are omitted. As shown inFIG.10, the controller100asserts the chip enable signal CEn (to an “L” level). Subsequently, the controller100sequentially issues a command, for example, “05h” for notifying that the read operation is perforated, address items “AD1” to “AD5”, and a command, for example, “E0h” for performing the read operation. In the selected memory10, the command and the address data are retained within the memory10each time the write enable signal WEn is toggled. Subsequently, the controller100sets the read enable signal REn to an “L” level during a certain period. The controller100sets the ODT enable signal ODTEN from an “L” level to an “H” level within this period. In this case, in the non-selected memory10that is usable by the ODT circuit60, since the read enable signal REn is at an “L” level, the ODT control circuit52selects the DOUT mode, and turns on the corresponding ODT circuit60. Meanwhile, in the non-selected memory10that does not use the ODT circuit60, the ODT control circuit52does not turn on the ODT circuit60irrespective of the ODT enable signal ODTEN. Subsequently, the read operation is performed in the selected memory10, and the read data “RD” and the clock signals DQS and DQSn are output according to the toggle of the read enable signals REn and RE. When the read operation of the selected memory10is completed, the controller100sets the chip enable signal CEn to an “H” level, and sets the ODT enable signal ODTEN to an “L” level. When the ODT enable signal ODTEN is at an “L” level, the non-selected memory10in which the ODT circuit60is usable turns off the ODT circuit60. 1.2.6 Operation Timing of ODT Circuit Hereinafter, an ON/OFF switching timing of the ODT circuit60and the ODT enable signal ODTEN will be described with reference toFIG.11. As shown inFIG.11, the memory10is set so as not to receive various signals including the read enable signal REn during a predetermined period after the write enable signal WEn is switched from an “L” level to an “H” level. Alternatively, the controller100may be set so as not to voluntarily issue various signals during this period. Hereinafter, the predetermined period, that is, a waiting period from a time at which the write enable signal WEn is switched from an “L” level to an “H” level until the read enable signal REn can be received is referred to as “tWHR”. For example, after the address data “AD5” is input in the write operation (FIG.9) and after the command “E0h” is input in the read operation (FIG.10), the waiting period tWHR is present. After the waiting period tWHR elapses, the memory10receives the read enable signal REn (the read enable signal REn becomes valid). During a period until 25 nsec or longer elapses after the waiting period tWHR ends, the controller100maintains the read enable signal REn at an “H” level in the write operation, and maintains the read enable signal at an “L” level in the read operation (hereinafter, referred to as a “REn maintaining period”). The controller100switches the ODT enable signal ODTEN from an “L” level to an “H” level in a period (for example, 20 nsec) from a time at which 5 nsec or longer elapses since the starting (that is, the ending of the waiting period tWHR) of the REn maintaining period until the REn maintaining period ends. That is, if 5 nsec or longer elapses since the starting of the REn maintaining period, the controller100can switch the ODT enable signal ODTEN in non-synchronization with other signals. At a timing when the ODT enable signal ODTEN is switched from an “L” level to an “H” level, the ODT control circuit52latches the read enable signal REn, and selects the control mode of the ODT circuit60. For example, the ODT control circuit52turns on the corresponding ODT circuit60after 25 nsec elapses from the switching the ODT enable signal ODTEN from an “L” level to an “H” level. For example, the ODT control circuit52turns off the corresponding ODT circuit60after 25 nsec elapses from the switching of the ODT enable signal ODTEN from an “H” level to an “L” level. 1.3 Advantage of Present Embodiment According to the present embodiment, it is possible to improve processing capability. Hereinafter, advantage of the present embodiment will be described. In the memory system1in which the controller100and the plurality of memories10are connected in common through the bus, reflection of a signal from the non-selected memory10is transferred to the selected memory10or the controller100which is an input destination of the signal, the reflected signal becomes a noise of the input signal. For such an issue, there is a method of suppressing the reflection of the signal using the ODT circuit60. For example, there is a method of respective transmitting commands (and address data items) for notifying the non-selected memory10that the use of the ODT circuit60is started and is ended before and after the write or read operation when the ON/OFF operation of the ODT circuit60is controlled in the non-selected memory10. However, in this case, since it is necessary to notify the non-selected memory10irrespective of the write or read operation, processing times in the write and read operations become longer, and thus, the processing capability of the memory system1is degraded. The state of the signal transmitted and received between the controller100and the selected memory10is different between the write operation and the read operation. More specifically, for example, the data are read according to the toggle of the read enable signal REn in the read operation, whereas the read enable signal REn is maintained at an “H” level in the write operation. Accordingly, it is preferable that the ODT circuit60corresponding to the read enable signal REn is used in the read operation and is not used in the write operation. As stated above, it is necessary to control the ON/OFF of the ODT circuit60depending on the operation state of the memory system. In contrast, in the configuration according to the present embodiment, the controller100can issue the signal (ODT enable signal ODTEN) for controlling the ODT circuit60. The controller100can transmit the ODT enable signal ODTEN to the memories10during the write and read operations. The memory10can control the ODT circuit60according to the ODT enable signal ODTEN. Thus, the controller100can omit the notification performed by the ODT circuit60to the non-selected memory10before and after the write or read operations. Accordingly, it is possible to reduce the processing times of the write and read operations, and thus, it is possible to the processing capability of the memory system. According to the present embodiment, it is possible to switch the control mode of the ODT according to the read enable signal REn. More specifically, when the ODT enable signal ODTEN is switched from an “L” level to an “H” level, the memory10selects the DIN mode if the read enable signal REn is at an “H” level, and selects the DOUT mode if the read enable signal is at an “L” level. Thus, the memory10can select the control state of the optimum ODT circuit60in the write and read operations. Accordingly, it is possible to effectively the noise due to the reflection of the signal, and thus, it is possible to the quality of the signal. Therefore, it is possible to suppress a malfunction due to the degradation of the signal, and thus, it is possible to improve the reliability of the memory system. 2. Second Embodiment Hereinafter, a second embodiment will be described. A difference from the first embodiment is that the configuration of the memory10is different and each memory chip includes the ODT circuit. Only a difference from the first embodiment will be described below. 2.1 Configuration of Memory The configuration of the memory10according to the present embodiment will be described with reference toFIGS.12and13. In the following description, the memory10_0will be described, but the other memories10(10_1,10_2, . . . ) have the same configuration. Initially, the sectional configuration of the memory10will be described. As shown inFIG.12, the memory10_0includes a package substrate40and eight memory chips70(70a to70h). For example, the plurality of memory chips70is sealed on the package substrate40by a mold resin (not shown). In the memory10_0according to the present embodiment, the interface chip20described inFIGS.2and3of the first embodiment is not used. Similarly to the memory chip30described inFIGS.2and3of the first embodiment, the memory chip70stores data from the controller100. The eight memory chips70(70a to70h) are layered, but the number of memory chips70is not limited to eight. The number of memory chips may be arbitrarily changed. Each memory chip70includes a plurality of terminals71for transmitting and receiving signals to and from the outside (controller100) on top surfaces of the memory chips70. The memory chips70a to70h are sequentially layered on the top surface of the package substrate40in a state in which the terminals71are exposed, for example, the centers of the memory chips are offset. The terminals71of the memory chips70are electrically connected to the package substrate40through, for example, metal wirings. Hereinafter, the configuration of the memory chip70will be described. In the following description, the memory chip70a will be described, but the other memory chips70b to70h have the same configuration. As shown inFIG.13, the memory chip70a includes an input and output control circuit50, a logic circuit51and an ODT control circuit52included in the interface chip20described inFIG.3of the first embodiment, and a memory cell array53included in the memory chip30. The memory chip70a includes terminals which respectively correspond to read enable signals RE and REn, a chip enable signal CEn, a command latch enable signal CLE, an address latch enable signal ALE, a write enable signal WEn, a write protect signal WPn, and an ODT enable signal ODTEN. Similarly to the first embodiment, the input and output control circuit50of the memory chip70a includes an ODT circuit60connected to terminals corresponding to data line DQ[7:0] and clock signals DQS and DQSn, and the logic circuit includes an ODT circuit60connected to terminals corresponding to read enable signals REn and RE. 2.2 Operation of ODT Circuit Hereinafter, the operation of the ODT circuit60included in the memory chip70will be described. The control flow of the ODT circuit60is the same as that of the first embodiment shown inFIG.6. Here, when the Set Feature is performed during the first operation, the controller100sets a parameter regarding the ODT circuit60for each memory10(interface chip20) in the first embodiment, whereas the controller sets the parameter regarding the ODT circuit60for each memory chip70in the present embodiment. In the second operation, the ODT control circuit52of each memory chip70controls the operation of the ODT circuit60according to the signal transmitted to and received from the controller100. 2.3 Advantage of Present Embodiment In the configuration according to the present embodiment, it is possible to obtain the same advantage as that of the first embodiment. In the configuration according to the present embodiment, since each memory chip70includes the ODT circuit60, whether or nut the ODT circuit60is operated may be set with respect to each memory chip70. Thus, the memory system1can perform the more detailed setting for suppressing the reflected signal. Accordingly, it is possible to more effectively reduce the noise due to the reflection signal, and thus, it is possible to improve the quality of the signal. 3. Third Embodiment Hereinafter, a third embodiment will be described. A difference from the first and second embodiments is that the chip enable signal CEn is also used in the determination when the control mode of the ODT circuit60is determined. Only a difference from the first and second embodiments will be described below. 3.1 Entire Configuration of Memory System Initially, the entire configuration of the memory system1will be described. In the memory system1according to the present embodiment, for the chip enable signals CEn, the controller100and the memories10(10_0,10_1,10_2, . . . ) are connected through individual signal lines. That is, the controller100can respectively transmit different chip enable signals CEn to the memories10by using the individual signal lines. Hereinafter, the chip enable signals are referred to as chip enable signals “CEnx” when the controller100transmits the chip enable signal CEn by using the individual signals, that is, when the chip enable signal indicate the plurality of chip enable signals CEn. The command latch enable signal CLE, the address latch enable signal ALE, the write enable signal Wen, and the ODT enable signal ODTEN may be transmitted using a common signal line, or may be transmitted using individual signal lines. 3.2 Control Mode Selection of ODT Circuit Initially, the selection of the control mode of the ODT circuit60will be described with reference toFIG.14. As shown inFIG.14, in the present embodiment, the ODT control circuit52latches the chip enable signal CEnx and the read enable signal REn at a timing when the ODT enable signal ODTEN is switched from an “L” level to an “H” level. When the chip enable signal CEnx and the read enable signal REn are at an “H” level, the ODT control circuit52selects the DIN mode, and turns on the corresponding ODT circuit60. When the chip enable signal CEnx is at an “H” level and the read enable signal REn is at an “L” level, the ODT control circuit52selects the DOUT mode, and turns on the corresponding ODT circuit60. When the chip enable signal CEnx is at an “L” level, the ODT control circuit52turns off the ODT circuit60irrespective of the read enable signal REn. For a period during which the ODT enable signal ODTEN is at an “L” level, the ODT control circuit52turns off the ODT circuit60. 3.3 Control of ODT Circuit in Write Operation Hereinafter, transmission and reception of signals between the controller100and the memory10in the write operation will be described with reference toFIG.15. As shown inFIG.15, initially, the controller100asserts the chip enable signal CEnx of the selected memory10(to an “L” level). The controller100maintains the non-selected memory10at an “H” level during the write operation of the chip enable signal CEnx. Subsequently, the controller100issues the command and address data for the write operation, and sets the ODT enable signal ODTEN to an “H” level. In this case, in the non-selected memory10in which the ODT circuit60is usable, since the chip enable signal CEnx and the read enable signal REn are at an “H” level, the ODT control circuit52selects the DIN mode, and turns the corresponding to the ODT circuit60. When the write operation of the selected memory10is completed, the controller100sets the chip enable signal CEn of the selected memory10to an “H” level, and sets the ODT enable signal ODTEN “to an “L” level. When the ODT enable signal ODTEN is at an “L” level, the non-selected memory10in which the ODT circuit60is usable turns off the ODT circuit60. 3.4 Control of ODT Circuit in Read Operation Hereinafter, the transmission and reception of the signal between the controller100and the memory10in the read operation will be described with reference toFIG.16. As shown inFIG.16, initially, the controller100asserts the chip enable signal CEnx of the selected memory10(to an “L” level). The controller100maintains the chip enable signal CEnx at an “H” level during the reading of the chip enable signal CEnx in the non-selected memory. Subsequently, the controller100issues the command and the address data for the read operation, and sets the read enable signal REn to an “L” level during a REn maintaining period. The controller100sets the ODT enable signal ODTEN to an “H” level within this period. In the non-selected memory10in which the ODT circuit60is usable, since the chip enable signal CEnx is at an “H” level and the read enable signal REn is at an “L” level, the ODT control circuit52selects the DOUT mode, and turns on the corresponding ODT circuit60. When the read operation of the selected memory10is completed, the controller100sets the chip enable signal CEnx of the selected memory10to an “H” level, and sets the ODT enable signal ODTEN to an “L” level. When the ODT enable signal ODTEN is set to an “L” level, the non-selected memory10in which the ODT circuit60is usable turns off the ODT circuit60. 3.5 Operation Timing of ODT Circuit Hereinafter, an ON/OFF switching timing of the ODT enable signal ODTEN and the ODT circuit60will be described with reference toFIG.17. As shown inFIG.17, the controller100sets the chip enable signal CEnx of the non-selected memory10to an “H” level in a state in which the chip enable signal CEnx becomes valid (a state in which the memory10can receive various signals) after, for example, a waiting period tWHR elapses. Thereafter (for example, after 10 nsec), the controller100sets the read enable signal REn to an “H” level in the write operation. Meanwhile, in the read operation, the controller100sets the read enable signal REn to an “L” level, and maintains the read enable signal at an “L” level for the REn maintaining period (25 nsec or longer). The controller100switches the ODT enable signal ODTEN from an “L” level to an “H” level during a period from a time at which 5 nsec or longer elapses since the starting (that is, the ending of the waiting period tWHR) of the REn maintaining period until the REn maintaining period is ended. For example, in the example ofFIG.17, the ODT enable signal ODTEN is set to an “H” level after 5 nsec (after 15 sec from a state in which the chip enable signal CEnx becomes valid) from the starting of the Ren maintaining period after 10 nsec from a state in which the chip enable signal CEnx becomes valid. The ODT control circuit52latches the chip enable signal CEnx and the read enable signal REn and selects the control mode of the ODT circuit60at a timing when the ODT enable signal ODTEN is switched from an “L” level to an “H” level, and turns on the corresponding ODT circuit60after, for example, 25 nsec elapses. 3.6 Advantage of Present Embodiment The present embodiment can be combined with the first and second embodiments. Thus, it is possible to obtain the same advantage as that of the first and second embodiments. In the configuration according to the present embodiment, the controller100transmits a different chip enable signal CEnx to each memory10. The ODT control circuit52can select the control mode of the ODT circuit60based on the chip enable signal CEnx and the read enable signal REn. Thus, the ODT control circuit52can operate the ODT circuit60only when the corresponding memory10(or the memory chip70) is in the non-selection state (state in which the chip enable signal CEnx is at an “H” level). That is, the memory system1can control the more optimum ODT circuit60depending on the selected memory10. Thus, it is possible to effectively reduce the noise due to the reflection of the signal, and thus, it is possible to improve the quality of the signal. 4. Fourth Embodiment Hereinafter, a fourth embodiment will be described. There is a difference from the third embodiment in that the ODT circuit60is turned on when the ODT enable signal ODTEN and the chip enable signal CEnx are at an “H” level. Only a difference from the third embodiment will be described below. 4.1 Control Mode Selection of ODT Circuit Initially, the selection of the control mode of the ODT circuit60will be described with reference toFIG.18. As shown inFIG.18, when the chip enable signal CEnx and the ODT enable signal ODTEN are set to an “H” level, if the read enable signal REn is at an “H” level, the ODT control circuit52selects the DIN mode, and turns on the corresponding ODT circuit60. Meanwhile, if the read enable signal REn is at an “L” level, the ODT control circuit52selects the DOUT mode, and turns on the corresponding ODT circuit60. The ODT control circuit52latches the read enable signal REn when the ODT circuit60is turned on. Thus, even though the read enable signal REn is changed from an “H” level to an “L” level or from an “L” level to an “H” level for a period during which the ODT circuit60is turned on, the ODT control circuit52maintains the DIN mode or the DOUT mode until the ODT circuit60is turned off. When at least one of the latch enable signal CEnx and the ODT enable signal ODTEN is at an “L” level, the ODT control circuit52turns off the ODT circuit60irrespective of the read enable signal REn. 4.2 Operating Timing of ODT Circuit Hereinafter, An ON/OFF switching timing of the ODT enable signal ODTEN and the ODT circuit60will be described with reference toFIG.19. InFIG.19, the chip enable signal CEnx of the non-selected memory10is maintained at an “H” level when the ODT enable signal ODTEN is at an “H” level. As shown inFIG.19, similarly to the third embodiment, the controller100sets the chip enable signal CEnx of the non-selected memory10to an “H” level in a state in which the chip enable signal CEnx becomes valid (state in which the memory10can receive various signals). Thereafter, the controller100switches the ODT enable signal from an “L” level to an “H” level in a period from a time at which 5 nsec or longer elapses since the starting of the REn maintaining period until the REn maintaining period is ended. The ODT control circuit52latches the read enable signal REn and selects the control mode of the ODT circuit60at a timing when both the chip enable signal CEnx and the ODT enable signal ODTEN are set to an “H” level. The ODT control circuit52turns on the corresponding ODT circuit60after, for example, 25 nsec elapses from a state in which the ODT enable signal ODTEN is switched from an “L” level to an “H” level. Subsequently, the controller100switches the ODT enable signal ODTEN from an “H” level to an “L” level. The controller100maintains the chip enable signal CEnx at an “H” level until, for example, 15 nsec or longer elapses after the ODT enable signal ODTEN is switched from an “H” level to an “L” level. The ODT control circuit52turns off the corresponding ODT circuit60after, for example, 25 nsec elapses from a state in which the ODT enable signal ODTEN is switched from an “H” level to an “L” level. The controller100may previously switch the ODT enable signal ODTEN from an “L” level to an “H” level such that the chip enable signal CEnx becomes valid. The controller100may switch the chip enable signal CEnx from an “H” level to an “L” level earlier than the ODT enable signal ODTEN. 4.3 Advantage of Present Embodiment The present embodiment can be combined with the first and second embodiments, and thus, it is possible to obtain the same advantage as that of the first and second embodiments. Further, according to the present embodiment, it is possible to obtain the same advantage as that of the third embodiment. Moreover, according to the present embodiment, the ODT control circuit52can turn on the ODT circuit60when both the chip enable signal CEnx and the ODT enable signal ODTEN are at an “H” level. 5. Fifth Embodiment Hereinafter, a fifth embodiment will be described. A difference from the first to fourth embodiments is that the write protect signal WPn has a function of the write protect control signal and a function of the control signal of the ODT circuit60. In the present embodiment, two examples will be described. Only a difference from the first to fourth embodiments will be described below. 5.1 First Example Initially, a first example of the present embodiment will be described. In the present example, the functions of the signal input from the terminal are different before and after the parameter is set by the Set Feature. 5.1.1 Entire Configuration of Memory System The entire configuration of the memory system1will be described. In the memory system1according to the present example, the controller100transmits different write protect signals WPn to the memories10(10_0,10_1,10_2, by using individual signal lines. Hereinafter, the write protect signal transmitted from the controller100to each memory10is referred to as a write protect signal “WPnx”, and a terminal corresponding to the write protect signal WPnx of each memory10is referred to as a “WPnx terminal”. Thus, in the present example, the write protect signal WPn is replaced with WPnx and the terminal corresponding to the ODT enable signal ODTEN is not used inFIGS.3and5of the first embodiment orFIG.13of the second embodiment. The latch enable signal CEn, the command latch enable signal CLE, the address latch enable signal ALE and the write enable signal WEn may be transmitted using a common signal line, or may be transmitted using individual signal lines. 5.1.2 Signal of WPnx Terminal Initially, relationship between the signal of the WPnx terminal and the memory10will be described with reference toFIG.20. As shown inFIG.20, the signal (write protect signal WPnx) of the WPnx terminal functions as the write protect control signal until the parameter regarding the ODT circuit60is set by the Set Feature (until the first operation), and functions as the control signal (ODT enable signal ODTEN) of the ODT circuit60after the parameter is set. More specifically, the controller100sets the write protect signal WPnx to an “L” level in order to prevent the write operation from being carried out in a state in which the power supply voltage is unstable when the memory10is started (powered ON). In this case, the write protect signal WPnx is processed as the write protect control signal, and the memory10prohibits the write operation (enables the write protect) for a period during which the write protect signal WPnx is at an “L” level. After the power supply voltage is fixed (stable), the controller100sets the write protect signal WPnx to an “H” level. In this case, the write protect signal WPnx is processed as the write protect control signal, and the memory10releases the prohibition of the write operation. Subsequently, the controller100performs the Set Feature, and sets the parameter regarding the ODT circuit60. The memory10processes the write protect signal WPnx as the ODT enable signal ODTEN after the parameter is set (the Set Feature is performed). More specifically, when the write protect signal WPnx is at an “L” level, the ODT control circuit controls such that the ODT circuit60is turned on. Meanwhile, when the write protect signal WPnx is at an “H” level, the ODT control circuit52controls such that the ODT circuit60is turned off. 5.1.3 Control Mode Selection of ODT Circuit The relationships ofFIGS.7,14and18described in the first, third, and fourth embodiments can be used as the control mode of the ODT circuit60according to the present example. In this case, the ODT enable signal ODTEN may be replaced with the write protect signal WPnx. 5.2 Second Example Hereinafter, a second example of the present embodiment will be described. The second example corresponds to a case where the write protect signal WPnx has a function of the write protect control signal even after the Set Feature is performed in the first example. Only a different from the first example will be described below. 5.2.1 Entire Configuration of Memory System The entire configuration of the memory system1will be described. In the memory system1according to the present example, the controller100respectively transmits different write protect signals WPnx and chip enable signals CEnx to the memories10(10_0,10_1,10_2, . . . ) by using individual signal lines. The command latch enable signal CLE, the address latch enable signal ALE, and the write enable signal WEn may be transmitted using a common signal line, or may be transmitted using individual signal lines. 5.2.2 Control Mode Selection ODT Circuit Initially, the selection of the control mode of the ODT circuit60will be described with reference toFIG.21. As shown inFIG.21, the ODT control circuit52latches the chip enable signal CEnx (individually for each memory10), the command latch enable signal CLE, the address latch enable signal ALE, the write enable signal WEn, and the read enable signal REn at a timing when the write protect signal WPnx is switched from an “H” level to an “L” level. When the chip enable signal CEnx and the write enable signal WEn are set to an “H” level and the command latch enable signal CEL and the address latch enable signal ALE are set to an “L” level, the ODT control circuit52determines that the write protect signal WPnx is the control signal of the ODT circuit60. When the read enable signal REn is set to an “H” level, the ODT control circuit52selects the DIN mode, and turns on the corresponding ODT circuit60. Meanwhile, when the read enable signal REn is set to an “L” level, the ODT control circuit52selects the DOUT mode, and turns on the corresponding ODT circuit60. When combinations of the chip enable signal CEnx, the command latch enable signal CLE, the address latch enable signal ALE, and the write enable signal WEn other than the above-described combination are used, the ODT control circuit52turns off the ODT circuit60. The memory10determines that the write protect signal WPnx is the write protect control signal, and prohibits the write operation. The ODT control circuit52turns off the ODT circuit60for a period during which the write protect signal WPnx is at an “H” level. 5.2.3 Control of ODT Circuit in Write Operation Hereinafter, the transmission and reception of the signal between the controller100and the memory10in the write operation will be described with reference toFIG.22. InFIG.22, the command latch enable signal CLEx, the address latch enable signal ALEx, and the write enable signal WEnx are different between the memories10. As shown inFIG.22, the controller100maintains the latch enable signals CEnx and the write enable signals WEnx in the non-selected memory10at an “H” level during the write operation, and maintain the command latch enable signals CLEx and the address latch enable signals ALEx at an “L” level. The controller100issues the command and the address data for the write operation, and then sets the write protect signal WPnx to an “L” level. In this case, in the non-selected memory10in which the ODT circuit60is usable, since the latch enable signal CEnx, the write enable signal Wen, and the read enable signal REn are set to an “H” level and the command latch enable signal CLE and tire address latch enable signal ALE arc set to an “L” level, the ODE control circuit52selects the DIN mode, and turns on the corresponding ODT circuit60. When the write operation in the selected memory10is completed, the controller100sets the chip enable signal CEn of the selected memory10to an “H” level, and sets the write protect signal WPnx to an “H” level. In the non-selected memory10in which the ODT circuit60is usable, when the write protect signal WPnx is set to an “H” level, the ODT control circuit52turns off the ODT circuit60. 5.2.4 Control of ODT Circuit in Read Operation Hereinafter, the transmission and reception of the data between the controller100and the memory10in the read operation will be described with reference toFIG.23. In the example ofFIG.23, similarly toFIG.22, a case where the command latch enable signal CLEx, the address latch enable signal ALEx and the write enable signal WEnx are different between the memories10will be described. As shown inFIG.23, the controller100maintains the chip enable signal CEnx and the write enable signal WEnx of the non-selected memory10at an “H” level and maintain the command latch enable signal CLEx and the address latch enable signal ALEx at an “L” level during the read operation. The controller100issues the command and the address data for the read operation, and then sets the read enable signal REn to an “L” level during the REn maintaining period. The controller100sets the write protect signal WPnx to an “L” level during this period. In the non-selected memory10in which the ODT circuit60is usable, since the chip enable signal CEnx and the write enable signal WEn are set to an “H’ level and the command latch enable signal CLE, the address latch enable signal ALE and the read enable signal REn are set to an “L” level, the ODT control circuit52selects the DOUT mode, and turns on the corresponding ODT circuit60. When the read operation of the selected memory10is completed, the controller100sets the chip enable signal CEnx of the selected memory10to an “H” level, and sets the write protect signal WPnx to an “H” level. In the non-selected memory10in which the ODT circuit60is usable, when the write protect signal WPnx is set to an “H” level, the ODT control circuit52turns off the ODT circuit60. 5.2.5 Operation Timing of ODT Circuit Hereinafter, the ON/OFF switching timing of the write protect signal WPnx and the ODT circuit60will be described with reference toFIG.24. As shown inFIG.24, in a state in which various signals are valid (state in which the memory10can receive various signals) after, for example, a waiting period tWHR elapses, the controller100sets the chip enable signal CEnx, the write enable signal WEnx and the read enable signal REn of the non-selected memory10to an “H” level, and sets the command latch enable signal CLEx and the address latch enable signal ALEx to an “L” level. Thereafter, the controller100switches the write protect signal WPnx from an “H” level to an “L” level in a period from a time at which the 5 nsec or longer elapses since starting of the REn maintaining period until the REn maintain period is ended. The ODT control circuit52latches the chip enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, the write enable signal WEnx, and the read enable signal REn at a timing when the write protect signal WPnx is switched to an “H” level. InFIG.24, since the chip enable signal CEnx and the write enable signal WEnx are set to an “H” level and the command latch enable signal CLEx and the address latch enable signal ALEx are set to an “L” level, the ODT control circuit52processes the write protect signal WPnx as the control signal of the ODT circuit60, and selects the DIN/DOUT mode depending on the “H”/“L” level of the read enable signal REn. The corresponding ODT circuit60is turned on after, for example, 25 nsec elapses from a state in which the signal of the WPnx terminal is switched from an “H” level to an “L” level. Subsequently, the controller100switches the write protect signal WPnx from an “L” level to an “H” level. The ODT control circuit52turns off the corresponding ODT circuit60after, for example, 25 nsec elapses from a state in which the write protect signal WPnx is switched from an “L” level to an “H” level. 5.3 Advantage of Present Embodiment According to the present embodiment, it is possible to obtain the same advantage as the first to fourth embodiments. In the present embodiment, it is possible to allow the write protect signal WPnx to have a function of the control signal of the write protect and a function of the control signal of the ODT circuit60. That is, the write protect signal WPn and the ODT enable signal ODTEN can be a common signal. Thus, the terminals corresponding to the ODT enable signals ODTEN of the controller100and the memory10and the data lines for transmitting and receiving the ODT enable signal ODTEN can be omitted. Accordingly, it is possible to prevent the number of terminals and the number of data lines from being increased in the memory system, and thus, it is possible to prevent a chip area from being increased. In the present embodiment, even after the parameter of the ODT circuit60is set due to the Set Feature, it is possible to allow one signal to have a function of the write protect control signal and a function of the control signal of the ODT circuit60. More specifically, the memory10latches the chip enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, the write enable signal WEnx, and the read enable signal REn at a timing when the write protect signal WPnx is switched from an “H” level to an “L” level. The memory10can determines whether or not the write protect signal WPnx is the write protect control signal or the control signal of the ODT circuit60depending the state of each signal. It is possible to prevent the malfunction of the ODT circuit60and the write protect by performing the determination using the chip enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, the write enable signal WEnx and the read enable signal REn. Accordingly, it is possible to improve the reliability of the memory system. Although it has been described in the present embodiment that it is determined whether or not the signal of the WPnx terminal is the write protect signal WPnx or the ODT enable signal ODTENx by using the chip enable signal CEnx, the command latch enable signal CLEx, the address enable signal ALEx, and the write enable signal WEnx, the type of the signals used in the determination and the combination of the logic levels of the signals are not limited. Although the write protect signal WPnx has a function of the ODT enable signal ODTEN in the present example, a signal that having the function of the ODT enable signal ODTEN is not limited to the write protect signal WPnx. 6. Sixth Embodiment Hereinafter, a sixth embodiment will be described. The sixth embodiment corresponds to a case where the chip enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, the write enable signal WEnx, the address latch enable signal ALEx, and the write enable signal WEnx are not latched in the second example of the fifth embodiment. Only a difference from the second example of the fifth embodiment will be described below. 6.1 Entire Configuration of Memory System Initially, the entire configuration of the memory system1will be described. In the memory system1according to the present embodiment, the write protect signal WPnx, the command latch enable signal CLEx, the address latch enable signal ALEx, and the write enable signal WEnx are transmitted from the controller100to the memories10by using Individual signal lines. 6.2 Control Mode Selection of ODT Circuit Hereinafter, the selection of the control mode of the ODT circuit60will be described toFIG.25. As shown inFIG.25, when the latch enable signal CEnx and the write enable signal WEnx are set to an “H” level and the command latch enable signal CLEx, the address latch enable signal ALEx and the write protect signal WPnx are set to an “L” level, if the read enable signal REn is at an “H” level, the ODT control circuit52selects the DIN mode, and turns on the ODT circuit60. Meanwhile, if the read enable signal REn is at an “L” level, the ODT control circuit52selects the DOUT mode, and turns of the ODT circuit60. The ODT control circuit52latches the read enable signal REn whets the ODT circuit60is turned on. Thus, even though the read enable signal REn is changed from an “H” level to an “L” level or from an “L” level to an “H” level for a period during which the ODT circuit60is turned on, the ODT control circuit52maintains the DIN mode or the DOUT mode until the ODT circuit60is turned off. When the write protect signal WPnx is at an “L” level in a state in which at least one of the latch enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, and the write enable signal WEnx is not at the above-describe logic level, the ODT control circuit52turns off the ODT circuit60. Then, the memory10turns into a write protect state, and prohibits the writing. Accordingly, even when the ODT circuit60is turned on, when the logic level of at least one of the chip enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, and the write enable signal WEnx is inverted, the memory10turns off the ODT circuit60, and is changed to the write protect state. When the write protect signal WPnx is at an “H” level, the ODT control circuit52turns off the ODT circuit60. 6.3 State Change of ODT Circuit from Control State to Write Protect State Hereinafter, a timing when the control state of the ODT circuit60is changed to a write protect state will be described with reference toFIG.26. As shown in FIG,26, when the write protect signal WPnx is changed from an “H” level to an “L” level in a state in which the chip enable signal CEnx and the write enable signal WEnx are set to an “H” level and the command latch enable signal CLEx and the address latch enable signal ALEx are set to an “L” level, the ODT control circuit52turns on the ODT circuit60. In this case, for example, when the write enable signal WEnx is changed from an “H” level to an “L” level, the ODT control circuit52turns off the ODT circuit60. The memory10is changed to the write protect state after, for example, 100 nsec elapses from a state in which the ODT circuit is turned off. Although inFIG.26the write enable signal WEnx is switched from an “H” level to an “L” level, the logic level of any one signal of the chip enable signal CEnx, the command latch enable signal CLEx, and the address latch enable signal ALEx may be switched. 6.3 Advantage of Present Embodiment In the configuration according to the present embodiment, it is possible to obtain the same advantage as that of the first to fifth embodiments. In the present embodiment, it is possible to continuously change the OFF operation of the ODT circuit60and the change of the ODT circuit to the write protect state by changing the logic level of any one of the chip enable signal CEnx, the command latch enable signal CLEx, the address latch enable signal ALEx, and the write enable signal WEnx in a state in which the ODT circuit60is turned on. 7. Seventh Embodiment Hereinafter, a seventh embodiment will be described. A difference from the first to sixth embodiments is that the control mode of the ODT circuit60is set to any one of the DIN mode and the DOUT mode during the Set Feature. Only a difference from the first to sixth embodiments will be described below. 7.1 Control Flow of ODT Circuit The control flow of the ODT circuit60will be described with reference toFIG.27. As shown inFIG.27, when the Set Feature (first operation) is carried out, the controller100initially selects anyone of the DIN mode and the DOUT mode, and sets the parameter. Subsequently, when the write or read operation is performed, the controller100changes the ODT enable signal ODTEN from an “L” level to an “H” level. The ODT control circuit52turns on the corresponding ODT circuit60in the DIN mode or the DOUT mode which is previously set in the Set Feature for a period during which the ODT enable signal ODTEN is at an “H” level. 7.2 Advantage of Present Embodiment According to the present embodiment, it is possible to obtain the same advantage as that of the first to sixth embodiments. In the present embodiment, the ODT control circuit52can control the operation of the ODT circuit60without selecting the control mode of the ODT circuit60by previously setting any one of the DIN mode and the DOUT mode due to the Set Feature. Thus, it is possible to simplify the configuration of the ODT control circuit52, and thus, it is possible to reduce the circuit area of the ODT control circuit52. Accordingly, it is possible to prevent the chip area from being increased. 8. Eighth Embodiment Hereinafter, an eighth embodiment will be described. The eighth embodiment corresponds to a case where the memory chips70a to70h that turn on the ODT circuits60are selected by the chip address data CADD in the second embodiment. Only a difference from the second embodiment will be described below. 8.1 Selection of Memory Chip The selection of the memory chips70a to70h will be simply described with reference toFIG.28.FIG.28is an explanatory diagram obtained by simplifyingFIG.12of the second embodiment. Although the topmost memory chip70h is selected inFIG.28, the present embodiment is not limited thereto. The plurality of memory chips70may be selected. As shown inFIG.28, the ODT control circuits52of the memory chip70(70a to70h) check the positions of the memories10on which the mounted memory chips70are mounted by the chip address data CADD transmitted from the controller100when the write or read operation is performed. For example, when the memory chip is the topmost memory chip70h, the ODT control circuit52turns on the corresponding ODT circuit60in response to the ODT enable signal ODTEN. Instead of receiving from the controller, the chip address data CADD may be stored in the memory chips70and retrieved therefrom. 8.2 Advantage of Present Embodiment According to the present embodiment, it is possible to obtain the same advantage as that of the second embodiment. In the present embodiment, it is possible to operate the ODT circuit60by selecting only the memory chip70of the memory10which is effective in reducing the reflected signal by the chip address data CADD. Accordingly, it is possible to control the more optimum ODT circuit60, and thus, it is possible to more effectively the noise due to the reflection of the signal. As a result, it is possible to improve the quality of the signal. In the present embodiment, since it is possible to check the memory chip70which is a writing or reading target by the chip address data CADD, it is possible to control the operation of the ODT circuit60depending on the target memory chip70. Accordingly, it is possible to control the more optimum ODT circuit60, and thus, it is possible to more effectively reduce the noise due to the reflection of the signal. As a result, it is possible to improve the quality of the signal. In the present embodiment, even though the ODT enable signal ODTEN is common to the memory chips70, it is possible to select the memory chip70that turns on the ODT circuit60by the chip address data CADD. Thus, it is possible to use a common signal line as the signal lines of the ODT enable signals that connect the controller100and the memories10. Accordingly, it is possible to simplify the configuration of the memory system, and thus, it is possible to prevent the chip area from being increased. 9. Modification Examples The memory system of the above-described embodiment includes the first nonvolatile semiconductor memory device (10ofFIG.1), and the controller (100ofFIG.1). The controller can transmit and receive the first signal, and the second signal (REn ofFIG.3) that controls the timing when the data is read in the read operation to and from the first nonvolatile semiconductor memory device. The first nonvolatile semiconductor memory device includes the first terminal which is connected to the controller and receives the second signal, the first circuit (60ofFIG.3) that includes the first and second resistance elements (63a and63b ofFIG.4) which are connected to the first terminal, the first switch element (61ofFIG.4) which electrically connects the first resistance element to the power supply voltage line (VCC ofFIG.4) and the second switch element (62ofFIG.4) which electrically connects the second resistance element to the ground voltage line (VSS ofFIG.4), and the second circuit (52ofFIG.3) that controls the first circuit by using the first signal (ODTEN ofFIG.3). When the logic level of the first signal is switched (L→H ofFIG.7), the second circuit turns off the first and second switch elements when the second signal is at the first logic level (H ofFIG.7), and turns on the first and second switch elements when the second signal is at the second logic level (L ofFIG.7). It is possible to provide the nonvolatile semiconductor memory device and the memory system capable of improving processing performance, according to the above-described embodiments. Embodiments are not limited to the above-described embodiments, and may be modified. The embodiments may be combined as possible. For example, the first example of the fifth embodiment and the eighth embodiment may be combined with the second embodiment, so that the terminal corresponding to the ODT enable signal ODTEN may be omitted and the memory chip70that turns on the ODT circuit60may be selected by the chip address data CADD. In the above-described embodiments, the controller100may include the ODT circuit60. For example, when the signal is transmitted and received between the memories10, the ODT circuit60of the controller100may be turned on. Although the ODT circuit60is connected to the terminals corresponding to the data line DQ[7:0] in the above-described embodiments, the clock signals DQS and DQSn and the read enable signals REn and RE, the terminals to which the ODT circuit60is connected are not limited thereto. Although the ODT circuit60connected to the terminals corresponding to the read enable signals REn and RE are turned off in the DIN mode and is turned on in the DOUT mode in the above-described embodiments, the ODT circuit60of which the ON and OFF states are switched in the DIN mode and the DOUT mode is not limited thereto. In the above-described embodiments, different resistance values may be set to the variable resistance elements63a and63b of the ODT control circuit52in the DIN mode and the DOUT mode. In the above-described embodiments, the interface chip20(or the memory chip70) that uses the ODT circuit60is not limited to the non-selected memory10(or the memory chip70). The above-described embodiments may be applied to any one of the plane NAND flash memory or the three-dimensional layered NAND flash memory. For example, the “connection” in the above-described embodiments includes a state in which components are indirectly connected with another component such as a transistor or a resistor interposed therebetween. The embodiments according to the present invention may be provided as follows. For example, when the memory cell transistor MT can retain 2-bit (four-value) data and threshold levels when any one of four values is retained are referred to as an E level (erase level), an A level, a B level, and a C level, (1) in the read operation, a voltage applied to a word line selected in a read operation at an A level is, for example, in a range of 0V to 0.55 V. The voltage is not limited to the above-described example, and may be in any range of 0.1 V to 0.21 V, 0.21 V to 0.31 V, 0.31 V to 0.4 V, 0.4 V to 0.5V, and 0.5 V to 0.55 V. A voltage applied to a word line selected in a read operation at a B level is, for example, in a range of 1.5 V to 2.3 V. The voltage is not limited to the above-described example, and may be in any range of 1.65 V to 1.8 V, 1.8V to 1.95 V, 1.95 V to 2.1 V, and 2.1 V to 2.3V. A voltage applied to a word line selected in a read operation at a C level is, for example, in a range of 3.0 V to 4.0 V. The voltage is not limited to the above-described example, and may be in any range of 3.0 V to 3.2 V, 3.2 V to 3.4 V, 3.4 V to 3.5 V, 3.5 V to 3.6 V, and 3.6 V to 4.0 V. A time (tR) of the read operation may be, for example, in a range of 25 μs to 38 μs, 38 μs to 70 μs, or 70 μs to 80 μs. (2) The write operation includes the program operation, and the verify operation, as described above. In the write operation, a voltage initially applied to a word line selected during the program operation is, for example, in a range of 13.7 V to 14.3 V. The voltage is not limited to the above-described example, and may be, for example, in any range of 13.7 V to 14.0 V, and 14.0 V to 14.6 V. A voltage initially applied to a selected word line when an odd-numbered word line is written and a voltage initially applied to a selected word line when an even-numbered word line is written may be changed. When the program operation is an incremental step pulse program (ISPP), for example, about 0.5 V is used as a step-up voltage. A voltage applied to the non-selection word line may be, for example, in a range of 6.0 V to 7.3 V The voltage is not limited to the above-described example, and the voltage may be, for example, in a range of 7.3 V to 8.4 V, or may be 6.0 V or less. A pulse voltage to be applied may be changed depending on whether or not the non-selection word line is an odd-numbered word line or an even-numbered word line. A time (tProg) of the write operation may be, for example, in a range of 1700 μs to 1800 μs, 1800 μs to 1900 μs, or 1900 μs to 2000 μs. (3) In the erase operation, a voltage initially applied to a well which is formed on the semiconductor substrate and on which the memory cell is arranged is, for example, in a range of 12 V to 13.6 V. The voltage is not limited to the above-described example, and the voltage may be, for example, in a range of 13.6 V to 14.8 v, 14.8 V to 19.0 V, 19.0 V to 19.8 V or 19.8 V to 21 V. A time (tErase) of the erase operation may be, for example, in a range of 3000 μs to 4000 μs, 4000 μs to 5000 μs, or 4000 μs to 9000 μs. (4) The memory cell has a structure in which a charge storage layer is arranged on the semiconductor substrate (silicon substrate) with a tunnel insulating film having a film thickness of 4 nm to 10 nm interposed therebetween. The charge storage layer can have a layered structure of an insulating film such as SiON or SiN having a film thickness of 2 nm to 3 nm and polysilicon having a film thickness of 3 nm to 8 nm. Metal such as Ru may be added to the polysilicon. An insulating film is formed on the charge storage layer. The insulating film includes, for example, a silicon oxide film having a film thickness of 4 nm to 10 nm interposed between a lower high-k film having a film thickness of 3 nm to 10 nm and an upper high-k film having a film thickness of 3 nm to 10 nm. The high-k film is made of HfO. The film thickness of the silicon oxide film may be greater than the thickness of the high-k film. A control electrode having a film thickness of 30 nm to 70 nm is formed on the insulating film with a material which has a film thickness of 3 nm to 10 nm and is used to adjust a work function interposed therebetween. Here, the material for adjusting a work function is a metal oxide film made of TaO, or a metal nitride film made of TaN. The control electrode may be made of W. Air gaps may be formed between the memory cells. While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Indeed, the novel embodiments described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions and changes in the form of the embodiments described herein may be made without departing from the spirit of the inventions. The accompanying claims and then equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the inventions. | 80,256 |
RE49784 | DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS Various example embodiments of the present invention will now be described more fully with reference to the accompanying drawings in which some example embodiments of the invention are shown. Without limiting the scope of the protection of the present invention, all the description and drawings of the embodiments will exemplarily be referred to an electron beam. However, the embodiments are not used to limit the present invention to specific charged particles. In the drawings, relative dimensions of each component and among every component may be exaggerated for clarity. Within the following description of the drawings, the same or like reference numbers refer to the same or like components or entities, and only the differences with respect to the individual embodiments are described. Accordingly, while example embodiments of the invention are capable of various modifications and alternative forms, embodiments thereof are shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that there is no intent to limit example embodiments of the invention to the particular forms disclosed, but on the contrary, example embodiments of the invention are to cover all modifications, equivalents, and alternatives falling within the scope of the invention. In this invention, “axial” means “in the optical axis direction of an electron optics element (such as a round lens or a multipole lens), or an imaging system or an apparatus”, “radial” means “in a direction perpendicular to the optical axis”, “on-axial” means “on or aligned with the optical axis, and “off-axis” means “not on or aligned with the optical axis”. In this invention, “an imaging system is aligned with an optical axis” means “all the electron optics elements (such round lens and multipole lens) are aligned with the optical axis”. In this invention, X, Y and Z axe form Cartesian coordinate. The optical axis of the primary projection imaging system is on the Z-axis, and the primary electron beam travels along the Z-axis. In this invention, “primary electrons” means “electrons emitted from an electron source and incident onto a being-observed or inspected surface of a sample, and “secondary electrons” means “electrons generated from the surface by the “primary electrons”. In this invention, “pitch” means an interval between two adjacent beamlets or beams on a plane. In this invention, “effective deflection plane of a deflector” means “the plane where the total deflection function of the deflector can be equivalent to happen”. Based on some conventional multi-beam apparatuses proposed in the CROSS REFERENCE, this invention proposes several methods to configure a new multi-beam apparatus with a variable total FOV. In the new apparatus, the total FOV can be variable in size, orientation and illumination angle. To clearly express the methods, the multi-beam apparatus inFIG.1Bis taken as an example. For sake of simplification in explanation, in the new apparatus, only three beamlets are shown but the number of beamlets can be anyone. In addition, one of the three beamlets is on-axis, but they can all be off-axis. In addition, the elements not related to the methods, such as the deflection scanning unit and the beam separator, are not shown or even not mentioned in the illustrations and the description of the embodiments. In each of those conventional multi-beam apparatuses, the plural beamlets are deflected towards the optical axis by the image-forming means. The deflection angles of the plural beamlets are set to minimize the off-axis aberrations of the plural probe spots due to the objective lens. Accordingly the plural deflected beamlets typically pass through or approach the front focal point of the objective lens, i.e. forming an on-axis crossover on or close to the front focal plane of the objective lens. The pitches of the plural probe spots therefore depend on the deflection angles of the plural beamlets and the first (or object) focal length of the objective lens. Hence the pitches can be varied by changing the deflection angles and/or the first focal length of the objective lens. For example, inFIG.1AorFIG.1B, the deflection angles α2and α3of the two off-axis beamlets102_2and102_3are set to minimize the off-axis aberrations of the probe spots102_2s and102_3s due to the objective lens131. Accordingly the beamlets102_2and102_3typically pass through or approach the front focal point of the objective lens131, i.e. forming the crossover CV on the optical axis and on or close to the front focal plane of the objective lens131. The pitch Ps between the probe spots102_1s and102_2s is determined by the deflection angle α2and the first focal length f of the objective lens131, and can be simply expressed as Ps≈α2·f. Similarly, the pitch Ps between the probe spots102_1s and102_3s can be simply expressed as Ps≈α3·f. FIG.3A,FIG.4AandFIG.5Ashow three embodiments300A,400A and500A of the new apparatus changing the pitches by varying the deflection angles, andFIG.6Ashows one embodiment600A changing the pitches by varying the first focal length. In the embodiment300A, the source-conversion unit320comprises one beamlet-limit means121with three beam-limit opening121_1,121_2and121_3, and one movable image-forming means322with three electron optics elements322_1,322_2and322_3. The effective deflection plane322_0of the movable image-forming means322can be moved along the optical axis300_1within the variation range322_0r. The pitches of the plural probe spots will become large as the effective deflection plane322_0is moved close to the objective131and vice versa. FIG.3Bshows the paths of three beamlets102_1,102_2and102_3when the effective deflection plane322_0is on the position D1. The movable condenser lens210collimates the primary electron beam102to be normally incident onto the source-conversion unit320. The beam-limit openings121_1˜121_3divide the primary electron beam102into one on-axis beamlet102_1, and two off-axis beamlets102_2and102_3. The two off-axis electron optics elements322_2and322_3deflect the beamlets102_2and102_3respectively towards the optical axis300_1. The three beamlets102_1˜102_3are focused onto the sample surface7by the objective lens131and therefore form three probe spots102_1s,102_2s and102_3s respectively. The deflection angles α2and α3of the beamlets102_2and102_3are set to minimize the off-axis aberrations of the probe spots102_2s and102_3s. Accordingly the beamlets102_2and102_3pass through or approach the front focal point of the objective lens131, i.e. forming a crossover on the optical axis300_1and on or close to the front focal plane thereof. The two pitches formed by the probe spots102_1s˜102_3s are approximately equal to α2·f and α3·f respectively. The f is the first focal length of the objective lens131. The effective deflection plane322_0inFIG.3Cis on the position D2closer to the objective131than the position D1. Accordingly, the deflection angles α2and α3are increased and the two pitches become larger. The probe spots102_2s and102_3s move outside from the previous positions (dash line) inFIG.3B. In the embodiment400A inFIG.4A, the source-conversion unit420comprises one more image-forming means124in comparison withFIG.1B. The image-forming means124with three electron optics elements124_1,124_2and124_3is below the imaging-forming means122, and can be moved in a radial direction. Accordingly the source-conversion unit420works in two modes. In the first mode as shown inFIG.4B, the image-forming means122is used to form three first virtual images of the single electron source101, and the image-forming means124is moved outside the path of the beamlets102_1˜102_3. In the second mode as shown inFIG.4C, the image-forming means122is switched off, and the image-forming means124is moved back to form three first virtual images of the single electron source101. The deflection angles α2and α3of the beamlets102_2and102_3are smaller in the first mode than in the second mode, and accordingly the two pitches are larger in the second mode. InFIG.4C, the probe spots102_2s and102_3s move outside from the previous positions (dash line) inFIG.4B. The embodiment500A inFIG.5Aemploys one transfer lens533and one field lens534between the source-conversion unit220and the objective lens131in comparison withFIG.1B. Accordingly the transfer lens533, the field lens534and the objective lens131constitute the primary projection imaging system.FIG.5Bshows the paths of the three beamlets102_1˜102_3. The movable condenser lens210collimates the primary electron beam102to be normally incident onto the source-conversion unit220. The beam-limit openings121_1˜121_3divide the primary electron beam102into one on-axis beamlet102_1, and two off-axis beamlets102_2and102_3. The two off-axis electron optics elements122_2and122_3deflect the beamlets102_2and102_3respectively towards the optical axis500_1. Consequently three first virtual images of the single electron source101are formed. Then the transfer lens533focuses the three beamlets102_1˜102_3onto the intermediate image plane PP1, i.e. projecting the three first virtual images thereon. Accordingly three second real images102_1m,102_2m and102_3m of the single electron source101are formed. The field lens534is located at the intermediate image plane PP1, and bends the off-axis beamlets102_2and102_3toward the optical axis500_1without influencing the focus situations thereof. After that, the objective lens131focuses the three beamlets102_1˜102_3onto the sample surface7, i.e. projecting the three second real images102_1m˜102_3m thereon. Consequently, on the sample surface7, the three beamlets102_1˜102_3form three probe spots102_1s,102_2s and102_3s respectively. InFIG.5B, the bending angles γ2and γ3of the beamlets102_2and102_3due to the field lens534are set to minimize the off-axis aberrations of the probe spots102_2s and102_3s, and the beamlets102_2and102_3accordingly pass through or approach the front focal point of the objective lens131, i.e. forming a crossover CV on the optical axis500_1and on or close to the front focal plane thereof. The pitch Ps between the probe spots102_1s and102_2s is determined by the bending angle γ2and the first focal length f of the objective lens131, and can be simply expressed as Ps≈γ2·f. Similarly, the pitch Ps between the probe spots102_1s and102_3s can be simply expressed as Ps≈γ3·f. The bending angles γ2and γ3change with the radial shifts of the second real images102_2m and102_3m, and the radial shifts change with the deflection angles α2and α3of beamlets102_2and102_3due to the electron optics elements122_2and122_3. Therefore the two pitches can be varied by adjusting the deflection angles α2and α3. InFIG.5C, the deflection angles α2and α3are larger than inFIG.5B. Consequently the two off-axis probe spots102_2S and102_3S are moved away from the previous positions (shown in dash line) inFIG.5Bto the current positions, and the pitches become larger. In the embodiment600A inFIG.6A, the first principal plane631_2of the objective lens631can be shifted along the optical axis600_1within the variation range631_2r. The axial shift can be done by mechanically moving the position of the objective lens631or electrically changing the shape and/or position of the objective lens field. As the first principal plane is closer to the sample surface7, the first focal length f will become small and the first focal plane will move toward the surface7. In addition, as the first focal plane moves down, the deflection angles of the plural beamlets decrease. Accordingly the pitches of the plural probe spots will decrease. FIGS.6B and6Cshow the paths of the three beamlets when the first principal plane631_2is respectively on the position D3and the position D4. The position D3is closer to the sample surface7than the position D4. Accordingly, the first focal length f and the deflection angles α2and α3of the beamlets102_2and102_3inFIG.6Bare smaller than inFIG.6C. InFIG.6C, the probe spots102_2s and102_3s move outside from the previous positions (dash line) inFIG.6B, and the two pitches become larger than inFIG.6B. The objective lens in one conventional multi-beam apparatus is an electromagnetic compound lens, as one embodiment131-1shown inFIG.1C. The objective lens comprises one magnetic lens and one electrostatic lens, and works in a retarding mode (the landing energy of an electron is lower than the energy of the electron passing through the objective lens) due to low geometric aberrations and low radiation damage on the sample. The magnetic lens is configured by the coil131_c1and the yoke131_y1with the pole-pieces131_mp1and131_mp2, and the electrostatic lens is formed by the pole-piece131_mp1, the field-control electrode131_e1and the sample8. The potential of the inner pole-piece131_mp1is higher than the sample8. The potential of the field-control electrode131_e1is set to control the electric field on the sample surface. The electric field can ensure the sample free of electrical breakdown, reduce the geometric aberrations of the plural probe spots, control the charge-up on the sample surface7by reflecting back a part of secondary electrons or enhance the collection of secondary electron beams. InFIG.1C, the shape of the magnetic field is not variable, and the shape of the electrostatic field can only be changed within a limited range. Hence the conventional objective lens is almost not electrically (changing the potentials of the electrodes and/or the excitation current of the coil) movable. Next three solutions for configuring the movable objective lens631are proposed in terms of the conventional objective lens131-1inFIG.1C, and respectively shown inFIGS.7A,7B and7C. InFIG.7A, the embodiment631-1comprises one more electrode631-1_e2between the inner pole-piece131_mp1and the field-control electrode131_e1in comparison withFIG.1C. Accordingly the electrostatic lens is formed by the inner pole-piece131_mp1, the electrode631-1_e2, the field-control electrode131_e1and the sample8. The electrostatic field shape of the electrostatic lens can be varied by adjusting the potential of the electrode131_e1and the potential of the electrode631-1_e2as well. As the potential of the electrode631-1_e2is adjusted to approach the potential of the inner pole-piece131_mp1, the electrostatic field is squeezed towards the sample, which is equal to moving the objective lens631-1towards the sample8. Accordingly the electrode631-1_e2can be called as a field-moving electrode. InFIG.7B, the embodiment631-2comprises two more electrodes631-2_e2and631-2_e3inside the bore of the yoke131_y1and above the field-control electrode131_e1in comparison withFIG.1C. Accordingly the electrostatic lens is formed by the electrodes631-2_e3and631-2_e2, the field-control electrode131_e1and the sample8. The potential of the electrodes631-2_e3is higher than the sample and can be equal to the inner pole-piece131_mp1. The electrostatic field shape of the electrostatic lens can be varied by adjusting the potential of the electrode131_e1and the potential of the electrode631-2_e2as well. Similar toFIG.7A, as the potential of the electrode631-2_e2is adjusted to approach the potential of the electrodes631-1_e3, the electrostatic field is squeezed towards the sample8, which is equal to moving the objective lens631-2towards the sample8. Accordingly the electrode631-2_e2can be called as a field-moving electrode. In comparison the embodiment631-1withFIG.7A, the magnetic lens can be placed closer to the sample8, and thereby providing a deeper magnetic immersion to the sample so as to generate lower aberrations. InFIG.7C, the embodiment631-3comprises one more coil631-3_c2and one more yoke631-3y2inside the bore of the yoke131_y1and above the inner pole-piece131_mp1in comparison withFIG.1C. Accordingly one lower magnetic lens, one upper magnetic lens and one electrostatic lens are formed. The lower magnetic lens generates one lower magnetic field by the coil131_c1through the lower magnetic-circuit gap G1between the inner and outer pole-pieces131_mp1and131_mp2of the yoke131_y1, while the upper magnetic lens forms one upper magnetic field by the coil631-3_c2through the magnetic-circuit gap G2between the inner pole-piece131_mp1and the upper pole-piece631-3_mp3of the yoke631-3_y2. The electrostatic lens is formed by the inner pole-piece131_mp1, the field-control electrode131_e1and the sample8. The distribution shape of the total magnetic field of the objective lens631-3changes with the combination of the upper and lower magnetic fields, therefore can be varied by adjusting the excitation ratio of the upper and lower magnetic lenses or the current ratio of the coils131_c1and631-3_c2. As the current ratio is adjusted higher, the total magnetic field of the objective lens631-3is squeezed towards the sample, which is equal to moving the objective lens631-3towards the sample8. Two extreme examples are the total magnetic field of the objective lens631-3locates the superior top when the coil131_c1turns off and the coil631-3-c2turn on, and the lowest when the coil131_c1turns on and the coil631-3_c2turns off. Each of the solutions inFIGS.7A and7Bcan be combined with the solution inFIG.7Cto configure more embodiments of the movable objective lens631. Next some methods of intentionally rotating the probe spot array will be proposed, which can be used to eliminate the orientation variation of the total FOV with respect to changes in the observing conditions and/or accurately match the orientations of sample patterns and the probe spot array. As mentioned above, the objective lens in one conventional multi-beam apparatus is typically an electromagnetic compound lens, such as the embodiment131-1shown inFIG.1C. Therefore appropriately combining the focusing powers of the magnetic lens and the electrostatic lens can rotate the probe spot array around the optical axis to a certain degree. For example, if the objective lens131inFIG.1Ais similar to the embodiment131-1inFIG.1C, the field-control electrode131_e1can be used to control the rotation of the probe spots102_2and102_3s to a certain degree as well as controlling the electrical field on the surface7. To keep the electrical field on the surface7weaker than a permissible value for the specimen safety, the potential of the field-control electrode131_e1can be varied within one specific range, such as −3 kV˜5 kV with respect to the sample8. The focusing power of the electrostatic lens changes with the potential of the field-control electrode131_e1, and accordingly the focusing power of the magnetic lens needs being changed to keep the plural beamlets focused on the sample surface7. The focusing power variation of the magnetic lens changes the rotation angles of the probe spots102_2s and102_3s. Hence, the rotation angles of the probe spots102_2s and102_3s can be adjusted by varying the potential of the field-control electrode131_e1within the specific range. For each of the foregoing embodiments300A,400A and500A of the new apparatus inFIGS.3A,4A and5A, if the objective lens131has a configuration similar to the embodiment131-1, the orientation of the probe spot array can be adjusted by this method. For the embodiment600A of the new apparatus inFIG.6A, if the movable objective lens631has a configuration similar to one of the embodiments631-1,631-2and631-3inFIGS.7A-7C, the field-control electrode131_e1and/or the corresponding field-moving electrode can be used to control the rotation of the probe spot array. For the embodiment631-3, the orientation can also be changed by varying the polarities of the magnetic fields of the upper magnetic lens and the lower magnetic lens. As well known, for a magnetic lens, the rotation angle is related to the polarity of the magnetic field but the focusing power is not. When the polarities of the magnetic fields of the upper magnetic lens and the lower magnetic lens are same, the upper magnetic lens and the lower magnetic lens rotate the probe spot array in a same direction. When the polarities are opposite to each other, the upper magnetic lens and the lower magnetic lens rotate the probe spot array in opposite directions. Hence the embodiment631-3can generate two different orientations of the probe spot array with respect to a required focusing power and the corresponding position of the first principal plane. For the embodiment500A inFIG.5A, the transfer lens533and the field lens534provide more possibilities to control the rotation of the probe spot array. One embodiment510A is shown inFIG.8A, wherein the electromagnetic compound transfer lens533-1comprises one electrostatic transfer lens533_11and one magnetic transfer lens533_12. The magnetic field of the magnetic transfer lens533_12can be adjusted to change the rotation of the probe spot array, and the electrostatic field of the electrostatic transfer lens533_11can be accordingly varied to keep the three second real images102_1m,102_2m and102_3m on the intermediate image plane PP1. Another embodiment520A is shown inFIG.8B, wherein the electromagnetic compound field lens534-1comprises one electrostatic field lens534_11and one magnetic field lens534_12. The magnetic field of the magnetic field lens534_12can be adjusted to change the rotation of the probe spot array, and the electrostatic field of the electrostatic field lens534_11can be accordingly varied to generate the required bending angles of the plural beamlets. In each of the foregoing embodiments, the plural beamlets are normal or substantially normal incident onto the sample surface, i.e. the incident angles or landing angles (angles formed with the normal of the sample surface) of the plural beamlets are approximately equal to zero. To effectively observe some patterns of a sample, the incident angles are better a little larger than zero. In this case, to ensure plural beamlets perform alike, the plural beamlets are required to have same incident angles. To do so, the crossover CV of the plural beamles needs to be shifted away from the optical axis. The shift of the crossover CV can be done by the image-forming means or one additional beamlet-tilting deflector. FIG.9Ashows how to tilt the plural beamlets102_1˜102_3by the image-forming means122in the conventional multi-beam apparatus200A. In comparison withFIG.1B, the deflection angles α1(equal to zero inFIG.1B), α2and α3of the beamlets102_1˜102_3respectively are added same or substantially same amounts so that the crossover CV of the beamlets102_1˜102_3is shifted away from the optical axis100_1and on or close to the first focal plane of the objective lens131. Accordingly the beamlets102_1˜102_3obliquely land on the surface7with same or nearly same landing angles. The plural beamlets102_1˜102_3in each of the embodiments300A,400A,500A and600A can be tilted by the corresponding image-forming means in the same way. For the embodiments300A,400A and600A, the paths of plural beamlets102_1˜102_3will be similar to those inFIG.9A. For the embodiment500A, the paths will be different, as shown inFIG.9B. In comparison withFIG.5B, the deflection angles α1(equal to zero inFIG.5B), α2and α3of the beamlets102_1˜102_3shift the three second real images102_1m,102_2m and102_3m same or substantially distances on the intermediate image plane PP1. Accordingly the crossover CV of the beamlets102_1˜102_3after bended by the field534, is still on or close to the first focal plane but shifted away from the optical axis500_1. FIG.10shows how to tilt the plural beamlets102_1˜102_3by one beamlet-tilting deflector135in one embodiment700A of the new apparatus. In comparison withFIG.1B, the beamlet-tilting deflector135deflects the beamlets102_1˜102_3together to shift the crossover CV away from the optical axis700_1and on or close to the front focal plane of the objective lens131. Similarly, one beamlet-tilting deflector can also be added to the embodiments300A,400A,500A and600A for tilting the plural beams together. The beamlet-tilting deflector can be placed between the source-conversion unit and the front focal plane of the objective lens, and is preferred close to the source-conversion unit. In addition, if the deflection scanning unit in one of the foregoing embodiments is above the front focal plane of the objective lens, it can shift the crossover of the plural beamlets and the additional beamlet-tilting deflector therefore is not needed. Although each of the foregoing embodiments of the new apparatus only employs one or two of the methods for varying the total FOV in size, orientation and incident angle, the methods can be combined in many ways. For example the new apparatus can use one movable image-forming means and one movable objective lens together, or use one movable objective lens, one transfer lens and one field lens together. Although the methods are shown and explained by taking the embodiment200A inFIG.1Bas an example, the methods can be applied to the other embodiments (such as the embodiment100A inFIG.1A) of the conventional apparatuses to configure more embodiments of the new multi-beam apparatus. In summary, based on the conventional multi-beam apparatuses proposed in the CROSS REFERENCE, this invention proposes several methods to configure a new multi-beam apparatus whose total FOV is variable in size, orientation and incident angle. Hence the new apparatus provides more flexibility to speed the sample observation and enable more kinds of samples observable. More specifically, the new apparatus can be used as a yield management to provide more possibilities to achieve a high throughput and detect more kinds of defects. Three methods are proposed to change the pitches of the plural beamlets on the sample surface for varying the size of the total FOV, i.e. using a movable image-forming means in the source-conversion unit, using a movable objective lens, and using a transfer lens and a field lens between the source-conversion unit and the objective lens. Three methods are employed to intentionally rotate the probe spot array for varying the orientation of the total FOV, i.e. using an electromagnetic compound objective lens and varying the electric field thereof, using one objective lens with two magnetic lenses and setting the magnetic fields thereof opposite in polarity, and using one magnetic lens in either or both of the transfer lens and the field lens. Three methods are proposed to shift the crossover of the plural beamlets away from the optical axis for equally varying the landing angles of the plural beamlets on the sample surface. The shift can be done by the image-forming means, or one additional beamlet-tilting deflector, or the deflection scanning unit. Although the present invention has been explained in relation to its preferred embodiment, it is to be understood that other modifications and variation can be made without departing the spirit and scope of the invention as hereafter claimed. | 27,064 |
RE49785 | DETAILED DISCUSSION IN CONJUNCTION WITH THE DRAWINGS FIG.1ashows the principle construction of a field device, for example, a field device formed as a measuring device for flow measurement. The field device can serve as indicated inFIG.1ae.g. for determining a measured variable x of a medium, for example, a liquid or a flowable dispersion, flowing in a pipeline. For such purpose, the field device includes a measuring transducer S for producing at least one measurement signal dependent on the measured variable x to be registered. In the example of an embodiment shown inFIG.1a, the measuring transducer S is formed by means of a measuring tube insertable into the course of the pipeline and, consequently, flowed-through during operation by the medium conveyed in the pipeline. The field device can, accordingly, for example, also be a magneto inductive flow measuring device (MID) suitable for measuring a volume flow rate. In the case of such a flow measuring device, the measuring of the volume flow rate occurs, as is known, based on a measurement voltage serving as measurement signal and induced by a magnetic field passing through the measuring tube, and, consequently, through the therein flowing medium, perpendicular to the flow direction. The measurement voltage has a voltage level dependent on an instantaneous flow velocity of the medium, respectively the volume flow rate derived therefrom and is sensed by means of two electrodes provided in the measuring transducer. For processing the at least one measurement signal dependent on the respective measured variable to be ascertained, for example, thus the previously indicated measurement voltage, not least of all also for conversion of such measurement signal into corresponding measured values, for example, thus measured values for the volume flow rate, the field device comprises, accommodated in an electronics housing H, a device electronics, which is correspondingly electrically connected to the measuring transducer S. The electronics housing H includes a housing foundation H′ as well as a housing closure H″ closing such. The housing foundation H′ can, such as quite usual in the case of electronics housings for field devices, for example, be embodied pot shaped or, such as evident from a combination ofFIGS.1a,1b and6, for example, also rather box shaped. The housing foundation H′ and/or the housing closure H″ can, furthermore, for example, in each case, be a formed part manufactured of a metal, for example, a steel or an aluminum alloy. The housing foundation H′ and/or the housing closure H″ can, for example, however, also be, in each case, at least partially or completely manufactured of a plastic. Housing foundation H′ and housing closure H″ can additionally, in each case, be manufactured by means of one of the primary forming methods correspondingly adapted to the respectively used material, for example, by casting, pressure casting or injection molding. The housing closure H″, for example, also a housing closure H″ manufactured from the same material as the housing foundation, can, as indicated inFIG.1b, be secured releasably to the housing foundation H′ by means of two or more, for example, four, screw connections. For additional processing of the respective measurement signal, the device electronics shown here includes a centrally arranged, measurement amplifier1. The measurement amplifier1can be formed, for example, by means of an instrument amplifier circuit and be additionally adapted to register the at least one measurement signal, for example, the mentioned measurement voltage, largely reaction freely and thereafter to amplify it. Placed above the measuring amplifier1is, furthermore, a display and interaction unit2, which includes, for example, a display element3embodied as an LCD display as well as an interaction element4formed by means of optical input keys. By means of the display element3, for example, a currently measured value for the measured variable, here, for example, the volume flow rate, and/or setting values of various operating parameters of the field device can be displayed. With help of the interaction element4a service person can provide corresponding inputs for control and/or programming of the device electronics. The respectively ascertained measured value can additionally, for example, also be transmitted via a fieldbus to a central control computer or to a programmable logic controller (PLC). For this, there is provided in the device electronics an IO circuit board5, namely, embodied on a circuit board, an in/output circuit, with which the device electronics, consequently the field device formed therewith, can be connected to a fieldbus. The IO circuit board5is designed to convert measured values into a data telegram suitable for the fieldbus, namely a data telegram corresponding to a respective fieldbus protocol. Different types of IO boards are available, which support different fieldbus protocols, such as, for example, HART, Profibus, ModBus, Ethernet IP, etc. The IO circuit board5shown inFIGS.2a,3a,respectivelyand4a, respectively,by way of example includes, for example, an Ethernet plug6as well as two, in each case, four poled socket connections7,8, via which the device electronics, consequently the field device formed therewith, can, for example, be connected to a serial fieldbus. The first four poled socket connection7includes mounted on the IO circuit board5an installed plug9, into which a corresponding connecting plug10is insertable. The second four poled socket connection8likewise includes mounted on the IO circuit board5an installed plug11, in which a corresponding connecting plug12is insertable. The two four poled connecting plugs10,11are, in each case, equipped with four spring clamp terminals for the connection of individual conductors of corresponding connecting cables. The device electronics shown inFIGS.2a,3a, and4aincludes, moreover, a power supply board13, namely a circuit of the device electronics, respectively of the field device formed therewith, embodied on a circuit board and embodied as a power supply, which is operated with a supply voltage provided by an external supply circuit ES remote from the field device, for example, a measurement transmitter power supply, a feed isolator or an alternating electrical current power supply. Power supply board13arranged in the example of an embodiment shown here alongside the measurement amplifier1is adapted to provide the different operating voltages required by the device electronics, respectively the field device formed therewith, during operation, for example, voltages of less than 20 V (volt). In the example of an embodiment shown here, the power supply board13is adapted to be operated with grid voltage, for example, thus with 230 V˜60 Hz (hertz), as supply voltage. The supply voltage is fed to the power supply board13via a connection cable14, for example, one formed by means of a two- or multiline cable, electrically connected to the supply circuit ES, and, consequently, extending partially externally of the electronics housing of the field device and further via a connection apparatus electrically connected thereto during operation. For electrically connecting the connection cable14with the power supply board13, the connection apparatus comprises a platform200, especially a platform200at least partially composed of an electrically insulating plastic and/or formed as an electronics insert at least partially encapsulating the device electronics, as well as a plug connector15mounted thereon. The plug connector15comprises a first plug connector part19secured to the platform200and at the same time electrically connected to the power supply board13as well as a second plug connector part20connectable with the connection cable14, respectively connected during operation and complementary to the first plug connector part19. The plug connector part19includes at least one contact pin19′ electrically connected to the circuit of the field device, while the plug connector part20comprises at least one contact socket20′, here namely electrically connectable, respectively connected, during operation, with at least one conductor of the connection cable14. Moreover, the plug connector part19and the plug connector part20are, as also directly evident from a combination ofFIGS.2a,2b,3a,3b,3c,4a,4b and6, releasably connected with one another; this, especially, in such a manner that the at least one contact socket20′ of the plug connector part20is plugged onto the at least one contact pin19′ of the plug connector part19to form a frictional interlocking and electrically conductively contacts such. The plug connector part19can—such as schematically shown—accordingly, for example, also be embodied as an installed plug, while the plug connector part20can be, for example, a socket. Since in the example of an embodiment shown here, the connection cable14to be connected by means of the connection apparatus serves for supplying the supply voltage, the plug connector part19has, such as indicated inFIG.3c, supplementally to the contact pin19′, at least one additional—second—contact pin19″ and the plug connector part20has, supplementally to the contact socket20′, at least one other—second—contact socket20″. In the case of supplying the device electronics with grid voltage, then, for example, the line conductor (L) can be connected to the contact socket20′ and the neutral conductor (N) to the additional contact socket20″ and, thus, both are led via the corresponding contact pin19′, respectively19″, further to the power supply board13. Additionally, also the, in given cases, provided protective conductor (PE) can be connected via the plug connector15—namely via another—third—contact socket20′″ as well as corresponding—third—contact pin19′″ with the power supply board13. Alternatively or supplementally, the protective conductor (PE) can be connected, for example, also to a grounded piece of sheet metal (not shown). For connecting the connection cable14to the plug connector part20embodied, for example, as a socket, plug connector part20can have, furthermore, e.g. corresponding—, for example, thus two or three—spring clamp elements21, of which each is electrically connected with a respective one of the contact sockets20′,20″,20′″ and in which the individual conductors (formed, for example, as Litz, respectively as solid, wires) of the connection cable14are tightly clamped. Plug connector part20accordingly includes in the example of an embodiment shown inFIG.3bexactly three spring clamp elements21for tight clamping of the individual conductors of the connection cable14. In such case, the connection cable14can, for example, however, also be designed as an only two conductor cable, of which a first conductor for the line conductor (L) is connected to the first contact socket20′ and a second conductor for the neutral conductor (N) is connected to the contact socket20″, in such a manner that the likewise present—third—contact socket20′ is unused. Alternatively thereto, the connection cable14can, however, for example, also be designed as a three line cable, which supplementally to the conductors for the line conductor and the neutral conductor includes, connected with the contact socket20′″, a third conductor for the protective conductor (PE). For plug connectors of the type being discussed, it is regularly required that for separating such a plug connector, here namely for the removal of the plug connector part20from the plug connector part19, respectively for pulling the at least one contact socket20′ from the at least one corresponding contact pin19′, a removal force of at least 15 N (Newton) must be exerted, respectively that with a removal force of less than 15 N acting on the second plug connector part20no removal of the plug connector part20from the plug connector part19, consequently no removal of the contact socket20′ from the contact pin19′, is effected. By such a requirement, it is intended that an overly easy, in given cases, also automatic releasing, of the plug connector part20from the plug connector part19, consequently an unintentional separating of the plug connector15during operation of the field device, can be prevented. Additionally, it is not permitted that the plug connector part20can be mistakenly pulled out, since this can represent an increased safety risk, especially in the direct vicinity of an electrically conductive liquid. In order to fulfill this requirement for device safety, respectivelyandto assure that a removal force of at least 15 N is required for removing the plug connector part20, the connection apparatus of the inventionfurtherincludes, as evident fromFIGS.2aand,2b,3a,3b, and3c,respectivelyandtheir combination,furthermore,a lid16for at least partially covering the plug connector15. Lid16is held movably on the platform200—here namely swingably, or pivotably, about an axis17—, and is at least partially composed, for example, of an electrically insulating plastic. Shown enlarged inFIG.4are the lid16as well as the bearing seats provided on the platform200for defining the axis17, respectively for the swingable mounting of the lid16. The lid16can—such as already indicated—, for example, be embodied as a formed plastic part. For the pivotable seating of the lid16, such includes a first mounting section28with a first pin29as well as a second mounting section30with a second pin31. A gap32is located between the—here right—mounting section28and the—here left—mounting section30. The mounting section30is embodied essentially more narrowly than the mounting section28and can, consequently, due to the gap32, be resiliently deformed to a certain degree. As further evident fromFIG.4, the seating shown here for the lid16comprises a recess33, a first bearing seat34for the pin29as well as a second bearing seat35for the pin31. For mounting the lid16into the seating, the mounting section30can be elastically deformed, so that the two pins29,31can pass into the corresponding bearing seats34,35and thereafter by letting the mounting section30return to its starting shape the two pins29,31become rotatably seated in the bearing seats34,35. The lid16can—such as directly evident from a combination ofFIGS.2a,2bas well as3a,3b—be swung between a first end position, in which the lid16at least partially covers the plug connector (FIG.2a;FIG.2b), and a second end position (FIG.3a;FIG.3b). In the example of an embodiment shown here, lid16can, for example, be pivoted around the axis17in the direction of the arrow18—inFIG.2a, respectivelyand2b,namely upwardly—,respectively opposite to the direction of the arrow18—inFIG.3a, respectivelyand3b,namely downwards—and so from the first end position shown inFIG.2a, respectivelyandand2b, into an opened position—,for example, namely into the second end position. The lid16of the connection apparatus of the invention is, especially, furthermore, adapted to be able to be swung into at least one open position located between the first end position and the second end position and in the open position—which is, in given cases, also coincident with the second end position—to expose the plug connector15to the extent that the at least one contact socket20′ of the second plug connector part20can be withdrawn from the at least one contact pin19′ of the first plug connector part19along a predetermined removal track, in that the second plug connector part20, with application of a removal force acting in the direction of the removal track, is, as indicated inFIG.3c, separated from the first plug connector part19. In an additional embodiment, the lid16is—not least of all for the protection of a service person against accidental contact with the supply voltage, in given cases, lying also above an allowable touch voltage, even in the case of opened electronics housing—, furthermore, additionally also adapted in the first end position to cover at least the plug connector part20connected with the first plug connector part19, consequently the so formed plug connector15, to the extent that even in the case of opened electronics housing a touching of voltage-carrying parts of the connection apparatus is prevented. In the example of an embodiment shown here, the lid16is—such as directly evident from the situation shown inFIG.2a, respectivelyand2b—so embodied that in the first end position it almost completely covers, respectively almost completely encases, the plug connector15. InFIGS.3aand,3b, respectivelyand3c, respectively,the lid16is, in each case, shown in an opened position—inFIG.3b, respectivelyand3c, respectively, namely, in each case, in an open position coincidental with the second end position—whereinFIGS.3a and3bshow, in each case, the lid16in an open position when at the same time plug connector part20is plugged onto the plug connector part19. Shown additionally is that the plug connector part19of the plug connector15is mounted directly on the power supply board13and that the plug connector part20in the case of lid swung into the open position can be plugged together with the plug connector part19, respectively withdrawn therefrom. In the case of removed housing closure H″ and at the same time lid16swung into the open position, the plug connector15is exposed to the extent that its plug connector part20can be easily pulled out of the plug connector part19by a service person, for instance, in order to isolate the device electronics from the supply circuit, respectively from the grid. The service person can additionally also in the case of lid swung into the open position plug the plug connector part20back onto the plug connector part19, in order, in this way, to connect the device electronics electrically with the connection cable, respectively to connect the field device electrically to the supply circuit. After plugging the plug connector part20into the plug connector part19, the lid16can be closed by swinging it from the open position into the first end position. This is schematically illustrated inFIG.3bby the arrow27. Then, additionally, also the housing closure H″ can be screwed back onto the housing foundation H′. Furthermore, the lid16of the connection apparatus of the invention is also provided, respectively adapted, at least in the first end position to secure the connected plug connector part20to the plug connector part19; this, especially, in such a manner that a removal force acting with less than 15 N on the second plug connector part20effects no removal of the at least one contact socket of the second plug connector part20from the at least one contact pin of the first plug connector part19, and/or in such a manner that for removal of the at least one contact socket20′ of the plug connector part20from the at least one contact pin19′ of the plug connector part19a removal force of greater than 15 N is required. For such purpose, the lid includes according to an embodiment of the invention on an inner side facing the plug connector at least one contact region16+, namely a portion, which is adapted to contact the second plug connector part20connected with the first plug connector part19, and, furthermore, the plug connector part20plugged into the plug connector part19includes on an outer side facing the lid16at least one contact region20+ corresponding to the contact region16+ of the lid16, namely a portion, which is adapted to contact the contact region16+ of the lid16. Advantageously, the portion of the lid16lying on the outer side of the plug connector part20can, in such case, be complementary to the mentioned outer side and so formed, respectively so embodied, that the mentioned portion of the lid16lies at least partially areally on the mentioned outer side of the plug connector part20and at the same time obstructs a releasing of the plug connector part20from the plug connector part19, respectively is formed such that its shape counteracts a removal of the plug connector part20from the plug connector part19. In an additional embodiment of the invention, the lid16is, consequently, furthermore, adapted to contact the second plug connector part20connected with the first plug connector part19to form a shape-based blocking between lid16and plug connector part20, especially a blocking counteracting a removal of the plug connector part20from the plug connector part19. For such purpose, the lid16is, according to an additional embodiment of the invention, furthermore, adapted in the first end position with at least the contact region16+ to contact the—here essentially complementary—contact region20+ of the plug connector part20, respectively the contact region16+ has a shape complementary to a shape of the contact region20+. Contact region16+ and contact region20+ can for achieving a sufficiently high holding force, namely requiring a removal force of at least 15 N, for example, be thus so formed and so embodied that in the case of lid16brought into the first end position, the contact regions16+,20+ cooperate to form a blocking between lid16and the plug connector part20based on shape for preventing removal of the plug connector part20from the plug connector part19. The contact region16+ of the lid16can, furthermore, be so embodied that it has at least one formed element24, for example, of pin or web shape, which in the first end position of the lid16correspondingly contacts the contact region20+ of the plug connector part20, respectively that it is formed by means of such a formed element24. In the example of an embodiment shown inFIGS.3a,3b,3c, a web serves as formed element24provided on the inner side of the lid16facing the plug connector15. It serves, consequently, for forming the aforementioned contact region16+. The function of the formed element24formed here as a web is yet again made clear inFIGS.5a and5b. The lid16brought also here, in each case, into the first end position is, in such case, in each case, shown sectioned along an imaginary cutting plane, such that the plug connector placed below the lid16can be seen. Plug connector part20is correspondingly shown plugged together with the plug connector part19—here sitting on the power supply board13. Plug connector part20includes three spring clamp elements21, in which the corresponding conductors—, formed for example, in each case, as solid wire, respectively as Litz wire—of the connection cable14are tightly clamped, via which the field device can, in turn, be fed the required supply voltage. For the case illustrated here, in which the lid16is placed in the closed position, namely in the first end position, the formed part24of the lid16lies on the second plug connector part20, whereby the plug connector15is secured against an otherwise possible separating. As directly evident from a combination ofFIG.5a, respectivelyand5b, withFIG.3a, respectivelyand3b, in the example of an embodiment shown here, besides the formed element24, a further formed element25—here formed essentially equally to the formed element24—is provided on the inner side of the lid16. Each of the at least two formed elements24,25—here namely formed as webs extending essentially parallel to one another—is additionally so formed that its underside—here namely forming the contact region16+—is embodied at least sectionally complementary to the contact region20+ of the plugged-in plug connector part20; this, especially, also in such a manner that in the first end position of the lid16each of the two—here, in each case, web shaped—formed elements24,25contacts the second plug connector part20areally. In such case, the height of each of the two formed elements24,25is so selected that the respective lower end of each of the two webs24,25areally contacts the contact region20+ of the plug connector part20located therebeneath, whereby, as a result, an automatic, respectively unintentional removal of the plug connector part20, not least of all also in the case of vibrations of the electronics housing, respectively of the platform200, is prevented. Moreover, a separation between a respective end of each of the formed elements24,25facing the axis17from the axis17can, furthermore, be so dimensioned that additionally and supplementally also at least one of these ends in the case of lid16located in the first end position contacts an additional corresponding contact region of the plug connector part20, in order further to improve the holding action of the shape-based blocking between lid16and plug connector part20. The securing of the plug connector part20connected with the plug connector part19can, moreover, however, also be supported by other measures, for example, also suppressing a spontaneous opening of the lid16during operation of the field device, thus measures such as e.g. corresponding detent elements of the connection apparatus and/or further formed elements provided on the housing closure. In an additional embodiment of the invention, lid1916and platform200are, consequently, furthermore, adapted in the first end position of the lid16to form a snap connection, namely such a connection, in the case of which, using respective inherent elasticity of lid1916and platform200, a shape-based interlocking is produced between lid1916and platform200, which interlocking can, upon actuation, be released. For forming such a snap connection, the lid in the case of this embodiment of the invention is, especially, also adapted in the first end position by means of at least one locking element22to engage in a corresponding locking element23of the platform200to form a—here self-holding, equally as well releasable by actuation—shape-interlocking. As directly evident from a combination ofFIGS.2aand,2b,3a,3b, respectivelyand3c, the locking element22of the lid16in the example of an embodiment shown here is essentially hook shaped, while the locking element23of the platform200corresponding to the at least one hook shaped locking element22of the lid is formed only by a web provided on the platform200, respectively a rib provided on the platform. The locking element23of the platform200can, however, for example, also be essentially hook shaped or, however, also essentially grommet shaped.FIG.2a, respectively2b, shows that in the case of lid16in the first end position the locking element22is engaged in the locking element23, in that a hook shaped end region of the locking element22viewed in the closing direction is placed behind the locking element23. In order to enable an easy as possible engaging of the locking element22in the locking element23, the hook shaped end region of the locking element22is, as,directly evident fromFIGS.3a,3b and3c, chamfered on a front side as viewed in the closing direction, in such a manner that in the case of the closing the lid16the locking element23of the platform200is pressed somewhat laterally by said front side, in order thereafter, namely after the hook shaped region has passed the locking element23, to be able to snap automatically back and so to engage the locking element23. In this way, the lid16is secured in the first end position, whereby also the plug connector15located therebeneath is secured against unintentional, respectively automatic releasing. An opening of the lid16is in the example of an embodiment shown here, conversely, only possible when a service person presses against a gripping recess26formed in the lid16. As a result of a deformation force exerted thereby on the gripping recess26, the locking element22moves inwardly toward the plug connector19, respectively away from the locking element23of the platform200. The deformation force must, in such case, be sufficiently large that the locking element22is freed completely from the locking element and completely releases the catch mechanism between the two locking element22,23. Conversely, the restoring forces brought about by the lid16, namely restoring forces counteracting deformation allowing an opening of the lid, must be sufficiently high that a spontaneous releasing of the snap closure, respectively a spontaneous opening of the lid16during operation of the field device, not least of all also in the case of vibrations of the electronics housing, respectively the therein accommodated device electronics, is safely prevented. FIG.6finally shows another variant of the invention, in the case of which for securing of the lid16brought into the first end position, consequently for securing the plug connector assembled by connecting the plug connector part20with the plug connector part19, the housing closure H″ and the lid16are adapted to contact one another in the installed position, namely in the case of lid16located in the first end position and housing closure H″ connected with the housing foundation H′, especially to contact one another in such a manner that a force—and/or shape interlocking opposing a swinging of the lid out of the first end position is formed between lid and housing closure. For such purpose, the housing closure H″ includes on an inner side facing the connection apparatus, respectively the device electronics, at least one contact region H#, namely a portion, which is adapted to contact the lid16located in the first end position, and the lid16includes on an outer side facing the housing closure at least one contact region16# corresponding to the contact region H# of the housing closure H′, namely a portion, which is adapted, in the installed position, to contact the contact region H# of the housing closure. As shown schematically inFIG.6, the contact region H# of the housing closure can be formed by providing the housing closure on the inner side facing the connection apparatus, respectively the device electronics, with at least one formed element30, for example, a pin shaped or web-shaped, formed element30, which is adapted, in the installed position, to form the contact region H# for contacting the corresponding contact region16# of the lid16located in the first end position, for instance, to form a shape-blocking between housing closure and lid. A so formed shape-based blocking can, moreover, also be so designed that in the installed position the formed element30secures the lid16in the first end position playfreely, for example, by dimensioning the formed element30such that in the installed position it supplementally experiences a deformation force, which effects a small, equally as well sufficient, elastic deformation of the formed element30for securing the lid16in the first end position. Particularly in the case of application of the aforementioned formed element30, however, for example, for the mentioned case, in which a snap connection is formed between the platform and the lid16brought into the first end position, the lid16and the plug connector15can, furthermore, be so matched to one another dimensionally that in the case of lid16brought into the end position, the lid and/or the plug connector15are so elastically deformed, that, as a result, additional holding forces are produced in the connection apparatus for holding the plug connector part20pressed against the plug connector part19, whereby the plug connector part20connected with the plug connector part19can be secured even better against a possible releasing from the plug connector part19. This can be implemented very simply, for example, by a suitably designed height for the formed elements24,25. | 31,435 |
RE49786 | DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The existing video coding standards, as well as those currently under definition, offer the possibility of partitioning the images that constitute digital video streams for the purpose of optimizing the coding and decoding processes. As shown inFIG.1, the H.264/AVC specification allows creating groups of macroblocks, wherein the images to be coded are subdivided into different types of groups, called slices, which are then coded independently of one another. For example, as shown inFIG.1in regard to the subdivision called “Type 2”, the macroblocks can be grouped into slices having an arbitrary shape, so as to allow the quality of the coded video to be selectively varied as a function of the position of any “regions of interest”. Instead,FIG.2shows a new type of image subdivision, called “tile”, which has been introduced into the specification of the new ITU/ISO/IEC HEVC (High Efficiency Video Coding) standard. This type of subdivision, based on the slice structure already existing in the H.264/AVC specification, has been introduced in order to allow parallelization of the video stream coding and decoding processes: the increasing spread and lower costs of parallel graphic processors (the so-called GPU's, Graphics Processing Units), which are now available even on mobile terminals such as telephones and PC tablets, have promoted the introduction of parallelization support tools which allow image formats to be brought to very high resolutions even on terminals typically having limited computational resources. The HEVC specification has defined tiles in such a way as to allow the images that constitute the video stream to be segmented into regions and to make the decoding thereof mutually independent. The decoding process, however, even when parallelized, is still carried out for the entire image only, and the segments cannot be used independently of one another. As aforementioned in the above paragraphs, it would be useful to be able to partition the video stream in such a way that different terminals can decide, automatically or upon instructions received from the user, which parts of the video should be decoded and sent to the display for visualization. FIGS.3,4,6and7illustrate different utilization scenarios where this kind of partitioning might prove useful. FIG.3shows a container video stream which, for example, may be in the 4K (3840×2160 pixel) format and may contain four independent HD (1920×1080 pixel) videos. A user equipped with a 4K decoder may decode and display the entire video, while a user equipped with a less powerful decoder may limit the decoding to a single HD stream at a time. FIG.4shows the transportation, as a single container video stream, of two stereoscopic video streams (in the form of two independent Left and Right video pairs), e.g., representing two different stereoscopic views of the same event, from which the user can choose the preferred view without necessarily having to decode the whole frame (with obvious implications in terms of energy consumption). FIG.5shows the composition of a stereoscopic video and the associated depth maps into a single video stream. In this case, a decoder of a stereoscopic television set may decode only the part relating to the two images of the stereoscopic pair, located in the upper half of the image; the lower part will thus not be decoded. Instead, a decoder of a auto-stereoscopic television set using the well-known 2D+Z technique (construction of synthetic views from a single image plus the associated depth map) might, for example, decode only the left half of the image, whereas the decoder of a more sophisticated auto-stereoscopic decoder may use both views and both depth maps to synthesize the intermediate views. FIG.7shows the composition of a dual-resolution 2D video (e.g., intended for a display in 21:9 format), located in the upper half of the image, and the corresponding stereoscopic view in side-by-side format in the lower region. The tile structure described in the HEVC specification is not sufficient to allow a decoder to properly recognize and decode the content transported by the container video. This problem can be solved by entering a suitable level of signalling describing which content is being transported in each one of the independently decodable regions and how to proceed in order to properly decode and display it. At least two different scenarios can be foreseen. In the first one, it is necessary to indicate the association between the single contents and at least one of the tiles into which the image has been disassembled, and its possible reassembly into a coherent video stream (for example, as shown inFIG.11, a stereoscopic video stream might be subdivided into two tiles and, while a 2D decoder must be informed about the possibility of decoding one single tile, a 3D decoder might not adopt any specific strategy and decode the entire stream). In the second scenario, instead, it is indicated the association between the single contents and each one of the tiles into which the image has been disassembled, and its possible reassembly into a coherent video stream (for example, a stereoscopic video stream may be subdivided into two tiles and, while a 2D decoder must be informed about the possibility of decoding one single tile, a 3D decoder must be informed about the necessity of decoding the entire stream). The proposed solution provides for entering a descriptor which indicates, for at least one of the tiles, one or more specific characteristics: for example, it must be possible to signal if the content is a 2D one or, in the case of a stereoscopic content, the type of frame packing arrangement thereof. Furthermore, it is desirable to indicate any “relationships” (joint decoding and/or display) between tiles; the view identifier (to be used, for example, in the case of multiview contents) and a message stating whether the view in question is the right view or the left view of a stereoscopic pair, or a depth map. By way of example, the solution is illustrated as pseudo code in the table ofFIG.12, which describes the structure of the signalling to be entered into the coded video stream by using the data structures already employed in the H.264/AVC and HEVC specifications. It is nonetheless possible to adopt analogous signalling structures allowing the content of one or more tiles to be described in such a way as to allow a decoder to decode them appropriately. Frame_packing_arrangement_type is an index that might correspond, for example, to the values commonly used in the MPEG2, H.264/AVC or SMPTE specifications, which catalogue the currently known and used stereoscopic video formats. Tile_content_relationship_bitmask is a bitmask that univocally describes, for each tile, its association with the other tiles into which the coded video stream has been subdivided. Content_interpretation_type provides the information necessary for interpreting the content of each tile. An example is specified in the table ofFIG.13. With reference to the above case, wherein a stereoscopic video is coded as two tiles, in order to ensure the decoding of just one view by a 2D decoder the following information will be associated with the tile 0:frame_packing_arrangement_type[0]=3tile_content_relationship_bitmask[0]=11view_id[0]=0content_interpretation_type[0]=2 It should be noted that this type of signalling might be used together with or instead of other tools, such as, for example, the cropping rectangle. The cropping rectangle technique, according to which it is mandatory to crop the part of the decoded frame inside a rectangle signalled by means of suitable metadata, is already commonly used for making “3D compatible” a stereoscopic video stream in the form of one of the frame packing arrangements that require the stereoscopic pair to be entered into a single frame.FIG.11bis illustrates, for example, a frame containing the so-called “side-by-side” frame packing arrangement, wherein only the left view (the gray one in figure) is contained in the cropping rectangle. Without tile partitioning, a 2D decoder should decode the whole frame, then apply the cropping and discard the right view (the white one inFIG.11bis). By using the method of the invention, it is instead possible to code and signal the two views as separate tiles, thereby allowing a 2D decoder to decode just the area contained in the cropping rectangle. Assuming, for example, that the video stream has been divided into four tiles, as shown inFIG.4, the relationship among the tiles would be described by the following values:frame_packing_arrangement_type[0]=3frame_packing_arrangement_type[1]=3frame_packing_arrangement_type[2]=3frame_packing_arrangement_type[3]=3tile_content_relationship_bitmask[0]=1100tile_content_relationship_bitmask[1]=1100tile_content_relationship_bitmask[2]=0011tile_content_relationship_bitmask[3]=0011view_id[0]=0view_id[1]=0view_id[2]=1view_id[3]=1content_interpretation_type[0]=2content_interpretation_type[1]=1content_interpretation_type[2]=2content_interpretation_type[3]=1 This signalling indicates to the decoder that tiles 0 and 1 belong to the same 3D video content (tile_content_relationship_bitmask=1100) in side-by-side (frame_packing_arrangement_type=3). The value of tile_content_relationship_bitmask allows the decoder to know that the two views (which belong to the same stereoscopic pair because tile view_id=0 for both tiles) are contained in different tiles (and hence, in this case, at full resolution). Content_interpretation_type allows to understand that tile 0 corresponds to the left view, while tile 1 corresponds to the right view. The same considerations apply to tiles 1 and 2. The arrangement ofFIG.6, instead, is described by the following signalling:frame_packing_arrangement_type[0]=3frame_packing_arrangement_type[1]=3frame_packing_arrangement_type[2]=6frame_packing_arrangement_type[3]=6tile_content_relationship_bitmask[0]=1111tile_content_relationship_bitmask[1]=1111tile_content_relationship_bitmask[2]=1010tile_content_relationship_bitmask[3]=0101view_id[0]=1view_id[1]=1content_interpretation_type[0]=2content_interpretation_type[1]=1content_interpretation_type[2]=5content_interpretation_type[3]=5 UnlikeFIG.4, tile_content_relationship_bitmask is 1111 for tiles 0 and 1. This means that there is a relationship among all tiles. In particular, tiles 2 and 3 are 2D contents (frame_packing_arrangement_type=6) containing a depth map (content_interpretation_type=5) respectively associated with tile 0 (tile_content_relationship_bitmask=1010) and with tile 1 (tile_content_relationship_bitmask=0101) In the syntax of the HEVC specification, this type of signalling could be easily coded as a SEI (Supplemental Enhancement Information) message: application information which, without altering the basic coding and decoding mechanisms, allows the construction of additional functions concerning not only the decoding, but also the next visualization process. As an alternative, the same signalling could be entered into the Picture Parameter Set (PPS), a syntax element that contains information necessary for decoding a dataset corresponding to a frame. The table ofFIGS.14a-14dincludes, highlighted in bold, the modifications, in the form of pseudo code, that need to be made to the syntax of the PPS of the HEVC standard in order to enter the above-mentioned signalling A further generalization might provide for entering the signalling into the Sequence Parameter Set (SPS): a syntax element that contains information necessary for decoding a dataset corresponding to a consecutive sequence of frames. The table ofFIGS.15a-15fincludes, highlighted in bold, the modifications, in the form of pseudo code, that need to be made to the syntax of the SPS of HEVC in order to enter the above-mentioned signalling, wherein multiservice_flag is a variable that informs about the presence of multiple services within each tile and num_tile is the number of tiles within one frame. FIG.5illustrates the selective tile decoding process. The video stream contains a pair of stereoscopic views, coded into two separate tiles. The latter are described by the same signalling used for representing the content ofFIG.4(in this case, however, the total number of tiles is 2). FIG.8is a block diagram of an apparatus or a group of apparatuses that can implement the coding technique of the present invention. N video contents S1-SNare inputted to a “source composer”. The “source composer” may be a separate component or may be integrated as an input stage of a suitable encoder. The source composer composes the container video stream that transports the N component video streams, and then outputs it towards an encoder. The source composer may optionally add the signalling required for describing to the encoder the format of the component video streams and their positions within the container video stream. An encoder receives the container video stream, constructs the tiles in such a way as to map them onto the structure of the single component video streams, generates the signalling describing the tiles, the structure of the component video streams and their relationships, and compresses the container video stream. If the “source composer” does not automatically generate the signalling that describes the component video streams, the encoder can be programmed manually by the operator. The compressed video stream outputted by the encoder can then be decoded in different ways, i.e., by selecting independent parts depending on the functional characteristics and/or computational resources of the decoder and/or of the display it is connected to. The audio of each component video stream can be transported in accordance with the specifications of the System Layer part adopted for transportation. A 2D decoder analyzes the bitstream, finds the signalling of the two tiles containing the two views, and decides to decode a single tile, displaying only one image compatible with a 2D display. A 3D decoder, instead, will decode both tiles and will proceed with stereoscopic visualization on a 3D display. Similarly,FIG.9shows a decoder which, when connected to the display, negotiates the characteristics (e.g., the resolution) of the video to be displayed and decides accordingly, in an autonomous manner, which part of the video stream is to be decoded. This decision might also be dictated by the manual intervention of a user: for example, in the event that the video being transmitted is a stereoscopic video coded into two tiles, and assuming that the user, although equipped with a 3D television set, wants nevertheless to watch that content in 2D format (such a decision may be manifested by pressing a specific remote control key), the decoder may adopt a different decoding strategy than the one it would have adopted automatically while negotiating the best display format with the television set. FIG.10shows, instead, the case wherein the decoder is located inside a gateway that receives the coded stream and must serve heterogeneous terminals, characterized by the possibility of supporting different formats of the video content (e.g., some devices may have the ability of displaying stereoscopic contents, while, at the same time, other devices might only have a 2D display). The gateway automatically negotiates with or receives configuration instructions from each device, and then decodes one or more parts of the input content in such a way as to adapt them to the characteristics of each requesting device. Therefore, the present invention relates to a method for generating a video stream by starting from a plurality of sequences of 2D and/or 3D video frames, wherein a video stream generator composes into a container video frame video frames coming from N different sources S1, S2, S3, SN. Subsequently, an encoder codes the single output video stream of container video frames by entering into it a signalling adapted to indicate the structure of the container video frames. The invention also relates to a method for regenerating a video stream comprising a sequence of container frames, each one comprising a plurality of 2D and/or 3D video frames coming from N different sources S1, S2, S3, SN. A decoder reads a signalling adapted to indicate the structure of the container video frames, and regenerates a plurality of video streams by extracting at least one or a subset of the plurality of video frames by decoding only those portions of the container video frames which comprise those video frames of the plurality of 2D and/or 3D video frames of the video streams which have been selected for display. | 16,763 |
RE49787 | BEST MODE FOR CARRYING OUT THE INVENTION The embodiments of the present invention are described by referring to diagrams. First Embodiment FIG.3is a block diagram showing the structure of a moving picture coding apparatus that embodies the moving picture coding method of the present invention. A picture coding apparatus1is an apparatus for performing compression coding on an input picture signal Vin and outputting a coded stream Str which has been coded into a bitstream by performing variable length coding and the like. As shown inFIG.3, such picture coding apparatus3is comprised of a motion estimation unit101, a motion compensation unit102, a subtraction unit103, an orthogonal transformation unit104, a quantization unit105, an inverse quantization unit106, an inverse orthogonal transformation unit107, an addition unit108, a picture memory109, a switch110, a variable length coding unit111and a quantization matrix holding unit112. The picture signal Vin is inputted to the subtraction unit103and the motion estimation unit101. The subtraction unit103calculates residual pixel values between each image in the input picture signal Vin and each predictive image, and outputs the calculated residual pixel values to the orthogonal transformation unit104. The orthogonal transformation unit104transforms the residual pixel values into frequency coefficients, and outputs them to the quantization unit105. The quantization unit105quantizes the inputted frequency coefficients using inputted quantization matrix WM, and outputs the resulting quantized values Qcoef to the variable length coding unit111. The inverse quantization unit106performs inverse quantization on the quantized values Qcoef using the inputted quantization matrix WM, so as to turn them into the frequency coefficients, and outputs them to the inverse orthogonal transformation unit107. The inverse orthogonal transformation unit107performs inverse frequency transformation on the frequency coefficients so as to transform them into residual pixel values, and outputs them to the addition unit108. The addition unit108adds the residual pixel values and each predictive image outputted from the motion estimation unit102, so as to form a decoded image. The switch110turns ON when it is indicated that such decoded image should be stored, and such decoded image is to be stored into the picture memory109. Meanwhile, the motion estimation unit101, which receives the picture signal Vin on a macroblock basis, detects an image area closest to an image signal in such inputted picture signal Vin within a decoded picture stored in the picture memory109, and determines motion vector(s) MV indicating the position of such area. Motion vectors are estimated for each block, which is obtained by further dividing a macroblock. When this is done, it is possible to use more than one picture as reference pictures. Here, since a plurality of pictures can be used as reference pictures, identification numbers (reference indices Index) to identify the respective reference pictures are required on a block-by-block basis. With the use of the reference indices Index, it is possible to identify each reference picture by associating each picture stored in the picture memory109with the picture number designated to such each picture. The motion compensation unit102selects, as a predictive image, the most suitable image area from among decoded pictures stored in the picture memory109, using the motion vectors detected in the above processing and the reference indices Index. The quantization matrix holding unit112holds the quantization matrix WM which has already been carried as a part of a parameter set and the matrix ID that identifies this quantization matrix WM in the manner in which they are associated with each other. The variable length coding unit111obtains, from the quantization matrix holding unit112, the matrix ID corresponding to the quantization matrix WM used for quantization. The variable length coding unit111also performs variable length coding on the quantization values Qcoef, the matrix IDs, the reference indices Index, the picture types Ptype and the motion vectors MV so as to obtain a coded stream Str. FIG.4is a diagram showing the correspondence between sequence parameter sets and picture parameter sets and pictures.FIG.5is a diagram showing a part of a structure of a sequence parameter set, andFIG.6is a diagram showing a part of a structure of a picture parameter set. While a picture is made up of slices, all the slices included in the same picture have identifiers indicating the same picture parameter set. In MPEG-4 AVC, there is no concept of a header, and common data is placed at the top of a sequence under the designation of a parameter set. There are two types of parameter sets, a picture parameter set PPS that is data corresponding to the header of each picture, and a sequence parameter set SPS corresponding to the header of a GOP or a sequence in MPEG-2. A sequence parameter set SPS includes the number of pictures that are available as reference pictures, image size and the like, while a picture parameter set PPS includes a type of variable length coding (switching between Huffman coding and arithmetic coding), default values of quantization matrices, the number of reference pictures, and the like. An identifier is assigned to a sequence parameter set SPS, and to which sequence a picture belongs is identified by specifying this identifier in a picture parameter set PPS. An identifier is also assigned to a picture parameter set PPS, and which picture parameter set PPS is to be used is identified by specifying this identifier in a slice. For example, in the example shown inFIG.4, a picture #1includes the identifier (PPS=1) of a picture parameter set PPS to be referred to by a slice included in the picture #1. The picture parameter set PPS #1includes the identifier (SPS=1) of a sequence parameter set to be referred to. Furthermore, the sequence parameter set SPS and the picture parameter set PPS respectively include flags501and601indicating whether or not quantization matrices are carried as shown inFIG.5andFIG.6, and in the case where the quantization matrices are to be carried, quantization matrices502and602are respectively described therein. The quantization matrix can be changed adaptively to the unit of quantization (for example, horizontal 4×vertical 4 pixels and horizontal 8×vertical 8 pixels). FIG.7is a diagram showing an example description of quantization matrices in a parameter set. Since a picture signal Vin consists of luma components and two types of chroma components, it is possible to use different quantization matrices for luma components and two types of chroma components separately when performing quantization. It is also possible to use different quantization matrices for intra-picture coding and inter-picture coding separately. Therefore, for example, as shown inFIG.7, it is possible to describe quantization matrices for a unit of quantization, luma components and two types of chroma components, and intra-picture coding and inter-picture coding, respectively. The operations for placing matrix IDs in the above-structured moving picture coding apparatus are explained.FIG.8is a flowchart showing the operations for placing a matrix ID. The variable length coding unit111obtains a quantization matrix WM used for quantization (Step S101). Next, the variable length coding unit111judges whether or not the obtained quantization matrix WM is held in the quantization matrix holding unit112(Step S102). Here, in the case whether the obtained quantization matrix WM is held in the quantization matrix holding unit112(YES in Step S102), the variable length coding unit111obtains the matrix ID corresponding to the obtained quantization matrix WM from the quantization matrix holding unit112(Step S103). Then, the variable length coding unit111places the obtained matrix ID in predetermined units (for example, per picture, slice or macroblock) (Step S104). On the other hand, in the case where the obtained quantization matrix WM is not held in the quantization matrix holding unit112(NO in Step S102), the quantization matrix holding unit112generates the matrix ID for this quantization matrix WM (Step S105). Then, the quantization matrix holding unit112holds this quantization matrix WM and the matrix ID in the manner in which they are associated with each other (Step S106). The variable length coding unit111places the generated matrix ID in predetermined units (for example, per picture, slice or macroblock) (Step S107). The variable length coding unit111describes the generated matrix ID and the quantization matrix WM in the parameter set (Step S108), Note that the parameter set in which these matrix ID and quantization matrix WM are described is carried earlier, in a coded stream Str, than the predetermined units (that is, coded data quantized using this quantization matrix WM) to which this matrix ID is placed. As described above, since quantization matrices WM are described in a parameter set and carried while only the matrix ID that identifies the quantization matrix WM used in predetermined units (for example, per picture, slice or macroblock) is placed therein, there is no need to describe the quantization matrix WM used in every predetermined unit. Therefore, it becomes possible to reduce the amount of data to be coded and achieve efficient coding. Note that it is possible to update a quantization matrix WM carried in a sequence parameter set SPS and carry the updated one (with the same matrix ID) in a picture parameter set PPS. In this case, the updated quantization matrix WM is used only when the picture parameter set PPS is referenced. It is also possible to include in a coded stream a flag indicating switching between the default quantization matrix WM and the quantization matrix WM identified by a matrix ID. In this case, the default quantization matrix WM is replaced with the quantization matrix WM identified by the matrix ID according to the flag. FIG.9is a block diagram showing a structure of a moving picture decoding apparatus that embodies the moving picture decoding method according to the present invention. The moving picture decoding apparatus2is an apparatus that decodes a coded stream obtained by the coding by the moving picture coding apparatus1as described above, and includes a variable length decoding unit201, a quantization matrix holding unit202, a picture memory203, a motion compensation unit204, an inverse quantization unit205, an inverse orthogonal transformation unit206and an addition unit207. The variable length decoding unit201decodes the coded stream Str, and outputs quantized values Qcoef, reference indices Index, picture types Ptype and motion vectors MV. The variable length decoding unit201also decodes the coded stream, identities a quantization matrix WM based on an extracted matrix ID, and outputs the identified quantization matrix WM. The quantization matrix holding unit202associates the quantization matrix WM which has already been carried in a parameter set with the matrix ID that identifies this quantization matrix WM, and holds them. The quantized values Qcoef, reference indices Index and motion vectors MV are inputted to the picture memory203, the motion compensation unit204and the inverse quantization unit205, and decoding processing is performed on them. The operations for the decoding are same as those in the moving picture coding apparatus1shown inFIG.3. Next, the operations for identifying a quantization matrix in the above-structured moving picture decoding apparatus are explained.FIG.10is a flowchart showing the operations for identifying a quantization matrix. The variable length decoding unit201decodes a coded stream Str and extracts a matrix ID placed in predetermined units (Step S201). Next, the variable length decoding unit201identities a quantization matrix WM from among quantization matrices held in the quantization matrix holding unit202, based on the extracted matrix ID (Step S202). Then, the variable length decoding unit201outputs the identified quantization matrix WM to the inverse quantization unit205(Step S203). As described above, while a quantization matrices WM are described in a parameter set and carried, it is possible, in predetermined units (for example, per picture, per slice or per macroblock), to decode a coded stream in which only the matrix ID that identifies the used quantization matrix WM is placed. Note that quantization matrices WM are described in a parameter set and carried in the present embodiment but the present invention is not limited to such case. For example, quantization matrices may be previously transmitted separately from a coded stream. By the way, since a picture signal Vin is made up of luma components and two types of chroma components as described above, it is possible to use different quantization matrices separately for luma components and two types of chroma components for quantization. It is also possible to use an uniform quantization matrix for all the components. Next, the operations for identifying quantization matrices to be used for chroma components are explained.FIG.11is a flowchart showing the operations for identifying quantization matrices to be used for chroma components. The variable length decoding unit201judges whether or not there is a quantization matrix for chroma components of the type corresponding to the current decoding among the quantization matrices WM identified as mentioned above (Step S301). For example, in the case where a quantized value Qcoef to be decoded is a first chroma component, it judges whether or not there is a quantization matrix for the first chroma components. In the case where a quantized value Qcoef to be decoded is a second chroma component, it judges whether or not there is a quantization matrix for the second chroma components. Here, if there is a quantization matrix for the corresponding type of chroma components (YES in Step S301), it outputs the corresponding chroma quantization matrix to the inverse quantization unit205as a matrix to be used (Step S302). On the other hand, if there is no such corresponding chroma quantization matrix ((NO in Step S301), the variable length decoding unit201judges whether or not there is a quantization matrix for another type of chroma components (Step S303). For example, in the case where a quantized value Qcoef to be decoded is a first chroma component, it judges whether or not there is a quantization matrix for the second chroma components. In the case where a quantized value Qcoef to be decoded is a second chroma component, it judges whether or not there is a quantization matrix for the first chroma components. Here, if there is a corresponding quantization matrix for another type of chroma components (YES in Step S303), it outputs the quantization matrix for another type of chroma components to the inverse quantization unit205as a matrix to be used (Step S304). On the other hand, if there is no quantization matrix for another type of chroma components (NO in Step S303), it outputs the quantization matrix for the luma components to the inverse quantization unit205as a matrix to be used (Step S305). As a result, it becomes possible to decode a coded stream even if there is no chroma quantization matrix. Second Embodiment The key points in the present embodiment are as follows. 1. If there are multiple sequence-level stream description data structures selectable by a different part of a video bitstream, the quantization matrix shall be carried in a data structure separate from any of the sequence header data structure. 2. Multiple quantization matrices customized by users are defined at the beginning of a sequence video stream. The quantization matrices shall be selectable at different pictures at different locations in a bitstream. MPEG-2 uses quantization matrix scheme but it did not use a set of matrices from which one of them can be selected. It has to reload a new matrix when a quantization matrix is updated. 3. How frequent the update would be performed is specified as syntax elements to apply the quantization updates, so that the quantization matrix update scheme is compatible with the above description. In the scheme of the present embodiment, MPEG-2 single effective quantization matrix and later update is only a special case of this update scheme. Next, the overview of the present embodiment is described. In some video coding standards, there may be several segments in a sequence that are encoded using different encoding configurations, and as such, they require different sequence or segment header descriptors for each segment in the sequence. As transmitting quantization matrix takes considerable number of bits, we place all quantization matrices used in a sequence somewhere separate from any of the sequence or segment headers. For segments of the sequence that use different sets of quantization matrices, it only needs to reference the quantization matrices, such as an identification number, rather than transmitting the matrix from an encoder to decoders every time the matrix is used, which is the mechanism that MPEG-2 has used. All the quantization matrices that are not specified in the video coderc's specification should be defined and grouped together. The segment or block of the bitstream that carries these quantization matrices should be placed at the beginning of the bitstream of a sequence before any encoded video data are transmitted. As choices that can be made by different video codec standards, those quantization matrices can be included as part of the video elementary stream, or can be carried out-of-band, such as in transport stream or in packets or in files separate from the main body of the video stream. In many codec specifications, such as MPEG-2, MPEG-4, there are lower-level data structures contained in a sequence segment, which organizes video data into “group of pictures”, pictures, slices, layers, macroblocks, so on. If a sequence segment header or descriptor references more than one set of quantization matrices, the choices of which one set to use will be left to lower level data structure to specify. This will be discussed later in this disclosure. For those sequence segments that references more than one set of quantization matrix, all the quantization matrices are carried in the beginning of a sequence. The decoder that has received all the quantization matrices shall keep these quantization in its memory in a way that, when the decoder references a particular quantization matrix, all the look up tables, if there are any, associated with the quantization matrices will be ready to use. In implementing the specification of the syntax, the capacity of the decoders has to be taken into consideration to fit the capacity limit into the application requirement the decoders fit to. Therefore, the number of quantization matrices available in any given time shall not exceed a certain range. In case that the decoder capacity does not allow storage of more than one set of quantization matrices, whenever a new set of quantization matrices become needed, the previously stored quantization matrix set has to be removed from decoder memory before the new one can be stored and become effective. This scenario becomes the same as that MPEG-2 has used in its specification. FIG.12is a diagram showing correspondence between quantization matrices carried as separate data and quantization matrices to be used for a sequence. In the example shown inFIG.12, it is described that quantization matrices Q-matrix1and Q-matrix3are used in a sequence SEQ1. It is also described that quantization matrices Q-matrix2, Q-matrix4and Q-matrix5are used in a sequence SEQ2, and a quantization matrix Q-matrix4is used in a sequence SEQ3. Next, features in the syntax to support the use of quantization matrix are explained. Quantization matrix can be fixed for an entire sequence or programs. But the more flexible way to achieve better quality is to allow quantization scheme and quantization matrices to be changed dynamically. In such case, the issue is at what data level that kind of changes should be allowed. It is understood that depending on complexity allowed by an application domain, there will be restriction on the number of quantization matrix sets to be allowed at what data levels. For all the stream data structure levels, that is, from sequence, segments, pictures, slices, to macroblocks, (macroblock has been used in almost all codec standards to mean 16×16 block of pixels, however, this dimension may change in proprietary or future codecs) we have in the bitstream a 6-bit flag containing the following bits (as shown in Table 1) to indicate what types of quantization are allowed to change at from one immediate lower level data to another. For example, in MPEG-4 AVC, the immediate lower level of “Sequence” is “Picture” and the immediate lower level of “Picture” is “Slice”. TABLE 1Bits representing quantization schemes and update rulesBit A1 bit for using only 4 × 4 uniform quantizationBit B1 bit for using only 4 × 4 non-uniform quantization schemeBit C1 bit for allowing 4 × 4 quantization scheme changes—changefrom one quantization matrix set to another or changes fromuniform quantization scheme to non-uniform quantization scheme.Bit D1 bit for using only 8 × 8 uniform quantizationBit E1 bit for using only 8 × 8 non-uniform quantization schemeBit F1 bit for allowing 8 × 8 quantization scheme changes—changefrom one quantization matrix set to another or changes fromuniform quantization scheme to non-uniform quantization scheme. Note that when only Bit A is set and Bit B is not set, Bit C cannot be set. Similarly, when only Bit D is set and Bit E is not set, Bit F cannot be set. When Bit B and Bit C are both set, it means quantization matrix set can change from one to another. One quantization matrix set contains one matrix per block coding mode. The block coding mode can be intra-prediction of certain direction, inter-predicted block, a bi-predicted block etc. Bit C and Bit F indicate changes of quantization scheme or quantization matrix set or both. If the bit for 8×8 non-uniform quantization with quantization matrix is set in the Sequence level in MPEG-4 AVC, the quantization matrix used in one “Picture” data can be different from other “Picture” data. At the highest level of data syntax, such as sequence header, if quantization matrix scheme is used, a default quantization set will be specified. When Bit C or Bit F is set for a data level, there will a flag for each of the lower level data headers to indicate whether the default quantization matrix set will be used in these levels. If the flag is positive in a lower data header, a new default quantization set for this data level will be defined and a 6-bit flag will be used at this data level to indicate whether the default will be changed in the further lower data level. This is followed in all data levels until the lowest level or the lowest level permitted by application requirement. When Bit C or Bit F is not set, there will not be this flag in lower data headers, and the default will be automatically assumed. There can be restrictions applicable in this recursive signaling method for transmitting information on quantization schemes, for example, restriction by the frequency of quantization matrix changes that has to be capped under a certain rate. Next, default and customizable quantization matrices are explained. In a video coding specification using non-uniform quantization matrix scheme, there may be several predefined matrices in a video codec specification. These default or prescribed matrices are known by compliant decoders and therefore there is no need to transfer the matrices to decoders. In similar way, these quantization matrices can be referenced in the same way as described above. When prescribed matrices are available, decoder shall add received customized matrices into its pool of quantization matrices. As described above, distinctive quantization matrices are indexed by identification numbers, which are assigned by encoder and transmitted to decoders. In organizing the quantization matrices in bitstream syntax, the quantization of the same size can be grouped together. Information regarding whether a matrix should be used for inter-coded blocks or intra-coded blocks, or whether a matrix should be used for luma or chroma can also be noted in their attributes. Next, update of a quantization matrix is explained. Video codec bitstream syntax can allow quantization matrices already known to decoders to be added or updated. When a quantization matrix is associated with a new identification number, this matrix is taken as a new quantization matrix and can be referenced by the new identification number. When the identification number has already been associated with a quantization matrix, the existing quantization matrix will be modified at decoders with the new matrix. Only quantization matrix of the same size as the old one can replace an old matrix. Encoder is responsible in keeping track of the active quantization matrices. During transmission of the updated quantization matrices, only the quantization matrix that needs to be updated is defined in the network packets. Next, carriage of quantization matrices in MPEG-4 AVC is explained. In MPEG-4 AVC, all video data and headers are packed into a bitstream layer called Network Abstract Layer (NAL). NAL is a sequence of many NAL units. Each NAL unit carries certain type of video data or data headers. MPEG-4 AVC also defines several picture data groups under one data hierarchy. The hierarchy starts at Sequence, which is described by Sequence Parameter Set. A “Sequence” can have pictures using different Picture Parameter Sets. Under “Picture”, there are slices, where slices have slice headers. A slice typically has many 16×16 blocks of pixels, called macroblocks. When we introduce quantization matrix scheme into MPEG-4 AVC, we can have user defined quantization matrices or encoder-provided matrices be carried over NAL units. The use of NAL units can be implemented in three different ways. (1) One NAL unit carries all the matrix information (including quantization tables) associated with each of the matrices. (2) Several NAL units each carries certain type of quantization matrices and their information. (3) Each NAL unit carries the definition of one quantization matrix. In the case (1) and (2), the NAL units will also provide the total number of quantization matrices. In case 3, the total number of user-defined quantization matrices is not explicitly given by the video elementary stream. Both encoder and decoder must count the total as they go. An example of case 2 is when 4×4 quantization matrices and 8×8 quantization matrices are grouped and each is carried in a NAL. In the sequence parameter set, MPEG-4 shall specify which quantization matrices it will use. It will define the 6-bit flag to indicate what quantization scheme will be used and whether it is allowed to change in the next level that is picture level, whose header is Picture Parameter Set. The sequence parameter set that references a subset of the defined quantization matrices shall list all the quantization matrix IDs, which includes those default to the video codec specification, and those defined specifically for the content by codec operators. Sequence parameter sets can carry some common quantization parameters. A sequence parameter set can declare a set of default quantization matrices each for inter and intra prediction for each 8×8 and 4×4 block for luma and inter and intra for chroma. Picture parameter set, slice header, and macroblock level, however, can declare their own set of quantization matrices to override higher level specification. However these quantization matrices must be available in the Sequence Parameter Set currently available. When quantization matrices are carried over NAL units, they can be transmitted at the beginning of the bitstream of the sequence. The position can be that it can either be located after or before the NAL unit carrying Sequence Parameter Sets. After the initial definition, additional customized quantization matrices can be inserted into bitstream to update or add new ones. The operation whether to add or to update is determined by the quantization matrix ID. If the ID exists, it is update. If the ID does not exist, the matrix will be added into the matrix pool. Third Embodiment Furthermore, if a program for realizing the moving picture coding method and the moving picture decoding method as shown in each of the aforementioned embodiments are recorded on a recording medium such as a flexible disk, it becomes possible to easily perform the processing presented in each of the above embodiments in an independent computer system. FIGS.13A,13B, and13Care illustrations for realizing the moving picture coding method and the moving picture decoding method described in each of the above embodiments, using a program stored in a storage medium such as a flexible disk in a computer system. FIG.13Bshows an external view of a flexible disk viewed from the front, its schematic cross-sectional view, and the flexible disk itself, whileFIG.13Aillustrates an example physical format of the flexible disk as a recording medium itself. The flexible disk FD is contained in a case F, and a plurality of tracks Tr are formed concentrically on the surface of the flexible disk FD the radius direction from the periphery, each track being divided into 16 sectors Se in the angular direction. Therefore, in the flexible disk storing the above-mentioned program, the program is recorded in an area allocated for it on the flexible disk FD. Meanwhile,FIG.13Cshows the structure required for recording and reading out the program on and from the flexible disk FD. When the program realizing the above moving picture coding method and moving picture decoding method is to be recorded onto the flexible disk FD, such program shall be written by the use of the computer system Cs via a flexible disk drive FDD. Meanwhile, when the moving picture coding method and the moving picture decoding method are to be constructed in the computer system Cs through the program for realizing these methods on the flexible disk FD, the program shall be read out from the flexible disk FD via the flexible disk drive FDD and then transferred to the computer system Cs. The above description is given on the assumption that a recording medium is a flexible disk, but an optical disc may also be used. In addition, the recording medium is not limited to this, and any other medium such as an IC card and a ROM cassette capable of recording a program can also be used. Fourth Embodiment The following describes application examples of the moving picture coding method and the moving picture decoding method as shown in the above embodiments as well as a system using them. FIG.14is a block diagram showing an overall configuration of a content supply system ex100that realizes a content distribution service. The area for providing a communication service is divided into cells of desired size, and base stations ex107˜ex110, which are fixed wireless stations, are placed in the respective cells. In this content supply system ex100, devices such as a computer ex111, a PDA (Personal Digital Assistant) ex112, a camera ex113, a cellular phone ex114, and a camera-equipped cellular phone ex115are respectively connected to the Internet ex101via an Internet service provider ex102, a telephone network ex104, and the base stations ex107˜ex110. However, the content supply system ex100is not limited to the combination as shown inFIG.14, and may be connected to a combination of any of them. Also, each of the devices may be connected directly to the telephone network ex104, not via the base stations ex107˜ex110, which are fixed wireless stations. The camera ex113is a device such as a digital video camera capable of shooting moving pictures. The cellular phone may be a cellular phone of a PDC (Personal Digital Communications) system, a CDMA (Code Division Multiple Access) system, a W-CDMA (Wideband-Code Division Multiple Access) system or a GSM (Global System for Mobile Communications) system, a PHS (Personal Handyphone system) or the like, and may be any one of these. Furthermore, a streaming server ex103is connected to the camera ex113via the base station ex109and the telephone network ex104, which enables live distribution or the like based on coded data transmitted by the user using the camera ex113. Either the camera ex113or a server and the like capable of performing data transmission processing may code the shot data. Also, moving picture data shot by a camera ex116may be transmitted to the streaming server ex103via the computer ex111. The camera ex116is a device such as a digital camera capable of shooting still pictures and moving pictures. In this case, either the camera ex116or the computer ex111may code the moving picture data. In this case, an LSI ex117included in the computer ex111or the camera ex116performs coding processing. Note that software for picture coding and decoding may be integrated into a certain type of storage medium (such as a CD-ROM, a flexible disk and a hard disk) that is a recording medium readable by the computer ex111and the like. Furthermore, the camera-equipped. cellular phone ex115may transmit the moving picture data. This moving picture data is data coded by an LSI included in the cellular phone ex115. In this content supply system ex100, content (e.g. a music live video) which has been shot by the user using the camera ex113, the camera ex116or the like is coded in the same manner as the above-described embodiments and transmitted to the streaming server ex103, and the streaming server ex103makes stream distributions of the content data to clients at their requests. The clients here include the computer ex111, the PDA ex112, the camera ex113, the cellular phone ex114and so forth capable of decoding the above coded data. The content supply system ex100with the above configuration is a system that enables the clients to receive and reproduce the coded data and realizes personal broadcasting by allowing them to receive, decode and reproduce the data in real time. The moving picture coding apparatus and moving picture decoding apparatus presented in the above embodiments can be used for coding and decoding to be performed in each of the devices making up the above system. An explanation is given of a cellular phone as an example. FIG.15is a diagram showing the cellular phone ex115that employs the moving picture coding method and the moving picture decoding method explained in the above embodiments. The cellular phone ex115has an antenna ex201for transmitting/receiving radio waves to and from the base station ex110, a camera unit ex203such as a CCD camera capable of shooting video and still pictures, a display unit ex202such as a liquid crystal display for displaying the data obtained by decoding video and the like shot by the camera unit ex203and video and the like received by the antenna ex201, a main body equipped with a set of operation keys ex204, a voice output unit ex208such as a speaker for outputting voices, a voice input unit ex205such as a microphone for inputting voices, a recording medium ex207for storing coded data or decoded data such as data of moving pictures or still pictures shot by the camera, data of received e-mails and moving picture data or still picture data, and a slot unit ex206for enabling the recording medium ex207to be attached to the cellular phone ex115. The recording medium ex207is embodied as a flash memory element, a kind of EEPROM (Electrically Erasable and Programmable Read Only Memory) that is an electrically erasable and rewritable non-volatile memory, stored in a plastic case such as an SD card. Next, referring toFIG.16, a description is given of the cellular phone ex115. In the cellular phone ex115, a main control unit ex311for centrally controlling the display unit ex202and each unit of the main body having the operation keys ex204is configured in a manner in which a power supply circuit unit ex310, an operation input control unit ex304, a picture coding unit ex312, a camera interface unit ex303, an LCD (Liquid Crystal Display) control unit ex302, a picture decoding unit ex309, a multiplexing/demultiplexing unit ex308, a recording/reproducing unit ex307, a modem circuit unit ex306, and a voice processing unit ex305are interconnected via a synchronous bus ex313. When a call-end key or a power key is turned on by a user operation, the power supply circuit unit ex310supplies each unit with power from a battery pack, and activates the camera-equipped digital cellular phone ex115to make it into a ready state. In the cellular phone ex115, the voice processing unit ex305converts a voice signal received by the voice input unit ex205in conversation mode into digital voice data under the control of the main control unit ex311comprised of a CPU, a ROM, a RAM and others, the modem circuit unit ex306performs spread spectrum processing on it, and a transmit/receive circuit unit ex301performs digital-to-analog conversion processing and frequency transformation processing on the data, so as to transmit the resultant via the antenna ex201. Also, in the cellular phone ex115, data received by the antenna ex201in conversation mode is amplified and performed of frequency transformation processing and analog-to-digital conversion processing, the modem circuit unit ex306performs inverse spread spectrum processing on the resultant, and the voice processing unit ex305converts it into analog voice data, so as to output it via the voice output unit ex208. Furthermore, when sending an e-mail in data communication mode, text data of the e-mail inputted by operating the operation keys ex204on the main body is sent out to the main control unit ex311via the operation input control unit ex304. In the main control unit ex311, after the modem circuit unit ex306performs spread spectrum processing on the text data and the transmit/receive circuit unit ex301performs digital-to-analog conversion processing and frequency transformation processing on it, the resultant is transmitted to the base station ex110via the antenna ex201. When picture data is transmitted in data communication mode, the picture data shot by the camera unit ex203is supplied to the picture coding unit ex312via the camera interface unit ex303. When picture data is not to be transmitted, it is also possible to display such picture data shot by the camera unit ex203directly on the display unit ex202via the camera interface unit ex303and the LCD control unit ex302. The picture coding unit ex312, which includes the moving picture coding apparatus according to the present invention, performs compression coding on the picture data supplied from the camera unit ex203using the coding method employed by the moving picture coding apparatus presented in the above embodiment, so as to convert it into coded picture data, and sends it out to the multiplexing/demultiplexing unit ex308. At this time, the cellular phone ex115sends voices received by the voice input unit ex205while the shooting by the camera unit ex203is taking place, to the multiplexing/demultiplexing unit ex308as digital voice data via the voice processing unit ex305. The multiplexing/demultiplexing unit ex308multiplexes the coded picture data supplied from the picture coding unit ex312and the voice data supplied from the voice processing unit ex305using a predetermined method, the modem circuit unit ex306performs spread spectrum processing on the resulting multiplexed data, and the transmit/receive circuit unit ex301performs digital-to-analog conversion processing and frequency transformation processing on the resultant, so as to transmit the processed data via the antenna ex201. When receiving, in data communication mode, moving picture file data which is linked to a Web page or the like, the modem circuit unit ex306performs inverse spread spectrum processing on the received signal received from the base station ex110via the antenna ex201, and sends out the resulting, multiplexed data to the multiplexing/demultiplexing unit ex308. In order to decode the multiplexed data received via the antenna ex201, the multiplexing/demultiplexing unit ex308separates the multiplexed data into a bitstream of picture data and a bitstream of voice data, and supplies such coded picture data to the picture decoding unit ex309and such voice data to the voice processing unit ex305via the synchronous bus ex313. Next, the picture decoding unit ex309, which includes the moving picture decoding apparatus according to the present invention, decodes the bitstream of the picture data using the decoding method paired with the coding method shown in the above-mentioned embodiment so as to generate moving picture data for reproduction, and supplies such data to the display unit ex202via the LCD control unit ex302. Accordingly, moving picture data included in the moving picture file linked to a Web page, for instance, is displayed. At the same time, the voice processing unit ex305converts the voice data into an analog voice signal, and then supplies this to the voice output unit ex208. Accordingly, voice data included in the moving picture file linked to a Web page, for instance, is reproduced. Note that the aforementioned system is not an exclusive example and therefore that at least either the moving picture coding apparatus or the moving picture decoding apparatus of the above embodiment can be incorporated into a digital broadcasting system as shown inFIG.17, against the backdrop that satellite/terrestrial digital broadcasting has been a recent topic of conversation. To be more specific, at a broadcasting station ex409, a bitstream of video information is transmitted, by radio waves, to a satellite ex410for communications or broadcasting. Upon receipt of it, the broadcast satellite ex410transmits radio waves for broadcasting, an antenna ex406of a house equipped with satellite broadcasting reception facilities receives such radio waves, and an apparatus such as a television (receiver) ex401and a set top box (STP) ex407decodes the bitstream and reproduces the decoded data. The moving picture decoding apparatus as shown in the above-mentioned embodiment can be implemented in the reproduction apparatus ex403for reading and decoding the bitstream recorded on a storage medium ex402that is a recording medium such as a CD and a DVD. In this case, a reproduced video signal is displayed on a monitor ex404. It is also conceivable that the moving picture decoding apparatus is implemented in the set top box ex407connected to a cable ex405for cable television or the antenna ex406for satellite/terrestrial broadcasting so as to reproduce it on a television monitor ex408. In this case, the moving picture decoding apparatus may be incorporated into the television, not in the set top box. Or, a car ex412with an antenna ex411can receive a signal from the satellite ex410, the base station ex107or the like, so as to reproduce a moving picture on a display device such as a car navigation system ex413mounted on the car ex412. Furthermore, it is also possible to code a picture signal by the moving picture coding apparatus presented in the above embodiment and to record the resultant in a recording medium. Examples include a DVD recorder for recording a picture signal on a DVD disc ex421and a recorder ex420such as a disc recorder for recording a picture signal on a hard disk. Moreover, a picture signal can also be recorded in an SD card ex422. If the recorder ex420is equipped with the moving picture decoding apparatus presented in the above embodiment, it is possible to reproduce a picture signal recorded on the DVD disc ex421or in the SD card ex422, and display it on the monitor ex408. As the configuration of the car navigation system ex413, the configuration without the camera unit ex203, the camera interface unit ex303and the picture coding unit ex312, out of the configuration shown inFIG.16, is conceivable. The same is applicable to the computer ex111, the television (receiver) ex401and the like. Concerning the terminals such as the cellular phone ex114, a transmitting/receiving terminal having both an encoder and a decoder, as well as a transmitting terminal only with an encoder, and a receiving terminal only with a decoder are possible as forms of implementation. As stated above, it is possible to employ the moving picture coding method and the moving picture decoding method presented in the above embodiments into any one of the above-described devices and systems. Accordingly, it becomes possible to achieve the effect described in the aforementioned embodiments. It should also be noted that the present invention is not limited to the above embodiments, and many variations or modifications thereof are possible without departing from the scope of the invention. Note that each function block in the block diagrams shown inFIGS.3and9can be realized as an LSI that is a typical integrated circuit apparatus. Such LSI may be incorporated in one or plural chip form (e.g. function blocks other than a memory may be incorporated into a single chip). Here, LSI is taken as an example, but, it can be called “IC”, “system LSI”, “super LSI” and “ultra LSI” depending on the integration degree. The method for incorporation into an integrated circuit is not limited to the LSI, and it may be realized with a private line or a general processor. After manufacturing of LSI, a Field Programmable Gate Array (FPGA) that is programmable or a reconfigurable processor that can reconfigure the connection and settings for the circuit cell in the LSI may be utilized. Furthermore, along with the arrival of technique for incorporation into an integrated circuit that replaces the LSI owing to a progress in semiconductor technology or another technique that has derived from it, integration of the function blocks may be carried out using the newly-arrived technology. Bio-technology may be cited as one of the examples. Among the function blocks, only a unit for storing data to be coded or decoded may be constructed separately without being incorporated in a chip form. INDUSTRIAL APPLICABILITY As described above, the moving picture coding method and the moving picture decoding method according to the present invention are useful as methods for coding pictures that make up a moving picture so as to generate a coded stream and for decoding the generated coded stream, in devices such as a cellular phone, a DVD device and a personal computer. | 47,068 |
RE49788 | DESCRIPTION OF EMBODIMENTS Underlying Knowledge Forming Basis of the Present Disclosure The inventors have found the following matter regarding the arithmetic coding and arithmetic decoding of the last position information described in the “Background” section. It is to be noted that in the following description, the last position information indicates a horizontal position and a vertical position of the last non-zero coefficient in a predetermined order in a current block. Here, the last position information includes a horizontal component (hereinafter referred to as “X component”) and a vertical component (hereinafter referred to as “Y component”). The X component indicates a horizontal position in the current block. The Y component indicates a vertical position in the current block. FIG.1is a block diagram showing an example of a configuration of an image decoding apparatus1000according to the underlying knowledge.FIG.2is a flowchart showing an example of an image decoding method according to the underlying knowledge. As shown inFIG.1, the image decoding apparatus1000includes a first decoding unit1001, a second decoding unit1002, a decoding control unit1003, and a reconstructing unit1004. The image decoding apparatus1000obtains a bit stream BS which includes the last position information. Then, the image decoding apparatus1000inputs the bit stream BS to the first decoding unit1001, the second decoding unit1002, and the decoding control unit1003. The decoding control unit1003manages whether each signal in the obtained bit stream BS is the X component or the Y component of the last position information. The first decoding unit1001arithmetically decodes a prefix part of the X component of the last position information included in the bit stream BS (S1001). More specifically, the first decoding unit1001decodes the prefix part of the X component by context adaptive binary arithmetic decoding. Here, the prefix part is a part of a binary signal of the X component or the Y component, which is coded by context adaptive binary arithmetic coding. Next, the first decoding unit1001determines whether or not the binary signal of the X component includes a suffix part (S1002). The suffix part is a part of the binary signal of the X component or the Y component, which is coded by bypass coding. The prefix part and the suffix part are determined according to each value (hereinafter referred also to as “last value”) of the X component and the Y component as shown inFIG.3AtoFIG.3D, for example. Thus, with a predetermined method, the first decoding unit1001can determine whether or not the binary signal of the X component includes the suffix part. More specifically, when the size of a transform block (hereinafter referred to as “transform size”) is 4×4, for example, the binary signal of the X component includes the prefix part only and does not include the suffix part regardless of the last value as shown inFIG.3A. Thus, the first decoding unit1001determines that the binary signal of the X component does not include the suffix part when the size of a block to be decoded is 4×4. In the case where the transform size is 8×8, for example, the first decoding unit1001determines that the decoded binary signal of the X component does not include the suffix part when any of binary symbol values up to the binary symbol value of the 4th bit of the binary signal of the X component is “1” as shown inFIG.3B. On the other hand, the first decoding unit1001determines that the decoded binary signal of the X component includes a suffix part having a fixed length of 2 bits when the binary symbol values up to the binary symbol value of the 4th bit of the binary signal of the X component are all “0”. In the case where the transform size is 16×16, for example, the first decoding unit1001determines that the decoded binary signal of the X component does not include the suffix part when any of the binary symbol values up to the binary symbol value of the 8th bit of the binary signal of the X component is “1” as shown inFIG.3C. On the other hand, the first decoding unit1001determines that the decoded binary signal of the X component includes a suffix part having a fixed length of 3 bits when the binary symbol values up to the binary symbol value of the 8th bit of the binary signal of the X component are all “0”. In the case where the transform size is 32×32, for example, the first decoding unit1001determines that the decoded binary signal of the X component does not include the suffix part when any of binary symbol values up to the binary symbol value of the 16th bit of the binary signal of the X component is “1” as shown inFIG.3D. On the other hand, the first decoding unit1001determines that the decoded binary signal of the X component includes a suffix part having a fixed length of 4 bits when the binary symbol values up to the binary symbol value of the 16th bit of the binary signal of the X component are all “0”. Here, when the binary signal of the X component includes the suffix part (Yes in S1002), the second decoding unit1002arithmetically decodes the suffix part having a predetermined, fixed bit length (S1003). More specifically, the second decoding unit1002arithmetically decodes the suffix part of the X component by bypass decoding. On the other hand, when the binary signal of the X component does not include the suffix part (No in S1002), the decoding process for the suffix part is skipped. The reconstructing unit1004reconstructs the X component of the last position information using the prefix part and the suffix part which have been decoded (S1004). More specifically, when the binary signal of the X component includes the suffix part, the reconstructing unit1004reconstructs the X component by debinarizing the binary signal including the decoded prefix part and suffix part. On the other hand, when the binary signal of the X component does not include the suffix part, the reconstructing unit1004reconstructs the X component by debinarizing the binary signal including the decoded prefix part. Next, the first decoding unit1001arithmetically decodes the prefix part of the Y component of the last position information as in Step S1001(S1005). After that, the first decoding unit1001determines whether or not the binary signal of the Y component includes the suffix part as in Step S1002(S1006). Here, when the binary signal of the Y component includes the suffix part (Yes in S1006), the second decoding unit1002arithmetically decodes the suffix part having a predetermined fixed length as in Step S1003(S1007). On the other hand, when the binary signal of the Y component does not include the suffix part (No in S1006), the decoding process for the suffix part is skipped. Lastly, the reconstructing unit1004reconstructs the Y component of the last position information as in Step S1004(S1008). More specifically, when the binary signal of the Y component includes the suffix part, the reconstructing unit1004reconstructs the Y component by debinarizing the binary signal including the decoded prefix part and suffix part. On the other hand, when the binary signal of the Y component does not include the suffix part, the reconstructing unit1004reconstructs the Y component by debinarizing the binary signal including the decoded prefix part. This is the manner in which the X component and the Y component included in the last position information are reconstructed. Next, variable-length coding and variable-length decoding will be described. H.264 employs context adaptive binary arithmetic coding (CABAC) as one of variable-length coding methods. The prefix part is coded by CABAC. In contrast, the suffix part is coded by bypass coding, which is arithmetic coding in which a fixed probability (e.g., “0.5”) is used. Hereinafter, context adaptive binary arithmetic decoding and bypass decoding will be described usingFIG.4toFIG.6. FIG.4is a flowchart showing context adaptive binary arithmetic decoding. It is to be noted thatFIG.4has been excerpted from Non Patent Literature 1. Unless otherwise specified, the description ofFIG.4is as given in Non Patent Literature 1. With the arithmetic decoding, first, context (ctxIdx) is inputted which is determined based on the signal type of a current signal to be decoded. Next, the following process is performed in Step S2001. First, qCodIRangeIdx is calculated from a first parameter codIRange indicating a current state of arithmetic decoding. Furthermore, pStateIdx is obtained which is a state value corresponding to ctxIdx. Then, codIRangeLPS corresponding to the two values (qCodIRangeIdx and pStateIdx) is obtained by reference to a table (rangeTableLPS). It is to be noted that codIRangeLPS indicates a state of arithmetic decoding when LPS has occurred in a state of arithmetic decoding indicated by the first parameter codIRange. LPS specifies one of the symbols “0” and “1” which has a lower probability of occurrence. Furthermore, a value obtained by subtracting the above-mentioned codIRangeLPS from the current codIRange is set to codIRange. Next, in Step S2002, a comparison is made between codIRange and a second parameter codIOffset which indicates a state of arithmetic decoding. Here, when codIOffset is greater than or equal to codIRange (Yes in S2002), the following process is performed in Step S2003. First, it is determined that LPS has occurred, and a value different from vaIMPS (“0” when vaIMPS=1, and “1” when vaIMPS=0) is set to binVal that is a decoding output value. vaIMPS indicates a specific value of MPS (“0” or “1”). MPS specifies one of the binary symbol values “0” and “1” which has a higher probability of occurrence. Furthermore, a value obtained by subtracting codIRange from the current codIOffset is set to the second parameter codIOffset that indicates a state of arithmetic decoding. Furthermore, the value of codIRangeLPS which has been set in Step S2001is set to the first parameter codIRange that indicates a state of arithmetic decoding. Next, in Step S2005, whether or not the value of pStateIdx is “0” is determined. Here, when the value of pStateIdx is “0” (Yes in S2005), it means that the probability of LPS is greater than the probability of MPS. Thus, the value of vaIMPS is switched over (i.e., “0” is set when vaIMPS=1, and “1” is set when vaIMPS=0) (Step S2006). On the other hand, when the value of pStateIdx is not “0” (No in S2005), the value of pStateIdx is updated based on a transform table transIdxLPS that is referred to when LPS occurs (Step S2007). Furthermore, when codIOffset is smaller than codIRange (No in S2002), it is determined that MPS has occurred. Thus, vaIMPS is set to binVal that is a decoding output value, and the value of pStateIdx is updated based on a transform table transIdxMPS that is referred to when MPS occurs (Step S2004). Lastly, normalization (RenormD) is performed (Step S2008), and the arithmetic decoding finishes. As shown above, with the context adaptive binary arithmetic decoding, multiple probabilities of symbol occurrence, which are probabilities of occurrence of binary symbols, are held in association with context indices. The contexts are switched according to a condition (e.g., value of an adjacent block), and thus, it is necessary to maintain the processing order. FIG.5is a flowchart showing bypass decoding. It is to be noted thatFIG.5has been excerpted from Non Patent Literature 1. Unless otherwise specified, the description ofFIG.5is as given in Non Patent Literature 1. First, the second parameter codIOffset that indicates a current state of arithmetic decoding is left-shifted (doubled). Furthermore, one bit is read out from the bit stream, and when the read-out bit is “1”, 1 is added to codIOffset (Step S3001). Next, when codIOffset is greater than or equal to the first parameter codIRange that indicates a state of arithmetic decoding (Yes in S3002), “1” is set to binVal that is a decoding output value, and a value obtained by subtracting codIRange from the current codIOffset is set to codIOffset (Step S3003). On the other hand, when codIOffset is smaller than the first parameter codIRange that indicates a state of arithmetic decoding (No in S3002), “0” is set to binVal that is a decoding output value (Step S3004). FIG.6is a flowchart for describing in detail the normalization (RenormD) shown in Step S2008inFIG.4.FIG.6has been excerpted from Non Patent Literature 1. Unless otherwise specified, the description ofFIG.6is as given in Non Patent Literature 1. When the first parameter codIRange that indicates a state of arithmetic decoding has become smaller than 0x100 (in base 16: 256 (in base 10)) (Yes in S4001), codIRange is left-shifted (doubled). Furthermore, the second parameter codIOffset that indicates a state of arithmetic decoding is left-shifted (doubled). Moreover, one bit is read out from the bit stream, and when the read-out bit is “1”, 1 is added to codIOffset (Step S4002). When codIRange eventually reaches 256 or greater by this process in Step S4002(No in S4001), the normalization finishes. This is the manner in which the arithmetic decoding is performed. However, with the above underlying knowledge, the X component and the Y component included in the last position information are decoded in sequence. That is to say, the X component and the Y component are placed one after the other in the bit stream. Therefore, when the last position information is to be arithmetically decoded, context adaptive binary arithmetic decoding and bypass decoding are alternately performed. This means that switching between the arithmetic decoding methods occurs many times, which hinders efficient arithmetic decoding of the last position information. In view of the foregoing, an image coding method according to an aspect of the present disclosure is an image coding method for coding last position information indicating a horizontal position and a vertical position of a last non-zero coefficient in a predetermined order in a current block to be coded, the image coding method including: binarizing a first component and a second component to generate a first binary signal and a second binary signal, respectively, the first component being one of a horizontal component and a vertical component which are included in the last position information, and the second component being the other of the horizontal component and the vertical component; coding a first partial signal and a second partial signal by first arithmetic coding, and coding a third partial signal and a fourth partial signal by second arithmetic coding different from the first arithmetic coding, the first partial signal being a part of the first binary signal, the second partial signal being a part of the second binary signal, the third partial signal being another part of the first binary signal, and the fourth partial signal being another part of the second binary signal; and placing the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal in a bit stream, wherein in the placing, (i) the coded second partial signal is placed next to the coded first partial signal, or (ii) the coded fourth partial signal is placed next to the coded third partial signal. With this, in the bit stream, a coded partial signal is followed by a partial signal which has been coded by the same arithmetic coding as the preceding partial signal. Thus, when the arithmetically coded last position information is decoded, it is possible to reduce the number of times the arithmetic decoding methods are switched as compared to the case where the partial signals arithmetically coded by different methods are alternately placed. In other words, it is possible to output a bit stream from which the last position information can be efficiently decoded. For example, the first arithmetic coding may be context adaptive binary arithmetic coding in which a variable probability updated based on a coded signal is used, and in the placing, the coded second partial signal may be placed next to the coded first partial signal. With this, context adaptive binary arithmetic coding can be used as the first arithmetic coding. This makes it possible to output a bit stream from which two coded partial signals can be efficiently decoded in series by context adaptive binary arithmetic decoding. For example, the second arithmetic coding may be bypass coding in which a fixed probability is used, and in the placing, the coded fourth partial signal may be placed next to the coded third partial signal. With this, bypass coding can be used as the first arithmetic coding. It is to be noted that bypass decoding makes parallel processing easier because the variable probability is not used. This makes it possible to output a bit stream from which two coded partial signals can be efficiently decoded in series or in parallel by bypass decoding. For example, the first arithmetic coding may be context adaptive binary arithmetic coding in which a variable probability updated based on a coded signal is used, the second arithmetic coding may be bypass coding in which a fixed probability is used, and in the placing, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal may be placed in the bit stream in the following order: the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal. With this, two partial signals coded by bypass coding can be placed next to two partial signals coded by context adaptive binary arithmetic coding. This makes it possible to further reduce the number of times the arithmetic decoding methods are switched when the last position information is decoded. In other words, it is possible to output a bit stream from which the last position information can be more efficiently decoded. For example, the first arithmetic coding may be context adaptive binary arithmetic coding in which a variable probability updated based on a coded signal is used, the second arithmetic coding may be bypass coding in which a fixed probability is used, and in the placing, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal may be placed in the bit stream in the following order: the coded first partial signal, the coded second partial signal, the coded fourth partial signal, and the coded third partial signal. With this, two partial signals coded by bypass coding can be placed next to two partial signals coded by context adaptive binary arithmetic coding. This makes it possible to further reduce the number of times the arithmetic decoding methods are switched when the last position information is decoded. In other words, it is possible to output a bit stream from which the last position information can be more efficiently decoded. Furthermore, with this, the coded fourth partial signal is placed next to the coded second partial signal, which makes it possible to output a bit stream from which the second binary signal can be obtained by a series of decoding processes. For example, the image coding method may further include: switching a coding process to either a first coding process compliant with a first standard or a second coding process compliant with a second standard; and adding, to the bit stream, identification information indicating either the first standard or the second standard with which the coding process switched to is compliant, wherein when the coding process is switched to the first coding process, the binarizing, the coding, and the placing may be performed as the first coding process. This makes it possible to switch between the first coding process compliant with the first standard and the second coding process compliant with the second standard. Furthermore, an image decoding method according to an aspect of the present disclosure is an image decoding method for decoding last position information indicating a horizontal position and a vertical position of a last non-zero coefficient in a predetermined order in a current block to be decoded, the image decoding method including: decoding, by first arithmetic decoding, a coded first partial signal and a coded second partial signal which are included in a bit stream, and decoding, by second arithmetic decoding different from the first arithmetic decoding, a coded third partial signal and a coded fourth partial signal which are included in the bit stream; and reconstructing a first component by debinarizing a first binary signal which includes the decoded first partial signal and the decoded third partial signal, and reconstructing a second component by debinarizing a second binary signal which includes the decoded second partial signal and the decoded fourth partial signal, the first component being one of a horizontal component and a vertical component which are included in the last position information, and the second component being the other of the horizontal component and the vertical component, wherein in the bit stream, (i) the coded second partial signal is placed next to the coded first partial signal, or (ii) the coded fourth partial signal is placed next to the coded third partial signal. With this, the last position information can be reconstructed by decoding of the bit stream in which a coded partial signal is followed by a partial signal which has been coded by the same arithmetic coding as the preceding partial signal. This makes it possible to reduce the number of times the arithmetic decoding methods are switched as compared to the case of decoding a bit stream in which the partial signals arithmetically coded by different methods are alternately placed. In other words, the last position information can be efficiently decoded. For example, in the bit stream, the coded second partial signal may be placed next to the coded first partial signal, and the first arithmetic decoding may be context adaptive binary arithmetic decoding in which a variable probability updated based on a decoded signal is used. With this, context adaptive binary arithmetic decoding can be used as the first arithmetic decoding. This makes it possible to efficiently decode two coded partial signals in series by context adaptive binary arithmetic decoding. For example, in the bit stream, the coded fourth partial signal may be placed next to the coded third partial signal, and the second arithmetic decoding may be bypass decoding in which a fixed probability is used. With this, bypass decoding can be used as the first arithmetic decoding. It is to be noted that bypass decoding makes parallel processing easier because the variable probability is not used. This makes it possible to efficiently decode two coded partial signals in series or in parallel by bypass decoding. For example, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal may be placed in the bit stream in the following order: the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal, the first arithmetic decoding may be context adaptive binary arithmetic decoding in which a variable probability updated based on a decoded signal is used, and the second arithmetic decoding may be bypass decoding in which a fixed probability is used. With this, it is possible to decode the bit stream in which two partial signals coded by bypass coding are placed next to two partial signals coded by context adaptive binary arithmetic coding. This makes it possible to further reduce the number of times the arithmetic decoding methods are switched when the last position information is decoded, thereby allowing more efficient decoding of the last position information. For example, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal may be placed in the bit stream in the following order: the coded first partial signal, the coded second partial signal, the coded fourth partial signal, and the coded third partial signal, the first arithmetic decoding may be context adaptive binary arithmetic decoding in which a variable probability updated based on a decoded signal is used, and the second arithmetic decoding may be bypass decoding in which a fixed probability is used. With this, it is possible to decode the bit stream in which two partial signals coded by bypass coding are placed next to two partial signals coded by context adaptive binary arithmetic coding. This makes it possible to further reduce the number of times the arithmetic decoding methods are switched when the last position information is decoded, thereby allowing more efficient decoding of the last position information. Furthermore, with this, the bit stream is coded in which the coded fourth partial signal is placed next to the coded second partial signal, thereby allowing the second binary signal to be obtained by a series of decoding processes. For example, the image decoding method may further include switching a decoding process to either a first decoding process compliant with a first standard or a second decoding process compliant with a second standard, according to identification information which is added to the bit stream and indicates either the first standard or the second standard, wherein when the decoding process is switched to the first decoding process, the decoding and the reconstructing may be performed as the first decoding process. This makes it possible to switch between the first decoding process compliant with the first standard and the second decoding process compliant with the second standard. It is to be noted that these general and specific aspects may be implemented using a system, an apparatus, an integrated circuit, a computer program, or a computer-readable recording medium such as a CD-ROM, or any combination of systems, apparatuses, integrated circuits, computer programs, or computer-readable recording media. Hereinafter, embodiments will be described in detail using the drawings. It is to be noted that each of the embodiments described below shows a general or specific example. The numerical values, shapes, materials, structural elements, the arrangement and connection of the structural elements, steps, the processing order of the steps etc., shown in the following embodiments are mere examples, and are therefore not intended to limit the scope of the Claims. Furthermore, among the structural elements in the following embodiments, structural elements not recited in any one of the independent claims representing the most generic concepts are described as arbitrary structural elements. Embodiment 1 FIG.7is a block diagram showing a functional configuration of an image decoding apparatus100according to Embodiment 1. The image decoding apparatus100decodes the last position information. Described here is the case where the coded last position information includes a coded first partial signal, a coded second partial signal, a coded third partial signal, and a coded fourth partial signal. As shown inFIG.7, the image decoding apparatus100includes an arithmetic decoding unit110and a reconstructing unit104. The arithmetic decoding unit110includes a first decoding unit101, a second decoding unit102, and a decoding control unit103. The image decoding apparatus100obtains a bit stream BS which includes the coded last position information. It is to be noted that in some cases the bit stream BS does not include the coded third partial signal or does not include the coded fourth partial signal. For example, the bit stream BS does not include the coded third partial signal or does not include the coded fourth partial signal when a block to be decoded is smaller than a predetermined size, or when the value (last value) of a first component or a second component included in the last position information is smaller than a predetermined value. Each of the coded first partial signal and the coded second partial signal corresponds to a prefix part which has been coded by context adaptive binary arithmetic coding, for example. Each of the coded third partial signal and the coded fourth partial signal corresponds to a suffix part which has been coded by bypass coding, for example. Here, in the bit stream BS, the coded second partial signal is placed next to the coded first partial signal, or, the coded fourth partial signal is placed next to the coded third partial signal. More specifically, in the bit stream BS, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal are placed in the following order: the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal, for example. Furthermore, in the bit stream BS, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal may be placed in the following order: the coded first partial signal, the coded second partial signal, the coded fourth partial signal, and the coded third partial signal, for example. The first decoding unit101decodes the coded first partial signal and the coded second partial signal by first arithmetic decoding. The first arithmetic decoding is context adaptive binary arithmetic decoding in which a variable probability updated based on a decoded signal is used, for example. In this case, the first decoding unit101decodes the coded first partial signal and the coded second partial signal by context adaptive binary arithmetic decoding. It is to be noted that the first arithmetic decoding need not be context adaptive binary arithmetic decoding. The second decoding unit102decodes the coded third partial signal and the coded fourth partial signal by second arithmetic decoding. For example, the second arithmetic decoding is bypass decoding in which a fixed probability is used. In this case, the second decoding unit102decodes the coded third partial signal and the coded fourth partial signal by bypass decoding. In doing so, the second decoding unit102may decode the coded third partial signal and the coded fourth partial signal in parallel. It is to be noted that the second arithmetic decoding need not be bypass decoding. More specifically, it is sufficient as long as the first arithmetic decoding and the second arithmetic decoding are different. The decoding control unit103manages, for each part of the bit stream BS, whether the part is the X component or the Y component of the last position information. It is to be noted that the decoding control unit103need not be included in the arithmetic decoding unit110. That is to say, the image decoding apparatus100need not include the decoding control unit103. In this case, it is sufficient as long as the first decoding unit101and the second decoding unit102manage the X component and the Y component. The reconstructing unit104reconstructs the first component that is one of the horizontal component and the vertical component included in the last position information, by debinarizing a first binary signal which includes the first partial signal and the third partial signal. Furthermore, the reconstructing unit104reconstructs the second component that is the other of the horizontal component and the vertical component included in the last position information, by debinarizing a second binary signal which includes the second partial signal and the fourth partial signal. Next, usingFIG.8AandFIG.8B, the following describes in detail operations of the image decoding apparatus100having the above configuration. Hereinafter, it is assumed that the first component is the X component and the second component is the Y component. It is also assumed that each of the first partial signal and the second partial signal is the prefix part and each of the third partial signal and the fourth partial signal is the suffix part. Furthermore, it is assumed that the suffix flag of the X component and the suffix flag of the Y component are set “OFF” as the default value. It is to be noted that the suffix flag is an internal flag indicating whether or not the binary signal of its corresponding component of the last position information includes the suffix part. FIG.8Ais a flowchart showing an example of processing operations of the image decoding apparatus100according to Embodiment 1. As forFIG.8A, the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the X component, and the coded suffix part of the Y component are consecutively placed in the bit stream BS in the following order: the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the X component, and the coded suffix part of the Y component. It is to be noted that in some cases the suffix part of each component is not included in the bit stream BS depending on the value of the component. First, the first decoding unit101decodes, from the bit stream BS, the coded prefix part of the X component by context adaptive binary arithmetic decoding (S101). For example, the first decoding unit101arithmetically decodes the coded prefix part on a one bit-by-one bit basis until a predetermined maximum length is reached or until “1” is decoded. Next, the first decoding unit101determines whether or not the binary signal of the X component includes the suffix part (S102). For example, the first decoding unit101determines that the binary signal of the X component includes the suffix part when the prefix part has the predetermined maximum length and the binary symbol values included in the prefix part are all “0”. It is to be noted that the maximum length of the prefix part is predetermined according to the transform size, for example. For example, the maximum length of the prefix part is determined in the manner shown inFIG.9BorFIG.9C. Here, when the binary signal of the X component includes the suffix part (Yes in S102), the first decoding unit101sets the suffix flag of the X component “ON” (S103). On the other hand, when the binary signal of the X component does not include the suffix part (No in S102), the first decoding unit101does not set the suffix flag of the X component “ON”. In other words, the suffix flag of the X component remains “OFF”, which is the default value. It is to be noted that the first decoding unit101may set the suffix flag of the X component “OFF” here. Next, the first decoding unit101decodes, by context adaptive binary arithmetic decoding, the coded prefix part of the Y component placed next to the coded prefix part of the X component (S104). More specifically, the first decoding unit101decodes the prefix part of the Y component in the same manner as the decoding of the prefix part of the X component. After that, the first decoding unit101determines whether or not the binary signal of the Y component includes the suffix part (S105). More specifically, the first decoding unit101determines whether or not the binary signal of the Y component includes the suffix part in the same manner as the determination as to whether or not the binary signal of the X component includes the suffix part. Here, when the binary signal of the Y component includes the suffix part (Yes in S105), the first decoding unit101sets the suffix flag of the Y component “ON” (S106). On the other hand, when the binary signal of the Y component does not include the suffix part (No in S105), the first decoding unit101does not set the suffix flag of the Y component “ON”. Next, the second decoding unit102determines whether or not the suffix flag of the X component is set “ON” (S107). Here, when the suffix flag of the X component is set “ON” (Yes in S107), the second decoding unit102decodes, by bypass decoding, the coded suffix part of the X component placed next to the coded prefix part of the Y component (S108). On the other hand, when the suffix flag of the X component is not set “ON” (No in S107), Step S108is skipped. The reconstructing unit104reconstructs the X component of the last position information by debinarizing the binary signal of the X component which includes both the prefix part and the suffix part or which includes the prefix part only (S109). For example, when the value of the X component is binarized as shown inFIG.3B, the reconstructing unit104reconstructs the X component value “5” by debinarizing the binary signal “000010”. Next, the second decoding unit102determines whether or not the suffix flag of the Y component is set “ON” (S110). Here, when the suffix flag of the Y component is set “ON” (Yes in S110), the second decoding unit102decodes, by bypass decoding, the coded suffix part of the Y component placed next to the coded suffix part of the X component or placed next to the coded prefix part of the Y component (S111). On the other hand, when the suffix flag of the Y component is not set “ON” (No in S110), Step S111is skipped. Lastly, the reconstructing unit104reconstructs the Y component of the last position information by debinarizing the binary signal of the Y component which includes both the prefix part and the suffix part or which includes the prefix part only (S112). It is to be noted that although the second decoding unit102inFIG.8Adecodes the suffix part of the Y component (S111) after decoding the suffix part of the X component (S108), the second decoding unit102may decode the suffix part of the X component and the suffix part of the Y component in parallel. This allows the second decoding unit102to arithmetically decode the last position information at a higher speed. Next, the following describes the case where the prefix part and the suffix part of each component are placed in the bit stream in an order different from that inFIG.8A. FIG.8Bis a flowchart showing another example of processing operations of the image decoding apparatus100according to Embodiment 1. It is to be noted that inFIG.8B, the processes performed in steps denoted by the same reference signs as those inFIG.8Aare basically the same as the processes described inFIG.8A. As forFIG.8B, the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the X component, and the coded suffix part of the Y component are consecutively placed in the bit stream BS in the following order: the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the Y component, and the coded suffix part of the X component. It is to be noted that in some cases the suffix part of each component is not included in the bit stream BS depending on the value of the component, as in the case ofFIG.8A. First, the first decoding unit101decodes the coded prefix part of the X component by context adaptive binary arithmetic decoding (S101). Then, the first decoding unit101determines whether or not the binary signal of the X component includes the suffix part (S102). Here, when the binary signal of the X component includes the suffix part (Yes in S102), the first decoding unit101sets the suffix flag of the X component “ON” (S103). On the other hand, when the binary signal of the X component does not include the suffix part (No in S102), the first decoding unit101does not set the suffix flag of the X component “ON”. Next, the first decoding unit101decodes, by context adaptive binary arithmetic decoding, the coded prefix part of the Y component placed next to the coded prefix part of the X component (S104). Then, the first decoding unit101determines whether or not the binary signal of the Y component includes the suffix part (S105). Here, when the binary signal of the Y component includes the suffix part (Yes in S105), the second decoding unit102decodes, by bypass decoding, the coded suffix part of the Y component placed next to the coded prefix part of the Y component (S111). On the other hand, when the binary signal of the Y component does not include the suffix part (No in S105), Step S111is skipped. Next, the reconstructing unit104reconstructs the Y component of the last position information by debinarizing the binary signal of the Y component which includes both the prefix part and the suffix part or which includes the prefix part only (S112). After that, the second decoding unit102determines whether or not the suffix flag of the X component is set “ON” (S107). Here, when the suffix flag of the X component is set “ON” (Yes in S107), the second decoding unit102decodes, by bypass decoding, the coded suffix part of the X component placed next to the coded prefix part or suffix part of the Y component (S108). On the other hand, when the suffix flag of the X component is not set “ON” (No in S107), Step S108is skipped. Lastly, the reconstructing unit104reconstructs the X component of the last position information by debinarizing the binary signal of the X component which includes both the prefix part and the suffix part or which includes the prefix part only (S109). By consecutively decoding the prefix part and the suffix part of the Y component in the above-described manner, it is possible to reconstruct the Y component without holding, in a memory, information indicating whether or not the binary signal of the Y component includes the suffix part (here, the suffix flag of the Y component). This reduces the capacity required of the memory. It is to be noted that in the flowcharts shown inFIG.8AandFIG.8B, it is not necessary to perform the determination regarding the suffix parts (S102and S105), the setting of the suffix flags (S103and S106), nor the determination regarding the suffix flags (S107and S110) when it is determined in advance based on information included in the bit stream, for example, that the binary signals of the X component and the Y component each include the suffix part. Next, the following describes an example of the decoding process on the coded suffix parts of the X component and the Y component (S108and S111). Described here is the case where the suffix parts are binarized by Golomb-Rice coding. With the Golomb-Rice coding, the length of each suffix part is not fixed. The suffix part can be divided into two parts, the first half and the second half. The second half is a fixed-length part having a length indicated by a rice parameter (hereinafter referred to as “RP”). The first half can be represented by: “1” that increases in the unit of a number representable by 2 to the RPth power (2RP) (e.g., in the unit of “4” when RP is “2”); and “0” that is set at the last bit position. More specifically, when RP is “2”, the length of the first half increases by 1 bit for each unit of 2 to the RPth power as follows: 0, 0, 0, 0, 10, 10, 10, 10, 110, 110, 110, 110, . . . . It is to be noted that here, the amount of information to be represented by the suffix part is known, and thus it is possible to omit the last “0” of the first half when the first half has the maximum length. For example, when RP is “2” and the maximum amount of information is “12”, the first half can be represented by any one of 0, 0, 0, 0, 10, 10, 10, 10, 11, 11, 11, and 11. By omitting the last “0” of the first half in this manner, the coding amount of the binary signal can be reduced by 1 bit. The maximum amount of information can be represented by the difference between the length in the transform size and the length of the prefix part. This reduces redundant bit(s). It is sufficient as long as RP is predetermined according to the transform size as shown inFIG.9DorFIG.9E, for example. This makes it possible to represent the suffix part with a binary signal having a length adapted to the transform size, and thus, the coding efficiency can be increased. The following describes, usingFIG.9A, operations of the second decoding unit102for decoding the suffix part binarized by Golomb-Rice coding as described above.FIG.9Ais a flowchart showing an example of processing operations of the second decoding unit102according to Embodiment 1. First, the second decoding unit102sets an RP value (S201). More specifically, the second decoding unit102refers to a predetermined table, for example, to set the RP value. The predetermined table in this case is a table shown inFIG.9DorFIG.9E, for example. It is to be noted that the second decoding unit102may set the RP value without referring to the table. The setting of the RP value will be described later in detail usingFIG.10AtoFIG.10D. Next, the second decoding unit102sets a Max value (S202). Here, the Max value indicates the maximum value of the length of the first half of the Golomb-Rice code. More specifically, the Max value indicates the shortest length of the binary signal that can represent a value obtained by subtracting the maximum length of the prefix part from the maximum value of the last value. Thus, the second decoding unit102derives the Max value by (i) subtracting the length of the prefix part from the maximum value of the last value and (ii) dividing the resultant value by 2 to the RPth power or performing a right shift operation on the resultant value by RP bit(s). It is to be noted that the maximum length of the prefix part may be varied according to the transform size as shown inFIG.9BorFIG.9C. Next, the second decoding unit102decodes, from the bit stream BS, a signal corresponding to 1 bit of the Golomb-Rice code by bypass decoding, and increments the count value (default is “0”) by 1 (S203). Here, when the decoded signal corresponding to 1 bit is “0” (Yes in S204), the decoding of the first half of the Golomb-Rice code finishes, and the process proceeds to Step S206. On the other hand, when the decoded signal is not “0” (when the decoded signal is “1”) (No in S204), it is determined whether or not the count value is equal to the Max value (S205). Here, when the count value is not equal to the Max value (No in S205), the process returns to Step S203. More specifically, the second decoding unit102decodes a signal corresponding to the next 1 bit of the Golomb-Rice code by bypass decoding. On the other hand, when the count value is equal to the Max value (Yes in S205), the decoding of the first half of the suffix part finishes, and the process proceeds to Step S206. Next, the second decoding unit102decodes the second half of the Golomb-Rice code (a binary signal having a fixed length of RP bit(s)) by bypass decoding (S206). Lastly, the second decoding unit102reconstructs the value represented by Golomb-Rice coding (S207). Here, the value is reconstructed by adding up the second half of the Golomb-Rice code and a value obtained by shifting, to the left by the RP bit(s), a value obtained by subtracting 1 from the value represented by the first half of the Golomb-Rice code. It is to be noted that in some cases the value of the binary signal of the second half is binarized in the form of a reversed value. In such cases, the second decoding unit102performs the reconstruction with this reverse taken into account. It is to be noted that it is sufficient as long as the decoding apparatus and the coding apparatus determine in advance whether or not the value of the binary signal is to be reversed. Neither the coding efficiency nor the processing load is affected regardless of whether or not the value of the binary signal is reversed. Next, the following describes, usingFIG.10AtoFIG.10D, a method of determining the RP value and the maximum length of the prefix part. FIG.10Ashows a method of determining the RP value and the maximum length of the prefix part according to the transform size. First, the second decoding unit102obtains the transform size (S301). Then, the second decoding unit102refers to a table as shown inFIG.9DorFIG.9Eindicating a relationship between the transform size and the RP value, to determine the RP value associated with the obtained transform size (S302). Furthermore, the second decoding unit102refers to a table as shown inFIG.9BorFIG.9Cindicating a relationship between the transform size and the maximum length of the prefix part, to determine the maximum length of the prefix part (S303). FIG.10Bshows a method of determining the RP value and the maximum length of the prefix part according to prediction information. First, the second decoding unit102obtains prediction information (S311). The prediction information is information related to prediction of a transform block which is a current block to be decoded. For example, the prediction information indicates whether the transform block is to be decoded by intra prediction or inter prediction. Furthermore, for example, the prediction information may be information indicating a prediction direction in intra prediction. Next, the second decoding unit102determines the RP value based on the prediction information (S312). For example, it is known that in the case of inter prediction, there are generally less high frequency components than in intra prediction. Thus, when the prediction information indicates inter prediction, it is sufficient as long as the second decoding unit102determines such an RP value that allows the X component and the Y component having small values to be represented by short binary signals. More specifically, when the prediction information indicates inter prediction, it is sufficient as long as the second decoding unit102determines an RP value smaller than an RP value determined when the prediction information indicates intra prediction. Furthermore, when the direction of intra prediction is the horizontal direction, it is generally expected that the Y component of the last position information is smaller than the X component. In view of this, when the prediction direction of intra prediction is the horizontal direction, it is sufficient as long as the second decoding unit102determines, as the RP value of the Y component, an RP value smaller than the RP value of the X component. It is to be noted that when the prediction direction of intra prediction is the vertical direction, it is sufficient as long as the second decoding unit102determines, as the RP value of the X component, an RP value smaller than the RP value of the Y component. Lastly, the second decoding unit102determines the maximum length of the prefix part based on the prediction information (S313). As described above, the second decoding unit102can vary the code length of the binary signal according to the prediction information, and thus, the coding efficiency can be increased. FIG.10Cshows a method of determining the RP value and the maximum length of the prefix part according to statistical information. First, the second decoding unit102obtains statistical information (S321). The statistical information is, for example, information on statistics of the length of the binary signal of the X component or the Y component included in the last position information of a previously decoded block. Next, the second decoding unit102determines the RP value based on the statistical information (S322). Lastly, the second decoding unit102determines the maximum length of the prefix part based on the statistical information (S323). As described above, the second decoding unit102can vary the code length of the binary signal according to the statistical information, and thus, the coding efficiency can be further increased. FIG.10Dshows a method of determining the RP value and the maximum length of the prefix part according to a previously-decoded one of the X component and the Y component. First, the second decoding unit102obtains a previously-decoded one of the X component and the Y component (S331). For example, the second decoding unit102obtains a previously-decoded X component when decoding a coded Y component. Furthermore, for example, the second decoding unit102may obtain a previously-decoded Y component when decoding a coded X component. Then, the second decoding unit102determines, using the previously-decoded one of the X component and the Y component, the RP value of the other, yet-to-be-decoded one of the X component and the Y component (S332). Generally, it is likely that the X component and the Y component have the same or similar values. Therefore, when the value of a previously-decoded X component is smaller than a certain value (e.g., half the transform size), for example, the second decoding unit102determines, as the RP value of the Y component, a value smaller than the RP value of the X component. Lastly, the second decoding unit102determines, using the previously-decoded one of the X component and the Y component, the maximum length of the prefix part of the other, yet-to-be-decoded one of the X component and the Y component (S333). As described above, the second decoding unit102can vary the code length of the binary signal according to a previously-decoded one of the X component and the Y component, and thus, the coding efficiency can be further increased. It is to be noted that the methods of determining the RP value and the maximum length of the prefix part shown inFIG.10AtoFIG.10Dmay be used in combination. For example, when there is no information to refer to, the second decoding unit102may determine the RP value based on a predetermined table, whereas when there is information to refer to, the second decoding unit102may determine the RP value according to the information which can be referred to. Moreover, the second decoding unit102may determine the maximum length of the prefix part in the same manner as the RP value. It is to be noted that when the values of the X component and the Y component are predicted to be large, it is sufficient as long as the second decoding unit102determines the maximum length of the prefix part to be shorter than when the X component and the Y component are predicted to be small. This further increases the coding efficiency. Next, the following describes, usingFIG.11AandFIG.11B, a time period required for arithmetic decoding of the coded last position information. FIG.11Ais a diagram for describing an example of arithmetic decoding according to Embodiment 1. As forFIG.11A, the following describes the case where the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the Y component, and the coded suffix part of the X component are included in the bit stream BS in this order. The part (a) ofFIG.11Ashows an example of the case where the prefix part and the suffix part of each component are arithmetically decoded in sequence. As for the part (a) ofFIG.11A, decoding of the prefix part of the X component of the last position information (LASTX_PREFIX), decoding of the prefix part of the Y component (LASTY_PREFIX), decoding of the suffix part of the Y component (LASTY_SUFFIX), and decoding of the suffix part of the X component (LASTX_SUFFIX) are performed in this order. Here, one might consider arithmetically decoding the last position information in parallel in order to increase the processing speed of the arithmetic decoding. However, since the prefix part is decoded by context adaptive binary arithmetic decoding, it is difficult to perform arithmetic decoding in parallel. To be more specific, a variable probability (probability of symbol occurrence) which is updated based on a coded signal is used in the arithmetic decoding of the prefix part. This means that it is necessary to successively read and update the probability of symbol occurrence. Therefore, it is difficult to parallelize the arithmetic decoding of the prefix part. On the other hand, it is relatively easy to parallelize the arithmetic decoding of the suffix part because the suffix part is decoded by bypass decoding. To be more specific, the variable probability updated based on a coded signal is not used in the arithmetic decoding of the suffix part, but a fixed probability (probability of symbol occurrence) is used. Therefore, it is relatively easy to parallelize the arithmetic decoding of the suffix part. In view of this, the arithmetic decoding of the suffix part may be parallelized bitwise as shown in the part (b) ofFIG.11A. This increases the processing speed of the arithmetic decoding of the last position information. Moreover, when the process is to be further parallelized, information related to the suffix part may be obtained from the bit stream BS, and the arithmetic decoding of the suffix part may start before context adaptive binary arithmetic decoding is completed, as shown in the part (c) ofFIG.11A, for example. This further increases the speed of decoding of the last position information. FIG.11Bis a diagram for describing an example of arithmetic decoding according to a comparable example. As forFIG.11B, the following describes the case where the coded prefix part of the X component, the coded suffix part of the X component, the coded prefix part of the Y component, and the coded suffix part of the Y component are included in the bit stream BS in this order. The part (a) ofFIG.11Bshows an example of the case where the prefix part and the suffix part of each component are arithmetically decoded in sequence. The processing time required in the case of the part (a) ofFIG.11Bis equal to the processing time required in the case of the part (a) ofFIG.11A. However, in the case of the part (a) ofFIG.11B, the number of times switching is performed between context adaptive binary arithmetic decoding and bypass decoding is larger than in the case of the part (a) ofFIG.11A. The part (b) ofFIG.11Bis a diagram for describing an example of the case where the arithmetic decoding of the suffix part is parallelized bitwise. As for the part (b) ofFIG.11B, bypass decoding of the suffix part is parallelized, and thus the processing time is shorter than in the part (a) ofFIG.11B. However, the decoding of the suffix part of the X component and the decoding of the suffix part of the Y component cannot be parallelized. Thus, the processing time in the part (b) ofFIG.11Bis longer than that in the part (b) ofFIG.11A. As described above, the image decoding apparatus100according to Embodiment 1 can efficiently decode the last position information. More specifically, the image decoding apparatus100can reconstruct the last position information by decoding the bit stream in which the coded binary signals of the X component and the Y component included in the last position information are placed after being classified into a group for context adaptive binary arithmetic decoding and a group for bypass decoding. This allows the image decoding apparatus100to reduce the number of times the arithmetic decoding methods are switched. Moreover, the image decoding apparatus100can arithmetically decode the coded last position information at high speed because it is possible to group partial signals that are to be decoded by bypass decoding, which can be performed in parallel. To be more specific, the image decoding apparatus100can reconstruct the last position information by decoding the bit stream in which a coded partial signal (e.g., the suffix part of the X component) is followed by a partial signal (e.g., the suffix part of the Y component) which has been coded by the same arithmetic coding as the preceding partial signal. Thus, the image decoding apparatus100can reduce the number of times the arithmetic decoding methods are switched and efficiently decode the last position information as compared to the case of decoding a bit stream in which partial signals which have been arithmetically coded by different methods are alternately placed. It is to be noted that the RP values and the maximum lengths of the prefix part shown inFIG.9BtoFIG.9Eare mere examples, and there may be different RP values and different maximum lengths of the prefix part. For example, the maximum length of the prefix part may be shorter and the suffix part may be longer. This further enables parallel arithmetic decoding and further increases the speed of arithmetic decoding. It is to be noted that each of the structural elements in the present embodiment may be configured in the form of an exclusive hardware product, or may be implemented by executing a software program suitable for the structural element. Each structural element may be implemented by means of a program executing unit, such as a CPU or a processor, reading and executing the software program recorded on a recording medium such as a hard disk or a semiconductor memory. Here, the software program for implementing the image decoding apparatus according to the present embodiment is a program described below. This program causes a computer to execute an image decoding method for decoding last position information indicating a horizontal position and a vertical position of a last non-zero coefficient in a predetermined order in a current block to be decoded, the image decoding method including: decoding, by first arithmetic decoding, a coded first partial signal and a coded second partial signal which are included in a bit stream, and decoding, by second arithmetic decoding different from the first arithmetic decoding, a coded third partial signal and a coded fourth partial signal which are included in the bit stream; and reconstructing a first component by debinarizing a first binary signal which includes the decoded first partial signal and the decoded third partial signal, and reconstructing a second component by debinarizing a second binary signal which includes the decoded second partial signal and the decoded fourth partial signal, the first component being one of a horizontal component and a vertical component which are included in the last position information, and the second component being the other of the horizontal component and the vertical component, wherein in the bit stream, (i) the coded second partial signal is placed next to the coded first partial signal, or (ii) the coded fourth partial signal is placed next to the coded third partial signal. Variation of Embodiment 1 The image decoding apparatus100according to Embodiment 1 may be included in an image decoding apparatus below.FIG.12is a block diagram showing an example of a configuration of an image decoding apparatus200according to a variation of Embodiment 1. The image decoding apparatus200decodes coded image data generated by compression coding. For example, the image decoding apparatus200receives coded image data on a block-by-block basis as a current signal to be decoded. The image decoding apparatus200performs variable-length decoding, inverse quantization, and inverse transform on the received current signal to reconstruct image data. As shown inFIG.12, the image decoding apparatus200includes an entropy decoding unit210, an inverse quantization and inverse transform unit220, an adder225, a deblocking filter230, a memory240, an intra prediction unit250, a motion compensation unit260, and an intra/inter switch270. The entropy decoding unit210performs variable-length decoding on an input signal (bit stream) to reconstruct quantized coefficients. Here, the input signal is a current signal to be decoded and corresponds to data on a block-by-block basis of the coded image data. The coded image data includes the coded last position information. Furthermore, the entropy decoding unit210obtains motion data from the input signal and outputs the motion data to the motion compensation unit260. It is to be noted that the image decoding apparatus100according to Embodiment 1 corresponds to part of the entropy decoding unit210. That is to say, the entropy decoding unit210decodes the coded last position information. The inverse quantization and inverse transform unit220performs inverse quantization on the quantized coefficients reconstructed by the entropy decoding unit210, to reconstruct transform coefficients. Then, the inverse quantization and inverse transform unit220performs inverse transform on the transform coefficients to reconstruct a prediction error. The adder225adds the prediction error and a prediction signal to generate a decoded image. The deblocking filter230applies a deblocking filter to the decoded image. The resultant decoded image is outputted as a decoded signal. The memory240is a memory for storing a reference image used in motion compensation. More specifically, the memory240stores the decoded image to which the deblocking filter has been applied. The intra prediction unit250performs intra prediction to generate a prediction signal (intra prediction signal). More specifically, the intra prediction unit250generates an intra prediction signal by performing intra prediction by reference to an image neighboring the current block to be decoded (input signal) in the decoded image generated by the adder225. The motion compensation unit260performs motion compensation based on the motion data outputted by the entropy decoding unit210, to generate a prediction signal (inter prediction signal). The intra/inter switch270selects either the intra prediction signal or the inter prediction signal, and outputs the selected signal to the adder225as the prediction signal. With the above configuration, the image decoding apparatus200decodes the coded image data generated by compression coding. Embodiment 2 The following describes an image coding apparatus according to Embodiment 2 using the drawings. FIG.13is a block diagram showing a functional configuration of an image coding apparatus300according to Embodiment 2. The image coding apparatus300codes the last position information. Described here is the case where the binary signal of the first component (first binary signal) included in the last position information includes the first partial signal and the third partial signal, whereas the binary signal of the second component (second binary signal) included in the last position information includes the second partial signal and the fourth partial signal. It is to be noted that the first component is one of the horizontal component and the vertical component, and the second component is the other of the horizontal component and the vertical component. As shown inFIG.13, the image coding apparatus300includes a binarizing unit310, an arithmetic coding unit320, and a placing unit330. The arithmetic coding unit320includes a first coding unit321, a second coding unit322, and a coding control unit323. The binarizing unit310binarizes the first component and the second component included in the last position information, to generate the first binary signal and the second binary signal. The first coding unit321codes, by first arithmetic coding, the first partial signal that is a part of the first binary signal and the second partial signal that is a part of the second binary signal. The first arithmetic coding is, for example, context adaptive binary arithmetic coding in which a variable probability updated based on a coded signal is used. It is to be noted that the first arithmetic coding need not be context adaptive binary arithmetic coding. The second coding unit322codes, by second arithmetic coding different from the first arithmetic coding, the third partial signal that is another part of the first binary signal and the fourth partial signal that is another part of the second binary signal. The second arithmetic coding is, for example, bypass coding in which a fixed probability is used. It is to be noted that the second arithmetic coding need not be bypass coding. That is to say, it is sufficient as long as the first arithmetic coding and the second arithmetic coding are different. The coding control unit323manages which one of the first to fourth partial signals is the signal received by the arithmetic coding unit320. It is to be noted that the coding control unit323need not be included in the arithmetic coding unit320. That is to say, the image coding apparatus300need not include the coding control unit323. The placing unit330places, in a bit stream, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal. Here, the placing unit330places the coded second partial signal next to the coded first partial signal, or places the coded fourth partial signal next to the coded third partial signal. More specifically, the placing unit330may place, for example, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal in the bit stream in the following order: the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal. Furthermore, the placing unit330may place, for example, the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal in the bit stream in the following order: the coded first partial signal, the coded second partial signal, the coded fourth partial signal, and the coded third partial signal. Next, usingFIG.14AandFIG.14B, the following describes operations of the image coding apparatus300having the above configuration. Hereinafter, it is assumed that the first component is the X component and the second component is the Y component. It is also assumed that each of the first partial signal and the second partial signal is the prefix part and each of the third partial signal and the fourth partial signal is the suffix part. Furthermore, it is assumed that the suffix flag of the X component and the suffix flag of the Y component are set “OFF” as the default value. It is to be noted that the suffix flag is an internal flag indicating whether or not the binary signal of its corresponding component of the last position information includes the suffix part. FIG.14Ais a flowchart showing an example of processing operations of the image coding apparatus300according to Embodiment 2. To be more specific,FIG.14Ashows a coding method for generating a bit stream which is decodable by the decoding method shown inFIG.8A. First, the binarizing unit310binarizes each of the X component and the Y component of the last position information (S401). More specifically, the binarizing unit310binarizes each of the X component and the Y component (last values) as shown inFIG.15, for example. Here, the suffix part is binarized by Golomb-Rice coding. Next, the first coding unit321codes, by context adaptive binary arithmetic coding, the prefix part of the X component included in the last position information (S402). Context adaptive binary arithmetic coding is coding corresponding to context adaptive binary arithmetic decoding shown inFIG.4. With context adaptive binary arithmetic coding, contexts are switched according to a condition, and a probability of symbol occurrence corresponding to the context switched to is obtained. Then, a binary symbol is arithmetically coded using the obtained probability of symbol occurrence. Furthermore, the probability value corresponding to the context is updated according to the coded binary symbol value (see Non Patent Literature 1). Next, the first coding unit321determines whether or not the binary signal of the X component includes the suffix part (S403). More specifically, the first coding unit321determines whether or not the binary signal of the X component includes the suffix part in the same manner as in Step S102inFIG.8A. Here, when the binary signal of the X component includes the suffix part (Yes in S403), the first coding unit321sets the suffix flag of the X component “ON” (S404). On the other hand, when the binary signal of the X component does not include the suffix part (No in S403), the first coding unit321does not set the suffix flag of the X component “ON”. In other words, the suffix flag of the X component remains “OFF”. It is to be noted that the first coding unit321may set the suffix flag of the X component “OFF” here. Next, the first coding unit321codes, by context adaptive binary arithmetic coding, the prefix part of the Y component included in the last position information (S405). After that, the first coding unit321determines whether or not the binary signal of the Y component includes the suffix part (S406). Here, when the binary signal of the Y component includes the suffix part (Yes in S406), the first coding unit321sets the suffix flag of the Y component “ON” (S407). On the other hand, when the binary signal of the Y component does not include the suffix part (No in S406), the first coding unit321does not set the suffix flag of the Y component “ON”. Next, the second coding unit322determines whether or not the suffix flag of the X component is set “ON” (S408). Here, when the suffix flag of the X component is set “ON” (Yes in S408), the second coding unit322codes the suffix part of the X component by bypass coding (S409). On the other hand, when the suffix flag of the X component is not set “ON” (No in S408), Step S409is skipped. The second coding unit322determines whether or not the suffix flag of the Y component is set “ON” (S410). Here, when the suffix flag of the Y component is set “ON” (Yes in S410), the second coding unit322codes the suffix part of the Y component by bypass coding (S411). On the other hand, when the suffix flag of the Y component is not set “ON” (No in S410), Step S411is skipped. Lastly, the placing unit330places, in the bit stream BS, the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the X component, and the coded suffix part of the Y component in this order (S412). Here, the placing unit330places, in the bit stream BS, the prefix part and the suffix part of each component in the order in which they have been coded. Next, the following describes the case where the prefix part and the suffix part of each component are placed in the bit stream in an order different fromFIG.14A. FIG.14Bis a flowchart showing another example of processing operations of the image coding apparatus300according to Embodiment 2. To be more specific,FIG.14Bshows a coding method for generating a bit stream which is decodable by the decoding method shown inFIG.8B. It is to be noted that inFIG.14B, the processes performed in steps denoted by the same reference signs as those inFIG.14Aare basically the same as the processes described inFIG.14A. First, the binarizing unit310binarizes each of the X component and the Y component of the last position information (S401). Next, the first coding unit321codes, by context adaptive binary arithmetic coding, the prefix part of the X component included in the last position information (S402). Next, the first coding unit321determines whether or not the binary signal of the X component includes the suffix part (S403). Here, when the binary signal of the X component includes the suffix part (Yes in S403), the first coding unit321sets the suffix flag of the X component “ON” (S404). On the other hand, when the binary signal of the X component does not include the suffix part (No in S403), the first coding unit321does not set the suffix flag of the X component “ON”. Then, the first coding unit321codes the prefix part of the Y component by context adaptive binary arithmetic coding (S405). After that, the first coding unit321determines whether or not the binary signal of the Y component includes the suffix part (S406). Here, when the binary signal of the Y component includes the suffix part (Yes in S406), the second coding unit322codes the suffix part of the Y component by bypass coding (S411). On the other hand, when the binary signal of the Y component does not include the suffix part (No in S406), Step S411is skipped. Next, the second coding unit322determines whether or not the suffix flag of the X component is set “ON” (S408). Here, when the suffix flag of the X component is set “ON” (Yes in S408), the second coding unit322codes the suffix part of the X component by bypass coding (S409). On the other hand, when the suffix flag of the X component is not set “ON” (No in S408), Step S409is skipped. Lastly, the placing unit330places, in the bit stream BS, the coded prefix part of the X component, the coded prefix part of the Y component, the coded suffix part of the Y component, and the coded suffix part of the X component in this order (S512). Here, the placing unit330places, in the bit stream BS, the prefix part and the suffix part of each component in the order in which they have been coded. By consecutively coding the prefix part and the suffix part of the Y component in the above-described manner, it is possible to code the binary signal of the Y component without holding, in a memory, information indicating whether or not the binary signal of the Y component includes the suffix part (the suffix flag of the Y component inFIG.14A). This reduces the capacity required of the memory. It is to be noted that in the flowcharts shown inFIG.14AandFIG.14B, it is not necessary to perform the determination regarding the suffix parts (S403and S406), the setting of the suffix flags (S404and S407), and the determination regarding the suffix flags (S408and S410) when it is determined in advance that the binary signals of the X component and the Y component each include the suffix part. Next, usingFIG.15, the following briefly describes a method of coding the prefix part and the suffix part included in the last position information. FIG.15is a diagram showing an example of binary signals of the last position information when the block size is 16×16. InFIG.15, the maximum length of the prefix part is “4” and RP is “2”. When the prefix part is shorter than the maximum length of the prefix part, the first coding unit321codes, by context adaptive binary arithmetic coding, as many “0” as the number indicated by the value of the X component. Lastly, the first coding unit321codes “1” by context adaptive binary arithmetic coding. In this case, the binary signal of the X component does not include the suffix part, and thus the coding of the X component finishes here. On the other hand, when the prefix part is longer than the maximum length of the prefix part, the first coding unit321codes, by context adaptive binary arithmetic coding, as many “0” as the number of the maximum length. Next, the second coding unit322codes the first half of the suffix part. More specifically, the second coding unit322adds “1” to the first half in the unit of the number representable by 2 to the RPth power (e.g., in the unit of “4” when RP is “2”), codes the resultant value, and lastly codes “0”. That is to say, when the value of the X component is greater than or equal to 4 and less than 8, the second coding unit322only codes “0” as the first half. When the value of the X component is greater than or equal to 8 and less than 12, the second coding unit322codes “10” as the first half. When the value of the X component is greater than or equal to 12 and less than 16, the second coding unit322codes “110” as the first half. It is to be noted that in the example ofFIG.15, the amount of information to be represented by the suffix part is “12” (16−4=12), and thus, when the value of the X component is greater than or equal to 12 and less than 16, instead of coding “110” as the first half, “11” which is obtained by omitting the last “0” of “110” is coded. This reduces the code length. Next, the second coding unit322codes the second half of the suffix part. The second half is a fixed-length part having a length indicated by the RP value. In the example ofFIG.15, the second half indicates a value which is obtained by binarizing a number among the numbers up to 2 to the RPth power and outputting the resultant value from the number on the left to the number on the right. More specifically, the second half indicates a value obtaining by binarizing 0, 1, 2, or 3. This is a mere example, and the coding efficiency is not affected in particular as long as there is consistency between the method used by the coding apparatus and the method used by the decoding apparatus. It is to be noted that even inFIG.14AandFIG.14B, it is possible to parallelize the coding of the suffix part and increase the speed of arithmetic coding as inFIG.11Adescribed in Embodiment 1. As described above, with the image coding apparatus300according to the present embodiment, in a bit stream, a coded partial signal (e.g., the suffix part of the X component) is followed by a partial signal (e.g., the suffix part of the Y component) which has been coded by the same arithmetic coding as the preceding partial signal. Thus, when the arithmetically coded last position information is decoded, it is possible to reduce the number of times the arithmetic decoding methods are switched as compared to the case where the partial signals arithmetically coded by different methods are alternately placed. That is to say, the image coding apparatus300can output a bit stream from which the last position information can be efficiently decoded. It is to be noted that each of the structural elements in the present embodiment may be configured in the form of an exclusive hardware product, or may be implemented by executing a software program suitable for the structural element. Each structural element may be implemented by means of a program executing unit, such as a CPU or a processor, reading and executing the software program recorded on a recording medium such as a hard disk or a semiconductor memory. Here, the software program for implementing the image coding apparatus according to the present embodiment is a program described below. This program causes a computer to execute an image coding method for coding last position information indicating a horizontal position and a vertical position of a last non-zero coefficient in a predetermined order in a current block to be coded, the image coding method including: binarizing a first component and a second component to generate a first binary signal and a second binary signal, respectively, the first component being one of a horizontal component and a vertical component which are included in the last position information, and the second component being the other of the horizontal component and the vertical component; coding a first partial signal and a second partial signal by first arithmetic coding, and coding a third partial signal and a fourth partial signal by second arithmetic coding different from the first arithmetic coding, the first partial signal being a part of the first binary signal, the second partial signal being a part of the second binary signal, the third partial signal being another part of the first binary signal, and the fourth partial signal being another part of the second binary signal; and placing the coded first partial signal, the coded second partial signal, the coded third partial signal, and the coded fourth partial signal in a bit stream, wherein in the placing, (i) the coded second partial signal is placed next to the coded first partial signal, or (ii) the coded fourth partial signal is placed next to the coded third partial signal. Variation of Embodiment 2 The image coding apparatus300according to Embodiment 2 may be included in an image coding apparatus below.FIG.16is a block diagram showing an example of a configuration of an image coding apparatus400according to a variation of Embodiment 2. The image coding apparatus400performs compression coding on image data. For example, the image coding apparatus400receives the image data on a block-by-block basis as an input signal. The image coding apparatus400performs transform, quantization, and variable-length coding on the input signal to generate a coded signal (bit stream). As shown inFIG.16, the image coding apparatus400includes a subtractor405, a transform and quantization unit410, an entropy coding unit420, an inverse quantization and inverse transform unit430, an adder435, a deblocking filter440, a memory450, an intra prediction unit460, a motion estimation unit470, a motion compensation unit480, and an intra/inter switch490. The subtractor405calculates a difference between the input signal and the prediction signal as a prediction error. The transform and quantization unit410transforms the prediction error in the spatial domain to generate transform coefficients in the frequency domain. For example, the transform and quantization unit410performs discrete cosine transform (DCT) on the prediction error to generate the transform coefficients. Furthermore, the transform and quantization unit410quantizes the transform coefficients to generate quantized coefficients. The entropy coding unit420performs variable-length coding on the quantized coefficients to generate a coded signal. Furthermore, the entropy coding unit420codes motion data (e.g., motion vector) detected by the motion estimation unit470, to output the coded signal with the motion data included therein. It is to be noted that the image coding apparatus300according to Embodiment 2 corresponds to part of the entropy coding unit420. That is to say, the entropy coding unit420codes the last position information. The inverse quantization and inverse transform unit430performs inverse quantization on the quantized coefficients to reconstruct transform coefficients. Furthermore, the inverse quantization and inverse transform unit430performs inverse transform on the reconstructed transform coefficients to reconstruct a prediction error. It is to be noted that the reconstructed prediction error lacks information due to the quantization and thus is not the same as the prediction error generated by the subtractor405. In other words, the reconstructed prediction error contains a quantization error. The adder435adds up the reconstructed prediction error and a prediction signal to generate a local decoded image. The deblocking filter440applies a deblocking filter to the local decoded image. The memory450is a memory for storing a reference image used in motion compensation. More specifically, the memory450stores the local decoded image to which the deblocking filter has been applied. The intra prediction unit460performs intra prediction to generate a prediction signal (intra prediction signal). More specifically, the intra prediction unit460generates an intra prediction signal by performing intra prediction by reference to an image neighboring the current block to be coded (input signal) in the local decoded image generated by the adder435. The motion estimation unit470detects motion data (e.g., motion vector) between the input signal and the reference image stored in the memory450. The motion compensation unit480performs motion compensation based on the motion data to generate a prediction signal (inter prediction signal). The intra/inter switch490selects either the intra prediction signal or the inter prediction signal, and outputs the selected signal to the subtractor405and the adder435as the prediction signal. With the above configuration, the image coding apparatus400performs compression coding on the image data. Although only some exemplary embodiments have been described above, the scope of the Claims of the present application is not limited to these embodiments. Those skilled in the art will readily appreciate that various modifications may be made in these exemplary embodiments and that other embodiments may be obtained by arbitrarily combining the structural elements of the embodiments without materially departing from the novel teachings and advantages of the subject matter recited in the appended Claims. Accordingly, all such modifications and other embodiments are included in the present disclosure. For example, although each embodiment above has specifically described the decoding or coding of the last position information, it is also possible to decode and code the X component and the Y component of a motion vector in the same manner as that described above. More specifically, it is possible to perform coding and decoding without buffering information indicating whether or not the suffix part of the Y component is present, by placing a bypass-coded part including the suffix part of the Y component and a positive/negative code and a bypass-coded part including the suffix part of the X component and a positive/negative code next to the prefix part of the X component (context-adaptive-coded part) and the prefix part of the Y component (context-adaptive-coded part). It is to be noted that the details of motion vector information are described in detail in Non Patent Literature 1 and thus a description thereof is omitted here. Furthermore, although the suffix part is binarized by Golomb-Rice coding in each embodiment above, the suffix part may be binarized with a different method. For example, the suffix part may be binarized with a fixed length as shown inFIG.3AtoFIG.3D. Moreover, the method of binarizing the X component and the Y component in each embodiment above is a mere example, and they may be binarized with a different binarizing method. For example, inFIG.3AtoFIG.3D, the last value may be binarized with “0” and “1” reversed. More specifically, inFIG.3B, the last value “3” may be binarized into “1110”, for example. Furthermore, although each embodiment above has shown the example where (i) the prefix part of the X component, the prefix part of the Y component, the suffix part of the X component, and the suffix part of the Y component are placed in this order or (ii) the prefix part of the X component, the prefix part of the Y component, the suffix part of the Y component, and the suffix part of the X component are placed in this order, the placing order of these prefix and suffix parts is not limited to this example. For example, the prefix part of the Y component and the prefix part of the X component may be placed in this order. Embodiment 3 The processing described in each of embodiments can be simply implemented in an independent computer system, by recording, in a recording medium, a program for implementing the configurations of the moving picture coding method (image coding method) and the moving picture decoding method (image decoding method) described in each of embodiments. The recording media may be any recording media as long as the program can be recorded, such as a magnetic disk, an optical disk, a magnetic optical disk, an IC card, and a semiconductor memory. Hereinafter, the applications to the moving picture coding method (image coding method) and the moving picture decoding method (image decoding method) described in each of embodiments and systems using thereof will be described. The system has a feature of having an image coding and decoding apparatus that includes an image coding apparatus using the image coding method and an image decoding apparatus using the image decoding method. Other configurations in the system can be changed as appropriate depending on the cases. FIG.17illustrates an overall configuration of a content providing system ex100for implementing content distribution services. The area for providing communication services is divided into cells of desired size, and base stations ex106, ex107, ex108, ex109, and ex110which are fixed wireless stations are placed in each of the cells. The content providing system ex100is connected to devices, such as a computer ex111, a personal digital assistant (PDA) ex112, a camera ex113, a cellular phone ex114and a game machine ex115, via the Internet ex101, an Internet service provider ex102, a telephone network ex104, as well as the base stations ex106to ex110, respectively. However, the configuration of the content providing system ex100is not limited to the configuration shown inFIG.17, and a combination in which any of the elements are connected is acceptable. In addition, each device may be directly connected to the telephone network ex104, rather than via the base stations ex106to ex110which are the fixed wireless stations. Furthermore, the devices may be interconnected to each other via a short distance wireless communication and others. The camera ex113, such as a digital video camera, is capable of capturing video. A camera ex116, such as a digital camera, is capable of capturing both still images and video. Furthermore, the cellular phone ex114may be the one that meets any of the standards such as Global System for Mobile Communications (GSM) (registered trademark), Code Division Multiple Access (CDMA), Wideband-Code Division Multiple Access (W-CDMA), Long Term Evolution (LTE), and High Speed Packet Access (HSPA). Alternatively, the cellular phone ex114may be a Personal Handyphone System (PHS). In the content providing system ex100, a streaming server ex103is connected to the camera ex113and others via the telephone network ex104and the base station ex109, which enables distribution of images of a live show and others. In such a distribution, a content (for example, video of a music live show) captured by the user using the camera ex113is coded as described above in each of embodiments (i.e., the camera functions as the image coding apparatus according to an aspect of the present disclosure), and the coded content is transmitted to the streaming server ex103. On the other hand, the streaming server ex103carries out stream distribution of the transmitted content data to the clients upon their requests. The clients include the computer ex111, the PDA ex112, the camera ex113, the cellular phone ex114, and the game machine ex115that are capable of decoding the above-mentioned coded data. Each of the devices that have received the distributed data decodes and reproduces the coded data (i.e., functions as the image decoding apparatus according to an aspect of the present disclosure). The captured data may be coded by the camera ex113or the streaming server ex103that transmits the data, or the coding processes may be shared between the camera ex113and the streaming server ex103. Similarly, the distributed data may be decoded by the clients or the streaming server ex103, or the decoding processes may be shared between the clients and the streaming server ex103. Furthermore, the data of the still images and video captured by not only the camera ex113but also the camera ex116may be transmitted to the streaming server ex103through the computer ex111. The coding processes may be performed by the camera ex116, the computer ex111, or the streaming server ex103, or shared among them. Furthermore, the coding and decoding processes may be performed by an LSI ex500generally included in each of the computer ex111and the devices. The LSI ex500may be configured of a single chip or a plurality of chips. Software for coding and decoding video may be integrated into some type of a recording medium (such as a CD-ROM, a flexible disk, and a hard disk) that is readable by the computer ex111and others, and the coding and decoding processes may be performed using the software. Furthermore, when the cellular phone ex114is equipped with a camera, the video data obtained by the camera may be transmitted. The video data is data coded by the LSI ex500included in the cellular phone ex114. Furthermore, the streaming server ex103may be composed of servers and computers, and may decentralize data and process the decentralized data, record, or distribute data. As described above, the clients may receive and reproduce the coded data in the content providing system ex100. In other words, the clients can receive and decode information transmitted by the user, and reproduce the decoded data in real time in the content providing system ex100, so that the user who does not have any particular right and equipment can implement personal broadcasting. Aside from the example of the content providing system ex100, at least one of the moving picture coding apparatus (image coding apparatus) and the moving picture decoding apparatus (image decoding apparatus) described in each of embodiments may be implemented in a digital broadcasting system ex200illustrated inFIG.18. More specifically, a broadcast station ex201communicates or transmits, via radio waves to a broadcast satellite ex202, multiplexed data obtained by multiplexing audio data and others onto video data. The video data is data coded by the moving picture coding method described in each of embodiments (i.e., data coded by the image coding apparatus according to an aspect of the present disclosure). Upon receipt of the multiplexed data, the broadcast satellite ex202transmits radio waves for broadcasting. Then, a home-use antenna ex204with a satellite broadcast reception function receives the radio waves. Next, a device such as a television (receiver) ex300and a set top box (STB) ex217decodes the received multiplexed data, and reproduces the decoded data (i.e., functions as the image decoding apparatus according to an aspect of the present disclosure). Furthermore, a reader/recorder ex218(i) reads and decodes the multiplexed data recorded on a recording medium ex215, such as a DVD and a BD, or (i) codes video signals in the recording medium ex215, and in some cases, writes data obtained by multiplexing an audio signal on the coded data. The reader/recorder ex218can include the moving picture decoding apparatus or the moving picture coding apparatus as shown in each of embodiments. In this case, the reproduced video signals are displayed on the monitor ex219, and can be reproduced by another device or system using the recording medium ex215on which the multiplexed data is recorded. It is also possible to implement the moving picture decoding apparatus in the set top box ex217connected to the cable ex203for a cable television or to the antenna ex204for satellite and/or terrestrial broadcasting, so as to display the video signals on the monitor ex219of the television ex300. The moving picture decoding apparatus may be implemented not in the set top box but in the television ex300. FIG.19illustrates the television (receiver) ex300that uses the moving picture coding method and the moving picture decoding method described in each of embodiments. The television ex300includes: a tuner ex301that obtains or provides multiplexed data obtained by multiplexing audio data onto video data, through the antenna ex204or the cable ex203, etc. that receives a broadcast; a modulation/demodulation unit ex302that demodulates the received multiplexed data or modulates data into multiplexed data to be supplied outside; and a multiplexing/demultiplexing unit ex303that demultiplexes the modulated multiplexed data into video data and audio data, or multiplexes video data and audio data coded by a signal processing unit ex306into data. The television ex300further includes: a signal processing unit ex306including an audio signal processing unit ex304and a video signal processing unit ex305that decode audio data and video data and code audio data and video data, respectively (which function as the image coding apparatus and the image decoding apparatus according to the aspects of the present disclosure); and an output unit ex309including a speaker ex307that provides the decoded audio signal, and a display unit ex308that displays the decoded video signal, such as a display. Furthermore, the television ex300includes an interface unit ex317including an operation input unit ex312that receives an input of a user operation. Furthermore, the television ex300includes a control unit ex310that controls overall each constituent element of the television ex300, and a power supply circuit unit ex311that supplies power to each of the elements. Other than the operation input unit ex312, the interface unit ex317may include: a bridge ex313that is connected to an external device, such as the reader/recorder ex218; a slot unit ex314for enabling attachment of the recording medium ex216, such as an SD card; a driver ex315to be connected to an external recording medium, such as a hard disk; and a modem ex316to be connected to a telephone network. Here, the recording medium ex216can electrically record information using a non-volatile/volatile semiconductor memory element for storage. The constituent elements of the television ex300are connected to each other through a synchronous bus. First, the configuration in which the television ex300decodes multiplexed data obtained from outside through the antenna ex204and others and reproduces the decoded data will be described. In the television ex300, upon a user operation through a remote controller ex220and others, the multiplexing/demultiplexing unit ex303demultiplexes the multiplexed data demodulated by the modulation/demodulation unit ex302, under control of the control unit ex310including a CPU. Furthermore, the audio signal processing unit ex304decodes the demultiplexed audio data, and the video signal processing unit ex305decodes the demultiplexed video data, using the decoding method described in each of embodiments, in the television ex300. The output unit ex309provides the decoded video signal and audio signal outside, respectively. When the output unit ex309provides the video signal and the audio signal, the signals may be temporarily stored in buffers ex318and ex319, and others so that the signals are reproduced in synchronization with each other. Furthermore, the television ex300may read multiplexed data not through a broadcast and others but from the recording media ex215and ex216, such as a magnetic disk, an optical disk, and a SD card. Next, a configuration in which the television ex300codes an audio signal and a video signal, and transmits the data outside or writes the data on a recording medium will be described. In the television ex300, upon a user operation through the remote controller ex220and others, the audio signal processing unit ex304codes an audio signal, and the video signal processing unit ex305codes a video signal, under control of the control unit ex310using the coding method described in each of embodiments. The multiplexing/demultiplexing unit ex303multiplexes the coded video signal and audio signal, and provides the resulting signal outside. When the multiplexing/demultiplexing unit ex303multiplexes the video signal and the audio signal, the signals may be temporarily stored in the buffers ex320and ex321, and others so that the signals are reproduced in synchronization with each other. Here, the buffers ex318, ex319, ex320, and ex321may be plural as illustrated, or at least one buffer may be shared in the television ex300. Furthermore, data may be stored in a buffer so that the system overflow and underflow may be avoided between the modulation/demodulation unit ex302and the multiplexing/demultiplexing unit ex303, for example. Furthermore, the television ex300may include a configuration for receiving an AV input from a microphone or a camera other than the configuration for obtaining audio and video data from a broadcast or a recording medium, and may code the obtained data. Although the television ex300can code, multiplex, and provide outside data in the description, it may be capable of only receiving, decoding, and providing outside data but not the coding, multiplexing, and providing outside data. Furthermore, when the reader/recorder ex218reads or writes multiplexed data from or on a recording medium, one of the television ex300and the reader/recorder ex218may decode or code the multiplexed data, and the television ex300and the reader/recorder ex218may share the decoding or coding. As an example,FIG.20illustrates a configuration of an information reproducing/recording unit ex400when data is read or written from or on an optical disk. The information reproducing/recording unit ex400includes constituent elements ex401, ex402, ex403, ex404, ex405, ex406, and ex407to be described hereinafter. The optical head ex401irradiates a laser spot in a recording surface of the recording medium ex215that is an optical disk to write information, and detects reflected light from the recording surface of the recording medium ex215to read the information. The modulation recording unit ex402electrically drives a semiconductor laser included in the optical head ex401, and modulates the laser light according to recorded data. The reproduction demodulating unit ex403amplifies a reproduction signal obtained by electrically detecting the reflected light from the recording surface using a photo detector included in the optical head ex401, and demodulates the reproduction signal by separating a signal component recorded on the recording medium ex215to reproduce the necessary information. The buffer ex404temporarily holds the information to be recorded on the recording medium ex215and the information reproduced from the recording medium ex215. The disk motor ex405rotates the recording medium ex215. The servo control unit ex406moves the optical head ex401to a predetermined information track while controlling the rotation drive of the disk motor ex405so as to follow the laser spot. The system control unit ex407controls overall the information reproducing/recording unit ex400. The reading and writing processes can be implemented by the system control unit ex407using various information stored in the buffer ex404and generating and adding new information as necessary, and by the modulation recording unit ex402, the reproduction demodulating unit ex403, and the servo control unit ex406that record and reproduce information through the optical head ex401while being operated in a coordinated manner. The system control unit ex407includes, for example, a microprocessor, and executes processing by causing a computer to execute a program for read and write. Although the optical head ex401irradiates a laser spot in the description, it may perform high-density recording using near field light. FIG.21illustrates the recording medium ex215that is the optical disk. On the recording surface of the recording medium ex215, guide grooves are spirally formed, and an information track ex230records, in advance, address information indicating an absolute position on the disk according to change in a shape of the guide grooves. The address information includes information for determining positions of recording blocks ex231that are a unit for recording data. Reproducing the information track ex230and reading the address information in an apparatus that records and reproduces data can lead to determination of the positions of the recording blocks. Furthermore, the recording medium ex215includes a data recording area ex233, an inner circumference area ex232, and an outer circumference area ex234. The data recording area ex233is an area for use in recording the user data. The inner circumference area ex232and the outer circumference area ex234that are inside and outside of the data recording area ex233, respectively are for specific use except for recording the user data. The information reproducing/recording unit400reads and writes coded audio, coded video data, or multiplexed data obtained by multiplexing the coded audio and video data, from and on the data recording area ex233of the recording medium ex215. Although an optical disk having a layer, such as a DVD and a BD is described as an example in the description, the optical disk is not limited to such, and may be an optical disk having a multilayer structure and capable of being recorded on a part other than the surface. Furthermore, the optical disk may have a structure for multidimensional recording/reproduction, such as recording of information using light of colors with different wavelengths in the same portion of the optical disk and for recording information having different layers from various angles. Furthermore, a car ex210having an antenna ex205can receive data from the satellite ex202and others, and reproduce video on a display device such as a car navigation system ex211set in the car ex210, in the digital broadcasting system ex200. Here, a configuration of the car navigation system ex211will be a configuration, for example, including a GPS receiving unit from the configuration illustrated inFIG.19. The same will be true for the configuration of the computer ex111, the cellular phone ex114, and others. FIG.22Aillustrates the cellular phone ex114that uses the moving picture coding method and the moving picture decoding method described in embodiments. The cellular phone ex114includes: an antenna ex350for transmitting and receiving radio waves through the base station ex110; a camera unit ex365capable of capturing moving and still images; and a display unit ex358such as a liquid crystal display for displaying the data such as decoded video captured by the camera unit ex365or received by the antenna ex350. The cellular phone ex114further includes: a main body unit including an operation key unit ex366; an audio output unit ex357such as a speaker for output of audio; an audio input unit ex356such as a microphone for input of audio; a memory unit ex367for storing captured video or still pictures, recorded audio, coded or decoded data of the received video, the still pictures, e-mails, or others; and a slot unit ex364that is an interface unit for a recording medium that stores data in the same manner as the memory unit ex367. Next, an example of a configuration of the cellular phone ex114will be described with reference toFIG.22B. In the cellular phone ex114, a main control unit ex360designed to control overall each unit of the main body including the display unit ex358as well as the operation key unit ex366is connected mutually, via a synchronous bus ex370, to a power supply circuit unit ex361, an operation input control unit ex362, a video signal processing unit ex355, a camera interface unit ex363, a liquid crystal display (LCD) control unit ex359, a modulation/demodulation unit ex352, a multiplexing/demultiplexing unit ex353, an audio signal processing unit ex354, the slot unit ex364, and the memory unit ex367. When a call-end key or a power key is turned ON by a user's operation, the power supply circuit unit ex361supplies the respective units with power from a battery pack so as to activate the cell phone ex114. In the cellular phone ex114, the audio signal processing unit ex354converts the audio signals collected by the audio input unit ex356in voice conversation mode into digital audio signals under the control of the main control unit ex360including a CPU, ROM, and RAM. Then, the modulation/demodulation unit ex352performs spread spectrum processing on the digital audio signals, and the transmitting and receiving unit ex351performs digital-to-analog conversion and frequency conversion on the data, so as to transmit the resulting data via the antenna ex350. Also, in the cellular phone ex114, the transmitting and receiving unit ex351amplifies the data received by the antenna ex350in voice conversation mode and performs frequency conversion and the analog-to-digital conversion on the data. Then, the modulation/demodulation unit ex352performs inverse spread spectrum processing on the data, and the audio signal processing unit ex354converts it into analog audio signals, so as to output them via the audio output unit ex357. Furthermore, when an e-mail in data communication mode is transmitted, text data of the e-mail inputted by operating the operation key unit ex366and others of the main body is sent out to the main control unit ex360via the operation input control unit ex362. The main control unit ex360causes the modulation/demodulation unit ex352to perform spread spectrum processing on the text data, and the transmitting and receiving unit ex351performs the digital-to-analog conversion and the frequency conversion on the resulting data to transmit the data to the base station ex110via the antenna ex350. When an e-mail is received, processing that is approximately inverse to the processing for transmitting an e-mail is performed on the received data, and the resulting data is provided to the display unit ex358. When video, still images, or video and audio in data communication mode is or are transmitted, the video signal processing unit ex355compresses and codes video signals supplied from the camera unit ex365using the moving picture coding method shown in each of embodiments (i.e., functions as the image coding apparatus according to the aspect of the present disclosure), and transmits the coded video data to the multiplexing/demultiplexing unit ex353. In contrast, during when the camera unit ex365captures video, still images, and others, the audio signal processing unit ex354codes audio signals collected by the audio input unit ex356, and transmits the coded audio data to the multiplexing/demultiplexing unit ex353. The multiplexing/demultiplexing unit ex353multiplexes the coded video data supplied from the video signal processing unit ex355and the coded audio data supplied from the audio signal processing unit ex354, using a predetermined method. Then, the modulation/demodulation unit (modulation/demodulation circuit unit) ex352performs spread spectrum processing on the multiplexed data, and the transmitting and receiving unit ex351performs digital-to-analog conversion and frequency conversion on the data so as to transmit the resulting data via the antenna ex350. When receiving data of a video file which is linked to a Web page and others in data communication mode or when receiving an e-mail with video and/or audio attached, in order to decode the multiplexed data received via the antenna ex350, the multiplexing/demultiplexing unit ex353demultiplexes the multiplexed data into a video data bit stream and an audio data bit stream, and supplies the video signal processing unit ex355with the coded video data and the audio signal processing unit ex354with the coded audio data, through the synchronous bus ex370. The video signal processing unit ex355decodes the video signal using a moving picture decoding method corresponding to the moving picture coding method shown in each of embodiments (i.e., functions as the image decoding apparatus according to the aspect of the present disclosure), and then the display unit ex358displays, for instance, the video and still images included in the video file linked to the Web page via the LCD control unit ex359. Furthermore, the audio signal processing unit ex354decodes the audio signal, and the audio output unit ex357provides the audio. Furthermore, similarly to the television ex300, a terminal such as the cellular phone ex114probably have 3 types of implementation configurations including not only (i) a transmitting and receiving terminal including both a coding apparatus and a decoding apparatus, but also (ii) a transmitting terminal including only a coding apparatus and (iii) a receiving terminal including only a decoding apparatus. Although the digital broadcasting system ex200receives and transmits the multiplexed data obtained by multiplexing audio data onto video data in the description, the multiplexed data may be data obtained by multiplexing not audio data but character data related to video onto video data, and may be not multiplexed data but video data itself. As such, the moving picture coding method and the moving picture decoding method in each of embodiments can be used in any of the devices and systems described. Thus, the advantages described in each of embodiments can be obtained. Furthermore, the present disclosure is not limited to embodiments, and various modifications and revisions are possible without departing from the scope of the present disclosure. Embodiment 4 Video data can be generated by switching, as necessary, between (i) the moving picture coding method or the moving picture coding apparatus shown in each of embodiments and (ii) a moving picture coding method or a moving picture coding apparatus in conformity with a different standard, such as MPEG-2, MPEG-4 AVC, and VC-1. Here, when a plurality of video data that conforms to the different standards is generated and is then decoded, the decoding methods need to be selected to conform to the different standards. However, since to which standard each of the plurality of the video data to be decoded conforms cannot be detected, there is a problem that an appropriate decoding method cannot be selected. In order to solve the problem, multiplexed data obtained by multiplexing audio data and others onto video data has a structure including identification information indicating to which standard the video data conforms. The specific structure of the multiplexed data including the video data generated in the moving picture coding method and by the moving picture coding apparatus shown in each of embodiments will be hereinafter described. The multiplexed data is a digital stream in the MPEG-2 Transport Stream format. FIG.23illustrates a structure of the multiplexed data. As illustrated inFIG.23, the multiplexed data can be obtained by multiplexing at least one of a video stream, an audio stream, a presentation graphics stream (PG), and an interactive graphics stream. The video stream represents primary video and secondary video of a movie, the audio stream (IG) represents a primary audio part and a secondary audio part to be mixed with the primary audio part, and the presentation graphics stream represents subtitles of the movie. Here, the primary video is normal video to be displayed on a screen, and the secondary video is video to be displayed on a smaller window in the primary video. Furthermore, the interactive graphics stream represents an interactive screen to be generated by arranging the GUI components on a screen. The video stream is coded in the moving picture coding method or by the moving picture coding apparatus shown in each of embodiments, or in a moving picture coding method or by a moving picture coding apparatus in conformity with a conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1. The audio stream is coded in accordance with a standard, such as Dolby-AC-3, Dolby Digital Plus, MLP, DTS, DTS-HD, and linear PCM. Each stream included in the multiplexed data is identified by PID. For example, 0x1011 is allocated to the video stream to be used for video of a movie, 0x1100 to 0x111F are allocated to the audio streams, 0x1200 to 0x121F are allocated to the presentation graphics streams, 0x1400 to 0x141F are allocated to the interactive graphics streams, 0x1B00 to 0x1B1F are allocated to the video streams to be used for secondary video of the movie, and 0x1A00 to 0x1A1F are allocated to the audio streams to be used for the secondary audio to be mixed with the primary audio. FIG.24schematically illustrates how data is multiplexed. First, a video stream ex235composed of video frames and an audio stream ex238composed of audio frames are transformed into a stream of PES packets ex236and a stream of PES packets ex239, and further into TS packets ex237and TS packets ex240, respectively. Similarly, data of a presentation graphics stream ex241and data of an interactive graphics stream ex244are transformed into a stream of PES packets ex242and a stream of PES packets ex245, and further into TS packets ex243and TS packets ex246, respectively. These TS packets are multiplexed into a stream to obtain multiplexed data ex247. FIG.25illustrates how a video stream is stored in a stream of PES packets in more detail. The first bar inFIG.25shows a video frame stream in a video stream. The second bar shows the stream of PES packets. As indicated by arrows denoted as yy1, yy2, yy3, and yy4inFIG.25, the video stream is divided into pictures as I pictures, B pictures, and P pictures each of which is a video presentation unit, and the pictures are stored in a payload of each of the PES packets. Each of the PES packets has a PES header, and the PES header stores a Presentation Time-Stamp (PTS) indicating a display time of the picture, and a Decoding Time-Stamp (DTS) indicating a decoding time of the picture. FIG.26illustrates a format of TS packets to be finally written on the multiplexed data. Each of the TS packets is a 188-byte fixed length packet including a 4-byte TS header having information, such as a PID for identifying a stream and a 184-byte TS payload for storing data. The PES packets are divided, and stored in the TS payloads, respectively. When a BD ROM is used, each of the TS packets is given a 4-byte TP_Extra_Header, thus resulting in 192-byte source packets. The source packets are written on the multiplexed data. The TP_Extra_Header stores information such as an Arrival_Time_Stamp (ATS). The ATS shows a transfer start time at which each of the TS packets is to be transferred to a PID filter. The source packets are arranged in the multiplexed data as shown at the bottom ofFIG.26. The numbers incrementing from the head of the multiplexed data are called source packet numbers (SPNs). Each of the TS packets included in the multiplexed data includes not only streams of audio, video, subtitles and others, but also a Program Association Table (PAT), a Program Map Table (PMT), and a Program Clock Reference (PCR). The PAT shows what a PID in a PMT used in the multiplexed data indicates, and a PID of the PAT itself is registered as zero. The PMT stores PIDs of the streams of video, audio, subtitles and others included in the multiplexed data, and attribute information of the streams corresponding to the PIDs. The PMT also has various descriptors relating to the multiplexed data. The descriptors have information such as copy control information showing whether copying of the multiplexed data is permitted or not. The PCR stores STC time information corresponding to an ATS showing when the PCR packet is transferred to a decoder, in order to achieve synchronization between an Arrival Time Clock (ATC) that is a time axis of ATSs, and an System Time Clock (STC) that is a time axis of PTSs and DTSs. FIG.27illustrates the data structure of the PMT in detail. A PMT header is disposed at the top of the PMT. The PMT header describes the length of data included in the PMT and others. A plurality of descriptors relating to the multiplexed data is disposed after the PMT header. Information such as the copy control information is described in the descriptors. After the descriptors, a plurality of pieces of stream information relating to the streams included in the multiplexed data is disposed. Each piece of stream information includes stream descriptors each describing information, such as a stream type for identifying a compression codec of a stream, a stream PID, and stream attribute information (such as a frame rate or an aspect ratio). The stream descriptors are equal in number to the number of streams in the multiplexed data. When the multiplexed data is recorded on a recording medium and others, it is recorded together with multiplexed data information files. Each of the multiplexed data information files is management information of the multiplexed data as shown inFIG.28. The multiplexed data information files are in one to one correspondence with the multiplexed data, and each of the files includes multiplexed data information, stream attribute information, and an entry map. As illustrated inFIG.28, the multiplexed data information includes a system rate, a reproduction start time, and a reproduction end time. The system rate indicates the maximum transfer rate at which a system target decoder to be described later transfers the multiplexed data to a PID filter. The intervals of the ATSs included in the multiplexed data are set to not higher than a system rate. The reproduction start time indicates a PTS in a video frame at the head of the multiplexed data. An interval of one frame is added to a PTS in a video frame at the end of the multiplexed data, and the PTS is set to the reproduction end time. As shown inFIG.29, a piece of attribute information is registered in the stream attribute information, for each PID of each stream included in the multiplexed data. Each piece of attribute information has different information depending on whether the corresponding stream is a video stream, an audio stream, a presentation graphics stream, or an interactive graphics stream. Each piece of video stream attribute information carries information including what kind of compression codec is used for compressing the video stream, and the resolution, aspect ratio and frame rate of the pieces of picture data that is included in the video stream. Each piece of audio stream attribute information carries information including what kind of compression codec is used for compressing the audio stream, how many channels are included in the audio stream, which language the audio stream supports, and how high the sampling frequency is. The video stream attribute information and the audio stream attribute information are used for initialization of a decoder before the player plays back the information. In the present embodiment, the multiplexed data to be used is of a stream type included in the PMT. Furthermore, when the multiplexed data is recorded on a recording medium, the video stream attribute information included in the multiplexed data information is used. More specifically, the moving picture coding method or the moving picture coding apparatus described in each of embodiments includes a step or a unit for allocating unique information indicating video data generated by the moving picture coding method or the moving picture coding apparatus in each of embodiments, to the stream type included in the PMT or the video stream attribute information. With the configuration, the video data generated by the moving picture coding method or the moving picture coding apparatus described in each of embodiments can be distinguished from video data that conforms to another standard. Furthermore,FIG.30illustrates steps of the moving picture decoding method according to the present embodiment. In Step exS100, the stream type included in the PMT or the video stream attribute information included in the multiplexed data information is obtained from the multiplexed data. Next, in Step exS101, it is determined whether or not the stream type or the video stream attribute information indicates that the multiplexed data is generated by the moving picture coding method or the moving picture coding apparatus in each of embodiments. When it is determined that the stream type or the video stream attribute information indicates that the multiplexed data is generated by the moving picture coding method or the moving picture coding apparatus in each of embodiments, in Step exS102, decoding is performed by the moving picture decoding method in each of embodiments. Furthermore, when the stream type or the video stream attribute information indicates conformance to the conventional standards, such as MPEG-2, MPEG-4 AVC, and VC-1, in Step exS103, decoding is performed by a moving picture decoding method in conformity with the conventional standards. As such, allocating a new unique value to the stream type or the video stream attribute information enables determination whether or not the moving picture decoding method or the moving picture decoding apparatus that is described in each of embodiments can perform decoding. Even when multiplexed data that conforms to a different standard is input, an appropriate decoding method or apparatus can be selected. Thus, it becomes possible to decode information without any error. Furthermore, the moving picture coding method or apparatus, or the moving picture decoding method or apparatus in the present embodiment can be used in the devices and systems described above. Embodiment 5 Each of the moving picture coding method, the moving picture coding apparatus, the moving picture decoding method, and the moving picture decoding apparatus in each of embodiments is typically achieved in the form of an integrated circuit or a Large Scale Integrated (LSI) circuit. As an example of the LSI,FIG.31illustrates a configuration of the LSI ex500that is made into one chip. The LSI ex500includes elements ex501, ex502, ex503, ex504, ex505, ex506, ex507, ex508, and ex509to be described below, and the elements are connected to each other through a bus ex510. The power supply circuit unit ex505is activated by supplying each of the elements with power when the power supply circuit unit ex505is turned on. For example, when coding is performed, the LSI ex500receives an AV signal from a microphone ex117, a camera ex113, and others through an AV IO ex509under control of a control unit ex501including a CPU ex502, a memory controller ex503, a stream controller ex504, and a driving frequency control unit ex512. The received AV signal is temporarily stored in an external memory ex511, such as an SDRAM. Under control of the control unit ex501, the stored data is segmented into data portions according to the processing amount and speed to be transmitted to a signal processing unit ex507. Then, the signal processing unit ex507codes an audio signal and/or a video signal. Here, the coding of the video signal is the coding described in each of embodiments. Furthermore, the signal processing unit ex507sometimes multiplexes the coded audio data and the coded video data, and a stream IO ex506provides the multiplexed data outside. The provided multiplexed data is transmitted to the base station ex107, or written on the recording medium ex215. When data sets are multiplexed, the data should be temporarily stored in the buffer ex508so that the data sets are synchronized with each other. Although the memory ex511is an element outside the LSI ex500, it may be included in the LSI ex500. The buffer ex508is not limited to one buffer, but may be composed of buffers. Furthermore, the LSI ex500may be made into one chip or a plurality of chips. Furthermore, although the control unit ex501includes the CPU ex502, the memory controller ex503, the stream controller ex504, the driving frequency control unit ex512, the configuration of the control unit ex501is not limited to such. For example, the signal processing unit ex507may further include a CPU. Inclusion of another CPU in the signal processing unit ex507can improve the processing speed. Furthermore, as another example, the CPU ex502may serve as or be a part of the signal processing unit ex507, and, for example, may include an audio signal processing unit. In such a case, the control unit ex501includes the signal processing unit ex507or the CPU ex502including a part of the signal processing unit ex507. The name used here is LSI, but it may also be called IC, system LSI, super LSI, or ultra LSI depending on the degree of integration. Moreover, ways to achieve integration are not limited to the LSI, and a special circuit or a general purpose processor and so forth can also achieve the integration. Field Programmable Gate Array (FPGA) that can be programmed after manufacturing LSIs or a reconfigurable processor that allows re-configuration of the connection or configuration of an LSI can be used for the same purpose. In the future, with advancement in semiconductor technology, a brand-new technology may replace LSI. The functional blocks can be integrated using such a technology. The possibility is that the present disclosure is applied to biotechnology. Embodiment 6 When video data generated in the moving picture coding method or by the moving picture coding apparatus described in each of embodiments is decoded, compared to when video data that conforms to a conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1 is decoded, the processing amount probably increases. Thus, the LSI ex500needs to be set to a driving frequency higher than that of the CPU ex502to be used when video data in conformity with the conventional standard is decoded. However, when the driving frequency is set higher, there is a problem that the power consumption increases. In order to solve the problem, the moving picture decoding apparatus, such as the television ex300and the LSI ex500is configured to determine to which standard the video data conforms, and switch between the driving frequencies according to the determined standard.FIG.32illustrates a configuration ex800in the present embodiment. A driving frequency switching unit ex803sets a driving frequency to a higher driving frequency when video data is generated by the moving picture coding method or the moving picture coding apparatus described in each of embodiments. Then, the driving frequency switching unit ex803instructs a decoding processing unit ex801that executes the moving picture decoding method described in each of embodiments to decode the video data. When the video data conforms to the conventional standard, the driving frequency switching unit ex803sets a driving frequency to a lower driving frequency than that of the video data generated by the moving picture coding method or the moving picture coding apparatus described in each of embodiments. Then, the driving frequency switching unit ex803instructs the decoding processing unit ex802that conforms to the conventional standard to decode the video data. More specifically, the driving frequency switching unit ex803includes the CPU ex502and the driving frequency control unit ex512inFIG.31. Here, each of the decoding processing unit ex801that executes the moving picture decoding method described in each of embodiments and the decoding processing unit ex802that conforms to the conventional standard corresponds to the signal processing unit ex507inFIG.31. The CPU ex502determines to which standard the video data conforms. Then, the driving frequency control unit ex512determines a driving frequency based on a signal from the CPU ex502. Furthermore, the signal processing unit ex507decodes the video data based on the signal from the CPU ex502. For example, the identification information described in Embodiment 4 is probably used for identifying the video data. The identification information is not limited to the one described in Embodiment 4 but may be any information as long as the information indicates to which standard the video data conforms. For example, when which standard video data conforms to can be determined based on an external signal for determining that the video data is used for a television or a disk, etc., the determination may be made based on such an external signal. Furthermore, the CPU ex502selects a driving frequency based on, for example, a look-up table in which the standards of the video data are associated with the driving frequencies as shown inFIG.34. The driving frequency can be selected by storing the look-up table in the buffer ex508and in an internal memory of an LSI, and with reference to the look-up table by the CPU ex502. FIG.33illustrates steps for executing a method in the present embodiment. First, in Step exS200, the signal processing unit ex507obtains identification information from the multiplexed data. Next, in Step exS201, the CPU ex502determines whether or not the video data is generated by the coding method and the coding apparatus described in each of embodiments, based on the identification information. When the video data is generated by the moving picture coding method and the moving picture coding apparatus described in each of embodiments, in Step exS202, the CPU ex502transmits a signal for setting the driving frequency to a higher driving frequency to the driving frequency control unit ex512. Then, the driving frequency control unit ex512sets the driving frequency to the higher driving frequency. On the other hand, when the identification information indicates that the video data conforms to the conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1, in Step exS203, the CPU ex502transmits a signal for setting the driving frequency to a lower driving frequency to the driving frequency control unit ex512. Then, the driving frequency control unit ex512sets the driving frequency to the lower driving frequency than that in the case where the video data is generated by the moving picture coding method and the moving picture coding apparatus described in each of embodiment. Furthermore, along with the switching of the driving frequencies, the power conservation effect can be improved by changing the voltage to be applied to the LSI ex500or an apparatus including the LSI ex500. For example, when the driving frequency is set lower, the voltage to be applied to the LSI ex500or the apparatus including the LSI ex500is probably set to a voltage lower than that in the case where the driving frequency is set higher. Furthermore, when the processing amount for decoding is larger, the driving frequency may be set higher, and when the processing amount for decoding is smaller, the driving frequency may be set lower as the method for setting the driving frequency. Thus, the setting method is not limited to the ones described above. For example, when the processing amount for decoding video data in conformity with MPEG-4 AVC is larger than the processing amount for decoding video data generated by the moving picture coding method and the moving picture coding apparatus described in each of embodiments, the driving frequency is probably set in reverse order to the setting described above. Furthermore, the method for setting the driving frequency is not limited to the method for setting the driving frequency lower. For example, when the identification information indicates that the video data is generated by the moving picture coding method and the moving picture coding apparatus described in each of embodiments, the voltage to be applied to the LSI ex500or the apparatus including the LSI ex500is probably set higher. When the identification information indicates that the video data conforms to the conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1, the voltage to be applied to the LSI ex500or the apparatus including the LSI ex500is probably set lower. As another example, when the identification information indicates that the video data is generated by the moving picture coding method and the moving picture coding apparatus described in each of embodiments, the driving of the CPU ex502does not probably have to be suspended. When the identification information indicates that the video data conforms to the conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1, the driving of the CPU ex502is probably suspended at a given time because the CPU ex502has extra processing capacity. Even when the identification information indicates that the video data is generated by the moving picture coding method and the moving picture coding apparatus described in each of embodiments, in the case where the CPU ex502has extra processing capacity, the driving of the CPU ex502is probably suspended at a given time. In such a case, the suspending time is probably set shorter than that in the case where when the identification information indicates that the video data conforms to the conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1. Accordingly, the power conservation effect can be improved by switching between the driving frequencies in accordance with the standard to which the video data conforms. Furthermore, when the LSI ex500or the apparatus including the LSI ex500is driven using a battery, the battery life can be extended with the power conservation effect. Embodiment 7 There are cases where a plurality of video data that conforms to different standards, is provided to the devices and systems, such as a television and a cellular phone. In order to enable decoding the plurality of video data that conforms to the different standards, the signal processing unit ex507of the LSI ex500needs to conform to the different standards. However, the problems of increase in the scale of the circuit of the LSI ex500and increase in the cost arise with the individual use of the signal processing units ex507that conform to the respective standards. In order to solve the problem, what is conceived is a configuration in which the decoding processing unit for implementing the moving picture decoding method described in each of embodiments and the decoding processing unit that conforms to the conventional standard, such as MPEG-2, MPEG-4 AVC, and VC-1 are partly shared. Ex900inFIG.35Ashows an example of the configuration. For example, the moving picture decoding method described in each of embodiments and the moving picture decoding method that conforms to MPEG-4 AVC have, partly in common, the details of processing, such as entropy coding, inverse quantization, deblocking filtering, and motion compensated prediction. The details of processing to be shared probably include use of a decoding processing unit ex902that conforms to MPEG-4 AVC. In contrast, a dedicated decoding processing unit ex901is probably used for other processing unique to an aspect of the present disclosure. Since the aspect of the present disclosure is characterized by entropy decoding in particular, for example, the dedicated decoding processing unit ex901is used for entropy decoding. Otherwise, the decoding processing unit is probably shared for one of deblocking filtering, motion compensation, and inverse quantization or all of the processing. The decoding processing unit for implementing the moving picture decoding method described in each of embodiments may be shared for the processing to be shared, and a dedicated decoding processing unit may be used for processing unique to that of MPEG-4 AVC. Furthermore, ex1000inFIG.35Bshows another example in that processing is partly shared. This example uses a configuration including a dedicated decoding processing unit ex1001that supports the processing unique to an aspect of the present disclosure, a dedicated decoding processing unit ex1002that supports the processing unique to another conventional standard, and a decoding processing unit ex1003that supports processing to be shared between the moving picture decoding method according to the aspect of the present disclosure and the conventional moving picture decoding method. Here, the dedicated decoding processing units ex1001and ex1002are not necessarily specialized for the processing according to the aspect of the present disclosure and the processing of the conventional standard, respectively, and may be the ones capable of implementing general processing. Furthermore, the configuration of the present embodiment can be implemented by the LSI ex500. As such, reducing the scale of the circuit of an LSI and reducing the cost are possible by sharing the decoding processing unit for the processing to be shared between the moving picture decoding method according to the aspect of the present disclosure and the moving picture decoding method in conformity with the conventional standard. INDUSTRIAL APPLICABILITY The image coding apparatus and the image decoding apparatus according to an aspect of the present disclosure are applicable to television receivers, digital video recorders, car navigation systems, mobile phones, digital cameras, or digital video cameras, for example. | 143,744 |
RE49789 | DETAILED DESCRIPTION For a better understanding of the present disclosure, various aspects of the present disclosure will be described in more detail with reference to the accompanying drawings. It should be understood that the detailed description is merely an illustration for the exemplary embodiments of the present disclosure rather than a limitation to the scope of the present disclosure in any way. Throughout the specification, the same reference numerals designate the same elements. The expression “and/or” includes any and all combinations of one or more of the associated listed items. It should be noted that in the specification, the expressions, such as “first,” “second,” and “third” are only used to distinguish one feature from another, rather than represent any limitations to the features. Thus, the first lens discussed below may also be referred to as the second lens or the third lens without departing from the teachings of the present disclosure. In the accompanying drawings, the thicknesses, sizes and shapes of the lenses have been slightly exaggerated for the convenience of explanation. Specifically, shapes of spherical surfaces or aspheric surfaces shown in the accompanying drawings are shown by examples. That is, the shapes of the spherical surfaces or the aspheric surfaces are not limited to the shapes of the spherical surfaces or the aspheric surfaces shown in the accompanying drawings. The accompanying drawings are merely illustrative and not strictly drawn to scale. Herein, the paraxial area refers to an area near the optical axis. If a surface of a lens is a convex surface and a position of the convex surface is not defined, it indicates that the surface of the lens is a convex surface at least in the paraxial area; and if a surface of a lens is a concave surface and a position of the concave surface is not defined, it indicates that the surface of the lens is a concave surface at least in the paraxial area. The surface closest to the object in each lens is referred to as the object-side surface, and the surface closest to the image plane in each lens is referred to as the image-side surface. It should be further understood that the terms “comprising,” “including,” “having” and variants thereof, when used in the specification, specify the presence of stated features, elements and/or components, but do not exclude the presence or addition of one or more other features, elements, components and/or combinations thereof. In addition, expressions such as “at least one of,” when preceding a list of listed features, modify the entire list of features rather than an individual element in the list. Further, the use of “may,” when describing the embodiments of the present disclosure, relates to “one or more embodiments of the present disclosure.” Also, the term “exemplary” is intended to refer to an example or illustration. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. It should be further understood that terms (i.e., those defined in commonly used dictionaries) should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. It should also be noted that the embodiments in the present disclosure and the features in the embodiments may be combined with each other on a non-conflict basis. The present disclosure will be described below in detail with reference to the accompanying drawings and in combination with the embodiments. Features, principles, and other aspects of the present disclosure are described below in detail. The optical imaging lens assembly according to exemplary embodiments of the present disclosure may include, for example, seven lenses (i.e., a first lens, a second lens, a third lens, a fourth lens, a fifth lens, a sixth lens, and a seventh lens) having refractive powers. The seven lenses are arranged in sequence from an object side to an image side along an optical axis. In the exemplary embodiments, the first lens may have a positive refractive power. An object-side surface of the first lens may be a convex surface. The second lens may have a negative refractive power. The third lens may have a positive refractive power. The fourth lens has a positive refractive power or a negative refractive power. The fifth lens has a positive refractive power or a negative refractive power. The sixth lens may have a positive refractive power. The seventh lens may have a negative refractive power. An object-side surface of the seventh lens may be a concave surface, and an image-side surface of the seventh lens may be a concave surface. In the exemplary embodiments, an image-side surface of the first lens may be a concave surface. In the exemplary embodiments, an object-side surface of the second lens may be a convex surface, and an image-side surface of the second lens may be a concave surface. In the exemplary embodiments, an object-side surface of the third lens may be a convex surface. In the exemplary embodiments, an object-side surface of the sixth lens may be a convex surface, and an image-side surface of the sixth lens may be a convex surface. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression f/EPD≤1.80. Here, f is the total effective focal length of the optical imaging lens assembly, and EPD is the entrance pupil diameter of the optical imaging lens assembly. More specifically, f and EPD may further satisfy: 1.58≤f/EPD≤1.76. The smaller the F-number Fno (i.e., the total effective focal length f of the lens assembly/the entrance pupil diameter EPD of the lens assembly) of the optical imaging lens assembly is, the larger the clear aperture of the lens assembly is, and the greater the amount of light entering the lens assembly in the same unit time is. The reduction of the F-number Fno may effectively enhance the brightness of the image plane, so that the lens assembly can better fulfill the shooting requirements when the light is insufficient (e.g., in cloudy and rainy days, or at dusk), and thus the lens assembly has the advantage of large aperture. When the lens assembly is configured to satisfy the conditional expression f/EPD≤1.60, the lens assembly may have the advantage of the large aperture. Thus, the amount of light passing through the system may be increased, thereby enhancing the illuminance of the image plane. At the same time, the aberration of the edge field-of-view may also be reduced. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression |f12/f34|≤0.3. Here, f12 is the combined focal length of the first lens and the second lens, and f34 is the combined focal length of the third lens and the fourth lens. More specifically, f12 and f34 may further satisfy: 0.061≤f12/f34|≤0.28. Reasonably distributing f12 and f34 is conductive to improving the optical performance of the imaging system. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression 4.5<f2/f7<11.0. Here, f2 is the effective focal length of the second lens, and f7 is the effective focal length of the seventh lens. More specifically, f2 and f7 may further satisfy: 4.94≤f2/f7≤10.02. By reasonably distributing the effective focal length of the second lens and the effective focal length of the seventh lens, the deflection angle of light may be reduced, thereby improving the imaging quality of the optical system. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression 0<R1/R4<1. Here, R1 is the radius of curvature of the object-side surface of the first lens, and R4 is the radius of curvature of the image-side surface of the second lens. More specifically, R1 and R4 may further satisfy: 0.35<R1/R4<0.65, for example, 0.40≤R1/R4≤0.63. The range of the ratio of the radius of curvature R1 of the object-side surface of the first lens to the radius of curvature R4 of the image-side surface of the second lens is reasonably controlled, which facilitates the system achieving the deflection of the optical path well. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression −1.5<R12/R14<−0.5. Here, R12 is the radius of curvature of the image-side surface of the sixth lens, and R14 is the radius of curvature of the image-side surface of the seventh lens. More specifically, R12 and R14 may further satisfy: −1.1<R12/R14<−0.8, for example, −1.08≤R12/R14≤−0.88. By reasonably controlling the ratio of R12 to R14, the aberration of the system can be easily balanced, thereby improving the imaging quality of the imaging system. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression TTL/ImgH≤1.50. Here, TTL is the total track length of the optical imaging lensassembly (i.e., the distance from the center of the object-side surface of the first lens to the image plane of the optical imaging lens assembly on the optical axis), and ImgH is the half of the diagonal length of the effective pixel area on the image plane. More specifically, TTL and ImgH may further satisfy: 1.40≤TTL/ImgH≤1.48. When the conditional expression TTL/ImgH≤1.50 is satisfied, the size of the system may be effectively compressed, which ensures the ultra-thin characteristic of the imaging lens assembly. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression −2.5<f/f7<−1.5. Here, f is the total effective focal length of the optical imaging lens assembly and f7 is the effective focal length of the seventh lens. More specifically, f and f7 may further satisfy: −2.1<f/f7<−1.8, for example, −2.07≤f/f7≤−1.98. By controlling the negative refractive power of the seventh lens within a reasonable range, the positive astigmatism in a reasonable range may be obtained, which can balance the negative astigmatism generated by the six lenses (i.e., the lenses between the object side and the seventh lens) before the seventh lens, so that the imaging system can obtain a good imaging quality. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression 0.3 mm<CT6<0.8 mm. Here, CT6 is the center thickness of the sixth lens on the optical axis. More specifically, CT6 may further satisfy: 0.4 mm<CT6<0.7 mm, for example, 0.46 mm≤CT6≤0.61 mm. By properly controlling the center thickness CT6 of the sixth lens, the optical element may be ensured to have a good processing characteristic. At the same time, the total track length TTL of the lens assembly may be ensured to be kept within a certain reasonable range. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression 2.0<f1/R1<3.0. Here, f1 is the effective focal length of the first lens, and R1 is the radius of curvature of the object-side surface of the first lens. More specifically, f1 and R1 may further satisfy: 2.1<f1/R1<2.6, for example, 2.20≤f1/R1≤2.55. By reasonably controlling the ratio of the effective focal length f1 of the first lens to the radius of curvature R1 of the object-side surface of the first lens, the deflection angle of the edge field-of-view at the first lens can be effectively controlled, and thus the sensitivity of the system can be effectively reduced. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression −0.2<CT1/f2<0. Here, CT1 is the center thickness of the first lens on the optical axis, and f2 is the effective focal length of the second lens. More specifically, CT1 and f2 may further satisfy: −0.1<CT1/f2<0, for example, −0.08≤CT1/f2<−0.04. Reasonably controlling the ratio of CT1 to f2 is conductive to ensuring the processing characteristic of the first lens and the spherical aberration contribution of the second lens. Thus, the imaging system has a good imaging quality in the on-axis field-of-view area. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression −1.5<f6/f7<−1.0. Here, f6 is the effective focal length of the sixth lens, and f7 is the effective focal length of the seventh lens. More specifically, f6 and f7 may further satisfy: −1.44≤f6/f7≤−1.08. By reasonably controlling the ratio of the effective focal length of the sixth lens to the effective focal length of the seventh lens, the residual spherical aberrations obtained after the balance between the sixth lens and the seventh lens can be balanced with the spherical aberrations generated by the five lenses (i.e., the lenses between the object side and the sixth lens) before the sixth lens. Thus, the fine adjustment on the spherical aberration of the system is realized, and the effect of reducing the aberration in the on-axis field-of-view area is achieved. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression −1.5<f7/R14<−1.0. Here, f7 is the effective focal length of the seventh lens, and R14 is the radius of curvature of the image-side surface of the seventh lens. More specifically, f7 and R14 may further satisfy: −1.3<f7/R14<−1.1, for example, −1.28≤f7/R14≤−1.14. By reasonably controlling the radius of curvature of the image-side surface of the seventh lens, the third-order comatic aberration of the seventh lens is controlled within a reasonable range. Thus, the comatic aberrations generated by the six lenses before the seventh lens can be balanced, so that the imaging system has a good imaging quality. In the exemplary embodiments, the optical imaging lens assembly of the present disclosure may satisfy the conditional expression 0<f6/f3<0.5. Here, f6 is the effective focal length of the sixth lens, and f3 is the effective focal length of the third lens. More specifically, f6 and f3 may further satisfy: 0.1<f6/f3<0.4, for example, 0.11≤f6/f3≤0.38. By reasonably controlling the ratio of f6 to f3, the spherical aberration contribution of the sixth lens and the spherical aberration contribution of the third lens can be reasonably controlled, so that the imaging system has a good imaging quality in the on-axis field-of view area. In the exemplary embodiments, the optical imaging lens assembly may further include at least one diaphragm, to further improve the imaging quality of the lens assembly. For example, the diaphragm may be disposed between the first lens and the second lens. Alternatively, the optical imaging lens assembly may further include an optical filter for correcting color deviations and/or a protective glass for protecting a photosensitive element on the image plane. The optical imaging lens assembly according to the above embodiments of the present disclosure may use a plurality of lenses, for example, the seven lenses described above. By reasonably distributing the refractive powers and the surface types of the lenses, the center thicknesses of the lenses, the spacing distances between the lenses on the axis, etc., it is possible to effectively reduce the size of the lens assembly, reduce the sensitivity of the lens assembly, and enhance the processibility of the lens assembly, so that the optical imaging lens assembly is more conductive to the production and processing and applicable to the portable electronic products. At the same time, the optical imaging lens assembly with the above configuration also has beneficial effects such as ultra-thin, miniaturization, large aperture, and high imaging quality. In the embodiments of the present disclosure, at least one of the surfaces of the lenses is an aspheric surface. The aspheric lens is characterized in that the curvature continuously changes from the center of the lens to the periphery. Different from a spherical lens having a constant curvature from the center of the lens to the periphery, the aspheric lens has a better radius-of-curvature characteristic, and has advantages of improving the distortion aberration and the astigmatic aberration. The use of the aspheric lens can eliminate as much as possible the aberrations that occur during the imaging, thereby improving the imaging quality. However, it should be understood by those skilled in the art that the various results and advantages described in the present specification may be obtained by changing the number of the lenses constituting the optical imaging lens assembly without departing from the technical solution claimed by the present disclosure. For example, although the optical imaging lens assembly having seven lenses is described as an example in the embodiments, the optical imaging lens assembly is not limited to include seven lenses. If desired, the optical imaging lens assembly may also include other numbers of lenses. Specific embodiments of the optical imaging lens assembly that may be applied to the above embodiments are further described below with reference to the accompanying drawings. Embodiment 1 An optical imaging lens assembly according to Embodiment 1 of the present disclosure is described below with reference toFIGS.1-2D.FIG.1is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 1 of the present disclosure. As shown inFIG.1, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a convex surface, and an image-side surface S10of the fifth lens E5is a concave surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 1 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 1. The radius of curvature and the thickness are both in millimeters (mm). TABLE 1materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.68250.78871.5556.10.0128S2aspheric8.30680.03283.8896STOsphericalinfinite0.0350S3aspheric4.66400.21721.6720.4−7.9131S4aspheric2.68390.3484−1.7896S5aspheric24.23410.34011.5556.125.7166S6aspheric−3.53720.03007.3000S7aspheric−3.57730.21771.5556.15.6401S8aspheric41.75120.1745−99.0000S9aspheric12.08790.33521.6720.446.2401S10aspheric5.13460.1816−79.5381S11aspheric7.38610.60691.5556.1−97.8337S12aspheric−1.37620.3036−8.4969S13aspheric−3.73310.35001.5455.7−2.2333S14aspheric1.56880.2340−9.6678S15sphericalinfinite0.21031.5264.2S16sphericalinfinite0.5740S17sphericalinfinite As may be obtained from Table 1, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. In this embodiment, the surface type x of each aspheric surface may be defined using, but not limited to, the following formula: x=ch21+1-(k+1)c2h2+∑Aihi.(1) Here, x is the sag—the axis-component of the displacement of the surface from the aspheric vertex, when the surface is at height h from the optical axis; c is the paraxial curvature of the aspheric surface, and c=1/R (i.e., the paraxial curvature c is the reciprocal of the radius of curvature R in Table 1 above); k is the conic coefficient (given in Table 1); and Ai is the correction coefficient of the ithorder of the aspheric surface. Table 2 below shows the high-order coefficients A4, A6, A8, A10, A12, A14, A16, A18, and A20applicable to the aspheric surfaces S1-S14in Embodiment 1. TABLE 2surfacenumberA4A6A8A10A12A14A16A18A20S1−9.6100E −6.4354E −−2.2752E −4.9383E −−6.8363E − 016.0365E − 01−3.2970E − 011.0100E − 01−1.3360E − 0203020101S2−9.9670E −1.1211E −1.8602E −−9.7186E −1.8102E + 00−1.9196E + 001.2028E + 00−4.1341E − 015.9939E − 0202010101S3−1.7887E −3.4329E −−4.8103E −7.4328E −−1.1333E + 001.2693E + 00−8.7261E − 013.2940E − 01−5.2440E − 0201010101S4−7.8170E −−2.1530E −1.1801E −−5.0751E +1.2193E + 01−1.7899E + 011.5876E + 01−7.7921E + 001.6308E + 0002020000S5−7.9840E −1.3189E −−8.5200E −2.4292E +−4.5264E + 005.3997E + 00−4.0601E + 001.8226E + 00−3.8096E − 0102010100S63.5613E −−2.0127E −9.6660E −−3.4935E +7.4444E + 00−9.4690E + 007.0676E + 00−2.8355E + 004.6899E − 0102010100S7−3.6800E −7.6484E −−4.3323E −1.1785E +−2.0201E + 002.4372E + 00−2.0035E + 009.5575E − 01−1.8947E − 0103020100S8−1.2773E −1.1835E −−2.2444E −3.0869E −5.4935E − 01−1.0628E + 009.8617E − 01−4.7910E − 019.7996E − 0201010102S9−2.2027E −2.3157E −−5.0670E −8.9234E −−1.2931E + 001.1957E + 00−5.7771E − 011.1223E − 01−8.3000E − 0401010101S10−1.7177E −1.9157E −−4.6011E −8.6283E −−1.0810E + 008.3132E − 01−3.6968E − 018.7028E − 02−8.9300E − 0301010101S11−5.0510E −3.6812E −−2.3171E −4.8139E −−5.2615E − 013.3309E − 01−1.2318E − 012.4682E − 02−2.0600E − 0302020101S12−1.5094E −2.5511E −−4.2149E −4.4916E −−2.8015E − 011.0389E − 01−2.2650E − 022.6860E − 03−1.3000E − 0401010101S13−1.3929E −1.5506E −2.9978E −−1.1730E −1.1160E − 032.5100E − 04−7.6000E − 057.6500E − 06−2.8000E − 0701020202S14−1.1865E −7.1242E −−3.3840E −1.1731E −−2.9400E − 035.1200E − 04−5.9000E − 053.9700E − 06−1.2000E − 0701020202 Table 3 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 1, the total effective focal length f of the optical imaging lens assembly, the total track length TTL (i.e., the distance from the center of the object-side surface S1of the first lens E1to the image plane S17on the optical axis) of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 3f1(mm)3.71f(mm)4.00f2(mm)−9.93TTL(mm)4.98f3(mm)5.68ImgH(mm)3.36f4(mm)−6.03f5(mm)−13.67f6(mm)2.18f7(mm)−2.01 The optical imaging lens assembly in Embodiment 1 satisfies at least one of the following conditions. f/EPD=1.58, here f is the total effective focal length of the optical imaging lens assembly, and EPD is the entrance pupil diameter of the optical imaging lens assembly. |f12/f34|=0.06, here f12 is the combined focal length of the first lens E1and the second lens E2, and f34 is the combined focal length of the third lens E3and the fourth lens E4. f2/f7=4.94, here f2 is the effective focal length of the second lens E2, and f7 is the effective focal length of the seventh lens E7. R1/R4=0.63, here R1 is the radius of curvature of the object-side surface S1of the first lens E1, and R4 is the radius of curvature of the image-side surface S4of the second lens E2. R12/R14=−0.88, here R12 is the radius of curvature of the image-side surface S12of the sixth lens E6, and R14 is the radius of curvature of the image-side surface S14of the seventh lens E7. TTL/ImgH=1.48, here TTL is the total track length of the optical imaging lens assembly, and ImgH is the half of the diagonal length of the effective pixel area on the image plane S17. f/f7=−1.99, here f is the total effective focal length of the optical imaging lens assembly, and f7 is the effective focal length of the seventh lens E7. CT6=0.61 mm, here CT6 is the center thickness of the sixth lens E6on the optical axis. f1/R1=2.20, here f1 is the effective focal length of the first lens E1, and R1 is the radius of curvature of the object-side surface S1of the first lens E1. CT1/f2=−0.08, here CT1 is the center thickness of the first lens E1on the optical axis, and f2 is the effective focal length of the second lens E2. f6/f7=−1.08, here f6 is the effective focal length of the sixth lens E6, and f7 is the effective focal length of the seventh lens E7. f7/R14=1.28, here f7 is the effective focal length of the seventh lens E7, and R14 is the radius of curvature of the image-side surface S14of the seventh lens E7. f6/f3=0.38, here f6 is the effective focal length of the sixth lens E6, and f3 is the effective focal length of the third lens E3. In addition,FIG.2Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 1, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.2Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 1, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.2Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 1, representing amounts of distortion at different viewing angles.FIG.2Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 1, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.2A-2Dthat the optical imaging lens assembly according to Embodiment 1 can achieve a good imaging quality. Embodiment 2 An optical imaging lens assembly according to Embodiment 2 of the present disclosure is described below with reference toFIGS.3-4D. In this embodiment and the following embodiments, for the purpose of brevity, the description of parts similar to those in Embodiment 1 will be omitted.FIG.3is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 2 of the present disclosure. As shown inFIG.3, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a convex surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 4 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 2. The radius of curvature and the thickness are both in millimeters (mm). TABLE 4materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.69340.75481.5556.1−0.0460S2aspheric5.66860.1078−11.9183STOsphericalinfinite0.0400S3aspheric5.42120.23001.6720.4−18.2078S4aspheric3.55590.2183−6.5924S5aspheric10.44770.47111.5556.161.8278S6aspheric−15.23230.0700−80.7875S7aspheric45.67900.25251.6720.499.0000S8aspheric9.83250.164042.6534S9aspheric−14.49160.28311.6720.499.0000S10aspheric−15.42060.1586−73.8173S11aspheric9.88260.49511.5556.137.8164S12aspheric−1.65470.2791−9.9228S13aspheric−2.85880.32621.5455.7−1.4621S14aspheric1.68110.3033−16.1601S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5561S17sphericalinfinite As may be obtained from Table 4, in Embodiment 2, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 5 shows the high-order coefficients applicable to each aspheric surface in Embodiment 2. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 5surface numberA4A6A8A10A12A14A16A18A20S1−2.5350E −1.0145E −−3.1309E −5.6998E −−6.6437E −4.8971E −−2.2201E −5.5676E − 02−5.8600E − 0302010101010101S2−5.7620E −5.0630E −8.3859E −−2.1507E −2.8456E −−2.3303E −1.1650E −−3.2450E − 023.8530E − 0302030201010101S3−1.2819E −−1.4773E −−2.2369E −6.7720E −−1.3000E +1.4322E +−8.7899E −2.7052E − 01−2.9030E − 0201010101000001S4−7.5860E −−2.7090E −8.0357E −−3.4884E +9.5854E +−1.6845E +1.8140E +−1.0869E + 012.7806E + 0002020100000101S5−7.1420E −1.1944E −−8.0707E −2.2062E +−3.4885E +2.6573E +−1.0300E −−1.3225E + 006.1824E − 0102010100000002S6−1.0921E −3.5019E −−3.8527E −1.0732E +−2.2377E +3.0822E +−2.4136E +9.4839E − 01−1.4123E − 0101020100000000S7−2.5378E −5.1600E −−1.8389E +4.1775E +−6.5243E −6.8301E +−4.3455E +1.4329E + 00−1.7397E − 0101010000000000S8−1.9886E −2.4443E −−2.7913E −−7.2550E −5.5365E −−6.7788E −4.1268E −−1.3907E − 012.2527E − 0201010102010101S9−1.7260E −3.1883E −−7.9364E −1.9253E +−3.5565E +4.1007E +−2.7863E +1.0264E + 00−1.5815E − 0101010100000000S10−1.7197E −4.5801E −4.1281E −4.2585E −−3.0715E −3.9925E −−2.2613E −6.0136E − 02−6.1600E − 0301020202010101S11−1.4290E −−1.7641E −1.5278E −1.7267E −−5.6933E −5.8103E −−3.0034E −7.9629E − 02−8.5800E − 0302010101010101S12−3.1100E −−7.8940E −1.6942E −−1.7014E −9.3437E −−2.9180E −5.0730E −−4.4000E − 041.3200E − 0503020101020203S13−2.8553E −2.7594E −−2.1155E −1.3942E −−6.1360E −1.6676E −−2.7100E −2.4200E − 04−9.2000E − 0601010101020203S14−1.5178E −1.2222E −−7.2300E −2.8620E −7.3000E −1.0720E −−6.4000E −−2.9000E − 064.2600E − 0701010202030305 Table 6 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 2, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 6f1(mm)4.15f(mm)3.88f2(mm)−16.33TTL(mm)4.82f3(mm)11.43ImgH(mm)3.34f4(mm)−18.87f5(mm)−411.43f6(mm)2.64f7(mm)−1.92 FIG.4Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 2, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.4Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 2, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.4Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 2, representing amounts of distortion at different viewing angles.FIG.4Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 2, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.4A-4Dthat the optical imaging lens assembly according to Embodiment 2 can achieve a good imaging quality. Embodiment 3 An optical imaging lens assembly according to Embodiment 3 of the present disclosure is described below with reference toFIGS.5-6D.FIG.5is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 3 of the present disclosure. As shown inFIG.5, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a convex surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a positive refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 7 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 3. The radius of curvature and the thickness are both in millimeters (mm). TABLE 7materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.68010.77421.5556.1−0.0224S2aspheric5.19230.1168−9.3561STOsphericalinfinite0.0400S3aspheric5.61210.23001.6720.4−25.5929S4aspheric3.65510.2044−8.1217S5aspheric9.34400.46891.5556.159.8335S6aspheric−17.72170.0700−89.5502S7aspheric28.56310.25051.672-0.434.2567S8aspheric8.56300.156138.8580S9aspheric−20.00000.28921.6720.481.6473S10aspheric−19.83930.1719−99.0000S11aspheric9.12290.48781.5556.132.4787S12aspheric−1.69950.2707−10.2471S13aspheric−3.02100.31781.5455.7−1.4137S14aspheric1.66010.3045−15.2913S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5573S17sphericalinfinite As may be obtained from Table 7, in Embodiment 3, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 8 shows the high-order coefficients applicable to each aspheric surface in Embodiment 3. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 8surface numberA4A6A8A10A12A14A16A18A20S1−2.5110E −1.0818E −−3.0971E −5.5640E −−6.3575E −4.5669E −−1.9996E −4.7892E − 02−4.7600E − 0302010101010101S2−5.0320E −−6.4500E −8.4655E −−1.9261E −2.4587E −−1.9882E −9.8900E −−2.7480E − 023.2560E − 0302030201010102S3−1.2023E −1.1884E −−2.0927E −7.1792E −−1.3992E +1.5598E +−9.9462E −3.3538E − 01−4.4970E − 0201010101000001S4−7.0790E −−6.8650E −9.5569E −−4.0189E +1.0873E +−1.8731E +1.9715E +−1.1538E + 012.8850E + 0002020100010101S5−5.9600E −5.9986E −−6.2202E −1.8806E +−3.4013E +3.4044E +−1.4350E +−2.2399E − 012.9631E − 0102020100000000S6−1.2867E −2.1240E −−1.0013E +2.1955E +−3.2117E +3.0916E +−1.7060E +4.1643E − 01−1.4020E − 0201010000000000S7−2.6235E −5.0293E −−1.4849E +2.5300E +−2.5912E +1.4054E +−8.6700E −−4.2226E − 011.5230E − 0101010000000003S8−2.0817E −2.8366E −−3.8914E −8.0413E −4.9164E −−7.4772E −5.0053E −−1.7380E − 012.6967E − 0201010102010101S9−1.3891E −1.6107E −−2.6656E −7.4229E −−1.8758E +2.6417E +−2.0439E +8.2287E − 01−1.3479E − 0101010101000000S10−1.4675E −−3.4440E −2.6558E −−4.0922E −2.8134E −−7.3580E −−2.3500E −3.1480E − 03−1.4000E − 0401020101010203S11−3.9900E −−2.3724E −3.4309E −−1.9006E −−1.4980E −2.8339E −−1.7499E −5.1120E − 02−5.9000E − 0303010101010101S121.0208E −−1.0144E −1.9555E −−1.8663E −9.6083E −−2.6920E −3.7640E −−1.7000E − 04−65.000E − 0602010101020203S13−2.8510E −2.7288E −−2.0701E −1.3592E −−5.9610E −1.6088E −−2.5800E −2.2800E − 04−8.5000E − 0601010101020203S14−1.5834E −1.3546E −−8.7290E −3.8896E−1.1770E −2.3080E −−2.7000E −1.6900E − 05−3.8000E − 0701010202020304 Table 9 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 3, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 9f1(mm)4.22f(mm)3.92f2(mm)−16.52TTL(mm)4.82f3(mm)11.28ImgH(mm)3.34f4(mm)−18.46f5(mm)2157.54f6(mm)2.67f7(mm)−1.95 FIG.6Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 3, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.6Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 3, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.6Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 3, representing amounts of distortion at different viewing angles.FIG.6Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 3, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.6A-6Dthat the optical imaging lens assembly according to Embodiment 3 can achieve a good imaging quality. Embodiment 4 An optical imaging lens assembly according to Embodiment 4 of the present disclosure is described below with reference toFIGS.7-8D.FIG.7is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 4 of the present disclosure. As shown inFIG.7, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 10 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 4. The radius of curvature and the thickness are both in millimeters (mm). TABLE 10materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.69290.71931.5556.1−0.0998S2aspheric6.29490.0984−16.2736STOsphericalinfinite0.0400S3aspheric5.45490.23001.6720.4−8.0637S4aspheric3.54460.2248−3.9727S5aspheric13.93870.48561.5556.156.0398S6aspheric−10.65430.060057.2530S7aspheric−87.37030.24661.6720.4−99.0000S8aspheric15.85500.168434.0353S9aspheric−12.24940.28371.6720.487.6792S10aspheric−18.25390.145210.2729S11aspheric10.14810.51601.5556.143.3042S12aspheric−1.68270.3108−10.5698S13aspheric−2.88630.32321.5455.7−1.3827S14aspheric1.66740.3026−16.7588S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5554S17sphericalinfinite As may be obtained from Table 10, in Embodiment 4, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 11 shows the high-order coefficients applicable to each aspheric surface in Embodiment 4. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 11surface numberA4A6A8A10A12A14A16A18A20S1−2.5890E −1.0865E −−3.5138E −6.7315E −−8.3500E −6.5883E −−3.2197E −8.7814E − 02−1.0140E − 0202010101010101S2−6.2480E −9.9910E −9.0788E −−2.6462E −3.8786E −−3.5028E −1.9258E −−5.8840E − 027.6400E − 0302030201010101S3−1.3177E −1.6835E −−2.4957E −7.2560E −−1.3738E +1.4515E +−7.7477E −1.4665E − 011.3634E − 0201010101000001S4−7.5470E −−4.3040E −1.0885E +−5.0563E +1.4662E +−2.7060E +3.0635E +−1.9343E + 015.2285E + 0002020000010101S5−8.9620E −2.4116E −−1.5112E +4.7468E +−9.0751E +1.0071E +−5.5574E +5.9752E − 014.8979E − 0102010000000100S6−1.1733E −−1.1623E −7.0810E −1.0801E +−4.2291E +7.8223E +−7.6858E +3.8581E + 00−7.8080E − 0101010300000000S7−2.9272E −7.5147E −−3.5448E +1.0605E +−2.0599E +2.5822E +−1.9902E +8.4883E + 00−1.5242E + 0001010001010101S8−1.8046E −1.7187E −−8.1840E −−4.4769E −1.0441E +−1.1093E +6.3482E −−1.9095E − 012.5334E − 0201010201000001S9−1.9603E −3.6782E −−8.0634E −1.6715E +−2.8911E +3.2928E +−2.2697E +8.6785E − 01−1.4164E − 0101010100000000S10−1.9583E −5.3010E −1.2246E −−1.7709E −−4.9240E −2.4633E −−1.8148E −5.5222E − 02−6.2500E − 0301020101020101S11−3.9140E −−9.1390E −−1.1181E −7.026E −−1.2754E +1.1743E +−5.9789E −1.6068E − 01−1.7790E − 0202020101000001S12−1.8100E −−3.1820E −1.1872E −−1.6136E −1.1427E −−4.6090E −1.0739E −−1.3500E − 037.1700E − 0502020101010202S13−2.9839E −3.1043E −−2.6363E −1.8559E −−8.5520E −2.4251E −−4.1100E −1.8400E − 04−1.5000E − 0501010101020203S14−1.4746E −1.1305E −−6.5200E −2.5753E −−6.7400E −1.0800E −−9.0000E −1.8500E − 061.4400E − 0701010102030305 Table 12 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 4, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 12f1(mm)4.02f(mm)3.85f2(mm)−15.97TTL(mm)4.82f3(mm)11.14ImgH(mm)3.34f4(mm)−20.14f5(mm)−57.01f6(mm)2.69f7(mm)−1.92 FIG.8Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 4, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.8Billustrates the astigmatic curve of the lens assembly according to Embodiment 4, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.8Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 4, representing amounts of distortion at different viewing angles.FIG.8Dillustrates the lateral color curve of the lens assembly according to Embodiment 4, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.8A-8Dthat the optical imaging lens assembly according to Embodiment 4 can achieve a good imaging quality. Embodiment 5 An optical imaging lens assembly according to Embodiment 5 of the present disclosure is described below with reference toFIGS.9-10D.FIG.9is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 5 of the present disclosure. As shown inFIG.9, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 13 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 5. The radius of curvature and the thickness are both in millimeters (mm). TABLE 13materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.67500.72731.5556.1−0.0623S2aspheric5.86180.1060−10.3301STOsphericalinfinite0.0400S3aspheric5.58400.23001.6720.4−11.2212S4aspheric3.52000.2132−4.4226S5aspheric2.60270.47651.5556.174.8032S6aspheric−9.47750.060049.4828S7aspheric−51.63120.25811.6720.4−99.0000S8aspheric13.73610.163453.6477S9aspheric−12.63350.28241.6720.489.3588S10aspheric−16.95330.1672−72.9299S11aspheric9.66740.48571.5556.137.6323S12aspheric−1.69450.2925−8.7349S13aspheric−2.92930.32561.5455.7−1.4382S14aspheric1.66590.3046−15.1421S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5574S17sphericalinfinite As may be obtained from Table 13, in Embodiment 5, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 14 shows the high-order coefficients applicable to each aspheric surface in Embodiment 5. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. surface numberA4A6A8A10A12A14A16A18A20S1−1.7260E −6.8051E −−2.2949E −4.4964E −−5.6729E −4.5059E −−2.1933E −5.8548E − 02−6.4900E − 0302020101010101S2−5.7290E −1.5112E −3.6099E −−1.1342E −1.5791E −−1.3998E −7.7662E −−2.4310E − 023.2580E − 0302020201010102S3−1.2131E −1.2347E −−1.2959E −4.6878E −−1.0693E +1.3614E +−9.6208E −3.4927E − 01−4.7830E − 0201010101000001S4−7.3950E −−6.9700E −7.0336E −−3.3506E +1.0202E +−1.9903E +2.3804E +−1.5835E + 014.5041E + 0002030100010101S5−6.5670E −5.9553E −−5.3307E −1.3721E +−1.7753E +7.6472E −2.8857E +−3.4441E + 001.3474E + 0002020100000200S6−1.1546E −−4.0930E −1.4215E −−9.5878E −2.5269E +−3.6575E +3.2872E +−1.7407E + 004.0778E − 0101020101000000S7−2.4432E −3.7026E −−1.1876E +2.2278E +−2.6523E +2.0459E +−8.0582E −−2.8830E − 029.0787E − 0201010000000001S8−1.8359E −2.3274E −−3.0643E −1.7276E −4.0842E −−5.0568E −2.5393E −−5.1220E − 022.9410E − 0301010102010101S9−1.6250E −2.1360E −−2.8721E −6.2611E −−1.6848E +2.5613E +−2.1179E +9.1352E − 01−1.6137E − 0101010101000000S10−1.6941E −−7.3110E −5.1071E −−9.0683E −8.4206E −−4.6180E −1.6512E −−3.8510E − 024.4030E − 0301010101010101S11−3.2230E −−1.6901E −4.5289E −5.1759E −−1.1239E −1.0955E +−5.7944E −1.6147E − 01−1.8530E − 0202010201000001S122.8779E −−1.5061E −2.1817E −−1.6309E −6.2391E −−8.4900E −−1.6200E −6.6000E − 04−6.0000E − 0502010101020303S13−2.7308E −2.2675E −−1.3912E −8.4432E −−3.7110E −1.0919E −−1.6700E −1.5000E − 04−5.7000E − 0601010102020203S14−1.5661E −1.3081E −−8.2490E −3.6520E −−1.1160E −2.2480E −−2.8000E −1.9000E − 05−5.2000E − 0701010202020304 Table 15 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 5, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 15f1(mm)4.05f(mm)3.94f2(mm)−14.97TTL(mm)4.80f3(mm)9.98ImgH(mm)3.36f4(mm)−16.27f5(mm)−76.47f6(mm)2.68f7(mm)−1.93 FIG.10Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 5, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.10Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 5, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.10Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 5, representing amounts of distortion at different viewing angles.FIG.10Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 5, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.10A-10Dthat the optical imaging lens assembly according to Embodiment 5 can achieve a good imaging quality. Embodiment 6 An optical imaging lens assembly according to Embodiment 6 of the present disclosure is described below with reference toFIGS.11-12D.FIG.11is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 6 of the present disclosure. As shown inFIG.11, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a convex surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a positive refractive power, an object-side surface S9of the fifth lens E5is a convex surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 16 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 6. The radius of curvature and the thickness are both in millimeters (mm). TABLE 16surfacesurfaceradius ofmaterialnumbertypecurvaturethicknessrefractive indexabbe numberconic coefficientOBJsphericalinfiniteinfiniteS1aspheric1.65260.77441.5556.1−0.0179S2aspheric4.91790.1227−7.9777STOsphericalinfinite0.0400S3aspheric6.04350.23001.6720.4−28.3104S4aspheric3.74950.1965−7.3895S5aspheric8.77750.46121.5556.159.7351S6aspheric−23.74480.0700−98.8063S7aspheric17.77890.25881.6720.489.8404S8aspheric7.46270.145633.5544S9aspheric201.75990.27881.6720.499.0000S10aspheric−497.17000.2044−99.0000S11aspheric8.55620.49431.5556.128.5352S12aspheric−1.73580.2558−10.1241S13aspheric−3.12430.31151.5455.7−1.4066S14aspheric1.62850.3050−14.5668S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5578S17sphericalinfinite As may be obtained from Table 16, in Embodiment 6, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 17 shows the high-order coefficients applicable to each aspheric surface in Embodiment 6. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 17surfacenumberA4A6A8A10A12A14A16A18A20S1−2.2990E−029.6412E−02−2.9850E−015.4329E−01−6.2498E−014.4874E−01−1.9448E−014.5436E−02−4.3200E−03S2−4.4900E−02−1.4090E−028.1942E−02−1.7777E−012.3282E−01−1.9819E−011.0449E−01−3.0790E−023.8680E−03S3−1.1630E−019.8568E−02−1.5952E−016.0029E−01−1.1718E+001.2694E+00−7.7053E−012.4000E−01−2.7720E−02S4−7.0630E−02−3.7810E−026.6015E−01−2.6832E+007.4011E+00−1.3205E+011.4426E+01−8.7536E+002.2675E+00S5−5.2210E−021.7792E−02−4.3394E−011.3392E+00−2.4129E+002.2781E+00−6.7545E−01−5.0271E−013.4176E−01S6−1.1854E−011.5745E−01−7.5891E−011.5284E+00−1.9096E+001.3801E+00−3.3095E−01−1.8477E−019.6125E−02S7−2.4843E−014.7234E−01−1.4941E+002.8342E+00−3.4064E+002.5451E+00−1.0222E+001.2813E−011.7206E−02S8−1.8674E−012.3413E−01−3.2258E−015.7694E−024.4253E−01−6.6750E−014.3720E−01−1.4424E−012.0347E−02S9−1.4461E−012.1000E−01−4.9195E−011.2525E+00−2.5242E+003.1256E+00−2.2424E+008.5625E−01−1.3428E−01S10−1.4717E−01−4.0000E−041.6840E−01−2.7910E−011.9195E−01−4.6170E−02−3.6100E−032.3850E−03−1.0000E−04S11−9.6500E−03−1.8147E−012.0645E−01−1.4400E−03−3.1467E−013.7506E−01−2.0770E−015.8326E−02−6.6600E−03S122.4436E−02−1.2564E−012.2571E−01−2.0861E−011.0152E−01−2.5130E−022.3990E−031.2200E−04−2.9000E−05S13−2.8427E−012.6953E−01−2.0218E−011.3204E−01−5.7670E−021.5471E−02−2.4600E−032.1500E−04−7.9000E−06S14−1.6803E−011.5103E−01−1.0319E−014.9357E−02−1.6240E−023.5450E−03−4.9000E−043.7500E−05−1.2000E−06 Table 18 shows the effective focal lengths f1-f7of the respective lenses in Embodiment 6, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 18f1(mm)4.21f(mm)3.95f2(mm)−15.46TTL(mm)4.82f3(mm)11.80ImgH(mm)3.34f4(mm)−19.51f5(mm)215.62f6(mm)2.69f7(mm)−1.95 FIG.12Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 6, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.12Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 6, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.12Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 6, representing amounts of distortion at different viewing angles.FIG.12Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 6, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.12A-12Dthat the optical imaging lens assembly according to Embodiment 6 can achieve a good imaging quality. Embodiment 7 An optical imaging lens assembly according to Embodiment 7 of the present disclosure is described below with reference toFIGS.13-14D.FIG.13is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 7 of the present disclosure. As shown inFIG.13, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 19 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 7. The radius of curvature and the thickness are both in millimeters (mm). TABLE 19materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.67700.73641.5556.1−0.0566S2aspheric5.65040.1091−9.5792STOsphericalinfinite0.0400S3aspheric5.57170.23001.6720.4−11.2918S4aspheric3.58900.2080−4.6149S5aspheric12.19070.47581.5556.175.4970S6aspheric−9.40600.060048.6557S7aspheric−58.48940.25391.6720.499.0000S8aspheric12.42120.160851.3574S9aspheric−12.76280.28911.6720.492.9118S10aspheric−16.56850.1617−44.7911S11aspheric9.31580.48681.5556.135.4018S12aspheric−1.71220.3004−9.0470S13aspheric−2.95420.32621.5455.7−1.4352S14aspheric1.67220.3045−14.7187S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5573S17sphericalinfinite As may be obtained from Table 19, in Embodiment 7, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 20 shows the high-order coefficients applicable to each aspheric surface in Embodiment 7. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 20surfacenumberA4A6A8A10A12A14S1−1.9030E−027.5352E−02−2.5016E−014.8666E−01−6.0904E−014.8019E−01S2−5.4640E−021.2288E−022.6543E−02−7.7780E−029.9760E−02−8.4420E−02S3−1.1890E−011.2950E−01−2.1427E−017.7503E−01−1.6828E+002.1105E+00S4−7.0740E−02−2.4680E−027.2864E−01−3.2732E+009.7183E+00−1.8780E+01S5−6.6870E−028.0941E−02−6.9384E−012.0745E+00−3.6917E+003.3671E+00S6−1.0324E−01−6.9140E−022.0517E−01−1.0637E+002.6216E+00−3.6931E+00S7−2.4602E−014.2832E−01−1.4790E+002.9561E+00−3.6749E+002.7958E+00S8−1.8124E−012.1875E−01−2.3501E−01−2.3922E−019.5595E−01−1.1901E+00S9−1.6076E−012.5397E−01−4.9472E−011.1880E+00−2.6258E+003.5744E+00S10−1.5446E−01−1.4282E−017.1051E−01−1.2868E+001.3156E+00−8.3280E−01S11−2.3350E−02−1.9653E−018.8314E−024.7121E−01−1.0930E+001.0875E+00S123.3003E−02−1.5378E−012.0922E−01−1.4299E−014.3131E−021.5880E−03S13−2.6632E−012.0595E−01−1.1276E−016.6190E−02−2.9530E−028.2360E−03S14−1.6128E−011.3708E−01−8.8350E−024.0417E−02−1.2900E−022.7510E−03surfacenumberA16A18A20S1−2.3186E−016.1452E−02−6.7700E−03S24.5863E−02−1.4180E−021.8750E−03S3−1.5152E+005.7618E−01−8.7480E−02S42.2425E+01−1.4954E+014.2738E+00S5−5.6571E−01−1.4283E+008.4680E−01S63.2825E+00−1.7308E+004.0448E−01S7−9.7928E−01−1.1882E−011.3513E−01S87.5466E−01−2.5232E−013.7370E−02S9−2.7909E+001.1589E+00−1.9827E−01S103.3780E−01−8.1750E−028.8720E−03S11−5.8336E−011.6465E−01−1.9120E−02S12−4.6000E−031.1260E−03−9.0000E−05S13−1.3600E−031.2300E−04−4.7000E−06S14−3.7000E−042.8100E−05−9.1000E−07 Table 21 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 7, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 21f1(mm)4.10f(mm)3.91f2(mm)−15.89TTL(mm)4.81f3(mm)9.80ImgH(mm)3.38f4(mm)−15.37f5(mm)−86.08f6(mm)2.69f7(mm)−1.94 FIG.14Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 7, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.14Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 7, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.14Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 7, representing amounts of distortion at different viewing angles.FIG.14Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 7, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.14A-14Dthat the optical imaging lens assembly according to Embodiment 7 can achieve a good imaging quality. Embodiment 8 An optical imaging lens assembly according to Embodiment 8 of the present disclosure is described below with reference toFIGS.15-16D.FIG.15is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 8 of the present disclosure. As shown inFIG.15, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a convex surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface511of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 22 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 8. The radius of curvature and the thickness are both in millimeters (mm). TABLE 22materialsurfacesurfaceradius ofrefractiveabbeconicnumbertypecurvaturethicknessindexnumbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.66810.67891.5556.1−0.1076S2aspheric6.47000.0977−14.5084STOsphericalinfinite0.0400S3aspheric6.32520.23461.6720.4−13.9417S4aspheric4.17950.2027−7.9043S5aspheric130.23060.45801.5556.199.0000S6aspheric−7.54960.070053.9205S7aspheric−15.37980.26311.6720.499.0000S8aspheric−314.83200.1356−99.0000S9aspheric−8.36010.26621.6720.451.2127S10aspheric−13.44160.1553−78.7624S11aspheric9.91060.46701.5556.144.5943S12aspheric−1.73650.3590−13.4666S13aspheric−3.03540.30831.5455.7−1.3098S14aspheric1.62960.3026−16.7446S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5554S17sphericalinfinite As may be obtained from Table 22, in Embodiment 8, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 23 shows the high-order coefficients applicable to each aspheric surface in Embodiment 8. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 23surfacenumberA4A6A8A10A12A14A16A18A20S1−2.7000E−021.3381E−01−4.7609E−011.0048E+00−1.348E+001.1376E+00−5.8510E−011.6553E−01−1.9570E−02S2−6.0890E−02−4.5000E−051.4826E−01−4.6498E−018.1381E−01−8.9752E−016.0390E−01−2.2540E−013.5723E−02S3−1.3370E−012.4910E−01−9.4772E−013.7054E+00−8.9618E+001.3295E+01−1.1864E+015.8601E+00−1.2288E+00S4−7.0870E−02−9.3510E−021.3573E+00−6.4228E+001.9222E+01−3.6966E+014.4062E+01−2.9617E+018.6336E+00S5−5.5950E−02−1.4029E−017.2036E−01−3.5267E+001.0430E+01−1.9359E+012.2043E+01−1.4172E+014.0089E+00S6−1.3976E−01−1.5729E−011.6681E+00−8.1718E+002.1503E+01−3.3904E+013.2455E+01−1.7436E+014.0322E+00S7−3.0373E−015.7895E−01−1.9464E+004.0577E+00−5.6361E+004.8159E+00−1.5019E+00−8.6748E−015.9068E−01S8−1.8090E−01−2.1730E−012.5574E+00−9.4381E+001.8761E+01−2.2527E+011.6492E+01−6.8388E+001.2376E+00S9−1.6898E−01−2.8920E−021.3734E+00−4.3093E+006.6017E+00−6.2090E+003.9630E+00−1.6668E+003.4116E−01S10−1.8094E−01−1.1353E−017.5605E−011.2196E+005.9388E−014.9136E−01−7.3783E−013.3389E−01−5.3470E−02S11−9.4500E−03−2.5279E−013.0755E−011.1036E−01−8.5286E−011.0697E+00−6.4076E−011.9293E−01−2.3430E−02S12−2.0570E−02−3.7170E−021.7938E−01−2.8558E−012.3254E−01−1.0782E−012.8998E−02−4.2300E−032.6100E−04S13−3.0751E−013.4077E−01−3.1625E−012.3588E−01−1.1315E−013.3205E−02−5.8000E−035.5300E−04−2.2000E−05S14−1.5369E−011.3093E−01−8.9180E−024.3295E−02−1.4420E−023.1540E−03−4.3000E−043.2200E−05−1.0000E−06 Table 24 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 8, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 24f1(mm)3.92f(mm)3.82f2(mm)−19.35TTL(mm)4.70f3(mm)13.09ImgH(mm)3.36f4(mm)−24.30f3(mm)−33.93f6(mm)2.75f7(mm)−1.93 FIG.16Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 8, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.16Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 8, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.16Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 8, representing amounts of distortion at different viewing angles.FIG.16Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 8, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.16A-16Dthat the optical imaging lens assembly according to Embodiment 8 can achieve a good imaging quality. Embodiment 9 An optical imaging lens assembly according to Embodiment 9 of the present disclosure is described below with reference toFIGS.17-18D.FIG.17is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 9 of the present disclosure. As shown inFIG.17, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 25 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 9. The radius of curvature and the thickness are both in millimeters (mm). TABLE 25surfacesurfaceradius ofmaterialnumbertypecurvaturethicknessrefractive indexabbe numberconic coefficientOBJsphericalinfiniteinfiniteS1aspheric1.65620.69381.5556.1−0.1366S2aspheric7.09910.0933−14.5353STOsphericalinfinite0.0400S3aspheric6.65660.23261.6720.43.0678S4aspheric3.99570.2121−3.4649S5aspheric33.38630.45591.5556.199.0000S6aspheric−8.68200.070061.8981S7aspheric−32.64490.24991.6720.422.6435S8aspheric19.52290.1578−49.7187S9aspheric−11.16810.29801.6720.483.6636S10aspheric−16.56670.155714.4277S11aspheric10.11200.45631.5556.144.6883S12aspheric−1.72080.3271−11.4462S13aspheric−3.02260.30091.5455.7−1.3309S14aspheric1.63950.2919−16.1993S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5447S17sphericalinfinite As may be obtained from Table 25, in Embodiment 9, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 26 shows the high-order coefficients applicable to each aspheric surface in Embodiment 9. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 26surfacenumberA4A6A8A10A12A14A16A18A20S1−2.2620E−021.0553E−01−3.7553E−017.8141E−01−1.0466E+008.8543E−01−4.6094E−011.3307E−01−1.6160E−02S2−6.0040E−02−1.0330E−022.0487E−01−6.1586E−011.0285E+00−1.0673E+006.7380E−01−2.3631E−013.5264E−02S3−1.2715E−011.9884E−01−5.0188E−011.9033E+00−4.6772E+006.9937E+00−6.2273E+003.0508E+00−6.3124E−01S4−7.2510E−02−6.9990E−021.4853E+00−7.8475E+002.5424E+01−5.1810E+016.4338E+01−4.4436E+011.3136E+01S5−8.4960E−021.2516E−01−1.1373E+004.4366E+00−1.0823E+011.6138E+01−1.3829E+015.7840E+00−6.4253E−01S6−2.1479E−015.3499E−01−2.4030E+006.3186E+00−1.0998E+011.2640E−01−8.9673E+003.4515E+00−5.3232E−01S7−3.2318E−016.8338E−01−2.2423E+004.2313E+00−4.4320E+001.5752E+001.8228E+00−2.3198E+007.7517E−01S8−2.1930E−012.5688E−013.2200E−03−1.6873E+004.5341E+00−6.1466E+004.7670E+00−2.0287E+003.7102E−01S9−1.7134E−011.2516E−013.4906E−01−1.4318E+002.0855E+00−1.6302E+007.2452E−01−1.7717E−012.0883E−02S10−1.7822E−01−9.1830E−026.9725E−01−1.3950E+001.4778E+00−9.1275E−013.3653E−01−6.9360E−026.1290E−03S11−8.6500E−03−3.7510E−017.9218E−01−9.1083E−014.8218E−01−2.1400E−02−1.0577E−014.9792E−02−7.3900E−03S125.1810E−03−1.4263E−013.5248E−01−4.3468E−013.0218E−01−1.2372E−012.9730E−02−3.9000E−032.1500E−04S13−3.0314E−013.2065E−01−2.7383E−011.9151E−01−8.7630E−022.4717E−02−4.1700E−033.8800E−04−1.5000E−05S14−1.5355E−011.3084E−01−8.7770E−024.1201E−02−1.3150E−022.7380E−03−3.5000E−042.4600E−05−7.0000E−07 Table 27 shows the effective focal lengths f1-f7of the respective lenses in Embodiment 9, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 27f1(mm)3.79f(mm)3.87f2(mm)−15.56TTL(mm)4.69f3(mm)12.67ImgH(mm)3.36f4(mm)−18.32f5(mm)−52.64f6(mm)2.73f7(mm)−1.94 FIG.18Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 9, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.18Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 9, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.18Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 9, representing amounts of distortion at different viewing angles.FIG.18Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 9, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.18A-18Dthat the optical imaging lens assembly according to Embodiment 9 can achieve a good imaging quality. Embodiment 10 An optical imaging lens assembly according to Embodiment 10 of the present disclosure is described below with reference toFIGS.19-20D.FIG.19is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 10 of the present disclosure. As shown inFIG.19, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a concave surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a positive refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 28 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 10. The radius of curvature and the thickness are both in millimeters (mm). TABLE 28surfacesurfaceradius ofmaterialconicnumbertypecurvaturethicknessrefractive indexabbe numbercoefficientOBJsphericalinfiniteinfiniteS1aspheric1.64900.69041.5556.1−0.1181S2aspheric5.91800.1016−15.7506STOsphericalinfinite0.0400S3aspheric5.69830.23001.6720.4−7.0855S4aspheric3.54280.2082−3.9431S5aspheric14.21900.46221.5556.1−23.9406S6aspheric−9.74170.060058.7646S7aspheric−119.89800.24071.6720.499.0000S8aspheric10.09400.1493−70.8319S9aspheric−65.09450.30061.6720.4−99.0000S10aspheric−61.81790.1830−99.0000S11aspheric10.13060.47061.5556.144.5735S12aspheric−1.71830.3213−11.9523S13aspheric−3.02410.30421.5455.7−1.3600S14aspheric1.63940.2907−15.7329S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5435S17sphericalinfinite As may be obtained from Table 28, in Embodiment 10, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 29 shows the high-order coefficients applicable to each aspheric surface in Embodiment 10. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 29surfacenumberA4A6A8A10A12A14A16A18A20S1−1.7380E−027.7566E−02−.2.8554E−016.0469E−01−8.1997E−016.9609E−01−3.6082E−011.0257E−01−1.2110E−02S2−6.2860E−028.9000E−031.1926E−01−3.9342E−016.7405E−01−7.1367E−014.5798E−01−1.6266E−012.4514E−02S3−1.3630E−011.7966E−01−3.1396E−011.1530E+00−2.7793E+003.9676E+00−3.3025E+001.4884E+00−2.7783E−01S4−8.2400E−02−7.8900E−039.9858E−01−5.1836E+001.6731E+01−3.4440E+014.3488E+01−3.0618E+019.2406E+00S5−7.9330E−021.6065E−01−1.4462E+005.8240E+00−1.4636E+012.2568E+01−2.0366E+019.4812E+00−1.5474E+00S6−1.7268E−011.9280E−01−8.8212E−012.0155E+00−2.9087E+002.5489E+00−9.4930E−01−2.0031E−011.8613E−01S7−2.9779E−015.4750E−01−1.8255E+003.8506E+00−5.1559E+004.2182E+00−1.7133E+003.9857E−021.2704E−01S8−2.1558E−013.6186E−01−6.5395E−016.2028E−01−1.7674E−01−3.1684E−013.9401E−01−1.8547E−013.5077E−02S9−1.8084E−011.1928E−013.7779E−01−1.6145E+002.6698E+00−2.5092E+001.3608E+00−3.7886E−013.9035E−02S10−1.9847E−016.1582E−021.3811E−01−3.1057E−012.4267E−01−6.3750E−02−5.2000E−033.5010E−03−6.2000E−05S11−2.3980E−02−2.1877E−013.5142E−01−2.6565E−01−5.8380E−022.3261E−01−1.5984E−014.8651E−02−5.7000E−03S12−1.9100E−02−4.3450E−021.6225E−01−2.2485E−011.6350E−01−6.8010E−021.6380E−02−2.1400E−031.1700E−04S13−3.0199E−013.1892E−01−2.7941E−012.0261E−01−9.5650E−022.7733E−02−4.8100E−034.5900E−04−1.9000E−05S14−1.5254E−011.2322E−01−7.6850E−023.3295E−02−9.7300E−031.8120E−03−2.0000E−041.0400E−05−1.3000E−07 Table 30 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 10, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 30f1(mm)3.96f(mm)3.89f2(mm)−14.69TTL(mm)4.71f3(mm)10.66ImgH(mm)3.34f4(mm)−13.97f5(mm)1779.54f6(mm)2.73f7(mm)−1.94 FIG.20Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 10, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.20Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 10, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.20Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 10, representing amounts of distortion at different viewing angles.FIG.20Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 10, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.20A-20Dthat the optical imaging lens assembly according to Embodiment 10 can achieve a good imaging quality. Embodiment 11 An optical imaging lens assembly according to Embodiment 11 of the present disclosure is described below with reference toFIGS.21-22D.FIG.21is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 11 of the present disclosure. As shown inFIG.21, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a convex surface. The fourth lens E4has a negative refractive power, an object-side surface S7of the fourth lens E4is a convex surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 31 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 11. The radius of curvature and the thickness are both in millimeters (mm). TABLE 31surfacesurfaceradius ofmaterialnumbertypecurvaturethicknessrefractive indexabbe numberconic coefficientOBJsphericalinfiniteinfiniteS1aspheric1.64120.69861.5556.1−0.1192S2aspheric5.75800.1026−16.4815STOsphericalinfinite0.0400S3aspheric5.42840.23001.6720.4−7.9765S4aspheric3.45840.2055−3.4895S5aspheric13.06460.44711.5556.137.5886S6aspheric−17.90560.0650−99.0000S7aspheric39.54400.27931.6720.4−62.8799S8aspheric16.36020.173747.7653S9aspheric−12.15470.26921.6720.487.3608S10aspheric−18.74590.1845−64.7304S11aspheric10.58420.49781.5556.141.4357S12aspheric−1.71310.2741−11.0587S13aspheric−3.00500.30661.5455.7−1.3581S14aspheric1.61210.2976−15.7143S15sphericalinfinite0.11001.5264.2S16sphericalinfinite0.5504S17sphericalinfinite As may be obtained from Table 31, in Embodiment 11, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 32 shows the high-order coefficients applicable to each aspheric surface in Embodiment 11. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 32surfacenumberA4A6A8A10A12A14A16A18A20S1−1.6240E−027.0344E−02−2.6148E−015.4968E−01−7.3946E−016.2268E−01−3.2092E−019.0937E−02−1.0720E−02S2−6.3190E−021.1604E−029.7205E−02−3.2132E−015.4132E−01−5.6494E−013.5854E−01−1.2624E−011.8889E−02S3−1.3608E−011.8562E−01−3.9985E−011.5701E+00−3.8963E+005.7667E+00−5.0323E+002.4024E+00−4.8255E−01S4−7.9540E−02−2.5910E−021.0713E+00−5.2608E+001.6271E+01−3.2328E+013.9608E+01−2.7157E+018.0043E+00S5−7.9240E−021.6525E−01−1.3571E+005.3378E+00−1.1373E+012.0927E+01−1.9571E+019.7706E+00−1.8691E+00S6−2.2401E−014.2030E−01−1.9596E+005.6196E+00−1.0869E+011.3811E+01−1.0781E+014.6252E+00−8.3228E−01S7−3.0103E−015.6466E−01−1.9663E+004.6390E+00−7.4520E+007.9855E+00−5.2942E+001.9057E+00−2.8973E−01S8−1.8959E−012.3251E−01−2.5152E−01−1.8550E−019.5978E−01−1.4359E+001.1311E+00−4.7758E−018.6829E−02S9−1.6698E−011.0682E−012.8352E−01−1.0654E+001.4622E+00−1.0733E+003.9277E−01−3.5080E−02−1.0150E−02S10−1.9234E−015.4477E−021.6822E−01−3.5857E−012.9158E−01−1.0800E−012.5089E−02−8.2900E−031.8160E−03S11−2.3410E−02−2.4441E−014.9879E−01−6.3858E−014.9699E−01−2.6359E−011.0016E−01−2.4950E−022.9750E−03S12−3.1300E−03−8.8940E−022.015311−01−2.2562E−011.4146E−01−5.1430E−021.0732E−02−1.1900E−035.3100E−05S13−3.0455E−013.1545E−01−2.6327E−011.8306E−01−8.3550E−022.3428E−02−3.9200E−033.6000E−04−1.4000E−05S14−1.5685E−011.3077E−01−8.3160E−023.6409E−02−1.0670E−021.9720E−03−2.1000E−049.9900E−06−5.5000E−08 Table 33 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 11, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 33f1(mm)3.97f(mm)3.95f2(mm)−15.02TTL(mm)4.73f3(mm)13.91ImgH(mm)3.35f4(mm)−42.12f5(mm)−52.79f6(mm)2.74f7(mm)−1.91 FIG.22Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 11, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.22Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 11, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.22Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 11, representing amounts of distortion at different viewing angles.FIG.22Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 11, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.22A-22Dthat the optical imaging lens assembly according to Embodiment 11 can achieve a good imaging quality. Embodiment 12 An optical imaging lens assembly according to Embodiment 12 of the present disclosure is described below with reference toFIGS.23-24D.FIG.23is a schematic structural diagram illustrating the optical imaging lens assembly according to Embodiment 12 of the present disclosure. As shown inFIG.23, the optical imaging lens assembly according to the exemplary embodiments of the present disclosure includes, sequentially from an object side to an image side along an optical axis, a first lens E1, a diaphragm STO, a second lens E2, a third lens E3, a fourth lens E4, a fifth lens E5, a sixth lens E6, a seventh lens E7, an optical filter E8, and an image plane S17. The first lens E1has a positive refractive power, an object-side surface S1of the first lens E1is a convex surface, and an image-side surface S2of the first lens E1is a concave surface. The second lens E2has a negative refractive power, an object-side surface S3of the second lens E2is a convex surface, and an image-side surface S4of the second lens E2is a concave surface. The third lens E3has a positive refractive power, an object-side surface S5of the third lens E3is a convex surface, and an image-side surface S6of the third lens E3is a concave surface. The fourth lens E4has a positive refractive power, an object-side surface S7of the fourth lens E4is a convex surface, and an image-side surface S8of the fourth lens E4is a concave surface. The fifth lens E5has a negative refractive power, an object-side surface S9of the fifth lens E5is a concave surface, and an image-side surface S10of the fifth lens E5is a convex surface. The sixth lens E6has a positive refractive power, an object-side surface S11of the sixth lens E6is a convex surface, and an image-side surface S12of the sixth lens E6is a convex surface. The seventh lens E7has a negative refractive power, an object-side surface S13of the seventh lens E7is a concave surface, and an image-side surface S14of the seventh lens E7is a concave surface. The optical filter E8has an object-side surface S15and an image-side surface S16. Light from an object sequentially passes through the surfaces S1-S16and finally forms an image on the image plane S17. Table 34 shows the surface type, the radius of curvature, the thickness, the material and the conic coefficient of each lens of the optical imaging lens assembly in Embodiment 12. The radius of curvature and the thickness are both in millimeters (mm). TABLE 34surfacesurfaceradius ofmaterialnumbertypecurvaturethicknessrefractive indexabbe numberconic coefficientOBJsphericalinfiniteinfiniteS1aspheric1.63680.69781.5556.1−0.1191S2aspheric5.72980.1028−16.7004STOsphericalinfinite0.0400S3aspheric5.39500.23001 .6720.4−7.9391S4aspheric3.40310.2045−3.1585S5aspheric11.97680.42731.5556.133.1956S6aspheric100.00000.0650−99.0000S7aspheric11.02780.27831.6720.4−35.9270S8aspheric15.40040.179389.0948S9aspheric−12.67490.26101.6720.487.5077S10aspheric−20.92260.1963−99.0000S11aspheric10.31940.50211.5556.142.4025S12aspheric−1.71450.2653−10.9203S13aspheric−3.00090.30301.5455.7−1.3538S14aspheric1.59360.2901−15.6887S15sphericalinfinite0.11001.5764.2S16sphericalinfinite0.5429S17sphericalinfinite As may be obtained from Table 34, in Embodiment 12, the object-side surface and the image-side surface of any lens among the first to seventh lenses E1-E7are both aspheric surfaces. Table 35 shows the high-order coefficients applicable to each aspheric surface in Embodiment 12. The surface type of each aspheric surface may be defined by the formula (1) given in Embodiment 1. TABLE 35surfacenumberA4A6A8A10A12A14A16A18A20S1−1.4420E−025.8328E−02−2.2036E−014.6401E−01−6.2591E−015.2639E−01−2.7046E−017.6127E−02−8.8700E−03S2−6.3200E−021.0365E−021.0113E−01−3.3138E−015.6127E−01−5.8938E−013.7619E−01−1.3319E−012.0041E−02S3−1.3583E−011.8423E−01−3.9722E−011.5816E+00−3.9708E+005.9412E+00−5.2412E+002.5294E+00−5.1357E−01S4−7.9920E−02−3.6300E−038.8641E−01−4.3594E+001.3594E+01−2.7436E+013.4222E+01−2.3885E+017.1622E+00S5−7.7760E−021.3463E−01−1.1467E+004.5245E+00−1.1454E+011.8127E+01−1.7135E+018.6299E+00−1.6539E+00S6−2.4825E−015.5658E−01−2.5078E+007.0824E+00−1.3517E+011.6976E+01−1.3167E+015.6618E+00−1.0329E+00S7−3.1361E−017.0620E−01−2.7089E+007.0846E+00−1.2641E+011.5041E+01−1.1275E+014.8087E+00−9.1042E−01S8−1.7584E−011.5842E−01−7.0100E−03−7.5617E−011.9530E+00−2.6181E+002.0132E+00−8.4612E−011.5239E−01S9−1.7130E−011.4790E−013.4917E−02−4.1790E−015.6992E−01−3.63371E−016.7390E−024.1375E−02−1.6240E−02S10−1.9690E−011.1871E−01−7.6880E−021.2201E−01−2.5342E−012.6379E−01−1.2553E−012.4995E−02−1.2500E−03S11−3.3320E−02−1.6708E−012.8210E−01−2.9849E−011.7105E−01−6.2290E−022.0035E−02−5.9200E−039.1100E−04S12−5.3000E−03−7.0400E−021.4942E−01−1.5643E−019.0951E−02−2.9930E−025.4000E−03−4.7000E−041.2800E−05S13−3.0506E−013.1576E−01−2.6300E−011.8255E−01−8.3170E−022.3271E−02−3.8800E−033.5600E−04−1.4000E−05S14−1.5689E−011.2924E−01−7.995013−023.3529E−02−9.2200E−031.5290E−03−1.3000E−041.8700E−062.8900E−07 Table 36 shows the effective focal lengths f1-f7 of the respective lenses in Embodiment 12, the total effective focal length f of the optical imaging lens assembly, the total track length TTL of the optical imaging lens assembly, and the half of the diagonal length ImgH of the effective pixel area on the image plane S17of the optical imaging lens assembly. TABLE 36f1(mm)3.96f(mm)3.91f2(mm)−14.51TTL(mm)4.70f3(mm)24.88ImgH(mtn)3.35f4(mm)56.90f5(mm)−48.92f6(mm)2.73f7(mm)−1.90 FIG.24Aillustrates the longitudinal aberration curve of the optical imaging lens assembly according to Embodiment 12, representing deviations of focal points of light of different wavelengths converged after passing through the lens assembly.FIG.24Billustrates the astigmatic curve of the optical imaging lens assembly according to Embodiment 12, representing a curvature of the tangential image plane and a curvature of the sagittal image plane.FIG.24Cillustrates the distortion curve of the optical imaging lens assembly according to Embodiment 12, representing amounts of distortion at different viewing angles.FIG.24Dillustrates the lateral color curve of the optical imaging lens assembly according to Embodiment 12, representing deviations of different image heights on the image plane after light passes through the lens assembly. It can be seen fromFIGS.24A-24Dthat the optical imaging lens assembly according to Embodiment 12 can achieve a good imaging quality. To sum up, Embodiments 1-12 respectively satisfy the relationships shown in Table 37 below. TABLE 37ConditionalEmbodimentExpression123456789101112f/EPD1.581.601.611.651.691.621.671.741.741.751.761.75|f12/f34|0.060.180.190.200.200.190.200.160.120.120.240.28f2/f74.948.498.478.317.757.938.1810.028.037.597.867.66R1/R40.630.480.460.480.480.440.470.400.410.470.470.48R12/R14−0.88−0.98−1.02−1.01−1.02−1.07−1.02−1.07−1.05−1.05−1.06−1.08TTL/ImgH1.481.441.441.441.431.441.421.401.401.411.411.40f/f7−1.99−2.02−2.01−2.01−2.04−2.03−2.01−1.98−2.00−2.01−2.07−2.06CT6 (mm)0.610.500.490.520.490.490.490.470.460.470.500.50f1/R12.202.452.512.372.422.552.442.352.292.402.422.42CT1/f2−0.08−0.05−0.05−0.05−0.05−0.05−0.05−0.04−0.04−0.05−0.05−0.05f6/f7−1.08−1.37−1.37−1.40−1.39−1.38−1.39−1.42−1.41−1.41−1.43−1.44f7/R14−1.28−1.14−1.17−1.15−1.16−1.20−1.16−1.19−1.18−1.18−1.19−1.19f6/f30.380.230.240.240.270.110.270.210.220.260.200.11 The present disclosure further provides an imaging device having a photosensitive element which may be a photosensitive charge-coupled device (CCD) or complementary metal-oxide semiconductor (CMOS) element. The imaging device may be an independent imaging device such as a digital camera, or may be an imaging module integrated in a mobile electronic device such as a mobile phone. The imaging device is equipped with the optical imaging lens assembly described above. The foregoing is only a description for the preferred embodiments of the present disclosure and the applied technical principles. It should be appreciated by those skilled in the art that the inventive scope of the present disclosure is not limited to the technical solution formed by the particular combinations of the above technical features. The inventive scope should also cover other technical solutions formed by any combinations of the above technical features or equivalent features thereof without departing from the concept of the invention, for example, technical solutions formed by replacing the features as disclosed in the present disclosure with (but not limited to) technical features with similar functions. | 100,272 |
RE49790 | DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS To make the objectives, technical solutions, and advantages of the embodiments clearer, the following clearly describes the technical solutions in the embodiments with reference to the accompanying drawings in the embodiments. Apparently, the described embodiments are some but not all of the embodiments. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments without creative efforts shall fall within the protection scope. An MSA solution may include a packet-based architecture and a radio access bearer-based (RAB based) architecture, the packet-based architecture is a 3C architecture for short, and the RAB-based architecture is a 1A architecture for short. In the 3C architecture, UE establishes a control plane connection only with a master evolved eNodeB (MeNB) serving the UE, only a MeNB establishes a control plane connection with a core network node, and only the MeNB establishes a user-plane data connection with the core network node. There is no connection between each secondary evolved eNodeB (SeNB) serving the UE and the core network node, and the SeNB exchanges data with the MeNB. That is, in the 3C architecture, only the MeNB performs signaling and data exchange with the core network node, and both data sent by the SeNB to a core network and data sent from the core network to the SeNB need to be forwarded by the MeNB. In the 1A architecture, a user equipment (UE) establishes a control plane connection only with an MeNB serving the UE, only an MeNB establishes a control plane connection with a core network node, and there is a user-plane data connection between the core network node and each of the MeNB and the SeNB. However, one service is transmitted on only one MeNB or SeNB. A system architecture evolution system is used as an example. In the 3C architecture, signaling exchange is performed only between an MeNB and a mobility management entity (MME), and data exchange is performed only between an MeNB and a serving gateway (S-GW). In the 1A architecture, signaling exchange is performed only between an MeNB and an MME, but data exchange is performed between an S-GW and each of an MeNB and an SeNB. Location information of UE in a network is obtained based on serving cell information of an eNB serving the UE, and location information of the UE may be transmitted to a core network node in an attach procedure, a tracking area update (TAU), a routing area update (RAU) procedure, or a service request procedure. In the MSA solution, only the MeNB establishes the control plane connection with the core network node in both the 3C architecture and the 1A architecture, and the location information of the UE is transmitted to the core network node by means of signaling in each procedure. Therefore, the core network node can receive only serving cell information of the MeNB that is sent by the MeNB. That is, in the MSA solution, the location information of the UE is obtained based on the serving cell information of the MeNB serving the UE. However, in the MSA solution, one MeNB and one or more SeNBs simultaneously provide services for the UE. Therefore, that only the serving cell information of the MeNB is reported to the core network node makes the location information of the UE not accurate enough. An operator providing a network service may perform control such as charging control, rate control, and priority control on the UE according to the location information of the UE. Therefore, if the location information of the UE is not accurate enough, control with a finer granularity cannot be performed on the UE. It should be noted that a method for reporting location information of user equipment, and an apparatus that are provided in the present embodiments are applicable not only to the system architecture evolution (SAE) system, but also to another network communications system such as a Universal Mobile Telecommunications System (UMTS). A difference is that different communications systems have different network architectures, but in the communications systems, the method provided in the embodiments may be used to report the location information of the user equipment. In the following embodiments, the SAE system architecture is used as an example to describe the method for reporting location information of user equipment provided in the present embodiments. In addition, in the embodiments, the MeNB and the SeNB may be separately an access node in any form. For example, the MeNB and the SeNB are respectively a macro eNB and a pico eNB in a same system, or both the MeNB and the SeNB are a macro eNB in a same system, or the MeNB and the SeNB are access point (AP) on an eNB and in a wireless local area network (WLAN) respectively. The MeNB and the SeNB only need to simultaneously provide services for the UE. FIG.1is a schematic structural diagram of Embodiment 1 of a master access node according to an embodiment. As shown inFIG.1, the master access node in this embodiment includes: an obtaining module11and a sending module12. The obtaining module11is configured to obtain location information of user equipment, where the location information of the user equipment includes serving cell information of at least one secondary access node of the user equipment. Specifically, the MeNB provided in this embodiment is configured to report the location information of the UE to a core network node, the MeNB provides a service for the UE, and the at least one SeNB also provides a service for the UE. The location information of the UE reflects a location of the UE, and generally, a coverage area of a serving cell of an MeNB is larger than a coverage area of a serving cell of an SeNB. Therefore, if the core network node obtains serving cell information of an SeNB serving the UE, a more accurate location of the UE is obtained. In this way, in comparison with a case in which only serving cell information of the MeNB is reported to the core network node, when the serving cell information of the SeNB serving the UE is also reported to the core network node, the core network node obtains location information of the UE with a finer granularity. Therefore, the MeNB provided in this embodiment includes the obtaining module11, and the obtaining module11is configured to obtain the location information of the UE, where the location information of the UE includes the serving cell information of the at least one SeNB of the UE. The serving cell information of the SeNB may be any information that can represent a feature of the SeNB. The obtaining module11may obtain the serving cell information of the SeNB by means of data exchange between the MeNB and the SeNB, or the obtaining module11may obtain the serving cell information of the SeNB by using information reported by the UE to the MeNB. The sending module12is configured to send the location information of the user equipment to a core network node, where the location information is used by the core network node to determine a control policy for the user equipment. Specifically, after the obtaining module11obtains location information of the UE, the sending module12sends the location information to the core network node. An SAE system is used as an example. The core network node includes an MME, an S-GW, a packet gateway (P-GW), a policy control and charging rules function (PCRF), and the like, the MME establishes a control plane connection with the MeNB, and the S-GW establishes a user-plane data connection with the MeNB. The sending module12may send the location information of the UE to the MME or the S-GW, the MME or the S-GW sends the location information of the UE to the PCRF by using the P-GW, and the PCRF configures different charging or control policies for the UE according to different location information of the UE, and sends the configured charging or control policies to an execution entity such as a policy and charging enforcement function (PCEF) entity or a bearer binding and event report function (BBERF), so as to perform corresponding control on the UE. Because the location information of the UE includes the serving cell information of the at least one SeNB of the UE, the core network node may obtain a more accurate location of the UE according to the location information, so as to formulate a control policy with a finer granularity for the UE. Because there is the control plane connection and the user-plane data connection between the MeNB and the core network node, the sending module12may send the location information of the UE to the core network node by means of control plane signaling, or the sending module12may send the location information of the UE to the core network node by using a user plane packet. In this embodiment, an MeNB obtains serving cell information of at least one SeNB of UE, and sends the information to a core network node, so that the core network node can implement control with a finer granularity over the UE. For two architectures in an MSA solution, the master access node shown inFIG.1performs different specific processing methods, which are described in detail in the following. In a 1A architecture, the MeNB and the SeNB separately establish a user-plane data connection with the core network node, that is, the MeNB and the SeNB separately establish a bearer with the core network node. Therefore, when the SeNB needs to provide a service for the UE, the sending module12in the MeNB may send a radio access bearer modification instruction message to the core network node, and the radio access bearer modification instruction message includes the location information of the UE. In this way, the location information of the UE may be sent to the core network node without a need of changing an existing signaling procedure. In this case, the serving cell information of the at least one SeNB of the UE includes: any one or more of identification information of a serving cell of the at least one SeNB of the UE, bearer information corresponding to a serving cell of the at least one SeNB of the UE, a tracking area identity of a serving cell of the at least one SeNB of the UE, or an access network type of a serving cell of the at least one SeNB of the UE. The SAE system is used as an example to describe the foregoing processing of the MeNB.FIG.2is a signaling flowchart of reporting location information by using a bearer modification procedure in an SAE system. As shown inFIG.2, an MME, an S-GW, a P-GW, and a PCRF in the SAE system are collectively referred to as a core network node. When an SeNB in a network starts to serve UE, an MeNB needs to notify the SeNB of related information such as network configuration, and in step S201, the MeNB may obtain serving cell information of the SeNB. The serving cell information of the SeNB may be any information that can represent a serving cell that is of the SeNB and that serves the UE, for example, any one or more of identification information of the serving cell of the SeNB, bearer information corresponding to the serving cell of the SeNB, a tracking area identity of the serving cell of the SeNB, or an access network type of the serving cell of the SeNB. The SeNB is newly added to serve the UE, bearer information of the UE changes, the SeNB needs to establish a bearer with each node in a core network, and there is no control plane connection between the SeNB and the MME. Therefore, in step S202, the MeNB needs to send an evolved packet system RAB (E-RAB) modification instruction message to the MME, to instruct the MME to modify the bearer information of the UE. The E-RAB modification instruction message carries location information of the UE. In this embodiment, only one MeNB and only one SeNB serve the UE, and serving cell information of the MeNB may be sent to the MME when the MeNB establishes a bearer with each node in the core network. Therefore, in this embodiment, the location information of the UE may include only the serving cell information of the SeNB, or the location information of the UE may include both the serving cell information of the MeNB and the serving cell information of the SeNB. After receiving the E-RAB modification instruction message, in step S203, the MME sends a bearer modification request message including the location information of the UE to the S-GW. In step S204, the S-GW sends, as required, the bearer modification request message including the location information of the UE to the P-GW. After receiving the location information of the UE, the P-GW sends the location information of the UE to the PCRF as required, and the PCRF determines a control policy for the UE according to the location information of the UE. A correspondence between the location information of the UE and the control policy for the UE may be preset in the PCRF, and after receiving the location information of the UE, the PCRF may determine the control policy for the UE. Alternatively, a rule for setting the control policy for the UE may be preset in the PCRF, and after receiving the location information of the UE, the PCRF may determine the control policy for the UE according to the preset rule. The control policy for the UE may include any one or more of a charging control policy for the UE, a rate control policy for the UE, a quality of service control policy for the UE, or a priority control policy for the UE. That is, the PCRF may formulate different control policies for the UE according to the location information of the UE, so as to control the UE from multiple aspects. After determining the control policy for the UE, the PCRF sends the control policy to a corresponding execution entity such as a PCEF or a BBERF, and each execution entity performs corresponding control on the UE according to the control policy sent by the PCRF. It should be noted that, if at least two SeNBs simultaneously provide services for the UE, the MeNB only needs to send serving cell information of any one or more SeNBs to the core network node, or the MeNB may send serving cell information of all SeNBs of the UE to the core network node. In a 3C architecture, because only the MeNB establishes a control plane connection and a user-plane data connection with the core network node, when the SeNB needs to provide a service for the UE, the sending module12in the MeNB also needs to report the location information of the UE to the core network node. However, because there is no bearer between the SeNB and the core network node, the sending module12cannot send the location information of the UE to the core network node by using a radio access bearer modification instruction message. A new control plane message may be defined herein, which is referred to as a location information update message. The location information update message is used to send the location information of the UE to the core network node when the location information of the UE changes. In this case, the serving cell information of the at least one SeNB of the UE includes: any one or more of identification information of a serving cell of the at least one SeNB of the UE, a quantity of data packets or data packets transmitted in a serving cell of the at least one SeNB of the UE, a tracking area identity of a serving cell of the at least one SeNB of the UE, or an access network type of a serving cell of the at least one SeNB of the UE. Alternatively, the serving cell information of the at least one SeNB of the UE includes multi-stream indication information, where the multi-stream indication information is used to indicate that at least two access nodes provide services for the UE. The SAE system is used as an example. In the 3C architecture, a signaling procedure for location information reporting is similar to that ofFIG.2, and a difference is only that the E-RAB modification instruction message is changed into the location information update message.FIG.3is a signaling flowchart of reporting location information by using a location information update procedure in an SAE system. As shown inFIG.3, an MME, an S-GW, a P-GW, and a PCRF in the SAE system are collectively referred to as a core network node. When an SeNB in a network starts to serve UE, an MeNB provides data forwarding for the SeNB, all data packets or data packets sent and received by the SeNB need to be forwarded by the MeNB, and in step S301, the MeNB may obtain serving cell information of the SeNB. The serving cell information of the SeNB may be any information that can represent a serving cell that is of the SeNB and that serves the UE, for example, any one or more of identification information of the serving cell of the SeNB, a quantity of data packets or data packets transmitted in the serving cell of the SeNB, a tracking area identity of the serving cell of the SeNB, or an access network type of the serving cell of the SeNB. Alternatively, the serving cell information of the SeNB may include multi-stream indication information. A difference between the embodiments shown inFIG.3andFIG.2is that the serving cell information of the SeNB of the UE inFIG.2includes the bearer information corresponding to the serving cell of the SeNB, but the serving cell information of the SeNB of the UE inFIG.3includes the quantity of data packets or data packets transmitted in the serving cell of the SeNB. This is because the SeNB establishes a bearer with the core network node inFIG.2, and the MeNB may obtain the serving cell information of the SeNB; but there is no bearer between the SeNB and the core network node inFIG.3, all data packets or data packets of the SeNB need to be forwarded by the MeNB, and the MeNB may obtain only the quantity of data packets or data packets transmitted in the serving cell of the SeNB. In addition, the multi-stream indication information indicates that at least two access nodes provide services for the UE, that is, when the MeNB learns that at least one SeNB also serves the UE, the MeNB may determine that the at least two access nodes provide the services for the UE. In step S302, the MeNB needs to send a location information update message to the MME, and send the location information of the UE to the MME, and the location information update message is used to send only the location information of the UE to the MME. In this embodiment, only one MeNB and only one SeNB serve the UE, and serving cell information of the MeNB may be sent to the MME when the MeNB establishes a bearer with each node in a core network. Therefore, in this embodiment, the location information of the UE may include only the serving cell information of the SeNB, or the location information of the UE may include both the serving cell information of the MeNB and the serving cell information of the SeNB. After receiving the location information update message, in step S303, the MME sends the location information update message including the location information of the UE to the S-GW. In step S304, the S-GW sends, as required, the location information update message including the location information of the UE to the P-GW. After receiving the location information of the UE, the P-GW sends the location information of the UE to the PCRF as required, and the PCRF determines a control policy for the UE according to the location information of the UE. A correspondence between the location information of the UE and the control policy for the UE may be preset in the PCRF, and after receiving the location information of the UE, the PCRF may determine the control policy for the UE. Alternatively, a rule for setting the control policy for the UE may be preset in the PCRF, and after receiving the location information of the UE, the PCRF may determine the control policy for the UE according to the preset rule. The control policy for the UE may include any one or more of a charging control policy for the UE, a rate control policy for the UE, a quality of service control policy for the UE, or a priority control policy for the UE. That is, the PCRF may formulate different control policies for the UE according to the location information of the UE, so as to control the UE from multiple aspects. After determining the control policy for the UE, the PCRF sends the control policy to a corresponding execution entity such as a PCEF or a BBERF, and each execution entity performs corresponding control on the UE according to the control policy sent by the PCRF. In addition, after receiving the location information update message, the P-GW may further send a reception confirmation message to the S-GW, and after receiving the reception confirmation message, the S-GW may further send the reception confirmation message to the MME. It should be noted that, if at least two SeNBs simultaneously provide services for the UE, the MeNB only needs to send serving cell information of any one or more SeNBs to the core network node, or the MeNB may send serving cell information of all SeNBs of the UE to the core network node. Another specific method for reporting location information of UE is in a 3C architecture. In the 3C architecture, because only the MeNB establishes a control plane connection and a user-plane data connection with the core network node, when the SeNB needs to provide a service for the UE, the sending module12in the MeNB also needs to report the location information of the UE to the core network node. However, the sending module12does not send the location information of the UE to the core network node by using a signaling message herein, but sends the location information of the UE to the core network node by using a user-plane data packet. In this case, the serving cell information of the at least one SeNB of the UE includes: any one or more of identification information of a serving cell of the at least one SeNB of the UE, a quantity of data packets or data packets transmitted in a serving cell of the at least one SeNB of the UE, a tracking area identity of a serving cell of the at least one SeNB of the UE, or an access network type of a serving cell of the at least one SeNB of the UE. The SAE system is used as an example, and the MME, the S-GW, the P-GW, and the PCRF in the SAE system are collectively referred to as the core network node. In the 3C architecture, a first general packet radio service (GPRS) tunneling protocol-user plane (GTP-U) packet sent by the MeNB to the S-GW includes the location information of the UE, where the location information of the UE may be in an extension header of the first GTP-U packet; or, a second GTP-U packet sent by the MeNB to the S-GW includes the location information of the UE, where the second GTP-U packet is a newly-added packet, and the packet is used to send only the location information of the user equipment. A specific method for obtaining location information of UE by an MeNB is the same as that of step S301. After receiving the location information of the UE by using a GTP-U packet, the S-GW sends the location information of the UE to the P-GW, the P-GW may further send the location information of the UE to the PCRF, and the PCRF may determine the control policy for the UE according to the location information of the UE. Exchange processes between the S-GW, the P-GW, and the PCRF are similar to those ofFIG.2and ofFIG.3. Details are not described herein. FIG.4is a schematic structural diagram of Embodiment 1 of a core network node according to an embodiment. As shown inFIG.4, the core network node in this embodiment includes: a receiving module41and a processing module42. The receiving module41is configured to receive location information of user equipment that is sent by a master access node, where the location information of the user equipment includes serving cell information of at least one secondary access node of the user equipment. Specifically, all nodes in a core network are collectively referred to as the core network node in this embodiment. For example, for an SAE system, the core network node includes an MME, an S-GW, a P-GW, a PCRF, and the like. The core network node includes the receiving module41, and the receiving module41may be disposed on any core network node as long as the receiving module41can receive the location information of the UE that is sent by the MeNB. The MeNB in this embodiment provides a service for the UE, and the at least one SeNB also provides a service for the UE. The location information of the UE reflects a location of the UE, and generally, a coverage area of a serving cell of an MeNB is larger than a coverage area of a serving cell of an SeNB. Therefore, if the core network node obtains serving cell information of an SeNB serving the UE, a more accurate location of the UE is obtained. In this way, in comparison with a case in which serving cell information of the MeNB is reported to the core network node, when the serving cell information of the SeNB serving the UE is reported to the core network node, the core network node obtains location information of the UE with a finer granularity. Therefore, the core network node provided in this embodiment includes the receiving module41, the receiving module41is configured to receive the location information of the user equipment that is sent by the MeNB, and the location information of the UE includes the serving cell information of the at least one SeNB of the UE. The serving cell information of the SeNB may be any information that can represent a feature of the SeNB. Because there is a control plane connection and a user-plane data connection between the MeNB and the core network node, the receiving module41may receive the location information of the UE that is sent by the MeNB by means of control plane signaling, or the receiving module41may receive the location information of the UE that is sent by the MeNB by using a user plane packet. The processing module42is configured to determine a control policy for the user equipment according to the location information of the user equipment. Specifically, the core network node provided in this embodiment further includes the processing module42, and the processing module42is configured to determine the control policy for the UE according to the location information of the UE. Because the location information of the UE includes the serving cell information of the at least one SeNB of the UE, the processing module42may obtain a more accurate location of the UE according to the location information, so as to formulate a control policy with a finer granularity for the UE. The processing module42may be disposed on any node that is in the core network node and that can determine the control policy for the UE, for example, the PCRF in the SAE system. The PCRF configures different charging or control policies for the UE according to different location information of the UE, and sends the configured charging or control policies to an execution entity such as a PCEF or a BBERF, so as to perform corresponding control on the UE. In this embodiment, an MeNB obtains serving cell information of at least one SeNB of UE, and sends the information to a core network node, so that the core network node can implement control with a finer granularity over the UE. For two architectures in the MSA solution, the core network node shown inFIG.4performs different specific processing methods, which are described in detail in the following. In a 1A architecture, the MeNB and the SeNB separately establish a user-plane data connection with the core network node, that is, the MeNB and the SeNB separately establish a bearer with the core network node. When the SeNB needs to provide a service for the UE, the receiving module41in the core network node may receive a radio access bearer modification instruction message sent by the MeNB, and the radio access bearer modification instruction message includes the location information of the UE. In this way, the location information of the UE that is sent by the MeNB may be received without a need of changing an existing signaling procedure. In this case, the serving cell information of the at least one SeNB of the UE includes: any one or more of identification information of a serving cell of the at least one SeNB of the UE, bearer information corresponding to a serving cell of the at least one SeNB of the UE, a tracking area identity of a serving cell of the at least one SeNB of the UE, or an access network type of a serving cell of the at least one SeNB of the UE. The SAE system is used as an example, and the MME, the S-GW, the P-GW, and the PCRF in the SAE system are collectively referred to as the core network node. The receiving module41is disposed in the MME, and the processing module42is disposed in the PCRF. For a specific method for reporting location information of UE, refer toFIG.2. In a 3C architecture, because only the MeNB establishes a control plane connection and a user-plane data connection with the core network node, when the SeNB needs to provide a service for the UE, the receiving module41in the core network node also needs to receive the location information of the UE that is reported by the MeNB. However, because there is no bearer between the SeNB and the core network node, in this case, the receiving module41cannot receive, by using the radio access bearer modification instruction message, the location information of the UE that is sent by the MeNB. A new control plane message may be defined herein, which is referred to as a location information update message. The location information update message is used to send the location information of the UE to the core network node when the location information of the UE changes. In this case, the serving cell information of the at least one SeNB of the UE includes: any one or more of identification information of a serving cell of the at least one SeNB of the UE, a quantity of data packets or data packets transmitted in a serving cell of the at least one SeNB of the UE, a tracking area identity of a serving cell of the at least one SeNB of the UE, or an access network type of a serving cell of the at least one SeNB of the UE. Alternatively, the serving cell information of the at least one SeNB of the UE includes multi-stream indication information, where the multi-stream indication information is used to indicate that at least two access nodes provide services for the UE. The SAE system is used as an example, and the MME, the S-GW, the P-GW, and the PCRF in the SAE system are collectively referred to as the core network node. The receiving module41is disposed in the S-GW, and the processing module42is disposed in the PCRF. For a specific method for reporting location information of UE, refer toFIG.3. Another specific method for reporting location information of UE is in a 3C architecture. In the 3C architecture, because only the MeNB establishes a control plane connection and a user-plane data connection with the core network node, when the SeNB needs to provide a service for the UE, the receiving module41on the core network node may receive, by using a user-plane data packet, the location information of the UE that is sent by the MeNB. In this case, the serving cell information of the at least one SeNB of the UE includes: any one or more of identification information of a serving cell of the at least one SeNB of the UE, a quantity of data packets or data packets transmitted in a serving cell of the at least one SeNB of the UE, a tracking area identity of a serving cell of the at least one SeNB of the UE, or an access network type of a serving cell of the at least one SeNB of the UE. The SAE system is used as an example, and the MME, the S-GW, the P-GW, and the PCRF in the SAE system are collectively referred to as the core network node. The receiving module41is disposed in the S-GW, and the processing module42is disposed in the PCRF. A first GTP-U packet sent by the MeNB includes the location information of the UE, where the location information of the UE may be in an extension header of the first GTP-U packet; or, a second GTP-U packet sent by the MeNB includes the location information of the UE, where the second GTP-U packet is a newly-added packet, and the packet is used to send only the location information of the user equipment. FIG.5is a schematic structural diagram of Embodiment 1 of a secondary access node according to an embodiment. As shown inFIG.5, the secondary access node in this embodiment includes: an obtaining module51and a sending module52. The obtaining module51is configured to obtain serving cell information of the SeNB of the UE. Specifically, the SeNB provided in this embodiment is applied to a 1A architecture. In the 1A architecture, an MeNB and the SeNB separately establish a user-plane data connection with a core network node, that is, the MeNB and the SeNB separately establish a bearer with the core network node. Therefore, both the MeNB and the SeNB may send a data packet to the core network node. In this way, the core network node may obtain the serving cell information of the SeNB by using the data packet sent by the SeNB. The location information of the UE reflects a location of the UE, and generally, a coverage area of a serving cell of an MeNB is larger than a coverage area of a serving cell of an SeNB. Therefore, if the core network node obtains serving cell information of an SeNB serving the UE, a more accurate location of the UE is obtained. In this way, in comparison with a case in which serving cell information of the MeNB is reported to the core network node, when the serving cell information of the SeNB serving the UE is reported to the core network node, the core network node obtains location information of the UE with a finer granularity. The SeNB includes the obtaining module51, and the obtaining module51is configured to obtain the serving cell information of the SeNB of the UE. The serving cell information of the SeNB may be any information that can represent a feature of the SeNB. The serving cell information of the SeNB of the UE includes: any one or more of identification information of a serving cell of the SeNB of the UE, bearer information corresponding to a serving cell of the SeNB of the UE, a tracking area identity of a serving cell of the SeNB of the UE, or an access network type of a serving cell of the SeNB of the UE. The sending module52is configured to: send the serving cell information of the SeNB of the UE to a core network node by using a first GTP-U packet, where the serving cell information of the SeNB of the UE is in an extension header of the first GTP-U packet; or send the serving cell information of the SeNB of the UE to a core network node by using a second GTP-U packet, where the second GTP-U packet is used to send only the serving cell information of the SeNB of the UE, and the serving cell information of the SeNB is used by the core network node to: after the core network node receives serving cell information of at least one SeNB of the UE, determine a control policy for the UE according to the serving cell information of the at least one SeNB of the UE. Specifically, after the obtaining module51obtains the serving cell information of the SeNB of the UE, the sending module52sends the serving cell information to the core network node. An SAE system is used as an example, and the core network node includes an MME, an S-GW, a P-GW, a PCRF, and the like. The S-GW establishes a user-plane data connection with the SeNB, the sending module52may send the serving cell information of the SeNB of the UE to the S-GW by using the first GTP-U packet, and the S-GW sends the serving cell information of the SeNB of the UE to the PCRF by using the P-GW. The serving cell information of the SeNB of the UE is in the extension header of the first GTP-U. Alternatively, the sending module52may send the serving cell information of the SeNB of the UE to the S-GW by using the second GTP-U packet, where the second GTP-U packet is a newly-added packet, and the second GTP-U packet is used to send only the serving cell information of the SeNB of the UE. After receiving serving cell information sent by the at least one SeNB in a network, the PCRF may determine a location of the UE, configure different charging or control policies for the UE according to the location, and send the configured charging or control policies to an execution entity such as a policy and charging enforcement function (PCEF) entity or a bearer binding and event report function (BBERF), so as to perform corresponding control on the UE. Because the core network node determines the location of the UE after receiving the serving cell information of the at least one SeNB of the UE, the core network node may obtain a more accurate location of the UE according to the location information, so that the core network node may formulate a control policy with a finer granularity for the UE. In this embodiment, an SeNB sends serving cell information of the SeNB of UE to a core network node by using a GTP-U packet, so that the core network node can implement control with a finer granularity over the UE. Further, in the embodiment shown inFIG.5, the control policy for the UE includes: any one or more of a charging control policy for the UE, a rate control policy for the UE, a quality of service control policy for the UE, or a priority control policy for the UE. FIG.6is a schematic structural diagram of Embodiment 2 of a core network node according to an embodiment. As shown inFIG.6, the core network node in this embodiment includes: a receiving module61and a processing module62. The receiving module61is configured to: receive serving cell information of an SeNB of user equipment that is sent by the SeNB by using a first GTP-U packet, where the serving cell information of the SeNB of the UE is in an extension header of the first GTP-U packet; or receive serving cell information of an SeNB of UE that is sent by the SeNB by using a second GTP-U packet, where the second GTP-U packet is used to send only the serving cell information of the SeNB of the UE. Specifically, all nodes in a core network are collectively referred to as the core network node in this embodiment. For example, for an SAE system, the core network node includes an MME, an S-GW, a P-GW, a PCRF, and the like. The core network node includes the receiving module61, and the receiving module61may be disposed on any core network node as long as the receiving module61can receive the serving cell information of the SeNB that is sent by the SeNB by using a GTP-U packet. In the SAE system, the receiving module61is disposed in the S-GW. The serving cell information of the SeNB of the UE reflects a location of the UE, and generally, a coverage area of a serving cell of an MeNB is larger than a coverage area of a serving cell of an SeNB. Therefore, if the core network node obtains serving cell information of an SeNB serving the UE, a more accurate location of the UE is obtained. In this way, in comparison with a case in which serving cell information of the MeNB is reported to the core network node, when the serving cell information of the SeNB serving the UE is reported to the core network node, the core network node obtains location information of the UE with a finer granularity. Therefore, the core network node provided in this embodiment includes the receiving module61, the receiving module61is configured to receive the serving cell information of the SeNB that is sent by the SeNB, and the serving cell information of the SeNB may be any information that can represent a feature of the SeNB. The receiving module61receives the serving cell information of the SeNB of the user equipment that is sent by the SeNB by using the first GTP-U packet, where the serving cell information of the SeNB of the UE is in the extension header of the first GTP-U. Alternatively, the receiving module61receives the serving cell information of the SeNB of the UE that is sent by the SeNB by using the second GTP-U packet, where the second GTP-U packet is a newly-added packet, and the second GTP-U packet is used to send only the serving cell information of the SeNB of the UE. The processing module62is configured to: after serving cell information of at least one SeNB of the UE is received, determine a control policy for the UE according to the serving cell information of the at least one SeNB of the UE. Specifically, the core network node provided in this embodiment further includes the processing module62, and the processing module62is configured to: after the serving cell information of the at least one SeNB of the UE is received, determine the control policy for the UE. Because the receiving module61receives the serving cell information of the at least one SeNB of the UE, the processing module62may obtain a more accurate location of the UE according to a serving cell information of the at least one SeNB of the UE, so as to formulate a control policy with a finer granularity for the UE. The processing module62may be disposed on any node that is in the core network node and that can determine the control policy for the UE, for example, the PCRF in the SAE system. The PCRF configures different charging or control policies for the UE according to different location information of the UE, and sends the configured charging or control policies to an execution entity such as a PCEF or a BBERF, so as to perform corresponding control on the UE. In this embodiment, an SeNB sends serving cell information of the SeNB of UE to a core network node by using a GTP-U packet, so that the core network node can implement control with a finer granularity over the UE. Further, in the embodiment shown inFIG.6, the control policy for the UE includes: any one or more of a charging control policy for the UE, a rate control policy for the UE, a quality of service control policy for the UE, or a priority control policy for the UE. FIG.7is a flowchart of Embodiment 1 of a method for reporting location information of user equipment according to an embodiment. As shown inFIG.7, the method in this embodiment includes the following steps. Step S701. A master access node obtains location information of user equipment, where the location information of the user equipment includes serving cell information of at least one secondary access node of the user equipment. Step S702. The master access node sends the location information of the user equipment to a core network node, where the location information is used by the core network node to determine a control policy for the user equipment. The method for reporting location information of user equipment in this embodiment is used to complete processing of the master access node shown inFIG.1, and implementation principles and technical effects thereof are similar. Details are not described herein. Further, in the embodiment shown inFIG.7, step S702includes: the master access node sends the location information of the user equipment to the core network node by means of control plane signaling. Further, in the embodiment shown inFIG.7, the serving cell information of the at least one secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the at least one secondary access node of the user equipment, bearer information corresponding to a serving cell of the at least one secondary access node of the user equipment, a tracking area identity of a serving cell of the at least one secondary access node of the user equipment, or an access network type of a serving cell of the at least one secondary access node of the user equipment; and step S702includes: the master access node sends the location information of the user equipment to the core network node by using a radio access bearer modification instruction message. Further, in the embodiment shown inFIG.7, the serving cell information of the at least one secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the at least one secondary access node of the user equipment, a quantity of data packets or data packets transmitted in a serving cell of the at least one secondary access node of the user equipment, a tracking area identity of a serving cell of the at least one secondary access node of the user equipment, or an access network type of a serving cell of the at least one secondary access node of the user equipment; or the serving cell information of the at least one secondary access node of the user equipment includes multi-stream indication information, where the multi-stream indication information is used to indicate that at least two access nodes provide services for the user equipment; and step S702includes: the master access node sends the location information of the user equipment to the core network node by using a location information update message. Further, in the embodiment shown inFIG.7, step S702includes: the master access node sends the location information of the user equipment to the core network node by using a first GTP-U packet, where the location information of the user equipment is in an extension header of the first GTP-U packet; or the master access node sends the location information of the user equipment to the core network node by using a second GTP-U packet, where the second GTP-U packet is used to send only the location information of the user equipment. The serving cell information of the at least one secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the at least one secondary access node of the user equipment, a quantity of data packets or data packets transmitted in a serving cell of the at least one secondary access node of the user equipment, a tracking area identity of a serving cell of the at least one secondary access node of the user equipment, or an access network type of a serving cell of the at least one secondary access node of the user equipment. Further, in the embodiment shown inFIG.7, the control policy for the user equipment includes: any one or more of a charging control policy for the user equipment, a rate control policy for the user equipment, a quality of service control policy for the user equipment, or a priority control policy for the user equipment. FIG.8is a flowchart of Embodiment 2 of a method for reporting location information of user equipment according to an embodiment. As shown inFIG.8, the method in this embodiment includes the following steps. Step S801. A core network node receives location information of user equipment that is sent by a master access node, where the location information of the user equipment includes serving cell information of at least one secondary access node of the user equipment. Step S802. The core network node determines a control policy for the user equipment according to the location information of the user equipment. The method for reporting location information of user equipment in this embodiment is used to complete processing of the core network node shown inFIG.4, and implementation principles and technical effects thereof are similar. Details are not described herein. Further, in the embodiment shown inFIG.8, step S801includes: the core network node receives the location information of the user equipment that is sent by the master access node by means of control plane signaling. Further, in the embodiment shown inFIG.8, the serving cell information of the at least one secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the at least one secondary access node of the user equipment, a tracking area identity of a serving cell of the at least one secondary access node of the user equipment, bearer information corresponding to a serving cell of the at least one secondary access node of the user equipment, or an access network type of a serving cell of the at least one secondary access node of the user equipment; and step S801includes: the core network node receives the location information of the user equipment that is sent by the master access node by using a radio access bearer modification instruction message. Further, in the embodiment shown inFIG.8, the serving cell information of the at least one secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the at least one secondary access node of the user equipment, a quantity of data packets or data packets transmitted in a serving cell of the at least one secondary access node of the user equipment, a tracking area identity of a serving cell of the at least one secondary access node of the user equipment, or an access network type of a serving cell of the at least one secondary access node of the user equipment; or the serving cell information of the at least one secondary access node of the user equipment includes multi-stream indication information, where the multi-stream indication information is used to indicate that at least two access nodes provide services for the user equipment; and step S801includes: the core network node receives the location information of the user equipment that is sent by the master access node by using a location information update message. Further, in the embodiment shown inFIG.8, step S801includes: the core network node receives the location information of the user equipment that is sent by the master access node by using a first GTP-U packet, where the location information of the user equipment is in an extension header of the first GTP-U packet; or a core network node receives the location information of the user equipment that is sent by the master access node by using a second GTP-U packet, where the second GTP-U packet is used to send only the location information of the user equipment. The serving cell information of the at least one secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the at least one secondary access node of the user equipment, a quantity of data packets or data packets transmitted in a serving cell of the at least one secondary access node of the user equipment, a tracking area identity of a serving cell of the at least one secondary access node of the user equipment, or an access network type of a serving cell of the at least one secondary access node of the user equipment. Further, in the embodiment shown inFIG.8, the control policy for the user equipment includes: any one or more of a charging control policy for the user equipment, a rate control policy for the user equipment, a quality of service control policy for the user equipment, or a priority control policy for the user equipment. FIG.9is a flowchart of Embodiment 3 of a method for reporting location information of user equipment according to an embodiment. As shown inFIG.9, the method in this embodiment includes the following steps. Step S901. A secondary access node obtains serving cell information of the secondary access node of user equipment. Step S902. The secondary access node sends the serving cell information of the secondary access node of the user equipment to a core network node by using a first GTP-U packet, where the serving cell information of the secondary access node of the user equipment is in an extension header of the first GTP-U packet; or the secondary access node sends the serving cell information of the secondary access node of the user equipment to a core network node by using a second GTP-U packet, where the second GTP-U packet is used to send only the serving cell information of the secondary access node of the user equipment, and the serving cell information of the secondary access node is used by the core network node to: after the core network node receives serving cell information of at least one secondary access node of the user equipment, determine a control policy for the user equipment according to the serving cell information of the at least one secondary access node of the user equipment; where the serving cell information of the secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the secondary access node of the user equipment, bearer information corresponding to a serving cell of the secondary access node of the user equipment, a tracking area identity of a serving cell of the secondary access node of the user equipment, or an access network type of a serving cell of the secondary access node of the user equipment. The method for reporting location information of user equipment in this embodiment is used to complete processing of the secondary access node shown inFIG.5, and implementation principles and technical effects thereof are similar. Details are not described herein. Further, in the embodiment shown inFIG.9, the control policy for the user equipment includes: any one or more of a charging control policy for the user equipment, a rate control policy for the user equipment, a quality of service control policy for the user equipment, or a priority control policy for the user equipment. FIG.10is a flowchart of Embodiment 4 of a method for reporting location information of user equipment according to an embodiment. As shown inFIG.10, the method in this embodiment includes the following steps. Step S1001. A core network node receives serving cell information of a secondary access node of user equipment that is sent by the secondary access node by using a first GTP-U packet, where the serving cell information of the secondary access node of the user equipment is in an extension header of the first GTP-U packet; or a core network node receives serving cell information of a secondary access node of user equipment that is sent by the secondary access node by using a second GTP-U packet, where the second GTP-U packet is used to send only the serving cell information of the secondary access node of the user equipment. Step S1002. After receiving serving cell information of at least one secondary access node of the user equipment, the core network node determines a control policy for the user equipment according to the serving cell information of the at least one secondary access node of the user equipment; where the serving cell information of the secondary access node of the user equipment includes: any one or more of identification information of a serving cell of the secondary access node of the user equipment, bearer information corresponding to a serving cell of the secondary access node of the user equipment, a tracking area identity of a serving cell of the secondary access node of the user equipment, or an access network type of a serving cell of the secondary access node of the user equipment. The method for reporting location information of user equipment in this embodiment is used to complete processing of the core network node shown inFIG.6, and implementation principles and technical effects thereof are similar. Details are not described herein. Further, in the embodiment shown inFIG.10, the control policy for the user equipment includes: any one or more of a charging control policy for the user equipment, a rate control policy for the user equipment, a quality of service control policy for the user equipment, or a priority control policy for the user equipment. Persons of ordinary skill in the art may understand that all or some of the steps of the method embodiments may be implemented by a program instructing relevant hardware. The program may be stored in a computer-readable storage medium. When the program runs, the steps of the method embodiments are performed. The foregoing storage medium includes: any medium that can store program code, such as a read only memory (ROM), a random access memory (RAM), a magnetic disk, or an optical disc. Finally, it should be noted that the foregoing embodiments are merely intended for describing the technical solutions, but not for limiting the present embodiments. Although the present embodiments are described in detail with reference to the foregoing embodiments, persons of ordinary skill in the art should understand that they may still make modifications to the technical solutions described in the foregoing embodiments or make equivalent replacements to some or all technical features thereof. Therefore, the protection scope of the present embodiments shall be subject to the protection scope of the claims. | 56,814 |
RE49791 | DETAILED DESCRIPTION Embodiments can provide for a scheduling user equipment uplink transmissions on an unlicensed carrier. According to a possible embodiment, a configuration indicating a window length can be received from a higher layer, where the higher layer can be higher than a physical layer. A grant can be received in a subframe, where the grant can be for transmitting a physical uplink shared channel on a serving cell operating on an unlicensed carrier. A set of subframes for possible transmission of the physical uplink shared channel can be determined based on the window length and the subframe in which the grant is received. Listen before talk can be performed on the unlicensed carrier to determine an earliest unoccupied subframe in the set of subframes. The physical uplink shared channel can be transmitted in the earliest unoccupied subframe in response to receiving the grant. According to another possible embodiment, a grant for transmitting physical uplink shared channel on a serving cell operating on an unlicensed carrier can be received in a subframe. A set of subframes can be determined for possible transmission of the physical uplink shared channel. Listen before talk can be performed on the unlicensed carrier to determine an earliest unoccupied subframe in the set of subframes. A physical uplink shared channel can be transmitted in multiple subframes within the set of subframes on the unlicensed carrier, starting with the earliest unoccupied subframe, in response to receiving the grant. According to another possible embodiment, listen before talk can be performed to determine when a subframe is available for uplink transmission. A sounding reference signal can be transmitted in a first discrete Fourier transform spread orthogonal frequency division multiplexing symbol of the subframe when listen before talk indicates that the subframe is available. A physical uplink shared channel can be transmitted in at least a portion of a remaining part of the subframe. FIG.1is an example block diagram of a system100according to a possible embodiment. The system100can include a first User Equipment (UE)110and a base station120. The base station120can be an Enhanced Node-B (eNB), such as a cellular base station, a Long Term Evolution (LTE) base station, or any other base station. The first UE110and the base station120can communicate on different cells130and140. The cell130can be a first cell, such as a primary cell and the UE110can be connected to the primary cell. The cell140can be a second cell, such as a secondary cell. Furthermore, the second cell140can be a cell that operates on unlicensed spectrum. The cells130and140can also be cells associated with other base stations, can be a macro cells, can be micro cells, can be femto cells, and/or can be any other cells useful for operation with a LTE network. The system100can also include a second UE112that can communicate with the base station120on cells132and142in a similar manner to the first UE110, where the cell132can be a primary cell and the cell142can be a secondary cell. The UEs110and112can be any devices that can access a wireless wide area network. For example, the UEs110and112can be wireless terminals, portable wireless communication devices, smartphones, cellular telephones, flip phones, personal digital assistants, personal computers having cellular network access cards, selective call receivers, tablet computers, or any other device that is capable of operating on a wireless wide area network. In operation, UE uplink Physical Uplink Shared Channel (PUSCH) transmissions can be supported using different approaches. For Frequency Division Duplex (FDD) with Transmission Time Interval (TTI) bundling disabled, if a UE receives an uplink grant in subframe n from an eNB, it can transmit PUSCH in subframe n+4 in response to that grant. For LTE, a subframe typically can have a 1 ms duration. For example, the 4 subframe duration between grant reception and UE transmission can be the maximum duration allowed for UE hardware processing, such as the time needed by the UE hardware to decode the grant and prepare the PUSCH transmission. The value “4” is an example value used throughout this disclosure, but in principle, it is possible to have a different value. For example, ‘n+4’ can effectively mean ‘n+dmax’ where dmax can be a maximum duration allowed for UE hardware processing after receiving a grant in subframe n. For FDD with TTI bundling enabled, if a UE receives an uplink grant in subframe n, it can transmit PUSCH in a predefined set of subframes {n+4, n+5, . . . n+4+L−1} in response to that grant, where L can be configured by higher layers that are higher than the physical layer. For Time Division Duplex (TDD), if a UE receives an uplink grant in subframe n, it can transmit PUSCH in a predefined subframe n+k in response to that grant, where k can be determined from predefined table(s) in an LTE specification. For TDD with TTI bundling enabled, if a UE receives a grant in subframe n, the UE can transmit PUSCH in a predefined set of subframes {n+k1, n+k2, . . . n +kL} in response to that grant, where L, k1 , and k2 . . . kL can be determined from predefined table(s) in the specification. For TDD, if an ‘ul index’ field, such as TDD Uplink/Downlink (UL/DL) configuration 0, is transmitted in the uplink grant and if a UE receives the uplink grant in subframe n, the UE can transmit PUSCH in a predefined subframe n+k, n+7, or both subframes, in response to that grant, depending on the ‘ul index’ field setting in the grant, where k can be determined from predefined table(s) in the specification. In all the above approaches, the UE can transmit PUSCH in one or multiple predefined subframes in response to receiving a grant. For operation in unlicensed spectrum due to regulatory requirements, and due the need to co-exist with other wireless systems, such as Wi-Fi, and LTE devices, such as UEs and eNBs, before transmitting on an unlicensed carrier, the LTE devices, such as UEs typically have to check whether the carrier is busy using some form of ‘Listen Before Talk’ (LBT) mechanism, and can begin transmissions only if the carrier is free. LBT typically can include measuring energy on the carrier, sometimes referred to as sensing, for a short duration, such as 9 us or 20 us, and determining whether the measured energy is less than a threshold, such as −82 dBm or −62 dBm. If the energy is less than the threshold, the carrier is determined to be free. Some examples of LBT can include the Clear Channel Assessment-Energy Detect (CCA-ED) and Clear Channel Assessment-Carrier Sense (CCA-CS) mechanisms defined in IEEE 802.11 specifications. CCA mechanisms specified in the ETSI EN 301 893 specification, and other forms of LBT. Transmissions on the carrier typically also have to follow Discontinuous Transmission (DCT) requirements. For example, an LTE device, such as a UE, can continuously transmit for Xms, such as where X can be 4 ms as per some regulations and up to 13 ms for some other regulations, after which it may have to cease transmission for some duration, sometimes referred as an idle period, perform LBT again, and reinitiate transmission only if LBT is successful. The LTE device may perform LBT towards the end of the idle period. Therefore, for operation in unlicensed spectrum, after a UE receives a grant from an eNB indicating the UE to perform transmission in unlicensed spectrum, the UE often may have to perform LBT, and transmit only if LBT is successful, such as when the carrier is determined to be free. The terms LBT and CCA are used interchangeably in the disclosed embodiments. Both terms refer to the aspect of the device having to check whether the carrier is free before transmission. If the carrier is busy, the UE may not transmit, such as when it has to skip a PUSCH transmission, and may have to wait for another scheduling grant from the eNB. For example, if a UE receives a grant in subframe n for transmission in subframe n+4, the UE may have to perform LBT that enables UE transmission in subframe n+4. If the carrier is free, the UE can transmit PUSCH in subframe n+4. If the carrier is busy, the UE may have to skip the transmission in subframe n+4 and wait for another grant. Since the eNB may not accurately predict in advance, such as in subframe n, when the carrier will be free near the UE, this approach may be inefficient, as it can lead to a number of skipped UE transmissions with each skipped UE transmission leading to an extra grant. Thus, embodiments can provide signaling enhancements that can address these and other issues. Some embodiments can provide signaling enhancements that give a UE multiple transmission opportunities for each received grant, and let the UE determine the subframe where the PUSCH is transmitted based on carrier availability, such as based on the result of LBT. An eNB can detect which transmission opportunities a UE has utilized based on, for example, blind detection. Allowing too much flexibility to the UE may increase eNB complexity, where the eNB receiver may have to blindly determine the subframe in which the PUSCH is transmitted by the UE. Given this, some embodiments provide signaling approaches that provide good trade-offs between UE transmission flexibility and eNB complexity. For some embodiments, the UE can be configured with a Primary cell (Pcell) that can operate on a licensed carrier and a Secondary cell (Scell) that can operate on an unlicensed carrier. The grant in response to which the UE transmits PUSCH on the unlicensed carrier can be received by the UE on either the Pcell, such as on a licened carrier, or the Scell, such as on an unlicensed carrier. The UE can perform LBT using the mechanisms described below. For some embodiments, the UE can send a Hybrid Automatic Repeat Request Identifier (HARQ ID) and HARQ sub identifier (HARQ subID) along with its PUSCH transmission or retransmission using the mechanisms described below. FIG.2is an example flowchart200illustrating a UE procedure for a first option for transmitting PUSCH on unlicensed carrier according to a possible embodiment. At205, the flowchart200can begin. At210, a UE can be configured via higher layers with a transmission opportunity window length (W), where W can be 1, 2, 3, or 4 subframes, and where W=1 can correspond to current LTE operation, such as a default value. The window length (W) may also be set to any other useful value. At220, the UE can receive an uplink grant in subframe n. The grant can contain bits indicating a HARQ ID, such as a 3 bit HARQ-ID. The number of bits used for indicating the HARQ ID may depend on a maximum number of HARQ processes (M_UL_HARQ). For example, for LTE uplink, the maximum number of HARQ processes can be either 8 for non-Multiple Input Multiple Output (MIMO) uplink or 16 for MIMO uplink (UL-MIMO) per component carrier. For UL-MIMO, two HARQ processes associated with the subframe n may be HARQ ID and HARQ ID+8 for transport block 1 and transport block 2 respectively, that may require indication of only HARQ ID for the lowest index, such as the enabled, transport block in the uplink grant. In this case, M_UL_HARQ can be set to 8. A transport block can be the data from the upper layer, such as a Medium Access Control (MAC) layer, given to the physical layer in a LTE system. Signaling of the HARQ ID can explicitly enable an eNB to schedule an uplink transmission asynchronously. For example, the retransmissions for a given uplink HARQ processes may be adaptable in time and need not occur with a fixed Round Trip Time (RTT). The uplink grant received by the UE can also contain bits indicating modulation and coding scheme (MCS) to be used for PUSCH transmission, bits indicating a resource allocation (RA) within a subframe, such as the Resource Blocks (RBs) within a subframe to use for PUSCH transmission, bit(s) indicating whether the grant is for new data, such as a grant for an initial or new transmission, or indicating the grant is retransmission (for example, by using a 1 bit New Data Indicator (NDI)), and other bits indicating additional control information. If the UE receives an uplink grant with HARQ ID x in subframe n, in response to the grant, the UE can attempt to transmit PUSCH in subframe n+4. If the carrier is not free for transmission in subframe n+4, such as when LBT is not successful, the UE can attempt PUSCH transmissions in subsequent subframes until a subframe is free or until the window length (W) is reached. For example, at230, a counter j can be set to zero. At240, the UE can perform LBT for transmitting PUSCH in subframe n+4+j. At250, the UE can determine whether the carrier is free based on the results of LBT. If the carrier is free, at260, with each PUSCH transmission, the UE can include the associated HARQ ID, such as the HARQ ID provided by the grant in response to which the PUSCH transmission is being made and the flowchart can end at295. The HARQ ID can be implicitly communicated by a Demodulation Reference Signal (DMRS), such as a cyclic shift for the DMRS and Orthogonal Cover Code (OCC) index, associated with the PUSCH transmission. Alternately, the HARQ ID can be explicitly sent as part of the PUSCH transmission. If the carrier is not free, at270, the UE can increment the counter j. At280, the UE can determine if the counter is still below the window value (W). If it is, the flowchart200can return to240and continue accordingly. If the counter has reached the window length value (W), at290, the UE can skip the PUSCH transmission for the HARQ ID (x) in response to the grant received in subframe n. At295, the flowchart200can end. If the UE has PUSCH transmissions for multiple grants queued up due to lack of carrier availability in previous transmissions, the UE can prioritize the PUSCH transmission corresponding to the earliest grant. For example, if the UE receives a grant in subframe n, such as for HARQ ID (x1), and another grant in subframe n+1, such as for HARQ ID (x2), and if LBT fails for subframe n+4 but is successful for subframe n+5, the UE can transmit the PUSCH corresponding to grant received in subframe n, such as the PUSCH corresponding to HARQ ID (x1), and can attempt to transmit the PUSCH corresponding to HARQ ID (x2) in subsequent subframes until the window length (W) is reached. Alternatively, higher layers may indicate the priority for HARQ ID's, and the UE can follow the priority order in determining which HARQ ID is prioritized for transmission, when multiple HARQ ID's have pending transmission. Alternatively, the UE can prioritize PUSCH transmissions based on its own prioritization rules, for example, based on the type of traffic associated with the PUSCH transmission. In another example, if LBT fails in subframe n+4 and succeeds in subframe n+5, if a power head room report becomes available in subframe n+4 or subframe n+5, the UE can transmit a PUSCH containing the power head room report in subframe n+5. The window length (W) can be an eNB implementation choice. For example, if an eNB picks W=4, the UE can get 4 attempts to transmit PUSCH for a given uplink grant, but the eNB may have to blindly attempt to decode PUSCH corresponding to a maximum of 4 separate grants for each scheduled UE in each subframe. If the eNB picks W=1, blind detection of PUSCH is not necessary, but the UE has only one attempt/transmission opportunity to send PUSCH and the UE can be more likely to skip the PUSCH transmission if LBT is not successful, such as when the channel is busy. Given the trade-offs involved, the eNB can pick a value for W depending on factors such as loading of the operating carrier and/or Quality of Service (QoS) requirements for the UE's UL traffic. In a first example, the eNB can pick a smaller value for W, such as W=1, when it determines that the carrier is mostly free, such as when LBT at the UE is more like to succeed, and can pick a larger value of W, such as W=4, when the carrier is busy, such as when LBT at the UE is less likely to succeed. In a second example, the eNB can pick a larger value of W while scheduling delay sensitive traffic and a smaller value of W for best effort traffic. In a third example, the eNB can pick a larger value of W for UEs whose PUSCH transmission subframes can be blindly detected with more confidence, such as for UEs that are closer to the eNB whose signals will be received by the eNB with higher SNR and hence the presence/absence of PUSCH from those UEs can be determined with more confidence than UEs with low receive SNR. FIGS.3a and3bare example flowcharts301and302illustrating a UE procedure for a second option for transmitting PUSCH on unlicensed carrier for initial transmission and retransmission according to a possible embodiment. In the first option, when the eNB configures W>1 and sends a grant to a UE indicating PUSCH transmission in a certain set of RBs, the RBs may be blocked for all subframes falling within the transmission window W. For example, W=4 and a grant is sent in subframe n, indicating PUSCH transmission in RBs 1-10, the UE can be allowed to transmit PUSCH in RBs 1-10 in subframes n+4, n+5, n+6, n+7. Since, the eNB does not know which subframe the UE may transmit; it cannot schedule those RBs for other UEs. Multiple User Multiple Input Multiple Output (MU MIMO) can be possible, albeit with possible restrictions, such as based on available DMRS cyclic shifts, same RB allocations for all the MU co-scheduled UEs. Also, since the UE transmits PUSCH in only one subframe of the window, the RB allocation for other subframes may be wasted even if the carrier is free. For example, for a grant sent in subframe n, if LBT at the UE succeeds for subframe n+4, the RBs 1-10 for subframes n+5, n+6 and n+7 are left unused. The eNB can send grants to the UE in subframes n+1, n+2, n+3 . . . assuming that the carrier is free in subframes n+5, n+6, n+7 respectively, but if the carrier is busy, the grants can be wasted, which may lead to unnecessary DL control overhead. The second option can attempt to address this issue by enabling the UE to make multiple PUSCH transmissions in response to a single grant. Compared to the first option, the second option may require additional bits in Downlink Control Information (DCI), such as 2 extra bits if W=4, 3 extra bits if W=8, etc. At305, the flowchart301can begin. At310a UE can receive an uplink grant in subframe n. The grant can contain bits indicating the HARQ ID (x), such as a 3 bit HARQ-ID. The grant can also contain bit(s) indicating whether the grant is for new data, such as an initial transmission or a new transmission, or the grant is not for new data, such as by using 1 a bit New Data Indicator (NDI). The grant can additionally contain additional bits, such as 2 bits. For the additional bits, if the grant is for new data, such as an initial transmission, based on a NDI toggle, the additional bits can indicate a window length (W). For example, 00 can indicate W=1 subframe, 01 can indicate W=2 subframes, 10 can indicate W=3 subframes, and 11 can indicate W=4 subframes. If the grant is for retransmissions, such as when NDI is not toggled, the additional bits can indicate a HARQ subID of the packet for which the retransmission is requested. The number of additional bits used can depend on the maximum allowed window length (Wmax). This can be fixed in the specification. Alternately, this can be a configurable value, indicated to the UE via higher layers. For example, if a Radio Resource Control (RRC) indicates Wmax=8, the UE can expect the UL grants to have 3 additional bits to indicate the ‘window length (W) or the HARQ subID’. The uplink grant received by the UE can also contain bits indicating a modulation and coding scheme (MCS) to be used for PUSCH transmission(s), bits indicating a resource allocation (RA) within a subframe, such as the RBs to use for PUSCH transmission(s), and other bits indicating additional control information. If at312, the NDI bit(s) indicate that the grant is for an initial transmission, the rest of flowchart301can be utilized. In particular, in response to the grant received in subframe n, the UE can transmit PUSCH in subframe n+4 if the LBT for subframe n+4 is successful. If the UE still has data in its UL buffer, the UE can transmit PUSCH in subframe n+5 in response to the same grant received in subframe n, if the LBT for subframe n+5 is also successful. The UE can continue transmitting PUSCH in subsequent subframes if LBT is successful for those subframes and the UE has data in its UL buffer until the window length (W) signaled in the grant is reached. With each PUSCH transmission, the UE can include the associated HARQ ID that was provided by the grant in response to which the PUSCH transmission(s) are being made. Since multiple PUSCH transmissions can be made in response to one grant and one HARQ ID, with each PUSCH transmission, the UE can also include a HARQ subID to enable the eNB to individually identify each PUSCH transmission. For an example when the grant received in subframe n has a HARQ ID of zero (x=0) and window length W=4, and assuming LBT is successful for all subframes for the window, the HARQ subID (y) can be set where the UE can send x=0 and y=0 for the first PUSCH transmission made in response to the grant in subframe n+4, where x is the HARQ ID and y is the HARQ subID. Then, if the UE UL buffer is not empty, the UE can send x=0 and y=1 for the second PUSCH transmission made in response to the grant in subframe n+5. If the UE UL buffer is still not empty, the UE can send x=0 and y=2 for the third PUSCH transmission made in response to the grant in subframe n+6. If the UE UL buffer is still not empty, the UE can send x=0 and y=3 for the fourth PUSCH transmission made in response to the grant in subframe n+7. For an example where the grant received in subframe n has a HARQ ID of zero (x=0), and a window length W=4 and assuming LBT is unsuccessful for subframe n+4 and n+6, but successful for subframes n+5 and n+7, the HARQ subID (y) can be set where the UE can send x=0 and y=0 for the first PUSCH transmission made in response to the grant in subframe n+5. If the UE UL buffer is not empty, the UE can send x=0 and y=1 for the second PUSCH transmission made in response to the grant in subframe n+7. When the eNB has to request a retransmission of a PUSCH that was transmitted by the UE along with HARQ ID (x) and HARQ subID (y), the eNB can include the same HARQ ID (x) and HARQ subID (y) in the re-transmission grant sent to the UE and can set the NDI bit(s) to indicate a retransmission request. For example, if at312, the NDI bit(s) indicate that the grant is for an initial transmission, at314, the HARQ subID can be set to 0 (y=0). The window length (W) can be determined using bit(s) indicating the ‘window length (W) or HARQ subID (y)’ (for example, if the grant is for an initial transmission, the UE can use those bits for determining window length (W); if the grant is for a re-transmission the UE can use those bits for determining HARQ subID). At316, a counter j can be set to zero. At318, LBT can be performed for transmitting in subframe n+4+j. If at320, LBT indicates the carrier is not free, at322, the counter j can be incremented. If at324the counter j has not reached the window length (W), LBT can be performed in a next subframe at318. If the carrier is free at320, then at326, PUSCH transmissions can be performed in subframe n+4+j and the PUSCH/DMRS can include the HARQ ID and the HARQ subID. If the UE uplink buffer is not empty at328, at330the HARQ subID can be incremented, i.e., y=y+1. If the UE uplink buffer is empty at328or if the counter j has reached the window length (W) at324, at332PUSCH transmissions can cease for the grant received in subframe n for that particular HARQ ID and at334, the flowchart301can end. If at312, the NDI bit(s) indicate that the grant is for a retransmission, the flowchart301can advance to336to branch to step350of flowchart302. In particular, in the flowchart302the additional bits in the grant can indicate the HARQ subID of the corresponding initial transmission for which PUSCH retransmission is requested as described earlier. The window length (W) can be the window length determined by the UE for the correponding initial transmission for which the PUSCH retransmission is requested. The UE can attempt to make the PUSCH retransmission in subframe n+4, and, if the carrier is not free for transmission in subframe n+4, such as when LBT is not successful for that subframe, the UE can attempt PUSCH retransmission in subsequent subframes until a subframe is available or until the window length is reached. The UE can include the HARQ ID and HARQ subID indicated by the retransmission grant along with its PUSCH retransmission. Note that unlike the initial/new transmission case, the UE may only send one PUSCH retransmission in response to a grant that indicates a retransmission. For example, at350the flowchart302can begin. At352, the window length (W) can be set based on the initial transmission. The HARQ subID can be determined using bits indicating the ‘window length (W) or the HARQ subID transmitted’ in the grant (for example, if the grant is for an initial transmission, the UE can use those bits for determining window length (W); if the grant is for a re-transmission, the UE can use those bits for determining HARQ subID). At354, a counter j can be set to zero. At356, LBT can be performed for transmitting PUSCH in subframe n+4+j on a carrier. If at358LBT indicates the carrier is free, at360PUSCH transmission can be performed in subframe n+4+j. The PUSCH/DMRS can include the HARQ ID, such as x, and the HARQ subID, such as y. If at358LBT indicates the carrier is busy, at362the counter j can be incremented. If at364the counter j is less than the window length (W), at356LBT can be performed for the next subframe. If the counter j has reached the window length (W), at366, the PUSCH retransmission can be skipped for the HARQ ID and the HARQ subID indicated in the grant received in subframe n. At368, the flowchart302can end. FIGS.4a and4bare example flowcharts401and402illustrating a UE procedure for a third option for transmitting PUSCH on unlicensed carrier for initial transmission and retransmission according to a possible embodiment. In the second option above, the UE may need to signal additional HARQ subID bits in addition to the HARQ ID bits along with its PUSCH transmissions to identify the individual PUSCH transmission(s) that are made in response to a single grant. For example, assuming 3 bits for HARQ ID and 2 bits for HARQ subID, the UE may have to send a total of 5 bits along with each of its PUSCH transmission. A third option can attempt to address this issue by avoiding the need to transmit a HARQ subID. For the third option, at405, the flowchart401can begin. At410, a UE can receive a window length (W). The window length (W) can be configured by higher layers or the window length (W) can be signaled using bits in a uplink grant. At412, the UE can receive an uplink grant in subframe n. The grant can contain bits indicating HARQ ID. For example, 3 bits can be used to indicate HARQ ID. The grant can also contain bit(s) indicating whether the grant is for new data, such as an initial transmission or new transmission, or not. For example this can be done, such as by using a 1 bit NDI. The uplink grant received by the UE can further contain bits indicating a Modulation and Coding Scheme (MCS) to be used for PUSCH transmission(s), bits indicating Resource Allocation (RA) within a subframe, such as RBs to use for PUSCH transmission(s), and other bits indicating additional control information. If at414the NDI bit(s) indicate that the grant is for an initial transmission, in response to the grant received in subframe n, the UE can transmit PUSCH in subframe n+4 if the LBT for subframe n+4 is successful. If the UE still has data in its UL buffer and if the LBT for subframe n+5 is also successful, the UE can transmit PUSCH in subframe n+5 in response to the same grant received in subframe n. The UE can continue transmitting PUSCH in subsequent subframes if LBT for those subframes is successful and the UE still has data in its UL buffer until a window length (W) is reached. With each PUSCH transmission, the UE can include an associated HARQ ID (x′), where x′ is the value of the associated HARQ ID. The associated HARQ ID (x′) transmitted by the UE can be determined from the HARQ ID (x) provided by the grant, such as the grant in response to which the PUSCH transmission(s) are being made. According to a possible implementation, the value of the associated HARQ ID (x′) can be determined using a formula x′=MOD(x+offset_value, M_UL_HARQ), where ‘offset_value’ is set to 0 for the first PUSCH transmission, and is incremented by one for each additional PUSCH transmission made in response to the same grant, M_UL_HARQ is the Maximum number of UL HARQ processes, and x is the HARQ ID sent with the uplink grant. The M_UL_HARQ value can be defined in the specification or set by higher layers. The formula can limit x′ to the M_UL_HARQ and other equations or processes can be used for the same effect. For an example where the grant received in subframe n has HARQ ID x=0 and window length W=4, assuming LBT is successful for all subframes for the window, and assuming M_UL_HARQ=8, the UE can send associated HARQ ID x′=0 for the first PUSCH transmission made in response to the grant in subframe n+4. If the UE UL buffer is not empty, the UE can send associated HARQ ID x′=1 for the second PUSCH transmission made in response to the grant in subframe n+5. If the UE UL buffer is still not empty, the UE can send associated HARQ ID x′=2 for the third PUSCH transmission made in response to the grant in subframe n+6. If the UE UL buffer is still not empty, UE can send associated HARQ ID x′=3 for the fourth PUSCH transmission made in response to the grant in subframe n+7. For an example where the grant received in subframe n has HARQ ID x=0 and window length W=4, assuming LBT is unsuccessful for subframe n+4 and n+6 but successful for subframes n+5 and n+7, and assuming Maximum number of UL HARQ processes=8, the UE can send associated HARQ ID x′=0 for the first PUSCH transmission made in response to the grant in subframe n+5. If the UE UL buffer is not empty, the UE can send associated HARQ ID x′=1 for the second PUSCH transmission made in response to the grant in subframe n+7. For example, at416, a counter j can be set to 0 and the offset_value can be set to 0. At418, LBT can be performed for transmitting PUSCH in subframe n+4+j. If at420, the carrier is not free, at422, the counter j can be incremented by 1. If j is less than the window length (W) at424, then LBT can be performed for a next subframe at418. If at420, the carrier is free, at426, x′ can be set to MOD (x+offset_value, M_UL_HARQ). At428, the PUSCH transmission can be performed in subframe n+4+j and PUSCH/DMRS can include the associated HARQ ID indication x′. If at430the UE uplink buffer is not empty, at432the offset_value can be incremented and the process can continue at422. If the uplink buffer is empty at430or the counter j has reached the window length (W) at434, the PUSCH transmissions can stop for HARQ ID x for the grant received in subframe n. At438, the flowchart401can end. If at414, the NDI indicates a retransmission, then the UE can determine that the eNB has requested a retransmission of a PUSCH that was transmitted by the UE with associated HARQ ID (x′). In the retransmission grant, the eNB can include the ame HARQ ID (x′) as the associated HARQ ID (x′) that was previously sent by the UE, and sets the NDI bits(s) to indicate a retransmission request. The flowchard401can then advance to step450of flowchart402via step436. The UE can then attempt to make the PUSCH retransmission in subframe n+4, and if the carrier is not free for transmission in subframe n+4, such as when LBT for subframe n+4 is not successful, the UE can attempt PUSCH retransmission in subsequent subframes until a subframe is available or until the window length (W) is reached. If a subframe counter j gets incremented for multiple subframes and does not remain smaller than window length (W), the UE can skip the PUSCH retransmission for HARQ ID x′ in response to the grant received in subframe n. When LBT determines the carrier is free, the UE can include the same associated HARQ ID (x′) indicated by the retransmission grant along with its PUSCH retransmission. Unlike the initial transmission case, the UE may only send one PUSCH retransmission in response to a grant that indicates a retransmission. For example, at452, a counter j can be set to 0. At454, LBT can be performed for transmitting PUSCH in subframe n+4+j. If the carrier is free at456, at458a PUSCH transmission can be performed in subframe n+4+j and PUSCH/DMRS can include the HARQ ID indication (x′) and the flowchart can end at466. If the carrier is not free at456, at460the counter j can be incremented. If at462the counter j is less than the window length W, at454LBT can be performed for transmitting PUSCH in a next subframe. If at462the counter j has reached the window length, at464the PUSCH transmission can be skipped for HARQ ID x′ from the grant received in subframe n. At466, the flowchart402can end. A UE procedure for a fourth option for transmitting PUSCH on unlicensed carrier for initial transmission and retransmission according to a possible embodiment can attempt to avoid a requirement for the UE to transmit HARQ ID along with its PUSCH transmissions. For example, the second option discussed above may require the UE to send the HARQ ID and also a HARQ sub ID, along with each PUSCH transmission to enable the eNB to uniquely identify the Transport Block(s) (TB(s)) associated with that PUSCH transmission. The third option discussed above may require the UE to send an associated HARQ ID, along with each PUSCH transmission to enable the eNB to uniquely identify the Transport Block(s) (TB(s)) associated with that PUSCH transmission. The fourth option can avoid the need for the UE to transmit HARQ ID along with its PUSCH transmissions. Compared to the second and third options, the fourth option can reduce scheduler flexibility for the eNB, but can also result in smaller uplink transmission overhead. In the fourth option, the UE can receive a grant in subframe n. The grant can contain bits indicating a HARQ ID (x) and the grant can also contain bits indicating a window of subframes with window length (W) in which the UE can transmit PUSCH in response to the grant. Alternatively, window length information can be sent to the UE via higher layers instead of including bits in the grant, which can reduce grant payload overhead. The grant can also include bit(s) indicating whether the grant is for a new transmission or a retransmission, such as by using NDI bits. The grant can contain multiple NDI bits, where each NDI bit (p) can correspond to one subframe (subframe n+4+m) in the window of subframes. For example, if the window length W=4, the grant can contain 4 NDI bits with the first bit corresponding to PUSCH transmission in subframe n+4, the second bit corresponding to PUSCH transmission in subframe n+5, and so on. The uplink grant received by the UE can also contain bits indicating a MCS to be used for PUSCH transmission(s), bits indicating Resource Allocation (RA) within a subframe, such as the RBs to use for PUSCH transmission(s), and other bits indicating additional control information. In response to the grant received in subframe n, the UE can make PUSCH transmissions in each subframe (subframe n+4+m) of the window of subframes for which LBT is successful. For subframes where the LBT is not successful, the UE can skip the PUSCH transmission and can wait for the eNB to send another grant requesting retransmission. The HARQ ID for each PUSCH transmission can be determined implicitly based on the subframe index of the subframe used for PUSCH transmission and the HARQ ID signaled in the grant. For example, if the grant in subframe n contains HARQ ID x, the UE's PUSCH transmission in subframe n+4+m can correspond to HARQ ID x″ where x″=MOD (x+m, M_UL_HARQ), and where 0<m<W is the position of the subframe within the window of subframes. Since the HARQ ID can be implicitly linked to subframe index (e.g. n+4+m), there may be no need for the UE to transmit the HARQ ID along with its PUSCH transmission. That is, the eNB can implicitly determine the HARQ ID x″ using the subframe index of the subframe in which PUSCH transmission is received from the UE (e.g. n+4+m), and the HARQ ID sent by the eNB in the grant (e.g., x) and the maximum number of uplink HARQ processes (M_UL_HARQ). Additional embodiments can provide options for performing LBT for uplink transmissions by the UE. For a PUSCH transmission in a subframe, such as subframes n+4 or n+5, according to a first possible implementation, the UE can start performing LBT in the time duration corresponding to the last Orthogonal Frequency multiplexing/Discrete Fourier Transform (OFDM/DFT)-Spread OFDM(A) (DFT-SOFDM (A)) symbol in a previous subframe, such as in subframe n+3 or n+4 respectively. DFT-SOFDM(A) can also be referred to as Single Carrier FDM(A) (SC-FDM(A)). According to second possible implementation, the UE can start performing LBT in the time duration corresponding to the first DFT-SOFDM symbol in the same subframe, such as subframes n+4, n+5 respectively. According to a third possible implementation, for each burst of contiguous PUSCH transmissions in multiple subframes, such as subframes {n+4, n+5, . . . }, the UE can start performing LBT in the time duration corresponding to multiple ending OFDM/DFT-SOFDM symbols of a subframe immediately preceding the burst, such as in subframe n+3. The eNB can send higher layer signaling to the UE based on which the UE can determine the minimum time duration for which it has to perform LBT before initiating a PUSCH transmission. The UE may also determine the maximum number of contiguous subframes in which it can transmit using higher layer signaling from the eNB. For example, the eNB can signal a ‘q’ value as specified in ETSI EN 301 893 specifications, such as in a clause describing channel access mechanism for load based equipment via higher layers. The UE can use the ‘q’ value to determine the minimum time duration for which it has to do LBT, such as using CCA and extended CCA mechanisms, before initiating the PUSCH transmission. The UE can also determine the maximum of contiguous subframes in which it can transmit PUSCH by deriving the maximum channel occupancy time using the ‘q’ value. To support scheduling of multiple UEs transmissions in the same subframe, UEs may need to perform LBT operation in the same time window. The transmission in the previous subframe may originate from the eNB (downlink) or another UE(s) (uplink). The eNB may configure the UEs to start performing LBT assessments no earlier than T1 sec from the start of the guard period, such as a last OFDM/DFT-SOFDM symbol duration in the first implementation, and end LBT no later than T2 sec from the start of the PUSCH transmission if CCA is successful. T1 and T2 may include Tx/Rx switching time and expected worst case propagation delay. The eNB may also configure the same or substantially similar, such as within a few us, Timing Advance (TA) value for the UEs. The TA value may be a fixed value TA1, such as 624 Ts, in the specification. If a UE using the second option above performs LBT using the second implementation, then the UE may need to perform LBT only once for each burst of contiguous PUSCH transmission subframes, instead of once for each PUSCH transmission subframe. For example, for the process illustrated in flowchart401, while the UE may have to perform LBT and check if the carrier is free for PUSCH transmission corresponding to subframe where j=0, it can also skip the step of performing LBT and checking if carrier is free for other values of j. If devices operating on the unlicensed carrier have to follow a maximum occupancy time requirement, the eNB can be expected to signal a W value that is roughly equal to the maximum channel occupancy time requirement. FIG.5is an example illustration of an uplink transmission500with LBT according to a possible embodiment. Typically for normal Cyclic Prefix (CP) there are 14 symbols in an LTE subframe (uplink or downlink), where each symbol can correspond to roughly 70 us duration. For a UE to perform uplink transmission in subframe n+4, the UE may have to perform LBT in the last DFT-SOFDM symbol of the previous subframe. If the previous subframe (n+3) was an uplink subframe, the UE would have to shorten its PUSCH transmissions in subframe n+3. The last symbol of an uplink subframe is typically reserved for PUSCH or SRS (Sounding Reference Signal) transmission from the UE to help eNB scheduling. Since LBT can disallow SRS transmissions in the last symbol, an alternate method can be useful to allow transmission of SRS from the UE to the eNB. FIG.6is an example illustration of uplink transmission600with LBT and SRS in a first DFT-SOFDM symbol of a subframe according to a possible embodiment. There may be three types of UE transmission on the uplink in unlicensed spectrum. For SRS transmission only, since a UEs LBT can disallow SRS transmissions in the last symbol of an uplink subframe, an alternate location for SRS transmission can be used. The UE can transmit SRS as soon as it senses a channel is free. Otherwise, the UE may have to transmit a reservation signal to keep the channel occupied until the time it is allowed to transmit the SRS. The UE can transmit the SRS in the first DFT-SOFDM symbol of an uplink subframe. This can allow a UE to do LBT immediately prior to the DFT-SOFDM symbol and transmit whenever the channel is free. To ensure that other UEs that are only performing PUSCH transmissions in that subframe are not affected, the eNB can signal to the other UEs to avoid PUSCH mapping to the first DFT-SOFDM symbol of the subframe. For PUSCH transmission only, a shortened PUSCH can be used, where no PUSCH is transmitted in the symbol reserved for LBT. PUSCH may not be transmitted in the first DFT-SOFDM symbol reserved for SRS in a subframe. This can be indicated using a field in uplink grant to the UE scheduled for PUSCH transmission. TABLE 1One Bit Field Uplink Grant for PUSCH TransmissionField inUplinkgrantfunctioncomment0No SRS symbol in theTransmit PUSCH withoutsubframerate-matching around 1stsymbol1First symbol in theTransmit PUSCH withsubframe is reservedrate-matching around 1stfor SRSsymbol Alternatively, a two bit field can be used to explicitly indicate whether there is an SRS symbol in the subframe, whether the UE's PUSCH has to be rate-matched around the SRS symbol, and which configuration is used for transmitting the SRS in the first symbol. TABLE 2Two Bit Field Uplink Grant for PUSCH TransmissionField inUplinkgrantFunction00No SRS symbol in theTransmit PUSCH withoutsubframerate-matching around 1stsymbol01First symbol in theTransmit PUSCH withsubframe is reservedrate-matching around 1stfor SRSsymbol10First symbol in theTransmit PUSCH withsubframe is reservedrate-matching around 1stfor SRS, transmit SRSsymbol, transmit SRS inusing firstthe first symbolconfiguration11First symbol in theTransmit PUSCH withsubframe is reservedrate-matching around 1stfor SRS, transmit SRSsymbol, transmit SRS inusing secondthe first symbolconfiguration The UE may lose the channel if it does LBT, such as the case where CCA performed by the UE is successful in the last symbol of the previous subframe, the UE does not have to transmit in the first OFDM symbol of the subframe, and the UE can attempt to transmit PUSCH in the remaining symbols of the subframe. Therefore, a UE that is configured to transmit PUSCH can always transmit SRS in the first symbol of the subframe, such as an unsolicited SRS just prior to transmitting PUSCH. The ‘01’ or ‘1’ value may then correspond to transmitting SRS using a third configuration, with SRS transmission in the first symbol. For PUSCH and SRS transmission, a UE that is scheduled to transmit both PUSCH and SRS transmission may transmit SRS in the first symbol of the subframe, followed by PUSCH in the rest of the subframe. An explicit aperiodic SRS transmission indicator can be used to indicate to the UE whether, and in which resources, the SRS is transmitted. In another alternative, a UE may be configured such that it performs LBT in 13thDFT-SOFDM symbol of subframe n+3, transmit SRS in 14thDFT-SOFDM symbol, such as a last symbol, of subframe n+3, and then transmit PUSCH in subframe n+4 in first to 12thDFT-SOFDM symbols, so it can again perform LBT in 13thsymbol of subframe n+4. FIG.7is an example flowchart700illustrating a user equipment procedure for transmitting the SRS according to a possible embodiment. At710, the flowchard700can begin. At720, an uplink grant can be received. The uplink grant can include a field requesting the SRS transmission. The uplink grant can also include a field indicating a SRS resource in the DFT-SOFDM symbol for transmission of SRS. The uplink grant can additionally include a field that indicates there is no SRS in the subframe. The uplink grant can further include a field that indicates a configuration for transmitting the SRS. Alternately, or in addition to receiving the uplink grant, a signal can received that indicates avoiding PUSCH mapping in the first DFT-SOFDM symbol of a subframe. PUSCH mapping can be abstained in the first DFT-SOFDM symbol of the subframe in response to receiving the signal that indicates avoiding PUSCH mapping in the first DFT-SOFDM symbol of the subframe. At730, listen before talk can be performed to determine when a subframe is available for uplink transmission. The listen before talk procedure can be performed on an unlicensed carrier in response to receiving the uplink grant. At740, a SRS can be transmitted in a first DFT-SOFDM symbol of the subframe when listen before talk indicates that the subframe is available. Transmission of SRS in the first DFT-SOFDM symbol can be performed in response to the field in the uplink grant requesting the SRS transmission. Transmission of the SRS in the first DFT-SOFDM symbol can also be performed in the SRS resource indicated by the field in the uplink grant. Transmission of the SRS in the first DFT-SOFDM symbol can additionally be performed even when the field that indicates there is no SRS in the subframe. Transmission of the SRS in the first DFT-SOFDM symbol can further be performed based on the field indicating the configuration for transmitting the SRS. At750, a PUSCH can be transmitted in at least a portion of a remaining part of the subframe. The portion of the remaining part of the subframe can exclude at least the last DFT-SOFDM symbol of the subframe. At760, the flowchart700can end. According to a possible embodiment, the eNB can include a HARQ ID, such as an UL HARQ ID, in the grant sent to the UE. While transmitting PUSCH in response to the grant, the UE can send the HARQ ID, such as the UL HARQ ID, along with the PUSCH transmission. For the second option discussed before, the UE can include both the HARQ ID and the HARQ-subID along with its PUSCH transmissions. The HARQ ID/HARQ subID can be transmitted by the UE using different approaches. For a first approach, a one-to-one mapping can be specified between UL HARQ ID and DMRS cyclic shift value. The UE can receive the UL HARQ ID in the UL grant and can use the corresponding DMRS cyclic shift value determined from the pre-specified mapping for transmitting or retransmitting PUSCH associated with that UL HARQ ID. For example, if the UL grant contains UL HARQ ID (x), the UE can transmit the corresponding PUSCH using DMRS cyclic shift x. For a second approach, the UE can multiplex bits indicating HARQ ID, and HARQ subID if needed, within its PUSCH transmission. The uplink HARQ ID, and HARQ subID if needed, can be multiplexed within PUSCH using different methods. One method for multiplexing the uplink HARQ ID, and HARQ subID if needed, can use Uplink Control Information (UCI) multiplexing type 1. In this case, the uplink HARQ ID, such as a HARQ ID having <3 bits, can be encoded using a block code to a particular code and the number of resource elements for transmission of the uplink HARQ ID can be determined, based on the uplink data MCS. The encoded uplink HARQ ID can mapped to a subset of resource elements from the set of resource elements assigned for PUSCH transmission. This subset can be determined based on a predetermined nile, such as in a set of or portion of DFT-SOFDM symbols in the subframe, such as OFDM symbols 1, 2, or in a set of resources, such as lowest indexed modulation symbols corresponding to the resource assignment. A similar approach can be used for HARQ subID, such as with 2 additional bits, with possibly joint encoding with the HARQ ID. Another method for multiplexing the uplink HARQ ID, and HARQ subID if needed, can multiplex the UL HARQ ID with uplink data using various additional methods. One method for multiplexing the UL HARQ ID with uplink data can use rate-matching. In this case, the encoded uplink HARQ ID can be mapped to a subset of modulation symbols and the encoded data can be mapped to the remaining subset of modulation symbols assigned for PUSCH transmission. This can be a useful mechanism if the eNB is aware that the encoded uplink HARQ ID is always sent by the UE. A similar approach can be used for a HARQ subID. Another method for multiplexing the UL HARQ ID with uplink data can use puncturing. In this case, the encoded data can be mapped to the all of the modulation symbols assigned for PUSCH transmission and the uplink HARQ ID can be mapped to a subset of modulation symbols, overwriting any encoded data. This can be a useful mechanism if the eNB is not always sure if the encoded uplink HARQ ID is always sent by the UE. Thus, in cases where the encoded uplink HARQ ID is not transmitted, the UE can use the subset of modulation symbols for PUSCH to improve the data performance. A similar approach can be used for a HARQ subID. In another method for multiplexing the uplink HARQ ID, and HARQ subID if needed, for UL-MIMO, the uplink HARQ ID information may be multiplexed with data on both UL-SCH transport blocks and possibly on the same modulation symbol resources. Other methods for multiplexing the uplink HARQ ID, and HARQ subID if needed, can include other types of UCI multiplexing on PUSCH, such as methods used in LTE for multiplexing CQI (Channel Quality Indicator) or PMI (Precoder Matrix Indicator) or RI (Rank Indicator) or HARQ-ACK (Hybrid ARQ Acknowledgments), and other methods. The HARQ ID may be encoded in multiple ways. For one way of encoding a HARQ ID, a CRC may be attached and the CRC-encoded HARQ ID may be coded using a block code such as Reed-Muller code or convolutional code. This can allow an eNB to reliably detect the HARQ-ID. A similar approach can be used for a HARQ subID. The HARQ ID can also be directly encoded using a block code such as Reed-Muller code or convolutional code. Since there is no CRC, there may be no reliable error detection, but this can enable a lower coding rate, which can result in improved performance. A similar approach can be used for a HARQ subID. For 1 or 2 bit HARQ ID/sub ID, the HARQ ID/sub ID bits can be mapped to a Binary Phase Shift Keying (BPSK)/Quadrature Phase Shift Keying (QPSK) symbol, and the BPSK/QPSK symbol can be used to modulate one of the demodulation reference signals in the subframe. The UE can indicate UL HARQ ID using a first method (for example, using the first approach described above) and UL HARQ subID using a second method (for example, using the second approach described above). FIG.8is an example block diagram of an apparatus800, such as the UE110or the UE112, according to a possible embodiment. The apparatus800can include a housing810, a controller820within the housing810, audio input and output circuitry830coupled to the controller820, a display840coupled to the controller820, a transceiver850coupled to the controller820, an antenna855coupled to the transceiver850, a user interface860coupled to the controller820, a memory870coupled to the controller820, and a network interface880coupled to the controller820. The apparatus800can perform the methods described in all the embodiments. The display840can be a viewfinder, a liquid crystal display (LCD), a light emitting diode (LED) display, a plasma display, a projection display, a touch screen, or any other device that displays information. The transceiver850can include a transmitter and/or a receiver. The audio input and output circuitry830can include a microphone, a speaker, a transducer, or any other audio input and output circuitry. The user interface860can include a keypad, a keyboard, buttons, a touch pad, a joystick, a touch screen display, another additional display, or any other device useful for providing an interface between a user and an electronic device. The network interface880can be a universal serial bus port, an Ethernet port, an infrared transmitter/receiver, a USB port, an IEEE 1398 port, a WLAN transceiver, or any other interface that can connect an apparatus to a network or computer and that can transmit and receive data communication signals. The memory870can include a random access memory, a read only memory, an optical memory, a flash memory, a removable memory, a hard drive, a cache, or any other memory that can be coupled to a wireless communication device. The apparatus800or the controller820may implement any operating system, such as Microsoft Windows®, UNIX®, or LINUX®, Android™, or any other operating system. Apparatus operation software may be written in any programming language, such as C, C++, Java or Visual Basic, for example. Apparatus software may also run on an application framework, such as, for example, a Java® framework, a .NET® framework, or any other application framework. The software and/or the operating system may be stored in the memory870or elsewhere on the apparatus800. The apparatus800or the controller820may also use hardware to implement disclosed operations. For example, the controller820may be any programmable processor. Disclosed embodiments may also be implemented on a general-purpose or a special purpose computer, a programmed microprocessor or microprocessor, peripheral integrated circuit elements, an application-specific integrated circuit or other integrated circuits, hardware/electronic logic circuits, such as a discrete element circuit, a programmable logic device, such as a programmable logic array, field programmable gate-array, or the like. In general, the controller820may be any controller or processor device or devices capable of operating an electronic device and implementing the disclosed embodiments. In operation according to a possible embodiment, the transceiver850can receive a configuration indicating a window length from a higher layer, where the higher layer is higher than a physical layer. The transceiver850can also receive a grant in a subframe, where the grant can be for transmitting a PUSCH on a serving cell operating on an unlicensed carrier. The grant for transmitting the PUSCH can include a HARQ ID. The controller820can determine a set of subframes for possible transmission of the PUSCH based on the window length and the subframe in which the grant is received. The set of subframes can include a number of subframes, where the number of subframes in the set of subframes can be equal to the window length. The controller820can also perform LBT on the unlicensed carrier to determine an earliest unoccupied subframe in the set of subframes. The transceiver850can transmit the PUSCH in the earliest unoccupied subframe in response to receiving the grant. The transceiver850can transmit the PUSCH in the earliest unoccupied subframe if the unoccupied subframe is unoccupied and if the unoccupied subframe is within the window length. The transceiver850can indicate the HARQ ID along with the PUSCH transmission. According to a possible implementation, the controller820can determine a demodulation reference signal cyclic shift value based on the HARQ ID and the transceiver850can transmit a demodulation reference signal using the determined cyclic shift value, along with the PUSCH transmission. According to another possible implementation, the transceiver850can indicate the HARQ ID along with the PUSCH transmission by multiplexing bits indicating the HARQ ID into a portion of resources assigned for the PUSCH transmission. The transceiver850can also receive a second grant in a second subframe, where the second grant can be for transmiffing a second PUSCH on the serving cell operating on the unlicensed carrier. The controller820can determine a second set of subframes for possible transmission of the second PUSCH based on the window length and the second subframe in which the second grant is received. The determined earliest unoccupied subframe can be a subframe in the second set of subframes. The controller820can then prioritize one of multiple PUSCH transmissions based on the order in which each corresponding PUSCH grant is received. The transceiver850can then transmit the prioritized PUSCH transmission in the earliest unoccupied subframe. The controller820can perform LBT a first subframe in the set of subframes, can determine the first subframe in the set of subframes is occupied, and can perform LBT on subsequent subframes in the set of subframes to determine an earliest unoccupied subframe in the set of subframes. The controller820can determine none of the subframes in the set of subframes are free for PUSCH transmission based on performing LBT, and can skip transmitting PUSCH for the grant if none of the subframes in the set of subframes are free for PUSCH transmission. In operation according to another possible embodiment, the transceiver850can receive, in a subframe, a grant for transmitting PUSCH on a serving cell operating on an unlicensed spectrum. The grant for transmitting PUSCH can include a HARQ ID. The controller820can determine a set of subframes for possible transmission of the PUSCH and perform LBT on the unlicensed carrier to determine an earliest unoccupied subframe in the set of subframes. The transceiver850can transmit a PUSCH in multiple subframes within the set of subframes on the unlicensed carrier, starting with the earliest unoccupied subframe, in response to receiving the grant. The transceiver850can include the HARQ ID in each PUSCH transmission in the multiple subframes. The transceiver850can also include a HARQ subID along with each PUSCH transmission in the multiple subframes. The HARQ subID can be for a particular PUSCH transmission in the multiple subframes. The HARQ subID can be set to 0 for the first PUSCH transmission, can be set to 1 for the second PUSCH transmission, and can be incremented for each subsequent PUSCH transmission. The controller820can determine a new HARQ ID for each PUSCH transmission made in response to the grant. The new HARQ ID can be determined based on the received HARQ ID and an order of the PUSCH transmission within the PUSCH transmission in the multiple subframes. The transceiver850can transmit each new HARQ ID along with each PUSCH transmission. The new HARQ ID can also be determined based on the received HARQ ID and a subframe index of the subframe where each PUSCH transmission is made. The transceiver850can then receive a second grant requesting a retransmission. The second grant can include the new HARQ ID that was previously transmitted. The transceiver850can then transmit PUSCH in response to the second grant to retransmit the data that is associated with the same new HARQ ID. In operation according to another possible embodiment, the transceiver850can receive an uplink grant. The uplink grant can include a field requesting the SRS transmission. The uplink grant can also include a field indicating a SRS resource in the DFT-SOFDM symbol for transmission of SRS. The uplink grant can additionally include a field that indicates there is no SRS in the subframe. The uplink grant can further include a field that indicates a configuration for transmitting the SRS. The controller820can perform LBT to determine when a subframe is available for uplink transmission. For example, the controller820can perform the LBT in response to the transceiver receiving the uplink grant. The controller820can perform LBT on an unlicensed carrier to determine when a subframe is available for uplink transmission. The transceiver850can transmit a SRS in a first DFT-SOFDM symbol of the subframe when LBT indicates that the subframe is available. The transmission of the SRS in the first DFT-SOFDM symbol can be performed in response to the field in the uplink grant requesting the SRS transmission. The transmission of the SRS in the first DFT-SOFDM symbol can also be performed even when the field that indicates there is no SRS in the subframe. The transmission of the SRS in the first DFT-SOFDM symbol can additionally be performed in the SRS resource indicated by the field in the uplink grant. The transmission of the SRS in the first DFT-SOFDM symbol can further be performed based on the field indicating the configuration for transmitting the SRS. The transceiver850can transmit PUSCH in at least a portion of a remaining part of the subframe. The portion of the remaining part of the subframe can exclude at least the last DFT-SOFDM symbol of the subframe. The transceiver850can also receive a signal that indicates avoiding PUSCH mapping in the first DFT-SOFDM symbol of a subframe. The controller820can then abstain from PUSCH mapping in the first DFT-SOFDM symbol of the subframe in response to receiving the signal that indicates avoiding PUSCH mapping in the first DFT-SOFDM symbol of the subframe. FIG.9is an example block diagram of a base station900, such as the eNB120, according to a possible embodiment. The base station900may include a controller910, a memory920, a database interface930, a transceiver940, Input/Output (I/O) device interface950, a network interface960, and a bus970. The base station900can implement any operating system, such as Microsoft Windows®, UNIX, or LINUX, for example. Base station operation software may be written in any programming language, such as C, C++, Java or Visual Basic, for example. The base station software can run on an application framework, such as, for example, a Java® server, a .NET® framework, or any other application framework. The transceiver940can create a data connection with the UE110. The controller910can be any programmable processor. Disclosed embodiments can also be implemented on a general-purpose or a special purpose computer, a programmed microprocessor or microprocessor, peripheral integrated circuit elements, an application-specific integrated circuit or other integrated circuits, hardware/electronic logic circuits, such as a discrete element circuit, a programmable logic device, such as a programmable logic array, field programmable gate-array, or the like. In general, the controller910can be any controller or processor device or devices capable of operating a base station and implementing the disclosed embodiments. The memory920can include volatile and nonvolatile data storage, including one or more electrical, magnetic, or optical memories, such as a Random Access Memory (RAM), cache, hard drive, or other memory device. The memory920can have a cache to speed access to specific data. The memory920can also be connected to a Compact Disc-Read Only Memory (CD-ROM), Digital Video Disc-Read Only memory (DVD-ROM), DVD read write input, tape drive, thumb drive, or other removable memory device that allows media content to be directly uploaded into a system. Data can be stored in the memory920or in a separate database. For example, the database interface930can be used by the controller910to access the database. The database can contain any formatting data to connect the terminal110to the network130. The I/O device interface950can be connected to one or more input and output devices that may include a keyboard, a mouse, a touch screen, a monitor, a microphone, a voice-recognition device, a speaker, a printer, a disk drive, or any other device or combination of devices that accept input and/or provide output. The I/O device interface950can receive a data task or connection criteria from a network administrator. The network connection interface960can be connected to a communication device, modem, network interface card, a transceiver, or any other device capable of transmitting and receiving signals to and from the network130. The components of the base station900can be connected via the bus970, may be linked wirelessly, or may be otherwise connected. Although not required, embodiments can be implemented using computer-executable instructions, such as program modules, being executed by an electronic device, such as a general purpose computer. Generally, program modules can include routine programs, objects, components, data structures, and other program modules that perform particular tasks or implement particular abstract data types. The program modules may be software-based and/or may be hardware-based. For example, the program modules may be stored on computer readable storage media, such as hardware discs, flash drives, optical drives, solid state drives, CD-ROM media, thumb drives, and other computer readable storage media that provide non-transitory storage aside from a transitory propagating signal. Moreover, embodiments may be practiced in network computing environments with many types of computer system configurations, including personal computers, hand-held devices, multi-processor systems, microprocessor-based or programmable consumer electronics, network personal computers, minicomputers, mainframe computers, and other computing environments. Embodiments can provide for a method including UE being configured by higher layers with a window length (W) parameter, receiving a grant for transmitting PUSCH on a serving cell operating in unlicensed spectrum, determining a set of subframes for possible transmission of PUSCH based on W and the subframe in which the grant is received, performing listen before talk on the inlicensed carrier to determine the earliest unoccupied subframe in the set of subframes, and transmitting PUSCH in that earliest subframe in response to the received grant. The method can include receiving a HARQ ID (x) in the grant and including the received HARQ ID (x) along with the PUSCH transmission. If multiple PUSCH transmissions due to multiple received grants are possible in the same subframe, the method can include prioritizing one of the multiple PUSCH transmissions based on the order in which the grants corresponding to the transmissions are received, and transmitting the prioritized PUSCH transmission in the earliest subframe. Embodiments can provide for a method including UE receiving a grant for transmitting PUSCH on a serving cell operating in unlicensed spectrum, determining a set of subframes for possible transmission of PUSCH, performing listen before talk on the unlicensed carrier to determine the earliest unoccupied subframe in the set of subframes, and making multiple PUSCH transmissions in multiple subframes within the set of subframes, starting with the earliest unoccupied subframe, in response to the received grant. The method can include determining the set of subframes for possible transmission of PUSCH using the subframe index of the subframe in which the grant is received and a window length parameter including a window length (W) that is either received in the grant or configured via higher layers. The method can include receiving a HARQ ID (x) in the grant and including the received HARQ ID (x) in each of the multiple PUSCH transmissions, in addition to the HARQ ID (x), including a HARQ subID (y) along with each of the multiple PUSCH transmissions, where the HARQ subID can be set to 0 (y=0) for the first PUSCH transmission, can be set to 1 (y=1) for the second PUSCH transmission, etc. The method can include receiving a second grant requesting a retransmission, wherein the second grant can include a HARQ ID and HARQ subID that was previously transmitted by the UE, and transmitting PUSCH in response to the second grant to retransmit data that is associated with the same HARQ ID and HARQ subID. The method can include receiving a HARQ ID (x) in the grant, determining a new HARQ ID (x′) for each PUSCH transmission made in response to the grant, and transmitting the new HARQ ID (x′) along with each PUSCH transmission, where the new HARQ ID (x′) can be determined based on the received HARQ ID (x) and the order of the PUSCH transmission within the multiple PUSCH transmissions. The method can include receiving a second grant requesting a retransmission, where the second grant can include a HARQ ID (x′) that was previously transmitted by the UE, and transmitting PUSCH in response to the second grant to retransmit the data that is associated with the same HARQ ID (x′). The method can include receiving a HARQ ID (x) in the grant, determining a new HARQ ID (x″) for each PUSCH transmission made in response to the grant, where the new HARQ ID (x″) can be determined based on the received HARQ ID (x) and the subframe index of the subframe where each PUSCH transmission is made, receiving a second grant requesting a retransmission, where the second grant can include a HARQ ID (x″) that was previously transmitted by the UE, and transmitting PUSCH in response to the second grant to retransmit the data that is associated with the same HARQ ID (x″). The method can include receiving multiple New Data Indicators (NDI's) within the grant, where each NDI value can be associated with each subframe within the determined set of subframes for possible transmission of PUSCH, and transmitting either new data or retransmission in that subframe according to the NDI value. Embodiments can provide for a UE determining a minimum time for performing clear channel assessment before determining that a carrier is unoccupied, a maximum channel occupancy time for contiguous transmission on the carrier, and/or a starting position of a symbol within a subframe for initiating clear channel assessment; for performing LBT, based on signaling received from eNB. Embodiments can also provide for a method including a UE performing LBT, transmitting SRS in the first OFDM symbol of an uplink subframe if LBT passes, and transmitting PUSCH in at least a portion of the remaining part of the subframe. The methods of this disclosure can be implemented on a programmed processor. However, the controllers, flowcharts, and modules may also be implemented on a general purpose or special purpose computer, a programmed microprocessor or microcontroller and peripheral integrated circuit elements, an integrated circuit, a hardware electronic or logic circuit such as a discrete element circuit, a programmable logic device, or the like. In general, any device on which resides a finite state machine capable of implementing the flowcharts shown in the figures may be used to implement the processor functions of this disclosure. While this disclosure has been described with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. For example, various components of the embodiments may be interchanged, added, or substituted in the other embodiments. Also, all of the elements of each figure are not necessary for operation of the disclosed embodiments. For example, one of ordinary skill in the art of the disclosed embodiments would be enabled to make and use the teachings of the disclosure by simply employing the elements of the independent claims. Accordingly, embodiments of the disclosure as set forth herein are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the disclosure. In this document, relational terms such as “first,” “second,” and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. The phrase “at least one of” followed by a list is defined to mean one, some, or all, but not necessarily all of, the elements in the list. The terms “comprises,” “comprising,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element proceeded by “a,” “an,” or the like does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element. Also, the term “another” is defined as at least a second or more. The terms “including,” “having,” and the like, as used herein, are defined as “comprising.” Furthermore, the background section is written as the inventor's own understanding of the context of some embodiments at the time of filing and includes the inventor's own recognition of any problems with existing technologies and/or problems experienced in the inventor's own work. | 74,052 |
RE49792 | DETAILED DESCRIPTION In the following description, numerous specific details are given to provide a thorough understanding of various exemplary embodiments. The embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. The sizes and relative positions of elements in the figures are not necessarily drawn to scale. For example, the shapes of various elements and angles may not be drawn to scale, and some of these elements may be enlarged and positioned to improve drawing legibility. Further, the particular shapes of the elements as drawn are not intended to convey any information regarding the actual shape of the particular elements and have been solely selected for ease of recognition in the drawings. The headings and reference signs provided herein are for the reader's convenience only and do not interpret the scope or meaning of the embodiments. FIGS.1and2are schematically representative of implantation of an implant device V such as e.g. a valve prosthesis at an implantation site such as e.g. a heart site such as a mitral valve site. In one or more embodiments, such a valve prosthesis V may include one or more prosthetic leaflets L as schematically shown in dashed lines inFIGS.1to3. The valve prosthesis V is schematically represented as an annular structure (body member) intended to be anchored at an annular site AS by means of one or more anchoring members10. Only one such anchoring member is shown inFIGS.1and2for ease of illustration. In one or more embodiments, the valve prosthesis V may be of a type adapted to be implanted by adopting a “sutureless” approach e.g. via non-invasive thoracic (micro)surgery or via percutaneous procedure. In one or more embodiments, the valve prosthesis V may be a collapsible valve prosthesis. The exemplary representation ofFIGS.1and2refers to an implantation approach which involves the conservation of the native valve structures e.g. the leaflets (and the chordae tendinae, not visible in the schematic representation ofFIGS.1and2). The representation ofFIGS.1and2is schematically exemplary of the annular site AS, that is the structure(s) of the body of the patient to which the implant device V is intended to be anchored. In various possible contexts of use, the body structure in question (e.g. the native leaflets) may be soft and/or weakened (e.g. due to a pathological state) and thus little able to support stresses. As exemplified inFIG.2, anchoring members10as per one or more embodiments are adapted to cooperate with such a body structure by “grasping” it, that is by wrapping/winding to a rolled up condition where the body structure (e.g. the native leaflets) may become firmly yet gently entrapped in the convoluted shape of the anchoring member once rolled up. The schematic representation of a valve prosthesis ofFIGS.1and2is exemplary of the applicability of one or more embodiments to devices such as e.g. different types of valve prostheses (a mitral valve prosthesis being just one possible choice among various valve types) and, more generally, to other types of implant devices such as e.g. stents (e.g. peripheral stents), stent-grafts, cardiac rhythm management devices and so on. Also, while one anchoring member10is shown inFIGS.1and2located at one end of the device V for simplicity of representation, plural anchoring members10(identical or having different sizes/shapes and configurations) may be associated to either or both ends of a single implant device V. Plural anchoring members10as illustrated inFIGS.1and2distributed with uniform/non-uniform spacing around an implant device such as a prosthetic valve may be exemplary of such arrangements including plural anchoring members. In one or more embodiments, the anchoring members may be spaced 90 degrees apart. In one or more embodiments, the anchoring members may be placed in opposing pairs, e.g. opposing pairs spaced 10-60 degrees apart. Such a placement may optionally match the typical anatomy of a mitral valve. As shown inFIGS.1and2, one or more embodiments of an anchoring member10may include an elongated element deployable to a deployed (e.g. expanded) condition—see e.g.FIG.1—for insertion in an animal body e.g. for locating the implant device V at an implantation site AS and retractable (collapsible) by winding/wrapping to a rolled up collapsed condition—see e.g.FIG.2—where the anchoring member grasps, that is captures a structure of a patient's body (e.g. the annular site AS as exemplified by the natural valve leaflets illustrated inFIGS.1and2) to anchor the implant device V at the implantation site. In one or more embodiments, the anchoring member10may include an elastic (optionally superelastic) material and be configured to be elastically biased towards the rolled up (collapsed) condition ofFIG.2: that is, in the absence of forces applied, the anchoring member will assume the rolled up condition. The member10may thus be deployed (e.g. unwound) to the extended condition ofFIG.1, maintained in such a condition (e.g. by one of the constraint members as exemplified in the following) and then permitted (e.g. by being released by the constraint member) to return e.g. (super) elastically to the rolled up condition ofFIG.2. Exemplary of materials adapted to exhibit such a behavior are any one or combination of flexibly resilient, medical grade materials including, for example, Nitinol, stainless steel, or other suitable metal or plastics having e.g. shape memory characteristics. In one or more embodiments, the anchoring member10may include a shape memory material and be configured to pass from the deployed condition ofFIG.1to the rolled up condition ofFIG.2via a shape memory effect, optionally stimulated by the application of e.g. thermal, optical or electrical energy. Materials such as Nitinol may exhibit both elastic/super-elastic properties and shape memory behavior and are thus cited as exemplary of both. In one or more embodiments, the anchoring member10may include a proximal portion10a which retains the deployed condition (e.g. inFIGS.1and2the portion10a substantially maintains the same rectilinear shape) and a distal portion10b which is subject to rolling up. In one or more embodiments, when in the rolled up condition, the anchoring member10may thus be generally hook-shaped. As used herein, “proximal” and “distal” may refer to the coupling condition of the anchoring member10to the implant device V. The “distal” portion10b subject to rolling up may thus be the portion of the anchoring member10opposed to the implant device V which is intended to cooperate with the patient body structure in anchoring the implant device at the implantation site. FIGS.3to5are exemplary of one or more embodiments of an implant device including one or more anchoring members10. ThroughoutFIGS.3to5an implant device V is exemplified in the form of a valve prosthesis (e.g. mitral) including an annular structure or body member such as a radially expandable stent-like support armature for the valve leaflets L (not visible in certain figures). As shown inFIGS.3to5, the stent-like structure may include plural annular members having a zig-zag pattern staggered along the axial direction of the stent structure, these annular members being connected by axial connection members or “links”. FIGS.3to5are exemplary of one or more embodiments of an implant device V including an annular (e.g. tubular) stent-like body or support structure (armature) extending axially—e.g. in an axial direction of the annular structure—between opposed ends of the device V. In the (purely exemplary) case of valve prosthesis as shown herein, the device may include two end openings at least approximately lying in respective notional end planes IEP and OEP. In exemplary embodiments for use e.g. at a mitral implantation site the end planes IEP and OEP correspond to blood inflow and blood outflow openings from the left atrium into the left ventricle of the heart. A desirable feature in such possible implantation is that the amount the implant device V protrudes into the ventricular chamber is reduced in order to minimize possible interference with (natural or prosthetic) aortic valve operation to control blood flow from the left ventricle into the aorta. FIG.3refers to an exemplary embodiment where four anchoring members10(angularly spaced 90° to one another over the valve periphery) may be one-piece with the armature of the implant device. In one or more embodiments, the proximal portions10a of the anchoring members10may also form the links of the stent structure. As shown inFIG.3, in one or more embodiments, the anchoring members10may be arranged (e.g. positioned, dimensioned and shaped) in such a way that in a rolled up (collapsed) condition wherein they provide anchoring of the implant device V to the body structure AS (see alsoFIG.2orFIG.12C) the anchoring members10may at least partly protrude radially outwardly of the annular structure of the device V while also at least partly protruding axially outwardly of the annular structure of the device V. That is, in one or more embodiments, in the rolled up (collapsed) condition the anchoring members10may at least partly protrude with respect to the end plane OEP of the annular structure of the device V to which they are associated. In one or more embodiments, this result may be achieved by causing (the distal portion10b of) the anchoring members10to be finally rolled up—that is wound up in the collapsed implantation condition—according to a e.g. spiral or helix-like trajectory centered around a point XWwhich is coplanar with the end plane OEP. Such a central region of the (final) rolled up/wound trajectory of the anchoring members10may be notionally identified as a center point of the trajectory. In one or more embodiments, design factors and/Or tolerances inherently associated with manufacturing the implant devices exemplified herein, may cause such a trajectory to correspond only approximately to a geometric curve having a single center point. For that reason, reference has been made previously to a trajectory centered e.g. having a locus of curvature points located “around”, that is in the vicinity of a point XWwhich is coplanar with the end plane OEP. In one or more embodiments, the result of having the anchoring members10at least partly protrude axially outwardly of the annular structure of the device V (also) in the collapsed implantation condition may be achieved by having the root of the distal portion10b, that is the region of the distal portion10b adjacent to the proximal portion10a of the anchoring members10to retain an axial orientation with respect to the annular structure of the device, while the rest of the distal portion10b undergoes the rolling up/winding movement towards the collapsed condition. In one or more embodiments the device V may thus include one or more anchoring members10including a proximal portion10a coextensive with the annular structure of the device V and a distal portion10b extending away from the annular structure of the device V: in the rolled up (collapsed) condition, the region of the distal portion10a adjacent to the proximal portion10a (that is adjacent to the annular structure of the device) in any case retains an axial orientation with respect to the annular structure of the device V. One or more embodiments as exemplified herein thus make it possible to minimize the amount the implant device V protrudes into the ventricular chamber. As exemplified inFIG.12Cthe (blood outflow) plane OEP will end up by being located in a recessed position with respect to the surrounding body structure AS “grasped” by the anchoring members10which retain the device V at the implantation site. This is in contrast e.g. with implementations as exemplified in US 2010/0312333 A1 wherein windable coils located at the opposed ends of the body member of the device can respectively contact the superior and inferior aspects of a native mitral annulus when the apparatus is in an expanded configuration. In addition to failing to exert any grasping action on the tissues of the mitral annulus, in the collapsed implantation condition, the coils of US 2010/0312333 are completely withdrawn within the body member of the device, which will cause the device to protrude significantly and undesirably into the ventricular chamber. FIG.4refers to exemplary embodiments where one or more anchoring members10may be coupled via welding (welding spots are schematically indicated at10c) to the structure of the implant device (e.g. to the axial links of the stent-like structure). FIG.5refers to an exemplary embodiment where one or more anchoring members10may be coupled to the implant device V (e.g. to the axial links of stent-like structure) via stitches. In one or more embodiments the stitches10d may include biocompatible material such as surgical thread. FIGS.6to9exemplify various possible embodiments of anchoring members10illustrated in the rolled up condition. The examples shown refer to anchoring members that have a general hook-like shape in the rolled up condition including a linear proximal portion10a and distal portion10b subject to winding. FIGS.6to9exemplify the possibility for one or more embodiments to include:a blade-like structure (FIG.6),a wire-like structure, with a solid structure, that is a solid circular cross-section (FIGS.7and9),a tubular structure, that is having a longitudinal cavity10d extending along the length of the anchoring member10(see alsoFIGS.13A,13B and14A to14C). FIGS.6to8exemplify the possibility for the winding trajectory to the rolled up condition to include a spiral-like trajectory (i.e. lying in a single plane). FIG.9exemplifies the possibility for the winding trajectory to the rolled up condition to include a helix-like trajectory (i.e. with the trajectory pitching into adjacent loops arranged side-by-side). It will be appreciated that the winding trajectory being spiral-like or helix-shaped may be independent of the anchoring member10being blade-like or wire-like, solid or tubular. FIG.10is exemplary of kinematics which may lead to the anchoring member10(e.g. the distal portion10b in the exemplary embodiments considered herein) to wind or wrap from the deployed condition (shown in dashed lines) to the rolled up condition shown in full lines. The arrow W is representative of the fact that such a winding or wrapping movement may involve a rotation in space of the distal end100of the anchoring member10. The related kinematics are further exemplified inFIGS.11A to11E. FIG.11Ais exemplary of an anchoring member10shown in the deployed condition. In one or more embodiments, the deployed condition of the anchoring member may not necessarily imply a rectilinear shape: as exemplified inFIG.11A, the anchoring member10may be at least slightly arched in the deployed condition. The sequence ofFIGS.11A to11Eis exemplary of a possible way of determining the angular extent of the winding or wrapping trajectory of the anchoring member10(e.g. due to elasticity and/or shape memory effect) from the deployed condition ofFIG.11Ato the rolled up condition ofFIG.11E. In the deployed condition ofFIG.11A, the distal portion10b, and particularly the proximal end100, points in a direction indicated by an arrow A. FIGS.11B,11C and11Dare exemplary of intermediate stages of a winding/wrapping movement. For instance, in winding from the deployed condition ofFIG.11Ato the condition ofFIG.11B, the distal end100will undergo a rotation of 90° (that is with the distal end100pointing in direction AIat 90° to the pointing direction A of the deployed condition). Passing from the condition ofFIG.11Ato the condition ofFIG.11Bthus represent a winding trajectory having an angular extent of 90°. In further winding from the condition ofFIG.11Bto the condition ofFIG.11C, the distal end100will undergo a further rotation of 90° (that is with the distal end100pointing in direction AIIat 180° to the pointing direction A of the deployed condition). Passing from the condition ofFIG.11Ato the condition ofFIG.11Cwill thus represent a winding trajectory having an angular extent of 180°. In further winding from the condition ofFIG.11Cto the condition ofFIG.11Dthe distal end100will undergo a further rotation of 90° (that is with the distal end100pointing in direction AIIIat 270° to the pointing direction A of the deployed condition). Passing from the condition ofFIG.11Ato the condition ofFIG.11Dwill thus represent a winding trajectory having an angular extent of 270°. Finally, in further winding from the condition ofFIG.11Dto the condition ofFIG.11Ethe distal end100will undergo a further rotation of 90° (that is with the distal end100pointing in direction AIVat 360° to the pointing direction A of the deployed condition). Passing from the condition ofFIG.11Ato the condition ofFIG.11Dthus represents a winding trajectory having an angular extent of 360°, that is a full loop or winding. Reference XWinFIG.11Edenotes the center region (locus) of the—e.g. spiral-like—trajectory of the distal portion10b the anchoring member10as finally rolled up (wound up) in the collapsed implantation condition. As indicated, in one or more embodiments the center region (e.g. axis) XWof the final collapsed trajectory of the anchoring member10may be at least approximately coplanar with the end plane OEP of the device V (seeFIG.3). The examples ofFIGS.6to8refer to possible embodiments (blade-like, wire-like or tubular, respectively) where winding/rolling to the final collapsed condition from a (notionally linear) deployed condition of the anchoring member10may involve a winding trajectory (that is a rotation of the distal end100) having an angular extent in excess of 360° (e.g. 360°+90°=450° in the example ofFIG.8and in excess of 450° in the examples ofFIGS.6and7). The example ofFIG.9refers to a possible embodiment wherein the helix-like winding trajectory to the rolled up condition from a notional linear deployed condition of the anchoring member10involves a winding trajectory (that is a rotation of the distal end100) having an angular extent which may be a multiple of 360° (approximately 3×360°, namely 1080°) to a final winding center/axis XW. In one or more embodiments, the winding trajectory of the anchoring member10from the deployed condition to the rolled up condition may have an angular extent between 180° (half turn) and 900° (two turns and a half, i.e. 360°+360°+180°). In one or more embodiments, the angular extent of the winding trajectory of the anchoring member10from the deployed condition to the rolled up condition may thus take into account factors such as the geometry of the body structure (e.g. valve annulus) used for anchoring and/or the nature of such a structure (e.g. soft/damaged tissue or leaflets). In one or more embodiments, an implant device V may thus include anchoring members10having different angular extents of their winding trajectories in order to match different local characteristics of the anchoring body structure(s). In one or more embodiments, the anchoring members (distal portion10b subject to winding) may have a width between 0.2 mm and 5 mm: lower values may be optionally selected for wire-like members; higher values may be optionally selected for blade-like members. In one or more embodiments, such widths may be constant. In one or more embodiments, such widths may be vary over the length of the anchoring member e.g. to optimize the grasping action of the body tissues e.g. at the beginning and at the end of the rolling/winding action. In one or more embodiments, the anchoring members (distal portion10b subject to winding) may have a length between 1.5 mm and 25 mm. In one or more embodiments, such values may be related to other parameters, e.g. a length of 1.5 mm being optionally selected for a winding trajectory over 180° to a final outer diameter of 1 mm and a length of 25 mm being optionally selected for a winding trajectory over 900° to a final outer diameter of 4 mm. In one or more embodiments, the anchoring members (distal portion10b subject to winding) may have a thickness between 0.1 and 0.5 mm. In one or more embodiments, the final collapsed trajectory (e.g. spiral like) of the anchoring member—measured “in air”, i.e. without any body structure grasped therein may involve a spacing (pitch) between adjacent turns or coils from zero (that is with no gaps or spacing therebetween) to 0.5 mm. FIGS.12A-12C,13A-13B,14A-14C,15A-15B and16A-16Care exemplary of various arrangements (or “kits”) for implanting an implant device V according to one or more embodiments. All these figures refer by way of the example to an implant device V such as e.g. a heart valve having a stent-like annular structure (armature) as exemplified inFIGS.3to5, namely a tubular stent-like armature having a set of anchoring members10located at one end thereof (e.g. end plane OEP). As indicated, the embodiments are not limited to valve prostheses as the implant devices to be anchored to a patient body. In one or more embodiments as exemplified herein, the proximal portions10a of the anchoring members10are generally co-extensive with the stent-like structure of the valve prosthesis and, in the final rolled-up (collapsed) implant condition, the proximal portions10b are intended to extend both radially and, at least partly, axially outwardly of the annular structure of the device V to provide anchoring of the implant device V to a body structure AS by protruding both radially and (at least in part) axially from one end (e.g. end plane OEP) of the annular structure. Coupling of the anchoring members10to the implant device V may be e.g. according to any of the exemplary embodiments ofFIGS.3to5; any other type of feasible coupling may be included in one or more embodiments. FIGS.12B and12Crefer by way of example to implantation of a valve prosthesis V at an annular site. This may be e.g. a mitral site, that is between the left atrium and the left ventricle of the heart, in order to permit blood flow from the atrium into the ventricle (downwardly, with respect to the exemplary figures herein) while preventing blood flow in the opposite direction. By way of example, reference is made to implantation performed with the conservation of native valve structures such as the native leaflets AS (and the chordae tendinae, not visible in the figures). One or more embodiments may lend themselves to such a technique, due to the capability of achieving secure anchoring of the valve V to the native valve structures without applying appreciable stress (particularly radial, i.e. dilation stress) onto these structures. The various arrangements exemplified refer to an implant device (e.g. valve V) of a collapsible type, namely intended to be positioned at the implantation site in a radially contracted condition (see for instanceFIGS.12A,14A and16A) and then expanded to a radially expanded condition (see e.g.FIGS.12B,14B and16B). In one or more embodiments, as exemplified herein, radial expansion may be produced by means of a balloon catheter including a distal balloon B inflatable from a contracted condition (FIGS.12A,14A,16A) to an inflated condition (FIGS.12B-12C,14B-14C and16B-16C). In one or more embodiments radial expansion of the implant device V may be by other means, e.g. due to self-expansion (elastic, shape memory) as known in the art. The figures illustrate one or more embodiments of constraint members adapted to cooperate with the anchoring member(s)10in order to maintain the anchoring member(s)10in a deployed condition for insertion in the patient's body and positioning at the implantation site to then release the anchoring member(s)10to permit the winding/wrapping movement to a rolled up condition. Such a winding/wrapping movement of the anchoring member(s)10(e.g. of the distal portions10b, in the embodiments illustrated) may lead the or each member to grasp the anchoring body structure (for instance the native valve leaflets AS ofFIGS.12B and12C) to secure anchoring of the implant device V at the implantation site, with minimum protrusion e.g. into the ventricular chamber. In the arrangement ofFIGS.12A to12Ca constraint member may be in the form of a tubular sheath S extending along an axis XS, the sheath being arranged to surround the collapsed implant device V with the anchoring member or members10extended to the deployed condition (FIG.12A). The sheath S may thus be able to maintain the anchoring member(s)10in the deployed condition by confining the anchoring member(s) by acting radially inwardly towards the axis XS. As exemplified inFIG.12B, the sheath S may be configured for instance, by including an elastically deformable material such as e.g. silicone—in such way to allow the radial (e.g. as balloon-driven) expansion of the implant device V while still surrounding and thus constraining the anchoring member or members10to the deployed condition. The sheath S may then withdraw along the axis XS as schematically represented inFIG.12Cin such a way as to uncover the anchoring member(s)10e.g. starting from the distal portion10b. Being no longer constrained by the sheath S, the distal portion10b will thus be able to undergo the winding/wrapping movement to the rolled up condition which provides anchoring to the body structures AS by having such structures wrapped by—and possibly within—the rolled up anchoring member(s)10(FIG.12C). A substantially similar delivery/implantation procedure may be adopted in the other exemplary arrangements illustrated in the subsequent figures, where various embodiments of constraint members are exemplified. For instance,FIGS.13A-13Brefer to anchoring members10having a tubular structure and thus having a longitudinal cavity into which a stiffening wire or mandrel SW may be inserted to maintain (acting from inside) the anchoring member10in the deployed condition (e.g. a rectilinear or substantially rectilinear condition). The stiffening wire SW may then withdrawn (i.e. extracted) out of the anchoring member10as schematically represented inFIG.13Bso that the anchoring member10(e.g. the distal portion10b), being no longer stiffened by the wire SW inserted therein may undergo the winding/wrapping movement to the rolled up condition. The sequence ofFIGS.14A to14Cexemplifies how an implantation procedure substantially corresponding to the one already exemplified in connection ofFIGS.12A to12Cmay be performed by locating the implant device V at the implantation site in a radially contracted condition with the stiffening wire(s) SW inserted into the anchoring member(s)10to maintain it or them in the deployed condition as the implant device V is located at the implantation site and then expanded. The stiffening wire(s) SW may then be extracted from the anchoring member(s)10to permit winding/wrapping to the rolled up anchoring condition exemplified inFIG.14C. FIGS.15A and15Bare exemplary of arrangements where a constraint action of the anchoring member(s)10to the deployed condition may be achieved by means of an inflatable balloon B1. In one or more embodiments, such a balloon B1may be a needle-like balloon as currently used to deliver and expand angioplasty stents such as e.g. coronary stents by means of balloon catheters. In one or more embodiments, the balloon B1may be of a “non-compliant” type. In one or more embodiments, in the inflated condition as exemplified inFIG.15A, the balloon B1may constrain an anchoring member10inserted therein (that is with the balloon B1vested onto the anchoring member10to form a tubular tunic around the member10) with the capability of effectively resisting an elastic bias bestowed onto the anchoring member10to cause it to wind to the rolled up condition once no longer constrained. The sequence ofFIGS.15A and15Bis exemplary of the balloon B1being deflated (by known means). Once deflated, the balloon B1becomes soft thus permitting the winding/wrapping movement of the anchoring member10located therein as exemplified inFIG.15B. The sequence ofFIGS.16A to16Cis exemplary of implantation procedures based on the same principles already described in connection withFIGS.12A to12C and14A to14C. Specifically,FIG.16Ais exemplary of the implantation arrangement being in a radially contracted (collapsed) condition of the implant device V with the anchoring member(s)10maintained in the deployed condition by means of a stiffening balloon B1in an inflated condition. FIG.16Bis exemplary of radial expansion of the implant device V with the anchoring member(s) still maintained in the deployed condition by the balloon B. Finally,FIG.16Cis exemplary of the balloon B1being deflated so that the anchoring member(s), no longer retained to the extended condition, are permitted to wind/wrap to the rolled up anchoring condition of the implant device V. The various exemplary implantation arrangements described herein lend themselves to be used both in connection with anchoring members that wind to the rolled up condition due to an elastic (e.g. super elastic) bias bestowed upon them and in connection with anchoring members that wind to the rolled up condition due to e.g. a shape memory effect other than elastic, such as a shape memory effect stimulated by the application of e.g. thermal, electrical or optical energy. The details and embodiments may vary, even significantly, with respect to what has been described herein by way of the example only, without departing from the scope of protection. The extent of protection is determined by the claims that follow. | 30,446 |
RE49793 | DETAILED DESCRIPTION Example embodiments of the inventive concepts will now be described more fully with reference to the accompanying drawings, in which example embodiments are shown. Example embodiments of the inventive concepts may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of example embodiments to those of ordinary skill in the art. In the drawings, the thicknesses of layers and regions are exaggerated for clarity. Like reference numerals in the drawings denote like elements, and thus their description will be omitted. As used herein the term “and/or” includes any and all combinations of one or more of the associated listed items. It will be understood that when an element is referred to as being “connected” or “coupled” to another element, it can be directly connected or coupled to the other element or intervening elements may be present. In contrast, when an element is referred to as being “directly connected” or “directly coupled” to another element, there are no intervening elements present. Other words used to describe the relationship between elements or layers should be interpreted in a like fashion (e.g., “between” versus “directly between,” “adjacent” versus “directly adjacent,” “on” versus “directly on”). It will be understood that, although the terms “first”, “second”, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of example embodiments. Spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as “below” or “beneath” other elements or features would then be oriented “above” the other elements or features. Thus, the exemplary term “below” can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises”, “comprising”, “includes” and/or “including,” if used herein, specify the presence of stated features, integers, steps, operations, elements and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components and/or groups thereof. Example embodiments of the inventive concepts are described herein with reference to cross-sectional illustrations that are schematic illustrations of idealized embodiments (and intermediate structures) of example embodiments. As such, variations from the shapes of the illustrations as a result, for example, of manufacturing techniques and/or tolerances, are to be expected. Thus, example embodiments of the inventive concepts should not be construed as limited to the particular shapes of regions illustrated herein but are to include deviations in shapes that result, for example, from manufacturing. For example, an implanted region illustrated as a rectangle may have rounded or curved features and/or a gradient of implant concentration at its edges rather than a binary change from implanted to non-implanted region. Likewise, a buried region formed by implantation may result in some implantation in the region between the buried region and the surface through which the implantation takes place. Thus, the regions illustrated in the figures are schematic in nature and their shapes are not intended to illustrate the actual shape of a region of a device and are not intended to limit the scope of example embodiments. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which example embodiments of the inventive concepts belong. It will be further understood that terms, such as those defined in commonly-used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. FIG.1is a circuit diagram of an image sensor according to example embodiments of the inventive concept. Referring toFIG.1, the image sensor may include a plurality of unit pixels, each of which includes a photoelectric conversion region PD, a transfer transistor Tx, a source follower transistor Sx, a reset transistor Rx, and a selection transistor Ax. The transfer transistor Tx, the source follower transistor Sx, the reset transistor Rx, and the selection transistor Ax may include a transfer gate TG, a source follower gate SF, a reset gate RG, and a selection gate SEL, respectively. A photoelectric conversion portion may be provided in the photoelectric conversion region PD. The photoelectric conversion portion may be a photodiode including an n-type impurity region and a p-type impurity region. The transfer transistor Tx may include a drain region serving as a floating diffusion region FD. The floating diffusion region FD may also serve as a source region of the reset transistor Rx. The floating diffusion region FD may be electrically connected to the source follower gate SF of the source follower transistor Sx. The source follower transistor Sx may be connected to the selection transistor Ax. The reset transistor Rx, the source follower transistor Sx, and the selection transistor Ax may be shared by adjacent pixels, and this makes it possible to increase an integration density of the image sensor. Hereinafter, an operation of the image sensor will be described with reference toFIG.1. In particular, when in a light-blocking state, a power voltage VDD may be applied to a drain region of the reset transistor Rx and a drain region of the source follower transistor Sx to turn on the reset transistor Rx and discharge electric charges from the floating diffusion region FD. Thereafter, if the reset transistor Rx is turned-off and external light is incident into the photoelectric conversion region PD, electron-hole pairs may be generated in the photoelectric conversion region PD. Holes may be moved toward the p-type doped region, and electrons may be moved toward and accumulated in the n-type doped region. If the transfer transistor Tx is turned on, the electric charges (e.g., electrons) may be transferred to and accumulated in the floating diffusion region FD. A change in amount of the accumulated charges may lead to a change in gate bias of the source follower transistor Sx, and this may lead to a change in source potential of the source follower transistor Sx. Accordingly, if the selection transistor Ax is turned on, an amount of the charges may be transmitted or read out as a signal through a column line. FIG.2is a layout illustrating an image sensor according to example embodiments of the inventive concept,FIGS.3A and3Bare sectional views taken along lines A-A′ and B-B′, respectively, ofFIG.2. Referring toFIGS.1,2,3A and3B, a substrate2may be provided to include unit pixel regions UP. The substrate2may be a silicon wafer, a silicon-on-insulator (SOI) substrate, or a substrate including a semiconductor epitaxial layer. The substrate2may include a first surface2a and a second surface2b opposite each other. The second surface2b may be arranged or configured in the image sensor such that light may be incident thereon, and is also referred to herein as a light-receiving surface2b. A pixel separation portion12may be provided in the substrate2to separate the unit pixel regions UP from each other. In plan view, the pixel separation portion12may be shaped like a mesh or grid. In example embodiments, the pixel separation portion12may have a height that is substantially equivalent to a thickness of the substrate2. The pixel separation portion12may be formed through the substrate2to connect or otherwise extend between the first and second surfaces2a and2b. The pixel separation portion12may include an insulating deep device isolation layer11and a conductive common bias line13therein. The deep device isolation layer11and the common bias line13may be in contact with each other. The pixel separation portion12may further include a channel-stop region10that is in contact with the deep device isolation layer11. The deep device isolation layer11may be formed of an insulating material, whose refractive index is different from that of the substrate2. For example, the deep device isolation layer DTI may be formed of at least one of a silicon oxide layer, a silicon nitride layer, or a silicon oxynitride layer. In the present embodiment, the deep device isolation layer11may be provided in contact with the first surface2a and spaced apart from the second surface2b. A top surface of the deep device isolation layer11adjacent to the second surface2b may have a curved or uneven structure. A distance from the second surface2b to a top surface6of the deep device isolation layer11may be a first distance D1between two adjacent pixel regions UP, and a second distance D2(which is less than or equal to D1) at an intersection of four adjacent pixel regions UP. The common bias line13may be formed of at least one of an undoped or doped polysilicon layer, a metal silicide layer, or a metal-containing layer. Since the deep device isolation layer11has the curved or uneven top surface, the common bias line13may have a curved or uneven top surface. A line-shaped edge or linear portion13a may be provided at an end portion of the common bias line13. The line-shaped edge13a may be electrically connected to an edge contact130and an external-voltage-applying wire132that are provided adjacent to the first surface2a. The common bias line13may be applied with a negative voltage via the external-voltage-applying wire132. The negative voltage applied to the common bias line13may fix or attract holes to a surface of the deep device isolation layer11, and this makes it possible to improve a dark current property of the image sensor. The channel-stop region10may be in contact with the second surface2b. For example, the photoelectric conversion part PD may be doped with n-type impurities, and the channel-stop region10may be doped with p-type impurities. Since the pixel separation portion12is formed to penetrate and extend through the substrate2from the first surface2a to the second surface2b, each of the unit pixel regions UP can be electrically or optically isolated from the others, and thus, it is possible to reduce or prevent cross talk between the unit pixel regions UP from occurring by a slantingly incident light (that is, in response to incident light at oblique angles relative to the light-receiving surface2b). Further, the photoelectric conversion part PD may be formed to be in contact with the sidewall of the pixel separation portion12and may have the same area as the unit pixel region UP, which can allow the image sensor to have an increased light-receiving area and/or an increased fill factor. A plurality of transistors Tx1, Tx2, Rx, Dx, and Sx and a plurality of wires may be provided on the first surface2a. A well region PW may be provided on the photoelectric conversion part PD. In example embodiments, the well region PW may be doped with p-type impurities. Shallow device isolation layers STI may be provided on the well region PW to define active regions AR of the transistors Tx1, Tx2, Rx, Dx, and Sx. The shallow device isolation layer STI may be formed to have a depth smaller than the deep device isolation layer11. In example embodiments, the shallow device isolation layer STI and the deep device isolation layer11may be connected to each other, thereby constituting or defining a single body or region. For example, as shown inFIG.3A, the shallow device isolation layer STI and the deep device isolation layer11may be formed between the unit pixel regions UP to have an inverted ‘T’ shape. In each of the unit pixel regions UP, the transfer gate TG serving as the gate electrode of the transfer transistor Tx1may be provided on the first surface2a of the substrate2. A gate insulating layer24may be interposed between the transfer gate TG and the substrate2. A top surface of the transfer gate TG may be higher than the first surface2a of the substrate2, and a bottom surface thereof may be positioned in the substrate2or the well PW. For example, the transfer gate TG may include a protruding portion21positioned on the substrate2and a buried portion22inserted into the substrate2. The floating diffusion region FD may be formed in a portion of the substrate2between an upper sidewall of the buried portion22and the shallow device isolation layer STI. The floating diffusion region FD may be doped with impurities having a different conductivity type from that of the well region PW. For example, the floating diffusion region FD may be doped with n-type impurities. A doped ground region26may be formed in a portion of the active region AR, which is spaced apart from the transfer gate TG by the shallow device isolation layer STI. The doped ground region26may be doped with impurities having the same conductivity type as that of the well region PW. For example, the doped ground region26may be doped with p-type impurities. In example embodiments, an impurity concentration of the doped ground region26may be higher than that of the well region PW. The floating diffusion region FD and the doped ground region26may be electrically connected to at least one of contact plugs and wires30that are disposed on the first surface2a. The first surface2a may be covered with a plurality of interlayered insulating layers32. An anti-reflecting layer38may be formed to cover wholly the second surface2b. In each of the unit pixel regions UP, a color filter42and a micro-lens44may be provided on the anti-reflecting layer38. The color filter42may be a portion of a color filter array including a plurality of color filters arranged in the form of matrix. In example embodiments, the color filter array may be provided to form the Bayer pattern including a red filter, a green filter, and a blue filter; however, embodiments of the present inventive concept are not limited to particular filter colors. For example, in other embodiments, the color filter array may be configured to include a yellow filter, a magenta filter and a cyan filter. In certain embodiments, the color filter array may further include a white filter. FIGS.4A through9Aare sectional views taken parallel to the line A-A′ ofFIG.2to illustrate a process of fabricating the image sensor ofFIG.2, andFIGS.4B through9Bare sectional views taken parallel to the line B-B′ ofFIG.2to illustrate a process of fabricating the image sensor ofFIG.2. Referring toFIGS.4A and4B, the substrate2including first and second opposing surfaces2a and2b is prepared. The substrate2may be a silicon wafer, a silicon-on-insulator (SOI) substrate, and/or a substrate including a semiconductor epitaxial layer. The substrate2may be doped with, for example p-type impurities. An ion implantation process may be performed to form the photoelectric conversion part PD and the well region PW in the substrate2. The photoelectric conversion part PD may be doped with, for example, n-type impurities, and the well region PW may be doped with, for example, p-type impurities. The photoelectric conversion part PD and/or the well region PW may be formed after the formation of the pixel separation portion12is complete. A first mask pattern3may be formed on the first surface2a. The substrate2adjacent to the first surface2a may be etched using the first mask pattern3as an etch mask, thereby forming the first trench4with a first depth D3. Referring toFIGS.5A and5B, an insulating layer is formed to fill the first trench4and is planarized to expose the first surface2a and the shallow device isolation layer STI. Referring toFIGS.6A and6B, a second mask pattern5may be formed to cover the first surface1a and define the pixel regions UP. The shallow device isolation layer STI and the substrate2may be etched using the second mask pattern5as an etch mask to form the second trench6having a second depth D4. The second trench6may be formed to include a plurality of grooves intersecting to each other, thereby having a grid- or mesh-like shape in plan view. Here, an amount of the substrate2that is etched is greater at an intersection between four adjacent pixel regions UP than between two adjacent pixel regions UP. That is, the etch amount of the substrate2may be larger at the intersection of the grooves, when compared with at each of the grooves. Accordingly, at this stage, the second trench6may have a third depth D5that is equivalent to or greater than the second depth D4. Further, the second trench6may have a curved or uneven bottom surface. For example, a distance from the second surface2b to the bottom surface of the second trench6may be a first height H1between two adjacent unit pixel regions UP and a second height H2, which is equivalent to or smaller than the first height H1, between four adjacent unit pixel regions UP. An ion implantation process P1may be performed to the substrate2covered with the second mask pattern5, and thus, the channel-stop region10may be formed in portions of the substrate2exposed by the second trench6. The channel-stop region10may be doped with, for example, p-type impurities. Referring toFIGS.7A and7B, the second mask pattern5may be removed, and then, the insulating layer11may be conformally deposited to cover the side and bottom surfaces of the second trench6. The conductive layer13may be deposited to fill the second trench6. A planarization process may be performed to expose the first surface2a, and thus, the deep device isolation layer11, the common bias line13, and the line-shaped edge13a may be formed in the second trench6. As a result, the pixel separation portion12including the deep device isolation layer11, the channel-stop region10, and the common bias line13may be formed to separate the unit pixel regions UP from each other. Referring toFIGS.8A and8B, the gate insulating layer24and the transfer gate TG may be formed on the first surface2a, and the floating diffusion region FD and the doped ground region26may be formed. The contact plugs and wires30and the interlayered insulating layers32may be formed on the first surface2a. In example embodiments, the edge contact130and the external-voltage-applying wire132, which are connected to the line-shaped edge13a, may be formed using the process of forming the contact plugs and wires30. Referring toFIGS.8A,8B,9A, and9B, the substrate2may be inverted or rotated in such a way that the second surface2b faces upward. A grinding or CMP process may be performed to remove a portion of the substrate2adjacent to the second surface2b by a first thickness T1and thereby to expose the channel-stop region10. Meanwhile, a variation in depth of the bottom surface of the deep device isolation layer11may be determined by that of the second trench6. Thus, if the pixel separation portion12included only the deep device isolation layer11, the polished surface of the substrate2(after the grinding or CMP process) may have a deteriorated surface flatness or uniformity, owing at least to the variation in depth of the bottom surface of the deep device isolation layer11. Further, during the grinding or CMP process, a stress may be exerted to an interface between the substrate2and the deep device isolation layer11to create many defects. The deterioration in surface uniformity or the increase of defects may result in increased variation in color between pixels or a deteriorated dark current property. In contrast, according to example embodiments of the inventive concept, the grinding or CMP process may be perform to expose the channel-stop region10, not the deep device isolation layer11, and thus, it is possible to improve the surface uniformity and reduce the number of defects in the grinding or CMP process. As a result, it is possible to realize the image sensor with an improved dark current property and a high image quality. Thereafter, as shown inFIGS.3A and3B, the anti-reflecting layer38, a first insulating layer39, a second insulating layer40, the color filter42, and the micro-lens44may be formed on the second surface2b of the substrate2. FIG.10is a layout illustrating an image sensor according to other example embodiments of the inventive concept.FIG.11is a sectional view taken along a line C-C′ ofFIG.10to illustrate the image sensor according to other example embodiments of the inventive concept. Referring toFIGS.10and11, according to other example embodiments of the inventive concept, the image sensor may include the substrate2with the pixel region PR, the optical black region OB, the pad region TR, and the edge region ER. The unit pixel regions UP may be provided in the pixel region PR, and the optical black region OB and the pad region TR may be provided spaced apart from the pixel region PR. The line-shaped edge13a may be provided in the edge region ER. The pixel separation portion12may include the deep device isolation layer11, the common bias line13, the channel-stop region10, and the shallow device isolation layer STI. In example embodiments, the deep device isolation layer11may be provided in contact with the second surface2b and spaced apart from the first surface2a. The channel-stop region10may be provided between the shallow device isolation layer STI and the deep device isolation layer11. Each or at least one of the deep device isolation layer11and the common source line13may have a curved or uneven bottom surface. An optical black pattern50may be provided on the optical black region OB. A through via52may be provided in the pad region TR to penetrate the first insulating layer39, the anti-reflecting layer38, and the substrate2. An insulating spacer46may be interposed between the through via52and the substrate2. A solder ball54may be attached to the through via52. The edge contact130and the external-voltage-applying wire132may be provided in the first insulating layer39of the edge region ER to be in contact with the line-shaped edge13a. The through via52, the optical black pattern50, and the external-voltage-applying wire132may be formed of the same material (e.g., tungsten) in some embodiments. The optical black pattern50may reduce or prevent light from being incident on or into a reference pixel provided thereunder. Since the reference pixel is in the light-blocking state, an amount of electric charges generated in the reference pixel (hereinafter, referred as to a reference charge amount) can be used to compare an amount of electric charges from the unit pixel regions UP (hereinafter, referred as to a unit charge amount), and to calculate a difference between the unit and reference charge amounts. This may make it possible to obtain more accurate signals from each unit pixel UP. Except for the above described differences, the image sensor according to other example embodiments of the inventive concept may be configured to have substantially similar features as those of the previously-described embodiments. FIGS.12through17are sectional views illustrating a process of fabricating the image sensor ofFIG.11. Referring toFIG.12, the first trench4may be formed, as shown inFIG.4A, and then, the second mask pattern5may be formed to cover the first mask pattern3and define a region for the channel-stop region10. The substrate2may be doped with impurities using the second mask pattern5as an ion injection mask to form the channel-stop region10. The channel-stop region10may be doped with, for example, p-type impurities. Referring toFIG.13, the first and second mask patterns3and5may be selectively removed to expose the first trench4. An insulating layer may be deposited to fill the first trench4, and then, the insulating layer may be etched to form the shallow device isolation layer STI having a flat or planar top surface. Referring toFIG.14, as described with reference toFIG.9A, the gate insulating layer24, the transfer gate TG, the floating diffusion region FD, the doped ground region26, the contact plugs and wires30, and the interlayered insulating layers32may be formed on or in the first surface2a of the substrate2. In contrast toFIG.9A, the edge contact130and the external-voltage-applying wire132may not be formed at this stage. Referring toFIG.15, the substrate2may be inverted or turned-over, and a grinding or CMP process may be performed to remove a portion of the substrate2adjacent to the second surface2b by a predetermined thickness. Here, the deep device isolation layer11may not be exposed during the grinding or CMP process, and thus, it is possible to reduce or prevent a polished surface of the substrate from having a reduced or lowered flatness or uniformity and to suppress surface defects from occurring. A portion of the substrate2adjacent to the second surface2b may be etched to form the second trench6exposing the channel-stop region10. Thereafter, an insulating layer and a conductive layer may be sequentially formed to fill the second trench6, and may be planarized to form the deep device isolation layer11, the common bias line13, and the line-shaped edge13a. Due to the presence of the channel-stop region10, it is possible to reduce a depth of the second trench6, which may make it possible to prevent or suppress an etch damage from occurring. Referring toFIG.16, the anti-reflecting layer38and the first insulating layer39may be sequentially stacked on the second surface2b. The first insulating layer39, the anti-reflecting layer38, and the substrate2may be patterned to form a through-via hole51a exposing the wire30on the pad region TR. The first insulating layer39may be patterned to form a first recess region51b on the optical black region OB. The first insulating layer39and the anti-reflecting layer38may be patterned to form a second recess region51c on the edge region ER. Referring toFIG.17, a conductive layer may be deposited and planarized to form the through via52, the optical black pattern50, and the edge contact and external-voltage-applying wire130and132filling the through-via hole51a, the first recess region51b, and the second recess region51c, respectively. Subsequent processes may be performed in the same or similar manner as that described in example embodiments of the inventive concept. FIG.18is a sectional view taken along a line C-C′ ofFIG.10to illustrate an image sensor according to still other example embodiments of the inventive concept. Referring toFIG.18, structural features of the image sensors according to the aforementioned embodiments may be combined to realize an image sensor according to still other example embodiments of the inventive concept. For example, according to still other example embodiments of the inventive concept, the image sensor may be configured to include the pixel separation portion12, whose structure is similar to that ofFIGS.3A and3B, and the edge contact130and the external-voltage-applying wire132, whose disposition is similar to that ofFIG.11. FIG.19is a block diagram illustrating an electronic device having an image sensor, according to example embodiments of the inventive concept. The electronic device may be any of various types of devices, such as a digital camera or a mobile device, for example. Referring toFIG.19, an illustrative digital camera system includes an image sensor100, a processor230, a memory300, a display410and a bus500. As shown inFIG.19, the image sensor100captures an external image under control of the processor230, and provides the corresponding image data to the processor230through the bus500. The processor230may store the image data in the memory300through the bus500. The processor230may also output the image data stored in the memory300, e.g., for display on the display device410. FIGS.20through24show examples of multimedia devices, to which image sensors according to example embodiments of the inventive concept can be applied. Image sensors according to example embodiments of the inventive concept can be applied to a variety of multimedia devices with an imaging function. For example, image sensors according to example embodiments of the inventive concept may be applied to a mobile phone or a smart phone2000as shown inFIG.20, to a tablet PC or a smart tablet PC3000as shown inFIG.21, to a laptop computer4000as shown inFIG.22, to a television set or a smart television set5000as shown inFIG.23, and/or to a digital camera or a digital camcorder6000as shown inFIG.24. According to example embodiments of the inventive concept, the image sensor may include a common bias line, to which a negative voltage can be applied, and which is disposed in a deep device isolation layer. Accordingly, it may be possible to fix or otherwise attract holes in a sidewall of deep device isolation layer and thereby improve a dark current property of the image sensor. While example embodiments of the inventive concepts have been particularly shown and described, it will be understood by one of ordinary skill in the art that variations in form and detail may be made therein without departing from the spirit and scope of the attached claims. | 30,589 |
RE49794 | DETAILED DESCRIPTION The present invention is generally directed to SRAM design to facilitate single fin cut in a double sidewall image transfer process for forming fins on a substrate having a fin pitch less than 40 nm and/or having a variable pitch associated with the formation of devices such as SRAM bitcells. In the double sidewall image transfer process, a first spacer is deposited on sidewalls of a first mandrel, which are then used as a second mandrel to form a pair of fins. The spacing between two paired fins is minimized as much as possible so as to maximize fin density. In the present invention, the fin pairs are created at two different spacings without requiring the minimum space for the standard sidewall structure. An enlarged space between paired fins is created by placing two first mandrel shapes close enough so as to overlap or merge two sidewall spacer shapes defined so as to form a wider second mandrel upon further processing. The fin pair created from the wider second mandrel can be spaced to about 2 times the fin pair created from the narrower second mandrel. In some special cases, the dummy FINI can be simply be eliminated instead of being shifted away from the adjacent active FINA. As will be described in greater detail below, the resulting wider fin pair spacing allows for reduced tolerance requirements for FINI removal patterning edge placement. Alternatively, the present invention allows a second wider spacing for paired active FINAs. Advantageously, increased tolerance for the active fin mask edge location is provided. Referring now toFIGS.1A-1M, there is shown a process sequence for forming fins of multi-gate structures in accordance with the present invention. Referring toFIG.1A, the process for forming a FinFET structure100may start with forming a stack of layers on top of a substrate102, wherein a fin pattern of the structure is formed utilizing a double sidewall image transfer process. It should be noted that the substrate102can be a bulk semiconductor substrate, a semiconductor-on-insulator substrate or the like. Further, the substrate102can be composed of silicon, silicon-germanium, germanium or any other suitable semiconductor materials in which fins for multi-gate devices can be formed. Furthermore, a portion of or the entire semiconductor substrate may be strained. A portion of or entire semiconductor substrate102may be amorphous, polycrystalline, or single-crystalline. In addition to the aforementioned types of semiconductor substrates, the semiconductor substrate102invention may also comprise a hybrid oriented (HOT) semiconductor substrate in which the HOT substrate has surface regions of different crystallographic orientation. The semiconductor substrate100may be doped, undoped or contain doped regions and undoped regions therein. The semiconductor substrate102may be strained, untrained, contain regions of strain and no strain therein, or contain regions of tensile strain and compressive strain. The stack of layers formed on substrate102may include, for example and starting from substrate102, a first dielectric layer104; a first hard mask layer106; a second dielectric layer108; a second hard mask layer110; and an organic planarization layer (OPL) or anti-reflective coating (ARC) cap layer112(e.g., bottom anti-reflective coating), all of which may be formed on top of one another and in sequence. The dielectric layers are not intended to be limited and may be the same or different. By way of example, the dielectric layers104,108may include silicon nitride, for example. Likewise, the hard mask layers106,110are not intended to be limited and may be the same or different. By way of example, the hard mask layers include amorphous silicon, for example, from which the respective mandrels are formed. As shown inFIGS.1A and1B, conventional photolithography and an anisotropic etch process (e.g., reactive ion etch) is used to define a first resist pattern114that is etched to define first mandrel features116and117patterned according to a minimum feature size, F, that is characteristic of the lithography process used. At least one of the mandrel features117is in close proximity to the other mandrel feature116such that subsequent spacer deposition, as will be described in greater detail below, results in an overlap or merger of the sidewall therebetween. The photolithography process may comprise, for example, introducing electromagnetic radiation such as ultraviolet light through an overlay mask to cure a photoresist material (not shown). Depending upon whether the resist is positive or negative, uncured portions of the resist are removed to form the first resist pattern114including openings to expose portions of the cap layer112and sacrificial first mandrel layer110. The material defining photo-resist layer may be any appropriate type of photo-resist materials, which may partly depend upon the device patterns to be formed and the exposure method used. For example, material of photo-resist layer114may include a single exposure resist suitable for, for example, argon fluoride (ArF); a double exposure resist suitable for, for example, thermal cure system; and/or an extreme ultraviolet (EUV) resist suitable for, for example, an optical process. Photo-resist layer may be formed to have a thickness ranging from about 30 nm to about 150 nm in various embodiments. First resist pattern114may be formed by applying any appropriate photo-exposure method in consideration of the type of photo-resist material being used. As noted above, the first resist pattern114is anisotropically etched to remove the first resist pattern114, the exposed portions of the OPL/ARC layer112and hardmask layer110such as by reactive ion etching (RIE) to define the first mandrel shapes. The first resist pattern114is configured to provide two first mandrel shapes116and117, wherein the first mandrel shapes116and117are close enough such that subsequent deposition of a spacer layer118(seeFIG.1C) overlaps or merges in the gap120therebetween, which can subsequently be used to form a wider second mandrel in the double sidewall image transfer process. In some embodiments, the overlap or merge may not be complete and a small gap may exist. In this embodiment, the size of the gap is such that it would act as a sub-threshold assist feature that would not print when forming the wider second mandrel as will be discussed below. Even if a pin hole or dent does exist on the second mandrel when formed, subsequent spacer deposition would not result in a resolvable FINI on the substrate. The first mandrel116and117may be formed of amorphous silicon and have different widths. However, it should be noted that other materials (e.g., germanium, silicon germanium) may also be used for the mandrels so long as there is an etch selectivity with respect to subsequently formed sidewall spacers thereon. The first mandrel shapes116a and116b have nearly vertical etch slopes or nearly vertical contact angles. By use of the terms “nearly vertical etch slope” or “nearly vertical contact angle” is meant an angle defined by the sidewall of the opening being formed of at least 80°, preferably about 90°, with the plane of the layer110being etched. The etching apparatus used in carrying out the anisotropic etch may comprise any commercially available reactive ion etching (RIE) apparatus, or magnetically enhanced reactive ion etching (MERIE) apparatus, capable of supporting a wafer of the size desired to be etched in which gases of the type used herein may be introduced at the flow rates to he discussed and a plasma maintained at the power levels required for the process. Such apparatus will be generally referred to herein as RIE apparatus, whether magnetically enhanced or not. Examples of such commercially available apparatus include the Precision 5000 magnetically enhanced reactive ion etcher available from Applied Materials, Inc.; the Rainbow reactive ion etcher by Lain; the reactive ion apparatus by legal Company; and the Quad reactive ion etcher by Drytek. As shown inFIG.1C, a spacer layer118(such as silicon dioxide or silicon nitride, Si3N4, for example) is then deposited onto the first mandrel shapes116and117. In accordance with one exemplary aspect, the spacer118is deposited through a conformal film deposition process, such as, for example, atomic layer deposition (ALD), molecular layer deposition (MLD), or quasi-ALD or MLD processes. As shown inFIG.1D, a portion of the spacer layer118is subsequently removed via an etch process so as to expose the top surfaces of the first mandrels116and117and form sidewall spacers124,126, where shown, having a thickness less than that permitted by the current ground rules. In addition, the sidewall spacers merge or overlap in the gap120between first mandrels116and117. Referring now toFIG.1E, the first mandrel structures116and117previously shown inFIG.1Dare stripped by any suitable dry and/or wet etch process, leaving the sidewall spacers124and126isolated, wherein sidewall spacer124has a width less than that of sidewall spacer126. That is, the sidewall spacer126is equal to the width defined by gap120and in one aspect is about two times the width of sidewall spacer124as a function of the sidewall merger or overlap from the previous step. Referring now toFIG.1F, the structure100is anisotropically etched to form the second mandrels128and130in layer106. Again, the sidewall spacers124and126are utilized as a hard mask to form the second mandrels128and130. The anisotropic etching process may include by reactive ion etching (RIE) to define the second mandrel shapes. The second mandrels128and130may be formed of amorphous silicon and have different widths, wherein mandrel130is about two times the width of mandrel128. However, like mandrel shapes116and117, it should be noted that other materials (e.g., germanium, silicon germanium) may also be used for the mandrels so long as there is an etch selectivity with respect to subsequently formed sidewall spacers thereon. The second mandrel shapes128and130have nearly vertical etch slopes or nearly vertical contact angles. As shown inFIG.1G, spacer layer132(such as silicon dioxide or silicon nitride, Si3N4, for example) is then deposited onto the second mandrel shapes128and130. In accordance with one exemplary aspect, the spacer layer132is deposited through a conformal Um deposition process, such as, for example, atomic layer deposition (ALD), molecular layer deposition (MLD), or quasi-ALD or MLD processes. An anisotropic etch is performed to remove portions of the spacer layer132as so to as form the sidewall spacers134as shown inFIG.1H. All of the sidewall spacers generally have the same width. Referring now toFIG.1I, the second mandrels128and130are removed by any suitable dry and/or wet etch process, leaving pairs136,138of sidewall spacers134. As shown, the distances between spacer pairs136,138vary as a function of the prior sidewall merger or overlap in the preceding step such that distance142is greater than distance140by about two times, Wherein the difference in thickness is defined by the overlap or merged sidewall spacers124,126used as a hard mask to form second mandrels128,130. It should be apparent that the spacer width is chosen to be the same as that of the desired width of the final fin shape (with any etch film erosion factored in). Thus, spacers are formed on the vertical walls of a mandrel and these spacers determine the final pattern widths and tolerances of the components being formed in the substrate. As shown inFIG.1J, the sidewall spacers134are then used as a hard mask such that an anisotropic etching process transfers the pattern defined by the sidewall spacers134to the underlying dielectric layer104, e.g., SiN layer. That is, airs146,148of isolated dielectric structures144are formed and have a width substantially the same as isolated sidewall spacers134. Likewise, the pairs146,148have spacing as previously described. Suitable anisotropic etch processes include RIE as previously discussed. When the dielectric layer104or108comprises silicon nitride, a wet etching solution with an etchant containing hydrofluoric/ethylene glycol (HF/EG) or hot phosphoric acid can be used. Alternatively, a dry etch process such as chemical downstream etch (CDE) or plasma etching can be used to etch silicon nitride. When the remaining mandrel structure comprises polysilicon, a wet etching solution with an etchant containing ammonia can be used. Alternatively, a dry etch process such as chemical downstream etch (CDE) or plasma etching can be used to etch remove polysilicon. The patterned dielectric layer104is then transferred into the substrate102to form pairs of fins150,152via an anisotropic etching process, e.g., a RIE process as shown inFIG.1K. Spacing between fins in pair152is about 2 times that of fins in pair150. As previously discussed, for some circuits, such as an SRAM bitcell, one needs to remove one of the fins in the pair, i.e., a single fin cut. The single fin to be cut is referred to as a dummy or inactive fin (i.e., FINI) and the other fin is referred to as an active fin (i.e., FINA). Referring now toFIG.1L, to “cut” inactive fins, a masked silicon etching step is required. Initially, a patterned mask layer160, e.g., a patterned photoresist mask, is formed above the substrate102. In the depicted example, the mask layer160has an opening162that is formed so to expose illustrative dummy fins164for removal, while masking the active device fins166that will be part of the final device. The inactive fins164are adjacent interior fins of fin pairs152having the enlarged spacing relative to the other fin pair150. In the depicted example, the two fins164will be removed to make room for an isolation region. However, as will be recognized by those skilled in the art, depending upon the desired final size of the isolation region, only one dummy fin164may be removed. Referring toFIG.1M, the two dummy tins164(i.e., FINI) are shown removed by an etching process such as a timed etching process. Any etching of the substrate102during the dummy fin etch process is not depicted. The resist is then removed to provide the desired fin structure including the desired active device fins166, (i.e., FINAs). In other embodiments shown inFIGS.1N-1O, the fin cut after the final fin reactive ionetch process are the exterior fins176. In the depicted example, the mask layer170has an openings172that is formed so to expose illustrative dummy fins176(FINIs) for removal, while masking the active device fins174(FINAs) that will be part of the final device. In the depicted example, two fins132b will be removed to make room for two isolation regions. However, as will be recognized by those skilled in the art, depending upon the desired final size of the isolation region, only one of the fins176may be removed, which would require masking of the other fin assuming it will become part of the final device. Referring toFIG.1O, the dummy fins have been removed by an etching process such as a timed etching process, wherein fins174(FINAs) are part of the final device. Any residual resist is then removed to provide the desired fin structure100including the desired active device fins. In some cases, with very tight fin pitches, the lithography and etching processes that are performed to remove the dummy fins can result in undesirable damage to the device fins, the fins that are intended for final use in the device10. The present invention advantageously increases the tolerances associated with the masked silicon etching step, thereby increasing. Oftentimes, misalignment can occur for a variety of reasons, e.g., variations on photolithography tools, materials and techniques, overlay errors, etc. Advantageously, the present invention allows the creation of FIN pairs at two spacings without requiring the minimum space for the standard sidewall structure, an enlarged space between paired FINs created by placing two mandrel (1) shapes close enough to overlap two sidewall shapes to form a wider mandrel (2). The FIN pair created from the wider mandrel (2) is spaced at about 2 times the narrow mandrel (2). The resulting wider FIN pair spacing allows reduced tolerance requirements for FINI removal patterning edge placement. Alternatively, the invention allows a second wider spacing for pair active FINAs. In one aspect, all dummy FINIs are simply eliminated and the step of FINA preserve can be skipped in the process. FIGS.2A-Cand3A-C provide a comparison of the tolerances achieved using a conventional double sidewall image transfer process without sidewall overlap or merger to form the second mandrel relative to a double sidewall image transfer process with sidewall overlap or merger to form the second mandrel, respectively. As shown inFIGS.2A and3A, the desired FinFET structure200for a single SRAM 6T bitcell includes 1 fin for a pull up (PU) transistor and 2 fins for forming a pass gate (PG) transistor and a pull down (PD) transistor, which require a single fin cut from fin pairs. Using a standard double sidewall image transfer process results in multiple fin pairs202at a minimal space as shown inFIG.2B, wherein the fins are generated with uniform or variable first mandrels. Because the fin pairs are at minimal space, the masked silicon etching step as is generally described above results in a tolerance of about 0.5 times the minimum fin space. As a result, the masked silicon etching step to remove inactive fins204in the pairs202corresponding to isolated regions between different active regions206,208is limited. By way of example, a 27 nm fin pitch with a 6 nm fin results in a tolerance of less than about 1.0.5 nm; and a 24 nm fin pitch with a 6 nm fin results in a tolerance of less than about 9 nm In contrast, the masked silicon etching step tolerances to form the single SRAM 6T bitcell in accordance with the present invention is markedly increased. As shown inFIG.3B, the sidewall overlap or merge to form the second mandrels results in fin pairs at minimal spacing (e.g., fin pair302) and fin pairs at about two times the minimal spacing (e.g., fin pair304). As a result, the tolerance associated with the masked silicon etching step to remove inactive fins306in the wider spaced fin pairs304corresponding to isolated regions between different active regions206,208is markedly increased to form the same SRAM fin structure200. By way of example, a 27 nm fin pitch with a 6 nm fin results in a tolerance of less than about 21 nm; and a 24 nm fin pitch with a 6 nm fin results in a tolerance of less than about 18 nm. That is, the tolerance doubled for the sidewall overlap/merge process relative to a standard double sidewall image transfer process. Still other aspects, features, and technical effects will be readily apparent to those skilled in this art from the following detailed description, wherein preferred embodiments are shown and described, simply by way of illustration of the best mode contemplated. The disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one more other features, integers, steps, operations, element components, and/or groups thereof. The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated The diagrams depicted herein are just one example. There may be many variations to this diagram or the steps (or operations) described therein without departing from the spirit of the invention. For instance, the steps may be performed in a differing order or steps may be added, deleted or modified. All of these variations are considered a part of the claimed invention. While the preferred embodiment to the invention had been described, it will be understood that those skilled in the art, both now and in the future, may make various improvements and enhancements which fall within the scope of the claims which follow. These claims should be construed to maintain the proper protection for the invention first described. | 21,626 |
RE49795 | BEST MODE Mode for Invention Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. FIG.1illustrates a construction of a system for providing a screen switching service during call counseling according to an embodiment of the present invention. As shown inFIG.1as a simple example, the system for providing a screen switching service during call counseling includes: a user terminal unit100for establishing a communication call by call origination or call termination; a counselor terminal unit200for establishing a communication call with the user terminal unit100and making a request for a screen switching service for switching a terminal screen of the user terminal unit100into a counsel data screen used for counseling; a screen switching service unit300for making a control to generate a data call for the user terminal unit100and then transfer a corresponding counsel data screen through the generated data call, in response to a request for a screen switching service from the counselor terminal unit200during a communication call between a customer and a counselor; and a content providing unit400for providing a counsel data screen. It is preferred that the counselor terminal unit200provides access route information for the counsel data screen and a telephone number of the user terminal unit100while making a request for a screen switching service to the screen switching service unit300. FIG.2illustrates a construction of the screen switching service unit300shown inFIG.1. As shown inFIG.2as an example, the screen switching service unit300includes: a service request receiving unit310for receiving a request for provision of a screen switching service for switching a terminal screen of the user terminal unit100into a counsel data screen for counseling from the counselor terminal unit200which is in a communication call with the user terminal unit100; a screen switching setting unit320for generating a data call for the user terminal unit100and forming screen switching control information including an access route for providing a corresponding counsel data screen through the generated data call, in response to a request for provision of a screen switching service during a communication call; and a transmitting unit330for transferring screen switching control information to the user terminal unit100. As used herein, the screen switching control information is information generated in response to a request for provision of a screen switching service and may be generated in various forms. First, in one of the various forms, the screen switching control information may have a function for making a request for operation of an application having been already stored in the user terminal unit100, wherein the application may be a Virtual Machine (VM) application. In this event, the user terminal unit100makes a direct access to the content providing unit400providing a corresponding counsel data screen based on Uniform Resource Locator (URL) information included in the screen switching control information by operating a corresponding application or makes an redirection access to the content providing unit400through the screen switching service unit300. FIG.3is a flowchart illustrating an operation process of the system for providing a screen switching service during call counseling shown inFIG.1. As shown inFIG.3as only an example, the operation process of the system for providing a screen switching service during call counseling is started by execution of a communication call between the user terminal unit100corresponding to a customer's terminal and the counselor terminal unit200of a customer center (step S100). Thereafter, the counselor terminal unit200requests the screen switching service unit300to provide a screen switching service while providing the screen switching service unit300with access route information for the counsel data screen and a telephone number of the user terminal unit100(steps S102to S106). Then, based on the provided information, the screen switching service unit300generates screen switching control information and transfers the generated screen switching control information to the user terminal unit100(steps S108and S110). The user terminal unit100executes a stored application based on the provided screen switching control information and then accesses the screen switching service unit300through a data call based on the URL information included in the screen switching control information (step S112and S114). Then, in response to the access request of the user terminal unit100, the screen switching service unit300reads the URL information for the content providing unit400and then connects the user terminal unit100to the content providing unit400through redirection based on the read URL information (step S116). The content providing unit400provides a counsel data screen to the screen switching service unit300, and the screen switching service unit300transfers the provided counsel data screen to the user terminal unit100(steps S118and S120). As described above, the screen switching control information may be configured to execute the application of the user terminal unit100. Of course, the user terminal unit100not only may access the content providing unit400through the screen switching service unit300by way of redirection, but may also directly access the content providing unit400. Thereafter, the user terminal unit100displays the provided counsel data screen on the terminal screen, so as to enable a customer to identify the counsel data screen used for the counseling during the communication call, so that the customer can use a more efficient counseling service. FIG.4illustrates a construction of a system for providing a screen switching service during call counseling according to another embodiment of the present invention. As shown inFIG.4as a simple example, the system for providing a screen switching service during call counseling includes: a user terminal unit500for establishing a communication call by call origination or call termination; a counselor terminal unit600for establishing a communication call with the user terminal unit500and making a request for a screen switching service for switching a terminal screen of the user terminal unit500into a counsel data screen used for counseling; a screen switching service unit700for making a control to generate a first data call for the user terminal unit500and then transfer a corresponding counsel data screen to the user terminal unit500through the generated first data call in response to a request for a screen switching service from the counselor terminal unit600during a communication call between a customer and a counselor and to transfer the counsel data screen to the counselor terminal unit600through a second data call generated in response to the request for the screen switching service from the counselor terminal unit600; and a content providing unit800for providing a counsel data screen. The screen switching service unit700may make a page control for the counsel data screen being displayed on the user terminal unit500in response to a control input of the counselor terminal unit600through the second data call. Further, it is preferred that the counselor terminal unit600provides access route information for the counsel data screen and a telephone number of the user terminal unit500while making a request for a screen switching service to the screen switching service unit700. FIG.5illustrates a construction of the screen switching service unit700shown inFIG.4. As shown inFIG.5as a simple example, the screen switching service unit700includes: a service request receiving unit710for receiving a request for provision of a screen switching service for switching a terminal screen of the user terminal unit500into a counsel data screen for counseling from the counselor terminal unit600which is in a communication call with the user terminal unit500; a screen switching setting unit720for generating a first data call for the user terminal unit500and forming first screen switching control information including an access route for providing a corresponding counsel data screen through the generated first data call in response to a request for provision of a screen switching service during a communication call, and forming second screen switching control information including an access route for providing a corresponding counsel data screen through a second data call generated in response to the request for provision of the screen switching service; and a transmitting unit730for transferring the first screen switching control information to the user terminal unit500and transferring the second screen switching control information to the counselor terminal unit600. Further, the screen switching setting unit720changes the first screen switching control information and second screen switching control information already formed in response to a control input of the counselor terminal unit600through the second data call for the counsel data screen. Then, the user terminal unit500changes the page of the counsel data screen being displayed on the terminal screen according to the changed first screen switching control information. Likewise, the counselor terminal unit600also changes the page of the counsel data screen according to the changed second screen switching control information. As in the embodiment described above, the first screen switching control information and the second screen switching control information may be generated in various forms, such as a form for operating an application. FIG.6is a flowchart illustrating an operation process of the system for providing a screen switching service during call counseling shown inFIG.4. As shown inFIG.6as only an example, the operation process of the system for providing a screen switching service during call counseling is started by execution of a communication call between the user terminal unit500corresponding to a customer's terminal and the counselor terminal unit600of a customer center (step S200). Thereafter, the counselor terminal unit600requests the screen switching service unit700to provide a screen switching service while providing the screen switching service unit700with access route information for the counsel data screen and a telephone number of the user terminal unit500(steps S202to S206). Then, based on the provided information, the screen switching service unit700generates first screen switching control information to be transferred to the user terminal unit500and second screen switching control information to be transferred to the counselor terminal unit600(step S208). Thereafter, the user terminal unit500executes a stored application based on the provided first screen switching control information and then accesses the screen switching service unit700through a first data call based on the URL information included in the first screen switching control information (step5210to S214). Then, in response to the access request from the user terminal unit500, the screen switching service unit700reads the URL information for the content providing unit800and then connects the user terminal unit500to the content providing unit800through redirection based on the read URL information (step S216). The content providing unit800provides a counsel data screen to the screen switching service unit700, and the screen switching service unit700transfers the provided counsel data screen to the user terminal unit500(steps5218and S220). As described above, the screen switching control information may be configured to execute the application of the user terminal unit500. Of course, the user terminal unit500not only may access the content providing unit800through the screen switching service unit700by way of redirection, but may also directly access the content providing unit800. Thereafter, the user terminal unit500displays the provided counsel data screen on the terminal screen (step S222). As in the case where the screen switching service unit700transfers the first screen switching control information to the user terminal unit500, after transferring the second screen switching control information through the already formed second data call to the counselor terminal unit600also, the screen switching service unit700requests the content providing unit800to provide a corresponding counsel data screen, upon receiving a response to the second screen switching control information (steps S224to S228). Then, the content providing unit800provides a corresponding counsel data screen to the screen switching service unit700and the screen switching service unit700transfers the provided counsel data screen to the counselor terminal unit600(steps S230and S232). The counselor terminal unit600displays the provided counsel data screen on the terminal screen and then transfers screen control information formed by a page control relating to the counseling of the counselor with respect to the counsel data screen to the screen switching service unit700(steps S234and S236). The screen switching service unit700changes the first screen switching control information and second screen switching control information already formed through the provided screen control information and then transfers them to the user terminal unit500and the counselor terminal unit600, respectively, and the counsel data screens being displayed on the user terminal unit500and the counselor terminal unit600are then changed, respectively (steps S238to S246). Although the present invention has been described above in connection with features, such as specific components of the present invention, several embodiments and drawings, these were provided merely to help a thorough understanding of the present invention but not intended to limit the present invention to the embodiments. A person ordinarily skilled in the art to which the present invention pertains can variously modify and change the specific features on the basis of the above disclosure. | 14,152 |
RE49796 | BEST MODE Mode for Invention Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. FIG.1illustrates a construction of a system for providing a screen switching service during call counseling according to an embodiment of the present invention. As shown inFIG.1as a simple example, the system for providing a screen switching service during call counseling includes: a user terminal unit100for establishing a communication call by call origination or call termination; a counselor terminal unit200for establishing a communication call with the user terminal unit100and making a request for a screen switching service for switching a terminal screen of the user terminal unit100into a counsel data screen used for counseling; a screen switching service unit300for making a control to generate a data call for the user terminal unit100and then transfer a corresponding counsel data screen through the generated data call, in response to a request for a screen switching service from the counselor terminal unit200during a communication call between a customer and a counselor; and a content providing unit400for providing a counsel data screen. It is preferred that the counselor terminal unit200provides access route information for the counsel data screen and a telephone number of the user terminal unit100while making a request for a screen switching service to the screen switching service unit300. FIG.2illustrates a construction of the screen switching service unit300shown inFIG.1. As shown inFIG.2as an example, the screen switching service unit300includes: a service request receiving unit310for receiving a request for provision of a screen switching service for switching a terminal screen of the user terminal unit100into a counsel data screen for counseling from the counselor terminal unit200which is in a communication call with the user terminal unit100; a screen switching setting unit320for generating a data call for the user terminal unit100and forming screen switching control information including an access route for providing a corresponding counsel data screen through the generated data call, in response to a request for provision of a screen switching service during a communication call; and a transmitting unit330for transferring screen switching control information to the user terminal unit100. As used herein, the screen switching control information is information generated in response to a request for provision of a screen switching service and may be generated in various forms. First, in one of the various forms, the screen switching control information may have a function for making a request for operation of an application having been already stored in the user terminal unit100, wherein the application may be a Virtual Machine (VM) application. In this event, the user terminal unit100makes a direct access to the content providing unit400providing a corresponding counsel data screen based on Uniform Resource Locator (URL) information included in the screen switching control information by operating a corresponding application or makes an redirection access to the content providing unit400through the screen switching service unit300. FIG.3is a flowchart illustrating an operation process of the system for providing a screen switching service during call counseling shown inFIG.1. As shown inFIG.3as only an example, the operation process of the system for providing a screen switching service during call counseling is started by execution of a communication call between the user terminal unit100corresponding to a customer's terminal and the counselor terminal unit200of a customer center (step S100). Thereafter, the counselor terminal unit200requests the screen switching service unit300to provide a screen switching service while providing the screen switching service unit300with access route information for the counsel data screen and a telephone number of the user terminal unit100(steps S102to S106). Then, based on the provided information, the screen switching service unit300generates screen switching control information and transfers the generated screen switching control information to the user terminal unit100(steps S108and S110). The user terminal unit100executes a stored application based on the provided screen switching control information and then accesses the screen switching service unit300through a data call based on the URL information included in the screen switching control information (step S112and S114). Then, in response to the access request of the user terminal unit100, the screen switching service unit300reads the URL information for the content providing unit400and then connects the user terminal unit100to the content providing unit400through redirection based on the read URL information (step S116). The content providing unit400provides a counsel data screen to the screen switching service unit300, and the screen switching service unit300transfers the provided counsel data screen to the user terminal unit100(steps S118and S120). As described above, the screen switching control information may be configured to execute the application of the user terminal unit100. Of course, the user terminal unit100not only may access the content providing unit400through the screen switching service unit300by way of redirection, but may also directly access the content providing unit400. Thereafter, the user terminal unit100displays the provided counsel data screen on the terminal screen, so as to enable a customer to identify the counsel data screen used for the counseling during the communication call, so that the customer can use a more efficient counseling service. FIG.4illustrates a construction of a system for providing a screen switching service during call counseling according to another embodiment of the present invention. As shown inFIG.4as a simple example, the system for providing a screen switching service during call counseling includes: a user terminal unit500for establishing a communication call by call origination or call termination; a counselor terminal unit600for establishing a communication call with the user terminal unit500and making a request for a screen switching service for switching a terminal screen of the user terminal unit500into a counsel data screen used for counseling; a screen switching service unit700for making a control to generate a first data call for the user terminal unit500and then transfer a corresponding counsel data screen to the user terminal unit500through the generated first data call in response to a request for a screen switching service from the counselor terminal unit600during a communication call between a customer and a counselor and to transfer the counsel data screen to the counselor terminal unit600through a second data call generated in response to the request for the screen switching service from the counselor terminal unit600; and a content providing unit800for providing a counsel data screen. The screen switching service unit700may make a page control for the counsel data screen being displayed on the user terminal unit500in response to a control input of the counselor terminal unit600through the second data call. Further, it is preferred that the counselor terminal unit600provides access route information for the counsel data screen and a telephone number of the user terminal unit500while making a request for a screen switching service to the screen switching service unit700. FIG.5illustrates a construction of the screen switching service unit700shown inFIG.4. As shown inFIG.5as a simple example, the screen switching service unit700includes: a service request receiving unit710for receiving a request for provision of a screen switching service for switching a terminal screen of the user terminal unit500into a counsel data screen for counseling from the counselor terminal unit600which is in a communication call with the user terminal unit500; a screen switching setting unit720for generating a first data call for the user terminal unit500and forming first screen switching control information including an access route for providing a corresponding counsel data screen through the generated first data call in response to a request for provision of a screen switching service during a communication call, and forming second screen switching control information including an access route for providing a corresponding counsel data screen through a second data call generated in response to the request for provision of the screen switching service; and a transmitting unit730for transferring the first screen switching control information to the user terminal unit500and transferring the second screen switching control information to the counselor terminal unit600. Further, the screen switching setting unit720changes the first screen switching control information and second screen switching control information already formed in response to a control input of the counselor terminal unit600through the second data call for the counsel data screen. Then, the user terminal unit500changes the page of the counsel data screen being displayed on the terminal screen according to the changed first screen switching control information. Likewise, the counselor terminal unit600also changes the page of the counsel data screen according to the changed second screen switching control information. As in the embodiment described above, the first screen switching control information and the second screen switching control information may be generated in various forms, such as a form for operating an application. FIG.6is a flowchart illustrating an operation process of the system for providing a screen switching service during call counseling shown inFIG.4. As shown inFIG.6as only an example, the operation process of the system for providing a screen switching service during call counseling is started by execution of a communication call between the user terminal unit500corresponding to a customer's terminal and the counselor terminal unit600of a customer center (step S200). Thereafter, the counselor terminal unit600requests the screen switching service unit700to provide a screen switching service while providing the screen switching service unit700with access route information for the counsel data screen and a telephone number of the user terminal unit500(steps S202to S206). Then, based on the provided information, the screen switching service unit700generates first screen switching control information to be transferred to the user terminal unit500and second screen switching control information to be transferred to the counselor terminal unit600(step S208). Thereafter, the user terminal unit500executes a stored application based on the provided first screen switching control information and then accesses the screen switching service unit700through a first data call based on the URL information included in the first screen switching control information (step S210to S214). Then, in response to the access request from the user terminal unit500, the screen switching service unit700reads the URL information for the content providing unit800and then connects the user terminal unit500to the content providing unit800through redirection based on the read URL information (step S216). The content providing unit800provides a counsel data screen to the screen switching service unit700, and the screen switching service unit700transfers the provided counsel data screen to the user terminal unit500(steps S218and S220). As described above, the screen switching control information may be configured to execute the application of the user terminal unit500. Of course, the user terminal unit500not only may access the content providing unit800through the screen switching service unit700by way of redirection, but may also directly access the content providing unit800. Thereafter, the user terminal unit500displays the provided counsel data screen on the terminal screen (step S222). As in the case where the screen switching service unit700transfers the first screen switching control information to the user terminal unit500, after transferring the second screen switching control information through the already formed second data call to the counselor terminal unit600also, the screen switching service unit700requests the content providing unit800to provide a corresponding counsel data screen, upon receiving a response to the second screen switching control information (steps S224to S228). Then, the content providing unit800provides a corresponding counsel data screen to the screen switching service unit700and the screen switching service unit700transfers the provided counsel data screen to the counselor terminal unit600(steps S230and S232). The counselor terminal unit600displays the provided counsel data screen on the terminal screen and then transfers screen control information formed by a page control relating to the counseling of the counselor with respect to the counsel data screen to the screen switching service unit700(steps S234and S236). The screen switching service unit700changes the first screen switching control information and second screen switching control information already formed through the provided screen control information and then transfers them to the user terminal unit500and the counselor terminal unit600, respectively, and the counsel data screens being displayed on the user terminal unit500and the counselor terminal unit600are then changed, respectively (steps S238to S246). Although the present invention has been described above in connection with features, such as specific components of the present invention, several embodiments and drawings, these were provided merely to help a thorough understanding of the present invention but not intended to limit the present invention to the embodiments. A person ordinarily skilled in the art to which the present invention pertains can variously modify and change the specific features on the basis of the above disclosure. | 14,154 |
RE49797 | DETAILED DESCRIPTION OF THE INVENTION The exemplary embodiments relate to magnetic junctions usable in magnetic devices, such as magnetic memories and/or logic devices, and the devices using such magnetic junctions. The magnetic memories may include magnetic random-access memories (MRAMs) and may be used in electronic devices employing nonvolatile memory. Such electronic devices include but are not limited to cellular phones, smart phones, tables, laptops and other portable and non-portable computing devices. The following description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements. Various modifications to the exemplary embodiments and the generic principles and features described herein will be readily apparent. The exemplary embodiments are mainly described in terms of particular methods and systems provided in particular implementations. However, the methods and systems will operate effectively in other implementations. Phrases such as “exemplary embodiment”, “one embodiment” and “another embodiment” may refer to the same or different embodiments as well as to multiple embodiments. The embodiments will be described with respect to systems and/or devices having certain components. However, the systems and/or devices may include more or less components than those shown, and variations in the arrangement and type of the components may be made without departing from the scope of the invention. The exemplary embodiments will also be described in the context of particular methods having certain steps. However, the method and system operate effectively for other methods having different and/or additional steps, substeps and/or steps in different orders that are not inconsistent with the exemplary embodiments. Thus, the present invention is not intended to be limited to the embodiments shown but is to be accorded the widest scope consistent with the principles and features described herein. The exemplary embodiments are described in the context of particular methods, magnetic junctions and magnetic memories having certain components. One of ordinary skill in the art will readily recognize that the present invention is consistent with the use of magnetic junctions and magnetic memories having other and/or additional components and/or other features not inconsistent with the present invention. The method and system are also described in the context of current understanding of the spin orbit interaction phenomenon, magnetic anisotropy, and other physical phenomenon. Consequently, one of ordinary skill in the art will readily recognize that theoretical explanations of the behavior of the method and system are made based upon this current understanding of spin transfer, magnetic anisotropy and other physical phenomena. However, the method and system described herein are not dependent upon a particular physical explanation. One of ordinary skill in the art will also readily recognize that the method and system are described in the context of a structure having a particular relationship to the substrate. However, one of ordinary skill in the art will readily recognize that the method and system are consistent with other structures. In addition, the method and system are described in the context of certain layers being synthetic and/or simple. However, one of ordinary skill in the art will readily recognize that the layers could have another structure. Furthermore, the method and system are described in the context of magnetic junctions having particular layers. However, one of ordinary skill in the art will readily recognize that magnetic junctions having additional and/or different layers not inconsistent with the method and system could also be used. Moreover, certain components are described as being magnetic, ferromagnetic, and ferrimagnetic. As used herein, the term magnetic could include ferromagnetic, ferrimagnetic or like structures. As used herein, “in-plane” is substantially within or parallel to the plane of one or more of the layers of a magnetic junction. Conversely, “perpendicular” and “perpendicular-to-plane” corresponds to a direction that is substantially perpendicular to one or more of the layers of the magnetic junction. The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It is noted that the use of any and all examples, or exemplary terms provided herein is intended merely to better illuminate the invention and is not a limitation on the scope of the invention unless otherwise specified. Further, unless defined otherwise, all terms defined in generally used dictionaries may not be overly interpreted. A magnetic device and method for programming the magnetic device are described. The magnetic device includes a plurality of magnetic junctions and at least one spin-orbit interaction (SO) active layer having a plurality of sidesand an axis. The SO active layer(s) carry a current in direction(s) substantiallyperpendicular to the plurality of sidesalong the axis. Each of the magnetic junction(s) is adjacent to the sides and substantially surrounds a portion of the SO active layer. Each magnetic junction includes a free layer, a reference layer and a nonmagnetic spacer layer between the pinned and free layers. The SO active layer(s) exert a SO torque on the free layer due to the current passing through the SO active layer(s). The free layer is switchable between stable magnetic states. The free layer may be written using the current and, in some aspects, another current driven through the magnetic junction. FIGS.1A-1Cdepict perspective, cross-section and top views of an exemplary embodiment of a magnetic device100including a vertical magnetic junction110programmable using SO torque. For clarity,FIGS.1A-1Care not to scale. In addition, portions of the magnetic device100such as bit lines, row and column selectors are not shown. The magnetic device100includes magnetic junctions110and a spin-orbit interaction (SO) active layer130analogous to the SO line described above. In some embodiments, selection devices (not shown) and other components may also be included. Not shown is an optional insertion layer that may be between the SO active layer130and the magnetic junction110. Typically, multiple magnetic junctions110and multiple SO active layer130may be included in the magnetic device100. The magnetic device100may be used in a variety of electronic devices. The magnetic junction110includes a free layer112, a nonmagnetic spacer layer114and a reference layer116. The magnetic junction110may also include optional polarization enhancement layer(s) (PEL(s)) having a high spin polarization. For example, a PEL might include Fe, CoFe and/or CoFeB. The PEL may be between the reference layer116and the nonmagnetic spacer layer114and/or between the nonmagnetic spacer layer114and the free layer. Contact, optional seed layer(s) and optional capping layer(s) may be present but are not shown for simplicity. An optional pinning layer (not shown) may be used to fix the magnetization (not shown) of the reference layer116. The optional pinning layer may be an AFM layer or multilayer that pins the magnetization (not shown) of the reference layer116by an exchange-bias interaction. However, in other embodiments, the optional pinning layer may be omitted or another structure may be used. In other embodiments, discussed below, the reference layer116and nonmagnetic spacer layer114might be omitted. Also not shown inFIGS.1A-1Cis the underlying substrate on which the components110and130are grown. In some embodiments, the substrate is in the x-y plane. In such an embodiment, the z direction is perpendicular to the plane and vertical. In such embodiments, the magnetic junction110has the plane of its layers112,114and116perpendicular to the plane of the substrate. Stated differently, the interfaces between the layers112,114and116would be at a nonzero angle from the substrate surface (not shown). In the embodiment shown, if the substrate is in the x-y plane, the interfaces are substantially perpendicular to the substrate. Consequently, the magnetic junction110may be considered to be a vertical magnetic junction. In other embodiments, the interfaces between the layers112,114and116may be tilted with respect to the substrate. For example, if the magnetic junction110is conical in profile instead of cylindrical or if the magnetic junction is cylindrical but has an axis that is not parallel to the z-axis. In other embodiments, the substrate oriented in another manner. For example, the substrate might be in the x-z plane or the y-z plane. In such embodiments, the axis of the SO active layer130is horizontal. In such embodiments, a portion of the magnetic junction110lies below the SO active layer130. However, such embodiments may be difficult to fabricate. The reference layer116is magnetic and may be a multilayer. For example, the reference layer116may be a synthetic antiferromagnet (SAF) including multiple ferromagnetic layers interleaved with and sandwiching nonmagnetic layer(s) such as Ru. Other multilayers may be used in the reference layer116. For example, the reference layer116may include or consist of one or more of CoFe, CoFeB, FeB, and/or CoPt. Note that as used herein CoFeB, FeB, CoB, CoPt and other materials listed denote alloys in which the stoichiometry is not indicated. For example, CoFeB may include (CoFe)1-xBx, where x is greater than or equal to zero and less than or equal to 0.5 as-deposited. For example, x may be at least 0.2 and not more than 0.4. Other materials and/or structures are possible for the reference layer116. The magnetic moment of the reference layer116may take on various configurations that are discussed below. The nonmagnetic NM spacer layer114is between reference layer116and the free layer112. The nonmagnetic spacer layer114may be a tunneling barrier layer. For example, the nonmagnetic spacer layer114may include or consist of MgO, aluminum oxide and/or titanium oxide. The MgO layer may be crystalline and have a 200 orientation for enhanced tunneling magnetoresistance (TMR). In other embodiments, the nonmagnetic spacer layer114may be a different tunneling barrier layer, may be a conductive layer or may have another structure. The free layer112is magnetic and may be a multilayer. The free layer112may be a SAF or other multilayer. For example, the free layer112may include or consist of one or more of CoFe, CoFeB and/or Fe. The magnetic moment of the free layer112may have various stable states that are discussed below. The free layer is adjacent to the sides of the SO active layer130. In the embodiment shown, the sides of the SO active layer130are cylindrical and perpendicular to the x-y plane. The free layer112is substantially perpendicular to the x-y plane and cylindrical. In the embodiment shown inFIGS.1A-1C, the free layer112adjoins, or shares an interface with, at least a portion of the sides of the SO active layer130. In another embodiment, a thin layer may be inserted between the free layer112and the SO active layer130. For example, such a layer may moderate/enhance SO torque. Although shown inFIGS.1A-1Cas completely surrounding the sides of the SO active layer130that are adjacent to the magnetic junction110, in other embodiments the free layer112may not completely enclose the SO active layer130. For example, there may be a section missing from the magnetic junction110shown inFIGS.1A-1C. In some embodiments, for example, not more than half of the magnetic junction on one side of the SO active layer130may be omitted. However, a magnetic junction110that completely surrounds a portion of the sides of the SO active layer130is generally desired. The magnetic junction110is configured such that the free layer112is switchable between stable magnetic states using a write current which is passed through the SO active layer130along the axis of the SO active layer130(e.g. along the z axis/±z direction inFIGS.1A-1C). Thus, the free layer112is programmable using SO torque. In some embodiments, the free layer112is programmable in the absence of a write current driven through the magnetic junction110. Stated differently, spin transfer torque (STT) is not needed to write to the magnetic junction110in some embodiments. In alternate embodiments, however, a modest current driven through the magnetic junction110and/or an external magnetic field/magnetic bias may be used to assist in switching the free layer magnetic moment. The SO active layer130is a layer that has a strong spin-orbit interaction and is used in switching the magnetic moment (not shown) of the free layer112. For example, the SO active layer may include or consist of materials having a large SO angle with large spin-orbit coupling such as one or more of T, W, IrMn, or Pt, or a topological insulator, such as BiTe, BiSe, BiSb, and/or SbTe. Although termed a “layer”, in the embodiment shown inFIGS.1A-1C, the current carrying line130consists of the SO active material. Thus, when used in connection with the SO materials, the term layer need not imply a particular shape or orientation to the substrate. For example, the SO active layer130need not be a thin, rectangular or planar. Although the line130consists of the SO active layer130inFIGS.1A-1C, in other embodiments, the line130may include other materials. For example, a higher conductivity material may replace or supplement the SO active layer130in regions distal from the magnetic junction110. In other embodiments, a higher resistivity/lower conductivity core might be used. A write current is driven along the length of the SO active layer130in the +z direction or the −z direction. This write current gives rise to an attendant SO interaction, which results in a spin-orbit torque used in writing to the free layer112. As discussed above, the stable magnetic states of the free layer112, as well as the reference layer116, may take on various configurations.FIGS.2A-2Cdepict exemplary embodiments of magnetic devices100and the magnetic moment of vertical magnetic junction110A,110B and110C. The magnetic junctions110A,110B and110C are analogous to the magnetic junction110. The magnetic junction110A includes free layer112A, nonmagnetic spacer layer114and reference layer116A that are analogous to the free layer112, nonmagnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112A,114and116A are analogous to those for the layers112,114and116. However, the magnetic moments113A and117A of the free layer112A and reference layer116A, respectively, are explicitly shown. The reference layer magnetic moment117A is along the z-axis. The free layer stable states are along the +z-direction and the −z-direction. Stated differently, the free layer112has its easy axis parallel to the z-axis shown inFIG.1A. The magnetic device100A may have improved scalability, may have fast switching (e.g. less than 0.5 nanoseconds) and may be thermally stable, but may require large current densities for switching in some embodiments. The magnetic junction110B includes free layer112B, nonmagnetic spacer layer114and reference layer1168116Bthat are analogous to the free layer112, nonmagnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112B,114and1168116Bare analogous to those for the layers112,114and116. However, the magnetic moments1138113Band1178117Bof the free layer112B and reference layer1168116B, respectively, are explicitly shown. The reference layer magnetic moment1178117Bcirculates around the z-axis and, therefore, around the SO active layer130. The free layer stable states also circulate around the z-axis. The magnetic device1008100Bmay have improved scalability, may use lower current densities for switching (e.g. less than 3 MA/cm2) and may be thermally stable, but may require larger switching times (e.g. greater than 10 nanoseconds). The magnetic junction110C includes free layer112C, nonmagnetic spacer layer114and reference layer116C that are analogous to the free layer112, nonmagnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112C,114and116C are analogous to those for the layers112,114and116. However, the magnetic moments113C and117C of the free layer112C and reference layer116C, respectively, are explicitly shown. The reference layer magnetic moment117C is radial. In the embodiment shown, the moment117C is toward the z-axis. In another embodiment, the moment117C might be radial away from the z-axis. Similarly, the free layer stable states are also radial. The magnetic device100C may deliver intermediate performance. For example, the magnetic device100C have improved scalability, may use interfacial perpendicular magnetic anisotropy (I-PMA) for improved thermal stability, may use intermediate current densities (e.g. greater than 20 MA/cm2) and may have somewhat smaller switching times (e.g. <1 nanosecond), but may be less thermally stable. Thus, three particular configurations of magnetic moments are shown in magnetic junctions110A,110B and110C. In another embodiment, other configurations might be used. Referring back toFIGS.1A-1C, the magnetic junction110may be read in a conventional manner. Thus, a read current insufficient to program the magnetic junction110using STT may be driven through the magnetic junction110in the direction perpendicular to at least some of the interfaces between the layers112,114and116. In the embodiment shown, the current may be driven radially (perpendicular to the z-axis) or in another direction such as along the y axis or along the x-axis. The resistance of the magnetic junction110is based on the orientation between the free layer magnetic moment and the reference layer magnetic moment. Thus, data may be read from the magnetic junction110by determining the resistance of the magnetic junction110. The magnetic junctions110A,110B and110C may be read in an analogous manner. In programming the magnetic junction110, however, a write current is driven through the SO active layer130and substantiallyperpendicular to the sides of the SO active layer130adjacent to the free layer112. In the embodiment shown, this isalong the z axis. Based on the direction of current, spins polarized in opposite directions may drift to opposing sides of the SO active layer130. Because the free layer112and magnetic junction110substantially surround the sides of the SO active layer130, all of these polarized spins may be used in writing to the free layer112. In some embodiments, the stable magnetic states of the free layer112are configured such that the SO torque due to these spins can switch the magnetic state of the free layer112. For example,FIGS.3A-3Bdepict exemplary embodiments of the magnetic moment of a free layer in the magnetic junction110B after switching using SO torque. As discussed above, the free layer112B has stable states circulating around the z-axis (the SO active layer130). Thus,FIGS.3A-3Bessentially depict the magnetic junction110B during writing if the magnetic moments circulate around the SO active layer130.FIG.3Adepicts the magnetic device100/100B when the current is driven through the SO active layer130out of the plane of the page. Thus, current density Jc+ is shown. Because of the SO effect, spins migrate to the sides of the SO active layer130, as shown. The spins on one side of the SO active layer130have opposite polarization to spins on the opposite side of the SO active layer130. These spins have exerted an SO torque on the free layer112, causing the free layer magnetic moment113B′ to be in the direction shown. In contrast,FIG.3Bdepicts the magnetic device100/100B when the current is driven through the SO active layer130into the plane of the page. Thus, current density Jc− is shown. Because of the SO effect, spins migrate to the sides of the SO active layer130, as shown. The spins on one side of the SO active layer130still have opposite polarization to spins on the opposite side of the SO active layer130. However, the orientations have flipped. These spins have exerted an SO torque on the free layer112, causing the free layer magnetic moment113B″ to be in the direction shown. Thus, in the embodiment shown inFIGS.3A and3B, the free layer112may be programmed using only an SO current Jc+/Jc− through the SO active layer130. In other embodiments, the programming might be assisted by an additional current and/or a magnetic field. For example, an STT current may be driven through the magnetic junction110B. Such a mechanism for programming could be used with the magnetic junctions110B,110C, and/or110D having the stable states of the free layer magnetic moment circulating around the z-axis, oriented radially with respect to the z-axis or along the z-axis. In such embodiments, the STT current may be used to select a final direction of the magnetic moment. Thus, a more modest STT current may be used to switch the free layer112in such embodiments. The magnetic devices100,100A,100B and100C may have improved performance. The free layer112/112A/112B/112C may be programmed using SO torque and a current driven through the SO active layer130. Because no STT write current is driven through the magnetic junction110for programming, damage to the magnetic junction110may be avoided. For example, breakdown of the tunneling barrier layer114may be circumvented. Even if an STT write current is driven through the magnetic junction110/110A/110B/110C, the magnitude of the current may be smaller. Thus, damage to the magnetic junction110/110A/110B/110C may be reduced or prevented. Moreover, the interface for the SO torque to act on the free layer112/112A/112B/112C may be enhanced. As such, a smaller write current may be driven through the SO active layer130while still writing to the magnetic junction110/110A/110B/110C. The configuration of the magnetic junction110/110A/110B/110C and SO active layer130may be more scalable and switching time reduced. Writing may be primarily achieved using a current through the SO active layer, while reading performed using a current through the magnetic junction. As a result, read and write may be separately optimized. FIGS.4-6depict top views of other exemplary embodiment of magnetic devices100D,100E and100F, respectively, including vertical magnetic junctions110D,110E and110F programmable using SO torque and SO active layer130D,130E and130F. The magnetic junctions110D,110E and110F are analogous to the magnetic junctions110,110A,110B and110C. The magnetic junction110D includes free layer112D, nonmagnetic spacer layer114D and reference layer116D that are analogous to the free layer112, non-magnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112D,114D and116D are analogous to those for the layers112,114and116. Similarly, the SO active layer130D is analogous to the SO active layer130. Consequently, the structure, function and materials used in the SO active layer130D are analogous to those used in the SO active layer130. The magnetic junction110D and SO active layer130D are elliptical in footprint instead of circular. Thus, the magnetic device100is not limited to a circular footprint. The magnetic junction110E includes free layer112E, nonmagnetic spacer layer114E and reference layer116E that are analogous to the free layer112, nonmagnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112E,114E and116E are analogous to those for the layers112,114and116. Similarly, the SO active layer130E is analogous to the SO active layer130. Consequently, the structure, function and materials used in the SO active layer130E are analogous to those used in the SO active layer130. The magnetic junction110E and SO active layer130E are square in footprint instead of circular. Thus, the magnetic device100is not limited to a circular footprint. In addition, an interlayer118is shown. This interlayer118resides between the SO active layer130E and the free layer112E. The layer118may be used to moderate (enhance and/or decrease) interaction between the free layer112E and the SO active layer130E. For example, the SO torque may be enhanced. The magnetic junction110F includes free layer112F, nonmagnetic spacer layer114F and reference layer116F that are analogous to the free layer112, nonmagnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112F,114F and116F are analogous to those for the layers112,114and116. Similarly, the SO active layer130F is analogous to the SO active layer130. Consequently, the structure, function and materials used in the SO active layer130F are analogous to those used in the SO active layer130. The magnetic junction110E and SO active layer130F are rectangular in footprint instead of circular. In addition, the magnetic junction110F is shown as not completely surrounding the SO active layer130F. Instead, aperture or slot119is present. However, as discussed above, in generally, it is desirable for the magnetic junction to surround the SO active layer in order to increase the area available for interaction via SO torque. FIGS.7A-7Bdepict perspective and top views of another exemplary embodiment of a magnetic device100G including vertical magnetic junction(s)110G programmable using SO torque. The magnetic junction100G is analogous to the magnetic junctions110,110A,110B,110C,110D,110E and110F. The magnetic junction110E includes free layer112, nonmagnetic spacer layer114and reference layer116that are analogous to the free layer112, nonmagnetic spacer layer114and reference layer116, respectively. Consequently, the structure, function and materials used in the layers112,114and116of the magnetic junction110G are analogous to those for the layers112,114and116of the magnetic junction(s)110,110A,110B,110C,110D,110E and110F. Similarly, the SO active layer130E is analogous to the SO active layer130. Consequently, the structure, function and materials used in the SO active layer130E are analogous to those used in the SO active layer130. However, the line131includes both the SO active layer130G and a core132. The core132may have a lower conductivity/higher resistivity than the SO active layer130G. For example, the core132may be formed of material(s) including but not limited to polysilicon, SiN and/or SiO. The magnetic device100G may share the benefits of the magnetic devices100,100A,100B,100C,100D,100E and/or100F. In addition, the current may be preferentially carried through the SO active layer130G, closer to the interface with the free layer112. As a result, the SO active layer130G and the line131may have improved efficiency in delivering SO torque to the free layer112. Thus, performance of the magnetic device100G may be further improved. FIGS.8A-8Cdepict perspective, cross-section and top views of an exemplary embodiment of a magnetic device100H including a vertical magnetic junction110H programmable using SO torque. For clarity,FIGS.8A-8Care not to scale. In addition, portions of the magnetic device100H such as bit lines, row and column selectors are not shown. The magnetic device100H includes magnetic junctions110H and a spin-orbit interaction (SO) active layer130analogous to the magnetic junction110,110A,110B,110C,110D,110E,110F and/or110G and SO active layer130and/or130G described above. In some embodiments, selection devices (not shown) and other components may also be included. Not shown is an optional interlayer, such as layer118, that may be between the SO active layer130and the magnetic junction110H. Typically, multiple magnetic junctions110H and multiple SO active layer130may be included in the magnetic device100H. The magnetic device100H may be used in a variety of electronic devices. The magnetic junction110H includes a free layer112that is analogous to the free layer112of the magnetic junction110. Thus, the materials and configuration of the free layer112in the magnetic junction110H is analogous to that in the magnetic junction110. For example, the free layer112may be a SAF or other multilayer. The magnetic junction110H may also include optional PEL(s) having a high spin polarization. Contact, optional seed layer(s) and optional capping layer(s) may be present but are not shown for simplicity. Although the free layer112is shown as adjoining the SO active layer130, in other embodiments, a layer, such as interlayer118, may be inserted between the sides of the SO active layer130and the free layer112. Further, although shown as completely surrounding the sides of the SO active layer130, in other embodiments, the free layer112may include an aperture or may terminate without completely surrounding the SO active layer130. Thus, the magnetic junction100H includes a free layer112. However, the nonmagnetic spacer layer114and a reference layer116of the magnetic junction110are omitted. Consequently, STT is not used in programming the free layer112. In some embodiments, an external magnetic field may be used in addition to SO torque to write to the free layer112. In addition, the magnetic junction110H is read using a current driven along the z-axis through the SO active layer130that is insufficient to program the free layer112. For example,FIGS.9A-9Fdepict cross-sectional views of an exemplary embodiment of the magnetic device100H including vertical magnetic junctions programmable using SO torque during writing and reading.FIGS.9A and9Bdepict the magnetic junction100H just after having been programmed.FIG.9Adepicts the magnetic device110H after a write current Jc+ has been driven through the SO active layer130. Thus, the free layer112has been written such that its magnetic moment113H is stable in the orientation shown.FIG.9Bdepicts the magnetic junction110H after write current Jc− has been driven through the SO active layer130. Thus, the free layer112has been written such that its magnetic moment113H′ is stable in the opposite direction. FIGS.9C-9Fdepict side views of the magnetic device100H during reading. The magnetic junction100H is read using currents having current densities J+ and J− driven along the z-axis through the SO active layer130. This current is insufficient to program the free layer112. The state of the free layer112is read using the difference in resistance due to the configurations of the spins in the SO active layer130and the magnetic moment of the free layer112.FIGS.9C and9Ddepict the magnetic device100H when the free layer magnetic moment circulates around the SO active layer130as shown (out of the plane of the page on one side of the layer130and into the plane of the page on the other). InFIG.9C, the current J+ results in spins of opposite orientation migrating to opposite sides of the SO active layer, as shown. With the current J+, the spins align with the magnetic moment of the free layer112and result in a resistance of R1+. As shown inFIG.9D, the spins in the SO active layer130are opposite to the magnetic moment of the free layer112. The resulting resistance is R1−. In addition, R1−>R1+. Thus, a differential measurement results in a negative difference in resistance between J+ and J−. FIGS.9E and9Fdepict a resistance measurement when the free layer112has a magnetic moment in the opposite direction. The current J+ results in the spins migrating within the SO active layer130in the same manner as forFIG.9C. However, in this case, the spins are in the opposite direction as the free layer magnetic moment and result in a resistance of R2+. For the current J−, the spins migrate as shown inFIG.9D. However, the spins now align with the magnetic moment of the free layer112and result in a resistance R2−. Further, R2−<R2+. Thus, a differential resistance measurement results in a positive difference in resistance between J+ and J−. Thus, the magnetic junction100H may be read and programmed using currents only through the SO active layer130. Although specific magnetic devices100,100A,100B,100C,100D,100E,100F,100G and100H and particular magnetic junctions110,110A,110B,110C,110D,110E,110F,110G and110H have been described herein, one of ordinary skill in the art will recognize that one or more of the features described herein may be combined in manners not explicitly shown. FIG.10is a perspective view of an exemplary embodiment of a memory200A that may use one or more of the magnetic devices100,100A,100B,100C,100D,100E,100F,100G,100H and/or other magnetic devices including a vertical magnetic junction written using SO torque. Only a portion of the magnetic memory200A is shown. For example, reading/writing column select drivers as well as word line select driver(s) are not shown. Note that other and/or different components may be provided. The memory200A includes a substrate202, lines201and203and memory cells210A. Each memory cell210A includes a selection transistor220A, magnetic junction212and SO active layer211. Although only one magnetic junction212per cell is shown, in other embodiments, additional magnetic junctions may be used. The SO active layer211is analogous to the SO active layer130and/or130G/line131. The magnetic junctions212are analogous to the magnetic junction(s)110,110A,110B,1100,110D,110E,110F,110G,110H and/or another vertical magnetic junction. In addition, as can be seen by the orientation of the magnetic junctions212with respect to the substrate202, the magnetic junctions212have interfaces (not shown) that may be substantially perpendicular to the substrate202. The transistor220A shown are planar transistors. In another embodiment, another selection device might be used. For example, an ovonic threshold selector (OTS) device might be used. In addition, also shown are lines201that may be used to drive current through the magnetic junction212for reading and/or writing. However, if a free layer only magnetic junction100H is used, the lines201may be omitted. Because the magnetic memory200A uses the magnetic junctions212and SO active layers211, the magnetic memory200A may enjoy the benefits described above. FIG.11is a perspective view of an exemplary embodiment of a memory200B that may use one or more of the magnetic devices100,100A,100B,100C,100D,100E,100F,100G,100H and/or other magnetic devices including a vertical magnetic junction written using SO torque. Only a portion of the magnetic memory200B is shown. For example, reading/writing column select drivers as well as word line select driver(s) are not shown. Note that other and/or different components may be provided. The memory200B includes a substrate202, lines201and203and memory cells210B. Each memory cell210B includes a selection transistor220B, magnetic junction212and SO active layer211. Although only one magnetic junction212per cell is shown, in other embodiments, additional magnetic junctions may be used. The SO active layer211is analogous to the SO active layer130and/or130G/line131. The magnetic junctions212are analogous to the magnetic junction(s)110,110A,110B,1100,110D,110E,110F,110G,110H and/or another vertical magnetic junction. In addition, as can be seen by the orientation of the magnetic junctions212with respect to the substrate202, the magnetic junctions212have interfaces (not shown) that may be substantially perpendicular to the substrate202. The transistor220B shown are planar transistors. In another embodiment, another selection device including but not limited to an OTS selection device might be used. Also shown are lines201that may be used to drive current through the magnetic junction212for reading and/or writing. However, if a free layer only magnetic junction100H is used, the lines201may be omitted. Also shown inFIG.11is additional selector230B. The selector230B may be an OTS selector or other analogous device. Because the magnetic memory200B uses the magnetic junctions212and SO active layers211, the magnetic memory200B may enjoy the benefits described above. In addition, use of two selection devices220B and230B may reduce or eliminate the sneak path for current. As such, performance may be further improved. FIG.12is a perspective view of an exemplary embodiment of a memory200C that may use one or more of the magnetic devices100,100A,100B,100C,100D,100E,100F,100G,100H and/or other magnetic devices including a vertical magnetic junction written using SO torque. Only a portion of the magnetic memory200C is shown. For example, reading/writing column select drivers as well as word line select driver(s) are not shown. Note that other and/or different components may be provided. The memory200C includes a substrate202, lines201and203and memory cells210C. Each memory cell210C includes a selection transistor220C, magnetic junction212and SO active layer211. An optional second selection device230C is also shown. Although only one magnetic junction212per cell is shown, in other embodiments, additional magnetic junctions may be used. The SO active layer211is analogous to the SO active layer130and/or130G/line131. The magnetic junctions212are analogous to the magnetic junction(s)110,110A,110B,110C,110D,110E,110F,110G,110H and/or another vertical magnetic junction. In addition, as can be seen by the orientation of the magnetic junctions212with respect to the substrate202, the magnetic junctions212have interfaces (not shown) that may be substantially perpendicular to the substrate202. Also shown are lines201that may be used to drive current through the magnetic junction212for reading and/or writing. However, if a free layer only magnetic junction100H is used, the lines201may be omitted. The transistor220C shown are vertical (three-dimensional) transistors instead of planar transistors. Because the magnetic memory200C uses the magnetic junctions212and SO active layers211, the magnetic memory200C may enjoy the benefits described above. In addition, if two selection devices220C and230C are used, the sneak path for current may be reduced or eliminated. As such, performance may be further improved. Further, the magnetic memory200C may be more scalable because of the use of three dimensional transistors220C. Thus, the magnetic memory200C may have enhanced performance. FIG.13depicts an exemplary embodiment of a schematic for a memory300A that may use one or more of the magnetic devices100,100A,100B,100C,100D,100E,100F,100G,100H and/or other magnetic devices including vertical magnetic junctions programmable using SO torque. Only a portion of the magnetic memory300A is shown. For example, reading/writing column select drivers as well as word line select driver(s) are not shown. Note that other and/or different components may be provided. The magnetic memory300A includes word lines301, Vcc/Vdd/ground/read voltage lines303, Vcc/Vdd/ground/floating lines305, output lines307that may connect to a sense amplifier, magnetic junctions312, SO active layers311, selection transistor320and optional additional selection device330A. The components311,312,320and (optionally)330A form cells310A. For simplicity only one cell is labeled. Each magnetic junction312is shown as connected to line307. However, if a free layer only magnetic junction100H is used this connection may be omitted. Because the magnetic memory300A uses the magnetic junctions312and SO active layers311, the magnetic memory300A may enjoy the benefits described above. In addition, if two selection devices320and330A are used, the sneak path for current may be reduced or eliminated. As such, performance may be further improved. If the transistor320is a vertical transistor such as the transistor220C, the magnetic memory300A may be more scalable. Thus, the magnetic memory300A may exhibit improved performance. FIG.14depicts an exemplary embodiment of a schematic for a memory300B that may use one or more of the magnetic devices100,100A,100B,100C,100D,100E,00F,100G,100H and/or other magnetic devices including vertical magnetic junctions programmable using SO torque. Only a portion of the magnetic memory300B is shown. For example, reading/writing column select drivers as well as word line select driver(s) are not shown. Note that other and/or different components may be provided. The magnetic memory300B is analogous to the magnetic memory300A. Consequently, the magnetic memory300B includes word lines301, Vcc/Vdd/ground/read voltage lines303, Vcc/Vdd/ground/floating lines305, output lines307that may connect to a sense amplifier, magnetic junctions312, SO active layers311and selection transistor320that are analogous to components301,303,305,307,312,311and320, respectively. The components311,312,320and (optionally)332B form cells310B. For simplicity only one cell is labeled. Each magnetic junction312is shown as connected to line307. However, if a free layer only magnetic junction100H is used this connection may be omitted. Each memory cell310B may include an optional diode332B. The diode332B may be used to eliminate the sneak path. In lieu of a diode332B, another configuration that functions as a diode may be used. Because the magnetic memory300B uses the magnetic junctions312and SO active layers311, the magnetic memory300B may enjoy the benefits described above. In addition, if the diodes332B are used, the sneak path for current may be reduced or eliminated. As such, performance may be further improved. If the transistor320is a vertical transistor such as the transistor220C, the magnetic memory300B may be more scalable. Thus, the magnetic memory300B may exhibit improved performance. FIGS.15-16depict perspective views of other exemplary embodiments of a magnetic devices400A and400B including multiple vertical magnetic junctions412programmable using SO torque. The magnetic junctions412are analogous to the magnetic junction(s)110,110A,110B,110C,110D,110E,110F,110G,110H and/or another vertical magnetic junction. Also shown are SO active layers411analogous to the SO active layers130and/or130G/line131. For simplicity, not all SO active layers411are labeled inFIG.15. Although a particular number of magnetic junctions are shown in each magnetic device400A and400B, in other embodiments, other number(s) may be used. In the magnetic device400B, isolation devices414are shown as interleaved between the magnetic junction412. For example, the isolation devices414might be vertical transistors analogous to the transistor220C. The magnetic devices400A and/or400B might be incorporated into a device utilizing the magnetic devices100,100A,100B,100C,100D,100E,100F,100G,100H and/or an analogous device. For example, one or more of the magnetic memories200A,200B,200C,300A and/or300B might use the magnetic device400A and/or400B. In some embodiments, the magnetic junctions412may be individually programmed using a combination of current driven through the SO active layers411(i.e. using SO torque) and a current driven through the magnetic junction (e.g. STT torque). Such embodiments include those in which the SO torque is collinear with the magnetization, such as the magnetic junction1008. For example, a write current that is insufficient to write to the magnetic junction412alone may be driven through the SO active layer411. Each magnetic junction412to be written may simultaneously have an STT current driven through it. For example, the STT current may be radial or simply in a particular direction that allows the STT current to pass through the interface(s) between the layers of the magnetic junction412. The combination of the currents driven in the appropriate directions writes to the desired magnetic junctions412. In some embodiments, an STT current driven in one direction through the magnetic junctions412to be switched aids in programming, while an STT current driven in the opposite direction through magnetic junctions412not to be switched prevents writing to such magnetic junctions from being programmed. In other embodiments, a current is driven through the SO active layer411. A small STT current may be driven through the magnetic junctions412desired to be written, for example to select the final direction of magnetization after programming. In some embodiments, the magnetic moment of the free layer of each magnetic junction412may be stable radially, in a manner analogous to the magnetic junction100C. A current driven through the SO active layer may destabilize the magnetic moments such that the free layer magnetic moments circulate around the SO active layer411. The final direction of magnetization may be set by applying a small STT current to the magnetic junction(s)412desired to be programmed. When the currents are removed, the magnetic junctions412are programmed in the desired radial direction. In another embodiment, the magnetic moment of the free layer of each magnetic junction412is stable axially (along the axis of the cylinder shown inFIGS.15and16) in a manner analogous to the magnetic junction100A. In such an embodiment, a current driven through the SO active layer may still destabilize the magnetic moments such that the free layer magnetic moments circulate around the SO active layer411. The final direction of magnetization may be set by applying a small STT current to the magnetic junction(s)412desired to be programmed. This STT torque has an axial direction due to the magnetic moment of the reference layer. When the currents are removed, the magnetic junctions412are programmed in the desired axial direction. FIG.17depicts an exemplary embodiment of a method500for fabricating a magnetic device programmable using SO torque and including vertical magnetic junctions. For simplicity, some steps may be omitted, performed in another order, include substeps and/or combined. Further, the method500may start after other steps in forming a magnetic memory have been performed. For simplicity, the method500is described in the context of the magnetic device100. However, other magnetic devices, including but not limited to the magnetic devices100A,100B,100C,100D,100E,100F,100G and/or100H may be formed. At least one SO active layer130is provided, via step502. Step502may include depositing and patterning the desired materials for each SO active layer130. In some embodiments, step502includes forming the low conductivity core132and the SO active layer130G on the core132. Thus, a pillar may be formed in step502. The interlay layer118may optionally be provided as part of step502. The magnetic junctions110may then be formed, via step504. Step504may include blanket depositing the layers for the free layer112, nonmagnetic spacer layer114, reference layer116and any additional layers desired in the magnetic junction110. Alternatively, the nonmagnetic spacer layer114and/or reference layer114might be omitted. Anneal(s) and/or other processing steps may also be performed. The magnetic junctions110may then be defined. For example, a planarization step may remove the portions of the magnetic junctions110connection layer112,114and116and the SO active layer130physically exposed. Fabrication may then be completed, via step506. For example, isolation and/or selection devices may be formed. If magnetic devices400A and/or400B are to be fabricated, then subsequent SO active layers130and magnetic junctions110may be formed. Using the method500, the magnetic devices100,100A,100B,00C100C,100D,100E,100F,100G, and/or analogous magnetic devices may be fabricated. As a result, the benefits of the magnetic devices100,100A,100B,00C100C,100D,100E,100F and/or100G may be achieved. FIG.18depicts an exemplary embodiment of a method510for programming a magnetic junction using SO torque. For simplicity, some steps may be omitted, performed in another order, include substeps and/or combined. Further, the method510may start after other steps have been performed. For simplicity, the method510is described in the context of the magnetic junction110. However, other magnetic junctions, including but not limited to the magnetic junctions110A,1106,110C,110D,110E,110F,110G,110H and/or an analogous magnetic junction may be programmed. The desired current is driven through the SO active layer130/line131, via step512. Thus, the current is driven along the axis of the SO active layer130/lienline131and substantiallyperpendicularparallelto the sides. In embodiments, in which the current through the SO torque is sufficient to program the device as desired, then the method510terminates. However, in some embodiments, multiple currents are used to program a magnetic junction. Thus, an additional STT current may be driven, via step512. In some embodiments, the STT current is driven through the magnetic junctions to be programmed. In such embodiments, the STT current is desired to assist in programming and/or select the final state of the free layer112. In other embodiments, the STT current may be driven through magnetic junctions whether or not they are to be programmed. In such embodiments, the direction of the STT current provided in step514depends upon whether the magnetic junction110is to be programmed. If so, the STT current is driven in a direction that adds to the SO torque. If not, the STT current is driven in a direction such that the STT torque opposes the SO torque. In some embodiments, the current through the SO active layer130commence at substantially the same time as the STT current. In other embodiments, the current through the SO active layer is started first, and the STT current commences later. Similarly, in some embodiments, the current through the SO active layer130may be terminated before the STT current goes to zero. In other embodiments, the STT current may be terminated before the current through the SO active layer130. In still other embodiments, the current through the SO active layer130and the STT current through the magnetic junction may be terminated at substantially the same time. However, in most embodiments, the current through the SO active layer130and the STT current overlap in time. Thus, the magnetic junctions110,110A,110B,110C,110D,110E,110F,110G,110H,212,312and/or412may be programmed. As a result, the benefits of the magnetic device(s)100,100A,100B,100C,100D,100E,100F,100G,100H,200,200B,200C,300A,300B,400A and/or400B may be achieved. A method and system for providing and using a magnetic junction and a memory fabricated using the magnetic junction has been described. The method and system have been described in accordance with the exemplary embodiments shown, and one of ordinary skill in the art will readily recognize that there could be variations to the embodiments, and any variations would be within the spirit and scope of the method and system. Accordingly, many modifications may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. | 51,641 |
RE49798 | DESCRIPTION OF THE PREFERRED EMBODIMENT A rolling car seat according to a preferred embodiment of the present invention will now be described with reference toFIGS.1to7bof the accompanying drawings. The rolling car seat10includes a car seat20, a wheel assembly50, a footrest38, and a handle assembly40. In one embodiment, the car seat20includes a back portion22and a seat portion36extending forwardly from the back portion22in the manner of a chair. More particularly, the back portion22may include opposed upper24and lower26ends, the seat portion36extending forwardly from the back portion lower end26. The car seat20may include a padded material situated on respective front surfaces of the back portion22and seat portion36. The back portion22includes a rear surface28. Preferably, the back portion22defines a recessed area30adjacent the lower end26thereof in which the wheel assembly50is housed at a withdrawn configuration as will be described in more detail below. The back portion22may also define seatbelt slots32configured to receive a vehicle seatbelt therethrough in order to mount the car seat20to a vehicle seat. In addition, the seat portion36may include a plurality of protection members (not numbered) that are configured to protect the front end of the seat portion36and prevent it from rolling. In addition, the back portion22may also define opposed vertical handle channels34into which the handle assembly40may be received. The opposed handle channels34extend substantially between back portion upper24and lower26ends, each handle channel34being configured to receive handle members of the handle assembly40. In some embodiments the handle assembly40may be viewed as extending directly out of a headrest. It should be noted that the handle channels34are shown in the drawings as openings in the back portion22. This is only shown open for clarity and it is understood that the handle channels34are preferably formed inside the back portion22and are not open, except at upper ends thereof. The footrest38is a panel that is coupled to the seat portion36and movable between an inward configuration positioned inside the seat portion36(FIG.1) and an outward configuration extending forwardly from the seat portion36(FIGS.3a and3b). More particularly, the footrest38is substantially inside the seat portion36at the inward configuration and is substantially outside the seat portion36at the outward configuration. The footrest also serves the function of not allowing the feet of taller children to reach the ground when the car seat is rolling and also not to allow children to push the car seat when it is at rest on the ground. The handle assembly40is operatively coupled to the back portion22of the car seat20. The handle assembly40is movable between a retracted configuration (FIG.2) in which the handle assembly40does not extend upwardly above the upper end24of the back portion22and an extended configuration (FIG.1) in which the handle assembly40extends upwardly above the upper end24of the back portion22as will be described below. The handle assembly40includes a plurality of handle members arranged in a telescopic configuration, the handle members42having appropriate diameters to be slidably arranged for movement in a moderate friction fit manner. The handle members may be referred to later as having an outermost member44, an innermost member48, or an inner member although the handle assembly40may not necessarily be constrained to any particular number of telescopic segments. For instance, a handle bar49may extend between upper end of the innermost handle members42by which a user may urge the handle assembly40between extended and retracted configurations. The wheel assembly50includes a pair of spaced apart wheels52operatively coupled to the car seat back portion22and interconnected by an axle54. The wheel assembly50is selectively movable between a withdrawn configuration adjacent the back portion22and a deployed configuration extending rearwardly from the back portion22. Preferably, the wheels52are situated in the recessed area30and not extending from the back portion at the withdrawn configuration and extending at least partially outside the recessed area30at the deployed configuration. It is understood that in some embodiments, the wheels may extend as wide as the car seat width or include wheels having an increased width so as to maximize stability. In addition, at least one wheel may include a wheel lock (not shown) that, when actuated, prevents the wheel from rotating. In some embodiments (not shown), the wheel assembly may include wheels that are fixed in the deployed configuration and are not movable between deployed and withdrawn configurations. As will be described below in detail, the handle assembly40and wheel assembly50include structures that cause each other to move cooperatively between their respective configurations. For instance, the wheel assembly is at the withdrawn configuration when the handle assembly40is at the retracted configuration (FIG.2). Even more particularly, the wheel assembly50is moved automatically to the withdrawn configuration when the handle assembly40is moved to the retracted configuration. The wheel assembly50includes respective mounting members56(one associated with each wheel52) pivotally coupled to the car seat back portion22at pivot point57and operatively coupled to a respective wheel52. In this way, each wheel assembly50is operatively coupled to the car seat20. A pivotal movement of each mounting member56at pivot point57causes the wheel assembly50to move between withdrawn and deployed configurations. For instance, the wheel assembly50is at the withdrawn configuration when the mounting members56are pivoted as shown inFIG.2and, on an enlarged scale,FIG.6b. By comparison, the wheel assembly50is at the deployed configuration when the mounting members56are pivoted as shown inFIG.1and, on an enlarged scale,FIG.6a. The back portion22of the car seat20may define an interlink channel58adjacent each mounting member56(FIGS.6a and6b). Each interlink channel58includes opposed upper58a and lower58b ends. A respective interlink channel58communicates a respective recessed area30with a respective handle channel34. Each mounting member56includes a retraction pin60extending outwardly from an outside surface thereof and is configured to extend through a respective interlink channel58and into a respective handle channel (FIG.7a). A retraction pin60is urged upwardly toward an upper end58a of a respective interlink channel58when the mounting member56is pivoted to urge the wheel assembly toward the deployed configuration. The retraction pin60is urged downwardly toward a lower end58b of a respective interlink channel58when the mounting member56is pivoted to urge the wheel assembly toward the withdrawn configuration. In further description of the linkage between the wheel assembly50and the handle assembly40, the outermost/lowermost handle member44of the plurality of handle members42is fixed in its position within the respective handle channel34(FIG.7a). With further reference toFIG.7a, a respective retraction pin60extends through a respective interlink channel58and into a respective handle channel34to a position adjacent a bottom end46of the outermost/lowermost handle member44when the wheel assembly50is at the deployed configuration, the retraction pin60being at the upper end58b of the respective interlink channel58. By comparison, a retraction pin60is downwardly displaced from the bottom end46of the lowermost handle member44when the wheel assembly50is at the withdrawn configuration, the retraction pin60being at the lower end58b of the respective interlink channel58(FIGS.5and7b). It is noted that there are two means for causing the wheel assembly50to move between configurations. First, a user may manually pull outwardly on the axle54to deploy the wheels, such as by inserting his foot under the axle54and urging it outwardly. It may be returned to the withdrawn configuration by manually pushing it back inward. Another means of moving the wheel assembly50to the withdrawn configuration is to urge the handle assembly to the retracted configuration. As the handle members42are urged downwardly into the handle channels34, a respective innermost/lowermost handle member44is moved downwardly below the bottom end46of the outermost (fixed) handle member44to bear against a respective retraction pin60and urge it downwardly in a respective interlink channel58(FIG.7b). As described above, movement of the retraction pin60to a lower end of an interlink channel58pivots the mounting member56so as to move the wheel assembly50to the withdrawn configuration. This movement is also observed by comparingFIG.7atoFIG.7b. In another aspect of the present invention, the mounting member56may also include a locking spring pin62, also commonly known as a spring plunger, adjacent the retraction pin60. The outermost handle member44defines an aperture (not shown) adjacent the bottom end46thereof. The locking spring pin62extends through the mounting member56and is biased to extend outwardly. Accordingly. when the mounting member56is pivoted to the position shown inFIGS.1,6a, and7a, the locking spring pin62is configured to be received automatically into the aperture so as to prevent any further movement of the mounting member56until the locking spring pin62is released as will be discussed below. The effect of actuation of the locking spring pin62, therefore, is to prevent any unintended movement of the wheel assembly50from the deployed configuration to the withdrawn configuration while it is being transported/rolled. In other words, the wheels will not surprisingly “retract” when in use. As described previously, the retraction pin60is urged downwardly in the interlink channel58when the innermost handle member48is retracted which pivots the mounting member56to the position that urges the wheel assembly50to the withdrawn configuration. More particularly, the innermost handle member48slides through and below the bottom end46of the outermost handle member44as shownFIG.7b. When this occurs, the innermost handle member48first contacts the locking spring pin62and dislodges it from the aperture—thus, disengaging the locking of the wheel assembly50. In use, the rolling car seat10may be strapped in to a vehicle seat by inserting a seat belt through the seat belt receiving slots32in a conventional manner. If, however, it is desired to remove the rolling car seat10from the vehicle and transport it to another location, whether to another vehicle or to a location for an entertainment event, the rolling car seat10may be removed from the vehicle and rolled to the desired location. Specifically, the wheel assembly50may be moved from a withdrawn configuration substantially in the recessed area30of the back portion22of the car seat20to a deployed configuration by urging it outwardly with a user's foot. This action results in the locking spring pin62being inserted into a lowermost handle member aperture, locking the wheel assembly50in the deployed configuration until specifically released by retraction of the innermost handle member48, as described above. Upon deployment of the wheel assembly50, the handle assembly40may be automatically deployed if the user has not already grasped the handle bar49to do so. The car seat20may then be tipped slightly backward onto the wheels52and rolled or pushed by the handle bar49to the desired location. Finally, the car seat20may be tipped forwardly onto its bottom. The handle assembly40may be urged downwardly by the user into the handle channels34which automatically causes the wheel assembly to be released and urged to the withdrawn configuration. It is understood that while certain forms of this invention have been illustrated and described, it is not limited thereto except insofar as such limitations are included in the following claims and allowable functional equivalents thereof. | 11,990 |
RE49799 | DETAILED DESCRIPTION Embodiments are described more fully below in sufficient detail to enable those skilled in the art to practice the system and method. However, embodiments may be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. The following detailed description is, therefore, not to be taken in a limiting sense. Various embodiments of the systems and methods described herein relate to the convenient and effective stabilization of a variety of trailer frame geometries, including trailers featuring a bare square or round jack post, a jack post terminating in a jack wheel, and/or a jack post terminating in a jack post foot or plate jack stand. As discussed above in the Background section, existing trailer stabilization mechanisms present a number of challenges in that they are inconvenient and oftentimes must be carried in the towing vehicle separate from the trailer to be stabilized after the trailer is unhitched. The existing mechanisms also fail to form any kind of integrated system between the jack stabilization accessories designed to stabilize the post, jack wheel, and/or post foot and the tire or wheel chock designed to immobilize at least one of the trailer's tires. As a result, when existing stabilizing structures and tire chocks are transported in the towing vehicle, they are likely to be separated from one another, to be lost or damaged in transport, or to be left unused due to the inconvenience of finding and accessing them when they are needed. In addition, embodiments of the trailer frame stabilizing accessory system disclosed herein are designed to be conveniently transported directly on the trailer frame itself as an integrated unit including a stabilizing block and a tire/wheel chock. Varying embodiments are configured to attach to a range of different trailer frame widths for transport and, in use, provide a raised stabilization height that reduces the amount of effort a user must invest in cranking the jack post to raise the stabilized trailer for attachment to the towing vehicle. Turning to the exemplary embodiments shown in the figures,FIGS.1-2illustrate perspective and exploded views, respectively, of one embodiment of a trailer stabilizing accessory system100for use with and transport upon a frame52of a towed trailer50, as shown inFIG.3. In this embodiment, the stabilizing accessory system100may include a stabilizing block102and a detachably attached tire or wheel chock assembly104. The stabilizing block102may include an upper body106that attaches to a lower body108in any appropriate manner including, for example, two socket head screws116and corresponding hex nuts118. In one embodiment, the lower body108may include an upper perimeter lip109configured to extend into thelowerupperbody106when the upper and lower bodies are stacked. The upper upper perimeter lip109may act to prevent moisture creep into the assembled stabilizing block102. A top insert120may detachably attach to the upper body106in any appropriate manner including, for example, a press or snap fit or via an additional socket head screw116and hex nut118, as shown. In this embodiment, each of the upper and the lower bodies106,108may form a ribbed interior to provide light-weight structural integrity capable of supporting at least the tongue weight of a class IV hitch, or 1400 lbs. A ribbed interior114of the lower body, as shown inFIG.2, may feature an insert compartment112configured to receive a rib pack insert110. Alternatively, the ribbed interior114of the lower body108may span an entirety of the interior114of the lower body, without the insert compartment112and the rib pack insert110, depending, on manufacturing methods, preferences, capabilities, and/or costs. The stabilizing block102may also include multiple tension-fit spacers122configured for insertion into the lower body108in a manner that modifies the lower body108as necessary to accommodate a variety of trailer frame rail widths for transport, as detailed further below. As shown inFIGS.1-4and in this embodiment, the stabilizing accessory system100may also include the wheel chock assembly104, configured for detachable attachment to the lower body108of the stabilizing block102viaaan integration hook128. In one embodiment, the wheel chock assembly104may include a wheel chock124having an upper surface126that features a concave, stepped curvature configured for placement adjacent to a trailer tire54of the towed trailer50(FIG.3), as shown inFIG.23, and a bottom surface134incorporating the integration hook128as well as a recessed passive magnet132(e.g., a commercially available, rectangular neodymium magnet) configured to further secure the assembly100to the frame52of the towed trailer50, as shown inFIG.4. In one embodiment, a small switchable magnet (not shown) may be incorporated into the wheel chock124, enabling the wheel chock124to be attached to any steel frame without attachment to the stabilizing block102. In one embodiment, the integration hook128may be a 90-degree integration hook designed to interface with the stabilizing block102, as shown. In other embodiments, the integration hook128or other integration mechanism configured to detachably attach the stabilizing block102and the wheel chock assembly104may take any appropriate size, shape, type, and/or configuration to effectively and detachably attach the wheel chock124to the stabilizing block102. For example, the integration hook may comprise a built-in projection (e.g., a continuation of the manufacturing mold for the wheel chock124) extending from the bottom surface134of the wheel chock124and configured to connect with the bottom of the block102. In this embodiment, the passive magnet132and the 90-degree integration hook128may be attached to the bottom surface134of the wheel chock124in any appropriate manner, including via an adhesive, a snap fit, an interference fit, or via one or more fasteners129, as shown. The wheel chock assembly104may also include a through hole130configured to receive a rope or tether136, which may be used to pull the wheel chock assembly104from beneath the tire54after use. Turning to the details of each of the components of the stabilizing accessory system100discussed above,FIGS.5-6illustrate top and bottom perspective views of one embodiment of the top insert120. In this embodiment, the top insert120may be configured for flush insertion into and attachment to the upper body106of the stabilizing block102, as shown inFIGS.1and4. In one embodiment, the top insert120may have a top surface138that forms a round recess140configured to receive a bare distal end of a round jack post56of the towed trailer50that does not terminate in a plate/foot or wheel at its distal end, as shown inFIG.21. Alternatively, a plate jack stand or foot58may be disposed upon the top surface138of the top insert120in a manner that overlaps the round recess140, as shown inFIG.22. In this embodiment, the round recess140may have a diameter of 2.5 inches and a depth of 1 inch. Other embodiments may feature any appropriate and/or desired dimensions or configurations. As discussed above, the top insert120may attach to the upper body102106via one of the socket head screws116through an attachment hole142or, alternatively, the insert120may attach via a press fit, a snap fit, or any other appropriate attachment mechanism or means. A bottom side of the insert may include a number of ribs146to provide lightweight structural support. FIGS.7-8illustrate top and bottom perspective views of one embodiment of the removeable rib pack110, respectively. In this embodiment, the rib pack110may be a structurally ribbed insert configured to fit within the insert compartment112of the lower body108(FIG.2) of the stabilizing block102to enhance the structural integrity of the lower body108. The rib pack110may have a top side148and a bottom side150. In one embodiment, the bottom side150may include a magnet recess152configured to receive a passive magnet151. In one embodiment, the passive magnet151may be of the same type or similar to the recessed passive magnet132of the wheel chock124, discussed above. For instance, the magnet151may be a commercially available, epoxy-coated rectangular neodymium magnet from, for example, Sunnyfore Magnet Company Limited. The rectangular magnet151may assist in preventing the stabilizing block102from sliding when installed upon the trailer frame52, as shown inFIG.4. In another embodiment, the interior114of the lower body108(FIG.2) may be comprised entirely of ribs such that the removeable rib pack is unnecessary and therefore excluded. In some embodiments, the rib pack110may be replaced with a switchable magnet, as discussed below in relation toFIG.17. FIGS.9-13illustrate top, front, rear, left/right, and bottom-plan views of the stabilizing block102, respectively, with the top insert120removed. In one embodiment, the stabilizing block102may have a footprint encompassing a length, l, of 7 inches, a width, w, of 7 inches, and a height, h, of 6.25 inches. In other embodiments, the stabilizing block102may have any appropriate dimensions necessary for stowing and transport upon and then stabilizing a jack of a trailer frame at an elevated height. If necessary and/or desired, two stabilizing blocks102may be stacked to provide a desired stabilization height. As shown inFIG.9, a top side154of the stabilizing block102is formed by a top side of the upper body106. In this embodiment, the top side154of the stabilizing block102may include a gradually recessed wheel dock156configured to receive and cradle a jack wheel60attached to a distal end of the trailer jack post56, as shown inFIG.20. The gradually recessed wheel dock156may accommodate jack wheels60of varying diameter, up to and including a 10-inch diameter. In one embodiment, the gradually recessed wheel dock156may terminate in a dual jack post cutout158configured to receive a distal end of either a round or a square jack post that does not terminate in a wheel. In one embodiment, the dual jack post cutout158may accommodate a round jack post having up to a 2.75-inch diameter or a square jack post having up to a 2.5-inch maximum width. The top side154may also include a perimeter lip160that orders the top side154and forms a recess configured to retain a plate jack stand or foot58, with our without installation of the top insert, as shown inFIG.22. In one embodiment, the perimeter lip160may have a 0.25-inch width, enabling the top side to accommodate up to a 6.5-inch square footprint of the plate jack stand58. In other embodiments, plate jack stands58with larger footprints may be disposed on top of the perimeter lip160such that they exceed the boundaries of the stabilizing block102. Opposing top rectangular notches162may be recessed into opposite ends of the top side154. In one embodiment, the top rectangular notches162may be rounded and configured to receive a securement strap62such as, for example, a bungee cord that wraps beneath the trailer frame52to affix the stabilizing block102to the frame52, as shown inFIG.4, where a pair of hook ends64of the securement strap62may leverage against a top surface155of the upper body106at the top side154of the stabilizing block102to secure the strap or cord62in place. In one embodiment, a combination lock (not shown) may be used as an added accessory for theft protection. The combination lock may be secured adjacent to the securement strap or cord62and secured at the rectangular notch162/top surface155of the upper body106. In another embodiment, the top side154may incorporate a level (not shown) to indicate whether the trailer50is level. FIGS.10-11illustrate respective plan views of a front side164and a rear side166of one embodiment of the stabilizing block102, formed by the mated upper and lower bodies106,108. In this embodiment, both of the front and the rear sides164,166may include the top rectangular notches162, discussed above, as well as a pair of opposing bottom rectangular notches168, which may each have a rounded or beveled profile configured to receives the securement strap or cord62ofFIG.4. In addition, the front side164may include an enclosure tab170extending downward from the upper body106and configured to enclose an end of the rib pack insert110. FIG.12illustrates a plan view of identical left/right sides172of one embodiment of the stabilizing block102, formed by the mated upper and lower bodies106,108. The left/right sides172reveal a center groove174within the lower body108. In this embodiment, the center groove174may form a base surface175and two opposing walls177configured to ride on the trailer frame52when the stabilizing block102is not in use. In one embodiment, the center groove174may have a 3-inch width, w1, between the two opposing walls177. FIG.13illustrates a plan view of a bottom side176of one embodiment of the stabilizing block102, formed by the lower body108and further detailing an exemplary configuration of the center groove174. Specifically, the base surface175of the center groove174may form opposing wheel chock slots178sized to receive the 90-degree integration hook128of the wheel chock assembly104, as shown inFIGS.14-15. Each end of the base surface175of the center groove174may include one of the wheel chock slots178, enabling one of the wheel chock assemblies104to be detachably attached at either (or both) of the left and right sides172of the stabilizing block102. Adjacent to each of the wheel chock slots178, the base surface175of the center groove174may feature opposing wheel chock recesses180, which receive the 90-degree integration hooks128such that they are set into and flush with the base surface175of the center groove174when the wheel chock assembly104is detachably attached to the stabilizing block102. A hex hole182may extend inward from each of the wheel chock recesses180. The hex holes182may be sized to receive the nuts118securing the upper body106to the lower body108via the fasteners116, as discussed above. In this embodiment, the base surface175may form up to eight spacer notches184, and each of the two opposing walls177of the center groove174may form a plurality of spacer slots186. The spacer notches184and the spacer slots186may each be configured to receive corresponding and aligned coupling features built into the tension fit spacers122, shown in the exploded view ofFIG.2and the assembled perspective view ofFIG.16. As shown and in this embodiment, each of the tension fit spacers122may have a dovetail side188featuring three projections190and a notched side192featuring three notches194. Each spacer122may also include two releasable tabs196extending upward therefrom. In one embodiment, each of the tension fit spacers122may have a width, w2, of 0.25 inches. By installing the tension fit spacers122along the sidewalls177of the center groove174, a user may adjust the width, w1, of the center groove174such that the groove174may accommodate a variety of widths of the trailer frame52. For example, as shown inFIG.16, two of the tension fit spacers122may be installed adjacent to each of the opposing walls177of the center groove174by inserting the releasable tabs196(FIG.2) of the spacers122into the spacer notches184in the base surface175of the center groove174(FIG.13) and by inserting the three dovetail projections190of the spacers122into the corresponding spacer slots186of the walls177of the groove174or, if one of the spacers122has previously been installed, into the corresponding notches194of the adjacent tension fit spacer122. In this regard, the stabilizing block102may be adjusted such that the center groove174may accommodate frame widths of 2, 2.5, and 3 inches. As discussed above and in one embodiment, the rib pack insert110may be replaced by a switchable magnet insert110a. In this regard,FIG.17illustrates an exploded view of one embodiment of a stabilizing block102a, andFIG.18provides a perspective view of one embodiment of a stabilizing accessory system100a including the stabilizing block102a including the switchable magnet insert110a. In this embodiment, the stabilizing block102a and the stabilizing accessory system100a are identical to the stabilizing block102and stabilizing accessory system100, discussed above, with the exception of the switchable magnet insert110a in the position of the rib pack insert110. In this embodiment, the switchable magnet insert110a may be press fit or be otherwise installed within the insert compartment112of the lower body108in any appropriate manner that places the magnet110a in appropriate proximity to the base surface175of the center groove174, such that the magnet is positioned to provide the requisite securement force that attaches the stabilization block102a to the steel trailer frame52, as shown inFIG.19, and that exposes an actuator, such as, for example, a handle196of the magnet insert110a to the user. In one embodiment, the switchable magnet insert110a may be any appropriate commercially available switched magnet such as, for example, a Magswitch Magsquare 400, having a magnetic strength of 400 lbs. when upright and engaged, and having a pull force of approximately 100 lbs. when the magnet insert110a is positioned on its side and operating through the base surface175of the center groove174(i.e., operating through the air/plastic gap created by the base surface175of the center groove174). The handle provided with the commercially available switchable magnet may be modified as necessary to allow the handle196to protrude from the stabilization block102a. In other embodiments, the actuator may be a switch, a lever, a wireless electronic actuator, or any other appropriate user-actuatable mechanism that allows a user to control the magnet insert110a to switch between an “engaged” state of the magnet insert110a and a “disengaged” state of the magnet insert110a. Thus, using the rectangular magnet132recessed into the bottom surface134of the wheel chock124and the switchable magnet insert110a embedded into the stabilizing block102a, the entirety of the stabilization accessory system100a may be magnetically attached to the steel trailer frame52on any rail portion that is three inches wide or less, as shown inFIG.19. Additionally, embodiments of the stabilizing block102,102a or the integrated stabilizing accessory system100,100a may ride on surfaces other than the trailer frame52, so long as those surfaces have a width that may be accommodated by the center groove174(e.g., a width of three inches or less) of the stabilizing block102,102a. For example, the stabilizing block102a may ride on a truck bumper. Further, the stabilizing block may be attached to an aluminum trailer frame or another aluminum surface through the attachment of a steel “sandwich” plate to the frame. In addition, embodiments of the stabilizing block102,102a may be paired with two wheel or tire chock assemblies104, one on each side of the block102,102a, as necessary and/or desired to stabilizing more than one trailer tire when the trailer50is not in transport. As discussed above, the entirety of embodiments of the stabilizing accessory system100,100a is configured for direct attachment to or stowing upon a trailer frame for transport and/or storage between stabilizing uses.FIG.24provides a flowchart depicting an exemplary method (250) of employing embodiments of the stabilization accessory system100,100a to stabilize a towed trailer when the trailer is not hitched to a towing vehicle and to stow the stabilization accessory system100,100a upon a frame of the trailer when the system100,100a is not in use. The method (250) may begin with configuring the stabilization block102,102a for the particular trailer jack to be stabilized—either a square or round jack post56, a jack wheel60, or a plate jack stand58(252). In this regard, the top insert120may be left in place (253) to stabilize plate jack stands58of varying sizes or smaller jack posts or removed (257) as appropriate to accommodate round or square jack posts of varying sizes and jack wheels of varying sizes. Once the stabilizing block102,102a is configured for the particular trailer, the trailer jack—post, wheel, or stand—may be disposed upon the top side154of the stabilizing block102,102a (254) by lowering the jack onto the stabilizing block102,102a until the trailer lifts off the ball mount of the towing vehicle. In one embodiment, two blocks102,102a may be stacked to provide an optimal stabilization height, thereby reducing the amount of work necessary to raise the trailer for reattachment to the towing vehicle. In addition to stabilizing the trailer jack, the wheel chock assembly104may be placed adjacent to one of the trailer tires54such that the upper surface126of the wheel chock124confronts the tire surface (255). Once stabilized, the trailer may sit indefinitely in its secured and stabilized position, without fear of sinking, rolling, or other types of destabilization. To stow embodiments of the stabilization accessory system102,102a100, 100afor transit after the ball mount on the towing vehicle is again secured to the trailer50and the jack is fully raised, the center groove174of the stabilization block102,102a may be configured to fit the width of the particular trailer frame52(e.g., 2 inch, 2.5 inch, 3 inch) by installing, if necessary, an appropriate number of the tension fit spacers122upon the walls177of the center groove174(256). Then the wheel chock assembly104and the stabilization block102,102a may be detachably attached via inserting the 90-degree integration hook128within one of the wheel chock slots178(258) before the stabilizing block102,102a and the wheel chock assembly104are placed upon the frame52such that the base surface175of the center groove174and the bottom surface134of the wheel chock124confront the trailer frame52(260). Once the stabilization system100,100a is in position, it may be secured to the frame (262), either by securing the securement strap or cord62about the frame and top rectangular notches162of the block102, as shown and discussed in relation toFIG.4(264), or by switching the magnet insert110a of the block102a from a disengaged to an engaged state via the handle196, as showninanddiscussed in relation toFIG.19(266). Once secured upon the trailer frame52, the stabilizing accessory system is prepared for transport. The system100,100a travels with the frame without the need to carry the system or its components within the towing vehicle. The stabilizing block and the tire chock are ready for use at any time and conveniently located within inches of the trailer jack in an easily accessible configuration that enables the user to quickly remove the system from the trailer frame for stabilizing use with a variety of trailer jack geometries. Embodiments of the components of the trailer stabilization system(s) discussed above may be formed of one or more hard, durable plastics that are formulated to withstand deteriorating UV damage, that will not scratch or otherwise damage the underlying trailer frame or other attachment surfaces, and that may support at least 1400 lbs. (the Class IV hitch tongue weight rating) during stabilizing use. For example, embodiments of the top insert120, the upper body106, the lower body108, the rib pack insert110, the tension fit spacers122, and the wheel chock124may be formed of twenty percent glass filled polypropylene with a UV inhibitor. The components may be manufactured using any appropriate manufacturing process, including, for example, an injection molding process and/or a 3D printing process. Further, the specific shapes, sizes, types, and dimensions of the stabilizing trailer systems aid their components discussed above are provided for illustrative purposes only, and an ordinarily skilled artisan is assumed to understand that the components of the system embodiments, and the particular features and configurations thereof, may take any appropriate size, shape, type, dimension, and/or configuration as necessary to carry out the integrated trailer-attachment and stabilization purposes described herein. For example, a stabilizing block is described as a cube-type configuration, but the shape of the stabilizing components, the number of sides, the center grooves, the post recesses, and/or any number of other features may vary in shape, size, type, and/or configuration. Embodiments of the trailer stabilizing systems described above provide a uniquely convenient solution addressing trailer stabilization and equipment storage. Embodiments of the systems ride on the frame of any standard sized trailer frame (2-inch, 2.5-inch, and 3-inch) and don't have to be transported separately inside the owner's towing vehicle. In addition, the systems serve as multifunctional stabilization tools and may be used to add height to the jack post during trailer storage to reduce the amount of post cranking required to raise and lower the jack post/wheel and, therefore, reduce the amount of work required to reattach the trailer to the towing vehicle. Further, embodiments of the trailer stabilization accessory systems provide a support mechanism for the jack wheel, as well as a round or square jack post alone or the jack plate oftentimes attached to the distal end of the jack post. This stabilization is provided while maintaining the jack post, wheel, or plate jack stand/foot off the ground and out of the dirt, mud, rocks, etc. upon which the trailer sits, thereby keeping the jack post free of debris and damage, while simultaneously increasing the footprint of the jack post and preventing sinkage. The systems also provide a mechanism to immobilize one or moreofthe trailer tires using the detachably attached wheel chock(s). The system is compact, conveniently stowed and towed, and fulfills most if not all of an owner's trailer stabilization needs in one convenient, easily-accessible, and elegant multi-purpose system. Although the above embodiments have been described in language that is specific to certain structures, elements, compositions, and methodological steps, it is to be understood that the technology defined in the appended claims is not necessarily limited to the specific structures, elements, compositions and/or steps described. Rather, the specific aspects and steps are described as forms of implementing the claimed technology. Since many embodiments of the technology can be practiced without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended. | 26,633 |
RE49800 | DETAILED DESCRIPTION The present invention is described with reference to the attached figures, where like reference numerals are used throughout the figures to designate similar or equivalent elements. The figures are not drawn to scale, and are provided merely to illustrate the instant invention. Several aspects of the invention are described below with reference to example applications for illustration. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details, or with other methods. In other instances, well-known structures or operations are not shown in detail to avoid obscuring the invention. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention. The present disclosure provides for a computer chassis design which includes a sled and a sliding bracket. The sliding bracket can include a removable power supplier socket on a first end and a sliding return lever on the second end. When the sled is removed from the computer chassis, the removable power supplier socket can move out of the chassis via a set of mechanisms. The set of mechanisms can include an elastic element to cause the power supplier socket to automatically rotate out of the chassis. This automatic movement of the power supplier socket allows the sled to be easily pulled out of the chassis, even if the sled is shaped to extend behind the power supplier socket. Therefore, the present disclosure also provides for a sled shaped with an option behind the power supplier socket. This disclosed computer chassis design provides for both: (1) an increased amount of available space on the sled; and (2) an ease of loading and unloading the sled from the computer chassis. The increased amount of available space can be used to hold more electronic components, including, for example, dual in-line memory modules. FIG.1shows a conventional computer chassis100, according to the prior art. Chassis100can include a sled110, a power supplier socket120, a cable routing portion130, and a chassis body140. The sled110can house computer components (not pictured). The power supplier socket120can receive cables from the cable routing portion130, and provide power to the components in the sled110. In a conventional chassis100, the sled110takes up the majority of space in the chassis body140, but the sled110is designed to be narrow enough to leave space in the chassis body140for the power supplier socket120and the cable routing portion130. In conventional chassis100, the sled110can slide into and out of the chassis body140, and the sled110is sized so as to not overlap with the power supplier socket120. Therefore, the power supplier socket120remains in place as the sled110loads or unloads from the chassis body140. Typically, a power supplier socket120is wider than the cables running to and from the power supplier socket120, in the cable routing portion130. Such a design, as shown inFIG.1, results in empty space140a in the chassis body140, which is not used by the sled110, and does not contain any computer components. Thus, empty space140a does not provide an efficient use of the area provided in a conventional chassis body140. In response to the space limitations of conventional computer chassis shown inFIG.1, the present disclosure provides for an exemplary computer chassis that makes use of the space140a.FIG.2shows an exemplary computer chassis200, according to an embodiment the present disclosure. Chassis200comprises a sled210, an indented portion212, extended space214, a removable power supplier socket220, a cable routing portion230, and a chassis body240. The sled210can house computer components, be received into a chassis body240, and allow space in the chassis body240for cable routing portion230. Sled210provides a different design than the conventional sled110(ofFIG.1), because sled210includes an indented portion212and extended space214. The indented portion212allows the sled210to extend beyond the removable power supplier socket220, which provides extended space214on the sled210where additional components can be housed. Therefore, sled210provides a greater area for housing computer components than the conventional sled110shown inFIG.1. The removable power supply socket220can be configured to automatically move into and out of the chassis body240, according to the mechanisms discussed below with respect toFIGS.3A-5D. FIGS.3A-5Dshow cut-away views of various positions of the computer chassis ofFIG.2, according to various embodiments of the present disclosure.FIGS.3A-5Dcan include many components and similar labels to components inFIG.2. In addition,FIGS.3A-5Dshow a sliding rail bracket310, a sliding return lever320, a set of mechanisms330, a stopping mechanism340. The sliding return lever320can include an elastic element410and a pivot mechanism420; the set of mechanisms330can include an elastic element430and a rotational element440. FIG.3Ashows an entirely-loaded position300A of the disclosed chassis, where the removable power socket220is fully received within the chassis240. The disclosed chassis ofFIG.2can include a sliding rail bracket310along an interior edge240a of the chassis body240. The sled210can slide along the sliding rail bracket310when loading into and out of chassis body240. The sliding rail bracket310can also be coupled to a removable power supply socket220via a set of mechanisms330(discussed further with respect toFIG.3B) located at a first end310a of the sliding rail bracket310. A second end310b of the sliding rail bracket310can provide a stopping mechanism340(discussed further with respect toFIG.5D). Lastly, sliding rail bracket310can include a sliding return lever320along a length of the sliding rail bracket310(discussed further with respect toFIG.3B). The sliding return lever320can be fixed within the chassis body240, so that movement of the sled210does not cause the sliding return lever320to move. In some examples of the present disclosure, the sliding return lever320can be fixed at a particular distance320a from the second end310b of the sliding rail bracket310. The particular distance320a can be a length of the removable power supplier socket220. FIG.3Bshows a partially-unloaded position300B of the disclosed chassis, where the sled210is unloaded from the chassis body240so that the removable power supply socket220is fully outside of the chassis body240. When the removable power supply socket220is outside of the chassis body240, the rear edge210a of the sled210engages with the sliding return lever320. FIG.3Bfurther shows a close-up view of the sliding return lever320, which includes an elastic element410and a pivot mechanism420. The pivot mechanism420can have a first portion420a, which receives the sled210as it is loaded into the chassis body240. A second portion420b of the pivot mechanism can be coupled to the elastic element410. Referring momentarily toFIG.5A, the sliding return lever420can be configured so that when the first portion420a receives the sled210as it is loaded into the chassis body240, the first portion420a can move towards the elastic element410. The movement of the first portion420a can pivot the second portion420b away from the elastic element410, which consequently loads the elastic element410. The elastic element can be an extension spring, for example. In other examples, the elastic element410can be any elastomer configured to be loaded when the sled210is loaded into the chassis body240. Referring back toFIG.3B, the set of mechanisms330can include an elastic element430and a rotational element440. The rotational element440can be a joint through which a portion of the elastic element430extends. The elastic element430can have a first portion430a extending along a length of the removable power socket220, and a second portion430b extending towards the body of the removable power socket220. Elastic element430in an unloaded position, where the removable power supplier socket220is configured to rotate away from the sled210due to the elastic force of the elastic element430. The elastic element430can be loaded when the power supplier socket220is rotated towards the sled210(for example, when a user is loading sled210into the chassis body240). For example, the elastic element430can be a compression spring. In other examples, the elastic element430can be any elastomer configured to be loaded when the power supplier socket220is rotated towards the sled210. FIG.4shows an exemplary computer sled transition400, where the sled210transitions from a loaded position in chassis body240to an unloaded position. As the sled210is pulled out of the chassis body240, elastic element410biases the first portion420a of pivot mechanism420to rotate away from the sliding bracket310, towards the sled210. When the rear edge210a of the sled210passes over a midpoint420c of the pivot mechanism420, the elastic element410can unload, and can exert force moving the sled210out of the chassis body340, along the sliding bracket310. When the power supplier socket220is out of the chassis body240, the elastic element430can exert force on the power supplier socket220, causing the power supplier socket220to rotate away from the chassis body240. Therefore, elastic elements410and430can contribute to automatic unloading of the sled210from the chassis body240. FIG.5Ashows an exemplary computer sled transition500A, where the sled210transitions from an unloaded position to a loaded position. As discussed earlier with respect toFIG.3B, the first portion420a of the pivot mechanism420can be pushed towards the sliding bracket310as sled210is loaded into the chassis body. This can load the elastic element410. FIG.5Bshows an exemplary computer sled transition500B. Transition500B follows after transition500A where sled210is pushed just past a midpoint420c of pivot mechanism420. Therefore, when sled210is loaded in chassis body240, elastic element410will be loaded. Removable power socket220can be rotated towards computer sled210as sled210is loaded into chassis body240. FIG.5Cshows an exemplary computer sled transition500C where sled210is fully loaded into chassis body240. Transition500C can occur after transition500B. Elastic element430is compressed against an interior edge240a of chassis body240. FIG.5Dshows how the stopping mechanism340is of a sufficient length to extend from the sliding rail bracket310to the sled210. The stopping mechanism340can receive a rear edge210a of the sled210as the sled210is being loaded into the chassis body240. Thereby, loading the sled210into the chassis body240can cause the sliding rail bracket310to slidably extend along the interior edge240a of the chassis body240. Altogether,FIGS.5A-5Dshow that sliding return lever320and mechanism330provide an apparatus to load and unload the computer sled without interference from the power supplier socket. This allows the disclosed chassis to make use of the space behind the power supplier socket, which is typically unused in conventional chassis designs. While various examples of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. Numerous changes to the disclosed examples can be made in accordance with the disclosure herein without departing from the spirit or scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above described examples. Rather, the scope of the invention should be defined in accordance with the following claims and their equivalents. Although the invention has been illustrated and described with respect to one or more implementations, equivalent alterations and modifications will occur to others skilled in the art upon the reading and understanding of this specification and the annexed drawings. In addition, while a particular feature of the invention may have been disclosed with respect to only one of several implementations, such feature may be combined with one or more other features of the other implementations as may be desired and advantageous for any given or particular application. The terminology used herein is for the purpose of describing particular examples only and is not intended to be limiting of the invention. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including,” “includes,” “having,” “has,” “with,” or variants thereof, are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.” Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. | 13,650 |
RE49801 | DETAILED DESCRIPTION OF THE INVENTION In the following, the same reference numerals are partly used for objects and functional units having the same or similar functional properties and the description thereof with regard to a figure shall apply also to other figures in order to reduce redundancy in the description of the embodiments. FIG.1shows a block diagram of an apparatus100for generating a bandwidth extended signal122for an input signal102according to an embodiment of the invention. The input signal102is represented, for a first band by a first resolution data, and for a second band by a second resolution data, the second resolution being lower than the first resolution. The apparatus100comprises a patch generator110connected to a combiner120. The patch generator120generates a first patch112from the first band of the input signal102according to a first patching algorithm and generates a second patch114from the first band of the input signal102according to a second patching algorithm. A spectral density of the second patch114generated according to the second patching algorithm is higher than a spectral density of the first patch112generated according to the first patching algorithm. The combiner120combines the first patch112, the second patch114and the first band of the input signal102to obtain the bandwidth extended signal122. Further, the apparatus100for generating a bandwidth extended signal122scales the input signal102according to the first patching algorithm and according to the second patching algorithm or scales the first patch112and the second patch114so that the bandwidth extended signal122fulfills a spectral envelope criterion. Spectral density means, for example, the density of different frequencies or frequency lines within a frequency band. For example, a frequency band reaching from 0 Hz to 10 kHz comprising frequency portions with frequencies of 4 kHz and 8 kHz has a lower spectral density than the same frequency band comprising frequency portions with frequencies of 2 kHz, 4 kHz, 6 kHz, 8 kHz and 10 kHz. Since the spectral density of the first patch112is lower than the spectral density of the second patch114, the first patch112comprises gaps in comparison with the second patch114. Therefore, the second patch114may be used to fill these gaps. Since both patches are based on the first band of the input signal102, both patches are related to the characteristic of the original signal corresponding to the input signal102. Therefore, the bandwidth extended signal122may be a good approximation of the original signal and the subjective quality or the audio quality of the bandwidth extension signal122may be significantly improved by using the described concept. In this way, more energy may be distributed between the remaining lines and, for example, a unnatural sound may be avoided. For example, the first patching algorithm may be a harmonic patching algorithm. Therefore, the patch generator110may generate the first patch112comprising only frequencies that are integer multiples of frequencies of the first band of the input signal102. A harmonic bandwidth extension may provide a good approximation of the tonal structure of the original signal, but this patching algorithm will leave gaps between the harmonic frequencies. These gaps may be filled by the second patch. For example, the second patching algorithm may be a mixing patching algorithm, which means that the patch generator110may generate the second patch114comprising integer multiples of frequencies of the first band of the input signal102(harmonic frequencies) and frequencies that are not integer multiples of the frequencies of the first band of the input signal102(non-harmonic frequencies). The non-harmonic frequencies may be used for filling the gaps of the first patch112. It may also be possible to combine the whole second patch114(including the harmonic frequencies) with the first patch112. In this example, an amplification of the harmonic frequencies due to the combination of the harmonic frequency portions of the first patch112and the second patch114may be taken into account by appropriately scaling the first patch112and/or the second patch114. The first patch112and the second patch114comprise at least partly the same frequency range. For example, the first patch112comprises a frequency band reaching from 4 kHz to 8 kHz and the second patch114comprises a frequency band from 6 kHz to 10 kHz. In some embodiments according to the invention, a lower cut of frequency of the first patch is equal to a lower cut of frequency of the second patch and an upper cut of frequency of the first patch112is equal to an upper cut of frequency of the second patch114. For example, both patches comprise a frequency band reaching from 4 kHz to 8 kHz. FIGS.2a and2bshow an example for a first patch112according to a first patching algorithm212and a second patch114according to a second patching algorithm214. For better illustration,FIG.2ashows only the first patches112andFIG.2bshows the first patches112and the corresponding second patches114.FIG.2aillustrates an example200for the first band202of the input signal102and two first patches112generated according to the first patching algorithm212. In this example, a patch comprises the same bandwidth as the first band202of the input signal102. The bandwidth may also be different. The upper cut-off frequency220of the first band202of the input signal102is denoted ‘Xover’ frequency (crossover frequency). In the example shown inFIG.2a, patches start at a frequency equal to a multiple of the crossover frequency Xover220. The frequency lines within the first patches112are integer multiples of the frequency lines of the first band202of the input signal102and may, for example, be generated by a phase vocoder. These first patches112comprise gaps in terms of missing frequency lines in comparison to the first band202of the input signal102. FIG.2badditionally shows an example250for the two corresponding second patches114. These patches are generated according to the second patching algorithm214and comprise harmonic and non-harmonic frequencies. The non-harmonic frequency lines may be used to fill the gaps of the first patches112. The frequency lines of the second patches114may be generated, for example, by a non-linear distortion. In this way, the gaps may not be filled arbitrarily as, for example, by filling the gaps with noise. The gaps are filled based on the first resolution data of the first band of the input signal and, therefore, based on the original signal. The first band of the input signal102may represent, for example, the low frequency band of an original audio signal encoded with high resolution. The second band of the input signal102may represent, for example, a high frequency band of the original audio signal and may be quantized by one or more parameters as, for example, spectral envelope data, noise data and/or missing harmonic data with low resolution. An original audio signal may be, for example, an audio signal recorded by a microphone before processing or encoding. Scaling the input signal according to the first patching algorithm and according to the second patching algorithm means, for example, that the input signal is scaled once according to the first patching algorithm before the first patch is generated and then the first patch is generated based on the scaled input signal, and that the input signal is scaled once according to the second patching algorithm before the second patch is generated and then the second patch is generated based on the scaled input signal, so that after the combination of the first patch, the second patch and the first band of the input signal, the bandwidth extended signal fulfills a spectral envelope criterion. Alternatively, the first patch and the second patch are scaled after their generation, so that the bandwidth extended signal also fulfills a spectral envelope criterion. Also a scaling of the input signal according to the first patching algorithm and according to the second patching algorithm in combination with a scaling of the first patch and the second patch may be possible. The combiner120may be, for example, an adder and the bandwidth extended signal122may be a weighted sum of the first patch112, the second patch114and the first band of the input signal102. Fulfilling a spectral envelope criterion means, for example, that a spectral envelope of the bandwidth extended signal is based on a spectral envelope data contained by the input signal. The spectral envelope data may be generated by an encoder and may represent the second band of an original signal. In this way, the spectral envelope of the bandwidth extended signal may be a good approximation of the spectral envelope of the original signal. The apparatus100may also comprise a core decoder for decoding the first band of the input signal102. The patch generator110and the combiner120may be, or example, specially designed hardware or part of a processor or micro controller or may be a computer program configured to run on a computer or a micro controller. The apparatus100may be part of a decoder or an audio decoder. FIG.3ashows a block diagram of an apparatus300for generating a bandwidth extended signal122from an input signal102according to an embodiment of the invention. In this example, the patch generator110comprises a phase vocoder310for generating the first patch and an amplitude clipper320for generating the second patch114. The phase vocoder310and the amplitude clipper320are connected to the combiner120. The phase vocoder310may spread the first band of the input audio signal102to generate the first patch112comprising harmonic frequencies. In a non-linear processing step, the amplitude clipper320may clip the input signal102to generate the second patch114comprising harmonic and non-harmonic frequencies. Alternatively to the amplitude clipper320, also a half-wave rectifier, a full-wave rectifier, a mixer or a diode used in the quadratic region of the characteristic curve may be used to generate non-harmonic frequencies based on the input signal102by a non-linear processing step. FIGS.3b,3c and3dshow examples for clipped and/or rectified input signals102to generate non-harmonic frequencies.FIG.3bshows a schematic illustration350of a clipped sinusoidal input signal102. By clipping the signal, points of discontinuity in the form of abrupt changes of the signal slope380are caused and harmonic and non-harmonic portions with higher frequencies are generated. Alternatively,FIG.3cshows a schematic illustration360of a half-wave rectified sinusoidal input signal102, also causing points of discontinuity380. Further, a combination of clipping and rectifying may be possible.FIG.3dshows a schematic illustration370of a clipped and full-wave rectified sinusoidal input signal102causing different points of discontinuity380. By clipping and/or rectifying or applying other methods of nonlinear processing generating points of discontinuity380, a wide spectrum of different frequencies may be generated. Therefore, a patch generated according to such a patching algorithm may comprise a high spectral density. FIG.4shows a block diagram of an apparatus400for generating a bandwidth extended signal122from an input signal102according to an embodiment of the invention. The apparatus400is similar to the apparatus shown inFIG.3a, but additionally comprises a spectral line selector410. The phase vocoder310and the amplitude clipper320are connected to the spectral line selector410and the spectral line selector410is connected to the combiner120. The spectral line selector410may select a plurality of frequency lines of the second patch114to obtain a modified second patch414that may be complementary to the first patch. A frequency line of the second patch114may be selected if a corresponding frequency line of the first patch112is missing. In other words, the spectral line selector410selects frequency lines of the second patch114for filling gaps of the first patch112and may disregard frequencies of the second patch114already contained by the first patch112. In this way, the modified second patch414may comprise gaps at frequencies already contained by the first patch112. In this example, the combiner120combines the first patch112, the modified second patch414and the first band of the input signal102. The spectral line selector410may be, for example, part of the patch generator110(as shown inFIG.4) or a separate unit. In the following, with reference toFIGS.5and6, possible implementations for a phase vocoder310are illustrated according to the present invention.FIG.5ashows a filterbank implementation of a phase vocoder, wherein an audio signal is fed to an input500and obtained at an output510. In particular, each channel of the schematic filterbank illustrated inFIG.5aincludes a bandpass filter501and a downstream oscillator502. Output signals of all oscillators from every channel are combined by a combiner, which is, for example, implemented as an adder and indicated at503in order to obtain the output signal. Each filter501is implemented such that it provides an amplitude signal on the one hand and a frequency signal on the other hand. The amplitude signal and the frequency signal are time signals illustrating a development of the amplitude in a filter501over time, while the frequency signal represents a development of the frequency of the signal filtered by a filter501. A schematical setup of filter501is illustrated inFIG.5b. Each filter501ofFIG.5amay be set up as inFIG.5b, wherein, however, only the frequencies f, supplied to the two input mixers551and the adder552are different from channel to channel. The mixer output signals of the mixers551are both lowpass filtered by lowpasses553, wherein the lowpass signals are different insofar as they were generated by local oscillator frequencies (LO frequencies), which are out of phase by 90°. The upper lowpass filter553provides a quadrature signal554, while the lower filter553provides an in-phase signal555. These two signals, i.e. Q, and I are supplied to a coordinate transformer556which generates a magnitude phase representation from the rectangular representation. The magnitude signal or amplitude signal, respectively, ofFIG.5aover time is output at an output557. The phase signal is supplied to a phase unwrapper558. At the output of the element558, there is no phase value present any more, which is between 0 and 360°, but a phase value, which increases linearly. This “unwrapped” phase value is supplied to a phase/frequency converter559which may, for example, be implemented as a simple phase difference calculator, which subtracts a phase of a previous point in time from a phase at a current point in time to obtain a frequency value for the current point in time or any other means for obtaining an approximation of a phase derivative. This frequency value is added to the constant frequency value fiof the filter channel i to obtain a temporarily varying frequency value at the output560. The frequency value at the output560has a direct component=fiand an alternating component=the frequency deviation by which a current frequency of the signal in the filter channel deviates from the average frequency fi. Thus, as illustrated inFIGS.5a and5b, the phase vocoder achieves a separation of the spectral information and the temporal information. The spectral information is contained in the special channel or in the frequency fi, which provides the direct portion of the frequency for each channel, while the temporal information is contained in the frequency deviation or the magnitude evolution over time, respectively. FIG.5cshows a manipulation as it is executed for the generation of the first patch according to the invention, in particular, using the phase vocoder310and, in more detail, inserted at the location of the dashed line of the illustrated circuit inFIG.5a. For time scaling, e.g. the amplitude signals A(t) in each channel or the frequency of the signals f(t) in each channel may be decimated or interpolated. For purposes of transposition, as it is useful for the present invention, an interpolation, i.e. a temporal extension or spreading of the signals A(t) and f(t) is performed to obtain spread signals A′(t) and f′(t), wherein the interpolation is controlled by the spreading factor598. The spreading factor can be selected, for example, so that the phase vocoder generates harmonic frequencies. By the interpolation of the phase variation, i.e. the value before the addition of the constant frequency by the adder552, the frequency of each individual oscillator502inFIG.5ais not changed. The temporal change of the overall audio signal is slowed down, however, i.e. by the factor 2. The result is a temporally spread tone having the original pitch, i.e. the original fundamental wave with its harmonics. By performing the signal processing illustrated inFIG.5c, the audio signal may be shrunk back to its original duration, e.g. by decimation of a factor 2, while all frequencies are doubled simultaneously. This leads to a pitch transposition by the factor 2 wherein, however, an audio signal is obtained which has the same length as the original audio signal, i.e. the same number of samples. As an alternative to the filterband implementation illustrated inFIG.5a, a transformation implementation of a phase vocoder may also be used as depicted inFIG.6. Here, the audio signal698is fed into an FFT processor, or more generally, into a Short-Time-Fourier-Transformation (STFT) processor600as a sequence of time samples. The FFT processor600is implemented to perform a temporal windowing of an audio signal in order to then, by means of an subsequent FFT, calculate both a magnitude spectrum and also a phase spectrum, wherein this calculation is performed for successive spectra which are related to blocks of the audio signal that are strongly overlapping. In an extreme case, for every new audio signal sample a new spectrum may be calculated, wherein a new spectrum may be calculated also e.g. only for each twentieth new sample. This distance ‘a’ in samples between two spectra is advantageously given by a controller602. The controller602is further implemented to feed an IFFT processor604which is implemented to operate in an overlap-add operation. In particular, the IFFT processor604is implemented such that it performs an inverse Short-Time-Fourier-Transformation by performing one IFFT per spectrum based on a magnitude spectrum and a phase spectrum, in order to then perform an overlap-add operation to obtain the resulting time signal. The overlap add operation is configured to eliminate the blocking effects introduced by the analysis window. A temporal spreading of the time signal is achieved by the distance ‘b’ between two spectra, as they are processed by the IFFT processor604, being greater than the distance ‘a’ between the spectra used in the generation of the FFT spectra. The basic idea is to spread the audio signal by the inverse FFTs simply being spaced further apart than the analysis FFTs. As a result, spectral changes in the synthesized audio signal occur more slowly than in the original audio signal. Without a phase rescaling in block606, this would, however, lead to frequency artifacts. When, for example, one single frequency bin is considered for which successive phase values by 45° are implemented, this implies that the signal within this filterband increases in the phase with a rate of ⅛ of a cycle, i.e. by 45° per time interval, wherein the time interval here is the time interval between successive FFTs. If now the inverse FFTs are being spaced farther apart from each other, this means that the 45° phase increase occurs across a longer time interval. This means that the frequency of this signal portion was unintentionally modified. To eliminate this artifact, the phase is rescaled by exactly the same factor by which the audio signal was spread in time. The phase of each FFT spectral value is thus increased by the factor b/a, so that this unintentional frequency modification is eliminated. While in the embodiment illustrated inFIG.5cthe spreading by interpolation of the amplitude/frequency control signals was achieved for one signal oscillator in the filterbank implementation ofFIG.5a, the spreading inFIG.6is achieved by the distance between two IFFT spectra being greater than the distance between two FFT spectra, i.e. ‘b’ being greater than ‘a’, wherein, however, for an artifact prevention a phase rescaling is executed according to the ratio ‘b/a’. The distance ‘b’ can be selected, for example, so that the phase vocoder generates harmonic frequencies. FIG.7shows a block diagram of an apparatus700for generating a bandwidth extended signal122from an input signal102according to an embodiment of the invention. The apparatus700is similar to the apparatus shown inFIG.1, but comprises a power controller710, a first power adjustment means720and a second power adjustment means730. The power controller710is connected to the first power adjustment means720and to the second power adjustment means730. The first power adjustment means720and the second power adjustment means730are connected to the patch generator110. The power controller710may control the scaling of the input signal according to the first and the second patching algorithm based on spectral envelope data contained by the input signal and based on patch scaling control data contained by the input signal. Alternatively, instead of the patch scaling control data contained by the input signal, at least one stored patch-scaling control parameter may be used. A patch scaling control parameter may be stored by a patch-scaling control parameter memory, which may be part of the power controller710or a separate unit. The first power adjustment means720may scale the input signal102according to the first patching algorithm and the second power adjustment means730may scale the input signal102according to the second patching algorithm. In other words, the input signal102may be pre-processed, so that the first and the second patch can be generated, so that the bandwidth extended signal fulfills the spectral envelope criterion. For this, the spectral envelope data may define the spectral envelope of the bandwidth extended signal122and the patch scaling control data or patch scaling control parameter may set the ratio between the first patch112and the second patch114or may set the absolute values of the first patch112and/or the second patch114. The first power adjustment means720and the second power adjustment means730may be part of the power controller710or separate units as shown inFIG.7. The power controller710may be part of the patch generator110or a separate unit as also shown inFIG.7. The power adjustment means720,730may be, for example, amplifiers or filters controlled by the power controller710. Alternatively, the scaling is done after generation of the patches. Fittingly,FIG.8shows a block diagram of an apparatus800for generating a bandwidth extended signal122from an input signal102according to an embodiment of the invention. The apparatus800is similar to the apparatus shown inFIG.7, but the power adjustment means720,730are arranged between the patch generator110and the combiner120. In this example, the patch generator110is connected to the first power adjustment means720and connected to the second power adjustment means730. The first power adjustment means720and the second power adjustment means730are connected to the combiner120. In this way, the first patch112can be scaled by the first power adjustment means720according to the first patching algorithm and the second patch114can be scaled by the second power adjustment means730according to the second patching algorithm. The power adjustment means are, again, controlled by the power controller710based on the spectral envelope data and the patch scaling control data or the patch scaling control parameter as described before. Alternatively, also a scaling or power adjustment of only one of the both patches followed by combining the patches by the combiner120and scaling the combined patches before combining the combined patches with the first band of the input signal102may be possible. In other words, first one patch may be scaled to realize a predefined ratio (for example, based on the patch scaling control data) between the two patches and then the combined patches are scaled (for example, based on the spectral envelope data) to fulfill the spectral envelope criterion. The patch scaling control data may comprise, for example, a simple factor or a plurality of parameters for a power distribution scaling. The patch scaling control data may indicate, for example, a power ratio between the first patch and the second patch over the full second band or full high frequency band or an absolute value for the power of the first patch and/or the second patch over the full second band or full high band and may be represented by at least one parameter. Alternatively, the patch scaling data comprises a factor for each of a plurality of subbands together constituting the second band or high frequency band, e.g. similar to the spectral envelope data per subband in spectral bandwidth replication applications. Alternatively, the patch scaling data may also indicate a transfer function of a filter. For example, parameters of a transfer function of a filter for scaling the first patch and/or parameters of a transfer function of a filter for scaling the second patch may be contained in the input signal. In this way, the parameters may represent a function of frequency. Another alternative may be patch scaling control parameters representing a differential function of the first patch and the second patch. According to this examples, the scaling of the input signal or the scaling of the first patch and the second patch may be based on the patch scaling control data comprising at least one parameter. FIG.9shows a block diagram of an apparatus900for generating a bandwidth extended signal122from an input signal102according to an embodiment of the invention. The apparatus900is similar to the apparatus shown inFIG.8, but comprises additionally a noise adder910, a missing harmonic adder920, a noise power adjustment means940and a missing harmonic power adjustment means950. The noise adder910is connected to the noise power adjustment means940, which is connected to the combiner120. The missing harmonic adder920is connected to the missing harmonic power adjustment means950, which is connected to the combiner120. Further, the power controller710is connected to the noise power adjustment means940and the missing harmonic power adjustment means950. The noise adder910may generate a noise patch912based on a noise data contained by the input signal102. The noise patch912may be scaled by the noise power adjustment means940. The power controller710may control the noise power adjustment means940based on the spectral envelope data and/or noise scaling data contained in the input signal102. In this way, the noise of an original signal may be approximated to improve the audio quality of the bandwidth extended signal. The missing harmonic adder920may generate a missing harmonic patch922based on a missing harmonic data contained in the input signal. The missing harmonic patch922may contain harmonic frequencies, which may only occur in the high frequency band of the original signal and, therefore, cannot be reproduced, if only the information of the low frequency band of the original signal in terms of the first band of the input signal102is available. The missing harmonic data may provide information about these missing harmonics. The missing harmonic patch922may be scaled by the missing harmonic power adjustment means950. The power controller710may control the missing harmonic power adjustment means950based on the spectral envelope data or based on a missing harmonic scaling data contained by the input signal102. The combiner120may combine the first patch112, the second patch114, the first band of the input signal102, the noise patch912and the missing harmonic patch922to obtain the bandwidth extended signal122. The power controller710, in combination with the power adjustment means, may scale the first patch112, the second patch114, the noise patch912and the missing harmonic patch922based on the spectral envelope data, so that the spectral envelope criterion is fulfilled. FIG.10shows a block diagram of an apparatus1000for providing a bandwidth reduced signal1032based on an input signal1002according to an embodiment of the invention. The apparatus1000comprises a spectral envelope data determiner1010, a patch scaling control data generator1020and an output interface1030. The spectral envelope data determiner1010and the patch scaling control data generator1020are connected to the output interface1030. The spectral envelope data determiner1010may determine spectral envelope data1012based on a high frequency band of the input signal1002. The patch scaling control data generator1020may generate patch scaling control data1022for scaling the bandwidth reduced signal1032at a decoder or for scaling a first patch and a second patch by the decoder so that a bandwidth extended signal generated by the decoder fulfills a spectral envelope criterion. The spectral envelope criterion is based on the spectral envelope data. The first patch is generated from a first band of the bandwidth reduced signal1032according to a first patching algorithm and the second patch is generated from the first band of the bandwidth reduced signal1032according to a second patching algorithm. A spectral density of the second patch generated according to the second patching algorithm is higher than a spectral density of the first patch generated according to the first patching algorithm. The output interface1030combines a low frequency band of the input signal1002, the spectral envelope data1012and the patch scaling control data1022to obtain the bandwidth reduced signal1032. Further, the output interface1030provides the bandwidth reduced signal1032for transmission or storage. The apparatus1000may also comprise a core coder for encoding the low frequency band of the input signal. The core encoder may be, for example, a differential encoder, an entropy encoder or a perceptual audio encoder. The apparatus1000may be part of an encoder configured to provide a signal for a decoder described above. The patch scaling control data1022may comprise, for example, a simple factor or a plurality of parameters for a power distribution scaling. The patch scaling control data may indicate, for example, a power ratio between the first patch and the second patch over the full high frequency band or an absolute value for the power of the first patch and/or the second patch over the full high frequency band and may be represented by at least one parameter. Alternatively, the patch scaling data comprises a factor determined for each of a plurality of subbands together constituting the high frequency band, e.g. similar to the spectral envelope data per subband in spectral bandwidth replication applications. Alternatively the patch scaling data may also indicate a transfer function of a filter. For example, parameters of a transfer function of a filter for scaling the first patch and/or parameters of a transfer function of a filter for scaling the second patch may be determined for generating the patch scaling control data. In this way, the parameters may be generated based on a function of frequency. Another alternative may be generating patch scaling control parameters representing a differential function of the first patch and the second patch. The patch scaling control data1022may be generated by analyzing the input signal1002and selecting patch scaling control parameters stored in a patch scaling control parameter memory based on the analysis of the input signal1002to obtain the patch scaling control data1022. Alternatively, the generation of the patch scaling control data1022may be realized by an analysis by synthesis approach. For this, the patch scaling control data generator1020may comprise additionally a patch generator (as described for the decoder) and a comparator. The patch generator may generate a first patch from the low frequency band of the input signal1002according to a first patching algorithm and a second patch from the low frequency band of the input signal1002according to a second patching algorithm. A spectral density of the second patch generated according to the second patching algorithm may be higher than a spectral density of the first patch generated according to the first patching algorithm. The comparator may compare the first patch, the second patch and the high frequency band of the input signal to obtain the patch scaling control data1022. In other words, the concept described before is also applied to the apparatus1000. In this way, the apparatus1000may extract the patch scaling control data1022by comparing the patches or the combined patches with the input signal, which may, for example, be an original audio signal. Additionally, the apparatus1000may also comprise a spectral line selector, a power controller, a noise adder and/or a missing harmonic adder as described before. In this way, also the noise data, the noise patch scaling control data, the missing harmonic data and/or the missing harmonic patch scaling control data may be extracted by an analysis by synthesis approach. Some embodiments according to the invention relate to an audio signal comprising a first band and a second band. The first band is represented by a first resolution data and the second band is represented by a second resolution data, wherein the second resolution is lower than the first resolution. The second resolution data is based on spectral envelope data of the second band and patch scaling control data of the second band for scaling the audio signal at a decoder or for scaling a first patch and a second patch by the decoder, so that a bandwidth extended signal generated by the decoder fulfills a spectral envelope criterion. The spectral envelope criterion is based on the spectral envelope data. The first patch is generated from the first band of the audio signal according to a first patching algorithm and the second patch is generated from the first band of the audio signal according to a second patching algorithm. A spectral density of the second patch generated according to the second patching algorithm is higher than a spectral density of the first patch generated according to the first patching algorithm. The audio signal may be, for example, a bandwidth reduced signal based on an original audio signal. The first band of the audio signal may represent a low frequency band of the original audio signal encoded with high resolution. The second band of the audio signal may represent a high frequency band of the original audio signal and may be quantized at least by two parameters, a spectral envelope parameter represented by the spectral envelope data and a patch scaling control parameter represented by the patch scaling control data. Based on such an audio signal, a decoder according to the concept described above may generate a bandwidth extended signal providing a good approximation of the original audio signal with improved audio quality in comparison with known concepts. FIG.11shows a flow chart of a method1100for generating a bandwidth extended signal from an input signal according to an embodiment of the invention. The input signal is represented, for a first band by a first resolution data, and for a second band by a second resolution data, the second resolution being lower than the first resolution. The method1100comprises generating1110a first patch, generating1120a second patch, scaling1130the input signal or scaling1130the first patch and the second patch and combining1140the first patch, the second patch and the first band of the input signal to obtain the bandwidth extended signal. The first patch is generated1110from the first band of the input signal according to a first patching algorithm and the second band is generated1120from the first band of the input signal according to a second patching algorithm. A spectral density of the second patch generated1120according to the second patching algorithm is higher than a spectral density of the first patch generated1110according to the first patching algorithm. The input signal may be scaled1130according to the first patching algorithm and according to the second patching algorithm or the first patch and the second patch may be scaled1130, so that the bandwidth extended signal fulfills a spectral envelope criterion. Further, the method1100may be extended by steps according to the concept described above. The method1100may be, for example, realized as a computer program for running on a computer or micro controller. FIG.12shows a flow chart of a method1200for providing a bandwidth reduced signal based on an input signal according to an embodiment of the invention. The method1200comprises determining1210spectral envelope data based on a high frequency band of the input signal, generating1220patch scaling control data, combining1230a low frequency band of the input signal, the spectral envelope data and the patch scaling control data to obtain the bandwidth reduced signal and providing1240the bandwidth reduced signal for transmission or storage. The patch scaling control data is generated1220for scaling the bandwidth reduced signal at a decoder or for scaling a first patch and a second patch by the decoder so that a bandwidth extended signal generated by the decoder fulfills a spectral envelope criterion. The spectral envelope criterion is based on the spectral envelope data. The first patch is generated from a low frequency band of the bandwidth reduced signal according to a first patching algorithm and the second patch is generated from the low frequency band of the bandwidth reduced signal according to a second patching algorithm. A spectral density of the second patch generated according to the second patching algorithm is higher than a spectral density of the first patch generated according to the first patching algorithm. Further, the method1200may be extended by steps according to the concept described above. The method1200may be, for example, realized as a computer program for running on a computer or micro controller. Some embodiments according to the invention relate to an apparatus for generating a bandwidth extended signal using a phase vocoder for bandwidth extension combined with non-linear distortion or noise-filling for a more dense spectrum. When applying the phase vocoder for spectral spreading, frequency lines move further apart. If gaps exist in the spectrum, e.g. by quantization, the same are even increased by the spreading. In an energy adaptation, remaining lines in the spectrum receive too much energy. This is prevented by filling the gaps, either by noise or by further harmonics, which may be gained by a non-linear distortion of the signal. This way, more energy may be distributed between the remaining lines. By the concentration of the energy in bands to only few frequency lines, a unnatural or metallic sound results. The energy of formerly more bands is summed up to the remaining ones. If there are no gaps in the spectrum, but—at least—noise is present, a part of the energy remains in the noise floor. By application of non-linear distortion, the spectrum may be densified again on the one hand by noise produced by the distortion, on the other hand by further harmonic portions steered by an appropriate selection of the signal portion to be distorted. The bandwidth extended signal then may be, for example, a weighted sum of a filtered distorted signal and a signal, which was generated with the help of the phase vocoder. In other words, the bandwidth extended signal may be a weighted sum of the first patch, the second patch and the first band of the input signal. Some embodiments according to the invention relate to a concept suitable for all audio applications where the full bandwidth is not available. For example, for the broadcast of audio contents using digital radio services, internet streaming or other audio communication applications, the described concept may be applied. While this invention has been described in terms of several embodiments, there are alterations, permutations, and equivalents which fall within the scope of this invention. It should also be noted that there are many alternative ways of implementing the methods and compositions of the present invention. It is therefore intended that the following appended claims be interpreted as including all such alterations, permutations and equivalents as fall within the true spirit and scope of the present invention. In particular, it is pointed out that, depending on the conditions, the inventive scheme may also be implemented in software. The implementation may be on a digital storage medium, particularly a floppy disk or a CD with electronically readable control signals capable of cooperating with a programmable computer system so that the corresponding method is executed. In general, the invention thus also consists in a computer program product with a program code stored on a machine-readable carrier for performing the inventive method, when the computer program product is executed on a computer. Stated in other words, the invention may thus also be realized as a computer program with a program code for performing the method, when the computer program product is executed on a computer. While this invention has been described in terms of several embodiments, there are alterations, permutations, and equivalents which fall within the scope of this invention. It should also be noted that there are many alternative ways of implementing the methods and compositions of the present invention. It is therefore intended that the following appended claims be interpreted as including all such alterations, permutations and equivalents as fall within the true spirit and scope of the present invention. | 42,401 |
RE49802 | DETAILED DESCRIPTION A method for the drying of a polyimide precursor such as a layer on a silicon substrate. The method may be significantly quicker than prior drying methods, while also resulting in polyimide layers with fewer or no defects. In some prior processes, the drying is incomplete as the layer is not sufficiently dried as the higher temperature imidization process is transitioned into, resulting in bubbling within the layer. The bubbles are voids which can result in faults that cause failures in the end product, such as microchips, for example. In some devices, multiple layers of polyimide may be used, with the possibility of failure compounded with each additional layer. In some prior processes, the polyimide precursor layer may become discolored due to exposure of the layer to oxygen at temperature. The layer may become brown, which will significantly interfere with the transmission of light through the cured polyimide layer. The layers may need to retain their clarity to allow for retention of sight of lower level alignment features or marks. In some aspects the polyimide layer may also be a photosensitive layer, and browning of the layer may interfere with the exposure of the layer. In embodiments of the present invention, the drying steps of the process not only result in a dried polyimide precursor layer with the advantages as listed above and described herein, but also result in the process oven having a very extremely low oxygen level, allowing for further processing of the substrates in that same process oven in an extremely low oxygen level environment. In some aspects, semiconductor die are molded into a plastic molding compound in support of Fan Out Wafer Level Packaging (FOWLP) fabrication. After the molding, a number of subsequent process steps may occur. Subsequent metallization steps may need to be done at very low pressures, and outgassing of the plastic molding compound interferes with this metallization step, by extending the time it takes to get to the reduced metallization pressure (vacuum level). Typically there may be a polyimide layer over the plastic molding compound, which is put in place prior to a metallization step. In some prior processes, an outgassing step for the plastic molding compound was needed, as well as a drying step for the polyimide precursor prior to imidization. In some embodiments of the present invention, a single process may be used to both outgas the plastic molding compound and to dry the polyimide precursor layer. As discussed below, polyimide precursor drying according to embodiments of the present invention provides the unusual, and significantly improved, circumstance of greatly reducing processing time while also significantly reducing defect levels in the polyimide layer after imidization, resulting in a higher overall throughput in a shorter time. Coupled with plastic molding compound outgassing during the later FOWLP steps, embodiments of the present invention may replace two longer process steps with a single shorter step (shorter than either of the previously required two steps). In an exemplary embodiment, a substrate is ready for further processing. In some aspects, the substrate may be a silicon wafer, which may have been doped or otherwise processed.FIG.1illustrates a substrate with a top surface101. The substrate100may be a silicon substrate. The substrate may be a circular silicon substrate of up to 14 inches in diameter.FIG.2illustrates a substrate100with a polyimide precursor layer102. The polyimide precursor102has a top surface103. A liquid polyimide precursor is applied over a substrate, or over prior layers already applied over a substrate. The polyimide precursor may have a solvent such as NMP. In some aspects, a drying process is implemented to completely or nearly completely dry the precursor layer prior to going to a higher temperature for imidization, as with temperature imidization processes.FIG.3illustrates a substrate with a polyimide precursor layer102. With a drying process, the solvent is liberated104from the polyimide precursor layer. At room temperature, NMP boils at approximately 205 C. A drawback with raising the polyimide precursor layer to the NMP boiling temperature is that the polyimide precursor layer may begin to skin over at 200 C.FIG.4illustrates a substrate100with a polyimide precursor layer102. In this illustrative example of a non-favored result, a skinning layer105has formed along the top surface103of the polyimide precursor layer102. A skinning layer105may interfere with the liberation of evaporating solvent from the polyimide precursor layer102. The skinning over of the polyimide precursor layer may trap the evaporating solvent within the polyimide precursor layer, interfering with liberation of gas from the layer as the solvent evaporates. Retained solvent may then result in large bubbles in the imidized layer as the volume of the solvent as a gas at the higher imidization temperatures increases, and then is made permanent as the polyimide layer becomes hard via imidization.FIG.5illustrates a non-favored condition wherein bubbles106have formed within the polyimide precursor layer102, and are being prevented from being liberated104from the polyimide precursor layer by the skinning layer105. FIG.6illustrates another non-favored condition wherein large bubbles107are forming within the polyimide precursor layer102. In some prior processes, driving the drying process with too low of a pressure to soon, as opposed to stepped drying pressures according to some embodiments of the present invention, may result in large bubble formation. Also, in cases where the polyimide precursor is not fully dried prior to the raising of temperature to imidization temperature, bubbles may form during this temperature rise as residual solvent evaporates but is trapped in the already hardening polyimide precursor layer as imidization is occurring. The resultant bubbles107reduce the reliability of the polyimide layer, and may result in faults in the completed semiconductor. Large bubbles may also travel to the surface of the drying polyimide precursor resulting in polyimide popping, leaving craters in the surface.FIG.7illustrates popped bubbles108in a polyimide layer102on a substrate100. The bubbles are then voids in a needed protective, insulating, layer which may result in faults in the final product semiconductor, using one example. In some embodiments of the present invention, the drying process is carried out in a process chamber with low pressure/vacuum capabilities. The process chamber may also include capability for inletting heated inert gas, such as nitrogen. The process chamber may also be able to be heated for supporting the drying process. The process chamber may also be able to be heated to even higher temperatures to support temperature imidization processing after the drying portion of the process. With reduced pressure, the solvent will boil at a lower temperature. For example, NMP boils at approximately 105 C at 50 Torr. Using an example of a substrate coated with a polyimide precursor, or a plurality of such coated substrates, the substrates are delivered into a process chamber. The process chamber may be heated to a temperature below the room temperature boiling point of the solvent. The solvent may be NMP and the initial heating temperature may be 150 C. The pressure used is subject to at least two conflicting constraints. On the one hand, the pressure should be reduced enough to evaporate the solvent, allowing for the low pressure liberation of the gas which permeates the liquid/gel precursor and is liberated to the low pressure chamber. On the other hand, too much evaporation, too quickly, could lead to aggregation of the gas into bubbles, which may lead to popping on the surface or other issues. Further, though, lowering the chamber pressure in further steps to a pressure even lower than 50 Torr creates more pressure differential between the bottom of the gel, against the substrate, and the low pressure chamber, better driving out the gas. These goals and risks are what are now addressed below. In an exemplary process according to some embodiments of the present invention, a polyimide precursor is applied to a silicon substrate. In some aspects, the polyimide precursor is applied directly over the silicon substrate. In some aspects, the polyimide precursor is applied over other layers already on a substrate, which may be other polyimide layers and metal layers, for example. In some aspects, the solvent used in the polyimide precursor is NMP. An expected thickness for semiconductor applications is in the range of 7-10 microns. Although a single substrate could be processed, in some aspects a plurality of substrates may be processed. As seen inFIG.8, a process oven201may be used to support a plurality of substrates203within a chamber202. The process oven may include internal heaters, heated inert gas inputs, and vacuum capability. The substrates are placed into the chamber202that has been heated to 150 C. In some aspects, the chamber is heated to a temperature in the range of 135 C to 180 C. The chamber pressure is reduced to a first drying pressure of 50 Torr. In some embodiments, the first drying pressure is in the range of 30-60 Torr. After reaching the first drying pressure, the chamber may then be flushed with a heated inert gas such as nitrogen at a pressure of 600 Torr. In some aspects the heated inert gas may be at a pressure in the range of 550 to 760 Torr. The nitrogen may be heated to the same temperature as the chamber, 150 C. The chamber pressure is then reduced to a second drying pressure of 25 Torr. In some embodiments, the second drying pressure is in the range of 15-30 Torr. After reaching the second drying pressure, the chamber may then be flushed with a heated inert gas such as nitrogen at a pressure of 600 Torr. In some aspects the heated inert gas may be at a pressure in the range of 550 to 760 Torr. The nitrogen may be heated to the same temperature as the chamber, 150 C. The chamber pressure is then reduced to a third drying temperature of 1 Torr. In some embodiments, the third drying pressure is in the range of 1-15 Torr. After reaching the third drying pressure, the chamber may then be filled with heated inert gas, such as nitrogen, up to 650 Torr, in preparation for imidization of the polyimide precursor. The substrates may then undergo temperature imidization in the same chamber. As described further below, the oxygen level in the process oven may now be very extremely low. The subsequent temperature imidization may occur at 350-375 C, and as further described below. In an exemplary embodiment further illustrating the timing of a process as described above, a process may begin with the heating of the process oven to a temperature of 150 C. A single substrate or a plurality of substrates within the process oven, which include a polyimide precursor including a solvent such as NMP, are put into the process oven which has been preheated to the temperature of 150 C. The process oven pressure is then reduced to a first drying pressure of 50 Torr. This portion of the process may take 2-3 minutes. The process oven is then flushed with preheated nitrogen heated to 150 C up to a pressure of 600 Torr. This portion of the process may take 2-3 minutes. The process oven pressure is then reduced to a second drying pressure of 25 Torr. This portion of the process may take 3-4 minutes. The process oven is then flushed with preheated nitrogen heated to 150 C up to a pressure of 600 Torr. This portion of the process may take 2-3 minutes. The process oven pressure is then reduced to a third drying pressure of 1 Torr. This portion of the process may take 4-5 minutes. The process oven is then flushed with preheated nitrogen heated to 150 C up to a pressure of 650 Torr. This portion of the process may take 2-3 minutes. The aforementioned steps have now greatly reduced the oxygen level in the process oven, as well as having removed all or nearly all of the solvent from the polyimide precursor with little or no bubbling or skinning of the polyimide precursor. The aforementioned steps combine the above mentioned advantages of reduced oxygen levels in the process oven and a precursor layer with little or no bubbling or skinning, while being performed more quickly than other currently used processes. The other currently used processes not only take longer, but they also result in polyimide precursor layers which have bubbling, skinning, popping, or other detrimental attributes, and further, do not have the sought after very low oxygen level. After the multi-step drying process, the substrates are now ready for temperature imidization. As discussed further below, the oxygen level in the process oven may now be down as low as approximately 1 ppm, as an end result of the drying process. An exemplary temperature imidization process may now include maintaining approximately 250 Torr in the process chamber while inputting heated nitrogen at the top of the process oven while pulling vacuum at the bottom of the process oven. The heated nitrogen and the oven temperatures may now be raised in unison, for example, to 350 C. At 4 C/minute, this heating process would take 50 minutes. At 350 C the oven and gas temperatures may be held for 1 hour for temperature imidization of the polyimide precursor. Although 350 C is an illustrative temperature using NMP, other temperatures may used for the temperature imidization. After the temperature imidization, the oven heaters may be turned off, which will result in a cooling of the oven. The heated nitrogen flow may be cooled at a rate which tracks the cooling oven. The vacuum pulsing as described above, in conjunction with the intervening flushing with nitrogen, provides another important benefit for the imidization process, which is already separately enhanced by the significantly enhanced drying. The vacuum pulsing and intervening flushing results in a much lower oxygen level in the process chamber as the substrates go further in the process. In contrast to prior methods which pull vacuum once for a combined drying/imidization process, the vacuum pulsing reduces the partial pressure of oxygen significantly, as each flushing with nitrogen resets the initial gas balance prior to the next pull of vacuum. The inflows of heated inert gas enhance the heating of the polyimide precursor layer, as well as the fixturing within the chamber and the chamber itself. The reduced pressure of the process described herein enhances, and speeds up, the evaporation of the solvent, and also allows for a temperature to be used for the evaporation that is below the skinning temperature of the polyimide precursor. The staging of the reduced pressure at sequentially lower pressures reduced bubbling which might occur by simply going straight to a very reduced pressure, and avoids the residual solvent which would remain if the very reduced pressure is not utilized. Residual solvent may inhibit the imidization of the polyimide precursor. The pulsing and flushing then further adds the benefit of a final chamber composition with significantly less oxygen than prior methods, reducing or eliminating the browning which may occur in the polyimide layer during temperature imidization in the presence of oxygen. With the tiered vacuum application, in conjunction with nitrogen flushing, oxygen levels may be driven very, very low. With the above-described process, the starting concentration of oxygen at the initial atmospheric conditions is approximately 230,000 parts per million (ppm). When the initial vacuum is applied down to 50 Torr, and then the chamber is refilled with nitrogen, the concentration of oxygen will have been reduced to approximately 15, 131 ppm. With the subsequent vacuum pull down to 25 Torr, and then refilling with nitrogen, the concentration of oxygen will have been reduced to approximately 498 ppm. With the final vacuum pull down to 1 Torr, and subsequent refilling with nitrogen, the resulting concentration of oxygen will be down to 0.65 ppm. The very, very, low oxygen concentrations that result allow for a subsequent processing, including temperature imidization, at oxygen concentrations well below any prior process. In actual practice, the purity of the nitrogen supply may become the active parameter in how low of an oxygen concentration can be reached. If the nitrogen supply is known to have 10 ppm oxygen, for example, then that will limit the depth of oxygen removal. Some processing chambers may have nitrogen availability with down to 1 ppm O2, and with such a system oxygen concentration can be driven down to approximately 1 ppm. Simple flushing of a chamber with pure nitrogen provides some reduction in oxygen concentration, but such processes are very time consuming and do not achieve results at all comparable to the above-described process. Further, the use of heated nitrogen for the re-filling steps in the above-described process works to minimize the effects of freezing than may have happened during the vacuum pull. As water boils at 72 C at 50 Torr, 26 C at 25 Torr, and −21 C at 1 Torr, the heated nitrogen input thus facilitated evaporation of any water than may be found in the devices being dried or outgassed. In addition to the reduction or elimination of browning, and the reduction or elimination of bubbling and popping in the polyimide precursor layer, the process as described herein adds another significant improvement that in spite of the much higher quality polyimide layer that results, the process is much quicker than prior processes. Using a process according to embodiments of this invention, a substrate, or a plurality of substrates, may be dried and temperature imidized in 3-3.5 hrs, whereas typically current processes may take up to 12 hours to dry and imidize a polyimide layer. With the increasing number of layers in modern semiconductor devices, which may include up to 17 polyimide layers, for example, the time and thus cost savings can be extremely significant. In some embodiments, the temperature of the oven during drying is 150 C. In some embodiments, the temperature of the oven is in the range of 135-180 C. In some embodiments, the first drying pressure is 50 Torr. In some embodiments, the first drying pressure is in the range of 30-60 Torr. In some embodiments, the second drying pressure is 25 Torr. In some embodiments, the second drying pressure is in the range of 15-30 Torr. In some embodiments, the third drying pressure is 1 Torr. In some embodiments, the third drying pressure is in the range of 1-15 Torr. In a further embodiment of the present invention, the process used to dry the polyimide precursor prior to temperature imidization may also be used to outgass plastic molding compound which may surround a semiconductor die in FOWLP fabrications. Initially, the rapid drying process of polyimide precursor layers may be done to support processing steps on the entire wafer. Each of the rapid drying steps may both reduce the time of the drying step relative to prior processes, and also increase reliability of the processed items. With each polyimide layer on the wafer buildup, processes according embodiments of the present invention present at least the advantages of reduced processing time, enhanced quality of the polyimide layers, and reduces oxygen levels after the drying step. Once the wafer is completed, the wafer may be sliced up into individual die. As seen inFIG.9, the die may be reconfigured to allow for subsequent molding steps. In some aspects, these die are then partially surrounded by a plastic molding compound, which may allow for fan out configurations.FIG.10illustrates an exemplary molding process. This post wafer, die level, processing may include adding polyimide layers, especially to allow for metallization of leads supporting the fan out configuration.FIG.11illustrates an exemplary completed fan out wafer level packaging configuration in cross-section. The plastic molding compound must be outgassed prior to the metallization process, and this step takes significant time. Further, the polyimide precursor layers should be dried prior to the temperature imidization process. In some embodiments of the present invention, a single process may be used to both outgas the plastic molding compound and to dry the polyimide precursor layer, as opposed to different processes of prior methods. Using the above-described polyimide precursor drying method will also outgas the plastic molding compound. In an exemplary embodiment, plastic molding compound is molded around a die. A polyimide precursor layer is applied over a surface which may comprise both the molding compound and the die. Prior to imidization of the polyimide precursor layer, the assembly is dried according to drying processes of the present invention, as described above. This quick process will both outgas the plastic molding compound, and dry the polyimide precursor layer, substituting one process for what had previously been two processes, and which may be of significantly shorter duration. The applicant builds cure ovens that are specifically designed to address the concerns of manufacturers of the cured characteristics of the multiple polyimide layers incorporated in Wafer-level Packaging (WLP)/Redistribution Layers (RDL) circuits. Polyimides are high temperature engineering polymers with excellent mechanical, thermal and electrical properties. The most important step of the process is the curing of the polyimide precursors, which can be done under atmospheric or vacuum process conditions. As discussed above, the objectives of a proper cure process are to complete the imidization process, optimize film adhesion performance, remove all residual solvents and extraneous gases, and remove photosensitive components. To convert the polyimide precursors to a stable polyimide film, an elevated temperature (˜250 C to 450 C) extended bake is required for complete imidization; it also drives off the N-methylpyrrolidone (NMP) casting solvents and orients the polymer chains for optimal electrical and mechanical properties. The imidization rate of the polyimide precursors need to be controlled to take into account the differences in thermal expansion coefficient between the polyimide film and the underlying substrate. If the imidization rate is not controlled properly, there can be localized mechanical stress variations across the wafer. In addition, if the casting solvents evolve non-uniformly across the wafer, film thickness non-uniformity can occur due to uneven imidization. The mechanical stress variations can be observed as wrinkled polyimide film or as distorted metal lines in the structures under the polyimide layer. The polyimide film can also delaminate because film adhesion performance has not been optimized. Because mechanical stress variations can affect the yield and reliability of the process, it is critical that controlled temperature ramp rates are used to provide a larger process window for the proper curing of a polyimide film. Non-uniform heating can cause a skin to form on the surface of the polyimide film during the curing process. The skin can prevent the efficient evolution of the casting solvents and other volatile gases. If a cured polyimide film still has residual solvents or other volatile gases, then localized areas of the polyimide film can rupture in a phenomenon known as “popcorning”. These ruptures occur in subsequent process steps in tools, which have either a high vacuum or a high temperature environment. This rupturing is due to the sudden release of gas bubbles/solvents trapped in the polyimide film that is not properly cured. In addition, a “solvent-free” polyimide film will minimize the queue time needed to allow for outgassing when the next process step is a high vacuum process, such as metallization. Photosensitive polyimides offer the advantage of simpler processing by eliminating the need for photoresist compared to standard non-photosensitive polyimides. This reduces the number of process steps. The curing process parameters, such as temperature, vary with the type of photosensitive precursors in the polyimide film. For some types of precursors, the photosensitive components can be difficult to evolve from the polyimide film. Residual photosensitive polyimide precursors can cause greater internal film-induced stress than those in a standard polyimide film. Some photosensitive polyimide precursors and their byproducts also have a tendency to form depositions on the process chamber walls. Heavy deposits can be difficult to remove if the byproducts are not efficiently removed from the chamber during the curing process. Furthermore, when these byproducts are exhausted from the chamber, they also need to be substantially removed from the exhaust stream as the byproducts can redeposit along the exhaust lines. In summary, the photosensitive components must be eliminated from the polyimide film and efficiently removed from the process chamber. The presence of oxygen in the process chamber inhibits the proper crosslinking of the polyimide precursors to polyimide thin film. The result is incomplete imidization which leads to a brittle film and variable stress in the polyimide film on the substrate. Also, ambient oxygen darkens the polyimide film. This film transparency is critical when multiple polyimide layers are used during subsequent processing. For multi-layer processes, the alignment marks for the process sequence can be obscured by the layers of low transparency polyimide films. In summary, pure nitrogen ambient is required to reduce the level of oxygen in the process chamber. As described above, embodiments of the present invention allow for more complete drying of polyimide precursor layers, more quickly, and with fewer defects, while also offering the additional advantage of the resulting dried substrates/layers residing in an extremely low oxygen level environment. The subsequent temperature imidization is then further enhanced in quality. In the case of wafer die with polyimide precursor layers and molding compound, the outgassing of the molding compound may occurs simultaneously with the polyimide precursor drying, further reducing the time needed for such a process, and with higher throughput. As evident from the above description, a wide variety of embodiments may be configured from the description given herein and additional advantages and modifications will readily occur to those skilled in the art. The invention in its broader aspects is, therefore, not limited to the specific details, representative apparatus and illustrative examples shown and described. Accordingly, departures from such details may be made without departing from the spirit or scope of the applicant's general invention. | 26,997 |
RE49803 | DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Now, some embodiments of the present invention will be described below, based on the drawings. In each of the embodiments, the configuration of a semiconductor device will be described in the order of manufacturing steps. First Embodiment An embodiment of the method of manufacturing a semiconductor device pertaining to the present invention will be described below, taking the method of manufacturing a PMOSFET as an example and referring to the manufacturing step sectional diagrams inFIGS.1A to2G. Incidentally, in the following description, the same configurations as those described in the background of the invention above will be denoted by the same symbols as used above. First, as shown inFIG.1A, a silicon substrate11composed of single crystal silicon is prepared, and device isolation regions are formed on the face side thereof. In this case, for example, device isolation regions of the STI (shallow trench isolation) structure are formed, in which trenches are formed on the face side of the silicon substrate11, and an insulating film composed of a silicon oxide film, for example, is buried in the trenches. Next, on the silicon substrate11in each area isolated by the device isolation regions, a gate electrode13composed of polysilicon, for example, is patterned, with a gate insulating film12composed of a silicon oxynitride film, for example, therebetween. In this case, in order that an offset insulating film14composed of a silicon nitride film, for example, is provided on the gate electrode13, films of materials for constituting the gate insulating films12, the gate electrodes13and the offset insulating films14are layered in a stacked state, and the stack of films is subjected to pattern etching. Here, the material constituting the gate insulating film12is not limited to the silicon oxynitride film, and may be a silicon oxide film or a metallic oxide film containing hafnium or aluminum. In addition, the gate electrode13is not limited to polysilicon, and may contain a metallic material. Next, as shown inFIG.1B, for example, a silicon nitride film15′ is formed over the silicon substrate11in the state of covering the gate insulating films12, the gate electrodes13, and the offset insulating films14. Subsequently, as shown inFIG.1C, the silicon nitride film15′ (seeFIG.1B) is etched back by a dry etching method, for example, whereby insulating side walls15are formed on side walls of the gate insulating film12, the gate electrode13, and the offset insulating film14. While the side walls15are described to be composed, for example, of silicon nitride film here, the side walls15may be composed of other film than the silicon nitride film, and may be configured of silicon oxide film or a stacked structure of these films. Next, as shown inFIG.1D, recess etching which includes in digging down the surface of the silicon substrate11is conducted. In this case, the recess etching of digging down the surface layer of the silicon substrate11is realized by etching which is conducted with use of the offset insulating film14on the gate electrode13and the side walls15as a mask, whereby recess regions16about 80 nm deep are formed. In the recess etching, an isotropic etching is conducted, whereby the recess region16can be broadened even to the lower side of the side walls15. Thereafter, a cleaning treatment is conducted using diluted hydrofluoric acid, whereby a natural oxide film on the surface of the silicon substrate11is removed. Incidentally, while an example in which the recess etching is conducted in the condition where the side walls15have been provided is described here, the present invention is applicable also to the case where the recess etching is carried out without the side walls15provided in advance. Subsequently, a mixed crystal layer containing silicon and atoms different in lattice constant from silicon is epitaxially grown, in an impurity-containing state, on the surfaces of the recess regions16, i.e., on the surfaces of the dug-down portions of the silicon substrate11. Here, an SiGe layer (mixed crystal layer) composed of silicon (Si) and atoms (Ge) larger than silicon in lattice constant and containing, for example, boron as an impurity is epitaxially grown, in view of the PMOSFET intended to be produced. In this case, as a characteristic feature of the present invention, on the surfaces of the dug-down portions of the silicon substrate11, the SiGe layer is epitaxially grown so as to contain boron with such a concentration gradient that the boron concentration therein increases along the direction from the side of the silicon substrate11toward the surface thereof. Here, the SiGe layer is composed of a first SiGe layer (first layer), a second SiGe layer (second layer) and a third SiGe layer (third layer) which are sequentially layered in a stacked state. Specifically, as shown inFIG.1E, on the surfaces of the dug-down portions of the silicon substrate11, i.e., on the surfaces of the recess regions16, the first SiGe layer21a is formed so as to contain boron in the lowest concentration among the three SiGe layers. Here, the first SiGe layer21a is epitaxially grown in a film thickness of one to 30 nm so as to obtain a boron concentration of 1×1018to 1×1019cm−3. As for the film forming conditions for the first SiGe layer21a, dichlorosilane (DCS), germanium hydride (GeH4) diluted with hydrogen (H2) to 1.5 vol %, hydrogen chloride (HCl), and diborane (B2H6) diluted with hydrogen (H2) to 100 ppm are used as film-forming gases, at gas flow rates of DCS/GeH4/HCl/B2H6=ten to 100/ten to 100/ten to 100/one to 50 (ml/min), a treating temperature of 650 to 750° C., and a treating pressure of 1.3 to 13.3 kPa. It is to be noted that the gas flow rates are volume flow rates in the normal state, here and hereinafter. Here, the first SiGe layer21a containing the impurity in the low concentration is located closer to the channel region, as compared with the second and third SiGe layers; therefore, diffusion of boron from the SiGe layer due to a heat treatment is restrained, and the short channel effect is prevented from being produced. Besides, in order to securely prevent the short channel effect, the film thickness of the first SiGe layer21a in the above-mentioned range is further preferably in the range of ten to 30 nm, within such a range as not to lower the carrier mobility in the PMOSFET produced. Incidentally, as has been described in the background of the invention above, there may be cases where an SiGe layer containing an impurity in a low concentration is formed on the surfaces on the recess regions, for convenience of film formation, even in the case of directly forming the SiGe layer on the surfaces of the recess regions without changing the film forming conditions. The formation of the first SiGe layer21a in this embodiment, however, is different from such an incidental case. Specifically, the first SiGe layer21a containing the impurity in the low concentration is formed so as to have a predetermined film thickness, by positively changing the film forming conditions. Next, as shown inFIG.1F, on the first SiGe layer21a, the second SiGe layer21b is epitaxially grown so as to contain the impurity with such a concentration gradient that the impurity concentration therein varies continuously from the impurity concentration in the first SiGe layer21a to the impurity concentration in the third SiGe layer which will be described later, along the direction from the first SiGe layer21a side toward the surface thereof. Here, in view of that the boron concentration in the first SiGe layer21a is in the range of 1×1018to 1×1019cm−3and that the boron concentration in the third SiGe layer is in the range of 1×1019to 5×1020cm−3, the second SiGe layer21b is so formed as to contain boron with such a concentration gradient that the boron concentration therein varies continuously from the range of 1×1018to 1×1019cm−3to the range of 1×1019to 5×1020cm−3, along the direction from the first SiGe layer21a side toward the surface thereof. The film thickness of the second SiGe layer21b is one to 20 nm. As for the film forming conditions for the second SiGe layer21b, the same film-forming gases as those in the case of the first SiGe layer21a are used. Of the film-forming gases, DCS, GeH4, and HCl are used at gas flow rates of DCS/GeH4/HCl=ten to 100/ten to 100/ten to 100 (ml/min). Besides, the gas flow rate of B2H6diluted by H2to 100 ppm is varied continuously from a value of one to 50 ml/min to a value of 50 to 300 ml/min. In addition, the treating temperature is set in the range of 650 to 750° C., and the treating pressure is in the range of 1.3 to 13.3 kPa. Here, the configuration in which the second SiGe layer21b as above is interposed between the first SiGe layer21a being the lowest of the three SiGe layers in impurity concentration and the third SiGe layer being the highest of the three SiGe layers in impurity concentration moderates the trouble in film formation due to the difference in impurity concentration between the first SiGe layer21a and the third SiGe layer. Therefore, the second SiGe layer21b may not necessarily be provided in the case where the difference in impurity concentration between the first SiGe layer21a and the third SiGe layer is small. In addition, while the second SiGe layer21b is here formed so as to contain the impurity in such a concentration gradient that the impurity concentration therein varies continuously along the direction from the side of the first SiGe layer21a toward the side of the third SiGe layer, the concentration variation may be stepwise. In that case, the B2H6gas flow rate is changed stepwise. Next, as shown inFIG.1G, on the second SiGe layer21b, the third SiGe layer21c is formed so as to contain the impurity in the highest concentration among the three SiGe layers. Here, the third SiGe layer21c is epitaxially grown to a film thickness of 50 to 100 nm so as to have a boron concentration of 1×1019to 5×1020cm−3. As for the film forming conditions for the third SiGe layer21c, the same film-forming gases as those in the cases of the first SiGe layer21a and the second SiGe layer21b are used at gas flow rates of DCS/GeH4/HCl/B2H6=ten to 100/ten to 100/ten to 100/50 to 300 (ml/min), a treating temperature of 650 to 750° C., and a treating pressure of 1.3 to 13.3 kPa. As a result, the SiGe layer21composed of the first SiGe layer21a, the second SiGe layer band the third SiGe layer21c which are sequentially layered in a stacked state is formed on the surfaces of the recess regions16. Since the recess regions16are formed to be about 80 nm deep, the recess regions16are filled sequentially with the first SiGe layer21a, the second SiGe layer21b and the third SiGe layer21c, and the third SiGe layer21c is in the state of being protuberant upward from the surface level of the silicon substrate11. In addition, the SiGe layer21contains boron as an impurity with such a concentration gradient that the impurity concentration therein increases along the direction from the side of the silicon substrate11toward the surface thereof. The SiGe layers21form the source/drain regions of the PMOSFET manufactured by the manufacturing method according to this embodiment, and the region of the silicon substrate11beneath the gate electrode13located between the SiGe layers21becomes the channel region18of the PMOSFET. The subsequent steps are carried out in the same manner as in the usual PMOSFET manufacturing method. For example, the face side of the SiGe layer21may be silicided to form a silicide layer. In this case, since the first SiGe layers21a located close to the channel region18contain the impurity in the low concentration as above-mentioned, diffusion A of the impurity is restrained even when a heat treatment is conducted after the formation of the SiGe layer21, and, therefore, the short channel effect is prevented from being generated. In this manner, a PMOSFET in which the channel region18is strained by the stress (compressive stress) imposed on the channel region18by the SiGe layers21is manufactured. According to the method of manufacturing a semiconductor device and the semiconductor device as above-described, the SiGe layer21is epitaxially grown so as to contain the impurity with such a concentration gradient that the impurity concentration therein increases along the direction from the side of the silicon substrate11toward the surface thereof, so that the diffusion A of the impurity from the SiGe layer21due to a heat treatment is restrained, and the short channel effect is prevented from being generated. Particularly, according to this embodiment, the SiGe layer21is composed of the three SiGe layers, and the first SiGe layer21a close to the channel region18is formed so as to contain the impurity in a lower concentration as compared with the other SiGe layers, so that the short channel effect can be securely prevented from being produced. In addition, since it is unnecessary to enlarge the distance between the SiGe layer21and the region beneath the gate electrode, a sufficient carrier mobility can be obtained. Therefore, transistor characteristics can be enhanced. Furthermore, according to the method of manufacturing a semiconductor device in this embodiment, the SiGe layer21having the impurity concentration gradient can be formed by a series of operations in which only the film forming conditions are changed, without changing the kinds of the film-forming gases, which is excellent on a productivity basis. Incidentally, while an example in which boron is contained as an impurity in the SiGe layer forming the source/drain regions of the PMOSFET has been described in the first embodiment above, other impurities than boron may be used, for example, gallium (Ga) or indium (In). For example, in the case of using Ga as the impurity, triethylgallium (Ga(C2H5)3) or trimethylgallium (Ga(CH3)3) is used as a film-forming gas, in place of B2H6used in the first embodiment above. Similarly, in the case of using In as the impurity, triethylindium (In(C2H5)3) or trimethylindium (In(CH3)3) is used, in place of B2H6, as a film-forming gas. Second Embodiment While the method of manufacturing a PMOSFET has been taken as an example in the description of the first embodiment above, in this embodiment a method of manufacturing an NMOSFET is taken as an example and description thereof will be made referring toFIGS.2A to2C. Incidentally, the steps up to the step of digging down the surface of a silicon substrate11are carried out in the same manner as the steps described referring toFIGS.1A to1Dabove. In the case of manufacturing an NMOSFET, first, as shown inFIG.2A, a silicon-carbon (SiC) layer (mixed crystal layer) composed of silicon (Si) and atoms (C) smaller in lattice constant than silicon and containing, for example, arsenic (As) as an impurity is epitaxially grown on the surfaces of recessed regions16, i.e., on the surfaces of the dug-down portions of the silicon substrate11. In this case, also, the SiC layer is epitaxially grown so as to contain As with such a concentration gradient that the As concentration therein increases along, the direction from the side of the silicon substrate11toward the surface thereof. Here, like in the first embodiment, the SiC layer is composed of a first SiC layer (first layer), a second SiC layer (second layer) and a third SiC layer (third layer) which are sequentially layered in a stacked state. Specifically, on the surfaces of the dug-down portions of the silicon substrate11, the first SiC layer22a is formed so as to be the lowest of the three SiC layer in impurity concentration. Here, the first SiC layer22a is formed in a film thickness of one to 30 nm so as to have an As concentration of 1×1018to 1×1019cm−3. As for the film forming conditions for the first SiC layer22a, DCS, monomethylsilane (SiH3CH3) diluted with hydrogen (H2) to one vol %, HCl, and arsenic hydride (AsH3) diluted with hydrogen to one vol % are used as film-forming gases, at gas flow rates of DCS/SiH3CH3/HCl/AsH3=ten to 100/one to 50/ten to 100/one to 25 (ml/min), a treating temperature of 650 to 750° C., and a treating pressure of 1.3 to 13.3 kPa. Here, as will be described later, the fist SiC layer22a containing the impurity in the low concentration is disposed to be the closest of the three SiC layers to the channel region, so that diffusion of As from the SiC layer due to a heat treatment is restrained, and the short channel effect is prevented from being produced. Besides, in order to securely prevent the short channel effect, the film thickness of the first SiC layer22a in the above-mentioned range is further preferably in the range of ten to 30 nm, within such a range as not to lower the carrier mobility in the NMOSFET produced. Next, as shown inFIG.2B, on the first SiC layer22a, the second SiC layer22b is formed so as to contain the impurity with such a concentration gradient that the impurity concentration therein varies continuously from the impurity concentration in the first SiC layer22a to the impurity concentration in the third SiC layer, along the direction from the side of the first SiC layer22a toward the surface thereof. Here, in view of that the As concentration in the first SiC layer22a is in the range of 1×118to 1×1019cm−3and that the As concentration in the third SiC layer is in the range of 1×1019to 5×1020cm−3as will be described later, the second SiC layer22b is so formed as to contain As with a concentration gradient such that the As concentration therein increases continuously from a value in the range of 1×1018to 1×1019cm−3to a value in the range of 1×1019to 5×1020cm−3. The film thickness of the second SiC layer22b is in the range of one to 20 nm. As for the film forming conditions for the second SiC layer22b, the same film-forming gases as in the case of the first SiC layer22a above are used. Like in the case of the first SiC layer22a, the gas flow rates of DCS, SiH3CH3and HCl are set as DCS/SiH3CH3/HCl=ten to 100/one to 50/ten to 100 (ml/min). On the other hand, the gas flow rate of AsH3diluted with H2to one vol % is varied continuously from a value in the range of one to 25 ml/min to a value in the range of 25 to 50 ml/min. Besides, the treating temperature is set in the range of 650 to 750° C., and the treating pressure in the range of 1.3 to 13.3 kPa. Here, the configuration in which the second SiC layer22b as above is interposed between the first SiC layer22a being the lowest of the three SiC layers in impurity concentration and the third SiC layer being the highest of the three SiC layers in impurity concentration moderates the trouble in film formation due to the difference in impurity concentration between the first SiC layer22a and the third SiC layer. Therefore, the second SiC layer22b may not necessarily be provided in the case where the difference in impurity concentration between the first SiC layer22a and the third SiC layer is small. In addition, while the second SiC layer22b is here formed so as to contain the impurity in such a concentration gradient that the impurity concentration therein varies continuously along the direction from the side of the first SiC layer22a toward the side of the third SiC layer, the concentration variation may be stepwise. In that case, the AsH3gas flow rate is changed stepwise. Next, as shown inFIG.2C, on the second SiC layer22b, the third SiC layer22c is formed so as to contain the impurity in the highest concentration among the three SiC layers. Here, the third SiC layer22c is formed in a film thickness of 50 to 100 nm so as to have an As concentration of 1×1019to 5×1020cm−3. As for the film forming conditions for the third SiC layer22c, the same film-forming gases as those in the cases of the first SiC layer22a and the second SiC layer22b are used at gas flow rates of DCS/SiH3CH3/HCl/AsH3=ten to 100/one to 50/ten to 100/25 to 50 (ml/min), a treating temperature of 650 to 750° C., and a treating pressure of 1.3 to 13.3 kPa. As a result, the SiC layer22composed of the first SiC layer22a, the second SiC layer22b and the third SiC layer22c which are sequentially layered in a stacked state is formed on the surfaces of the recess regions16. Since the recess regions16are formed to be about 80 nm deep, the recess regions16are filled sequentially with the first SiC layer22a, the second SiC layer22b and the third SiC layer22c, and the third SiC layer22c is in the state of being protuberant upward from the surface level of the silicon substrate11. In addition, the SiC layer22contains As as an impurity with such a concentration gradient that the impurity concentration therein increases along the direction from the side of the silicon substrate11toward the surface thereof. The SiC layers22form the source/drain regions of the NMOSFET manufactured by the manufacturing method according to this embodiment, and the region of the silicon substrate11beneath the gate electrode13located between the SiC layers22becomes the channel region18of the NMOSFET. The subsequent steps are carried out in the same manner as in the usual NMOSFET manufacturing method. For example, the face side of the SiC layer22may be silicided to form a silicide layer. In this case, since the first SiC layers22a located close to the channel region18contain the impurity in the low concentration as above-mentioned, diffusion A of the impurity is restrained even when a heat treatment is conducted after the formation of the SiC layer22, and, therefore, the short channel effect is prevented from being generated. In this manner, an NMOSFET in which the channel region18is strained by the stress (compressive stress) imposed on the channel region18by the SiC layers22is manufactured. According to the method of manufacturing a semiconductor device and the semiconductor device as above-described, the SiC layer22is epitaxially grown so as to contain the impurity with such a concentration gradient that the impurity concentration therein increases along the direction from the side of the silicon substrate11toward the surface thereof, so that the diffusion A of the impurity from the SiC layer22due to a heat treatment is restrained, and the short channel effect is prevented from being generated. Particularly, according to this embodiment, the SiC layer22is composed of the three SiC layers, and the first SiC layer22a close to the channel region18is formed so as to contain the impurity in a lower concentration as compared with the other SiC layers, so that the short channel effect can be securely prevented from being produced. In addition, since it is unnecessary to enlarge the distance between the SiC layer22and the region beneath the gate electrode, a sufficient carrier mobility can be obtained. Therefore, transistor characteristics can be enhanced. MODIFIED EXAMPLE 1 While an example in which As is contained as an impurity in the SiC layer for forming the source/drain regions of the NMOSFET has been described in the second embodiment above, phosphorus (P) may be used, in place of As, as the impurity. In this case, also, the first SiC layer22a is formed in a film thickness of one to 30 nm so as to contain P as the impurity in a concentration in the range of 1×1018to 1×1019cm−3. As for the film forming conditions for the first SiC layer22a, DCS, SiH3CH3diluted with hydrogen (H2) to one vol %, HCl, and phosphorus hydride (PH3) diluted with H2to 50 ppm are used as film-forming gases, at gas flow rates of DCS/SiH3CH3/HCl/PH3=ten to 100/one to 50/ten to 100/one to 150 (ml/min), a treating temperature of 650 to 750° C., and a treating pressure of 1.3 to 13.3 kPa. Next, on the first SiC layer22a, a second SiC layer22b is formed in a film thickness of one to 20 nm so as to contain P as an impurity with such a concentration gradient that the impurity concentration therein increases from a value in the range of 1×1018to 1×1019cm−3to a value in the range of 1×1019to 5×1020cm−3, along the direction from the side of the first SiC layer22a toward the surface thereof. As for the film forming conditions for the second SiC layer22b, the same film-forming gases as in the case of the first SiC layer22a above are used. The gas flow rates of DCS, SiH3CH3and HCl are set as DCS/SiH3CH3/HCl=ten to 100/one to 50/ten to 100 (ml/min). On the other hand, the gas flow rate of PH3diluted with H2to 50 ppm varied continuously or stepwise from a value in the range of one to 150 ml/min to a value in the range of 150 to 300 ml/min. Besides, the treating temperature is set in the range of 650 to 750° C., and the treating pressure in the range of 1.3 to 13.3 kPa. Next, on the second SiC layer22b, the third SiC layer22c is formed in a film thickness of 50 to 100 nm so as to contain P as an impurity in a concentration in the range of 1×1019to 5×1020cm−3. As for the film forming conditions for the third SiC layer22c, the same film-forming gases as those in the cases of the first SiC layer22a and the second SiC layer22b are used at gas flow rates of DCS/SiH3CH3/HCl/PH3=ten to 100/one to 50/ten to 100/150 to 300 (ml/min), a treating temperature of 650 to 750° C., and a treating pressure of 1.3 to 13.3 kPa. By the method of manufacturing an NMOSFET and the NMOSFET as just-described, also, the same effects as in the second embodiment above can be displayed. Incidentally, in the first and second embodiments and the modified example 1 above, descriptions have been made of examples in which the mixed crystal layer composed of a SiGe layer or SiC layer is configured of the first layer, the second layer and the third layer sequentially layered in a stacked state. The first layer and the third layer are each formed to maintain an impurity concentration in a predetermined range, and the second layer is so formed as to have such a concentration gradient that the impurity concentration therein increases continuously from the first layer side toward the third layer side. However, such a configuration is non-limitative of the present invention. For example, the mixed crystal layer may be composed of a plurality of layers containing an impurity with such a concentration gradient that the impurity concentration increases stepwise along the direction from the silicon substrate side toward the surface thereof. Otherwise, the mixed crystal layer may be composed of a single layer containing an impurity with such a concentration gradient that the impurity concentration increases continuously along the direction from the silicon substrate side toward the surface thereof. It should be noted here, however, that the portion, near the channel region, of the mixed crystal layer preferably has a region kept at a low impurity concentration in a film thickness of ten to 30 nm. In addition, while a method of manufacturing a semiconductor device by which a PMOSFET or NMOSFET is produced has been described in each of the above embodiments, the present invention is applicable also to the case of producing a CMOS (Complementary Metal Oxide Semiconductor) FET in which both a PMOSFET and an NMOSFET are mounted. It should be understood by those skilled in the art that various modifications, combinations, sub-combinations and alterations may occur depending on design requirements and other factors insofar as they are within the scope of the appended claims or the equivalents thereof. | 27,519 |
RE49804 | The drawings are not necessarily to scale, and emphasis is instead being placed upon illustrating the principles of the solution. DETAILED DESCRIPTION The embodiments herein relate to methods and apparatus which are configured for one or more of the following:To facilitate control of the set of active antenna ports used for physical signal transmissions in order to reduce the physical signal interference,For assisted user equipment measurement processing, andFor enhanced cell planning adopted for heterogeneous network deployments. The three parts may be viewed as separate embodiments or may form any combination. FIG.5depicts an embodiment of a communications network500. The communications network500may use technologies such as LTE, WiMAX etc. In a network500, a mixture of cells of differently sized and overlapping coverage areas may be deployed. A cell is a geographical area where radio coverage is provided by a base station. For example, the network500may comprise a pico cell501a deployed within the coverage area of a macro cell501b. The pico cell501a may be associated with a pico base station503a. The pico base station503a serves the pico cell501a. The macro cell501b may be associated with a macro base station503b. The macro base station503b serves the macro cell501b. In the following description, the reference number501will be used for indicating a cell in general, and the reference number503will be used for indicating a base station in general. The base station503may be e.g. a pico base station, a macro base station, Home Base Station (HBS), radio base station, e nodeB (eNB), base station, relay, remote radio heads etc, or any other network unit capable to communicate over a radio carrier with a user equipment505. The user equipment505may be present within the cell501and served by the base station503. More than one cell can be associated with one base station. As a network500may comprises a plurality of nodes, a base station may, in some embodiments, be called a network node. A base station503comprises at least one antenna port (not shown), e.g. antenna port 0. Each antenna port is configured to transmit and receive signals from the base station503to e.g. one or more user equipment505. In other words, each antenna ports comprise receivers and transmitters. Other examples of network nodes are, for instance, positioning nodes, Operations & Maintenance (O&M) nodes etc. A downlink (DL) is the link from a base station503down to one or more user equipments505, and an uplink (UL) is the link from a user equipment505up to a base station503. A user equipment505comprised in the network500is assigned to a certain cell, which is referred to as the serving cell. In the following, the user equipment505comprises for example, mobile telephones, pagers, headsets, laptop computers and other mobile terminals, and the like. In a broader sense, user equipment505may also be understood as a general wireless device or any device equipped with a radio interface and even small base stations capable of receiving signals in downlink, sensors, relays, etc. fall into this category and thus covered by the current invention. Dynamic Control of the Set of Active Antenna Ports for Physical Signal Transmissions For backward-compatibility reasons, CRS cannot be turned off completely in a subframe103,401as illustrated inFIGS.1and4. For example, the 3GPP standard requires that for RSRP determination, the CRS R0, i.e. CRS on antenna port 0, shall be used, meaning that CRS has to always be transmitted at least from antenna port 0. If the user equipment505can reliably detect that R1, i.e. CRS on antenna port 1, is available, the user equipment505can use R1in addition to R0to determine RSRP. Some methods exist for signaling the antenna information, but they are not dynamic and flexible enough to support the operation of heterogeneous network as explained above. In accordance with embodiments herein, the set of active antenna ports may be activated/deactivated dynamically to control the RS interference. In a specific example, a reduced set of active antenna ports is associated with low-interference subframes, which are used to improve performance of some user equipments, to minimize or avoid RS interference from the strongly interfering cells. The strongly interfering cells may be defined by their absolute or relative, e.g. with respect to the serving cell, signal strength. The cells or base stations may also be sometimes classified as strong interferers when they are associated to base station503of a higher power class, e.g. macro cells may be viewed in this way as stronger interferers compared to pico cells Low-interference subframes, seen from the perspective of the user equipment505, imply a reduced level of received interference. A reduced level of interference may be achieved by e.g. scheduling less user equipments on data channels. A similar effect may be achieved by configuring positioning subframes or empty Multimedia Broadcast/Multicast Service (MBSFN) Single Frequency Network (MBSFN) subframes, without transmitting broadcast data. Further, the interference in the network is improved by including the times corresponding to such subframes. The reduced level of received interface may also be achieved by using Almost Blank Subframes (ABS). ABS may be defined as subframes with reduced transmission power and/or activity. Low-interference subframes may be associated with a time with specific interference conditions. In relation to antenna ports associated with low-interference subframes, it should be noted this refers to antenna ports seen by the receiver side that face different interference. Thus, the transmitter does not face any interference. Embodiments of a suitable method will now be described with reference to the combined signaling diagram and flowchart depicted inFIG.6and with reference toFIG.5illustrating embodiments of a communication network500. The method comprises at least some of the following steps, which steps may as well be carried out in another suitable order than described below. Step601 The base station503determines the time when the RS transmissions have to be performed from fewer antenna ports, i.e. when reduced or low interference is desired. The time is associated with low-interference, i.e. low-interference subframes. A subframe may represent a time interval or time period Step602 The base station503determines the set of cells where the reduced set of antenna ports shall apply. Step603 The base station503determines the reduced set of antenna ports in at least one cell from the set determined in step602. The fewer antenna ports may comprise a subset of an original set of antenna ports. Step604 In some embodiments, the base station503informs the user equipment505about a temporary change of the set of active antenna ports and (optionally) about a time interval during which the reduced set of antenna ports shall apply. In other words, the base station503may or may not inform the user equipment505about the time interval. Step605 The base station503transmits the RS from the reduced set of antenna ports. Step606 In some embodiments, the user equipment505performs measurements and reporting in the reduced set of antenna ports. Step607 The base station503re-initiates or restores the RS transmissions from the original set of antenna ports. Step608 The base station503informs the user equipment505about the restored RS transmissions. Those steps need not to be carried out in the exact order listed above and some steps may be omitted. The steps are described in more detail below, and each step description corresponds to a respective set of separate embodiments. The embodiments may also be combined. Step601: Determining the Time when the RS Transmissions have to be Performed from a Fewer Antenna Ports The switch time to a reduced set of active antenna ports, i.e. the switch time to the temporary change, may occur in accordance to a signaled pattern, or periodically or by a trigger. A signaled pattern may be the same as the pattern of low-interference subframes or almost blank subframes intended to improve the interference situation for user equipment505that may otherwise potentially have poor performance. A trigger for the temporary change may be based, for example, on a determined indication that the interference from a certain cell, e.g., cell 1, causes unacceptable performance degradation in some area of another cell, e.g., cell 2. The indication may be deduced from a measurement, such as signal quality measurements in cell 2 in that area, and where the indication may be communicated by cell 2 to cell 1 via the X2 interface. In one embodiment, the indication in cell 1 is received from a network node, e.g., an Operations & Maintenance (O&M) node (not shown), which collects different measurements from different cells. In another embodiment, the indication in cell 1 is deduced by cell 1 itself based on the available measurements. Step602: Determining the set of cells where the reduced set of antenna ports shall apply Below are possible options for deciding the cells where the set of active antenna ports may be reduced, i.e. the temporary change of active antenna ports:a. The set of active antenna ports may be changed in all cells in the network500, orb. The set of active antenna ports may be changed in all macro cells105, orc. The set of active antenna ports may be changed in cells with given overlapping RS patterns, e.g., corresponding to a certain frequency shift, ord. The set of active antenna ports may be changed in macro cells with RS patterns overlapping with the RS pattern of a lower-power node in its proximity, ore. The reduced set of active antenna ports may be pre-configured by the operator in the selected cells or configured by O&M. Step603: Determining the Reduced Set of Antenna Ports in at Least One Cell in the Network In an example, the number of CRS antenna ports is reduced from 2 or larger to 1 antenna port, which means increasing the effective reuse factor, or non-overlapping frequency shifts, from 3 to 6. The set of active antenna ports is configured to avoid interference from at least one strong interferer. In one example, macro cells may be considered as strong interferers compared to pico cells. In another example, CSG femto cells may be considered as strong interferers e.g. compared to pico or macro cells. In one embodiment, antenna port 0 shall always be included in the set of active antenna ports e.g. when the reference signals are CRS and CRS transmissions are required from at least the antenna port 0, but this may be not necessarily in other embodiments of the present solution. In another embodiment, the set of active antenna ports in one layer of nodes, e.g., macro layer, is chosen to avoid the overlap with patterns reserved for another layer, e.g., pico node. More details on the reserved patterns are provided below. In yet another embodiment, the set of active antenna ports is decided depending on the CRS transmission pattern and/or the set of active antenna ports in the interfering neighbor cell, the information on the active set of antenna ports may be exchanged among the neighbor cells over the X2 interface. Step604: Informing the UE about the Temporary Change of the Set of Active Antenna Ports and (Optionally) about the Time Periods During which the Reduced Set of Antenna Ports Apply At least two ways of acquiring this information by the user equipment505are envisioned: the information is pre-determined and known to the user equipment505(a) or it is signaled by the network to the user equipment505(b). (a) The pre-determined information may comprise:The reduced set of antenna ports.The periodicity of time intervals when the reduced set of antenna ports applies.The consecutive time interval when the reduced set of antenna ports applies.The configured bandwidth where the reduced set of active antenna ports applies. An indication whether it applies to the control region only. (b) Information signaled to the user equipment505:An indication that a pre-defined reduced set may be used during a pre-defined interval with a pre-defined periodicity, or At least some part of the information described in604(a) For example, only the number of antenna ports in the reduced set may be signaled, if desired. The signaled information may be by nature user equipment-specific, e.g. user equipments505in a challenging area, or cell-specific and thus broadcast, e.g., via one or more suitable information elements in one or more suitable SIBs. (c) In another embodiment, the user equipment behavior is such that the user equipment505may assume that the pre-defined, pre-configured or the signaled reduced set configuration applies starting with the low-interference or almost blank subframes about which the user equipment505has the information. Some examples of such information may be the received by the user equipment Almost Blank Subframes (ABS) pattern(s), defined as subframes with reduced transmission power and/or activity, and a measurement pattern signaled over RRC by the serving base station. Another example is a positioning subframe configuration signaled by the network to facilitate positioning. The information about the set of active antenna ports in such subframes may thus be signaled together with the low-interference subframe or almost blank subframe configuration. Step605: Transmitting the RS from the Reduced Set of Antenna Ports(a) The transmitting the RS from the reduced set of antenna ports may be periodic.(b) The pre-defined or pre-configured or dynamically configured reduced set of active antenna ports in a cell is invoked by an event, e.g., triggering together low-interference subframes. Step606: Measuring and Reporting in the Reduced Set of Antenna Ports Some user equipments505may conduct some measurements only during the time when the RS are transmitted from the reduced set of antenna ports and the other user equipments (not shown) may not use these subframes for measurements, e.g., when these user equipments505are scheduled in such subframes with a low probability. The conducted measurements may also be reported to the network or be used internally in the user equipment505. Such measurement coordination may be an advantage, for example, when high interference is expected in some subframes so that some user equipments505connected to pico cells501a may not able to perform measurements in these subframes. Step607: Restoring the RS Transmissions from the Original Set of Antenna Ports in the Cell(a) The restoring may be performed by a stop-trigger, or(b) The restoring may be performed after the configured interval is over, or(c) The restoring may be performed associated with the end of low-interference subframes. Step608: Informing the User Equipment505about the Restored RS Transmissions(a) The user equipment505behavior may be such that the user equipment505may assume that the cell switches to the original antenna port configuration for RS in the end of low-interference subframes so the decision is made by the user equipment505autonomously, or(b) An indicator may be sent to user equipments505, e.g., by broadcast via a suitable SIB in the cell, that the original set of antenna ports will be restored. Time-Frequency Resources where the Reduced Set of Active Antenna 5 Ports can Apply: FIGS.7a-cillustrates an example of a reduced set of active antenna ports. The hatched regions illustrate a control region. The squares illustrate CRS reference signals for antenna port 0 and the circles illustrates CRS reference signal for antenna port 1. The reduced set of active antenna ports apply in the following scenarios:(1) Within the entire resource block, one subframe in time, over the system bandwidth or a configured bandwidth, which may be smaller than the system bandwidth, as illustrated inFIG.7a, or(2) Within the control region of the subframe over the system bandwidth or a configured bandwidth, which may be smaller than the system bandwidth, as illustrated inFIG.7b, or(3) Within a subset of subcarriers and/or a subset of symbols of each resource block within a given subframe and over the system bandwidth or a configured bandwidth, which can be smaller than the system bandwidth, as illustrated inFIG.7c.(a) An example of using fewer transmit antenna ports in a part of the subframe is when that part collides with, for example, synchronization signals in other cells in a asynchronous network, where such blanking can be pre-determined for a given synchronization requirement which would in turn also pre-determine the user equipment measurement behavior.(b) In one embodiment (not compliant with Release 8), the active set of antenna ports is chosen based on the number of allowed for transmission subcarriers. RS Transmit Power With more than one active antenna ports, a cell has a possibility to boost the CRS power by 3 dB by just reusing the power from the resource elements, also referred to as REs, where another CRS is transmitted from another antenna. By configuring one antenna port, the CRS Energy Per Resource Element (EPRE) in the cell is more likely to be at the level assuming the constant EPRE across the transmission bandwidth, which may be viewed as a way to control the CRS EPRE and thus keep the CRS interference from the given cell at a lower level. The method described above will now be described seen from the perspective of the base station503.FIG.8is a flowchart describing the present method in the base station503for enabling interference coordination in a communication network500. The base station503comprises a plurality of antenna ports. Each antenna port is configured to transmit a reference signal. The reference signals are not specifically transmitted to any user equipment505, even though the user equipment505may receive some assistance in other scenarios. The signaling of the reference signal to a user equipment is not dedicated signal. The reference signal may be received by a plurality of user equipments505. Each antenna port is associated with a respective cell101,105. In some embodiments, a plurality of antenna ports is associated with each respective cell101,105. In some embodiments, the interference coordination is implemented with respect to a high interference area of a cell. The method comprises the steps to be performed by the base station503: Step801 This step corresponds to step601inFIG.6. In some embodiments, the base station503determines a time when the reference signal is to be transmitted from a reduced set of antenna ports. The time is associated with low interference, i.e. low interference subframes. The reference signal is transmitted from the subset of the antenna ports to the user equipment505at the determined time. Step802 In some embodiments, the base station503informs the user equipment505about the determined time. Step803 This step corresponds to step602inFIG.6. The base station503determines a set of cells101,105where transmissions of reference signals is to be performed from a reduced set of the plurality of antenna ports. In some embodiments, the determined subset of antenna ports is configured to avoid interference from an interfering cell101,105or reduce interference to another cell501. Step804 This step corresponds to step603inFIG.6. The base station503determines a subset of antenna ports in at least one cell501of the determined set of cells101,105. The subset of antenna ports is associated with low interference, i.e. low interference subframes. In some embodiments, the subset of antenna ports is pre-configured. In some embodiments, at least one of: the determined time and information of the subset of antenna ports, is obtained from a network node (not shown) in the communication network (500). The network node may be a base station different from the base station503, i.e. via X2. The network node may be e.g. a radio network node (BS) or another network node such as O&M node. Step805 This step corresponds to step604inFIG.6. In some embodiments, the base station503informs the user equipment505about the subset of antenna ports. Step806 This step corresponds to step604inFIG.6. In some embodiments, the base station503determines a time interval during which the subset set of antenna ports shall apply. Step807 This step corresponds to step604inFIG.6. In some embodiments, the base station503informs the user equipment505about the time interval. Step808 This step corresponds to step605inFIG.6. The base station503transmits the reference signal from the subset of antenna ports associated with low interference, i.e. low interference subframes, enabling interference coordination in the communication network500. In some embodiments, the reference signal is transmitted to the user equipment505. In some embodiments, the transmissions from the reduced set of antenna ports apply to a part of system bandwidth. In some embodiments, the transmissions from the reduced set of antenna ports in a cell101,105are periodic or invoked by an event. In some embodiments, the signaling from the base station503is not dedicated to a specific user equipment505, but may be transmitted to a plurality of user equipments505in the communication network500, e.g., the signaling may be cell-specific and transmitted over the cell area, and thus potentially may be used by any user equipment505performing measurements on that cell. In some embodiments, the signaling from the base station503is dedicated to a specific user equipment505. Step809 This step corresponds to step607inFIG.6. In some embodiments, the base station503re-initiates the reference signal transmissions from the plurality of antenna ports. Step810 This step corresponds to step607inFIG.6. In some embodiments, the base station503informs the user equipment505about the re-initiated reference signal transmissions. Step811 This step corresponds to step606inFIG.6. In some embodiments, the base station503receives measurements from the user equipment505. To perform the method steps shown inFIG.8for enabling interference coordination in the communication network500. The base station503comprises a base station arrangement as shown inFIG.9. The base station503comprises a plurality of antenna ports. Each antenna port is configured to transmit a reference signal. Each antenna port is associated with a respective cell101,105. In some embodiments, the interference coordination is implemented with respect to a high interference area of a cell. The base station503further comprises a processor901which is configured to determine a set of cells101,105where transmissions of reference signals is to be performed from a reduced set of the plurality of antenna ports. The processor901is further configured to determine a subset of antenna ports in at least one cell101,105of the determined set of cells101,105. In some embodiments, the determined subset of antenna ports is configured to avoid interference from an interfering cell101,105or from another cell501. In some embodiments, the subset of antenna ports is pre-configured. The base station503further comprises a transmitter1800configured to transmit the reference signal from the subset of antenna ports associated with low interference, i.e. low interference subframes, enabling interference coordination in the communication network500. The transmitter1800is described in more detail in relation toFIG.18below. In some embodiments, the transmissions from the reduced set of antenna ports apply to a part of system bandwidth. And, in some embodiments the transmissions from the reduced set of antenna ports in a cell101,105are periodic or invoked by an event. In some embodiments, the processor901is further configured to determine a time when the reference signal is to be transmitted from a reduced set of antenna ports. The time is associated with low interference, i.e. low interference subframes. The reference signal is transmitted from the subset of the antenna ports at the determined time. In some embodiments, the processor901is further configured to inform the user equipment505about the determined time, and to inform the user equipment505about the subset of antenna ports. In some embodiments, at least one of the determined time and information of the subset of antenna ports, is obtained from a network node. In some embodiments, the processor901is configured to determine a time interval during which the subset set of antenna ports shall apply, and to inform the user equipment505about the time interval. In some embodiments, the processor901is further configured to re-initiate the reference signal transmissions from the plurality of antenna ports, and to inform the user equipment505about the re-initiated reference signal transmissions. In some embodiments, the processor901is configured to receive measurements from the user equipment505. The method described above will now be described seen from the perspective of the user equipment505.FIG.10is a flowchart describing the present method in the user equipment505. The method comprises the further steps to be performed by the user equipment505: Step1001 This step corresponds to step601inFIG.6. In some embodiments, the user equipment505receives information from the base station503about a time. The time indicates when the reference signal is to be received from a subset of antenna ports. The time is associated with low interference, i.e. low interference subframes. Step1002 This step corresponds to step604inFIG.6. In some embodiments, the user equipment505receives information from the base station503about the subset of antenna ports. In some embodiments, the subset of antenna ports is pre-defined. In some embodiments, the subset of antenna ports is pre-defined for a layer of nodes. Step1003 This step corresponds to step604inFIG.6. In some embodiments, the user equipment505receives information from the base station503about a time interval. The time interval indicates a time period during which the subset set of antenna ports shall apply. In some embodiments, the information about the time interval comprises an indication on whether a subset of antenna ports applies or not in the time associated with low interference subframes, i.e. specific interference conditions, e.g. when only pico cells are transmitting and thus the expected interference is only from pico cells. Step1004 The user equipment505determines whether a reference signal is to be received during specific interference conditions. In other words, the user equipment505determines whether a reference signal is to be received from a subset of antenna ports associated with low interference, i.e. low interference subframes. The subset of antenna ports is comprised in a base station503. The subset of antenna ports is associated with at least one cell501. In some embodiments, the determining whether a reference signal is to be received from a subset of antenna ports is based on at least one of a reference signal pattern and a set of active antenna ports in an interfering neighbour cell501. The antenna port information is exchanged over the X2 interface. The set of active antenna ports is determined depending on the CRS transmission pattern and/or the set of active antenna ports in the interfering neighbour cell. In other words, the information of the active set of antenna ports can be exchanged among the neighbour cells over the X2 interface. Step1005 This step corresponds to step605inFIG.6. The user equipment505receives a reference signal from the subset of antenna ports. The subset of antenna ports is comprised in a base station503. In some embodiments, the reference signal is received from the subset of the antenna ports at the time. Step1006 This step corresponds to step607inFIG.6. In some embodiments, the user equipment505receives information from the base station503about re-initiated reference signal transmissions. Step1007 This step corresponds to step606inFIG.6. In some embodiments, the user equipment505performs measurements on the subset of antenna ports. Step1008 This step corresponds to step606inFIG.6. In some embodiments, the user equipment505transmits the measurements to the base station503. To perform the method steps shown inFIG.10the user equipment505comprises a user equipment arrangement as shown inFIG.11andFIG.19. The user equipment505comprises a processor1916which is configured to receive a reference signal from a subset of antenna ports. The subset of antenna ports is comprised in a base station503. In some embodiments, the subset of antenna ports is pre-defined, and in some embodiments the subset of antenna ports is pre-defined for a layer of nodes. The processor1916is further configured to determine whether the reference signal is to be received from a subset of antenna ports being comprised in a base station503. The subset of antenna ports is associated with at least one cell501. The user equipment arrangement is further described in relation toFIG.19below. In some embodiments, the processor1916is further configured to receive information from the base station503about a time. The time indicates when the reference signal is to be received from a subset of antenna ports, and the time is associated with low interference, i.e. low interference subframes. In some embodiments, the reference signal is received from the subset of the antenna ports at the time. In some embodiments, the processor1916is further configured to receive information from the base station503about the subset of antenna ports. In some embodiments, the processor1916is further configured to receive information from the base station503about a time interval. The time interval indicates a time period during which the subset set of antenna ports shall apply. In some embodiments, the information about the time interval comprises an indication on whether a subset of antenna ports applies or not in the time associated with low interference subframes, i.e. associated with specific interference conditions. In some embodiments, the processor1916is further configured to receive information from the base station503about re-initiated reference signal transmissions. In some embodiments, the processor1916is further configured to perform measurements on the subset of antenna ports. In some embodiments, the antenna1902is further configured to transmit the measurements to the base station503. Method and Apparatus for Assisted User Equipment Measurement Processing The user equipment505receives the assistance information from the network about the strongest interferer(s) and, based on this information, the user equipment505selects the desired number of the most critical interferers and use the information to improve the control channel decoding, CRS measurements, channel estimation, e.g., by not including the unreliable part of the channel information, etc. The assistance data may comprise one or more of:A set of PCIs (Physical Cell Identifier), based on which the user equipment505can, for example, determine the RS pattern.Transmit bandwidth of the interferers.Channel-related information or the information based on which the channel information may be deduced, e.g., exploit the channel reciprocity in TDD.Number of antenna ports. The assistance information may be signaled together with the configuration of the low transmission activity pattern determining when low-interference subframes or almost blank subframes occur. The assistance data may be tailored specifically for heterogeneous networks, e.g., includes the information for specific layer nodes, e.g., about only the cells with higher transmit power than the current one or only the CSG cells. The assistance data are typically transmitted to a certain user equipment505. That user equipment505is connected to the network500and is assigned to a certain cell, which is then the serving cell. In one embodiment, the assistance data is signaled by the serving cell which in turn either autonomously obtains this information, e.g., based on collected measurements or from the O&M, or receives this information from another node, e.g., the interfering macro cell “identifies” itself via the X2-interface to the pico cells501a located in the range of that macro cell501b coverage. In another embodiment, the assistance data is transmitted to the user equipment505to assist in its operation in the identified specifically challenging interference conditions and may thus be triggered when such a condition is detected. E.g. when the user equipment505enters a Closed Group Subscriber (CSG) cell coverage area but cannot connect to the cell the macro cell501b can signal the assistance information to the user equipment505which includes also the identity of the Home eNB (HeNB). The Home NodeB is the base station503of the CSG cell. CSG is called “Closed subscriber group” because even if the user equipment505can detect a strong signal, and good signal quality, for that cell, the user equipment505cannot connect to it, i.e. “Closed . . . ”. This leaves 5 the macro cell501b being the serving cell for that user equipment505. In yet another embodiment, the assistance data is extracted by the user equipment505autonomously from a special-purpose assistance data signaled by the network500, e.g.:From the OTDOA positioning assistance data which the user equipment505may receive being positioned or may request from the network by sending a positioning request which may indicate a preferred positioning method, e.g., Observed Time Difference of Arrival (OTDOA), for which the assistance data of interest may be expected.From the mobility lists comprising at least the identities of neighbor cells, which in most cases will be also the strongest interferers. Methods and apparatus for assisted user equipment measurement processing will now be described with reference to the flowchart depicted inFIG.12. The methods and apparatus are configured to implement at least the following: Step1201 The user equipment505identifies the set of strongest interferers, using one of the approaches described above. Step1202 The user equipment505decides the set of the most crucial interferers, i.e., the set may be smaller than that obtained in Step1201due to, for example, user equipment505capability. The decision may also account for efficient cell grouping, and identifying deriving the set of the time-frequency resources affected by these interferers by utilizing the knowledge of the RS transmit pattern. Step1203 The user equipment performs puncturing on the identified time-frequency resources when measuring the signal in the user equipment505side. In more detail, puncturing of time-frequency resources is equivalent to excluding the identified time-frequency resources or setting the weights on the identified time-frequency resources to zero when performing measurements. The method described above for assisted user equipment measurement processing will now be described seen from the perspective of the user equipment505. The method in the user equipment may be transparent to the network, and will enable interference mitigation in the communication network500. The user equipment505is associated with a cell501of a plurality of cells in a communication network500.FIG.13is a flowchart describing the present method in the user equipment505. The method comprises the steps to be performed by the user equipment505: Step1301 This step corresponds to step1201inFIG.12. The user equipment505acquires information about a set of interfering cells501among the plurality cells501. The set of interfering cells are strong interferes. The acquiring of information may be performed by extracting, see step1302, or receiving the information. In some embodiments, each cell in the set of interfering cells is associated with a strong interfering signal, which strong interfering signal has a signal strength above a threshold. In some embodiments, the information about interfering cells501comprises assistance data. In some embodiments, the assistance data comprises at least one of a set of physical layer cell identities, a transmit bandwidth of an interfering cell501, channel-related information and a number of antenna ports. In some embodiments, the information about interfering cells501is acquired, i.e. received, from a serving cell or a network node (not shown) within the communication network500. The network node may be a radio network node and non-radio network nodes, e.g., a positioning node or other coordinating node. For the sake of simplicity, only radio network nodes are shown inFIG.5. For example, OTDOA assistance data may be received from a network node which is not a radio node, but for example a positioning node in the core network. Ultimately in the physical layer, the data are of transmitted by the radio base station over the radio link to the user equipment505, but the information is transmitted over a higher-layer protocol which is between the positioning node and user equipment505and the transmitted data are then transparent to the radio base station. In another example, the information may be transmitted by the serving or other radio base station, and in this case it any radio network node503. In some embodiments, the set of interfering cells501is a subset of the set of interfering cells. The subset of cells may be based on at least one of: user equipment capability, cell grouping, a desired number of most critical interfering cells to account for puncturing, and impact on an interference level. Step1302 This step corresponds to step1201inFIG.12. In some embodiments, the user equipment505autonomously extracts the assistance data from the acquired information. Step1303 This step corresponds to step1203inFIG.12. The user equipment505identifies a set of time-frequency resources affected by the subset of interfering cells501. In some embodiments, the identifying a set of time-frequency resources is based on a reference signal transmit pattern. Step1304 This step corresponds to step1203inFIG.12. The user equipment505performs puncturing on the identified time-frequency resources. In more detail, Puncturing of time-frequency resources is equivalent to excluding the identified time-frequency resources or setting the identified time-frequency resources to zero. To perform the method steps shown inFIG.13for assisted user equipment measurement processing, the user equipment505comprises a user equipment arrangement as shown inFIG.11andFIG.19. The user equipment505is associated with a cell501of a plurality of cells501in a communication network500. The user equipment505comprises a processor1916configured to acquire, i.e. extract or receive, information about a set of interfering cells501among the plurality of cells501. In some embodiments, the information about interfering cells501is received from a serving cell or a network node within the communication network500. In some embodiments, the set of interfering cells501is a subset of the set of interfering cells, which subset of cells is based on at least one of: user equipment capability, cell grouping, a desired number of most critical interfering cells to account for puncturing, and an impact on an interference level. The processor1916is further configured to identify a set of time-frequency resources affected by the set of interfering cells501, and to perform puncturing on the identified time-frequency resources. In some embodiments, the identifying a set of time-frequency resources is based on a reference signal transmit pattern. In some embodiments, the assistance data comprises at least one of a set of physical layer cell identities, a transmit bandwidth of an interfering cell501, channel-related information and a number of antenna ports. In some embodiments, the processor1916is further configured to autonomously extracting the assistance data from the acquired information. The method described above for assisted user equipment measurement processing which enables interference coordination in a communication network500will now be described seen from the perspective of the network node503. The network node503is associated with a cell501. The network node503comprises information about a set of interfering cells101,105.FIG.14is a flowchart describing the present method in the network node503. The method comprises the steps to be performed by the network node503: Step1401 This step corresponds to step1201inFIG.12. The network node503acquires information about a set of interfering cells501among the plurality cells501. The set of interfering cells are strong interferes. The acquiring of information may be performed by extracting, or receiving the information. In some embodiments, the information about interfering cells501comprises assistance data. In some embodiments, the assistance data comprises at least one of a set of physical layer cell identities, a transmit bandwidth of an interfering cell501, channel-related information and a number of antenna ports. In some embodiments, the information about interfering cells501is acquired, i.e. received, from a serving cell or another network node (not shown) within the communication network500. In some embodiments, the set of interfering cells501is a subset of the set of interfering cells, which subset of cells is based on at least one of: user equipment capability, cell grouping, a desired number of most critical interfering cells to account for puncturing, and an impact on an interference level. In some embodiments, each cell in the set of interfering cells is associated with a strong interfering signal, which strong interfering signal has a signal strength above a threshold. Step1402 This step corresponds to step1201inFIG.12. The network node503transmits information about a set of interfering cells501among a plurality of cells501to a user equipment505. The set of interfering cells501are strong interferers, enabling interference coordination in the communication network500. In some embodiments, the information about interfering cells501comprises assistance data. In some embodiments, the assistance data comprises at least one of a set of physical layer cell identities, a transmit bandwidth of an interfering cell501, channel-related information and a number of antenna ports. In some embodiments, the network node503is associated with an interfering macro cell501b. In some embodiments, the transmitting information about the set of interfering cells is triggered upon detecting challenging interference conditions for the user equipment505in the communication network500. To perform the method steps shown inFIG.14for enabling interference coordination in a communication network500the network node503comprises a network node arrangement as shown inFIG.15. The network node503is associated with a cell501. The network node503comprises information about a set of interfering cells101,105. The network node503comprises a processor1501configured to acquire information about a set of interfering cells501among a plurality cells501. Further, the network node comprises one or more antennas1902configured to transmit1201the information about the set of interfering cells501among a plurality cells501to a user equipment505. The transmitted information is based on the acquired information. The set of interfering cells501are strong interferers, enabling interference coordination in the communication network500. In some embodiments, the information about interfering cells501comprises assistance data. In some embodiments, the network node503is associated with an interfering macro cell501b. In some embodiments, the one or more antenna(s)1902are further configured to transmit the information about the set of interfering cells to the user equipment505when challenging interference conditions for the user equipment505are detected in the communication network500. The challenging interference conditions may, for example, comprise a received signal quality level below a certain threshold reported by the user equipment505, radio link failure statistics for that user equipment505, or low signal quality expected for the user equipment505based on the network knowledge about the serving cell and interfering neighbor cells for that user equipment505, which may also be complemented with the knowledge about the expected relative received signal strengths of these cells for the user equipment505. The present mechanism for enabling interference coordination in the communication network500may be implemented through one or more processors, such as a processor1501depicted inFIG.15, together with computer program code for performing the functions of the present solution. Methods and Apparatus for Enhanced Cell Planning Adopted for Heterogeneous Network Deployments In accordance with embodiments herein, a subset of RS patterns, e.g., a subset of 6 possible frequency shifts for CRS, is reserved for at least one layer of node, e.g., low-power nodes, and this information is used for deciding the active set of antenna ports. With such a reservation, the macro-cell CRS interference to CRS of low-power nodes may be avoided. The signal patterns comprise one or more pattern identities. In one embodiment, the low-power node fetches, i.e. requests, the reserved pattern identity, or alternatively, own PCI, from the macro network, e.g., from O&M, which signals this information in reply. This can be done by a newly installed low-power node which “joins” the network500. In a scenario with sparsely located low-power nodes, the reserved set comprises one RS pattern. But in general, the set of available reserved pattern identities is dynamically maintained by the network500, e.g., the hosting macro cell, and it depends on the pattern in use in the area. Using the reserved set of patterns for one layer, e.g., pico nodes, in combination with almost blank subframes, i.e. no control and/or data transmissions, allows to completely avoid CRS interference between the layers when the reserved patterns for one layer are orthogonal to those used by the other-layer nodes. In one embodiment, the reserved set of patterns is designed accounting for the set of active antenna ports to be used by the other layer in low-interference or almost blank subframes. For example:If the set of active antenna ports is empty, which may be possible in future 3GPP Releases, for the macro layer in some area, then all patterns may be reused by the other layer of nodes in the same area.If one antenna port is to be used by the macro layer, e.g., the set of active antenna ports comprises one antenna port, then the effective CRS pattern reuse is six, so one or two patterns, or even more, depending on the low-power node density, can be reserved for the other layer.If two to four antenna ports are to be used by the macro layer, then the effective CRS pattern reuse is three, so one pattern could then be reserved for the other layer leaving two orthogonal patterns to the macro layer. It is straightforward that such a reservation scheme can be designed for any number of layers of nodes in the network. The method described above for enhanced cell planning adopted for heterogeneous network deployments which enables interference coordination in a communication network500will now be described seen from the perspective of the network node503. The network node503comprises a plurality of antenna ports. Each antenna port is configured to transmit a reference signal according to a signal pattern. The transmission of the reference signal is non-dedicated, i.e. it may be received by a plurality of user equipments505.FIG.16is a flowchart describing the present method in the network node503. The method comprises the steps to be performed by the network node503: Step1601 In some embodiments, the network node503reserves a subset of signal patterns for at least one layer of network node503. The subset of signal patterns is reserved from a plurality of signal patterns or indications to signal patterns, and the subset of signal patterns is associated with low interference subframes. In some embodiments, subset of signal patterns is reserved for a group of cells or a group of network nodes503. The person skilled in the art can recognize that a set of cells is associated with a radio network node, and a set of cells comprises at least one cell. In some embodiments, the group network nodes503belong to a layer. In some embodiments, the reserved subset of signal patterns is dynamically maintained by the communication network500. In some embodiments, the reserved subset of signal pattern is designed accounting for the set of active antenna ports to be used by another layer in low-interference or blank sub frames. In some embodiments, the blank sub frames are almost blank sub frames. Step1602 The network node503decides an active set of antenna ports from the plurality of antenna ports based on a reserved subset of signal pattern or indications to signal patterns associated with at least one layer of network node. The subset of signal patterns is associated with low interference subframes and reserved from the plurality of signal patterns or indications to signal patterns. In some embodiments, the deciding and active set of antenna ports is further based on low interference subframes. Low interference subframes is associated with time periods with reduced interference. Step1603 The network node503transmits reference signals from the decided active set of antenna ports to a user equipment505according to the reserved subset of signal pattern, enabling interference coordination in the communication network500. The transmission of the signal reference signal is non-dedicated, i.e. it may be received by a plurality of user equipments505. To perform the method steps shown inFIG.16for enabling interference coordination in a communication network500, the network node503comprises a network node arrangement as shown inFIG.17. The network node503comprises a plurality of antenna ports. Each antenna port is configured to transmit a reference signal according to a signal pattern. The network node503comprises a processor1701configured to decide an active set of antenna ports from the plurality of antenna ports based on a reserved subset of signal patterns associated with at least one layer of network node503. In some embodiments, the plurality of signal patterns comprises one or more pattern identities. The subset of signal patterns associated with low interference subframes and reserved from a plurality of signal patterns or indications to signal patterns. The network node503further comprises a transmitter1800configured to transmit reference signals from the decided active set of antenna ports to a user equipment505according to the reserved subset of signal pattern, enabling interference coordination in the communication network500. The transmission of the signal reference signal is non-dedicated, i.e. it may be received by a plurality of user equipments505. In some embodiments, the deciding an active set of antenna ports is further based on blank sub frames. In some embodiments, the blank sub frames are almost blank sub frames. In some embodiments, the processor1701is further configured to reserve a subset of signal patterns for at least one layer of network node503. The subset of signal patterns is reserved from the plurality of signal patterns, and the subset of signal patterns is associated with low interference subframes. In some embodiments, the subset of signal patterns is reserved for a group of network nodes503. In some embodiments, the group network nodes503belong to a layer. In some embodiments, the plurality of signal patterns or indications to signal patterns is pre-configured in the network node, configured based on the information received from a second network node within the communication network or configured based on the information obtained from a macro cell501b associated with a base station503. In some embodiments, the reserved subset of signal patterns is dynamically maintained by the communication network500. In some embodiments, the reserved subset of signal pattern is designed accounting for the set of active antenna ports to be used by another layer in low-interference or almost blank sub frames. As described above, methods and apparatus in accordance with embodiments herein implement one or more of the following aspects:Facilitate control of the set of active antenna ports used for RS transmissions in order to reduce the RS interference.Including the signaling and the interfaces that may be involved in the method.Assisted UE measurement processing.Including the signaling and the interfaces that may be involved in the method.Enhanced cell planning adopted for heterogeneous network deployments. Such methods and apparatus have at least the following technical advantages:Reduced CRS interference in the control region, on CRS, and data channels leading to the improved system performance and in particular in heterogeneous deployments.Facilitating UE measurements with some of the disclosed methods by introducing the new signaling reducing the UE complexity.Reduced over-estimation of the radio channel quality for legacy macro UEs, which may include low-interference subframes in the interference measurements, although they will only be scheduled in subframes with potentially much higher interference.Enhanced cell planning aiming at the improved performance with heterogeneous deployments. FIG.18is a block diagram of an example of a portion of transmitter1800for a communication system that uses the signals described above, i.e. the reference signals. The transmitter1900may be comprised in e.g. a base station503, a network node503etc. As known for a skilled person, a communication system is equivalent to a communication network500. Several parts of such a transmitter1800are known and described for example in Clauses 6.3 and 6.4 of 3GPP TS 36.211. Reference signals having symbols are described above are produced by a suitable generator1802and provided to a modulation mapper1804that produces complex-valued modulation symbols. A layer mapper1806maps the modulation symbols onto one or more transmission layers, which generally correspond to antenna ports as described above. An Resource Element (RE) mapper1808maps the modulation symbols for each antenna port onto respective Res1808, and an OFDM signal generator1810produces one or more complex-valued time-domain OFDM signals for eventual transmission. It will be appreciated that the functional blocks depicted inFIG.18can be combined and re-arranged in a variety of equivalent ways, and that many of the functions can be performed by one or more suitably programmed digital signal processors, such as the processor901illustrated inFIG.9, processor1501illustrated inFIG.15and the processor1701illustrated inFIG.17. Moreover, connections among and information provided or exchanged by the functional blocks depicted inFIG.18can be altered in various ways to enable a device to implement the methods described above and other methods involved in the operation of the device in a digital communication system. FIG.19is a block diagram of an arrangement1900in a user equipment505that may implement the methods described above. It will be appreciated that the functional blocks depicted inFIG.19can be combined and re-arranged in a variety of equivalent ways, and that many of the functions can be performed by one or more suitably programmed digital signal processors, such as processor1916illustrated inFIG.11and processor1916illustrated inFIG.19. Moreover, connections among and information provided or exchanged by the functional blocks depicted inFIG.19can be altered in various ways to enable a user equipment505to implement other methods involved in the operation of the user equipment505. As depicted inFIG.19, a user equipment505receives a downlink (DL) radio signal through an antenna1902and typically down-converts the received radio signal to an analog baseband signal in a front end receiver (Fe RX)1904. The baseband signal is spectrally shaped by an analog filter1906that has a bandwidth BW0, and the shaped baseband signal generated by the filter1906is converted from analog to digital form by an analog-to-digital converter (ADC)1908. The digitized baseband signal is further spectrally shaped by a digital filter1910that has a bandwidth BWsync, which corresponds to the bandwidth of synchronization signals or symbols included in the DL signal. The shaped signal generated by the filter1910is provided to a cell search unit1912that carries out one or more methods of searching for cells as specified for the particular communication system, e.g., 3G LTE. Typically, such methods involve detecting predetermined primary and/or secondary synchronization channel (P/S-SCH) signals in the received signal. The digitized baseband signal is also provided by the ADC1908to a digital filter1914that has the bandwidth BM, and the filtered digital baseband signal is provided to a processor1916that implements a fast Fourier transform (FFT) or other suitable algorithm that generates a frequency-domain (spectral) representation of the baseband signal. A channel estimation unit1918receives signals from the processor1916and generates a channel estimate Hi,jfor each of several subcarriers i and cells j based on control and timing signals provided by a control unit1920, which also provides such control and timing information to the processor1916. The estimator1918provides the channel estimates Hito a decoder1922and a signal power estimation unit1924. The decoder1922, which also receives signals from the processor1916, is suitably configured to extract information from RRC or other messages as described above and typically generates signals subject to further processing in the UE505(not shown). The estimator1924generates received signal power measurements, e.g., estimates of reference signal received power (RSRP), received subcarrier power S, signal to interference ratio (SIR), etc. The estimator1924can generate estimates of RSRP, reference signal received quality (RSRQ), received signal strength indicator (RSSI), received subcarrier power Si, SIR, and other relevant measurements, in various ways in response to control signals provided by the control unit1920. Power estimates generated by the estimator1924are typically used in further signal processing in the UE505. The estimator1924(or the searcher1912, for that matter) is configured to include a suitable signal correlator for handling the RS and other signals described above. In the arrangement depicted inFIG.19, the control unit1920keeps track of substantially everything needed to configure the searcher1912, processor1916, estimation unit1918, and estimator1924. For the estimation unit1918, this includes both method and cell identity, for reference signal extraction and cell-specific scrambling of reference signals. Communication between the searcher1912and the control unit1920includes cell identity and, for example, cyclic prefix configuration. The control unit1920determines which estimation method is used by the estimator1918and/or by the estimator1924for measurements on the detected cell(s) as described above. In particular, the control unit1920, which typically can include a correlator or implement a correlator function, can receive information signaled by the eNB503and can control the on/off times of the Fe RX2004as described above. The control unit and other blocks of the UE505can be implemented by one or more suitably programmed electronic processors, collections of logic gates, etc. that processes information stored in one or more memories. The stored information can include program instructions and data that enable the control unit to implement the methods described above. It will be appreciated that the control unit typically includes timers, etc. that facilitate its operations. The methods and apparatus described can be implemented in heterogeneous deployments, but they are not limited to them, and neither are they limited to the 3GPP definition of heterogeneous network deployments. For example, the methods and apparatus can be adopted also for traditional macro deployments and/or networks operating more than one radio access technology (RAT). The methods are particularly useful for signals transmitted with a pre-defined time-frequency pattern and a limited set of available patterns, implying high collision probability and thus high interference in certain parts of the spectrum. LTE cell-specific reference signals (CRS) are an example of such signals. It will be appreciated that the methods and devices described above can be combined and re-arranged in a variety of equivalent ways, and that the methods can be performed by one or more suitably programmed or configured digital signal processors and other known electronic circuits, e.g., discrete logic gates interconnected to perform a specialized function, or application-specific integrated circuits. Many aspects of embodiments herein are described in terms of sequences of actions that can be performed by, for example, elements of a programmable computer system. User equipments505embodying embodiments herein include, for example, mobile telephones, pagers, headsets, laptop computers and other mobile terminals, and the like. Moreover, the embodiments herein may additionally be considered to be embodied entirely within any form of computer-readable storage medium having stored therein an appropriate set of instructions for use by or in connection with an instruction-execution system, apparatus, or device, such as a computer-based system, processor-containing system, or other system that can fetch instructions from a medium and execute the instructions. It will be appreciated that procedures described above are carried out repetitively as necessary, for example, to respond to the time-varying nature of communication channels between transmitters and receivers. In addition, it will be understood that the methods and apparatus described here can be implemented in various system nodes. To facilitate understanding, many aspects of embodiments herein are described in terms of sequences of actions that can be performed by, for example, elements of a programmable computer system. It will be recognized that various actions could be performed by specialized circuits, e.g., discrete logic gates interconnected to perform a specialized function or application-specific integrated circuits, by program instructions executed by one or more processors, or by a combination of both. Wireless devices implementing embodiments herein may be included in, for example, mobile telephones, pagers, headsets, laptop computers and other mobile terminals, base stations, and the like. Moreover, the embodiments herein can additionally be considered to be embodied entirely within any form of computer-readable storage medium having stored therein an appropriate set of instructions for use by or in connection with an instruction-execution system, apparatus, or device, such as a computer-based system, processor-containing system, or other system that can fetch instructions from a storage medium and execute the instructions. As used here, a “computer-readable medium” can be any means that can contain, store, or transport the program for use by or in connection with the instruction-execution system, apparatus, or device. The computer-readable medium can be, for example but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device. More specific examples, a non-exhaustive list, of the computer-readable medium include an electrical connection having one or more wires, a portable computer diskette, a random-access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), and an optical fiber. Thus, the embodiments herein maybe embodied in many different forms, not all of which are described above, and all such forms are contemplated to be within the scope of embodiments herein. For each of the various aspects of the embodiments, any such form may be referred to as “logic configured to” perform a described action, or alternatively as “logic that” performs a described action. It should be noted that the word “comprising” does not exclude the presence of other elements or steps than those listed and the words “a” or “an” preceding an element do not exclude the presence of a plurality of such elements. | 64,786 |
RE49805 | Throughout the drawings, like reference numerals will be understood to refer to like parts, components, and structures. DETAILED DESCRIPTION The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of various embodiments of the present disclosure as defined by the claims and their equivalents. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the various embodiments described herein can be made without departing from the scope and spirit of the present disclosure. In addition, descriptions of well-known functions and constructions may be omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the present disclosure. Accordingly, it should be apparent to those skilled in the art that the following description of various embodiments of the present disclosure is provided for illustration purpose only and not for the purpose of limiting the present disclosure as defined by the appended claims and their equivalents. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component surface” includes reference to one or more of such surfaces. Although ordinal numbers such as “first”, “second”, and so forth will be used to describe various components, those components are not limited by the terms. The terms are used only for distinguishing one component from another component. For example, a first component may be referred to as a second component and likewise, a second component may also be referred to as a first component, without departing from the teaching of the inventive concept. The term “and/or” used herein includes any and all combinations of one or more of the associated listed items. The terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting of the embodiments. As used herein, the singular forms are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “has” when used in this specification, specify the presence of a stated feature, number, step, operation, component, element, or a combination thereof but do not preclude the presence or addition of one or more other features, numbers, steps, operations, components, elements, or combinations thereof. The terms used herein, including technical and scientific terms, have the same meanings as terms that are generally understood by those skilled in the art, as long as the terms are not differently defined. It should be understood that terms defined in a generally-used dictionary have meanings coinciding with those of terms in the related technology. As long as the terms are not defined obviously, they are not ideally or excessively analyzed as formal meanings. An embodiment of the present disclosure proposes an apparatus and circuit for processing Carrier Aggregation (CA). An embodiment of the present disclosure proposes an apparatus and circuit for processing CA using a reference Component Carrier (CC). An embodiment of the present disclosure proposes an apparatus and circuit for processing CA using one reference clock. An embodiment of the present disclosure proposes an apparatus and circuit for processing CA by considering a deployment scenario for various CCs. An apparatus and method proposed in an embodiment of the present disclosure may be applied to various mobile communication systems such as a Long Term Evolution (LTE) mobile communication system, a Long Term Evolution-Advanced (LTE-A) mobile communication system, a High Speed Downlink Packet Access (HSDPA) mobile communication system, a High Speed Uplink Packet Access (HSUPA) mobile communication system, a High Rate Packet Data (HRPD) mobile communication system proposed in a 3rdGeneration Project Partnership 2 (3GPP2), a Wideband Code Division Multiple Access (WCDMA) mobile communication system proposed in a 3GPP2, a Code Division Multiple Access (CDMA) mobile communication system proposed in a 3GPP2, an Institute of Electrical and Electronics Engineers (IEEE) mobile communication system, an Evolved Packet System (EPS), and the like. FIG.1Aschematically illustrates an internal structure of a CA processing apparatus in a wireless communication system according to an embodiment of the present disclosure; FIG.1Bschematically illustrates an internal structure of a CC processor, such as the CC processor #0110inFIG.1A, according to an embodiment of the present disclosure; FIG.1Cschematically illustrates an internal structure of a CC processor, such as the CC processor #1120inFIG.1A, according to an embodiment of the present disclosure; and FIG.1Dschematically illustrates an internal structure of a CC processor, such as the CC processor # N130inFIG.1A, according to an embodiment of the present disclosure. Prior to a description ofFIGS.1A to1D, it will be noted that an internal structure of a CA processing apparatus inFIGS.1A to1Dis an internal structure of a CA processing apparatus based on a frequency compensator. Referring toFIG.1A, the CA processing apparatus includes a plurality of reception antennas, e.g., M reception antennas, i.e., a reception antenna ANT #1to a reception antenna ANT #M, a plurality of CC processors, e.g., N+1 CC processors, i.e., a CC processor #0110, a CC processor #1120, . . . , a CC processor # N130, a controller140, a reference clock generator150, a plurality of reception Phase Lock Loop (PLL) units, e.g., N+1 reception PLL units, i.e., a reception PLL unit #0160-0, a reception PLL unit #1160-1, . . . , a reception PLL unit #N160-N, and a plurality of transmission PLL units, e.g., N+1 transmission PLL units, i.e., a transmission PLL unit #0170-0, a transmission PLL unit #1170-1, . . . , a transmission PLL unit #N170-N. Referring toFIG.1B, the CC processor #0110includes M Frequency Down-Converters (FDCs), i.e., an FDC #1111-1, . . . , an FDC # M111-M which are coupled to M reception antennas, i.e., a reception antenna ANT#1to a reception antenna ANT#M, respectively, M Frequency Up-Converters (FUCs), i.e., an FUC #1113-1, . . . , an FUC # M113-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M Reception Frequency Offset Compensators (RFOCs), i.e., an RFOC #1115-1, . . . , an RFOC #M115-M which are coupled to the M FDCs, respectively, M Transmission Frequency Offset Compensators (TFOCs), i.e., a TFOC #1117-1, . . . , a TFOC #M117-M which are coupled to the M FUCs, respectively, and a frequency offset estimator119. Referring toFIG.1C, the CC processor #1120includes M FDCs, i.e., an FDC #1121-1, . . . , an FDC # M121-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M FUCs, i.e., an FUC #1123-1, . . . , an FUC # M123-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M RFOCs, i.e., an RFOC #1125-1, . . . , an RFOC #M125-M which are coupled to the M FDCs, respectively, M TFOCs, i.e., a TFOC #1127-1, . . . , a TFOC #M127-M which are coupled to the M FUCs, respectively, and a frequency offset estimator129. Referring toFIG.1D, the CC processor # N130, as the last CC processor, includes M FDCs, i.e., an FDC #1131-1, . . . , an FDC # M131-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M FUCs, i.e., an FUC #1133-1, . . . , an FUC # M133-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M RFOCs, i.e., an RFOC #1135-1, . . . , an RFOC #M135-M which are coupled to the M FDCs, respectively, M TFOCs, i.e., a TFOC #1137-1, . . . , a TFOC #M137-M which are coupled to the M FUCs, respectively, and a frequency offset estimator139. As illustrated inFIGS.1A to1D, the CA processing apparatus includes only one reference clock generator, i.e., the reference clock generator150, and the reference clock generator150generates a reference clock. For example, the reference clock generator150may be implemented as a Temperature Compensated Crystal Oscillator (TCXO) or a Digitally Compensated Crystal Oscillator (DCXO). InFIGS.1A to1D, while the reference clock generator150is implemented as a TCXO or a DCXO, the reference clock generator150may be implemented with various forms. Each of the reception PLL units, i.e., the reception PLL unit #0160-0, the reception PLL unit #1160-1, . . . , the reception PLL unit #N160-N, is connected to the reference clock generator150, and generates a Reception Carrier Frequency (RCF) for each CC using the reference clock which is generated in the reference clock generator150. The reception PLL unit #0160-0generates an RCF for a CC #0, and the reception PLL unit #1160-1generates an RCF for a CC #1. In this way, the reception PLL unit #N160-N, as the last reception PLL unit, generates an RCF for a CC #N. Each of the transmission PLL units, i.e., the transmission PLL unit #0170-0, the transmission PLL unit #1170-1, . . . , the transmission PLL unit #N170-N, is connected to the reference clock generator150, and generates a Transmission Carrier Frequency (TCF) for each CC using the reference clock which is generated in the reference clock generator150. The transmission PLL unit #0170-0generates a TCF for the CC #0, and the transmission PLL unit #1170-1generates a TCF for the CC #1. In this way, the transmission PLL unit #N170-N, as the last transmission PLL unit, generates a TCF for the CC #N. The CA processing apparatus includes one reference clock generator150, and includes PLL units which may generate a TCF and an RCF for each CC based on the one reference clock generator150for each transmission path and each reception path. If it is assumed that a Reference Reception Carrier Frequency Signal (RRCFS) for a CC#n (n=0, 1, 2, . . . , N) is “Rx_fn” and a Reference Transmission Carrier Frequency Signal for the CC#n is “Tx_fn”, the Rx_fn is provided to an FDC for receiving a carrier frequency signal for each CC#n and the Tx_fn is provided to an FUC for transmitting the carrier frequency signal. For example, an RRCFS for the CC #0is “Rx_f0”, an RTCFS for the CC #0is “Tx_f0”, the Rx_f0is provided to the FDC #1111-1to the FDC #M111-M for receiving a carrier frequency signal of the CC #0, and the Tx_f0is provided to the FUC #1113-1to the FUC #M113-M for transmitting the carrier frequency signal of the CC #0. Further, an RRCFS for the CC #1is “Rx_f1”, an RTCFS for the CC #1is “Tx_f1”, the Rx_f1is provided to the FDC #1121-1to the FDC #M121-M for receiving a carrier frequency signal of the CC #1, and the Tx_f1is provided to the FUC #1123-1to the FUC #M123-M for transmitting the carrier frequency signal of the CC #1. In this way, an RRCFS for the CC #N, as the last CC, is “Rx_fN”, an RTCFS for the CC #N is “Tx_fN”, the Rx_fN is provided to the FDC #1131-1to the FDC #M131-M for receiving a carrier frequency signal of the CC #N, and the Tx_fN is provided to the FUC #1133-1to the FUC #M133-M for transmitting the carrier frequency signal of the CC #N. A frequency offset estimator included in each CC processor is connected to M RFOCs included in a related CC processor, and estimates a frequency offset CC#n_Fo as a difference between an RRCFS which is provided to each CC processor through the N+1 reception PLL units included in the CA processing apparatus, i.e., the reception PLL unit #0160-0, the reception PLL unit #1160-1, . . . , the reception PLL unit #N160-N and a received carrier frequency signal. The frequency offset estimator119included in the CC processor #0110is connected to the RFOC #1115-1, . . . , the RFOC #M115-M, and estimates a CC#0_Fo as a frequency offset which is a difference between an RRCFS Rx_f0which is provided through the reception PLL unit #0160-0, the reception PLL unit #1160-1, . . . , the reception PLL unit # N160-N, and the received carrier frequency signal. The frequency offset estimator129included in the CC processor #1120is connected to the RFOC #1125-1, . . . , the RFOC #M125-M, and estimates a CC#1_Fo as a frequency offset which is a difference between an RRCFS Rx_f1which is provided through the reception PLL unit #0160-0, the reception PLL unit #1160-1, . . . , the reception PLL unit # N160-N, and the received carrier frequency signal. In this way, the frequency offset estimator129, as the last frequency offset estimator included in the CC processor #N130, is connected to the RFOC #1135-1, . . . , the RFOC #M135-M, and estimates a CC#N_Fo as a frequency offset which is a difference between an RRCFS Rx_fN which is provided through the reception PLL unit #0160-0, the reception PLL unit #1160-1, . . . , the reception PLL unit # N160-N, and the received carrier frequency signal. Each CC processor compensates a transmission frequency offset and a reception frequency offset, a description of which will be provided below. Firstly, an operation of compensating the reception frequency offset in each CC processor will be described. An RFOC included in each CC processor compensates a reception frequency offset using the frequency offset CC#n_Fo output from a frequency offset estimator included in a related CC processor. For example, in the CC processor #0110, the RFOC #1115-1is connected to the FDC #1111-1, and estimates the reception frequency offset using the CC#0_Fo as the frequency offset output from the frequency offset estimator119. In this way, the RFOC #M115-M, as the last RFOC, is connected to the FDC #M111-M, and estimates the reception frequency offset using the CC#0_Fo. In the CC processor #1120, the RFOC #1125-1is connected to the FDC #1121-1, and estimates the reception frequency offset using the CC#1_Fo as the frequency offset output from the frequency offset estimator129. In this way, the RFOC #M125-M, as the last RFOC, is connected to the FDC #M121-M, and estimates the reception frequency offset using the CC#1_Fo. In the CC processor # N130, as the last CC processor, the RFOC #1135-1is connected to the FDC #1131-1, and estimates the reception frequency offset using the CC#N_Fo as the frequency offset output from the frequency offset estimator139. In this way, the RFOC #M135-M, as the last RFOC, is connected to the FDC #M131-M, and estimates the reception frequency offset using the CC#N_Fo. Secondly, an operation of compensating the transmission frequency offset in each CC processor will be described. A TFOC included in each CC processor compensates a transmission frequency offset using the frequency offset CC#n_Fo output from the frequency offset estimator included in a related CC processor. For example, in the CC processor #0110, the TFOC #1117-1is connected to the FUC #1113-1, and estimates the transmission frequency offset using the CC#0_Fo as the frequency offset output from the frequency offset estimator119. In this way, the TFOC #M117-M, as the last TFOC, is connected to the FUC #M113-M, and estimates the transmission frequency offset using the CC#0_Fo. In the CC processor #1120, the TFOC #1127-1is connected to the FUC #1123-1, and estimates the transmission frequency offset using the CC#1_Fo as the frequency offset output from the frequency offset estimator129. In this way, the TFOC #M127-M, as the last TFOC, is connected to the FUC #M123-M, and estimates the transmission frequency offset using the CC#1_Fo. In the CC processor # N130, as the last CC processor, the TFOC #1137-1is connected to the FUC #1133-1, and estimates the transmission frequency offset using the CC#N_Fo as the frequency offset output from the frequency offset estimator139. In this way, the TFOC #M137-M, as the last TFOC, is connected to the FUC #M133-M, and estimates the transmission frequency offset using the CC#N_Fo. For example, each of the TFOCs and the RFOCs in each CC processor may be implemented as a phase rotator such as a COordinate Rotation DIgital Computer (CORDIC), or a Read Only Table (ROM) table, or a module which may convert a frequency of a signal such as a complex multiplier based-phase converter. In an embodiment of the present disclosure, the TFOCs and the RFOCs are implemented as phase rotators, ROM tables, or phase converters. However, it will be understood by those of ordinary skill in the art that the TFOCs and the RFOCs may be implemented with various forms. An operation of a CA processing apparatus according to an embodiment of the present disclosure will be described with reference toFIGS.1A to1D. A reference clock for the CA processing apparatus compensates a frequency offset based on a frequency offset which is estimated in a frequency offset estimator included in a related CC processor corresponding to a CC which is selected from among N+1 CCs, i.e., the CC#0to the CC#N, i.e., a reference frequency offset. In this case, a frequency offset compensator included in a transmission path and a reception path is not operated for the selected CC. The CA processing apparatus may perform a reference clock control operation based on a CC which has the best channel quality among the N+1 CCs, i.e., the CC#0to the CC#N. Here, the channel quality may be determined using various metrics such as a Carrier-to-Interference and Noise Ratio (CINR), Reference Signal Received Power (RSRP), a Reference Signal Received Quality (RSRQ), a Reference Signal Strength Indicator (RSSI), a Channel Quality Indicator (CQI), and a BLock Error Rate (BLER) for a control channel or a data channel for each CC. InFIGS.1A to1D, the various metrics such as the CINR, the RSRP, the RSRQ, the RSSI, the CQI, and the BLER are used for selecting a CC used for the reference clock control operation. However, it will be understood by those of ordinary skill in the art that metrics used for selecting the CC used for the reference clock control operation are not limited. The CA processing apparatus may perform a reference clock control operation based on a CC having the best channel quality among N+1 CCs, i.e., the CC#0to the CC#N. For example, a period of selecting a CC used for the reference clock control operation may be a measurement period by which various metrics such as the CINR, the RSRP, the RSRQ, the RSSI, the CQI, and the BLER are measured. If the various metrics such as the CINR, the RSRP, the RSRQ, the RSSI, the CQI, and the BLER are filtered, the period of selecting the CC used for the reference clock control operation may be set to a multiple of the measurement period. A frequency offset which is estimated in a frequency offset estimator included in CC processors corresponding to remaining CCs which are not used for controlling the reference clock is used for compensating a frequency offset through TFOCs and RFOCs included in a related CC processor. FIG.2Aschematically illustrates an internal structure of a CA processing apparatus in a wireless communication system according to an embodiment of the present disclosure; FIG.2Bschematically illustrates an internal structure of a CC processor, such as the CC processor #0210inFIG.2A, according to an embodiment of the present disclosure; FIG.2Cschematically illustrates an internal structure of a CC processor, such as the CC processor #1220inFIG.2A, according to an embodiment of the present disclosure; and FIG.2Dschematically illustrates an internal structure of a CC processor, such as the CC processor # N230inFIG.2A, according to an embodiment of the present disclosure. Prior to a description ofFIGS.2A to2D, it will be noted that an internal structure of a CA processing apparatus inFIGS.2A to2Dis an internal structure of a CA processing apparatus based on PLL control. Referring toFIG.2A, the CA processing apparatus includes a plurality of reception antennas, e.g., M reception antennas, i.e., a reception antenna ANT #1to a reception antenna ANT #M, a plurality of CC processors, e.g., N+1 CC processors, i.e., a CC processor #0210, a CC processor #1220, . . . , a CC processor # N230, a controller240, a reference clock generator250, a plurality of reception PLL units, e.g., N+1 reception PLL units, i.e., a reception PLL unit #0260-0, a reception PLL unit #1260-1, . . . , a reception PLL unit #N260-N, and a plurality of transmission PLL units, e.g., N+1 transmission PLL units, i.e., a transmission PLL unit #0270-0, a transmission PLL unit #1270-1, . . . , a transmission PLL unit #N270-N. Referring toFIG.2B, the CC processor #0210includes M FDCs, i.e., an FDC #1211-1, . . . , an FDC # M211-M which are coupled to M reception antennas, i.e., a reception antenna ANT#1to a reception antenna ANT#M, respectively, M FUCs, i.e., an FUC #1213-1, . . . , an FUC # M213-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, and a frequency offset estimator215which is connected to each of the M FDCs. Referring toFIG.2C, the CC processor #1220includes M FDCs, i.e., an FDC #1221-1, . . . , an FDC# M221-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M FUCs, i.e., an FUC #1223-1, . . . , an FUC # M223-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, and a frequency offset estimator225which is connected to each of the M FDCs. Referring toFIG.2D, the CC processor # N230, as the last CC processor, includes M FDCs, i.e., an FDC #1231-1, . . . , an FDC # M231-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, M FUCs, i.e., an FUC #1233-1, . . . , an FUC # M233-M which are coupled to the reception antenna ANT#1to the reception antenna ANT#M, respectively, and a frequency offset estimator235which is connected to each of the M FDCs. As illustrated inFIGS.2A to2D, the CA processing apparatus includes one reference clock generator, i.e., the reference clock generator250, and the reference clock generator250generates a reference clock. For example, the reference clock generator250may be implemented as a TCXO or a DCXO. InFIGS.2A to2D, while the reference clock generator250is implemented as a TCXO or a DCXO, the reference clock generator250may be implemented with various forms. Each of the reception PLL units, i.e., the reception PLL unit #0260-0, the reception PLL unit #1260-1, . . . , the reception PLL unit #N260-N, is connected to the reference clock generator250, and generates a reception carrier frequency for each CC using the reference clock which is generated in the reference clock generator250. The reception PLL unit #0260-0generates a reception carrier frequency for a CC #0, and the reception PLL unit #1260-1generates a reception carrier frequency for a CC #1. In this way, the reception PLL unit #N260-N, as the last reception PLL unit, generates a reception carrier frequency for a CC #N. Each of the transmission PLL units, i.e., the transmission PLL unit #0270-0, the transmission PLL unit #1270-1, . . . , the transmission PLL unit #N270-N, is connected to the reference clock generator250, and generates a transmission carrier frequency for each CC using the reference clock which is generated in the reference clock generator250. The transmission PLL unit #0270-0generates a transmission carrier frequency for the CC #0, and the transmission PLL unit #1270-1generates a transmission carrier frequency for the CC #1. In this way, the transmission PLL unit #N270-N, as the last transmission PLL unit, generates a transmission carrier frequency for the CC #N. The CA processing apparatus includes one reference clock generator250, and includes PLL units which may generate a TCF and an RCF for each CC based on the one reference clock generator for each transmission path and each reception path. If it is assumed that an RRCFS for a CC#n (n=0, 1, 2, . . . , N) is “Rx_fn” and an RTCFS for the CC#n is “Tx_fn”, the Rx_fn is provided to an FDC for receiving a carrier frequency signal for each CC#n and the Tx_fn is provided to an FUC for transmitting the carrier frequency signal. For example, an RRCFS for the CC #0is “Rx_f0”, an RTCFS for the CC #0is “Tx_f0”, the Rx_f0is provided to the FDC #1211-1to the FDC #M211-M for receiving a carrier frequency signal of the CC #0, and the Tx_f0is provided to the FUC #1213-1to the FUC #M213-M for transmitting the carrier frequency signal of the CC #0. Further, an RRCFS for the CC #1is “Rx_f1”, an RTCFS for the CC #1is “Tx_f1”, the Rx_f1is provided to the FDC #1221-1to the FDC #M221-M for receiving a carrier frequency signal of the CC #1, and the Tx_f1is provided to the FUC #1223-1to the FUC #M223-M for transmitting the carrier frequency signal of the CC #1. In this way, an RRCFS for the CC #N, as the last CC, is “Rx_fN”, an RTCFS for the CC #N is “Tx_fN”, the Rx_fN is provided to the FDC #1231-1to the FDC #M231-M for receiving a carrier frequency signal of the CC #N, and the Tx_fN is provided to the FUC #1233-1to the FUC #M233-M for transmitting the carrier frequency signal of the CC #N. A frequency offset estimator included in each CC processor is connected to M RFOCs included in a related CC processor, and estimates a frequency offset CC#n_Fo as a difference between an RRCFS, which is provided to each CC processor through the N+1 reception PLL units included in the CA processing apparatus, i.e., the reception PLL unit #0260-0, the reception PLL unit #1260-1, . . . , the reception PLL unit #N260-Nn and a received carrier frequency signal. The frequency offset estimator215included in the CC processor #0210is connected to the FDC #1211-1, . . . , the FDC #M211-M, and estimates a CC#0_Fo as a frequency offset which is a difference between an RRCFS Rx_f0which is provided through the reception PLL unit #0260-0, the reception PLL unit #1260-1, . . . , the reception PLL unit # N260-N, and the received carrier frequency signal. The frequency offset estimator225included in the CC processor #1220is connected to the FDC #1221-1, . . . , the FDC #M221-M, and estimates a CC#1_Fo as a frequency offset which is a difference between an RRCFS Rx_f1which is provided through the reception PLL unit #0260-0, the reception PLL unit #1260-1, . . . , the reception PLL unit # N260-N, and the received carrier frequency signal. In this way, the frequency offset estimator235, as the last frequency offset estimator included in the CC processor #N230, is connected to the FDC #1231-1, . . . , the FDC #M231-M, and estimates a CC#N_Fo as a frequency offset which is a difference between an RRCFS Rx_fN which is provided through the reception PLL unit #0260-0, the reception PLL unit #1260-1, . . . , the reception PLL unit # N260-N, and the received carrier frequency signal. The CA processing apparatus inFIGS.2A to2Dcompensates a frequency offset estimated in each CC by controlling a reception PLL unit and a transmission PLL unit for a related CC, a description of which will be provided followed. Firstly, a scheme in which the CA processing apparatus compensates the frequency offset estimated in each CC by controlling the reception PLL unit for the related CC will be described. The frequency offset CC#0_Fo for the CC#0is inputted to the reception PLL unit #0260-0, thereby the reception PLL unit #0260-0compensates the estimated frequency offset CC#0_Fo. The frequency offset CC#1_Fo for the CC#1is inputted to the reception PLL unit #1260-1, thereby the reception PLL unit #1260-1compensates the estimated frequency offset CC#1_Fo. The frequency offset CC#N_Fo for the CC#N is inputted to the reception PLL unit #N260-N, thereby the reception PLL unit #N260-N compensates the estimated frequency offset CC#N_Fo. Secondly, a scheme in which the CA processing apparatus compensates the frequency offset estimated in each CC by controlling the transmission PLL unit for the related CC will be described. The frequency offset CC#0_Fo for the CC#0is inputted to the transmission PLL unit #0270-0, thereby the transmission PLL unit #0270-0compensates the estimated frequency offset CC#0_Fo. The frequency offset CC#1_Fo for the CC#1is inputted to the transmission PLL unit #1270-1, thereby the transmission PLL unit #1270-1compensates the estimated frequency offset CC#1_Fo. The frequency offset CC#N_Fo for the CC#N is inputted to the transmission PLL unit #N270-N, thereby the transmission PLL unit #N270-N compensates the estimated frequency offset CC#N_Fo. An operation of a CA processing apparatus according to an embodiment of the present disclosure will be described with reference toFIGS.2A to2D. A reference clock for the CA processing apparatus compensates a frequency offset based on a frequency offset which is estimated in a frequency offset estimator included in a related CC processor corresponding to a CC which is selected from among N+1 CCs, i.e., the CC#0to the CC#N, i.e., a reference frequency offset. The CA processing apparatus may perform a reference clock control operation based on a CC which has the best channel quality among the N+1 CCs, i.e., the CC#0to the CC#N. Here, the channel quality may be determined using various metrics such as a CINR, an RSRP, an RSRQ, an RSSI, a CQI, and a BLER for a control channel or a data channel for each CC. InFIGS.2A to2D, the various metrics such as the CINR, the RSRP, the RSRQ, the RSSI, the CQI, and the BLER are used for selecting a CC used for the reference clock control operation. However, it will be understood by those of ordinary skill in the art that metrics used for selecting the CC used for the reference clock control operation are not limited. The CA processing apparatus may perform a reference clock control operation based on a CC having the best channel quality among N+1 CCs, i.e., the CC#0to the CC#N. For example, a period of selecting a CC used for the reference clock control operation may be a measurement period by which various metrics such as the CINR, the RSRP, the RSRQ, the RSSI, the CQI, and the BLER are measured. If the various metrics such as the CINR, the RSRP, the RSRQ, the RSSI, the CQI, and the BLER are filtered, the period of selecting the CC used for the reference clock control operation may be set to a multiple of the measurement period. Meanwhile, a frequency offset which is estimated in a frequency offset estimator included in CC processors corresponding to remaining CCs which are not used for controlling the reference clock is used for controlling a related transmission/reception PLL unit and compensating a frequency offset. The frequency offset which is estimated in the frequency offset estimator included in the CC processors corresponding to the remaining CCs which are not used for controlling the reference clock is used for compensating the frequency offset through TFOCs and RFOCs included in a related CC processor. InFIGS.2A to2D, a CA processing apparatus compensates a frequency by compensating a frequency offset for a transmission PLL unit and a reception PLL unit in each CC without using a separated frequency offset compensator, so there is a need for providing a control signal from a MOdulator/DE-Modulator (MODEM) to a Radio Frequency Integrated Circuit (RFIC) by a frequency offset compensation period. A CC processing circuit and/or a CC processing apparatus according to embodiments of the present disclosure as described inFIGS.1A to2Dprocesses a CA with reference to a case in which the number of processors for receiving a signal is equal to the number of processors for transmitting a signal. However, it will be understood by those of ordinary skill in the art that the number of processors for receiving the signal may be equal to or different from the number of processors for transmitting the signal. Further, it will be understood by those of ordinary skill in the art that the number of antennas and the number of CCs in a CC processing circuit and/or a CC processing apparatus according to embodiments of the present disclosure as described inFIGS.1A to2Dare not limited. As is apparent from the foregoing description, an embodiment of the present disclosure enables processing CA using a reference CC. An embodiment of the present disclosure enables processing CA using one reference clock. An embodiment of the present disclosure enables processing CA by considering a deployment scenario for various CCs. An embodiment of the present disclosure enables processing CA without using a reference clock for each CC thereby minimizing a cost and a size. An embodiment of the present disclosure enables compensation of a frequency offset per CC thereby providing various deployment scenarios and flexibly processing CA. So, in an apparatus which uses a relatively low-priced reference clock such as a Home evolved Node B (HeNB) and a repeater, flexible and stable CA implement is possible. An embodiment of the present disclosure enables controlling generation of a reference clock based on a CC which has the best channel quality among CCs thereby stably controlling a clock. While the present disclosure has been shown and described with reference to various embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure as defined by the appended claims and their equivalents. | 33,702 |
RE49806 | DESCRIPTION OF EXAMPLE EMBODIMENTS Overview Techniques are presented herein to facilitate latency measurements in a networking environment. A first network device receives a packet for transport within a network domain that comprises a plurality of network devices. The plurality of network devices have a common time reference, that is, they are time synchronized. The first network device generates timestamp information indicating time of arrival of the packet at the first network device. The first network device inserts into the packet a tag that comprises at least a first subfield and a second subfield. The first subfield comprises a type indicator to signify to other network devices in the network domain that the tag includes timestamp information, and the second subfield includes the timestamp information. The first network device sends the packet into the network domain to another network device. Other network devices in the network domain which receive that packet can then make latency measurements, insert another tag, overwrite the tag, and perform various other operations described herein. Example Embodiments Reference is first made toFIG.1.FIG.1shows a network domain or system10comprising a plurality of network devices20(1)-20(N) that are all synchronized to a common time reference30. That is, all of the network devices20(1)-20(N) of interest in the network domain10have the same global time reference, determined by IEEE 1588 Precision Time Protocol (PTP) or other methods now known or hereinafter developed. For simplicity, the term “node” is also used herein synonymously with the term “network device”. A packet40enters the network domain10at some edge node, e.g., network device20(1) in the example ofFIG.1, and departs the network domain10at another edge node, e.g., network device20(N). Presented herein are techniques to determine latency at any point in the network domain for a packet as it traverses through the network domain10. One particular latency measure that is of interest is the end-to-end latency, that is, the elapsed time (latency) for a packet to travel between an ingress port of edge network device20(1) to an egress port of edge network device20(N) of network domain10. A timestamp tag (TTAG) is inserted into a packet40by the edge network device20(1) of the network domain10. The TTAG includes timestamp information indicating time of arrival at network device20(1). All of the network devices in the network domain10that receive the packet40(with the inserted TTAG) can perform measurements based on the timestamp information contained in TTAG inserted into packet40, and perform other operations, including adding another TTAG, overwriting an existing TTAG, adding another timestamp value into an existing TTAG, etc., as will described in more detail hereinafter. As indicated inFIG.1, any network device in the network domain10can measure and report the latency based on the TTAG contained in a packet. However, not all network devices must understand a TTAG. In cases in which a network device does not understand a TTAG contained in a packet, the TTAG can be skipped as part of packet processing or in the case of Ethernet packets, some switches will process the packet up to the TTAG and skip the rest of the packet. The network devices20(1)-20(N) shown inFIG.1can be any network device now known or hereinafter developed, including a switch, router, gateway, a software stack on a host device, virtual network interface cards (VNICs) virtual switches, physical network interface cards (including those that support virtualization). FIG.1further shows a network management station50that may take a variety of forms, e.g., server computer, virtualized server, etc., that communicates with each network device20(1)-20(N) for purposes of configuring the network devices to insert TTAGs, make latency measurements, report latency measurements, and to receive latency measurements from the network devices20(1)-20(N). Turning now toFIG.2, a more detailed description is provided for the components of a network device that are configured to perform the TTAG insertion and latency measurement operations presented herein.FIG.2shows a simplified diagram of two network devices20(1) and20(2), though it should be understood that each network device20(1)-20(N) in a network domain that is to participate in the techniques presented herein is configured in a similar manner as that shown for network devices20(1) and20(2) inFIG.2. Specifically, each network device20(1)-20(N) includes multiple ports, and for simplicity an ingress port21and egress22are shown inFIG.2. Furthermore, each network device includes a timestamp logic unit23, a latency measurement unit24, packet processing logic26, a central processing unit (CPU)28and memory29. The packet processing logic26is representative of the conventional packet processing components in a network device, such as buffers, switch tables, switch fabric, queues, etc., that operate to determine whether to drop, forward (and via a particular egress port), switch, etc., a particular packet based on the contents of the header of the packet. The details of the packet processing logic26are not described herein because they are well known in the art, and do not pertain to the timestamping techniques presented herein. The timestamp logic unit23generates a timestamp upon arrival of the packet at an ingress port21of the network device. The timestamp is with respect to the common time reference30used by all network devices in the network domain. The timestamp logic unit23may insert the TTAG into a packet40immediately upon arrival at the ingress port, and then forward the packet to be processed by the packet processing logic26, insert the TTAG in parallel with the processing of the packet by the packet processing logic26, or after processing of the packet by the packet processing logic26. Examples of various formats of a TTAG are presented hereinafter in connection withFIGS.3A-3D. The TTAG is inserted in any manner that does not interfere with the normal processing of the packet by the network devices. The timestamp logic unit23may also be configured to insert additional information into a TTAG, including one or more bits to indicate a validity of the timestamp value, one or more bits to indicate a timing precision of the timestamp value. In general, precision is system or network domain wide and is pre-negotiated among the network devices with respect to the common time reference30. When a new timestamp value is to be inserted into a packet, a network device uses either ingress port timestamp from the common time reference30(synchronized clock) or an invalid value of zero. Invalid values are preserved across the network domain, as described further hereinafter. Since any device can serve as an edge node in a network domain, each network device includes latency measurement24which is configured to perform a latency computation (current time minus the timestamp value contained in a TTAG of a received packet). For example, the latency measurement unit24in network device20(2) may compute the latency associated with packet40using the timestamp value contained in the TTAG inserted by edge network device20(1). The CPU28may perform higher level latency analysis and reporting operations based on software instructions contained in memory29. The memory29may also serve for additional storage of latency measurements. The CPU28may send latency measurements to a local or remotely located computing device that is used by a network administrator to monitor performance of network domain20. Moreover, the CPU28in any given network device may receive commands or instructions from a network management station (FIG.1) to control the TTAG-related operations in a network device, latency measurements made by a network device, etc. Memory29may comprise read only memory (ROM), random access memory (RAM), magnetic disk storage media devices, optical storage media devices, flash memory devices, electrical, optical, or other physical/tangible memory storage devices. The CPU is, for example, a microprocessor or microcontroller. Thus, in general, the memory29may comprise one or more tangible (non-transitory) computer readable storage media (e.g., a memory device) encoded with software comprising computer executable instructions and when the software is executed (by the CPU28) it is operable to perform the operations described herein. The timestamp logic unit23and latency measurement unit24may be embodied by digital logic gates configured to perform the operations described herein, or in another form, by software stored in memory29and executed by CPU28to perform the operations described herein. In another example, the timestamp logic unit23and latency measurement unit24may be integrated or embedded with the packet processing logic26, which itself may be embodied by one or more application specific integrated circuits (ASICs). As shown inFIG.2, when a network device receives from another network device a packet that includes a TTAG, there are several options for operations that may be performed. First, the network device can measure latency from the edge node or any other node that inserted a TTAG in the packet. Second, the network device can do nothing, leave the TTAG as is and process the packet in the ordinary course. Third, the network device can overwrite an existing TTAG in the packet with a new TTAG (and timestamp of arrival) at this network device. Fourth, the network device can insert an additional TTAG into the packet. For example, multiple TTAGs can be inserted such as through tunnels or if negotiated across ports. Fifth, the network device can insert an additional timestamp value (based on time of arrival at this network device) into an existing TTAG of the packet. The CPU28in one or more network devices may be configured, through software stored in memory29, to insert additional TTAGs into a packet, overwrite an existing TTAG or insert another timestamp value in a TTAG as described further hereinafter. In any case, the network device processes the packet as it normally would if the TTAG were not present. As shown inFIG.2, network device20(2) sends packet40on in the network domain with any existing TTAGs, a newly overwritten TTAG, etc., under control of the CPU28. Reference is now made toFIGS.3A-3Efor examples of various formats of TTAGs.FIG.3Aillustrates a first basic form of a TTAG100, including a first Type subfield110and a second Timestamp subfield120. The Type subfield110is used to identify the “type” as a TTAG which allows any network device to recognize the TTAG. The independence of timestamp information contained in a TTAG from any other existing format liberates current network devices or CPUs to determine system-wide time. In one example, the Type subfield110is 8 bytes such as that specified by an Ethertype subfield in an Ethernet frame. The Timestamp subfield120is a 48 bit number having a format of an unsigned rolling 48 bit binary number value, e.g., having 100 picosecond resolution. When clock time increments to zeros for all 48 LSBs, the Timestamp subfield uses a value of one instead. A value of one repeats unlike one's complement. Thus, a lower 48 bit clock time of 0 and 1 both map to Timestamp subfield value of 1. FIG.3Bshows an example format of a TTAG101with an explicit validity bit shown at130. The validity bit130is configured so that if it takes on a first value, e.g., logic “1”, the timestamp value in Timestamp subfield120is valid, and if the validity bit takes on a second value, e.g., logic “0”, the timestamp value in the Timestamp subfield120is invalid. Invalid timestamp values are preserved across the network domain by other network devices that receive a packet with a TTAG indicated to contain an invalid timestamp value. There is another way to signify an invalid timestamp value in a packet without using the explicit validity bit130. A Timestamp subfield value of zero represents an invalid timestamp. Thus, when the value contained in Timestamp subfield130is all zeros, a network device construes this as indicating that the timestamp contained in the TTAG is invalid. The subfield can be compatible with timestamp always valid in the network when invalid capability is disabled in the network domain. Thus, a predetermined bit pattern (e.g., all zeros) in the Timestamp subfield130indicates that the timestamp information of the Timestamp subfield is not valid. FIG.3Cillustrates another format of a TTAG shown at reference numeral102. In this example, there is an additional precision subfield140that contains a bit pattern configured to indicate precision of the timestamp value contained in the Timestamp subfield120. The concept of network-wide pre-negotiated precision was described above. FIG.3Dillustrates still another format of a TTAG shown at reference numeral103. This example shows that there is both the explicit validity bit130and precision subfield140. FIG.3Eillustrates yet another format of a TTAG shown at reference numeral104. TTAG104includes multiple Timestamp fields120(1),120(2), etc. Each Timestamp subfield can contain a different timestamp value inserted by the same network device or by different network devices. Turning toFIG.4, a general diagram is shown of a packet40having one or more TTAGs100(1),100(2), etc., therein. In the simple case, a packet will have only one TTAG at any given time. However, there is utility in the capability of multiple TTAGs in a packet. For example, multiple TTAGs can be inserted in situations when packets are encapsulated in tunnels or if negotiated across ports of network devices. Furthermore, each packet that has a TTAG inserted into it does not affect the networking operations performed by any network device that receives the packet. Any network device can obtain information from the TTAGs contained in packets and thereby obtain visibility to latency within the network. In some implementations of the techniques described herein, the number of TTAGs that can be inserted into a packet is limited in number to, for example, six (6) or some number between one (1) and ten (10). In other implementations, the number of TTAGs that can be inserted into a packet is unlimited, in which any device that receives the packet within the network for passing the packet to a destination from a source can insert a TTAG into the packet. In some implementations, when the maximum number of TTAGs that can be inserted into a packet is reached, downstream network devices cannot insert TTAGs into the packet. In yet other implementations, when the maximum number of TTAGs that can be inserted into a packet is reached, downstream network devices are allowed to over-write TTAGs on a first-in, first-out basis. There are numerous possibilities for locating the TTAG information in the packet. The TTAG can be inserted within a Layer 2 portion of the packet. This is in contrast to conventional approaches that perform application-specific packet time measurements at Layer 3. For example, one conventional packet time measurement approach collects runtime measurement of packets based on an application-specific determination of packet arrivals at Layer 3, as opposed to incorporating timestamp tag information directly into all packets at Layer 2 as accomplished using the techniques presented herein. In some implementations, such as for Internet Protocol Version 4 (IPv4) or IPv6 packets, the TTAG can be provided immediately after the virtual local area network (VLAN) subfield and immediately before the IPv4 or IPv6 field in the packet header portion of the packet, in which the TTAG is meshed in the protocol stack within the header portion of the packet. Other locations for insertions of the TTAG within a packet may be envisioned while remaining within the spirit and scope of the techniques presented herein. Turning now toFIG.5, a flow chart is presented that illustrates an operational flow200with respect to network devices that insert and interpret TTAGs in packets as the packets traverse through a network domain. At210, a packet at a first network device (e.g., ingress edge node for the packet) of a network domain is received. The packet is for transport through the network domain, and the network domain includes a plurality of network devices, e.g., as depicted inFIG.1. At220, the first network device generates timestamp information indicating time of arrival of the packet at the first network device. As explained above in connection withFIG.1, the timestamp is generated with respect to a time reference that is common across all of the network devices in the network domain. At230, the first network device inserts into the packet a tag that comprises at least a first subfield and a second subfield. The first subfield comprising a type indicator to signify to other network devices in the network domain that the tag includes timestamp information, and the second subfield includes or contains the timestamp information. At240, the first network device sends the packet to another network device in the network domain, using the normal packet processing functions for the packet. At250, another network device in the network domain receives the packet, and can perform any one or more of: (i) measuring latency with respect to first network device based on timestamp information in tag, (ii) overwriting tag with new tag, (iii) adding an additional tag to the packet, and (iv) adding an additional timestamp to an existing tag, or (v) doing nothing and processing the packet in the normal course without performing any of operations (i)-)(iv). At250, the network device sends the packet on in the network in the ordinary course of packet processing. Operations240and250are repeated at subsequent network devices in the network domain as the packet travels through the network domain. As explained above in connection withFIGS.1and2, a network management station may receive reports as to latency values measured by network devices in the network domain. The network management station may also configure the various network devices to perform more specialized tagging of packets, depending on certain applications supported in the network, tunnels supported in the network, etc. The latency measurements made by network devices at the edge of the network domain and at various points in between allow a network administrator to understand how the network domain is handling traffic and whether there are network congestion issues within a particular portion of the network domain. Thus, particular implementations of the subject matter have been described. Other implementations are within the scope of the following claims. In some cases, the actions recited in the claims can be performed in a different order and still achieve desirable results. In addition, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In certain implementations, multitasking and parallel processing may be advantageous. The above description is intended by way of example only. | 19,215 |
RE49807 | DETAILED DESCRIPTION FIGS.1through12Bdiscussed below, and the various embodiments used to describe the principles of the present disclosure in this patent document are by way of illustration only and should not be construed in any way to limit the scope of the disclosure. Those skilled in the art will understand that the principles of the present disclosure may be implemented in any suitably arranged method and apparatus. For convenience of description, the following abbreviations used in this patent document are defined.eNB=enhanced node BUE=user equipmentCA=carrier aggregationCoMP=coordinated multi-pointUL=uplinkDL=downlinkPDSCH=physical downlink shared channelPUSCH=physical uplink shared channelPUCCH=physical uplink control channelPDCCH=physical downlink control channelePDCCH=enhanced PDCCHRS=reference signalCSI-RS=channel-state-information reference signalCRS=cell-specific reference signalDMRS=demodulation reference signalHARQ=Hybrid Automatic repeat-reqestACK=Acknowledgement signalDCI=downlink control informationTPC=transmit power controlPCell=primary serving cellSCell=secondary serving cellRRC=radio resource control (layer)TM=transmission modeSR=scheduling requestQoS=Quality of Service The following documents and standards descriptions are hereby incorporated into the present disclosure as if fully set forth herein:REF1—3GPP TS 36.211 v10.5.0, “E-UTRA, Physical channels and modulation”;REF2—3GPP TS 36.212 v10.5.0, “E-UTRA, Multiplexing and Channel coding”;REF3—3GPP TS 36.213 v10.5.0, “E-UTRA, Physical Layer Procedures”; andREF4—Draft 3GPP TR 36.932 v0.1.0, “Scenarios and Requirements for Small Cell Enhancement for E-UTRA and E-UTRAN”. FIG.1illustrates an example wireless network100according to this disclosure. As shown inFIG.1, the wireless network100includes an eNodeB (eNB)101, eNB102, and eNB103. The eNB101communicates with eNB102and eNB103. The eNB101also communicates with Internet protocol (IP) network130, such as the Internet, a proprietary IP network, or other data network. FIG.1illustrates an example wireless network100according to this disclosure. The embodiment of the wireless network100shown inFIG.1is for illustration only. Other embodiments of the wireless network100could be used without departing from the scope of this disclosure. As shown inFIG.1, the wireless network100includes an eNodeB (eNB)101, an eNB102, and an eNB103. The eNB101communicates with the eNB102and the eNB103. The eNB101also communicates with at least one Internet Protocol (IP) network130, such as the Internet, a proprietary IP network, or other data network. The eNB102provides wireless broadband access to the network130for a first plurality of user equipments (UEs) within a coverage area120of the eNB102. The first plurality of UEs includes a UE111, which may be located in a small business (SB); a UE112, which may be located in an enterprise (E); a UE113, which may be located in a WiFi hotspot (HS); a UE114, which may be located in a first residence (R); a UE115, which may be located in a second residence (R); and a UE116, which may be a mobile device (M) like a cell phone, a wireless laptop, a wireless PDA, or the like. The eNB103provides wireless broadband access to the network130for a second plurality of UEs within a coverage area125of the eNB103. The second plurality of UEs includes the UE115and the UE116. In some embodiments, one or more of the eNBs101-103may communicate with each other and with the UEs111-116using 5G, LTE, LTE-A, WiMAX, or other advanced wireless communication techniques. Depending on the network type, other well-known terms may be used instead of “eNodeB” or “eNB,” such as “base station” or “access point.” For the sake of convenience, the terms “eNodeB” and “eNB” are used in this patent document to refer to network infrastructure components that provide wireless access to remote terminals. Also, depending on the network type, other well-known terms may be used instead of “user equipment” or “UE,” such as “mobile station,” “subscriber station,” “remote terminal,” “wireless terminal,” or “user device.” For the sake of convenience, the terms “user equipment” and “UE” are used in this patent document to refer to remote wireless equipment that wirelessly accesses an eNB, whether the UE is a mobile device (such as a mobile telephone or smartphone) or is normally considered a stationary device (such as a desktop computer or vending machine). Dotted lines show the approximate extents of the coverage areas120and125, which are shown as approximately circular for the purposes of illustration and explanation only. It should be clearly understood that the coverage areas associated with eNBs, such as the coverage areas120and125, may have other shapes, including irregular shapes, depending upon the configuration of the eNBs and variations in the radio environment associated with natural and man-made obstructions. As described in more detail below, one or more of the eNBs101-103includes processing circuitry configured to receive the UCI on the prioritized PUxCH. The UE is power-limited, wherein the UE is scheduled to transmit uplink control information (UCI) to the CG1 on one or more physical uplink channels (PUxCHs). The UE prioritized a PUxCH in response to being power limited. AlthoughFIG.1illustrates one example of a wireless network100, various changes may be made toFIG.1. For example, the wireless network100could include any number of eNBs and any number of UEs in any suitable arrangement. Also, the eNB101could communicate directly with any number of UEs and provide those UEs with wireless broadband access to the network130. Similarly, each eNB102-103could communicate directly with the network130and provide UEs with direct wireless broadband access to the network130. Further, the eNB101,102, and/or103could provide access to other or additional external networks, such as external telephone networks or other types of data networks. FIGS.2A and2Billustrate example wireless transmit and receive paths according to this disclosure. In the following description, a transmit path200may be described as being implemented in an eNB (such as eNB102), while a receive path250may be described as being implemented in a UE (such as UE116). However, it will be understood that the receive path250could be implemented in an eNB and that the transmit path200could be implemented in a UE. In some embodiments, the transmit path200and receive path250are configured to receive the UCI on the prioritized PUxCH. The UE is power-limited, wherein the UE is scheduled to transmit uplink control information (UCI) to the CG1 on one or more physical uplink channels (PUxCHs). The UE prioritized a PUxCH in response to being power limited. The transmit path200includes a channel coding and modulation block205, a serial-to-parallel (S-to-P) block210, a size N Inverse Fast Fourier Transform (IFFT) block215, a parallel-to-serial (P-to-S) block220, an add cyclic prefix block225, and an up-converter (UC)230. The receive path250includes a down-converter (DC)255, a remove cyclic prefix block260, a serial-to-parallel (S-to-P) block265, a size N Fast Fourier Transform (FFT) block270, a parallel-to-serial (P-to-S) block275, and a channel decoding and demodulation block280. In the transmit path200, the channel coding and modulation block205receives a set of information bits, applies coding (such as a low-density parity check (LDPC) coding), and modulates the input bits (such as with Quadrature Phase Shift Keying (QPSK) or Quadrature Amplitude Modulation (QAM)) to generate a sequence of frequency-domain modulation symbols. The serial-to-parallel block210converts (such as de-multiplexes) the serial modulated symbols to parallel data in order to generate N parallel symbol streams, where N is the IFFT/FFT size used in the eNB102and the UE116. The size N IFFT block215performs an IFFT operation on the N parallel symbol streams to generate time-domain output signals. The parallel-to-serial block220converts (such as multiplexes) the parallel time-domain output symbols from the size N IFFT block215in order to generate a serial time-domain signal. The add cyclic prefix block225inserts a cyclic prefix to the time-domain signal. The up-converter230modulates (such as up-converts) the output of the add cyclic prefix block225to an RF frequency for transmission via a wireless channel. The signal may also be filtered at baseband before conversion to the RF frequency. A transmitted RF signal from the eNB102arrives at the UE116after passing through the wireless channel, and reverse operations to those at the eNB102are performed at the UE116. The down-converter255down-converts the received signal to a baseband frequency, and the remove cyclic prefix block260removes the cyclic prefix to generate a serial time-domain baseband signal. The serial-to-parallel block265converts the time-domain baseband signal to parallel time domain signals. The size N FFT block270performs an FFT algorithm to generate N parallel frequency-domain signals. The parallel-to-serial block275converts the parallel frequency-domain signals to a sequence of modulated data symbols. The channel decoding and demodulation block280demodulates and decodes the modulated symbols to recover the original input data stream. Each of the eNBs101-103may implement a transmit path200that is analogous to transmitting in the downlink to UEs111-116and may implement a receive path250that is analogous to receiving in the uplink from UEs111-116. Similarly, each of UEs111-116may implement a transmit path200for transmitting in the uplink to eNBs101-103and may implement a receive path250for receiving in the downlink from eNBs101-103. Each of the components inFIGS.2A and2Bcan be implemented using only hardware or using a combination of hardware and software/firmware. As a particular example, at least some of the components inFIGS.2A and2Bmay be implemented in software, while other components may be implemented by configurable hardware or a mixture of software and configurable hardware. For instance, the FFT block270and the IFFT block215may be implemented as configurable software algorithms, where the value of size N may be modified according to the implementation. Furthermore, although described as using FFT and IFFT, this is by way of illustration only and should not be construed to limit the scope of this disclosure. Other types of transforms, such as Discrete Fourier Transform (DFT) and Inverse Discrete Fourier Transform (IDFT) functions, could be used. It will be appreciated that the value of the variable N may be any integer number (such as 1, 2, 3, 4, or the like) for DFT and IDFT functions, while the value of the variable N may be any integer number that is a power of two (such as 1, 2, 4, 8, 16, or the like) for FFT and IFFT functions. AlthoughFIGS.2A and2Billustrate examples of wireless transmit and receive paths, various changes may be made toFIGS.2A and2B. For example, various components inFIGS.2A and2Bcould be combined, further subdivided, or omitted and additional components could be added according to particular needs. Also,FIGS.2A and2Bare meant to illustrate examples of the types of transmit and receive paths that could be used in a wireless network. Any other suitable architectures could be used to support wireless communications in a wireless network. FIG.3illustrates an example UE116according to this disclosure. The embodiment of the UE116illustrated inFIG.3is for illustration only, and the UEs111-115ofFIG.1could have the same or similar configuration. However, UEs come in a wide variety of configurations, andFIG.3does not limit the scope of this disclosure to any particular implementation of a UE. As shown inFIG.3, the UE116includes an antenna305, a radio frequency (RF) transceiver310, transmit (TX) processing circuitry315, a microphone320, and receive (RX) processing circuitry325. The UE116also includes a speaker330, a main processor340, an input/output (I/O) interface (IF)345, a keypad350, a display355, and a memory360. The memory360includes a basic operating system (OS) program361and one or more applications362. The RF transceiver310receives, from the antenna305, an incoming RF signal transmitted by an eNB of the network100. The RF transceiver310down-converts the incoming RF signal to generate an intermediate frequency (IF) or baseband signal. The IF or baseband signal is sent to the RX processing circuitry325, which generates a processed baseband signal by filtering, decoding, and/or digitizing the baseband or IF signal. The RX processing circuitry325transmits the processed baseband signal to the speaker330(such as for voice data) or to the main processor340for further processing (such as for web browsing data). The TX processing circuitry315receives analog or digital voice data from the microphone320or other outgoing baseband data (such as web data, e-mail, or interactive video game data) from the main processor340. The TX processing circuitry315encodes, multiplexes, and/or digitizes the outgoing baseband data to generate a processed baseband or IF signal. The RF transceiver310receives the outgoing processed baseband or IF signal from the TX processing circuitry315and up-converts the baseband or IF signal to an RF signal that is transmitted via the antenna305. The main processor340can include one or more processors or other processing devices and execute the basic OS program361stored in the memory360in order to control the overall operation of the UE116. For example, the main processor340could control the reception of forward channel signals and the transmission of reverse channel signals by the RF transceiver310, the RX processing circuitry325, and the TX processing circuitry315in accordance with well-known principles. In some embodiments, the main processor340includes at least one microprocessor or microcontroller. The main processor340is also capable of executing other processes and programs resident in the memory360, such as operations for selecting a physical uplink channel (PUxCH) as described herein. The main processor340can move data into or out of the memory360as required by an executing process. In some embodiments, the main processor340is configured to execute the applications362based on the OS program361or in response to signals received from eNBs or an operator. The main processor340is also coupled to the I/O interface345, which provides the UE116with the ability to connect to other devices such as laptop computers and handheld computers. The I/O interface345is the communication path between these accessories and the main controller340. The main processor340is also coupled to the keypad350and the display unit355. The operator of the UE116can use the keypad350to enter data into the UE116. The display355may be a liquid crystal display or other display capable of rendering text and/or at least limited graphics, such as from web sites. The memory360is coupled to the main processor340. Part of the memory360could include a random access memory (RAM), and another part of the memory360could include a Flash memory or other read-only memory (ROM). AlthoughFIG.3illustrates one example of UE116, various changes may be made toFIG.3. For example, various components inFIG.3could be combined, further subdivided, or omitted and additional components could be added according to particular needs. As a particular example, the main processor340could be divided into multiple processors, such as one or more central processing units (CPUs) and one or more graphics processing units (GPUs). Also, whileFIG.3illustrates the UE116configured as a mobile telephone or smartphone, UEs could be configured to operate as other types of mobile or stationary devices. FIG.4illustrates an example deployment scenario400of small cells402and macro cells404according to this disclosure. In some embodiments, regarding small cell enhancement, 3PP TR 36.932 REF4 describes the target scenarios of a small-cell study. Small cell enhancement may target with and without macro coverage, outdoor and indoor small cell deployments, and ideal and non-ideal backhaul. Both sparse and dense small cell deployments may be considered. In various embodiments with and without macro coverage, as shown inFIG.4, small cell enhancement can target the deployment scenario in which small cell nodes are deployed under the coverage of one or more overlaid E-UTRAN macro-cell layer(s) in order to boost the capacity of the already-deployed cellular network. In various embodiments, example scenarios can include: 1) where the UE is in coverage of both the macro cell and the small cell simultaneously; and 2) where the UE is not in coverage of both the macro cell and the small cell simultaneously. FIG.4also shows the scenario where small cell nodes, such as the small cell node in an area406, are not deployed under the coverage of one or more overlaid E-UTRAN macro-cell layer(s)408. This scenario may also be the target of the small cell enhancement SI. FIGS.5A and5Billustrate an example quasi-cell502, new carrier type (NCT) cell504, and backward compatible cell506according to this disclosure. In some embodiments, the quasi-cell502is co-channel-deployed on a carrier (or a carrier frequency) together with cells504and506. The quasi-cell502and the cells504and506may have been placed in two geographically separated locations. Quasi-cell502is identified by a quasi-cell specific discovery signal (and discovery identifier or “ID”). An advanced UE can identify quasi-cell502by detecting a quasi-cell specific discovery signal, while a legacy UE may not identify quasi-cell502. The network can make use of the quasi-cell502to transmit physical downlink shared channel (PDSCH) data to both the legacy UE and the advanced UE. When the advanced UE receives PDSCH data from quasi-cell502, the advanced UE may be aware that it is receiving the PDSCH data from quasi-cell502. Even when the legacy UE receives PDSCH data from quasi-cell502, the operation of quasi-cell502is transparent to the legacy UE, and the legacy UE does not know the existence of quasi-cell502as it operates according to the legacy specification where no specific protocols are defined for the quasi-cells. In some embodiments, quasi-cell502may not be a traditional cell, as it does not carry PSS/SSS to be used for identifying the cell and physical cell ID (PCI). In some embodiments, in 3GPP LTE, there may be a number of downlink (DL) assignment downlink control information (DCI) formats, which convey scheduling information, such as set of scheduled physical resource blocks (PRB)s, transmission rank, set of antenna port numbers, modulation and coding scheme, transmit power control (TPC) command for PUCCH, and the like. Example DL assignment DCI formats can be found in 36.212 REF2, which include DCI format 1A/1C/2/2A/2B/2C/2D. In this disclosure, the phrase “DL assignment DCI format” is used for referring to these DCI formats and variants of them. In some embodiments, in the legacy RAN2 specification (36.331 v10.5.0), Pcell, Scell and serving cell may be defined in the following manner:Primary Cell (Pcell): The cell, operating on the primary frequency, in which the UE either performs the initial connection establishment procedure or initiates the connection re-establishment procedure, or the cell indicated as the primary cell in the handover procedure.Secondary Cell (Scell): A cell, operating on a secondary frequency, which may be configured once an RRC connection is established and which may be used to provide additional radio resources.Serving Cell: For a UE in RRC_CONNECTED not configured with CA, there is only one serving cell comprising of the primary cell. For a UE in RRC_CONNECTED configured with CA, the term “serving cells” is used to denote the set of one or more cells including the primary cell and all secondary cells. In some embodiments, in the media access control/radio resource control (MAC/RRC) layer perspective (RAN2), the Pcell (macro) handles mobility and initial access of the UE, while the Scell is used for data transmission/reception. This way, too frequent handover between multiple pico cells can be avoided. In physical (PHY) layer specifications (RAN1), in some embodiments, the terms Pcell and Scell are adopted to define UE behaviors associated with UL/DL control signaling. Some examples are: PUCCHs are transmitted only in the Pcell; when only the Pcell transmits PDSCH to a UE configured with multiple serving cells, the UE transmits the corresponding HARQ-ACK using PUCCH format 1a/1b; when an Scell transmits PDSCH to the UE, the UE transmits the corresponding HARQ-ACK using PUCCH format 3 (as in Table 1); and common DL control signaling (PDCCH/ePDCCH common search space) is transmitted only in the Pcell. In various embodiments of this disclosure, the Pcell is defined in Rel-10/11 as the legacy Pcell. FIGS.6A through6Dillustrate example inter-eNB CA and CoMP systems600a-600d according to this disclosure. InFIGS.6A through6D, communications occur between a UE606a-606d and two eNBs, namely eNB602a-602d and eNB604a-604d. The eNBs are operating in the same carrier frequency inFIGS.6C and6Dand in two different carrier frequencies inFIGS.6A and6B. InFIGS.6A through6D, one of the two eNBs (cell 1) is a macro eNB, while the other eNB (cell 2) is a pico eNB. However, the concepts in this disclosure can generally apply to two eNBs of any types. The eNBs may be connected with a slow backhaul, where one message transmission from one eNB to the other eNB (or signaling delay between two eNBs) may take more than a few milli-seconds, such as tens of milli-seconds (or subframes). FIG.6Aillustrates a frequency division duplex (FDD) inter-eNB CA system600a. The system600a includes eNBs602a and604a and UE606a. In system600a, UE606a is configured with two serving cells on two different carrier frequencies. The UE606a transmits and receives signals to/from the macro eNB602a on carrier frequencies f1-DL and f1-UL, respectively. The UE606a transmits and receives signals to/from the pico eNB604a on carrier frequencies f2-DL and f2-UL, respectively. FIG.6Billustrates a time division duplex (TDD) inter-eNB CA system600b. The system600b includes eNBs602b and604b and UE606b. In some embodiments, in system600b, UE606b is configured with two serving cells on two different carrier frequencies. The UE606b transmits and receives signals to/from the macro eNB602b on carrier frequencies F1, and the UE606b transmits and receives signals to/from the pico eNB604b on carrier frequencies F2. FIG.6Cillustrates an FDD inter-eNB COMP system600c. The system600c includes eNBs602c and604c and UE606c. In some embodiments, the UE606c is configured to support simultaneous reception of 2 PDSCHs from two serving cells (such as the macro and pico cells) on the same carrier frequency, f1-DL for DL and f1-UL for UL. FIG.6Dillustrates a TDD inter-eNB COMP system600d. The system600d includes eNBs602d and604d and UE606d. In some embodiments, the UE606d is configured with a transmission mode (TM) supporting reception of 2 PDSCHs from two serving cells (such as the macro and pico cells) on the same carrier frequency, F1. For the operations described inFIGS.6A through6D, in some embodiments, the UE may be configured with two serving cells (operating in two carrier frequencies in the cases ofFIGS.6A and6Bor in the same carrier frequency in the cases ofFIGS.6C and6D) according to 3GPP LTE Rel-10 carrier-aggregation specifications. In the Rel-10 carrier aggregation, the assumption is that two cells are either co-located in a single site or, while not co-located, the backhaul delay is negligible (or the signaling delay between the two cells is significantly less than one subframe) so that the two cells in two different sites can operate as if they are in a single site. In such an example, the downlink/uplink scheduling information (such as for PDSCH and PUSCH) of the two cells are dynamically available at each of the two cells. There are several Rel-10 carrier aggregation operations that rely on the assumption of the dynamically available scheduling information. One such example is PUCCH HARQ-ACK transmissions. In Rel-10, PUCCH can be transmitted only on the primary cell (Pcell) out of the two cells. A PUCCH resource in response to dynamically scheduled PDSCHs is determined by at least one of the dynamically available information, such as a CCE index of a PDCCH scheduling the PDSCH in the Pcell, a state of a TPC field in the PDCCH scheduling the secondary cell's (Scell's) PDSCH, and/or the like. FIGS.7A-7Billustrate a primary CA group (PCG)702and a secondary CA group (SCG)704according to an advantageous embodiment of the present disclosure. In an embodiment, the association of cell(s) with the special cell(s) can be realized by grouping cells configured to the UE into one or more CA groups. A CA group can contain one or more than one cells. The cells that are grouped into a CA group are associated with a particular eNodeB (e.g. either serving eNodeB or drift eNodeB). The Uplink Control Information (UCI) (e.g. HARQ-ACK, CSI) for the SCell(s) in one CA group, is transmitted to the cell(s) belonging to the same CA group. In other words, the UCI for cell(s) in one CA group may never be transmitted to the cell(s) in another CA group. In an embodiment, the CA group comprising of the PCell may be referred to as the Primary CA group (PCG) and the CA group not comprising of the PCell may be referred to as the Secondary CA group (SCG). There may be one PCG but there can be zero, one, or more than one SCG. In an embodiment, the eNodeB handling the PCG may be referred to as the PCG eNodeB, and the eNodeB handling the SCG may be referred to as the SCG eNodeB. In an embodiment,FIG.7Aillustrates a configuration of primary702a and secondary704a CA groups (CG) for inter-eNB CA scenarios. Primary CG702a and second CG704a are sometimes called CG1 and CG2, respectively. Assuming coordination over X2 interface, Rel-10/11 basic CA framework can be maintained but enhanced with eNB-centric procedures:‘Main’ RRC connection to the macro cell (cell 1), ‘sub’-RRC connection to the small cell (or pico, or cell 2).(a) Still only one real RRC connection, i.e. RAN node having a signaling connection to the CN.Carriers are grouped based on their associations with eNBs: Primary Carrier Group (PCG) and one or more Secondary Carrier Group (SCG).No cross carrier scheduling possible between CGs. Cross carrier scheduling within each CG is still possible.The UL carriers of respective CG should belong to different Timing Advance Groups (TAG).Random access procedures performed fully in respective CG.UCIs belonging to different CG are transmitted in the UL carrier(s) of respective CG. In an embodiment,FIG.7Billustrates a configuration of 1st702b and 2nd704b primary CA groups for inter-eNB CA scenarios. 1st PCG702b and the 2nd PCG704b are sometimes called CG1 and CG2, respectively. Assume no coordination over X2 interface (however coordination may be possible over S1), each CG is independently RRC connected (dual RRC connections).RRC connection state of each cell at a given time can be different.(a) If both RRC connected, two C-RNTIs(b) Amount of traffic going through each eNB is controlled at S-GW. In an embodiment, it is also possible to define a CG to be the same as a Timing Advance Group (TAG) with the properties as described above for CG. Physical channels to carry UCI: Aperiodic CSI is carried on a PUSCH, regardless of whether HARQ-ACK/SR is fed back in the same subframe or not for the same CG. HARQ-ACK/SR is carried on PUCCH format 1/1a/1b/3 and PUCCH format 1b with channel selection if not multiplexed with periodic CSI and if no PUSCH is scheduled in the same CG; on PUCCH format 2a/2b/3 if multiplexed with periodic CSI and if no PUSCH is scheduled in the same CG; on PUSCH if at least one PUSCH is scheduled in the same CG. Periodic CSI is carried in PUCCH format 2 if no PUSCH is scheduled in the same CG; on PUSCH if at least one PUSCH is scheduled in the same CG. Periodic CSI prioritization/dropping rule REF3 describes the following on the periodic CSI feedback. The following CQI/PMI and RI reporting types with distinct periods and offsets are supported for the PUCCH CSI reporting modes given in Table 7.2.2-3:Type 1 report supports CQI feedback for the UE selected sub-bandsType 1a report supports subband CQI and second PMI feedbackType 2, Type 2b, and Type 2c report supports wideband CQI and PMI feedbackType 2a report supports wideband PMI feedbackType 3 report supports RI feedbackType 4 report supports wideband CQIType 5 report supports RI and wideband PMI feedbackType 6 report supports RI and PTI feedback Table 1 represents PUCCH Reporting Type Payload size per PUCCH Reporting Mode and Mode State: PUCCHPUCCH Reporting ModesReportingMode 1-1Mode 2-1Mode 1-0Mode 2-0TypeReportedMode State(bits/BP)(bits/BP)(bits/BP)(bits/BP)1Sub-bandRI = 1NA4 + LNA4 + LCQIRI > 1NA7 + LNA4 + L1aSub-band8 antenna ports RI = 1NA8 + LNANACQI/8 antenna ports 1 < RI < 5secondNA9 + LNANAPMI8 antenna ports RI > 4NA7 + LNANA2Wideband2 antenna ports RI = 166NANACQI/PMI4 antenna ports RI = 188NANA2 antenna ports RI > 188NANA4 antenna ports RI > 11111NANA2aWideband8 antenna ports RI < 3NA4NANAfirst PMI8 antenna ports 2 < RI < 8NA2NANA8 antenna ports RI = 8NA0NANA2bWideband8 antenna ports RI = 188NANACQI/8 antenna ports 1 < RI < 41111NANAsecond8 antenna ports RI = 41010NANAPMI8 antenna ports RI > 477NANA2cWideband8 antenna ports RI = 18NANANACQI/first8 antenna ports 1 < RI ≤ 411NANANAPMI/8 antenna ports 4 < RI ≤ 79NANANAsecond8 antenna ports RI = 87NANANAPMI3RI2/4 antenna ports, 2-1111layer spatialmultiplexing8 antenna ports, 2-1NANANAlayer spatialmultiplexing4 antenna ports, 4-2222layer spatialmultiplexing8 antenna ports, 4-2NANANAlayer spatialmultiplexing8-layer spatial3NANANAmultiplexing4WidebandRI = 1 or RI > 1NANA44CQI5RI/first8 antenna ports, 2-4NANANAPMIlayer spatialmultiplexing8 antenna ports, 4 and58-layer spatialmultiplexing6RI/PTI8 antenna ports, 2-NA2NANAlayer spatialmultiplexing8 antenna ports, 4-NA3NANAlayer spatialmultiplexing8 antenna ports, 8-NA4NANAlayer spatialmultiplexing In case of collision of a CSI report with PUCCH reporting type 3, 5, or 6 of one serving cell with a CSI report with PUCCH reporting type 1, 1a, 2, 2a, 2b, 2c, or 4 of the same serving cell the latter CSI report with PUCCH reporting type (1, 1a, 2, 2a, 2b, 2c, or 4) has lower priority and is dropped. For a serving cell and UE configured in transmission mode10, in case of collision between CSI reports of same serving cell with PUCCH reporting type of the same priority, and the CSI reports corresponding to different CSI processes, the CSI reports corresponding to all CSI processes except the CSI process with the lowest CSIProcessIndex are dropped. If the UE is configured with more than one serving cell, the UE transmits a CSI report of only one serving cell in any given subframe. For a given subframe, in case of collision of a CSI report with PUCCH reporting type 3, 5, 6, or 2a of one serving cell with a CSI report with PUCCH reporting type 1, 1a, 2, 2b, 2c, or 4 of another serving cell, the latter CSI with PUCCH reporting type (1, 1a, 2, 2b, 2c, or 4) has lower priority and is dropped. For a given subframe, in case of collision of CSI report with PUCCH reporting type 2, 2b, 2c, or 4 of one serving cell with CSI report with PUCCH reporting type 1 or 1a of another serving cell, the latter CSI report with PUCCH reporting type 1, or 1a has lower priority and is dropped. For a given subframe and UE configured in transmission mode1-9for all serving cells, in case of collision between CSI reports of different serving cells with PUCCH reporting type of the same priority, the CSI of the serving cell with lowest ServCellIndex is reported, and CSI of all other serving cells are dropped. For a given subframe and serving cells with UE configured in transmission mode10, in case of collision between CSI reports of different serving cells with PUCCH reporting type of the same priority and the CSI reports corresponding to CSI processes with same CSIProcessIndex, the CSI reports of all serving cells except the serving cell with lowest ServCellIndex are dropped. For a given subframe and serving cells with UE configured in transmission mode10, in case of collision between CSI reports of different serving cells with PUCCH reporting type of the same priority and the CSI reports corresponding to CSI processes with different CSIProcessIndex, the CSI reports of all serving cells except the serving cell with CSI reports corresponding to CSI process with the lowest CSIProcessIndex are dropped. For a given subframe, in case of collision between CSI report of a given serving cell with UE configured in transmission mode1-9, and CSI report(s) corresponding to CSI process(es) of a different serving cell with the UE configured in transmission mode10, and the CSI reports of the serving cells with PUCCH reporting type of the same priority, the CSI report(s) corresponding to CSI process(es) with CSIProcessIndex>1 of the different serving cell are dropped. For a given subframe, in case of collision between CSI report of a given serving cell with UE configured in transmission mode1-9, and CSI report corresponding to CSI process with CSIProcessIndex=1 of a different serving cell with the UE configured in transmission mode10, and the CSI reports of the serving cells with PUCCH reporting type of the same priority, the CSI report of the serving cell with highest ServCellIndex is dropped. In REF 3, the prioritization of one type of periodic CSI over another is described in a way that the de-prioritized CSI is always dropped. However, in some embodiments of the current disclosure, the de-prioritized CSI is differently handled even if the same prioritization rules are considered. When the UE inFIG.6operates in one of the configurations inFIG.7, the PUCCH transmissions for the two CGs are independently configured, and hence the UE may be scheduled to transmit two PUCCHs on the two UL Pcells in the two CGs in a subframe. The UE's transmitting two PUCCHs in one subframe can be problematic, because the UE may experience power limitation in the subframe. When the UE is power limited, the UE cannot transmit the two PUCCHs with fully configured power, and the UE may have to reduce the power of at least one of the PUCCHs to meet the UE's power class (e.g., the UE's total transmission power cannot exceed 23 dBm, or Pcmax≤23 dBm). When the power-reduced PUCCH is received together with other full-power PUCCH at an eNB, the power-reduced PUCCH may not be as reliably received as the full-power PUCCH, especially when the power-reduced PUCCH and the full-power PUCCH are transmitted in a same pair of PRBs. This issue is similar to near-far effects happening in CDMA systems. To resolve the “near-far” effects, it is proposed that at least in case of power limitation, the UE drops one PUCCH out of the two scheduled PUCCHs and transmits only one PUCCH according to a PUCCH prioritization rule. FIG.8illustrates an example process800for Collision handling when multiple PUCCHs are scheduled in a sub-frame according to an embodiment of this disclosure. The processes depicted here could be used by any suitable devices, such as the eNBs and UEs inFIG.6. In an embodiment, consider a UE inFIG.6operating in one of the configurations inFIG.7. In operations802and804, the UE is scheduled to transmit a set of UCI (e.g., HARQ-ACK, CSI, SR, or the like) to each of the CGs 1 and 2 in subframe n. Additionally, no PUSCHs have been scheduled for the UE to be transmitted in subframe n. In an embodiment, for each CG, a subset of UCI is selected from the set of UCI intended for the CG, and a PUCCH format to carry the subset of UCI is determined, according to Rel-11 CA procedure. In operation806, the UE selects one out of the two PUCCHs to transmit in subframe n. The selected PUCCH is determined according to a prioritization rule and the other PUCCH is dropped. FIG.9illustrates an example process900for Collision handling when multiple PUCCHs are scheduled in a sub-frame according to an embodiment of this disclosure. The processes depicted here could be used by any suitable devices, such as the eNBs and UEs inFIG.6. In an embodiment, consider a UE inFIG.6operating in one of the configurations inFIG.7. In operations902and904, the UE is scheduled to transmit a set of UCI (e.g., HARQ-ACK, CSI, SR, or the like) to each of the CGs 1 and 2 in subframe n. Additionally, no PUSCHs have been scheduled for the UE to be transmitted in subframe n. In an embodiment, for each CG, a subset of UCI is selected from the set of UCI intended for the CG, and a PUCCH format to carry the subset of UCI is determined, according to Rel-11 CA procedure. Furthermore, the UE operation of transmitting PUCCH in the subframe depends upon whether the UE is power-limited in the current subframe or not. The UE is said power-limited if total power, i.e., the sum of the individually calculated two PUCCHs' powers is greater than the UE's power class, or PCMAX(i) dB (or {circumflex over (P)}CMAX(i) in linear scale). In operation906, if the UE is not power limited, then at operation908, the two PUCCHs are simultaneously transmitted on their respective CGs. In operation906, if the UE is power limited, then at operation910, the UE transmits, in operation912, only one of the two PUCCHs, where in operation910, the one selected PUCCH is determined according to a prioritization rule. In one or more embodiments, the term “selected” may be a prioritization of one PUCCH over another. For example, power may be allocated to a selected PUCCH with remaining power allocated to any other PUCCHs. For processes800and900, a prioritization rule for the colliding PUCCHs has to be defined. In this application, we propose the following for that. In an embodiment, PUCCH format dependent prioritization exists where one PUCCH format is prioritized over another PUCCH format. PUCCH formats carrying HARQ-ACK can be regarded as more important for the system operation than PUCCH formats carrying CSI. Hence, a PUCCH format carrying HARQ-ACK is prioritized over a PUCCH format carrying CSI. For example, PUCCH format 1a/1b is prioritized over PUCCH format 2. Between PUCCH formats carrying HARQ-ACK, PUCCH formats for CA are prioritized over PUCCH formats for non-CA, as the PUCCH formats for CA carry more information than the PUCCH formats for non-CA. For example, PUCCH format 3 used for carrying HARQ-ACK and PUCCH format 1a/1b with channel selection is prioritized over PUCCH format 1a/1b. Between a PUCCH format carrying multiple types of information (e.g., HARQ-ACK and CSI) and a PUCCH format carrying a single type of information, the PUCCH format carrying multiple types of information is prioritized, for minimizing the loss. For example, PUCCH format 2a/2b is prioritized over PUCCH format 1a/1b and PUCCH format 2. For example, PUCCH format 3 carrying HARQ-ACK and CSI is prioritized over PUCCH format 3 carrying HARQ-ACK only. Between PUCCH format 1 (only positive SR) and PUCCH format 2 (only periodic CSI), positive SR is prioritized. In this embodiment, the UE can send positive SR without interruption owing to CSI feedback in another CG. Considering these three prioritization principles, alternatives for the complete prioritization list are summarized below (where ‘A<B’ means that A has smaller priority than B): Alt 1: PUCCH format 2<PUCCH format 1<PUCCH format 1a/1b<PUCCH format 2a/2b<PUCCH format 1a/1b with channel selection<PUCCH format 3 carrying HARQ-ACK only<PUCCH format 3 carrying HARQ-ACK and CSI. Here, between two PUCCH formats used for HARQ-ACK in CA, PUCCH format 3 is prioritized over PUCCH format 1a/1b with channel selection because PUCCH format 3 can potentially carry more HARQ-ACK information bits than PUCCH format 1a/1b with channel selection. Alt 2: PUCCH format 2<PUCCH format 1<PUCCH format 1a/1b<PUCCH format 2a/2b<PUCCH format 1a/1b with channel selection=PUCCH format 3 carrying HARQ-ACK only<PUCCH format 3 carrying HARQ-ACK and CSI. Here, the two PUCCH formats used for HARQ-ACK in CA are equally prioritized. Alt 3: PUCCH format 2<PUCCH format 1; and a PUCCH format conveying a larger HARQ-ACK payload is prioritized over a PUCCH format conveying a smaller HARQ-ACK payload. The HARQ-ACK payload is determined by a number of configured cells in a CG, a respective PDSCH transmission mode (conveying either one or two transport blocks) and, for a TDD system, a maximum number of DL subframes for which a UE transmits HARQ-ACK in an UL subframe (this maximum number of DL subframes is also referred to as a bundling window). Tie-breaking rules: The PUCCH format dependent prioritization can be firstly used to determine which PUCCH format to transmit in the subframe. However, it may happen that the two PUCCHs have the same PUCCH format or that two PUCCHs may have the same priority (e.g. as in Alt 2 above). Then tie-breaking rules are necessary for the UE to determine the PUCCH to transmit in the subframe. Between two identical PUCCH formats for HARQ-ACK/SR, or two PUCCH formats for HARQ-ACK/SR with the same priority: Two alternatives are considered. Alt 1: PUCCH scheduled in the CG with a lower CG index among the two configured CGs is transmitted. Alternatively, when PCG and SCG are configured, PCG is prioritized over SCG, and only the PUCCH scheduled in the PCG is transmitted. This is beneficial if the SCG is primarily used to carry best-effort traffic and the PCG is primarily used to carry traffic with more stringent QoS requirement. Alt 2: First compare the number of HARQ-ACK bits in the two PUCCHs; if a first PUCCH carries more HARQ-ACK bits than a second PUCCH, only the first PUCCH is transmitted. Here, the number of HARQ-ACK bits may imply the number of configured HARQ-ACK bits, calculated based upon the configured TMs in the configured serving cells and, for a TDD system, the bundling window size. If the first and the second PUCCHs carry the same number of HARQ-ACK bits, PUCCH in the CG with a lower CG index among the two configured CGs is transmitted; or alternatively, PCG is prioritized over SCG, and only the PUCCH scheduled in the PCG is transmitted. Between two identical PUCCH formats for CSI, or two PUCCH formats for CSI with the same priority: Alt 1: PUCCH scheduled in the CG with a lower CG index among the two configured CGs is transmitted. When PCG and SCG are configured, PCG is prioritized over SCG, and only the PUCCH scheduled in the PCG is transmitted. This is beneficial if the SCG is primarily used to carry best-effort traffic and the PCG is primarily used to carry traffic with more stringent QoS requirement. Alt 2: First compare CSI type carried in the two scheduled PUCCHs; if a first PUCCH carries more prioritized CSI type than a second PUCCH, only the first PUCCH is transmitted (See the background section of Periodic CSI dropping rule). If the first and the second PUCCHs carry the same type of CSI, PUCCH in the CG with a lower CG index among the two configured CGs is transmitted; or alternatively, PCG is prioritized over SCG, and only the PUCCH scheduled in the PCG is transmitted. In another alternative, we may consider an RRC-configuration based prioritization. In one example, CGs are configured with CG indices. The PUCCH scheduled in a CG with the smallest index is prioritized over the other PUCCHs. Power allocation when PUCCH and PUSCH with UCI are scheduled in a subframe Consider a UE inFIG.6operating in one of the configurations inFIG.7. Suppose the UE is scheduled to transmit a set of UCI (HARQ-ACK, CSI, SR, or the like) to each of CGs 1 and 2 in subframe n. Further suppose that at least one PUSCH for a first CG has been scheduled for the UE to be transmitted in subframe n, but the UE is not scheduled to transmit any PUSCHs on a second CG. Then, for the second CG (without PUSCH), a subset of UCI is selected from the set of UCI intended for the CG, and a PUCCH format to carry the subset of UCI is determined, according to the Rel-11 CA procedure. In addition, for the first CG (with PUSCH(s)), a subset of UCI is selected from the UCI intended for the CG and multiplexed on one selected PUSCH according to the Rel-11 CA procedure. At times, e.g., at subframe i, the sum of the powers for PUCCH and PUSCH with UCI may exceed the UE's power class {circumflex over (P)}CMAX(i) (i.e., the UE is power limited). To resolve the power limitation in this embodiment, two alternative methods, i.e., Method 3 and Method 4 are considered. Method 3: When power-limited, the power prioritization is that PUCCH>PUSCH with UCI>PUSCH without UCI. In this embodiment, a PUSCH transmission with UCI in serving cell j and the other PUSCH transmission without UCIs in any of the remaining serving cells on the first CG should be power-controlled so that the total transmit power of the UE would not exceed {circumflex over (P)}CMAX(i), as in the following: Firstly, assign full power PPUCCH(i) on the PUCCH. Secondly, give the smaller of the full power {circumflex over (P)}PUSCH,j(i) and the remaining power, to PUSCH with UCI in serving cell j. Finally, equally scale the remaining power to PUSCHs without UCI in serving cell c's. In this embodiment, the UE obtains {circumflex over (P)}PUSCH,j(i) and {circumflex over (P)}PUSCH,c(i) according to P^PUSCH,j(i)=min(P^PUSCH,j(i),(P^CMAX(i)-P^PUCCH(i)))and∑c∉jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-P^PUCCH(i)-P^PUSCH,j(i)). where {circumflex over (P)}PUCCH(i) is the linear value of PPUCCH(i), {circumflex over (P)}PUSCH,c(i) is the linear value of PPUSCH,c(i), {circumflex over (P)}CMAX(i) is the linear value of the UE total configured maximum output power PCMAXdefined in REF6 in subframe i and w(i) is a scaling factor of {circumflex over (P)}PUSCH,c(i) for serving cell c where 0≤w (i)≤1, In case there is no PUCCH transmission in subframe i{circumflex over (P)}PUCCH(i)= Method 4: When power limited, power prioritization is dependent upon the contents of the UCI carried on the PUSCH and the PUCCH. When PUCCH is prioritized over PUSCH with UCI, the UE obtains {circumflex over (P)}PUSCH,j(i) and {circumflex over (P)}PUSCH,c(i) according to P^PUSCH,j(i)=min(P^PUSCH,j(i),(P^CMAX(i)-P^PUCCH(i)))and∑c≠jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-P^PUCCH(i)-P^PUSCH,j(i)). On the other hand, when PUSCH with UCI is prioritized over PUCCH, two alternatives are considered. In one alternative (PUCCH Power Allocation Alt 1), the UE obtains {circumflex over (P)}PUSCH,j(i) and {circumflex over (P)}PUSCH,c(i) according to P^PUCCH(i)=min(P^PUCCH(i),(P^CMAX(i)-P^PUSCH,j(i)))and∑c≠jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-P^PUCCH(i)-P^PUSCH,j(i)). This alternative ensures that the less-prioritized PUCCH is still transmitted, even if the transmission power is reduced. In another alternative (PUCCH Power Allocation Alt 2), the PUCCH is transmitted only when the UL transmission is not power limited; the PUCCH is dropped when the UL transmission is power limited. In other words, the UE obtains {circumflex over (P)}PUSCH,j(i) and {circumflex over (P)}PUSCH,c(i) according to P^PUCCH(i)={P^PUCCH(i),ifP^PUSCH,j(i)+P^PUCCH(i)≤P^CMAX(i)0otherwise,and∑c≠jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-P^PUCCH(i)-P^PUSCH,j(i)). According to this alternative, the PUCCH is transmitted with its full power whenever the PUCCH is transmitted, and the PUCCH is dropped (or is assigned with zero power) when the remaining power after allocating full power to {circumflex over (P)}PUSCH,j(i) is not sufficient to transmit the PUCCH with the full power. This method eliminates the near-far effect. In one alternative, a PUSCH with UCI is prioritized over a PUCCH in at least one of the following cases: The PUSCH carries aperiodic CSI. The PUSCH is transmitted in the CG with lower index than the CG in which the PUCCH is scheduled. The eNB can configure CG indices for the configured CGs. The PUSCH carries UCI with higher priority than the UCI carried by the PUCCH For example, the PUSCH carries HARQ-ACK and the PUCCH does not carry HARQ-ACK. For example, the PUSCH carries HARQ-ACK with higher payload than the HARQ-ACK carried by the PUCCH Otherwise, the PUCCH is prioritized over the PUSCH with UCI. Aperiodic CSI is most prioritized so that an eNB can expect to receive aperiodic CSI whenever the eNB has triggered the aperiodic CSI in a respective CG. Between HARQ-ACK/SR and periodic CSI, HARQ-ACK/SR is prioritized to ensure reliable HARQ operation. Power allocation when at least two PUSCHs with UCI are scheduled in a subframe Consider a UE inFIG.6operating in one of the configurations inFIG.7. Suppose the UE is scheduled to transmit a set of UCI (HARQ-ACK, CSI, SR, or the like) to each of CGs 1 and 2 in subframe n. Further suppose that at least one PUSCH for each of a first CG and a second CG has been scheduled for the UE to be transmitted in subframe n. For each of the first and the second CGs (with PUSCH(s)), a subset of UCI is selected from the UCI intended for the CG and multiplexed on one selected PUSCH according to the Rel-11 CA procedure. At times, e.g., at subframe i, the sum of the powers for PUCCH and PUSCH with UCI may exceed the UE's power class {circumflex over (P)}CMAX(i) i.e., the UE is power limited. In this embodiment, PUSCH transmissions with UCI in serving cell j1 and serving cell j2 the other PUSCH transmission without UCIs in any of the remaining serving cells should be power-controlled so that the total transmit power of the UE would not exceed {circumflex over (P)}CMAX(i) The set of serving cell indices for carrying PUSCHs with UCI are denoted by J, which is J={j1, j2} in this embodiment. Two alternative methods for resolving the power limitation issue, i.e., Method 5 and Method 6 are considered as in the following. Method 5: When power limited, the two PUSCHs with UCI are equally prioritized over the PUSCHs without UCI in the power control, as in the following: If the sum of the two PUSCH transmission powers in serving cell j1 and j2 exceeds total power (i.e., {circumflex over (P)}PUSCH,j1(i)+{circumflex over (P)}PUSCH,j2(i)>{circumflex over (P)}CMAX(i)), then, apply the same scaling factor w(i) for the PUSCHs with UCI so that the total power does not exceed {circumflex over (P)}CMAX(i) (i.e., (i.e.,∑j∈Jw(i)·P^PUSCH,j(i)≤P^CMAX(i)), and assign 0 power to the other PUSCHs. Otherwise, firstly assign full power to PUSCH transmissions with UCI in serving cell j1 and j2; then equally split the remaining power to PUSCHs without UCI in serving cell c's (i.e.,∑c∉Jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-∑j∈JP^PUSCH,j(i))). Method 6: When power limited, power allocation to a PUSCH carrying UCI with higher priority is more prioritized, than the UCI carried by the other PUSCH. When PUSCH in serving cell j1 is prioritized over PUSCH in serving cell j2 in the power allocation, the power control is performed according to the following: If the sum of the two PUSCH transmission powers in serving cell j1 and j2 exceeds total power (i.e., {circumflex over (P)}PUSCH,j1(i)+{circumflex over (P)}PUSCH,j2(i)>{circumflex over (P)}CMAX(i)), then, assign full power to the PUSCH in serving cell j1, and assign the remaining power to the PUSCHs in serving cell j2 (i.e., {circumflex over (P)}PUSCH,j2(i)=min({circumflex over (P)}PUSCH,j2(i), ({circumflex over (P)}PUSCH,j2(i), ({circumflex over (P)}CMAX(i)−{circumflex over (P)}PUSCH,j1(i)))), and assign 0 power to the other PUSCHs. Otherwise, first assign full power to PUSCH transmissions with UCI in serving cell j1 and j2; then apply the same scaling factor w(i) for the PUSCHs without UCI in serving cell c's so that the total power does not exceed {circumflex over (P)}CMAX(i) (i.e., ∑c∉Jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-∑j∈JP^PUSCH,j(i))). In one alternative UCI prioritization, aperiodic CSI (with/without HARQ-ACK/SR)>HARQ-ACK/SR (with or without periodic CSI)>Periodic CSI (without HARQ-ACK). When all the PUSCHs with UCI carry the same priority UCI, alternative methods for the power limitation case are: Alt 1: The same scaling factor is applied to the PUSCHs with UCI so that the total transmission power does not exceed P^CMAX(i)(i.e.,∑j∈Jw(i)·P^PUSCH,j(i)≤P^CMAX(i)) Alt 2: The PUSCH transmitted in the PCG is prioritized and the PUSCH transmitted in the SCG is allocated the remaining power or its transmission is suspended by the UE. Alt 3: The UE decides which of the PUSCHs to prioritize depending upon the contents of the UCI. When the same priority UCI is HARQ-ACK/SR, one PUSCH carrying more number of HARQ-ACK bits is prioritized over another PUSCH in the power allocation. When the numbers of HARQ-ACK bits are identical for all the PUSCHs with UCI, one of Alt 1 or Alt 2 is used for the power allocation. When the same priority UCI is periodic CSI, one PUSCH carrying more prioritized periodic CSI according to Rel-11 periodic CSI prioritization/dropping rule is prioritized over another PUSCH in the power allocation. When the types of periodic CSI are identical, one of Alt 1 or Alt 2 is used for the power allocation. Embodiment: CG-Priortization-Index Based Prioritization For simplicity, we propose CG-prioritization-index based prioritization for UCI transmission. Here, it is noted that the eNB can configure CG-prioritization-index for the configured CGs in the higher layer (e.g., RRC). We denote the RRC information element (IE) configuring a CG by CG-Config. In one alternative, the CG-prioritization-index is the same as the CG index (CG-Identity), and it is not explicitly signaled. In this embodiment, the CG-Config may look like: CG-Config {...CG-Identity Integer...} In one example, CG-Identity for the PCG has the smallest value among the configured CG-Identity values. In another example CG-Identity for the PCG is equal to 0 and CG-Identity for SCGs is greater than 0. In one alternative, the CG-prioritization-index (CG-Prioritization-Identity) is configured as a field in the IE configuring a CG. In this embodiment, the CG-Config may look like: CG-Config {...CG-Identity IntegerCG-Prioritization-Identity Integer...} In one alternative, two CG-prioritization-indices are configured per CG, one for HARQ-ACK (CG-Prioritization-HARQ-ACK-Identity) and the other for periodic CSI (CG-Prioritization-PCSI-Identity). In this embodiment, the CG-Config may look like: CG-Config {...CG-Identity IntegerCG-Prioritization-HARQ-ACK-Identity IntegerCG-Prioritization-PCSI-Identity Integer...} When two PUCCHs are scheduled in a subframe for the UE: In one alternative, the PUCCH scheduled in a CG with the lowest CG-prioritization-index is transmitted, while the other PUCCHs are dropped. In another alternative, when power is not limited, both PUCCHs are transmitted; when power is limited, the PUCCH scheduled in a CG with the lowest CG-prioritization-index is transmitted, while the other PUCCHs are dropped. When power limited, when PUCCHs and PUSCHs with UCI are scheduled for the UE in a subframe, between the PUxCHs for UCI transmission, the PUxCH scheduled in a CG with a lower CG-prioritization-index is prioritized in power allocation. In case PUSCHs without UCI are also scheduled in the same subframe, the remaining power after allocating the power to the PUxCH(s) are allocated to the PUSCHs without UCI, applying equal power scaling. When power limited, when two PUSCHs with UCI are scheduled for the UE in a subframe, the two PUSCHs with UCI are prioritized over PUSCHs without UCI in the power allocation. Between the PUSCHs with UCI, the PUSCH with UCI carried in the CG with smaller CG-prioritization-index is prioritized over the other PUSCH. If the sum of the two PUSCH transmission powers in serving cell j1 and j2, exceeds total power (i.e., {circumflex over (P)}PUSCH,j1(i)+{circumflex over (P)}PUSCH,j2(i)>{circumflex over (P)}CMAX(i)), then, assign full power to the PUSCH in serving cell j=min(j1, j2) and assign the remaining power to the PUSCHs in the other serving cell (for example, if j=j1, then the other serving cell is j2, and {circumflex over (P)}PUSCH,j2(i)=min({circumflex over (P)}PUSCH,j2(i), ({circumflex over (P)}CMAX(i)−{circumflex over (P)}PUSCH,j1(i)))), and assign 0 power to the other PUSCHs. Otherwise, firstly assign full power to PUSCH transmissions with UCI in serving cell j1 and j2; then equally split the remaining power to PUSCHs without UCI in serving cell c's (i.e.,∑c∉Jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-∑j∈JP^PUSCH,j(i))). FIG.10illustrates an example process1000for overall CG prioritization rule for UCI transmissions according to an embodiment of this disclosure. The processes depicted here could be used by any suitable devices, such as the eNBs and UEs inFIG.6. In an embodiment, In an embodiment, consider a UE inFIG.6operating in one of the configurations inFIG.7. In operations1002and1004, the UE is scheduled to transmit a set of UCI (e.g., HARQ-ACK, CSI, SR, or the like) to each of the CGs 1 and 2 in subframe n. Additionally, no PUxCHs have been scheduled for the UE to be transmitted in subframe n. In an embodiment, for each CG, a subset of UCI is selected from the set of UCI intended for the CG, and a PUxCH format to carry the subset of UCI is determined, according to Rel-11 CA procedure. PUxCH may be either a PUSCH or a PUCCH. Furthermore, the UE operation of transmitting PUxCH in the subframe depends upon whether the UE is power-limited in the current subframe or not. The UE is said power-limited if total power, i.e., the sum of the individually calculated two PUxCHs' powers is greater than the UE's power class, or dB (or in linear scale). In operation1006, if the UE is not power limited, then at operation1008, the two PUxCHs are simultaneously transmitted on their respective CGs. In operation1006, if the UE is power limited, then at operation1010, the UE transmits only one of the two PUxCHs, where in operation1010, the one selected PUxCH is determined according to a prioritization rule. In one or more embodiments, the term “selected” may be a prioritization of one PUxCH over another. For example, power may be allocated to a selected PUxCH with remaining power allocated to any other PUxCHs. In operation1014, a determination is made to whether there are any other PUSCHs scheduled. If there are not any other PUSCHs scheduled, then in operation1016, the UE transmits the n PUxCHs. If there are other PUSCHs, then in operation1018, the UE determines if the UE is power-limited when trying to transmit the PUSCHs as well as the PUxCHs carrying UCI. If not, then in operation1020, the UE assigns full power to the PUSCHs as well as PUxCHs carrying UCI, and transmits all the physical UL signals. If yes in operation1018, then the UE applies power scaling for the PUSCHs, and transmits all the physical UL signals. In an embodiment, a UE is configured with Nconf CGs. In one subframe, the UE is scheduled to transmit CSI in N CGs, where N≤Nconf. Relying on the Rel-11 procedure for each CG, the UE figures out that CSI for N1 CGs are supposed to be carried on PUCCH and the UE figures out that CSI for N2 CGs are supposed to be carried on PUSCH, where N=N1+N2. Then, the UE applies CG prioritization for UCI transmissions, as in the following. When not power limited, all the scheduled UL physical channels are transmitted in the subframe. The UE is said power-limited in subframe i if total power, i.e., the sum of the individually calculated scheduled PUxCHs' powers in subframe i is greater than the UE's power class, or PCMAX(i) dB (or {circumflex over (P)}CMAX(i) in linear scale). When power limited, the UCI transmitted in a CG in a lower CG index is prioritized. Among all the N PUxCH carrying UCI (i.e., PUxCH can be either PUCCH or PUSCH), the UE first tries to assign full power to the one PUxCH carrying UCI scheduled in the lowest CG index. For PUxCH carrying UCI scheduled in the CG with the second lowest CG index, the power allocation method is to choose a minimum value between the scheduled power value for the PUxCH according to the power control equation, and the remaining power. The power allocation continues in the same way until either all the PUxCHs carrying UCI are allocated with some powers, or there is no remaining power. This procedure can be represented by the following equation. P^PU×CH,nk+1(i)=min(P^PU×CH,nk+1(i),(P^CMAX(i)-∑l=IkP^PU×CH,nl(i))) Here, nkis the CG index for which the k-th prioritized PUxCH is scheduled. In one alternative, nkis the k-th smallest CG-prioritization-index among the N CG indices. In another alternative, the k-th prioritized PUxCH is determined by the UCI contents, according to the previous methods disclosed in this application. In one alternative, tie breaks according to the CG-prioritization-index, where a lower CG index prioritized. In another alternative, tie breaks according to one of the HARQ-ACK CG-prioritization-index and periodic CSI CG-prioritization-index, depending on the type of tie. For example, if the tie happens such that both tie CGs carry the periodic CSI (or HARQ-ACK), then between the two tie CGs, the CG with smallest periodic CSI (or HARQ-ACK) CG-prioritization-index is prioritized. For preventing near-far effects from happening for PUCCH transmissions, we may further impose a constraint. In one alternative, the constraint is such that any PUCCH that cannot be transmitted with full power is dropped. In other words, if {circumflex over (P)}PUCCH,nk+1(i) calculated from the above equation is less than the originally calculated power (i.e., {circumflex over (P)}PUCCH,nk+1(i) on the right hand side equation), the PUCCH is dropped and zero power is assigned to the PUCCH. In another alternative, the constraint is such that only one PUCCH (the most prioritized PUCCH) is transmitted in any given subframe. All the other scheduled PUCCHs will be assigned with zero power. This method is motivated for ensuring a simple specification. If there is any remaining power after allocating power to the N PUxCHs, equal power scaling is applied to allocate power to PUSCHs without UCI. This procedure can be represented by the following equation. ∑c∉Jw(i)·P^PUSCH,c(i)≤(P^CMAX(i)-∑l=1NP^PUSCH,nl(i)). FIG.11illustrates an example process1100for overall CG prioritization rule for UCI transmissions according to an embodiment of this disclosure. The processes depicted here could be used by any suitable devices, such as the eNBs and UEs inFIG.6. Process1100is similar to process1000, except in operation1110, the UE prioritizes one PUxCH instead of selects. In an embodiment, there may be a prioritization rule based on duplexing scheme/frame structure type. A UE can be configured with multiple cells that include one or more FDD cells and one or more TDD cells. A different duplexing method (FDD or TDD) among cells configured to a UE can result in different characteristics for respective UL transmissions. For a power limited UE, this motivates a dependence of an UL power allocation method or of a transmission prioritization rule on characteristics of respective UL transmissions. When the multiple cells are not-collocated, the UL transmissions should be targeted to their respective carrier groups. For example, UCI and UL data for a cell in a carrier group should be conveyed in UL resource belonging to the carrier group. FIGS.12A-12Billustrate example processes1202for rule based prioritization on duplexing scheme/frame structure type according to an embodiment of this disclosure. The processes depicted here could be used by any suitable devices, such as the eNBs and UEs inFIG.6. In process1200, at operation1202, the UE determines if it is power-limited when trying to transmit n scheduled PUxCHs. If the UE is not power-limited, at operation1208, the UE transmits all the n PUxCHs with full power. If the UE is power-limited, then in process1200a, the UE, at operation1204, prioritizes the PUxCH in a TDD cell over an FDD cell. Then, in operation1206, the UE transmits a m PUxCHs out of n PUxCHs, where m≤n, after applying the prioritization. In process1200b, between operation1202and operation1204, if the UE is power limited, the UE, at operation1203b, prioritizes PUxCH in a primary cell. In different embodiments, there may be different approaches to power allocation in the UL. Approach 1: UL power allocation to a TDD cell is prioritized over a FDD cell. This is motivated by the fact that there fewer subframes in a TDD cell than in a FDD cell for transmitting UCI or UL data and a UCI payload, such as a HARQ-ACK payload, is often larger in a TDD cell than in a FDD cell (for example, for TDD UL/DL configurations 1/2/3/4/5). Therefore, an impact from an incorrect reception of UCI or UL data in a TDD cell can be higher than in a FDD cell and UL power allocation to the TDD cell can be prioritized. Approach 2: UL power allocation in the primary cell in the primary carrier group is prioritized (regardless of the frame structure type of the cell). Approach 1 can then applied to the rest of the cells, i.e. TDD cell(s) is(are) prioritized over FDD cell(s). This can be beneficial because the primary carrier group may deliver important messages for the UE (control or configuration messages) and therefore the reception reliability for UCI or UL data to the primary cell should be prioritized. Approach 2a: The primary cell is prioritized for UL power allocation. Approach 1 can then be applied to the rest of the cells. This approach can be applied, e.g., when a UE is configured with N cells located in N different sites (in other words, the N cells may belong to N different CGs). Embodiment: Prioritization Rule Based on HARQ-ACK Payload Size In TDD, an HARQ-ACK feedback can be in response to multiple PDSCHs in a bundling window, comprising multiple consecutive downlink subframes. This implies that an HARQ-ACK feedback associated with a larger bundling window size may contain more information. Based on this observation, approach 3 and approach 4 are proposed, as prioritization rules for embodiments corresponding to the FIGURES as disclosed herein. Approach 3: UL power allocation is prioritized for a cell with a larger maximum bundling window size. If a maximum bundling window size is a same for two cells, a conventional prioritization or a prioritization as described in previous embodiments can apply. For TDD, the maximum bundling window size is determined by the size of the downlink association set, M. Table 2 shows the downlink association set for different TDD UL-DL configurations [3]. Table 3 shows the maximum M for each TDD UL-DL configuration, for FDD, and their corresponding priority according to Approach 3. For example, the maximum bundling window size for a TDD cell with UL-DL configurations 1/2/3/4/5 is larger than that of a FDD cell and of a TDD cell with UL-DL configuration 0/6. Hence, a TDD cell with UL-DL configuration 1/2/3/4/5 has higher priority over a FDD cell or a TDD cell with UL-DL configuration 0/6. It is noted that for Approach 3, a priority for UL power allocation for a TDD cell over a FDD cell is effectively TDD UL-DL configuration dependent as the FDD cell can have higher priority than a TDD cell with UL-DL configuration 0/6. Approach 3 can also be used to determine a priority for UL power allocation between two TDD cells with different UL-DL configurations. TABLE 2Downlink association set index:TDD UL-DLSubframe nConfiguration01234567890——6—4——6—41——7, 64———7, 64—2——8, 7, 4, 6————8, 7, 4, 6——3——7, 6, 116, 55, 4—————4——12, 8, 7, 116, 5, 4, 7——————5——13, 12, 9, 8, 7,———————5, 4, 11, 66——775——77— TABLE 3Prioritization according to maximum bundling window sizeTDD UL-DLSubframe nConfiguration01234567890——6—4——6—41——7, 64———7, 64—2——8, 7, 4, 6————8, 7, 4, 6——3——7, 6, 116, 55, 4—————4——12, 8, 7, 116, 5, 4, 7——————5——13, 12, 9, 8, 7,———————5, 4, 11, 66——775——77— Approach 4: UL power allocation is prioritized for a cell with a larger bundling window size in a given subframe. For example, for TDD UL-DL configuration 1, HARQ-ACK transmission in subframe 2 or 7 can have higher priority in a TDD cell than in a FDD cell since they can have a larger bundling window size. Approach 4A: UL power allocation for HARQ-ACK signal transmissions is prioritized according to the actual HARQ-ACK information payload transmitted by a UE. The UE, knowing an actual number of HARQ-ACK information bits it transmits in a respective PUCCH, including HARQ-ACK information bits for which the UE did not detect a PDCCH as they can be determined by a value of a DAI field in a PDCCH the UE detects in a subsequent subframe [3], can prioritize power for the PUCCH that includes a larger number of actual HARQ-ACK information bits in a given subframe. For example, for a same number of HARQ-ACK information bits per DL subframe, if in a first cell a UE is configured with TDD UL-DL configuration 2 and in a second cell the UE is configured with TDD UL-DL configuration 3, the UE can prioritize power allocation for PUCCH transmissions in UL subframe 2 to the second cell if it includes respective HARQ-ACK information for all subframes in Table 2 (subframes 7, 6, 11) while for the first cell it includes respective HARQ-ACK information for only two subframes (such as subframes 8, 7). Approach 5: A network can configure to a UE the UL power allocation approach (e.g. Approach 1-4), for example via RRC. Embodiment: Overall Prioritization Rule for FDD/TDD CA A prioritization rule can also be based on combination of frame structure type and the physical channel type, or combination of frame structure type and the payload type. Some examples are provided below: Approach 6: For prioritizing UL power allocation, PUCCH on TDD cell>PUCCH on FDD cell>PUSCH on TDD cell>PUSCH on FDD cell (where A>B indicates A has higher priority over B). This approach gives priority for UL power allocation first to PUCCH over PUSCH and second to TDD over FDD in order to ensure the reception reliability for PUCCH regardless of the frame structure type. Approach 7: For prioritizing UL power allocation, PUCCH on TDD cell>PUCCH on FDD cell>PUSCH with UCI on TDD cell>PUSCH with UCI on FDD cell>PUSCH without UCI on TDD cell>PUSCH without UCI on FDD cell. This approach is similar to Approach 6 except that PUSCH with UCI is prioritized over PUSCH without UCI. Approach 8: For prioritizing UL power allocation, UCI subframe on TDD cell>UCI subframe on FDD cell>non-UCI subframe on TDD cell>non-UCI subframe on FDD cell. This approach gives priority first to UL transmission with UCI over UL transmission without UCI, and second to TDD over FDD in order to ensure protection to UCI transmission regardless of the frame structure type. Approach 9: For prioritizing UL power allocation, HARQ-ACK transmission on TDD cell>HARQ-ACK transmission on FDD cell>PUCCH on TDD cell>PUCCH on FDD cell>PUSCH on TDD cell>PUSCH on FDD cell. This approach specifically prioritizes HARQ-ACK over other UCI types. Approach 10: For prioritizing UL power allocation, HARQ-ACK transmission on TDD cell>HARQ-ACK transmission on FDD cell>PUCCH on TDD cell>PUCCH on FDD cell>PUSCH with UCI on TDD cell>PUSCH with UCI on FDD cell>PUSCH without UCI on TDD cell>PUSCH without UCI on FDD cell. This approach is similar to Approach 9 except that that PUSCH with UCI is prioritized over PUSCH without UCI. In all approaches above, when two cells are considered to have equal priority based on the above rules, rules disclosed in previous embodiments can serve for UL power allocation. Although the present disclosure has been described with an exemplary embodiment, various changes and modifications may be suggested to one skilled in the art. It is intended that the present disclosure encompass such changes and modifications as fall within the scope of the appended claims. | 72,077 |
RE49808 | DETAILED DESCRIPTION FIG.1illustrates a wireless communication network10that may be, but is not limited to, an E-UTRAN network that is configured according to the relevant 3GPP specifications. The network10includes a radio access network (RAN)12, and an associated core network14. The RAN12includes a number of radio base stations16, which may be, for example, “evolved Node Bs,” also referred to as eNBs. The core network14includes a packet data gateway18, such as a “System Architecture Evolution (SAE) Gateway (GW).” With emphasis on processing features and configurations related to seamless handover of a mobile station20from one base station16to another,FIG.1illustrates one base station16playing the role of “source base station,” and another base station16playing the role of “target base station.” For ease of discussion, the source base station16is denoted as source base station16-1and the target base station16is denoted as target base station16-2. Focusing particularly on uplink communications flowing from the mobile station20to the gateway18via the base stations16, one sees that the mobile station20includes a Packet Data Convergence Protocol (PDCP) processor32, and that the base stations16include corresponding PDCP processors30. Assuming that the source base station16-1currently is supporting uplink communications from the mobile station20, the mobile station20transmits packet data to the gateway18based on forming PDCP protocol data units—often referred to as “protocol data units”—based on ciphering and (optionally) compressing PDCP service data units—often referred to as “service data units”. For example, uplink packet data to be transmitted from the mobile station20to the gateway18is formatted into PDCP service data units, which are then processed into PDCP protocol data units for over-the-air transmission to the source base station16-1. In turn, the source base station16-1processes the received PDCP protocol data units to obtain corresponding PDCP service data units, which it then transfers to the gateway18. Because the PDCP service data units should be transferred to the gateway in order of transmission sequence, the PDCP uplink processing includes assigning sequence numbers to the transmitted PDCP protocol data units. In this manner, the source base station16-1may identify PDCP protocol data units that are received out of sequence at the source base station16-1. The source base station16-1may temporarily buffer the PDCP Service data units corresponding to the out-of-sequence PDCP protocol data units. Among other advantages, the teachings presented herein provide advantageous source and target base station processing wherein such buffered PDCP service data units are forwarded from the source base station16-1to the target16-2in support of seamless handover of the mobile station20from the source base station16-1to the target base station16-2. More particularly, according to one or more embodiments taught herein, an interface24communicatively couples the source base station16-1to the target base station16-2, and that interface24is used by the source base station16-1to forward service data units and corresponding sequence number information to the target base station16-2during handover execution. These forwarded service data units are identified by reference number “26” and the sequence number information is identified by reference number “28” inFIG.1. The forwarded service data units26are those service data units that correspond to protocol data units received out of sequence at the source base station16-1and that have not been transferred to the gateway18. In other words, the forwarded service data units26are those service data units being held at the source base station16-1for sequential transfer to the gateway18. Correspondingly, the sequence number information28indicates at least sequence numbers corresponding to the forwarded service data units. In other words, the forwarded sequence number information indicates the sequence numbers of the out-of-sequence protocol data units corresponding to the forwarded service data units26. Alternatively, the sequence number information28may include sequence numbers corresponding to the missing service data units. Thus, as taught herein in one or more embodiments, a method of supporting seamless handover of a mobile station20from a source base station16-1to a target base station16-2is characterized by, during handover execution, receiving at the target base station16-2service data units and sequence number information forwarded from the source base station16-1. The forwarded service data units comprise service data units being held at the source base station16-1for sequential transfer to the associated core network14and the forwarded sequence number information indicates sequence numbers corresponding to the forwarded service data units. The method continues with reordering the forwarded service data units as needed at the target base station16-2for sequential transfer from the target base station16-2to the associated core network14. In at least one embodiment, reordering the forwarded service data units as needed at the target base station16-2for sequential transfer from the target base station16-2to the associated core network14includes the target base station16-2identifying missing service data units based on the forwarded sequence number information, and requesting retransmission by the mobile station20of the protocol data units corresponding to the missing service data units. In at least one such embodiment, the method is further characterized by the target base station16-2receiving the retransmitted protocol data units and processing them to obtain the missing service data units, and reordering the thus obtained service data units with the forwarded service data units as needed for sequential transfer to the associated core network14. The method is further characterized in one or more embodiments in that the target base station16-2processes the forwarded sequence number information to identify protocol data units received at the target base station16-2from the mobile station20that are duplicative with regard to service data units previously transferred from the source base station16-1to the associated core network14. The target base station16-2also processes the forwarded sequence number information to identify protocol data units for which retransmission by the mobile station is required for reordering of the forwarded service data units for sequential transfer from the target base station16-2to the associated core network14. In at least one embodiment, forwarded service data units are successfully deciphered versions of corresponding protocol data units that were received out of sequence at the source base station16-1at or before initiation of handover and have not been transferred as service data units from the source base station16-1to the associated core network14. Note that in such embodiments, or in at least one other embodiment, the forwarded service data units are successfully deciphered and decompressed versions of corresponding protocol data units that were received out of sequence at the source base station16-1at or before initiation of handover and have not been transferred as service data units from the source base station16-1to the associated core network14. Note, too, that in at least one embodiment of the method, the forwarded sequence number information indicates the sequence number corresponding to the service data unit most recently transferred from the source base station16-1to the associated core network14, or indicates the sequence number corresponding to a last in sequence received service data unit, or indicates the sequence number corresponding to the service data unit next expected to be transferred from the source base station16-1to the associated core network14. (The “last in sequence received service data unit” denotes the last service data unit received in sequence from the mobile station20by way of receiving uplink protocol data units from the mobile station20.) In any case, to better understand protocol and service data units using PDCP as an example,FIG.2illustrates that each base station16includes a PDCP processor30, which may be a functional processing element implemented in software, hardware, or any combination thereof. (The mobile station20includes a like PDCP processor32.) One sees that functionally the PDCP processor30forms downlink PDCP protocol data units for over-the-air transmission to the mobile station20by applying ciphering and (header) compression to PDCP service data units incoming from the gateway18. Notably, the PDCP processor30also generates/assigns a sequence number to each PDCP protocol data unit to enable sequential ordering and processing of PDCP service data units at the mobile station20. The PDCP processor32at the mobile station20thus receives downlink PDCP protocol data units from a base station16, and decompresses/deciphers them to obtain corresponding PDCP service data units. The receiver operation also includes the removal of sequence number information. Similarly, one sees that functionally the PDCP processor32forms uplink PDCP protocol data units for over-the-air transmission to a base station16by applying ciphering and optionally applying header compression to PDCP service data units representing desired transmit information. Notably, the PDCP processor32also generates/assigns a sequence number to each PDCP protocol data unit to enable sequential ordering and processing of PDCP service data units at the base station16. The base station16thus receives uplink PDCP protocol data units from the mobile station20, and its PDCP processor30decompresses/deciphers them to obtain correcponding PDCP service data units, where the sequence numbering has been removed. For further details and examples, one may refer to TS 36.323, version 8.0.0, as released by the 3GPP. Of particular interest with respect to PDCP processing, the base stations16-1and16-2are configured to support seamless handover of the mobile station20. In general, it will be understood by those skilled in the art that the base stations16represent complex computation platforms that provide a comprehensive set of communication control and call processing functions and that such systems are subject to wide variation in terms of their implementation.FIG.3thus will be understood as a non-limiting example of a functional implementation of a base station16in support of seamless handover processing. InFIG.3, the base station16-x (where “x” denotes “1” or “2” with respect toFIG.1) includes a number of functional circuits or sub-systems, including a gateway interface circuit40, a base station interface42, which may be considered to be part of the logical inter-base-station interface24introduced inFIG.1, a wireless communication interface44for wireless communications with the mobile station20(and other mobile stations), and control/processing circuits46for carrying out communication control and processing, and for carrying on general base station operations. The control/processing circuits46are, for example, microprocessor-based circuits, which may operate according to one or more computer programs stored in a computer-readable medium within the base station16-x. Of course, it should be understood that the control/processing circuits46may comprise hardware, software, or any combination thereof. With that in mind, the control/processing circuits46include a handover processor48, along with the earlier-illustrated PDCP processor30, which, again, may be implemented in software, hardware, or any combination thereof. Those skilled in the art will recognize that the PDCP processor30may comprise part of a larger layered protocol stack, and that its operations are coordinated with Radio Link Control (RLC) and Medium Access Control (MAC) processing. The base station16-x selectively operates as a source base station, e.g.,16-1inFIG.1, and as a target base station, e.g.,16-2inFIG.1. Referring again to reference numbers inFIG.1, and with regard to target base station operation, the base station16-2implements a method of supporting seamless handover of mobile stations20from the source base station16-1. In one or more embodiments, the method is characterized by, during handover execution, receiving at the target base station16-2PDCP service data units26and sequence number information28forwarded from the source base station16-1, where the forwarded service data units26and sequence number information28correspond to service data units being held at the source base station16-1for sequential transfer to the core network14, and where the forwarded sequence number information indicates the sequence numbers corresponding to the forwarded service data units. The method is further characterized by reordering the forwarded PDCP service data units as needed at the target base station16-2for sequential transfer from the target base station to the associated core network. In at least one embodiment, reordering the forwarded PDCP service data units as needed at the target base station16-2for sequential transfer from the target base station16-2to the associated core network14includes the target base station16-2identifying missing service data units based on the forwarded sequence number information28, and requesting retransmission by the mobile station20of the protocol data units corresponding to the missing service data units. The method may be further characterized in that the forwarded sequence number information28indicates sequence numbers corresponding to the forwarded service data units, and further indicates a sequence number corresponding to the PDCP service data unit most recently transferred from the source base station16-1to the associated core network14. The sequence number information28may also include sequence numbers of the service data units that are missing at the source base station16-1. Such information may be transmitted in the form of a reception status message sent from the source base station16-1to the target base station16-2during handover execution. In at least one embodiment, the forwarded sequence number information28further indicates a sequence number of the PDCP protocol data unit corresponding to the PDCP service data unit most recently transferred from the source base station16-1to the associated core network14. That is, the forwarded sequence number information may indicate sequence numbers of the PDCP protocol data units corresponding to the forwarded PDCP service data units26, and may further indicate the highest sequence number corresponding to PDCP service data units already transferred in proper sequence from the source base station16-1to the associated core network14. As noted earlier, instead of indicating the sequence number corresponding to the service data unit most recently transferred from the source base station16-1to the associated core network14, the forwarded sequence number information may indicate the next higher sequence number. The method may be further characterized in that the target base station16-2processes the forwarded sequence number information28to identify PDCP protocol data units received at the target base station16-2from the mobile station20that are duplicative with regard to PDCP service data units previously transferred from the source base station16-1to the associated core network14, and processes the forwarded sequence number information28to identify PDCP protocol data units for which retransmission by the mobile station20is required for reordering of the forwarded PDCP service data units26, for sequential transfer from the target base station16-2to the associated core network14, e.g., the gateway18. The method may be further characterized in that the forwarded PDCP service data units26are successfully deciphered versions of corresponding PDCP protocol data units that were received out of sequence at the source base station16-1at or before initiation of handover and have not been transferred from the source base station16-1to the associated core network14. If header compression is used, then the forwarded service data units may be decompressed. In this regard, then, it is not necessary for the target base station16-2to have knowledge of ciphering keys in use at the source base station16-1, nor is it necessary for the source base station16-1to transfer header compression state information to the target base station16-2. The complementary seamless handover method at the source base station16-1is characterized by, during handover execution, forwarding from the source base station16-1to the target base station16-2PDCP service data units26and sequence number information28corresponding to PDCP protocol data units received out of sequence at the source base station16-1and not yet transferred by the source base station16-1to the associated core network14. In other words, the source base station16-1forwards the service data units it is holding for sequential transfer. As noted, such transfer may be further characterized in that the forarded PDCP service data units26are successifully deciphered versions of the PDCP protocol data units received out of sequence at the source base station16-1and not yet transferred by the source base station16-1to the associated core network14. Correspondingly, the forwarded sequence number information28indicates the sequence numbers of such out-of-sequence PDCP protocol data units. Still further, the seamless handover method as implemented at the source base station16-1may be characterized in that the source base station16-1further includes in the forwarded sequence number information28an indication of the sequence number for the PDCP protocol data unit corresponding to the PDCP service data unit most recently transferred from the source base station16-1to the associated core network14, or an indication of the sequence number corresponding to the last in sequence received service data unit. Alternatively, it may transfer the sequence number corresponding to the service data unit next expected to be transferred from the source base station16-1to the associated core network14. Thus, according to the example illustration ofFIG.3, seamless source-to-target handover is supported in one or more embodiments by configuring a target base station16-2to include a (base station) interface42and a handover processor48. In at least one such embodiment, the interface42is operative to receive PDCP service data units26and sequence number information28forwarded from the source base station16-1, where the forwarded service data units26are those service data units being held at the source base station16-1for sequential transfer to the associated core network14, and the forwarded sequence number information indicates corresponding sequence numbers for the forwarded service data units. Correspondingly, the handover processor48is operative to reorder the forwarded PDCP service data units as needed at the target base station16-2, for sequential transfer from the target base station16-2to the associated core network14. For complementary source base station operations, the handover processor48and the associated interface42provide for forwarding from the source base station16-1to the target base station16-2PDCP service data units26and sequence number information28. As noted, the forwarded PDCP service data units26and sequence number information28correspond to PDCP protocol data units received out of sequence at the source base station16-1and not yet transferred by the source base station16-1to the associated core network14. Of course, the mobile station20also includes one or more processing circuits, e.g., a microprocessor-based system that implements the PDCP processor32shown inFIG.1, along with being configured to support seamless handover from the source base station16-1to the target base station16-2. In at least one embodiment, the mobile station20includes one or more processing circuits that are characterized by being operative to retransmit PDCP protocol data units for the missing PDCP service data units, responsive to retransmission requests received from the target base station, and using new ciphering and header compression states to regenerate the PDCP protocol data units for retransmission using corresponding PDCP service data units buffered at the mobile station20. In this manner, the target base station16-2uses the forwarded sequence number information28at least in part to identify missing service data units for which protocol data units retransmission by the mobile station20is required. In this sense, the retransmission(s) are required so that the handover processor48in the target base station16-2can reorder the forwarded PDCP service data units26, and transfer them to the associated core network14in the correct sequence. Further, in at least one embodiment, the mobile station20is configured for supporting seamless handover from a source base station16-1to a target base station16-2, and is characterized by a handover processor that is operative to regenerate new protocol data units for missing service data units and transmit the regenerated protocol data units responsive to signaling from the target base station16-2that indicates which service data units are missing at the target base station16-2, or equivalently indicates which service data units have been successfully received at the target base station16-2. The regenerated protocol data units are regenerated from corresponding service data units buffered at the mobile station20. In at least one such embodiment, the mobile station20is further characterized in that the regenerated protocol data units are regenerated using at least one of new ciphering states and new header compression states. Further, in at least one embodiment, the mobile station20is further characterized in that the mobile station20forgoes retransmission of those service data units that are indicated by the target base station16-2as having been successfully received. With the above in mind, then, those skilled in the art will appreciate that the teachings herein include, in one or more embodiments, sending information, including forwarded service data units, from a first base station, e.g., source base station16-1, to a second base station, e.g., target base station16-2, for seamless handover of a mobile station20. Here, the base stations16and the mobile station20represent respective end-points of a protocol controlled link, e.g., a PDCP link. In at least one aspect, the teachings herein address service data unit reordering at the target base station16-2based on sending information, e.g., a status message, from the source base station16-1to the target base station16-2. In at least one embodiment, the message includes information about the service data units or protocol data units that have been successfully received at the source base station16-1. This information can be used in the target base station16-2to request the retransmission of missing service data units after the handover is completed. The same status information can be used for duplicate detection in the target base station16-2, in case the target base station16-2receives data that has already been delivered by the source base station16-1to the gateway18. In at least one embodiment, uplink mobility as part of seamless handover comprises sending all cumulatively correctly received data—i.e., all sequentially received or successfully reordered PDCP service data units—is sent via an “S1 interface” to gateway18in the associated core network14. The gateway18comprises, in an E-UTRAN embodiment, a System Architecture Evolution (SAE) Gateway (GW). Upon initiation of handover, the source base station16-1sends a status message to the target base station16-2via the logical interface24connecting these two base stations. (In LTE, this interface is named the “X2” interface. (In case the source and target base stations are not logically interconnected with the “X2” interface, then the aforementioned communication including data forwarding and status message transfer may be relayed via the core network14, i.e., by using the two logical S1 interfaces between the two base stations16and the core network14.) The status message describes the reception status of service data units in the source base station16-1. Note, that the status message does not necessarily represent the status at the mobile station20, which is the data sender for uplink communications. The status message, which may be embodied in or otherwise accompany the forwarded sequence number information28described earlier herein, may include the status of which service data units have been forwarded to the gateway18by the source base station16-1over the S1 interface. Further, as noted, the source base station16-1also forwards those service data units26that have been received in the source base station16-1but not yet delivered to the gateway18, i.e., those service data units being held in the source base station16-1because they are not received in-sequence and are waiting reordering at the source base station16-1. As explained earlier, such service data units are temporarily buffered at the source base station16-1rather than being transferred to the gateway18. Assuming these buffered service data units are forwarded from the source base station16-1to the target base station16-2, the mobile station20retransmits protocol data units to the target base station16-2that correspond to the missing service data units. The mobile station20performs such retransmission by, for example, generating new PDCP protocol data units for the missing PDCP service data units missing at the target base station16-2. Note that the mobile station20generally retains service data units while awaiting acknowledgment for the correspondingly transmitted protocol data units, and these retained copies can be used for protocol data unit regeneration and retransmission. The mobile station20also is, in one or more embodiments, configured to use new ciphering and header compression states for retransmitting the missing PDCP service data units. The information included in the status message sent from the source base station16-1to the target base station16-2can be used by the target base station16-2to request retransmissions by the mobile station20, using known ARQ mechanisms (e.g. in the RLC protocol). The status message in one or more embodiments includes at least a sequence number (SN) that indicates up to which SN the data has been correctly received at the source base station16-1. The target base station16-2can be configured to determine which service data units are missing based on the sequence numbers corresponding to the forwarded service data units26. However, in at least one embodiment, the source base station16-1explicitly indicates the missing data, such as in the form of a data list or bit-map. In addition to the ARQ related information, the status report may also include information on the protocol data units that were (or were not) successfully decompressed and/or deciphered. Doing so allows the target base station16-2to request retransmission of service data units that were correctly received in the source in an ARQ sense at the source base station16-1but were not successfully decompressed or deciphered, i.e. the corresponding protocol data units were successfully received, but the source base station16-1may have failed in processing service data units from the received protocol data units. By way of non-limiting example,FIG.4“logically” illustrates a seamless handover of the mobile station20from the source base station16-1to the target base station16-2. The diagram is a “logical” illustration in the sense that it shows the logical condition of transmit and receive statuses for PDCP service data units transmitted from the mobile station20to the source base station16-1and/or to the target base station16-2. These illustrated status indicators may or may not represent the literal data structures used in the mobile station20and in the base stations16for managing PDCP-based uplink communications, but rather are for purposes of discussion. InFIG.4, the source and target base stations16-1and16-2, respectively, operate according to the teaching presented herein for seamless handover. For discussion purposes, it is assumed that the mobile station20has transmitted a number of PDCP protocol data units to the source base station16-1, with some of them received successfully and some of them not. The illustrated status indicators50indicate the status at the mobile station20of those transmitted PDCP service data units, and they indicate that PDCP protocol data units having sequence numbers 3-13 have been transmitted from the mobile station20to the source base station16-1in advance of the handover. However, as noted, not all of the PDCP protocol data units were successfully received at the source base station16-1, and the received status indicators52at the source base station16-1illustrate an example case, wherein PDCP service data units have been successfully received (including successful decompression/deciphering) for PDCP protocol data units having sequence numbers 3, 4, 5, 6, 8, 11, and 12. Contrastingly, PDCP service data units have not been successfully received for sequence numbers 7, 9, and 10. As such, the PDCP service data units 8, 11, and 12 are considered as having been received out-of-sequence. Also of note inFIG.4are the transferred PDCP service data units54. These service data units54represent those PDCP service data units already transferred from the source base station16-1to the associated core network14(e.g., gateway18) before handover execution. Thus, during handover execution, the source base station16-1forwards the PDCP service data units26that were received out of sequence and are awaiting reordering for transfer to the gateway18. In this example, the forwarded PDCP service data units are 8, 11, and 12. That is, the forwarded PDCP service data units are those corresponding to the 8th, 11th, and 12th PDCP protocol data units in the sequence, which were successfully received at the source base station16-1, but received out of sequence. As already noted, the source base station16-1forwards the sequence number information28corresponding to these forwarded PDCP service data units, and, in one or more embodiments, the sequence number information28includes an indication of the highest sequence number of PDCP service data units already transferred up to the gateway18—i.e., the most recently sequentially transferred PDCP service data unit. In this example, that value is “6.” Different ways of coding this information can be applied, e.g. where the most recently sequentially transferred PDCP service data unit may be indicated (“6”), or alternatively, the next PDCP service data unit to be sequentially transferred is indicated (“7”). In complementary fashion, the target base station16-2uses the received sequence number information28to request selective retransmissions by the mobile station20, while avoiding unnecessary retransmissions and thereby improving handover efficiency. More particularly, the target base station16-2processes the received sequence number information28, which may include or comprise the status message information discussed earlier herein, to identify the missing PDCP protocol data units that the mobile station20needs to retransmit to allow the target base station16-2to properly sequence the forwarded PDCP service data units26for transfer to the gateway18. Thus, the status indicators56represent the status of the mobile station20sometime after handover, assuming that retransmission requests (e.g., ARQ procedures) at the target base station16-2have prompted the mobile station20to retransmit the missing data. That is, one sees that the missing data for sequence numbers 7, 9, 10, and 13 has been successfully retransmitted in the form of PDCP protocol data units from the mobile station20to the target base station16-2. The PDCP service data units58corresponding to the retransmitted PDCP protocol data units are explicitly shown on the uplink to the target base station16-2. Note that hatching is used to indicate retransmitted data. Continuing with the example, the received status indicators60at the target base station16-2illustrate that the target base station16-2has obtained the missing data needed to properly reorder the forwarded PDCP service data units26. Thus, the target base station16-2transfers the retransmitted PDCP service data units and the forwarded PDCP service data units26in proper sequence order to the gateway18. The set of transferred PDCP service data units62indicates that transfer. Of course,FIG.4stands as a representative example, and is not limiting. Indeed, the present invention is not limited to the foregoing discussion and accompanying drawings. Instead, the present invention is limited only by the following claims and their legal equivalents. | 33,152 |
RE49809 | DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The making and using of the presently preferred embodiments are discussed in detail below. It should be appreciated, however, that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed are merely illustrative of specific ways to make and use the invention, and do not limit the scope of the invention. An embodiment provides signaling storm recovery for WiFi authentication processes with an integrated evolved packet core (EPC) network. An embodiment provides IEEE 802.11 Access Network Query Protocol (ANQP)-based authentication signaling storm prevention mechanisms, which may include providing network authentication status indications to a user equipment (UE). For example, in some embodiments, when a UE attempts to connect to a particular wireless local area network (WLAN), an access network (AN) indicates whether the authentication, authorization, and accounting (AAA) server is overload in the WLAN domain. If so, the UE implements an authentication retry policy (e.g., as set by the network) or selects another network rather than attempting to connect to the overloaded domain. The authentication retry policy may include implementing a retry timer or selecting another AN belonging to another operator to connect to after a maximum number of authentication attempts. In other embodiments, an AN may transmit an indication for whether authentication by a new user is permitted. If new user authentication is not currently permitted, the UE may implement an authentication retry policy or select another network. These indications may be transmitted by the AN using IEEE 802.11 ANQP. Other embodiments may also use a server's Access Network Discovery and Selection Function (ANDSF) policy to transmit the network authentication status indications and/or to configure authentication retry policies on UEs. FIG.1illustrates Generic Advertisement Service (GAS) and ANQP operation during device authentication. First, a user chooses to connect to Wi-Fi, and the user's device (e.g., UE102) scans for available hotspots. IEEE 802.11u GAS is used to provide for Layer 2 transport of an advertisement protocol's frames between UE102and a server in network106prior to authentication using access network (AN)104's ANQP, a query/response operation. Access network104may be any suitable access network, such as, a WiFi hotspot, Access Point (AP), universal terrestrial radio access network (UTRAN), evolved UTRAN (E-UTRAN), and the like. The information provided through the ANQP typically includes the different features and available services of network106. In some embodiments, network106is a WLAN that is owned by, subscribed to, or has roaming relationship with the UE102's cellular operator. ANQP may also be used to provide UE102with one or more authentication status indications, which may notify UE102of an authentication server overload, whether new users are allowed to connect to a particular server, and the like. After UE102determines which AN to connect to, UE102carries out an authentication process, connects to an AN104, and joins network106. The authentication process may include interfacing with an authentication, authorization, and accounting (AAA) server (or a different authentication server) and home location registers (HLRs)108. Network detection and selection policies, such as an ANDSF policy, may also set out parameters for determining when and how UE102selects ANs and/or other networks (e.g., cellular networks). UE102may be any of the devices illustrated inFIG.1, such as a cell phone, laptop, tablet, smart sensor, handheld or consumer electronic device, and other user devices that have a WiFi interface that can interact with a WiFi network. These devices also may be able to interact with other types of communication networks, such as a cellular network. Access network (AN)104and one or more UEs can form a basic service set (BSS), which is the basic building block of an IEEE 802.11 WLAN. AN104may communicate with an AN controller or an ANQP server, which can be collocated or not with AN104. A BSS generally can be identified by a service set identifier (SSID), which is configured and may be broadcasted by AN104. FIG.2illustrates a flow diagram showing a network using IEEE 802.11 ANQP query/response messages to transmit an authentication server overload indication in accordance with various embodiments. In step202, a user's device (e.g., UE102) may send an ANQP query requesting authentication server overload status. The ANQP query may be sent to an AN (e.g., AN104) of a network which the user wishes to connect to. In step204, an ANQP response from a network device (e.g., AN104) including an overload indication for whether authentication server (e.g., AAA server108or another authentication server) is overloaded. Authentication server108may be associated with an operator of a home network to which UE102belongs, or authentication server108may be associated with a visitor network through which UE102can reach to its home network (e.g., when UE102is in a roaming mode). Based on the received overload indication, in step206, UE102implements a network authentication and selection policy. The network authentication and selection policy may include UE102deciding to continue authentication with AN104, implement an authentication retry policy, select another network, and the like. For example, if the received overload indication indicates the authentication server is overloaded, UE102may decide not to continue the authentication process. Accordingly, UE102may implement an authentication retry policy. For example, the UE may wait for a retry timer to expire before another authentication attempt with AN104or select another AN (e.g., belonging to another operator) to connect to if a maximum number of authentication attempts has been made. Alternatively, if the received overload indication indicates the authentication server is overloaded, UE102may simply select another operator's network to connect to. As another example, if the ANQP response indicates the authentication server is not overloaded, then the UE may decide to continue the authentication process with AN104/network106. AlthoughFIG.2illustrates the overload indication being transmitted using an ANQP response/query protocol, in other embodiments, the overload indication may be transmitted to UE102from the network using any other suitable means (e.g., broadcasted in a beacon, transmitted as a probe response, in an ANDSF policy, and the like). The overload indication may be transmitted using any suitable format. In some embodiments, the overload indication is transmitted as an independent ANQP information element. For example,FIG.3Aillustrates an example information element format300in accordance with The WiFi Alliance's Hotspot 2.0 standard. Information element format300includes Info ID field302, Length field304, OI field306, Type field308, Subtype field310, Reserved filed312, and Payload filed314. Info ID field302is a 2-octet field whose value is an ANQP vendor-specific element. Length field304is a 2-octet field whose value is used to determine the length of Payload field314. For example, Length field304's value may be a constant (or offset) plus the length of Payload field314. OI field306is a 3-octet field used to identify the network's operator. For example, network operators may register for an operator-specific OI value (e.g., as set by The WiFi Alliance). These operator-specific OI values are known by devices operating in accordance with Hotspot 2.0 and may be used to identify the operator of the network. Type field308is a 1-octet field allocated from the WiFi Alliance technology identifier assignment to indicate a Hotspot 2.0 ANQP information element type is being transmitted. Subtype field310is a 1-octect field whose value is used to determine the subtype of the transmitted information element. For example, the value of Subtype field310may correlate with information element subtypes in a Subtype definition table320(e.g., Table 3 of Hotspot 2.0 as reproduced inFIG.3B). Subtype field308may be used to indicate an overload indication information element is transmitted. In such embodiments, an overload indication element type may be added to Table 3 of Hotspot 2.0 and assigned a corresponding value (e.g., one of reserved values 12-255). Reserved field312is a 1-octet field that may be used to ensure that the header of the ANQP information element (e.g., fields302through310) is word aligned. Payload field314is a variable length field containing information specific to the information element and may be used to indicate AAA server108(or another authentication server) is overloaded. The value of Payload field314may also be an overload percentage, other relative quantity measure (e.g., an index), or other relevant information. The implemented network authentication and selection policy may vary depending on the values of payload field314. Different overload percentages (or other relative overload conditions) may trigger different network authentication and selection policies/authentication retry policies. For example, a UE retry timer maybe shorter for slightly overloaded servers compared to very overloaded servers. In other embodiments, the overload indication may be transmitted using a different information element format, which may include more or less fields than fields302through314as illustrated inFIG.3A. In other embodiments, the overload indication may be added as an additional field in an existing ANQP network authentication type information element, 3GPP cellular network information element, another information element associated with the device's home network, or the like. For example, the overload indication may be included in a field added to a wide area network (WAN) metric information element, a network access indicator (NAI) home realm query information element, or another suitable information element. FIG.4is a flow diagram showing a network using IEEE 802.11 ANQP query/response messages to transmit an authentication permission indication in accordance with various embodiments. The authentication permission indication indicates whether a new user's device (e.g., UE102) that seeks authentication is currently allowed. This indication may be used to prevent additional new users from worsening an existing transaction overload situation in the network with additional authentication attempts. In step402, UE102sends an ANQP query to the network requesting new user permission status. In step404, an ANQP response from a network device (e.g., AN104) includes an authentication permission indication, which indicates whether the network is currently accepting authentication attempts by new users. For example, new user authentication attempts may not be accepted by the network when the authentication server (e.g., AAA server108or another suitable authentication server) is overloaded, when the authentication server experiences downtime (e.g., due to failure, planned maintenance, planned upgrades, and the like), when other devices (e.g., databases/other servers) associated with the authentication server is overloaded/experiencing downtime, when the WLAN associated with the authentication server desires to keep existing user's/user's services at a certain level, and the like. Based on the received authentication permission indication, in step306, UE102implements a network authentication and selection policy. The network authentication and selection policy may include UE102deciding to continue authentication with AN104, implement an authentication retry policy, select another network, and the like. For example, if the received authentication permission indication indicates new user authentication attempts are not currently allowed, UE102may decide not to continue the authentication process. Accordingly, UE102may implement an authentication retry policy. For example, the UE may wait for a retry timer to expire before another authentication attempt with AN104or select another AN (e.g., belonging to another operator) to connect to if a maximum number of authentication attempts has been made. Alternatively, if the received authentication permission indication indicates new user authentication attempts are not currently allowed, UE102may simply select another operator's network to connect to. As another example, if the ANQP response indicates new users authentication attempts are permitted, UE102may continue the authentication process with AN104. AlthoughFIG.4illustrates the authentication permission indication being transmitted using an ANQP response/query protocol, in other embodiments, the authentication permission indication may be transmitted to UE102from the network using any other suitable means (e.g., broadcasted in a beacon, a probe response, in an ANDSF policy, and the like). Furthermore, the authentication permission indication may be transmitted in lieu of or in addition to the overload indication. For example, in some situations a server may still allow new users even though it is overloaded. Thus, both an overload indication and an authentication permission indication may be transmitted. The UE may decide whether to continue authentication with the network based on a policy (e.g., an ANDSF policy), which may be configured by the UE's operator. In some embodiments, multiple authentication permission indications may be transmitted. For example, an AN may provide a connection to a WLAN owned by a first operator, and the AN also provide home network access to another operator's network (e.g., when the other operator's UEs are in a roaming mode). A first authentication permission indication may be transmitted for the first operator's WLAN, which may be used to indicate whether new users of the first operator may authentication with the AN or WLAN. The first authentication permission indication may be transmitted in a response message or broadcast message. A second authentication permission indication may be transmitted for home network access to users of the second operator. The second authentication permission indication may be used to indicate whether the second operator's users may access the second operator's home network directly or indirectly using the AN. The second indication may be based on server load of both the first operator's WLAN and the second operator's network. The second authentication permission indication may be transmitted as an ANQP response associated with the second operator's home network information in a UE's ANQP query. Thus, multiple authentication permission indications may be transmitted by an AN. In some embodiments, the authentication permission indication may be transmitted as a separate information element. For example, format300ofFIG.3Amay be used to transmit an authentication permission indication. In such embodiments, Subtype field308and Table320may be updated accordingly to indicate an authentication permission indication is being transmitted. In other embodiments, the authentication permission indication may be transmitted in a new field of an existing ANQP information element. AlthoughFIG.4illustrates an ANQP protocol used to transmit an authentication permission indication, other network selection and discovery mechanisms, such as ANDSF may be used to transmit the indication. Furthermore, whileFIGS.2and4illustrate two example network authentication status indications relating to authentication server status, network authentication status indications may be used by other management network nodes to indicate other network conditions such as network selection functions, quality of service (QoS), policy control functions, and the like. For example, the network authentication status indication may be used to indicate the QoS levels currently supported by a network server (e.g., when video transmissions are not supported). If UE102desires a higher QoS level (e.g., if UE desires video transmissions), UE102may decide not to continue the authentication process and implement an authentication retry policy or select another network. For some operators that do not want network node information to be visible to UEs, the overload indication may be changed to only indicate whether there is a generic authentication transaction overload in the network, not whether a particular network server is overloaded. FIG.5illustrates a flow diagram showing a network implementing an authentication signaling storm prevention mechanism in accordance with various embodiments. The network may implement an operator-defined authentication retry policy to a user's device (e.g., UE102) when authentication fails or when the UE decides not to continue an authentication process (e.g., based on one or more authentication status indications). In step502the network may transmit the authentication retry policy to UE102, for example, from ANDSF server no as part of an ANDSF server policy (e.g., as part of the inter-system mobility policy (ISMP) or inter-system router policy (ISRP) routine rules). Alternatively the authentication retry policy may be transmitted as a separate network policy or pre-configured on UE102by the operator. The authentication retry policy may be specific to particular ANs and WLANs network (labeled as WiFi A). For example, different authentication retry policies may be configured for different WLANs. Furthermore, the authentication retry policy may be a generic UE retry policy for the selected network (WiFi A) when the UE confronts difficulty in connecting to the network, or the authentication retry policy may be directed at one or more specific authentication failure scenarios (e.g., when the UE loses the connection with the current WLAN and tries to reconnect to the network). The authentication retry policy may include a backoff or retry timer (e.g., 1 minute), a maximum number (e.g., 3) of authentication attempts with the selected network, and the like. If UE102cannot successfully connect to the selected network after the maximum number of authentication attempts, UE102may select another network (e.g., belonging to another operator) to connect to. When UE102is on a roaming connection, the authentication retry policy may also include a policy that indicates whether UE102is allowed to select another network if the initial connection attempt fails or if another connection attempt may be made after the duration (e.g., 1 min) set by the retry timer expires. Other authentication retry policies may implement retry timers of different lengths and/or implement a different maximum number of authentication attempts. Furthermore, other authentication retry policies may implement different authentication retry parameters. In step504, UE102fails to authenticate with the selected network. Selection of WiFi A may be done by UE102based on selection criteria also set by the ANDSF policy. Failure to authenticate with WiFi A may include UE102failing to establish a connection, receiving an overload indication indicating the authentication server is overloaded, receiving an authentication permission indication indicating new user authentication attempts are not permitted, and the like. In step506, UE102waits for a retry timer to expire (e.g., after 1 min) before attempting to connect to WiFi A again. After the retry timer expires, in step508, UE102attempts the authentication procedure again with WiFi A. If after the maximum number of authentication attempts all end in failure, UE102may select another network (e.g., belonging to another operator) to connect to. FIG.6Aillustrates a flow diagram of a process flow600for user device behavior in accordance with various embodiments. In step602, the user device (e.g., UE102) selects an AN (e.g., AN104) for establishing a network connecting to a network (e.g., WLAN106). The AN may be associated with a network owned by, subscribed to, or has a roaming relationship with the user device's operator. Selection of an appropriate AN may be done in accordance with a network selection policy, e.g., an ANDSF policy, configured by the operator. In step604, the user's device receives one or more network authentication status indications, for example, through an ANQP query/response, a broadcasted beacon, probe response, in the ANDSF policy, or the like. The network authentication status indications may include an overload indication (e.g., indicating whether the authentication server associated with the selected network is overloaded), a authentication permission indication (e.g., indicating whether the authentication is accepting new user authentication requests), or the like. In step606, the user's device implements a network authentication and selection policy based on the received network authentication status indications. For example, when the user's device receives a authentication status indication indicating the authentication server is overloaded or that the network is not currently allowing authentication attempts by new users, the user's device may decide not to continue the authentication process or selects a different AN (e.g., belonging to a different operator) to connect to. If the user decides not to continue authentication, the user's device may implement an authentication retry policy. The authentication retry policy may include a retry timer before another authentication attempt with the selected network. The authentication retry policy may also include a maximum number of authentication attempts before selecting another AN (e.g., belonging to a different operator) to connect to. As another example, if the user device decides to continue the authentication process, the user's device authenticates and connects with the selected network through the selected AN. FIG.6Billustrates a flow diagram of a process flow620for network device behavior in accordance with various embodiments. In step622, the network device (e.g., AN622) determines a network's authentication status (e.g., whether or not a network authentication server is overloaded or accepting new users). Based on the network's authentication status, in step624, the network device may transmit one or more network authentication status indications to a user's device. For example, the network device may transmit an overload indication, a authentication permission indication, a network selection function indication, a quality of service (QoS) indication, a policy control function indication, and the like based on the network's status. FIG.7is a block diagram of a processing system700that may be used for implementing the devices and methods disclosed herein. Specific devices may utilize all of the components shown, or only a subset of the components, and levels of integration may vary from device to device. Furthermore, a device may contain multiple instances of a component, such as multiple processing units, processors, memories, transmitters, receivers, etc. The processing system may comprise a processing unit equipped with one or more input/output devices, such as a speaker, microphone, mouse, touchscreen, keypad, keyboard, printer, display, and the like. The processing unit may include a central processing unit (CPU), memory (e.g., a non-transitory computer readable storage medium), a mass storage device (e.g., a non-transitory computer readable storage medium), a video adapter, and an I/O interface connected to a bus. The bus may be one or more of any type of several bus architectures including a memory bus or memory controller, a peripheral bus, video bus, or the like. The CPU may comprise any type of electronic data processor. The memory may comprise any type of system memory such as static random access memory (SRAM), dynamic random access memory (DRAM), synchronous DRAM (SDRAM), read-only memory (ROM), a combination thereof, or the like. In an embodiment, the memory may include ROM for use at boot-up, and DRAM for program and data storage for use while executing programs. The mass storage device may comprise any type of storage device configured to store data, programs, and other information and to make the data, programs, and other information accessible via the bus. The mass storage device may comprise, for example, one or more of a solid state drive, hard disk drive, a magnetic disk drive, an optical disk drive, or the like. The video adapter and the I/O interface provide interfaces to couple external input and output devices to the processing unit. As illustrated, examples of input and output devices include the display coupled to the video adapter and the mouse/keyboard/printer coupled to the I/O interface. Other devices may be coupled to the processing unit, and additional or fewer interface cards may be utilized. For example, a serial interface such as Universal Serial Bus (USB) (not shown) may be used to provide an interface for a printer. The processing unit also includes one or more network interfaces, which may comprise wired links, such as an Ethernet cable or the like, and/or wireless links to access nodes or different networks. The network interface allows the processing unit to communicate with remote units via the networks. For example, the network interface may provide wireless communication via one or more transmitters/transmit antennas and one or more receivers/receive antennas. In an embodiment, the processing unit is coupled to a local-area network or a wide-area network for data processing and communications with remote devices, such as other processing units, the Internet, remote storage facilities, or the like. While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications and combinations of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to the description. It is therefore intended that the appended claims encompass any such modifications or embodiments. | 26,186 |
RE49810 | EXAMPLES The following examples and comparative examples are provided to illustrate certain embodiments of the invention, but should not be construed as limiting the invention in scope. Baseline Determination of Calcium, Zinc, and Iron Milk samples from infant formula (SIMILAC® NEOSURE®, Abbott Laboratories, Abbott Park, Ill.) and human breast milk were prepared. Six piglets were fed with a 5% glucose solution in deionized water ad libitum for 36 hours prior to the administration of the milk samples to the test subjects to flush minerals from the blood stream and achieve homeostasis. At the end of the 36 hours of glucose feeding, three of the six piglets were provided with non-thickened infant formula, and the remaining three were provided with non-thickened human breast milk. The samples were provided to each test subject ad libitum for about 48 hours. At the end of 48 hours, approximately 2 ml of blood was drawn from the test subjects and analyzed for calcium, iron, and zinc levels in accordance with the methods described in Miller-Ihli, “Trace element determinations in foods and biological samples using inductively coupled plasma atomic emission spectrometry and flame atomic absorption spectrometry,” J. Agr & Food Chem. 44:9 (1996). The average values were calculated and are shown in the table below. Milk TypeIron (mg/L)Calcium (mg/L)Zn (mg/L)Formula0.07130.501.05Breast Milk0.06528.451.14 The above results in were obtained from calculations based on test subject data show in the table below. Piglet I.DFe (mg/L)Ca (mg/L)Zn (mg/L)Baseline GroupB-0070.07530.211.02FormulaB-0100.07131.021.05B-0110.06830.271.07Average0.07130.501.05Baseline GroupB-0140.06828.11.12Breast MilkB-0280.06329.071.09B-0320.06428.191.21Average0.06528.451.14 Example 1 and Comparative Example 1 Test subjects provided with xanthan only thickened formula or breast milk, and test subject provided with xanthan and ascorbic acid thickened formula or breast milk. Prior to providing test subject with xanthan only thickened formula or breast milk, and with xanthan and ascorbic acid thickened formula or breast milk, test subjects were fed with a 5% glucose solution as described in Comparative Example 1, and provided with the milk samples ad libitum for about 48 hours. Samples of xanthan only thickened formula or breast milk, and xanthan and ascorbic acid thickened formula or breast milk were prepared in amounts as shown in the table below: Example 1Comparative Example 1Xanthan and AscorbicXanthan Thickened MilkAcid Thickened MilkXanthan1.5%Xanthan1.5%Ascorbic Acid—Ascorbic Acid0.002%Milk98.5%Milk~98.5%(Formula or Breast Milk)(Formula or Breast Milk) Of twelve test subjects, six test subjects were provided with xanthan thickened formula, and the remaining six were provided with xanthan thickened breast milk. Blood levels of iron, calcium, and zinc for tests subjects provided with xanthan thickened milk were obtained as described above. The same tests subjects administered xanthan thickened formulas were administered xanthan and ascorbic acid thickened formula on a separate occasion. The same tests subjects given xanthan thickened breast milk were administered xanthan and ascorbic acid thickened breast milk on a separate occasion. Blood levels of iron, calcium, and zinc for tests subjects provided with xanthan and ascorbic acid thickened milk were obtained as described in Comparative Example 1 above. Average blood levels of iron, calcium, and zinc were calculated for the thickened formula with results as shown in the table below: Thickened Formula Comparison of Blood Mineral Levels (mg/L)Between Xanthan Thickened Formula and Xanthanand Ascorbic Acid Thickened FormulaXanthan andXanthanAscorbic AcidMineralThickened FormulaThickened FormulaPercentType(Comparative Example 1)(Example 1)IncreaseIron0.0430.06653.5Calcium27.53309.0Zinc0.951.049.5 The above results were obtained from calculations based on test subject data show in the table below: Piglet I.DFe (mg/L)Ca (mg/L)Zn (mg/L)Test SubjectsB-0720.04628.280.96Fed XanthanB-0210.05127.890.96ThickenedB-0610.03927.270.93FormulaB-1110.04127.320.89B-0980.03828.091.01B-0250.04226.320.93Average0.04327.530.95Test SubjectsB-0720.07129.070.98Fed Xanthan andB-0210.06830.081Ascorbic AcidB-0610.06529.450.99ThickenedB-1110.06229.91.01FormulaB-0980.0730.81.1B-0250.05930.711.14Average0.06630.001.04 Similar results were obtained for the thickened breast milk as shown in the table below: Comparison of Blood Mineral Levels (mg/L) BetweenXanthan Thickened Breast Milk and Xanthan andAscorbic Acid Thickened Breast MilkXanthan andXanthanAscorbic AcidMineralThickened Breast MilkThickened Breast MilkPercentType(Example 1)(Example 1)IncreaseIron0.0490.07144.9Calcium25.6328.3710.7Zinc0.850.9612.9 The above results were obtained from calculations based on test subject data show in the table below. Piglet I.DFe (mg/L)Ca (mg/L)Zn (mg/L)Test SubjectsB-0170.04922.80.92Fed XanthanB-0290.04525.340.95ThickenedB-0530.05126.790.82FormulaB-0420.05325.670.85B-0500.04826.050.83B-0380.04827.140.75Average0.04925.630.85Test SubjectsB-0170.06628.220.98Fed Xanthan andB-0290.06928.950.94Ascorbic AcidB-0530.07629.820.96ThickenedB-0420.07328.091.04FormulaB-0500.06227.220.92B-0380.07827.890.89Average0.07128.370.96 The above results demonstrate that, in comparison to baseline levels of minerals in the bloodstream from administering un-thickened infant formula and un-thickened breast milk in Comparative Example 1, bloodstream mineral levels of infant formula and breast milk thickened with xanthan are less than baseline levels, indicating that the minerals and likely binding to xanthan, resulting in decreased levels in the bloodstream. The use of ascorbic acid results in improved bioavailability of calcium, iron, and zinc over infant formula and breast milk thickened only with xanthan. A comparison between average baseline mineral levels from Comparative Example 1 and average mineral levels resulting from milk thickened with xanthan only is presented in the table below. Comparison of Baseline Blood MineralLevels and Xanthan Thickened MilkXanthan Thickened FormulaXanthan Thickened Breast MilkFeCaZnFeCaZnBaseline0.07130.501.05Baseline0.06528.451.14LevelLevel(mg/L)(mg/L)Xanthan0.04327.530.95Xanthan0.04925.630.85ThickenedThickenedFormulaBreast MilkLevelLevel(mg/L)(mg/L)Difference0.0282.970.1Difference0.0162.820.29(mg/L)(mg/L)Percent39.49.79.5Percent24.69.925.1DifferenceDifference In comparison to baseline levels of minerals in the bloodstream from administering un-thickened infant formula and un-thickened breast milk in Comparative Example 1, bloodstream mineral levels of infant formula and breast milk thickened with xanthan and ascorbic acid are closer to baseline levels. A comparison between average baseline mineral levels from Comparative Example 1 and average mineral levels resulting from milk thickened with xanthan and ascorbic acid is presented in the table below. Comparison of Baseline Blood Mineral Levelsand Xanthan and Ascorbic Acid Thickened MilkXanthan and Ascorbic AcidXanthan and Ascorbic AcidThickened FormulaThickened Breast MilkFeCaZnFeCaZnBaseline0.07130.51.05Baseline0.06528.451.14LevelLevel(mg/L)(mg/L)Xanthan +0.06630.01.04Xanthan +0.07128.370.96AscorbicAscorbicAcidAcidThickenedThickenedFormulaBreast MilkLevelLevel(mg/L)(mg/L)Difference0.0050.50.01Difference−0.0060.090.19(mg/L)(mg/L)Percent7.711.630.96Percent−8.70.3116.23DifferenceDifference Compared to baseline levels, xanthan-only thickened milk resulted in a decreased availability of Fe, Ca, and Zn, which is believed to be indicative of binding of Fe, Ca, and Zn to xanthan. Xanthan- and ascorbic-acid-thickened milk resulted in availability levels much closer to baseline levels, which is believed to be indicative of ascorbic acid intervening with binding of Fe, Ca, and Zn to xanthan. The −8.7 value for iron indicates that more iron was bioavailable in the thickened milk than in the unthickened milk, and this is believed to be due to a reduction of Fe3+or other iron in the milk. Example 2 A powdered thickener composition is prepared by combining xanthan gum, ascorbic acid, and maltodextrin in the amounts listed in the table below: Thickener CompositionIngredientWt %Xanthan Gum55%Ascorbic Acid0.07%Maltodextrin45% These ingredients are combined in a mixer and mixed until the components are evenly distributed. Example 3 A thickened breast milk product is prepared by combining 5.5 g of the thickener composition of Example 2 with 200 mL of breast milk. The thickened breast milk product has a composition as shown in the table below. Thickened Breast Milk ProductComponentWt %Xanthan Gum1.5%Ascorbic Acid0.002%Maltodextrin1.2%Breast Milk97.3% The thickener composition is added to a feeding bottle containing 200 mL of breast milk. The contents of the feeding bottle are then agitated by shaking for about 10 seconds until the thickener composition has dispersed and the contents are thickened. Example 4 A baby formula product is prepared by combining 35.2 grams of ENFAMIL PREMIUM® Infant (Mead Johnson & Company, LLC) and 250 mL of water according to label instructions, and 8 g of the thickener composition of Example 2. The thickened baby formula product has a composition as shown in the table below. Thickened Baby Formula ProductComponentWt %Xanthan Gum1.5%Ascorbic Acid0.002%Maltodextrin1.2%ENFAMIL PREMIUM ® Infant12.0%Water85.3% Baby formula and the thickener composition are combined into an empty feeding bottle. Water is added to the feeding bottle. The contents of the feeding bottle are then agitated by stirring with a spoon for about 20 seconds until the powdered components are evenly dispersed and the baby formula is thickened. Example 5 To provide breast milk or baby formula to an infant with dysphagia, the thickened breast milk product of Example 3 or baby formula of Example 4 is administered to an infant with dysphagia. The thickened breast milk is thickened to have a viscosity of between 100 to 1000 centipoise. Except as otherwise clearly indicated by context, all weight percentages expressed herein are on a dry solids basis. All references cited herein are hereby incorporated by reference in their entireties. Uses of singular terms such as “a,” “an,” are intended to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms. Any description of certain embodiments as “preferred” embodiments, and other recitation of embodiments, features, or ranges as being preferred, or suggestion that such are preferred, is not deemed to be limiting. The invention is deemed to encompass embodiments that are presently deemed to be less preferred and that may be described herein as such. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to illuminate the invention and does not pose a limitation on the scope of the invention. Any statement herein as to the nature or benefits of the invention or of the preferred embodiments is not intended to be limiting. This invention includes all modifications and equivalents of the subject matter recited herein as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. The description herein of any reference or patent, even if identified as “prior,” is not intended to constitute a concession that such reference or patent is available as prior art against the present invention. No unclaimed language should be deemed to limit the invention in scope. Any statements or suggestions herein that certain features constitute a component of the claimed invention are not intended to be limiting unless reflected in the appended claims. Neither the marking of the patent number on any product nor the identification of the patent number in connection with any service should be deemed a representation that all embodiments described herein are incorporated into such product or service. | 12,404 |
RE49811 | DESCRIPTION OF THE PREFERRED EMBODIMENT All patents and publications referred to herein are hereby incorporated by reference for all purposes. Unless the substituents for a particular formula are expressly defined for that formula, they are understood to carry the definitions set forth in connection with the preceding formula to which the particular formula makes reference. As noted above, the invention provides compounds of formula I: and pharmaceutically acceptable salts thereof, wherein L is a bond or is —C(R3,R4)—; X is —C(R3,R4)N(R5)—, —C(O)N(R4)—, —N(R4)C(O)—, —C(R4,R5)—, —N(R4)—, —O—, —S—, —C(O)—, —S(O)2—, —S(O)2N(R4)— or —N(R4)S(O)2—; R1is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl; R2is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, mono or dialkylthiocarbamoyl, alkyl-S-alkyl, -heteroaryl-aryl, -alkyl-heteroaryl-aryl, —C(O)—NH-aryl, -alkenyl-heteroaryl, —C(O)-heteroaryl, or -alkenyl-heteroaryl-aryl; R3is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, oxo (═O), —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl; wherein the alkyl and ring portion of each of the above R1, R2, and R3groups is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6alkyl), —C(O)O(C1-C6alkyl), —CONR′R″, —OC(O)NR′R″, —NR′C(O)R″, —CF3, —OCF3, —OH, C1-C6alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR′R″, —SO2R′, —NO2, or NR′R″, wherein R′ and R″ are independently H or (C1-C6) alkyl, and wherein each alkyl portion of a substituent is optionally further substituted with 1, 2, or 3 groups independently selected from halogen, CN, OH, NH2; and R4and R5are independently H or alkyl, provided that when R3and R4are on the same carbon, and R3is oxo, then R4is absent. Preferred compounds of formula I include compounds wherein L is a bond. Preferred compounds of formula I also include compounds wherein L is a bond and X is —C(R3R4)—. More preferably, R3and R4form an oxo (═O) group. Preferred compounds of formula I also include compounds R1is H. Preferred compounds of formula I also include compounds wherein R1is optionally substituted aryl. Preferably, aryl is phenyl. Also preferably, phenyl is unsubstituted or is substituted with halogen. Preferred halogen substituents are Cl and F. Preferred compounds of formula I further include compounds wherein R2is OH. Preferred compounds of formula I further include compounds wherein R2is C1-C6alkyl, more preferably C1-C3alkyl, and even more preferably, CH3. Preferred compounds of formula I further include compounds wherein R2is alkenylaryl. Preferably, the aryl portion of alkenylaryl is phenyl or naphthyl, optionally substituted with 1 or 2 of halogen, cyano, or hydroxy. Preferred compounds of formula I further include compounds wherein R2is -alkenyl-heteroaryl. Preferred compounds of formula I further include compounds wherein R2is -alkenyl-heteroaryl-aryl. Preferred compounds of formula I include compounds of formula I-1: and pharmaceutically acceptable salts thereof, wherein: R1is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl; and R2is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, mono or dialkylthiocarbamoyl, alkyl-S-alkyl, -heteroaryl-aryl, -alkyl-heteroaryl-aryl, —NH-aryl, -alkenyl-heteroaryl, -heteroaryl, —NH-alkyl, —NH-cycloalkyl, or -alkenyl-heteroaryl-aryl, wherein the alkyl and ring portion of each of the above R1, and R2groups is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6alkyl), —C(O)O(C1-C6alkyl), —CONR′R″, —OC(O)NR′R″, —NR′C(O)R″, —CF3, —OCF3, —OH, C1-C6alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR′R″, —SO2R′, —NO2, or NR′R″, wherein R′ and R″ are independently H or (C1-C6) alkyl, and wherein each alkyl portion of a substituent is optionally further substituted with 1, 2, or 3 groups independently selected from halogen, CN, OH, NH2. Preferred compounds of the formula I include those of formula II: and pharmaceutically acceptable salts thereof, wherein: Y is —C(R4,R5)—, —N(R4)—, —O—, or —C(O)—; R1is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl; R2is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, mono or dialkylthiocarbamoyl, alkyl-S-alkyl, -heteroarylaryl, -alkyl-heteroaryl-aryl, —C(O)—NH-aryl, -alkenyl-heteroaryl, —C(O)-heteroaryl, or -alkenyl-heteroaryl-aryl; R3is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, oxo (═O), —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl; wherein the alkyl and ring portion of each of the above R1, R2, and R3groups is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6alkyl), —C(O)O(C1-C6alkyl), —CONR′R″, —OC(O)NR′R″, —NR′C(O)R″, —CF3, —OCF3, —OH, C1-C6alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR′R″, —SO2R′, —NO2, or NR′R″, wherein R′ and R″ are independently H or (C1-C6) alkyl, and wherein each alkyl portion of a substituent is optionally further substituted with 1, 2, or 3 groups independently selected from halogen, CN, OH, NH2; and R4and R5are independently H or alkyl. More preferred compounds of the formula II include those wherein: Y is —C(R4,R5)— or —N(R4)—; R1is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl; R2is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, mono or dialkylthiocarbamoyl, alkyl-S-alkyl, -heteroarylaryl, -alkyl-heteroaryl-aryl, —C(O)—NH-aryl, -alkenyl-heteroaryl, —C(O)-heteroaryl, or -alkenyl-heteroaryl-aryl; wherein the alkyl and ring portion of each of the above R1and R2groups is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6alkyl), —C(O)O(C1-C6alkyl), —CONR4R5, —OC(O)NR4R5, —NR4C(O)R5, —CF3, —OCF3, —OH, C1-C6alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR4R5, —SO2R4R5, —NO2, or NR4R5, and wherein each alkyl portion of a substituent is optionally further substituted with 1, 2, or 3 groups independently selected from halogen, CN, OH, NH2; R3is H, alkyl, or oxo (═O); and R4and R5are independently H or (C1-C6)alkyl. More preferred compounds of the formula II include those wherein Y is —NH—. Preferred compounds of formula II include those wherein R3is oxo. Preferred compounds of formula II include those wherein R3is methyl. Preferred compounds of formula II also include those wherein R1is H. Preferred compounds of formula II further include those wherein R1is optionally substituted aryl. Preferably, the aryl is phenyl, either unsubstituted or substituted with 1 or 2 halogen groups. Preferably, halogen is chloro or fluoro. Preferred compounds of formula II also include compounds wherein R2is alkyl or cycloalkyl. Preferred compounds of formula II also include compounds wherein R2is aryl or -alkylaryl. Preferred aryl in either group is phenyl. Preferred alkyl in alkylaryl is C1-C3alkyl, either straight chain or branched. The aryl groups may be unsubstituted or substituted. Preferred substituents include 1, 2, 3, 4, or 5 (preferably 1 or 2) groups independently chosen from halogen, hydroxy, alkyl, cyanoalkyl, aminoalkyl, thioalkoxy, trifluoromethyl, haloalkoxy, aryloxy, and alkoxy. Preferred compounds of formula II also include compounds wherein R2is heterocycloalkyl or -alkyl-heterocycloalkyl. Preferred heterocycloalkyl in either group is piperidinyl, piperazinyl, pyrrolidinyl, and morpholinyl. The heterocycloalkyl groups may be unsubstituted or substituted. Preferred substituents include 1, 2, 3, 4, or 5 (preferably 1 or 2) groups independently chosen from halogen, hydroxy, alkyl, cyanoalkyl, aminoalkyl, thioalkoxy, trifluoromethyl, haloalkoxy, aryloxy, oxo, and alkoxy. Preferred compounds of formula II also include compounds wherein R2is heteroaryl or -alkyl-heteroaryl. Preferred heteroaryl in either group is pyridinyl, imidazolyl, indolyl, carbazolyl, thiazolyl, benzothiazolyl, benzooxazolyl, purinyl, and thienyl. The heteroaryl groups may be unsubstituted or substituted. Preferred substituents include 1, 2, 3, 4, or 5 (preferably 1 or 2) groups independently chosen from halogen, hydroxy, alkyl, cyanoalkyl, aminoalkyl, thioalkoxy, trifluoromethyl, haloalkoxy, aryloxy, and alkoxy. The invention also provides methods for treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of a hyperproliferative disease, an inflammatory disease, or an angiogenic disease, which includes administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or administration of a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment or prevention. One preferred hyperproliferative disease which the compounds of the invention are useful in treating or preventing is cancer, including as non-limiting examples thereof solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma and paragangliomas, and hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplastic syndromes. The foregoing list is by way of example, and is not intended to be exhaustive or limiting. Other preferred diseases which can be treated or prevented with the compounds of the invention include inflammatory diseases, such as inter alia inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erythematosus, and insulin-dependent diabetes mellitus. Other preferred diseases which can be treated or prevented with the compounds of the invention include angiogenic diseases, such as diabetic retinopathy, arthritis, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome. The invention further provides a process for preparing sphingosine kinase inhibitors. In one embodiment, the process comprises contacting a precursor compound having the formula: with a compound having the formula: H2N—R2under conditions sufficient to produce compounds having the formula: wherein: R1and R2are as defined above. The process further comprises reducing an adamantlyamide, as shown above, to an adamantylamine by contact with Zn(BH4)2. In another embodiment, the process for the preparation of sphingosine kinase inhibitors comprises contacting a precursor compound having the formula: with a compound having the formula: R2—Br or R2C(O)Cl under conditions sufficient to produce compounds having the formula: wherein: R1, R2and R3are as defined earlier. In a further embodiment, the process comprises contacting a precursor compound having the formula: with a compound having the formula: H2N—R2or R2C(O)H under conditions sufficient to produce compounds having the formula: wherein: R1, R2and R3are as defined earlier. The invention also provides pharmaceutical compositions that include a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, as active ingredient, in combination with a pharmaceutically acceptable carrier, medium, or auxiliary agent. The pharmaceutical compositions of the present invention may be prepared in various forms for administration, including tablets, caplets, pills or dragees, or can be filled in suitable containers, such as capsules, or, in the case of suspensions, filled into bottles. As used herein “pharmaceutically acceptable carrier medium” includes any and all solvents, diluents, or other liquid vehicle; dispersion or suspension aids; surface active agents; preservatives; solid binders; lubricants and the like, as suited to the particular dosage form desired. Various vehicles and carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof are disclosed in Remington's Pharmaceutical Sciences (Osol et al. eds., 15th ed., Mack Publishing Co.: Easton, Pa., 1975). Except insofar as any conventional carrier medium is incompatible with the chemical compounds of the present invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, the use of the carrier medium is contemplated to be within the scope of this invention. In the pharmaceutical compositions of the present invention, the active agent may be present in an amount of at least 1% and not more than 99% by weight, based on the total weight of the composition, including carrier medium or auxiliary agents. Preferably, the proportion of active agent varies between 1% to 70% by weight of the composition. Pharmaceutical organic or inorganic solid or liquid carrier media suitable for enteral or parenteral administration can be used to make up the composition. Gelatin, lactose, starch, magnesium, stearate, talc, vegetable and animal fats and oils, gum polyalkylene glycol, or other known excipients or diluents for medicaments may all be suitable as carrier media. The pharmaceutical compositions of the present invention may be administered using any amount and any route of administration effective for treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of a hyperproliferative disease, an inflammatory disease, and an angiogenic disease. Thus the expression “therapeutically effective amount,” as used herein, refers to a sufficient amount of the active agent to provide the desired effect against target cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject; the particular SK inhibitor; its mode of administration; and the like. The pharmaceutical compounds of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. “Unit dosage form,” as used herein, refers to a physically discrete unit of therapeutic agent appropriate for the animal to be treated. Each dosage should contain the quantity of active material calculated to produce the desired therapeutic effect either as such, or in association with the selected pharmaceutical carrier medium. Typically, the pharmaceutical composition will be administered in dosage units containing from about 0.1 mg to about 10,000 mg of the agent, with a range of about 1 mg to about 1000 mg being preferred. The pharmaceutical compositions of the present invention may be administered orally or parentally, such as by intramuscular injection, intraperitoneal injection, or intravenous infusion. The pharmaceutical compositions may be administered orally or parenterally at dosage levels of about 0.1 to about 1000 mg/kg, and preferably from about 1 to about 100 mg/kg, of animal body weight per day, one or more times a day, to obtain the desired therapeutic effect. Although the pharmaceutical compositions of the present invention can be administered to any subject that can benefit from the therapeutic effects of the compositions, the compositions are intended particularly for the treatment of diseases in humans. The pharmaceutical compositions of the present invention will typically be administered from 1 to 4 times a day, so as to deliver the daily dosage as described herein. Alternatively, dosages within these ranges can be administered by constant infusion over an extended period of time, usually 1 to 96 hours, until the desired therapeutic benefits have been obtained. However, the exact regimen for administration of the chemical compounds and pharmaceutical compositions described herein will necessarily be dependent on the needs of the animal being treated, the type of treatments being administered, and the judgment of the attending physician. In certain situations, the compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E-configurations. Likewise, all tautomeric forms are also intended to be included. Non-toxic pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The invention also encompasses prodrugs of the compounds of the present invention. The invention also encompasses prodrugs of the compounds of the present invention. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and prodrugs of the compounds encompassed by the present invention. The invention provides compounds of formula I and II which are inhibitors of SK, and which are useful for modulating the sphingomyelin signal transduction pathway, and in treating and preventing hyperproliferative diseases, inflammatory diseases, and angiogenic diseases. The compounds of the invention can be prepared by one skilled in the art based only on knowledge of the compound's chemical structure. The chemistry for the preparation of the compounds of this invention is known to those skilled in the art. In fact, there is more than one process to prepare the compounds of the invention. Specific examples of methods of preparation can be found herein and in the art. As discussed above, sphingolipids are critically important in regulating the balance between cell proliferation and apoptosis. Sphingosine-1-phosphate is produced by the enzyme SK and stimulates the proliferation of tumor cells. Concurrent depletion of ceramide by the action of SK blocks apoptosis. The compounds of the invention are inhibitors of human SK. Therefore, inhibition of SK activity according to the invention will attenuate tumor cell proliferation and promote apoptosis. Therefore, the compounds of the invention are useful as anticancer agents. Furthermore, since cell hyperproliferation is a required process in the development of atherosclerosis and psoriasis, the compounds of the invention, which are SK inhibitors, are useful in the treatment of these, and other, hyperproliferative diseases. Additionally, inappropriate activation and/or proliferation of specific classes of lymphocytes results in chronic inflammatory and autoimmune diseases. Consequently, compounds of the invention are also useful in the treatment of these diseases. Additionally, inappropriate angiogenesis results in a variety of diseases, as described below. Consequently, compounds of the invention are also useful in the treatment of these diseases. Definitions The definitions and explanations below are for the terms as used throughout this entire document, including both the specification and the claims. It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. The symbol “—” in general represents a bond between two atoms in the chain. Thus CH3—O—CH2—CH(Ri)—CH3represents a 2-substituted-1-methoxypropane compound. In addition, the symbol “-” represents the point of attachment of the substituent to a compound. Thus for example aryl(C1-C6)alkyl- indicates an alkylaryl group, such as benzyl, attached to the compound at the alkyl moiety. Where multiple substituents are indicated as being attached to a structure, it is to be understood that the substituents can be the same or different. Thus for example “Rmoptionally substituted with 1, 2 or 3 Rqgroups” indicates that Rmis substituted with 1, 2, or 3 Rqgroups where the Rqgroups can be the same or different. The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substituent is independent of the other. As used herein, the terms “halogen” or “halo” indicate fluorine, chlorine, bromine, or iodine. The term “heteroatom” means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term “nitrogen” includes a substitutable nitrogen in a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from nitrogen, oxygen or sulfur, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl). The term “alkyl”, as used herein alone or as part of a larger moiety, refers to a saturated aliphatic hydrocarbon including straight chain, branched chain or cyclic (also called “cycloalkyl”) groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range, e.g. “1-20”, is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The cycloalkyl can be monocyclic, or a polycyclic fused system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cycolpentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl. The alkyl or cycloalkyl group may be unsubstituted or substituted with 1, 2, 3 or more substituents. Examples of such substituents including, without limitation, halo, hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkly, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2-thienyl)ethyl, hyroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, and diethylaminoethyl. The term “cycloalkylalkyl”, as used herein alone or as part of a larger moiety, refers to a C3-C10cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. The term “alkenyl”, as used herein alone or as part of a larger moiety, refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain, branched chain or cyclic groups having at least one carbon-carbon double bond. Preferably, the alkenyl group has 2 to 20 carbon atoms. More preferably, it is a medium size alkenyl having 2 to 10 carbon atoms. Most preferably, it is a lower alkenyl having 2 to 6 carbon atoms. The alkenyl group may be unsubstituted or substituted with 1, 2, 3 or more substituents. Examples of such substituents including, without limitation halo, hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkly, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Depending on the placement of the double bond and substituents, if any, the geometry of the double bond may be entgegen (E) or zusammen (Z), cis, or trans. Examples of alkenyl groups include ethenyl, propenyl, cis-2-butenyl, trans-2-butenyl, and 2-hyroxy-2-propenyl. The term “alkynyl”, as used herein alone or as part of a larger moiety, refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight chain, branched chain or cyclic groups having at least one carbon-carbon triple bond. Preferably, the alkynyl group has 2 to 20 carbon atoms. More preferably, it is a medium size alkynyl having 2 to 10 carbon atoms. Most preferably, it is a lower alkynyl having 2 to 6 carbon atoms. The alkynyl group may be unsubstituted or substituted with 1, 2, 3 or more substituents. Examples of such substituents including, without limitation, halo, hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkly, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Examples of alkynyl groups include ethynyl, propynyl, 2-butynyl, and 2-hyroxy-3-butylnyl. The term “alkoxy”, as used herein alone or as part of a larger moiety, represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, and fluoroethoxy. The term “aryl”, as used herein alone or as part of a larger moiety, refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Additionally, the aryl group may be substituted or unsubstituted by various groups such as hydrogen, halo, hydroxy, alkyl, haloalkyl, alkoxy, nitro, cyano, alkylamine, carboxy or alkoxycarbonyl. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, benzodioxole, and biphenyl. Preferred examples of unsubstituted aryl groups include phenyl and biphenyl. Preferred aryl group substituents include hydrogen, halo, alkyl, haloalkyl, hydroxy and alkoxy. The term “heteroalkyl”, as used herein alone or as part of a larger moiety, refers to an alkyl radical as defined herein with one or more heteroatoms replacing a carbon atom with the moiety. Such heteroalkyl groups are alternately referred to using the terms ether, thioether, amine, and the like. The term “heterocyclyl”, as used herein alone or as part of a larger moiety, refers to saturated, partially unsaturated and unsaturated heteroatom-containing ring shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Said heterocyclyl groups may be unsubstituted or substituted at one or more atoms within the ring system. The heterocyclic ring may contain one or more oxo groups. The term “heterocycloalkyl”, as used herein alone or as part of a larger moiety, refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring may be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole. Preferred monocyclic heterocycloalkyl groups include piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Heterocycloalkyl radicals may also be partially unsaturated. Examples of such groups include dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. The term “heteroaryl”, as used herein alone or as part of a larger moiety, refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Additionally, the heteroaryl group may be unsubstituted or substituted at one or more atoms of the ring system, or may contain one or more oxo groups. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, carbazole and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, benzopyrazolyl, purinyl, benzooxazolyl, and carbazolyl. The term “acyl” means an H—C(O)— or alkyl-C(O)— group in which the alkyl group, straight chain, branched or cyclic, is as previously described. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, and caproyl. The term “aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl. The term “solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degress of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Exemplary solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule(s) is/are H2O. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, a carbon atom that is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, which are well known to those in the art. Additionally, entiomers can be characterized by the manner in which a solution of the compound rotates a plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (−) isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the specification and claims is intended to include both individual enantiomers as well as mixtures, racemic or otherwise, thereof. Certain compounds of this invention may exhibit the phenomena of tautomerism and/or structural isomerism. For example, certain compounds described herein may adopt an E or a Z configuration about a carbon-carbon double bond or they may be a mixture of E and Z. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biologic assays. As used herein, “SK-related disorder”, “SK-driven disorder”, and “abnormal SK activity” all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, SK catalytic activity. Inappropriate catalytic activity can arise as the result of either: (1) SK expression in cells that normally do not express SK, (2) increased SK catalytic activity leading to unwanted cellular process, such as, without limitation, cell proliferation, gene regulation, resistance to apoptosis, and/or differentiation. Such changes in SK expression may occur by increased expression of SK and/or mutation of SK such that its catalytic activity is enhanced, (3) decreased SK catalytic activity leading to unwanted reductions in cellular processes. Some examples of SK-related disorders, without limitation, are described elsewhere in this application. The term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts. The term “modulation” or “modulating” refers to the alteration of the catalytic activity of SK. In particular, modulating refers to the activation or, preferably, inhibition of SK catalytic activity, depending on the concentration of the compound or salt to which SK is exposed. The term “catalytic activity” as used herein refers to the rate of phosphorylation of sphingosine under the influence of SK. The term “contacting” as used herein refers to bringing a compound of this invention and SK together in such a manner that the compound can affect the catalytic activity of SK, either directly, i.e., by interacting with SK itself, or indirectly, i.e., by altering the intracellular localization of SK. Such “contacting” can be accomplished in vitro, i.e. in a test tube, a Petri dish or the like. In a test tube, contacting may involve only a compound and SK or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect an SK-related disorder can be determined before the use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to allow contact of the compounds with SK including, but not limited to, direct cell microinjection and numerous techniques for promoting the movement of compounds across a biological membrane. The term “in vitro” as used herein refers to procedures performed in an artificial environment, such as for example, without limitation, in a test tube or cell culture system. The skilled artisan will understand that, for example, an isolate SK enzyme may be contacted with a modulator in an in vitro environment. Alternatively, an isolated cell may be contacted with a modulator in an in vitro environment. The term “in vivo” as used herein refers to procedures performed within a living organism such as, without limitation, a human, mouse, rat, rabbit, bovine, equine, porcine, canine, feline, or primate. The term “IC50” or “50% inhibitory concentration” as used herein refers to the concentration of a compound that reduces a biological process by 50%. These processes can include, but are not limited to, enzymatic reactions, i.e. inhibition of SK catalytic activity, or cellular properties, i.e. cell proliferation, apoptosis or cellular production of S1P. As used herein, “administer” or “administration” refers to the delivery of a compound or salt of the present invention or of a pharmaceutical composition containing a compound or salt of this invention to an organism for the purpose of prevention or treatment of an SK-related disorder. As used herein, the terms “prevent”, “preventing” and “prevention” refer to a method for barring an organism from acquiring an SK-related disorder. As used herein, the terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating an SK-mediated disorder and/or its attendant symptoms. The term “organism” refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal. In a preferred aspect of this invention, the organism is a mammal. In a particularly preferred aspect of this invention, the mammal is a human being. A “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. The term “pharmaceutically acceptable salt” refers to those salts that retain the biological effectiveness of the parent compound. Such salts include: (1) acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. As used herein, the term a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Typically, this includes those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. An “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Example, without limitations, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. The term “therapeutically effective amount” as used herein refers to that amount of the compound being administered that is effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms of the disease. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount that has the effect of: (1) reducing the size of the tumor, (2) inhibiting, i.e. slowing to some extent, preferably stopping, tumor metastasis, (3) inhibiting, i.e. slowing to some extent, preferably stopping, tumor growth, and/or (4) relieving to some extent, preferably eliminating, one or more symptoms associated with the cancer. The compounds of this invention may also act as a prodrug. The term “prodrug” refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the “prodrug”), carbamate or urea. The compounds of this invention may also be metabolized by enzymes in the body of the organism, such as a human being, to generate a metabolite that can modulate the activity of SK. Such metabolites are within the scope of the present invention. Indications Sphingosine kinase (SK), whose catalytic activity is modulated by the compounds and compositions of this invention, is a key enzyme involved in signaling pathways that are abnormally activated in a variety of diseases. The following discussion outlines the roles of SK in hyperproliferative, inflammatory and angiogenic diseases, and consequently provides examples of uses of the compounds and compositions of this invention. The use of these compounds and compositions for the prevention and/or treatment of additional diseases in which SK is abnormally activated are also within the scope of the present invention. Hyperproliferative Diseases. The present invention relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of hyperproliferative diseases. More specifically, the invention relates to compounds and pharmaceutical compositions that inhibit the enzymatic activity of SK for the treatment and/or prevention of hyperproliferative diseases, such as cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis. The following discussion demonstrates the role of SK in several of these hyperproliferative diseases. Since the same processes are involved in the above listed diseases, the compounds, pharmaceutical compositions and methods of this invention will be useful for the treatment and/or prevention of a variety of diseases. Sphingosine-1-phosphate and ceramide have opposing effects on cancer cell proliferation and apoptosis. Sphingomyelin is not only a building block for cellular membranes but also serves as the precursor for potent lipid messengers that have profound cellular effects. Stimulus-induced metabolism of these lipids is critically involved in cancer cell biology. Consequently, these metabolic pathways offer exciting targets for the development of anticancer drugs. Ceramide is produced by the hydrolysis of sphingomyelin in response to growth factors or other stimuli. Ceramide induces apoptosis in tumor cells, but can be further hydrolyzed by the action of ceramidase to produce sphingosine. Sphingosine is then rapidly phosphorylated by SK to produce S1P, which is a critical second messenger that exerts proliferative and antiapoptotic actions. For example, microinjection of S1P into mouse oocytes induces DNA synthesis. Additionally, S1P effectively inhibits ceramide-induced apoptosis in association with decreased caspase activation. Furthermore, ceramide enhances apoptosis in response to anticancer drugs including Taxol and etoposide. These studies in various cell lines consistently indicate that S1P is able to induce proliferation and protect cells from ceramide-induced apoptosis. A critical balance, which may be termed a ceramide/S1P rheostat, has been hypothesized to determine the fate of the cell. In this model, the balance between the cellular concentrations of ceramide and S1P determines whether a cell proliferates or undergoes apoptosis. Upon exposure to mitogens or intracellular oncoproteins, the cells experience a rapid increase in the intracellular levels of S1P and depletion of ceramide levels. This situation promotes cell survival and proliferation. In contrast, activation of sphingomyelinase in the absence of activation of ceramidase and/or SK results in the accumulation of ceramide and subsequent apoptosis. SK is the enzyme responsible for S1P production in cells. RNA encoding SK is detected in most tissues. A variety of proliferative factors, including PKC activators, fetal calf serum and platelet-derived growth factor (Olivera et al., 1993, Nature 365: 557), EGF, and TNFα (Dressler et al., 1992, Science 255: 1715) rapidly elevate cellular SK activity. SK activity is increased by phosphorylation of the enzyme by ERK (Pitson et al., 2003, EMBO J 22: 5491), while S1P promotes signaling through the Ras-Raf-Mek-Erk pathway, setting up an amplification cascade for cell proliferation. Sphingosine kinase and S1P play important roles in cancer pathogenesis. An oncogenic role of SK has been demonstrated. In these studies, transfection of SK into NIH/3T3 fibroblasts was sufficient to promote foci formation and cell growth in soft-agar, and to allow these cells to form tumors in NOD/SCID mice (Xia et al., 2000, Curr Biol 10: 1527). Additionally, inhibition of SK by transfection with a dominant-negative SK mutant or by treatment of cells with the nonspecific SK inhibitor DMS blocked transformation mediated by oncogenic H-Ras. As abnormal activation of Ras frequently occurs in cancer, these findings suggest a significant role of SK in this disease. SK has also been linked to estrogen signaling and estrogen-dependent tumorigenesis in MCF-7 cells (Nava et al., 2002, Exp Cell Res 281: 115). Other pathways or targets to which SK activity has been linked in hyperproliferative diseases include VEGF signaling via the Ras and MAP kinase pathway (Shu et al., 2002, Mol Cell Biol 22: 7758), protein kinase C (Nakade et al., 2003, Biochim Biophys Acta 1635: 104), TNFα (Vann et al., 2002, J Biol Chem 277: 12649), hepatocyte nuclear factor-1 and retinoic acid receptor alpha, intracellular calcium and caspase activation. While the elucidation of downstream targets of S1P remains an interesting problem in cell biology, sufficient validation of these pathways has been established to justify the development of SK inhibitors as new types of antiproliferative drugs. Cellular hyperproliferation is a characteristic of a variety of diseases, including, without limitation, cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis. Therefore, the compounds, pharmaceutical compositions and methods of this invention will be useful for the prevention and/or treatment of cancer, including solid tumors, hematopoietic cancers and tumor metastases. Such cancers may include, without limitation, solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma and paragangliomas. Additionally, such cancers may include, without limitation, hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplastic syndromes. Psoriasis is a common chronic disfiguring skin disease that is characterized by well-demarcated, red, hardened and scaly plaques that may be limited or widespread. While the disease is rarely fatal, it has serious detrimental effects on the quality of life of the patient, and this is further complicated by the lack of effective therapies. There is therefore a large unmet need for effective and safe drugs for this condition. Psoriasis is characterized by local keratinocyte hyperproliferation, T cell-mediated inflammation and by localized angiogenesis. Abnormal activation of SK has been implicated in all of these processes. Therefore, SK inhibitors are expected to be of use in the therapy of psoriasis. Mesangial cell hyperproliferative disorders refer to disorders brought about by the abnormal hyperproliferation of mesangial cells in the kidney. Mesangial hyperproliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy, and malignant nephrosclerosis, as well as such disorders such as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. As the hyperproliferation of mesangial cells is induced by growth factors whose action is dependent on increased signaling through SK, the SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the therapy of these mesangial cell hyperproliferative disorders. In addition to inflammatory processes discussed below, atherosclerosis and restenosis are characterized by hyperproliferation of vascular smooth muscle cells at the sites of the lesions. As the hyperproliferation of vascular smooth muscle cells is induced by growth factors whose action is dependent of increased signaling through SK, the SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the therapy of these vascular disorders. Inflammatory Diseases. The present invention also relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of inflammatory diseases. More specifically, the invention relates to compounds and pharmaceutical compositions that inhibit the enzymatic activity of SK for the treatment and/or prevention of inflammatory diseases, such as inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus. The following discussion demonstrates the role of SK in several of these inflammatory diseases. Since the same processes are involved in the above listed diseases, the compounds, pharmaceutical compositions and methods of this invention will be useful for the treatment and/or prevention of a variety of diseases. Inflammatory bowel disease (IBD) encompasses a group of disorders characterized by pathological inflammation of the lower intestine. Crohn's disease and ulcerative colitis are the best-known forms of IBD, and both fall into the category of “idiopathic” IBD because their etiologies remain to be elucidated, although proposed mechanisms implicate infectious and immunologic mediators. Studies on the etiology and therapy of IBD have been greatly facilitated by the development of several animal models that mimic the clinical and immunopathological disorders seen in humans. From studies with these models, it is clear that the full manifestations of IBD are dependent on synergy between the humoral and cellular immune responses. The notion that immune cells and cytokines play critical roles in the pathogenesis of IBD is well established; however, the molecular mechanisms by which this occurs are not yet clearly defined. As discussed below, cytokines that promote inflammation in the intestine afflicted with IBD, all activate a common mediator, sphingosine kinase (SK). Most prominently, tumor necrosis factor-α (TNFα) has been shown to play a significant role in IBD, such that antibody therapy directed against this cytokine, i.e. Remicade, may be a promising treatment. TNFα activates several processes shown to contribute to IBD and is necessary for both the initiation and persistence of the Th1 response. For example, TNFα has been shown act through the induction of nuclear factor kappa B (NFκB) which has been implicated in increasing the proinflammatory enzymes nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2). COX-2 has been shown to play a key role in the inflammation of IBDs through its production of prostaglandins, and oxidative stress such as that mediated by nitric oxide produced by NOS has also shown to exacerbate IBD inflammation. A common pathway of immune activation in IBDs is the local influx of mast cells, monocytes, macrophages and polymorphonuclear neutrophils which results in the secondary amplification of the inflammation process and produces the clinical manifestations of the diseases. This results in markedly increased numbers of mast cells in the mucosa of the ileum and colon of patients with IBD, which is accompanied by dramatic increases in TNFα (He, 2004, World J Gastroenterology 10 (3): 309). Additional mast cell secretory products, including histamine and tryptase, may be important in IBDs. Therefore, it is clear that inflammatory cascades play critical roles in the pathology of IBDs. The mechanisms and effects of the sphingolipid interconversion have been the subjects of a growing body of scientific investigation. Sphingomyelin is not only a structural component of cellular membranes, but also serves as the precursor for the potent bioactive lipids ceramide and sphingosine 1-phosphate (S1P). A ceramide:S1P rheostat is thought to determine the fate of the cell, such that the relative cellular concentrations of ceramide and S1P determine whether a cell proliferates or undergoes apoptosis. Ceramide is produced by the hydrolysis of sphingomyelin in response to inflammatory stresses, including TNFα, and can be hydrolyzed by ceramidase to produce sphingosine. Sphingosine is then rapidly phosphorylated by sphingosine kinase (SK) to produce S1P. Ceramidase and SK are also activated by cytokines and growth factors, leading to rapid increases in the intracellular levels of S1P and depletion of ceramide levels. This situation promotes cell proliferation and inhibits apoptosis. Deregulation of apoptosis in phagocytes is an important component of the chronic inflammatory state in IBDs, and S1P has been shown to protect neutrophils from apoptosis in response to Fas, TNFα and ceramide. Similarly, apoptosis of macrophages is blocked by S1P. In addition to its role in regulating cell proliferation and apoptosis, S1P has been shown to have several important effects on cells that mediate immune functions. Platelets, monocytes and mast cells secrete S1P upon activation, promoting inflammatory cascades at the site of tissue damage. Activation of SK is required for the signaling responses, since the ability of TNFα to induce adhesion molecule expression via activation of NFκB is mimicked by S1P and is blocked by the SK inhibitor dimethylsphingosine (Xia et al., 1998, Proc Natl Acad Sci USA 95: 14196). Similarly, S1P mimics the ability of TNFα to induce the expression of COX-2 and the synthesis of PGE2, and knock-down of SK by RNA interference blocks these responses to TNFα but not S1P (Pettus et al., 2003, FASEB J 17: 1411). S1P is also a mediator of Ca2+influx during neutrophil activation by TNFα and other stimuli, leading to the production of superoxide and other toxic radicals (Mackinnon, 2002, Journal of Immunology 169(11): 6394). A model for the roles of sphingolipid metabolites in the pathology of IBDs involves a combination of events in the colon epithelial cells and recruited mast cells, macrophages and neutrophils. Early in the disease, immunologic reactions or other activating signals promote the release of inflammatory cytokines, particularly TNFα from macrophages and mast cells. The actions of TNFα are mediated through its activation of S1P production. For example, TNFα induces S1P production in endothelial cells (Xia et al., 1998, Proc Natl Acad Sci USA 95: 14196), neutrophils (Niwa et al., 2000, Life Sci 66: 245) and monocytes by activation of sphingomyelinase, ceramidase and SK. S1P is a central player in the pathway since it has pleiotropic actions on the mucosal epithelial cells, macrophages, mast cells and neutrophils. Within the mucosal cells, S1P activates NFκB thereby inducing the expression of adhesion molecules, COX-2 resulting in PGE2synthesis, and NOS producing nitric oxide. Together, these chemoattractants and the adhesion molecules promote neutrophil infiltration into the mucosa. At the same time, S1P activates the neutrophils resulting in the release of oxygen free radicals that further inflame and destroy epithelial tissue. Similarly, S1P promotes the activation and degranulation of mast cells. As the processes involved in IBDs are induced by cytokines and growth factors whose action is dependent on increased signaling through SK, the SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the therapy of IBDs. Rheumatoid arthritis (RA) is a chronic, systemic disease that is characterized by synovial hyperplasia, massive cellular infiltration, erosion of the cartilage and bone, and an abnormal immune response. Studies on the etiology and therapy of rheumatoid arthritis have been greatly facilitated by the development of animal models that mimic the clinical and immunopathological disorders seen in humans. From studies in these models, it is clear that the full manifestations of RA are dependent on synergy between the humoral and cellular immune responses. The notion that immune cells, especially neutrophils, and cytokines play critical roles in the pathogenesis of arthritis is well established. However, the mechanisms by which this occurs are not fully elucidated. The early phase of rheumatic inflammation is characterized by leukocyte infiltration into tissues, especially by neutrophils. In the case of RA, this occurs primarily in joints where leukocyte infiltration results in synovitis and synovium thickening producing the typical symptoms of warmth, redness, swelling and pain. As the disease progresses, the aberrant collection of cells invade and destroy the cartilage and bone within the joint leading to deformities and chronic pain. The inflammatory cytokines TNFα, IL-1β and IL-8 act as critical mediators of this infiltration, and these cytokines are present in the synovial fluid of patients with RA. Leukocytes localize to sites of inflammatory injury as a result of the integrated actions of adhesion molecules, cytokines, and chemotactic factors. In lipopolysaccharide-induced arthritis in the rabbit, the production of TNFα and IL-1β in the initiative phase of inflammation paralleled the time course of leukocyte infiltration. The adherence of neutrophils to the vascular endothelium is a first step in the extravasation of cells into the interstitium. This process is mediated by selecting, integrins, and endothelial adhesion molecules, e.g. ICAM-1 and VCAM-1. Since TNFα induces the expression of ICAM-1 and VCAM-1 and is present in high concentrations in arthritic joints, it is likely that this protein plays a central role in the pathogenesis of the disease. This is supported by the clinical activity of anti-TNFα therapies such as Remicade. After adherence to the endothelium, leukocytes migrate along a chemoattractant concentration gradient. A further critical process in the progression of RA is the enhancement of the blood supply to the synovium through angiogenesis. Expression of the key angiogenic factor VEGF is potently induced by pro-inflammatory cytokines including TNFα. Together, these data point to important roles of TNFα, leukocytes, leukocyte adhesion molecules, leukocyte chemoattractants and angiogenesis in the pathogenesis of arthritic injury. Early in the disease, immunologic reactions or other activating signals promote the release of inflammatory cytokines, particularly TNFα and IL-1β from macrophages and mast cells. Ceramide is produced by the hydrolysis of sphingomyelin in response to inflammatory stresses, including TNFα and IL-1β (Dressler et al., 1992, Science 255: 1715). Ceramide can be further hydrolyzed by ceramidase to produce sphingosine which is then rapidly phosphorylated by SK to produce S1P. Ceramidase and SK are also activated by cytokines and growth factors, leading to rapid increases in the intracellular levels of S1P and depletion of ceramide levels. This situation promotes cell proliferation and inhibits apoptosis. Deregulation of apoptosis in phagocytes is an important component of the chronic inflammatory state in arthritis, and S1P has been shown to protect neutrophils from apoptosis in response to Fas, TNFα and ceramide. Similarly, apoptosis of macrophages is blocked by S1P. In addition to its role in regulating cell proliferation and apoptosis, S1P is a central player in the pathway since it has pleiotropic actions on the endothelial cells, leukocytes, chondrocytes and synovial cells. Within the endothelial cells, S1P activates NFκB thereby inducing the expression of multiple adhesion molecules and COX-2 resulting in PGE2synthesis. Together, this chemoattractant and the adhesion molecules promote neutrophil infiltration into the synovium. At the same time, S1P directly activates the neutrophils resulting in the release of oxygen free radicals that destroy joint tissue. Progression of RA is associated with a change from a Th1 to a Th2 environment, and sphingosine is selectively inhibitory toward Th1 cells. Consequently, inhibiting the conversion of sphingosine to S1P should attenuate the progression of the disease. Platelets, monocytes and mast cells secrete S1P upon activation, promoting inflammatory cascades at the site of tissue damage (Yatomi et al., Blood 86: 193 (1995)). S1P also promotes the secretion of proteases from chondrocytes that contribute to joint destruction. Finally, S1P-mediated expression of VEGF promotes the angiogenesis necessary to support the hyperproliferation of synovial cells. Consequently, inhibiting the conversion of sphingosine to S1P should attenuate the progression of the disease. As the processes involved in arthritis are induced by cytokines and growth factors whose action is dependent on increased signaling through SK, the SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the prevention and/or therapy of arthritis. Atherosclerosis is a complex vascular disease that involves a series of coordinated cellular and molecular events characteristic of inflammatory reactions. In response to vascular injury, the first atherosclerotic lesions are initiated by acute inflammatory reactions, mostly mediated by monocytes, platelets and T lymphocytes. These inflammatory cells are activated and recruited into the subendothelial vascular space through locally expressed chemotactic factors and adhesion molecules expressed on endothelial cell surface. Continuous recruitment of additional circulating inflammatory cells into the injured vascular wall potentiates the inflammatory reaction by further activating vascular smooth muscle (VSM) cell migration and proliferation. This chronic vascular inflammatory reaction leads to fibrous cap formation, which is an oxidant-rich inflammatory milieu composed of monocytes/macrophages and VSM cells. Over time, this fibrous cap can be destabilized and ruptured by extracellular metalloproteinases secreted by resident monocytes/macrophages. The ruptured fibrous cap can easily occlude vessels resulting in acute cardiac or cerebral ischemia. This underlying mechanism of atherosclerosis indicates that activation of monocyte/macrophage and VSM cell migration and proliferation play critical roles in the development and progression of atherosclerotic lesions. Importantly, it also suggests that a therapeutic approach that blocks the activities of these vascular inflammatory cells or smooth muscle cell proliferation should be able to prevent the progression and/or development of atherosclerosis. SK is highly expressed in platelets allowing them to phosphorylate circulating sphingosine to produce S1P. In response to vessel injury, platelets release large amounts of S1P into the sites of injury which can exert mitogenic effects on VSM cells by activating S1P receptors. S1P is also produced in activated endothelial and VSM cells. In these cells, intracellularly produced S1P functions as a second messenger molecule, regulating Ca2+homeostasis associated with cell proliferation and suppression of apoptosis. Additionally, deregulation of apoptosis in phagocytes is an important component of the chronic inflammatory state of atherosclerosis, and S1P protects granulocytes from apoptosis. Together, these studies indicate that activation of SK alters sphingolipid metabolism in favor of S1P formation, resulting in pro-inflammatory and hyper-proliferative cellular responses. In addition to its role in regulating cell proliferation and apoptosis, S1P has been shown to have several important effects on cells that mediate immune functions. Platelets and monocytes secrete cytokines, growth factors and S1P upon activation, promoting inflammatory cascades at the site of tissue damage. For example, TNFα has been shown to act through the induction of nuclear factor kappa B (NFκB), which has been implicated in increasing the proinflammatory enzymes nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2). COX-2 may play a key role in the inflammation of atherosclerosis through its production of prostaglandins, and oxidative stress such as that mediated by nitric oxide produced by NOS has also shown to exacerbate inflammation. Activation of SK is required for signaling responses since the ability of inflammatory cytokines to induce adhesion molecule expression via activation of NFκB is mimicked by S1P. Similarly, S1P mimics the ability of TNFα to induce the expression of COX-2 and the synthesis of PGE2, and knock-down of SK by RNA interference blocks these responses to TNFα but not S1P. S1P is also a mediator of Ca+influx during granulocyte activation, leading to the production of superoxide and other toxic radicals. Together, these studies indicate that SK is a new molecular target for atherosclerosis. The use of inhibitors of SK as anti-atherosclerosis agents will prevent the deleterious activation of leukocytes, as well as prevent infiltration and smooth muscle cell hyperproliferation, making the compounds, pharmaceutical compositions and methods of this invention useful for the treatment and/or prevention of atherosclerosis. The physiological endpoint in asthma pathology is narrowing of the bronchial tubes due to inflammation. In a large portion of asthma cases, the inflammation is initiated and later amplified by exposure to allergens. Upon inhalation, these allergens, bind to circulating IgE and then bind to the high-affinity FcϵRI surface receptors expressed by inflammatory cells residing in the bronchial mucosa. This extracellular binding leads to a cascade of signaling events inside the inflammatory cells, culminating in activation of these cells and secretion of multiple factors that trigger the cells lining the bronchial airways to swell, resulting in restricted bronchial tubes and decreased air exchange. The inflammation process in response to the initial exposure to allergen may not completely subside. Furthermore, additional exposures may lead to an exaggerated response called bronchial hyper-reactivity. This hyper-reactive state can lead to a permanent condition of restricted airways through airway remodeling. Consequently, unchecked inflammatory responses to initial allergen exposure may result in chronic inflammation and permanent bronchiolar constriction. Therefore, inhibiting or diminishing this exaggerated inflammation would likely decrease the symptoms associated with asthma. Many studies have revealed the involvement of mast cells in the inflammatory process leading to asthma, and SK has been shown to be involved in allergen-stimulated mast cell activation, a critical step in the bronchial inflammatory process. In rat basophilic leukemia RBL-2H3 cells, IgE/Ag binding to the high-affinity FcϵRI receptor leads to SK activation and conversion of sphingosine to S1P (Choi et al., 1996, Nature 380: 634). The newly formed S1P increases intracellular calcium levels, which is necessary for mast cell activiation. Alternately, high concentrations of sphingosine decrease IgE/Ag exposure-mediated leukotriene synthesis and diminishe cytokine transcription and secretion (Prieschl et al., 1999, J Exp Med 190: 1). In addition to the key role of SK and S1P in mast cell activation, S1P also has direct effects on downstream signaling in the asthma inflammation pathway. Ammit and coworkers demonstrated increased S1P levels in bronchoalveolar lavage (BAL) fluid collected from asthmatic patients 24 hours after allergen challenge compared with non-asthmatic subjects (Ammit et al., 2001, FASEB J 15: 1212). In conjunction with the finding that activated mast cells produce and secrete S1P, these results reveal a correlation between S1P and the asthmatic inflammatory response. To evaluate a possible role of SK and S1P exposure to cell response, ASM cultures were grown in the presence of S1P (Ammit et al., 2001 Id.). Furthermore, airway smooth muscle (ASM) cells are responsive to S1P- and SK-dependent stimuli, such as TNFα and IL-1β. Treatment with S1P increases phosphoinositide hydrolysis and intracellular calcium mobilization, both of which promote ASM contraction. Furthermore, S1P treatment increases DNA synthesis, cell number and accelerated progression of ASM cells from G1to S phase. In addition to the direct effects on ASM cells, S1P also regulates secretion of cytokines and expression of cell adhesion molecules that amplify the inflammatory response through leukocyte recruitment and facilitating extracellular component interaction. S1P, like TNFα, induces IL-6 secretion and increases the expression of cell adhesion molecules such as VCAM-1, ICAM-1 and E-selectin (Shimamura et al., 2004, Eur J Pharmacol 486: 141). In addition to the effects of S1P on mast cell activation, the multiple roles of S1P, and hence SK, in the bronchiolar inflammatory phase of asthma pathogenesis clearly indicate an opportunity for pharmacologic intervention in both the acute and chronic phases of this disease. Overall, SK is a target for new anti-asthma therapies. The use of inhibitors of SK as anti-asthma agents will inhibit cytokine-mediated activation of leukocytes, thereby preventing the deleterious activation of leukocytes, as well as preventing airway smooth muscle cell hyperproliferation, making the compounds, pharmaceutical compositions and methods of this invention useful for the treatment and/or prevention of asthma. Chronic obstructive pulmonary disease (COPD), like asthma, involves airflow obstruction and hyperresponsiveness that is associated with aberrant neutrophil activation in the lung tissue. This is clinically manifested as chronic bronchitis, fibrosis or emphysema, which together make up the fourth leading cause of death in the United States. Since activation of inflammatory cells by chemical insults in COPD occurs through NFκB-mediated pathways similar to those activated during asthma, it is likely that the compounds, pharmaceutical compositions and methods of this invention will also be useful for the treatment and/or prevention of COPD. Inflammation is involved in a variety of skin disorders, including psoriasis, atopic dermatitis, contact sensitivity and acne, which affect more than 20% if the population. Although topical corticosteroids have been widely used, their adverse effects prevent long-term use. Since the inflammatory responses typically involve aberrant activation of signaling pathways detailed above, it is likely that the compounds, pharmaceutical compositions and methods of this invention will also be useful for the treatment of these skin diseases. A variety of diseases including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus can be induced by inappropriate activation of T cells. Common features of the pathogenesis of these diseases include infiltration by mononuclear cells, expression of CD4 and CD8 autoreactive T cells, and hyperactive signaling by inflammatory mediators such as IL-1, IL-6 and TNFα. Since the inflammatory responses typically involve aberrant activation of signaling pathways detailed above, it is likely that the compounds, pharmaceutical compositions and methods of this invention will also be useful for the treatment of these T cell-mediated diseases of immunity. Angiogenic Diseases. The present invention also relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of diseases that involve undesired angiogenesis. More specifically, the invention relates to the use of chemical compounds and compositions that inhibit the enzymatic activity of sphingosine kinase for the treatment and/or prevention of angiogenic diseases, such as diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome. The following discussion demonstrates the role of SK in several of these angiogenic diseases. Since the same processes are involved in the above listed diseases, the compounds, pharmaceutical compositions and methods of this invention will be useful for the treatment and/or prevention of a variety of diseases. Angiogenesis refers to the state in the body in which various growth factors or other stimuli promote the formation of new blood vessels. As discussed below, this process is critical to the pathology of a variety of diseases. In each case, excessive angiogenesis allows the progression of the disease and/or the produces undesired effects in the patient. Since conserved biochemical mechanisms regulate the proliferation of vascular endothelial cells that form these new blood vessels, i.e. neovascularization, identification of methods to inhibit these mechanisms are expected to have utility for the treatment and/or prevention of a variety of diseases. The following discussion provides further details in how the compounds, compositions and methods of the present invention can be used to inhibit angiogenesis in several of these diseases. Diabetic retinopathy is a leading cause of vision impairment, and elevation in the expression of growth factors contributes to pathogenic angiogenesis in this disease. In particular, vascular endothelial growth factor (VEGF) is a prominent contributor to the new vessel formation in the diabetic retina (Frank et al., 1997, Arch Ophthalmol 115: 1036, Sone et al., 1997, Diabetologia 40: 726), and VEGF has been shown to be elevated in patients with proliferative diabetic retinopathy (Aiello et al., 1994, N Engl J Med 331: 1480). In addition to diabetic retinopathy, several other debilitating ocular diseases, including age-related macular degeneration and choroidal neovascularization, are associated with excessive angiogenesis that is mediated by VEGF and other growth factors (Grant et al., 2004, Expert Opin Investig Drugs 13: 1275). In the retina, VEGF is expressed in the pigmented epithelium, the neurosensory retina, the pericytes and the vascular smooth muscle layer. VEGF induces endothelial cell proliferation, favoring the formation of new vessels in the retina (Pe'er et al., 1995, Lab Invest 72: 638). At the same time, basic fibroblast growth factor (bFGF) in the retina is activated, and this factor acts in synergy with VEGF such that the two together induce the formation of new vessels in which the subendothelial matrix is much weaker than in normal vessels. Additionally, VEGF facilitates fluid extravasation in the interstitium, where exudates form in the retinal tissue. VEGF also promotes the fenestration of endothelial cells, a process that can give rise to intercellular channels through which fluids can leak, and disrupts tight junctions between cells. Thus, reduction of VEGF activity in the retina is likely to efficiently reduce the development and progression of retinal angiogenesis and vascular leakage which underlie the retinopathic process. The pro-inflammatory cytokine TNFα has also been demonstrated to play a role in diabetic retinopathy since it alters the cytoskeleton of endothelial cells, resulting in leaky barrier function and endothelial cell activation (Camussi et al., 1991, Int Arch Allergy Appl Immunol 96: 84). These changes in retinal endothelial cells are central in the pathologies of diabetic retinopathy. A link between the actions of VEGF and SK may be involved in driving retinopathy. SK has been shown to mediate VEGF-induced activation of ras- and mitogen-activated protein kinases (Shu et al., 2002, Mol Cell Biol 22: 7758). VEGF has been shown to enhance intracellular signaling responses to S1P, thereby increasing its angiogenic actions (Igarashi et al., 2003, Proc Natl Acad Sci USA 100: 10664). S1P has also been shown to stimulate NFκB activity (Xia et al., 1998, Proc Natl Acad Sci USA 95: 14196) leading to the production of COX-2, adhesion molecules and additional VEGF production, all of which have been linked to angiogenesis. Furthermore, the expression of the endothelial isoform of nitric oxide synthase (eNOS), a key signaling molecule in vascular endothelial cells and modulates a wide array of function including angiogenic responses, is regulated by SK (Igarashi et al., 2000 J Biol Chem 275: 32363). Clearly, SK is a central regulator of angiogenesis, supporting our hypothesis that its pharmacological manipulation may be therapeutically useful. S1P has also been shown to stimulate NFκB production which has been demonstrated to be angiogenic. NFκB leads to the production of Cox2, adhesion molecules and additional VEGF production, all of which have been linked to angiogenesis. One of the most attractive sites of intervention in this pathway is the conversion of sphingosine to S1P by the enzyme SK. SK is the key enzyme responsible for the production of S1P synthesis in mammalian cells, which facilitates cell survival and proliferation, and mediates critical processes involved in angiogenesis and inflammation, including responses to VEGF (Shu et al., 2002, Mol Cell Biol 22: 7758) and TNFα (Xia et al., 1998, Proc Natl Acad Sci USA 95: 14196). Therefore, inhibition of S1P production is a potentially important point of therapeutic intervention for diabetic retinopathy. The role of angiogenesis in cancer is well recognized. Growth of a tumor is dependent on neovascularization so that nutrients can be provided to the tumor cells. The major factor that promotes endothelial cell proliferation during tumor neovascularization is VEGF. As discussed above, signaling through VEGF receptors is dependent on the actions of SK. Therefore, the compounds, pharmaceutical compositions and methods of this invention will have utility for the treatment of cancer. More than 50 eye diseases have been linked to the formation of choroidal neovascularization, although the three main diseases that cause this pathology are age-related macular degeneration, myopia and ocular trauma. Even though most of these causes are idiopathic, among the known causes are related to degeneration, infections, choroidal tumors and or trauma. Among soft contact lens wearers, choroidal neovascularization can be caused by the lack of oxygen to the eyeball. As the choroidal neovascularization is induced by growth factors whose action is dependent on increased signaling through SK, the SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the therapy of disorders of choroidal neovascularization. Hemangiomas are angiogenic diseases characterized by the proliferation of capillary endothelium with accumulation of mast cells, fibroblasts and macrophages. They represent the most frequent tumors of infancy, and are characterized by rapid neonatal growth (proliferating phase). By the age of 6 to 10 months, the hemangioma's growth rate becomes proportional to the growth rate of the child, followed by a very slow regression for the next 5 to 8 years (involuting phase). Most hemangiomas occur as single tumors, whereas about 20% of the affected infants have multiple tumors, which may appear at any body site. Several studies have provided insight into the histopathology of these lesions. In particular, proliferating hemangiomas express high levels of proliferating cell nuclear antigen (a marker for cells in the S phase), type IV collagenase, VEGF and FGF-2. As the hemangiomas are induced by growth factors whose action is dependent on increased signaling through SK, the SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the therapy of hemangiomas. Psoriasis and Kaposi's sarcoma are angiogenic and proliferative disorders of the skin. Hypervascular psoriatic lesions express high levels of the angiogenic inducer IL-8, whereas the expression of the endogenous inhibitor TSP-1 is decreased. Kaposi's sarcoma (KS) is the most common tumor associated with human immunodeficiency virus (HIV) infection and is in this setting almost always associated with infection by human herpes virus 8. Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells and endothelial cells forming blood vessels. KS is a cytokine-mediated disease, highly responsive to different inflammatory mediators like IL-1β, TNF-α and IFN-γ and angiogenic factors. As the progression of psoriasis and KS are induced by growth factros whose action is dependent on increased signaling through SK, and SK inhibitory compounds, pharmaceutical compositions and methods of this invention are expected to be of use in the therapy of these disorders. EXAMPLES The present invention may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention. Representative compounds of the invention include those in Tables 1 and 2. Structures were named using Chemdraw Ultra, version 7.0.1, available from CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, Mass. 02140, USA. TABLE 1Representative compounds of the invention.CmpdChemical nameYR3R1R213-(4-Chloro-phenyl)- adamantane-1-carboxylic acid isopropylamideNH═O23-(4-Chloro-phenyl)- adamantane-1-carboxylic acid cyclopropylamideNH═O33-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2-ethylsulfanyl-ethyl)-amideNH═O43-(4-Chloro-phenyl)- adamantane-1-carboxylic acid phenylamideNH═O5Adamantane-1-carboxylic acid (4-hydroxy-phenyl)-amideNH═OH63-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (4-hydroxy-phenyl)-amideNH═O7Acetic acid 4-{[3-(4-chloro- phenyl)-adamantane-1- carbonyl]-amino}-phenyl esterNH═O83-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2,4-dihydroxy-phenyl)-amideNH═O93-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (3-hydroxymethyl-phenyl)- amideNH═O10Adamantane-1-carboxylic acid (4-cyanomethyl-phenyl)-amideNH═OH113-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (4-cyanomethyl-phenyl)-amideNH═O123-(4-Chloro-phenyl)- adamantane-1-carboxylic acid benzylamideNH═O133-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-tert-butyl-benzylamideNH═O143-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-methylsulfanyl-benzylamideNH═O153-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3-trifluoromethyl-benzylamideNH═O163-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-trifluoromethyl-benzylamideNH═O173-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3,5-bis-trifluoromethyl- benzylamideNH═O183-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3-fluoro-5-trifluoromethyl- benzylamideNH═O193-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 2-fluoro-4-trifluoromethyl- benzylamideNH═O203-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3,5-difluoro-benzylamideNH═O213-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3,4-difluoro-benzylamideNH═O223-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3,4,5-trifluoro-benzylamideNH═O233-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3-chloro-4-fluoro-benzylamideNH═O243-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-fluoro-3-trifluoromethyl- benzylamideNH═O253-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 2-chloro-4-fluoro-benzylamideNH═O263-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-chloro-3-trifluoromethyl- benzylamideNH═O273-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3-aminomethyl-2,4,5,6- tetrachloro-benzylamideNH═O283-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [1-(4-chloro-phenyl)-ethyl]- amideNH═O293-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [1-(4-bromo-phenyl)-ethyl]- amideNH═O303-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-methanesulfonyl- benzylamideNH═O313-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-dimethylamino-benzylamideNH═O323-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-trifluoromethoxy- benzylamideNH═O333-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3-trifluoromethoxy- benzylamideNH═O343-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-phenoxy-benzylamideNH═O35Adamantane-1-carboxylic acid 3,4-dihydroxy-benzylamideNH═OH363-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 3,4-dihydroxy-benzylamideNH═O373-(4-Chloro-phenyl)- adamantane-1-carboxylic acid phenethyl-amideNH═O383-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]- amideNH═O393-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(4-bromo-phenyl)-ethyl]- amideNH═O403-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(4-hydroxy-phenyl)-ethyl]- amideNH═O413-(4-Chloro-phenyl)- adamantane-1-carboxylic acid 4-phenoxy-benzylamideNH═O423-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(3-bromo-4-methoxy- phenyl)-ethyl]-amideNH═O43Adamantane-1-carboxylic acid [2-(3,4-dihydroxy-phenyl)- ethyl]-amideNH═OH443-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(3,4-dihydroxy-phenyl)- ethyl]-amideNH═O453-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2-benzo[1,3]dioxol-5-yl- ethyl)-amideNH═O463-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(3-phenoxy-phenyl)-ethyl]- amideNH═O473-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(4-phenoxy-phenyl)-ethyl]- amideNH═O483-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (3-phenyl-propyl)-amideNH═O493-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (biphenyl-4-ylmethyl)-amideNH═O50Adamantane-1-carboxylic acid (1-methyl-piperidin-4-yl)- amideNH═OH513-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (1-methyl-piperidin-4-yl)- amideNH═O523-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (4-methyl-piperazin-1-yl)- amideNH═O533-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (3-tert-butylamino-propyl)- amideNH═O543-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (3-pyrrolidin-1-yl-propyl)- amideNH═O553-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)- propyl]-amideNH═O56Adamantane-1-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)- ethyl]-amideNH═OH573-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)- ethyl]-amideNH═O583-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2-morpholin-4-yl-ethyl)-amideNH═O593-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2-piperazin-1-yl-ethyl)-amideNH═O60Adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amideNH═OH613-(4-Fluoro-phenyl)- adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amideNH═O623-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amideNH═O63Adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amideNH═OH643-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2-pyridin-4-yl-ethyl)-amideNH═O653-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (3-imidazol-1-yl-propyl)-amideNH═O663-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (2-methyl-1H-indol-5-yl)- amideNH═O673-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (1H-tetrazol-5-yl)-amideNH═O683-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (9-ethyl-9H-carbazol-3-yl)- amideNH═O69Adamantane-1-carboxylic acid [4-(4-chloro-phenyl)-thiazol-2- yl]-amideNH═OH703-(4-Chloro-phenyl)- adamantane-1-carboxylic acid [4-(4-chloro-phenyl)-thiazol-2-NH═O713-(4-Chloro-phenyl)- adamantane-1-carboxylic acid benzothiazol-2-ylamideNH═O723-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (5-chloro-benzooxazol-2-yl)- amideNH═O733-(4-Chloro-phenyl)- adamantane-1-carboxylic acid (9H-purin-6-yl)-amideNH═O75[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]- isopropyl-amineNHH764- and -phenolNHH77[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(4- trifluoromethyl-benzyl)-amineNHH78[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(2- fluoro-4-trifluoromethyl- benzyl)-amineNHH79[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(4- fluoro-3-trifluoromethyl- benzyl)-amineNHH80[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(4- trifluoromethoxy-benzyl)- amineNHH81[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-[2-(3- phenoxy-phenyl)-ethyl]-amineNHH82[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(1- methyl-piperidin-4-yl)-amineNHH83[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(4- methyl-piperazin-1-yl)-amineNHH84N-tert-Butyl-N′-[3-(4-chloro- phenyl)-adamantan-1- ylmethyl]-propane-1,3-diamineNHH85[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(3- pyrrolidin-1-yl-propyl)-amineNHH86[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-[2-(1- methyl-pyrrolidin-2-yl)-ethyl]- amineNHH87[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(2- morpholin-4-yl-ethyl)-amineNHH88[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]- pyridin-4-ylmethyl-amineNHH89[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-(9- ethyl-9H-carbazol-3-yl)-amineNHH90[3-(4-Chloro-phenyl)- adamantan-1-ylmethyl]-[5-(4- chloro-phenyl)-thiazol-2-yl]- amineNHH911-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethylamineNHCH3H92{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}- isopropyl-amineNHCH393Phenyl-[1-(3-phenyl- adamantan-1-yl)-ethyl]-amineNHCH394{1-[3-(4-Fluoro-phenyl)- adamantan-1-yl]-ethyl}- phenyl-amineNHCH395{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}- phenyl-amineNHCH396(1-Adamantan-1-yl-ethyl)- benzyl-amineNHCH3H97Benzyl-[1-(3-phenyl- adamantan-1-yl)-ethyl]-amineNHCH398Benzyl-{1-[3-(4-fluoro- phenyl)-adamantan-1-yl]- ethyl}-amineNHCH399Benzyl-{1-[3-(4-chloro- phenyl)-adamantan-1-yl]- ethyl}-amineNHCH3100(4-tert-Butyl-benzyl)-{1-[3-(4- chloro-phenyl)-adamantan-1- yl]-ethyl}-amineNHCH3101[1-(4-Bromo-phenyl)-ethyl]- {1-[3-(4-chloro-phenyl)- adamantan-1-yl]-ethyl}-amineNHCH3102(1-Adamantan-1-yl-ethyl)-[2- (4-bromo-phenyl)-ethyl]-amineNHCH3H103[2-(4-Bromo-phenyl)-ethyl]- {1-[3-(4-chloro-phenyl)- adamantan-1-yl]-ethyl}-amineNHCH3104(1-Adamantan-1-yl-ethyl)-(1- methyl-piperidin-4-yl)-amineNHCH3H105(1-Methyl-piperidin-4-yl)-[1- (3-phenyl-adamantan-1-yl)- ethyl]-amineNHCH3106{1-[3-(4-Fluoro-phenyl)- adamantan-1-yl]-ethyl}-(1- methyl-piperidin-4-yl)-amineNHCH3107{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(1- methyl-piperidin-4-yl)-amineNHCH3108{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(4- methyl-piperazin-1-yl)-amineNHCH3109{1-[3-(Phenyl)-adamantan-1- yl]-ethyl}-pyridin-4-ylmethyl- amineNHCH3110{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(6- chloro-pyridin-3-ylmethyl)- amineNHCH3111{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(2- pyridin-4-yl-ethyl)-amineNHCH3112{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(3H- imidazol-4-ylmethyl)-amineNHCH3113{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(2- methyl-1H-indol-5-yl)-amineNHCH3114{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(9- ethyl-9H-carbazol-3-yl)-amineNHCH3115{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(9- ethyl-9H-carbazol-3-ylmethyl)- amineNHCH31169-Ethyl-9H-carbazole-3- carboxylic acid {1-[3-(4- chloro-phenyl)-adamantan-1- yl]-ethyl}-amideNHCH31171-{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-3-(4- chloro-3-trifluoromethyl- phenyl)-ureaNHCH31181-{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-3-(4- chloro-3-trifluoromethyl- phenyl)-ureaNHCH3119(4-Bromo-thiophen-2- ylmethyl)-{1-[3-(4-chloro- phenyl)-adamantan-1-yl]- ethyl}-amineNHCH3120{1-[3-(4-Chloro-phenyl)- adamantan-1-yl]-ethyl}-(4- phenyl-thiophen-2-ylmethyl)- amineNHCH3 TABLE 2Representative compounds of the invention.CmpdChemical name RR1R21213-Phenyl-adamantane-1-carboxylic acidOH1223-(4-Fluoro-phenyl)-adamantane-1- carboxylic acidOH1233-(4-Chloro-phenyl)-adamantane-1- carboxylic acidOH1241-Adamantan-1-yl-ethanoneHCH31251-(3-Phenyl-adamantan-1-yl)- ethanoneCH31261-[3-(4-Fluoro-phenyl)-adamantan- 1-yl]-ethanoneCH31271-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-ethanoneCH31282-(Adamantane-1-carbonyl)-malonic acid dimethyl esterH1292-[3-(4-Chloro-phenyl)-adamantane- 1-carbonyl]-malonic acid dimethyl ester1303-(4-Chloro-phenyl)-1-[3-(4-chloro- phenyl)-adamantan-1-yl]-propenone1314-{3-[3-(4-Chloro-phenyl)- adamantan-1-yl]-3-oxo-propenyl}- benzonitrile1321-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-3-(4-hydroxy-phenyl)- propenone1331-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-3-naphthalen-2-yl-propenone1341-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-3-(6-chloro-pyridin-3-yl)- propenone1351-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-3-(1H-imidazol-4-yl)- propenone1361-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-3-(9-ethyl-9H-carbazol-3-yl)- propenone1371-[3-(4-Chloro-phenyl)-adamantan- 1-yl]-3-(4-phenyl-thiophen-2-yl)- propenone General methods. NMR spectra were obtained on Varian 300 instruments in CDCl3DMSO-d6. Chemical shifts are quoted relative to TMS for1H- and13C-NMR spectra. Solvents were dried and distilled prior to use. Reactions requiring anhydrous conditions were conducted under an atmosphere of nitrogen and column chromatography was carried out over silica gel (Merck, silica gel 60, 230-400 mesh) All reagents and commercially available materials were used without further purification. Example1 Method for the synthesis of 3-(4-chloro-phenyl)adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide, Compound 62 As an example, a process for the synthesis of Compound 62 is described in Scheme 1. The direct bromination of adamantane-1-carboxylic acid (1) in the presence of aluminum chloride (AlCl3) gave 3-bromide derivative (2) of 1 which was converted to (3) by the reaction of Friedel-Crafts reaction. 3 was reacted with thionyl chloride (SOCl2) to give 3-R-substituted-1-adamantanecarbonyl chlorides 4. By reaction 4 with a substituted amine, for example, 4-aminomethylpyridin (5), in THF, (6, also represented as Compound 62) and related amide compounds were obtained. More specifically, adamantane-1-carboxylic acid (1) (45 g, 0.25 mol) was added to mixture of AlCl3(45 g, 0.34 mol) and Br2(450 g) at 0° C. and stirred at 0-10° C. for 48 hrs, kept 5 hrs at about 20° C., poured on to 500 g crushed ice, diluted with 300 ml CHCl3and decolorized with solid Na2S2O5. The aqueous phase was extracted with Et2O (50 ml×2). The combined organic solution was washed with H2O and extracted with 10% NaOH. The alkaline extraction was acidified with 2N H2SO4and provided 49 g (yield=75.7%) of 3-bromo-adamantane-1-carboxylic acid (2). Over a 30 minute period, 3-bromo-adamantane-1-carboxylic acid (2) (16.0 g, 61.7 mmol) in 50 ml of dry chlorobenzene at −10° C. was added to 100 ml dry chlorobenzene and 9.3 g, 70 mmol AlCl3. The mixture was then warmed to room temperature for 1 hour and then heated to 90° C. for 10 hours. The mixture was then poured onto 200 g of crushed ice, and the filtered to provide 14.2 g (yield=79.3%) of 3-(4-chloro-phenyl)-adamantane-1-carboxylic acid (3). 3 reacted with an equimolar amount of 1,1′-carbonyl diimidazole (CDI) to give intermediate 3-R-substituted-1-adamantanecarbonyl imidazole (4). By reaction of 4 with a substituted amine, the corresponding adamantylamide was obtained. For example, reaction of 3 with 4-aminomethylpyridine (5), in toluene, produced {3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amide} (6 also represented as Compound 62) with a yield of 92.6% and a melting point of 128-130° C.1H NMR(300 MHz, CDCl3) δ 1.72-2.25(m, 12H, Admant-CH), 4.44-4.46 (d, J=6 Hz, 2H, CH2-Py), 6.18 (m, 1H, HN), 7.13-7.15 (d, J=6 Hz, 2H, H-Py), 7.15-7.30 (m, 4H, H-Ph), 8.52-8.54 (d, J=6 Hz, 2H, H-Py);13C NMR(300 MHz, CDCl3) δ 28.98, 35.73, 36.71, 38.77, 42.18, 42.37, 44.88, 122.38, 125.30, 126.57, 128.56, 129.26, 148.39, 150.20 177.76; MS m/z (rel intensity) 381.50 (MH+, 100), 383.41 (90), 384.35(80). Example 2 A Second Method for the Synthesis of Compound 62 A second method for the synthesis of Compound 62 and related adamantylamides is described in Scheme 2. 3-phenyl substituted intermediate (3) was prepared as described above. 3 reacted with 1,1′-carbonyldiimidazole (CDI) to give 3-R-substituted-1-adamantanecarbonylimidazole intermediate (4). By reaction of 4 with a substituted amine, for example 4-aminomethylpyridine 5, in toluene, 6 {3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid(pyridin-4-ylmethyl)-amide} was obtained. A diverse set of substituted aryladamantanes can be efficiently synthesized by condensation of various aromatic compounds with 2, and a variety of such compounds are commercially available. Additionally, amidation of 3 can be efficiently completed using a variety of coupling reagents and primary amine-containing compounds. The following Example provides several representatives of the products of this process; however, these methods can be adapted to produce many structurally related adamantylamides that are considered to be subjects of this invention. Example 3 Synthesis of Adamantylamides The methods described in Example 1 or 2 were used to prepare a library of substituted adamantylamides. Data provided below include: the amount synthesized, the yield of the amidation reaction, the melting point (m.p.) of the compound, mass spectral (MS) data for the compound, and NMR spectral data for the compound. Compound 1: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid isopropylamide. Yield=81%; m.p.: 140-141.5° C.; MS m/z (rel intensity) 332 (MH+, 95). Compound 2: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid cyclopropylamide. 90 mg, Yield=78.3%; m.p.: 145-148° C.;1H NMR(300 MHz, CDCl3) δ 0.44-0.46 (m, 2H, CH2), 0.76-0.78 (m, 2H, CH2), 1.59-1.92 (m, 12H, Admant-CH), 2.25 (s, 2H, Admant-CH), 2.62-2.65 (m, 1H, CH), 5.64 (m, 1H, HN), 7.28-7.30 (m, 4H, H-Ph);13C NMR(300 MHz, CDCl3) δ 6.7, 22.7, 28.8, 35.5, 36.5, 38.4, 42.0, 44.5, 126.2, 128.1, 131.4, 148.2, 178.5; MS m/z (rel intensity) 330.46 (MH+, 100), 331.47 (25), 332.46(35). Compound 3: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2-ethylsulfanyl-ethyl)-amide. 180 mg, Yield=92.0%; m.p.: 101-103° C.;1H NMR(300 MHz, CDCl3) δ 1.24-1.29 (t, J=7.5 Hz, 3H, CH3), 1.74-1.97 (m, 12H, Admant-CH), 2.27 (s, 2H, Admant-CH), 2.52-2.59 (q, J=7.5 Hz, 2H, CH2), 2.65-2.70 (t, J=7.5 Hz, 2H, CH2), 3.41-3.47 (m, 2H, CH2), 6.12(m, 1H, HN), 7.24-7.28 (m, 4H, Ar—H), 7.38-7.45 (m, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 15.1, 25.7, 29.0, 31.6, 35.8, 36.7, 38.3, 38.6, 42.0, 42.3, 44.7, 126.6, 128.5, 148.6, 177.6; MS m/z (rel intensity) 373.6 (MH+, 100) 374.6 (25), 375.6(40). Compound 4: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid phenylamide. 120 mg, Yield=68.5%; m.p.: 190-192° C.; MS m/z (rel intensity)366(MH+, 35). Compound 5: Adamantane-1-carboxylic acid (4-hydroxy-phenyl)-amide. 77 mg, Yield=57%; m.p.: 224-226° C.; MS m/z (rel intensity) 272 (MH+, 50). Compound 6: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (4-hydroxy-phenyl)-amide. Yield=66%; m.p.: 240-242° C.;1H NMR(200 MHz, CDCl3) δ 0.86-2.32(m, 14H, Admant-H), 6.75-6.78 (d, J=9 Hz, 2H, Ar—H), 7.26-7.33 (m, 6H, Ar—H);13C NMR(300 MHz, CDCl3) δ 23.7, 28.8, 29.4, 29.7, 30.3, 35.5, 38.5.3, 38.7, 42.0, 44.6, 115.7, 122.5, 126.3, 128.3, 140.6, 173.6; MS m/z (rel intensity) 382 (MH+, 50). Compound 7: Acetic acid 4-{[3-(4-chloro-phenyl)-adamantane-1-carbonyl]-amino}-phenyl ester. 140 mg, Yield=85%; m.p.: 176-178° C.; MS m/z (rel intensity) 424 (MH+, 75), 425(50), 426(55). Compound 8: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2,4-dihydroxy-phenyl)-amide. 5 mg, Yield=4%; m.p.: 242-244° C.; MS m/z (rel intensity) 398 (MH+, 20). Compound 9: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (3-hydroxymethyl-phenyl)-amide. 74 mg, Yield=38%; m.p.: 173-175° C.; MS m/z (rel intensity) 396 (MH+, 90). Compound 10: Adamantane-1-carboxylic acid (4-cyanomethyl-phenyl)-amide. 5.1 mg, Yield=4%; m.p.: 184-186° C.; MS m/z (rel intensity) 295 (MH+, 50). Compound 11: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (4-cyanomethyl-phenyl)-amide. 92 mg, Yield=46%; mp: 157-159° C.; MS m/z (rel intensity) 405 (MH+, 20). Compound 12: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid benzylamide. 144 mg, Yield=75.8%; m.p.: 134-136° C.; MS m/z (rel intensity) 380(MH+, 75). Compound 13: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-tert-butyl-benzylamide. 35 mg, Yield=62%; m.p.: 187-189° C.; MS m/z (rel intensity) 436 (MH+, 30). Compound 14: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-methylsulfanyl-benzylamide. 100 mg, Yield=47%; m.p.: 139-141° C.;1H NMR(300 MHz, CDCl3) δ 1.73-1.98 (m, 12H, Admant-CH), 2.26 (s, 2H, Admant-CH), 2.47 (s, 3H, SCH3), 4.38-4.40 (d, J=6 Hz, 2H, CH2), 5.84 (s(br), 1H, HN), 7.16-7.24 (m, 4H, Ar—H), 7.26-7.30 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 15.9, 28.8, 35.5, 36.5, 38.4, 41.7, 42.0, 42.9, 44.6, 126.2, 126.7, 128.2, 131.4, 135.2, 137.5, 148.1, 177.2; MS m/z (rel intensity) 426.6 (MH+, 100), 427.6 (30), 428.6 (32). Compound 15: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3-trifluoromethyl-benzylamide. 190 mg, Yield=81%; oil;1H NMR(300 MHz, CDCl3) δ 1.58-2.00 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.50-4.52 (d, J=6 Hz, 2H, CH2), 6.02 (m, 1H, HN), 7.26-7.29 (m, 4H, Ar—H), 7.44-7.54 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 35.5, 36.5, 38.5, 41.8, 42.0, 42.8, 44.5, 124.0, 126.2, 128.1, 129.0, 130.7, 139.9, 148.3, 177.2; MS m/z (rel intensity) 448.2 (MH+, 100). Compound 16: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-trifluoromethyl-benzylamide. 180 mg, Yield=80%; m.p.: 165-167° C.;1H NMR(300 MHz, CDCl3) δ0 1.74-1.99 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.48-4.50 (d, J=6 Hz, 2H, CH2), 6.03 (m, 1H, HN), 7.24-7.30 (m, 4H, Ar—H), 7.34-7.36 (d, J=6 Hz, 2H, Ar—H), 7.57-7.59 (d, J=6 Hz, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 35.7, 36.7, 38.3, 38.7, 42.2, 42.3, 43.1, 43.9, 44.8, 125.9, 126.6, 127.9, 128.5, 131.9, 142.9, 148.4, 177.8; MS m/z (rel intensity) 448.2 (MH+, 100). Compound 17: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide. 168 mg, Yield=65%; m.p.: 125-127° C.;1H NMR(300 MHz, CDCl3) δ 1.75-2.00 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.53-4.55 (d, J=6 Hz, 2H, CH2), 6.24 (m, 1H, HN), 7.23-7.30 (m, 4H, Ar—H), 7.69 (s, 2H, Ar—H), 7.77 (s, 1H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.9, 35.6, 36.7, 38.6, 42.0, 42.2, 42.6, 44.7, 121.5, 125.5, 126.5, 127.6, 128.5, 131.8, 141.8, 148.4, 178.1; MS m/z (rel intensity) 516.2 (MH+, 100). Compound 18: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3-fluoro-5-trifluoromethyl-benzylamide. 210 mg, Yield=90%; m.p.: 92-94° C.;1H NMR(300 MHz, CDCl3) δ 1.75-2.00 (m, 12H, Admant-CH), 2.29 (s, 2H, Admant-CH), 4.48-4.50 (d, J=6 Hz, 2H, CH2), 6.07 (m, 1H, HN), 7.14-7.29 (m, 7H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.9, 35.6, 36.6, 38.3, 38.7, 42.0, 42.1, 42.6, 44.7, 111.7, 112.0, 117.7, 118.0, 119.8, 126.5, 128.5, 131.8, 143.2, 148.4, 161.2, 164.5, 178.1; MS m/z (rel intensity) 466.2 (MH+, 100). Compound 19: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 2-fluoro-4-trifluoromethyl-benzylamide. 156 mg, Yield=67%; m.p.: 190-192° C.;1H NMR(300 MHz, CDCl3) δ 1.60-1.96 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.51-4.53 (d, J=6 Hz, 2H, CH2), 6.08 (m, 1H, HN), 7.26-7.44 (m, 7H, Ar—H);13C NMR(300 MHz, CDCl3) δ 15.7, 29.0, 35.7, 36.7, 38.7, 42.2, 44.8, 113.3, 121.5, 126.6, 128.5, 130.8, 131.9, 148.4, 177.7; MS m/z (rel intensity) 466.1 (MH+, 100). Compound 20: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3,5-difluoro-benzylamide. 160 mg, Yield=85%; m.p.: 59-61° C.;1H NMR(300 MHz, CDCl3) δ 1.75-2.03 (m, 12H, Admant-CH), 2.29 (s, 2H, Admant-CH), 4.38-4.41 (d, J=6 Hz, 2H, CH2), 6.00 (m, 1H, HN), 6.67-6.81 (m, 3H, Ar—H), 7.29(s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.9, 35.7, 36.7, 38.1, 38.7, 42.1, 42.3, 42.8, 44.1, 44.7, 103.0, 110.2, 126.6, 128.5, 131.9, 148.4, 164.9, 178.0; MS m/z (rel intensity) 416.59 (MH+, 100), 417.59 (35), 418.59 (40), 419.60(20). Compound 21: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3,4-difluoro-benzylamide. 179 mg, Yield=86%; m.p.: 100-102° C.;1H NMR(300 MHz, CDCl3) δ 1.74-1.98 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.38-4.41 (d, J=6 Hz, 2H, CH2), 5.96 (m, 1H, HN), 6.98 (s, 1H, Ar—H), 7.06-7.12 (m, 2H, Ar—H), 7.24-7.30 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 35.7, 36.7, 38.7, 42.0, 42.1, 42.7, 44.8, 116.7, 117.7, 123.7, 126.6, 128.5, 148.5, 177.8; MS m/z (rel intensity) 416.4 (MH+, 100). Compound 22: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3,4,5-trifluoro-benzylamide. 195 mg, Yield=90%; m.p.: 106-108° C.;1H NMR(300 MHz, CDCl3) δ 1.75-1.98 (m, 12H, Admant-CH), 2.29 (s, 2H, Admant-CH), 4.36-4.38 (d, J=6 Hz, 2H, CH2), 6.03 (m, 1H, HN), 6.82-6.89 (t, J=7.5 Hz, 2H, Ar—H), 7.28 (s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.9, 35.6, 36.7, 38.7, 42.1, 42.4, 44.7, 111.3, 111.4, 111.5, 123.3, 125.5, 126.6, 128.5, 129.8, 131.8, 135.6, 148.4, 178.0; MS m/z (rel intensity) 434.5 (MH+, 100). Compound 23: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3-chloro-4-fluoro-benzylamide. 143 mg, Yield=66.2%; m.p.: 112-114° C.;1H NMR(300 MHz, CDCl3) δ 1.74-1.98 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.37-4.39 (d, J=6 Hz, 2H, CH2), 5.99 (m, 1H, HN), 7.08 (s, 1H, Ar—H), 7.10-7.12 (m, 1H, Ar—H), 7.28-7.30 (m, 5H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 35.5, 36.5, 38.5, 41.8, 42.0, 42.3, 44.6, 116.8, 126.2, 127.2, 128.2, 129.6, 148.0, 177.2; MS m/z (rel intensity) 432.5 (MH+, 50). Compound 24: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-fluoro-3-trifluoromethyl-benzylamide. 220 mg, Yield=94%; m.p.: 111-113° C.;1H NMR(300 MHz, CDCl3) δ 1.72-1.96 (m, 12H, Admant-CH), 2.25 (s, 2H, Admant-CH), 4.39-4.41 (d, J=6 Hz, 2H, CH2), 6.31-6.34 (m, 1H, HN), 7.03-7.22 (m, 2H, Ar—H), 7.25-7.29 (m, 3H, Ar—H), 7.38-7.45 (m, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 35.5, 36.7, 37.7, 38.6, 38.7, 42.1, 42.3, 43.2, 44.7, 117.3, 126.2, 126.5, 128.5, 133.2, 148.4, 177.8; MS m/z (rel intensity) 466.6 (MH+, 100). Compound 25: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 2-chloro-4-fluoro-benzylamide. 145 mg, Yield=97.3%; m.p.: 132-134° C.;1H NMR(300 MHz, CDCl3) δ 1.72-2.03 (m, 12H, Admant-CH), 2.25 (s, 2H, Admant-CH), 4.45-4.47 (d, J=6 Hz, 2H, CH2), 6.23 (m, 1H, HN), 6.90-6.96 (m, 1H, Ar—H), 7.08-7.18 (m, 2H, Ar—H), 7.26-7.33 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 35.7, 36.7, 38.4, 38.6, 41.2, 42.2, 42.4, 44.7, 114.4, 117.0, 126.6, 128.5, 131.5, 148.5, 163.7, 177.7; MS m/z (rel intensity) 432.54 (MH+, 100), 433.55 (25), 434.54(80), 435.54(30), 436.64(25). Compound 26: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-chloro-3-trifluoromethyl-benzylamide. 136 mg, Yield=92.0%; m.p.: 77-79° C.;1H NMR(300 MHz, CDCl3) δ 1.58-1.99 (m, 12H, Admant-CH), 2.29 (s, 2H, Admant-CH), 4.45-4.47 (d, J=6 Hz, 2H, CH2), 6.05 (m, 1H, HN), 7.26-7.31 (m, 4H, H-Ph), 7.36-7.39(d, J=9 Hz, 1H, Ar—H), 7.44-7.47(d, J=9 Hz, 1H, Ar—H), 7.66 (s, 1H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.7, 35.5, 36.5, 38.5, 41.9, 42.3, 44.6, 126.2, 126.4, 128.3, 131.6, 131.8, 137.8, 148.0, 177.3; MS m/z (rel intensity) 482.55 (MH+, 100), 483.55 (35), 484.35(70). Compound 27: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3-aminomethyl-2,4,5,6-tetrachloro-benzylamide. 70 mg, Yield=31%; m.p.: 170-172° C.;1H NMR(300 MHz, CDCl3) δ 1.60 (s, 2H, NH2), 1.72-1.94 (m, 12H, Admant-CH), 2.25 (s, 2H, Admant-CH), 4.19 (s, 2H, CH2), 4.79-4.81 (d, J=6 Hz, 2H, CH2), 5.91 (m(br), 1H, HN), 7.26-7.27 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.7, 35.5, 36.4, 38.4, 40.9, 41.9, 43.7, 44.5, 122.9, 125.2, 125.9, 126.2, 128.1, 129.3, 131.4, 131.8, 134.1, 134.3, 139.2, 148.0, 176.6; MS m/z (rel intensity) 546.9 (MH+, 100). Compound 28: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [1-(4-chloro-phenyl)-ethyl]-amide. 113 mg, Yield=53%; m.p.: 204-206° C. (B);1H NMR(300 MHz, CDCl3) δ 1.44-1.46 (d, J=6 Hz, 3H, CH3), 1.58-1.94 (m, 12H, Admant-CH), 2.27 (s, 2H, Admant-CH), 5.06-5.11 (m, 1H, CH), 5.75-5.78 (m(br), 1H, HN), 7.20-7.31 (m, 8H, Ar—H);13C NMR(300 MHz, CDCl3) δ 22.0, 29.0, 35.7, 36.7, 38.6, 38.7, 41.8, 42.2, 44.8, 48.1, 126.3, 126.6, 127.7, 128.5, 129.0, 131.8, 133.2, 142.3, 148.5, 176.6; MS m/z (rel intensity) 428.4 (MH+, 100). Compound 29: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide. 69 mg, Yield=29%; m.p.: 218-220° C.; MS m/z (rel intensity) 472 (MH+, 80), 474(MH+, 100); Compound 30: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-methanesulfonyl-benzylamide. 189 mg, Yield=82%; m.p.: 115-117° C.;1H NMR(300 MHz, CDCl3) δ1.75-2.00 (m, 12H, Admant-CH), 2.29 (s, 2H, Admant-CH), 3.02(s, 3H, CH3), 4.51-4.53 (d, J=6 Hz, 2H, CH2), 6.19 (m, 1H, HN), 7.16-7.28 (m, 4H, Ar—H), 7.40-7.43 (d, J=9 Hz, 2H, Ar—H), 7.84-7.87 (d, J=9 Hz, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 35.5, 35.7, 36.7, 37.7, 38.5, 38.7, 42.0, 42.2, 44.6, 44.7, 117.7, 125.6, 126.6, 127.7, 128.1, 129.9, 131.7, 137.4, 139.1, 145.9, 148.6, 178.0; MS m/z (rel intensity) 458.3 (MH+, 100). Compound 31: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-dimethylamino-benzylamide. 161 mg, Yield=76.1%; m.p.: 154-156° C.;1H NMR(300 MHz, CDCl3) δ 1.72-1.97 (m, 12H, Admant-CH), 2.36 (s, 2H, Admant-CH), 2.94 (s, 6H, N(CH3)2), 4.32-4.34 (d, J=6 Hz, 2H, CH2), 5.73 (m, 1H, HN), 6.68-6.71 (d, J=9 Hz, 2H, Ar—H), 7.13-7.16(d, J=9 Hz, 2H, Ar—H), 7.28 (s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 15.7, 29.0, 35.8, 38.7, 40.9, 42.3, 43.4, 44.8, 112.9, 126.6, 128.5, 129.2, 137.7, 140.9, 173.4; MS m/z (rel intensity) 422.66 (M+, 100), 423.66 (MH+, 90), 424.64(60). Compound 32: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-trifluoromethoxy-benzylamide. 200 mg, Yield=86.2%; m.p.: 119-121° C.;1H NMR(300 MHz, CDCl3) δ 1.72-2.02(m, 12H, Admant-CH), 2.24 (s, 2H, Admant-CH), 4.39-4.41 (d, J=6 Hz, 2H, CH2), 6.27 (s, 1H, HN), 7.06-7.26 (m, 8H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 35.7, 35.8, 36.7, 38.4, 38.7, 42.1, 42.4, 42.8, 43.6, 44.8, 121.2, 121.6, 126.3, 126.6, 128.5, 128.7, 129.1, 137.5, 148.4, 177.9; MS m/z (rel intensity) 464.4 (MH+, 70). Compound 33: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3-trifluoromethoxy-benzylamide. 200 mg, Yield=86%; oil;1H NMR(300 MHz, CDCl3) δ 1.75-2.00 (m, 12H, Admant-CH), 2.28 (s, 2H, Admant-CH), 4.45-4.47 (d, J=6 Hz, 2H, CH2), 6.00 (m, 1H, HN), 7.01-7.19 (m, 3H, Ar—H), 7.24-7.38 (m, 5H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 35.7, 36.7, 38.7, 42.0, 42.2, 42.8, 44.8, 119.8, 125.9, 126.6, 128.5, 130.2, 131.8, 141.5, 148.6, 149.7, 177.8; MS m/z (rel intensity) 464.2 (MH+, 100). Compound 34: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 4-phenoxy-benzylamide. 170 mg, Yield=72.0%; m.p.: 121-123° C.;1H NMR(300 MHz, CDCl3) δ 1.58-1.99 (m, 12H, Admant-CH), 2.27 (s, 2H, Admant-CH), 4.41-4.43 (d, J=6 Hz, 2H, CH2), 5.88 (m, 1H, HN), 6.95-7.02 (m, 3H, Ar—H), 7.09-7.14(m, 1H, Ar—H), 7.20-7.36(m, 9H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 35.6, 36.5, 38.5, 42.0, 42.9, 43.9, 44.6, 118.8, 118.9, 123.3, 128.2, 129.0, 129.6, 131.4, 133.1, 148.1, 156.5, 156.9, 176.9; MS m/z (rel intensity) 472.36 (MH+, 100), 473.36 (30), 474.37(30). Compound 35: Adamantane-1-carboxylic acid 3,4-dihydroxy-benzylamide. 143 mg, Yield=48%; m.p.: 184-186° C.; MS m/z (rel intensity) 302 (MH+, 8). Compound 36: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid 3,4-dihydroxy-benzylamide. 134 mg, Yield=65%; m.p.: 73-75° C.; MS m/z (rel intensity) 412 (MH+, 10). Compound 37: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid phenethyl-amide. 150 mg, Yield=76%; m.p.: 123-125° C.; MS m/z (rel intensity) 394 (MH+, 14). Compound 38: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide. 156 mg, Yield=78%; m.p.: 103-105° C.; MS m/z (rel intensity) 412 (MH+, 52), 413(17), 414(20). Compound 39: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(4-bromo-phenyl)-ethyl]-amide. 30 mg, Yield=55%; m.p.: 114-116° C.; MS m/z (rel intensity) 472 (MH+, 38), 474(MH+, 42); Compound 40: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(4-hydroxy-phenyl)-ethyl]-amide. 112 mg, Yield=55%; m.p.: 174-176° C.; MS m/z (rel intensity) 410 (MH+, 100), 411(25), 412(33). Compound 41: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide. 159 mg, Yield=75%; m.p.: 108-110° C.; MS m/z (rel intensity) 424 (MH+, 55), 425(18), 426(20). Compound 42: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(3-bromo-4-methoxy-phenyl)-ethyl]-amide. 220 mg, Yield=87.5%; oil;1H NMR(300 MHz, CDCl3) δ 1.63-1.89 (m, 12H, Admant-CH), 2.25 (s, 2H, Admant-CH), 2.71-2.76(t, J=7.5 Hz, 2H, CH2), 3.42-3.48(q, J=12 Hz, 2H, NCH2), 3.87 (s, 3H, OCH3), 5.62 (s(br), 1H, NH), 6.82-6.84 (d, J=6 Hz, 1H, Ar—H), 7.07-7.09 (d, J=6 Hz, 1H, Ar—H), 7.27-7.30 (m, 4H, Ar—H), 7.36 (s, 1H, Ar—H);13C NMR (300 MHz, CDCl3) δ 29.0, 34.6, 35.7, 36.7, 38.6, 40.8, 41.9, 42.2, 44.8, 56.5, 112.3, 111.7, 126.6, 128.5, 128.6, 129.0, 132.8, 133.9, 148.6, 154.7, 177.6; MS m/z (rel intensity) 502 (MH+, 80), 503 (25), 504(MH+, 100), 505 (33); Compound 43: Adamantane-1-carboxylic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide. 69 mg, Yield=24%; mp: 98-100° C.;1H NMR(300 MHz, DMSO-d6) δ 0.94-0.98(m, 2H, CH2), 1.60-1.95 (m, 15H, Admant-CH), 3.12-3.15 (m, 2H, CH2), 6.39-6.41 (d, J=6 Hz, 1H, Ar—H), 6.54(s, 1H, Ar—H), 6.60-6.62 (d, J=6 Hz, 1H, Ar—H), 7.35 (s, 1H, NH);13C NMR(300 MHz, DMSO-d6) δ 27.6, 29.4, 35.1, 36.9, 37.8, 38.6, 44.6, 46.4, 114.8, 116.9, 119.4, 131.4, 145.6, 164.4; MS m/z (rel intensity) 316.5 (MH+, 50), 317.5 (8). Compound 44: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide. 100 mg, Yield=47.0%; m.p.: 124-126° C.; MS m/z (rel intensity) 426 (MH+, 100). Compound 45: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2-benzo [1,3]dioxol-5-yl-ethyl)-amide. 190 mg, Yield=87%; oil;1H NMR(300 MHz, CDCl3) δ 1.71-1.90(m, 12H, Admant-CH), 2.24 (s, 2H, Admant-CH), 2.70-2.75(t, J=6 Hz, 2H, CH2), 3.42-3.48(q, J=6 Hz, 2H, CH2), 5.61 (m, 1H, NH), 5.93 (s, 2H, CH2), 6.60-6.63(d, J=9 Hz, 1H,Ar—H), 6.67(s, 1H, Ar—H), 6.73-6.76(d, J=9 Hz, 1H,Ar—H), 7.26-7.29 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.6, 28.8, 35.4, 35.5, 36.4, 38.3, 40.6, 41.6, 42.0, 43.8, 44.5, 100.8, 108.2, 109.0, 121.5, 126.2, 128.1, 132.5, 146.0, 148.2, 177.0; MS m/z (rel intensity) 438.28 (MH+, 100), 439.29 (45), 440.28(55). Compound 46: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(3-phenoxy-phenyl)-ethyl]amide. 200 mg, Yield=82%; m.p.: 114-116° C.;1H NMR(300 MHz, CDCl3) δ 1.70-1.95 (m, 12H, Admant-CH), 2.23 (s, 2H, Admant-CH), 2.75-2.80(t, J=7.5 Hz, 2H, CH2), 3.45-3.51(q, J=12 Hz, 2H, NCH2), 5.63 (s(br), 1H, NH), 6.83-7.01 (m, 5H, Ar—H), 7.07-7.18 (m, 2H, Ar—H), 7.22-7.35 (m, 6H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 29.0, 35.8, 36.7, 38.6, 40.7, 41.9, 42.3, 44.8, 116.9, 117.1, 119.2, 119.4, 123.5, 123.6, 123.9, 126.6, 128.5, 130.0, 130.2, 141.7, 148.3, 157.4, 177.7; MS m/z (rel intensity) 486.58 (MH+, 93), 487.56 (60), 488.55(68), 489.54 (25). Compound 47: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(4-phenoxy-phenyl)-ethyl]-amide. 224 mg, Yield=92%; m.p.: 88-90° C.;1H NMR(300 MHz, CDCl3) δ 1.71-1.90 (m, 12H, Admant-CH), 2.24 (s, 2H, Admant-CH), 2.77-2.81(t, J=6 Hz, 2H, CH2), 3.48-3.51(m, 2H, NCH2), 5.63 (s(br), 1H, NH), 6.94-7.00 (m, 4H, Ar—H), 7.09-7.35 (m, 9H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.1, 29.3, 35.2, 35.8, 36.7, 38.7, 40.9, 41.9, 42.3, 44.8, 118.9, 119.4, 123.5, 126.6, 128.6, 129.3, 130.0, 130.4, 131.8, 134.2, 148.7, 156.1, 157.6, 177.5; MS m/z (rel intensity) 486.58 (MH+, 93), 487.56 (60), 488.55(68), 489.54 (25). Compound 48: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (3-phenyl-propyl)-amide. 195 mg, Yield=59%; m.p.: 97-100° C.; MS m/z (rel intensity) 408 (MH+, 55). Compound 49: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (biphenyl-4-ylmethyl)-amide. 200 mg, Yield=87.7%; m.p.: 208-210° C.;1H NMR(300 MHz, CDCl3) δ 1.74-2.09 (m, 12H, Admant-CH), 2.26 (s, 2H, Admant-CH), 4.48-4.50 (d, J=6 Hz, 2H, CH2), 5.94 (m, 1H, HN), 7.29-7.37 (m, 6H, Ar—H), 7.42-7.46(m, 3H, Ar—H), 7.55-7.59(m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 15.7, 29.0, 35.8, 36.7, 38.8, 42.0, 42.3, 43.4, 44.9, 126.6, 127.3, 127.6, 127.7, 128.4, 128.5, 129.0, 137.7, 140.9, 148.5, 177.4; MS m/z (rel intensity) 456.59 (MH+, 90), 457.57 (20), 458.56(30). Compound 50: Adamantane-1-carboxylic acid (1-methylpiperidin-4-yl)-amide. 120 mg, Yield=76%; m.p.: 157-159° C.; MS m/z (rel intensity) 277 (MH+, 100). Compound 51: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (1-methyl-piperidin-4-yl)-amide. 136 mg, Yield=74.4%; m.p.: 146-148° C.;1H NMR(300 MHz, CDCl3) δ 1.06-2.77(m, 25H, Admant-CH, 4.44-3.70 (m, 1H, CH), 5.41-5.43 (m, 1H, HN), 7.26-7.29 (m, 4H, H—Ar);13C NMR(300 MHz, CDCl3) δ 11.6, 29.1, 32.5, 35.8, 36.7, 38.6, 41.9, 42.2, 44.8, 46.0, 46.4, 54.7, 126.6, 128.5, 131.8, 148.6, 176.8; MS m/z (rel intensity) 387 (MH+,100). Compound 52: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (4-methyl-piperazin-1-yl)-amide. 182 mg, Yield=66.2%; m.p.: 142-147° C.; MS m/z (rel intensity) 387 (MH+, 48). Compound 53: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (3-tert-butylamino-propyl)-amide. 160 mg, Yield=79%; oil;1H NMR(300 MHz, CDCl3) δ 1.11(s, 9H, 3CH3), 1.69-1.95 (m, 14H, Admant-CH, CH2), 2.18 (m, 1H, HN), 2.25 (s, 2H, Admant-CH), 2.70-2.74 (t, J=6 Hz, 2H, CH2), 3.33-3.38 (m, 2H, CH2), 7.16-7.27 (m, 4H, Ar—H), 7.42 (m, 1H, HN);13C NMR(300 MHz, CDCl3) δ 28.5, 28.7, 29.1, 29.4, 35.9, 36.7, 38.8, 39.3, 39.7, 41.1, 41.8, 42.3, 42.6, 45.0, 46.0, 51.8, 126.3, 128.3, 128.4, 148.8, 177.8; MS m/z (rel intensity) 403.1 (MH+, 100). Compound 54: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide. 184 mg, Yield=92%; m.p.: 86-88° C.;1H NMR(300 MHz, CDCl3) δ 1.63-1.92 (m, 18H, Admant-CH, CH2), 2.24 (s, 2H, Admant-CH), 2.50 (s,4H, CH2), 2.58-2.62 (t, J=6 Hz, 2H, CH2), 3.33-3.38 (m, 2H, CH2), 7.19-7.28 (m, 4H, Ar—H), 7.92 (m, 1H, HN);13C NMR(300 MHz, CDCl3) δ 23.7, 26.5, 29.1, 35.9, 36.7, 38.7, 40.7, 41.7, 42.3, 44.9, 54.4, 56.4, 126.6, 128.4, 129.6, 131.6, 148.8, 177.6; MS m/z (rel intensity) 401.25(MH+, 100). Compound 55: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide. 190 mg, Yield=98%; oil;1H NMR(300 MHz, CDCl3) δ 1.60-2.12 (m, 16H, cyclo-CH2, Admant-CH), 2.27 (s, 2H, Admant-CH), 2.36-2.47 (t, J=7.5 Hz, 2H, cyclo-CH2), 3.15-3.20 (t, J=7.5 Hz, 2H, CH2), 3.32-3.42 (m, 4H, CH2), 7.09 (m, 1H, HN), 7.18-7.32 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 18.2, 26.5, 29.1, 31.1, 35.0, 35.9, 36.7, 38.5, 39.5, 42.0, 42.4, 44.8, 47.6, 126.7, 128.4, 166.5, 177.9; MS m/z (rel intensity) 415.6 (MH+, 100). Compound 56: Adamantane-1-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide. 23 mg, Yield=33%; m.p.: 82-84° C.; MS m/z (rel intensity) 291 (MH+, 100). Compound 57: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide. 200 mg, Yield=61.7%; Oil;1H NMR(300 MHz, CDCl3) δ 1.68-2.36(m, 24H, Admant-CH, 2.98-3.04 (m, 1H, CH*), 3.17-3.27 (m, 1H, Ha), 3.45-3.53 (m, 1H, Hb), 7.24-7.30 (m, 4H, H—Ar);13C NMR(300 MHz, CDCl3) δ 22.9, 28.6, 29.1, 29.5, 35.9, 36.7, 38.6, 40.9, 41.7, 42.4, 44.7, 57.3, 65.0, 126.5, 128.4, 131.6, 148.8, 177.4; MS m/z (rel intensity) 401 (MH+, 100). HCL salt: m.p.: 68-70° C. Compound 58: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2-morpholin-4-yl-ethyl)-amide. 147 mg, Yield=73%; m.p.: 110-112° C.; MS m/z (rel intensity) 403 (MH+, 100). Compound 59: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2-piperazin-1-yl-ethyl)-amide. 144 mg, Yield=72%, oil;1H NMR(300 MHz, CDCl3) δ 1.65-1.97 (m, 15H, NH, cyclo-CH2, Admant-CH), 2.27 (s, 2H, Admant-CH), 2.36-2.50 (m, 6H, cyclo-CH2), 2.87-2.90 (m, 2H, CH2), 3.30-3.95 (m, 2H, CH2), 6.34 (m, 1H, HN), 7.18-7.29 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 35.6, 36.4, 38.4, 41.6, 42.1, 44.5, 46.2, 52.7, 54.1, 56.8, 126.3, 128.2, 148.4, 156.2, 177.3; MS m/z (rel intensity) 402.6 (MH+, 100). Compound 60: Adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amide. 200 mg, Yield=74%; m.p.: 155-157° C.; MS m/z (rel intensity) 285.63 (MH+, 100), 286.71 (40). Compound 61: 3-(4-Fluoro-phenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amide. 105 mg, Yield=97%; oil; MS m/z (rel intensity) 365 (MH+, 90). Compound 62: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amide. Yield=92.6%; m.p.: 128-130° C.;1H NMR(300 MHz, CDCl3) δ 1.72-2.25 (m, 12H, Admant-CH), 4.44-4.46 (d, J=6 Hz, 2H, CH2-Py), 6.18 (m, 1H, HN), 7.13-7.15 (d, J=6 Hz, 2H, H-Py), 7.15-7.30 (m, 4H, H-Ph), 8.52-8.54 (d, J=6 Hz, 2H, H-Py);13C NMR(300 MHz, CDCl3) δ 28.98, 35.73, 36.71, 38.77, 42.18, 42.37, 44.88, 122.38, 125.30, 126.57, 128.56, 129.26, 148.39, 150.20 177.76; MS m/z (rel intensity) 381.50 (MH+, 100), 383.41 (90), 384.35(80). Compound 63: Adamantane-1-carboxylic acid (2-pyridin-4-yl-ethyl)-amide. 175 mg, Yield=61%; m.p.: 151-153° C.; MS m/z (rel intensity) 285 (MH+, 100). Compound 64: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2-pyridin-4-yl-ethyl)-amide. 70 mg, Yield=55.7%; m.p.: 144-147° C.; MS m/z (rel intensity) 395 (MH+, 100). Compound 65: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (3-imidazol-1-yl-propyl)-amide. 195 mg, Yield=95%; m.p.: 128-130° C.;1H NMR(300 MHz, CDCl3) δ 1.70-2.00 (m, 14H, CH2, Admant-CH), 2.27 (s, 2H, Admant-CH), 3.25-3.32 (m, 2H, CH2), 3.96-4.00 (m, 2H, CH2), 5.65 (m, 1H, HN), 6.95 (s, 1H, imdazol-H), 7.07 (s, 1H, imidazol-H), 7.26-7.28 (m, 4H, Ar—H), 7.49 (s, 1H, imidazol-H);13C NMR(300 MHz, CDCl3) δ 29.0, 31.5, 35.7, 36.7, 37.0, 38.6, 41.9, 42.2, 44.8, 45.0, 119.1, 126.3, 126.6, 128.5, 129.8, 131.8, 137.3, 148.5, 178.0; MS m/z (rel intensity) 398.66 (MH+, 100), 399.62 (45), 400.63(60), 401.60(20). Compound 66: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (2-methyl-1H-indol-5-yl)-amide. Yield=56%; m.p.: 145-147° C.; MS m/z (rel intensity) 419 (MH+, 35). Compound 67: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (1H-tetrazol-5-yl)-amide. 120 mg, Yield=67%; m.p.: >240° C.; MS m/z (rel intensity) 358.2 (MH+, 100), 359.1 (35), 361.1(60). Compound 68: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide. 111 mg, Yield=46%; m.p.: 165-167° C.; MS m/z (rel intensity) 482.67 (MH+, 100), 483.67(65), 484.66(55). Compound 69: Adamantane-1-carboxylic acid [4-(4-chloro-phenyl)-thiazol-2-yl]-amide. 182 mg, Yield=49%; m.p.: 162-164° C.; MS m/z (rel intensity) 373 (MH+, 100). Compound 70: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid [4-(4-chloro-phenyl)-thiazol-2-yl]-amide. Yield=56%; m.p.: 172-174° C.; MS m/z (rel intensity) 483 (MH+, 20). Compound 71: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid benzothiazol-2-ylamide. Yield=48.8%; m.p.: 209-211° C.; MS m/z (rel intensity) 423 (MH+, 50). Compound 72: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (5-chloro-benzooxazol-2-yl)-amide. Yield=45%; oil; MS m/z (rel intensity) 441 (MH+, 18). Compound 73: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (9H-purin-6-yl)-amide. 180 mg, Yield=88.2%; oil;1H NMR(300 MHz, CDCl3) δ 1.84-2.21 (m, 13H, NH, Admant-CH), 2.38 (s, 2H, Admant-CH), 7.07 (s, 1H, Ar—H), 7.30 (m, 4H, Ar—H), 7.63 (s, 1H, Ar—H), 8.38 (s, 1H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 35.5, 36.7, 37.7, 38.7, 42.1, 44.6, 45.1, 117.7, 123.2, 125.5, 126.5, 126.6, 128.7, 129.9, 130.1, 132.1, 137.4, 147.8, 174.3; MS m/z (rel intensity) 408.6 (MH+, 100). Example 4 Method for the Conversion of Adamantylamides into Adamantylamines As an example, a process for the synthesis of adamantylamine compounds is described in Scheme 3. A number of adamantylamides, prepared as described above, were converted to their corresponding adamantylamines by reduction of the carbonyl group with Zn(BH4)2(Scheme 3). Zinc borohydride (Zn(BH4)2) was prepared by methods known in the art. Briefly, 20.8 g (165 mmol) of freshly fused ZnCl2and 12.9 g (330 mmol) of NaBH4were placed in a dried 250 ml side arm flask fitted with a reflux condenser. To this, 250 ml of dry THF was added using a double-ended needle, and the mixture was stirred for 24 h at room temperature. The active hydride content of the supernatant solution was estimating by quenching aliquots with 2N H2SO4and estimating the amount of hydrogen that was evolved using a gas burette. The final supernatant solution contained 0.66 M Zn(BH4)2, and was used for further reactions as follows. The general method for the conversion of adamantylamides into the corresponding adamantylamines involved combining 100 mg of an adamatanylamide with 2.0 ml of Zn(BH4)2(0.36 M, 2.3 mmol) in THF. The mixture was refluxed for 24 h, and any excess hydride present was quenched by the addition of 1 ml of water. Typically, the mixture was then saturated with K2CO3and the supernatant layer was filtered and dried over K2CO3, and the solvent was removed by evaporation. The residue was then purified by flash chromatography (ethyl acetate:hexane=1:4) to give the adamantylamine compound. The following Example provides several representatives of the products of this process; however, these methods can be adapted to produce many structurally related adamantylamines that are considered to be subjects of this invention. Example 5 Synthesis of Adamantylamines The methods described in Example 4 were used to prepare a library of substituted adamantylamines. Data provided below include: the amount synthesized, the yield of the reduction reaction; the melting point (m.p.) of the compound; mass spectral (MS) data for the compound; and NMR spectral data for the compound. Compound 75: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-isopropyl-amine. 39 mg, Yield=41%; oil; MS m/z (rel intensity) 318 (MH+, 20). Compound 76: 4-{[3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-amino}-phenol. 75 mg, Yield=66%; oil;1H NMR (300 MHz, CDCl3) δ 1.60-1.86(m, 12H, Admant-H), 2.22(s, 2H, Admant-H), 2.58-2.62(m, 1H, NH), 2.83(s, 2H, CH2), 6.53-6.56(d, J=9 Hz, 2H, Ar—H), 6.68-6.71(d, J=9 Hz, 2H, Ar—H), 7.28(s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 14.3, 29.0, 34.9, 36.1, 36.7, 39.9, 42.6, 46.3, 57.4, 114.1, 116.1, 126.3, 128.1, 131.2, 143.2, 147.3, 148.9; MS m/z (rel intensity) 368.6 (MH+, 100), 369.6 (50), 370.6(30). Compound 77: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(4-trifluoromethyl-benzyl)-amine. 23 mg, Yield=28%; oil;1H NMR(300 MHz, CDCl3) δ 1.55-1.83(m, 13H, Admant-H, NH), 2.18(s, 2H, Admant-H), 2.32(s, 2H, NCH2), 3.84(s, 2H, NCH2), 7.27(s, 4H, Ar—H), 7.43-7.45 (d, J=6 Hz, 2H, Ar—H), 7.56-7.58(d, J=6 Hz, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.1, 34.7, 36.3, 36.7, 40.0, 42.7, 46.5, 54.1, 61.7, 125.1, 126.3, 128.0, 131.1, 144.9, 149.1; MS m/z (rel intensity) 434.4 (MH+, 60), 435.4 (25), 436.4(30). Compound 78: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(2-fluoro-4-trifluoromethyl-benzyl)-amine. 21 mg, Yield=24%; oil;1H NMR(300 MHz, CDCl3) δ 1.55-1.83(m, 12H, Admant-H), 2.20(s, 2H, Admant-H), 2.32(s, 2H, CH2), 3.88(s, 2H, Ar—CH2), 7.26-7.27(s, 4H, Ar—H), 7.29-7.31 (m, 2H, Ar—H), 7.49-7.53 (m, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 34.6, 36.2, 36.7, 39.9, 42.7, 46.5, 47.6, 61.7, 112.4, 112.7, 120.8, 126.3, 128.0, 130.4, 131.8, 149.1; MS m/z (rel intensity) 452.7 (MH+, 100), 453.7 (30), 454.7(40). Compound 79: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(4-fluoro-3-trifluoromethyl-benzyl)-amine. 24 mg, Yield=38%; oil;1H NMR(300 MHz, CDCl3) δ 1.28-1.82(m, 12H, Admant-H), 2.19(s, 2H, Admant-H), 2.51-2.55(m, 1H, CH2), 2.88-2.90(m, 1H, CH2), 3.40(s, 1H, NH), 3.76-3.80 (m, 1H, CH2), 4.08-4.13(m, 1H, CH2), 7.14-7.29(m, 5H, Ar—H), 7.57 (m, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.5, 34.3, 35.5, 36.4, 39.8, 41.9, 42.1, 46.3, 61.2, 66.7, 117.4, 117.7, 126.0, 128.2, 129.0, 130.5, 131.6, 135.9, 147.7, 158.1, 161.5; MS m/z (rel in ensity) 452.4 (MH+, 100), 453.4 (50), 454.4(60). Compound 80: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(4-trifluoromethoxy-benzyl)-amine. 23 mg, Yield=36%; oil;1H NMR(300 MHz, CDCl3) δ 1.28-1.80(m, 12H, Admant-H), 2.15(s, 2H, Admant-H), 2.53-2.57(m, 1H, NCH2), 2.84-2.90(m, 1H, NCH2), 3.38(m, 1H, NH), 3.68-3.75(m, 1H, NCH2), 4.14-4.19(m, 1H, NCH2), 7.13-7.16(d, J=9 Hz, 2H, Ar—H), 7.36-7.39(d, J=9 Hz, 2H, Ar—H), 7.2-5-7.27(m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.5, 29.0, 34.6, 36.3, 39.7, 40.0, 42.7, 46.5, 53.9, 61.7, 66.2, 120.7, 121.2, 126.0, 126.3, 128.1, 129.0, 131.6, 132.9, 147.9; MS m/z (rel intensity) 450.6 (MH+, 70), 451.6 (30), 452.6(40). Compound 81: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-[2-(3-phenoxy-phenyl)-ethyl]-amine. 27 mg, Yield=42%; oil;1H NMR(300 MHz, CDCl3) δ 1.50-1.82 (m, 13H, Admant-CH, NH), 2.16 (s, 2H, Admant-CH), 2.34(s, 2H, CH2), 2.76-2.84(m, 4H, NCH2), 5.63 (s(br), 1H, NH), 6.83-7.01 (m, 5H, Ar—H), 7.07-7.18 (m, 2H, Ar—H), 7.22-7.35 (m, 6H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.1, 34.6, 36.1, 36.7, 40.0, 42.7, 46.5, 52.1, 62.3, 116.4, 118.8, 119.1, 123.1, 123.6, 126.3, 128.0, 129.5, 142.2, 149.1, 157.1; MS m/z (rel intensity) 472.4 (MH+, 100), 473.3 (70), 474.3(80). Compound 82: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(1-methyl-piperidin-4-yl)-amine. 12 mg, Yield=6%; oil; MS m/z (rel intensity) 373.6 (MH+, 100), 374.6 (25), 375.6(36). Compound 83: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(4-methyl-piperazin-1-yl)-amine. Yield=12%; oil;1H NMR(300 MHz, CDCl3) δ 1.54-1.82(m, 12H, Admant-H), 2.17(s, 2H, Admant-H), 2.52(s, 2H, CH2), 2.63(s, 3H, NCH3), 2.77-2.80(m, 4H, NCH2), 2.98-3.15 (m, 4H, NCH2), 7.28(s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.8, 29.0, 34.3, 36.2, 39.8, 40.0, 42.3, 42.6, 45.9, 46.5, 50.4, 51.5, 54.6, 58.5, 59.6, 60.3, 126.3, 128.0, 131.2, 148.1, 149.4; MS m/z (rel intensity) 374.7 (MH+, 30), 375.7(5), 376.7(8). Compound 84: N-tert-Butyl-N′-[3-(4-chloro-phenyl)-adamantan-1-ylmethyl]-propane-1,3-diamine. Yield=18%; oil;1H NMR(300 MHz, CDCl3) δ 1.29-1.32 (m,6H, CH2), 1.55-1.90 (m, 21H, Admant-CH, C(CH3)3), 2.21-2.46 (m, 2H, Admant-CH), 2.42-2.87 (m, 2H, NH), 3.29-3.31(d, J=6 Hz, 2H, CH2), 7.26-7.28 (m, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 26.4, 26.6, 28.6, 28.7, 28.8, 36.2, 38.2, 38.4, 38.6, 39.7, 42.7, 44.6, 126.3, 128.0; MS m/z (rel intensity) 389.6 (MH+, 100). Compound 85: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(3-pyrrolidin-1-yl-propyl)-amine. 15 mg, Yield=15%; m.p.: 138-140° C.;1H NMR(300 MHz, CDCl3) δ 1.56-1.91 (m, 18H, Admant-CH, CH2), 2.21-2.46 (m, 5H, Admant-CH, NH, CH2), 2.72-2.89 (m,6H, CH2), 3.52(m, 2H, CH2), 7.26-7.28 (m, 4H, Ar—H);13C NMR (300 MHz, CDCl3) δ 22.8, 22.9, 23.3, 28.6, 29.8, 34.6, 35.6, 36.6, 39.6, 39.8, 42.1, 42.2, 46.1, 56.6, 61.2, 61.3, 62.2, 126.2, 128.2, 131.5, 147.9; MS m/z (rel intensity) 387.6 (MH+, 100), 388.6 (60), 389.6(65). Compound 86: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine. 23 mg, Yield=24%; oil;1H NMR(300 MHz, CDCl3) δ 1.54-1.87(m, 20H, CH2, Admant-H), 2.18(s, 2H, Admant-H), 2.29-2.41 (m, 4H, CH2), 2.62(m, 3H, NCH3), 2.87-3.18(m, 1H, NCH), 3.36 (m, 1H, NH), 7.27(s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 29.0, 36.2, 36.7, 40.0, 40.6, 42.7, 46.6, 48.6, 57.2, 64.7, 126.3, 128.0; MS m/z (rel intensity) 387.4 (MH+, 100), 388.4 (33), 389.4(40). Compound 87: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(2-morpholin-4-yl-ethyl)-amine. 9 mg, Yield=9%; oil;1H NMR(300 MHz, CDCl3) δ 1.57-1.90(m, 16H, Admant-H), 2.25(s, 2H, Admant-H), 2.36-2.47(m, 4H, CH2), 2.73-2.99(m, 4H, NCH2), 3.57-3.58(m, 2H, NCH2), 4.32 (m, 1H, NH), 7.27(s, 4H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.6, 29.1, 35.7, 36.2, 39.7, 40.0, 46.6, 47.4, 53.8, 54.5, 55.4, 62.9, 67.1, 126.1, 16.3, 128.0, 128.2; MS m/z (rel intensity) 389.7 (MH+, 100), 390.7 (33), 391.7(40). Compound 88: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-pyridin-4-ylmethyl-amine. Yield=72%; oil;1H NMR (300 MHz, CDCl3) δ 1.55-1.84(m, 12H, Admant-H), 2.20(s, 2H, CH2), 2.29(s, 2H, Admant-H), 3.90(s, 2H, Ar—CH2), 7.26-7.28(s, 4H, Ar—H), 7.49-7.51 (d, J=6 Hz, 2H, Ar—H), 8.59-8.51 (d, J=6 Hz, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.9, 34.6, 36.0, 36.5, 39.8, 42.5, 46.3, 52.6, 61.7, 123.9, 126.2, 127.9, 128.0, 131.0, 146.8, 148.9, 154.6; MS m/z (rel intensity) 367.7 (MH+, 100), 368.7(35), 369.7(60). Compound 89: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-(9-ethyl-9H-carbazol-3-yl)-amine. 77 mg, Yield=81%; oil; MS m/z (rel intensity) 468 (MH+, 20). Compound 90: [3-(4-Chloro-phenyl)-adamantan-1-ylmethyl]-[5-(4-chloro-phenyl)-thiazol-2-yl]-amine. 15.5 mg, Yield=21%; oil; MS m/z (rel intensity) 469 (MH+, 30). Example 6 Methods for the Synthesis of Adamantylethylamine and Adamantylethylamide Compounds As an example, a process for the synthesis of adamantylethylamine and adamantylethylamide compounds is described in Scheme 4. Substituted-1-adamantanecarbonyl chlorides (4) were prepared as described in Example 1. Reaction of 4 with dimethyl malonate in toluene in the presence of sodium hydroxide yielded dimethyl (3-R-substituted-phenyl-1-adamantanecarbonyl)malonates (5), which were hydrolyzed by a mixture of acetic acid with water and sulfuric acid (CH3COOH—H2O—H2SO4ratio 10:3:1) to afford the corresponding 3-R-substituted-phenyl-1-adamantyl methyl ketone (6). Ketone 6 was reacted with formamide and formic acid (Leukart reaction) to yield 7, which can be modified by either alkylation or acylation to produce adamantylethylamine compounds (8) or adamantylethylamide compounds (9). A second method for the synthesis of adamantylethylamine compounds is described in Scheme 5. 3-R-substituted-phenyl-1-adamantyl methyl ketone (6) was prepared as described above. By reaction of 6 with a substituted primary amine in formic acid, i.e. a Wallach reaction, the corresponding adamantylethylamine compound (8) can be obtained. For example, by reaction of 4-chloro-6 with 4-amino-1-methylpiperidine, which was synthesized by converting N-methyl piperidone to the corresponding oxime followed by reduction to the amino compound using lithium aluminum hydride (LiAlH4), {1-[3-(4-chloro-phenyl)-adamantan-1-yl]-ethyl}-(1-methyl-piperidin-4-yl)-amine, also referred to as Compound 107, was obtained. The following Example provides several representatives of the products of these processes; however, these methods can be adapted to produce many structurally related adamantylethylamine or adamantylethylamide compounds that are considered to be subjects of this invention. Example 7 Synthesis of Adamantylethylamine Compounds The methods described in Example 6 were used to prepare a library of substituted adamantylethylamine compounds. Data provided below include: the amount synthesized, the yield of the reaction; the melting point (m.p.) of the compound; and mass spectral (MS) data for the compound. Compound 91: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethylamine. Yield=77%; oil;1H NMR(300 MHz, CDCl3) δ 0.95-0.98(m, 3H, CH3), 1.30-2.22(m, 16H, Admant-CH, NH2), 4.24-4.30 (m, 1H, CH), 7.26-7.29 (m, 4H, H—Ar); MS m/z (rel intensity) 290.4 (MH+, 40). Compound 92: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-isopropyl-amine. Yield=27%; oil;1H NMR(300 MHz, CDCl3) δ 0.91-0.94(d, J=6 Hz, 6H, 2CH3), 1.15-1.68 (m, 12H, Admant-CH), 1.81 (m, 3H, CH3), 2.19 (s, 2H, Admant-CH), 3.74-3.76 (m, 1H, HN), 4.24-4.30 (m, 1H, CH), 7.26-7.29 (m, 4H, H—Ar). Compound 93: Phenyl-[1-(3-phenyl-adamantan-1-yl)-ethyl]-amine. Compound 94: {1-[3-(4-Fluoro-phenyl)-adamantan-1-yl]-ethyl}-phenyl-amine. Compound 95: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-phenyl-amine. Yield=19%; oil. Compound 96: (1-Adamantan-1-yl-ethyl)-benzyl-amine. Yield=64%; m.p.: 62-64° C.;1H NMR(300 MHz, CDCl3) δ 1.12-1.16(d, J=8 Hz, 3H, CH3), 1.56-2.01(m, 17H, Admant-CH, CH2), 3.03 (m, 1H, HN), 4.24-4.40 (m, 1H, CH), 7.26-7.30 (m, 4H, Ar—H), 8.32(s, 1H, Ar—H);13C NMR (300 MHz, CDCl3) δ 11.6, 29.1, 32.5, 35.8, 36.7, 38.6, 41.9, 42.2, 44.8, 46.0, 46.4, 54.7, 126.6, 128.5, 131.8, 148.6; MS m/z (rel intensity) 270.5 (MH+, 10). Compound 97: Benzyl-[1-(3-phenyl-adamantan-1-yl)-ethyl]-amine. Yield=41%; oil. Compound 98: Benzyl-{1-[3-(4-fluoro-phenyl)-adamantan-1-yl]-ethyl}-amine. Yield=42%; oil;1H NMR(300 MHz, CDCl3) δ 0.92-0.95 (d, J=6 Hz, 3H, CH3), 1.49-2.10 (m, 21H, Admant-CH, CH2), 2.19-2.29 (m, 6H, NCH), 2.79-2.94 (m, 1H, HN), 6.94-7.04 (m, 2H, Ar—H), 7.28-7.35 (m, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.98, 35.73, 36.71, 38.77, 42.18, 42.37, 44.88, 122.38, 125.30, 126.57, 128.56, 129.26, 148.39, 150.2; MS m/z (rel intensity) 364.5 (MH+, 75), 365.5 (20). Compound 99. Benzyl-{1-[3-(4-chloro-phenyl)-adamantan-1-yl]-ethyl}-amine. Yield=25%; oil;1H NMR(300 MHz, CDCl3) δ 1.13-1.17(d, J=8 Hz, 3H, CH3), 1.59-2.05(m, 15H, Admant-CH, CH2), 2.23(s, 2H, Admant-H), 3.03 (m, 1H, HN), 4.04-4.10 (m, 1H, CH), 7.20-7.31 (m, 8H, Ar—H), 8.33-8.35(s, 1H, Ar—H);13C NMR(300 MHz, CDCl3) δ 11.6, 29.1, 32.5, 35.8, 36.7, 38.6, 41.9, 42.2, 44.8, 46.0, 46.4, 54.7, 126.6, 128.5, 131.8, 148.6; MS m/z (rel intensity) 380.4 (MH+, 80) Compound 100: (4-tert-Butyl-benzyl)-{1-[3-(4-chloro-phenyl)-adamantan-1-yl]-ethyl}-amine. Yield=2%; oil; MS m/z (rel intensity) 436.3 (MH+, 30). Compound 101: [1-(4-Bromo-phenyl)-ethyl]-{1-[3-(4-chloro-phenyl)-adamantan-1-yl]ethyl}-amine. Yield=3%; oil; MS m/z (rel intensity) 472.2 (MH+, 98), 474.2 (MH+, 100). Compound 102: (1-Adamantan-1-yl-ethyl)-[2-(4-bromo-phenyl)-ethyl]-amine. Yield=0.4%; oil; MS m/z (rel intensity) 362.2 (M−H+, 98), 364.2 (M−H+, 100). Compound 103: [2-(4-Bromo-phenyl)-ethyl]-{1-[3-(4chloro-phenyl)-adamantan-1-yl]-ethyl}-amine. Yield=11%; oil; MS m/z (rel intensity) 472.1 (MH+, 50), 474.1(MH+, 60). Compound 104: (1-Adamantan-1-yl-ethyl)-(1-methyl-piperidin-4-yl)-amine. Yield=16%; oil;1H NMR(300 MHz, CDCl3) δ 0.91-0.94 (d, J=9 Hz, 3H, CH3), 1.43-2.00 (m, 23H, Admant-CH, CH2), 2.25 (m, 3H, NCH3), 2.47-2.50 (m, 1H, NH), 2.76-2.80 (m, 2H, HC—N); MS m/z (rel intensity) 275.2 (M−H+, 45). Compound 105: (1-Methyl-piperidin-4-yl)-[1-(3-phenyl-adamantan-1-yl)-ethyl]-amine. Yield=29%; oil;1H NMR (300 MHz, CDCl3) δ 0.92-0.95 (d, J=6 Hz, 3H, CH3), 1.49-2.10 (m, 21H, Admant-CH, CH2), 2.19-2.29 (m, 6H, NCH), 2.79-2.94 (m, 1H, HN), 6.94-7.04 (m, 2H, Ar—H), 7.28-7.35 (m, 5H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.98, 35.73, 36.71, 38.77, 42.18, 42.37, 44.88, 122.38, 125.30, 126.57, 128.56, 129.26, 148.39, 150.2; MS m/z (rel intensity) 353.6 (MH+, 85), 354.6 (25). Compound 106: {1-[3-(4-Fluoro-phenyl)-adamantan-1-yl]-ethyl}-(1-methyl-piperidin-4-yl)-amine. Yield=11%; oil;1H NMR(300 MHz, CDCl3) δ 0.92-0.95 (d, J=6 Hz, 3H, CH3), 1.49-2.10 (m, 21H, Admant-CH, CH2), 2.19-2.29 (m, 6H, NCH), 2.79-2.94 (m, 1H, HN), 6.94-7.04 (m, 2H, Ar—H), 7.28-7.35 (m, 2H, Ar—H);13C NMR(300 MHz, CDCl3) δ 28.98, 35.73, 36.71, 38.77, 42.18, 42.37, 44.88, 122.38, 125.30, 126.57, 128.56, 129.26, 148.39, 150.2; MS m/z (rel intensity) 371.5 (MH+, 85), 372.5 (50), 373.5(8). Compound 107: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(1-methyl-piperidin-4-yl)-amine. Yield=28%; oil;1H NMR(300 MHz, CDCl3) δ 0.95-0.98(d, J=6 Hz, 3H, CH3), 1.30-2.75(m, 29H, Admant-CH, 3.74-3.76 (m, 1H, HN), 4.24-4.30 (m, 1H, CH), 7.26-7.29 (m, 4H, H—Ar); MS m/z (rel intensity) 387.3 (MH+, 65). Compound 108: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(4-methyl-piperazin-1-yl)-amine. Yield=23%; oil; MS m/z (rel intensity) 389.2 (MH+, 100). Compound 109: [1-(3-Phenyl-adamantan-1-yl)-ethyl]-pyridin-4-ylmethyl-amine. Yield=16%; oil; MS m/z (rel intensity) 347.2 (MH+, 30). Compound 110: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(6-chloro-pyridin-3-ylmethyl)-amine. Yield=18%; oil; MS m/z (rel intensity) 415.2 (MH+, 20). Compound 111: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(2-pyridin-4-yl-ethyl)-amine. Oil. Compound 112: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(3H-imidazol-4-ylmethyl)-amine. Oil. Compound 113: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(2-methyl-1H-indol-5-yl)-amine. Yield=5%; oil; MS m/z (rel intensity) 417.2 (M+−H, 15). Compound 114: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(9-ethyl-9H-carbazol-3-yl)-amine. Yield=60%; m.p.: 70-72° C.; MS m/z (rel intensity) 482 (M+, 50), 483(MH+, 25), 484(20). Compound 115: {1-[3-(4Chloro-phenyl)-adamantan-1-yl]-ethyl}-(9-ethyl-9H-carbazol-3-ylmethyl)-amine. Yield=13%; oil; MS m/z (rel intensity) 496.2 (M−H+, 30). Compound 116: 9-Ethyl-9H-carbazole-3-carboxylic acid {1-[3-(4-chloro-phenyl)-adamantan-1-yl]-ethyl}-amide. Yield=28. Compound 117: 1-{1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-3-(4-chloro-3-trifluoromethyl-phenyl)-urea. Yield=6%; m.p.: 103-105° C.; MS m/z (rel intensity) 511.2 (MH+, 5). Compound 118: 1-{1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-3-(4-chloro-3-trifluoromethyl-phenyl)-urea. m.p: 103-105° C.;1H NMR(300 MHz, DMSO-d6) δ 1.05-1.07 (d, J=6 Hz, 3H, CH3), 1.50-1.80 (m, 12H, Admant-CH), 2.18 (s, 2H, Admant-CH), 3.62-3.68 (m, 1H, CH), 4.83-4.86 (m, 1H, HN), 6.91-6.94 (m, 1H, NH—Ar), 7.20-7.28 (m, 4H, Ar—H), 7.32-7.35 (d, J=9 Hz, 1H, Ar—H), 7.48-7.51 (d, J=9 Hz, 1H, Ar—H), 7.60 (s, 1H, Ar—H);13C NMR(300 MHz, CDCl3) δ 15.2, 28.8, 36.0, 36.5, 37.6, 37.8, 42.4, 54.0, 56.1, 117.8, 122.8, 126.2, 128.1, 131.8, 132.7, 154.6; MS m/z (rel intensity) 511 (MH+, 5). Compound 119: (4-Bromo-thiophen-2-ylmethyl)-{1-[3-(4-chloro-phenyl)-adamantan-1-yl]-ethyl}-amine. Yield=8%; oil; MS m/z (rel intensity) 464.1 (MH+, 50). Compound 120: {1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethyl}-(4-phenyl-thiophen-2-ylmethyl)-amine. Yield=8%; oil; m/z (rel intensity) 463.0 (MH+, 100). Example 8 Method for the Synthesis of Adamantylpropenones As an example, a process for the synthesis of adamantylpropenone compounds is described in Scheme 5. 3-R-substituted-phenyl-1-adamantyl methyl ketone (6) was prepared as described above. By reaction of 6 with a substituted aldehyde, the corresponding adamantylpropenone compound (10) can be obtained. For example, by reaction of 4-chloro-6 with 4-hydroxybenzylaldehyde, 1-[3-(4-chlorophenyl)-adamantan-1-yl]-3-(4-hydroxy-phenyl)-propenone, also referred to as Compound 132, was obtained. Example 9 Synthesis of Adamantylpropenones The methods described in Example 6 were used to prepare a library of substituted adamantylpropenone compounds. Data provided below include: the yield of the reaction; the melting point (m.p.) of the compound; and mass spectral (MS) data for the compound. Compound 121: 3-Phenyl-adamantane-1-carboxylic acid. Compound 122: 3-(4-Fluoro-phenyl)-adamantane-1-carboxylic acid. Compound 123: 3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid. Yield=79%. Compound 124: 1-Adamantan-1-yl-ethanone. m.p.: 44-46° C. Compound 125: 1-(3-Phenyl-adamantan-1-yl)-ethanone. Yield=54%;1H NMR(300 MHz, CDCl3) δ 1.73-2.10(m, 12H, Admant-CH), 2.14 (s, 3H, CH3), 2.27 (s, 2H, Admant-CH), 7.25-7.26(m, 1H, Ar—H), 7.30-7.36 (m, 4H, H—Ar). Compound 126: 1-[3-(4-Fluoro-phenyl)-adamantan-1-yl]-ethanone. Yield=59%; 59%; oil;1H NMR(300 MHz, CDCl3) δ 1.73-1.90(m, 12H, Admant-CH), 2.10 (s, 3H, CH3), 2.27 (s, 2H, Admant-CH), 6.96-7.04(m, 2H, Ar—H), 7.28-7.35 (m, 2H, H—Ar). Compound 127: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-ethanone. Yield=54% (2 steps); m.p.: 54-56° C. Compound 128: 2-(Adamantane-1-carbonyl)-malonic acid dimethyl ester. Yield=80%; oil. Compound 129: 2-[3-(4-Chloro-phenyl)-adamantane-1-carbonyl]-malonic acid dimethyl ester. Yield=91%; oil. Compound 130: 3-(4-Chloro-phenyl)-1-[3-(4-chloro-phenyl)-adamantan-1-yl]-propenone. Yield=18%. Compound 131: 4-{3-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-oxo-propenyl}-benzonitrile. Compound 132: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-(4-hydroxy-phenyl)-propenone. Yield=16%; m.p.: 87-89° C.; MS m/z (rel intensity) 393.2 (MH+, 100). Compound 133: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-naphthalen-2-yl-propenone. Yield=20%; m.p.: 82-84° C. Compound 134: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-(6-chloro-pyridin-3-yl)-propenone. Yield=4%. Compound 135: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-(1H-imidazol-4-yl)-propenone. Yield=3%; oil. Compound 136: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-(9-ethyl-9H-carbazol-3-yl)-propenone. Yield=3%; m.p.: 138-140° C. Compound 137: 1-[3-(4-Chloro-phenyl)-adamantan-1-yl]-3-(4-phenyl-thiophen-2-yl)-propenone. Yield=13%. Example 10 Assays for Inhibition of Human SK Activity An assay for identifying inhibitors of recombinant human SK has been established (French et al., 2003, Cancer Res 63: 5962). cDNA for human SK was subcloned into a pGEX bacterial expression vector, which results in expression of the enzyme as a fusion protein with glutathione-5-transferase, and the fusion protein is then purified on a column of immobilized glutathione. SK activity is measured by incubation of the recombinant SK with [3H]sphingosine and 1 mM ATP under defined conditions, followed by extraction of the assay mixture with chloroform:methanol under basic conditions. This results in the partitioning of the unreacted [3H]sphingosine into the organic phase, while newly synthesized [3H]S1P partitions into the aqueous phase. Radioactivity in aliquots of the aqueous phase is then quantified as a measure of [3H]S1P formation. There is a low background level of partitioning of [3H]sphingosine into the aqueous phase, and addition of the recombinant SK greatly increases the formation of [3H]S1P. A positive control, DMS, completely inhibits SK activity at concentrations above 25 μM. In an alternate assay procedure, the recombinant human SK was incubated with unlabeled sphingosine and ATP as described above. After 30 minutes, the reactions were terminated by the addition of acetonitrile to directly extract the newly synthesized S1P. The amount of S1P in the samples is then quantified as follows. C17base D-erythro-sphingosine and C17S1P are used as internal standards for sphingosine and S1P, respectively. These seventeen-carbon fatty acid-linked sphingolipids are not naturally produced, making these analogs excellent standards. The lipids are then fractionation by High-Performance Liquid Chromatography using a C8-reverse phase column eluted with 1 mM methanolic ammonium formate/2 mM aqueous ammonium formate. A Finnigan LCQ Classic LC-MS/MS is used in the multiple reaction monitoring positive ionization mode to acquire ions at m/z of 300 (precursor ion)→282 (product ion) for sphingosine and 380→264 for S1P. Calibration curves are generated by plotting the peak area ratios of the synthetic standards for each sphingolipid, and used to determine the normalized amounts of sphingosine and S1P in the samples. Example 11 Inhibition of Human SK by Compounds of this Invention Each Compound of this invention was tested for its ability to inhibit recombinant SK using the LC/MS/MS assay described above. Typically, the Compounds were individually dissolved in dimethylsulfoxide and tested at a final concentration of 6 μg/ml. The results for the assays are shown in Table 3. The data demonstrate that compounds of Formula I demonstrate a range of abilities to inhibit the in vitro activity of recombinant SK. Several Compounds caused complete suppression of SK activity at the concentration of 6 micrograms/ml (corresponding to approximately 15 micromolar). As detailed in the Examples below, significantly greater concentrations of the Compounds can be achieved in the blood of mice receiving the Compounds by oral administration, indicating that the Compounds are sufficiently potent to be therapeutically useful. Although many of the Compounds inhibited the purified SK enzyme, it was useful to determine their abilities to inhibit endogenous SK in an intact cell. We have previously described an intact cell assay where, following treatment with a test compound, MDA-MB-231 human breast carcinoma cells are incubated with [3H]sphingosine at a final concentration of 1 μM (French et al., Cancer Res 63: 5962 (2003)). The cells take up the exogenous [3H]sphingosine and convert it to [3H]S1P through the action of endogenous SK. The resulting [3H]S1P is isolated via charge-based separation as indicated above. The results from this assay are indicated in Table 3. The data demonstrate that many of the Compounds that inhibit purified SK also inhibit SK activity in the intact cell. For potency studies, MDA-MB-231 cells were exposure to varying concentrations of a test Compound and then assayed for conversion of [3H]sphingosine to [3H]S1P. Each of Compounds decreased [3H]S1P formation in a dose dependent fashion, with IC50values ranging from 15 to 64 μM. These results demonstrate that compounds of formula I or II effectively inhibit SK activity in intact cells. TABLE 3Inhibition of SK activity.Recombinant SKCellular S1PCellular S1PCompound(% inhibition)(% inhibition)IC50(μM)1380ND20NDND36NDND44414ND510017ND6729015710096ND8490ND98440ND1039ND11170ND12363ND13780ND1419NDND168NDND1756NDND180NDND200NDND2165NDND2256NDND230NDND2420NDND2547NDND2636NDND2750NDND286NDND29550ND301NDND3174NDND3217NDND3310NDND340NDND35870ND363772ND372436ND384034ND391926ND4010052ND416723ND425NDND4300ND443388354564NDND464NDND4726NDND483614ND4933NDND50044ND51848825525461ND5352NDND5495NDND558NDND563340ND57308360586755ND590NDND60023ND615824ND6213922663039ND64418063653NDND66928ND6710NDND68170ND694013ND70334ND71270ND72141ND7353NDND74028ND75ND41ND7642NDND7727NDND7843NDND7919NDND805NDND8167NDND8275NDND836088168484NDND850NDND866NDND87755564881NDND89371ND902616ND9370NDND1040NDND114334651118775ND13038NDND13141NDND1328NDND13336NDND13452NDND13564NDNDHuman SK was incubated with 6 μg/ml of the indicated compounds, and then assayed for activity as described above.Values in the column labeled “Recombinant SK (% inhibition)” represent the percentage of SK activity that was inhibited. MDA-MB-231 cells were incubated with 20 μg/ml of the indicated compounds and then assayed for endogenous SK activity as indicated above.Values in the column labeled “Cellular S1P (% inhibition)” represent the percentage of S1P production that was inhibited. Additionally, MDA-MB-231 cells were treated with varying concentration of certain compounds and the amount of S1P produced by the cells was determined.Values in the column labeled “Cellular S1P IC50(μM)” represent the concentration of compound required to inhibit the production of S1P by 50%.ND = not determined. Example 12 Selectivity of SK Inhibitors of this Invention A common problem with attempts to develop protein kinase inhibitors is the lack of selectivity toward the target kinase since the majority of these compounds interact with nucleotide-binding domains that are highly conserved among kinases. To determine if compound of this invention are non-selective kinase inhibitors, the effects of the SK inhibitor, Compound 62, on a diverse panel of 20 purified kinases was determined. The compound was tested at a single concentration of 50 μM. The kinases and the effects of the SK inhibitor are shown in Table 4. The data indicate high specificity of Compound 62 for SK in that none of the 20 diverse kinase tested were significantly inhibited by this compound. The panel included both serine/threonine kinases and tyrosine kinases, as well as several that are regulated by their interaction with lipids. Overall, the data indicate that the biological effects of the compounds of this invention are not mediated by off-target inhibition of protein kinases. TABLE 4Selectivity of Compound 62.CompoundCompoundKinase62Kinase62Ca2+/calmodulin PK IV81 ± 3MEK kinase 1104 ± 3Abl98 ± 0CHK1142 ± 13Aurora-A103 ± 1EFGR101 ± 3Protein kinase C α86 ± 5Fyn84 ± 5Protein kinase C ϵ101 ± 1cSrc115 ± 3CDK1/cyclinB105 ± 1IKKα150 ± 16CDK2/cyclinE106 ± 6PKA104 ± 5P38 MAP kinase 194 ± 2PKBα95 ± 2P38 MAP kinase 2109 ± 5PKBγ105 ± 8PDK1116 ± 3cRaf96 ± 5Values represent the percent of control activity of the indicated kinase in the presence of 50 μM of Compound 62. Example 13 Cytotoxicity Profiles of SK Inhibitors of this Invention To further assess the biological efficacies of the Compounds in intact cells, each Compound was evaluated for cytotoxicity using human cancer cell lines. These experiments followed methods that have been extensively used. Cell lines tested included MCF-7 human breast adenocarcinoma cells and MCF-10A non-transformed human breast epithelial cells. The indicated cell lines were treated with varying doses of the test Compound for 48 h. Cell survival was then determined using the SRB binding assay (Skehan et al., 1990, J Natl Cancer Inst 82: 1107), and the concentration of compound that inhibited proliferation by 50% (the IC50) was calculated. The cytotoxicities of the compounds of this invention are summarized in Table 5. Values (in μM) represent the mean±sd for replicate trials. As the data show, the compounds of this invention are antiproliferative at sub-to-low-micromolar. In many cases, the transformed MCF-7 cells were significantly more sensitive than were the non-transformed MCF-10A cells. This indicates that the Compounds will inhibit the growth of tumor cells without inducing toxicity to normal cells within the patient. Overall, the data demonstrate that these Compounds are able to enter intact cells and prevent their proliferation, making them useful for the indications described above. TABLE 5Anticancer activity of compounds of this invention.MCF-7MCF-10ACompoundIC50(μM)IC50(μM)123151220ND318ND4721375ND30651573ND84794991710ND17011878712119913511151436ND15>112ND1617ND1717ND1819ND19>108ND2033ND2127ND2218ND2323ND2417ND2587ND2619ND278ND2864ND2971063014ND3174ND3224ND3330ND34>106ND3519ND36139375127389403915106406374167142>100ND4327ND44694517ND4691ND4716ND48NDND4968ND50181ND518255210155311ND5411ND55NDND5610ND576858203659NDND607ND61NDND6217216311ND6482065NDND66195367NDND68541046930106707103712111872267380ND743707511ND765ND77NDND7830ND79NDND80NDND81NDND82NDND835ND84NDND85NDND865ND8738338811ND8974419096107915492269315ND940.6ND9522689699970.5ND983ND990.7ND1000.3ND10110ND1022ND103NDND10434ND10551410626107111085ND10926ND1106ND11113ND1125ND11314ND1145591151ND1166ND1173ND118NDND11911ND120108ND12113176122155182123489512411105125859126261276161283463129161051307ND13127ND13217ND13313ND13416ND1353ND1368ND1379NDThe cytotoxicity of the indicated Compounds toward human breast cancer cells (MCF-7) and non-transformed human breast epithelial cells (MCF-10A) were determined.Values represent the mean IC50for inhibition of cell proliferation.ND = not determined. Example14 Survey of Anticancer Activity of SK Inhibitors of this Invention The data provided above demonstrate the abilities of compounds of this invention to inhibit the proliferation of human breast carcinoma cells. To examine the range of anticancer activity of representative compounds, the chemotherapeutic potencies of Compounds 62 and 57 towards a panel of varied human tumor cell lines representing several major tumor types were determined. The data are described in Table 6, and demonstrate that the compounds of this invention have anticancer activity against a wide variety of cancers. TABLE 6Potencies of SK inhibitors toward human tumor cell lines.IC50(μM)IC50(μM)Cell LineTissueCompound 62Compound 571025LUmelanoma33.7 ± 2.77.2 ± 0.8A-498kidney12.2 ± 6.08.0 ± 3.5Caco-2colon11.8 ± 5.63.2 ± 2.0DU145prostate21.9 ± 1.58.7 ± 3.3Hep-G2liver6.0 ± 2.65.0 ± 1.8HT-29colon48.1 ± 7.69.6 ± 4.0MCF-7breast, ER+18.4 ± 7.412.1 ± 3.1MDA-MB-231breast, ER−29.1 ± 11.112.5 ± 2.5Panc-1pancreas32.8 ± 0.114.1 ± 6.3SK-OV-3ovary10.5 ± 2.69.2 ± 2.8T24bladder39.4 ± 7.412.7 ± 2.8Sparsely plated cells were treated with an SK inhibitor for 48 hours, and cell viability was determined using sulforhodamine B staining and compared to vehicle-(DMSO) treated cells.Values are the mean ± sd for at least three separate experiments. Example 15 In vivo Toxicity of SK Inhibitors of this Invention For example, Compounds 62 and 57 were found to be soluble to at least 15 mg/ml (˜30-40 mM) in DMSO:PBS for intraperitoneal (IP) administration or PEG400 for oral dosing. Acute toxicity studies using IP dosing demonstrated no immediate or delayed toxicity in female Swiss-Webster mice treated with up to at least 50 mg/kg of Compounds 62 and 57. Repeated injections in the same mice every other day over 15 days showed similar lack of toxicity. Each of the compounds could also be administered orally to mice at doses up to at least 100 mg/kg without noticeable toxicity. Example 16 Pharmacokinetics of SK Inhibitors of this Invention Oral pharmacokinetic studies were performed on Compounds 62 and 57. Each compound was dissolved in PEG400 and administered to female Swiss-Webster mice at a dose of 100 mg/kg by oral gavage. Mice were anesthetized and blood was removed via cardiac puncture at 5 minutes, 30 minutes, 1, 2, and 8 hours. Concentrations of the test compounds were determined using liquid-liquid extraction, appropriate internal standards and reverse phase HPLC with UV detection. Control blood samples were run to identify compound-specific peaks. Pharmacokinetic parameters were calculated using the WINNONLIN analysis software package (Pharsight). Non-compartmental and compartmental models were tested, with the results shown in Table 7 derived from the best fit equations. TABLE 7Oral pharmacokinetic data for SKI inhibitors.DoseAUC0→∞tmaxCmaxCompound(mg/kg)(μg * h/mL)(μM * h)(h)(μM)t1/2(h)621001724520.555.87.357100451112.03.819.3 These studies demonstrate that substantial amounts of each compound can be detected in the blood 1 h after oral dosing. Both compounds have excellent PK properties, with Area Under the Curve (AUC) and Cmax(maximum concentration reached in the blood) values exceeding the IC50for recombinant SK catalytic activity, as well as for S1P formation in the intact cell model for at least 8 h. The high half-life suggests prolonged activity, which will diminish the need for frequent dosing regimens. These PK properties demonstrate that the compounds of this invention have excellent drug properties, specifically high oral availability with low toxicity. Oral bioavailability studies were performed on Compound 62 dissolved in 0.375% Tween-80. Female Swiss-Webster mice were dosed with 50 mg/kg Compound 62 either intravenously or orally. Mice were anesthetized and blood was removed by cardiac puncture at time points ranging from 1 minute to 8 hours. Concentrations of Compound 62 were quantified using liquid-liquid extraction and reverse phase HPLC coupled to an ion trap quadrapole mass spectrometer. Control blood samples were spiked with known amounts of internal standard and analyte to identify compound-specific peaks and to develop standard curves for quantification. Pharmacokinetic parameters were calculated using the WINNONLIN analysis software package (Pharsight). Non-compartmental and compartmental models were tested, with the results from the best fitting models shown in Table 8. TABLE 8Bioavailability data for Compound 62.DoseAUC0→∞AUC0→∞TmaxCmaxCmaxT1/2Route(mg/kg)(μg * h/ml)(μM * h)(h)(μg/ml)(μM)(h)IV5056.9137031.1741.4Oral5037.590.10.258194.5 Blood levels of Compound 62 exceeded the IC50for inhibition of SK activity during the entire study. Comparison of oral versus intravenous pharmacokinetics of Compound 62 revealed very good oral bioavailability properties (F=AUC (oral)/AUC (iv)=0.66). These results demonstrate that Compound 62 has excellent drug properties, specifically good oral availability with low toxicity. Example 17 Antitumor Activity of SK Inhibitors of this Invention The antitumor activity of the representative SK inhibitors were evaluated using a syngeneic tumor model that uses the mouse JC mammary adenocarcinoma cell line growing subcutaneously in immunocompetent Balb/c mice (Lee et al., 2003, Oncol Res 14: 49). These cells express elevated levels of SK activity relative to non-transformed cells, as well as the multidrug resistance phenotype due to P-glycoprotein activity. The data are shown inFIGS.1and2. InFIG.1, Balb/c mice, 6-8 weeks old, were injected subcutaneously with 106JC cells suspended in phosphate-buffered saline. The SK inhibitors Compounds 62 and 57 were dissolved in PEG400 and administered to mice every-other day at a dose of 100 mg/kg. Body weights and tumor volumes were monitored daily. InFIG.1, tumor growth is expressed as the tumor volume relative to day 1 for each animal. As indicated inFIG.1, tumor growth in animals treated with either SK inhibitor was significantly lower (>70% decreased at day 16) than tumor growth in control animals. Compounds 62 and 57 inhibited tumor growth relative to controls by 69 and 78%, respectively. The insert ofFIG.1indicates the body weight of the animals during this experiment. No significant difference in the body weights of animals in the three groups was observed, indicating the lack of overt toxicity from either SK inhibitor. Dose-response studies with Compound 62 demonstrated that the compound has antitumor activity when orally administered at doses of 35 kg/kg or higher (FIG.2). No toxicity to the mice were observed at any dose. Additional compounds of this invention were tested for their ability to inhibit the growth of JC adenocarcinoma cells in mice. The results are summarized in Table 9. TABLE 9In vivo antitumor activity of SK inhibitors.CompoundIn vivo activity44active - ip51active - ip and po57active - po62active - ip and po107active - ipThe indicated compounds were tested in the JC tumor model using either intraperitoneal (ip) or oral (po) administration.A compound is indicated as being active if it suppressed tumor growth by at least 60% relative to tumors in control animals. Example 18 In vivo Effects of SK Inhibitors on VEGF-induced Vascular Permeability The effects of VEGF on vascular leakage in vivo were measured as described by Miles and Miles (Miles et al., 1952, J Physiol 118: 228). Groups of female athymic nude mice (approximately 20 g) were given intraperitoneal injections of DMSO alone or Compound 62 (75 mg/kg) in a volume of 50 microliters. In some experiments, Compound 62 was administered by oral gavage at a dose of 100 mg/kg. After 30 minutes, 100 μL of 0.5% Evan's blue dye in PBS was administered by tail vein injection. Thirty minutes later, mice received the first of 3 sequential (every 30 minutes) intradermal injections of VEGF (400 ng in 20 μL of PBS per injection) on the left hind flank. As a control, similar injections of PBS were administered on the right hind flank. Thirty minutes after the last injection, leakage of the dye from the vasculature into the skin was assessed by measuring the length and width of the spots of blue-colored skin using calipers. Administration of an intradermal bolus of VEGF results in leakage of the protein-bound dye into the skin indicating a local increase in vascular permeability. As indicated inFIG.3, when Compound 62 was administered by either intraperitoneal injection or oral gavage one hour before the VEGF treatment, vascular leakage (determined three hours later) was markedly reduced. Therefore, SK inhibitors of this invention have the ability to suppress in vivo vascular leakage in response to VEGF. Example 19 In vivo Effects of SK Inhibitors on Diabetic Retinopathy Male Sprague-Dawley rats weighing 150-175 g were used. Diabetes was produced by intraperitoneal injection of streptozotocin (65 mg/kg in citrate buffer) after overnight fasting. Sham-injected non-diabetic animals were also carried as controls. Blood glucose was measured three days post-injection and animals with blood glucose over 250 mg/dL were used as diabetic rats for the study. Blood glucose levels and body weights were monitored weekly throughout the study. On Day 45, retinal vascular permeability was measured in a group of control and diabetic rats (Antonetti et al., 1998, Diabetes 47: 1953, Barber et al., 2005, Invest Ophthalmol Vis Sci 46: 2210). Briefly, animals were weighed, anesthetized with ketamine/xylazine (80/0.8 mg/kg) and injected with fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA; Sigma catalog number A-9771) into the femoral vein. Following 30 minutes of FITC-BSA circulation, the rats were sacrificed by decapitation. Trunk blood was collected to measure the FITC-BSA concentration, and eyes were quickly enucleated. Each eye was placed in 4% paraformaldehyde for 1 hour and frozen in embedding medium in a bath of isopentane and dry ice. The paraffin-embedded eyes were sectioned on a microtome making 10 μm sections. Sections were dewaxed and viewed with an Olympus OM-2 fluorescence microscope fitted with a Sony CLD video camera. Fluorescence intensities of digital images were measured using Leica Confocal Software (Version 2.61, build 1538, LCS Lite, 2004). The average retinal intensity for each eye was then normalized to non-injected controls analyzed in the same manner and to the plasma fluorescence of the animal. Through serial sectioning of the eye, this technique enables quantification of varied vascular permeability in the retina (Antonetti et al., 1998, Diabetes 47: 1953, Barber et al., 2005, Ibid.). The remaining control animals were maintained for an additional 6 weeks, i.e. until Day 87, as were the remaining diabetic rats that were divided into untreated, low-dose Compound 62 (25 mg/kg) or high-dose Compound 62 (75 mg/kg) treatment groups. Compound 62 was administered by intraperitoneal injection (dissolved in 0.375% Tween-80) 5 days per week from Day 45 to Day 87. On Day 87, all remaining animals were tested for retinal vascular permeability as described above. Sections were also stained for SK immunoreactivity using rabbit polyclonal antibodies, and counterstained for nuclei using Hoescht stain. Hyperglycemic rats were left untreated for 45 days to allow the progression of retinopathy. At that time, control and diabetic rats were evaluated for retinal vascular permeability by measuring the leakage of FITC-labeled BSA into the retina using quantitative image analyses. The diabetic animals had substantial increases in the leakage of the labeled BSA into the inner plexiform and outer nuclear layers of the retina. Quantification of the images indicated that there is an approximately 4-fold increase in the amount of FITC-BSA leakage in the retinas from diabetic rats. Therefore, substantial diabetes-induced vascular damage was present before the initiation of treatment with the SK inhibitor. All of the surviving rats were sacrificed on Day 87 and retinopathy was measured as the leakage of FITC-BSA into the retina. As indicated inFIG.4, retinal vascular permeability in the diabetic rats was significantly elevated compared with the control rats. Diabetic animals that had been treated with the SK inhibitor Compound 62, at either dose, had substantially reduced levels of FITC-BSA leakage than did the untreated diabetic rats. This effect of the compound was manifested in both the inner plexiform layer and the outer nuclear layer of the retina. Immunohistochemistry with the SK antibody described above was used to evaluate the expression of SK in the retinas of these animals. Fluorescence in the retinal pigment epithelium and the outer segment was non-specific since it was present in samples incubated in the absence of the SK antibody. Retinal sections from control rats had only low levels of specific staining for SK; whereas, SK expression was markedly elevated in the ganglion cell layer and in specific cell bodies and projections at the interface of the inner nuclear layer and the inner plexiform layer. Elevated SK expression was also observed in both the low-dose and the high-dose Compound 62-treated animals. Therefore, the long-term hyperglycemic state appears to be associated with elevation of retinal SK levels that are not normalized by treatment with the SK inhibitor. This expression data indicates that Compound 62 very effectively suppresses SK activity in the diabetic retina, thereby preventing the increased vascular permeability normally present in retinopathy. Example 20 Inhibition of TNFα-induction of NFκB by SK Inhibitors The excellent aqueous solubility of Compound 62 allowed it to be evaluated in an NFκB reporter cell line (FIG.5). Fibroblasts transfected with an NFκB response element linked to luciferase produce high levels of luciferase upon exposure to TNFα. Activation of NFκB by TNFα was dose-dependently suppressed by the SK inhibitor, Compound 62. Example 21 Inhibition of TNFα-induced Adhesion Molecule Expression by SK Inhibitors Like endothelial cells in the body, HUVECs will proliferate in response to several growth factors, and will respond to inflammatory cytokines such as TNFα and IL-1β. Western analyses were conducted with human endothelial cells to evaluate the effects of the SK inhibitors on signaling proteins known to be regulated by TNFα. In these experiments, the cells were serum-starved for 24 hours and then exposed to TNFα (100 ng/mL) for 6 hours. Cell lysates from treated cells were assayed for the adhesion molecules ICAM-1 and VCAM-1. TNFα caused marked increases in the expression levels of adhesion proteins involved in leukocyte recruitment, including ICAM-1 and VCAM-1. These effects of TNFα were inhibited by treating the cells with Compound 62, such that the induction of both proteins was completely abrogated by 25 μM Compound 62. Example 22 Inhibition of TNFα-induced Prostaglandin Synthesis by SK Inhibitors To determine the effects of the SK inhibitors on Cox-2 activity, an ELISA assay was used to measure PGE2production by IEC6 rat intestinal epithelial cells and human endothelial cells treated with TNFα. Exposure of either type of cell to TNFα resulted in marked increases in Cox-2 activity, measured as the production of PGE2(FIG.6). This induction of Cox-2 activity by TNFα was strongly suppressed by Compound 62. Overall, these data demonstrate that inhibition of SK will be effective in blocking the inflammatory cascade in cells initiated by TNFα. This is expected to alleviate the pathology of diseases several inflammatory diseases, including IBD, arthritis, atherosclerosis and asthma. Example 23 In vivo Effects of SK Inhibitors in an Acute Model of Inflammatory Bowel Disease We have conducted experiments with SK inhibitors using the dextran sulfate sodium (DSS) model of IBD. In these experiments, male C57BL/6 mice were provided with standard rodent diet and water ad libitum. After their acclimation, the animals were randomly divided into groups of 5 or 6 for DSS (40,000 MW from ICN Biomedicals, Inc., Aurora, Ohio)— and drug-treatment. The SK inhibitors were dissolved in PEG400, and given once daily by oral gavage in a volume of 0.1 mL per dose. Dipentum, an FDA-approved anti-colitis drug whose active ingredient, olsalazine, is converted to 5-aminosalicylic acid in vivo, was used as a positive control. The mice were given normal drinking water or 2% DSS and treated orally with an SK inhibitor or Dipentum at a dose of 50 mk/kg daily. The body weight of each animal was measured each day, and the Disease Activity Index (DAI) was scored for each animal on Days 4-6. On Day 6, the animals were sacrificed by cervical dislocation and the entire colon was removed and measured to the nearest 0.1 cm. Portions of the colons were then fixed, sectioned and their histologies were assessed on a blinded basis to determine their Histology Score. Other portions of the colons were used for biochemical analyses of inflammation markers. The DAI monitors weight loss, stool consistency and blood in the stool and is a measure of disease severity. Animals receiving normal drinking water and PEG as a solvent control had very low DAIs throughout the experiment (FIG.7). Exposure of the mice to DSS in their drinking water markedly induced IBD symptoms, including weight loss and the production of loose, bloody stools. The intensity of the disease progressively increased from Day 4 to the time the mice were sacrificed on Day 6. Treatment of the animals receiving DSS with Compound 62 or Dipentum reduced the intensity of the IBD manifestations in the mice, most dramatically on Day 6. The SK inhibitors and Dipentum were essentially equivalent in their abilities to reduce the DAI of mice receiving DSS. It should be noted that this acute model produces rapid and dramatic symptoms of IBD, making it a very stringent assay for drug testing. On Day 6, the animals were sacrificed by cervical dislocation and the entire colon was measured to assess shortening due to scarring and damage, and then fixed, sectioned and examined histologically on a blinded basis. Compared with the water control group, the colons of mice treated with DSS and PEG were significantly shortened (FIG.8). DSS-treated mice that were also treated with Compound 62 or Dipentum had colons of intermediate length, indicating substantial protection by the drugs. Again, the response to either of the SK inhibitors was at least as good as that of mice treated with Dipentum. Histological examination of colon sections from the various treatment groups were consistent with the DAI endpoint, revealing marked damage in the DSS-alone group that was reduced or negated in the SK inhibitor-treated animals. Colons from water-treated control animal demonstrated normal morphology, while colons from DSS alone-treated mice were severely inflamed and damaged. Numerous neutrophils were present throughout the section, along with severely damaged crypts, and moderate inflammatory infiltration with submucosal edema. Colons from animals treated with DSS and Compound 62 showed no or mild crypt damage, no or low levels of inflammatory cell infiltration and no edema in the submucosa. As a quantifiable measure of damage, the colons were graded for their Histology Score, which is based on inflammation severity, inflammation extent, crypt damage and the percentage of surface area demonstrating the characteristic. These morphologies were scored on a blinded basis. As indicated inFIG.9, animals receiving DSS in their drinking water had substantially higher Histology Scores (representing moderate-to-severe IBD) than animals receiving normal drinking water (which had some mild inflammation, possibly due to the PEG vehicle). As with the other assays, the Histology Scores of mice given an SK inhibitor or Dipentum were consistently lower than the DSS-alone animals, although not all animals were fully protected. DAI scores and histology scores correlated well for the individual animals, confirming that the DAI score as an excellent indicator of colon inflammation and damage. Myeloperoxidase (MPO) activity, which is reflective of neutrophil influx into the colon, is often used as measure of inflammation, and was assayed in the colons of the mice from the DSS-colitis studies. As indicated inFIG.10, MPO activity was highly elevated in the DSS-alone animals compared to water controls. The increase in MPO activity was markedly attenuated in mice receiving daily doses of Compound 62 or Dipentum. This reduction in the activity of the neutrophil marker is consistent with the decreased occurrence of granulocytes observed in the H&E-stained colon sections. Therefore, the level of colonic MPO appears to be an excellent biomarker for the extent of tissue infiltration by inflammatory leukocytes. Several cytokines involved in inflammation were measured using the Luminex 100 System that allows the quantification of multiple cytokines and growth factors in a small sample volume. We examined the Th1 cytokine IFN-γ, the regulatory IL-10 cytokine, as well as the macrophage-derived pro-inflammatory cytokines, TNFα, IL-1β, IL-6 in colon samples from mice in the DSS model of colitis.FIG.11depicts the results of these assays, and indicates that DSS-treatment promoted the accumulation of all of the cytokines in the colon. Importantly, the elevations of all of the pro-inflammatory proteins, i.e. IFN-γ, IL-1β, IL-6 and TNFα, were attenuated in mice treated with either an SK inhibitor or Dipentum. Conversely, levels of the anti-inflammatory cytokine IL-10were not suppressed by the SK inhibitors. As a final measure of the effects of the SK inhibitors in this acute model, S1P levels were assayed in the colons of the DSS-treated animals using an LC-MS/MS method. This technique allows us to examine correlations between biologic activity and changes in S1P levels in animals treated with the SK inhibitors. Samples of colons from animals from the DSS-colitis experiments were homogenized in cold PBS, spiked with internal standards (C17analogs of sphingosine and S1P) and processed by liquid-liquid extraction. Ratios of analyte to internal standard for each sphingolipid were determined. S1P levels were markedly higher in the colons from DSS-treated mice as compared to the water controls (FIG.12). Importantly, animals that were treated with Compound 62 had markedly lower levels of colonic S1P than the DSS-alone samples. Example 24 In vivo Effects of SK Inhibitors in a Chronic Model of Inflammatory Bowel Disease A 35-day model of IBD was used to evaluate the effectiveness of the SK inhibitors in mice that experience multiple cycles of DSS-induced inflammation. This chronic model is similar to the acute model, except that the DSS concentration in the drinking water is lower and animals receive periodic exposure to DSS (DSS on days 1-7, water on Days 8-13, DSS on day 14-21, water on Days 22-27 and then DSS until the completion of the study on Day 35). In these experiments, treatment of the mice with an SK inhibitor or Dipentum began on Day 28 and continued daily until the completion of the study. The DAI index was monitored every other day until Day 28 and then daily until Day 35. Animals were sacrificed on Day 35, and changes in the colon length and cytokine profiles were measured. Cyclic exposure of mice to DSS in their drinking water caused reversible increases in the DAI (FIG.13). Treatment of the mice with Compound 62 or Dipentum during the third exposure to DSS significantly suppressed the increase in DAI experienced by the control mice (P<0.001 for all three compounds on Day 35). The colon lengths of DSS-treated mice were significantly shorter than the water-treated control animals (4.9±0.2 cm vs. 7.8±0.3 cm) reflecting inflammation-induced scarring. As in the acute model, the colons of animals treated with Compound 62 or Dipentum were of intermediate length (6.2±0.2 and 6.1±0.2 cm, respectively). This is a significant finding since the animals were untreated for the first and second DSS cycles. Therefore, suppression of inflammation-induced colon contraction can be reversed by effective anti-IBD drugs. Immunohistochemistry revealed that SK expression was present in low levels in the colons of control, non-DSS treated mice. SK expression was elevated in the colons of DSS treated mice compared to water controls with this expression clearly reduced in DSS mice also receiving Compound 62. S1P levels in the colons of the chronic colitis model mice were assessed in an identical manner as described for the acute model, and revealed results similar to those in the acute model with elevated S1P levels in DSS alone treated mice as compared to water controls (FIG.14). Treatment with Compound 62 (oral 50 mg/kg daily; 7 days prior to sacrifice) resulted in significant reductions of S1P levels (FIG.14). The levels of the pro-inflammatory cytokines TNFα, IL-1β, IFN-γ and IL-6 were substantially increased in the colons of mice treated chronically with DSS; whereas, the level of IL-10 was unchanged (FIG.15). Mice treated with Compound 62 during the final DSS cycle had reduced levels of the pro-inflammatory cytokines, while animals treated with Dipentum expressed cytokine profiles equivalent to the DSS-alone group. This may reflect the presence of high numbers of resident immune cells in the colons of mice exposed chronically to DSS. However, the elevation in cytokine levels in the SK inhibitor-treated mice does not result in increased DAI or colon shortening, indicating that signaling induced by the inflammatory cytokines had been blocked. For comparison, the levels of the same cytokines in the serum of the mice at the time of sacrifice were also determined. As indicated inFIG.16, the circulating levels of these cytokines are markedly lower than the colonic levels reflecting the local inflammation in this model. DSS increased the circulating levels of IL-1β, IFN-γ, IL-6 and IL-10, while TNFα remained below the detection limit of the assay. None of the test compounds affected the circulating levels of IL-1β or INF-γ; however, both Compound 62 and Dipentum reduced the serum level of IL-6. Therefore, serum levels of IL-6 may be a useful pharmacodynamic marker for the anti-inflammatory effects of the SK inhibitors during clinical testing. Example 25 In vivo Effects of SK Inhibitors in the Collagen-Induced Arthritis Model in Mice The anti-arthritis activities of the SK inhibitor Compound 62 were assessed in the Collagen-Induced Arthritis (CIA) model. Female DBA/1 mice were injected subcutaneously in the tail with chicken immunization-grade type II collagen (Chondrex) emulsified in complete Freund's adjuvant (Sigma) at 2 mg/mL. Three weeks later, the mice received a collagen booster in incomplete Freund's adjuvant and were monitored daily thereafter for arthritic symptoms. Once mice reached a threshold paw thickness and clinical score, they were randomized into the following treatment groups: Compound 62 (100 mg/kg given orally each day for 6 days per week) or vehicle (0.375% Tween-80 given under the same schedule). The severity of disease in each animal was quantified by measurement of the hind paw volume with digital calipers. Each paw was scored based upon perceived inflammatory activity, in which each paw receives a score of 0-3 as follows: 0=normal; 1=mild, but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; 2=moderate redness and swelling of the ankle and wrist and 3=severe redness and swelling of the entire paw including digits, with an overall score ranging from 0-12. Differences among treatment groups were tested using ANOVA. As indicated inFIG.17, treatment with either SK inhibitor dramatically slowed the inflammation response, measured as either the Average Clinical Score (FIG.10A) or the Average Hind Paw Diameter (FIG.10B), with significant decreases beginning at Day 5 of treatment for both endpoints. By the end of the experiment on Day 12, Compound 62 caused a 90% reduction in the increase in hind paw thickness, and a 67% reduction in clinical score compared with vehicle-treated mice. Since a 30% reduction in symptoms is considered demonstrative of anti-arthritic activity in this assay, the SK inhibitor surpasses the criteria for efficacy in this model. On Day 12, the mice were euthanized and their hind limbs were removed, stripped of skin and muscle, formalin-fixed, decalcified and paraffin-embedded. The limbs were then sectioned and stained with hematoxylin/eosin. Tibiotarsal joints were evaluated histologically for severity of inflammation and synovial hyperplasia. Collagen-Induced Arthritis resulted in a severe phenotype compared with non-induced mice, manifested as severe inflammation and synovial cell infiltration, as well as significant bone resorption. Mice that had been treated with Compound 62 had significantly reduced histologic damage, correlating with the paw thickness and clinical score data. Example 26 In vivo Effects of SK Inhibitors in the Adjuvant-Induced Arthritis Model in Rats Adjuvant-induced arthritis is another widely used assay that recapitulates many features of human rheumatoid arthritis, and so is useful in the evaluation of new drug candidates. Age- and weight-matched male Lewis rats (150-170 g) were injected subcutaneously in the tail with 1 mg of Mycobacterium butyricum (Difco, killed dried) suspended in 0.1 ml of light mineral oil. Symptoms of immune reactivity were present after 2 weeks. Responsive rats were randomized into treatment groups, and received oral daily doses (1 ml) of: solvent alone (0.375% Tween-80); 100 mg/kg Compound 62; 35 mg/kg Compound 62; or 5 mg/kg Compound 62, or intraperitoneal injections of indomethacin (5 mg/kg) every other day as a positive control. The severity of disease in each animal was quantified by measurement of the hind paw thickness. As above, a reduction of 30% or greater was considered to be an indication of anti-inflammatory activity in this model. As indicated inFIG.17, solvent alone-treated rats demonstrated a progressive increase in paw thickness over the course of the next 10 days. Compound 62 inhibited this arthritic response in a dose-dependent manner, with the highest dose having similar therapeutic efficacy as indomethacin. Compound 62 at doses of 5, 35 or 100 mg/kg resulted in 13, 42 and 76 percent reductions in the arthritic response, respectively. Thus, Compound 62 is highly effective in this arthritis model. | 192,073 |
RE49812 | DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS An electronic apparatus according to the present invention and an angular velocity acquisition method therefor will hereinafter be described in detail with reference to the drawings. <First Embodiment> (Electronic Apparatus) FIG.1A,FIG.1BandFIG.1Care schematic structural diagrams showing a plurality of examples in which the present invention has been applied in an electronic apparatus. FIG.2is a functional block diagram showing a first embodiment of an electronic apparatus according to the present invention. The present invention is applied in an electronic apparatus which has at least an angular velocity detection function and provides a user with various services using information regarding the user's exercise status, movement trajectory, and the like. More specifically, the present invention can be applied in a portable or wearable electronic apparatus, such as a smartwatch having a wristwatch-type or wristband-type outer appearance as shown inFIG.1A, an outdoor device20including a GPS Roger and a navigation terminal as shown inFIG.1B, and a tablet terminal or a smartphone30shown inFIG.1C. Note that the present invention is not limited to the electronic apparatuses shown in the drawings, and can be applied in a smart device or a sensor device that is worn on an arm, a leg, or the head of a human body, the neck or the chest on the trunk, or the waist, and detects and stores angular velocities of a corresponding body part. In the descriptions below, these electronic apparatuses are collectively referred to as “electronic apparatus100” for convenience of explanation. The electronic apparatus100according to the first embodiment of the present invention includes, for example, an acceleration sensor110, a magnetic sensor120, an angular velocity sensor (gyro sensor)130, a communication interface section (hereinafter briefly referred to as “communication I/F section”)140, an input operation section150, an output section160, a control section (processor)170, a memory section180, and a power supply section190, as shown inFIG.2. The acceleration sensor110measures the rate of change (acceleration) in the movement speed of the electronic apparatus100which occurs in response to the movement of the user's body. This acceleration sensor110, which includes a triaxial acceleration sensor, detects acceleration components (acceleration signals) in three axial directions orthogonal to one another, and outputs them as acceleration data. The magnetic sensor120, which includes a triaxial magnetic sensor, detects the earth's magnetic field as geomagnetic components (magnetic signals) in three axial directions orthogonal to one another, and outputs it as magnetic data (or three-dimensional direction data). The angular velocity sensor130measures change (angular velocity) in the movement direction of the electronic apparatus100which occurs in response to the movement of the user's body. This angular velocity sensor130, which includes a triaxial angular velocity sensor, detects angular velocity components (angular velocity signals) in the rotation directions of rotational movements around three axes orthogonal to one another, and outputs them as angular velocity data. Note that the three axial directions of the acceleration sensor110and the three axial directions of the angular velocity sensor130are set to be the same directions, respectively. Pieces of sensor data (acceleration data, magnetic data, angular velocity data) acquired by the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130are respectively associated with time data and stored in a predetermined storage area of the memory section180. The acceleration sensor110and the angular velocity sensor130function as a motion sensor, and pieces of sensor data (acceleration data and magnetic data) detected by these sensors are used when the control section170described later detects the user's body movement and exercise status, a specific directional force applied on the electronic apparatus100, and the like. Magnetic data detected by the magnetic sensor120is used when azimuth directions relative to the electronic apparatus100are calculated in the control section170. In this embodiment, the acceleration sensor110and the magnetic sensor120function as a magnetic gyro sensor, and pieces of sensor data (acceleration data and magnetic data) detected by these sensors are used when angular velocity is calculated in the control section170. The communication I/F section140transmits and receives various types of data to and from an information and communication apparatus (a personal computer, a smartphone, etc.) outside the electronic apparatus100or a network. Here, in the communication via the communication I/F section140, a predetermined wired or wireless communication method is used, which includes a transfer method where data is transferred via a storage medium such as a memory card. The input operation section150includes, for example, an operation switch152and a touch panel154provided on the housing of the electronic apparatus100(the smartwatch10, the outdoor device20, the smartphone30) shown inFIG.1. This input operation section150is used for various types of input operations, such as an operation related to the operation power supply of the electronic apparatus100or application software, an operation of setting an item for which a notification is given by the output section160(a display section, a sound section, etc.) described below. The output section160has a display section162, a sound section164, a vibration section (not shown in the drawing), and the like provided in the housing of the electronic apparatus100. This output section160visually, aurally, or tactually provides the user with or notifies the user of information regarding the user's exercise status, movement trajectory, or the like and information regarding the execution status of the later-described angular velocity calculation processing which are generated based on sensor data acquired by at least the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130described above. Note that, in a case where the electronic apparatus100is a smart device or a sensor device that is worn on the body and used only for detecting and collecting sensor data of a corresponding body part, a configuration excluding the output section160may be adopted. The control section (processor)170is an arithmetic processing unit (computer) having a clocking function, such as a CPU (Central Processing Unit) or a MPU (Micro Processing Unit), and controls operations such as sensing operations by the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130and an operation of generating information regarding the user's exercise status, movement trajectory, or the like based on acquired sensor data, by executing a predetermined control program and a predetermined algorithm program. In this embodiment, the control section170controls the operations of the angular velocity sensor130and the magnetic gyro sensor constituted by the magnetic sensor120or constituted including the acceleration sensor110and the magnetic sensor120, and thereby controls a processing operation for acquiring adequate angular velocity data. Note that a method for acquiring angular velocity data in the present embodiment is described later in detail. The memory section180associates sensor data acquired by the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130, and various types of data generated (calculated) in the control section170with time data, and stores them in the predetermined storage area. This memory section180stores control programs and algorithm programs that are executed in the control section170. Note that these programs may be incorporated in advance in the control section170. In addition, the memory section180may be partially or entirely in a form of a removable storage medium such as a memory card, and may be structured to be removable from the electronic apparatus100. The power supply section190supplies driving power to each section of the electronic apparatus100. As the power supply section190, a primary battery such as a commercially-available coin-shaped battery, a secondary battery such as a lithium-ion battery, and a power supply by energy harvest technology for generating electricity by energy such as vibrations, light, heat, and electro-magnetic waves can be used singly or in combination. (Angular Velocity Acquisition Method for Electronic Apparatus) Next, an angular velocity acquisition method for the electronic apparatus according to the first embodiment is described with reference to the drawings. Note that the below-described angular velocity acquisition method (flowchart shown inFIG.3) for the electronic apparatus100is achieved by the control section170performing processing in accordance with a predetermined control program and a predetermined algorithm program. FIG.3andFIG.4are flowcharts showing an example of the angular velocity acquisition method for the electronic apparatus according to the present embodiment. FIG.5is a timing chart showing the usage status of magnetic data in the present embodiment. In the angular velocity acquisition method for the electronic apparatus100according to the present embodiment, first, when the electronic apparatus100is turned on, the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130are activated, and start sensing operations (Step S102), as shown in the flowchart inFIG.3. Subsequently, the control section170judges whether or not there is any disturbance or magnetic anomaly in a magnetic field around the magnetic sensor120at this point (Step S104). More specifically, the control section170first synchronizes the acceleration sensor110and the magnetic sensor120constituting a magnetic gyro sensor with the angular velocity sensor130so as to operate them, and detects angular velocity from each output therefrom (Step S120), as shown in the flowchart inFIG.4. Subsequently, the control section170compares the angular velocities detected respectively by the magnetic gyro sensor and the angular velocity sensor130with each other (Step S122). Then, the control section170judges whether a difference between them, which is a result of the comparison, is within a threshold range set in advance (Step S124). Here, a difference of an output from the magnetic gyro sensor with respect to (with reference to) an output from the angular velocity sensor is determined as the comparison result, based on an assumption that the output from the angular velocity sensor is accurate. Note that the output of the angular velocity sensor130can be maintained to be accurate by well-known calibration processing being performed periodically or constantly. Then, when judged at Step S124that the comparison result is within the threshold range, the control section170judges that there is no magnetic field disturbance or magnetic anomaly and the magnetic sensor120is not being affected by any disturbance noise. That is, in this case, the control section170judges that the output of the magnetic sensor120is reliable (Step S126). Conversely, when judged that the comparison result is not within the threshold range, the control section170judges that there is a magnetic field disturbance or magnetic anomaly and the magnetic sensor120is being affected by a disturbance noise. That is, in this case, the control section170judges that the output of the magnetic sensor120is not reliable (Step S126). Note that the series of processing operations shown inFIG.4is hereinafter referred to as “reliability judgment processing” for convenience of explanation. At Step S124, when judged that the comparison result is within the threshold range (NO at Step S104), the control section170temporarily stops the sensing operation of the angular velocity sensor130(Step S106). Then, the control section170performs an operation of detecting angular velocity by using the magnetic gyro sensor constituted by the magnetic sensor120or by the acceleration sensor110and the magnetic sensor120(Step S108). That is, when there is no magnetic field disturbance or magnetic anomaly and the output of the magnetic sensor120is reliable, the control section170selects the method of detecting angular velocity by the magnetic gyro sensor. At Step S104, when judged that there is a magnetic field disturbance or magnetic anomaly (YES at Step S104), the control section170judges whether the angular velocity sensor130is operating (Step S110). Then, when judged that the angular velocity sensor130is operating (YES at Step S110), the control section170performs an operation of detecting angular velocity by the angular velocity sensor130(Step S114). When judged that the angular velocity sensor130is not operating (NO at Step S110), the control section170activates the angular velocity sensor130(Step S112), and performs an operation of detecting angular velocity by the angular velocity sensor130(Step S114). That is, when there is a magnetic field disturbance or magnetic anomaly and the output of the magnetic sensor120is not reliable, the control section170selects the method of detecting angular velocity by the angular velocity sensor130. Regarding the angular velocity detected by the magnetic gyro sensor at Step S108or the angular velocity detected by the angular velocity sensor at Step S114, the control section170associates it with time data, and stores it in the predetermined storage area of the memory section180as angular velocity data (Step S116). Also, the control section170uses it when, for example, generating information regarding the user's exercise status, movement trajectory, etc. This series of processing operations of the flowchart ofFIG.3by the control section170is periodically repeated, for example, at predetermined time intervals. Note that, although omitted in the flowchart ofFIG.3, the control section170constantly monitors for an input operation of stopping or ending the series of processing operations and change in the operation status while performing these processing operations, and forcibly ends this series of processing operations when the input operation or the status change is detected. More specifically, the control section170detects a power off operation by the user, a decrease in the battery remaining amount of the power supply section190, anomaly in a function or an application being executed, or the like, and forcibly stops and ends the series of processing operations. In the angular velocity acquisition method according the present embodiment, for example, the following method can be applied as the method of detecting (calculating) angular velocity by the magnetic gyro sensor constituted by the magnetic sensor120or constituted including the acceleration sensor110and the magnetic sensor120. That is, first, the control section170calculates speed in three-dimensional space based on the temporal change amounts of the outputs of the acceleration sensor110and the magnetic sensor120. Here, the strength and direction of geomagnetism in a specific position and area are basically constant and do not change. With acceptance on this point, for example, if a change in the direction of geomagnetism is detected when the magnetic sensor120is being operated at fixed time intervals, the control section170judges that the change in the direction of geomagnetism has occurred by the rotation of the magnetic sensor120(electronic apparatus100), and detects the rotation status. As a result, angular velocities related to three axes defined by the magnetic sensor120can be calculated. As the magnetic data usage method according to the present embodiment, for example, the following methods can be applied. That is, geomagnetism in three axial directions which is detected by the magnetic sensor120in the present embodiment is used when angular velocity is calculated by the acceleration sensor110and the magnetic sensor120functioning as a magnetic gyro sensor as described above. In addition, it is used as the output of the magnetic sensor120itself when information regarding the user's exercise status, movement trajectory, etc. is generated. Accordingly, in the present embodiment, a data usage method using a time-sharing technique can be adopted in which an operation (A) where geomagnetism data in three axial directions detected by the magnetic sensor120as shown in (a) ofFIG.5is used by the magnetic gyro sensor and an operation (B) where the data is used with the magnetic sensor120being used as it is are alternately and repeatedly performed at predetermined time intervals, as shown in (b) ofFIG.5. By the usage of a series of data detected by the magnetic sensor120being switched for every period as described above, the processing load on the control section170can be reduced. Also, in the present embodiment, a data usage method using a parallel processing technique can be adopted in which the operation (A) where the geomagnetism data in three axial directions shown in (a) ofFIG.5is used by the magnetic gyro sensor and the operation (B) where the data is used with the magnetic sensor120being used as it is are simultaneously performed in parallel, as shown in (c) ofFIG.5. By data detected by the magnetic sensor120being shared in parallel by use as just described, no data gap occurs and reliable angular velocity, exercise information, and the like can be provided. As described above, in the present embodiment, when a magnetic field around the magnetic sensor120is stable, the angular velocity sensor130enters a stop state and angular velocity is acquired by the magnetic gyro sensor using the outputs of the acceleration sensor110and the magnetic sensor120. As a result of this configuration, the acceleration sensor110and the magnetic sensor120whose power consumptions are small as compared to that of the angular velocity sensor130can be used. Accordingly, the power consumption of the electronic apparatus100is reduced, which contributes to the improvement of the driving time. In addition, a reliable and adequate angular velocity can be acquired. More specifically, magnetic sensors and acceleration sensors generally operate with an electric current of the order of tens to hundreds of microamperes. By contrast, angular velocity sensors operate with an electric current of the order of milliamperes. Thus, by the angular velocity acquisition method according to the present embodiment being applied, the power consumption of the electronic apparatus100can be significantly reduced as compared to a method where angular velocity is acquired only by an angular velocity sensor. In addition, when the magnetic sensor120is affected by disturbance noise and therefore its output is abnormal, the angular velocity sensor130which is not affected by the surrounding magnetic field can be used, so that a reliable and adequate angular velocity can be acquired. (Modification Example) Next, a modification example of the above-described embodiment is described. In the angular velocity acquisition method according to the above-described embodiment, the method of judging whether or not there is any disturbance or magnetic anomaly in a magnetic field around the magnetic sensor120(Step S104) has been described, in which angular velocity detected (calculated) by the magnetic gyro sensor constituted by the magnetic sensor120or by the acceleration sensor110and the magnetic sensor120and angular velocity detected by the angular velocity sensor130are compared with each other. However, the present invention is not limited thereto and the following methods can be adopted. (1) The control section170judges whether or not the total value of outputs in three axial directions from the magnetic sensor120or the value of an output in a specific axial direction is larger than a threshold value set in advance. Then, the control section170judges that there is a disturbance or magnetic anomaly in a magnetic field around the magnetic sensor120when the output value is larger than the threshold value, or judges that there is no disturbance or magnetic anomaly in the magnetic field around the magnetic sensor120when the output value is not larger than the threshold value. Here, in order to prevent the reduction of the judgment accuracy due to a sudden or momentary magnetic field disturbance or magnetic anomaly, the control section170should preferably judge that there is a magnetic field disturbance or magnetic anomaly when a state where the output value of the magnetic sensor120is larger than the threshold value continues for a predetermined time or is detected more than a predetermined number of times in a predetermined period. (2) The control section170judges whether there is change in the output of the magnetic sensor120when there is no change in the output of the acceleration sensor110or when the value of a change in the output of the acceleration sensor110is equal to or less than a threshold value set in advance. Then, when a change occurs in the output of the magnetic sensor120or when the value of a change in the output of the magnetic sensor120is equal to or larger than a threshold value set in advance, the control section170judges that there is a disturbance or magnetic anomaly in a magnetic field around the magnetic sensor120. That is, in a normal situation, when the electronic apparatus100is not being moved or used, no change occurs in the outputs of the acceleration sensor110and the magnetic sensor120. Accordingly, if a change occurs in the output of the magnetic sensor120in this situation, a judgment can be made that the magnetic sensor120is being affected by a disturbance noise (magnetic field disturbance or magnetic anomaly). (3) The control section170calculates the strength and direction of a magnetic field at the current location of the electronic apparatus100based on the output of the magnetic sensor120, and judges whether the values of the strength and direction of the magnetic field (geomagnetism) at the current location are unusual values that are different from the values of the usual strength and direction of the magnetic field. That is, in any area on the earth, the strength and direction of each magnetic field attributed to geomagnetism are basically definite and already known. Accordingly, when the values of the strength and direction of a magnetic field calculated based on the output of the magnetic sensor120is unusual values that are different from the values of the usual strength and direction of the magnetic field, the control section170judges that there is a disturbance or magnetic anomaly in the magnetic field around the magnetic sensor120. Here, information regarding the current location of the electronic apparatus100may be acquired by a positioning section using GPS or the like being added to the structure of the electronic apparatus100shown inFIG.2. Also, a configuration may be adopted in which it is acquired by the user selecting an area or a region where the electronic apparatus100is currently located. Based on this information, the usual strength and direction of a magnetic field can be estimated. <Second Embodiment> Next, an angular velocity acquisition method for an electronic apparatus according to a second embodiment of the present invention is described with reference to the drawings. Note that, here, descriptions of part of the method that is equal to the first embodiment are simplified. FIG.6,FIG.7A,FIG.7BandFIG.7Care flowcharts showing an example of the angular velocity acquisition method for the electronic apparatus according to the second embodiment. In the first embodiment and its modification, the method has been described in which where or not there is any disturbance or magnetic anomaly in a magnetic field around the magnetic sensor120is judged, and a method for detecting angular velocity is selected based on a result of this judgment. In the second embodiment, in addition to this judgment processing, processing is performed in which whether the output of the magnetic sensor120is reliable is judged, and calibration processing for the magnetic sensor120is performed based on a result of this judgment. This angular velocity acquisition method (flowcharts inFIG.6,FIG.7A,FIG.7BandFIG.7C) for the electronic apparatus100is also achieved by the control section170performing processing according to a predetermined control program and a predetermined algorithm program, as in the first embodiment. Here, the control section170corresponds to an offset judgment section and a calibration control section. In the angular velocity acquisition method according to the second embodiment, when the electronic apparatus100is turned on, the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130are activated (Step S202), and the control section170judges whether calibration processing for the magnetic sensor120is necessary (Step S204), as shown in the flowchart ofFIG.6. Specifically, as in the case of the reliability judgment processing (Step S120to Step S126) shown in the flowchart ofFIG.4in the first embodiment, the control section170synchronizes the acceleration sensor110and the magnetic sensor120constituting a magnetic gyro sensor with the angular velocity sensor130so as to operate them, and detects angular velocity from each output therefrom (Step S120). Subsequently, the control section170compares the individually detected angular velocities with each other (Step S122). Then, when the comparison result (difference) is within a predetermined threshold range (Step S124), the control section170judges that calibration processing is not necessary because the offset value of the magnetic sensor120is a known value and its output is reliable (Step S126). Conversely, when the comparison result is not within the predetermined threshold range (Step S124), the control section170judges that calibration processing is necessary because the offset value of the magnetic sensor120has been changed from the known value and its output is not reliable (Step S126). When judged at Step S204that calibration processing for the magnetic sensor120is necessary (YES at Step S204), the control section170performs predetermined calibration processing (Step S206). Then, after performing the calibration processing, the control section170performs processing operations equivalent to those of Step S104to Step S116in the first embodiment (the flowchart inFIG.3), and acquires angular velocity data detected by the magnetic gyro sensor or the angular velocity sensor130. Note that the calibration processing for the magnetic sensor120herein may be automatically performed by a well-known calibration method, or may be manually performed by the user being prompted to perform it. That is, the control section170judges whether or not there is any disturbance or magnetic anomaly in a magnetic field around the magnetic sensor120at this point (Step S208). Then, when judged that there is no magnetic field disturbance or magnetic anomaly (NO at Step S208), the control section170temporarily stops the sensing operation of the angular velocity sensor130(Step S210), and performs an operation of detecting angular velocity by the magnetic gyro sensor (Step S212). Conversely, when judged that there is a magnetic field disturbance or magnetic anomaly (YES at Step S208), the control section170starts the angular velocity sensor130(Step S214and Step S216) to perform an angular velocity detection operation thereby (Step S218). Then, the control section170associates the detected angular velocity with time data, and stores it in the predetermined storage area of the memory section180as angular velocity data (Step S220). Note that, in the processing of judging whether or not there is any disturbance or magnetic anomaly in the magnetic field around the magnetic sensor120at Step S208, processing operations may be performed which are the same as those of the reliability judgment processing shown in the flowchart ofFIG.4in the first embodiment. As another method for judging whether or not there is any disturbance or magnetic anomaly in the magnetic field around the magnetic sensor120, a method may be adopted in which, in the processing of judging whether calibration processing for the magnetic sensor120is necessary at Step S204, whether or not there is a magnetic field disturbance or magnetic anomaly is judged based on whether the result of the comparison (difference) between the angular velocities is within the predetermined threshold range. Next, the control section170judges whether calibration processing for the magnetic sensor120is necessary based on the reliability of the output of the magnetic sensor120, as shown in the flowcharts ofFIG.7A,FIG.7BandFIG.7C(Step S230, Step S240, and Step S250). Specifically, in judgment processing at Step S230, the control section170detects angular velocity by either the magnetic gyro sensor or the angular velocity sensor130, acquires the data of the angular velocity (Step S220), and then performs processing operations that are the same as those of the above-described processing (at Step S204) for judging whether or not calibration processing for the magnetic sensor120is necessary. That is, the control section170synchronizes the acceleration sensor110and the magnetic sensor120constituting the magnetic gyro sensor with the angular velocity sensor130so as to operate them, and judges whether a result of comparison (difference) between individually detected angular velocities is out of the predetermined threshold range. When the comparison result is out of the predetermined threshold range (YES at Step S230), the control section170judges that calibration processing is necessary because the offset value of the magnetic sensor120has been changed from the known value and its output is not reliable. In this case, the control section170returns to Step S206, performs calibration processing for the magnetic sensor120, and then acquires angular velocity data by performing the processing operations at Step S208and the following steps. Conversely, when the comparison result is within the predetermined threshold range (NO at Step S230), the control section170judges that calibration processing is not necessary because the offset value of the magnetic sensor120is normal and its output is reliable. In this case, the control section170acquires angular velocity data by performing the processing operations at Step S208and the following steps without performing calibration processing for the magnetic sensor120. In judgment processing at Step S240, the control section170judges whether time elapsed from preceding calibration processing for the magnetic sensor120has exceeded a predetermined threshold value. When judged that the elapsed time has exceeded the threshold value (YES at Step S240), the control section170judges that calibration processing is necessary because the offset value of the magnetic sensor120may not be normal (accurate) and therefore its output is not reliable. In this case, the control section170returns to Step S206, and performs calibration processing for the magnetic sensor120. Conversely, when judged that the elapsed time has not exceeded the threshold value (NO at Step S240), the control section170presumes that the offset value of the magnetic sensor120is a known value and its output is reliable, and therefore judges that calibration processing is not necessary. In this case, the control section170performs the processing operations at Step S208and the following steps without performing calibration processing for the magnetic sensor120. In judgment processing at Step S250, the control section170refers to a history of outputs of the magnetic gyro sensor collected in the past, and thereby judges whether or not there is any disturbance or magnetic anomaly in the magnetic field around the magnetic sensor120. In this history of outputs of the magnetic gyro sensor, when the number of times a magnetic field disturbance or magnetic anomaly has been observed is larger than a predetermined threshold value (YES at Step S250), the control section170judges that calibration processing is necessary because the offset value of the magnetic sensor120may not be normal (accurate) and therefore its output is not reliable. In this case, the control section170returns to Step S206and performs calibration processing for the magnetic sensor120. Conversely, when the number of times a magnetic field disturbance or magnetic anomaly has been observed is less than the predetermined threshold value (NO at Step S250), the control section170judges that calibration processing is not necessary because the offset value of the magnetic sensor120is a known value and therefore its output is reliable. In this case, the control section170performs the processing operations at Step S208and the following steps without performing calibration processing for the magnetic sensor120. As described above, in this embodiment, in addition to the processing operations of the angular velocity acquisition method of the first embodiment, the control of the execution of calibration processing for correcting the offset value of the magnetic sensor120is performed based on whether the output of the magnetic sensor120is reliable. As a result of this configuration, the offset value of the magnetic sensor120constituting the magnetic gyro sensor can be constantly corrected to an accurate value, whereby the power consumption of the electronic apparatus100can be reduced and a more reliable and adequate angular velocity can be acquired. (Modification Example) Next, a modification example of the above-described embodiment is described. In the above-described embodiment, the processing for judging whether calibration processing for the magnetic sensor120is necessary is performed at Step S204after the activation of each sensor. However, the present invention is not limited thereto. Specifically, a configuration may be adopted in which, after the activation of each sensor, the calibration processing for the magnetic sensor120at Step S206is automatically performed without the judgment processing at Step S204. As a result of this configuration, the necessity judgment processing regarding calibration processing for the magnetic sensor120can be included in one of the processing operations at Step S230, Step S240and Step S250, whereby a processing load immediately after the activation of the electronic apparatus100can be reduced. Also, in the method of the present embodiment, when angular velocities individually detected by the magnetic gyro sensor and the angular velocity sensor are compared with each other based on the premise that the output of the angular velocity sensor is accurate, and the output of the magnetic gyro sensor is different from (different with reference to) that of the angular velocity sensor130by more than a threshold value, the offset value of the magnetic sensor120is judged to have been changed from a known value, and calibration processing is performed. However, the present invention is not limited thereto. That is, a configuration may be adopted in which, when angular velocities individually detected by the magnetic gyro sensor and the angular velocity sensor are compared with each other based on the premise that the output of the magnetic gyro sensor is accurate, and the output of the angular velocity sensor130is different from (different with reference to) that of the magnetic gyro sensor by a value significantly larger than a threshold value, the offset value of the angular velocity sensor130is judged to have been changed from a known value, and calibration processing for the angular velocity sensor130is performed. Here, the output of the magnetic sensor120constituting the magnetic gyro sensor can be maintained at an accurate value by calibration processing being performed immediately after the activation of the acceleration sensor110, the magnetic sensor120, and the angular velocity sensor130, as shown at Step S206. Moreover, in the present invention, a configuration may be adopted in which the method of judging whether calibration processing for the magnetic sensor120is necessary in the above-described embodiment and the above-described method of judging whether calibration processing for the angular velocity sensor130is necessary by judging whether the offset value of the angular velocity sensor130has been changed from a known value are both performed, whereby the offset value of the magnetic sensor120and the offset value of the angular velocity sensor130are maintained at known values. By this configuration, the output of the angular velocity sensor130or the outputs of the magnetic gyro sensor and the angular velocity sensor130can be maintained at accurate values, whereby a reliable and adequate angular velocity can be acquired. Furthermore, in the above-described embodiments and their modification examples, the method using the magnetic gyro sensor has been described in which angular velocity is detected (calculated) using the outputs of the acceleration sensor110and the magnetic sensor120. However, the present invention is not limited thereto and a method may be adopted in which angular velocity is detected (calculated) based only on the output of the magnetic sensor120). While the present invention has been described with reference to the preferred embodiments, it is intended that the invention be not limited by any of the details of the description therein but includes all the embodiments which fall within the scope of the appended claims. | 37,869 |
RE49813 | BEST MODE Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims thereof as well as the appended drawings. To achieve these and other advantages and in accordance with the purpose of the present invention, as embodied and broadly described, To further achieve these and other advantages and in accordance with the purpose of the present invention, It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. MODE FOR INVENTION Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings. First of all, terminologies or words used in this specification and claims are not construed as limited to the general or dictionary meanings and should be construed as the meanings and concepts matching the technical idea of the present invention based on the principle that an inventor is able to appropriately define the concepts of the terminologies to describe the inventor's invention in best way. The embodiment disclosed in this disclosure and configurations shown in the accompanying drawings are just one preferred embodiment and do not represent all technical idea of the present invention. Therefore, it is understood that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents at the timing point of filing this application. According to the present invention, terminologies not disclosed in this specification can be construed as the following meanings and concepts matching the technical idea of the present invention. Specifically, ‘coding’ can be construed as ‘encoding’ or ‘decoding’ selectively and ‘information’ in this disclosure is the terminology that generally includes values, parameters, coefficients, elements and the like and its meaning can be construed as different occasionally, by which the present invention is non-limited. In this disclosure, in a broad sense, an audio signal is conceptionally discriminated from a video signal and designates all kinds of signals that can be auditorily identified. In a narrow sense, the audio signal means a signal having none or small quantity of speech characteristics. Audio signal of the present invention should be construed in a broad sense. Yet, the audio signal of the present invention can be understood as an audio signal in a narrow sense in case of being used as discriminated from a speech signal. Although coding is specified to encoding only, it can be construed as including both encoding and decoding. FIG.1is a schematic block diagram of an audio signal processing apparatus according the present invention. Referring toFIG.1, an encoder100of an audio signal processing apparatus according the present invention includes a pair of coding units (i.e., a rectangular coding unit120R and a non-rectangular coding unit120N or a first coding unit120-1and a second coding unit120-2) and is able to further include a signal classifier110and a multiplexer130. In this case, the rectangular coding unit120R is a coding unit to which a rectangular coding scheme is applied. In particular, the rectangular coding scheme means a coding scheme of applying a window having a rectangular shape, while a non-rectangular coding scheme means a coding scheme of applying a window having a non-rectangular shape. Moreover, the first and second coding units120-1and120-2are units for applying first and second coding schemes based on different domains, respectively. In this case, the domains can include a linear prediction domain, a frequency domain, a time domain and the like. For instance, the first coding scheme is a coding scheme based on the linear prediction domain and the second coding scheme is a coding scheme based on the frequency domain. And, definitions and properties according to domain types shall be descried in detail later. The encoder100is able to include three specific coding units (i.e., A coding unit120A, B coding unit120B and C coding unit120C). For example shown inFIG.1, A coding scheme applied to the A coding unit120A is a rectangular coding scheme and corresponds to a first coding scheme. B coding scheme applied to the B coding unit120B is a non-rectangular coding scheme and corresponds to a first coding scheme. C coding scheme applied to the C coding unit120C is a non-rectangular coding scheme and corresponds to a second coding scheme. As mentioned in the foregoing description, the drawing shown inFIG.1is just exemplary, by which the present invention is non-limited. For clarity and convenience of the following description, the example shown inFIG.1is taken as a reference. Optionally, the A, B and C coding schemes can correspond to ACELP (algebraic code excited linear prediction), TCX (transform coded excitation) and MDCT (modified discrete Fourier transform), respectively, by which the present invention is non-limited. The A, B and C coding schemes shall be described in detail with reference to details of the rectangular coding scheme, the non-rectangular coding scheme, the first coding scheme and the second coding scheme later. The signal classifier110analyzes characteristics of an input audio signal and then determines to apply which one of the above-mentioned at least two coding schemes to a current frame or subframe based on the analyzed characteristics. According to the determination, coding scheme information is generated. As mentioned in the foregoing description, the at least two coding schemes correspond to the rectangular and non-rectangular coding schemes, the first and second coding schemes or the A to C coding schemes, by which the present invention is non-limited. For instance, in case of the examples shown inFIG.1, the coding scheme information can include coding identification information and subcoding identification information. In this case, the coding identification information indicates either the first coding scheme or the second coding scheme for a current frame. In case that a current frame corresponds to the first coding scheme, the subcoding identification information is the information indicating whether the first coding scheme is the A coding scheme or the B coding scheme per frame or subframe. Afterwards, the signal classifier110generates the coding scheme information and then delivers it to the multiplexer130. Meanwhile, under the control of the signal classifier110, the input signal is classified per frame or subframe and is then inputted to the rectangular/non-rectangular coding unit120R/120N or the first/second coding unit120-1/120-2. In case of the example shown inFIG.1, the input signal is inputted one of the A to C coding units102A to120C. In case of the example shown inFIG.1, each of the A to C coding units120A to120C delivers data, which is a result from encoding the input signal by the corresponding coding scheme, to the multiplexer120. The multiplexer130generates at least bitstream by multiplexing the coding scheme information and the data which is the result of the coding performed by the corresponding unit. Meanwhile, a decoder200of the audio signal processing apparatus according to the present invention includes at least two decoding units220R and220N or220-1and220-2and is able to further include a demultiplexer210. In this case, the at least two decoding units are components in aspect of decoding to correspond to the former at least two coding units and include a rectangular decoding unit220R and a non-rectangular decoding unit220N (or a first decoding unit220-1and a second decoding unit220-2), respectively. In a manner similar to that of the encoder100, the at least two decoding units can include A to C decoding units220A to220C, respectively. A rectangular coding scheme applied by the rectangular decoding unit220R and a non-rectangular coding scheme applied by the non-rectangular decoding unit220N are as good as those explained in the foregoing description. And, a first coding scheme applied by the first decoding unit220-1and a second coding scheme applied by the second decoding unit220-2are as god as those explained in the foregoing description. As mentioned in the foregoing description, in case that the A to C decoding units220A to220C are included as shown inFIG.1, A to C coding schemes used by the respective coding units shall be described in detail later. Afterwards, the demultiplexer210extracts the coding scheme information and the data per frame or subframe from the at least one bitstream. The extracted data is forwarded to the corresponding decoding unit220A,220B or220C according to the coding scheme information. Finally, each of the decoding units decodes the data by the corresponding decoding scheme to generate an output audio signal. In the following description, embodiments of the audio signal processing apparatus according to the present invention shown inFIG.1are described in order. FIG.2is a block diagram of an encoder according to a first embodiment of the present invention, andFIG.3is a block diagram of a decoder according to a first embodiment of the present invention. In particular, the first embodiments relates to an embodiment for compensating such a defect as aliasing and the like when a block encoded by a rectangular coding scheme come in contact with a block encoded by a non-rectangular coding scheme. Referring toFIG.2, like the former encoder100shown inFIG.1, an encoder100A according to a first embodiment includes a rectangular coding unit120R and a non-rectangular coding unit120N and is able to further include a multiplexer130. In particular, the rectangular coding unit120R includes a rectangular scheme coding part122and a rectangular scheme synthesis part124. And, the non-rectangular coding unit120N includes a compensation information generating part128and is able to further include a non-rectangular scheme coding part126. First of all, an input signal is divided by a unit of block and is then inputted to the rectangular coding unit120R or the non-rectangular coding unit120N per block. In this case, the block is a unit corresponding to a frame or a subframe. In the following description, a coding scheme per frame (e.g., rectangular coding scheme, non-rectangular coding scheme) is examined with reference toFIG.4andFIG.5and various methods for compensating a defect (e.g., aliasing, etc.) generated from a transition to a heterogeneous coding scheme (e.g., rectangular coding scheme or non-rectangular coding scheme) are described with reference toFIGS.6to11.FIGS.4to11are preferentially described and the components shown inFIG.2andFIG.3shall be described again. FIG.4shows a configuration unit of an audio signal and a coding scheme per configuration unit. Referring toFIG.4, it can be observed that an audio signal is configured with a series of frames including an ithframe (frame i) and an (i+1)thframe (frame i+1). In particular, it can be recognized that a single frame includes a plurality of subframes (e.g., 4 subframes). Moreover,FIG.4shows that a different coding scheme is applicable to each frame or subframe. In particular,FIG.4shows an example that there are three kinds of coding schemes [i.e., A coding scheme (ACELP), B coding scheme (TCX) and C coding scheme (FD)]. For instance, a frame can be configured with a plurality of subframes (e.g., 4 subframes). And, the A coding scheme (e.g., ACELP) is applicable per subframe, as shown in an ithframe shownFIG.4(A). The B coding scheme (e.g., TCX) is applicable to 1 subframe, 2 contiguous subframes and 4 contiguous subframes (i.e., one frame), as shown in an ithframe ofFIG.4(B) and ithand (i+1)thframes shown inFIG.4(D). The C coding scheme (e.g., FD) is applicable not by a subframe unit but by a frame unit, as shown inFIG.4(A) andFIG.4(B), by which the present invention is non-limited. FIG.5is a diagram for transition to a heterogeneous coding scheme (i.e., rectangular coding scheme and non-rectangular coding scheme). Referring toFIG.5(A-1), a transition in Nthblock is made to a rectangular coding scheme and a transition in (N+1)thblock is made to a non-rectangular coding scheme. On the contrary, referring toFIG.5(A-2), a transition in Nthblock is made to a non-rectangular coding scheme and a transition in (N+1)thblock is made to a rectangular coding scheme. In this case, a block can correspond to a frame or subframe explained in the foregoing description. Namely, the Nthor (N+1)thframe or subframe can include a frame or subframe. In particular, total four kinds of combinations (e.g., frame-frame, frame-subframe, subframe-frame and subframe-frame) are possible. The example of the transition from the rectangular coding scheme to the non-rectangular coding scheme, as shown inFIG.5(A-1), can be discovered from the former cases shown inFIG.4(A) toFIG.4(D). As mentioned in the foregoing description with reference toFIG.1, the A coding scheme (ACELP) corresponds to the rectangular coding scheme, while each of the B coding scheme (TCX) and the C coding scheme (FD) corresponds to the non-rectangular coding scheme. The case (i.e.,FIG.5(A-1)) of the transition from the A coding scheme (ACELP) to the B coding scheme (TCX) or the C coding scheme (FD) corresponds to one of the parts indicated by dotted line shown inFIG.5(B-1) toFIG.5(B-4). On the contrary, the case [i.e.,FIG.5(A-2)] of the transition from the non-rectangular coding scheme to the rectangular coding scheme, i.e., the case of the transition from the B coding scheme (TCX) or the C coding scheme (FD) to the A coding scheme (ACELP) is not indicated inFIG.5(B-1) toFIG.5(B-4) but can be discovered from two or three locations (e.g., 1stand 2ndblocks inFIG.5(B-2), etc.). Thus, such a defect as aliasing and the like can be generated due to asymmetry from a location at which a rectangular window and a non-rectangular window come in contact with each other. In the following description, a method of compensating this defect is described with reference toFIGS.6to9. FIG.6is a diagram for characteristics when a rectangular window and a non-rectangular window are overlapped with each other.FIG.7is a diagram for a correction part (CP), an aliasing part (AP) and an uncompensated signal. In particular,FIG.6corresponds to a case that a rectangular window is followed by a non-rectangular window. Yet, a case that a non-rectangular window is followed by a rectangular window in a manner of being overlapped with the following rectangular window shall be explained later in this disclosure. Referring toFIG.6, it can be observed that a rectangular window and a non-rectangular window are overlapped with each other in part. Regarding an audio signal including blocks A to F, a rectangular window is applied to both of the block B and the block C and a non-rectangular window is applied to the blocks C to F. In particular, the rectangular window and the non-rectangular window are overlapped with each other at the block C.FIG.6(a) toFIG.6(d) show that results from applying windowing, folding, unfolding and windowing to the blocks A to F in order. In this case, each of the windowing, folding, unfolding and windowing is applied to a corresponding block in order for the application of time domain aliasing cancellation (TDAC) in association with a non-rectangular window. Referring toFIG.6(a), a rectangular window is applied to each of the block B and the block C (i.e., dotted blocks) and a non-rectangular window is applied to each of the blocks C to F. C(L1) indicates a result from applying a part L1of the non-rectangular window to the block C. And, D(L2) indicates a result from applying a part L2of the non-rectangular window to the block D. subsequently, if the folding is performed on the non-rectangular window applied result, it results in the blocks shown inFIG.6(b). In this case, Er, Dr or the like means that the folding is performed on the corresponding blocks and that the folded blocks are then reversed with reference to a block boundary. Afterwards, the unfolding is performed to result in the diagram shown inFIG.6(c). Finally, if a non-rectangular window is applied to the unfolded blocks, the same result as shown inFIG.6(d) is generated. In particular, an uncompensated signal corresponding to the block D of the original signal, i.e., a signal acquired as the transmitted data only can be represented as follows. Uncompensated signal=(−Cr(L1)r+D(L2))(L2) [Formula 1] In Formula 1, ‘C’ indicates data corresponding to the block C, ‘D’ indicates data corresponding to the block D, ‘r’ indicates reversion, ‘L1’ indicates a result from applying the part L1of the non-rectangular window, and ‘L2’ indicates a result from applying the part L2of the non-rectangular window. In the following description, a method of compensating an uncompensated signal to become identical or similar to an original signal is described with reference toFIGS.7to9. First of all, referring toFIG.7, an uncompensated signal corresponding to Formula 1 is shown. Meanwhile, a non-rectangular window has symmetry. Characteristics of the non-rectangular window, as shown inFIG.8, are explained as follows.FIG.8is a diagram for a characteristic of a non-rectangular window with symmetry (i.e., condition for TDAC). Li2+Ri2=1, where i=1 or 2 L1r=R2 L2r=R1[Formula 2] In Formula 2, ‘L1’ indicates a left first part, ‘L2’ indicates a left second part, ‘R1’ indicates a right first part, and ‘R2’ indicates a right second part. Hence, if the above characteristics of the non-rectangular window are applied, Formula 1 can be summarized in the following. Uncompensated signal=(−Cr(L1)r+D(L2))(L2)=D(L2)2−Cr(R2L2) (because L1r=R2) [Formula 3] Hence, in order for the uncompensated signal to become equal to the original signal D, i.e., in order to perform a perfect compensation, a needed signal is shown inFIG.7and can be represented as follows. Needed signal for perfect compensation=original signal−uncompensated signal=D−(D(L2)2−Cr(R2L2)) [Formula 4-1] Meanwhile, using the characteristics shown in Formula 2, Formula 4-1 can be summarized into the following. Needed signal for perfect compensation=D(R2)2+C(R2L2) (because 1−L22=R22) [Formula 4-2] In Formula 4-2, a first term (D(R2)2) corresponds to a correction part and a second term (Cr(R2L2)) can be named an aliasing part. If homogeneous windows (e.g., non-rectangular window and non-rectangular window) are overlapped with each other, the correction part CP and the aliasing part AP correspond parts to be deleted in a manner of being added by performing time domain aliasing cancellation (TDAC). In other words, since heterogeneous windows (i.e., rectangular window and non-rectangular window) are overlapped with each other, the correction part CP and the aliasing part AP are remaining errors instead of being cancelled. Specifically, the correction part CP corresponds to a part of a current block (e.g., block D) (i.e., a block behind a window crossing point) to which a non-rectangular window (particularly, R2) is applied. And, the aliasing part AP corresponds to a part of a previous block (e.g., block C) (i.e., a block behind a window crossing point) (e.g., a block at which a rectangular window and a non-rectangular block are overlapped with each other) to which a non-rectangular window (particularly, R2and L2)is applied. Meanwhile, since a decoder is able to reconstruct a previous block (e.g., block C) using data of the previous block, it is able to generate a prediction of an aliasing part using the reconstructed previous block. This is represented as Formula 5. Prediction of aliasing part=qCr(R2L2) [Formula 5] Meanwhile, an error of an aliasing part, which is a difference (or a quantization error) between a prediction of the aliasing part and an original aliasing part can be represented as Formula 6. Error of aliasing part=er(R2L2)=Cr(R2L2)−qCr(R2L2) [Formula 6] Using Formula 5 and Formula 6, Formula 4-2 is summarized into Formula 7. Needed signal for perfect compensation=D(R2)2+Cr(R2L2)=D(R2)2+(qCr+er)(R2L2) [Formula 7] In Formula 7, D(R2)2indicates a correction part CP, qCr (R2L2) indicates a prediction of an aliasing part AP, and er(R2L2) indicates an error of the aliasing part. Hence, the signal needed for perfect compensation is a sum of the correction part CP and the aliasing part AP, as shown in Formula 7. In the following description, three kinds of methods for compensating a correction part CP and an aliasing part AP are explained with reference toFIG.9. FIG.9is a diagram for embodiments of a compensation signal for compensating a correction part and/or an aliasing part. Referring toFIG.9, a compensation signal of a first embodiment shown inFIG.9(A) includes a correction part CP and an error of an aliasing part, while a compensation signal of a second embodiment shown inFIG.9(B) includes a correction part CP only. According to a third embodiment shown inFIG.9(B), a compensation signal is not sent to a decoder but a correction part CP and an aliasing part AP are estimated by the decoder. Method A: Compensation signal=D(R2)2+er(R2L2), where ‘D’ is a reconstructed signal [Formula 8-1] In case of a compensation signal according to the first embodiment, as mentioned in the foregoing description with reference to Formula 5, a prediction of an aliasing part AP can be obtained by a decoder based on data of a previous block (i.e., a block corresponding to an overlapped part between a rectangular window and a non-rectangular window) without transmission from an encoder to a decoder. Even if a compensation signal includes a correction part CP and an error of an aliasing part, the decoder is able to generate a prediction of the aliasing part. Therefore, it is able to obtain a signal for perfect compensation (cf. Formula 7). According to the first embodiment, it is able to save the number of bits by transmitting an error instead of the aliasing part AP itself. Moreover, it is able to obtain a perfectly compensated signal by compensating the error of the aliasing part AP. According to the second embodiment, a compensation signal includes a signal corresponding to a correction part CP only. Method B: Compensation signal=D(R2)2, where a reconstructed signal is D−er(R2L2) [Formula 8-2] As mentioned in the foregoing description (or like the first embodiment), a decoder generates a prediction of an aliasing part AP and then obtains a compensated signal using a compensation signal corresponding to a correction part CP together with the prediction. According to the second embodiment, since an error of the aliasing part AP may remain in the compensated signal, a reconstruction rate or a sound quality may be degraded. Yet, a compression ratio of the compensation signal can be raised higher than that of the first embodiment. According to the third embodiment, a compensation signal is not transmitted but a decoder estimates a correction part CP and an aliasing part AP. Method C: Compensation signal=Not transmitted, generated compensation signal in the decoder=qCr(L2R2)+D(R2)2, where a reconstructed signal is D−er(L2)/(R2) [Formula 8-3] As mentioned in the foregoing description (or like the first embodiment and the second embodiment), a prediction of an aliasing part AP can be generated by a decoder. Meanwhile, a correction part CP can be generated in a manner of compensating a window shape for a signal corresponding to a current block (e.g., block D). In particular, qCr((L2R2) generated using data of the previous block (qC) is added to un-compensated signal like the formula 1. Then D(L2)2−er(L2R2) is generated, by dividing D(L2)2−er(L2R2) by (L2)2(which may correspond to adding D(R2)2to D(L2)2−er(L2R2)), D−er(R2)/(L2) is obtained. In formula 8-3, quantized error of current block (block D) is not represented. A reconstruction rate of the third embodiment may be lower than that of the first or second embodiment. Yet, since the third embodiment does not need bits for transmitting a compensation signal at all, a compression ratio of the third embodiment is considerably high. FIG.10is a diagram for examples of a non-rectangular window in combination of heterogeneous windows (i.e., rectangular window and non-rectangular window) shown inFIG.6. In the examples of a non-rectangular window, as shown inFIG.10(A) toFIG.10(C), each corner is not rectangular but has an ascending line with a slope. Shapes of non-rectangular windows corresponding toFIG.10(A) toFIG.10(C) can be represented as Table 1. TABLE 1Total lengthLeft zero partAscending lineTop lineDescending lineRight zero part(A)N/4 or 2560N/4 or 2560N/4 or 2560(B)N/2 or 512N/8 or 128N/4 or 256N/4 or 256N/4 or 256N/8 or 128(C)N or 1024N3/8 or 384N/4 or 2563N/4 or 768N/4 or 256N/8 or 128In Table 1, ‘N’ indicates a frame length and a numeral indicates the number of samples (e.g., ‘256’ indicates 256 samples.). Referring to Table 1 andFIG.10, each of the windows of the three kinds of types can have ascending and descending lines of which widths are set to N/4 and N/4, respectively. In this case, ‘N’ indicates a frame length. Non-rectangular windows shown inFIG.10(A) toFIG.10(C) can respectively correspond to windows in mode1, mode2and mode3of the B coding scheme (e.g., TCX), by which the present invention is non-limited. As mentioned in the foregoing description with reference toFIG.4, the mode1corresponds to the window when the B coding scheme is applied to one subframe. The mode2corresponds to the window when the B coding scheme is applied to two contiguous subframes. And, the mode3corresponds to the window when the B coding scheme is applied to four contiguous subframes, i.e., one frame. In the above description, the examples of the non-rectangular window corresponding to the B coding scheme are explained. Examples of a non-rectangular window corresponding to the C coding scheme (e.g., MDCT) shall be described later together with an audio signal processing apparatus according to a second embodiment. FIG.11is a diagram for a case that a rectangular window following a rectangular window is overlapped. In particular,FIG.11shows a case that a rectangular window is overlapped after a non-rectangular window, whereasFIG.6shows a case that a rectangular window is followed by a non-rectangular window. Referring toFIG.11(A), like the case shown inFIG.6, it can be observed that a correction part CP and an aliasing part AP are generated from a block corresponding to a non-rectangular window. Since the block, at which non-rectangular and rectangular windows are overlapped, is not a previous block but a following block unlikeFIG.6, it is able to generate a prediction of the aliasing part AP using data of the following block. Moreover, by transmitting one of the examples of the compensation signal described with reference toFIG.9, it is able to solve a defect (i.e., the correction part CP and the aliasing part AP) generated due to the overlapping between the non-rectangular and rectangular windows. Referring toFIG.11(B), an embedding part EP of a rectangular window is embedded as an aliasing part AP in data coded according to a coding scheme corresponding to a non-rectangular window. Assuming that a whole signal corresponding to a rectangular window is set to D and that an embedding part EP is set to Crw, the embedding part EP can be represented as Formula 9. Crw=Cr(L1)r+D(R2) [Formula 9] For reference, the signal is a signal before a decoder applies a window. The embedding part EP (Crw) can be calculated by a decoder. Instead of coding the whole signal D according to a rectangular coding scheme, transmission can be performed by encoding ‘D−Crw’ (i.e., a transmission part TP shown in the drawing) only. And, the transmission part TP is represented as Formula 10. TP=D−Crw=−Cr(L1)r−D(1−R2) [Formula 10] The decoder is able to reconstruct an original signal in a manner of overlapping unfolded data corresponding to a non-rectangular coding scheme with data corresponding to a rectangular coding scheme. In the above description so far, contents for compensating the defect in case of the overlapping of the heterogeneous coding schemes and the heterogeneous windows (i.e., rectangular window and non-rectangular window) are explained in detail with reference toFIGS.4to11. In the following description, an audio signal processing apparatus and method according to a first embodiment are explained with reference toFIG.2andFIG.3again. Referring now toFIG.2, explained in the following description is a case that Nthblock and (N+1)thblock correspond to a rectangular coding scheme and a non-rectangular coding scheme, respectively. Of course, a reverse case that Nthblock and (N+1)thblock correspond to a non-rectangular coding scheme and a rectangular coding scheme, respectively is applicable as mentioned in the foregoing description with reference toFIG.10(A). The rectangular scheme coding part122encodes Nthblock of an input signal according to a rectangular coding scheme and then delivers the encoded data (for clarity, this data is named a first data) to the rectangular scheme synthesis part124an the multiplexer130. In this case, as mentioned in the foregoing description, the rectangular coding scheme is the coding scheme for applying a rectangular window. ACELP belongs to the rectangular coding scheme, by which the present invention is non-limited. The rectangular scheme coding part122is able to output a result encoded by applying a rectangular window to be block B and the block C by the A coding scheme inFIG.6. The rectangular scheme synthesis part124generates a prediction of an aliasing part AP using the encoded data, i.e., the first data. In particular, the rectangular scheme synthesis part124generates an output signal by performing decoding with the rectangular coding scheme. For instance, the block C (and the block B) is reconstructed into its original form by the A coding scheme. Using the output signal and the non-rectangular window, the prediction of the aliasing part AP is obtained, In this case, the prediction of the aliasing part AP can be represented as Formula 5. In Formula 5, ‘qC’ indicates the output signal and ‘R2L2’ indicates the non-rectangular window. And, the prediction of the aliasing part AP is inputted to the compensation information generating part128. The non-rectangular scheme coding part126generates an encoded data (for clarity, named a second data) by encoding the (N+1)thblock by the non-rectangular coding scheme. For instance, the second data can correspond to a result from applying the non-rectangular window to the blocks C to F and then folding the blocks. As mentioned in the foregoing description, the non-rectangular coding scheme can correspond to the B coding scheme (e.g., TCX) or the C coding scheme (e.g., MDCT), by which the present invention is non-limited. And, the second data is delivered to the multiplexer130. The compensation information generating part124generates a compensation signal using the prediction of the aliasing part and an original input signal. In this case, the compensation signal can be generated according to one of the three kinds of the methods shown inFIG.9. In case of using the method A, both of the prediction of the aliasing part and the original input signal are used. In case of using the method B, the original input signal is used only. In case of the method C, the compensation signal is not generated. Each of the three kinds of the methods is applicable to a whole frame or subframes in the same manner. Alternatively, in consideration of a bit efficiency of each frame, a different method is applicable to each frame. Definition and generation process of the compensation signal are explained in the foregoing description with reference toFIGS.6to9and shall not be redundantly explained in the following description. Meanwhile, the compensation signal generated by the compensation information generating part124is delivered to the multiplexer130. The multiplexer130generates at least one bitstream by multiplexing the first data (e.g., data of the Nthblock), the second data (e.g., data of the (N+1)thblock) and the compensation signal together and then transmits the generated at least one bitstream to an encoder. Of course, like the former multiplexer130shown inFIG.1, the latter multiplexer130enables coding scheme information and the like to be contained in the corresponding bitstream. Referring toFIG.3, like the former decoder200shown inFIG.1, a decoder200A according to a first embodiment of the present invention includes a rectangular decoding unit220R and a non-rectangular decoding unit220N and is able to further include a demultiplexer210. In this case, the non-rectangular decoding unit220N includes a compensation part228. In particular, the rectangular decoding unit220R is able to further include a rectangular scheme decoding part222and an aliasing prediction part224. And, the non-rectangular decoding unit220N is able to further include a non-rectangular scheme decoding part226. The demultiplexer210extracts the first data (e.g., data of the Nthblock), the second data (e.g., data of the (N+1)thblock) and the compensation signal from the at least one bitstream. In this case, the compensation signal can correspond to one of the three types described with reference toFIG.9. The rectangular scheme decoding part222generates an output signal by decoding the first data by the rectangular coding scheme. This is as good as obtaining the block C (and the block B) shown inFIG.6. Like the rectangular scheme synthesis part124shown inFIG.2, the aliasing prediction part224generates a prediction of the aliasing part using the output signal and a non-rectangular window. In this case, the prediction of the aliasing part may correspond to Formula 5. The non-rectangular scheme decoding part226generates a signal by decoding the second data by the non-rectangular coding scheme. Since the generated signal is the signal before the compensation of aliasing and the like, it corresponds to the uncompensated signal mentioned in the foregoing description. Hence, this signal can be equal to the former signal represented as Formula 1. The compensation part228generates a signal reconstructed using the compensation signal delivered from the demultiplexer210, the prediction of the aliasing part obtained by the aliasing prediction part224and the uncompensated signal generated by the non-rectangular scheme decoding part226. In this case, the reconstructed signal is the same as described with reference toFIG.9and Formulas 8-1 to 8-3. In the following description, an audio signal processing apparatus according to a second embodiment is explained with reference toFIG.12andFIG.13. First of all, regarding the first embodiment, the Nthblock corresponds to the rectangular coding scheme (e.g., A coding scheme) and the (N+1)thblock corresponds to the non-rectangular coding scheme (e.g., B coding scheme or C coding scheme), and vice versa. On the contrary, regarding the second embodiment, when (N+1)thblock corresponds to the C coding scheme, a window type of the C coding scheme is changed according to whether Nthblock corresponds to a rectangular coding scheme (e.g., A coding scheme). In this case, it is a matter of course that the Nthblock and the (N+1)thblock can be switched to each other in order. FIG.12is a block diagram of an encoder according to a second embodiment of the present invention. Referring toFIG.12, like the first embodiment, an encoder100B according to a second embodiment includes a rectangular coding unit120R and a non-rectangular coding unit120N. Yet, the non-rectangular coding unit120N further includes a window type determining part127. The rest of components (i.e., a rectangular scheme coding part122and a rectangular scheme synthesis part124, a non-rectangular scheme coding part126and a compensation information generating part128) have the same functionality of the former components of the same names according to the first embodiments. And, the same parts shall not be described in the following description. In case that a second block (i.e., a current block) is encoded by a non-rectangular coding scheme, the window type determining part127determines a type of a window of the second block according to whether a first block (e.g., a previous block, a following block, etc.) is encoded by a rectangular coding scheme. In particular, if the second block is encoded by the C coding scheme belonging to the non-rectangular coding schemes and a window applied to the second block belongs to a transition window class, the window type determining part127determines the type (and a shape) of the window of the second block according to whether the first block is encoded by the rectangular coding scheme. Examples of the window type are shown in Table 1. TABLE 1Examples of window type in non-rectangular coding scheme (particularly, C coding scheme)Window shapePrevious/Width ofWidth ofWindowName perfollowingLeft zeroascendingTopdescendingRight zerotypeClassificationshapeblockintervallinelinelineinterval1Only-longNon-Irrespective0N0N0windowtransitionwindow2Long_startTransitionSteepC coding0N7N/16N/87N/16windowwindowlong_startschemewindowGentleRectangular3N/8N/43N/8long_startwindowwindow3ShirtNon-Irrespective0Overlapping of 8 short parts, eachwindowtransitionalhaving ascending and descending linewindowwidth set to N/84Long_stopTransitionSteepC coding7N/16N/87/16NN0windowwindowlong_stopschemewindowGentleRectangular3N/8N/43N/8long_stopwindowwindow5Stop_startTransitionSteepC coding7N/16N/87N/8N/87N/16windowwindowstop_startschemewindowGentleRectangular3N/8N/43N/4N/43N/8stop_startwindowwindowIn Table 1, ‘N’ indicates a frame length, 1,024 or 960 samples or the like. Referring to Table 1, 2nd, 4thand 5thwindows (i.e., a long_start window, a long_stop window and a stop_start window) among total 5 windows belong to a transition window class. The window belonging to the transition window class, as shown in the table, differs in shape according to a previous or following block corresponds to a rectangular window. In case corresponding to a rectangular coding scheme, a width of an ascending or descending line is N/4. Yet, it can be observed that a class of a transition window has a width of an ascending or descending line becomes N/8 in case corresponding to a non-rectangular coding scheme (e.g., C coding scheme). FIG.13is a block diagram of a decoder according to a second embodiment of the present invention. FIG.14is a diagram of a shape of a transition window according to whether a rectangular coding scheme is applied to a previous block. Although a right non-rectangular shown inFIG.14(A) orFIG.14(B) corresponds to the long_stop window shown in Table 1, it can be replaced by a long_start window or a stop_start window. Referring toFIG.14(A), in case that a previous block corresponds to a rectangular window, an ascending line of a transition window of a current block has a first slope. Referring toFIG.14(B), in case that a previous block does not correspond to a rectangular window (particularly, in case that a previous block corresponds to a window of the C coding scheme), an ascending line of a transition window of a current block has a second slope. In this case, the first slope is gentler than the second slope. And, a width of the first slope can correspond to twice greater than that of the second slope. In particular, the width of the first slope is N/4, while the width of the second slope is N/8. In other words, the window type determining part127preferentially determines a type of a window corresponding to a current block, generates window type information for specifying a specific window applied to the current block (e.g., a frame or subframe) among a plurality of windows (i.e., for indicating a window type), and then delivers the generated window type information to the multiplexer130. In case that the type of the window corresponding to the current block is classified into a transition window, the window type determining part127determines a shape of a window, and more particularly, a width (and a corresponding top line and a length of a left or right zero part) of an ascending or descending line according to whether a previous or following block corresponds to a rectangular coding scheme and then applies the determined window shape to the current block. Meanwhile, like the former compensation information generating part128of the first embodiment, the compensation information generating part128generates a compensation signal when heterogeneous windows (e.g., a non-rectangular window and a rectangular window) are overlapped with each other (e.g., the case corresponding to (A) inFIG.14). As mentioned in the foregoing description, since a defect generated from the heterogeneous windows overlapped with each other can be corrected using the compensation signal, 50% of the heterogeneous windows can be overlapped instead of 100%. Since the heterogeneous windows need not to be overlapped with each other by 100%, it is not necessary to narrow a width of an ascending or descending line of each window classified into a transition window. Therefore, a window can have a slope relatively gentler than that of the case of the 100% overlapping. Referring toFIG.13, in a decoder200B according to a second embodiment, a non-rectangular decoding unit220N further includes a window shape determining part127rather than that of the first embodiment. In the following description, components having the same names of the former components of the first embodiment shall not be explained in detail. In case that a current block or a second block corresponds to a non-rectangular coding scheme (particularly, the C coding scheme), the window shape determining part127determines a specific window (i.e., a window type) applied to the current block among a plurality of windows based on the window type information delivered from the demultiplexer210. In case that a window of a current block belongs to a transition window class, the window shape determining part127determines a shape of a window of the determined window type according to whether a previous/following block (i.e., a first block) is coded by a rectangular coding scheme. In particular, if the previous/following block is encoded by the rectangular coding scheme and a window of the current block belongs to the transition window class, as mentioned in the foregoing description, the window shape is determined to have an ascending or descending line with a first slope gentler than a second slope. For instance, in case of a long_start window, the window shape is determined as a gentle long_start window (having a descending line with a first slope (e.g., N/4) in Table 1. In case of a long_stop window, the window shape is determined as a gentle long_stop window (e.g., an ascending line with a first slope (N/4)). And, in case of a stop_start window, the window shape is determined in the same manner. In this case, as mentioned in the foregoing description, the first slope (e.g., N/4) is gentler than the second slope. In particular, the second slope is a slope of an ascending or descending line of a steep transition window (e.g., a steep long_stop window, etc.). The window type and shape determined in the above manner are delivered to the non-rectangular scheme decoding part226. Subsequently, the non-rectangular scheme decoding part226generates an uncompensated signal by decoding a current block by the non-rectangular scheme according to the determined window type and shape. Like the first embodiment, in case that the overlapping of heterogeneous windows (e.g., a rectangular window and a non-rectangular window) occurs, the compensation part228generates a reconstructed signal using the uncompensated signal and the compensation signal (and the prediction of the aliasing part). In the following description, an audio signal processing apparatus according to a third embodiment is explained with reference toFIG.15andFIG.16. The third embodiment includes the first coding unit120-1, the second coding unit120-2, the first decoding unit220-1and the second decoding unit220-2in the former audio signal processing apparatus shown inFIG.1. In particular, when a current block (e.g., Nthblock) is encoded by a second coding scheme (i.e., C coding scheme), according to whether a following block [e.g., (N+1)thblock] is encoded by a first coding scheme (i.e., A coding scheme or B coding scheme), a shape of a current window corresponding to the current block is determined by the third embodiment. FIG.15is a block diagram of an encoder according to a third embodiment of the present invention. Referring toFIG.15, in an encoder100C according to a third embodiment, a first coding unit120-1includes a first scheme coding part122-1and a second coding unit120-2includes a second scheme coding part126-2and a window type determining part127-2. And, the encoder100can further include a multiplexer130. In this case, an input signal is inputted to the first coding unit120-1or the second coding unit120-2by a unit of block (e.g., a frame, a subframe, etc.). The first scheme coding part122-1encodes the input signal by a first coding scheme and the second scheme coding part126-2encodes the input signal by a second coding scheme. In this case, the first and second coding schemes are as good as those described with reference toFIG.1. In particular, the first coding scheme is a linear prediction domain based coding scheme and the second coding scheme can correspond to a frequency domain based scheme. Meanwhile, as mentioned in the foregoing description with reference toFIG.1, the first coding scheme can include the A coding scheme (e.g., ACELP) corresponding to the rectangular window scheme and the B coding scheme (e.g., TCX) corresponding to the non-rectangular window scheme and the second coding scheme can include the C coding scheme (e.g., MDCT) corresponding to the non-rectangular window scheme. In case that the input signal corresponds to the second coding scheme, the window type determining part127-2determines a window type and shape of a current block with reference to a characteristic (and a window type) of a previous or following block, generates window type information indicating the window type corresponding to the current block (frame or subframe), and then delivers the generated window type information to the multiplexer130. In the following description, a window type is explained in detail with reference to Table 1, a window type and shape of a current block according to a coding scheme of a previous/following block are explained with reference toFIG.17andFIG.19, and the components shown inFIG.15andFIG.16are then explained again. First of all, one example of a window type corresponding to a second coding scheme can be identical to Table 1. Referring to Table 1, windows (e.g., only-long, long_start, short, long_stop and stop_start) of total five types exist. In this case, the only-long window is a window applied to a signal suitable for a long window due to a stationary characteristic of the signal and the short window is a window applied to a signal suitable for a short window due to a transient characteristic of the signal. The long_start window, the long_stop window and the stop_start window, which are classified as transition windows, are necessary for a process of transition to the short window (or a window with a first coding scheme) from the only-long window or a process for transition to the only-long window (or a window with a first coding scheme) from the short window. The stop_start window is the window used if a previous/following frame corresponds to the short window (or a window with a first coding scheme) despite that a long window is suitable for a current block or frame. Shapes of the windows of the five types shown in Table 1 are examined in detail as follows. First of all, each of the only-long, short, and stop_start windows has horizontal symmetry, while the rest of the windows have horizontal asymmetry. The long_start window includes a zero part in a right half only, whereas the long_stop window includes a zero part in a left half only. In the following description, a process for determining a window shape of a current frame according to a previous frame or a following frame is explained in detail. First of all, if a previous frame is an only-long window and a current frame is a long_start window, a shape of a current long_start window can be determined according to whether a following frame corresponds to a short window or a window with a first coding scheme. In particular, a slope of a descending line of the long_start window can vary. A long_start window having a gentle slope of a descending line shall be named a gentle long_start window (cf. a name per shape in Table 1) and a long_start window having a steep slope of a descending line shall be named a steep long_start window. This shall be described in detail with reference toFIG.17as follows. FIG.17is a diagram of a long_start window combined with a first coding scheme window or a short window.FIG.17(A-1)/(A-2) shows a combination between a long_start window and a window of a first coding scheme.FIG.17(B) shows a combination between a long_start window and a short window. In particular, a window of a first coding scheme shown inFIG.17(A-1) is a window corresponding to ‘A scheme’ (i.e., rectangular window scheme). And,FIG.17(A-2) shows a window corresponding to ‘B coding scheme’ (non-rectangular window scheme) in the first coding scheme window. Referring toFIG.17(A-1) andFIG.17(A-2), in case that a following frame corresponds to a first coding scheme, a current long_start window includes a descending line having a first slope. Referring toFIG.17(B), in case that a following frame corresponds to a second coding scheme (i.e., a short window), a current long_start window includes a descending line having a second slope. A width of the first slope can be twice greater than that of the second slope and can correspond to N/4, where ‘N’ is a length of a frame. Besides, the width of the first slope amounts to 256 samples and can correspond to ⅛ of a total length of the long_start. Like the case shown inFIG.17(A-1), in case that a rectangular window is overlapped with a long_start window followed by the rectangular window, as mentioned in the foregoing descriptions of the first and second embodiments, it is able to compensate a correction part (CP) and an aliasing part (AP) using a received compensation signal. If this compensation is not performed, the long_start window should be 100% overlapped with the rectangular window. Therefore, in order not to waste bits, a slope of a descending line overlapped with the rectangular window should have been set steep. Yet, as the above-mentioned compensation is enabled, a sound quality avoids being distorted with 50% of the overlapping with the rectangular window. Hence, a slope of the descending line can be maintained as the first slope shown inFIG.17(A-1). Thus, as the descending line is gently maintained with the first slope, a crossing point between the two windows becomes a point at 3N/2. If 100% of the overlapping is achieved, a crossing point between the two windows should become 3N/2-N/16. In particular, the corresponding crossing point is ahead of that o the case shown inFIG.17(A-1) by N/16. In other words, in case that a following window is a window corresponding to a first coding scheme, 50% of the overlapping is acceptable. Hence, a descending line of a long_start window is maintained gentle with a first slope. As a result, a location of a crossing point becomes the same location (e.g., a point of 3N/2 from a window start point) if the following window follows the first or second coding scheme or is irrespective of the first or second coding scheme. Thus, as the crossing points become equal to each other, interwindow transition becomes different. This shall be described together with a fourth embodiment later in this disclosure. Referring toFIG.17(B), as a second slope is matched to a slope of an ascending line of a window corresponding to a following frame (i.e., a second coding scheme), a condition of RDAC is met. In this case, the meaning of ‘being matched’ may indicate that an absolute value of a slope is identical. In particular, a width of a slope of a descending line is N/4 and a width of a slope of an ascending line of a following frame is N/4 as well. Referring now to Table 1, a short window has a single shape irrespective of a coding scheme of a previous or following block. This is explained with reference toFIG.18as follows.FIG.18is a diagram of a short window overlapped with a first coding scheme window (A) or a second coding scheme window (B). Referring toFIG.18(A-1), a first coding scheme, and more particularly, a rectangular coding scheme (e.g., A coding scheme) appears behind a short window. Referring toFIG.18(A-2), a first coding scheme, and more particularly, a non-rectangular coding scheme (e.g., B coding scheme) appears behind a short window. Irrespective of a case that a short window is overlapped with a window of a first coding scheme following the short window, as shown inFIG.18(A-1) orFIG.18(A-2), or a case that a short window is overlapped with a window (particularly, a long_stop window) of a second coding scheme following the short window, as shown inFIG.18(B), a slope (cf. ‘slope A’ in the drawing) of a descending line of the short window is identical. Thus, the reason why the short window in the identical shape is possible is explained as follows. First of all, as mentioned in the foregoing descriptions of the first and second embodiments, even if a rectangular coding scheme appears behind a short window, it is able to compensate a correction part (CP) and an aliasing part (AP) using a compensation signal [FIG.18(A-1)]. This is possible if 50% of the overlapping is achieved only. And, a descending line of a last one of 8 short parts (i.e., triangular shapes) included in a short window needs not to have a steep slope as well. Therefore, it is able to maintain a relatively gentle slope (i.e., ‘slope A’) (e.g., width of N/8, where N is a frame length) at the same level of an ascending line, as shown inFIG.18(A-1) [like the case shown inFIG.17(A-1). Accordingly, it is able to use a short window of an identical shape irrespective of whether a following block corresponds to a first or second coding scheme. Meanwhile, if a current frame is a long_stop window and a following frame is an only-long window, a shape of a current long_stop window can be determined according to a previous frame corresponds to a window of a first coding scheme. This shall be explained in detail with reference to a fourth embodiment. Referring now toFIG.15, the window type determining part127-2, as mentioned in the foregoing description with reference to Table 1, determines a specific window to apply to a current block among of a plurality of windows, generates window type information indicating the determined specific window, and then delivers the generated window type information to the multiplexer. Afterwards, the multiplexer130generates at least one stream by multiplexing data (e.g., data of (N+1)thblock) encoded by a first coding scheme, data (e.g., data of Nthblock) encoded by a second coding scheme and the window type information together. Referring toFIG.16, a decoder200C according to a third embodiment includes a first decoding unit220-1and a second decoding unit220-2and is able to further include a demultiplexer210. The first decoding unit220-1includes a first scheme decoding part222-1and the second decoding unit20-2includes a second scheme decoding part226-2and a window shape determining part227-2. The demultiplexer210receives the coding scheme information (e.g., coding identification information and subcoding identification information) described with reference toFIG.1and then delivers data to the first decoding unit220-1or the second decoding unit220-2per block based on the received coding scheme information. Moreover, the demultiplexer210extracts the window type information and then delivers it to the second decoding unit220-2. In this case, the window type information can include information indicating one of the five kinds of window types corresponding to Table 1. Yet, as mentioned in the foregoing description, a window type of a current block can be limited due to a coding scheme or window type of a previous or following block instead of the availability o all of the five kinds of window types. Hence, the window type information may include the information indicating one of two or three kinds of types except unavailable window types instead of indicating one of total five kinds. This transition limitation shall be additionally explained together with a fourth embodiment later. The first scheme decoding part222-1is a component configured to perform a process reverse to that of the first scheme encoding part122-1. The first scheme decoding part222-1generates an output signal [e.g., an output signal of (N+1)thblock] by decoding data by a first coding scheme (e.g., ACELP, TCX, etc.). And, the second scheme decoding part226-2generates an output signal (e.g., an output signal of Nthblock) by decoding data by a second coding scheme (e.g., MDCT, etc.). The window shape determining part227-2identifies a window type of a current block based on the window type information and then determines a window type among the window types according to a coding scheme of a previous or following block. As mentioned in the foregoing description with reference toFIG.17, if a current window is a long_start window and a previous window is an only-long window, a window shape is determined by selecting either a steep long_start window or a gentle long_start window according to whether a following window corresponds to a first coding scheme or a second coding scheme. In the example described with reference toFIG.18, if a current block is a short window, a short window of the same shape is determined irrespective of a window type of a following block. Subsequently, the second scheme decoding part226-2applies the window in the shape determined by the window shape determining part227-2to the current block. In the following description, a fourth embodiment of the present invention is explained with reference toFIGS.19to23. A fourth embodiment of the present invention determines a window shape of a current block according to a coding scheme o a previous block, whereas the third embodiment determines a window shape of a current block according to a coding scheme of a following block. Thus, the fourth embodiment of the present invention is almost identical to the third embodiment of the present invention but just differs from the third embodiment in determining a window shape. And, the redundant description of the same parts shall be omitted from the following description. FIG.19is a block diagram of an encoder according to a fourth embodiment of the present invention, andFIG.20is a block diagram of a decoder according to a fourth embodiment of the present invention. Referring toFIG.19andFIG.20, components of an encoder100D and a decoder200D according to a fourth embodiment of the present invention are almost identical to the respective components of the former encoder and decoder100C and200C according to the third embodiment of the present invention shown inFIG.15andFIG.16but the fourth embodiment of the present invention differs from the third embodiment of the present invention in that Nthblock and (N+1)thblock are encoded by a first coding scheme and a second coding scheme, respectively. Therefore, the former description of the same parts explained with reference toFIG.15andFIG.16shall be substituted for the description of the fourth embodiment of the present invention. A window type determining part127-2determines a window of a current block in consideration of inter-block window transition. In particular, the window type determining part127-2determines a window type and shape of a current block [e.g., (N+1)thblock] according to whether a previous block (e.g., Nthblock) is coded by a first coding scheme. In particular, in case that a previous block is coded by a first coding scheme, one (e.g., a short window, a long_stop window and a stop_start window) of three types except an only-log window and a long_start window among 5 kinds of types shown in Table 1 is determined as a window type. Thus, without going through a transition window necessary for inter-coding scheme transition in the first coding scheme, it is able to directly move to a short window used in the second coding scheme or a transition window (i.e., a long_stop window or a stop_start window) used for transition between a short window and a long window. Such an inter-window path is shown inFIG.21.FIG.21is a table of inter-window paths or transitions. Referring toFIG.21, a row direction indicates a window corresponding to a previous block, while a column direction indicates a window corresponding to a current block. A part having a mark of circle or star indicates an available window transition path. For instance, in case that a previous block corresponds to an only-long window, an only-long window o a long_start window is available for a current block only. Referring to the star marks, in case that a previous block is a block corresponding to a first coding scheme (e.g., ACELP or TCX), as mentioned in the foregoing description, one of a short window, a long_stop window and a stop_start window can become a window corresponding to a second coding scheme. In particular, it is unnecessary to go through a window (e.g., a window corresponding to 1,152 samples) separately provided for a transition to a second coding scheme from a first coding scheme. This is because a crossing point coincides irrespective of a coding scheme, as mentioned in the foregoing description of the third embodiment. The following description is made with reference toFIG.22andFIG.23. FIG.22is a diagram for a case of transition to a long_stop window in a first coding scheme, which corresponds to the star mark ★ (1) shown inFIG.21.FIG.23is a diagram for a case of transition to a short window in a first coding scheme, which corresponds to the star mark ★ (2) shown inFIG.21. First of all,FIG.22(A) shows a crossing between a window corresponding to a rectangular coding scheme (e.g., ACELP) belonging to a first coding scheme and a long_stop window.FIG.22(B) shows a crossing between a window corresponding to a non-rectangular coding scheme (e.g., TCX) belonging to a first coding scheme and a long_stop window. In bothFIG.22(A) andFIG.22(B), it can be observed that a transition to a long_stop window from a block corresponding to a first coding scheme is possible. Since a rectangular window is shown inFIG.22(A), as mentioned in the foregoing description of the first or second embodiment, it is able to compensate a correction part (CP) and an aliasing part (AP), which are errors caused by the overlapping between a rectangular window and a non-rectangular window. Hence, 50% of the overlapping is enough and an ascending line of a long_stop window, as mentioned in the foregoing description with reference toFIG.14(A), can have a gentle slope (e.g., N/4 width). Accordingly, since an interwindow crossing point is located in a distance of N/2, a long-sop window corresponding to 1.024 samples or a length of 2N (where N indicates a frame) can be directly connected unlike the case that 100% of the overlapping is required. A third case (i.e., a transition to a stop_start window) is not shown inFIG.21. Like the case of the long_stop window or the short window, a stop_start window corresponds to 1,024 samples or has a length of 2N. In this case, it is able to make a direct transition to a stop_start window from a window corresponding to a first coding scheme. In case ofFIG.22(A), a slope of an ascending line of a long_stop window shall be described in addition to the second embodiment. In case that a current frame and a following frame are a long_stop window and an only-long window, respectively, a shape of a current long_stop window can be determined according to whether a previous frame corresponds to a window of a first coding scheme. This is as good as the former description with reference toFIG.14. In particular, like the case shown inFIG.14(A), in case that a previous frame corresponds to a first coding scheme [e.g., A coding scheme (i.e., a rectangular coding scheme) inFIG.14(A)], an ascending line of a current long_stop window has a first slope. Like the case shown inFIG.14(B), in case that a previous frame corresponds to a second coding scheme [e.g., C coding scheme (i.e., a non-rectangular coding scheme) inFIG.14(B)], an ascending line of a current long_stop window has a second slope. In this case, the first slope is gentler than the second slope. Referring now to the fourth embodiment, as mentioned in the above description with reference toFIG.21, in case that a previous block and a current block correspond to a first coding scheme and a second coding scheme, respectively, one of a short window, a long_stop window and a stop_start window is determined. The window type determining part127-2shown inFIG.19determines a window type of a current block by referring to coding schemes and window types of previous and following blocks. In doing so, the window type determining part127-2determines the window type of the current block according to the above-explained path limitation. Occasionally, the window type determining part12702determines a shape of a window of the current block as well. Afterwards, the window type determining part127-2delivers window type information indicating the determined window type to the multiplexer130. The second scheme coding part126-2encodes the current block according to the second coding scheme using the determined window type and shape. And, the multiplexer130generates at least one bitstream by multiplexing the data of the previous block, the data of the current block and the window type information of the current block together. Referring toFIG.20, components except the window shape determining part227-2have functions or roles similar to the former components shown inFIG.16and shall not described in detail in the following description. The window shape determining part227-2determines a specific window for a current block among a plurality of windows based on window type information. In doing so, it is able to determine one of a plurality of the windows in consideration of the transition limitation shown inFIG.21. This is explained in detail as follows. Referring toFIG.21, if a current block corresponds to a second coding scheme, the total number of kinds of available window types does not exceed3according to a window type of a previous block [e.g., 2, 3, 3, 2, 3 and 3 kinds from the top in order]. Hence, the window type information can be encoded with 2 bits. One example of the window type information is shown in Table 2. TABLE 2Window type informationwindow type infoonly-long window0long_start window1short window2long_stop window3stop_start window1 If window type information is set to 1, it indicates a long_start window and a stop_start window, i.e., two cases. Meanwhile, according to the transition limitation disclosed inFIG.21, in case that a previous block corresponds to a first coding scheme, a short window, a long_stop window and a stop_start window are available for a current block only. Hence, in the above two cases, the stop_start window is determined as a window of the current block except one case violating the limitation (i.e., a long_start window). The window shape determining part227-2determines a window shape such as a slope of an ascending line of the current block, a slope of a descending line of the current block and the like based on the coding scheme of the previous or following block, according to the above-determined window type. Thus, the fourth embodiment has been described so far. In the following description, another method for solving a problem of a window transition between a first coding scheme and a second coding scheme is explained with reference toFIG.24. FIG.24is a diagram for a case that a first coding scheme window is overlapped with a short window in a new shape. As mentioned in the foregoing description, when a block of a first coding scheme and a block of a second coding scheme are adjacent to each other, it is not possible for the two blocks to be overlapped with each other by 50%. Instead, since the two blocks should be overlapped with each other by 10%, a crossing point is located ahead of a point N/2. In order to solve this problem of mismatch, a transition block having a length of 1,152 should be provided between the block of the first coding scheme and the block of the second coding scheme. In particular, although it is necessary to go over into a short window belonging to the second coding scheme behind the block of the first coding scheme, a long window having a length of 1,152 should be gone through. Therefore, in this case, a long window is applied to a current block that should be processed with a short window and a short window is applied to a following block. Thus, since a current block supposed to be processed with a short window is processed with a long window due to a transition problem, a sound quality becomes distorted. In addition to the long window having the length of 1,152, in case that a short window, which includes total 9 short parts including a short part, having a length of 1,152 is used, as shown inFIG.24, the problem of the sound quality distortion is reduced. Yet, as mentioned in the foregoing description, the short window having the length of 1,152 shown inFIG.24is applicable only if a crossing point variation due to the 50% overlapping and a corresponding direct transition (cf. Third or fourth embodiment) are impossible. In the following description, a fifth embodiment of the present invention is explained with reference toFIG.25andFIG.26. According to the fifth embodiment of the present invention, in case that a current block (e.g., Nthblock) corresponds to a non-rectangular coding scheme (e.g., TCX) belonging to a first coding scheme, a window shape of a current block is determined according to whether a previous or following block [e.g., (N−1)thor (N+1)thblock] corresponds to a short window of a second coding scheme.FIG.25is a block diagram of an encoder according to a fifth embodiment of the present invention. Referring toFIG.25, since an encoder100E according to a fifth embodiment of the present invention is almost identical to the former encoder100C/100D of the third/fourth embodiment except a mode determining part123-2, the redundant description shall be omitted from the following description. First of all, when a current block corresponds to a first coding scheme, the mode determining part123-1identifies whether the current block corresponds to a rectangular coding scheme (e.g., ACELP) or a non-rectangular coding scheme (e.g., TCX). If the current block corresponds to the non-rectangular coding scheme, the mode determining part123determines one of modes1to3. As each of the modes1to3can correspond to a length for applying the non-rectangular scheme thereto, one of a single subframe, two contiguous subframes and four contiguous subframes (i.e., a single frame) can be determined. Moreover, the length can be determined into one of 256 samples, 512 samples and 1,024 samples, as shown inFIG.28. Thus, in case of a non-rectangular coding scheme, after a mode has been determined, a shape of a window of a current block is determined according to whether a window of a previous or following block is a short window. This process is explained in detail with reference toFIG.27andFIG.28as follows. FIG.27(A) is a diagram for a case that a window corresponding to a first coding scheme (e.g., TCX) is overlapped with a short window.FIG.27(A) is a diagram for a case that a window corresponding to a first coding scheme (e.g., TCX) is overlapped with or a long_stop window. In particular,FIG.27(A) shows a window corresponding to the mode1(cf. Shape1and Shape2inFIG.28) among windows of a first coding scheme andFIG.27(B) also shows a window corresponding to the mode1(cf. Shape1and Shape2inFIG.28) among windows of a first coding scheme. In more particular,FIG.27(A) is identical toFIG.23(B), whileFIG.27(B) is identical toFIG.22(B). In case that a window corresponding to a first coding scheme is overlapped with a long_stop window, as shown inFIG.27(B), the window corresponds to Shape1and has a descending line of which width is equal to a width (e.g., N/4) of an ascending line of the long_stop window. In particular, a first slope of a descending line of Shape1is matched to a slope of an ascending line of a non-short window (e.g., long_stop window) of a next frame. In this case, the meaning of ‘match’ can indicate that an absolute value of a slope is equal. On the contrary, in case that a window corresponding to a first coding scheme is overlapped with a short window, as shown inFIG.27(A), the window corresponds to Shape2and has a descending line of which width is equal to a width (e.g., N/5) of an ascending line of the short window. In particular, a second slope of a descending line of Shape2is matched to a slope of an ascending line of a short window of a next frame. Thus, a width of a descending or ascending line can vary according to a previous or following block is a short window. By equalizing the width, it is able to met the TDAC condition described with reference toFIG.8, Therefore, the sound quality distortion can be considerable reduced if the TDAC condition is met. FIG.28is a table of a window corresponding to a non-rectangular scheme among first coding schemes varying within Shape1to Shape4. Referring toFIG.28, according to whether a previous block and/or a following block corresponds to a short window, it can be observed that a shape of a window by a non-rectangular scheme belonging to a first coding scheme varies from Shape1to Shape4. In case that each of the previous block and the following block does not correspond to the short window, Shape1indicates a case that a width of an ascending line L and a width of a descending line R correspond to 256 samples (i.e., N/4) and 256 samples (i.e., N/4), respectively. In Shape2, since the following block corresponds to the short window only, a width of a descending line R is reduced into 128, a top line M is increased by 64, and a right zero part ZR is increased by 64. In shape3, since the previous block corresponds to the short window only, a width of an ascending line L is reduced into 128 only, a length of a left zero part ZL is increased by 64 greater than that of Shape 1, and a length of a top line M is increased by 64 greater than that of Shape1. Shape4indicates a case that each of the previous block and the following block corresponds to the short window. In Shape4, an ascending line L corresponds to 128 and a descending line R corresponds to 128, irrespective of a mode (e.g., mode1, mode2and mode3). For reference, windows corresponding to modes1to3in Shape1can be equal toFIG.10(A),FIG.10(B) andFIG.10(C), respectively. Moreover, the previous block corresponds to a last subframe of a previous frame at least and the following block can correspond to a first subframe of a following frame at least. Referring now toFIG.25, when a first coding scheme (particularly, a non-rectangular scheme) is applied, the mode determining part123-1determines one of a plurality of so modes including the modes1to3shown inFIG.28. Information corresponding to the determined mode can be encoded together with the above-mentioned subcoding identification information. For instance, if the subcoding identification information is set to 0, it is able to indicate A coding scheme (i.e., a rectangular coding scheme as a first coding scheme). If the subcoding identification information is set to 1 to 3, it is able to indicate the modes1to3of B coding scheme (i.e., a non-rectangular coding scheme as a first coding scheme), respectively. Once the mode is determined, the mode determining part123-1determines a shape of a window among Shapes1to4according to whether a previous block and/or a following block corresponds to a short window. And, the multiplexer123-1generates at least one bitstream by multiplexing the subcoding identification information, data of the current block and data of the previous or following block together. Referring toFIG.26, the window shape determining part223-2determines whether a current block is encoded by A coding scheme (i.e., a rectangular coding scheme) or B coding scheme (i.e., a non-rectangular coding scheme) belonging to a first coding scheme using the subcoding identification information. Moreover, in case of the B coding scheme, using the subcoding identification information, the window shape determining part223-2identifies one of the modes1to3. The window shape determining part223-2determines a shape of a window for the determined mode in a manner of identifying one of the Shapes1to4by determining whether a previous block and/or a following block corresponds to a short window. The rest of components shall not be described from the following description. An encoder100F and a decoder200F according to a sixth embodiment of the present invention are described with reference toFIGS.29to32as follows. According to the sixth embodiment of the present invention, it is determined whether to perform a long-term prediction (LTP) according to a coding scheme of a previous block. FIG.29is a block diagram of an encoder according to a sixth embodiment of the present invention andFIG.30is a block diagram of a decoder according to a sixth embodiment of the present invention. Referring toFIG.29andFIG.30, an encoder100F and a decoder200F according to a sixth embodiment of the present invention are similar to the former encoder100E and the decoder200E of the fifth embodiment of the present invention but differ in including a long prediction determining part121-1and a long prediction control part221-2. The long prediction determining part121-2determines whether to perform a long term prediction on a current block according to whether a first coding scheme (e.g., ACELP, TCX) or a second coding scheme (e.g., MDCT) is applied to a previous block. This is explained in detail with reference toFIG.31andFIG.32as follows. FIG.31shows examples of a coding scheme per block (frame or subframe).FIG.31(A) toFIG.31(B-3) show examples that a block having a first coding scheme (e.g., ACELP) applied to thereto appears behind a block having a second coding scheme (e.g., MDCT) applied thereto, respectively. Thus, in case that there is a change of a coding scheme [mode switching], efficiency of a long term prediction in the first coding scheme (e.g., ACELP) may be considerably lowered.FIG.32is a diagram for one examples of a signal waveform related to a long term prediction.FIG.32(A) shows an example that a second coding scheme (e.g., MDCT) and a rectangular coding scheme (e.g., ACELP) of a first coding scheme are applied to a previous block and a following block, respectively according to a characteristic of a signal.FIG.32(B) shows one example of a signal of a block corresponding to a first coding scheme and a waveform of a signal as a result of performing a long term prediction (LTP). For a block after a second coding scheme, an original signal exists in a previous memory instead of a residual signal as a result of performing a linear prediction. Since a long term prediction is based on waveform correlation, if the long term prediction is applied to the above case, it is inevitable that coding efficiency is considerably lowered. Referring toFIG.32(B), it can be observed that there is no big difference in waveform between a long term prediction result and an original signal. Therefore, in this case, it is able to save bits allocated to the long term prediction without applying the long term prediction that lowers coding efficiency considerably. Referring toFIG.31(B-1), a long term prediction (LTP) may not be unconditionally applied to a first appearing block (i.e., a first frame) after applying a second coding scheme (e.g., MDCT). Occasionally, referring toFIG.31(B-2), it is able to adaptively apply a long term prediction (LTP). For instance, only if coding efficiency is good in applying a long term prediction (LTP), the long term prediction (LTP) is performed. Thus, in case that the long term prediction is conditionally performed, it is able to set a long term flag (LTP flag) indicating whether a long term prediction (LTP) has been performed. Moreover, referring toFIG.31(B-3), a long term prediction is not performed on blocks (e.g., 2ndto fourth blocks) unconditionally as well as a first appearing block or may not be performed thereon conditionally. Thus, in case that a long term prediction is not used conditionally, it is able to set a long term flag for a random block having a small effect of the long term prediction instead of setting a long term flag on a boundary with a block corresponding to a second coding scheme only. For instance, a long term prediction may not be performed in a voiceless part, a mute part or other music parts, in which a pitch does not exist, despite coding by a first coding scheme. Referring now toFIG.29, as mentioned in the foregoing description, the long prediction determining part121-1determines by a block unit whether to perform a long term prediction, based on a coding scheme of a previous block. If the long term prediction is not performed conditionally, the long term prediction determining part121-1delivers the long term flag (LTP flag) to the multiplexer130. In case of a block corresponding to a first coding scheme, if a long term prediction (LTP) is not performed, the first scheme coding part122-1generates new information amounting to bits that are saved in case of not performing the long term prediction. Examples of the new information are described as follows. 1) It is able to utilize an excitation codebook. In particular, more code books are designed rather than previous codebooks or a dedicated codebook in a size of surplus bits. In case of using the dedicated codebook, an excitation signal is generated by a combination of an excitation by an original codebook and an excitation by an additional codebook. In case of the dedicated codebook, it is possible to use a codebook configured to encode a pitch component well like the functionality of a long term prediction. 2) It is able to enhance quantization performance of LPC coefficient by allocating additional bits to a linear prediction coding [LPC]. 3) It is able to allocate bits to code a compensation signal (i.e., a signal for compensating correction and aliasing parts generated from the overlapping between a non-rectangular window of a second coding scheme and a rectangular window of a first coding scheme) of the first or second embodiment. 4) Transmission amounting to saved bits is not performed. In particular, since a used bit amount is variable as many as a frame in case of audio coding, the saved bits are utilized in other frames. Meanwhile, the first scheme coding part122-1delivers additional bits to the multiplexer130by encoding the new information for a block on which the long term prediction is not performed. Finally, the multiplexer130generates at least one bitstream by multiplexing the long term flag (LTP flag), the additional bits corresponding to the new information and data corresponding to each block together. Referring toFIG.30, in case that a long term prediction is not performed conditionally, the demultiplexer210extracts the long term flag (LTP flag) and then delivers it to the long term prediction control part221-2. If the long term prediction is not performed unconditionally in consideration of a coding scheme of a previous block, the long term prediction control part221-2determines whether the previous block corresponds to a second coding scheme. If the long term prediction is not performed conditionally despite that the coding scheme of the previous block corresponds to the second coding scheme, the long term prediction control part221-2determines whether to perform the long term prediction based on the long term flag (LTP flag) delivered from the multiplexer130. If so, the first scheme decoding part222-1performs the long term prediction on a block becoming a target of the long term prediction according to the determination made by the long term prediction control part222-1. In case that additional bits are transmitted, the first scheme decoding part222-1extracts the new information corresponding to the additional bits and then performs decoding of the corresponding block based on the extracted new information. In the following description, applications of the encoder and decoder according to the present invention described with reference toFIG.1andFIG.2are explained. FIG.33is a diagram for an example of an audio signal encoding apparatus to which an encoder according to an embodiment of the present invention is applied, andFIG.34is a diagram for an example of an audio signal decoding apparatus to which a decoder according to an embodiment of the present invention is applied. Referring toFIG.33, an audio signal encoding apparatus300includes an encoder100according to the present invention and further includes a plural channel encoder310, a band extension coding unit320and a multiplexer330. In this case, the multiplexer300can include the former multiplexer130described with reference toFIG.1. The plural channel encoder310receives a plurality of channel signal (e.g., at least two channel signals) (hereinafter named a multi-channel signal) and then downmixes a plurality of the received channel signal to generate a mono or stereo downmix signal. And, the plural channel encoder310generates spatial information required for upmixing the downmix signal into a multi-channel signal. In this case, the spatial information can include channel level difference information, inter-channel correlation information, a channel prediction coefficient, downmix gain information and the like. Optionally, in case that the audio signal encoding apparatus300receives a mono signal, the plural channel encoder310does not downmix the received mono signal but the mono signal bypasses the plural channel encoder310. The band extension encoder320is able to generate spectral data corresponding to a low frequency band and extension information for high frequency band extension by applying a band extension scheme to the downmix signal outputted from the plural channel encoder310. In particular, spectral data of a partial band of the downmix signal is excluded and the band extension information for reconstructing the excluded data can be generated. The signal generated by the band extension coding unit320is inputted to an A coding unit120A, a B coding unit120B or a C coding unit120C according to coding scheme information generated by a signal classifier (not shown in the drawing) (e.g., the former signal classifier110shown inFIG.1). The A to C coding units10A to120C are identical to the former coding units described with reference toFIG.1and the redundant description shall be omitted from the following description. Additional contents are described as follows. First of all, in case that a specific frame or segment of the downmix signal has a dominant speech characteristic, the A coding unit120A encodes the downmix signal by the A coding scheme (i.e., a rectangular coding scheme belonging to a first coding scheme). In this case, the A coding scheme can follow AMR-WB (adaptive multi-rate wideband) standard, by which the present invention is non-limited. Meanwhile, the A coding unit120A is able to further use a linear prediction coding (LPC) scheme. In case that a harmonic signal has high redundancy on a time axis, it can be modeled by linear prediction for predicting a current signal from a past signal. In this case, if the linear prediction coding scheme is adopted, coding efficiency can be raised. Meanwhile, the A coding unit120A can include a time domain encoder. Secondly, in case that audio and speech characteristics coexist in a specific frame or segment of the downmix signal, the B coding unit120B encodes the downmix signal by the B coding scheme (i.e., a non-rectangular coding scheme belonging to the first coding scheme). In this case, the B coding scheme may correspond to TCX (transform coded excitation), by which the present invention is non-limited. In this case, the TCX can include a scheme for performing frequency transform on an excitation signal obtained from performing linear prediction (LPC). In this case, the frequency transform can include MDCT (modified discrete cosine transform). Thirdly, in case that a specific frame or segment of the downmix signal has a dominant audio characteristic, the C coding unit120C encodes the downmix signal by the C coding scheme (i.e., a non-rectangular coding scheme belonging to a second coding scheme). In this case, the C coding scheme can follow AAC (advanced audio coding) standard or HEAAC (high efficiency advanced audio coding) standard, by which the present invention is non-limited. Meanwhile, the C coding unit120C can include an MDCT (modified discrete transform) encoder. And, the multiplexer330generates at least one bitstream by multiplexing spatial information, band extension information and the signal encoded by each of the A to C coding units120A to120C together. Referring toFIG.34, an audio signal decoding apparatus400includes a demultiplexer410, A to C decoding units220A to220C, a band extension decoding unit420and a plural channel decoder430. The demultiplexer410extracts the data encoded by the A to C coding schemes, the band extension information, the spatial information and the like from an audio signal bitstream. The A to C decoding units220A to220C correspond to the former A to C encoding units120A to120C to perform reverse processes thereof, respectively and their details shall be omitted from the following description. The band extension decoding unit420reconstructs a high frequency band signal based on the band extension information by performing a band extension decoding scheme on an output signal of each of the A to C decoding units220A to220C. In case that the decoded audio signal is a downmix signal, the plural channel decoder430generates an output channel signal of a multichannel signal stereo signal included) using the spatial information. The audio signal processing apparatus according to the present invention is available for various products to use. Theses products can be mainly grouped into a stand alone group and a portable group. A TV, a monitor, a settop box and the like can be included in the stand alone group. And, a PMP, a mobile phone, a navigation system and the like can be included in the portable group. FIG.35shows relations between products, in which an audio signal processing apparatus according to an embodiment of the present invention is implemented. Referring toFIG.35, a wire/wireless communication unit510receives a bitstream via wire/wireless communication system. In particular, the wire/wireless communication unit510can include at least one of a wire communication unit510A, an infrared unit510B, a Bluetooth unit510C and a wireless LAN unit510D. A user authenticating unit520receives an input of user information and then performs user authentication. The user authenticating unit520can include at least one of a fingerprint recognizing unit520A, an iris recognizing unit520B, a face recognizing unit520C and a voice recognizing unit520D. The fingerprint recognizing unit520A, the iris recognizing unit520B, the face recognizing unit520C and the speech recognizing unit520D receive fingerprint information, iris information, face contour information and voice information and then convert them into user informations, respectively. Whether each of the user informations matches pre-registered user data is determined to perform the user authentication. An input unit530is an input device enabling a user to input various kinds of commands and can include at least one of a keypad unit530A, a touchpad unit530B and a remote controller unit530C, by which the present invention is non-limited. A signal coding unit540performs encoding or decoding on an audio signal and/or a video signal, which is received via the wire/wireless communication unit510, and then outputs an audio signal in time domain. The signal coding unit540includes an audio signal processing apparatus545. As mentioned in the foregoing description, the audio signal processing apparatus545corresponds to the above-described encoder100(first to sixth embodiments included) or the decoder200(first to sixth embodiments included). Thus, the audio signal processing apparatus545and the signal coding unit including the same can be implemented by at least one or more processors. A control unit550receives input signals from input devices and controls all processes of the signal decoding unit540and an output unit560. In particular, the output unit560is an element configured to output an output signal generated by the signal decoding unit540and the like and can include a speaker unit560A and a display unit560B. If the output signal is an audio signal, it is outputted to a speaker. If the output signal is a video signal, it is outputted via a display. FIG.36is a diagram for relations of products provided with an audio signal processing apparatus according to an embodiment of the present invention.FIG.36shows the relation between a terminal and server corresponding to the products shown inFIG.35. Referring toFIG.36(A), it can be observed that a first terminal500.1and a second terminal500.2can exchange data or bitstreams bi-directionally with each other via the wire/wireless communication units. Referring toFIG.36(B), it can be observed that a server600and a first terminal500.1can perform wire/wireless communication with each other. An audio signal processing method according to the present invention can be implemented into a computer-executable program and can be stored in a computer-readable recording medium. And, multimedia data having a data structure of the present invention can be stored in the computer-readable recording medium. The computer-readable media include all kinds of recording devices in which data readable by a computer system are stored. The computer-readable media include ROM, RAM, CD-ROM, magnetic tapes, floppy discs, optical data storage devices, and the like for example and also include carrier-wave type implementations (e.g., transmission via Internet). And, a bitstream generated by the above mentioned encoding method can be stored in the computer-readable recording medium or can be transmitted via wire/wireless communication network. INDUSTRIAL APPLICABILITY Accordingly, the present invention is applicable to processing and outputting an audio signal. While the present invention has been described and illustrated herein with reference to the preferred embodiments thereof, it will be apparent to those skilled in the art that various modifications and variations can be made therein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of the appended claims and their equivalents. | 96,513 |
RE49814 | DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS In the following description, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of various exemplary embodiments. It is apparent, however, that various exemplary embodiments may be practiced without these specific details or with one or more equivalent arrangements. In other instances, well-known structures and devices are shown in block diagram form in order to avoid unnecessarily obscuring various exemplary embodiments. In the accompanying figures, the size and relative sizes of layers, films, panels, regions, etc., may be exaggerated for clarity and descriptive purposes. Also, like reference numerals denote like elements. When an element or layer is referred to as being “on,” “connected to,” or “coupled to” another element or layer, it may be directly on, connected to, or coupled to the other element or layer or intervening elements or layers may be present. When, however, an element or layer is referred to as being “directly on,” “directly connected to,” or “directly coupled to” another element or layer, there are no intervening elements or layers present. For the purposes of this disclosure, “at least one of X, Y, and Z” and “at least one selected from the group consisting of X, Y, and Z” may be construed as X only, Y only, Z only, or any combination of two or more of X, Y, and Z, such as, for instance, XYZ, XYY, YZ, and ZZ. Like numbers refer to like elements throughout. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. Although the terms first, second, etc. may be used herein to describe various elements, components, regions, layers, and/or sections, these elements, components, regions, layers, and/or sections should not be limited by these terms. These terms are used to distinguish one element, component, region, layer, and/or section from another element, component, region, layer, and/or section. Thus, a first element, component, region, layer, and/or section discussed below could be termed a second element, component, region, layer, and/or section without departing from the teachings of the present disclosure. Spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper,” and the like, may be used herein for descriptive purposes, and, thereby, to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the drawings. Spatially relative terms are intended to encompass different orientations of an apparatus in use, operation, and/or manufacture in addition to the orientation depicted in the drawings. For example, if the apparatus in the drawings is turned over, elements described as “below” or “beneath” other elements or features would then be oriented “above” the other elements or features. Thus, the exemplary term “below” can encompass both an orientation of above and below. Furthermore, the apparatus may be otherwise oriented (e.g., rotated 90 degrees or at other orientations), and, as such, the spatially relative descriptors used herein interpreted accordingly. The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting. As used herein, the singular forms, “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Moreover, the terms “comprises,” “comprising,” “includes,” and/or “including,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, components, and/or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Various exemplary embodiments are described herein with reference to sectional illustrations that are schematic illustrations of idealized exemplary embodiments and/or intermediate structures. As such, variations from the shapes of the illustrations as a result, for example, of manufacturing techniques and/or tolerances, are to be expected. Thus, exemplary embodiments disclosed herein should not be construed as limited to the particular illustrated shapes of regions, but are to include deviations in shapes that result from, for instance, manufacturing. The regions illustrated in the drawings are schematic in nature and their shapes are not intended to illustrate the actual shape of a region of a device and are not intended to be limiting. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is a part. Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense, unless expressly so defined herein. A transistor display panel according to an exemplary embodiment will be described with reference toFIG.1andFIG.2. FIG.1is a top plan view of a transistor display panel according to an exemplary embodiment,FIG.2Ais a cross-sectional view taken along line II-II′ ofFIG.1, andFIG.2Bis a cross-sectional view taken along line III-III′ ofFIG.1. Referring toFIG.1,FIG.2A, andFIG.2B, a transistor display panel according to an exemplary embodiment includes a substrate110, and a plurality of transistor Qs and Qd positioned on the substrate110 The transistors Qs and Qd may be transistors of the display device. For example, when the display device is an organic light emitting diode display, the transistors may be a driving transistor Qd and a switching transistor Qs positioned in a pixel area. In the drawings, a first direction D1and a second direction D2are perpendicular to each other, and are parallel to a horizontal section of the substrate110. A structure shown when observing the surface formed by the first direction D1and the second direction D2is referred to as a plane structure. Further, a third direction D3is perpendicular to the first and second directions D1and D2and is parallel to a vertical section of the substrate110. The third direction D3may be mainly represented in the cross-sectional structure, and is referred to as a cross-sectional direction. In the cross-sectional structure, if a constituent element is positioned on any other constituent element, it means that two constituent elements are arranged in the third direction D3, and other constituent elements may be positioned between the two constituent elements. Referring toFIG.2A, the driving transistor Qd includes a driving voltage line172and a first electrode124positioned on the substrate110, a first insulating layer111covering the driving voltage line172and the first electrode124, a semiconductor130positioned on the first insulating layer111, a second insulation layer140positioned on the semiconductor130, and an electrode layer150positioned on the second insulating layer140. The substrate110may be a substrate including an organic material, an inorganic material, glass, or a metal such as stainless steel. On the substrate110, a driving voltage line172for transferring a driving signal and a first electrode124are spaced apart from each other by a predetermined interval. In this case, the first electrode124is positioned to overlap the semiconductor130described below. Accordingly, the first electrode124can serve as a light blocking film. That is, the first electrode124prevents external light from reaching the semiconductor130, thereby preventing deterioration of the characteristics of the semiconductor130and controlling a leakage current of the transistor. Further, the driving voltage line172and the first electrode124may be formed with a conductive material such as a metal, and may be formed as a single layer or as multiple layers (multilayer). The driving voltage line172and the first electrode124are positioned at the same layer. As described, according to this disclosure, since the driving voltage line172and the first electrode124are positioned at the same layer, they can be simultaneously formed by the same process, so that the manufacturing process can be simplified. Next, the first insulating layer111covering the driving voltage line172and the first electrode124is positioned on the substrate110. The first insulation layer111functions to protect the semiconductor130and improve the characteristics of the semiconductor130by preventing permeation of an impurity to the semiconductor130from the substrate110. Accordingly, the first insulating layer111may be referred to as a “buffer layer”. In this case, the first insulating layer111, for example, may have a thickness of about 3000 Å to about 5000 Å. The first insulating layer111, for example, may include an inorganic insulation material such as a silicon oxide (SiOx), a silicon nitride (SiNx), aluminum oxide (Al2O3), hafnium oxide (HfO3), yttrium oxide (Y2O3), and the like. In addition, the first insulation layer111may be formed as a single layer or as multiple layers (multilayer). In further detail, when the first insulation layer111is formed as a double layer, a lower layer may include a silicon nitride (SiNx) and an upper layer may include a silicon oxide (SiOx). The semiconductor130overlapping the first electrode124is positioned on the first insulating layer111. The semiconductor130includes a channel131overlapping a gate electrode151, and a source region133and a drain region135positioned at respective sides of the channel131. When a gate-on voltage is applied to the gate electrode124, the source region133and the drain region135may be determined depending on a direction of carriers that flow through the channel131, and the carriers flow to the drain electrode135from the source region133. Thus, when the transistor TR operates, electrons flow to the drain region135from the source region133in an n-type transistor, and holes flow to the drain region135from the source region133in a p-type transistor. In this case, the source region133may be electrically connected with the pixel electrode191and the first electrode124of the display device through a source electrode153. Further, the drain region135may be electrically connected with the driving voltage line172through a drain electrode155. The channel131, the source region133, and the drain region135may include the same material. For example, the channel131, the source region133, and the drain region135may respectively include the same oxide. Such a metallic oxide may exemplarily include an oxide of a metal such as zinc (Zn), indium (In), gallium (Ga), tin (Sn), titanium (Ti), and the like, or a combination of a metal such as zinc (Zn), indium (In), gallium (Ga), tin (Sn), titanium (Ti), and the like, and an oxide thereof. In further detail, the oxide may include at least one of zinc oxide (ZnO), zinc-tin oxide (ZTO), zinc-indium oxide (ZIO), indium oxide (InO), titanium oxide (TiO), indium-gallium-zinc oxide (IGZO), and indium-zinc-tin oxide (IZTO). Further, the channel131, the source region133, and the drain region135may include a semiconductor material, such as polysilicon. A carrier concentration of the source region133and the drain region135, which are conductors, is different from that of the channel131. For example, when the carrier concentration of the channel131is, for example, 1018/cm3or less, the carrier concentration of the source region133and the drain region135may be 1018/cm3or more. In addition, a gradient where the carrier concentration is gradually changed may be formed at a boundary between the source region133and the channel131or a boundary between the drain region135and the channel131. Further, the source region133and the drain region135may include a material that is reduced from an oxide semiconductor included in the semiconductor130. For example, the source region133and the drain region135may further include at least one of fluorine (F), hydrogen (H), and sulfur (S) in addition to the oxide semiconductor included in the semiconductor130. At least one of fluorine (F), hydrogen (H), and sulfur (S) included in the source region133and the drain region135may have a concentration of 1015/cm3or more. A gradient where a concentration of at least one of fluorine (F), hydrogen (H), and sulfur (S) is gradually changed may exist at a boundary between the source region133and the channel131or a boundary between the drain region135and the channel131. The source region133and the drain region135may be formed by making the oxide semiconductor that forms the semiconductor130conductive using plasma treatment and the like. For example, the oxide semiconductor may be made conductive by plasma-treating the oxide semiconductor under a hydrogen gas atmosphere and dispersing hydrogen into the oxide semiconductor such that the source region133and the drain region135can be formed. Next, the second insulating layer140is positioned on the semiconductor130. The second insulation layer140may be a single layer or multiple layers (multilayer). When the second insulation layer140is formed as a single layer, the second insulation layer140may include an insulation material such as a silicon oxide (SiOx), a silicon nitride (SiNx), a silicon oxynitride (SiON), aluminum oxide (Al2O3), hafnium oxide (HfO3), yttrium oxide (Y2O3), and the like. Further, when the second insulation layer140is formed as a multilayer, a lower layer that contacts the semiconductor130may include an insulation oxide such as a silicon oxide (SiOx), aluminum oxide (Al2O3), hafnium oxide (HfO3), yttrium oxide (Y2O3), and the like to improve an interface property of the semiconductor130and prevent permeation of an impurity into the semiconductor130, and at least one layer that is formed above the semiconductor130may include various insulation materials such as a silicon oxide (SiOx) and a silicon nitride (SiNx). The second insulating layer140may be formed to have a thickness less than the first insulating layer111. That is, the second insulating layer140, for example, may have a thickness of about 500 Å to about 1500 Å. Further, in this exemplary embodiment, the second insulating layer140may be formed on the entire surface of the substrate110, and the second insulating layer140may be referred to as a “gate insulation layer”. If the second insulating layer140is formed only on the portion corresponding to the gate electrode151, the transistor may be damaged due to a short circuit occurring between the gate electrode151and the semiconductor130. Accordingly, the second insulating layer140may be formed on the entire surface of the substrate110. The first insulating layer111and the second insulating layer140may include a first contact hole163connecting the first electrode124and the source electrode153, and a second contact hole165connecting the driving voltage line172and the drain electrode155. Further, the second insulating layer140may include a third contact hole143connecting the source region133and the source electrode153, and a fourth contact hole145connecting the drain region135and the drain electrode155. Next, the electrode layer150including the drain electrode155, the gate electrode151, and the source electrode153is positioned on the second insulating layer140. The drain electrode155, the gate electrode151, and the source electrode153are spaced apart from each other at the same layer, and the drain electrode155and the source electrode153are positioned at opposite sides of the gate electrode151. As described above, according to this exemplary embodiment, since the drain electrode155, the gate electrode151, and the source electrode153are positioned at the same layer, no additional insulating film formation and contact hole formation steps are required to form them, and the number of process steps and the number of masks required can be reduced. In addition, in comparison with the case where the drain electrode155, the source electrode153, and the gate electrode151are positioned at different layers, it is possible to prevent damage of the semiconductor due to etching since the etching depth in the step of forming the contact hole for electrically connecting the drain electrode155and the source electrode153to the semiconductor can be significantly reduced. In the transistor display panel according to this exemplary embodiment, the first electrode124and the semiconductor130are electrically connected through the source electrode153. In further detail, the first electrode124is connected with the source electrode153through the first contact hole163, and the source electrode153is connected with the source region133through the third contact hole143. Further, the driving voltage line172is connected with the drain electrode155through the second contact hole165, and the drain electrode155is connected with the drain region135through the fourth contact hole145. The first electrode124may receive a bias rather than being electrically connected to the source region133. Thus, when a fixed bias is applied to the semiconductor130, the output saturation characteristic of the transistor can be improved, and for example, the output current of the transistor can be less affected by a source voltage or a drain voltage in the saturation area of the transistor. Further, the first electrode124may be in an electrically floated state rather than being electrically connected to the source region133or receiving a bias. In addition, the drain electrode155, the gate electrode151, and the source electrode153may be formed as a single conductive layer, or may be formed as multiple layers (multilayer) that includes at least two conductive layers, each made of a different material. In this case, the semiconductor130overlaps the gate electrode151, interposing the second insulation layer140therebetween. Accordingly, the second insulation layer140may cover most of the semiconductor130. Further, the channel region131may overlap most of the gate electrode151in the third direction D3, and the source region133and the drain region135may not overlap most of the gate electrode151in the third direction D3. Next, an interlayer insulation layer160is positioned on the electrode layer150. The interlayer insulation layer160may be a single layer or a multilayer. When the interlayer insulation layer160is formed as a single layer, the interlayer insulation layer160may include an inorganic insulation material, such as a silicon oxide (SiOx), a silicon nitride (SiNx), a silicon oxynitride (SiON), a silicon oxyfluoride (SiOF), and the like. Specifically, the interlayer insulation layer160may include at least one of a silicon nitride (SiNx) and a silicon oxynitride (SiON) to reduce resistance of the source region133and the drain region135by injecting hydrogen (H) therein. When the interlayer insulation layer160is formed as a multilayer, the lowest layer may include at least one of a silicon nitride (SiNx) and a silicon oxynitride (SiON) that are capable of introducing hydrogen (H) into the source region133and the drain region135, and a middle layer or an upper layer that includes, for example, a silicon oxide (SiOx), may be formed on the lowest layer. In addition, when the interlayer insulation layer160is formed as a multilayer, another layer that includes a material such as a silicon nitride (SiNx) or a silicon oxynitride (SiON) may be further formed on the middle layer that includes a silicon oxide (SiOx). Next, a passivation layer180may be positioned on the interlayer insulation layer160. The passivation layer180may include at least one of an inorganic insulation material and an organic insulation material, and may be formed as a single layer or multiple layers (multilayer). In this case, the passivation layer180may have a substantially flat upper surface. The interlayer insulation layer160and the passivation layer180include a pixel contact hole181exposing the source electrode153. Further, a pixel electrode191is positioned on the passivation layer180. The pixel electrode191may include a transparent conductive material, such as indium tin oxide (ITO), indium zinc oxide (IZO), and the like. In this case, the pixel electrode191is electrically connected with the source electrode173through the pixel contact hole181, and thus, may receive, for example, a data voltage. Consequently, in this exemplary embodiment, each of the pixel electrode191and first electrode124is electrically connected with the source region133through the source electrode153. Next, referring toFIG.2B, the switching transistor Qs includes a data line171positioned on the substrate110, a first insulating layer111covering the data line171, a semiconductor1130positioned on the first insulating layer111, a second insulation layer140covering the semiconductor1130, and a drain electrode1155, a gate electrode1151, and a source electrode1153positioned on the second insulation layer140. The data line171transmits the data signal, and may be positioned at the same layer as the driving voltage line172and the first electrode124of the driving transistor Qd, as described above. Accordingly, the data line171may include the same material as the driving voltage line172and the first electrode124. The drain electrode1155is connected with the data line171through a contact hole1165, a drain region1135is connected with the drain electrode1155through a contact hole1145, and a source region1133is connected with the source electrode1153through a contact hole1143. A description regarding the substrate110, the first insulating layer111, and the second insulation layer140is the same as the description of the above-described constituent elements, and thus, is omitted. The semiconductor1130, the drain electrode1155, the gate electrode1151, and the source electrode1153of the switching transistor Qs may have the same structure and material as the above-described semiconductor130, drain electrode155, gate electrode151, and source electrode153of the driving transistor Qd, and thus, the description thereof is omitted. Referring toFIG.2AandFIG.1, the gate electrode151of the driving transistor Qd is connected with the source electrode1153of the switching transistor Qs, and thus, may be supplied with a gate signal. Further, the gate electrode1151of the switching transistor Qs is electrically connected with a gate line121, and thus, may be supplied with the gate signal. In this case, the gate line121extends in a direction crossing the data line171. According to an exemplary embodiment, the first electrode124of the transistor is electrically connected with the source region133via the source electrode153. Accordingly, a source voltage, which is a voltage of the source region133, may be applied to the first electrode124. As described, when the source voltage is applied to the first electrode124, a current change rate (i.e., a current slope) in a saturation area is decreased in a voltage-current characteristic graph so that an output saturation characteristic of the transistor can be improved. When the transistor has a superior output saturation characteristic, the transistor TR becomes more insensitive to undesirable voltage fluctuations of the source region133caused by deterioration of various connected elements, such as an emission element connected to the transistor, for example, such that an output current of the transistor TR can be less affected. Thus, the transistor according to the present exemplary embodiment can be advantageous as a driving transistor of a display device such as an organic light emission display, and may also be advantageous for forming an external current sensing circuit. In addition, as described above, because the second insulation layer140is positioned on the entire surface of the substrate110, it is possible to prevent the mobility from being reduced due to an electric field induced between the gate electrode151and the semiconductor130, thereby improving the stability of the transistor. Although in this exemplary embodiment the driving transistor Qd has the cross-sectional structure shown inFIG.2Aand the switching transistor Qs has the cross-sectional structure ofFIG.2B, the cross-sectional structures of the transistors are not limited thereto, and the switching transistor Qs may also have the cross-sectional structure including the first electrode124, as shownFIG.2A. While the above-describedFIG.2AandFIG.2Bare cross-sectional views of a portion of the transistor display panel shown inFIG.1, a plane structure of the transistor display panel having a cross-sectional structure like inFIG.2AandFIG.2Bis not limited to that ofFIG.1.FIG.1shows a part of the transistor display panel of an organic light emitting diode display including a driving transistor Qd and a switching transistor Qs. However, an exemplary embodiment is not limited to the organic light emitting diode display, and may be applied to various display devices such as a liquid crystal display. Next, a method for manufacturing of the transistor display panel having the cross-sectional structure shown inFIG.2Aaccording to an exemplary embodiment will be described with reference toFIG.3toFIG.8. FIG.3toFIG.8are cross-sectional views showing a method for manufacturing of a transistor display panel according to an exemplary embodiment. First, referring toFIG.3, a first conductive material, such as a metal, is deposited on the substrate110, and then patterned so that the driving voltage line172and the first electrode124are formed. In this case, the first conductive material may be deposited by sputtering and the like, and patterned by using a photosensitive material such as a photoresist and a mask. When the transistor is a transistor for a liquid crystal display (LCD), a first capacitor electrode128a and the data line171of the switching transistor Qs, which are integrally connected to the first electrode124of the driving transistor Qd, may be simultaneously formed by this process. Next, referring toFIG.4, an inorganic material is deposited on the substrate110having the driving voltage line172and the first electrode124to form the first insulating layer111, and then the semiconductor130is formed thereon. In this case, as the inorganic material, for example, a silicon oxide (SiOx), a silicon nitride (SiNx), aluminum oxide (Al2O3), hafnium oxide (HfO3), yttrium oxide (Y2O3), and the like may be used, and the first insulating layer111may be deposited by chemical vapor deposition (CVD). Further, a semiconductor material, such as zinc oxide (ZnO), zinc-tin oxide (ZTO), zinc-indium oxide (ZIO), indium oxide (InO), titanium oxide (TiO), indium-gallium-zinc oxide (IGZO), indium-zinc-tin oxide (IZTO), and the like, is deposited on the first insulation layer111using chemical vapor deposition and then patterned using a second mask such that the semiconductor130is formed. Next, referring toFIG.5, inorganic insulating material is deposited on the substrate110having the semiconductor130to form the second insulating layer140. In this case, as the inorganic material, for example, the above-described insulating material may be used, and the second insulating layer140may be deposited by chemical vapor deposition (CVD). Referring toFIG.6, the first insulating layer111and the second insulation layer140are then etched to form the first contact hole163and the second contact hole165, the second insulation layer140is etched to form the third contact hole143and the fourth contact hole145, and then the source region133, the drain region135, and the channel131may be formed. In this case, the first to fourth contact holes163,165,143, and145may be simultaneously formed, or the first contact hole163and the second contact hole165may be formed first after the first insulating layer111is formed, and then the second insulating layer140may be formed thereon and the third contact hole143and the fourth contact hole145may be formed, but the inventive concept is not limited thereto. Further, the first to fourth contact holes163,165,143, and145may be formed by at least one of wet etching and dry etching. In this case, according to this exemplary embodiment, the source region133and the drain region135may be connected by etching only the third contact hole143and fourth contact hole145, and thus, excessive etching of the semiconductor130can be prevented. Accordingly, operating characteristics of the transistor can be improved. Hydrogen is dispersed to the semiconductor130through the third contact hole143and the fourth contact hole145by performing a plasma treatment in a hydrogen gas atmosphere to make the source region133and the drain region135conductive, and an area not being conductive by being blocked by the upper electrode125may be formed as the channel131. Next, referring toFIG.7, the second conductive material is deposited on the second insulating layer140, and then patterned so that the electrode layer150including the drain electrode155, the gate electrode151, and the source electrode153is formed. As the second conductive material, for example, a metal such as copper (Cu), aluminum (Al), silver (Ag), molybdenum (Mo), chromium (Cr), tantalum (Ta), titanium (Ti), and the like, or a metal alloy thereof, may be used, but the inventive concept is not limited thereto. In this case, the second conductive material may be deposited by sputtering. The second conductive material may be patterned by depositing a photosensitive material on the second conductive material and dry etching or dry etching with a mask. As described, according to the method for manufacturing of the transistor display panel of this disclosure, the drain electrode155, the gate electrode151, and the source electrode153may be simultaneously formed by a single process. When the transistor is a driving transistor Qd for a liquid crystal display (LCD), a second capacitor electrode128b, which is integrally connected to the gate electrode151, may be simultaneously formed by this process. Next, referring toFIG.8, the interlayer insulation layer160and the passivation layer180covering the electrode layer150are sequentially formed by chemical vapor deposition and the like. In this case, as a material for the interlayer insulation layer160, for example, an inorganic insulating material such as a silicon oxide (SiOx), a silicon nitride (SiNx), a silicon oxynitride (SiON), and a silicon oxyfluoride (SiOF) may be used, and as a material for the passivation layer180, for example, an organic insulating material such as a polyacrylate resin, an epoxy resin, a phenolic resin, a polyamide resin, a polyimide resin, an unsaturated polyester resin, a polyphenylene ether resin, a polyphenylene sulfide resin, or benzocyclobutene (BCB) may be used, but the inventive concept is not limited thereto. Subsequently, the pixel contact hole181is formed by etching the interlayer insulation layer160and the passivation layer180, and the pixel electrode191is formed on the pixel contact hole181, such that the transistor display panel having the cross-sectional structure as shownFIG.2Amay be formed. As described above, according to the method for manufacturing of the transistor display panel of this exemplary embodiment, since the drain electrode155, the gate electrode151, and the source electrode153are simultaneously formed, the forming step and the etching step for additional forming the insulating film having a thickness of about 5000 Å or more can be omitted, as compared with the conventional method in which the drain electrode155and the source electrode153are formed in layers different from that of the gate electrode151. Accordingly, according to the method for manufacturing of the transistor display panel of this exemplary embodiment, the manufacturing process can be simplified and the number of masks required can be reduced, so that the productivity can be effectively improved. Next, display devices including the transistor display panel according to an exemplary embodiment of this disclosure will be described with reference toFIG.9toFIG.11. FIG.9is an equivalent circuit diagram of one pixel of a display device according to an exemplary embodiment, andFIG.10is a cross-sectional view of a display device according to an exemplary embodiment. In this case, the display device is an organic light emitting diode display, and may include the transistor according to the above-described exemplary embodiment. Accordingly, the same description regarding to the above-described constituent elements will be omitted. Referring toFIG.9along withFIG.1, one pixel PX of the display device that includes the transistor display panel according to the exemplary embodiment includes a plurality of signal lines121,171, and172, a plurality of transistors Qs and Qd that are connected with the plurality of signal lines121,171, and172, and an organic light emitting diode OLED. The transistors Qs and Qd include a switching transistor Qs and a driving transistor Qd. The signal lines121,171, and172include a plurality of gate lines121that transmit a gate signal Sn, a plurality of data lines171that transmit a data signal Dm, and a plurality of driving voltage lines172that transmit a driving voltage ELVDD. The gate lines121extend in the first direction D1and are substantially parallel to each other, and the data lines171extend in the second direction D2and are substantially parallel to each other. Although the driving voltage line172is shown extending in the second direction D2, the driving voltage line172may extend in the first direction D1or the second direction D2, or may have a web shape including a portion extending in the first direction D1and a portion extending in the second direction D2. Although not shown in the figures, one pixel PX may further include a thin film transistor and a capacitor in order to compensate a current applied to the organic light emitting element. The switching transistor Qs includes a control terminal, an input terminal, and an output terminal. The control terminal is connected to the gate line121, the input terminal is connected to the data line171, and the output terminal is connected to the driving transistor Qd. The switching transistor Qs transmits the data signal Dm applied to the data line171to the driving transistor Qd in response to the gate signal Sn applied to the gate line121. The driving transistor Qd also includes a control terminal, an input terminal, and an output terminal. The control terminal is connected to the switching transistor Qs as the output terminal of the switching transistor Qs, the input terminal is connected to the driving voltage line172, and the output terminal is connected to the organic light emitting diode OLED. The driving transistor Qd outputs an output current Id, the magnitude of which varies according to a voltage applied between the control terminal and the output terminal. The storage capacitor Cst is connected between the control terminal and the input terminal of the driving thin film transistor Qd. In this case, the storage capacitor Cst charges a data signal applied to the control terminal of the driving thin film transistor Qd, and maintains the charge of the data signal even after the switching thin film transistor Qs is turned off. The storage capacitor Cst includes the first capacitor electrode128a and the second capacitor electrode128b, as shown inFIG.1. Particularly, the first capacitor electrode128a is positioned at the same layer as the first electrode124and is integrally connected to the first electrode124. Further, the second capacitor electrode128b is positioned at the same layer as the gate electrode151and is integrally connected to the gate electrode151. The organic light emitting diode OLED includes an anode connected to the output terminal of the driving thin film transistor Qd and a cathode connected to a common voltage ELVSS. The organic light emitting diode OLED displays an image by emitting light, the magnitude of which varies depending on a current of the driving thin film transistor Qd. The organic light emitting diode OLED may include an organic material that uniquely emits one or more of primary colors such as red, green, and blue, and the organic light emitting device displays a desired image with a spatial sum of these colors. The switching thin film transistor Qs and the driving thin film transistor Qd may be n-channel field effect transistors (FET) or p-channel field effect transistors. Further, a connection relationship between the switching and driving thin film transistors Qs and Qd, the storage capacitor Cst, and the organic light emitting diode OLED can be changed. The cross-sectional structure shown inFIG.9will be described in detail with reference toFIG.10. However, the same description regarding the above-described constituent elements will be omitted. As shown inFIG.10, a pixel defining layer360is positioned on the passivation layer180and the pixel electrode191. The pixel defining layer360includes an opening that exposes the pixel electrode191. The pixel defining layer360may include an inorganic material, such as polyacrylics, polyimides, and the like. An emission layer370is positioned in the opening of the pixel defining layer360over the pixel electrode191, and a common electrode270is positioned on the emission layer370. The pixel electrode191, the emission layer370, and the common electrode270form the organic light emitting diode OLED. The pixel electrode191may be an anode of the organic light emitting diode OLED, and the common electrode270may be a cathode of the organic light emitting diode OLED. Light emitted from the emission layer370may be reflected several times, passed through the substrate110, and then be emitted down through the substrate110, or may be emitted above the substrate110without passing through the substrate110. Although not shown in the figures, an encapsulation layer may be formed on the common electrode270to protect the organic light emitting diode OLED. Next,FIG.11is a cross-sectional view of a display device according to an exemplary embodiment. The display device according to the present exemplary embodiment is a liquid crystal display (LCD), and may include the transistor according to the above-described exemplary embodiment. Here, the same description regarding to the above-described constituent elements will be omitted. As shown inFIG.11, a liquid crystal layer3including liquid crystal molecules31is positioned on the pixel electrode191. An insulation layer210encapsulating the liquid crystal layer3with the substrate110is positioned on the liquid crystal layer3 The insulation layer210may be of a substrate type. An opposed electrode280may be positioned under or over the insulation layer210. The opposed electrode280may generate an electric field to the liquid crystal layer3with the pixel electrode191, thereby controlling the direction of the liquid crystal molecules31. However, the opposed electrode280may be positioned between the substrate110and the liquid crystal layer3. The opposed electrode280may include a transparent conductive material such as ITO, IZO, and the like. For example, a common voltage may be applied to the opposed electrode280. Next, alignment layers21and11are respectively positioned between the liquid crystal layer3and the insulation layer210, and between the liquid crystal layer3and the pixel electrode191. The alignment layers11and21control the initial arrangement of the liquid crystal molecules31when no electric field is generated in the liquid crystal layer3. The alignment layers11and21may be adjacent to the liquid crystal layer3. The display device according to the present exemplary embodiment may further include a backlight for supplying light as a light-receiving type of display device. The back-light may be positioned under the substrate110. In addition, the transistor display panel according to an exemplary embodiment may be included in various display devices. Although certain exemplary embodiments and implementations have been described herein, other embodiments and modifications will be apparent from this description. Accordingly, the inventive concept is not limited to such embodiments, but rather to the broader scope of the presented claims and various obvious modifications and equivalent arrangements. | 40,529 |
RE49815 | Throughout the drawings, it should be noted that like reference numbers are used to depict the same or similar elements, features, and structures. DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention as defined by the claims and their equivalents. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the invention, in addition, descriptions of well-known functions and constructions may be omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention is provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their eqivalents. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component surface” includes a reference to one or more of such surfaces. Exemplary embodiments of the present invention provide a scheme that prevents a user equipment that receives a Multimedia Broadcast Multicast Service (MBMS) service from double decoding/buffering for receiving a Physical Downlink Shared CHannel (PDSCH) in a Multimedia/Broadcast over a Single Frequency Network (MBSFN) subframe. FIG.2is a downlink channel mapping diagram used for MBSFN transmission according to an exemplary embodiment of the present invention. Referring toFIG.2, a Multicast CHannel (MCH)200is used between a Media Access Control (MAC) layer and a physical layer and mapped to a Physical Multicast CHannel (PMCH)205. A PDSCH210is mainly used as a unicast object. FIG.3a view illustrating a structure of a downlink frame used in a Long Term Evolution (LTE) system according to an exemplary embodiment of the present invention. Referring toFIG.3, a radio frame300includes 10 subframes305, each of which exists as either ‘a general subframe310’ used for general data transmission/reception or a ‘multimedia broadcast multicast service single frequency network (referred to as ‘MBSFN’ hereinafter) subframe315’ used for broadcasting. There are differences between the general and MBSFN subframes in their structures and the numbers of each, such as the number of Orthogonal Frequency Division Multiplexing (OFDM) symbols, a length of a cycle prefix, a Cell-specific Reference Signal (CRS), etc. In the Rel-8 and Rel-9 systems, the MBSFN subframe had been used only for transmitting broadcast or multicast data. However, the system has progressed such that, after the LTE Rel-10 system, the MBSFN subframe can be not only used for the broadcast or the multicast, but also for a unicast. In an LTE system, for effectively using a PDSCH, a multiantenna technique and a transmission mode related to a Reference Signal (RS) are distinctively set. There are TM 1 to TM 9 in current LTE Rel-10, wherein each user equipment has one TM. TM 8 and TM 9 are newly defined in Rel-9 and Rel-10, respectively. The TM-9 supports a Single User-Multi-Input Multi-Output (SU-MIMO) with a maximum of 8 ranks. The TM 9 supports transmission of multiple layers and in demodulation, using Rel-10 DeModulation Reference Signal (DMRS), it is possible to transmit a maximum of 8 layers. Further, although in the Rel-10 system a precoded DMRS is transmitted, there is no need to inform a receiver of a corresponding precoder index. Also, for supporting the TM 9, a Downlink Control Information (DCI) format 2C is newly defined. The User Equipment (UE) released before the Rel-10 does not try decoding in an MBSFN subframe. Therefore, allowing all UEs to attempt decoding in the MBSFN subframes causes previously released UEs to request an upgrade. In an exemplary embodiment of the present invention, instead of allowing all UEs to receive unicast data in an MBSFN subframe, the function is only applied to UEs that need the information, for example, high-speed data communication. More particularly, the TM 9 among the above-mentioned TMs is a transmission mode in that transmission efficiency is maximized by using multimedia antennas. In an exemplary embodiment of the present invention, by receiving unicast data even in an MBSFN subframe, a base station sets a UE in which it is needed to increase a data throughput into the TM 9 and allows only the UE to which the TM 9 is set to receive the unicast data in the MBSFN subframe. In an LTE system, transmitting/receiving unicast data is informed through a Physical Downlink Control Channel (PDCCH) where the data transmission and reception are caused and actual data are transmitted through a PDSCH. Before receiving the actual data, a UE analyzes the PDCCH and determines whether there is resource assigning information assigned to the UE. Through a more complex process, the MBSFN obtains resource assigning information. The base station informs the UE of a transmission location of a Multicast Control CHannel (MCCH) in each MBSFN provided by a cell through broadcast information of System Information Block (SIB)13. The MCCH includes the resource assigning information for MBSFN. The UE decodes the MCCH, such that the UE recognizes the transmission location of the MBSFN subframe. The reason why the MBMS provides the resource assigning information through a scheme different from a prior unicast is because it must be possible to allow the MBMS to provide it to a UE in a standby mode. Therefore, the transmission location of control channel MCCH is transferred through the broadcast information of SIB13. FIG.4is a signal diagram illustrating a procedure of receiving MBSFN by a UE. Referring toFIG.4, a UE400receives SIB2from a base station (i.e., evolved Node B (eNB))405in step410. Information indicating subframes used for an MBSFN transmission object is included in an MBSFN-SubframeConfigList Information Element (IE) of SIB2. An MBSFN-SubframeConfig IE is included in the MBSFN-SubframeConfigList IE, and indicates which subframe of a radio frame may become an MBSFN subframe. Table 1 contains a configuration of the MBSFN-SubframeConfig IE. TABLE 1-- ASN1STARTMBSFN-SubframeConfig ::=SEQUENCE {radioframeAllocationPeriodENUMERATED {n1, n2, n4,n8, n16, n32},radioframeAllocationOffsetINTEGER (0..7),subframeAllocationCHOICE {oneFrameBIT STRING (SIZE(6)),fourFramesBIT STRING (SIZE(24))}}-- ASN1STOP In Table 1, radioFrameAllocationPeriod and radioFrameAllocationOffset are used for supporting a radio frame including an MBSFN subframe. The radio frame has the MBSFN subframe that satisfies the following Equation 1. SFN med radioFrameAllocationPeriod=radioFrameAllocationOffset [Equation 1] In Equation 1, the SFN denotes a system frame member, and supports a radio frame number. The SFN has a range of 0 to 1023 and is repeated. The subframeAllocation indicates which subframe is an MBSFN subframe in the radio frame indicated by Equation 1. The subframeAllocation may indicate the MBSFN subframe in units of one radio frame or four radio frames. When one radio frame is used, the MBSFN subframe is indicated in oneFrame IE. The MBSFN subframe may exist in one subframe or more of 1st, 2nd, 3rd, 6th, 7th, and 8th subframes among 10 subframes. Thus, the oneFrame IE indicates the MBSFN subframe among the above-listed subframes using 6 bits. When the unit of four radio frames is used, the MBSFN subframe is indicated in a fourFrames IE. Using a total of 24 bits for covering four radio frames, the MBSFN is indicated among the above-listed subframes every frame. Therefore, the UE may exactly recognize which subframe becomes the MBSFN subframe, by using the MBSFNSubframeConfigList IE. If the UE400desires MBSFN reception, the UE400receives the SIB13from the base station405in step415. The location information, which is transmitted through the MCCH of each MBSFN area provided by a cell, is included in the MBSFN-AreaInfoList IE of the SIB13. The UE400uses the location information to receive the MCCH in step420. Information indicating a resource location used to transmit the MBSFN is included in the MBSFNAreaConfiguration IE of the MCCH. The UE400uses the information to receive an MBSFN subframe in step425. The UE400obtains a location of the MBSFN subframe transmitted through a Multicast Traffic CHannel (MTCH), which is desired by MCH scheduling information MAC CE and is one control element of the received MAC Packet Data Unit (PDU) in step430. The UE400uses the scheduling information to decode a desired MTCH in step435. As described above, in LTE Rel-10, only a TM 9 0E may exclusively use a subframe assigned for MBSFN transmission for a unicast object. That is, although the subframe is reserved as an MBSFN subframe in an MBSFN-SubframeConfigList IE, the TM 9 UE may use it for the unicast object. Either a normal Cyclic Prefix (CP) or an extended CP may be applied for the subframe used for the unicast object. However, for the MBSFN subframe, only the extended CP may be applied. Thus, if the UE is not previously informed through the MBSFN-SubframeConfigList IE whether the subframes indicated through the MBSFN are for an actual MBSFN transmission object or for a unicast object, the UE must try decoding twice by applying the normal CP and the extended CP for the corresponding MBSFN subframes, respectively. After determining the object, the decoding result of applying an unsuitable CP type will be abolished. Since these dual decoding/buffering operations of the UE cause an increased system load, a method is required for effectively controlling it. First Exemplary Embodiment A UE obtains an MBSFN-SubframeConfigList IE through an SIB2, and determines which subframe in a corresponding cell may be used for an MBSFN subframe. A UE to which a TM 9 is set cannot use the MBSFN subframe for a unicast object. Thus, according to the presence of an MBMS service, the UE will be operated as follows:UE to which TM 9 is not set and which does not receive an MBMS serviceSince a PDCCH for a unicast object is not received in an MBSFN subframe, a received DownLink (DL) assignment is ignored. It is operated for a UpLink (UL) grant and a Physical Hybrid Automatic Repeat reQuest (HARQ) Indicator CHannel (PHICH).UE to which TM 9 is not set and which receives an MBMSThe UE obtains MBMS setting (configuration) information of an MCCH and MCH scheduling information of a PMCH and identifies which MBSFN subframe an MBMS service is received through.The MBSFN subframe is decoded by applying an extended CP.Since there is not any PDSCH reception through remaining MBSFN subframes, received DL assignment is ignored. It is normally operated for a UL grant and a PHICH. A UE to which a TM 9 is set may use an MBSFN subframe for a unicast object. Therefore, according to presence of an MBMS service, the UE will be operated as follows:UE to which TM 9 is set and which receives an MBMS serviceThe UE obtains MBMS setting information of an MCCH and MCH scheduling information of a PMCH and identifies which MBSFN subframe an MBMS service is received through.The MBSFN subframe is decoded by applying an extended CP.The UE grasps that an MBMS service is transmitted on an MBSFN subframe (remainders except for a receiving MBMS service by itself) using MCH scheduling information.The UE determines that a DL assignment does not exist in the MBMS service on which the MBMS service is transmitted, and ignores it even if the DL assignment is received. It is normally operated for a UL grant and a PHICH.By the above procedure, an MBSFN subframe through which a PMCH decoding is indicated (or an MBMS service is transmitted) or a TM-9 UE obtains a PDCCH from remaining MBSFN subframes except for a Positioning Reference Signal (PRS) subframe occasion caused by the PRS subframe setting, and decodes a PDSCH which is scheduled to a corresponding UE. At this time, until the PDCCH decoding is completed, PDSCH data are buffered in the subframes by applying a normal CP.UE to which TM 9 is set and which does not receive an MBMS serviceThe UE obtains MBMS setting information of an MCCH and MCH scheduling information of a PMCH, and identifies which MBSFN subframe an MBMS service is transmitted on.Since a DL assignment does not exist in the MBSFN subframe, the UE ignores the DL assignment even if it is received. A UE grant or a PHICH is normally operated. If the information is not received, the UE obtains a PDCCH even from the MBSFN subframes, and decodes a PDSCH which is scheduled to a corresponding UE. At this time, until the PDCCH decoding is completed, the UE buffers PDSCH data by applying a normal CP.By the above procedure, an MBSFN subframe through which an MBMS service is transmitted or a TM-9 UE obtains a PDCCH from remaining MBSFN subframes except for a PRS subframe occasion caused by the PRS subframe setting, and decodes a PDSCH which is scheduled to a corresponding UE.UE to which TM 9 is set and which obtains (or has) valid MBMS setting information and valid MCH scheduling information.The UE performs the same operations as ‘the UE to which a TM 9 is set and which does not receive an MBMS described above. FIG.5is a flowchart illustrating a data receiving procedure of a UE according to the first exemplary embodiment of the present invention. Referring toFIG.5, a UE receives an SIB2in step500. The UE determines whether an MBSFN-SubframeConfigList IE is included in the SIB2in step505. If the MBSFN-SubframeConfigList IE is not included in the SIB2, the UE terminates a process of receiving a PDSCH at an MBSFN and operates according to the prior art. On the other hand, if the MBSFN-SubframeConfigList IE is included in the SIB2, the UE determines whether a transmission mode set for a corresponding UE is a TM 9 in step510. If the transmission mode set for a corresponding UE is not a TM 9, the UE terminates the process of receiving a PDSCH at the MBSFN and operates according to the prior art. On the other hand, if the transmission mode set for a corresponding UE is the TM 9, the UE receives an SIB13and obtains MBMS setting information (configuration information) (that is, MBSFN-AreaInfoList is IE) in step515. The MBMS setting information includes information that the UE needs for receiving an MBMS service at a corresponding cell. For example, MCCH configuration information on which MBMS control information is transmitted. The UE uses the MBMS setting information and obtains MBSFNAreaConfiguration information of an MCCH in step520. The UE identifies a PMCH configuration of each MBSFN area from the MBSFNAreaConfiguration information, and obtains MCH Scheduling Information (SI) by receiving a PMCH. The MCH scheduling information indicates an MBSFN subframe through which an MTCH for each PMCH is transmitted. And, the UE receives an MTCH corresponding to an MBMS service which it is interested to receive. In an exemplary implementation, the TM 9 UE uses the MCH scheduling information to continuously grasp to which MBSFN subframe the MBMS service is provided, recognizes the fact that PDSCH transmission is not performed in the MBSFN subframe to which the MBMS service is provided, and does not buffer a PDSCH in the corresponding MBSFN subframe. The UE determines whether the corresponding MBSFN subframe is an MBSFN subframe for actual PMCH transmission for each subframe. The UE performs the determination procedure using the MCH scheduling information. If the UE has not yet obtained the MCH scheduling information, the UE determines that all MBSFN subframes are not an MBSFN subframe for the PMCH transmission. That is why it is impossible to receive a PDSCH through the corresponding MBSFN frame if the UE determines that a specific MBSFN frame is used. If it is impossible to determine whether an arbitrary MBSFN subframe is for the purpose of PMCH transmission, the UE preferably regards the corresponding MBSFN subframe as for the PMCH transmission. The PMCH transmission includes MCCH transmission, MTCH transmission, and MCH scheduling information transmission. The PMCH is set with respect to each MBSFN area (such that MCH scheduling information is defined and transmitted for each MBSFN area), and the UE conventionally receives only a PMCH of an MBSFN area provided by an MMS service that is desires. According to an exemplary embodiment of the present invention, the UE recognizes all MBSFN subframes, for PMCH transmission by obtaining MCH scheduling information of all MBSFN area which include a corresponding cell as well as an MBSFN area provided by an MBMS service which the UE itself desires to receive. As a result, the UE compresses at a minimum, the MBSFN subframes which are able to be transmitted through PDSCH transmission are compressed, and minimizes a data area buffering and minimizes false alarm of DL assignment. The UE determines an MBSFN subframe for actual PMCH transmission, and determines whether a PRS exists in the MBSFN subframe. The PRS is a type of a reference signal which performs a positioning method used for obtaining location information of the UE. The location of the subframe for the PRS is provided from a positioning server and provides through a Non-Access-Stratum (NAS) container to the UE. The UE knows the location of the subframe for transmitting the PRS through a PRS-Info Ie. The following Table 2 presents a configuration of PRS-Infra IE. TABLE 2-- ASN1STARTPRS-Info ::= SEQUENCE {prs-BandwidthENUMERATED { n6, n15, n25, n50,n100, ... },n75,prs-ConfigurationIndexINTEGER (0..4095),numDL-FramesENUMERATED {sf-1, sf-2, sf-4, sf-6,...},...,prs-MutingInfo-r9 CHOICE {po2-r9BIT STRING (SIZE(2)),po4-r9BIT STRING (SIZE(4)),po8-r9BIT STRING (SIZE(8)),po16-r9BIT STRING (SIZE(16)),...}OPTIONAL-- Need OP}-- ASN1STOP In Table 2, the prs-Bandwidth indicates a frequency bandwidth used for transmitting the PRS. For example, the n6means 6 Resource Blocks (RBs), and the numDL-Frames indicates whether the PRS transmission is continuously caused in NPRS subframes. The NPRS of continuous subframes transmitting the PRS is called a positioning occasion. The PRS positioning occasion is transmitted periodically and repeatedly, and the PRS positioning occasion is moot through the prs-MutingInfo IE at a specific time point. A moot pattern has a period of units of PRS positioning occasions and has one of 2, 4, 8, and 16 periods. The UE may obtain information about which PRS positioning occasion is made moot in a bitmap type. Thus, the UE may exactly know a subframe of transferring the PRS using the PRS-Info IE. The UE identifies whether a corresponding MBSFN subframe is for transmitting a PMCH or a PRS in step525. If the corresponding MBSFN subframe is for transmitting the PMCH or PRS, the UE determines that it is not a PDSCH subframe for a unicast object. In the case, the process goes to step535. Conversely, if the corresponding MBSFN subframe is not for transmitting the PMCH or RPS, the UE determines that it is a PDSCH subframe for a unicast object. In this case, the process goes to step530. If the MBSFN subframe is for transmitting the PMCH or PRS, the UE performs a necessary operation in step535. If the PMCH transmission is a PMCH related to an MBMS service which the UE desires to receive, that is an MCCH or an MTCH related to an MBMS service which the UE desires to receive, or an MBSFN subframe through which MCH scheduling information is transmitted, the UE receives a data region and decodes it by applying an extended CP. If the PMCH transmission is related to a PMCH without regard to the MBMS service, the UE receives only a control region (or non-MBSFN region), but does not receive a data region (or MBSFN region). If an MBSFN subframe is not for transmitting a PMCH (that is, a corresponding MBSFN subframe is not an MBSFN subframe which is indicated as arbitrary MTCH transmission occurs in MCH scheduling information), but determines that that is no PRS transmission, the UE determines that there is PDSCH transmission in the corresponding MBSFN subframe and performs a necessary operation in step530. That is, the UE receives a control region, decodes a PDCCH, and buffers a data region until the PDCCH decoding is completed. At this time, a normal CP or an extended CP is applied to the data region. And, after terminating the PDCCH decoding, the UE receives a data region of the corresponding subframe and decodes the PDSCH if there is a PDSCH transmission for itself in the corresponding MBSFN subframe If there is no PDSCH transmission for itself, the UE stops receiving/buffering the data region of the corresponding subframe and deletes the buffered data region. The UE repeats the steps523,530and535for each MBSFN subframe. The first exemplary embodiment of the present invention will be summarized as follows: When a UE is configured in transmission mode 9, in the subframes indicated by the higher layer parameter mbsfn-SubframeConfigList except in subframes for the serving cell i) indicated by higher layers to decode PMCH or, ii) configured by higher layers to be part of a positioning reference signal occasion and the positioning reference signal occasion is only configured within MBSFN subframes and the cyclic prefix length used in subframe #0is normal cyclic prefix, the UE shall, upon detection of a PDCCH with Cyclic Redundancy Check (CRC) scrambled by the Cell Radio Network Temporary ID (C-RNTI) with DCT format 1A or 2C intended for the UE decode the corresponding PDSCH in the same subframe. Second Exemplary Embodiment The second exemplary embodiment has a very similar operation to that of the first exemplary embodiment, but has a feature of exactly indicating a PDSCH subframe for a unicast purpose in MCH scheduling information. The MCH scheduling information is provided in a type of MAC CE to a UE, and has a form as shown inFIG.6. FIG.6is a view illustrating a configuration of scheduling information according to an exemplary embodiment of the present invention. Referring toFIG.6, an LCID600indicates a logical channel ID of an MTCH. A stop MTCH605indicates an order number of a subframe at an MCH scheduling period. The MTCH is stopped at a subframe location corresponding to the stop MTCH. A new LCID which indicates a PDSCH subframe of a unicast object is defined in the present exemplary embodiment. For example, LCID-11111 may be used for indicating a PDSCH of a unicast object. FIG.7is a flowchart illustrating a data receiving process of a UE according to the second exemplary embodiment of the present invention. Referring toFIG.7, since steps700to715are substantially the same as the steps500to515of the first exemplary embodiment, a detailed description thereof will be omitted hereinafter. The UE obtains MBSFNAreaConfiguration information of an MCCH using MBMS configuration information in step720. The UE indicates a PMCH configuration of each MBSFN region in the MBSFNAreaConfiguration information, receives a PMCH, and obtains MCH scheduling information. The MCH scheduling information indicates an MBSFN subframe through which an MTCH for each PMCH is transmitted and a PDSCH subframe of a unicast object. The UE receives the MTCH corresponding to an MBMS service which it desires to receive. Further, the PDSCH scheduled for the UE in a subframe of a unicast object may be decoded. According to the present exemplary embodiment, a TM 9 UE grasps which MBSFN subframe the MBMS service is provided in, using the MCH scheduling information, and recognizes which MBSFN subframe is used for the unicast object, using the MCH scheduling information. The UE determines whether a corresponding MBSFN subframe is for actual PMCH transmission for each MBSFN subframe using MCH scheduling information. Further, the UE determines whether the corresponding MBSFN subframe is for a unicast subframe for each MBSFN subframe using the information. If the UE does not yet obtain the MCH scheduling information, the UE determines that all MBSFN subframes are not of an MBSFN subframe for PMCH transmission. The UE identifies not only a subframe for a unicast object, but also PRS existence in the MBSFN subframe. The PRS is used for performing a positioning method which is used to obtain location information of the UE. The locations of subframes for the PRS are provided from a positioning server, and informed through an NAS container to the UE. The UE determines whether the MBSFN subframe is indicated as an MBSFN frame for PDSCH transmission and is not for the PRS in step725. If the MBSFN subframe is not indicated as an MBSFN frame for PDSCH transmission or is for the PRS, the UE determines that the corresponding MBSFN subframe is not a PDSCH subframe for the unicast object. In this case, the process goes to step735. On the contrary, if the MBSFN subframe is indicated as an MBSFN frame for PDSCH transmission or is not for the PRS, the UE determines that the corresponding MBSFN subframe is of a PDSCH subframe for the unicast object. In this case, the process goes to step730. If the MBSFN subframe is an MBSFN which is not indicated as for PDSCH transmission, or for the PRS, the UE performs an operation necessary for the PMCH transmission in step735. If the PMCH transmission is a PMCH related to an MBMS service which the UE desires to receive, that is an MCCH or an MTCH related to an MBMS service which the UE desires to receive, or an MBSFN subframe through which MCH scheduling information is transmitted, the UE receives a data region and decodes it by applying an extended CP. If the PMCH transmission is related to a PMCH without regard to the MBMS service, the UE receives only a control region (or non-MBSFN region), but does not receive a data region (or MBSFN region). If an MBSFN subframe is indicated as an MBSFN subframe and is determined that it is not for the PRS, the UE determines that the PDSCH transmission may occur in the corresponding MBSFN subframe and performs a necessary operation in step730. That is, the UE receives a control region, decodes a PDCCH, and buffers a data region until the PDCCH decoding is completed. At this time, a normal CP or an extended CP is applied to the data region. And, after terminating the PDCCH decoding, the UE receives a data region of the corresponding subframe and decodes the PDSCH if there is PDSCH transmission for itself in the corresponding MBSFN subframe, and if there is no PDSCH transmission for itself, the UE stops receiving/buffering the data region of the corresponding subframe and deletes the buffered data region. The UE repeats the steps752,730and735for each MBSFN subframe. FIG.8is a block diagram illustrating a UE according to an exemplary embodiment of the present invention. Referring toFIG.8, the UE transmits and receives data and the like through an upper layer device810to and from an upper layer, and transmits and receives control messages through a control message processor815. And, when the UE transmits a control signal or data to a base station, after multiplexing it according to a control of a controller820, the UE transmits data through a transceiver800. When receiving, after receiving a physical signal through the transceiver800according to a control of the controller820, the UE demultiplexes a received signal through a multiplexer/demultiplexer805and transfers it to the upper layer or the control message processor815according to each of message information. More particularly, the controller820may perform a process for an MBSFN subframe according to a scheme ofFIG.5orFIG.7. Further, the transceiver800, the control message processor815, the upper layer device810, and the multiplexer/demultiplexer805may perform operations necessary for processes ofFIGS.5and7. According to an exemplary embodiment of the present invention, there is an effect that allows a UE supporting an MBMS to effectively receive data. Since computer program instructions may be mounted in a processor of a general computer, a special computer, or other programmable data processing equipment, instructions performed through a processor of a computer or other programmable data processing equipment generates means for performing functions described in block(s) of the flowcharts. Since the computer program instructions may be stored in computer or computer readable memory capable of orienting a computer or other programmable data processing equipment to implement functions in a specific scheme, instructions stored in the computer or computer readable memory may produce manufacturing articles involving an instruction means executing functions described in block(s) of the flowcharts. Because the computer program instructions may be mounted on a computer or other programmable data processing equipment, a series of operation steps are performed in the computer or other programmable data processing equipment to create a process executed by the computer such that instructions performed by the computer or other programmable data processing equipment may provide steps for executing functions described in block(s) of the flowcharts. Further, each block may indicate a part of a module, a segment, or a code including at least one executable instruction for executing specific logical function(s). It should be noted that several execution examples may generate functions described in blocks out of order. For example, two continuously shown blocks may be simultaneously performed, and the blocks may be performed in a converse order according to corresponding functions. As used herein, the term “˜ unit” refers to a software or a hardware structural element such as a Field Programmable Gate Array (FPGA) or an Application Specific Integrated Circuit (ASIC), and the “˜ unit” perform some roles. However, the “˜ unit” is not limited to software or hardware. The “˜ unit” can be configured to be stored in an addressable storage medium and to play at least one processor. Accordingly, for example, the “˜ unit” includes software structural elements, object-oriented software structural elements, class structural elements, task structural elements, processors, functions, attributes, procedures, subroutines, segments of a program code, drivers, firmware, microcode, circuit, data, database, data structures, tables, arrays, and variables. Functions provided in structural elements and “˜ units” may be engaged by the smaller number of structural elements and “˜ units”, or may be divided by additional structural elements and “˜ units”. Furthermore, structural elements and “˜ units” may be implemented to play a device or at least one CPU in a security multimedia card. Although exemplary embodiments of the present invention have been described in detail hereinabove, it should be clearly understood that many variations and modifications of the basic inventive concepts herein taught which may appear to those skilled in the present art will still fall within the spirit and scope of the present invention, as defined in the appended claims. | 31,544 |
RE49816 | DETAILED DESCRIPTION OF THE INVENTION One aspect of the present invention relates to a compound of Formula (I): wherein R1is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl and bi-heteroaryl, monocyclic and bicyclic heterocyclyl and bi-heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl and bi-heteroaryl, monocyclic and bicyclic heterocyclyl and bi-heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —CF3, C1-6alkyl, and C1-6alkoxy; R2is independently selected at each occurrence thereof from the group consisting of H, D, C1-6alkyl, —CH2OC1-6alkyl, —CH2Ar, and —CH2heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6alkoxy; R3is independently selected at each occurrence thereof from the group consisting of H, D, —CH2OC1-6alkyl, —(CH2)mC(O)NHR5, and —(CH2)mC(O)NR6R7; R4is selected from the group consisting of —C(O)(CH2)1Ph, —C(O)CH2NR6R7, —SO2Ar, —SO2C1-6alkyl, —SO2C3-6cycloalkyl, —C(O)(CH2)nHet, —C(O)C(O)Het, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, —C(O)CF3, heteroaryl, —C(O)R10, and —(CH2)1NR6R7, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6alkoxy; R5is selected from the group consisting of C1-6alkyl, C1-6alkoxy, non-aromatic heterocycle, —NR6R7, and —CR8R9; R6, R7, R8, and R9are each independently selected from the group consisting of H, D, C1-6alkyl, and —(CH2)kOH; or R6and R7are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, or morpholine ring; or R8and R9are taken together with the carbon to which they are attached to form an oxetane ring; R10is monocyclic carbocycle or fused bicyclic carbocycle; X is —(CH2)q—, —O—, or —(CD2)q—; Y is O or S; k is 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; q is 0, 1, or 2; and s is 0 or 1; or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof. As used above, and throughout the description herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this technology belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. The term “cycloalkyl” means a non-aromatic mono- or multicyclic ring system of about 3 to about 7 carbon atoms, preferably of about 5 to about 7 carbon atoms. Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term “monocyclic carbocycle” means a monocyclic ring system of 5 to about 8 ring carbon atoms, preferably 5 or 6. The ring is nonaromatic, but may contain one or more carbon-carbon double bonds. Representative monocyclic carbocycles include cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. The term “fused bicyclic carbocycle” means a bicyclic ring system consisting of about 8 to 11 ring carbon atoms, preferably 9 or 10. One or both of the rings is/are aromatic. Representative fused bicyclic carbocycles include indenyl, indanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, and the like. The term “aryl” means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. Representative aryl groups include phenyl and naphthyl. The term “heteroaryl” means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multicyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “Heteroaryl”. Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyridyl, 2-oxopyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like. As used herein, “biheteroaryl” or “bi-heteroaryl” refers to a heteroaryl group substituted by another heteroaryl group. As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to 18-membered ring (radical) which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this application, the heterocycle may be a monocyclic, or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycle may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Examples of such heterocycles include, without limitation, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Further heterocycles and heteroaryls are described in Katritzky et al., eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, N.Y. (1984), which is hereby incorporated by reference in its entirety. As used herein, “biheterocyclyl” or “bi-heterocyclyl” refers to a heterocyclyl group substituted by another heterocyclyl or heterocycle group. The term “non-aromatic heterocycle” means a non-aromatic monocyclic system containing 3 to 10 atoms, preferably to about 7 carbon atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. Representative non-aromatic heterocycle groups include pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino , piperazinyl, tetrohydro-2H-oxazinyl, and the like. The term “monocyclic” used herein indicates a molecular structure having one ring. The term “polycyclic” or “multi-cyclic” used herein indicates a molecular structure having two or more rings, including, but not limited to, fused, bridged, or spiro rings. Terminology related to “protecting”, “deprotecting,” and “protected” functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes described herein, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups.” Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991), which is hereby incorporated by reference in its entirety. The term “alkoxy” means groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purposes of the present patent application, alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain, or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring. Thus, for example, phenyl substituted by alkoxy may be, for example, A compound with a hydroxy group drawn next to a nitrogen on a heterocycle can exist as the “keto” form. For example, 3-(2-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)propanoic acid can exist as 3-(2-oxo-2,3-dihydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)propanoic acid. The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo. The term “substituted” or “substitution” of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded. “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term “optionally substituted” is used to indicate that a group may have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom's normal valency is not exceeded and the identity of each substituent is independent of the others. Up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy. “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term “method of treating” means amelioration or relief from the symptoms and/or effects associated with the disorders described herein. As used herein, reference to “treatment” of a patient is intended to include prophylaxis. The term “compounds of the invention”, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits. The term “pharmaceutically acceptable salts” means the relatively non-toxic, inorganic, and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates, malonates, salicylates, propionates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like (see, for example, Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66:1-9 (1977) and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, which are hereby incorporated by reference in their entirety). Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. The sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases which include, for example, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use, such as ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trim- ethylamine, ethylamine, basic amino acids, e.g., lysine and arginine, dicyclohexylamine, and the like. The term “pharmaceutically acceptable prodrugs” as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commen- surate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design and Applications of Prodrugs” p. 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1-38 (1992); J. Pharm. Sci., 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692 (1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987), which are incorporated herein by reference in their entirety. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. The term “solvate” refers to a compound of Formula I in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The term “therapeutically effective amounts” is meant to describe an amount of compound of the present invention effective in increasing the levels of serotonin, norepinephrine, or dopamine at the synapse and thus producing the desired therapeutic effect. Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition, and medical history; the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and, the nature and severity of the condition being treated. The term “pharmaceutical composition” means a composition comprising a compound of Formula (I) and at least one component comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifingal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols. The term “pharmaceutically acceptable” means it is, within the scope of sound medical judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. The term “pharmaceutically acceptable dosage forms” means dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules, and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., latest edition. Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (−)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. This technology also envisions the “quaternization” of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization. In the characterization of some of the substituents, it is recited that certain substituents may combine to form rings. Unless stated otherwise, it is intended that such rings may exhibit various degrees of unsaturation (from fully saturated to fully unsaturated), may include heteroatoms and may be substituted with lower alkyl or alkoxy. Compounds of Formula (I) can be produced according to known methods. For example, compounds of Formula (I) wherein s is 0 can be prepared according to Scheme 1 and Scheme 2 outlined below. Coupling of the carboxylic acid (1) with the amine (2) leads to formation of the compound (3). The coupling reaction can be carried out in a variety of solvents, for example in methylene chloride (CH2Cl2), tetrahydrofuran (THF), dimethylformamide (DMF), or other such solvents or in the mixture of such solvents. During the coupling process, the non-participating carboxylic acids or amines on the reacting set of amino acids or peptide fragments can be protected by a suitable protecting group which can be selectively removed at a later time if desired. A detailed description of these groups and their selection and chemistry is contained in “The Peptides, Vol. 3”, Gross and Meinenhofer, Eds., Academic Press, New York, 1981, which is hereby incorporated by reference in its entirety. Thus, useful protective groups for the amino group are benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (t-BOC), 2,2,2-trichloroethoxycarbonyl (Trot), t-amytoxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-(trichlorosilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), phthaloyl, acetyl (Ac), formyl, trifluoroacetyl, and the like. Alternatively, carboxylic acid bearing protecting group (PG) (4) can be coupled with the amine (2) to form compound (5). Following the deprotection reaction, compound (6) can be reacted with compound (11), R4-LG (wherein LG is a suitable leaving group), to form final product (3). Compounds of Formula (I) wherein s is 1 can be prepared according to the general schemes outlined below (Scheme 3 and Scheme 4). The compounds of the present invention may be prepared by stepwise coupling of the amino acids. The coupling reactions are conducted in solvents such as methylene chloride (CH2Cl2), tetrahydrofuran (THF), dimethylformamide (DMF), or other such solvents. During the coupling process, the non-participating carboxylic acids or amines on the reacting set of amino acids or peptide fragments can be protected by a suitable protecting group which can be selectively removed at a later time if desired. A detailed description of these groups and their selection and chemistry is contained in “The Peptides; Vol. 3”, Gross and Meinenhofer, L ds Academic Press, New York, 1981, which is hereby incorporated by reference in its entirety. Thus, useful protective groups for the amino group are benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (t-BOC), 2,2,2-trichloroethoxycarbonyl (Troc), t-amyloxycarbonyl, t-methoxybenzyloxycarbonyl, 2-(trichlorosilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), phthaloyl, acetyl (Ac), formyl, trifluoroacetyl, and the like. Carboxylic acid bearing protecting group (PG) (4) is coupled with the amine (2) to form compound (5). Following the deprotection the reaction, compound (6) is coupled with another acid (7) to form final product (8). Alternatively, carboxylic acid bearing protecting group (PG) (4) can be coupled with the amine (6) to form compound (9). Following the deprotection reaction, compound (10) can be reacted with compound (11), R4-LG (wherein LG is a suitable leaving group), to form final product. (8). In one embodiment, compound has the Formula (Ia): wherein R1ais selected from the group consisting of monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6alkoxy; R2ais selected from the group consisting of C1-6alkyl, —CH2OC1-6alkyl, —CH2Ar, and heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6alkoxy; R1as selected from the group consisting of —CH2OC1-6alkyl, —CH2C(O)NHR5a, and —CH2C(O)R5a; R4ais selected from the group consisting of —C(O)(CH2)1Ph, —C(O)CH2NR6aR7a, —SO2Ar, —SO2C1-6alkyl, —C(O)(CH2)nHet, —C(O)C1-6alky, —C(O)CF3, heteroaryl, and —(CH2)1NR6aR7a, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6akoxy; R5ais selected from the group consisting of C1-6alkyl, C1-6alkoxy, non-aromatic heterocycle, —NR6aR7a, and —CR8aR9a; R6a, R7a, R8a, and R9aare each independently selected from the group consisting of H, C1-6alkyl, and —(CH2)kOH; or R6aand R7aare taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, azetidine, or morpholine ring; or R8aand R9aare taken together with the carbon to which they are attached to form an oxetane ring; n is 0, 1, 2, or 3; and k is 1, 2, or 3. Another embodiment relates to the compound of Formulae (I) where R1is selected from the group consisting of and R11is selected from the group consisting of halogen, cyano, —CF3, C1-6alkyl, and C1-6alkoxy. Another embodiment relates to the compound of Formuae (I) where R2is selected from the group consisting of Me, —CH(Me)2, —CH2OMe, Another embodiment relates to the compound of Formulae (I) where R3is selected from the group consisting of —CH2OMe, Another embodiment relates to the compound of Formulae (I) where R4is selected from the group consisting of trifluoroacetyl, p is 0, 1, 2, or 3; r is 0, 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, or 4; and R is selected from the group consisting of H, halogen, cyano, C1-6alkyl, and C1-6alkoxy. Another embodiment relates to the compound of Formulae (I) where the compound has a structure selected from the group consisting of: A second aspect of the present invention relates to a method of treating cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders in a subject or for providing immunosuppression for transplanted organs or tissues in a subject. This method includes administering to the subject in need thereof a compound of the Formula (I): wherein R1is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl and bi-heteroaryl, monocyclic and bicyclic heterocyclyl and bi-heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl and bi-heteroaryl, monocyclic and bicyclic heterocyclyl and bi-heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —CF3, C1-6alkyl, and C1-6alkoxy; R2is independently selected at each occurrence thereof from the group consisting of H, D, C1-6alkyl, 'CH2OC1-6alkyl, —CH2Ar, and —CH2heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6alkoxy; R3is independently selected at each occurrence thereof from the group consisting of H, D, —CH2OC1-6alkyl, —(CH2)mC(O)NHR5, and —(CH2)mC(O)NR6R7; R4is selected from the group consisting of —C(O)(CH2)1Ph, —C(O)CH2NR6R7, —SO2Ar, —SO2C1-6alkyl, —SO2C3-6cycloalkyl, —C(O)(CH2)nHet, —C(O)C(O)Het, —C(O)C1-6alkyl, C(O)OC1-6alkyl, —C(O)CF3, heteroaryl, —C(O)R10, and —(CH2)1NR6R7, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6alkyl, and C1-6alkoxy; R5is selected from the group consisting of C1-6alkyl, C1-6alkoxy, non-aromatic heterocycle, —NR6R7, and CR8R9; R6, R7, R8, and R9are each independently selected from the group consisting of H, D, C1-6alkyl, and —(CH2)kOH; or R6and7are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, or morpholine ring; or R8and R9are taken together with the carbon to which they are attached to form an oxetane ring; R10is monocyclic carbocycle or fused bicyclic carbocycle; X is —(CH2)q—, —O—, or —(CD2)q—; Y is O or S; k is 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; q is 0, 1, or 2; and s is 0 or 1. In one embodiment, an autoimmune disorder is treated. The autoimmune disorder is selected from the group consisting of arthritis, colitis, multiple sclerosis, lupus, systemic sclerosis, and sjögren syndrome. In another embodiment, immunosuppression is provided for transplanted organs or tissues. The immunosuppression is used to prevent transplant rejection and graft-verse-host disease. In another embodiment, an inflammatory disorder is treated. The inflammatory disorder is Crohn's disease or ulcerative colitis. In yet another embodiment, cancer is treated. The cancer is selected from the group consisting of neoplastic disorders, hematologic malignancies, and lymphocytic malignancies. While it may be possible for compounds of Formula (I) to be administered as raw chemicals, it will often be preferable to present them as a part of a pharmaceutical composition. Accordingly, another aspect of the present invention is a pharmaceutical composition containing a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In practicing the method of the present invention, agents suitable for treating a subject can be administered using any method standard in the art. The agents, in their appropriate delivery form, can be administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, or intranasally. The compositions of the present invention may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions, or emulsions. The agents of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or it may be enclosed in hard or soft shell capsules, or it may be compressed into tablets, or they may be incorporated directly with the food of the diet. Agents of the present invention may also be administered in a time release manner incorporated within such devices as time-release capsules or nanotubes. Such devices afford flexibility relative to time and dosage. For oral therapeutic administration, the agents of the present invention may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of the agent, although lower concentrations may be effective and indeed optimal. The percentage of the agent in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of an agent of the present invention in such therapeutically useful compositions is such that a suitable dosage will be obtained. Also specifically contemplated are oral dosage forms of the agents of the present invention. The agents may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. (Abuchowski and Davis, “Soluble Polymer Enzyme Adducts,” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y, pp. 367-383 (1981), which are hereby incorporated by reference in their entirety). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. Preferred for pharmaceutical usage, as indicated above, are polyethylene glycol moieties. The tablets, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, sucrulose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup may contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor. The agents of the present invention may also be administered parenterally. Solutions or suspensions of the agent can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. When it is desirable to deliver the agents of the present invention systemically, they may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Intraperitoneal or intrathecal administration of the agents of the present invention can also be achieved using infusion pump devices such as those described by Medtronic, Northridge, Calif. Such devices allow continuous infusion of desired compounds avoiding multiple injections and multiple manipulations. In addition to the formulations described previously, the agents may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The agents of the present invention may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the agent of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The agent of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer. Effective doses of the compositions of the present invention, for the treatment of cancer or pathogen infection vary depending upon many different factors, including type and stage of cancer or the type of pathogen infection, means of administration, target site, physiological state of the patient, other medications or therapies administered, and physical state of the patient relative to other medical complications. Treatment dosages need to be titrated to optimize safety and efficacy. The percentage of active ingredient in the compositions of the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.01 to about 100 mg/kg body weight, preferably about 0.01 to about 10 mg/kg body weight per day by inhalation, from about 0.01 to about 100 mg/kg body weight, preferably 0.1 to 70 mg/kg body weight, more especially 0.1 to 10 mg/kg body weight per day by oral administration, and from about 0.01 to about 50 mg/kg body weight, preferably 0.01 to 10 mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health, and other characteristics which can influence the efficacy of the medicinal product. The products according to the present invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day. EXAMPLES The following examples are provided to illustrate embodiments of the present invention but are by no means intended to limit its scope. Example 1—General Procedure for HATU Mediated Amide Bond Formation Carboxylic acid (1.0 eq.), O-(7-Azabenzotriazol-1-yl)-N, N,N,N′-tetramethyluronium hexafluorophosphate (HATU) (1.2 eq.) and 1-Hydroxy-7-Azabenzotriazole (HOAt) 0.6M in DMF (1.0 eq.) were dissolved in DMF under argon atmosphere. The solution was cooled to 0° C. and amine (1.1 eq.) was added. After stirring for 5 minutes at 0° C., Hünig's base (3-4 eq.) was added. The reaction mixture was stirred at 0° C. After completion of reaction (1 h; monitored by LCMS), water was added to reaction mixture and stirred 30 minutes. Product was isolated either by filtration or ethyl acetate extraction. Example 2—General Procedure for EDC Mediated Amide Bond Formation Carboxylic acid (1.0 eq.), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (1.2 eq.) and 1-Hydroxybenzotriazole (HOBt) (1.3 eq.) were dissolved in DMF under argon atmosphere. The solution was cooled to 0° C. and amine (1.1 eq.) was added. After stirring for 5 minutes at 0° C., Hünig's base (2-3 eq.) was added. The reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature overnight. Example 3—General Procedure for Boc-Deprotection The substrate was dissolved in dichloromethane and the solution was cooled to 0° C. Trifluoroacetic acid (20% v/v with respect to dichloromethane) was added to the solution drop wise at 0° C. with constant stirring. The mixture was allowed to warm to room temperature slowly (over a period of 1 hour), and stirred until the completion of reaction (monitored by LCMS). Excess trifluoroacetic acid and dichloromethane were evaporated and crude was dried under vacuum. Example 4—General Procedure for O-Debenzylation The substrate was dissolved in methanol. Palladium on carbon (10%) was added carefully. Residual air from the flask was removed and flushed with hydrogen. The mixture was stirred at room temperature under hydrogen atmosphere using a hydrogen balloon. After completion of reaction (3-4 hours; monitored by LCMS), the mixture was filtered through celite. Filtrate was evaporated and dried under vacuum to give product. Example 5—Preparation of tert-butyl (S)-(3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)carbamate (DPLG-2122) DPLG-2122 was prepared following the general procedure for HATU mediated coupling of Boc-4-F-Phe-OH (2.00 g, 7.06 mmol) and 1-naphthylmethylamine (1.17 mL, 7.77 mmol). After completion of reaction (1 h), 100 mL water was added to the reaction mixture. A precipitate was formed. The mixture was stirred for 15 minutes and filtered. The precipitate was washed with water and dried to give 2.96 g (99%) product.1H NMR (500 MHz, DMSO-d6) δ 8.47 (t, J=5.8 Hz, 1H), 8.03 (dd, J=6.3, 3.4 Hz, 1H), 7.94 (dd, J=6.2, 3.4 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.55-7.52 (m, 2H), 7.44-7.41 (m, 1H), 7.38-7.36 (m, 1H), 7.28-7.25 (m, 2H), 7.07-7.00 (m, 3H), 4.74 (d, J=5.6 Hz, 2H), 4.25-4.15 (m, 1H), 2.93 (dd, J=13.6, 5.1 Hz, 1H), 2.77 (dd, J=13.6, 10.0 Hz, 1H), 1.30 (s, 9H). Example 6—Preparation of (S)-2-amino-3-(4-fluorophenyl)-N-(naphthalen-1-ylmethyl)propanamide 2,2,2-trifluoroacetate (DPLG-2123) DPLG-2123 was prepared by following the general procedure for Boc-deprotection of DPLG-21046 (2.96 g, 7.00 mmol). The crude was triturated with diethyl ether and filtered to give product as a white solid (2.54 g, 83%).1H NMR (500 MHz, DMSO-d6) δ 8.91-8.88 (m, 1H), 8.30 (bs, 3H), 7.98-7.94 (m, 2H), 7.89 (d, J=8.2 Hz, 1H), 7.58-7.55 (m, 2H), 7.44 (dd, J=8.2, 7.0 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.22-7.19 (m, 2H), 7.09-7.06 (m, 2H), 4.81 (dd, J=15.1, 5.8 Hz, 1H), 4.69 (dd, J=15.1, 5.1 Hz, 1H), 4.04-4.01 (m, 1H), 3.06-2.98 (m, 2H). Example 7—Preparation of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (DPLG-2134) DPLG-2134 was prepared following the general procedure for HATU mediated coupling of Boc-Asp(OBn)OH (356 mg, 1.1 mmol) and (S)-2-amino-3-(4-fluorophenyl)-N-(naphthalen-1-ylmethyl)propanamide 2,2,2-trifluoroacetate (436 mg, 1.0 mmol). After completion of reaction (3 h), the mixture was precipitated by the addition of 100 mL water. The mixture was stirred for 15 minutes and filtered. The precipitate was dried to give 627 mg (quant.) product.1H NMR (500 MHz, DMSO-d6) δ 8.51 (t, J=5.7 Hz, 1H), 8.01-7.99 (m, 1H), 7.96-7.94 (m, 2H), 7.85 (d, J=8.2 Hz, 1H), 7.56-7.52 (m, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.39-7.29 (m, 6H), 7.20-7.17 (m, 3H), 7.02-6.98 (m, 2H), 5.12-5.04 (m, 2H), 4.71 (d, J=5.6 Hz, 2H), 4.56-4.51 (m, 1H), 4.34 (td, J=8.7, 5.1 Hz, 1H), 2.99-2.95 (m, 1H), 2.87-2.80 (m, 1H), 2.69 (dd, J=16.2, 5.0 Hz, 1H), 2.57-2.52 (m, 1H), 1.36 (s, 9H). Example 8—Preparation of (S)-benzyl 3-amino-4-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (DPLG-2135) DPLG-2135 was synthesized by following the general procedure for Boc-deprotection of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (627 mg, 1 mmol). After completion of reaction dichloromethane and excess trifluoroacetic acid were evaporated. The crude was washed with diethyl ether to give product (628 mg, 98%).1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J=8.2 Hz, 1H), 8.62 (t, J=5.7 Hz, 1H), 8.18 (bs, 3H), 8.02-7.99 (m, 1H), 7.96-7.93 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.56-7.51 (m, 2H), 7.44-7.34 (m, 6H), 7.31 (d, J=7.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.08-7.04 (m, 2H), 5.18 (dd, J=12.5 Hz, 1H), 5.14 (d, J=12.5 Hz, 1H), 4.77-4.69 (m, 2H), 4.61 (td, J=8.5, 5.6 Hz, 1H), 4.10-4.18 (m, 1H), 3.04-2.97 (m, 2H), 2.87-2.80 (m, 2H). Example 9—Preparation of (S)-benzyl 4-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropana-mido)butanoate (DPLG-2138) DPLG-2138 was prepared following the general procedure for HATU mediated coupling of 3-phenylpropanoic acid (162 mg, 1.08 mmol) and (S)-benzyl 3-amino-4-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (628 mg, 0.98 mmol). After completion of reaction (3 h), the mixture was precipitated by the addition of 100 mL water. The mixture was stirred for 15 minutes and filtered. The precipitate was dried to give 600 mg (93%) product.1H NMR (500 MHz, DMSO-d6) δ 8.45 (t, J=5.7 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.03-8.01 (m, 1H), 7.95-7.93 (m, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.56-7.51 (m, 2H), 7.44-7.41 (m, 1H), 7.38-7.30 (m, 6H), 7.27-7.24 (m, 2H), 7.20-7.15 (m, 5H), 7.02-6.98 (m, 2H), 5.04 (s, 2H), 4.72 (d, J=5.6 Hz, 2H), 4.67 (td, J=8.2, 5.8 Hz, 1H), 4.51 (td, J=8.5, 5.4 Hz, 1H), 2.99 (dd, J=13.8, 5.4 Hz, 1H), 2.84 (dd, J=13.8, 8.8 Hz, 1H), 2.77-2.72 (m, 3H), 2.54-2.49 (m, 1H), 2.39-2.32 (m, 2H). Example 10—Preparation of (S)-4-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido) butanoic acid (DPLG-2141) DPLG-2141 was synthesized by following the general procedure for O-debenzylation of DPLG-2138 (600 mg, 0.91 mmol). The product (518 mg, quant.) was isolated as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.50 (t, J=6.0 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.06-8.03 (m, 2H), 7.95-7.93 (m, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.57-7.52 (m, 2H), 7.44-7.41 (m, 1H), 7.34-7.32 (m, 1H), 7.27-7.24 (m, 2H), 7.20-7.15 (m, 5H), 7.01-6.97 (m, 2H), 4.72 (d, J=5.7 Hz, 2H), 4.58-4.53 (m, 1H), 4.48 (td, J=8.4, 5.1 Hz, 1H), 3.01 (dd, J=13.8, 5.3 Hz, 1H), 2.84 (dd, J=13.8, 8.9 Hz, 1H), 2.78-2.74 (m, 2H), 2.60 (dd, J=16.5, 6.2 Hz, 1H), 2.41-2.31 (m, 3H). Example 11—Preparation of DPLG-21054 DPLG-21054 was synthesized by following the general protocol for HATU mediated coupling of Boc-Asp-OBn (2.00 g, 6.19 mmol) with O-tert-butyl hydroxylamine hydrochloride (855.2 mg, 6.81 mmol). After completion of reaction, water was added. Mixture was extracted with ethyl acetate twice. Combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Organic layer was evaporated to give product as colorless paste (2.40 g, 98%). The crude was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.43-7.27 (m, 5H), 7.21 (d, J=8.3 Hz, 1H), 5.11 (s, 2H), 4.43-4.36 (m, 1H), 2.55 (dd, J=14.8, 5.9 Hz, 1H), 2.40 (dd, J=14.8, 8.0 Hz, 1H), 1.36 (s, 9H), 1.13 (s, 9H). Example 12—Preparation of DPLG-21055 DPLG-21055 was synthesized by following the general procedure for Boc-deprotection of DPLG-21054 (2.40 g, 6.08 mmol). Crude was dried under vacuum to give colorless paste (2.48 g, quant.). Product was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.36 (bs, 3H), 7.44-7.34 (m, 5H), 5.23-5.19 (m, 2H), 4.47-4.39 (m, 1H), 2.71 (d, J=5.3 Hz, 2H), 1.13 (s, 9H). Example 13—Preparation of DPLG-21056 DPLG-21056 was synthesized by following the general procedure for HATU mediated coupling of 3-phenylpropanoic acid (991.1 mg, 6.60 mmol) with DPLG-21055 (2.45 g, 6.00 mmol). After completion of reaction, water was added. A white precipitate was formed. White precipitate was filtered, washed with water, and dried to give product (2.02 g, 79%). Product was used in the next step without further purification. Complex NMR due to presence of 90:10 rotamers.1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.15 (s, 0.1H), 8.37 (d, J=7.8 Hz, 0.9H), 8.30 (d, J=7.7 Hz, 0.1H), 7.38-7.31 (m, 5H), 7.27-7.24 (m, 2H), 7.20-7.14 (m, 3H), 5.10 (s, 2H), 4.74-4.71 (m, 0.1H), 4.67-4.62 (m, 0.9H), 2.77 (t, J=7.9 Hz, 2H), 2.57 (dd, J=15.0, 6.2 Hz, 1H), 2.46-2.37 (m, 3H), 1.12 (s, 9H). Example 14—Preparation of DPLG-21059 DPLG-21059 was synthesized by following the general procedure for O-debenzylation of DPLG-21056 (1.98 g, 4.64 mmol). Product (1.55 g, 99%) was isolated as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.33 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.29-7.23 (m, 2H), 7.22-7.14 (m, 3H), 4.64-4.46 (m, 1H), 2.81-2.76 (m, 2H), 2.54-2.46 (m, 1H), 2.43-2.37 (m, 2H), 2.35 (dd, J=14.8, 7.5 Hz, 1H), 1.13 (s, 9H). Example 15—Preparation of (S)—N4-(tert-butoxy)-N1(S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(3-phenylpropanamido)succinamide (DPLG3) DPLG3 was prepared following the general procedure for HATU mediated coupling of PhCH2CH2C(O)-Asp(CON-HOtBu)-OH (1.35 g, 4.00 mmol) and H-4F-Phe-CH2-naphth TFA salt (1.92 g, 4.40 mmol). After completion of reaction, 100 mL water was added. A white precipitate was formed. Precipitate was filtered and washed with ethanol. The precipitate was triturated with methanol and filtered. Precipitate was dried to give 1.73 g (67%) pure product as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.53 (t, J=5.8 Hz, 1H), 8.11-8.04 (m, 3H), 7.97-7.91 (m, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.59-7.50 (m, 2H), 7.43 (dd, J=8.1, 7.1 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.29-7.23 (m, 2H), 7.22-7.13 (m, 5H), 7.03-6.95 (m, 2H), 4.76 (dd, J=15.3, 5.9 Hz, 1H), 4.70 (dd, J=15.3, 5.7 Hz, 1H), 4.63-4.54 (m, 1H), 4.51-4.43 (m, 1H), 3.04 (dd, J=13.8, 5.0 Hz, 1H), 2.82 (dd, J=13.8, 9.2 Hz, 1H), 2.78-2.72 (m, 2H), 2.46 (dd, J=14.9, 6.4 Hz, 1H), 2.39-2.32 (m, 2H), 2.27 (dd, J=14.9, 7.8 Hz, 1H), 1.11 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 171.38, 170.70, 170.45, 167.61, 160.93 (d, 7=242.0 Hz), 141.26, 134.21, 133.83 (d, J=3.3 Hz), 133.24, 130.98 (d, J=8.2 Hz), 130.83, 128.48, 128.32, 128.11, 127.50, 126.22, 125.88, 125.77, 125.42, 125.37, 123.45, 114.71 (d, 7=21.1 Hz) 80.58, 54.29, 49.63, 40.23, 36.80, 36.45, 34.65, 30.97, 6.26.19F NMR (471 MHz, DMSO-d6) δ −119.28 (tt, J=9.3, 5.3 Hz). Example 16—Preparation of tert-butyl ((S)-1-(((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (Boc-Ser(OMe)-4F-Phe-naphth, DPLG-2049) Boc-β-methoxyalanine dicyclohexylamine (80 mg, 0.2 mmol) was dissolved in DMF (4 mL). The solution was cooled to 0° C. and dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate (90.5 mg, 0.22 mmol) was added in one portion. 30 μL triethylamine was added and mixture was stirred at 0° C. for 15 minutes. A solution of amine (TFA.H-4F-Phe-naphth) (87.3 mg, 0.2 mmol) in 1 mL DMF and 30 μL Et3N was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with chloroform and washed with 1N HCl, water, aq. NaHCO3, water and brine. The organic layer was evaporated and purified by column chromatography to give product with traces of urea (dipyrrolidin-1 -ylmethanone) byproduct. The crude was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 8.46 (t, J=5.6 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.02-8.00 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.56-7.53 (m, 2H), 7.43 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H), 7.22-7.19 (m, 2H), 7.04-6.99 (m, 2H), 6.88 (d, J=8.1 Hz, 1H), 4.72 (d, J=5.6 Hz, 2H), 4.61-4.54 (m, 1H), 4.14-4.10 (m, 1H), 3.35 (d, J=6.1 Hz, 2H), 3.15 (s, 3H), 3.00 (dd, J=13.8, 5.4 Hz, 1H), 2.84 (d, J=13.8, 8.8 Hz, 1H), 1.45-1.30 (m, 9H). Example 17—Preparation of (S)-2-amino-N—((S)-3-(4-fluorophenyl)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-3-methoxypropanamide (H-Ser(OMe)-4F-Phe-naphth, DPLG-2050) DPLG-2050 was synthesized by following the general procedure for Boc-deprotection of Boc-Ser(OMe)-4F-Phe-naphth (from previous step). After completion of reaction (3 h), excess trifluoroacetic acid and dichloromethane were evaporated. Crude product was washed with diethyl ether and dried to give product 70.0 mg (65% for 2 steps).1H NMR (500 MHz, DMSO-d6) 67 8.80 (d, J=8.2 Hz, 1H), 8.65 (t, J=5.6 Hz, 1H), 8.14 (bs, 3H), 8.02-7.99 (m, 1H), 7.98-7.95 (m, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.58-7.53 (m, 2H), 7.43 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (dd, J=7.0, 1.2 Hz, 1H), 7.26-7.23 (m, 2H), 7.10-7.05 (m, 2H), 4.74 (d, J=5.6 Hz, 2H), 4.62 (td, J=8.5, 5.7 Hz, 1H), 3.97 (m, 1H), 3.66 (dd, J=10.7, 3.6 Hz, 1H), 3.56 (dd, J=10.7, 7.0 Hz, 1H), 3.26 (s, 3H), 3.00 (dd, J=13.7, 5.7 Hz, 1H), 2.85 (dd, J=13.7, 8.8 Hz, 1H). Example 18—Preparation of (S)-3-(4-fluorophenyl)-2-((S)-3-methoxy-2-(3-phenylpropanamido)propanamido)-N-(naphthalen-1-ylmethyl)propanamide(3-Phenylpropanoyl-Ser(OMe)-4F-Phe-naphth, DPLG-2054) DPLG-2054 was prepared by following the general procedure for EDCI coupling of TFA.H-Ser(OMe)-4F-Phe-naphth (16 mg, 0.03 mmol) and 3-phenylpropanoic acid (5.4 mg, 0.036 mg). The product was purified by HPLC to give 5.8 mg (29%) of product.1H NMR (500 MHz, Chloroform-d) δ 7.92-7.91 (m, 1H), 7.87-7.86 (m, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.54-7.50 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.34 (d, J=6.9 Hz, 1H), 7.28-7.24 (m, 2H), 7.22-7.19 (m, 1H), 7.12-7.10 (m, 2H), 7.06-7.03 (m, 2H), 6.86-6.82 (m, 2H), 6.44 (t, J=5.7 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 6.08 (d, J=6.3 Hz, 1H), 4.90 (dd, J=14.6, 5.7 Hz, 1H), 4.78 (dd, J=14.6, 5.2 Hz, 1H), 4.68 (dt, J=8.5, 6.5 Hz, 1H), 4.34 (td, J=6.7, 4.4 Hz, 1H), 3.50 (dd, J=9.4, 4.4 Hz, 1H), 3.14-3.08 (m, 2H), 3.05 (dd, J=14.0, 6.6 Hz, 1H), 2.99 (s, 3H), 2.86-2.79 (m, 2H), 2.43 (t, J=7.7 Hz, 2H). Example 19—Preparation of (S)-3-(4-fluorophenyl)-2-(S)-3-methoxy-2-(4-methylphenylsulfonamido)propanamido)-N-(naphthalen-1-ylmethyl)propanamide (Ts-Ser(OMe)-4F-Phe-naphth, DPLG-2052) TFA.H-Ser(OMe)-4F-Phe-naphth (13.4 mg, 0.025 mmol) was dissolved in dichloromethane and the solution was cooled to 0° C. Triethylamine (28 μL) followed by TsCl (6 mg+20 mg) were added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred overnight. Dichloromethane was evaporated and the crude was dissolved in ethylacetate. The solution was washed with water, 1N HCl followed by brine. The product was purified by HPLC to give 7.8 mg (54%) of product.1H NMR (500 MHz, DMSO-d6) δ 8.39 (t, J=5.9 Hz, 1H), 8.27 (d, J=8.1 Hz, 1H), 8.00-7.93 (m, 3H), 7.84 (d, J=8.3 Hz, 1H), 7.61-7.59 (m, 2H), 7.55-7.53 (m, 2H), 7.40 (dd, J=8.2, 7.0 Hz, 1H), 7.27-7.24 (m, 3H), 7.17-7.13 (m, 2H), 7.04-7.00 (m, 2H), 4.70 (d, J=5.7 Hz, 2H), 4.38 (td, J=8.0, 6.1 Hz, 1H), 3.96-3.93 (m, 1H), 3.26-3.24 (m, 2H), 3.02 (s, 3H), 2.88 (dd, J=13.7, 6.0 Hz, 1H), 2.67 (dd, J=13.7, 8.0 Hz, 1H), 2.32 (s, 3H). Example 20—Preparation of tert-butyl (S)-(1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)carbamate (Boc-Ala-naphth) Boc-Ala-OSu (286 mg, 1.0 mmol) and 1-naphthylmethylamine (160 ↑l, 1.1 mmol) were dissolved in dichloromethane (10 mL). The solution was cooled to 0° C. and triethylamine (100 μL) was added. Reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature. After completion of reaction, dichloromethane was evaporated and crude was suspended in water. Water layer was extracted twice with ethyl acetate. The combined organic layer was washed with aq. NaHCO3, water, 1N HCl and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give product (320 mg, 97%), which was used in next step without further purification.1H NMR (500 MHz, Chloroform-d) δ 7.96 (d, J=8.1 Hz, 1H), 7.87 (dd, J=7.5, 1.7 Hz, 1H), 7.80 (dd, J=6.9, 2.5 Hz, 1H), 7.59-7.48 (m, 2H), 7.44-7.40 (m, 2H), 6.44 (s, 1H), 4.96-4.88 (m, 3H), 4.18-4.15 (m, 1H), 1.37 (d, J=7.1 Hz, 3H), 1.34 (s, 9H). Example 21—Preparation of (S)-2-amino-N-(naphthalen-1-ylmethyl)propanamide 2,2,2-trifluoroacetate (H-Ala-naphth, DPLG-2026) DPLG-2026 was synthesized by following the general procedure for Boc-deprotection of Boc-Ala-naphth (158 mg, 0.48 mmol). After completion of reaction (3 h), dichloromethane and excess TFA were evaporated. The crude product was dried under vacuum to give product (164 mg, quant.).1H NMR (500 MHz, DMSO-d6) δ 8.91 (t, J=5.7 Hz, 1H), 8.15 (bs, 3H), 8.07-8.04 (m, 1H), 7.99-7.97 (m, 1H), 7.91-7.87 (m, 1H), 7.60-7.55 (m, 2H), 7.51-7.48 (m, 2H), 4.85 (dd, J=15.2, 5.7 Hz, 1H), 4.78 (dd, J=15.2, 5.5 Hz, 1H), 3.91-3.86 (m, 1H), 1.37 (d, J=7.0 Hz, 3H). Example 22—Preparation of tert-butyl ((S)-3-methoxy-1-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Boc-Ser(OMe)-Ala-naphth, DPLG-2032) H-Ala-naphth TFA salt (0.24 mmol) was dissolved in 3 mL dimethylformamide and basified with N-methylmorpholine. Boc-Ser(OMe)-OH (96 mg, 0.24 mmol) was added to the solution. The mixture was cooled to 0° C. and dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate (103 mg, 0.25 mmol) were added in one portion. The reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was dried over anhydrous Na2SO4and evaporated. The product was purified by silica gel column chromatography (eluent ethylacetate and hexane) to give 95 mg (92%) of product.1H NMR (500 MHz, DMSO-d6) δ 8.29 (t, J=5.8 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H), 8.03-8.01 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.48-7.45 (m, 1H), 7.42 (dd, J=7.0, 1.4 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 4.36-4.31 (m, 1H), 4.19-4.15 (m, 1H), 3.47-3.39 (m, 2H), 3.15 (s, 3H), 1.37 (s, 9H), 1.25 (d, J=7.1 Hz, 3H). Example 23—Preparation of (S)-2-amino-3-methoxy-N—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)propanamide 2,2,2-trifluoroacetate (H-Ser(OMe)-Ala-naphth, DPLG-2038) DPLG-2038 was synthesized by following the general procedure for Boc-deprotection of Boc-Ser(OMe)-Alanaphth (95 mg, 0.22 mmol). After completion of reaction, dichloromethane and excess trifluoroacetic acid were evaporated and crude was triturated with diethylether. The mixture was filtered to give corresponding amine TFA salt (60 mg, 61%) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=7.6 Hz, 1H), 8.51 (t, J=5.7 Hz, 1H), 8.18 (bs, 3H), 8.05-8.03 (m, 1H), 7.97-7.95 (m, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.58-7.54 (m, 2H), 7.49-7.43 (m, 2H), 4.80-4.72 (m, 2H), 4.45-4.39 (m, 1H), 4.03 (m, 1H), 3.65 (dd, J=10.7, 3.8 Hz, 1H), 3.56 (dd, J=10.7, 7.2 Hz, 1H), 3.25 (s, 3H), 1.28 (d, J=7.0 Hz, 3H). Example 24—Preparation of (S)-3-methoxy-N—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(3-phenylpropanamido)propanamide (3-Phenylproapanamide-Ser(OMe)-Ala-naphth, DPLG-2048) DPLG-2048 was prepared following the general procedure for EDC coupling of 3-phenylpropianic acid (16.5 mg, 0.11 mmol) with TFA.H-Ser(OMe)-Ala-naphth (44.3 mg, 0.1 mmol). The crude was purified by silica gel column chromatography to give 44.1 mg (87%) of product.1H NMR (500 MHz, DMSO-d6) δ 8.24-8.18 (m, 2H), 8.15 (d, J=7.8 Hz, 1H), 8.04-8.02 (m, 1H), 7.96-7.94 (m, 1H), 7.86-7.84 (m, 1H), 7.56-7.53 (m, 2H), 7.45-7.40 (m, 2H), 7.27-7.24 (m, 2H), 7.20-7.16 (m, 3H), 4.75 (d, J=5.7 Hz, 2H), 4.50 (dt, J=7.9, 6.0 Hz, 1H), 4.36-4.30 (m, 1H), 3.45-3.41 (m, 2H), 3.12 (s, 3H), 2.79 (t, J=7.9 Hz, 2H), 2.47-2.44 (m, 2H), 1.26 (d, J=7.1 Hz, 3H). Example 25—Preparation of N—((S)-3-methoxy-1-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-5-methylisoxazole-3-carboxamide (5-methylisoxazole-3-carbamide-Ser(OMe)-Ala-naphth, DPLG-2040) DPLG-2040 was prepared following the general procedure for EDC mediated coupling of 5-methyl-iso-oxazole-3-carboxylic acid (9.2 mg, 0.072 mmol) with TFA.H-Ser (OMe)-Ala-naphth (28.0 mg, 0.06 mmol). The product was purified by HPLC to give 16.3 mg (62%) of product.1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J=7.9 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.32 (t, J=5.8 Hz, 1H), 8.04-8.02 (m, 1H), 7.96-7.94 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.48-7.42 (m, 2H), 6.56 (d, J=1.1 Hz, 1H), 4.76-4.68 (m, 3H), 4.39-4.34 (m, 1H), 3.64-3.58 (m, 2H), 3.19 (s, 3H), 2.47 (s, 3H), 1.27 (d, J=7.1 Hz, 3H).13C NMR (126 MHz, DMSO) δ 172.19, 171.82, 168.93, 159.05, 158.95, 134.77, 133.72, 131.25, 128.96, 128.04, 126.66, 126.28, 125.85, 125.58, 123.84, 101.82, 72.05, 58.64, 53.19, 48.97, 39.57, 18.71, 12.31. Example 26—Preparation of N—((S)-3-methoxy-1-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-4 -carboxamide (2-methylthiazole-4-carboxamide-Ser(OMe)-Ala-naphth, DPLG-2039) DPLG-2039 was prepared following the general procedure for EDCI coupling of 2-methylthiazole-4-carboxylic acid (10.3 mg, 0.072 mmol) and TFA.H-Ser(OMe)-Ala-naphth (28.0 mg, 0.06 mmol). The product was purified by HPLC to give 14.3 mg (52%) mg of product.1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=7.6 Hz, 1H), 8.32 (t, J=5.7 Hz, 1H), 8.13 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 8.04-8.02 (m, 1H), 7.96-7.94 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.49-7.42 (m, 2H), 4.76 (d, J=5.7 Hz, 2H), 4.71 (dt, J=8.2, 5.5 Hz, 1H), 4.42-4.36 (m, 1H), 3.65 (dd, J=10.0, 6.1 Hz, 1H), 3.58 (dd, J=10.0, 4.9 Hz, 1H), 3.17 (s, 3H), 2.72 (s, 3H), 1.27 (d, J=7.0 Hz, 3H).13C NMR (126 MHz, DMSO) δ 172.14, 169.22, 166.95, 160.38, 149.16, 134.76, 133.73, 131.26, 128.96, 128.06, 126.67, 126.29, 125.86, 125.62, 124.73, 123.85, 72.68, 58.74, 52.69, 48.94, 40.67, 19.22, 18.77. Example 27—Preparation of tert-butyl (S)-(1-(((1H-indol-4-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (Boc-Ala-Indole, DPLG-2022) Boc-Ala-OSu (515 mg, 1.8 mmol) was dissolved in 10 mL dry dichloromethane. The solution was cooled to 0° C. and a solution of 4-(aminomethyl)indole (263 mg, 1.8 mmol) in DMF (2 mL) was added. The reaction mixture was warmed to room temperature and stirred overnight. After completion of reaction, dichloromethane was evaporated. The crude solid was dissolved in ethyl acetate and washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give product (560 mg, 98%), which was pure by NMR.1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.17 (t, J=5.8 Hz, 1H), 7.32-7.29 (m, 2H), 7.01 (t, J=7.6 Hz, 1H), 6.90-6.87 (m, 2H), 6.48-6.47 (m, 1H), 4.58 (dd, J=15.2, 6.0 Hz, 1H), 4.47 (dd, J=15.2, 5.5 Hz, 1H), 4.05-3.99 (m, 1H), 1.38 (s, 9H), 1.20 (d, J=7.1 Hz, 3H). Example 28—Preparation of (S)—N-((1H-indol-4-yl)methyl)-2-aminopropanamide (H-Ala-indole, DPLG-2025) DPLG-2025 was synthesized by following the general procedure for Boc-deprotection of Boc-Ala-Indole (276 mg, 0.87 mmol). After completion of reaction (2 h) dichloromethane and excess TFA were evaporated. The crude product was dissolved in water and washed with dichloromethane. The water layer was frozen and lyophilized to give solid product (213 mg 74%).1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.76 (t, J=5.8 Hz, 1H), 8.05 (bs, 3H), 7.36-7.32 (m, 2H), 7.04 (t, J=7.6 Hz, 1H), 6.93-6.90 (m, 1H), 6.50-6.48 (m, 1H), 4.63 (dd, J=14.9, 5.8 Hz, 1H), 4.53 (dd, J=14.9, 5.4 Hz, 1H), 3.84-3.80 (m, 1H), 1.35 (d, J=6.9 Hz, 3H). Example 29—Preparation of tert-butyl ((S)-1-(((S)-1-(((1H-indol-4 -yl)methyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Boc-Ala-Ala-Indole, DPLG-2028) (S)—N-((1H-indol-4-yl)methyl)-2-aminopropanamide (33.1 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (2 mL) and triethylamine (28 μL, 0.2 mmol) was added. The solution was cooled to 0° C. and Boc-Ala-OSu was added in one portion. A white precipitate appeared. After 30 minutes, the solvent was evaporated and the crude was dissolved in ethyl acetate. The solution was washed with water, NaHCO3solution followed by brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give product (38.0 mg, 98%).1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.34-8.31 (m, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.32-7.29 (m, 2H), 7.03-7.00 (m, 2H), 6.86 (d, J=7.2 Hz, 1H), 6.47-6.45 (m, 1H), 4.55 (dd, J=15.1, 5.8 Hz, 1H), 4.50 (dd, J=15.1, 5.6 Hz, 1H), 4.37-4.29 (m, 1H), 3.99-3.93 (m, 1H), 1.37 (s, 9H), 1.23 (d, J=7.0 Hz, 3H), 1.16 (d, J=6.6 Hz, 3H). Example 30—Preparation of (S)—N-((1H-indol-4-yl)methyl)-2-((S)-2-aminopropanamido)propanamide 2,2,2-trifluoroacetate (H-Ala-Ala-Indole, DPLG-2033) DPLG-2033 was synthesized by following the general procedure for Boc-deprotection of tert-butyl ((S)-1-4(S)-1-4(1H-indol-4-yl)methyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (240 mg, 0.618 mmol). After completion of reaction (4 h), excess trifluoroacetic acid and dichloromethane were evaporated and the crude was washed twice with diethyl ether to give product (193 mg, 78%).1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.59 (d, J=7.7 Hz, 1H), 8.46 (t, J=5.7 Hz, 1H), 8.06 (bs, 3H), 7.33-7.30 (m, 2H), 7.04-7.01 (m, 1H), 6.87 (d, J=7.2 Hz, 1H), 6.48 (d, J=2.8 Hz, 1H), 4.57 (dd, J=15.1, 5.7 Hz, 1H), 4.51 (dd, J=15.1, 5.5 Hz, 1H), 4.44-4.38 (m, 1H), 3.87 (m, 1H), 1.33 (d, J=7.0 Hz, 3H), 1.27 (d, J=7.0 Hz, 3H). Example 31—Preparation of N—((S)-1-(((S)-1-(((1H-indol-4-yl)methyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-4 -carboxamide (2-methylthiazole-4-carboxamide-Ala-Ala-Indole, DPLG-2042) DPLG-2042 was prepared following the general procedure for EDC mediated coupling of 2-methylthiazole-4-carboxylic acid (21 mg, 0.144 mmol) and (S)—N-((1H-indol-4-yl)methyl)-2-((S)-2-aminopropanamido) propanamide 2,2,2-trifluoroacetate (50.0 mg, 0.12 mmol). The crude was purified by HPLC to give 16.0 mg (32%) of product.1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (t, J=5.9 Hz, 1H), 8.28 (d, J=7.7 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.11 (s, 1H), 7.32-7.29 (m, 2H), 7.04-7.01 (m, 1H), 6.87 (d, J=7.1 Hz, 1H), 6.48 (t, J=2.2 Hz, 1H), 4.59-4.48 (m, 3H), 4.41-4.35 (m, 1H), 2.72 (s, 3H), 1.32 (d, J=7.0 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H).13C NMR (126 MHz, DMSO) δ 172.14, 171.88, 166.82, 160.09, 149.42, 136.22, 130.45, 126.57, 125.37, 124.46, 121.16, 117.64, 110.86, 79.64, 48.73, 48.59, 41.07, 19.36, 19.21, 19.00. Example 32—Preparation of N—((S)-1-(((S)-1-(((1H-indol-4-yl)methyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-5-methylisoxazole-3-carboxamide (5-methylisoxazole-3-carboxamide-Ala-Ala-Indole, DPLG-2041) DPLG-2041 was prepared following the general procedure for EDC mediated coupling of 5-methyl-iso-oxazole-3-carboxylic acid (18.3 mg, 0.144 mmol) and (S)—N-((1H-indol-4-yl)methyl)-2-((S)-2-aminopropanamido) propanamide 2,2,2-trifluoroacetate (50.0 mg, 0.12 mmol). The product was purified by HPLC to give 6.1 mg (13%) of product.1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.58 (d, J=7.4 Hz, 1H), 8.32 (t, J=5.8 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.32-7.29 (m, 2H), 7.02 (t, J=7.6 Hz, 1H), 6.87 (d, J=7.1 Hz, 1H), 6.54 (s, 1H), 6.48-6.47 (m, 1H), 4.58-4.45 (m, 3H), 4.38-4.33 (m, 1H), 2.47 (s, 3H), 1.32 (d, J=7.1 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H).13C NMR (126 MHz, DMSO) δ 172.21, 171.67, 171.62, 159.08, 158.75, 136.22, 130.44, 126.56, 125.37, 121.16, 117.63, 110.85, 101.80, 99.82, 49.01, 48.74, 41.06, 18.98, 18.44, 12.30. Example 33—Preparation of N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparagine (DPLG-2076) DPLG-2076 was synthesized by following the general procedure for O-debenzylation of benzyl N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparaginate (592 mg, 1.5 mmol). After completion of reaction (5 h), the mixture was filtered through celite and filterate was evaporated to give product (450 mg, 98%).1H NMR (500 MHz, Chloroform-d) δ 9.28 & 8.98 (s, rotamers, 1H), 6.92 & 5.76 (bs, rotamers, 1H), 4.59-4.47 (m, 1H), 3.22-2.69 (m, 2H), 1.44 (s, 9H), 1.27 & 1.24 (s, rotamers, 9H). Example 34—Preparation of Benzyl N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparaginyl-L-alaninate (DPLG-2081) DPLG-2081 was prepared by following the general procedure for HATU mediated coupling of N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparagine (304 mg, 1 mmol) and O-benzylalanine hydrochloride (237 mg, 1.1 mmol). After completion of reaction (4 h), water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic layer was evaporated and the crude product was purified by recrystallization with ethanol-water to give pure product (276 mg, 59%).1H NMR (500 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.51-7.34 (m, 6H), 6.13 & 5.89 (bs, rotamers, 1H), 5.20 (d, J=12.4 Hz, 1H), 5.15 (d, J=12.4 Hz, 1H), 4.60-4.45 (m, 2H), 2.79-2.66 (m, 1H), 2.49-2.45 (m, 1H), 1.46 (s, 9H), 1.41 (d, J=7.2 Hz, 3H), 1.26 (s, 9H). Example 35—Preparation of N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparaginyl-L-alanine (DPLG-2092) DPLG-2092 was synthesized by following the general procedure for O-debenzylation of benzyl N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparaginyl-L-alaninate (150 mg, 0.32 mmol). After completion of reaction, mixture was filtered through celite and evaporated to give product (120 mg, quant.).1H NMR (500 MHz, DMSO-d6) δ 12.96 (bs, 1H), 10.37 (s, 1H), 7.94 (d, J=6.7 Hz, 1H), 7.01 (d, J=6.6 Hz, 1H), 4.28-4.23 (m, 1H), 4.10-4.04 (m, 1H), 2.39 (dd, J=14.4, 4.4 Hz, 1H), 2.27 (dd, J=14.4, 9.9 Hz, 1H), 1.37 (s, 9H), 1.23 (d, J=7.2 Hz, 3H), 1.14 (s, 9H). Example 36—Preparation of tert-butyl ((4S,7S)-4,12,12-trimethyl-1-(naphthalen-1-yl)-3,6,9-trioxo-11-oxa-2,5,10-triazatridecan-7-yl)carbamate (DPLG-2095) DPLG-2095 was prepared following the general procedure for HATU mediated coupling of N4-(tert-butoxy)-N2-(tert-butoxycarbonyl)-L-asparaginyl-L-alanine (120 mg, 0.32 mmol) and 1-naphthylmethylamine (56 μl, 0.38 mmol). After completion of reaction (6 h), the mixture was precipitated with water. The precipitate was filtered and dried to give product (153 mg, 93%).1H NMR (500 MHz, DMSO-d6) δ 0.26 (s, 1H), 8.47 (t, J=5.7 Hz, 1H), 8.06-8.04 (m, 1H), 8.01 (d, J=7.4 Hz, 1H), 7.96-7.94 (m, 1H), 7.86-7.84 (m, 1H), 7.57-7.52 (m, 2H), 7.48-7.43 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 4.74 (d, J=5.8 Hz, 2H), 4.32-4.26 (m, 2H), 2.46 (dd, J=14.6, 5.5 Hz, 1H), 2.29 (dd, J=14.6, 8.5 Hz, 1H), 1.37 (s, 9H), 1.24 (d, J=7.0 Hz, 3H), 1.13 (s, 9H). Example 37—Preparation of (S)-2-amino-N4-(tert-butoxy)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2097) DPLG-2097 was synthesized by following the general procedure for Boc-deprotection of tert-butyl ((4S,7S)-4,12,12-trimethyl-1-(naphthalen-1-yl)-3,6,9-trioxo-11-oxa-2,5,10-triazatridecan-7-yl)carbamate (118 mg, 0.23 mmol). After completion of reaction, excess trifluoroacetic acid and dichloromethane were evaporated. The crude was triturated with diethyl ether to give product (120 mg, 98%).1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.71 (d, J=7.3 Hz, 1H), 8.58 (t, J=5.7 Hz, 1H), 8.16 (s, 3H), 8.07-8.05 (m, 1H), 7.97-7.95 (m, 1H), 7.87-7.85 (m, 1H), 7.58-7.53 (m, 2H), 7.49-7.44 (m, 2H), 4.79-4.71 (m, 2H), 4.39-4.34 (m, 1H), 4.13 (m, 1H), 2.70 (dd, J=16.4, 4.9 Hz, 1H), 2.56 (dd, J=16.4, 8.1 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H), 1.15 (s, 9H). Example 38—Preparation of (S)—N4-(tert-butoxy)-N14(S)-1-((naphthalen-1-ylmethyl)amino)-1-oxo-propan-2-yl)-2-(pyrazine-2-carboxamido)succinamide (DPLG-2098) DPLG-2098 was prepared by following the general procedure for HATU mediated coupling of pyrazine-2-carboxylic acid (2.5 mg, 0.02 mmol) and (S)-2-amino-N4-(tertbutoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol). The crude was purified by HPLC to give 10.3 mg (99%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.19 (d, J=1.4 Hz, 1H), 8.94 (d, J=8.1 Hz, 1H), 8.92 (d, J=2.5 Hz, 1H), 8.78 (t J=2.0 Hz, 1H), 8.50 (t J=5.8 Hz, 1H), 8.37 (d, J=7.3 Hz, 1H), 8.07-8.05 (m, 1H), 7.95-7.93 (m, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.48-7.44 (m, 2H), 4.85-4.81 (m, 1H), 4.75 (d, J=5.8 Hz, 2H), 4.36-4.30 (m, 1H), 2.68 (dd, J=14.7, 7.2 Hz, 1H), 2.63 (dd, J=14.7, 5.2 Hz, 35 1H), 1.27 (d, J=7.1 Hz, 3H), 1.06 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 172.34, 170.17, 167.99, 162.82, 148.35, 144.51, 143.88, 134.86, 133.69, 131.25, 128.94, 127.92, 126.62, 126.21, 125.85, 125.63, 123.84, 81.09, 50.50, 49.19, 40.63, 35.39, 26.62, 18.44. Example 39—Preparation of (S)—N4-(tert-butoxy)-2-(2-morpholinoacetamido)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2099) DPLG-2099 was prepared by following the general procedure for HATU mediated coupling of morpholine-4-acetic acid (3.0 mg, 0.02 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol). The crude was purified by HPLC to give 10.6 mg (98%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.50 (t, J=5.8 Hz, 1H), 8.20 (d, J=7.3 Hz, 1H), 8.08-8.06 (m, 1H), 7.98-8.02 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (dd, J=7.0, 2.6 Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.44 (m, 2H), 4.73 (d, J=5.7 Hz, 2H), 4.62-4.57 (m, 1H), 4.31-4.27 (m, 1H), 3.61 (t, J=4.6 Hz, 4H), 2.94 (s, 2H), 2.50-2.43 (m, 6H), 1.25 (d, J=7.2 Hz, 3H), 1.11 (s, 9H). Example 40—Preparation of S)—N4-(tert-butoxy)-2-((4-methylphenyl)sulfonamido)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2091) ((S)-2-amino-N4-(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol) was dissolved in dichloromethane and dimethylformamide (1 mL+1 mL) and the solution was cooled to 0° C. 4-(Dimethylamino)pyridine (1.2 mg, 0.01 mmol), Hunig's base (11 mL, 0.06 mmol) and 4-toluene-sulphonyl chloride (0.02 mmol) were added and the solution was allowed to warm to room temperature. After completion of the reaction (5 h), mixture was diluted with dichloromethane and washed with water. The organic layer was evaporated and purified by HPLC to give product (5.1 mg, 45%).1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.33 (t, J=6.0 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.08-8.06 (m, 1H), 7.94-7.92 (m, 1H), 7.83 (d, J=7.6, 1H), 7.65 (d, J=7.9 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.41 (m, 2H), 7.32 (d, J=7.9 Hz, 2H), 4.74 (dd, J=15.3, 6.1 Hz, 1H), 4.64 (dd, J=15.3, 5.7 Hz, 1H), 4.10-4.07 (m, 1H), 3.92-3.86 (m, 1H), 2.42 (dd, J=14.8, 7.7 Hz, 1H), 2.36 (s, 3H), 2.22 (dd, J=14.8, 6.5 Hz, 1H), 1.09-1.06 (m, 12H).13C NMR (126 MHz, DMSO-d6) δ 172.14, 169.91, 167.48, 134.89, 133.67, 131.25, 129.69, 128.91, 127.86, 127.13, 126.60, 126.34, 126.22, 126.18, 125.80, 125.64, 123.85, 81.10, 53.41, 49.06, 40.58, 36.34, 26.68, 21.41, 18.08. Example 41—Preparation of (S)—N4-(tert-butoxy)-2-(2-methylthiazole-4-carboxamido)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl) succinamide (DPLG-2102) DPLG-2102 was prepared by following the general pro-cedure for HATU mediated coupling of 2-methylthiazole-3-carboxylic acid (2.9 mg, 0.02 mmol) and (S)-2-amino-N4(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol). The crude was purified by HPLC to give 8.4 mg (77%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.52 (t, J=5.8 Hz, 1H), 8.32 (d, J=7.3 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 8.12 (s, 1H), 8.08-8.06 (m, 1H), 7.96-7.94 (m, 1H), 7.84 (dd, J=7.0, 2.5 Hz, 1H), 7.56-7.52 (m, 2H), 7.48-7.44 (m, 2H), 4.78-4.74 (m, 3H), 4.35-4.29 (m, 1H), 2.71 (s, 3H), 2.63 (dd, J=14.6, 7.3 Hz, 1H), 2.58 (dd, J=14.6, 5.3 Hz, 1H), 1.26 (d, J=7.1 Hz, 3H), 1.07 (s, 9H).13C NMR (125 MHz, DMSO-d6) δ 172.36, 170.42, 167.98, 166.75, 160.36, 149.21, 134.86, 133.69, 131.26, 128.94, 127.91, 126.63, 126.22, 125.87, 125.64, 124.70, 123.85, 81.11, 50.30, 49.14, 40.63, 35.60, 26.64, 19.20, 18.50. Example 42—Preparation of (S)—N4-(tert-butoxy)-2-(5-methylisoxazole-3-carboxamido)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2105) DPLG-2105 was prepared by following the general procedure for HATU mediated coupling of 5-methylisoxazole-3-carboxylic acid (2.5 mg, 0.02 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol). The crude was purified by HPLC to give 10.2 mg (97%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.48 (t, J=5.8 Hz, 1H), 8.27 (d, J=7.4 Hz, 1H), 8.06-8.04 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (dd, J=7.4, 1.9 Hz, 1H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 2H), 6.54 (s, 1H), 4.79-4.76 (m, 1H), 4.74 (d, J=5.8 Hz, 2H), 4.34-4.28 (m, 1H), 2.60 (dd, J=14.7, 5.5 Hz, 1H), 2.55 (dd, J=14.7, 8.0 Hz, 1H), 2.47 (s, 3H), 1.25 (d, J=7.1 Hz, 3H), 1.09 (s, 9H).13C NMR (125 MHz, DMSO-d6) δ 171.88, 171.36, 169.73, 167.46, 158.45, 158.36, 134.38, 133.22, 130.78, 128.47, 127.47, 126.17, 125.76, 125.40, 125.16, 123.37, 101.31, 80.59, 50.03, 48.65, 40.15, 34.65, 26.20, 18.10, 11.83. Example 43—Preparation of (S)—N4-(tert-butoxy)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxo-propan-2-yl)-2-(oxirane-2-carboxamido)succinamide (DPLG-2103) DPLG-2103 was prepared by following the general procedure for HATU mediated coupling of potassium oxirane-2-benzoate (2.5 mg, 0.02 mmol) and (S)-2-amino-N4-(tertbutoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol). The crude was purified by HPLC to give 8.0 mg (82%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.48 (t, J=5.8 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.08-8.06 (m, 1H), 7.96-7.94 (m, 1H), 7.84 (dd, J=7.3, 2.1 Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.43 (m, 2H), 4.74 (d, J=5.8 Hz, 2H), 4.62 (td, J=8.1, 5.7 Hz, 1H), 4.31-4.25 (m, 1H), 3.46 (dd, J=4.3, 2.5 Hz, 1H), 2.90 (dd, J=6.4, 4.3 Hz, 1H), 2.77 (dd, J=6.4, 2.5 Hz, 1H), 2.55-2.51 (m, 1H), 2.42 (dd, J=14.7, 8.0 Hz, 1H), 1.25 (d, J=7.1 Hz, 3H), 1.12 (s, 9H).13C NMR (125 MHz, DMSO-d6) δ 171.90, 169.94, 167.57, 167.40, 134.40, 133.23, 130.79, 128.47, 127.45, 126.17, 125.76, 125.39, 125.19, 123.38, 80.60, 49.54, 48.60, 48.23, 45.59, 40.15, 34.83, 26.23, 18.05. Example 44—Preparation of (S)—N4-(tert-butoxy)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(2,2,2-trifluoroacetamido)succinamide (DPLG-2106) (S)-2-amino-N4-(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (10.6 mg, 0.02 mmol) was dissolved in 1 mL tetrahydrofuran and the solution was cooled to 0° C. The mixture was basified with N-methylmorpholine (4.4 mL, 0.04 mmol). Trifluoroacetic anhydride (2.8 mL, 0.02 mmol) was added, and mixture was stirred for one hour at 0° C. The crude was purified by HPLC to give pure product (8.3 mg, 81%).1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.67 (s, 1H), 8.48 (t, J=5.7 Hz, 1H), 8.41 (d, J=7.3 Hz, 1H), 8.06-8.04 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.57-7.53 (m, 2H), 7.48-7.43 (m, 2H), 4.74-4.70 (m, 3H), 4.33-4.27 (m, 1H), 2.63 (dd, J=15.2, 5.0 Hz, 1H), 2.54-2.49 (m, 1H), 1.26 (d, J=7.1 Hz, 3H), 1.12 (s, 9H).13C NMR (125 MHz, DMSO-d6) δ 172.37, 169.53, 167.42, 134.87, 133.70, 131.25, 128.94, 127.93, 126.63, 126.24, 125.86, 125.58, 123.84, 81.08, 50.66, 49.19, 40.62, 34.60, 26.65, 18.50.19F NMR (471 MHz, DMSO, C6F6 external reference) 6-71.81. Example 45—Preparation of (S)—N4-(tert-butoxy)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(4 -phenylbutanamido)succinamide (DPLG-2127) DPLG-2127 was prepared by following the general procedure for HATU mediated coupling of 4-phenylbutanoic acid (5.4 mg, 0.033 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (17.3 mg, 0.033 mmol). The crude was purified by HPLC to give 15.7 mg (85%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.46 (t, J=5.9 Hz, 1H), 8.11-8.06 (m, 3H), 7.95-7.93 (m, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.45 (d, J=5.0 Hz, 2H), 7.28-7.25 (m, 2H), 7.19-7.16 (m, 3H), 4.75 (dd, J=15.3, 5.9 Hz, 1H), 4.70 (dd, J=15.3, 5.7 Hz, 1H), 4.60-4.56 (m, 1H), 4.30-4.24 (m, 1H), 2.56-2.50 (m, 3H), 2.34 (dd, J=14.8, 7.8 Hz, 1H), 2.13 (t, J=7.4 Hz, 2H), 1.80-1.74 (m, 2H), 1.24 (d, J=7.0 Hz, 3H), 1.10 (s, 9H).13C NMR (125 MHz, DMSO-d6) δ 172.43, 172.37, 171.03, 168.12, 142.26, 134.87, 133.69, 131.26, 128.93, 128.77, 128.70, 127.90, 126.62, 126.21, 126.17, 125.84, 125.67, 123.85, 99.99, 80.99, 50.17, 49.05, 35.24, 35.10, 35.04, 27.48, 26.70, 18.55. Example 46—Preparation of (S)—N4-(tert-butoxy)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(2-phenylacetamido)succinamide (DPLG-2142) DPLG-2142 was prepared by following the general procedure for HATU mediated coupling of phenylacetic acid (4.9 mg, 0.036 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (17.3 mg, 0.033 mmol). The crude was purified by HPLC to give 12.1 mg (68%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.47 (t, J=5.9 Hz, 1H), 8.36 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.4 Hz, 1H), 8.09-8.07 (m, 1H), 7.95-7.93 (m, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.45 (d, J=5.0 Hz, 2H), 7.29-7.19 (m, 5H), 4.76 (dd, J=15.3, 6.0 Hz, 1H), 4.69 (dd, J=15.3, 5.8 Hz, 1H), 4.60-4.56 (m, 1H), 4.29-4.23 (m, 1H), 3.46 (s, 2H), 2.56-2.51 (m, 1H), 2.37 (dd, J=14.9, 7.3 Hz, 1H), 1.22 (d, J=7.1 Hz, 3H), 1.10 (s, 9H).13C NMR (126 MHz, DMSO) δ 172.37, 170.90, 170.54, 168.07, 136.60, 134.91, 133.69, 131.28, 129.51, 128.93, 128.60, 127.90, 126.77, 126.63, 126.20, 125.84, 125.72, 123.87, 81.03, 50.18, 49.12, 42.40, 40.58, 35.30, 26.71, 18.41. Example 47—Preparation of benzyl (S)-3-((tertbutoxycarbonyl)amino)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (DPLG-2074) DPLG-2074 was prepared following the general procedure for HATU mediated coupling of N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (217 mg, 0.67 mmol) and (S)-2-amino-N-(naphthalen-1-ylmethyl)propanamide (230 mg, 0.67 mmol). The product was isolated by ethyl acetate extraction and purified by recrystallization with ethanol-water (yield=302 mg, 85%).1H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.76 (dd, J=7.0, 2.4 Hz, 1H), 7.53-7.46 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.28 (m, 3H), 7.26-7.24 (m, 2H), 6.76 (d, J=7.6 Hz, 1H), 6.64 (m, 1H), 5.45 (d, J=8.4 Hz, 1H), 4.96 (d, J=11.9 Hz, 1H), 4.93 (d, J=11.9 Hz, 1H), 4.86 (d, J=5.4 Hz, 2H), 4.45-4.35 (m, 2H), 2.86 (dd, J=17.1, 4.6 Hz, 1H), 2.67 (dd, J=17.1, 6.7 Hz, 1H), 1.39-1.38 (m, 12H). Example 48—Preparation of benzyl (S)-3-amino-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (DPLG-2114) DPLG-2114 was synthesized by following the general procedure for Boc-deprotection of benzyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (50 mg, 0.094 mmol). After completion of reaction (3 h), excess trifluoroacetic acid and dichloromethane were evaporated and the crude was dried under vacuum. The crude product (51 mg, quant.) was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J=7.4 Hz, 1H), 8.50 (t, J=5.8 Hz, 1H), 8.26 (d, J=5.1 Hz, 3H), 8.04-8.02 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.56-7.51 (m, 2H), 7.48-7.42 (m, 2H), 7.39-7.34 (m, 5H), 5.16 (d, J=12.3 Hz, 1H), 5.12 (d, J=12.3 Hz, 1H), 4.79-4.70 (m, 2H), 4.41-4.35 (m, 1H), 4.21-4.18 (m, 1H), 3.00 (dd, J=17.5, 4.0 Hz, 1H), 2.81 (dd, J=17.5, 8.7 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H). Example 49—Preparation of benzyl (S)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoate (DPLG-2115) DPLG-2115 was prepared following the general procedure for HATU mediated coupling of 3-phenylproapanoic acid (15.5 mg, 0.103 mmol) and benzyl (S)-3-amino-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (51 mg, 0.094 mmol). After completion of reaction (4 h), the mixture was precipitated by the addition of 50 mL water. The white precipitate was filtered and dried to give product (50 mg, 94%).1H NMR (500 MHz, DMSO-d6) δ 8.34 (t, J=5.8 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H), 8.05-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.84 (dd, J=7.6, 1.7 Hz, 1H), 7.56-7.51 (m, 2H), 7.47-7.42 (m, 2H), 7.37-7.30 (m, 5H), 7.27-7.24 (m, 2H), 7.20-7.15 (m, 3H), 5.04 (s, 2H), 4.74 (d, J=5.7 Hz, 2H), 4.69 (td, J=8.1, 5.7 Hz, 1H), 4.32-4.26 (m, 1H), 2.82-2.77 (m, 3H), 2.57 (dd, J=16.2, 8.3 Hz, 1H), 2.40 (t, J=7.9 Hz, 2H), 1.23 (d, J=7.1 Hz, 3H). Example 50—Preparation of (S)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoic acid (DPLG-2124) Benzyl (S)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxo -3-(3 -phenylpropanamido)butanoate (50 mg, 0.088 mmol) was dissolved in 5 mL ethanol and 1 mL dimethylformamide. 20 mg palladium on carbon (10%) was added carefully and the mixture was stirred under hydrogen atmosphere. The reaction was not complete after 24 hours. The mixture was filtered through celite, evaporated, and purified by HPLC to give product (22.5 mg, 54%).1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.37 (m, 1H), 8.23 (d, J=7.7 Hz, 1H), 8.07-8.04 (m, 2H), 7.96-7.94 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.42 (m, 2H), 7.28-7.25 (m, 2H), 7.21-7.15 (m, 3H), 4.74 (d, J=5.8 Hz, 2H), 4.61-4.56 (m, 1H), 4.31-4.25 (m, 1H), 2.80 (t, J=7.9 Hz, 2H), 2.67 (dd, J=16.6, 6.1 Hz, 1H), 2.48-2.39 (m, 3H), 1.23 (d, J=7.1 Hz, 3H). Example 51—Preparation of (S)—N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-N4-(oxetan-3-yl)-2-(3 -phenylpropanamido)succinamide (DPLG-2130) DPLG-2130 was prepared following the general procedure for HATU mediated coupling of (S)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4 -oxo-3-(3-phenylpropanamido)butanoic acid (12.4 mg, 0.026 mmol) and 3-aminoxetane (2.2 μL, 0.031 mmol). The mixture was purified by HPLC to give product (12.0 mg, 87%).1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=6.4 Hz, 1H), 8.44 (t, J=5.8 Hz, 1H), 8.21 (d, J=7.3 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.07-8.05 (m, 1H), 7.95-7.94 (m, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.57-7.52 (m, 2H), 7.47-7.42 (m, 2H), 7.27-7.24 (m, 2H), 7.19-7.15 (m, 3H), 4.76 (dd, J=15.4, 5.9 Hz, 1H), 4.70 (dd, J=15.4, 5.8 Hz, 1H), 4.64-4.51 (m, 4H), 4.34-4.22 (m, 3H), 2.78 (t, J=7.8 Hz, 2H), 2.58 (dd, J=15.2, 7.5 Hz, 1H), 2.44-2.40 (m, 3H), 1.25 (d, J=7.2 Hz, 3H).13C NMR (126 MHz, DMSO) δ 172.43, 171.96, 171.01, 169.79, 141.67, 134.83, 133.68, 131.25, 128.94, 128.72, 128.61, 127.90, 126.63, 126.32, 126.23, 125.81, 125.56, 123.81, 77.44, 77.28, 50.01, 49.15, 44.28, 40.63, 37.82, 37.12, 31.42, 18.31. Example 52—Preparation of benzyl (S)-3-((4-methylphenyl)sulfonamido)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (DPLG-2079) Benzyl (S)-3-amino-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (55 mg, 0.01 mmol) was dissolved in 5 mL dichloromethane, and triethylamine (42 μl, 0.3 mmol) was added. The solution was cooled to 0° C. and 4-toluenesulfonylchloride (23 mg, 0.12 mmol) was added. After completion of reaction, the mixture was diluted in dichloromethane and washed with 1N HCl followed by brine. The organic layer was evaporated to give product (22 mg, 37%).1H NMR (500 MHz, DMSO-d6) δ 8.25-8.17 (m, 3H), 8.02-8.00 (m, 1H), 7.94-7.92 (m, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.29 (m, 9H), 4.98 (d, J=12.6 Hz, 1H), 4.91 (d, J=12.6 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 4.18 (m, 1H), 4.03-3.97 (m, 1H), 2.68-2.64 (m, 1H), 2.46-2.41 (m, 1H), 2.35 (s, 3H), 1.10 (d, J=7.0 Hz, 3H). Example 53—Preparation of (S)-3-((4-methylphenyl)sulfonamido)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (DPLG-2088) DPLG-2088 was synthesized by following the general procedure for O-debenzylation of benzyl (S)-3-((4-methylphenyl)sulfonamido)-4-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (21 g, 0.0357 mmol). The isolated crude was purified by HPLC to give product (12.1 mg, 68%).1H NMR (500 MHz, DMSO-d6) δ 12.41 (bs, 1H), 8.32 (bs, 1H), 8.20 (d, J=7.3 Hz, 1H), 8.04-8.02 (m, 1H), 7.95-7.93 (m, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 4.70 (d, J=5.8 Hz, 2H), 4.08-4.06 (m, 1H), 4.01-3.96 (m, 1H), 2.54-2.50 (m, 1H), 2.36 (s, 3H), 2.28 (dd, J=16.3, 7.3 Hz, 1H), 1.11 (d, J=7.1 Hz, 3H). Example 54—Preparation of (S)—N4,N4-diethyl-2-((4-methylphenyl)sulfonamido)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2090) DPLG-2090 was prepared following the general procedure for HATU mediated coupling of (S)-3-((4-methylphenyl)sulfonamido)-4-((((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (5.0 mg, 0.01 mmol) and diethyl amine hydrochloride (1.6 mg, 0.015 mmol). The mixture was purified by HPLC to give the product (4.0 mg, 73%).1H NMR (500 MHz, DMSO-d6) δ 8.36 (d, J=7.4 Hz, 1H), 8.26 (t, J=6.0 Hz, 1H), 8.09-8.03 (m, 2H), 7.94-7.92 (m, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.70-7.67 (m, 2H), 7.54-7.51 (m, 2H), 7.42-7.34 (m, 4H), 4.77 (dd, J=15.5, 6.2 Hz, 1H), 4.60 (dd, J=15.5, 5.7 Hz, 1H), 4.09-4.06 (m, 1H), 3.96-3.90 (m, 1H), 3.15-2.98 (m, 3H), 2.94-2.87 (m, 1H), 2.70 (dd, J=16.2, 9.4 Hz, 1H), 2.43 (dd, J=16.2, 4.7 Hz, 1H), 2.36 (s, 3H), 1.11 (d, J=7.2 Hz, 3H), 0.95 (t, J=7.1 Hz, 3H), 0.77 (t, J=7.0 Hz, 3H).13C NMR (126 MHz, DMSO) δ 172.30, 170.23, 168.80, 142.95, 139.00, 134.85, 133.64, 131.21, 129.75, 128.91, 127.78, 127.05, 126.57, 126.16, 125.75, 125.30, 123.74, 53.43, 49.20, 41.75, 36.18, 21.39, 17.74, 14.19, 13.15. Example 55—Preparation of (S)—N4-(tert-butoxy)-2-((4-methylphenyl)sulfonamido)-N1-((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2091) DPLG-2091 was prepared following the general procedure for HATU mediated coupling of (S)-3-((4-methylphenyl)sulfonamido)-4-((((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (5.0 mg, 0.01 mmol) and O-tert-butyl hydroxylamine hydrochloride (2 mg, 0.015 mmol). The mixture was purified by HPLC to give the product (3.3 mg, 56%).1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.33 (t, J=6.0 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.08-8.06 (m, 1H), 8.01 (bs, 1H), 7.94-7.92 (m, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.9 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.40 (m, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.73 (dd, J=15.4, 6.0 Hz, 1H), 4.64 (dd, J=15.4, 5.7 Hz, 1H), 4.10-4.07 (m, 1H), 3.92-3.86 (m, 1H), 2.42 (dd, J=14.9, 7.7 Hz, 1H), 2.36 (s, 3H), 2.22 (dd, J=14.9, 6.6 Hz, 1H), 1.08-1.06 (m, 12H).13C NMR (126 MHz, DMSO) δ 172.14, 169.91, 167.48, 134.89, 133.67, 131.25, 129.69, 128.91, 127.86, 127.13, 126.60, 126.34, 126.22, 126.18, 125.80, 125.64, 123.85, 81.10, 53.41, 49.06, 40.58, 36.34, 26.68, 21.41, 18.08. HRMS calc. for C29H36N4O6S [M+H]′: 591.2253. Found: 591.2271. Example 56—Preparation of (S)-benzyl 2-((S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanamido)propanoate ( PhCH2CH2 CO-Asp (CONHOtBu)-Ala-OBn, DPLG-2063) DPLG-2063 was prepared by following the general procedure for HATU mediated coupling of (S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanoic acid (33.6 mg, 0.1 mmol) and H-Ala-OBn.HCl (21.5 mg, 0.1 mmol). After completion of the reaction, the mixture was precipitated by the addition of cold water. The precipitate was filtered and dried to give the product (27 mg, 54%).1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.31 (d, J=7.0 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.40-7.32 (m, 5H), 7.28-7.25 (m, 2H), 7.20-7.15 (m, 3H), 5.11 (s, 2H), 4.66 (td, J=9.0, 4.9 Hz, 1H), 4.33-4.27 (m, 1H), 2.80-2.76 (m, 2H), 2.41-2.37 (m, 3H), 2.26 (dd, J=14.8, 9.5 Hz, 1H), 1.29 (d, J=7.2 Hz, 3H), 1.14 (s, 9H). Example 57—Preparation of (S)-2-((S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanamido)propanoic acid (PhCH2CH2CO-Asp(CON-HO′Bu)-Ala-OH, DPLG-2067) DPLG-2067 was synthesized by following the general procedure for O-debenzylation of (S)-benzyl 2-((S)-4-(tertbutoxylamino)-4-oxo-2-(3-phenylpropanamido)butanamido)propanoate (25.0 mg, 0.05 mmol). After completion of the reaction (5 h), the mixture was filtered through celite. The filtrate was evaporated and dried under vacuum to give the product (20 mg, quant.).1H NMR (500 MHz, DMSO-d6)δ 12.35 (s, 1H), 9.75 (s, 1H), 7.80 (s, 1H), 7.20-7.17 (m, 2H), 7.12-7.09 (m, 1H), 7.01 (d, J=7.4 Hz, 2H), 4.32-4.28 (m, 1H), 3.67-3.61 (m, 1H), 2.67-2.58 (m, 2H), 2.43-2.37 (m, 1H), 2.34-2.28 (m, 1H), 2.23-2.21 (m, 2H), 1.15 (d, J=6.8 Hz, 3H), 1.12 (s, 9H). Example 58—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-1-oxo-1-((quinolin-4 -ylmethyl)amino)propan-2-yl)-2-(3-phenylpropanami-do)succinamide (DPLG-20681 DPLG-2068 was prepared by following the general procedure for HATU mediated coupling of N4-(tert-butoxy)-N2-(3-phenylpropanoyl)-L-asparaginyl-L-alanine (5.0 mg, 0.0123 mmol) and quinolin-4-ylmethylamine dihydrochloride (2.8 mg, 0.0123 mmol). The crude was purified by HPLC to give 2.0 mg (30%) of product.1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.84 (d, J=4.5 Hz, 1H), 8.60 (t, J=6.0 Hz, 1H), 8.29 (d, J=7.1 Hz, 1H), 8.19-8.15 (m, 2H), 8.05 (dd, J=8.5, 1.3 Hz, 1H), 7.80-7.76 (m, 1H), 7.66-7.63 (m, 1H), 7.40 (d, J=4.4 Hz, 1H), 7.27-7.24 (m, 2H), 7.20-7.15 (m, 3H), 4.80-4.78 (m, 2H), 4.64-4.59 (m, 1H), 4.30-4.27 (m, 1H), 2.80-2.77 (m, 2H), 2.56-2.51 (m, 1H), 2.44-2.40 (m, 2H), 2.35 (dd, J=14.9, 7.1 Hz, 1H), 1.29 (d, J=7.1 Hz, 3H), 1.06 (s, 9H).13C NMR (126 MHz, DMSO) δ 172.37, 171.41, 170.72, 167.72, 150.12, 147.30, 144.63, 141.24, 129.42, 129.30, 128.27, 128.13, 126.65, 125.94, 125.85, 123.50, 118.92, 80.55, 64.91, 49.62, 48.81, 36.73, 34.82, 30.95, 26.19, 17.72. HRMS calc. for C30H37N5O5 [M+H]+: 548.2873. Found: 548.2857. Example 59—Preparation of (S)—N4-(tert-butoxpropan-2-yl)-2-(3-phenylpropanami-do)succinamide (DPLG-2073) DPLG-2073 was prepared by following the general procedure for HATU mediated coupling of N4-(tert-butoxy)-N2-(3-phenylpropanoyl)-L-asparaginyl-L-alanine (5.0 mg, 0.0123 mmol) and quinolin-5-ylmethylamine (2.0 mg, 0.0123 mmol). The crude was purified by HPLC to give 4.7 mg (70%) of product.1H NMR (500 MHz, DMSO-d6)δ 10.39 (s, 1H), 8.92-8.91 (m, 1H), 8.55 (d, J=8.6 Hz, 1H), 8.51 (t, J=6.0 Hz, 1H), 8.18-8.15 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.70 (dd, J=8.5, 7.0 Hz, 1H), 7.57-7.54 (m, 2H), 7.27-7.24 (m, 2H), 7.19-7.15 (m, 3H), 4.79 (dd, J=15.4, 6.1 Hz, 1H), 4.70 (dd, J=15.4, 5.7 Hz, 1H), 4.61-4.56 (m, 1H), 4.27-4.21 (m, 1H), 2.80-2.76 (m, 2H), 2.53-2.48 (m, 1H), 2.43-2.39 (m, 2H), 2.33 (dd, J=14.8, 7.2 Hz, 1H), 1.23 (d, J=7.1 Hz, 3H), 1.10 (s, 9H).3C NMR (126 MHz, DMSO) δ 172.42, 171.86, 170.99, 168.15, 150.64, 148.44, 141.70, 135.99, 132.49, 129.36, 128.90, 128.74, 128.60, 126.39, 126.31, 126.22, 121.75, 81.04, 70.24, 50.08, 49.12, 37.19, 35.28, 31.41, 26.70, 18.32. HRMS calc. for C30H37N5O5 [M+H]′: 548.2873. Found: 548.2879. Example 60—Preparation of (S)—N1—((S)-1-(((1H-indol-4-yl)methyl)amino)-1-oxopropan-2-yl)-N4-(tert-butoxy)-2-(3-phenylpropanam-ido)succinamide (DPLG-2083) DPLG-2083 was prepared by following the general procedure for HATU mediated coupling of N4-(tert-butoxy)-N2-(3-phenylpropanoyl)-L-asparaginyl-L-alanine (5.0 mg, 0.0123 mmol) and 4-(aminomethyl)indole (1.8 mg, 0.0123 mmol). The crude was purified by HPLC to give 5.8 mg (88%) of product.1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.35 (s, 1H), 8.36 (t, J=5.9 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.32-7.25 (m, 4H), 7.20-7.16 (m, 3H), 7.01 (t, J=7.6 Hz, 1H), 6.89 (d, J=7.1 Hz, 1H), 6.52-6.51 (m, 1H), 4.61-4.48 (m, 3H), 4.28-4.24 (m, 1H), 2.81-2.77 (m, 2H), 2.53-2.49 (m, 1H), 2.46-2.38 (m, 2H), 2.33 (dd, J=14.8, 7.6 Hz, 1H), 1.23 (d, J=7.1 Hz, 3H), 1.13 (s, 9H).13C NMR (126 MHz, DMSO) δ 172.15, 171.85, 170.85, 168.06, 141.73, 136.20, 130.54, 128.75, 128.63, 128.60, 126.61, 126.31, 125.31, 121.14, 117.76, 110.77, 81.01, 50.13, 49.00, 41.04, 37.24, 35.31, 31.43, 26.72, 18.68. HRMS calc. for C29H37N5O5 [M+H]′: 558.2692. Found: 558.2698. Example 61—Preparation of tert-butyl (S)-(3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)carbamate (Boc-Ser(OMe)-naphth, DPLG-2078) DPLG-2078 was prepared following the general procedure for HATU coupling. Reaction was carried using Boc-β-methoxyalanine dicyclohexylamine (1.202 g, 3.0 mmol) and 1-naphthylmethylamine (484 mL, 3.3 mmol). After completion of the reaction 150 mL water was added to the reaction mixture and extracted twice with ethyl acetate (2×150 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by silica gel column chromatography using a gradient of 20%-40% ethyl acetatehexane to give 1.05 g (98%) of pure product.1H NMR (500 MHz, Chloroform-d) δ 7.96 (d, J=8.4 Hz, 1H), 7.87-7.85 (m, 1H), 7.79 (dd, J=7.2, 2.4 Hz, 1H), 7.54-7.48 (m, 2H), 7.44-7.39 (m, 2H), 6.73 (m, 1H), 5.40 (m, 1H), 4.91 (m, 2H), 4.27 (m, 1H), 3.82 (dd, J=9.0, 4.1 Hz, 1H), 3.47 (dd, J=9.0, 6.2 Hz, 1H), 3.28 (s, 3H), 1.37 (s, 9H). Example 62—Preparation of (S)-2-amino-3-methoxy-N-(naphthalen-1-ylmethyl)propanamide 2,2,2-trifluoroacetate (H-Ser(OMe)-naphth, DPLG-2082) DPLG-2082 was synthesized by following the general procedure for Boc deprotection of DPLG-2120 (72 mg, 0.02 mmol). After completion of the reaction (4 h), dichloromethane and excess TFA were evaporated and dried under high vacuum. The paste was soluble in diethyl ether. Diethyl ether solution was extracted with water. The water layer was frozen and lyophilized to give product (67 mg, 90%).1H NMR (500 MHz, DMSO-d6) δ 8.94 (t, J=5.5 Hz, 1H), 8.20 (bs, 3H), 8.04-8.02 (m, 1H), 7.98-7.95 (m, 1H), 7.89-7.87 (m, 1H), 7.59-7.54 (m, 2H), 7.51-7.48 (m, 2H), 4.85 (dd, J=15.2, 5.7 Hz, 1H), 4.77 (dd, J=15.2, 5.4 Hz, 1H), 4.05-4.03 (m, 1H), 3.70-3.63 (m, 2H), 3.28 (s, 3H). Example 63—Preparation of Benzyl (S)-3-((tertbutoxycarbonyl)amino)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (DPLG-2126) DPLG-2126 was prepared following the general procedure of HATU mediated coupling of N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (378 mg, 1.17 mmol) and (S)-2-amino-3-methoxy-N-(naphthalen-1-ylmethyl)propanamide (435.6 mg, 1.17 mmol). After completion of the reaction (2 h), the mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was evaporated and the crude was recrystallized from ethanol-water mixture to give 576 mg (88%) pure product.1H NMR (500 MHz, DMSO-d6) δ 8.50 (t, J=5.7 Hz, 1H), 8.04-8.02 (m, 1H), 7.95-7.91 (m, 2H), 7.84 (dd, J=7.0, 2.4 Hz, 1H), 7.56-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.38-7.28 (m, 6H), 5.09 (d, J=12.6 Hz, 1H), 5.05 (d, J=12.6 Hz, 1H), 4.75 (d, J=5.7 Hz, 2H), 4.49-4.45 (m, 1H), 4.43-4.39 (m, 1H), 3.58 (dd, J=9.7, 5.5 Hz, 1H), 3.48 (dd, J=9.7, 5.1 Hz, 1H), 3.24 (s, 3H), 2.81 (dd, J=16.4, 5.1 Hz, 1H), 2.61 (dd, J=16.4, 9.0 Hz, 1H), 1.38 (s, 9H). Example 64—Preparation of (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (DPLG-2131) DPLG-2131 was synthesized by following the general procedure for O-debenzylation of benzyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (113 mg, 0.2 mmol). After completion of the reaction (4 h), the mixture was filtered through celite. The filtrate was evaporated and dried under vacuum to give the product (94 mg, 99%).1H NMR (500 MHz, DMSO-d6) δ 8.54 (t, J=5.7 Hz, 1H), 8.05-8.03 (m, 1H), 7.96-7.94 (m, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.84 (dd, J=7.2, 2.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.19 (d, J=7.9 Hz, 1H), 4.75 (d, J=5.7 Hz, 2H), 4.48-4.44 (m, 1H), 4.32-4.28 (m, 1H), 3.59 (dd, J=9.7, 5.5 Hz, 1H), 3.49 (dd, J=9.7, 5.1 Hz, 1H), 3.24 (s, 3H), 2.64 (dd, J=16.4, 5.5 Hz, 1H), 2.46 (dd, J=16.4, 8.3 Hz, 1H), 1.38 (s, 9H). Example 65—Preparation of tert-butyl ((4S,7S)-4-(methoxymethyl)-12,12-dimethyl-1-(naphthalen-1-yl)-3,6,9-trioxo-11-oxa-2,5,10-triazatridecan-7 -yl)carbamate (DPLG-2133) DPLG-2133 was prepared following the general procedure of HATU mediated coupling of (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (710 mg, 1.5 mmol) and 0-tert-butyl hydroxylamine hydrochloride (226 mg, 1.8 mmol). After completion of the reaction the mixture was precipitated by the addition of 100 mL water. The precipitate was filtered and dried to give 692 mg (85%) pure product.1H NMR (500 MHz, DMSO-d6)δ 10.27 (s, 1H), 8.57-8.55 (m, 1H), 8.06-8.04 (m, 1H), 7.96-7.94 (m, 2H), 7.85-7.83 (m, 1H), 7.56-7.53 (m, 2H), 7.48-7.43 (m, 2H), 7.01 (d, J=7.8 Hz, 1H), 4.75 (d, J=5.8 Hz, 2H), 4.48-4.44 (m, 1H), 4.35-4.30 (m, 1H), 3.59 (dd, J=9.8, 5.6 Hz, 1H), 3.51-3.48 (m, 1H), 3.24 (s, 3H), 2.47 (dd, J=14.8, 5.5 Hz, 1H), 2.33-2.28 (m, 1H), 1.37 (s, 9H), 1.13 (s, 9H). Example 66—Preparation of (S)-2-amino-N4-(tertbutoxy)-N1—((S)-3 -methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (DPLG-2137) DPLG-2137 was synthesized by following the general procedure for Boc deprotection of tert-butyl ((4S,7S)-4-(methoxymethyl)-12,12-dimethyl-1-(naphthalen-1-yl)-3,6,9-trioxo-11-oxa-2,5,10-triazatridecan-7-yl)carbamate (692 mg, 1.27 mmol). The isolated crude was triturated with diethyl ether to give pure product (691 mg, 97%).1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.81 (d, J=7.5 Hz, 1H), 8.67 (t, J=5.8 Hz, 1H), 8.20 (bs, 3H), 8.07-8.05 (m, 1H), 7.96-7.95 (m, 1H), 7.86-7.84 (m, 1H), 7.57-7.53 (m, 2H), 7.47-7.45 (m, 2H), 4.80-4.72 (m, 2H), 4.56-4.53 (m, 1H), 4.22-4.19 (m, 1H), 3.63 (dd, J=9.9, 6.0 Hz, 1H), 3.53 (dd, J=9.9, 4.5 Hz, 1H), 3.26 (s, 3H), 2.72 (dd, J=16.3, 5.1 Hz, 1H), 2.58 (dd, J=16.3, 7.6 Hz, 1H), 1.15 (s, 9H). Example 67—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-3 -methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(3-phenylpropanamido)succinamide (DPLG-2086) DPLG-2086 was prepared following the general procedure for HATU mediated coupling of (S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanoic acid (11.0 mg, 0.033 mmol) and [(S)-2-amino-3-methoxy-N-(naphthalen-1-ylmethyl)propanamide] (H-Ser(OMe)-naphth) (11.0 mg, 0.03 mmol). The product was purified by HPLC (yield 15.3 mg, 88%).1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.58 (t, J=5.8 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.11 (d, J=7.7 Hz, 1H), 8.09-8.07 (m, 1H), 7.95-7.93 (m, 1H), 7.84-7.82 (m, 1H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 4.78 (dd, J=15.4, 5.9 Hz, 1H), 4.71 (J=15.4, 5.7 Hz, 1H), 4.68-4.64 (m, 1H), 4.45-4.42 (m, 1H), 3.60 (dd, J=9.7, 5.9 Hz, 1H), 3.51 (dd, J=9.7, 4.7 Hz, 1H), 3.24 (s, 3H), 2.80-2.77 (m, 2H), 2.53-2.49 (m, 1H), 2.43-2.39 (m, 2H), 2.34 (dd, J=14.8, 7.6 Hz, 1H), 1.11 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.94, 171.38, 169.66, 168.05, 141.70, 134.69, 133.65, 131.22, 128.89, 128.76, 128.58, 127.85, 126.59, 126.32, 126.18, 125.83, 125.54, 123.87, 81.02, 72.27, 58.74, 53.69, 50.11, 40.72, 37.24, 35.30, 31.45, 26.71. HRMS calc. for C32H40N4O6 [M+H]′: 577.3026. Found: 577.3005. Example 68—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)succinamide (DPLG-2143) DPLG-2143 was prepared following the general procedure for HATU mediated coupling of morpholin 4-yl-acetic acid (3.2 mg, 0.022 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-3 -methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (11.2 mg, 0.02 mmol). The product was purified by HPLC (yield 9.5 mg, 83%).1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.60 (t, J=5.8 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 8.07-8.05 (m, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.95-7.93 (m, 1H), 7.83 (t, J=4.8, 1H), 7.56-7.52 (m, 2H), 7.45-7.44 (m, 2H), 4.74 (d, J=5.8 Hz, 2H), 4.67-4.63 (m, 1H), 4.47-4.43 (m, 1H), 3.62-3.58 (m, 5H), 3.51 (dd, J=9.8, 4.7 Hz, 1H), 3.23 (s, 3H), 2.92 (s, 2H), 2.54-2.36 (m, 6H), 1.11 (s, 9H).13C NMR (126 MHz, DMSO) δ 170.54, 169.22, 168.97, 167.59, 134.20, 133.20, 130.75, 128.45, 127.41, 126.14, 125.74, 125.38, 125.07, 123.40, 99.52, 80.60, 71.80, 66.13, 61.34, 58.27, 53.18, 49.23, 40.29, 34.89, 26.24. Example 69—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((napthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(5-methylisoxazole-3-carboxamido)succinamide (DPLG-2144) DPLG-2144 was prepared following the general procedure for HATU mediated coupling of 5-methylisoxazole-3-carboxylic acid (2.8 mg, 0.022 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (11.2 mg, 0.02 mmol). The product was purified by HPLC (yield 10.2 mg, 92%).1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.65 (d, J=8.1 Hz, 1H), 8.60 (t, J=5.8 Hz, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.05-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.85-7.83 (m, 1H), 7.54-7.52 (m, 2H), 7.46-7.43 (m, 2H), 6.54 (s, 1H), 4.84-4.80 (m, 1H), 4.74 (d, J=5.8 Hz, 2H), 4.50-4.47 (m, 1H), 3.59 (dd, J=9.7, 5.9 Hz, 1H), 3.51 (dd, J=9.7, 5.0 Hz, 1H), 3.23 (s, 3H), 2.62-2.54 (m, 2H), 2.47 (s, 3H), 1.09 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.40, 170.13, 169.17, 167.41, 158.43, 158.35, 134.17, 133.20, 130.74, 128.44, 127.41, 126.13, 125.74, 125.38, 125.03, 123.38, 101.31, 80.60, 71.83, 58.27, 53.11, 50.03, 40.28, 34.66, 26.21, 11.83. Example 70—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-((4-methylphenyl)sulfonamido)succinamide (DPLG-2150) (S)-2-amino-N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (22.4 mg, 0.04 mmol) was dissolved in 2 mL dichloromethane and the solution was cooled to 0° C. 4-(Dimethylamino)pyridine (1.2 mg, 0.01 mmol), Hunig's base (17 mL, 0.12 mmol), and 4-toluenesulphonyl chloride were added and the solution was allowed to warm to room temperature. After completion of the reaction (4 h), the mixture was diluted with dichloromethane and washed with water. Organic layer was evaporated and purified by HPLC to give product (15.1 mg, 63%).1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.48 (t, J=5.9 Hz, 1H), 8.23 (d, J=7.7 Hz, 1H), 8.07-8.05 (m, 1H), 7.99 (bs, 1H), 7.94-7.92 (m, 1H), 7.83-7.81 (m, 1H), 7.66 (d, J=7.9 Hz, 2H), 7.55-7.51 (m, 2H), 7.44-7.42 (m, 2H), 7.32 (d, J=7.9 Hz, 2H), 4.75 (dd, J=15.5, 6.0 Hz, 1H), 4.68 (dd, J=15.5, 5.8 Hz, 1H), 4.24-4.20 (m, 1H), 4.15-4.12 (m, 1H), 3.46 (dd, J=9.6, 5.1 Hz, 1H), 3.31 (dd, J=9.6, 5.0 Hz, 1H), 3.22 (s, 3H), 2.40 (dd, J=14.8, 7.4 Hz, 1H), 2.36 (s, 3H), 2.19 (dd, J=14.8, 6.7 Hz, 1H), 1.08 (s, 9H).13C NMR (126 MHz, DMSO) δ 170.45, 169.48, 167.37, 142.90, 138.58, 134.66, 133.64, 131.20, 129.75, 128.87, 127.81, 127.13, 126.56, 126.16, 125.80, 125.51, 123.88, 81.09, 72.05, 58.78, 53.62, 53.30, 40.68, 36.45, 26.69, 21.44. Example 71—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(2 -phenylacetamido)succinamide (DPLG-2222) DPLG-2222 was prepared following the general procedure for HATU mediated coupling of phenylacetic acid (4.5 mg, 0.033 mmol) and (S)-2-amino-N4-(tert-butoxy)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (16.8 mg, 0.03 mmol). The product was purified by HPLC (yield 9.8 mg, %).1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 8.39 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.08-8.06 (m, 1H), 7.95-7.93 (m, 1H), 7.83 (dd, J=6.9, 2.5 Hz, 1H), 7.55-7.53 (m, 2H), 7.46-7.44 (m, 2H), 7.29-7.19 (m, 5H), 4.77 (dd, J=15.5, 6.0 Hz, 1H), 4.70 (dd, J=15.5, 5.7 Hz, 1H), 4.67-4.63 (m, 1H), 4.45-4.41 (m, 1H), 3.58 (dd, J=9.7, 5.9 Hz, 1H), 3.50-3.47 (m, 3H), 3.22 (s, 3H), 2.56-2.50 (m, 1H), 2.38 (dd, J=14.9, 7.5 Hz, 1H), 1.10 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.33, 170.56, 169.64, 167.99, 136.59, 134.70, 133.64, 131.21, 129.51, 128.89, 128.60, 127.83, 126.76, 126.59, 126.18, 125.83, 125.54, 123.88, 81.02, 72.22, 58.71, 53.71, 50.14, 42.37, 40.71, 35.31, 26.71. Example 72—Preparation of (S) N4-(tert-butoxy)-N1—((S)-3methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(4-phenylbutanamido)succinamide (DPLG-2223) DPLG-2223 was prepared following the general procedure for HATU mediated coupling of 4-phenylbutyric acid (5.4 mg, 0.033 mmol) and (S)-2-amino-1V4-(tert-butoxy)-N1-((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide (16.8 mg, 0.03 mmol). The product was purified by HPLC (yield 10.5 mg, 59%).1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.56 (t, J=5.7 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.06-8.03 (m, 2H), 7.94-7.93 (m, 1H), 7.84-7.82 (m, 1H), 7.55-7.51 (m, 2H), 7.45-7.42 (m, 2H), 7.28-7.22 (m, 2H), 7.19-7.15 (m, 3H), 4.78-4.69 (m, 2H), 4.66-4.61 (m, 1H), 4.45-4.42 (m, 1H), 3.59 (dd, J=9.8, 5.9 Hz, 1H), 3.50 (dd, J=9.8, 4.8 Hz, 1H), 3.20 (s, 3H), 2.56-2.50 (m, 3H), 2.35 (dd, J=14.8, 8.1 Hz, 1H), 2.13 (t, J=7.5 Hz, 2H), 1.76 (p, J=7.5 Hz, 2H), 1.10 (s, 9H).13C NMR (126 MHz, DMSO) δ 172.05, 170.96, 169.18, 167.59, 141.79, 134.19, 133.18, 130.74, 128.42, 128.30, 128.22, 127.38, 126.12, 125.70, 125.36, 125.03, 123.38, 80.51, 71.84, 58.24, 53.11, 49.70, 40.25, 34.72, 34.63, 34.57, 27.04, 26.24. Example 73—Preparation of benzyl (S)-3-amino-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (DPLG-2192) DPLG-2192 was synthesized by following the general procedure for Boc deprotection of benzyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate (225 mg, 0.4 mmol). Yield=230 mg, quant.1H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J=7.8 Hz, 1H), 8.57 (t, J=5.8 Hz, 1H), 8.27 (bs, 3H), 8.03-8.01 (m, 1H), 7.95-7.93 (m, 1H), 7.84 (dd, J=7.1, 2.4 Hz, 1H), 7.56-7.50 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.33 (m, 5H), 5.14 (d, J=12.4 Hz, 1H), 5.11 (d, J=12.4 Hz, 1H), 4.79-4.71 (m, 2H), 4.56 (ddd, J=7.8, 6.0, 4.8 Hz, 1H), 4.26 (m, 1H), 3.60 (dd, J=9.8, 6.0 Hz, 1H), 3.53 (dd, J=9.8, 4.8 Hz, 1H), 3.26 (s, 3H), 3.01 (dd, J=17.5, 4.0 Hz, 1H), 2.81 (dd, J=17.5, 8.7 Hz, 1H). Example 74—Preparation of benzyl (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-(methylsulfonamido)-4-oxobutanoate (DPLG-2196) Benzyl (S)-3-amino-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (29 mg, 0.05 mmol) and N,N-dimethylaminopyridine (1 mg) were suspended in dichloromethane (1 mL). Triethylamine was added (21 μL, 0.15 mmol). The resulting transparent solution was cooled to 0° C. and methanesulphonyl chloride (6 μl, 0.075 mmol) was added. After completion of reaction (1 h), the product was isolated by ethyl acetate extraction and purified by HPLC to give product (16.5 mg, 61%).1H NMR (500 MHz, DMSO-d6) δ 8.45 (t, J=5.8 Hz, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.03-8.01 (m, 1H), 7.95-7.93 (m, 1H), 7.85-7.82 (m, 1H), 7.70 (bs, 1H), 7.57-7.50 (m, 2H), 7.46-7.43 (m, 2H), 7.36-7.31 (m, 5H), 5.09-5.04 (m, 2H), 4.74 (d, J=5.8 Hz, 2H), 4.54-4.48 (m, 1H), 4.34-4.31 (m, 1H), 3.59 (dd, J=9.8, 6.0 Hz, 1H), 3.52 (dd, J=9.8, 5.0 Hz, 1H), 3.24 (s, 3H), 2.87 (s, 3H), 2.83 (dd, J=16.4, 5.3 Hz, 1H), 2.63 (dd, J=16.4, 8.7 Hz, 1H). Example 75—Preparation of (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-(methylsulfonamido)-4-oxobutanoic acid (DPLG-2203) DPLG-2203 was synthesized by following the general procedure for O-debenzylation of benzyl (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-(methyl sulfonamido)-4 -oxobutanoate (16.5 mg, 0.03 mmol). The reaction mixture was filtered through celite and evaporated to give the product (11.0 mg, 80%).1H NMR (500 MHz, DMSO-d6) δ 8.53 (t, J=5.8 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.05-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.83 (dd, J=7.2, 2.2 Hz, 1H), 7.57-7.52 (m, 2H), 7.47-7.43 (m, 2H), 4.78-4.71 (m, 2H), 4.52-4.48 (m, 1H), 4.23 (dd, J=7.9, 5.7 Hz, 1H), 3.60 (dd, J=9.8, 6.1 Hz, 1H), 3.54 (dd, J=9.8, 4.9 Hz, 1H), 3.24 (s, 3H), 2.91 (s, 3H), 2.68 (dd, J=16.4, 5.7 Hz, 1H), 2.49-2.45 (m, 1H). Example 76—Preparation of (S)—N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(methylsulfonamido)-N4-(oxetan-3-yl)succinamide (DPLG-2219) DPLG-2219 was prepared following the general procedure for HATU mediated coupling of (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-(methylsulfonamido)-4-oxobutanoic acid (6.8 g, 0.015 mmol) and 3-aminoxetane (1.2 μL, 0.0165 mmol). The crude was purified by HPLC to give product (5.2 mg, 68%).1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=6.3 Hz, 1H), 8.50 (t, J=5.8 Hz, 1H), 8.42 (d, J=7.9 Hz, 1H), 8.06-8.04 (m, 1H), 7.95-7.93 (m, 1H), 7.84 (dd, J=7.8, 1.7 Hz, 1H), 7.57-7.52 (m, 3H), 7.47-7.42 (m, 2H), 4.78 (dd, J=15.5, 6.0 Hz, 1H), 4.70 (dd, J=15.5, 5.7 Hz, 1H), 4.65-4.57 (m, 2H), 4.54-4.47 (m, 2H), 4.36-4.30 (m, 2H), 4.25-4.22 (m, 1H), 3.63 (dd, J=9.8, 6.3 Hz, 1H), 3.57 (dd, J=9.8, 4.5 Hz, 1H), 3.24 (s, 3H), 2.89 (s, 3H), 2.63 (dd, J=15.4, 7.3 Hz, 1H), 2.49-2.45 (m, 1H).13C NMR (126 MHz, DMSO) δ 171.25, 169.48, 169.44, 134.62, 133.66, 131.22, 128.91, 127.90, 126.62, 126.22, 125.80, 125.47, 123.85, 77.43, 77.24, 72.19, 58.69, 53.56, 53.38, 44.31, 41.07, 40.76, 38.81. Example 77—Preparation of benzyl (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-344-methylphenyl)sulfonamido)-4-oxobutanoate (DPLG-2199) Benzyl (S)-3-amino-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4 -oxobutanoate 2,2,2-trifluoroacetate (48 mg, 0.083 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (35 μl, 0.25 mmol) was added. The resulting solution was cooled to 0° C., and 4-toluenesulphonyl chloride (23.8 mg, 0.125 mmol) was added. After completion of reaction (2 h), the crude was isolated by ethyl acetate extraction and purified by HPLC to give product (11.0 mg, 22%).1H NMR (500 MHz, DMSO-d6) δ 8.36 (t, J=5.8 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 8.19 (d, J=8.9 Hz, 1H), 8.02-8.00 (m, 1H), 7.94-7.92 (m, 1H), 7.83 (dd, J=7.2, 2.3 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.55-7.50 (m, 2H), 7.45-7.41 (m, 2H), 7.38-7.29 (m, 7H), 4.97 (d, J=12.6 Hz, 1H), 4.91 (d, J=12.6 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 4.28 (dt, J=8.5, 5.6 Hz, 1), 4.23 (td, J=7.7, 5.3 Hz, 1H), 3.42 (dd, J=9.6, 5.2 Hz, 1H), 3.35-3.32 (m, 1H), 3.23 (s, 3H), 2.65 (dd, J=16.0, 5.6 Hz, 1H), 2.41 (dd, J=16.0, 8.2 Hz, 1H), 2.35 (s, 3H). Example 78—Preparation of (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-((4-methylphenyl)sulfonamido)-4-oxobutanoic acid (DPLG-2227) DPLG-2227 was synthesized by following the general procedure for O-debenzylation of benzyl (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-3-((4 -methylphenyl) sulfonamido)-4 -oxobutanoate (11.0 mg, 0.0178 mmol). Yield=7.5 mg, 80%.1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.39 (t, J=5.7 Hz, 1H), 8.20 (d, J=7.7 Hz, 1H), 8.13-8.10 (m, 1H), 8.03-8.01 (m, 1H), 7.95-7.93 (m, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.40 (m, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.72 (d, J=5.7 Hz, 2H), 4.23-4.16 (m, 2H), 3.44 (dd, J=9.6, 5.1 Hz, 1H), 3.36-3.33 (m, 1H), 3.23 (s, 3H), 2.54-2.49 (m, 1H), 2.36 (s, 3H), 2.27 (dd, J=16.3, 7.5 Hz, 1H). Example 79—Preparation of (S)—N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-24(4 -methylphenyl) sulfonamido)-N4-(oxetan-3-yl)succinamide (DPLG-2229) DPLG-2229 was prepared following the general procedure for HATU mediated coupling of (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2 -yl)amino)-3-((4 -methylphenyl) sulfonamido)-4-oxobutanoic acid (7.5 mg, 0.014 mmol) and 3-aminoxetane (1.1 mL, 0.0154 mmol). The product was purified by HPLC (yield=6.4 mg, 78%).1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=5.7 Hz, 1H), 8.45 (t, J=6.0 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H), 8.05-8.03 (m, 2H), 7.94-7.92 (m, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.39 (m, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.73 (dd, J=15.6, 5.9 Hz, 1H), 4.68 (dd, J=15.6, 5.8 Hz, 1H), 4.54-4.44 (m, 3H), 4.30-4.12 (m, 4H), 3.52 (dd, J=9.6, 5.2 Hz, 1H), 3.32-3.29 (m, 1H), 3.22 (s, 3H), 2.51-2.46 (m, 1H), 2.36 (s, 3H), 2.27 (dd, J=15.0, 6.1 Hz, 1H).13C NMR (126 MHz, DMSO) δ 170.12, 169.03, 168.59, 142.44, 138.28, 134.18, 133.18, 130.74, 129.30, 128.44, 127.38, 126.61, 126.13, 125.75, 125.32, 124.90, 123.41, 76.94, 76.74, 71.56, 58.34, 53.25, 52.75, 43.75, 40.27, 38.45, 21.00. Example 80—Preparation of tert-butyl (S)-(1-(((1H-indol-4-yl)methyl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (Boc-Ser(OMe)-indole, DPLG-2153) DPLG-2153 was prepared following the general procedure of HATU mediated coupling of Boc-β-methoxyalanine dicyclohexylamine (50 mg, 0.125 mmol) and 4-(aminomethyl)indole (20 mL, 0.138 mmol). The product was isolated by ethyl acetate extraction and purified by silica-gel column chromatography (yield 40 mg, 93%).1H NMR (500 MHz, Chloroform-d) δ 8.57 (bs, 1H), 7.35 (dd, J=8.1, 2.0 Hz, 1H), 7.22-7.20 (m, 1H), 7.16-7.12 (m, 1H), 7.02-7.00 (m, 1H), 6.74 (bs, 1H), 6.58-6.56 (m, 1H), 5.42 (m, 1H), 4.76 (m, 2H), 4.28 (m, 1H), 3.85-3.82 (m, 1H), 3.49 (dd, J=9.3, 6.3 Hz, 1H), 3.32 (s, 3H), 1.41 (s, 9H). Example 81—Preparation of (S)—N1—((S)-1-(((1H-indol-4-yl)methyl)amino)-3-methoxy-1-oxopropan-2-yl)-N4-(tert-butoxy)-2-(3-phenylpropanamido)succinamide (DPLG-2161) Tert-butyl (S)-(1-(((1H-indol-4-yl)methyl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (40 mg, 0.115 mmol) was added to 2 mL 4N HCl in dioxane at 20° C. Within 30 minutes the reaction mixture turned red. LCMS showed completion of the reaction. Dioxane and HCl were evaporated. The crude was coupled with (S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanoic acid (16.8 mg, 0.05 mmol) following the general procedure for HATU mediated coupling. The product was purified by HPLC to give pure product (8.2 mg, 29%).1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.36 (s, 1H), 8.46 (t, J=5.9 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.30 (t, J=2.8 Hz, 1H), 7.29-7.25 (m, 3H), 7.20-7.15 (m, 3H), 7.02-6.99 (m, 1H), 6.89 (d, J=7.2 Hz, 1H), 6.51 (t, J=2.4 Hz, 1H), 4.67-4.63 (m, 1H), 4.55 (dd, J=15.2, 5.9 Hz, 1H), 4.49 (dd, J=15.2, 5.9 Hz, 1H), 4.44-4.41 (m, 1H), 3.57 (dd, J=9.8, 6.0 Hz, 1H), 3.50 (dd, J=9.8, 4.7 Hz, 1H), 3.23 (s, 3H), 2.81-2.75 (m, 2H), 2.53-2.47 (m, 1H), 2.44-2.38 (m, 2H), 2.33 (dd, J=14.9, 8.0 Hz, 1H), 1.12 (s, 9H). Example 82—Preparation of tert-butyl (S)-(3-methoxy-1-((3-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate (DPLG-2154) DPLG-2154 was prepared following the general procedure of HATU mediated coupling of Boc-β-methoxyalanine dicyclohexylamine (100 mg, 0.25 mmol) and 3-methoxybenzyl amine (36 mL, 0.275 mmol). The product was isolated by ethyl acetate extraction and purified by silica-gel column chromatography (yield 74 mg, 87%).1H NMR (500 MHz, Chloroform-d) δ 7.26-7.22 (m, 1H), 6.86-6.84 (m, 1H), 6.82-6.80 (m, 2H), 6.75 (t, J=6.2 Hz, 1H), 5.42 (bs, 1H), 4.47-4.46 (m, 2H), 4.28 (m, 1H), 3.85 (dd, J=9.2, 3.8 Hz, 1H), 3.80 (s, 3H), 3.51 (dd, J=9.2, 6.2 Hz, 1H), 3.38 (s, 3H), 1.44 (s, 9H). Example 83—Preparation of (S)-2-amino-3-methoxy-N-(3-methoxybenzyl)propanamide 2,2,2 trifluoroacetate (DPLG-2158) DPLG-2158 was synthesized by following the general procedure for Boc-deprotection of tert-butyl (S)-(3-methoxy-1-((3-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate (74 mg, 0.219 mmol). After 2 h, dichloromethane and excess TFA were evaporated and crude was dried under vacuum to give product (70 mg, 91%).1H NMR (500 MHz, Chloroform-d) δ 9.13 (bs, 1H), 8.01 (bs, 2H), 7.56 (t, J=5.8 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.80 (dd, J=8.3, 2.5 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.73-6.72 (m, 1H), 4.41-4.35 (m, 2H), 4.29 (dd, J=15.0, 5.5 Hz, 1H), 3.75 (s, 3H), 3.73 (dd, J=10.4, 4.7 Hz, 1H), 3.67 (dd, J=10.4, 5.3 Hz, 1H), 3.32 (s, 3H). Example 84—Preparation of (S)—N4-(tert-butoxy)-N1—-((S)-3-methoxy-1-((3 -methoxybenzyl)amino)-1-oxopropan-2-yl)-2-(3 -phenylpropanamido)succinamide (DPLG-2160) DPLG-2160 was prepared following the general procedure for HATU mediated coupling of (S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanoic acid (15.8 mg, 0.047 mmol) and (S)-2-amino-3-methoxy-N-(3-methoxybenzyl)propanamide 2,2,2 trifluoroacetate (18.4 mg, 0.052 mmol). The product was purified by HPLC (yield 16.2 mg, 62%).1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.51 (t, J=6.1 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.27-7.25 (m, 2H), 7.21-7.15 (m, 4H), 6.82-6.81 (m, 2H), 6.77 (dd, J=8.1, 2.4 Hz, 1H), 4.67-4.63 (m, 1H), 4.40-4.37 (m, 1H), 4.30-4.21 (m, 2H), 3.72 (s, 3H), 3.61 (dd, J=9.8, 5.9 Hz, 1H), 3.50 (dd, J=9.8, 4.6 Hz, 1H), 3.25 (s, 3H), 2.80-2.76 (m, 2H), 2.53-2.48 (m, 1H), 2.43-2.39 (m, 2H), 2.34 (dd, J=14.8, 7.6 Hz, 1H), 1.11 (s, 9H). Example 85—Preparation of tert-butyl (S)-(1-((2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (DPLG-2184) DPLG-2184 was prepared following the general procedure of HATU mediated coupling of Boc-β-methoxyalanine dicyclohexylamine (200 mg, 0.5 mmol) and 2,3-dimethoxybenzyl amine (83 μl, 0.55 mmol). The product was isolated by ethyl acetate extraction and purified by silica-gel column chromatography (yield=184 mg, quant.).1H NMR (500 MHz, DMSO-d6) δ 8.24 (t, J=5.9 Hz, 1H), 7.00-6.97 (m, 1H), 6.93 (dd, J=8.3, 1.7 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.81 (dd, J=7.6, 1.7 Hz, 1H), 4.31-4.23 (m, 2H), 4.20-4.15 (m, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.48-3.46 (m, 2H), 3.24 (s, 3H), 1.38 (s, 9H). Example 86—Preparation of (S)-2-amino-N-(2,3-dimethoxybenzyl)-3-methoxypropanamide 2, 2, 2-trifluoroacetate (DPLG-2190) DPLG-2190 was synthesized by following the general procedure for Boc-deprotection of tert-butyl (S)-(1-((2, 3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (180 mg, 0.49 mmol). Crude product was dried under vacuum to give viscous paste, which upon standing turned solid.1H NMR (500 MHz, DMSO-d6) δ 8.78 (t, J=5.7 Hz, 1H), 8.21 (bs, 3H), 7.05-7.02 (m, 1H), 6.97 (dd, J=8.2, 1.6 Hz, 1H), 6.83 (dd, J=7.6, 1.6 Hz, 1H), 4.36 (dd, J=15.1, 5.7 Hz, 1H), 4.31 (dd, J=15.1, 5.6 Hz, 1H), 4.04-4.01 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.66 (d, J=5.1 Hz, 2H), 3.30 (s, 3H). Example 87—Preparation of benzyl (S)-3-((tertbutoxycarbonyl)amino)-4-(((S)-1-(2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxobutanoate (DPLG-2191) DPLG-2191 was prepared following the general procedure of HATU mediated coupling of N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (159 mg, 0.49 mmol) and (S)-2-amino-N-(2,3-dimethoxybenzyl)-3-methoxypropanamide 2,2,2-trifluoroacetate (0.49 mmol, from previous step). The product was isolated by ethyl acetate extraction and recrystallized with ethanol-water (yield=245 mg, 87% for 2 steps).1H NMR (500 MHz, DMSO-d6) δ 8.29 (t, J=5.8 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.38-7.31 (m, 5H), 7.28 (d, J=8.0 Hz, 1H), 7.00-6.97 (m, 1H), 6.92 (dd, J=8.2, 1.6 Hz, 1H), 6.78 (dd, J=7.7, 1.6 Hz, 1H), 5.08 (d, J=12.6 Hz, 1H), 5.05 (d, J=12.6 Hz, 1H), 4.45-4.37 (m, 2H), 4.31-4.23 (m, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.56 (dd, J=9.7, 5.6 Hz, 1H), 3.46 (dd, J=9.7, 5.1 Hz, 1H), 3.24 (s, 3H), 2.82-2.78 (m, 1H), 2.61 (dd, J=16.3, 8.9 Hz, 1H), 1.37 (s, 9H). Example 88—Preparation of benzyl (S)-3-amino-4-(((S)-1-(2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (DPLG-2197) DPLG-2197 was synthesized by following the general procedure for Boc-deprotection of benzyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-((2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxobutanoate (115 mg, 0.2 mmol). The crude was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J=7.8 Hz, 1H), 8.37 (t J=5.9 Hz, 1H), 8.26 (bs, 3H), 7.39-7.34 (m, 5H), 6.99 (t, J=7.9 Hz, 1H), 6.93 (dd, J=8.3, 1.6 Hz, 1H), 6.78 (dd, J=7.7, 1.6 Hz, 1H), 5.14 (d, J=12.4 Hz, 1H), 5.11 (d, J=12.4 Hz, 1H), 4.55-4.51 (m, 1H), 4.33-4.23 (m, 3H), 3.78 (s, 3H), 3.71 (s, 3H), 3.59 (dd, J=9.9, 6.2 Hz, 1H), 3.52 (dd, J=9.9, 4.8 Hz, 1H), 3.27 (s, 3H), 3.02 (dd, J=17.5, 4.1 Hz, 1H), 2.82 (dd, J=17.5, 8.8 Hz, 1H). Example 89—Preparation of benzyl (S)-4-(((S)-1-((2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoate (DPLG-2200) DPLG-2200 was prepared following the general procedure of HATU mediated coupling of 3-phenylpropanoic acid (33 mg, 0.22 mmol) and benzyl (S)-3-amino-4-(((S)-1-((2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxobutanoate 2,2,2-trifluoroacetate (0.2 mmol, from previous step). The reaction mixture was precipitated with water and the precipitate was filtered and dried to give product (110 mg, 91% for 2 steps). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J=7.9 Hz, 1H), 8.24 (t, J=5.9 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.38-7.32 (m, 5H), 7.28-7.25 (m, 2H), 7.18-7.15 (m, 3H), 6.99 (t, J=7.9 Hz, 1H), 6.92 (dd, J=8.0, 1.6 Hz, 1H), 6.79 (dd, J=7.5, 1.6 Hz, 1H), 5.04 (s, 2H), 4.74 (td, J=8.1, 5.7 Hz, 1H), 4.42 (dt, J=7.8, 5.4 Hz, 1H), 4.31-4.24 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.56 (dd, J=9.8, 5.8 Hz, 1H), 3.47 (dd, J=9.8, 5.0 Hz, 1H), 3.24 (s, 3H), 2.85-2.77 (m, 3H), 2.59 (dd, J=16.2, 8.3 Hz, 1H), 2.41-2.38 (m, 2H). Example 90—Preparation of (S)-4-(((S)-1-((2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoic acid (DPLG-2204) Benzyl (S)-4-(((S)-1-((2,3-dimethoxybenzyl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoate (110 mg, 0.18 mmol) was dissolved in 30 mL methanol, and 35 mg palladium on carbon (10%) was added carefully. The air of flask was replaced by hydrogen and the mixture was stirred at room temperature under hydrogen atmosphere for 2 days. The reaction was not complete. Mixture was filtered through celite. The filterate was evaporated and purified by HPLC to give 40 mg product (50% bsrm; 16.0 mg starting material was recovered).1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.27-8.24 (m, 2H), 7.95 (d, J=7.9 Hz, 1H), 7.28-7.25 (m, 2H), 7.20-7.15 (m, 3H), 6.99 (t, J=7.9 Hz, 1H), 6.93 (dd, J=8.2, 1.5 Hz, 1H), 6.80 (dd, J=7.7, 1.5 Hz, 1H), 4.66-4.60 (m, 1H), 4.43-4.38 (m, 1H), 4.28 (d, J=5.9 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.56 (dd, J=9.7, 5.8 Hz, 1H), 3.47 (dd, J=9.7, 5.0 Hz, 1H), 3.24 (s, 3H), 2.79 (t, J=7.9 Hz, 2H), 2.68 (dd, J=16.6, 5.9 Hz, 1H), 2.48-2.39 (m, 3H). Example 91—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-1-((2,3-dimethoxybenzyl)amino-3-methoxy-1-oxopropan-2-yl)-2-(3-phenylpropanmido)succinamide (DPLG-2211) DPLG-2211 was prepared following the general procedure for HATU mediated coupling of 0-tert-butyl hydroxylamine hydrochloride (6.6 mg, 0.0525 mmol) and (S)-4-(((S)-1-((2,3 -dimethoxybenzyl)amino)-3 -methoxy-1-oxopropan-2-yl)amino)-4-oxo -3-(3 -phenylpropanamido)butanoic acid (18.0 mg, 0.035 mmol). After completion of reaction (1 h), the mixture was diluted with water and extracted with ethyl acetate. The organic layer was evaporated and purified by HPLC to give the product (11.0 mg, 54%).1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.37 (t, J=6.0 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.28-7.25 (m, 2H), 7.19-7.15 (m, 3H), 6.98 (t, J=7.9 Hz, 1H), 6.92 (dd, J=8.1, 1.6 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.67-4.63 (m, 1H), 4.40 (dt, J=7.6, 5.3 Hz, 1H), 4.31-4.24 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.59 (dd, J=9.8, 6.0 Hz, 1H), 3.49 (dd, J=9.8, 4.6 Hz, 1H), 3.24 (s, 3H), 2.80-2.76 (m, 2H), 2.52-2.48 (m, 1H), 2.43-2.39 (m, 2H), 2.33 (dd, J=14.9, 7.8 Hz, 1H), 1.11 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.97, 171.35, 169.68, 168.02, 152.58, 146.48, 141.70, 132.79, 128.76, 128.58, 126.32, 124.13, 120.29, 111.99, 81.02, 72.26, 60.39, 58.73, 56.12, 53.56, 50.10, 37.38, 37.24, 35.27, 31.44, 26.70. Example 92—Preparation of tert-butyl (S)-(3-methoxy-1-oxo -1-((quinolin-8-ylmethyl)amino)propan-2-yl)carbamate (DPLG-2175) DPLG-2175 was prepared following the general procedure for HATU coupling of Boc-β-methoxyalanine dicyclohexylamine (80 mg, 0.02 mmol) and quinolin-8-ylmethylamine dihydrochloride (46 mg, 0.2 mmol) in 2 mL dimethylformamide. (Note: reaction mixture was not soluble in dimethylformamide) After completion of the reaction (3 h), water was added to the reaction mixture (the reaction mixture turned transparent) and extracted twice with chloroform. The combined organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by HPLC to give 68.5 mg (95%) of pure product.1H NMR (500 MHz, DMSO-d6) δ 8.96-8.94 (m, 1H), 8.46 (t, J=6.2 Hz, 1H), 8.39 (dd, J=8.1, 1.6 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.64 (d, J=7.1 Hz, 1H), 7.58 (dd, J=8.3, 4.2 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 4.96-4.87 (m, 2H), 4.26-4.22 (m, 1H), 3.54-3.53 (m, 2H), 3.27 (s, 3H), 1.39 (s, 9H). Example 93—Preparation of (S)-2-amino-3-methoxy-N-(quinolin-8-ylmethyl)propanamide bis (2,2,2-trifluoroacetate) (DPLG-2181) DPLG-2181 was synthesized by following the general procedure for Boc-deprotection of tert-butyl (S)-(3-methoxy-1-oxo -1-((quinolin-8-ylmethyl)amino)propan-2-yl)carbamate (68.5 mg, 0.19 mmol). The crude was used in next step.1H NMR (500 MHz, DMSO-d6) δ 8.98 (dd, J=4.2, 1.8 Hz, 1H), 8.95 (t, J=5.9 Hz, 1H), 8.42 (dd, J=8.2, 1.8 Hz, 1H), 8.22 (bs, 3H), 7.93 (dd, J=8.1, 1.5 Hz, 1H), 7.67 (dd, J=7.1, 1.5 Hz, 1H), 7.62-7.58 (m, 2H), 5.02 (dd, J=15.9, 5.9 Hz, 1H), 4.96 (dd, J=15.9, 5.7 Hz, 1H), 4.13-4.10 (m, 1H), 3.75-3.69 (m, 2H), 3.32 (s, 3H). Example 94—Preparation of benzyl (S)-3-((tertbutoxycarbonyl)amino)-4-(((S)-3-methoxy-1-oxo-1-((quinolin-8-ylmethyl)amino)propan-2-yl)amino)-4-oxobutanoate (DPLG-2188) DPLG-2188 was prepared following the general procedure for HATU mediated coupling of N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (61.4 mg, 0.19 mmol) and (S)-2-amino-3-methoxy-N-(quinolin-8-ylmethyl)propanamide bis(2,2,2-trifluoroacetate) (0.19 mmol, from previous step). After completion of reaction (1 h), reaction mixture was diluted with water and extracted twice with ethyl acetate. Ethyl acetate layer was dried over anhydrous Na2SO4and evaporated. The crude was dried under high1H NMR (500 MHz, DMSO-d6) δ 8.96 (dd, J=4.3, 1.8 Hz, 1H), 8.49 (t, J=5.9 Hz, 1H), 8.43 (dd, J=8.3, 1.8 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.63 (dd, J=7.1, 1.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.37-7.30 (m, 6H), 5.09 (d, J=12.7 Hz, 1H), 5.05 (d, J=12.7 Hz, 1H), 4.96 (dd, J=16.4, 6.0 Hz, 1H), 4.89 (dd, J=16.4, 5.9 Hz, 1H), 4.51-4.48 (m, 1H), 4.43 (td, J=8.5, 5.0 Hz, 1H), 3.63 (dd, J=9.7, 5.5 Hz, 1H), 3.52 (dd, J=9.7, 5.1 Hz, 1H), 3.28 (s, 3H), 2.85-2.81 (m, 1H), 2.62 (dd, J=16.2, 8.9 Hz, 1H), 1.38 (s, 9H). Example 95—Preparation of benzyl (S)-3-amino-4-(((S)-3-methoxy-1-oxo-1-((quinolin-8-ylmethyl)amino)propan-2-yl)amino)-4-oxobutanoate bis(2,2,2-trifluoroacetate) (DPLG-2194) DPLG-2194 was synthesized by following the general procedure for Boc-deprotection of benzyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-3-methoxy-1-oxo -1-((quinolin-8-ylmethyl)amino)propan-2-yl)amino)-4 -oxobutanoate (0.19 mmol, from previous step). After completion of the reaction (3 h), excess trifluoroacetic acid and dichloromethane were evaporated. Crude paste was washed twice with diethyl ether to give product as off white solid (yield=111 mg, 84% for 3 steps).1H NMR (500 MHz, DMSO-d6)8 8.94 (dd, J=4.2, 1.8 Hz, 1H), 8.87 (d, J=7.8 Hz, 1H),67J=6.0 Hz, 1H), 8.39 (dd, J=8.4, 1.8 Hz, 1H), 8.27 (bs, 3H), 7.88 (dd, J=8.1, 1.5 Hz, 1H), 7.61 (dd, J=7.2, 1.5 Hz, 1H), 7.58-7.54 (m, 2H), 7.40-7.31 (m, 5H), 5.13 (J=12.5 Hz, 1H), 5.10 (d, J=12.5 Hz, 1H), 4.97 (dd, J=16.4, 6.1 Hz, 1H), 4.90 (dd, J=16.4, 5.9 Hz, 1H), 4.62-4.58 (m, 1H), 4.27 (m, 1H), 3.66 (dd, J=9.8, 6.0 Hz, 1H), 3.57 (dd, J=9.8, 4.8 Hz, 1H), 3.30 (s, 3H), 3.04 (dd, J=17.5, 3.9 Hz, 1H), 2.85-2.80 (m, 1H). Example 96—Preparation of benzyl (S)-4-(((S)-3-methoxy-1-oxo-1-((quinolin-8-ylmethyl)amino)propan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoate (DPLG-2198) DPLG-2198 was prepared following the general procedure for HATU mediated coupling of 3-phenylpropanoic acid (26.4 mg, 0.176 mmol) and benzyl (S)-3-amino-4-(((S)-3-methoxy-1-oxo-1-((quinolin-8-ylmethyl)amino)propan-2-yl)amino)-4-oxobutanoate bis(2,2,2-trifluoroacetate) (111 mg, 0.16 mmol). After completion of the reaction (3 h), the mixture was precipitated with water. The precipitate was filtered and dried to give the product (77 mg, 81%).1H NMR (500 MHz, DMSO-d6) δ 8.94 (dd, J=4.2, 1.8 Hz, 1H), 8.43 (t, J=6.1 Hz, 1H), 8.38 (dd, J=8.3, 1.8 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.87 (dd, J=8.1, 1.5 Hz, 1H), 7.61 (dd, J=7.2, 1.5 Hz, 1H), 7.57-7.53 (m, 2H), 7.35-7.30 (m, 5H), 7.27-7.24 (m, 2H), 7.19-7.15 (m, 3H), 5.03 (s, 2H), 4.95 (dd, J=16.4, 6.1 Hz, 1H), 4.90 (dd, J=16.4, 5.9 Hz, 1H), 4.77 (td, J=8.2, 5.7 Hz, 1H), 4.49 (dt, J=7.8, 5.3 Hz, 1H), 3.62 (dd, J=9.7, 5.8 Hz, 1H), 3.52 (dd, J=9.7, 5.0 Hz, 1H), 3.28 (s, 3H), 2.85-2.77 (m, 3H), 2.59 (dd, J=16.2, 8.4 Hz, 1H), 2.42-2.38 (m, 2H). Example 97—Preparation of (S)-4-(((S)-3-methoxy-1-oxo-1-(((1,2,3,4-tetrahydroquinolin-8-yl)methyl)amino)propan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoic acid (DPLG-2202) Benzyl (S)-4-(((S)-3-methoxy-1-oxo-1-((quinolin-8-ylmethyl)amino)propan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoate (73 mg, 0.122 mmol) was dissolved in 3 mL methanol and 25 mg 10 palladium on carbon (10%) was added. The mixture was stirred overnight under hydrogen atmosphere. The mixture was filtered through celite, evaporated, and purified by HPLC to give the product (19 mg, 30%).1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.26-8.23 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 7.28-7.25 (m, 2H), 7.21-7.15 (m, 3H), 6.81 (dd, J=7.5, 1.5 Hz, 1H), 6.76 (dd, J=7.5, 1.5 Hz, 1H), 6.40 (t, J=7.4 Hz, 1H), 4.63 (td, J=7.8, 5.8 Hz, 1H), 4.40 (dt, J=7.7, 5.4 Hz, 1H), 4.08 (dd, J=15.3, 6.1 Hz, 1H), 4.03 (dd, J=15.3, 5.9 Hz, 1H), 3.56 (dd, J=9.8, 5.8 Hz, 1H), 3.47 (dd, J=9.8, 5.0 Hz, 1H), 3.24 (s, 3H), 3.22 (t, J=5.5 Hz, 2H), 2.80 (t, J=7.9 Hz, 2H), 2.70-2.65 (m, 3H), 2.48-2.39 (m, 3H), 1.79-1.74 (m, 2H). Example 98—Preparation of (S)—N4-(tert-butoxy)-N−1—((S)-3-methoxy-1-oxo-1-(((1,2,3,4-tetrahydroquinolin-8-yl)methyl)amino)propan-2-yl)-2-(3 -phenylpropanamido)succinamide (DPLG-2226) DPLG-2226 was prepared following the general procedure for HATU mediated coupling of (S)-4-(((S)-3-methoxy-1-oxo-1-(((1,2,3,4 -tetrahydroquinolin-8-yl)methyl)amino)propan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoic acid (19.0 mg, 0.037 mmol) and O-tert-butylhydroxylamine hydrochloride (5.1 mg, 0.041 mmol). The product was purified by HPLC (17.9 mg, 83%).1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.41 (t, J=6.1 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.28-7.25 (m, 2H), 7.20-7.15 (m, 3H), 6.84 (d, J=7.5 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.38 (t, J=7.4 Hz, 1H), 5.24-5.20 (m, 1H), 4.67-4.62 (m, 1H), 4.40-4.37 (m, 1H), 4.10 (dd, J=15.1, 6.3 Hz, 1H), 4.00 (dd, J=15.1, 5.8 Hz, 1H), 3.60 (dd, J=9.8, 5.9 Hz, 1H), 3.49 (dd, J=9.8, 4.5 Hz, 1H), 3.24 (s, 3H), 3.22-3.21 (m, 2H), 2.80-2.76 (m, 2H), 2.66 (t, J=6.4 Hz, 2H), 2.52-2.48 (m, 1H), 2.42-2.39 (m, 2H), 2.35 (dd, J=14.8, 7.5 Hz, 1H), 1.79-1.74 (m, 2H), 1.14 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.45, 170.86, 169.46, 167.61, 142.51, 141.23, 128.29, 128.11, 128.00, 126.47, 125.85, 121.30, 120.04, 114.64, 80.59, 71.75, 58.29, 53.09, 49.63, 41.33, 36.77, 34.84, 30.99, 27.16, 26.26, 21.33. Example 99—Preparation of (S)—N4-(tert-butoxy)-N1—(S)-3-methoxy-1-oxo 1-((quinolin-8-ylmethyl)amino)propan-2-yl)-2-(3-phenylpropanamido)succinamide (DPLG-2220) DPLG-2220 was prepared following the general procedure for HATU mediated coupling of (S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanoic acid (20.2 mg, 0.06 mmol) and (S)-2-amino-3-methoxy-N-(quinolin-8-ylmethyl)propanamide bis(2,2,2-trifluoroacetate) (32.2 mg, 0.066 mmol). The product was purified by HPLC (yield=21.6 mg, 62%).1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.95 (dd, J=4.2, 1.8 Hz, 1H), 8.57 (t, J=6.1 Hz, 1H), 8.38 (dd, J=8.3, 1.8 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.87 (dd, J=8.3, 1.5 Hz 1H), 7.63 (dd, J=7.4, 1.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.28-7.25 (m, 2H), 7.20-7.17 (m, 3H), 4.98-4.89 (m, 2H), 4.71-4.67 (m, 1H), 4.50-4.46 (m, 1H), 3.66 (dd, J=9.7, 5.8 Hz, 1H), 3.55 (dd, J=9.7, 4.7 Hz, 1H), 3.29 (s, 3H), 2.80-2.77 (m, 2H), 2.55-2.51 (m, 1H), 2.42 (td, J=7.6, 3.6 Hz, 2H), 2.35 (dd, J=14.7, 7.7 Hz, 1H), 1.06 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.95, 171.47, 169.97, 168.04, 150.09, 145.84, 141.70, 136.89, 136.79, 128.76, 128.58, 128.10, 127.15, 126.89, 126.67, 126.32, 121.86, 80.98, 72.30, 58.78, 53.74, 50.11, 39.16, 37.25, 35.29, 31.45, 26.66. Example 100—Preparation of tert-butyl (S)-(3-methyl-1-((naphthalen-1-ylmethyl)amino)-1-oxobutan-2-yl)carbamate (DPLG-2218) DPLG-2218 was prepared following the general procedure for HATU mediated coupling of Boc-Val-OH (217 mg, 1 mmol) and 1-naphthylmethylamine (161 μL, 1.1 mmol). The product was isolated by ethyl acetate extraction and purified by recrystallization with ethanol/water (322 mg, 90%).1H NMR (500 MHz, DMSO-d6) δ 8.37 (t, J=5.7 Hz, 1H), 8.07-8.05 (m, 1H), 7.95-7.93 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.55-7.52 (m, 2H), 7.49-7.42 (m, 2H), 6.71 (d, J=8.9 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 3.84-3.81 (m, 1H), 1.96-1.89 (m, 1H), 1.38 (s, 9H), 0.83 (d, J=6.5 Hz, 6H). Example 101—Preparation of (S)-2-amino-3methyl-N-(naphthalen-1-ylmethyl)butanamide 2,2,2-trifluoroacetate (DPLG-2221) DPLG-2221 was synthesized by following the general procedure for Boc-deprotection of tert-butyl (S)-(3-methyl-1-((naphthalen-1-ylmethyl)amino)-1-oxobutan-2-yl)carbamate (107 mg, 0.3 mmol). After completion of reaction (3 h), excess trifluoroacetic acid and dichloromethane were evaporated to give a paste. The paste was treated with hexane and left overnight. A white solid appeared, which was isolated by decantation of hexane. The solid was dried under vacuum to give pure product (97 mg, 87%).1H NMR (500 MHz, DMSO-d6) δ 8.94 (t, J=5.7 Hz, 1H), 8.19 (d, J=5.2 Hz, 3H), 8.08-8.07 (m, 1H), 7.98-7.96 (m, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.58-7.47 (m, 4H), 4.90 (dd, J=14.9, 5.8 Hz, 1H), 4.73 (dd, J=14.9, 5.1 Hz, 1H), 3.63-3.61 (m, 1H), 2.10-2.03 (m, 1H), 0.91-0.88 (m, 6H). Example 102—Preparation of (S)—N4-(tert-butoxy)-N1—((S)-3-methyl-1-((naphthalen-1-ylmethyl)amino)-1-oxobutan-2-yl)-2-(3 -phenylpropanamido)succinamide (DPLG-2224) DPLG-2224 was prepared following the general procedure for HATU mediated coupling of (S)-4-(tert-butoxyamino)-4-oxo-2-(3-phenylpropanamido)butanoic acid (20.2 mg, 0.06 mmol) and (S)-2-amino-3-methyl-N-(naphthalen-1-ylmethyl)butanamide 2,2,2-trifluoroacetate (24.4 mg, 0.066 mmol). The product was purified by HPLC (yield=12.2 mg, 35%).1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.52 (t, J=5.8 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.09-8.06 (m, 1H), 7.95-7.93 (m, 1H), 7.86-7.83 (m, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.56-7.51 (m, 2H), 7.48-7.45 (m, 2H), 7.27-7.24 (m, 2H), 7.20-7.15 (m, 3H), 4.79-4.65 (m, 3H), 4.20-4.17 (m, 1H), 2.81-2.77 (m, 2H), 2.50-2.47 (m, 1H), 2.42-2.39 (m, 2H), 2.31 (dd, J=14.8, 8.0 Hz, 1H), 2.04-1.99 (m, 1H), 1.12 (s, 9H), 0.81 (d, J=6.8 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H).13C NMR (126 MHz, DMSO) δ 171.97, 171.27, 170.98, 168.00, 141.67, 134.92, 133.72, 131.31, 128.92, 128.76, 128.58, 128.01, 126.59, 126.33, 126.24, 126.10, 125.84, 124.02, 80.99, 58.24, 50.18, 37.27, 35.05, 31.48, 30.93, 26.72, 19.67, 18.13. Example 103—Preparation of benzyl (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4 -oxo -3-(3 -phenylpropanamido)butanoate (DPLG-2195) DPLG-2195 was prepared following the general procedure for HATU mediated coupling of 3-phenylpropanoic acid (50 mg, 0.33 mmol) and DPLG-2192 (173 mg, 0.3 mmol). Reaction mixture was precipitated by the addition of 5 water. The precipitate was filtered and dried to give pure product (149 mg, 83%).1H NMR (500 MHz, DMSO-d6) δ 8.44 (t, J=5.8 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.04-8.02 (m, 1H), 7.94-7.93 (m, 1H), 7.84-7.81 (m, 1H), 7.56-7.50 (m, 2H), 7.46-7.43 (m, 2H), 7.37-7.25 (m, 7H), 7.19-7.15 (m, 3H), 5.03 (s, 2H), 4.76-4.72 (m, 3H), 4.46 (dt, J=7.9, 5.4 Hz, 1H), 3.57 (dd, J=9.7, 5.8 Hz, 1H), 3.48 (dd, J=9.7, 5.1 Hz, 1H), 3.23 (s, 3H), 2.82-2.76 (m, 3H), 2.58 (dd, J=16.2, 8.4 Hz, 1H), 2.41-2.38 (m, 2H). Example 104—Preparation of (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxo-3-(3-phenylpropanamido)butanoic acid (DPLG-2201) DPLG-2201 was synthesized by following the general procedure for O-debenzylation of benzyl (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4 -oxo-3-(3-phenylpropanamido)butanoate (145 mg, 0.24 mmol). Yield=120 mg, 99%.1H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.52 (t, J=5.8 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.06-8.03 (m, 2H), 7.95-7.93 (m, 1H), 7.84-7.82 (m, 1H), 7.57-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.28-7.25 (m, 2H), 7.20-7.15 (m, 3H), 4.74 (d, J=5.8 Hz, 2H), 4.63 (td, J=7.6, 6.1 Hz, 1H), 4.44 (dt, J=7.8, 5.4 Hz, 1H), 3.58 (dd, J=9.7, 5.8 Hz, 1H), 3.49 (dd, J=9.7, 5.0 Hz, 1H), 3.23 (s, 3H), 2.79 (t, J=7.9 Hz, 2H), 2.66 (dd, J=16.5, 6.2 Hz, 1H), 2.46-2.38 (m, 3H). Example 105—Preparation of (S)—N4-(tert-butyl)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(3-phenylpropanamido)succinamide (DPLG-2230) DPLG-2230 was prepared following the general procedure for HATU mediated coupling of (S)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4 -oxo-3-(3-phenylpropanamido)butanoic acid (15.2 mg, 0.03 mmol) and tert-butylamine (9.5 μL, 0.09 mmol). The product was purified by HPLC to give pure product (8.7 mg, 52%).1H NMR (500 MHz, DMSO-d6) δ 8.66 (t, J=5.9 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.07-8.05 (m, 1H), 7.94-7.92 (m, 1H), 7.83-7.81 (m, 1H), 7.55-7.50 (m, 3H), 7.46-7.15 (m, 2H), 7.28-7.25 (m, 2H), 7.20-7.15 (m, 3H), 4.79 (dd, J=15.6, 6.0 Hz, 1H), 4.70 (dd, J=15.6, 5.8 Hz, 1H), 4.63-4.59 (m, 1H), 4.45-4.41 (m, 1H), 3.63 (dd, J=9.8, 6.1 Hz, 1H), 3.54 (dd, J=9.8, 4.4 Hz, 1H), 3.24 (s, 3H), 2.78 (t, J=7.9 Hz, 2H), 2.55-2.51 (m, 1H), 2.43-2.34 (m, 3H), 1.14 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.34, 171.21, 169.26, 169.15, 141.26, 134.21, 133.16, 130.71, 128.43, 128.27, 128.12, 127.32, 126.08, 125.84, 125.68, 125.33, 124.87, 123.32, 71.76, 58.24, 53.32, 50.09, 49.74, 40.25, 38.46, 36.75, 31.05, 28.36. Example 106—Preparation of tert-butyl ((S)-4-(tertbutylamino)-1-(((S)-3 -methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-1,4-dioxobutan-2-yl)carbamate (DPLG-2237) DPLG-2237 was prepared following the general procedure for HATU mediated coupling of (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (DPLG-2131, DPLG-2215, DPLG-2236) (118 mg, 0.25 mmol) and tert-butylamine (32 mL, 0.3 mmol). The product was isolated by ethylacetate extraction and purified by HPLC (yield=37.0 mg).1H NMR (500 MHz, DMSO-d6) δ 8.59 (t, J=5.8 Hz, 1H), 8.05-8.03 (m, 1H), 7.98-7.93 (m, 2H), 7.84-7.82 (m, 1H), 7.55-7.51 (m, 2H), 7.46-7.43 (m, 3H), 6.93 (d, J=8.1 Hz, 1H), 4.79-4.70 (m, 2H), 4.47-4.43 (m, 1H), 4.31-4.26 (m, 1H), 3.61 (dd, J=9.7, 5.7 Hz, 1H), 3.51 (dd, J=9.7, 4.8 Hz, 1H), 3.24 (s, 3H), 2.50-2.45 (m, 1H), 2.33 (dd, J=14.9, 7.8 Hz, 1H), 1.36 (s, 9H), 1.18 (s, 9H). Example 107—Preparation of (S)-2-amino-N4-(tertbutyl)-N1—((S)-3 -methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide 2,2,2-trifluoroacetate (DPLG-2242) DPLG-2242 was synthesized by following the general procedure for Boc-deprotection of tert-butyl ((S)-4-(tertbutylamino)-1-(((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-1,4 -dioxobutan-2-yl)carbamate (34.4 mg, 0.065 mmol). Yield=32 mg, 91%.1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J=7.7 Hz, 1H), 8.67 (t, J=5.8 Hz, 1H), 8.14 (bs, 3H), 8.04-8.02 (m, 1H), 7.95-7.93 (m, 1H), 7.88 (s, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.47-7.43 (m, 2H), 4.80-4.72 (m, 2H), 4.53 (ddd, J=7.7, 5.9, 4.6 Hz, 1H), 4.16-4.13 (m, 1H), 3.63 (dd, J=9.8, 5.9 Hz, 1H), 3.53 (dd, J=9.8, 4.6 Hz, 1H), 3.26 (s, 3H), 2.73 (dd, J=16.7, 5.2 Hz, 1H), 2.60-2.55 (m, 1H), 1.21 (s, 9H). Example 108—Preparation of (S)—N4-(tert-butyl)-N1((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)-2-(5-methylisoxazole-3-carboxamido)succinamide (DPLG-2244) DPLG-2244 was synthesized following the general procedure for HATU mediated coupling of (S)-2-amino-N4-(tert-butyl)-N1—((S)-3-methoxy-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)succinamide 2,2,2-trifluoroacetate (21.7 mg, 0.04 mmol) and 5-methylisoxazole-3-carboxylic acid (5.6 mg, 0.044 mmol). The product was purified by HPLC to give pure product (18.6 mg, 87%).1H NMR (500 MHz, DMSO-d6) δ 8.62 (t, J=5.8 Hz, 1H), 8.56 (d, J=8.0 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.05-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.85-7.82 (m, 1H), 7.54-7.51 (m, 3H), 7.45-7.43 (m, 2H), 6.54 (s, 1H), 4.80-4.74 (m, 3H), 4.50-4.46 (m, 1H), 3.60 (dd, J=9.8, 5.9 Hz, 1H), 3.53 (dd, J=9.8, 4.9 Hz, 1H), 3.23 (s, 3H), 2.58 (d, J=6.7 Hz, 2H), 2.47 (s, 3H), 1.16 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.38, 170.37, 169.19, 168.90, 158.48, 158.27, 134.17, 133.19, 130.72, 128.44, 127.40, 126.11, 125.72, 125.36, 124.97, 123.35, 101.30, 71.81, 58.25, 53.14, 50.21, 50.14, 40.29, 38.09, 28.33, 11.84. Example 109—Preparation of DPLG-2231 DPLG-2231 was synthesized by following the general procedure of EDC mediated coupling of Boc-Glu-OBn (5.06 g, 15.0 mmol) with tert-butylamine (2.37 mL, 22.5 mmol). After completion of the reaction, water was added to the mixture. The mixture was extracted twice with ethyl acetate. The combined organic layer was washed with aq. NaHCO3, water, 1N HCl, water followed by saturated brine solution. Ethyl acetate layer was dried over anhydrous Na2SO4and evaporated to give product (5.78 g, 98%) as white solid. The product was used in next step without further purification.1H NMR (500 MHz, Chloroform-d) δ 7.43-7.29 (m, 5H), 5.58 (s, 1H), 5.27 (d, J=8.3 Hz, 1H), 5.20 (d, J=12.3 Hz, 1H), 5.13 (d, J=12.3 Hz, 1H), 4.36-4.23 (m, 1H), 2.22-2.06 (m, 3H), 2.02-1.87 (m, 1H), 1.42 (s, 9H), 1.32 (s, 9H). Example 110—Preparation of DPLG-2233 DPLG-2233 was synthesized by following the general procedure for Boc-deprotection of DPLG-21002 (3.68 g, 9.38 mmol). After completion of the reaction (5 h), excess trifluoroacetic acid and dichloromethane were evaporated. Crude was dried under high vacuum to give product (3.81 g, quant.) as a colorless paste. Product was used in the next step without further purification.1H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 3H), 7.42-7.29 (m, 5H), 6.07 (bs, 1H), 5.27 (d, J=11.9 Hz, 1H), 5.20 (d, J=11.9 Hz, 1H), 4.24-4.16 (m, 1H), 2.53-2.44 (m, 1H), 2.43-2.34 (m, 1H), 2.34-2.24 (m, 1H), 2.24-2.13 (m, 1H), 1.30 (d, J=2.1 Hz, 9H). Example 111—Preparation of DPLG-2234 DPLG-2234 was synthesized by following the general procedure for HATU mediated coupling of 3-phenylpropanoic acid (82.6 mg, 0.55 mmol) and DPLG-21008 (203.2 mg, 0.5 mmol). After completion of the reaction, the mixture was diluted with water and extracted twice with ethyl acetate. Combined organic layer was washed with aq. NaHCO3, water, 1N HCl, water followed by saturated brine solution. Ethyl acetate layer was dried over anhydrous Na2SO4and evaporated. Crude was purified by column chromatography to give product (193 mg, 91%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J=7.4 Hz, 1H), 7.41-7.30 (m, 5H), 7.30-7.21 (m, 3H), 7.21-7.13 (m, 3H), 5.13 (d, J=12.6 Hz, 1H), 5.10 (d, J=12.6 Hz, 1H), 4.31-4.20 (m, 1H), 2.80-2.76 (m, 2H), 2.45-2.38 (m, 2H), 2.07 (t, J=7.7 Hz, 2H), 1.97-1.84 (m, 1H), 1.79-1.67 (m, 1H), 1.22 (s, 9H). Example 112—Preparation of DPLG-2239 DPLG-2239 was synthesized by following the general procedure for O-debenzylation of DPLG-2234 (180 mg, 0.34 mmol). The product was isolated as a white solid (140 mg, 99%).1H NMR (500 MHz, DMSO-d6) δ 8 12.58 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.37 (s, 1H), 7.27-7.13 (m, 5H), 4.19-4.11 (m, 1H), 2.81 (t, J=7.9 Hz, 2H), 2.49-2.36 (m, 2H), 2.10-1.98 (m, 2H), 1.96-1.85 (m, 1H), 1.76-1.63 (m, 1H), 1.23 (s, 9H). Example 113—Preparation of DPLG-2243 DPLG-2243 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2239 (20.1 mg, 0.06 mmol) and H-Ser(OMe)-CH2-naphth TFA salt (22.3 mg, 0.06 mmol). The crude was purified by HPLC to give product (18.8 mg, 54%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.55 (t, J=5.8 Hz, 1H), 8.10-8.00 (m, 3H), 7.96-7.92 (m, 1H), 7.83 (dd, J=6.1, 3.4 Hz, 1H), 7.56-7.50 (m, 2H), 7.47-7.43 (m, 2H), 7.35 (s, 1H), 7.28-7.23 (m, 2H), 7.21-7.13 (m, 3H), 4.75 (d, J=5.7 Hz, 2H), 4.51 (dt, J=7.7, 5.6 Hz, 1H), 4.27 (td, J=8.3, 5.3 Hz, 1H), 3.55 (dd, J=9.7, 6.0 Hz, 1H), 3.50 (dd, J=9.7, 5.4 Hz, 1H), 3.24 (s, 3H), 2.79 (t, J=7.9 Hz, 2H), 2.48-2.37 (m, 2H), 2.03 (t, J=8.0 Hz, 2H), 1.92-1.78 (m, 1H), 1.77-1.60 (m, 1H), 1.22 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.59, 171.54, 171.19, 169.39, 141.27, 134.15, 133.21, 130.74, 128.44, 128.25, 128.14, 127.44, 126.15, 125.83, 125.75, 125.36, 124.94, 123.37, 71.94, 58.24, 52.65, 52.28, 49.83, 40.30, 36.76, 32.64, 31.03, 28.50, 28.26. Example 114—Preparation of DPLG-2255 DPLG-2255 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2239 (18.4 mg, 0.055 mmol) and H-Ala-CH2-naphth TFA salt (17.1 mg, 0.05 mmol). The crude was purified by HPLC to give product (20.2 mg, 74%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.45 (t, J=5.7 Hz, 1H), 8.10-8.01 (m, 3H), 7.98-7.90 (m, 1H), 7.84 (dd, J=7.5, 1.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.50-7.41 (m, 2H), 7.35 (s, 1H), 7.29-7.22 (m, 2H), 7.22-7.11 (m, 3H), 4.76 (dd, J=14.2, 4.6 Hz, 1H), 4.73 (dd, J=14.2, 4.5 Hz, 1H), 4.37-4.27 (m, 1H), 4.27-4.18 (m, 1H), 2.79 (t, J=7.9 Hz, 2H), 2.47-2.36 (m, 2H), 2.09-2.00 (m, 2H), 1.90-1.79 (m, 1H), 1.75-1.63 (m, 1H), 1.24 (d, J=7.1 Hz, 3H), 1.22 (s, 9H).13C NMR (126 MHz, DMSO) δ 172.13, 171.56, 171.22, 171.16, 141.29, 134.36, 133.24, 130.78, 128.47, 128.24, 128.15, 127.48, 126.17, 125.82, 125.77, 125.38, 125.07, 123.37, 52.28, 49.83, 48.28, 40.18, 36.74, 32.64, 31.01, 28.50, 28.29, 18.24. Example 115—Preparation of DPLG-2238 TFA.H-Glu(CONHtBu)-OH (203.0 mg, 0.5 mmol) was dissolved in dichloromethane (6 mL) and triethylamine (140 μL, 1.0 mmol) was added. After stirring the mixture for 10 minutes at room temperature, TsCl (143.0 mg, 0.75 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. Dichloromethane was evaporated, and the crude was dissolved in ethyl acetate. The solution was washed with water, 1N HCl followed by brine. The product was purified by column chromatography to give product (177.0 mg, 79%) as white solid.1H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J=8.5 Hz, 2H), 7.35-7.29 (m, 3H), 7.20 (d, J=8.0 Hz, 2H), 7.18-7.13 (m, 2H), 5.52 (s, 1H), 5.47 (d, J=9.1 Hz, 1H), 4.91 (d, J=12.2 Hz, 1H), 4.87 (d, J=12.2 Hz, 1H), 3.93-3.84 (m, 1H), 2.38 (s, 3H), 2.33-2.11 (m, 3H), 1.88-1.77 (m, 1H), 1.35 (s, 9H). Example 116—Preparation of DPLG-2254 DPLG-2254 was prepared by following the general procedure for O-debenzylation of DPLG-2238 (170 mg, 0.38 mmol). The product (135 mf, quant.) was isolated as a white solid.1H NMR (500 MHz, Chloroform-d) δ 7.69 (d, J=7.9 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.15-5.91 (m, 2H), 3.82-3.69 (m, 1H), 2.39 (s, 3H), 2.35-2.27 (m, 1H), 2.21-2.12 (m, 1H), 2.11-2.02 (m, 1H), 1.99-1.88 (m, 1H), 1.31 (s, 9H). Example 117—Preparation of DPLG-2256 DPLG-2256 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2254 (29.0 mg, 0.08 mmol) and H-Ala-CH2-naphth TFA salt (27.4 mg, 0.08 mmol). The crude was purified by HPLC to give product (32.8 mg, 74%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.43 (t, J=5.7 Hz, 1H), 8.09 (d, J=7.3 Hz, 1H), 8.04-7.98 (m, 1H), 7.97-7.90 (m, 1H), 7.86 (bs, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.58-7.49 (m, 2H), 7.49-7.42 (m, 1H), 7.42-7.39 (m, 1H), 7.38 (s, 1H), 7.30 (d, J=7.9 Hz, 2H), 4.75 (dd, J=15.4, 5.8 Hz, 1H), 4.69 (dd, J=15.4, 5.6 Hz, 1H), 4.11-4.01 (m, 1H), 3.74-3.67 (m, 1H), 2.34 (s, 3H), 2.11-1.93 (m, 2H), 1.77-1.66 (m, 1H), 1.66-1.56 (m, 1H), 1.21 (s, 9H), 1.07 (d, J=7.0 Hz, 3H).13C NMR (126 MHz, DMSO) δ 171.85, 171.05, 169.95, 142.40, 137.98, 134.29, 133.24, 130.77, 129.23, 128.46, 127.51, 126.66, 126.17, 125.78, 125.37, 125.11, 123.37, 55.78, 49.84, 48.11, 40.14, 32.34, 29.23, 28.46, 20.94, 18.15. Example 118—Preparation of DPLG-3010 DPLG-3010 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2254 (42.8 mg, 0.12 mmol) with 3-aminopropanamide hydrochloride (22.4 mg, 0.18 mmol). After completion of the reaction, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic layer was evaporated and purified by HPLC to give product (21.9 mg, 43%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 7.88-7.74 (m, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.40-7.25 (m, 4H), 6.82 (s, 1H), 3.58-3.42 (m, 1H), 3.12-2.89 (m, 2H), 2.36 (s, 3H), 2.07 (t, J=7.1 Hz, 2H), 2.02-1.85 (m, 2H), 1.69-1.50 (m, 2H), 1.19 (s, 9H).13C NMR (126 MHz, DMSO) δ 172.77, 171.16, 170.43, 142.78, 138.02, 129.51, 126.75, 56.32, 50.08, 35.21, 34.74, 32.31, 29.10, 28.62, 21.12. Example 119—Preparation of DPLG-3023 DPLG-3023 was synthesized by following the general procedure for EDC mediated coupling of Boc-Asp(OH)-OBn (5.01 g, 15.49 mmol) with tert-butyl amine (2.44 mL, 23.24 mmol). After completion of the reaction, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was washed with aq. NaHCO3, water, 1N HCl, water followed by saturated brine solution. Ethyl acetate layer was dried over anhydrous Na2SO4and evaporated to give product (5.80 g, 99%) as a white solid. The product was used in next step without further purification.1H NMR (500 MHz, Chloroform-d) δ 7.33 (s, 2H), 7.36-7.26 (m, 2H), 5.84 (d, J=8.7 Hz, 1H), 5.40 (bs, 1H), 5.21 (d, J=12.4 Hz, 1H), 5.14 (d, J=12.4 Hz, 1H), 4.54-4.47 (m, 1H), 2.79 (dd, J=15.8, 5.0 Hz, 1H), 2.62 (dd, J=15.8, 4.2 Hz, 1H), 1.42 (s, 9H), 1.29 (s, 9H). Example 120—Preparation of DPLG-3047 DPLG-3047 was synthesized by following the general procedure for Boc-deprotection of DPLG-21009 (3.84 g, 10.15 mmol). After completion of the reaction (3 h), excess trifluoroacetic acid and dichloromethane were evaporated. Crude was dried under high vacuum to give a colorless paste. The compound was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 8.36 (bs, 3H), 7.85 (s, 1H), 7.46-7.29 (m, 5H), 5.24 (d, J=12.6 Hz, 1H), 5.18 (d, J=12.6 Hz, 1H), 4.39-4.29 (m, 1H), 2.83-2.66 (m, 2H), 1.22 (s, 9H). Example 121—Preparation of DPLG-21012 DPLG-21012 was synthesized by following the general procedure for the HATU mediated coupling of 3-phenylpropanoic acid (1.68 g, 11.17 mmol) with DPLG-21011 (3.98 g, 10.15 mmol). After completion of the reaction, water was added. A white precipitate was formed. The precipitate was filtered and washed with water. The precipitate was dried in air to give product (3.92 g, 94%) as a white solid.1H NMR (500 MHz, Chloroform-d) δ 7.39-7.29 (m, 5H), 7.29-7.23 (m, 2H), 7.21-7.14 (m, 3H), 6.88 (d, J=8.0 Hz, 1H), 5.32 (s, 1H), 5.20 (d, J=12.3 Hz, 1H), 5.14 (d, J=12.3 Hz, 1H), 4.84-4.77 (m, 1H), 2.95 (t, J=7.9 Hz, 2H), 2.81 (dd, J=15.7, 4.4 Hz, 1H), 2.61-2.47 (m, 3H), 1.28 (s, 9H). Example 122—Preparation of DPLG-21013 DPLG-21013 was synthesized by following the procedure for O-debenzylation of DPLG-21012 (1.44 g, 3.50 mmol). The product (1.11 g, 99%) was isolated as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.29-7.23 (m, 2H), 7.23-7.13 (m, 3H), 4.52-4.44 (m, 1H), 2.83-2.76 (m, 2H), 2.49-2.44 (m, 1H), 2.44-2.34 (m, 3H), 1.22 (s, 9H). Example 123—Preparation of DPLG-2294 DPLG-2294 was synthesized by following the general procedure for HATU mediated coupling of 3-phenylpropanoyl-Glu(CONHtBu)-OH (46.8 mg, 0.14 mmol) and H-Ala-OBn HCl salt (33.0 mg, 0.154 mmol). After completion of the reaction, water was added to the reaction mixture and extracted twice ethyl acetate. The combined organic layer was washed 1N HCl followed by brine and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated, and the crude was recrystallized from ethanol-water to give product (37.3 mg, 54%) as white solid.1H NMR (500 MHz, Chloroform-d) δ 7.58 (d, J=7.2 Hz, 1H), 7.40-7.29 (m, 5H), 7.29-7.23 (m, 3H), 7.22-7.15 (m, 2H), 6.89 (d, J=6.7 Hz, 1H), 5.58 (s, 1H), 5.19 (d, J=12.3 Hz, 1H), 5.13 (d, J=12.3 Hz, 1H), 4.59-4.49 (m, 1H), 4.43-4.35 (m, 1H), 2.95 (t, J=8.2 Hz, 2H), 2.57-2.46 (m, 2H), 2.26-2.19 (m, 2H), 1.96-1.88 (m, 2H), 1.42 (d, J=7.3 Hz, 3H), 1.36 (s, 9H). Example 124—Preparation of DPLG-2297 DPLG-2297 was synthesized by following the general procedure for O-debenzylation of DPLG-2294 (37.3 mg, 0.075 mmol). The product (30.0 mg, quant.) was isolated as white solid.1H NMR (500 MHz, DMSO-d6) δ 12.51 (bs, 1H), 8.10 (bs, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.32-7.24 (m, 2H), 7.23-7.13 (m, 3H), 4.29-4.20 (m, 1H), 4.20-4.10 (m, 1H), 2.80 (t, J=7.9 Hz, 2H), 2.45-2.41 (m, 2H), 2.02 (t, J=8.2 Hz, 2H), 1.89-1.78 (m, 1H), 1.70-1.57 (m, 1H), 1.30-1.16 (m, 12H). Example 125—Preparation of DPLG-3012 DPLG-3012 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2297 (14.2 mg, 0.035 mmol) with 2-(1-naphthyl)ethylamine hydrochloride (8.0 mg, 0.0385 mmol). The crude was purified by HPLC to give product (15.6 mg, 80%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.18 (d, J=8.2 Hz, 1H), 8.09-8.01 (m, 2H), 7.96 (d, J=7.5 Hz, 1H), 7.92 (dd, J=8.1, 1.6 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.58-7.49 (m, 2H), 7.42 (dd, J=8.3, 6.9 Hz, 1H), 7.40-7.33 (m, 2H), 7.30-7.23 (m, 2H), 7.23-7.19 (m, 2H), 7.19-7.13 (m, 1H), 4.26-4.16 (m, 2H), 3.48-3.33 (m, 2H), 3.22-3.14 (m, 2H), 2.82 (t, J=8.0 Hz, 2H), 2.49-2.40 (m, 2H), 2.10-1.99 (m, 2H), 1.89-1.79 (m, 1H), 1.75-1.63 (m, 1H), 1.23 (s, 9H), 1.18 (d, J=7.1 Hz, 3H). Example 126—Preparation of DPLG-3013 DPLG-3013 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2297 (14.2 mg, 0.035 mmol) with O-phenylhydroxylamine hydrochloride (5.6 mg, 0.0385 mmol). The crude was purified by HPLC to give product (7.6 mg, 44%) as a white solid. Complex NMR due to presence of 71:29 rotamers.1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 0.71H), 11.86 (s, 0.29H), 8.37 (d, J=7.3 Hz, 0.29H), 8.28 (d, J=6.8 Hz, 0.71H), 8.10 (d, J=7.4 Hz, 0.29H), 8.03 (d, J=7.9 Hz, 0.71H), 7.40-7.11 (m, 8H), 7.07-6.94 (m, 3H), 4.34-4.19 (m, 2H), 2.80 (t, J=8.0 Hz, 1.42H), 2.76-2.70 (m, 0.58H), 2.48-2.35 (m, 2H), 2.02 (t, J=8.1 Hz, 2H), 1.88-1.75 (m, 1H), 1.75-1.60 (m, 1H), 1.37-1.28 (m, 3H), 1.26-1.16 (m, 9H). Example 127—Preparation of DPLG-2293 DPLG-2293 was synthesized by following the general procedure for HATU mediated coupling of Ts-Glu (CONHtBu)-OH (64.0 mg, 0.18 mmol) and H-Ala-OBn HCl salt (43.0 mg, 0.20 mmol). After completion of the reaction, water was added to the reaction mixture to give a white precipitate. The precipitate was filtered, washed with water, and dried to give product (76.0 mg, 82%).1H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J=8.4 Hz, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.40-7.29 (m, 5H), 7.29-7.20 (m, 2H), 6.70 (d, J=7.1 Hz, 1H), 5.47 (s, 1H), 5.17 (d, J=12.3 Hz, 1H), 5.11 (d, J=12.3 Hz, 1H), 4.42-4.34 (m, 1H), 3.75-3.66 (m, 1H), 2.39 (s, 3H), 2.29-2.19 (m, 1H), 2.18-2.07 (m, 1H), 1.92-1.80 (m, 2H), 1.36 (s, 9H), 1.26 (d, J=7.2 Hz, 3H). Example 128—Preparation of DPLG-2296 DPLG-2296 was synthesized by following the general procedure for O-debenzylation of DPLG-2293 (76.0 mg, 0.147 mmol). The product (63.0 mg, quant.) was isolated as white solid.1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J=6.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.37 (s, 1H), 7.31 (d, J=8.0 Hz, 2H), 3.85-3.76 (m, 1H), 3.71-3.63 (m, 1H), 2.36 (s, 3H), 2.11-2.02 (m, 1H), 2.02-1.93 (m, 1H), 1.75-1.63 (m, 1H), 1.63-1.52 (m, 1H), 1.21 (s, 9H), 1.06 (d, J=7.1 Hz, 3H). Example 129—Preparation of DPLG-3014 DPLG-3014 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2296 (15.0 mg, 0.035 mmol) with 3-(trifluoromethyl)benzylamine (5.5 μL, 0.0385 mmol). The crude was purified by HPLC to give product (13.5 mg, 66%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.47 (t, J=6.1 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.60-7.48 (m, 4H), 7.36-7.29 (m, 3H), 4.37 (dd, J=15.7, 6.0 Hz, 1H), 4.32 (dd, J=15.7, 6.0 Hz, 1H), 4.07-3.97 (m, 1H), 3.73-3.64 (m, 1H), 2.35 (s, 3H), 2.07-1.92 (m, 2H), 1.75-1.65 (m, 1H), 1.65-1.55 (m, 1H), 1.19 (s, 9H), 1.07 (d, J=7.1 Hz, 3H). Example 130—Preparation of DPLG-3015 DPLG-3015 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2296 (15.0 mg, 0.035 mmol) with iso-butylamine (4 μl, 0.0385 mmol). The crude was purified by HPLC to give product (11.2 mg, 66%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J=7.4 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.78 (t, J=6.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.37 (s, 1H), 7.32 (d, J=7.9 Hz, 2H), 4.04-3.94 (m, 1H), 3.72-3.63 (m, 1H), 2.96-2.86 (m, 1H), 2.84-2.75 (m, 1H), 2.36 (s, 3H), 2.06-1.92 (m, 2H), 1.72-1.53 (m, 3H), 1.21 (s, 9H), 1.03 (d, J=7.0 Hz, 3H), 0.80 (d, J=6.7 Hz, 6H).13C NMR (126 MHz, DMSO) δ 171.74, 171.03, 169.86, 142.44, 137.93, 129.26, 126.65, 55.80, 49.84, 48.01, 45.90, 32.26, 29.16, 28.46, 28.01, 20.96, 19.98, 18.31. Example 131—Preparation of DPLG-3016 DPLG-3016 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2296 (15.0 mg, 0.035 mmol) with 2-(1-naphthyl)ethylamine hydrochloride (8.0 mg, 0.0385 mmol). The crude was purified by HPLC to give product (16.0 mg, 78%) as white solid.1H NMR (500 MHz, DMSO-d6) δ 8.17 (d, J=8.2 Hz, 1H), 8.04 (t, J=5.7 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.59-7.46 (m, 2H), 7.45-7.38 (m, 2H), 7.36-7.30 (m, 3H), 4.02-3.92 (m, 1H), 3.74-3.66 (m, 1H), 3.47-3.36 (m, 1H), 3.35-3.31 (m, 1H), 3.16 (t, J=7.6 Hz, 2H), 2.36 (s, 3H), 2.09-1.95 (m, 2H), 1.77-1.66 (m, 1H), 1.66-1.56 (m, 1H), 1.21 (s, 9H), 0.99 (d, J=7.0 Hz, 3H).13C NMR (126 MHz, DMSO) δ 171.82, 171.06, 169.85, 142.43, 137.95, 135.23, 133.43, 131.52, 129.26, 128.56, 126.80, 126.66, 126.03, 125.59, 125.55, 123.66 55.81, 49.86, 47.99, 39.69, 32.34, 32.29, 29.17, 28.48, 20.95, 18.22. Example 132—Preparation of DPLG-3017 DPLG-3017 was synthesized by following the general procedure for HATU mediated coupling of DPLG-2296 (15.0 mg, 0.035 mmol) with O-phenylhydroxylamine hydrochloride (5.6 mg, 0.0385 mmol). The crude was purified by HPLC to give product (12.0 mg, 66%) as white solid. Complex NMR due to 86:14 rotamers.1H NMR (500 MHz, DMSO-d6) δ 11.95 (s, 0.86H), 11.92 (s, 0.14), 8.25 (d, J=6.9 Hz, 0.86H), 8.12 (d, J=7.4 Hz, 0.14H), 7.86 (d, J=8.9 Hz, 1H), 7.68-7.59 (m, 2H), 7.40-7.24 (m, 5H), 7.06-6.90 (m, 3H), 4.16-4.06 (m, 0.14H), 4.02-3.89 (m, 0.86H), 3.78-3.68 (m, 1H), 2.37 (s, 2.58H), 2.32 (s, 0.42H), 2.13-2.01 (m, 1H), 2.01-1.90 (m, 1H), 1.79-1.65 (m, 1H), 1.65-1.52 (m, 1H), 1.28-1.16 (m, 9H), 1.13 (d, J=7.1 Hz, 3H).13C NMR (126 MHz, DMSO) δ 170.97, 170.27, 169.42, 159.32, 142.39, 138.12, 129.40, 129.20, 126.66, 122.28, 112.66, 55.50, 49.83, 46.04, 32.30, 29.16, 28.45, 20.96, 17.37. Example 133—Preparation of DPLG-3066 DPLG-3066 was prepared by following the general procedure for HATU mediated coupling of 3-phenylpropanoyl-Asp(CONHtBu)-OH (16.0 mg, 0.05 mmol) and H-4F-Phe-CH2-naphth TFA salt (21.8 mg, 0.05 mmol). The mixture was purified by HPLC to give product (26.0 mg, 83%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.62 (t, J=5.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.10-8.04 (m, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.96-7.91 (m, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.57-7.50 (m, 2H), 7.48 (s, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.29-7.23 (m, 2H), 7.23-7.12 (m, 5H), 7.02-6.95 (m, 2H), 4.80 (dd, J=15.4, 6.0 Hz, 1H), 4.69 (dd, J=15.4, 5.6 Hz, 1H), 4.57-4.50 (m, 1H), 4.50-4.41 (m, 1H), 3.10 (dd, J=13.8, 4.5 Hz, 1H), 2.82 (dd, J=13.8, 9.6 Hz, 1H), 2.79-2.68 (m, 2H), 2.52-2.48 (m, 1H), 2.41-2.32 (m, 2H), 2.29 (dd, J=15.0, 6.6 Hz, 1H), 1.15 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.14, 170.98, 170.50, 169.13, 160.88 (d, J=241.8 Hz), 141.26, 134.21, 134.03, 133.20, 130.92 (d, J=8.0 Hz), 130.77, 128.46, 128.28, 128.08, 127.41, 126.15, 125.84, 125.71, 125.31, 125.17, 123.35, 114.66 (d, J=21.6 Hz), 54.30, 50.09, 49.67, 40.22, 38.23, 36.76, 36.18, 31.07, 28.37. Example 134—Preparation of DPLG-3083 DPLG-3083 was prepared by following the general procedure for HATU mediated coupling of 3-phenylpropanoyl-Glu(CONHtBu)-OH (23.4 mg, 0.07 mmol) and H-4F-Phe-CH2-naphth TFA salt (36.7 mg, 0.084 mmol). The mixture was purified by HPLC to give product (32.6 mg, 73%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.54 (t, J=5.7 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.05-8.00 (m, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.96-7.91 (m, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.58-7.50 (m, 2H), 7.46-7.39 (m, 1H), 7.34-7.29 (m, 2H), 7.28-7.12 (m, 7H), 7.05-6.96 (m, 2H), 4.73 (d, J=5.7 Hz, 2H), 4.61-4.49 (m, 1H), 4.25-4.14 (m, 1H), 3.00 (dd, J=13.7, 5.5 Hz, 1H), 2.85 (dd, J=13.7, 9.0 Hz, 1H), 2.81-2.69 (m, 2H), 2.48-2.33 (m, 2H), 1.98 (t, J=8.0 Hz, 2H), 1.86-1.73 (m, 1H), 1.71-1.58 (m, 1H), 1.23 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 171.56, 171.35, 171.18, 170.64, 160.94 (d, J=241.4 Hz), 141.27, 134.14, 133.72, 133.23, 130.98 (d, J=7.6 Hz), 130.79, 128.46, 128.25, 128.13, 127.51, 126.19, 125.82, 125.76, 125.33, 125.20, 123.40, 114.70 (d, J=21.2 Hz), 53.99, 52.39, 49.84, 40.23, 36.76, 32.64, 31.01, 28.51, 28.28. Example 135—Preparation of DPLG-3084 DPLG-3084 was prepared by following the general procedure for HATU mediated coupling of Ind-oxal-Asp (CONHtBu)-OH (18 mg, 0.05 mmol) and H-4F-Phe-CH2-naphth TFA salt (24 mg, 0.055 mmol). The mixture was purified by HPLC to give product (18.0 mg, 55%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.76 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.61 (t, J=5.8 Hz, 1H), 8.28-8.21 (m, 2H), 8.07-8.00 (m, 1H), 7.97-7.91 (m, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.59-7.49 (m, 4H), 7.46-7.38 (m, 1H), 7.33 (d, J=7.1 Hz, 1H), 7.31-7.25 (m, 2H), 7.24-7.17 (m, 2H), 7.01-6.91 (m, 2H), 4.74 (d, J=5.6 Hz, 2H), 4.70-4.62 (m, 1H), 4.58-4.48 (m, 1H), 3.04 (dd, J=13.7, 5.1 Hz, 1H), 2.85 (dd, J=13.7, 9.1 Hz, 1H), 2.58-2.52 (m, 2H), 1.17 (s, 9H).13C NMR (126 MHz, DMSO) δ 181.01, 170.44, 170.17, 168.91, 162.72, 160.91 (d, J=241.6 Hz), 138.59, 136.25, 134.15, 133.76, 133.22, 130.99 (d, J=8.5 Hz), 130.80, 128.47, 127.52, 126.20, 125.77, 125.33, 123.52, 123.40, 122.65, 121.29, 114.70 (d, J=20.3 Hz), 112.60, 112.11, 54.33, 50.15, 50.09, 40.27, 38.00, 36.59, 28.37. Example 136—Preparation of DPLG-3040 DPLG-3040 was synthesized by following the general procedure for HATU mediated coupling of Boc-4F-Phe-OH (283 mg, 1.0 mmol) with iso-butylamine (100 μL, 1.0 mmol). After completion of the reaction, water was added to precipitate the product. The precipitate was filtered, washed with water, and dried to give product (230 mg, 68%).1H NMR (500 MHz, Chloroform-d) δ 7.21-7.11 (m, 2H), 7.01-6.92 (m, 2H), 5.90 (s, 1H), 5.06 (s, 1H), 4.29-4.19 (m, 1H), 3.08-2.92 (m, 4H), 1.69-1.58 (m, 1H), 1.41 (s, 9H), 0.86-0.74 (m, 6H).1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=5.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.12-7.04 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 4.10 (td, J=9.4, 5.0 Hz, 1H), 2.95-2.78 (m, 3H), 2.72 (dd, J=13.7, 9.9 Hz, 1H), 1.70-1.59 (m, 1H), 1.30 (s, 8H), 1.24 (s, 1H), 0.82-0.76 (m, 6H). Example 137—Preparation of DPLG-3043 DPLG-3043 was synthesized by following the general procedure for Boc-deprotection of Boc-4F-Phe-Ibu (220 mg, 0.65 mmol). The crude product (230 mg, quant.) was used in next step without further purification.1H NMR (500 MHz, Chloroform-d) δ 7.61 (s, 3H), 7.23-7.11 (m, 2H), 7.07-6.95 (m, 2H), 6.73 (t, J=5.9 Hz, 1H), 4.42-4.30 (m, 1H), 3.18 (dd, J=13.9, 6.4 Hz, 1H), 3.08 (dd, J=13.9, 8.7 Hz, 1H), 3.03-2.93 (m, 1H), 2.91-2.79 (m, 1H), 1.64-1.49 (m, 1H), 0.76 (d, J=6.7 Hz, 3H), 0.73 (d, J=6.7 Hz, 3H). Example 138—Preparation of DPLG-3046 DPLG-3046 was synthesized by following the general procedure for HATU mediated coupling of Ts-Glu (COHtBu)-OH (35.6 mg, 0.1 mmol) with H-4F-Phe-Ibu TFA salt (38.8 mg, 0.11 mmol). The mixture was purified by HPLC to give product (27.4 mg) as white solid.1H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J=8.2 Hz, 1H), 7.92-7.82 (m, 2H), 7.56 (d, J=7.9 Hz, 2H), 7.32 (s, 1H), 7.24 (d, J=7.9 Hz, 2H), 7.21-7.13 (m, 2H), 7.10-7.01 (m, 2H), 4.33-4.21 (m, 1H), 3.60 (td, J=8.1, 5.5 Hz, 1H), 2.89 (dt, J=12.9, 6.4 Hz, 1H), 2.85-2.71 (m, 2H), 2.63 (dd, J=13.6, 8.4 Hz, 1H), 2.32 (s, 3H), 2.00-1.80 (m, 2H), 1.67-1.46 (m, 3H), 1.21 (s, 9H), 0.81-0.68 (m, 6H). Example 139—Preparation of DPLG-3049 DPLG-3049 was synthesized by following the general protocol for HATU mediated coupling of Indole-3-glyoxylic acid (189 mg, 1.0 mmol) and H-Asp(CONHtBu)-OBn TFA salt (432 mg, 1.1 mmol). After completion of the reaction, water was added to the reaction mixture. A white precipitated appeared which was filtered, washed with water, and dried to give product (270 mg, 60%).1H NMR (500 MHz, Chloroform-d) δ 10.14 (s, 1H), 9.13 (d, J=3.3 Hz, 1H), 8.42-8.34 (m, 2H), 7.47 (dd, J=6.6, 2.3 Hz, 1H), 7.34-7.23 (m, 7H), 5.54 (s, 1H), 5.23 (d, J=12.4 Hz, 1H), 5.19-5.12 (m, 1H), 5.11-5.03 (m, 1H), 2.80 (dd, J=15.2, 5.8 Hz, 1H), 2.74 (dd, J=15.2, 5.3 Hz, 1H), 1.29 (s, 9H).13C NMR (126 MHz, CDCl3) δ 179.61, 170.76, 168.78, 162.60, 139.33, 136.24, 135.30, 128.72, 128.56, 128.41, 126.86, 124.09, 123.31, 122.44, 113.14, 112.12, 67.73, 51.99, 49.58, 39.23, 28.78. Example 140—Preparation of DPLG-3052 DPLG-3052 was prepared by following the general procedure for O-debenzylation of Ind-oxal-Asp(CONHtBu)OBn (265 mg, 0.59 mmol). Crude was purified by HPLC to give product (112 mg, 53%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 12.27 (d, J=3.3 Hz, 1H), 8.82-8.75 (m, 2H), 8.26-8.20 (m, 1H), 7.57 (s, 1H), 7.56-7.52 (m, 1H), 7.32-7.23 (m, 2H), 4.69-4.60 (m, 1H), 2.67 (dd, J=15.1, 7.2 Hz, 1H), 2.59 (dd, J=15.1, 5.0 Hz, 1H), 1.22 (s, 9H).13C NMR (126 MHz, DMSO) δ 181.25, 172.26, 168.78, 162.78, 138.64, 136.25, 126.14, 123.53, 122.66, 121.28, 112.60, 112.11, 50.16, 48.97, 37.16, 28.44. Example 141—Preparation of DPLG-3053 DPLG-3053 was prepared by following the general procedure for HATU mediated coupling of Ind-oxal-Asp (CONHtBu)-OH (7.2 mg, 0.02 mmol) and H-Ala-CH2-naphth TFA salt (7.5 mg, 0.022 mmol). The mixture was purified by HPLC to give product (6.4 mg, 56%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 12.26 (d, J=3.4 Hz, 1H), 8.77 (d, J=3.2 Hz, 1H), 8.71 (d, J=8.1 Hz, 1H), 8.52 (t, J=5.8 Hz, 1H), 8.30-8.21 (m, 2H), 8.08-8.02 (m, 1H), 7.97-7.91 (m, 1H), 7.86-7.80 (m, 1H), 7.57 (s, 1H), 7.56-7.49 (m, 3H), 7.47-7.41 (m, 2H), 7.31-7.24 (m, 2H), 4.75 (d, J=5.8 Hz, 2H), 4.70-4.60 (m, 1H), 4.38-4.25 (m, 1H), 2.66-2.54 (m, 2H), 1.27 (d, J=7.1 Hz, 3H), 1.17 (s, 9H).13C NMR (126 MHz, DMSO) δ 181.15, 171.92, 170.01, 168.98, 162.84, 138.58, 136.24, 134.38, 133.22, 130.78, 128.47, 127.46, 126.15, 125.74, 125.38, 125.14, 123.51, 123.35, 122.64, 121.28, 112.59, 112.12, 50.18, 50.07, 48.68, 40.20, 40.02, 39.85, 39.69, 39.52, 39.35, 39.19, 39.02, 38.10, 28.36, 18.07. Example 142—Preparation of DPLG-21001 DPLG-21001 was synthesized by following the general procedure for HATU mediated coupling of Boc-β-(4-pyridyl)-L-alanine (55.48 mg, 0.2 mmol) and 1-naphthylmethylamine (32 mL, 0.22 mmol). After completion of the reaction, water was added. A white precipitate was formed. Mixture was extracted with ethyl acetate twice. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was evaporated and dried to give a colorless paste. Crude was purified by HPLC to give pure product as a white solid (57 mg, 70%).1H NMR (500 MHz, DMSO-d6) δ 8.51 (t, J=5.7 Hz, 1H), 8.49-8.37 (m, 2H), 8.10-8.01 (m, 1H), 7.99-7.91 (m, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.61-7.50 (m, 2H), 7.49-7.36 (m, 2H), 7.34-7.22 (m, 2H), 7.11 (d, J=8.7 Hz, 1H), 4.83-4.67 (m, 2H), 4.35-4.13 (m, 1H), 2.98 (dd, J=13.6, 4.7 Hz, 1H), 2.81 (dd, J=13.6, 10.3 Hz, 1H), 1.30 & 1.16 (s, rotamers, 9H). Example 143—Preparation of DPLG-21023 DPLG-21023 was synthesized by following the procedure for Boc-deprotection of DPLG-21001 (50 mg, 0.123 mmol). After completion of the reaction, excess trifluoroacetic acid and dichloromethane were evaporated. Crude was dried under high vacuum to give colorless paste. The paste was triturated with diethyl ether to give a white solid. Diethyl ether was decanted, and white solid was dried under vacuum to give product (65 mg, 99%). The product was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 9.01 (t, J=5.5 Hz, 1H), 8.74-8.58 (m, 2H), 8.43 (s, 3H), 8.00-7.93 (m, 2H), 7.89 (d, J=8.2 Hz, 1H), 7.60-7.52 (m, 4H), 7.45 (dd, J=8.2, 7.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 4.80 (dd, J=15.0, 5.6 Hz, 1H), 4.73 (dd, J=15.0, 5.3 Hz, 1H), 4.33-4.05 (m, 1H), 3.24 (dd, J=13.7, 6.6 Hz, 1H), 3.18 (dd, J=13.7, 7.6 Hz, 1H). Example 144—Preparation of DPLG-21033 DPLG-21033 was synthesized by following the general procedure for HATU mediated coupling of DPLG-21013 (12.8 mg, 0.04 mmol) and DPLG-21023 (25.6 mg, 0.048 mmol). After completion of the reaction, the mixture was purified by HPLC to give product (20.1 mg, 83%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.66 (t, J=5.9 Hz, 1H), 8.47-8.36 (m, 2H), 8.33 (d, J=8.4 Hz, 1H), 8.11-8.05 (m, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.58-7.51 (m, 2H), 7.50 (s, 1H), 7.46-7.38 (m, 2H), 7.29-7.14 (m, 7H), 4.82 (dd, J=15.4, 6.0 Hz, 1H), 4.70 (dd, J=15.4, 5.6 Hz, 1H), 4.60-4.48 (m, 2H), 3.18 (dd, J=14.0, 4.3 Hz, 1H), 2.87 (dd, J=14.0, 10.1 Hz, 1H), 2.81-2.70 (m, 2H), 2.52-2.48 (m, 1H), 2.38-2.26 (m, 3H), 1.14 (s, 9H).13C NMR (126 MHz, DMSO) δ 171.19, 171.12, 170.26, 169.18, 148.96, 147.25, 141.26, 134.17, 133.22, 130.78, 128.49, 128.29, 128.11, 127.46, 126.20, 125.85, 125.75, 125.35, 125.19, 124.66, 123.34, 53.21, 50.11, 49.71, 40.31, 38.15, 36.76, 36.18, 31.05, 28.37. Example 145—Preparation of DPLG-21035 Boc-4F-Phe-OH (849.87 mg, 3.00 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (690.12 mg, 3.60 mmol) were dissolved in dichloromethane (15.00 mL) under argon atmosphere. Benzyl alcohol (389.30 mg, 3.60 mmol) was added to the mixture at 23° C. The solution was cooled to 0° C. and triethylamine (0.5 mL, 3.60 mmol) was added. Reaction mixture was allowed to warm to room temperature (23° C.) slowly and stirred at room temperature overnight. Dichloromethane was evaporated, and crude solid was extracted using ethyl acetate and water. Organic layer was washed with aq. NaHCO3, 1N HCl, water followed by saturated brine solution. Ethyl acetate layer was dried over anhydrous Na2SO4and evaporated to give crude product. Crude was purified by combi-flash to give pure product (909 mg, 81%) as white solid.1H NMR (500 MHz, Chloroform-d) δ 7.39-7.33 (m, 3H), 7.33-7.28 (m, 2H), 7.02-6.94 (m, 2H), 6.93-6.85 (m, 2H), 5.18 (d, J=12.2 Hz, 1H), 5.09 (d, J=12.2 Hz, 1H), 4.98 (d, J=8.2 Hz, 1H), 4.64-4.56 (m, 1H), 3.08 (dd, J=14.0, 6.0 Hz, 1H), 3.02 (dd, J=14.0, 5.9 Hz, 1H), 1.42 (s, 9H). Example 146—Preparation of DPLG-21037 DPLG-21037 was synthesized by following the general procedure for Boc-deprotection of DPLG-21035 (485.5 mg, 1.3 mmol). After completion of the reaction, excess trifluoroacetic acid and dichloromethane were evaporated. Crude was dried under vacuum to give colorless paste. Crude was dissolved in diethyl ether to give a clear solution. The solution was kept at −20° C. overnight to crystallize the product. Product was filtered and dried (yield 467 mg, 93%).1H NMR (500 MHz, DMSO-d6) δ 8.66-8.36 (m, 3H), 7.40-7.34 (m, 3H), 7.32-7.24 (m, 2H), 7.24-7.18 (m, 2H), 7.15-7.07 (m, 2H), 5.19-5.13 (m, 2H), 4.40-4.34 (m, 1H), 3.17-3.10 (m, 1H), 3.07 (dd, J=14.1, 7.5 Hz, 1H). Example 147—Preparation of DPLG-21040 DPLG-21040 was synthesized by following the general procedure for HATU mediated coupling of DPLG-21013 (193 mg, 0.06 mmol) with DPLG-21037 (233 mg, 0.06 mmol). After completion of the reaction, water was added. A white precipitate was formed. Precipitate was filtered and dried in air to give product (310 mg, 89%) as white solid. The product was used in next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 8.27-8.22 (m, 1H), 7.98-7.92 (m, 1H), 7.39-7.14 (m, 13H), 7.08-7.01 (m, 2H), 5.11-5.04 (m, 2H), 4.65-4.56 (m, 1H), 4.55-4.44 (m, 1H), 3.06-2.91 (m, 2H), 2.78-2.75 (m, 2H), 2.41-2.33 (m, 3H), 2.30-2.15 (m, 1H), 1.21 (s, 9H). Example 148—Preparation of DPLG-21042 DPLG-21042 was synthesized by following the general procedure for O-debenzylation of DPLG-21040 (300 mg, 0.52 mmol). The product (248 mg, 98%) was isolated as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.95-7.87 (m, 1H), 7.34 (s, 1H), 7.29-7.14 (m, 7H), 7.09-7.03 (m, 2H), 4.62-4.54 (m, 1H), 4.40-4.31 (m, 1H), 3.07-3.00 (m, 1H), 2.93-2.84 (m, 1H), 2.80-2.74 (m, 2H), 2.45-2.14 (m, 4H), 1.21 (s, 9H). Example 149—Preparation of DPLG-21049 DPLG-21049 was synthesized by following the general procedure for HATU mediated coupling of DPLG-21042 (19.4 mg, 0.04 mmol) with 4-phenylbenzylamine (8.1 mg, 0.044 mmol). After completion of the reaction, the mixture was purified by HPLC to give pure product (14.0 mg, 54%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.64 (t, J=6.0 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.55 (m, 2H), 7.53 (s, 1H), 7.50-7.42 (m, 2H), 7.39-7.33 (m, 1H), 7.32-7.21 (m, 6H), 7.21-7.13 (m, 3H), 7.09-6.99 (m, 2H), 4.58-4.23 (m, 4H), 3.14 (dd, J=13.9, 4.6 Hz, 1H), 2.89-2.80 (m, 1H), 2.80-2.70 (m, 2H), 2.53-2.50 (m, 1H), 2.43-2.25 (m, 3H), 1.19 (s, 9H). Example 150—Preparation of DPLG-21050 DPLG-21050 was synthesized by following the general procedure for HATU mediated coupling of DPLG-21042 (19.4 mg, 0.04 mmol) with 3-phenylbenzylamine (8.1 mg, 0.044 mmol). After completion of the reaction, the mixture was purified by HPLC to give pure product (13.2 mg, 51%) as a white solid.1H NMR (599 MHz, DMSO-d6) δ 8.66 (t, J=6.1 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.57-7.44 (m, 5H), 7.42-7.34 (m, 2H), 7.30-7.12 (m, 7H), 7.06-6.96 (m, 2H), 4.57-4.29 (m, 4H), 3.14 (dd, J=13.9, 4.5 Hz, 1H), 2.89-2.80 (m, 1H), 2.80-2.69 (m, 2H), 2.54-2.50 (m, 1H), 2.42-2.26 (m, 3H), 1.17 (s, 9H). Example 151—Proteasome Inhibitory Studies of Various N,C Capped Dipeptides Measurement of IC50s All inhibitory assays for N,C capped dipeptides were performed in a black solid-bottom 96-well plate. In general, compound plates were prepared starting from 10 mM in 3× series dilution to 15 μM. 1 μl of DMSO stock was transferred to a black 96-well plate and 100 μL of reaction mixture were added 15 μM N-acetyl-Alanine-Asparagine-Tryptophan-7-amino-4-methylcourmarin (Ac-ANW-AMC) or 25 μM succinyl-Leucine-Leucine-Valine-Tyrosine-7-amino-4-methyl-courmarin (succ-LLVY-AMC), 0.4 nM hu i-20S β5i-subunit or 0.2 nM hu c-20S β5c-subunit, 0.02% SDS, 1% BSA, 0.5 mM EDTA in 20 mM HEPES buffer at pH7.5. The plates were then spun at 1000 rpm for 1 minute, and the fluorescence units of each well were recorded at λex=360 nm, λem=460 nm for 2 hours. The slopes of the initial linear range of the time course were used to calculate the velocity, and relative activities were normalized to the velocities of the DMSO control. The data were fit dose-response equation with restriction of 0% activity and 100% activity in PRISM to avoid the possible miscalculation of IC50s when complete inhibition was not achieved. For compounds with IC50s lower than 5 nM, further dilutions were used. For beta 2c, beta 2i (N-acetyl-Leucine-Leucine-Arginine-7-amino-4-methylcourmarin [Ac-LLR-AMC], beta 1c (N-acetyl-Leucine-Leucine-glutamate-7-amino-4-methylcourmarin [Ac-LLE-AMC]) and betali (N-acetyl-Proline-Alanine-Leucine-7-amino-4-methylcourmarin [Ac-PAL-AMC]) inhibition, only one concentration of compounds at 100 μM was tested. Example 152—Proteasome Inhibitory Studies of Various N,C Capped Dipeptides Structure—Activity Relationship (SAR) Studies Compounds were incubated in an 11-point series of dilutions with the Karpas lymphoma cell line, which expresses i-20S constitutively (Blackburn et al., “Characerization of a New Series of Non-Covalent Proteasome Inhibitors with Exquisite Potency and Selectivity for the 20S BetaS-Subunit,” Biochem. J. 430:461-476 (2010), which is hereby incorporated by reference in its entirety), for 4 hours, and the IC50s of the inhibitors were determined using a cell-based Proteasome-Glo™ assay (Promega, Cat. No. G8660) to measure the proteasome activity inside the cells after removal of compound from the medium (Table 4 andFIG.5B). Example 153—DPLG-3 Induces Autophagy RAW264 GFP-LC3 cells were incubated with vehicle DMSO control, DPLG-3 (10 nM), or the inactive congener DPLG-2032 (1 μM) at 37° C. overnight. Prior to fixation with 4% paraformaldehyde, the cells were treated with bafilomycin A (20 nM), an inhibitor of the late phase of autophagy, for 4 hours. The fluorescent images taken of these different sample treatments (FIGS.7A-C) indicated that the DPLG-3 induces autophagy. Autophagy is a highly conserved process in eukaryotic cells that degrades a large proportion of cytosolic proteins and organelles. It involves the formation of double membrane complexes that fuse with lysosomes to form autolysosomes, where engulfed proteins or organelles are degraded by lysosomal proteases (Fleming et al., “Chemical Modulators of Autophagy as Biological Probes and Potential Therapeutics,” Nature Chemical Biology 7:9-17 (2011), which is hereby incorporated by reference in its entirety). Stresses such as nutrient starvation, hypoxia, protein aggregates, ER stress, pathogens, and DNA damage induce autophagy (Kroemer et al., “Autophagy and the Integrated Stress Response,” Mol. Cell 40:280-293 (2010), which is hereby incorporated by reference in its entirety). Autophagy plays critical roles in many physiological and patho-physiological processes. It has been shown that pharmacological induction of autophagy in mice with rapamycin increases the lifespan of the mice (Harrison et al., “Rapamycin Fel Latee in Life Extends Lifespan in Genetically Heterogeneous Mice,” Nature 460:392-395 (2009), which is hereby incorporated by reference in its entirety). Autophagy has also been demonstrated to protect against infectious diseases, such as infections caused by the bacteria Mycobacterium tuberculosis, Salmonella enterica, Shigella flexneri, Listeria monocytogenes, etc. and parasites such as Toxoplasma gondii, or by certain viruses (Levine et al., “Autophagy in Immunity and Inflammation,” Nature 469: 323-335 (2011), which is hereby incorporated by reference in its entirety). Autophagy also protects against neurodegeneration, as it is the main clearance route for aggregation-prone proteins and unfolded proteins that are not polyubiquitinated (Rubinsztein, D., “The Roles of Intracellular Protein-Degradation Pathways in Neurodegeneration,” Nature 443:780-786 (2006), which is hereby incorporated by reference in its entirety). Up-regulation of autophagy is hence considered to have potential therapeutic value in a variety of diseases. Example 154—DPLG-3 Mitigated TNBS-Induced Colitis in Mice Trinitrobenzene sulfonic acid (TNBS)-induced colitis exhibits a heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic, similarly to human Crohn's disease (CD). In this model, administration of a neutralizing monoclonal antibody against the p40 subunit shared by IL-12/IL-23 fully rescued mice from the disease-associated body weight loss. This is consistent with the degree of systemic neutralization of the cytokine, as measured by serum levels of IL-12/IL-23 p40 induced in TNBS-treated mice (not shown). Moreover, treatment of TNBS-injected mice with DPLG-3 via I.P. injection at day −1, 1 and 3 relative to the time of TNBS challenge strongly inhibited colitis-induced weight loss (FIG.4D) in a dose-dependent manner (3 mg/kg, 6 mg/kg and 12 mg/kg). DPLG-3 did not cause detectable adverse effects. Example 155—DPLG-3 Strongly Restricts the Growth of Established Mammary Tumor In Vivo 4T1 is a tumor cell line isolated from a single spontaneously arising mammary tumor from a BALB/BfC3H mouse (mouse mammary tumor virus-positive) (Miller et al., “Characterization of Metastatic Heterogeneity among Sub-populations of a Single Mouse Mammary Tumor: Heterogeneity in Phenotypic Stability,” Invasion Metastasis 33:22 (1983), which is hereby incorporated by reference in its entirety). It is an excellent model system for breast cancer research, because its tumor development is well characterized both oncologically and immunologically. The 4T1 mammary tumor, which is triple-negative (TN) for the expression of estrogen receptor alpha, progesterone receptor, and Her2, closely mimics human breast cancer in its anatomical site, immunogenicity, growth characteristics, and metastatic properties (Pulaski et al., “Reduction of Established Spontaneous Mammary Carcinoma Metastases ollowing Immunotherapy with Major Histocompatibility Complex Class II and B7.1 Cell-Based Tumor Vaccines,” Cancer Res 58:1486 (1998), which is hereby incorporated by reference in its entirety). The tumor growth and metastatic spread of 4T1 cells closely resembles stage IV breast cancer (Mi et al., “Differential Osteopontin Expression in Phenotypically Distinct Subclones of Murine Breast Cancer Cells Mediates Metastatic Behavior,” J. Biol. Chem. 279: 46659-46667 (2004), which is hereby incorporated by reference in its entirety). In this experiment, 4T1 mammary carcinoma cells (1×105) were injected subcutaneously into the abdominal mammary gland area of recipient mice in 0.1 ml of a single-cell suspension in PBS on day 0 as described previously (Zhang et al., “A Novel Role of Hematopoietic CCL5 in Promoting Triple-Negative Mammary Tumor Progression by Regulating Generation of Myeloid-Derived Suppressor Cells,” Cell Res. 23(3):394-408 (2013), which is hereby incorporated by reference in its entirety). Primary tumors were measured by their surface areas every other day. On Day 10, DPLG-3 in 30 ml of DMSO or DMSO alone was injected into mice by i.p. daily at 6 mg/kg. On Day 20, mice were sacrificed and tumors excised, measured by volume (ml) or by weight (mg). The results, shown inFIGS.8A-B(4 mice per group), demonstrate the efficacy of DPLG-3 in reducing the size and weight of this tumor. The difference between the control group and the DPLG-3 treatment group is highly significant (*, p<0.05 by Student T test). This study indicates that these inhibitors will likely be useful in reducing inflammation-induced cancers. Example 156—Discussion of Examples 1-155 In comparing proteasomes across species, certain similarities between the Mycobacterium tuberculosis (Mtb) proteasome and hu i-20S were found. Both preferred certain P1 aromatic amino acids in N-acetyl-tripeptide-AMC substrates and small hydrophobic amino acids in P3 (Blackburn et al., “Characterization of a New Series of Non-Covalent Proteasome Inhibitors with Exquisite Potency and Selectivity for the 20S BetaS-Subunit,” Biochem. J. 430:461-476 (2010); Lin et al., “Distinct Specificities of Mycobacterium Tuberculosis and Mammalian Proteasomes for N-acetyl Tripeptide Substrates,” J. Biol. Chem. 283:34423-34431 (2008); Fan et al, “Oxathiazolones Selectively Inhibit the Human Immunoproteasome over the Constitutive Proteasome”. ACS Med Chem Lett. 5(4):405-10 (2014), which are hereby incorporated by reference in their entirety). The data are shown inFIGS.1A-B. Moreover, the Mtb proteasome and hu β5i share a spacious 51 pocket that is larger than that in constitutive proteasomes (Lin et al., “N,C-Capped Dipeptides with Selectivity for Mycobacterial Proteasome Over Human Proteasomes: Role of S3 and 51 Binding Pockets,” J. Am. Chem. Soc. 135:9968-9971 (2013), which is hereby incorporated by reference in its entirety). A high throughput screen against the Mtb proteasome led to discovery of a novel class of 1,3,4-oxathiazol-2-ones (Table 1) that inhibit the Mtb proteasome selectively over hu c-20S (Lin et al., “Inhibitors Selective for Mycobacterial Versus Human Proteasomes,” Nature 461:621-626 (2009), which is hereby incorporated by reference in its entirety). 1,3,4-oxathiazol-2-ones TABLE 1Kinetic parameters of selected oxathiazolones vs i-20S β5i and hu c-20S β5c.Hu20S (β5iHu20S (β5c*kinact×KIkinact/KIkinact/KIIDR103(s−1)(μM)(M−1s−1)(M−1s−1)RatioHT10430.252.0128.90.2645HT11710.770.761012.210.1100HT20041.541.410930.234750*The plots of kobsvs [I] for hu c-20S were linear. Individual kinact and KIcannot be derived; instead, kinact/KIvalues were derived from the slopes of the plots. Oxathiazolones inhibit the Mtb proteasome via a competitive, irreversible mechanism that results in cyclocarbonylation of the β-OH and α-NH2of the active site Thr1Nof the Mtb proteasome. This is accompanied by a marked conformational change in the loop around the active site that was implicated in favoring suicide-substrate inhibition vs. hydrolysis of the reaction intermediate. Of the 6 pairs of amino acids that are critical for species selectivity, only two pairs are conserved in human β2c, one pair in hu β1c, β1i, and β2i, and none in hu β5c or β5i. Thus, it was predicted that oxathiazolones active against the Mtb proteasome might inhibit hu β5i. Indeed, some exhibited extremely high selectivity for hu β5i over hu β5c. Table 1, shows 3 such compounds tested; see (Fan et al., “Oxathiazolones Selectively Inhibit the Human Immunoproteasome over the Constitutive Proteasome,” ACS Med. Chem. Lett. 5(4):405-410 (2014), which is hereby incorporated by reference in its entirety). However, the half-lives of oxathiazolones range from 7 minutes to 3 hours in culture medium and even less in plasma, a drawback for drug development. Further evidence for structural similarity between the Mtb20S and hu i-20S β5i comes from a series of dipeptide boronates with P1 naphthylAlaB(OH)2(Table 2), which were designed and synthesized to selectively inhibit Mtb20S over hu c-20S β5c. Although there was little selectivity between Mtb20s and hu c-20S β5c, these dipeptide boronates inhibited hu i-2S β5i over hu c-20S β5c with a selectivity index (SI) up to 17-fold. TABLE 2Kinetic parameters of selected dipeptideboronates vs hu i-20S β5i and c-20S β5c.IC50 (μM)Mtb20Si-20S β5ic-20S β5iRatioBA10.070.00880.10612.0BA20.100.00840.14317.1BA1, R = NaphthylBA2, R = Phenyl Substrate preferences for proteasomes from bacteria, yeast, and cows were profiled, using a library of 6000 N-acetyl-P3-P2-P1-AMCs (Lin et al., “Distinct Specificities of Mycobacterium Tuberculosis and Mammalian Proteasomes for N-acetyl Tripeptide Substrates,” J. Biol. Chem. 283:34423-34431 (2008), which is hereby incorporated by reference in its entirety), and a library of 1,600 N,C-capped dipeptides for screening (FIG.1A) (Lin et al., “N,C-Capped Dipeptides with Selectivity for Mycobacterial Proteasome Over Human Proteasomes: Role of S3 and 51 Binding Pockets,” J. Am. Chem. Soc. 135:9968-9971 (2013), which is hereby incorporated by reference in its entirety). These results indicated that the combination of 51 and S3 determines substrate selectivity between hu c-20S and hu i-20S. Hu i-20S prefers P1-Trp/Tyr and P3-Gly/Thr/Pro, whereas hu c-20S prefers P1-AlaNal/Leu and P3-Trp/Tyr. Focusing on developing proteasome inhibitors that are reversible and selective N,C-capped dipeptides for the bacterial proteasome over the human proteasome, it was required to find inhibitors of the same class that are reversible and selective for hu i-20S β5i over hu c-20S β5c (FIG.1A), based on both substrate profiling and structural analysis. X-ray crystal structures of mouse c-20S and i-20S reinforced the finding that the 51 pocket in i-20S is significantly bigger than that in c-20S, while the S3 pockets look similar between the c-20S and the i-20S (Huber et al., “Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor Specificity,” Cell 148:727-738 (2012), which is hereby incorporated by reference in its entirety). In vitro evaluations of several N,C-capped dipeptides indicated that most of the compounds tested had aqueous solubilities of 200-300 μM and t1/2>2 hours in human plasma and dog plasma. In vitro intrinsic clearance by liver microsomes was relatively high: 1.5-14.3 L/h/kg by human and 3.1-28.2 L/h/kg by rat microsomes. A dipeptide, DPLG-2, that was designed for Mtb20S, was stable with t1/2>24 hours in human plasma (Lin et al., “N,C-Capped Dipeptides with Selectivity for Mycobacterial Proteasome Over Human Proteasomes: Role of S3 and 51 Binding Pockets,” J. Am. Chem. Soc. 135: 9968-9971 (2013), which is hereby incorporated by reference in its entirety). In vitro metabolism studies revealed that the most vulnerable site for microsomal CYP-induced hydroxylation was the α-C of the neo-pentyl Asn, with lesser reactivity at the P1 benzyl position (Blackburn et al., “Optimization of a Series of Dipeptides with a P3 [small beta]-Neopentyl Asparagine Residue as Non-Covalent Inhibitors of the Chymotrypsin-Like Activity of Human 20S Proteasome,” Med Chem Comm 3:710-719 (2012), which is hereby incorporated by reference in its entirety). DPLG-3 was designed by introducing a naphthyl group in the P1 position and N-(tBuO)—As in the P3 position (FIG.1B). The structure of DPLG-3 (purity>95%) was confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Its competitive inhibition and selectivity for hu i-20S β5i versus hu c-20S β5c (Table 3) and its selectivity for β5i over β2i and β1i were also confirmed. Since the sequence identities between human c-20S and mouse c-20S and between human i-20S β5i and mouse i-20S β5i are 97% and 92.6%, respectively, it was predicted that DPLG-3 will potently and selectively inhibit mouse i-20S β5i over mouse c-20S β5c in a comparable manner to its selective inhibition of human i-20S β5i. In support of this expectation for preserved selectivity across the human-mouse comparison, ONX 0914 potently and relatively selectively inhibited human and mouse i-20S over human and mouse c-20S, respectively (Huber et al., “Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor Specificity,” Cell 148:727-738 (2012), which is hereby incorporated by reference in its entirety). At concentrations up to 50 μM, DPLG-3 was not cytotoxic against HepG2 human hepatoma cells, mouse bone marrow derived macrophages (BMDMs), human peripheral blood mononuclear cells (purchased from New York Blood Bank), or a human B-lymphoma cell line. Because the i-20S plays important physiological roles in modulating innate and adaptive immune responses, DPLG-3's biological properties in experimental colitis and in inflammatory macrophages were investigated. Crohn's disease (CD) is a major form of inflammatory bowel disease (IBD) that may arise from the interplay of commensal and pathogenic bacteria, genetic mutations, and immunoregulatory defects (Packey et al., “Interplay of Commensal and Pathogenic Bacteria, Genetic Mutations, and Immunoregulatory Defects in the Pathogenesis of Inflammatory Bowel Diseases,” J. Intern. Med. 263:597-606 (2008); Mumy et al., “The Role of Neutrophils in the Event of Intestinal Inflammation,” Curr. Opin. Pharmacol. 9:697-701 (2009), which are hereby incorporated by reference in their entirety) in both innate and adaptive immune systems (Arseneau et al., “Innate and Adaptive Immune Responses Related to IBD Pathogenesis,” Curr. Gastroenterol. Rep. 9:508-512 (2007), which is hereby incorporated by reference in its entirety). In CD, there is a sustained activation of mucosal immune responses of the Th1 and Th17 types, perhaps reflecting constitutive activation, failure of down-regulatory mechanisms, or continued stimulation resulting from changes in the epithelial mucosal barrier (Mashimo et al., “Impaired Defense of Intestinal Mucosa in Mice Lacking Intestinal Trefoil Factor,” Science 274:262-265 (1996); Al-Sadi et al., “Mechanism of Cytokine Modulation of Epithelial Tight Junction Barrier,” Front Biosci. 14:2765-2778 (2009), which are hereby incorporated by reference in their entirety). CD has a strong genetic basis (Ogura et al., “A Frameshift Mutation in NOD2 Associated with Susceptibility to Crohn's Disease,” Nature 411:603-606 (2001); Hugot et al., “Association of NOD2 Leucine-Rich Repeat Variants with Susceptibility to Crohn's Disease,” Nature 411:599-603 (2001), which are hereby incorporated by reference in their entirety). Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular bacterial sensor and an important regulator of host resistance to microbial challenge as well as tissue homeostasis. The gene encoding NOD2, CARD15, was the first CD susceptibility gene identified (Ogura et al., “A Frameshift Mutation in NOD2 Associated with Susceptibility to Crohn's Disease,” Nature 411:603-606 (2001); Hugot et al., “Association of NOD2 Leucine-Rich Repeat Variants with Susceptibility to Crohn's Disease,” Nature 411:599-603 (2001), which are hereby incorporated by reference in their entirety). Three main variants of NOD2, R702W, G908R, and 1007fs, together account for ˜80% of NOD2 mutations independently associated with susceptibility to CD (Lesage et al., “CARD15/NOD2 Mutational Analysis and Genotype-Phenotype Correlation in 612 Patients with Inflammatory Bowel Disease,” Am. J. Hum. Genet. 70:845-857 (2002); Hugot et al., “Prevalence of CARD15/NOD2 Mutations in Caucasian Healthy People,” Am. J. Gastroenterol. 102:1259-1267 (2007), which are hereby incorporated by reference in their entirety). All three mutations are located near or within the leucine rich repeat domain (LRR) of NOD2 that is involved in ligand binding. How these human NOD2 mutants contribute to the development and pathogenesis of CD is controversial (Girardin et al., “Nod2 is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection,” J. Biol. Chem. 278: 8869-8872 (2003); Watanabe et al., “NOD2 is a Negative Regulator of Toll-like Receptor 2-Mediated T Helper Type 1 Responses,” Nat. Immunol. 5:800-808 (2004); Kobayashi et al., “Nod2-Dependent Regulation of Innate and Adaptive Immunity in the Intestinal Tract,” Science 307:731-734 (2005); Maeda et al., “Nod2 Mutation in Crohn's Disease Potentiates NF-kappaB Activity and IL-1beta Processing,” Science 307:734-738 (2005); Noguchi et al., “A Crohn's Disease-Associated NOD2 Mutation Suppresses Transcription of Human IL10 by Inhibiting Activity of the Nuclear Ribonucleoprotein hnRNP-A1,” Nat. Immunol. 10:471-479 (2009), which are hereby incorporated by reference in their entirety). A gain-of-function property of these mutants was identified, which is to inhibit IL-10 gene transcription by interfering with the p38 MAPK-mediated phosphorylation of a novel transcription factor, heterogeneous nuclear ribonucleoprotein A1 (Noguchi et al., “A Crohn's Disease-Associated NOD2 Mutation Suppresses Transcription of Human IL10 by Inhibiting Activity of the Nuclear Ribonucleoprotein hnRNP-A1, ” Nat. Immunol. 10:471-479 (2009), which is hereby incorporated by reference in its entirety), providing a plausible mechanistic explanation for the lack of adequate control of chronic intestinal mucosal inflammation associated with CD. Genetic studies have identified mutations in the IL-12//IL-23 pathway associated with the pathogenesis of CD (Duerr et al., “A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene,” Science 314:1461-1463 (2006), which is hereby incorporated by reference in its entirety), including JAK2, TYK2, IL12RB1 and IL12B (Wang et al., “An IFN-Gamma-Inducible Transcription Factor, IFN Consensus Sequence Binding Protein (ICSBP), Stimulates IL-12 p40 Expression in Macrophages,” J. Immunol. 165:271-279 (2000), which is hereby incorporated by reference in its entirety). IL-12 and IL-23 are crucial cytokines with respect to IBD that are involved in the development and effector functions of Th1 and Th17 cells, respectively (Shih et al., “Recent Advances in IBD Pathogenesis: Genetics and Immunobiology,” Curr. Gastroenterol. Rep. 10:568-575 (2008), which is hereby incorporated by reference in its entirety). Clinical studies have strongly implicated the importance of high levels of IL-12 and IL-23 in CD pathogenesis (Monteleone et al., “Interco leukin 12 is Expressed and Actively Released by Crohn's Disease Intestinal Lamina Propria Mononuclear Cells,” Gastroenterology 112:1169-1178 (1997); Schmidt et al., “Expression of Interleukin-12-Related Cytokine Transcripts in Inflammatory Bowel Disease: Elevated Interleukin-23p19 and Interleukin-27p28 in Crohn's Disease but not in Ulcerative Colitis,” Inflamm. Bowel Dis. 11:16-23 (2005); Penack et al., “NOD2 Regulates Hematopoietic Cell Function During Graft-versus-Host Disease,” J. Exp. Med. 206:2101-2110 (2009), which are hereby incorporated by reference in their entirety). Consistent with that, monoclonal antibody blockade of p40 (IL12B), the shared subunit of both IL-12 and IL-23, is therapeutically beneficial (Mannon et al., “Anti-Interleukin-12 Antibody for Active Crohn's Disease,” N. Engl. J. Med. 351:2069-2079 (2004); Fuss et al., “Both IL-12p70 and IL-23 are Synthesized During Active Crohn's Disease and are Down-Regulated by Treatment with Anti-IL-12 p40 Monoclonal Antibody,” Inflamm. Bowel Dis. 12:9-15 (2006); Melmed et al., “Future Biologic Targets for IBD: Potentials and Pitfalls,” Nat. Rev. Gastroenterol. Hepatol. 7:110-117 (2010), which are hereby incorporated by reference in their entirety). TNBS-induced experimental colitis studies showed that hematopoietic NOD2 is required to control experimental colitis and that the pathogenesis of this model is dependent on IL-12/IL-23 and is rescued by DPLG-3. In the trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis mouse model, it is shown by bone marrow chimeras that NOD2 deficiency in the hematopoietic compartment critically regulates experimental colitis (FIGS.2A-D). TNBS-induced colitis exhibited heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic, similar to this progression in human CD (Mashimo et al., “Impaired Defense of Intestinal Mucosa in Mice Lacking Intestinal Trefoil Factor,” Science 274:262-265 (1996); Al-Sadi et al., “Mechanism of Cytokine Modulation of Epithelial Tight Junction Barrier,” Front Biosci. 14:2765-2778 (2009); Ogura et al., “A Frameshift Mutation in NOD2 Associated with Susceptibility to Crohn's Disease,” Nature 411:603-606 (2001), which are hereby incorporated by reference in their entirety). In this model, Watanabe et al. also showed that administration of muramyl dipeptide (MDP), the natural ligand of NOD2, protected mice from colitis by downregulating multiple Toll-like receptor (TLR)-mediated innate responses (TLR2, 4, and 9), including the production of IL-12 and IFN-γ (Hugot et al., “Association of NOD2 Leucine-Rich Repeat Variants with Susceptibility to Crohn's Disease,” Nature 411:599-603 (2001), which is hereby incorporated by reference in its entirety). Recent work in this area has further established that MDP, through activation of the NOD2 signaling pathway, induces a transcriptional regulator called CCAAT/enhancer-binding protein a (C/EBPa) to control IL-12 production and reduce colitis pathogenesis. Thus, C/EBPa KO mice, like NOD2-deficient mice, are more susceptible to colitis-associated weight loss than WT mice (FIG.3A). Further, C/EBPa KO mice completely lose responsiveness to MDP-mediated rescue of colitis pathogenesis. Use of a neutralizing monoclonal antibody against the p40 subunit shared by IL-12/IL-23 fully rescued WT and C/EBPa KO mice from the disease (FIG.3A), consistently with the degree of systemic neutralization of the cytokine, as measured by serum levels of IL-12 induced in TNBS-treated mice (FIG.3B). Moreover, administration of the immune proteasome inhibitor DPLG-3 to TNBS-treated WT mice via i.v. injection strongly inhibited colitis-associated pathogenesis (FIG.3C). Pathogenesis of TNBS-induced experimental colitis is dependent on IL-12/IL-23 and is rescued by DPLG-3. Trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice exhibits a heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic, similarly to human CD (Noguchi et al., “A Crohn's Disease-Associated NOD2 Mutation Suppresses Transcription of Human IL10 by Inhibiting Activity of the Nuclear Ribonucleoprotein hnRNP-A1,” Nat. Immunol. 10:471-479 (2009); Alex et al., “Distinct Cytokine Patterns Identified from Multiplex Profiles of Murine DSS and TNBS-Induced Colitis,” Inflamm. Bowel Dis. 15:341-352 (2009); Sarra et al., “IL-23/IL-17 Axis in IBD,” Inflamm. Bowel Dis. 16:1808-1813 (2010); Holler et al., “Prognostic Significance of NOD2/CARD15 Variants in HLA-Identical Sibling Hematopoietic Stem Cell Transplantation: Effect on Long-Term Outcome is Confirmed in 2 Independent Cohorts and may be Modulated by the Type of Gastrointestinal Decontamination,” Blood 107: 4189-4193 (2006), which are hereby incorporated by reference in their entirety). In this model, administration of a neutralizing monoclonal antibody against the p40 subunit shared by IL-12/IL-23 fully rescued mice from the disease-associated body weight loss (FIG.2A), consistent with the degree of systemic neutralization of the cytokine, as measured by serum levels of IL-12/IL-23 p40 induced in TNBS-treated mice (FIG.2B). Moreover, treatment of TNBS-injected mice with DPLG-3 via one-time i.v. injection at the time of TNBS challenge strongly inhibited colitis-induced weight loss (FIG.2C). DPLG-3 differentially regulates cytokine production in macrophages. To further explore the mechanisms underlying the treatment effects of DPLG-3 on TNBS-induced colitis, the cytokine expression at both the protein and mRNA levels in macrophages was analyzed.FIG.4Ashows that in LPS-activated macrophages, DPLG-3 dose-dependently inhibited the production of TNF-α, IL-12/IL-23p40 and IL-12. Noticeably, production of IL-12 and IL-23 was more sensitive to the inhibitory effects of DPLG-3 than that of TNF-α by a factor of 10-20. In contrast, DPLG-3 dose-dependently induced IL-6 production on its own, while having no significant effects on IL-10 production (FIG.4B). Similar degrees of the inhibitory effects of DPLG-3 on IL-12 and IL-23 production were observed at the level of mRNA expression of the IL-12p35 and p40 genes (FIG.4C), suggestive of transcriptional regulation. The differentially cytokine-regulating property of DPLG-3 is in contrast to that of ONX 0914, which is inhibitory for all cytokines analyzed (Muchamuel et al., “A Selective Inhibitor of the Immuno-proteasome Subunit LMP7 Blocks Cytokine Production and Attenuates Progression of Experimental Arthritis,” Nat. Med. 15:781-787 (2009), which is hereby incorporated by reference in its entirety). The positive effects in vitro and in vivo of DPLG-3 led to performance of SAR studies to develop and test similar compounds that inhibit the enzymes of the immunoproteasomes more specifically than their counterparts in the constitutive human proteasome. The dipeptide compounds and their relative inhibitory results on the βcomponent of the human immunoproteasome (β5i) and constitutive proteasome (β5c) are described in Examples 151 and 152. The inhibitory effect of DPLG-3 in vivo tests in addition to the colitis model described above can be found in Examples 153 and 155. Encouraged by DPLG-3's positive effects in vitro and in vivo, in an effort to expand the hit library with the objectives to improve the potency, selectivity, solubility, and lipophilic ligand efficiency, applicants designed, synthesized, and enzymatically evaluated >30 dipeptides (all compounds' purity >95%). Table 3 lists the inhibition kinetic parameters, selectivity index, and calculated log Ps of selected dipeptides. Hill slopes of all compounds were <1.0 (FIG.5A). The log P was reduced from 4.66 to <3. To determine if they were able to penetrate cell membranes, the compounds were incubated in an 11-point series of dilutions with the Karpas lymphoma cell line, which expresses i-20S constitutively (Blackburn et al., “Characterization of a New Series of Non-Covalent Proteasome Inhibitors with Exquisite Potency and Selectivity for the 20S BetaS-Subunit,” Biochem. J. 430:461-476 (2010), which is hereby incorporated by reference in its entirety), for 4 hours, and the IC50s of the inhibitors were determined using a cell-based Proteasome-Glo™ assay (Promega, Cat. No. G8660) to measure the proteasome activity inside the cells after removal of the compound from the medium (Table 4 andFIG.5B). Contra to the effect of Bortezomib, inhibition of immunoproteasome by DPLG-3 and DPLG-2086 in Karpas cells did not result in the accumulation of poly-ubiquitinated proteins (FIG.5C). Their cytotoxicity against the Karpas lymphoma cells was determined (Table 4). The LD50s (Table 4) correlated with the IC50s for c-20S inhibition, as the LD50s were equal to or slightly higher than the IC50s for c-20S inhibition (FIG.6). However, the IC50s for the inhibition of i-20S appeared to be irrelevant for their cytotoxicity, as seen with DPLG-3, DPLG-2106 and DPLG-2127. Moreover, DPLG-3 did not cause accumulation of poly-ubiquitinylated (poly-Ub proteins, in contrast to Bortezomib and DPLG-2086). This is further evidence for the i-20S selectivity of DPLG-3, because the i-20S's activator, PA28 (Preckel et al., “Impaired Immunoproteasome Assembly and Immune Responses in PA28−/− mice,” Science 286:2162-2165 (1999), which is hereby incorporated by reference in its entirety), does not specifically recruit poly-Ub proteins for degradation (Rechsteiner et al., “Mobilizing the Proteolytic Machine: Cell Biological Roles of Proteasome Activators and Inhibitors,” Trends in Cell Biology 15:27-33 (2005), which is hereby incorporated by reference in its entirety). Although DPLG-2086 is partly selective for i-20S over c-20S, it is still a relatively potent inhibitor of c-20S; thus the accumulation of poly-Ub proteins during treatment with DPLG-2086 is likely due to its inhibition of c-20S. TABLE 3Kinetic parameters and calculated logP for N,C-capped dipeptidesIC50 (μM)Hu i-LD50IDStructures20SHu c-20SSIa(μM)DPLG-30.003642.1>11,0002.04DPLG-203277.8>100—37DPLG-204834.959.81.7>100DPLG-2054>10075.8<0.8>100DPLG-20580.0110.484434.4DPLG-20683.0628.49.3>100DPLG-20731.3713.310>100DPLG-20830.0250.24100.254DPLG-20860.00380.23600.46DPLG-20910.0262.3885.3DPLG-20984.31>100>23>100DPLG-20990.5341.979>100DPLG-21021.755.93342DPLG-21050.0311.23918DPLG-21060.146.5467.8DPLG-210957.1>100>2>100DPLG-21270.02315.6680>100DPLG-21300.467917067.8DPLG-21420.0285.01809.1DPLG-21430.2519.678>100DPLG-21440.0090.62691.47DPLG-21500.00440.611390.8DPLG-21600.00940.098100.05DPLG-22110.2451.2854.18DPLG-2219PKS22194.73>100>21>100DPLG-2220PKS22200.0701.35196.27DPLG-2224PKS22240.00430.22853>100DPLG-2226PKS22261.1578.168>100DPLG-2222PKS22220.0110.73870>100DPLG-2223PKS22230.00650.7671184.47DPLG-2229PKS22290.06919.3236>100DPLG-2230PKS22300.00550.498901.11DPLG-2243PKS22430.000120.02952460.062DPLG-2244PKS22440.01250.82662.20DPLG-22550.00150.12800.028DPLG-2256PKS22560.000090.0313430.034DPLG-3012PKS30120.939.6510.44.16DPLG-3013PKS30130.230.662.911.03DPLG-3014\ PKS30140.0250.42170.96DPLG-3016PKS30160.712.8146.03DPLG-3017PKS30170.0990.6066.33DPLG-3053PKS30530.000750.0751000.22DPLG-3066PKS30660.0053>100>190000.198DPLG-3083PKS30830.00330.3901.20DPLG-3084PKS30840.00140.037260.084DPLG-21033PKS210330.00530.43883—DPLG-21049PKS210490.1330.705—DPLG-21050PKS210500.026>100>3846—aSI: selectivity index;blogP: calculated with ChemDraw. TABLE 4IC50s of the N,C-dipeptides inhibiting proteasome insidethe Karpas 1106p cells and their LD50 against Karpas.Proteasome-glo ®LD50 (μM)IDβ5-IC50 (μM)KarpasDPLG-30.112.04DPLG-2032>100>100DPLG-20580.00934.4DPLG-20830.160.254DPLG-20860.0050.46DPLG-20910.0645.3DPLG-21061.467.8DPLG-21270.16>100DPLG-21301.1367.8DPLG-21500.0090.8DPLG-21600.0190.05Bortezomib0.00060.0017Karpas: subtype of lymphoma; Proteasome-glo ®: test of proteasome inhibition in intact cells. Although the invention has been described in detail, for the purpose of illustration, it is understood that such detail is for that purpose and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the following claims. | 220,107 |
RE49817 | For a better understanding of the invention reference is made to the following detailed description of the preferred embodiments thereof which should be taken in conjunction with the prior described drawings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Various aspects of the present invention will evolve from the following detailed description of the preferred embodiments thereof which should be referenced to the prior described drawings. The mechanism of the present application as a whole is depicted in the drawings by reference character10. Mechanism10is used in a floor structure12. Floor sections14and16of floor structure12represent glass floor units employed with the mechanism of the present application. With reference now toFIG.2, it may be observed that mechanism10is shown in use with glass floor units14and16relative to a foundation or ground surface18. It should be noted that glass floor units14and16are of similar construction. Thus, the following description with respect to glass floor unit14also applies to glass floor unit16. Glass floor unit14includes an upper portion20which consists of multi-laminate glass of durable construction. Lower or bottom portion22is fashioned with fire-rated glass which includes a plurality of glass layers24with fire resistant gel layers26therebetween. Glass floor units14and16are available as 120 minute fire rated SL-II-XL units available from Saftifirst of Brisbane, Calif. In addition, a fire-rated fiber tape layer28overlies glass floor units14and16to create a walking surface30. The mechanism of the present application is also employed with a base32that rests on foundation or ground surface18. Base32is formed with a closure34which may be a galvanized metallic container such as one formed of galvanized metal such as Jet Kote. A grout filler76lies within closure34and encases a metallic beam38. Beam38is stabilized within closure34by fasteners40. A plurality of fire barrier composite blocks42lie atop closure34. Metallic plate44, which may be composed of steel, is welded to beam38and extends upwardly between glass floor units14and16. Foam fillers46,48,50, and52lie adjacent the edges of glass floor units14and16. Fillers46,48,50, and52may take the form of a material known as Willseal 600 manufactured and distributed by Willseal USA of Hudson, N.H. Also depicted inFIG.2is mechanism10that is shown in more detail onFIG.3. Mechanism10includes a receiver54having an internally threaded surface56. Receiver54is generally cylindrical and is welded or otherwise fastened to metallic plate44. In addition, mechanism10includes a support58which may be in the form of a flattened or sheet-like member. As shown inFIG.3, support58has extended into contact with the undersurface60of upper portion20of glass floor unit14. A cavity62within glass floor unit14allows the extension of support58into this position. An adjuster64is also shown inFIGS.2and3. Adjuster64may take the form of a bolt66having an external thread68. Bolt66extends through support58. Nut70is fixed to bolt66such that bolt66and nut70are allowed to turn relative to support58. Thus, nut70and bolt66serves as a connector71linking support58to adjuster64. Needless to say, threaded surface68of bolt66threadingly engages threaded surface66of receiver54in this regard. Directional arrow72indicates the ability of adjuster66to turn. Such turning of bolt66in a counter-clockwise direction will exert an upward force on glass floor units14and16causing an upward deflection of walking surface30. Likewise, the turning of adjuster bolt66in a clockwise direction will tend to cause a slump or depression of walking surface30. Directional arrow74depicts such expansion or depression of walking surface30due to the movement of adjuster64. Needless to say, enough clearance exists to allow support58to rotate relative to adjuster64. Turning toFIG.4, it may be seen that support58has been rotated from a position between glass floor units14and16and out of contact with glass floor units14and16into a position (in phantom) in contact with glass floor units14and16. Such rotation of support58allows the installation of mechanism10and the movement of support into the position shown inFIG.3for its operation, after placement of glass units14and16and prior to the installation of foam fillers46,48,50, and52. A removable overlying hat channel74allows a user to gain access to adjuster66and, thus, move support58relative to and into contact with glass units14and16. It should also be noted that the upward movement of support58through the method, heretofore described, will also relieve pressure or stress between bottom surfaces76and78with composite blocks42. Such relief of pressure or stress on glass blocks14and16prevents damage to the same due to forces on walking surface30of a normal or abnormal genre. Viewing nowFIG.5, it may be seen that mechanism10is being employed with glass unit16against a wall or jam80. Mechanism10is similar to mechanism10as depicted inFIGS.2and3. Also, base82is similar to base32prior described. Foam fillers84and86of Willseal 600 are employed with shims adjacent well80. Again, directional arrow90indicates the upward or downward pressure or movement on glass floor unit16dependent on the operation of mechanism10as heretofore described with respect with mechanism10found inFIGS.2and3. In operation, glass floor units are placed on base32,FIG.3or base82,FIG.5. To initiate the operation of a mechanism10, support58is rotated into position as shown inFIG.3andFIG.5from the position indicated in solid line inFIG.4. In position within cavity62,FIG.3or within cavity92,FIG.5, mechanism10may be operated specifically by the turning of adjusters64, directional arrow72. The turning of adjuster64will move bolt66upwardly or downwardly relative to base through the threading engagement of exterior threaded surface68of bolt66with internal thread56of receiver54. Of course, fixed nut70contacts support58during the upward movement of support58during this operation. Glass floor units14and16will be allowed to travel toward base32,FIG.3or base82,FIG.5or lifted therefrom according to directional arrow74,FIG.3, or directional arrow90,FIG.5. Walking surface30will then be either bowed or depressed to a degree through the operation of mechanism10. While in the foregoing, embodiments of the present application have been set forth in considerable detail for the purposes of making a complete disclosure of the application. Numerous changes may be made in such details without departing from the spirit and the principles of the invention sought for patenting. | 6,603 |
RE49818 | DETAILED DESCRIPTION Various embodiments will be described hereinafter with reference to the accompanying drawings. In general, according to one embodiment, an information processing apparatus includes a memory comprising a buffer area, a first storage, a second storage and a driver. The buffer area is reserved in order to transfer data between the driver and a host system that requests for data writing and data reading. The driver is configured to write data into the second storage and read data from the second storage in units of predetermined blocks using the first storage as a cache for the second storage. The driver is further configured to reserve a cache area in the memory, between the buffer area and the first external storage, and between the buffer area and the second storage. The driver is further configured to manage the cache area in units of the predetermined blocks. FIG.1is an exemplary diagram showing a system configuration of an information processing apparatus according to an embodiment. The information processing apparatus is implemented as a personal computer. As shown inFIG.1, the information processing apparatus includes a central processing unit (CPU)11, a memory controller hub (MCH)12, a main memory13, an I/O control hub (ICH)14, a graphics processing unit (GPU, or display controller)15, a video memory (VRAM)15A, a sound controller16, a basic input/output system-read only memory (BIOS-ROM)17, an HDD18, an SSD19, an optical disc drive (ODD)20, various peripheral devices21, an electrically erasable programmable ROM (EEPROM)22, and an embedded controller/keyboard controller (EC/KBC)23. The CPU11is a processor that controls the other components of the information processing apparatus, and executes the various programs loaded into the main memory13from the HDD18or ODD20. The programs the CPU11may execute include OS110that manages resources, an HDD/SSD driver (cache driver)120and various application programs130that operate under the control of the OS110. The HDD/SSD driver120is a program that controls the HDD18and the SSD19. In the information processing apparatus, the SSD19is used, either in part or in entirety, as a cache for the HDD18, thereby to access the HDD18faster than otherwise. The HDD/SSD driver120is configured to make the SSD19function as a cache. The operating principle of the HDD/SSD driver120will be described below, in detail. If a part of the SSD19is used as a cache for the HDD18, the other part of the SSD19is allocated as a data area that the various application programs130, for example, can use, merely issuing commands to the SSD19. If the entire SSD19is used as a cache for the HDD18, the existence of the SSD19is concealed to the various application programs130, etc. The CPU11also executes a BIOS stored in the BIOS-ROM17. The BIOS is a hardware control program. Hereinafter, the BIOS stored in the BIOS-ROM17will be described as BIOS17in some cases. The MCH12operates as a bridge that connects the CPU11and the ICH14, and also as a memory controller that controls the access to the main memory13. The MCH12includes the function of performing communication with the GPU15. The GPU15operates as a display controller to control the display incorporated in or connected to the information processing apparatus. The GPU15includes the VRAM15A and incorporates an accelerator that generates, in place of the CPU11, the images that the various programs may display. The ICH14incorporates an integrated device electronics (IDE) controller that controls the HDD19, SSD19and ODD20. The ICH14also controls the various peripheral devices21connected to a peripheral component interconnection (PCI) bus. Further, the ICH14includes the function of performing communication with the sound controller16. The sound controller16is a sound source device that outputs audio data items the various programs may play back, to a speaker or the like which is either incorporated in or connected to the information processing apparatus. The EEPROM22is a memory device configured to store, for example, ID data of the information processing apparatus and environment-setting data. The EC/KBC23is a one-chip micro processing unit (MPU) in which an embedded controller and a keyboard controller are integrated. The embedded controller manages power. The keyboard controller controls data input at a keyboard and a pointing device. FIG.2is an exemplary conceptual diagram illustrating the operating principle of the HDD/SSD driver that operates in the information processing apparatus configured as described above. A user buffer250is an area reserved in the main memory13by the OS110, which the application programs130uses to write data in the HDD18or read data from the HDD18. The HDD/SSD driver120performs a process of writing data in the HDD18so that the data may be written in the user buffer250, or a process of storing, in the user buffer250, the data read from the HDD18. That is, the user buffer250is a storage area reserved in the main memory13in order to achieve data transfer between a higher system (host system) and the HDD/SSD driver120. As described above, the information processing apparatus uses the SSD19as a cache for the HDD18, thereby accessing the HDD18faster than otherwise. Thus, the HDD/SSD driver120, which controls the HDD18and the SSD19, reserves an L1 cache area201in the main memory13, between the user buffer250, on the one hand, and the HDD18and SSD19, on the other. In this embodiment, the SSD19is used as a storage medium that functions as a cache for the HOD18. Nonetheless, a data storage medium can of course be used instead, as a nonvolatile cache (NVC). The HDD/SSD driver120manages the L1 cache area201in the main memory13, in units of blocks each having a size of, for example, 64byteskilobytes. The HDD/SSD driver120receives a write request or a read request from the host system, the former requesting data writing into the HDD18, and the latter requesting data reading from the HDD18. The HDD/SSD driver120divides the write request into write-request segments associated with data blocks, respectively, and the read request into read-request segments associated with data blocks, respectively. The HDD/SSD driver120issues the write-request segments or read-request segments, as needed, to the HDD18or the SSD19. In order to manage the data in the L1 cache area201and the data in the SSD19(used as cache for the HDD18), the HDD/SSD driver120reserves a management data storage area202in the main memory13. (Process of Reading Data) How the HDD/SSD driver120reads data in response to a read request coming from the host system will be explained first. If all read data is stored in the L1 cache area201, the HDD/SSD driver120stores the data in the L1 cache area210into the user buffer250(a3inFIG.2). The HDD/SSD driver120then notifies the host system that the data reading process has been completed. If a part of the read data exists in the L1 cache area201, the HDD/SSD driver120reads the other part of the data, which does not exist in the L1 cache area201, from the HDD18into the L1 cache area201(a5inFIG.2), and stores, in the user buffer250, the data request by the host system (a3inFIG.2). At this point, the HDD/SSD driver120notifies the host system that the data reading process has been completed. Thereafter, the HDD/SSD driver120reserves a space in the SSD19and accumulates the request data in this space (a8inFIG.2). At the time the data is stored in the user buffer250, or before the data is accumulated in the SSD19, the HDD/SSD driver120notifies the host system that the data reading process has been completed. The host system can therefore go to the next process. Note that the HDD/SSD driver120reserves a space in the SSD19, by using an unused area or an area which does not hold data to be written to the HDD18and which remains not accessed longer than any other area. Whenever necessary, the HDD/SSD driver120reserves a space in the SSD19in the same way. If the read data does not exist in the L1 cache area201, but exists in the SSD19, the HDD/SSD driver120reads the data stored in the SSD19and stores the data into the user buffer250(a9inFIG.2). Then, the HDD/SSD driver120notifies the host system that the data reading process has been completed. If the read data does not exist in the L1 cache area201and if a part of the data exists in the SSD19, the HDD/SSD driver120reserves a space in the L1 cache area201. Then, the HDD/SSD driver120reads a part of the data from the SSD19and the data from the HDD18and stores them in the space thus reserved in the L1 cache area201(a5and a7inFIG.2). To reserve a space in the L1 cache area201, the HDD/SSD driver120uses an unused area or an area which does not hold data to be written to the HDD18and not accumulated in the SSD19and which remains not accessed longer than any other area. Whenever necessary, the HDD/SSD driver120reserve a space in the L1 cache area201in the same way. The HDD/SSD driver120stores the data read, i.e., requested data read into the space reserved in the L1 cache area201, into the user buffer250(a3inFIG.2). Then, the HDD/SSD driver120notifies the host system that the data reading process has been completed. Thereafter, the HDD/SSD driver120reserves a space in the SSD19and accumulates the data in the space reserved in the SSD19(a8inFIG.2). If the read data exists neither in the L1 cache area201nor the SSD19, the HDD/SSD driver120reserves a space in the L1 cache area201and reads the data stored in the HDD18into the space reserved in the L1 cache area201(a5inFIG.2). The HDD/SSD driver120stores the data read into the space reserved in the L1 cache area201, i.e., data requested, into the user buffer250(a3inFIG.2). Then, the HDD/SSD driver120notifies the host system that the data reading process has been completed. Thereafter, the HDD/SSD driver120reserves a space in the SSD19and accumulates the data in the space reserved in the SSD19(a8inFIG.2). (Process of Writing Data) How the HDD/SSD driver120writes data in response to a write request coming from the host system will now be explained. If the data to update exits in the L1 cache area201only, not in the SSD19at all, the HDD/SSD driver120rewrites the data stored in the L1 cache area201(a4inFIG.2) and notifies the host system that the data writing process has been completed. Thereafter, the HDD/SSD driver120reserves a space in the SSD19and accumulates the rewritten data in the space reserved in the SSD19(a8inFIG.2). If the data to update exits in both the L1 cache area201and the SSD19, the HDD/SSD driver120invalidates the data in the SSD19and rewrites the data stored in the L1 cache area201(a4inFIG.2). Then, the HDD/SSD driver120notifies the host system that the data writing process has been completed. Thereafter, the HDD/SSD driver120reserves a space in the SSD19and accumulates the rewritten data in the space reserved in the SSD19(a8inFIG.2). If the data to update exits in the SSD19only, not in the L1 cache area201, the HDD/SSD driver120rewrites the data stored in the SSD19(a10inFIG.2). Then, the HDD/SSD driver120notifies the host system that the data writing process has been completed. If the data to update exits in neither the SSD19nor the L1 cache area201, the HDD/SSD driver120reserves a space in the L1 cache area201and stores the write data, in the space reserved in the L1 cache area201(a4inFIG.2). Then, the HDD/SSD driver120notifies the host system that the data writing process has been completed. Thereafter, the HDD/SSD driver120reserves a space in the SSD19and accumulates the data stored in the L1 cache area201, in the space reserved in the SS19(a9inFIG.2). (Process of Flushing Data) The HDD/SSD driver120performs a process of flushing data, transferring, to the HDD18, data that has not ever been written in the HDD18. That is, the HDD/SSD driver120writes the data stored in the L1 cache area201into the HDD18(a6inFIG.2). The data stored in the SSD19is written into the HDD18, after it has been stored in the L1 cache area201(a7and a6inFIG.2). In the information processing apparatus, the SSD19is thus used as a cache for the HDD18. The HDD/SSD driver120, which controls the HDD18and the SSD19, reserves an L1 cache area201in the main memory13, between the user buffer250, on the one hand, and the HDD18and SSD19, on the other. Moreover, the HDD/SSD driver120manages the L1 cache area201in units of blocks, whereby data is transferred between the HDD18and the SSD19at high speed and high efficiency (a3to a8inFIG.2). The host system may issue a write force-unit access (FUA) request for a process of writing data in the write-through mode. In this case, the HDD/SSD driver120not only performs the ordinary data writing process, but also issues a write FUA request to the HDD18, upon receiving the write FUA request. Then, the HDD/SSD driver120notifies the host system of the completion of the data writing process after it has received a notification of the data writing process from the HDD18. As described above in conjunction with “(Process of Reading Data),” the HDD/SSD driver120reads the data stored in the SSD19and stores the data into the user buffer250if the data to read does not exist in the L1 cache area201, but exists in the SSD19(a9inFIG.2). This data reading process may be performed via the L1 cache area201. That is, the HDD/SSD driver120may first reserve a space in the L1 cache area201, may then read the data stored in the SSD19and store the same into the space, and may finally store this data into the user buffer250(a7and a3inFIG.2). In this case, the data can be read again, as needed, from the L1 cache area201that achieves higher performance than the SSD19. Assume that the data to read does not exist in the L1 cache area201, but exists in the SSD19. Then, to read the data stored in the SSD19and store the same into the user buffer250, a parameter indicating whether the data should be read via the L1 cache area201or not may be supplied to the HDD/SSD driver120. If this is the case, only one driver, i.e., HDD/SSD driver120, can cope with both a system in which data should not better be read via the L1 cache area201(a9inFIG.2) and a system in which data should better be read via the L1 cache area201(a7and a3inFIG.2). As described above in conjunction with “(Process of Writing Data),” the HDD/SSD driver120notifies the host system of the completion of the data writing process when the data is accumulated in the L1 cache area201or the SSD19. This operating mode shall hereinafter be referred to as “write-back (WB) mode.” The information processing apparatus can operate not only in the WB mode, but also in the write-through (WT) mode. In the WT mode, the HDD/SSD driver120may accumulate data in the L1 cache area201or the SSD19and wire the data into the HDD18, and may then notify the host system of the completion of the data writing process. Further, a parameter indicating whether the data should be written in the WB mode or the WT mode may be supplied to the HDD/SSD driver120. How the HDD/SSD driver120operates in the WI mode in response to a write request coming from the host system in will be explained below. The data to update may exist in the L1 cache area201only, that is, the data may exist in the L1 cache area201but not in the SSD19. In this case, the HDD/SSD driver120rewrites the data in both the L1 cache area201and the HDD18(a4and a2inFIG.2). When the data is written in both the L1 cache area201and the HDD18, the HDD/SSD driver120notifies the host system of the completion of the data writing process. When the data is completely rewritten in the HDD18, the HDD/SSD driver120reserves a space in the SSD19, and accumulates the data stored in the L1 cache area201, in the space reserved in the SSD19(a8inFIG.2). The data to update may exist in both the L1 cache area201and the L1 cache area201. In this case, the HDD/SSD driver120rewrites the data in both the L1 cache area201and the L1 cache area201(a4, a10and a2inFIG.2). When the data is so rewritten, the HDD/SSD driver120notifies the host system of the completion of the data writing process. As the data is rewritten in the SSD19, first, HDD/SSD driver120may invalidate the data stored in the SSD19. After the data has been rewritten in the L1 cache area201(a4inFIG.2), HDD/SSD driver120may reserve a space in the SSD19and may then accumulate the rewritten data in the space reserved in the SSD19(a8inFIG.2). The data to update may exist in the SSD19only, that is, it may exist in the SSD19but not in the L1 cache area201. If this is the case, the HDD/SSD driver120rewrites data in both the SSD19and the HDD18(a10and a2inFIG.2). When the data is rewritten in both the SSD19and the HDD18, the HDD/SSD driver120notifies the host system of the completion of data rewriting process. The data to update may exist in neither the L1 cache area201nor the SSD19. In this case, the HDD/SSD driver120rewrites data in the HDD18(a2inFIG.2). After the data is so rewritten, the HDD/SSD driver120notifies the host system of the completion of the data rewriting process. The data rewriting process performed if the data to rewrite exists in neither the L1 cache area201nor the SSD19includes writing new data (i.e., replacing invalid data with valid data). The HDD/SSD driver120thus operates in the WB mode or the WT mode in accordance with the parameter. One driver, i.e., HDD/SSD driver120, can therefore cope with both a system in which data should better be write in the WB more and a system in which data should better be write in the WT mode. Further, in the WT mode, the HDD/SSD driver120may not rewrite the data to update, if stored in the SSD19, but may instead invalidate the data stored in the SSD19. This operating mode shall be called “WI mode.” If the WI mode is selected in accordance with the parameter, the HDD/SSD driver120can operate more efficiently if the SSD19has a lower data-rewriting performance than the HDD18. (Process of Managing Data) As described above, the HDD/SSD driver120manages the L1 cache area201reserved in the main memory13, in units of blocks, and writes and reads data into and from the HDD18in units of blocks. How the HDD/SSD driver120manages data will be now explained. In the WB mode, a write request coming from the host system does not always request that data be written in units of blocks. If one block is composed of128sectors, it must be determined which sectors hold valid data and which sectors hold the data (Dirty) to be written to the HDD18. To this end, the HDD/SSD driver120provides an existent-sector bit map (“A” ofFIG.3) and a dirty-sector bit map (“B” ofFIG.3), each for the blocks of the L1 cache area201in the main memory13and the SSD19(part of the SSD19used as a cache for the HDD18). The existent-sector bit map and the dirty-sector bit map are provided as management data managed in the management data storage area202. The existent-sector bit map is management data representing which sector in the associated block is valid. The dirty-sector bit map is management data representing which sector in the associated block is dirty. These two sector bit maps hold bits, as shown inFIG.4, each representing the state of each sector in the block. Hence, if one block is composed of128sectors, either sector bit map holds 128 bits, or 16 bytes, for each block. These two bit maps are managed. The HDD/SSD driver120can therefore use the L1 cache area201reserved in the main memory13and the SSD19, thereby appropriately writing or reading data into and from the HDD18. As described above, the dirty-sector bit map is provided to determine which sector is dirty in each block. Therefore, a large storage capacity is required, which is (number of blocks in the L1 cache area201+the number of blocks in the SSD19)×16 bytes. In view of this, the HDD/SSD driver120may not provide the dirty-sector bit map, and may provide a Dirty flag and a Partial flag (both shown inFIG.5) for each block in the L1 cache area201of the main memory13and for each block in the SSD19used as cache for the HDD18. The Dirty flag indicates whether the data (Dirty) to be written to the HDD18exists in the block. The Partial flag indicates whether the data (Dirty) existing in the block is partial or not. These flags are provided as management data managed in the management data storage area202reserved in the main memory13. The dirty flag is true if the data (Dirty) to be written to the HDD18exists in the block, and is false if the data (Dirty) to be written to the HDD18does not exist in the block. The Partial flag is true if all sectors exist in the block, and is false if only some sectors exist in the block. Since all sectors exist in the block if the Partial flag is false, the existent-sector bit map need not be referred to, in some cases. (Nonvolatile Operation) The HDD/SSD driver120performs a nonvolatile operation so that the data accumulated in the SSD19may be used even after the information processing apparatus has been activated again. The nonvolatile operation is based on the assumption that the host system includes a function of transmitting a shutdown notice to the HDD/SSD driver120. Even after transmitting the shutdown notice to the HDD/SSD driver120, the host system may indeed issue a write request or a read request, but to the HDD/SSD driver120only. To perform the nonvolatile operation on these conditions, the HDD/SSD driver120reserves a management data save area191reserved in the SSD19, for storing the management data controlled in the management data storage area202reserved in the main memory13. After receiving the shutdown notice, the HDD/SSD driver120operates in the WT mode even if the WB mode is set, and starts a flush operation. At the time the flush operation is completed, the HDD/SSD driver120guarantees that the write data remains neither in the L1 cache area201of the main memory13nor in the SSD19. When the flush operation is completed, the HDD/SSD driver120stores the management data held in the management data storage area202reserved in the main memory13, into the management data save area191reserved in the SSD19. At this point, the HDD/SSD driver120needs to write an existent-sector bit map, but no dirty data exists. Therefore, the HDD/SSD driver120need not write a dirty-sector bit map or a Dirty flag/a Partial flag. After writing the management data from the management data storage area202reserved in the main memory13into the management data save area191reserved in the SSD19, the HDD/SSD driver120operates, not changing the management data and not causing data contradiction between the HDD18and the SSD19. That is, the HDD/SSD driver120rewrites data in both the HDD18and the SSD19when it receives a write request from the host system and the SSD19holds the data to update, and does not perform the accumulation (learning) of the read data in the SSD19in response to a read request. After the information processing apparatus is activated again, the HDD/SSD driver120loads the management data stored in the management data save area191reserved in the SSD19, into the management data storage area202reserved in the main memory13, without initializing the management data. (This is because the main memory13, which has the L1 cache area201, is volatile.) The HDD/SSD driver120initializes only the management data about the L1 cache area201. By performing the nonvolatile operation described above, the HDD/SSD driver120makes it possible to use the data accumulated in the SSD19, even after the information processing apparatus has been activated again, and can guarantee that the write data remains neither in the L1 cache area201of the main memory13nor in the SSD19. In most systems, another module (capable of accessing the HDD18), such as the BIOS17, operates before the HDD/SSD driver120operates. If there remains data not written into the HDD18, the module (e.g., BIOS17) must have a function of controlling the cache (i.e., the SSD19and the L1 cache area201of the main memory13). In the information processing apparatus, however, the BIOS17or the like need not have the function of controlling the cache. This is because the HDD/SSD driver120performs the nonvolatile operation, guaranteeing that the write data remains neither in the L1 cache area201of the main memory13nor in the SSD19. (Guarantee of Data in Nonvolatile Operation) The HDD/SSD driver120includes a function, which will be described. This function is for determining whether the data accumulated in the SSD19is consistent with the data stored in the HDD19. If the HDD/SSD driver120determines that the data accumulated in the SSD19is not consistent with the data stored in the HDD19, it will perform a volatile operation to destroy the data accumulated in the SSD19. To perform this function, the HDD/SSD driver120provides an Ownership flag (shown inFIG.6) in the management data save area191reserved in the SSD19. The Ownership flag has a value “Driver” or the other value “None.” The value “Driver” indicates that the HDD/SSD driver120is operating. The value “None” indicates that the HDD/SSD driver120is not operating. When the HDD/SSD driver120is loaded, the HDD/SSD driver120checks the Ownership flag. If the Ownership flag has the value “None,” the HDD/SSD driver120determines that the data accumulated in the SSD19can be guaranteed as consistent with the data stored in the HDD19, and then loads the management data stored in the management data save area191, from the SSD19to the L1 cache area201of the main memory13. If the Ownership flag does not have the value “None,” the HDD/SSD driver120determines that the data accumulated in the SSD19cannot be guaranteed as consistent with the data stored in the HDD19, and then initializes the management data and makes the SSD19volatile (invalid). The rule of updating the Ownership flag will be explained. The HDD/SSD driver120rewrites the Ownership flag to the value “Driver” before it starts a cache operation. In order to save the management data after the completion of the cache operation in the nonvolatile operation, the HDD/SSD driver120rewrites the Ownership flag to the value “None.” The data cannot be guaranteed as consistent with the data stored in the HDD19if the power-supply interruption, a clash or a hang-up occurs while the data information apparatus is operating. Nonetheless, the reliability of the data can be raised because the HDD/SSD driver120uses the data accumulated in the SSD19only if the data consistency can be guaranteed by using the Ownership flag as described above. As described above, the HDD/SSD driver120alone guarantees the data in the nonvolatile operation. Nevertheless, another module (i.e., BIOS17, here) capable of accessing the HDD18before the HDD/SSD driver120starts operating may have a minimal cache controlling function to perform the nonvolatile operation as described below, even if the module has written data into the HDD18. In this case, the Ownership flag can have a third value “BIOS,” which indicates that the BIOS17is operating. Hence, the value “None” indicates that neither the BIOS17nor the HDD/SSD driver120is operating. Note that a write trace area is reserved in the management data save area191. When activated, the BIOS17examines the Ownership flag. If the Ownership flag has the value “None,” the BIOS17determines that the data consistency can be guaranteed and then rewrites the Ownership flag to the value “BIOS.” If the Ownership flag has not the value “None,” the BIOS17determines that the data consistency cannot be guaranteed. In this case, the BIOS17leaves the Ownership flag not rewritten. If the BIOS17finds that the data consistency can be guaranteed, it therefore changes the Ownership flag to the value “BIOS.” In this case, the BIOS17accumulates write commands for writing data into the HDD18, in units of blocks as shown inFIG.7, in the write trace area reserved in the management data save area191, when it writes data into the HDD18. Since the write command is written in units of blocks, no request length is required. That is, the logical block addresses (LBAs) of the respective data blocks are used, thereby reducing the amount of trace data. If the write trace area overflows, the BIOS17first stops accumulating the write commands, and then rewrites the Ownership flag to the value “None.” On the other hand, the HDD/SSD driver120examines the Ownership flag, when it is loaded. If the Ownership flag has the value “BIOS,” the HDD/SSD driver120finds that the data consistency can be guaranteed. The HDD/SSD driver120then loads the management data from the management data save area191reserved in the SSD19into the management data storage area202reserved in the main memory13. Further, the HDD/SSD driver120refers to the write trace area reserved in the management data save area191of the SSD19. If the data to update exists in the SSD19, the HDD/SSD driver120invalidates this data. If the Ownership flag has not the value “BIOS,” HDD/SSD driver120determines that the data consistency cannot be guaranteed. In this case, the HDD/SSD driver120initializes the management data and makes the SSD19volatile (invalid). Then, the HDD/SSD driver120rewrites the Ownership flag to the value “None” when the management data is stored after the completion of the flush operation during the above-mentioned nonvolatile operation. The nonvolatile operation can thus be performed even if the other module writes data into the HDD18, only by adding a minimal function to the other module capable of accessing the HDD18(e.g., BIOS17) before the HDD/SSD driver120starts operating. The data consistency cannot be guaranteed (i) if data in the HDD18is rewritten not via the HDD/SSD driver120, for example, the data is rewritten by a program booted from the CD-ROM set in the ODD20, (ii) if the HDD18or the SSD19are replaced by others, or (iii) if the HDD18or SSD19is removed from the information processing apparatus, data in the HDD18or SSD19is then updated in any other information processing apparatus and the HDD18or SSD19is incorporated back into the information processing apparatus. The HDD/SSD driver120has a function of determining, in such an event, that the data consistency cannot be guaranteed. This function that the HDD/SSD driver120has will be described below. Assume that the HDD18and the SSD19used in the information processing apparatus has two functions. One function is to hold data pertaining to individuals (hereinafter referred to as “individual data”) and provide the same in response to a request. The other function is to hold the data representing the number of times the power switch has been closed and provide this data in response to a request. It is also assumed that the number of times the power switch has been closed is updated when data is written not through the HDD/SSD driver120. It is further assumed that the information processing apparatus can incorporate a plurality of HDDs18. To implement these functions, the HDD/SSD driver120reserves an area in the management data save area191of the SSD19. In this area, the individual data is recorded, together with the number of times the power switch has been closed, as shown inFIG.8. The HDD/SSD driver120acquires the individual data and the number of times the power switch has been closed from the SSD19and the HDD18, respectively, at the time of loading. Then, the HDD/SSD driver120compares the individual data about the SSD19and HDD18, stored in the area reserved in the management data save area191of the SSD19, with the number of times the power switch has been closed. The individual data acquired from the SSD19may differ from the individual data recorded in the management data save area191, or the number of times the power switch has been closed, recorded in the management data save area191, may not be smaller by one than the number now acquired from the SSD19. In this case, the HDD/SSD driver120determines that the data consistency cannot be guaranteed, initializes the management data, and makes the SSD19volatile (invalid). The individual data acquired from the HDD18may differ from the individual data recorded in the management data save area191, or the number of times the power switch has been closed, recorded in the management data save area191, may not be smaller by one than the number now acquired from the HDD18. If this is the case, the HDD/SSD driver120determines that the data consistency cannot be guaranteed for the HDD18, initializes the management data about the HDD18, and invalidates the management data about the HDD18, which is stored in the SSD19. The HDD/SSD driver120writes the number of times the SSD19and HDD18have been turned on, in the management data save area191of the SSD19, when the management data is saved after the completion of the flush operation during the above-mentioned nonvolatile operation. Thus, the data consistency can be determined not to be guaranteed in various cases where the data cannot be guaranteed as consistent with the data stored in the HDD19. (Cache Control by BIOS) Not only the HDD/SSD driver120, but also the BIOS17may utilize the data accumulated in the SSD19. How the BIOS17utilizes the data will be explained. When activated, the BIOS17checks the data consistency by using not only the Ownership flag, but also the individual data about the SSD19and HDD18and the number of times the SSD19and HDD18have been turned on (the power cycle counter). If the BIOS17determines that the data consistency can be guaranteed, it rewrites the Ownership flag to the value “BIOS.” If the BIOS17determines that the data consistency cannot be guaranteed, it leaves the Ownership flag not rewritten. In the process of reading data, when data consistency is guaranteed, the BIOS17reads the read data from the SSD19if the data exists, in its entirety, in the SSD19. Otherwise, or if the data exists, in part, in the SSD19or if the data does not exist at all in SSD19, the BIOS17reads data from the HDD18. When data consistency is not guaranteed, the BIOS17reads the read data from the HDD18only. In the process of writing data, the BIOS17writes data into the HDD18only. When the data consistency is guaranteed, the BIOS18invalidates data to update, if any, in the SSD19. If the BIOS17operates as described above, write commands for writing data need not be recorded, as shown inFIG.7, in the write trace area reserved in the management data save area191of the SSD19. This additional simple function enables the BIOS17to utilize the data accumulated in the SSD19, thereby to shorten the activation time. If the data to update exists in the SSD19at the time of writing data, the BIOS17may write the data into both the HDD18and the SSD19. In general, the BIOS17cannot operate to write data into both the HDD18and the SSD19in parallel, so it is therefore disadvantageous in terms of ability. In view of this, the BIOS17may be a module able to write data into both the HDD18and the SSD19in parallel. In this case, data can be written into not only the HDD18, but also the SSD19. If the BIOS17also utilizes the data accumulated in the SSD19, it must refer to the existent-sector bit map in order to determine whether all data to read exists in the SSD19. In view of the limited ability of the BIOS17, it is too much for the BIOS17to refer to the existent-sector bit map. A technique that enables the BIOS17to determine whether all data to read exists in the SSD19, without the necessity of referring to the existent-sector bit map, will be explained below. When the HDD/SSD driver120stores the management data after the completion of the flush operation during the above-mentioned nonvolatile operation, the HDD/SSD driver120invalidates block of the SSD19for which the Partial flag is true, indicating that some sectors exist in the block. Any block (.e., Partial block) holding a part of effective data is thereby expelled from the SSD19after the shutdown. This makes it easier to determine whether all data to read exists in the SSD19. Moreover, the existent-sector bit map need not be written since the Partial block has been expelled at the time of the shutdown. If the Partial block is invalidated as described above when the management data is saved after the completion of the flush operation during the above-mentioned nonvolatile operation, the hit rate in reading data after the management data has been stored will decrease. A technique will be explained, which facilitates determining whether all read data exists in the SSD19, without decreasing the hit rate after the management data has been stored. After the completion of the flush operation during the above-mentioned nonvolatile operation, the HDD/SSD driver120saves the management data, regardless of the Partial flag. The BIOS17reads data from the SSD19if all the data exists in the SSD19and if the Partial flag is false (that is, all sectors exist in the block). When activated, the HDD/SSD driver120invalidates any block for which the Partial flag is true. This sequence also makes it unnecessary to write the existent-sector bit map at the time of saving the management data. (High-Speed Boot) The data used to achieve boot in any information processing apparatus is read, every time from the same area in most cases. The information processing apparatus according to this embodiment uses a technique of achieving boot at high speed. This technique will be described below. To achieve the high-speed boot, the HDD/SSD driver120provides a Pin flag (shown inFIG.9) for each block, in both the L1 cache area201of the main memory13and that part of the SSD19, which is used as a cache for the HDD18. The Pin flag indicates that the data has been used to achieve the boot. The BIOS17sets the Pin flag associated with the block if the read data exists in the SSD19. If the read data does not exist in the SSD19, the BIOS17accumulates the identifier and block LBA of the HDD19in the trace area reserved in the management data save area191of the SSD19. In this case, software is provided as one of the various application programs130, which operates when the OS110is activated. When this software starts operating, it transmits an activation completion notice to the HDD/SSD driver120. When the HDD/SSD driver120is activated or when it receives the activation completion notice, it reads data from the HDD18into the SSD19and sets the Pin flag associated with the block of the SSD19, by referring to the trace the BIOS17has accumulated in the management data save area191of the SSD19. If the data to read until the activation completion notice arrives exists in the L1 cache area201of the main memory13or in the SSD19, the HDD/SSD driver120sets the Pin flag associated with the block. If the data to read does not exist in the SSD19, the HDD/SSD driver120reads the data from the HDD18into the SSD19and then sets the Pin flag associated with the block of the SSD19. Thereafter, the HDD/SSD driver120utilizes the L1 cache area201of the main memory13or the SSD19, writing data to the HDD18or reading data from the HDD18, as requested by the host system. Thus, the HDD/SSD driver120exchanges data in the L1 cache area201of the main memory13or the SSD19, so that the data accessed last may be accumulated before the data accessed previously. At this point, the HDD/SSD driver120performs a control not to invalidate the data in the SSD19, for which the Pin flag is set (even if the data has been accessed a long time before). That is, the hit rate in reading data stored in the SSD19at the time of the booting is increased, because the data used to achieve the boot is read from the same area in most cases. This helps to accomplish the boot at high speed. When the HDD/SSD driver120saves the management data in the management data save area191of the SSD19at the time of the shutdown, it resets all Ping flags and then starts writing the management data. All Ping flags are reset at the time of the shutdown, because every time the boot is achieved, the learning of the read data must be performed for the next boot. As a result, the boot at high speed can be sufficiently accomplished even if the data area used to achieve the boot is changed to another. A write (rewrite) request may be made to write the data for which the Pin flag is set. A method of coping with this case will be explained. As described above, the data for which the Pin flag is set has a high possibility of being read at the next boot. However, this possibility is low, if a write request is made for the data. In this case, the BIOS17and the HDD/SSD driver120reset the Pin flag for the data. This is because even the data used in the boot has a low possibility of being read at the next boot. In view of this, the Pin flag for such data is reset, invalidating the data as needed. The area for achieving the boot can therefore be used for other data. This increases the hit rate. As described above, the data for which the Pin flag is set has a high possibility of being read at the next boot. This is why the HDD/SSD driver120performs a control so that the data accumulated in the SSD19may not be invalidated. The data therefore remains in the SSD19, inevitably reducing the storage capacity of the SSD19that is used as a cache. The HDD/SSD driver120monitors the amount of data for which the Pin flag is set. If the amount of data exceeds a preset value, the HDD/SSD driver120stops setting the Pin flag, thereby excluding the subsequent data (used in the boot) as data to remain in the SSD19. The storage capacity of the SSD19used as a cache therefore is limited, preventing a decrease in the cache hit rate. (Option Process in Response to the Flush/Write FUA Request) If a flush/write FUA request is strictly processed, the write-back operation will be greatly impaired in terms of performance. Therefore, the HDD/SSD driver120performs an “option flush process” function in response to the flush/write FUA request. The “option flush process” function can be “enabled” or “disabled.” If the function is enabled, the HDD/SSD driver120will operate as described below. In the write-through operation (WT mode or after the receipt of the shutdown notice in the WB mode), the HDD/SSD driver120strictly processes the flush/write FUA request, no matter whether the “option flush process” function is set to “Enable” or “Disable.” If the “option flush process” function is set to “Enable,” the HDD/SSD driver120strictly processes the flush/write FUA request. That is, in response to the flush FUA request, the HDD/SSD driver120writes all write data existing in the L1 cache area201of the main memory13and the SSD19, which is not written yet, into the HDD18. The HDD/SSD driver120then issues a Flush request to the HDD18. When the process response to the issued flush request is finished, the HDD/SSD driver120notifies the host system of the completion of the process response to the flush FUA request. In response to the write FUA request, the HDD/SSD driver120operates as described above. The “option flush process” function may be set to “Disable” during the write-back operation. If this is the case, the HDD/SSD driver120does nothing in response to the flush FUA request, and transmits a completion notice to the host system. In response to the write FUA request, the HDD/SSD driver120processes this request as an ordinary write request (that is, not as a write FUA request), and transmits a completion notice to the host system. In this case, the HDD/SSD driver120starts the flush operation at one or both of the following events. One event is the lapse of a prescribed time from the previous flush operation. The other event is that the number of the blocks (Dirty blocks), each containing data not written yet from the SSD19into the HDD18, exceeds a predetermined value. The HDD/SSD driver120flushes all Dirty blocks when it starts the flush operation. Having the “option flush process” function, which can be set to either “Enable” or “Disable,” the HDD/SSD driver120can work well for both a user who wants to preserve the data at the expense of the performance, and a user who wants to maintain the performance at the expense of the data preservation. In addition, the operating time of the HDD18can be shortened, reducing the power consumption, because the data not written yet into the HDD18is flushed altogether. (Data Merging Process) As indicated above, the HDD/SSD driver120reserves the L1 cache area201in the main memory13, between the user buffer250, on the one hand, and the HDD18and SSD19, on the other. Further, the HDD/SSD driver120manages the data stored in the L1 cache area201, in units of blocks. The HDD/SSD driver120includes a function of merging the data in the L1 cache area201or SSD19with the data in the HDD18at high efficiency. This function will be explained below. The data in the L1 cache area201or SSD19must be merged with the data in the HDD18if a part of the read data is stored in the L1 cache area201or if the read data is not stored in the L1 cache area201and is stored in part in the SSD19. Generally, data is read from a plurality of areas reserved in the HDD18, and a plurality of read requests must be issued to the HDD18. Therefore, a plurality of read requests must be issued to the SSD19, too, in order to merge the data in the SSD19with the data in the HDD18. However, if a plurality of read requests are issued, the overhead will increase. In order to prevent such an overhead increase, the HDD/SSD driver120first reserves a merge buffer203in the main memory13. The merge buffer203has the same size as the block size. One or more merge buffers may be reserved in the main memory13, each used under exclusive control. Alternatively, a plurality of merge buffers203may be reserved, each for one block in the L1 cache area201. To merge the data stored in the L1 cache area201with the data stored in the HDD18, the HDD/SSD driver120reads data, in a minimal amount necessary, from the HDD18into a merge buffer203. As shown inFIG.10, the “minimal amount necessary” ranges from the head sector (lacking valid data) to the tail sector (lacking valid data), in one block stored in the L1 cache area201. After reading this amount of data from the HDD18into a merge buffer203, the HDD/SSD driver120copies the data lacking in the L1 cache area201, from the merge buffer203. To merge the data stored in the SSD19with the data stored in the HDD18, the HDD/SSD driver120reads data, in a minimal amount necessary, from the SSD19into the L1 cache area201, and reads data, in a minimal amount necessary, from the HDD18into a merge buffer203. After reading these amounts of data from the SSD19and the HDD18, respectively, the HDD/SSD driver120copies the data lacking in the L1 cache area201, from the merge buffer203. The merge buffers203can be utilized in the flush operation, too. During the flush operation, data is written into the HDD18, exclusively from the L1 cache area201. The valid data in the L1 cache area201may be dispersed and may ultimately be flushed. If this is the case, a plurality of write requests must be issued to the HDD18, inevitably increasing the overhead. If the valid data in the L1 cache area201is dispersed, the HDD/SSD driver120reads data, in a minimal amount necessary, from the HDD18into a merge buffer203. After reading this amount of data from the HOD18into the merge buffer203and merging this data into the L1 cache area201, the HDD/SSD driver120finishes writing data into the HDD18by issuing one write request. (Page Control) The function the HDD/SSD driver120has to write data at high efficiency will be described below. The SSD19, which is a nonvolatile cache (NVC), can read and write data in units of sectors. In the SSD19, however, the data is managed in units of pages in most cases. Data not mounting to one page is written in three steps. First, the present data is read in units of pages. Then, each page is merged with the data to write. Finally, the resulting data is written in units of pages. Inevitably, the data is written at a lower speed than in the case it is written in units of pages. Therefore, the HDD/SSD driver120performs a control of the data writing from the L1 cache area201into the SSD19, so that the data written may have a size multiples of page size as measured from the page boundary. The data representing the page size of the SSD19can be acquired by two methods. In one method, the HDD/SSD driver120acquires the data from the SSD19. In the other method, the data is given, as a set of data item (e.g., parameter), to the HDD/SSD driver120. In order to write the data having a size multiples of page size as measured from the page boundary, from the L1 cache area201into the SSD19, the HDD/SSD driver120allocates the storage area of the SSD19in units of pages and sets the block size as a multiple of the page size. (Set Associative) In order to increase the cache retrieval speed, the HDD/SSD driver120can use a set associative method to manage the data stored in the L1 cache area201and SSD19(used as cache for the HDD18). More specifically, the HDD/SSD driver120manages such a table as shown inFIG.11, in the management data storage area202reserved in the main memory13, for both the L1 cache area201and the SSD19. Of the LBA indicating a block, some lower n bits are used as “Index” representing the number of entries in the table. The table is controlled so that data equivalent to the maximal number of Ways may be accumulated for any block that has “Index.” Using the set associative method, the HDD/SSD driver120may monitor, for each “Index,” the number of data items for which Pin flags are set, thereby to prevent the number of such data items from exceeding a value prescribed for the “Index.” Moreover, using the set associative method, the HDD/SSD driver120may start the flush operation when the number of the Dirty blocks of any “Index” exceeds a predetermined value, if the “option flush process” function is set to “Disable.” As has been described, the SSD19is used as a cache for the HDD18in the information processing apparatus. In order to access the HDD18faster, the HDD/SSD driver120that controls the HDD18and the SSD19reserves the L1 cache area201in the main memory13, between the user buffer250, on the one hand, and the HDD18and SSD19, on the other, and manages the data stored in the L1 cache area201, in units of blocks. The speed and efficiency of the data transfer between the HDD18and the SSD19is thereby increased. The various modules of the systems described herein can be implemented as software applications, hardware and/or software modules, or components on one or more computers, such as servers. While the various modules are illustrated separately, they may share some or all of the same underlying logic or code. While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Indeed, the novel embodiments described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions and changes in the form of the embodiments described herein may be made without departing from the spirit of the inventions. The accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the inventions. | 51,416 |
RE49819 | DETAILED DESCRIPTION In the following detailed description, reference is made to the accompanying drawing figures which form a part hereof, and which show by way of illustration specific embodiments of the invention. It is to be understood by those of ordinary skill in this technological field that other embodiments may be utilized, and structural, electrical, as well as procedural changes may be made without departing from the scope of the present invention. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or similar parts. The term ‘mobile terminal’, as used herein, may indicate a mobile phone, a smart phone, a laptop computer, a digital broadcast receiver, a personal digital assistant (PDA), a portable multimedia player (PMP), a navigation device, a tablet computer, an electronic-book (e-book) reader, and the like. In this disclosure, the terms ‘module’ and ‘unit’ can be used interchangeably. FIG.1illustrates a block diagram of a mobile terminal100according to an embodiment of the present invention. Referring toFIG.1, the mobile terminal100may include a wireless communication unit110, an audio/video (A/V) input unit120, a user input unit130, a sensing unit140, an output unit150, a memory160, an interface unit170, a controller180, and a power supply unit190. Here, when the above constituent elements are implemented, two or more of the constituent elements may be combined into one constituent element, or one constituent element may be divided into two or more constituent elements, if appropriate. The wireless communication unit110may include a broadcast reception module111, a mobile communication module113, a wireless internet module115, a short-range communication module117, and a global positioning system (GPS) module119. The broadcast reception module111may receive broadcast signals and/or broadcast-related information from an external broadcast management server through a broadcast channel. The broadcast channel may be a satellite channel or a terrestrial channel. The broadcast management server may be a server which generates broadcast signals and/or broadcast-related information and transmits the generated broadcast signals and/or the generated broadcast-related information or may be a server which receives and then transmits previously-generated broadcast signals and/or previously-generated broadcast-related information. The broadcast-related information may include broadcast channel information, broadcast program information and/or broadcast service provider information. The broadcast signals may include a TV broadcast signal, a radio broadcast signal, a data broadcast signal, the combination of a data broadcast signal and a TV broadcast signal or the combination of a data broadcast signal and a radio broadcast signal. The broadcast-related information may be provided to the mobile terminal100through a mobile communication network. In this case, the broadcast-related information may be received by the mobile communication module113, rather than by the broadcast reception module111. The broadcast-related information may come in various forms. For example, the broadcast-related information may come in the form of digital multimedia broadcasting (DMB) electronic program guide (EPG) or digital video broadcasting-handheld (DVB-H) electronic service guide (ESG). The broadcast reception module111may receive broadcast signals using various broadcasting systems, such as DMB-terrestrial (DMB-T), DMB-satellite (DMB-S), media forward link only (MediaFLO), DVB-H, and integrated services digital broadcast-terrestrial (ISDB-T). In addition, the broadcast reception module111may be suitable not only for the above-mentioned digital broadcasting systems but also for nearly all types of broadcasting systems other than those set forth herein. The broadcast signal and/or the broadcast-related information received by the broadcast reception module111may be stored in the memory160. The mobile communication module113may transmit wireless signals to or receives wireless signals from at least one of a base station, an external terminal, and a server through a mobile communication network. The wireless signals may include various types of data according to whether the mobile terminal100transmits/receives voice call signals, video call signals, or text/multimedia messages. The wireless internet module115may be a module for wirelessly accessing the internet. The wireless internet module115may be embedded in the mobile terminal100or may be installed in an external device. The wireless internet module115may be embedded in the mobile terminal100or may be installed in an external device. The wireless internet module115may use various wireless internet technologies such as wireless local area network (WLAN), Wireless Broadband (WiBro), World Interoperability for Microwave Access (Wimax), and High Speed Downlink Packet Access (HS-DPA). The short-range communication module117may be a module for short-range communication. The short-range communication module117may use various short-range communication techniques such as Bluetooth, radio frequency identification (RFID), infrared data association (IrDA), ultra wideband (UWB), and ZigBee. The GPS module119may receive position information from a plurality of GPS satellites. The A/V input unit120may be used to receive audio signals or video signals. The A/V input unit120may include a camera module121and a microphone123. The camera module121may process various image frames such as still images or moving images captured by an image sensor during a video call mode or an image capturing mode. The image frames processed by the camera module121may be displayed by a display module151. The image frames processed by the camera module121may be stored in the memory160or may be transmitted to an external device through the wireless communication unit110. The mobile terminal100may include two or more cameras121. The microphone123may receive external audio signals during a call mode, a recording mode, or a voice recognition mode and may convert the received sound signals into electrical audio data. During the call mode, the mobile communication module113may convert the electrical sound data into data that can be readily transmitted to a mobile communication base station, and may then output the data obtained by the conversion. The microphone123may use various noise removal algorithms to remove noise that may be generated during the reception of external sound signals. The user input unit130may generate key input data based on user input for controlling the operation of the mobile terminal100. The user input unit130may be implemented as a keypad, a dome switch, or a static pressure or capacitive touch pad which is capable of receiving a command or information by being pushed or touched by a user. Alternatively, the user input unit130may be implemented as a wheel, a jog dial or wheel, or a joystick capable of receiving a command or information by being rotated. Still alternatively, the user input unit130may be implemented as a finger mouse. In particular, if the user input unit130is implemented as a touch pad and forms a mutual layer structure with the display module151, the user input unit130and the display module151may be collectively referred to as a touch screen. The sensing unit140may determine a current state of the mobile terminal100such as whether the mobile terminal100is opened or closed, the position of the mobile terminal100and whether the mobile terminal100is placed in contact with the user, and may generate a sensing signal for controlling the operation of the mobile terminal100. For example, when the mobile terminal100is a slider-type mobile phone, the sensing unit140may determine whether the mobile terminal100is opened or closed. In addition, the sensing unit140may determine whether the mobile terminal100is powered by the power supply unit190and whether the interface unit170is connected to an external device. The sensing unit140may include a detection sensor141, a pressure sensor143and a motion sensor145. The detection sensor141may detect an approaching object or whether there is an object nearby the mobile terminal100without mechanical contact. More specifically, the detection sensor141may detect an approaching object based on a change in an alternating current (AC) magnetic field or a static magnetic field, or the rate of change of capacitance. The sensing unit140may include two or more detection sensors141. The pressure sensor143may determine whether pressure is being applied to the mobile terminal100or may measure the magnitude of pressure, if any, applied to the mobile terminal100. The pressure sensor143may be installed in a certain part of the mobile terminal100where the detection of pressure is necessary. For example, the pressure sensor143may be installed in the display module151. In this case, it is possible to differentiate a typical touch input from a pressure touch input, which is generated by applying greater pressure than that used to generate a typical touch input, based on a signal output by the pressure sensor143. In addition, it is possible to determine the magnitude of pressure applied to the display module151upon receiving a pressure touch input based on the signal output by the pressure sensor143. The motion sensor145may determine the location and motion of the mobile terminal100using an acceleration sensor or a gyro sensor. Generally, acceleration sensors are a type of device for converting a vibration in acceleration into an electric signal. With recent developments in micro-electromechanical system (MEMS) technology, acceleration sensors have been widely used in various products for various purposes ranging from detecting large motions such as car collisions as performed in airbag systems for automobiles to detecting minute motions such as the motion of the hand as performed in gaming input devices. In general, two or more acceleration sensors representing different axial directions are incorporated into a single package. There are some cases when the detection of only one axial direction, for example, a Z-axis direction, is necessary. Thus, when an X- or Y-axis acceleration sensor, instead of a Z-axis acceleration sensor, is required, the X- or Y-axis acceleration sensor may be mounted on an additional substrate, and the additional substrate may be mounted on a main substrate. Gyro sensors are sensors for measuring angular velocity, and may determine the relative direction of the rotation of the mobile terminal100to a reference direction. The output unit150may output audio signals, video signals and alarm signals. The output unit150may include the display module151, an audio output module153, an alarm module155, and a haptic module157. The display module151may display various information processed by the mobile terminal100. For example, if the mobile terminal100is in a call mode, the display module151may display a user interface (UI) or a graphic user interface (GUI) for making or receiving a call. If the mobile terminal100is in a video call mode or an image capturing mode, the display module151may display a UI or a GUI for capturing or receiving images. If the display module151and the user input unit130form a mutual layer structure and are thus implemented as a touch screen, the display module151may be used not only as an output device but also as an input device capable of receiving information by being touched by the user. If the display module151is implemented as a touch screen, the display module151may also include a touch screen panel and a touch screen panel controller. The touch screen panel is a transparent panel attached onto the exterior of the mobile terminal100and may be connected to an internal bus of the mobile terminal100. The touch screen panel keeps monitoring whether the touch screen panel is being touched by the user. Once a touch input to the touch screen panel is received, the touch screen panel transmits a number of signals corresponding to the touch input to the touch screen panel controller. The touch screen panel controller processes the signals transmitted by the touch screen panel, and transmits the processed signals to the controller180. Then, the controller180determines whether a touch input has been generated and which part of the touch screen panel has been touched based on the processed signals transmitted by the touch screen panel controller. The display module151may include electronic paper (e-paper). E-paper is a type of reflective display technology and can provide as high resolution as ordinary ink on paper, wide viewing angles, and excellent visual properties. E-paper can be implemented on various types of substrates such as a plastic, metallic or paper substrate and can display and maintain an image thereon even after power is cut off. In addition, e-paper can reduce the power consumption of the mobile terminal100because it does not require a backlight assembly. The display module151may be implemented as e-paper by using electrostatic-charged hemispherical twist balls, using electrophoretic deposition, or using microcapsules. The display module151may include at least one of an LCD, a thin film transistor (TFT)-LCD, an organic light-emitting diode (OLED), a flexible display, and a three-dimensional (3D) display. The mobile terminal100may include two or more display modules151. For example, the mobile terminal100may include an external display module (not shown) and an internal display module (not shown). The audio output module153may output audio data received by the wireless communication unit110during a call reception mode, a call mode, a recording mode, a voice recognition mode, or a broadcast reception mode or may output audio data present in the memory160. In addition, the audio output module153may output various sound signals associated with the functions of the mobile terminal100such as receiving a call or a message. The audio output module153may include a speaker and a buzzer. The alarm module155may output an alarm signal indicating the occurrence of an event in the mobile terminal100. Examples of the event include receiving a call signal, receiving a message, and receiving a key signal. Examples of the alarm signal output by the alarm module155include an audio signal, a video signal and a vibration signal. More specifically, the alarm module155may output an alarm signal upon receiving an incoming call or message. In addition, the alarm module155may receive a key signal and may output an alarm signal as feedback to the key signal. Therefore, the user may be able to easily recognize the occurrence of an event based on an alarm signal output by the alarm module155. An alarm signal for notifying the user of the occurrence of an event may be output not only by the alarm module155but also by the display module151or the audio output module153. The haptic module157may provide various haptic effects (such as vibration) that can be perceived by the user. If the haptic module157generates vibration as a haptic effect, the intensity and the pattern of vibration generated by the haptic module157may be altered in various manners. The haptic module157may synthesize different vibration effects and may output the result of the synthesization. Alternatively, the haptic module157may sequentially output different vibration effects. The haptic module157may provide various haptic effects, other than vibration, such as a haptic effect obtained using a pin array that moves perpendicularly to a contact skin surface, a haptic effect obtained by injecting or sucking in air through an injection hole or a suction hole, a haptic effect obtained by giving a stimulus to the surface of the skin, a haptic effect obtained through contact with an electrode, a haptic effect obtained using an electrostatic force, and a haptic effect obtained by realizing the sense of heat or cold using a device capable of absorbing heat or generating heat. The haptic module157may be configured to enable the user to recognize a haptic effect using the kinesthetic sense of the fingers or the arms. The mobile terminal100may include two or more haptic modules157. The memory160may store various programs necessary for the operation of the controller180. In addition, the memory160may temporarily store various data such as a list of contacts, messages, still images, or moving images. The memory160may include at least one of a flash memory type storage medium, a hard disk type storage medium, a multimedia card micro type storage medium, a card type memory (e.g., a secure digital (SD) or extreme digital (XD) memory), a random access memory (RAM), and a read-only memory (ROM). The mobile terminal100may operate a web storage, which performs the functions of the memory160on the internet. The interface unit170may interface with an external device that can be connected to the mobile terminal100. The interface unit170may be a wired/wireless headset, an external battery charger, a wired/wireless data port, a card socket for, for example, a memory card, a subscriber identification module (SIM) card or a user identity module (UIM) card, an audio input/output (I/O) terminal, a video I/O terminal, or an earphone. The interface unit170may receive data from an external device or may be powered by an external device. The interface unit170may transmit data provided by an external device to other components in the mobile terminal100or may transmit data provided by other components in the mobile terminal100to an external device. When the mobile terminal100is connected to an external cradle, the interface unit170may provide a path for supplying power from the external cradle to the mobile terminal100or for transmitting various signals from the external cradle to the mobile terminal100. The controller180may control the general operation of the mobile terminal100. For example, the controller180may perform various control operations regarding making/receiving a voice call, transmitting/receiving data, or making/receiving a video call. The controller180may include a multimedia player module181, which plays multimedia data. The multimedia player module181may be implemented as a hardware device and may be installed in the controller180. Alternatively, the multimedia player module181may be implemented as a software program. The power supply unit190may be supplied with power by an external power source or an internal power source and may supply power to the other components in the mobile terminal100. The mobile terminal100may include a wired/wireless communication system or a satellite communication system and may thus be able to operate in a communication system capable of transmitting data in units of frames or packets. The exterior of the mobile terminal100will hereinafter be described in detail with reference toFIGS.2and3. Various embodiments presented herein can be implemented using nearly any type of mobile terminal, such as a folder-type, a bar-type, a swing-type and a slider-type mobile terminal. However, for convenience, it is assumed that the mobile terminal100is a bar-type mobile terminal equipped with a touch screen. FIG.2illustrates a front perspective view of the mobile terminal100. Referring toFIG.2, the exterior of the mobile terminal100may be formed by a front case100-1and a rear case100-2. Various electronic devices may be installed in the space formed by the front case100-1and the rear case100-2. The front case100-1and the rear case100-2may be formed of a synthetic resin through injection molding. Alternatively, the front case100-1and the rear case100-2may be formed of a metal such as stainless steel (STS) or titanium (Ti). The display module151, a first audio output module153a, a first camera121a, and first through third user input modules130a through130c may be disposed in the main body of the mobile terminal100, and particularly, in the front case100-1. Fourth and fifth user input modules130d and130e and the microphone123may be disposed on one side of the rear case100-2. If a touch pad is configured to overlap the display module151and thus to form a mutual layer structure, the display module151may serve as a touch screen. Thus, the user can enter various information simply by touching the display module151. The first audio output module153a may be implemented as a receiver or a speaker. The first camera121a may be configured to be suitable for capturing a still or moving image of the user. The microphone123may be configured to properly receive the user's voice or other sounds. The first through fifth user input modules130a through130e and sixth and seventh user input modules130f and130g may be collectively referred to as the user input unit130. The user input unit130may adopt various tactile manners as long as it can offer tactile feedback to the user. For example, the user input unit130may be implemented as a dome switch or touch pad capable of receiving a command or information by being pushed or touched by the user; or a wheel, a jog dial or wheel, or a joystick capable of receiving a command or information by being rotated. More specifically, the first through third user input modules130a through130c may be used to make or receive a call, move a mouse pointer, scroll a display screen, and enter various commands such as ‘start’, ‘end’, and ‘scroll’ to the mobile terminal100, the fourth user input module130d may be used to select an operating mode for the mobile terminal100, and the fifth user input module130e may serve as a hot key for activating certain functions of the mobile terminal100. The first user input module130a may allow the user to, the second user input module130b may be used to enter various numerals, characters or symbols, and the third and fourth user input modules130c and130d may be used as hot keys for activating certain functions of the mobile terminal100. FIG.3illustrates a rear perspective view of the mobile terminal100. Referring toFIG.3, a second camera121b may be disposed at the rear of the rear case100-2. The sixth and seventh user input modules130f and130e and the interface unit170may be disposed on one side of the second body100B. The second camera121b may have a different photographing direction from the first camera121a shown inFIG.2. In addition, the first and second cameras121a and121b may have different resolutions. A camera flash and a mirror may be disposed near the second camera121b. The camera flash may be used to illuminate a subject when the user attempts to capture an image of the subject with the second camera121b. The mirror may be used for the user to prepare himself or herself for taking a self shot. A second audio output module (not shown) may be additionally provided in the rear case100-2. The second audio output module may realize a stereo function along with the first audio output module153a. The second audio output module may also be used in a speaker-phone mode. The interface unit170may serve as a pathway for allowing the mobile terminal100to exchange data with an external device. Not only an antenna105for making or receiving a call but also an antenna105for receiving a broadcast signal may be disposed on one side of the rear case100-2. The antennas may be installed so as to be able to be retracted from the rear case100-2. The power supply unit190, which supplies power to the mobile terminal100, may be disposed in the rear case100-2. The power supply unit may be a rechargeable battery and may be coupled to the rear case100-2so as to be attachable to or detachable from the rear case100-2. The second camera121b and the other elements that have been described as being provided in the rear case100-2may be provided in the front case100-1. In addition, the first camera121a may be configured to be rotatable and thus to cover the photographing direction of the second camera121b. In this case, the second camera121b may be optional. FIG.4is a flowchart depicting a method of controlling the operation of a mobile terminal according to an embodiment of the present invention. Referring toFIG.4, block S200includes displaying a main screen showing a predefined number of upper-level icons on the display module, such as display module151. The main screen may be a display screen that can be displayed when the booting of the mobile terminal is complete or when the mobile terminal is booted and released from a lock state. The upper-level icons may include icons frequently used by the user or icons selected by the user. That is, icons frequently used or selected by the user may be set to be displayed on the main screen as the upper-level icons. In addition to basic icons, icons corresponding to applications downloaded from web stores may be displayed on the main screen. However, if too many icons are displayed on the main screen at the same time, the number of programs or the amount of data that should be present in the random access memory (RAM) of the mobile terminal may increase, and thus, the processing speed of the mobile terminal may decrease. To minimize or eliminate this and other issues, only a predefined number of icons including, for example, the icons frequently used or selected by the user, may be displayed on the main screen. Icon-related information (such as a brief description or the current state of use of each of the upper-level icons) may be displayed near each of the upper-level icons. The icon-related information may be modified or edited by the user. Alternatively, the user may configure various other information, icon name, or memo to be displayed near each of the upper-level icons, instead of the icon-related information. If the icon-related information is selected in response to a touch input, for example, a character input window may be displayed, and thus, the user may modify or edit the icon-related information using the character input window. If one of the upper-level icons is dragged for more than a predetermined (e.g., threshold) distance (S205), then the display screen may show a group of lower-level icons, if any, of the corresponding upper-level icon on the display module (S210). On the other hand, if one of the upper-level icons is dragged less than the predetermined distance, the corresponding upper-level icon may be moved to a position where it has been dragged. Alternatively, if one of the upper-level icons is dragged toward a certain direction, a group of lower-level icons, if any, of the corresponding upper-level icon may be displayed. On the other hand, if one of the upper-level icons is dragged toward a direction other than the certain direction, the corresponding upper-level icon may be moved to a position where it has been dragged. If one of the upper-level icons is dragged in a predetermined manner, the dragged upper-level icon may be displayed differently from the other non-dragged upper-level icons so as to be easily distinguishable. For example, the dragged upper-level icon may be highlighted, whereas the other non-dragged upper-level icon may be blurred or otherwise distinguished. A group of lower-level icons to be displayed when one of the upper-level icons is dragged in a predetermined manner may be set in advance. The lower-level icons displayed in operation5210may be icons for executing sub-menu functions of the upper-level icon selected in operation5205or may be sub-folder icons of the upper-level icon dragged by more than the predetermined distance in operation5205. The length or color of icon-related information of an upper-level icon may vary according to the number of lower-level icons that belong to the upper-level icon. Therefore, the user can determine how many lower-level icons belong to an upper-level icon based on icon-related information of the upper-level icon. If one of the lower-level icons displayed in operation S210is touched (S215), a predefined operation corresponding to the touched lower-level icon may be performed (S220). If one of the upper-level icons displayed on the main screen is touched, instead of being dragged more than the predetermined distance (S225), a predefined operation corresponding to the touched upper-level icon may be performed (S230). That is, some of the upper-level icons displayed on the main screen can be readily executed simply by being touched. According to this embodiment, it is possible to execute most or all of the functions of the mobile terminal100with only a few manipulations. In addition, it is possible to improve the processing speed of the mobile terminal by restricting the number of icons that are displayed on the main screen. FIG.5is a flowchart depicting a method of controlling the operation of a mobile terminal according to further embodiments of the present invention. Referring toFIG.5, operations S300, S325and S330may be implemented in the same or similar manner as that described with regard toFIG.4, and thus, further description thereof will be omitted. In operation S305, if one of a plurality of upper-level icons displayed on a main screen is dragged by more than a predetermined distance, a selection window may be displayed from which the user can choose one of a number of lower-level icons, if any, of the dragged upper-level icon on the display module (S310). The selection window may be displayed at the top or bottom of the dragged upper-level icon as a popup window, for example. In operation S315, if one of the lower-level icons included in the selection window is selected by being touched, a predefined operation corresponding to the selected lower-level icon may be performed (S320). According to theFIG.5embodiment, each of the upper-level icons may be executed without the need to switch from one display screen to another display screen. The embodiments ofFIGS.4and5, for example, will now be described in further detail with reference toFIGS.6through14. FIGS.6and7depict icons of a main screen of a mobile terminal according to embodiments of the present invention. InFIG.6, basic icons for executing basic functions of the mobile terminal100may be displayed on a typical main screen400together with icons corresponding to applications downloaded from various web stores or obtained from other sources. If there are too many icons to be displayed all at once, or the number of icons otherwise exceeds a threshold, the user may scroll the main screen (e.g., sideways) in order to search for and execute any desired icon. Consider now the scenario in which not all the icons displayed on the main screen400may satisfy a predetermined condition (e.g., regarding the frequency of use). For example, referring toFIG.7, only a few icons401,403,405,407and409may satisfy the predetermined condition regarding the frequency of use. FIGS.8through11depict various display screens of a mobile terminal operating, for example, in accordance with the various embodiments presented with regard to the method ofFIG.4. In particular,FIG.8(a)shows a display screen420on which a plurality of upper-level icons are displayed. In this example, these icons satisfy a condition regarding the frequency of use or are selected by the user and may also be selected as upper-level icons. Next, a main screen may be configured using such upper-level icons. More specifically, referring toFIG.8(b), the icons that satisfy the above-noted predetermined condition may be arranged in a particular location, such a row435along one edge (e.g., a left edge) of a display screen430. Icons that do not satisfy the predetermined condition may be arranged on the right side of the icons (or other location) that are included in row435. In the example ofFIG.8(c), the icons that do not satisfy the predetermined condition may be deleted from the display screen420, thereby obtaining a main screen440that only includes (e.g., excludes other icons) the icons that satisfy the predetermined condition. Since only certain icons are selected as upper-level icons and are thus displayed on the main screen440, it is possible to simplify the configuration of the main screen440. A number of lower-level icons of each upper-level icon may be classified into one or more function groups according to their functions, for example, into a fun entertainment function group including game and DMB features and a call-related function group including a call feature, a short message service (SMS) feature, a multimedia messaging service (MMS) feature and a long message service (LMS) feature. A number of lower-level icons of each upper-level icon may be configured as sub-folders of a corresponding upper-level icon, and may thus be able to be easily selected by the user. Referring toFIG.9(a), icon-related information such as a brief description or the frequency of use of each upper-level icon and information regarding a number of lower-level icons of each upper-level icon may be displayed on a main screen450. Referring toFIG.9(b), if one of a plurality of upper-level icons displayed on the main screen450is touched465, and the touched upper-level icon does not have any lower-level icons to choose from and can thus be readily executed, an operation corresponding to the touched upper-level icon may be performed. Referring toFIG.9(c), an example of this execution is shown in display screen470. Referring toFIGS.10(a) and10(b), if one of a plurality of upper-level icons displayed on a main screen480is dragged485(e.g., to the right), a display screen490showing a number of lower-level icons of the dragged upper-level icon483may be displayed. Then, the user can select and execute one of the lower-level icons from the display screen490. FIGS.11and12depict display screens showing examples of icon drag-and-drop operations. Referring toFIG.11, an icon503may be moved from one position to another on a display screen500, and a new icon may be added to the display screen500through a simple drag-and-drop. More specifically, if an icon is dragged by more than a predetermined distance (e.g., a threshold distance), a number of lower-level icons, if any, of the icon may be displayed. On the other hand, if an icon is dragged by less than the predetermined distance, the icon may be moved to a position where it has been dragged. Referring toFIG.12(a), a plurality of upper-level icons are shown displayed on an icon setting screen510together with other icons that can be set as lower-level icons, i.e., lower-level icon candidates. The icon setting screen510may be provided by a predetermined menu. The upper-level icons may be configured to be displayed along with the lower-level icon candidates, instead of icon-related information, in accordance with a predefined user input. If there are too many lower-level icon candidates to be displayed all at once, the icon setting screen510may be configured to be able to be scrolled (e.g., sideways). When the icon setting screen510is scrolled, the upper-level icons may remain fixed at their initial positions so that only the lower-level icon candidates can be scrolled through. Referring toFIG.12(b), if one of the lower-level icon candidates503is dragged505over an upper-level icon507, the icon503may be set as a lower-level icon of the upper-level icon507. Then, referring toFIG.12(c), a display screen515may be obtained by deleting the icon503from the icon setting screen510. Thereafter, icon-related information of the upper-level icon507may be updated according to the addition of the icon503as a new lower-level icon of the icon507. If desired, the icon-related information of the upper-level icon507may be modified or edited in accordance with a user command. In this manner, an icon may be set as a lower-level icon of an upper-level icon by dragging the icon over the upper-level icon. FIGS.13and14depict various display screens of a mobile terminal operating, for example, in accordance with the various embodiments presented with regard to the method ofFIG.5. Referring toFIG.13, if one of a plurality of upper-level icons displayed on a main screen520is dragged525(e.g. to the right) a selection window527showing a number of lower-level icons of the dragged upper-level icon may be displayed (e.g., at the bottom of the dragged upper-level icon) as a popup window. Then, the user can touch and execute one of the lower-level icons from the selection window527. The lower-level icons may be configured not to be readily executed after being selected by a touch of the selection window527. In this case, the user can readily execute one of the lower-level icons from the selection window527via a downward or other directional drag within the selection window527. In more detail as a further example,FIG.13shows displaying a first icon group (e.g., on the left side of the screen) of a plurality of icons on the display of the mobile terminal100. In general, each icon of the first icon group is associated with an application (e.g., messaging, phone call, clock, and the like) that is executable on the mobile terminal. As indicated, user contact may occur at a first location of the display (e.g., dashed lines523) relative to a displayed location of a particular icon523. Further detected is user contact representing a dragging525, for example, may occur over a distance beginning from the first location. Generally, the dragging represents substantially continual user contact from the first location over the distance. After the dragging occurs over a threshold distance (which can be system or user defined), a second group of icons (e.g., icons527) are displayed in an icon display region (e.g., region527). In this example, each icon of the second icon group may be associated with an application that is executable on the mobile terminal. Referring toFIG.14, the length or color of icon-related information displayed on a main screen530may vary according to the number of lower-level icons of each upper-level icon, as indicated by reference numerals531,533,535and539. For an upper-level icon having no lower-level icons, no icon-related information may be displayed, as indicated by reference numeral537. Therefore, it is possible to easily determine the number of lower-level icons of each upper-level icon. As noted previously, various embodiments can be realized as code that can be read by a processor (such as a mobile station modem (MSM)) included in a mobile terminal and that can be written on a computer-readable recording medium. The computer-readable recording medium may be any type of recording device in which data is stored in a computer-readable manner. Examples of the computer-readable recording medium include a ROM, a RAM, a CD-ROM, a magnetic tape, a floppy disc, an optical data storage, and a carrier wave (e.g., data transmission through the Internet). The computer-readable recording medium can be distributed over a plurality of computer systems connected to a network so that computer-readable code is written thereto and executed therefrom in a decentralized manner. Functional programs, code, and code segments needed for realizing various embodiments can be constructed by one of ordinary skill in the art based upon the teachings herein. As described above, only a few icons that are selected based on their frequency of use or other parameter or condition (e.g., type, size, date of creation, and the like) and/or in accordance with a user command, may be displayed on a main screen. Then, if one of the icons is dragged by more than a predetermined distance, a number of lower-level icons, if any, of the dragged icon may be displayed. Therefore, it is possible to easily execute most of the functions of a mobile terminal with a few manipulations. Therefore, it is possible to simplify the configuration of a main screen, reduce the number of programs or the amount of data that should be present in a RAM of a mobile terminal and thus improve the processing speed of a mobile terminal. Although embodiments may be implemented using the exemplary series of operations described herein, additional or fewer operations may be performed. Moreover, it is to be understood that the order of operations shown and described is merely exemplary and that no single order of operation is required. In addition, the foregoing embodiments are merely exemplary and are not to be construed as limiting the present invention. The present teaching can be readily applied to other types of apparatuses and processes. The description of the present invention is intended to be illustrative, and not to limit the scope of the claims. Many alternatives, modifications, and variations will be apparent to those skilled in the art. | 40,755 |
RE49820 | The drawings are not necessarily to scale. The drawings are merely representations, not intended to portray specific parameters of the invention. The drawings are intended to depict only typical embodiments of the invention, and therefore should not be considered as limiting in scope. In the drawings, like numbering represents like elements. DETAILED DESCRIPTION OF THE INVENTION Illustrative embodiments will now be described more fully herein with reference to the accompanying drawings, in which embodiments are shown. This disclosure may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of this disclosure to those skilled in the art. In the description, details of well-known features and techniques may be omitted to avoid unnecessarily obscuring the presented embodiments. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of this disclosure. As used herein, the singular forms “a”, “an”, and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, the use of the terms “a”, “an”, etc., do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term “set” is intended to mean a quantity of at least one. It will be further understood that the terms “comprises” and/or “comprising”, or “includes” and/or “including”, when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof. Reference throughout this specification to “one embodiment,” “an embodiment,” “embodiments,” “exemplary embodiments,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” “in embodiments” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment. The terms “overlying” or “atop”, “positioned on” or “positioned atop”, “underlying”, “beneath” or “below” mean that a first element, such as a first structure (e.g., a first layer) is present on a second element, such as a second structure (e.g. a second layer) wherein intervening elements, such as an interface structure (e.g. interface layer) may be present between the first element and the second element. As indicated above, an approach for forming a semiconductor device is provided. In general, the device is formed by providing a metal layer, a cap layer over the metal layer, and an ultra low k layer over the cap layer. A via is then formed through the ultra low k layer and the cap layer. Once the via is formed, a barrier layer (e.g., cobalt (Co), tantalum (Ta), cobalt-tungsten-phosphide (CoWP), titanium (Ti), tantalum nitride (TaN), ruthenium (Ru), or other metal capable of acting as a copper (CU) diffusion barrier is selectively applied to a bottom surface of the via. A liner layer (e.g., manganese (MN) or aluminum (AL)) is then applied to a set of sidewalls of the via. The via may then be filled with a subsequent metal layer (with or without a seed layer), and the device may the then be further processed (e.g., annealed). Referring now toFIGS.1A-Da progression (A1-A4) for forming a semiconductor device10according to an embodiment of the present invention is shown. As depicted in step A1, a metal layer12(e.g., copper) is provided, over which a cap layer14and an ultra low k layer16(e.g., dielectric) are formed. A via18is then formed though ultra low k layer16and cap layer14. A barrier layer20is then selectively applied to the bottom surface of via18as shown. As depicted, barrier layer20is only positioned along the bottom surface of via18(not along the side walls of via18). In this embodiment, barrier layer20is typically cobalt (Co), but may also be tantalum (Ta), cobalt-tungsten-phosphide (CoWP), titanium (Ti), tantalum nitride (TaN), ruthenium (Ru), or other metal capable of acting as a copper (CU) diffusion barrier. Moreover, as shown inFIG.1, barrier layer20may be applied via selective chemical vapor deposition (CVD). In any event, once barrier layer20has been applied, a liner layer22may be applied to the sidewalls of via (and optionally over barrier layer20and/or an upper surface of ultra low k layer16) in step A2. The liner layer22may be manganese (Mn), aluminum (Al) or the like. After the liner layer22has been applied, via18will be filled with a metal layer24(e.g., Cu) in step A3. Optionally, a seed layer may be applied prior to applying metal layer24. Regardless, in step A4, further processing may be applied to device10such as annealing or thermal budging, which converts liner layer22to MNSixOywhile leaving barrier layer20intact. Referring toFIGS.2A-D, a progression (B1-B4) for forming a semiconductor device50is shown. Device50will be formed in a similar fashion to device10ofFIG.1. As depicted in step B5, a metal layer52(e.g., copper) is provided, over which a cap layer54and an ultra low k layer56(e.g., dielectric) are formed. A via58is then formed though ultra low k layer56and cap layer54. A barrier layer60is then selectively applied to the bottom surface of via58as shown (and along upper surface of ultra low k layer56). As depicted, barrier layer60is only positioned along the bottom surface (not along the side walls of via58) and is provided/applied via collimated pressurized vapor deposition (PVD). In this embodiment, barrier layer60is typically tantalum (Ta), but may also be cobalt (Co), cobalt-tungsten-phosphide (CoWP), titanium (Ti), tantalum nitride (TaN), ruthenium (Ru), or other metal capable of acting as a copper (CU) diffusion barrier. In any event, once barrier layer60has been applied, a liner layer62may be applied to the sidewalls of via (and optionally over barrier layer60) in step B2. The liner layer62may be manganese (Mn), aluminum (Al) or the like. After the liner layer62has been applied, via58will be filled with a metal layer64(e.g., Cu) in step B3. Optionally, a seed layer may be applied prior to applying metal layer64. Regardless, in step B4further processing may be applied to device50such as annealing or thermal budging, which converts liner layer62to MNSixOywhile leaving barrier layer60intact. Referring toFIGS.3A-D, a progression (C1-C4) for forming a semiconductor device100is shown. Device100will be formed in a similar fashion to device10ofFIG.1. As depicted in step C1, a metal layer102(e.g., copper) is provided, over which a cap layer104and an ultra low k layer106(e.g., dielectric) are formed. A via108is then formed though ultra low k layer106and cap layer104. A barrier layer110is then selectively applied to the bottom surface of via108as shown. As depicted, barrier layer110is only positioned along the bottom surface of via108(not along the side walls of via108), and along an upper surface of ultra low k layer106. Moreover, barrier layer provided/applied via gas cluster ion beam (GSIB) infusion. In this embodiment, barrier layer110is typically Ta, but may be may be cobalt (Co), cobalt-tungsten-phosphide (CoWP), titanium (Ti), tantalum nitride (TaN), ruthenium (Ru), or other metal capable of acting as a copper (CU) diffusion barrier. In any event, once barrier layer110has been applied, a liner layer112may be applied to the sidewalls of via (and optionally over barrier layer110) in step C2. The liner layer112may be manganese (Mn), aluminum (Al) or the like. After the liner layer112has been applied, via108will be filled with a metal layer114(e.g., Cu) in step C3. Optionally, a seed layer may be applied prior to applying metal layer114. Regardless, in step C4further processing may be applied to device100such as annealing or thermal budging, which converts liner layer112to MNSixOywhile leaving barrier layer110intact. Referring toFIGS.4A-D, steps D1-D2demonstrate that barrier layer160and liner layer162may be applied in any order (e.g., barrier layer160need not be applied to a vial58's bottom surface prior to applying liner layer162to side walls of via158). Specifically, as shown, device150is formed by providing a metal layer152(e.g., copper), over which a cap layer154and an ultra low k layer156(e.g., dielectric) are formed. A via158is then formed though ultra low k layer106and cap layer104. As shown, liner layer160(e.g., manganese (Mn), aluminum (Al), etc.) is applied to side walls (and a top surface of ultra low k layer156) in step D1. In step D2, barrier layer160may then be applied using any of the materials and/or techniques discussed above in conjunction withFIGS.1-3. Although not shown in separate steps, it is understood that to complete device150, a metal layer164will be provided via158(e.g., with or without a seed layer), and device150will be subjected to additional processing (e.g., annealing, etc.). In various embodiments, design tools can be provided and configured to create the data sets used to pattern the semiconductor layers as described herein. For example, data sets can be created to generate photomasks used during lithography operations to pattern the layers for structures as described herein. Such design tools can include a collection of one or more modules and can also include hardware, software, or a combination thereof. Thus, for example, a tool can be a collection of one or more software modules, hardware modules, software/hardware modules, or any combination or permutation thereof. As another example, a tool can be a computing device or other appliance on which software runs or in which hardware is implemented. As used herein, a module might be implemented utilizing any form of hardware, software, or a combination thereof. For example, one or more processors, controllers, application-specific integrated circuits (ASIC), programmable logic arrays (PLA)s, logical components, software routines, or other mechanisms might be implemented to make up a module. In implementation, the various modules described herein might be implemented as discrete modules or the functions and features described can be shared in part or in total among one or more modules. In other words, as would be apparent to one of ordinary skill in the art after reading this description, the various features and functionality described herein may be implemented in any given application and can be implemented in one or more separate or shared modules in various combinations and permutations. Even though various features or elements of functionality may be individually described or claimed as separate modules, one of ordinary skill in the art will understand that these features and functionality can be shared among one or more common software and hardware elements, and such description shall not require or imply that separate hardware or software components are used to implement such features or functionality. While the invention has been particularly shown and described in conjunction with exemplary embodiments, it will be appreciated that variations and modifications will occur to those skilled in the art. For example, although the illustrative embodiments are described herein as a series of acts or events, it will be appreciated that the present invention is not limited by the illustrated ordering of such acts or events unless specifically stated. Some acts may occur in different orders and/or concurrently with other acts or events apart from those illustrated and/or described herein, in accordance with the invention. In addition, not all illustrated steps may be required to implement a methodology in accordance with the present invention. Furthermore, the methods according to the present invention may be implemented in association with the formation and/or processing of structures illustrated and described herein as well as in association with other structures not illustrated. Therefore, it is to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention. | 12,492 |
RE49821 | DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A description will be given below of embodiments of the present invention with reference to the accompanying drawings by taking, as main examples, double height and triple height circuit cells. 1. First embodiment: Embodiment in which the double height cell to which the present invention is applied is shown by four application examples (circuit examples). In the first and second application examples, the effect obtained by the application of the present invention will be described by using comparative examples 1 and 2. 2. Second embodiment: Embodiment of a triple height cell to which the present invention is applied. 3. Third embodiment: Embodiment of an L-shaped cell (double height cell having the same functionality as a triple height cell) to which the present invention is applied. 4. Modification examples: Two modification examples relating to a substrate contact will be described. 1. First Embodiment 1. Overall Layout FIG.1is a diagram schematically illustrating a plan view of an integrated circuit according to embodiments with a focus on the cell layout. InFIG.1, each of rectangular areas is called a cell. The cells denoted by reference numeral SC are standard cells. The standard cell SC is a predesigned and standardized functional circuit cell registered in a library such as an inverter or a NAND gate. Although being a collection of data, the standard cell SC may refer to part of a device manufactured based on the data. Although a detailed description will be given later, standard cells registered in a library are combined and laid out in the design phase of a semiconductor integrated circuit. As a result of the layout, source voltage lines and reference voltage lines (e.g., GND lines) are roughly connected together on data. Connecting signal and other lines after the layout provides the desired circuit. The layout of cells and disposition of wirings up to this point is conducted on the data level using a design support apparatus. Although being a schematic plan view of the semiconductor integrated circuit with a focus on the cell layout,FIG.1can also serve as a data-level cell layout diagram. In a semiconductor integrated circuit1shown inFIG.1, the standard cells SC of a variety of sizes are combined and laid out, thus achieving a desired circuit. Here, the desired circuit can be achieved at will depending on what the functional circuits of the standard cells SC are and how the cells are combined so long as the desired circuit is a logic circuit.FIG.1is a generalized diagram, and it is arbitrary what the desired circuit is. The standard cell design system is used in the design process of ASIC (Application Specific Integrated Circuit) and ASSP (Application Specific Standard Product). ASIC is an IC developed and manufactured to meet a specific application requirement of each customer. ASSP is an IC designed and developed as a general-purpose part for a plurality of customers. A description will be given below of the size of the standard cell SC. In the standard cell SC, the cell length in the direction along one of two sides that are orthogonal to each other is commonly standardized. This cell length direction will be hereinafter referred to as the “standard cell length direction.” There may not be only one, but a few sizes or, for example, three sizes, in the standard cell length direction (standard cell lengths) in an entire IC. It should be noted, however, that there has been, up until today, one unified standard cell length, when viewed locally, as in a single circuit block or a circuit adapted to achieve a desired function. One of the major characteristics of the embodiments of the present invention is that there are a plurality of standard cell lengths in a local circuit such as a single circuit block or a circuit adapted to achieve a desired function. In relation to this characteristic, common single height standard cells SHSC and multi-height standard cells MHSC, both serving as the standard cells SC, are mixed in the example shown inFIG.1. Here, two types of multi-height standard cells MHSC are shown, a double height standard cell WHSC having a standard cell length twice that of a single height standard cell SHSC and a triple height standard cell THSC having a standard cell length that is three times that of a single height standard cell SHSC. The cell size can be determined at will in the direction orthogonal to the standard cell length direction. Although the cell size may be determined at will, it is common that there are fixed discrete sizes that can be used (specified by the grid number) for reasons of design efficiency or to meet the demand for consistency. The direction orthogonal to the standard cell length direction will be hereinafter referred to as the “arbitrary cell length direction.” In a circuit block as shown inFIG.1, the VDD and VSS lines extend in the arbitrary cell length direction and are arranged alternately in the standard cell length direction. The gap between the VDD and VSS lines is appropriate to the height of the single height standard cell SHSC. Further, the double height standard cell WHSC includes a type denoted by reference numeral WHSC1. The double height standard cell WHSC1has the two VSS lines that are disposed, one along each of the two short sides, in the standard cell length direction, with the VDD line passing through the same cell WHSC1at the center between the two VSS lines. Further, the double height standard cell WHSC includes a type denoted by reference numeral WHSC2. In contrast to the double height standard cell WHSC1, the double height standard cell WHSC2has the two VDD lines that are disposed, one along each of the two short sides, with the VSS line passing through the same cell WHSC2at the center between the two VDD lines. Although only one of these two types may be used, the two types are mixed here from the viewpoint of layout efficiency. [Single Height Layout] Next, the reason will be clarified why the single height standard cells SHSC and multi-height standard cells MHSC are mixed in the same circuit block by stating the disadvantages of the major techniques adapted to design a semiconductor integrated circuit with only single height cells. FIGS.2A to2Cillustrate three types of single height standard cells designed by a single height layout technique to form a CMOS logic circuit. Each of these single height standard cells SHSC_1, SHSC_2and SHSC_3has two doped regions, namely, a P-type doped region13P and an N-type doped region13N, arranged parallel to each other between the VDD and VSS lines. The P-type doped region13P serves as the sources or drains of PMOS transistors. The N-type doped region13N serves as the sources or drains of NMOS transistors. The reason for this is that the inverter is the basic building block of CMOS logic circuits. Polysilicon gate electrodes20A and20B forming an inverter input are arranged linearly so as to be orthogonal to a rectangular region including a P-type doped region13P (hereinafter denoted by the same reference numeral as the P-type doped region13P and referred to as the “PMOS active region13P”). The polysilicon gate electrodes20A and20B are also arranged linearly so as to be orthogonal to a rectangular region including an N-type doped region13N (hereinafter denoted by the same reference numeral as the N-type doped region13N and referred to as the “NMOS active region13N”) (FIGS.2A and2C). Therefore, the single height standard cells have a height (standard cell length) appropriate to that of a complementary transistor pair (NMOS and PMOS pair). In such a standard cell configuration, vertically long common gate electrodes of the complementary transistor pair (hereinafter the CMOS gate lines) are arranged side by side. This leads to an increased number of internal wirings adapted to connect CMOS gate lines or a CMOS gate line and other node (e.g., transistor source and drain). Moreover, because such a number of internal wirings must be provided in a limited space, the wiring pattern is inevitably complex. This leads to many vertices and bends in the metal and polysilicon layouts, thus resulting in a complex shape. In leading-edge processes, the more complex the pattern shape is, the more design rule restrictions are imposed. Further, a complex pattern shape leads to a long time required to perform optical proximity correction (OPC) in the mask preparation or is disadvantageous from the viewpoint of design for manufacturing (DFM). Here, the term “DFM (design for manufacturing)” refers to a technique adapted to resolve the LSI manufacturing problems at the design stage. In the cell layout, a simple shape provides a device less susceptible to variations at the time of manufacture. Therefore, this aspect is important. Further, difficulty in performing OPC, for example, may lead to a reduced yield of physical device. The viewpoints described above constitute the first disadvantage of designing a logic circuit with only the single height standard cells SHSC. A high likelihood of producing wasted space is the second disadvantage. Standard cells used, for example, for a clock tree may be laid out with a changed size ratio between the MVOS and NMOS to ensure that the clock delay is the same. For example, a standard cell (SHSC_2:FIG.2B) may be used that has a larger-than-normal PMOS (SHSC_1:FIG.2A). Alternatively, a standard cell (SHSC_3:FIG.2C) may be used that has a smaller-than-normal NMOS. In this case, enlarging the PMOS active region13P horizontally leads to a vacancy in the NMOS transistor forming region as shown inFIG.2B. Conversely, reducing the NMOS active region13N vertically does not increase the area of the standard cell SC itself but leads to a reduced area usage efficiency. These constitute wasted spaces in exchange for necessary functions, which is one of the reasons why high density packaging cannot be achieved. The embodiments of the present invention propose a complementary transistor pair (e.g., CMOS pair) standard cell configuration that resolves the above two disadvantages. The present invention is applied to a complementary in-phase driven standard cell of all the types of complementary transistor pair standard cells. Three layout configuration examples of the complementary in-phase driven double height standard cells WHSC to which the present invention is applied will be shown below together with circuit examples. First Application Example FIG.3is an equivalent circuit diagram of a half adder cell as a circuit example of the standard cell SC to which the present invention is applied. The half adder shown inFIG.3is broadly divided into a carry-out section (CO section) and a single-bit addition section (Sum section). The half adder is a circuit designed to receive first and second input bits (A1and A2) and output a half addition bit (S) and a carry-out bit (hereinafter the CO bit). The half addition bit represents the result of half addition in the first digit. The CO bit represents a carry. It should be noted that the gates of the CMOS pairs that are supplied, for example, with the same input inFIG.3are indicated by bi-directional arrows. The carry-out (CO) section includes a NAND circuit and an inverter. The NAND circuit includes two PMOS transistors P1and P2and two NMOS transistors N1and N2. The inverter includes a PMOS transistor P3and an NMOS transistor N3. The NAND circuit and inverter are connected by a wiring denoted by reference numeral31(internal wiring31) where an inverted carry-out hit (NCO) appears. The P1-N1CMOS pair is supplied with the first input bit A1. The P2-N2CMOS pair is supplied with the second input bit A2. The single-bit addition (Sum) section includes four PMOS transistors P4to P7and four NMOS transistors N4to N7and has the inverted carry-out bit (NCO) and the first and second input bits (A1and A2) as its inputs. Although performing a single bit addition, the same section produces a single bit output. Therefore, the same section performs a half addition operation adapted to produce a “0” output with the help of the inverted carry-out bit (NCO) that is “0 (e.g., low level)” when both the first and second input bits A1and A2are “1 (e.g., high level).” In such a configuration, when the two input bits (A1and A2) are both low, the PMOS transistors P1and P2are ON. Therefore, the NCO is high, and the CO is low. As a result, no carry is generated. On the other hand, both the PMOS transistors P5and P6are ON. This pulls an inverted half addition bit (NS) up to high level. The NS is the potential of an internal connection line33forming the input node of the inverter at the final stage. As a result, an internal connection line34outputs a low level as the half addition bit (S). When the two input bits (A1and A2) are high and low, respectively, the PMOS transistor P1is OFF but the PMOS transistor P2is ON. Similarly, therefore, the NCO is high, and the CO is low. As a result, no carry is generated. On the other hand, both the NMOS transistors N4and N5are ON. This pulls the inverted half addition bit (NS) down to low level. Therefore, a high level is output as the half addition bit (5). When the two input bits (A1and A2) are low and high, respectively, the PMOS transistor P2is OFF but the PMOS transistor P1is ON. Similarly, therefore, the NCO is high, and the CO is low. As a result, no carry is generated. On the other hand, both the NMOS transistors N4and N6are ON. This pulls the inverted half addition bit (NS) down to low level. Therefore, a high level is output as the half addition bit (S). When the two input bits (A1and A2) are both high, the NMOS transistors N1and N2are ON, which stands in contrast to the above three cases. Therefore, the NCO is low, and the CO is high. As a result, a carry is generated. On the other hand, because the NCO is low, the PMOS transistor P4is ON although the PMOS transistors P5and P6, provided in parallel with the PMOS transistor P4, are OFF. This pulls the inverted half addition bit (NS) up to high level. Therefore, a low level is output as the half addition bit (S). FIG.4is a layout diagram of the circuit shown inFIG.3designed by applying an embodiment of the present invention. The standard cell illustrated inFIG.4is an example of the double height standard cell WHSC1(FIG.1) having the VDD line disposed at the center. In this double height standard cell WHSC1, a VDD line30D extends in the arbitrary cell length direction (horizontal direction) at the center of the standard cell length direction (vertical direction). Further, two VSS lines, i.e., VSS lines30S1and30S2, are disposed. The VSS line30S1is arranged along the center of the width of one of the short sides of the horizontal outer frame of the cell. The VSS line30S2is arranged along the center of the width of the other of the short sides thereof. The VSS lines30S1and30S2are arranged parallel to each other, and also parallel to the VDD line30D. The VDD line30D and VSS lines30S1and30S2are formed by patterning the first wiring layer (1M). The circuit (CO section) adapted to generate the carry-out bit (CO bit) is provided on the lower half of the cell in such a manner as to have the VSS line30S1and share the VDD line30D. On the other hand, the circuit (Sum section) adapted to generate the half addition bit (S) is provided on the upper half of the cell in such a manner as to have the VSS fine30S2and share the VDD line30D. Two active regions of the same conductivity type, i.e., PMOS active regions11P and12P, are arranged line-symmetrically with respect to the center line of the power line (VDD line30D) passing through the cell. Further, an NMOS active region11N is arranged between the PMOS active region11P and VSS line30S1, and an NMOS active region12N between the PMOS active region12P and VSS line30S2. Surrounded by an element isolation insulating layer10, these four active regions are isolated from one another and arranged to be horizontally long in shape and parallel to the power line. It should be noted that the CO section has six transistors whereas the Sum section has eight. Therefore, the PMOS and NMOS active regions12P and12N are longer in shape than the NMOS and PMOS active regions11N and11P. Three common gate electrodes21to23are arranged linearly in such a manner as to penetrate the four active regions vertically (in the slumlord cell length direction). The common gate electrode21serves as a common gate of the transistors (P1, N1, P5and N5) adapted to receive the first input bit A1shown inFIG.3. The positions of the above transistors are shown inFIG.4by the same reference numerals. The common gate electrode22serves as a common gate of the transistors (P2, N2, P6and N6) adapted to receive the second input bit A2shown inFIG.3. Further, the common gate electrode23serves as a common gate of the transistors (P3, N3, P4and N4) adapted to receive the inverted carry-out hit shown inFIG.3. The positions of the above transistors are also shown inFIG.4by the same reference numerals. On the other hand, a common gate electrode24for the remaining two transistors (P7and N7) is shorter than the other three and penetrates the PMOS and NMOS active regions12P and12N because the two transistors must receive the inverted half addition bit (NS) in the Sum section. Internal wirings31to35shown inFIG.3are provided as the wirings of the first wiring layer (1M) and shaped as shown inFIG.4to connect the sources, drains and gates of different transistors. The specific connection relationship is obvious with reference toFIG.3, and therefore is omitted. [Characteristics of the Layout to Which the Present Invention is Applied] A first characteristic of the layout is that the connection rule with the single layout power line arrangement is maintained. That is, the relationship between the VSS line30S1and VDD line30D and that between the VSS line30S2and VDD line30D are appropriate to the standard cell length of the single height standard cell SHSC (FIG.1). These relationships allow for power lines to be shared between a single height cell and double height cell when they are arranged adjacent to each other. For this reason, the double height standard cell WHSC1has a standard cell length which is a plurality of or M (≥2, M=2 in this case) times the basic cell length which is the standard cell length of a single height cell. A second characteristic of the layout is that the gate electrodes of the plurality of or M (M=2 in this case) complementary transistor pairs to be driven in phase are arranged linearly as common gate electrodes. This commonization of gate electrodes contributes to a reduced number of internal wirings, thus providing leeway in the layout of other internal wirings. When there is leeway in the layout of internal wirings, wirings may be laid out without forming a complex shape, possibly contributing to improved yield and ease of manufacturing. Further, there is no need to connect the gates together using the upper layer wirings, thus providing leeway in the layout of the upper layer wirings. In the case of this circuit example in particular, there is no need to connect the gates together in the higher second wiring layer, as in the comparative examples which will be described layer, thus ensuring effective use of multi-wiring resources and providing reduced cost. A third characteristic of the layout is that active regions of the same conductivity type (11N and12N) are arranged line-symmetrically with respect to (M−1) power lines passing midway therebetween, or the one VDD line30D because M=2. A fourth characteristic of the layout is that all the gate electrodes overlapping the portion of the element isolation insulating layer10located within the width of separation between the two active regions are the common gate electrodes21to23of the complementary transistor pairs to be drive in phase. In contrast, the common gate electrode24is not a common electrode of a plurality of complementary transistor pairs, but is instead a common electrode of NMOS and PMOS transistors in a single complementary transistor pair. Such an electrode does not overlap any portion of the element isolation insulating layer10located within the width of separation between the two active regions (instead overlaps the portion of the same layer10located outside the width of separation). The fourth characteristic is obvious when we consider the case in which this characteristic is not present. That is, we assume that two gate electrodes, one extending from up to down and another extending from down to up into the width of separation between the two active regions, are separated within the same width. In this case, a space for separating the electrodes is required in addition to the alignment tolerance required to reliably align the gate electrodes with the active regions in consideration of the misalignment of the photomask. As a result, there are limits to reducing the space between the active regions. In the case of the layout shown inFIG.4to which the present invention is applied, on the other hand, the gate electrodes are not separated. Therefore, there is no need to consider the tolerance in this portion, nor there is any need to provide a separation space. All what is required is a separation width for element separation. However, so long as this width is secured, it is possible to bring the two active regions close to each other to the extent possible, thus providing leeway in the standard cell length direction. Because the standard cell length is determined to be M times the basic cell length which is the standard cell length of a single height cell, the standard cell length can be changed only by reviewing the basic cell length. This leeway provides a larger channel width (commonly also called the gate length) in the determined standard cell length direction, thus contributing to a larger transistor size or providing leeway in the layout of other internal wirings. When there is leeway in the arrangement of internal wirings, wirings may be laid out without forming a complex shape, contributing to improved yield and ease of manufacturing. The above characteristics are also available when triple or higher standard cells which will be described later are used. A description will be given next of comparative examples to which the present invention is not applied to further clarify the effects of the above characteristics. Comparative Example 1 FIG.5is a layout diagram of comparison example 1 in which the same circuit (FIG.3) as shown inFIG.4is achieved with horizontally long single height cells. The circuits shown inFIGS.4and5are basically extremely similar except for the communization of gate electrodes. Like components are denoted by like reference numerals, and the description thereof is omitted. InFIG.5, the CO and Sum sections are arranged parallel to each other between the VDD line30D and a VSS line30S so that the CO and Sum sections can be supplied with power from these lines. Further, while the single common gate electrode21is linearly arranged inFIG.4, two common gate electrodes21A and21B, each for a CMOS pair, are arranged one on the left and the other on the right inFIG.5. Similarly, while the single common gate electrode22is provided inFIG.4, two common gate electrodes22A and22B are arranged one on the left and the other on the right inFIG.5. Still similarly, while the single common gate electrode23is provided inFIG.4, two common gate electrodes23A and23B are arranged one on the left and the other on the right inFIG.5. Because the two common gate lines are arranged separately, the pairs of gate electrodes shown by bi-directional arrows inFIG.5must be electrically shorted together. A first approach to making these connections would be to achieve horizontal connections using the common gate electrodes themselves (gate polysilicon layer). In order to short the common gate electrodes21A and21B together, it is necessary, for example, to expand the space between the PMOS active region11P or12P and VDD line30D in the standard cell length direction. Further, in order to short the common gate electrodes22A and22B together, it is necessary, for example, to expand the space between the NMOS active region11N or12N and VSS line30S in the standard cell length direction. Even in this case, the common gate electrodes23A and23B cannot be shorted together. As a result, it is inevitable that this remaining pair of common gate electrodes should be shorted together using the first wiring layer (1M). With the first approach, the cell length must be expanded in the standard cell length direction so as to secure a space for arranging two common gate electrodes. However, this gives rise to significant wasted space in the standard cell array as a whole, which makes this approach unacceptable. For this reason, a second approach would be to use the second wiring layer (2M). If the branches for the active region contacts of the power lines (30D and30S) and internal wirings (31to33) are moved backward inFIG.5, it seems possible to secure a space for arranging the first wiring layer (1M) adapted to short out at least one common gate line. However, it is impossible in terms of space to connect all three. Therefore, at least one of them must use the higher second wiring layer (2M). On the other hand, the connections between the first and second input bits A1and A2and half addition bit (S) and the unshown adjacent cell are not shown inFIG.5. The second wiring layer (2M) may be used to make connections with the adjacent cell, which is, however, not necessary in the pattern shown inFIG.5. The input and output lines of these three bits can be achieved by changing the pattern of the first wiring layer (1M). Even in such a case, the layout shown inFIG.5which requires the use of the second wiring layer (2M) merely for connecting the common gate electrodes is disadvantageous in that it may result in significantly increased cost due to wasteful use of wiring resources. As described above, both the first and second approaches are disadvantageous in that they are highly likely to result in significantly increased cost. The layout shown inFIG.4is superior to the comparative example shown inFIG.5in that it will not incur such a disadvantage. It should be noted that the CO section shown inFIG.4has a vacant space which is not present in the CO section shown inFIG.5. However, this vacant space exists in the arbitrary cell length direction. As is clear fromFIG.1, there are inherently many vacant spaces in the arbitrary cell length direction. Therefore, even if the size in the arbitrary cell length direction is increased as a result of the application of an embodiment of the present invention, the increased size will lead to no increase or an extremely slight, if any, increase in cost, if anything, the advantage gained by the application of the present invention, namely, the advantage that there is no need to expand the standard cell length or use the upper wirings more than offsets the disadvantage that the size in the arbitrary cell length direction is larger. Therefore, the application of the present invention is effective in reducing cost. Further, as a result of an embodiment of the application of the present invention, the wiring pattern layouts for the first wiring layer (1M) and polysilicon are simpler in shape thanks to fewer vertices and bends. The application of the present invention is advantageous from the viewpoint of design for manufacturing (DFM) in that it contributes to reduced man-hours for mask preparation including the OPC process and design, thus providing further reduced manufacturing cost and improved yield. Second Application Example FIGS.6A and6Billustrate a circuit symbol and equivalent circuit diagram of a clock buffer cell. A clock buffer cell is a cell including an even number of stages of cascaded inverters. This type of cell is designed so that the clock output from the cell has the same duty ratio to the extent possible. Therefore, a clock buffer is characterized in including larger-than-normal PMOS transistors or smaller-than-normal NMOS transistors. A specific clock buffer circuit includes two cascaded inverters INV1and INV2shown inFIG.6A. Each of the inverters INV1and INV2includes two inverters connected in parallel as shown inFIG.6B. Thus, when each of the inverters INV1and INV2of the clock buffer at the first and second stages includes two inverters connected in parallel, the inverters offer sufficient driving capability. In addition, the present invention is more readily applicable to the clock buffer. FIG.7illustrates an example in which the circuit shown inFIG.6is laid out with a double height cell. In this layout diagram, a VDD line31D is arranged at the center of the standard cell length and extends in the arbitrary cell length direction. Two VSS lines31S1and31S2are arranged parallel to the VDD line31D and along the center of the width of one of the short sides on both sides along the standard cell length. These three power lines are formed by using the second wiring layer (2M). A specific description of the circuit configuration in the cell and the connections is omitted because the circuit itself is simple. Here, the element isolation insulating layer10, PMOS active regions11P and12P, and NMOS active regions11N and12N are arranged in the same manner as in the first application example as like components as those in the first application example denoted by like reference numerals. Contact with the active regions is achieved by providing branches of the power lines in the first application example. Here, however, contact with the active regions is achieved by providing power connection lines39D1,39D2,39S1and39S2that are formed with the first wiring layer (1M). Internal wirings36and37are formed with the first wiring layer (1M) to connect the inverters INV1and INV2together as shown inFIG.6B. On the other hand, an internal wiring38is formed with the first wiring layer (1M) to serve as an output wiring of the inverter INV2. The same wiring38extends under the VDD line31D in the standard cell length direction. Common gate electrodes25and26are arranged parallel to each other and extend in the standard cell length direction as with the common gate electrodes21to23(FIG.4) in the first application example. It should be noted that the CMOS pairs formed by these common gate lines are shown in the layout diagram ofFIG.7. These CMOS pairs are denoted by like reference numerals as those inFIG.6B. In this layout, PMOS transistors can be formed as far as in the region close to the VDD line which cannot be used in an ordinary single height cell, as with the layout inFIG.4. Further, it is possible to design the layout with a simple wiring layer pattern without increasing the size in the standard cell length direction in the wiring layers up to the first wiring layer (1M). This makes it possible to increase the PMOS size without increasing the cell area or vacant spaces, thus providing a low-cost semiconductor integrated circuit with high yield. FIG.8is a layout diagram of a cell having a VSS line31S that is arranged at the center of the standard cell length and extends in the arbitrary cell length direction. This layout is also possible in the first application example shown inFIG.4. The cell shown inFIG.8differs from that shown inFIG.7in that the VSS line31S is arranged at the center, and that VDD lines31D1and31D2are arranged along the short sides of the cell on both sides in the standard cell length direction. As a result, the layout of the NMOS and PMOS transistors the standard cell length direction is opposite to that shown inFIG.7. The cell shown inFIG.8is similar to that shown inFIG.7in all other respects. Comparative Example 2 FIG.9is a layout diagram of a cell that serves as a comparative example of those shown inFIGS.7and8. In the horizontal layout shown inFIG.9, it is impossible to bring the PMOS active regions close to the VDD line as can be done in the cell shown inFIG.7and bring the NMOS active regions close to the VSS line as can be done in the cell shown inFIG.8. The cell shown inFIG.9is disadvantageous in that the transistors are limited by the above two aspects and cannot be increased in size. Further, each of the common gate electrodes25and26is H-shaped. As a result, the same electrodes25and26are disadvantageous in that they require a larger layout area in the arbitrary cell length direction than the same electrodes25and26in linear shape shown inFIGS.7and8. Moreover, an internal wiring denoted by reference numeral36+37that serves the purpose of the internal wirings36and37shown inFIGS.7and8and the internal wiring38are complex in shape. Because of these reasons, this cell has a larger size in the arbitrary cell length direction. Moreover, it is difficult to perform the OPC process when the cell is miniaturized. As a result, it is highly likely that the yield will decline. In other words, the cell layouts shown inFIGS.7and8to which the present invention is applied resolve the disadvantages of the cell layout shown inFIG.9. Third Application Example FIG.10illustrates an equivalent circuit diagram of a third application example according to the modification of the second application example. As compared to the clock buffer shown inFIG.6B, that shown inFIG.10has a large PMOS transistor P10a rather than the two PMOS transistors P11and P12provided in the inverter INV1shown inFIG.6B. The same holds true for the inverter INV2. That is, the clock buffer shown inFIG.10has a large PMOS transistor P10b rather than the two PMOS transistors P13and P14shown inFIG.6B. FIG.11illustrates a plan view of a cell that achieves the circuit shown inFIG.10. The comparison of the cells shown inFIGS.7and11reveals that the two separate PMOS active regions12P and11P inFIG.7are replaced by a single vertically long PMOS active region13P inFIG.11. This eliminates the need for an isolation region (part of the element isolation insulating layer10) between the active regions required inFIG.7, thus making it possible to increase the sizes of the PMOS transistors. Alternatively, if the PMOS transistors are maintained in the same size, it is possible to increase the sizes of the NMOS transistors. It should be noted that the cell shown inFIG.11can be modified in the same manner as the cell shown inFIG.7is modified to provide the cell shown inFIG.8. Fourth Application Example FIGS.12A and12Billustrate a circuit symbol and equivalent circuit diagram of a clock buffer cell capable of dividing the output into a plurality of branches as another modification example of the clock buffer cell shown inFIGS.6A and6B. The circuit shown inFIGS.12A and12Bdiffers from that shown inFIGS.6A and6Bin that the inverter INV2at the subsequent stage is divided into inverters INV2A and INV2B, each of which has an output node. InFIG.12B, an internal wiring38A making up the output node of the inverter INV2A and an internal wiring38B making up the output node of the inverter INV2B are provided separately from each other. The circuit shown inFIGS.12A and12Bis similar to that shown inFIGS.6A and6Bin all other respects. FIG.13illustrates an example in which the circuit shown inFIG.12is laid out with a double height cell. In the clock buffer with branched outputs, the output node is separated into the internal wirings38A and38B. As a result, there is no need for the internal wiring of the output node to intersect the VDD line31D at the center. This makes it possible to form the VDD line31D (and VSS lines31S1and31S2) with the first wiring layer (1M) as illustrated inFIG.13. The connections between the power lines and active regions are achieved by the branch power lines extending from the main power lines. The circuit shown inFIG.13is similar to that shown inFIG.7in all other respects. 2. Second Embodiment The second embodiment is a modification of the circuits shown inFIGS.7and8using a triple height cell that has a standard cell length that is three times the basic cell length. FIG.14illustrates a layout diagram according to the second embodiment. If, for example, the double height portion of the upper two stages inFIG.14is considered to be the same as the cell shown inFIG.8, the lowermost stage portion is added to the cell shown inFIG.8. Alternatively, if the double height portion of the lower two stages inFIG.14is considered to be the same as the cell shown inFIG.7, the uppermost stage portion is added to the cell shown inFIG.7. InFIG.14, the additional portions are denoted by new reference numerals from the former viewpoint. It should be noted that the equivalent circuit achieved by the layout diagram shown inFIG.14includes three parallel inverters in place of each of the inverters INV1and INV2shown inFIG.6B. In the additional portion, reference numeral10P denotes a PMOS active region, and reference numeral10N an NMOS active region. Further, a VSS line denoted by reference numeral31D0is added. The VDD lines31D0and31D1are provided respectively with the power connection lines39S2and39D2that are formed with the first wiring layer (1M). The same lines39S2and39D2are branch lines adapted to connect the NMOS active region10N and PMOS active region10P respectively to the power lines. It should be noted that the internal wiring36+37is disposed to extend as long as the length of three basic cells. However, the internal wirings36and37can be similarly connected together to extend as long as the length of two standard cells inFIGS.7and8. Therefore, this is nota special characteristic of a triple height cell. Other components of the cell shown inFIG.14can be basically explained by analogy of the double height cells shown inFIGS.7and8. It should be noted that the corrections made by changing a double height cell to a triple height cell can be applied to multi-height cells equal to or greater than triple height cell using the same technique. Still further, the advantages of a double height cell are similarly inherited by multi-height cells equal to or greater than triple height cell. 3. Third Embodiment Multi-height cells equal to or greater than triple height cell can be used to produce a non-rectangular cell that is bent in the shape of L as a whole. In a layout example according to the standard cell system as shown inFIG.1, in general, there are likely many gaps in the arbitrary cell length direction. However, there is often not much leeway in space in the standard cell length direction. Therefore, if one wishes to increase the number of CMOS pairs as a whole while restricting the height in the standard cell length direction, this goal can be achieved by accommodating some of the CMOS pairs in the L-shaped bent portion in the arbitrary cell length direction. This solution often produces no wasted layout area. The third embodiment is designed to meet such a need. The layout as shown inFIG.15can be, for example, used. InFIG.15, a cell having three CMOS pairs as that shown inFIG.14is achieved by combining the layout of the double height cell shown inFIG.7and the layout the CMOS pairs on the right side of the single height cell shown inFIG.9. It should be noted, however, that the two metal wiring layers shown inFIG.9are used. On the other hand, a common gate line denoted by reference numeral27has a shape in plan view that is divided into branches under the VDD line31D for three CMOS pairs. These CMOS pairs make up three parallel inverters in the first stage. Three parallel inverters in the subsequent stage include three CMOS pairs formed by connecting a common gate electrode28and the H-shaped common gate electrode26(refer toFIG.9) together with the internal wiring36+37that is formed with the first wiring layer (1M). In addition to the above, a power branch line connected to the NMOS active region12N is denoted by reference numeral39S0, and a power branch line connected to the PMOS active region12P by reference numeral39D0. All other components were already described with reference toFIGS.7and9, and therefore the description thereof is omitted. In the present embodiment, the functions of a triple height cell can be achieved with the standard cell height of a double height cell. This allows a greater degree of freedom in the layout, making it possible to choose between the layouts shown inFIGS.14and15according to the conditions surrounding the layout location when many triple height cells are laid out. This is significantly advantageous in that more efficient layout is possible. It should be noted, however, that the common gate line27is divided into branches where it intersects the VDD line31D inFIG.15. Therefore, the PMOS active regions12P and11P cannot be brought very close to the VDD line31D. However, the layout shown inFIG.15has advantages that more than offset the above disadvantage, which makes this layout effective. It should be noted that, including this third embodiment, the number of complementary transistor pairs to be driven in phase or N need not necessarily agree with the number of complementary transistor pairs or M that is appropriate to the standard cell length of multi-height layout. That is, a multi-height layout is possible that satisfies the relationship N≥M≥2. 4. Modification Examples Modification examples of substrate contacts will be shown next. In the first to third embodiments, substrate contacts are not shown in the layout diagrams. FIGS.16and17illustrate two examples of how to arrange substrate contacts. These figures illustrate in detail the substrate contact portions of the cell shown inFIG.4. The same substrate contact layout technique is similarly applicable to the other layout diagrams. Basically, in order to dispose gate polysilicon layer wirings (common gate lines) in the presence of substrate contacts SCH, the same contacts SCH and doped regions are removed, as appropriate only where the gate polysilicon layers are disposed. Here, the substrate contacts SCH are also referred to as taps. More specifically, an N-type doped region14N that is higher in concentration is formed on the surface of the tap region where the PMOS active regions12P and11P and the element isolation insulating layer10are connected together in the deep side of the substrate. The substrate contacts SCH serve as connection plugs between the N-type doped region14N and first wiring layer (1M). This allows for the channel forming regions of the PMOS transistors formed in the PMOS active regions11P and12P to be supplied with VDD voltage from the VDD line30D. Further, the source region of the PMOS transistors is supplied with power by the branch from the VDD line30D and the contacts connected to the branch. On the other hand, many substrate contacts SCH are provided in the VSS lines30S1and30S2for the same purpose as above. The substrate contacts SCH in these areas are provided to connect the NMOS active region11N or12N to the VSS voltage. Strictly speaking, the channel forming region formed in the NMOS active region11N or12N or the substrate is connected to the VSS voltage. That is, a P-type doped region14P that is higher in concentration is formed on the surface of the tap region where the NMOS active region12N or11N and the element isolation insulating layer10are connected together in the deep side of the substrate. The substrate contacts SCH serve as connection plugs between the P-type doped region14P and first wiring layer (1M). This allows for the channel funning regions of the NMOS transistors formed in the NMOS active regions11N and12N to be supplied with VSS voltage. Further, the source region of the NMOS transistors is supplied with power by the branch from the VSS line30S1or30S2and the contacts connected to the branch. Alternatively, a tapless circuit cell having none of the substrate contacts SCH (referred to as the taps) as shown inFIG.17may be used. In order to provide the substrate contacts SCH not provided by the tapless circuit cell, a tap cell2is also used. The tap cell2is laid out as appropriate in the gap formed as appropriate in the arbitrary cell direction shown inFIG.1. Therefore, careful consideration is given to ensure that the layout of the circuit cell is not affected by the tap cell2. The first to third embodiments described above provide the following advantages. Firstly, the number of horizontal (arbitrary cell length direction) metal wirings can be reduced, thus allowing for effective use of the metal wiring resources. Secondly, increased wiring resources eliminate the need to is use metal in the upper layers. Thirdly, polysilicon gate wirings (common gate lines) are disposed where they would not exist if the present invention was not applied, thus eliminating the horizontal polysilicon gate wirings and providing increased wiring resources. Fourthly, the polysilicon gate wirings are simpler in shape. Fifthly, thanks to the polysilicon gate wirings that are simpler in shape, there is more layout area in the diffusion regions (active regions) or the layout is easier to do. Sixthly, since the metal and polysilicon wirings and diffusion regions are easier to lay out, the geometries are no longer complex, which is effective from the viewpoint of design for manufacturing (DFM). Seventhly, where a VDD line is shared in a multi-height cell, the PMOS size can be increased, thus providing improved transistor mounting area efficiency. Similarly, where a VSS line is shared in a multi-height cell, the NMOS size can be increased, thus providing improved transistor mounting area efficiency also in this respect. The above advantages are achieved by elaborately taking advantage of the fact that, in a CMOS circuit, a signal is commonly connected to the gate terminals of the paired PMOS and NMOS transistors. In the case of an inverter, for example, a signal is connected to the gate terminals of the CMOS pair. In the first to third embodiments, when the cell input signals and the intracell signals are connected to the gate terminals of a plurality of CMOS pairs, a multi-height cell is intentionally used to lay out these CMOS pairs vertically. The present application contains subject matter related to that disclosed in Japanese Priority Patent Application JP 2009-198547 filed in the Japan Patent Office on Aug. 28, 2009, the entire content of which is hereby incorporated by reference. It should be understood by those skilled in the art that various modifications, combinations, sub-combinations and alterations may occur depending on design requirements and other factor in so far as they are within the scope of the appended claims or the equivalents thereof. | 46,841 |
RE49822 | DETAILED DESCRIPTION In accordance with an embodiment, a single-band right-hand circularly-polarized patch antenna comprises a ground plane and a patch connected to each other with at least four (4) wires for which the wire shape and location of the end points are selected such that they do not cause an antenna mismatch, and the electrical current carried in the wires produces an extra electromagnetic field subtracted from the patch electromagnetic field in the nadir direction. In accordance with the embodiment, this facilitates an antenna with low DP level (i.e., Down/Up level) in the nadir direction and with a smaller (and shorter) ground plane until the size (i.e., length) of the ground plane is as long as the patch, and there is no additional power supply necessary to power the wires. As noted previously, it is well-known that patch antennas are widely used in GNSS systems due to their low height which enables the design of certain low-profile devices. As shown inFIG.1, a conventional patch antenna includes radiating patch101located over ground plane102, the lateral dimension (length) of ground plane102being longer than that of patch101. As also noted previously, one example of an antenna providing for low DP level in the nadir direction is described in U.S. Pat. No. 9,184,503, and shown inFIG.2, where the antenna's design includes the length of ground plane206that is equal to or smaller than the length of patch201which is disposed above flat metal ground plane202. To achieve this design, loop radiator207is located around patch205hereby the radiator is excited by dual-wire lines209connected to a separate power supply (not shown). In this design, there is a dielectric filler made in the form of two dielectric discs203and204with holes for exciting pins205and cavity210. Between these elements, there are the dual-wire lines209to power loop radiator207, and reference dielectric substrate211to fix it. The power supply provides excitation of loop radiator207with such amplitude and phase that the field of patch201is subtracted from the field of loop radiator207. However, potential drawbacks are overall design complexity and the requirement of a separate supply line to power the loop radiator. FIG.3shows a schematic of GNSS antenna302positioned above Earth304. As used herein, the term “Earth” includes both land and water environments. To avoid confusion with “electrical” ground (as used in reference to a ground plane), “geographical” ground (as used in reference to land) is not used herein. To simplify the illustration shown inFIG.3, supporting structures for GNSS antenna302are not shown. Shown inFIG.3is a reference Cartesian coordinate system with X-axis301and Z-axis305. The Y-axis (not shown) points into the plane of the illustration ofFIG.3. In an open-air environment, the +Z (up) direction, referred to as the zenith, points towards the sky, and the −Z (down) direction, referred to as the nadir, points towards Earth304. The X-Y plane lies along the local horizon plane. InFIG.3, electromagnetic waves (carrying electromagnetic signals) are represented by rays with an elevation angle θewith respect to the horizon. The horizon corresponds to θe=0 deg; the zenith corresponds to θe=+90 deg; and the nadir corresponds to θe=−90 deg. Rays incident from the open sky, such as ray310and ray312, have positive values of elevation angle. Rays reflected from Earth304, such as ray314, have negative values of elevation angle. Herein, the region of space with positive values of elevation angle is referred to as the “direct signal region” and is also alternatively referred to as the “forward (or top) hemisphere”. Herein, the region of space with negative values of elevation angle is referred to as the “multipath signal region” and is also alternatively referred to as the “backward (or bottom) hemisphere”. Ray310impinges directly on the antenna302and is referred to as the direct ray310; the angle of incidence of the direct ray310with respect to the horizon is θe. Ray312impinges directly on Earth304; the angle of incidence of ray312with respect to the horizon is θe, and assume ray312is specularly reflected. Ray314(i.e., reflected ray314), impinges on the antenna302; the angle of incidence of relfected ray315with respect to the horizon is −θe. To numerically characterize the capability of an antenna to mitigate the reflected signal, the following ratio is commonly used: DU(θe)=F(-θe)F(θe)(E1) The parameter DU(θe) (Down/Up ratio) is equal to the ratio of the antenna pattern level F(−θe) in the backward hemisphere to the antenna pattern level F(θe) in the forward hemisphere at the mirror angle, where F represents a voltage level. Expressed in dB, the ratio is: DU(θe) (dB)=20 log DU(θe) (E2) A commonly used characteristic parameter is the Down/Up ratio at θe=+90 deg DU90=DU(θe=90°)=F(-90°)F(90°)(E3) The geometry of antenna systems is described with respect to the illustrative Cartesian coordinate system shown inFIG.4.FIG.4shows a perspective view with a Cartesian coordinate system having origin o401, x-axis403, y-axis405, and z-axis407. The coordinates of point P411are P(x, y, z). Let {right arrow over (R)}421represent the vector from o to P. The vector {right arrow over (R)} can be decomposed into the vector {right arrow over (r)}427and the vectorh429, whereris the projection of {right arrow over (R)} onto the x-y plane, and {right arrow over (h)} is the projection of {right arrow over (R)} onto the z-axis407. The coordinates of P411can also be expressed in the spherical coordinate system and in the cylindrical coordinate system. In the spherical coordinate system, the coordinates of P are P(R,θ,φ), where R=|{right arrow over (R)}| is the radius, θ423is the polar angle measured from the x-y plane, and φ425is the azimuthal angle measured from the x-axis. In the cylindrical coordinate system, the coordinates of P are P(r,θ,h), where r=|{right arrow over (r)}| is the radius, φ is the azimuthal angle, and h=|{right arrow over (h)}| is the height measured parallel to the z-axis. In the cylindrical coordinate axis, the z-axis is referred to as the longitudinal axis. In geometrical configurations that are azimuthally symmetric about z-axis407, the z-axis is referred to as the longitudinal axis of symmetry, or simply the axis of symmetry (if there is no other axis of symmetry under discussion). The polar angle θ is more commonly measured down from the +z-axis 0≤θ≤π). Here, the polar angle θ423is measured from the x-y plane for the following reason. If the z-axis407refers to the z-axis of an antenna system, and the z-axis407is aligned with the geographic Z-axis305inFIG.3, then the polar angle θ223will correspond to the elevation angle θeinFIG.3; that is, −90°≤θ≤+90°, where θ=0° corresponds to the horizon, θ=+90° corresponds to the zenith, and θ=−90° corresponds to the nadir. FIG.5Ashows single band antenna500in accordance with an embodiment. In particular, a single-band right-hand circularly polarized patch antenna comprising ground plane502, patch501and dielectric substrate503. The right-hand circular-polarization mode can be implemented in a well-known manner by an excitation circuit connected to excitation pins (not shown). There are also four wires505-1,505-2,505-3and505-4. Each wire has starting point P1and end point P4as will be further discussed herein below. At starting point P1the wire is connected to ground plane502, and at end point P4the wire is connected to patch501. Wires505-1,505-2,505-3and505-4have the same (or substantially the same) design and are arranged in a rotational symmetrical manner about vertical z-axis407(as shown inFIG.4) as such passing through a center of the antenna. For ease of discussion, hereinafter the designation505-n will be understood to refer to and describe wires505-1,505-2,505-3, and505-4(i.e., n=1, 2, 3, 4), as the context dictates Wire505-n (e.g.,505-1) consists of three segments506-n (e.g.,506-1),507-n (e.g.,507-1) and508-n (e.g.,508-1) and has four characteristic points P1, P2, P3and P4, as shown inFIG.5B, and each of the segments has starting and end points. That is, for segment506-n, P1and P2are starting and end points, and for segment507-n, P2and P3are starting and end points respectively, and for segment508-n, such starting and end points are P3and P4. Coordinates of points P1, P2, P3and P4can be determined in a cylindrical coordinate system with the origin at point O510located onto patch501, i.e., the vertical coordinate of patch501is zero. The cylindrical coordinate system has vertical axis407in the antenna center that is oriented from ground plane502to patch501. The angular coordinate is counted from the x-axis, the direction of which can be arbitrarily selected. As shown inFIG.5B, this direction is parallel to the side of patch501. The angular coordinate increases counterclockwise as observed from the side of the positive direction of the vertical axis. Point P1has coordinates r1,φ1,z1, P2has coordinates r2,φ2,z2, point P3has coordinates r3,φ3,z3, and point P4has coordinates r4,φ4,z4. Segment506-n is vertical, and hence r=r2, φ=φ2. Segment507-n is horizontal, respectively z2=z3. Segment508-n is vertical and r3=r4, φ3=φ4. Segment506-n is connected to the ground plane at point P1, segment508-n is connected to the patch at P4. Horizontal segment507-n is located over the patch (e.g., patch501), i.e., z2>0. Angular coordinate φ1of segment506-n connected to the ground plane (e.g., ground plane502) is greater than angular coordinate φ3of segment508-n being connected to the patch. Thus, φ1>φ3. The positional relationship of segments506-n and508-n will now be discussed. Using a top view, the imaginary line connecting the coordinate origin and a point of segment507-n will rotate counterclockwise when moving from point P3belonging to segment508-n to point P2belonging segment506-n. Thus, the imaginary line connecting any point of wire505-n will rotate counterclockwise when moving from the end point of wire505-n (i.e., P4) to the starting point of wire505-n (i.e., P1). In this way, it will be understood that when moving along vertical segments (508-n,506-n) the imaginary line does not rotate. The orientation and the positional relationship of the wires, as described above, in the right-hand circularly polarized antenna results in an electric current in horizontal segments507-n such that the associated field is subtracted from the field of patch501in the nadir direction. As a result, the total antenna field in the nadir direction is substantially reduced. The reduction is due, in part, to the specific orientation of the plurality of wires such that the reduction of the total antenna field in the nadir direction is, illustratively, a function of variations between the first electromagnetic field associated with the plurality of wires and the second electromagnetic field associated with the radiating patch. In accordance with the embodiment, this variation is represented and determined by subtracting the second and first electromagnetic fields. The length of each horizontal segment507-n lies close to a quarter of the wavelength, and the segments along with ground plane502can be interpreted as segments of a transmission line which are shorted at their ends by segments506-n. These transmission lines are connected to patch501by segments508-n. It is well-known that a short-circuited transmission line that is a quarter wavelength long has open-circuit impedance, and this why these connections do not cause the mismatch of the antenna formed by patch501and ground plane502. FIG.6Ashows a further embodiment of dual-band stacked-patch antenna600comprising ground plane602, LF patch601and HF patch (HF)609. In the space between HF609patch and LF601patch there is dielectric610. In the space between LF patch601and ground plane602there is dielectric603. LF patch601is a ground plane for patch HF609. There are also four wires505-1,505-2,505-3, and505-4, the design and orientation of which is as described herein above, for example, with respect toFIG.5Bthere is the division of wire505-n into segments506-n,507-n and508-n, and segments507-n are above LF patch601. Again, in accordance with this further embodiment, the total antenna field in the nadir direction is substantially reduced as described previously. The length of each horizontal segment507-n is close to a quarter of a wavelength on the frequency of LF band (i.e., around 60 mm). The segments along with ground plane602can be considered as segments of a transmission line shorted at their ends by segments506-n. The transmission lines are connected to LF patch601via segments508-n. It is well-known, as noted above, that a short-circuited transmission line that is a quarter wavelength long has an open-circuit impedance such that these connections do not cause the mismatch of the antenna formed by patch601and ground plane602. Each of wires505-n is connected to ground plane602and LF patch601through reactive impedance elements611-n (e.g.,611-1,611-2,611-3, and611-4) and612-n (e.g.,612-1and612-2). Wire505-1has a starting point P1and end point P4. At point P1wire505-1is connected to reactive impedance element611-1. Element611-1is in turn connected to ground plane603. At point P4wire505-1is connected to impedance element612-1. Element612-1is in turn connected to LF patch601. Elements611-n and612-n ensure a short circuit mode within LF band and an operation mode with practically open-circuit conditions within HF band. Such connecting eliminates undesirable effects of wires505-n in HF band. Also, in accordance with an embodiment, elements612-n can be eliminated such that wires505-n can be directly connected to patch601at points P4. Wires505-n and reactive impedance elements611-n and612-n are arranged in a rotational symmetrical manner to vertical z-axis407passing through the antenna center. Each of reactive impedance elements611-n and612-n, as shown inFIG.6B, can be made as a segment of a shorted-circuit transmission line613-n with series capacitor614-n. Also, as shown inFIG.6B, a reference plane from which the phase of the element's reflection factor is counted out is depicted with circles618. FIG.6Cshows a side view of dual band antenna600in a further embodiment where only reactive impedance elements611-n are present, and there are no reactive impedance elements612-n. Each transmission line613-n (see,FIG.6B) is implemented in the form of micro strip line616-n (i.e., one or more of the reactive impedance elements include a micro strip line), and dielectric substrate615is located under ground plane602such that on this substrate there are micro strip lines616-n shorted at their ends by employing metallized holes617-n. Antenna ground plane602serves as a ground plane for micro strip lines616-n, and each wire505-n passes through an opening in the dielectric substrate with the respective end connected to capacitor614-n. The other end of capacitor614-n is connected to a segment of micro strip line616-n.FIG.6Dshows a bottom view of micro strip line616-n fromFIG.6Cwhere elements614-n (e.g., elements614-1,614-2,614-3, and614-4) are arranged in a rotational symmetrical manner to vertical z-axis407, and elements616-n (e.g.,616-1,616-2,616-3, and616-4) and617-n (e.g.,617-1,617-2,617-3, and617-4) are similarly arranged on dielectric substrate615. FIG.7shows plot700of phase of reflection factor versus frequency for element611-n (as depicted inFIGS.6C and6D) where the length of line616-n is 1180 mil, the capacity of capacitor614-n is 1 pF, dielectric permeability of the substrate615is 3.2 and the height of the substrate is 31 mil. It can be seen from plot700that on LF frequencies (i.e., approximately 1200 MHz) the phase of the reflection factor is close to 180 degrees which corresponds to a shorted-circuit mode. On HF frequencies (i.e., approximately 1570 MHz) the phase of the reflection factor is approximately 0 degrees which corresponds to open-circuit conditions. In a further antenna embodiment, wires505-n can be arranged such that the wires do not protrude outside of LF patch601in the top view, and this is depicted inFIG.8Aillustrating a side view thereof. Only wire505-n (e.g.,505-1) is visible and passes through opening801-1in dielectric603and LF patch601without connecting with it. In this case, the size of ground plane602can be both greater than that of LF patch601and equal to it.FIG.8Bshows an isometric view of this embodiment where all four wires505-1,505-2,505-3, and505-4are visible, and including openings801-2,801-3, and801-4in dielectric603and in LF patch601. Another embodiment, antenna900shown inFIG.9A, includes each wire505-n (e.g.,505-1) turned in a certain angle α about vertical z-axis901-n (e.g., z-axis901-1) located in the center of segment508-n (e.g.,508-1) belonging to wire505-n. In accordance with this embodiment, the wire segments are formed to be straight in nature. The division of wire505-n into segments506-n (e.g.,506-1),507-n (e.g.,507-1) and508-n (e.g.,508-1) is shown inFIG.5B. Wires505-n are arranged in a rotational symmetrical manner to vertical z-axis407located in the antenna center.FIG.9Apresents such a structure, z-axis901-n (e.g.,901-1) is shown for the case n=1. As a variant, segments507-n (e.g.,507-1,507-2,507-3, and507-4) are formed to be bent (i.e., not straight) as illustrated inFIG.9Bshowing illustrative antenna905. In accordance with the embodiment shown inFIG.10A, the LF patch and HF patch can be circular with capacitive elements being used instead of dielectric. As shown, antenna1000has LF patch1001over ground plane1002, and HF patch1009is over LF patch. Capacitive elements of the LF band are made in the form of interdigital structure1020arranged along the perimeter of LF patch1001, and capacitive elements of the HF band are also made as interdigital structure1021along the perimeter of HF patch1009. As configured in this embodiment, an interdigital structure (e.g., interdigital structures1020and1021) is a set of wire pairs. For LF interdigital structure1020, one wire in the pair is connected to ground plane1002, and the other wire to LF patch1001. For HF interdigital structure1021, one wire in the pair is connected to LF patch1001, and the other wire to HF patch1009. FIG.10Bshows a side of view of the antenna embodiment shown inFIG.10A. The parameters of the antenna structure according to designations1025-1,1025-2,1025-3,1030-1,1030-2, and1030-3shown inFIG.10Bare as follows: L154 mm(1025-1)L271 mm(1025-2)L355 mm(1025-3)L4105 mm(1025-4)H18 mm(1030-1)H212 mm(1030-2)H310 mm(1030-3) FIGS.11A and11Bshow graphs1100and1105, respectively, reflecting experimental results of DU ratio for the antenna embodiment shown inFIG.10A. Elements with reactive impedance611-n are configured in accordance withFIGS.6C and6D. InFIG.11A, graph1100is representative of a frequency 1230 MHz (LF band). Plot1101corresponds to the presence of wires505-n, and plot1102to the absence of wires505-n. As evident fromFIG.11A, the presence of wires505-n results in a substantial reduction in DU ratio such that this ratio decreases from −8 dB up to −22 dB in the nadir direction. InFIG.11B, graph1105is representative of a frequency 1575 MHz (HF band). Plot1103corresponds to the presence of impedance elements611-n, and plot1104corresponds to the absence of impedance elements611-n and at that wires505-n are connected directly to ground plane1002. As evident fromFIG.11B, the presence of elements611-n reduces DU ratio from −8 up to −15 dB in the nadir direction. The foregoing Detailed Description is to be understood as being in every respect illustrative and exemplary, but not restrictive, and the scope of the invention disclosed herein is not to be determined from the Detailed Description, but rather from the claims as interpreted according to the full breadth permitted by the patent laws. It is to be understood that the embodiments shown and described herein are only illustrative of the principles of the present invention and that various modifications may be implemented by those skilled in the art without departing from the scope and spirit of the invention. Those skilled in the art could implement various other feature combinations without departing from the scope and spirit of the invention. | 20,330 |
RE49823 | DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention as defined by the claims and their equivalents. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention is provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their equivalents. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component surface” includes reference to one or more of such surfaces. Exemplary embodiments of the present invention provide an apparatus and method for transmitting and receiving signals in a mobile communication system. In addition, exemplary embodiments of the present invention provide an apparatus and method for allowing multiple Radio Units (RUs) to transmit/receive control channel signals in a shared way, and to transmit/receive data channel signals independently in a mobile communication system. It will be assumed herein that the mobile communication system is a 3rdGeneration Partnership Project (3GPP) Long-Term Evolution (LTE) mobile communication system. However, it will be understood by those of ordinary skill in the art that the signal transmission/reception apparatus and method proposed by the exemplary embodiments of the present invention may be used not only in the 3GPP LTE mobile communication system, but also in any other mobile communication system, such as an Institute of Electrical and Electronics Engineers (IEEE) 802.16m communication system. FIG.3schematically illustrates a configuration of a 3GPP LTE mobile communication system according to an exemplary embodiment of the present invention. Referring toFIG.3, the 3GPP LTE mobile communication system includes an evolved Node B (eNB)311, at least one, for example, 4 RUs313,315,317, and319, and at least one User Equipment (UE, not shown). The eNB311manages control channels and data channels in different ways, thereby increasing overall system capacity and making it possible to reduce the overhead caused by frequent handover of UEs. A method of managing control channels and data channels by the eNB311inFIG.3will be described below with reference toFIG.4. FIG.4schematically illustrates a method of managing control channels and data channels by the eNB311inFIG.3according to an exemplary embodiment of the present invention. Referring toFIG.4, the eNB311controls the RUs313,315,317, and319. The RUs313,315,317, and319transmit the same control channel signals in a shared way under control of the eNB311, but transmit data channel signals individually under control of the eNB311. A method of controlling transmission of control channel signals and data channel signals of the RUs313,315,317, and319by the eNB311will be described in detail below. First, a method of controlling transmission of control channel signals of the RUs313,315,317, and319by the eNB311will be described below. The eNB311controls the RUs313,315,317, and319to transmit the same control channel signals so that a specific UE may acquire a macro combining gain when receiving the control channel signals. When the RUs313,315,317, and319transmit the same control channel signals in this way, interference between control channels may not occur, so the specific UE may acquire a macro combining gain. Second, a method of controlling transmission of data channel signals of the RUs313,315,317, and319by the eNB311will be described below. The eNB311enables the RUs313,315,317, and319to transmit data channel signals independently. In other words, the eNB311controls each of the RUs313,315,317, and319to transmit data channel signals only to the UE that the RU itself has selected, thereby making it possible to multiplex data channel signals targeting different UEs during their transmission using the same frequency resources. The eNB311may determine the UE to which each of the RUs313,315,317, and319will transmit data channel signals, taking into account at least one of various parameters, such as locations of UEs, and load balancing. For example, the eNB311may control each of the RUs313,315,317, and319to transmit data channel signals to the UE located in the shortest distance. Because the RUs313,315,317, and319may multiplex data channel signals targeting different UEs during their transmission using the same frequency resources, interference may occur between data channels in the boundaries among the RUs313,315,317, and319. Therefore, an exemplary embodiment of the present invention minimizes interference between data channels in the boundaries among the RUs313,315,317, and319using an interference control method, thereby increasing capacities of UEs located in the boundaries among the RUs313,315,317, and319. As described above, because the RUs313,315,317, and319can multiplex data channel signals targeting different UEs during their transmission using the same frequency resources, their resource efficiency and system capacity are higher than those of the repeater system of the related art. An internal structure of the eNB311inFIG.3will be described below with reference toFIG.5. FIG.5illustrates an internal structure of the eNB311inFIG.3according to an exemplary embodiment of the present invention. Referring toFIG.5, the eNB311includes a Digital Unit (DU)511, which includes a control channel manager513, a data channel manager515, and a MUltipleXing (MUX) and connection unit517. The control channel manager513generates DownLink (DL) control channel signals. The control channel manager513receives scheduling information from the data channel manager515and generates DL control channel signals based on the scheduling information. The data channel manager515performs a scheduling operation, generates scheduling information corresponding to the results of the scheduling operation, and transmits the scheduling information to the control channel manager513. The data channel manager515generates DL data channel signals based on the scheduling information. The MUX and connection unit517multiplexes the DL control channel signals generated by the control channel manager513and the DL data channel signals generated by the data channel manager515, and transmits them to the RUs313,315,317, and319. Although the RUs313,315,317, and319are connected to the MUX and connection unit517in the case ofFIG.5since the configuration of the 3GPP LTE mobile communication system described inFIG.3is considered, it will be understood by those of ordinary skill in the art that the MUX and connection unit517may be connected to all RUs in the coverage area serviced by the eNB311. The MUX and connection unit517transmits UpLink (UL) data channel signals received from the RUs313,315,317, and319to the data channel manager515. The RUs313,315,317, and319perform Radio Frequency (RF) processing on the DL control channel signals and DL data channel signals transmitted by the MUX and connection unit517, and transmit them to their associated UEs. The RUs313,315,317, and319are connected to the eNB311through, for example, an optic fiber, and exchange signals with the eNB311using, for example, a Common Public Radio Interface (CPRI). Preferably, the RUs313,315,317, and319may be installed to contribute to forming strong electric fields in spatially different areas. In other words, the RUs313,315,317, and319may be installed to be spatially separated as illustrated inFIG.3, if they have, for example, omni-directional antennas. On the other hand, if the RUs313,315,317, and319have directional antennas, they may be installed in the same location. In the latter case, strong-electric field areas may be expanded by setting different bore-sights for the directional antennas. An internal structure of the control channel manager513inFIG.5will be described below with reference toFIG.6. FIG.6illustrates an internal structure of the control channel manager513inFIG.5according to an exemplary embodiment of the present invention. Referring toFIG.6, the control channel manager513includes a control channel reference signal generator611, a control channel signal generator613, and a MUX615. The control channel signal generator613generates control channel signals based on the scheduling information received from the data channel manager515. The control channels may include, for example, a Physical Broadcast Channel (PBCH), a Physical Downlink Control Channel (PDCCH), a Physical Control Format Indicator Channel (PCFICH), etc. The control channel reference signal generator611generates control channel reference signals used to demodulate control channel signals for UEs. The control channel reference signals may include, for example, cell-specific reference signals. The MUX615multiplexes the control channel reference signals generated by the control channel reference signal generator611and the control channel signals generated by the control channel signal generator613, and outputs them to the MUX and connection unit517. An internal structure of the data channel manager515inFIG.5will be described below with reference toFIG.7. FIG.7illustrates an internal structure of the data channel manager515inFIG.5according to an exemplary embodiment of the present invention. Referring toFIG.7, the data channel manager515includes a channel measurer711, a scheduler713, a channel quality receiver715, a data channel generator717, a data channel reference signal generator719, and a MUX721. The data channel manager515enables multiple RUs to transmit data channel signals to different UEs independently. In other words, the data channel manager515enables the eNB311to transmit different data channel signals to multiple UEs by reusing the same frequency resources. The data channel manager515determines UEs which are spatially separated if possible, as UEs that transmit data channel signals by reusing the same frequency resources, thereby minimizing interference between data channels. Because the data channel signals, unlike the control channel signals, are not equally transmitted by all RUs, if a UE receives the data channel signals based on only the channel estimates for the reference signals transmitted equally by all RUs, for example, for the control channel reference signals, its receive success rate may be poor. Therefore, it is preferable that each of the RUs transmits a data channel reference signal to a UE individually, to which the RU itself will transmit data channel signals so that the UE may receive the data channel signals based on a channel estimate for the data channel reference signal, or may estimate a channel for the data channel signals based on both the control channel reference signal and beamforming weight information. For convenience, it will be assumed herein that RUs transmit data channel reference signals independently, and UEs receive data channel signals based on the data channel reference signals. The data channel reference signals may include, for example, dedicated reference signals. The 3GPP LTE mobile communication system may transmit the dedicated reference signals in accordance with Transmission Mode 7 when using the Release 8 standard, and may transmit the dedicated reference signals in accordance with Transmission Mode 7 or Transmission Mode 8 when using the Release 9 standard. The channel quality receiver715receives channel quality information that each UE has measured and transmitted through the MUX and connection unit517, and transmits the received channel quality information to the scheduler713. An internal structure of the channel measurer711inFIG.7will be described below with reference toFIG.8. FIG.8illustrates an internal structure of the channel measurer711inFIG.7according to an exemplary embodiment of the present invention. Referring toFIG.8, the channel measurer711includes a plurality of, for example, 4 UE signal detectors811-1,811-2,811-3, and811-4, and a plurality of, for example, 4 channel information measurers813-1,813-2,813-3, and813-4. Signals received from RUs through the MUX and connection unit517, i.e., signals transmitted by UEs, are delivered to their associated UE signal detectors. For example, a signal received from the RU313is delivered to the UE signal detector811-1. A signal received from the RU315is delivered to the UE signal detector811-2. A signal received from the RU317is delivered to the UE signal detector811-3. A signal received from the RU319is delivered to the UE signal detector811-4. The UE signal detectors811-1,811-2,811-3, and811-4detect their associated UE signals from the signals received from the MUX and connection unit517, and output the detected UE signals to their associated channel information measurers813-1,813-2,813-3, and813-4connected thereto. In other words, the UE signal detector811-1outputs its detected UE signal to the channel information measurer813-1. The UE signal detector811-2outputs its detected UE signal to the channel information measurer813-2. The UE signal detector811-3outputs its detected UE signal to the channel information measurer813-3. The UE signal detector811-4outputs its detected UE signal to the channel information measurer813-4. The channel information measurers813-1,813-2,813-3, and813-4measure information about channels between associated UEs and RUs based on the UE signals detected by the UE signal detectors811-1,811-2,811-3, and811-4, respectively, and output the measured channel information to the scheduler713. The channel information may include channel powers and channel coefficients between associated UEs and RUs. An operation of the channel measurer711will be described in additional detail below. Signals received from RUs through the MUX and connection unit517are output to their associated UE signal detectors. The UE signal detectors, which receive Sounding Reference Signals (SRSs) that UEs have transmitted in a UL, may detect their associated UE signals based on the SRSs transmitted by the UEs, and output the detected UE signals to their associated channel information measurers. The channel information measurers measure channel information based on the UE signals detected by the UE signal detectors. An operation of the scheduler713inFIG.7will be described below with reference toFIG.9. FIG.9illustrates an operation of the scheduler713inFIG.7according to an exemplary embodiment of the present invention. Referring toFIG.9, in step911, the scheduler713calculates a scheduling metric for each unit resource based on channel qualities of UEs. The unit resource may include, for example, a sub band. In step913, the scheduler713determines a UE having the maximum scheduling metric, for each unit resource. In step915, the scheduler713calculates a scheduling metric when in addition to the UE having the maximum scheduling metric, another UE determined based on the channel quality information is additionally assigned to a unit resource, using channel information between UEs and RUs. In step917, the scheduler713additionally determines a UE having the maximum scheduling metric, for each unit resource. In step919, the scheduler713determines if the scheduling metric increases due to the additional determination of a UE. If the scheduling metric does not increase, the scheduler713finally determines the determined UEs as UEs to which it will transmit data signals using the unit resource in step921, thereby completing the scheduling operation. However, if it is determined in step919that the scheduling metric increases, the scheduler713determines the determined UEs as UEs to which it will transmit data signals using the unit resource in step923, and then returns to step915. Referring toFIG.9, the scheduler713determines a UE having the maximum scheduling metric when transmitting data channel signals using a relevant unit resource based on the channel qualities of UEs, and determines if the scheduling metric increases when transmitting data channel signals to another UE in addition to the determined UE using a related unit resource based on the channel information between UEs and RUs. If it is determined that the scheduling metric increases, the scheduler713determines the determined UEs as UEs to which it will transmit data channel signals using the unit resource, and determines again whether to additionally assign a UE to which it will transmit data channel signals using the unit resource. On the other hand, if the scheduling metric does not increase, the scheduler713finally determines the determined UEs as UEs to which it will transmit data channel signals using the unit resource, completing the scheduling operation. After completing the scheduling operation, the scheduler713outputs the scheduling information corresponding to the finally determined UEs to the data channel generator717and the control channel manager513. The scheduler713may determine only one UE or multiple UEs at the same time, for each unit resource. The scheduler713may allow one RU to transmit data channel signals to UEs, or allow multiple RUs to transmit data channel signals to UEs together. The scheduler713outputs the channel information to the data channel generator717so that the data channel generator717may determine a beamforming weight it will apply to data channels if necessary. An internal structure of the data channel generator717inFIG.7will be described below with reference toFIG.10. FIG.10illustrates an internal structure of the data channel generator717inFIG.7according to an exemplary embodiment of the present invention. Referring toFIG.10, the data channel generator717includes a beamforming weight calculator1011, an encoding/modulation/channelization processor1013, and a beamforming processor1015. The data channel generator717receives scheduling information from the scheduler713, and receives traffic data targeting a UE, which is assigned to a related unit resource based on the scheduling information, i.e., to which it will transmit data channel signals using the unit resource. The beamforming weight calculator1011generates a beamforming weight to be used for a data channel based on the scheduling information, and outputs the beamforming weight to the beamforming processor1015and the data channel reference signal generator719. The encoding/modulation/channelization processor1013performs encoding/modulation/channelization on the input traffic data, and outputs the results to the beamforming processor1015. The beamforming processor1015performs beamforming processing on the signals output from the encoding/modulation/channelization processor1013, and outputs transmission signals for RUs to the MUX721. The data channel reference signal generator719generates reference signals for data channels, i.e., data channel reference signals. The data channel reference signal generator719performs the same beamforming processing even on the data channel reference signals, using the beamforming weights output from the beamforming weight calculator1011, and outputs them to the MUX and connection unit517. Instead of generating data channel reference signals as described above, it is also possible to allow a UE to estimate a channel of data channel signals based on the control channel reference signals and beamforming weight information. In this case, the data channel reference signal generator719is allowed not to generate data channel reference signals. The MUX721multiplexes the signals output from the data channel generator717and the data channel reference signal generator719, and outputs the results to the MUX and connection unit517. An internal structure of the MUX and connection unit517inFIG.5will be described below with reference toFIG.11. FIG.11illustrates an internal structure of the MUX and connection unit517inFIG.5according to an exemplary embodiment. Referring toFIG.11, the MUX and connection unit517includes a control channel copier1111and a MUX1113. The control channel copier1111generates control channel signals for RUs by copying a control channel signal so that all RUs may transmit the same control channel signals, and then outputs them to the MUX1113for RUs individually. The MUX1113receives the signals output from the control channel copier1111and the data channel signals generated for RUs by the data channel manager515, multiplexes them for RUs individually, and transmits the results to the associated RUs. The MUX1113outputs the signals that RUs have received from UEs, to the data channel manager515. Although not illustrated in separate drawings, each of RUs may include a transmitter for transmitting various signals, a receiver for receiving various signals, and a controller for controlling operations of the transmitter and the receiver. The transmitter, the receiver and the controller may be realized as separate units, or integrated in a single unit. Likewise, a UE may include a transmitter for transmitting various signals, a receiver for receiving various signals, a controller for controlling operations of the transmitter and the receiver, and an estimator for estimating various signals. The transmitter, the receiver, the controller and the estimator may be realized as separate units, or integrated in a single unit. As is apparent from the foregoing description, the exemplary embodiments of the present invention allow multiple RUs to transmit control channel signals in the same way, and to transmit data channel signals independently, thereby contributing to an increase in the capacity of UEs and a reduction in the outage probability, and preventing overhead due to the frequent handover of UEs. While the invention has been shown and described below with reference to certain exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents. | 22,863 |
RE49824 | DESCRIPTION OF EXAMPLE EMBODIMENTS Overview In one embodiment, a server or other computing device manages meetings in a virtual meeting room on behalf of a virtual meeting room owner. A request is received from an attendee to join a meeting in the virtual meeting room. A determination is made, based on configurations set by the virtual meeting room owner, whether to connect the attendee to a virtual waiting room. The attendee is connected to the virtual waiting room in accordance with the configurations set by the virtual meeting room owner. Example Embodiments Presented herein are embodiments for a virtual waiting room. The virtual waiting room allows a single virtual meeting room to be used for adjacent meetings while avoiding the problem of participants of the second meeting inadvertently joining an earlier meeting that is running beyond its planned end time. Often when attendees join early it results in an unintentional barge-in on the previous meeting. The virtual waiting room may also be used when virtual meeting room is not already in use, but the host or meeting room owner has not yet logged into the virtual meeting room. The virtual waiting room allows meeting participants to be collected until the meeting room owner is available to join the meeting. The virtual waiting room involves the allocation of resources to support some connectivity state with respect to the joining attendees. There is a range of functions that may be provided by the virtual waiting room, as described below. It is appreciated that as more functions are provided in the virtual waiting room, more computing/connectivity resources of a meeting server/video conference bridge would be needed. It is advantageous to keep the virtual waiting room simple to use but have (optionally) available all the modes of interactions familiar from real-world waiting rooms. More specifically, presented herein are embodiments for the waiting room to become ready for attendees/invitees, for waiting room attendees to interact with each other while in the virtual waiting room, and for meeting room owner interactions with the virtual waiting room interactions. In one form, the virtual meeting room may be supported by web-based meeting resources dedicated to a particular user, called the virtual meeting room owner. In this case, the virtual meeting room is accessed via web-based resources, and there is a universal resource link (URL) uniquely dedicated to a particular user who is the virtual meeting room owner. The virtual meeting room is said to be a personal or private virtual meeting room. In another form, the virtual meeting room may be supported by video conference bridge resources dedicated to a particular user. In this case, the virtual meeting room is a personal video conference bridge number uniquely dedicated to a particular user who is the virtual meeting room owner, and the virtual meeting room is accessed via video conference bridge resources. In either case, whether a web-based meeting resources or video conference bridge resources, essentially a single resource is allocated to an “owner” or “host” and to access it attendees need to simply enter or click on a URL, e.g., https://www.webserviceprovider.com/join/meeting_room_owner_name, or by dialing or entering a video conference bridge number (or perhaps entering a PIN). Referring first toFIG.1, a high level diagram is shown of a system10that supports the virtual waiting room embodiments presented here. The system includes a server20that communicates, via network30, with a plurality of user devices40(1)-40(N). Each user device40(1)-40(N) runs a meeting client application42(1)-42(N), respectively. The user devices40(1)-40(N) may take on a variety of forms, including, without limitation, a desktop computer, a laptop computer, a smartphone, a tablet computer, a thin client device, a dedicated video terminal, etc. Each user device may further include a video camera44, a microphone46and a loudspeaker48. Moreover, each user device may include a physical keyboard or software keyboard and mouse/pointing device or feature. For simplicity, these components are shown only on user device40(1), though it is to be understood that user devices40(2)-40(N) may also include these components. In still another example, a user device may be a video conference endpoint having an integrated camera and microphone. The meeting client applications42(1)-42(N) may be a browser application (with any suitable plug-in software), a smartphone application, a tablet application, or a hosted virtual desktop application running in a data center (cloud computing environment) on behalf of a thin client device. The network30may include any combination of a wired wide area network, wireless wide area network, wired local area network, wireless local area network, etc. The server20executes software to support virtual meeting rooms or a personal video conference bridge to which users can connect via their respective user devices40(1)-40(N). The virtual meetings may include audio and/or video of the respective users, as well as shared content (documents, data, audio, and video) among a plurality of user participants during a meeting. A given user may be assigned his own personal virtual meeting room such that any meeting he/she scheduled is conducted in that personal meeting room. He/she is said to be the owner of his/her personal meeting room. The term “host” also corresponds to the meeting room owner in this context. A user can personalize his/her virtual personal meeting room with various attributes. In accordance with embodiments presented herein, the server20may support both a virtual meeting room pictorially represented at reference numeral50and a virtual waiting room pictorially represented at reference numeral60for a virtual meeting room owner. For example, the virtual meeting room50may be associated with the URL https://www.webserviceprovider.com/join/meeting_room_owner_name, or with a particular video conference bridge number (a sequence of numbers of a predetermined length, e.g., 556323411). As explained further hereinafter, the server20instantiates a virtual waiting room for a meeting room owner when attendees for a next meeting hosted by the meeting owner connect to the server to join the next meeting when there is a meeting still in progress in the virtual meeting room, or when there is no in-progress meeting but the owner has not yet connected to server to open the virtual meeting room. The server20also communicates, via network30, with a calendar server70and an enterprise organization directory80. The calendar server70maintains schedules for users, including scheduling of virtual meetings supported by the meeting server20. The enterprise organization directory80stores data for users in an enterprise organization and relationships between users, e.g., corporate organizational hierarchy. The server20may be a meeting server that manages the operations of web-based meetings, or a video conference bridge that manages operations of video conferences (which can also support content sharing and other features that are available in web-based meetings). Reference is now made toFIG.2.FIG.2shows an example user interface (UI) screen for a first meeting, called an existing meeting, shown at reference numeral100. The UI100for the existing meeting includes allocated regions for video for the various meeting participants, including a region102for video for the meeting host, region104for video for attendee1and region106for attendee2. In addition, there is a region108for a participant to share content. For example, a meeting attendee may share content at any given time during the virtual meeting. For purposes of explanation, the first meeting, meeting1, is from 1-2 pm and a second meeting, meeting2, is planned for 2-3 pm. The virtual meeting room is not scheduled, rather it is dedicated to the meeting room owner. However, the meeting room owner typically notifies attendees of the planned meeting time and meeting room identifier (e.g., a universal resource locator) for joining purposes. The meeting room may have no awareness of the identification of invitees. Operation is as follows. The meeting room owner enters the virtual meeting room for meeting1. Any participants can join the virtual meeting room once the owner enters the meeting room, that is, once the owner logs into the meeting room. At some point towards the end of meeting1, the behavior of the room changes. From this time on, new attendees do not enter the virtual meeting room (even though the owner is in the room). This is because such attendees that join typically towards the very end of a meeting are connecting for the next meeting, and not for the existing meeting. Thus, attendees attempting to join at this point forward are staged in a “virtual waiting room” and the owner may signaled that people are waiting for the next meeting.FIG.2shows at reference numeral120, in dotted line, the meeting room for meeting2, yet to be started. This is for illustration purposes only. If attendees for meeting2join while meeting1is still in-progress (towards the end of meeting1), the virtual waiting room will be instantiated and the attendees for meeting2are connected into the virtual waiting room according to configurations set by the meeting room owner. The virtual meeting room operation changes as it approaches a “meeting boundary”—the time when one meeting ends and the other begins. After a meeting has lasted for some minimum time with the room owner and at least one other attendee, the waiting room is enabled to be opened, either automatically or manually. There are several ways to mark this boundary time, as described below. Reference is now made toFIG.3.FIG.3illustrates a flow chart for a configuration process200by which the meeting room owner may set configurations for instantiating a virtual waiting room associated with his/her virtual meeting room. The process200may be performed at any time so that the meeting room owner can make changes/updates to the configurations for the virtual waiting room. At210, it is determined whether the meeting room owner wishes to manually trigger the virtual waiting room when needed. If manual instantiation of the virtual waiting room is desired by the meeting room owner, then at210, the meeting server will display a trigger button or other user interface element that is displayed to the meeting room owner when attendees to the next meeting join towards the end of an existing meeting that is still in-progress. Otherwise, the process continues to215. With the manual instantiation of the virtual waiting room, the room owner could realize that the second meeting will be starting soon and set an “open waiting room” indication so that the waiting room will be used for any attendees that join the virtual meeting room from that time onward. An explicit notification informs attendees to wait and they will be automatically entered into the meeting room (from the virtual waiting room) when the previous meeting ends. They do not have to retry to join the second meeting. At215, the meeting room owner is given the option of having the waiting room automatically open X (e.g., 5) minutes before the start of a planned meeting. The meeting room owner can select the value for X, and this information is stored at220by the meeting server. With this configuration, the virtual waiting room automatically opens X minutes before the start of the planned meeting and any attendees that join the meeting room from that point onward are directed into the virtual waiting room. At225, if the meeting room owner does not choose the option at215, the option is presented to the meeting room owner to automatically open the waiting room X minutes before typical meeting start times, e.g., on the hour or half-hour. At230, if this option is selected, information is stored by the server. Thus, at225and230, the meeting room operation may change at the times that meeting conventionally end (typically the end of the hour or half hour—controlled by a user setting). The waiting room automatically opens a pre-specified number of minutes before this time. If the meeting room owner does not choose option225, then at235, the option is presented to set a desired/predetermined waiting room open time. This may be set for a specific planned meeting on an ad hoc basis when the meeting room owner sends out an invite for a meeting. At240, the server receives the predetermined time from the meeting room owner at which to open the waiting room, and stores this information. This could be integrated with an existing calendar scheduler. The meeting room uses a pre-specified time before the time of next meeting to automatically open the waiting room for attendees. Once the existing meeting (meeting1) ends (e.g., 3 minutes after 2 pm) and people in that meeting have exited the room, the room owner can signal the server to let the people in the virtual waiting room enter virtual meeting room for the next meeting (meeting2). They enter as usual and the next meeting starts. If an attendee from meeting1is also invited to meeting2he or she can simply stay in the room as the owner admits people from the waiting room to start meeting. FIG.4Aillustrates, at reference numeral250, an example user interface element and notification presented to the meeting room owner, in accordance with the configuration set at step210inFIG.3. The notification and user interface button are presented to the meeting room owner only during an existing meeting, and includes text to explain that there are attendees waiting for the next meeting, and that the meeting room owner can click a button to open the virtual waiting room so that those attendees/invitees who are waiting can be connected to the virtual waiting room. In other words, analogous to a real meeting room, the notification at250informs the meeting room owner that there are one or more invitees who have requested to enter the room, but have not been allowed to enter yet. In another example, the virtual waiting room may be automatically opened (auto-starts) as people attempt to join the main meeting room, in which case the meeting room owner/host is notified appropriately. Still another virtual waiting room option that can be used to determine the virtual waiting room experience for attendees and the meeting room owner, is based on whether there is access to the list of invitees to the next meeting for which the virtual waiting room may be needed. If the server has access to the names/identifiers of the invitees for the next meeting, then those persons may be handled differently in terms of their access to the virtual waiting room. For example, persons who were on the original list of invitees set up by the meeting room owner may be automatically put into the virtual waiting room when they join and an existing meeting is in process in the meeting room. Conversely, persons who were not on the original list of invitees but obtain the invitation (perhaps forwarded from an invitee on the original list) do not get automatically directed into the virtual waiting room. They simply are notified that the meeting room is not available, and are advised to attempt to log in again later. In still another example, if an invitee is invited to both the current meeting (but has not joined it yet) and the next meeting, the invitee is admitted to the current meeting. As still a further variation, certain attendees who have a predetermined position within an organization or predetermined relationship to the meeting owner or to other attendees of a meeting may be handled differently in terms of their access to the virtual meeting room. For example, if a person who is in the senior leadership of an organization or the “boss” of the meeting owner joins a meeting room while another meeting is in-progress, the meeting server would recognize the importance of such persons and automatically place them in the virtual meeting room, and present a notification (audio or text) only to the meeting room owner in the existing meeting, the notification indicating that persons of high importance (perhaps including their names) have joined and are in the virtual waiting room. FIG.4Billustrates an example notification260that may be presented to the meeting room owner when a senior executive or the meeting room owner's “boss” has joined for the next meeting. The notification indicates the name of the person who has joined and his/her title or relationship to the meeting room owner, and also indicates that person has been sent the virtual waiting room, waiting for the start of the next meeting. This will alert the meeting room owner to finish the existing meeting promptly so that he/she does not keep the important person waiting too long in the virtual waiting room. It should be understood that the virtual waiting room embodiments presented herein may be useful when the virtual meeting room owner has not yet connected to the virtual meeting room, not just because he/she is in another meeting in the virtual meeting room. For example, the virtual meeting room owner may be away from his user device, in another meeting outside of his/her virtual meeting room, etc. FIG.5illustrates a flow chart for a method300performed by the server that manages meetings in a virtual meeting room on behalf of a virtual meeting room owner (host). In particular, the method300involves operations performed by the server in determining whether persons are connected into a virtual waiting room when they join for a meeting in the virtual meeting room either at a time when another meeting is in progress in the virtual meeting room or when the virtual meeting room owner has not joined the meeting for other reasons. At310, a request is received from an attendee to join a meeting in the virtual meeting room. At320, the meeting server determines, based on configurations set by the virtual meeting room owner, whether to connect the attendee to a virtual waiting room. At330, the server connects the attendee to the virtual waiting room in accordance with the configurations set by the virtual meeting room owner. If the attendee request to connect to the virtual meeting room/waiting room is denied, a notification would be presented to the attendee (e.g., “Your Request to Enter the Meeting Room is Denied.”) The operations of the virtual waiting room can vary according to tradeoffs between resource consumption and waiting experience. Reference is now made toFIG.6.FIG.6illustrates a flow chart400that depicts the various operations that are possible in the virtual waiting room, and which may be configurable by the virtual meeting room owner. The process starts at410where the virtual meeting room owner sets the capabilities of the virtual waiting room. At420, a configuration can be set in which a simple text and/or audio message is played out to the invitees/attendees in the virtual waiting room. The message may be as simple as “Your meeting will start once the host joins. Please wait here in the virtual waiting room. Thank you.” The video message may be of the meeting room owner. FIG.7Ashows an example of a text message displayed to users who are connected to a virtual waiting room. The message, shown at reference numeral500, may simply state: “The host/meeting room owner is not yet available. Please wait.” In addition to or instead of a text message, the meeting server may play out an audio or video message explaining that the room owner is not yet available, either because he/she is finishing a previous meeting or because he/she is away and has not connected to the system yet. That message may be repeated to ensure the attendees realize they should wait. The waiting attendees have no way to interact with each other. At430, a configuration can be set in which a video program/segment is played to those in the virtual waiting room. FIG.7Bshows a video program510may be played out to the attendees. The video program may be an advertisement promoting a product or service, an instruction video, a company video memorandum, etc. The text message500indicating that the attendees should wait, may also be presented. Again, the waiting attendees have no way to interact with each other in this example. At440, a configuration may be set to display a roster/list of the attendees/invitees who are in the virtual waiting room. This may be useful so that people can see who else has already joined a planned meeting and is waiting in the virtual waiting room. FIG.7Cillustrates a list or roster of attendees/invitees who are in the virtual meeting room is shown. The list or roster, shown at reference numeral520, is displayed to the attendees so each attendee knows who else has already joined the meeting. The meeting room owner/host's name is shown in italics to indicate that he/she has not yet joined. The attendees may or may not have the ability to interact with each other. For example, the attendees may have the ability to chat with each other, as shown at reference numeral525. At450, a configuration may be set to enable full (audio, video and content sharing) interaction between attendees in the virtual waiting room while waiting for the meeting owner to end a meeting in-progress in the virtual meeting room. This allows the persons who are connected to the virtual waiting room to begin conducting business amongst themselves. Once the meeting room owner joins, all of the attendees in the virtual waiting room are seamlessly moved into the virtual meeting room, with all functions (recording, content sharing, video, audio) that were ongoing on the virtual waiting room continuing, uninterrupted, in the virtual meeting room. FIG.7Dillustrates a version of the virtual waiting room in which full audio, video and content sharing interaction is enabled among attendees. Icons may be presented next to each attendee's name in the roster520to indicate who is speaking at any moment. There is a shared content window530that allows any attendee to share content for viewing by other attendees. In addition, video from each of the attendees may be presented, as shown at reference numerals540(1)-540(4). Thus,FIG.7Dillustrates an example in which the waiting attendees may be placed in a virtual waiting room that has all the capabilities of the virtual meeting room—they can see, and hear each other for example. A splash screen and an on-screen reminder may be presented to explain that the meeting has not yet started but attendees can interact as they would expect in a virtual meeting room. Any combination of the configurations shown inFIG.7A-7Dmay be possible. In all of the configurations described herein, once the virtual meeting room owner joins the meeting (either by ending the prior meeting in the virtual meeting room or logging in to the meeting server and starting the planned meeting), the virtual waiting room is at that point closed so that anyone else who joins the meeting will join the virtual meeting room. In all these virtual waiting room capabilities examples, waiting attendees are signaled that the room owner is not yet available and they should wait. The server may also notify the room owner, in an in-progress meeting, that attendees for the next meeting are waiting. In accordance with the embodiments described herein in connection withFIGS.1-7A-7D, attendees are automatically directed into the virtual waiting room, according to configurations set by the meeting room owner, or according to default configurations. The meeting room owner does not have to make decisions about referring attendees to the waiting room, etc. The meeting room owner may be notified that there are waiting attendees but does not have to act on that information. This simplifies use of the meeting room and avoids unnecessary meeting interruptions, particularly when a meeting room owner has back-to-back meetings. Reference is now made toFIGS.8and9A-9Dfor examples of interactions between the meeting room owner and a waiting attendee. Referring first toFIG.8, in this example, virtual meeting room100includes attendee video102and104and shared content108. At reference numeral550is a textual notification to the meeting owner indicating that there are other attendees for the next meeting in the virtual waiting room. The names of the attendees in the virtual waiting room may also be included in the textual notification550. There is no direct interaction between the meeting room owner and the waiting attendees in this example. The meeting room owner is only notified that there are waiting attendees, and possibly their identities. The meeting room owner/host may be notified that people are arriving and waiting by a second active presence screen on their display. The host may also prompted to message the attendees with an expected start time (like “running over, meeting starting in 2 minutes”). This can be implemented using an Extensible Messaging and Presence Protocol (XMPP) messaging infrastructure. The host may be presented with a user interface control, shown at reference numeral560, to bring attendees in the virtual waiting room into the virtual meeting room which results in the temporary virtual meeting room resources being returned to the system. FIGS.9A-9Dillustrate progressively more complex scenarios for interactions between a meeting room owner and a waiting attendee.FIG.9Aillustrates an example in which a virtual meeting room owner Tom is conducting a meeting with Charles. The meeting room600includes video of Charles shown at610, and Tom's shared content (white-board, documents, slides, etc.)620. During this meeting in virtual meeting room600, a new meeting attendee Bob arrives. Since Tom is still in a meeting with Charles, Bob is automatically put into a virtual waiting room, according to any of the embodiments described above in connection withFIGS.1-7D. Video for Bob, shown at reference numeral630, is presented to Tom. Only Tom, the meeting room owner, sees the video of Bob. Tom can signal to Bob that he is still in another meeting (with Charles), and asks Bob to wait. For example, Tom may send a chat message, click a button (shown at640) that will cause the meeting server to notify Bob that Tom is still in a meeting, etc. The notification to Tom that Bob has joined can have a quick reply option with one or more pre-established (“canned”) responses that can be selected. FIG.9Billustrates a scenario similar toFIG.9Abut taken a step further. In this scenario, the meeting room owner Tom asks the meeting attendee Charles to hold for a moment. Tom then clicks a button650that causes the meeting server to switch to a full voice and video conversation with Bob (who is in the virtual waiting room). The meeting room owner Tom and attendee Bob briefly interact via voice and video. By clicking the button again, Tom returns to the meeting room with Charles and Bob stays in the virtual waiting room. When Tom ends the meeting with Charles, Bob is admitted to the meeting room with Tom. FIGS.9C and9Dillustrate a scenario similar toFIG.8B, but taken still further. At some point after the meeting room owner Tom interacts with Bob via voice and video, by clicking the button650and clicking the button650again to return to the meeting with Charles, the meeting room owner Tom decides that Bob should be admitted/added to the in-progress meeting with Charles. To add/admit Bob to the meeting, the meeting room owner Tom clicks another button660. When this happens, Bob is added to the in-progress meeting and an example of the user interface that Tom sees is shown inFIG.9D. Bob is moved from the virtual waiting room and added to the virtual meeting room with any other attendee already in the virtual meeting room. The meeting room owner Tom, attendee Charles and attendee Bob can all interact with each other in the virtual meeting room. Once Bob is added to the virtual meeting room, and assuming there is nobody else in the virtual waiting room, the virtual waiting room can be closed and the resources for the virtual waiting room can be released. When the virtual waiting room concepts are applied to a video conference bridge, the virtual waiting room is a temporary waiting bridge for users who are joining a video conference bridge before the allocated start time or before the host/bridge owner is ready for them to join. Furthermore, the participants and host would be provided with feedback mechanisms to make the waiting user experience and comfortable, natural and productive as possible as described above in connection withFIGS.3-7D. Like the virtual waiting room, the temporary waiting bridge is supported by a secondary pool of bridge resources made available and allocated ahead of meeting start times (say within 5 minutes), as described above. Moreover, like the examples described above, an ‘early condition’ is set on the server if the video conference bridge is already in use and new attendees, not in the current meeting are attempting to join. The early condition can exceed the end time of the previous meeting in the case of a meeting overrun. This caters for the case where attendees join on time or late but the previous meeting is still running. While in this mode attendees who join ahead of the host being ready for the next meeting are temporarily hosted on the temporary allocated bridge resource. To summarize, embodiments are presented herein to prevent next meeting attendees from inadvertently barging into an in-progress meeting in a virtual meeting room. A visual feedback is presented to attendees to show that the virtual meeting room/video conference bridge is currently in use and that they are in a holding place, i.e., a virtual meeting room or temporary conference bridge. A visual feedback may be presented to the host/owner to show that people are gathering or in place for the next meeting. A mechanism may be provided to allow the host to indicate to newly arriving attendees that the meeting will begin shortly. A meeting can start more naturally without awkward interruptions in a previous meeting. FIG.10illustrates a block diagram of the server20, according to an example embodiment. The server20may take the form of an application running in a data center or cloud computing environment. The server20includes one or more processors700, a network interface unit710and a memory720. The processor700may be a microprocessor or microcontroller, or several instances of such devices. The network interface unit710may include one or more network interface cards that enable network connectivity for the server20. The memory may720may include read only memory (ROM), random access memory (RAM), magnetic disk storage media devices, optical storage media devices, flash memory devices, electrical, optical, or other physically tangible (i.e., non-transitory) memory storage devices. Thus, in general, the memory720may comprise one or more tangible (non-transitory) computer readable storage media (e.g., memory device(s)) encoded with software or firmware that comprises computer executable instructions. To this end, the memory720stores instructions for meeting room control software730, which in turn includes instructions for virtual waiting room control software740and virtual waiting room configuration information750indicating default configurations as well as configurations set by a meeting room owner. When processor(s)700execute the meeting room control software730, the processor(s)700perform the operations described above in connection withFIGS.1-9D. The above description is intended by way of example only. Various modifications and structural changes may be made therein without departing from the scope of the concepts described herein and within the scope and range of equivalents of the claims. | 31,907 |
RE49825 | DETAILED DESCRIPTION Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. If a plurality of definitions for a term exist herein, those in this section prevail unless stated otherwise. “Alkyl,” by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. The term “alkyl” is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms (C1-C20alkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (C1-C10alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (C1-C6alkyl). The term ‘cyclic monovalent hydrocarbon radical” also includes multicyclic hydrocarbon ring systems having a single radical and between 3 and 12 carbon atoms. Exemplary multicyclic cycloalkyl rings include, for example, norbornyl, pinyl, and adamantly. “Alkanyl,” by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like. “Alkenyl,” by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. “Alkynyl,” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. “Aryl,” by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. In some embodiments, an aryl group comprises from 6 to 20 carbon atoms (C6-C20aryl). In other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C6-C15aryl). In still other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C6-C10aryl). “Arylalkyl,” by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl group as, as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. In some embodiments, an arylalkyl group is (C6-C30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C10) alkyl and the aryl moiety is (C6-C20) aryl. In other embodiments, an arylalkyl group is (C6-C20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) alkyl and the aryl moiety is (C6-C12) aryl. In still other embodiments, an arylalkyl group is (C6-C15) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C5) alkyl and the aryl moiety is (C6-C10) aryl. “Compounds” refers to compounds encompassed by structural formulae disclosed herein and includes any specific compounds within these formulae whose structure is disclosed herein. Compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to,2H,3H,13C,14C,15N,18O,17O, etc. Compounds may exist in unsolvated or unhydrated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention. Further, it should be understood, when partial structures of the compounds are illustrated, that brackets indicate the point of attachment of the partial structure to the rest of the molecule. “Halo,” by itself or as part of another substituent refers to a radical —F, —Cl, —Br or —I. “Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” by themselves or as part of other substituents, refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms), are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups which can replace the carbon atoms include, but are not limited to, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)2—, —S(O)NH—, —S(O)2NH— and the like and combinations thereof. The heteroatoms or heteroatomic groups may be placed at any interior position of the alkyl, alkenyl or alkynyl groups. Typical heteroatomic groups which can be included in these groups include, but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR501R502—, ═N—N═, —N═N—, —N═N—NR503R404, —PR505—, —P(O)2—, —POR506—, —O—P(O)2—, —SO—, —SO2—, —SnR507R508— and the like, where R501, R502, R503, R504, R505, R506, R507and R508are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. “Heteroaryl,” by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring systems, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, the heteroaryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, the heteroaryl group comprises from 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine. “Heteroarylalkyl” by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used. In some embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and the heteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments, the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl. “Parent Aromatic Ring System” refers to an unsaturated cyclic or polycyclic ring system having a conjugated it electron system. Specifically included within the definition of “parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. “Parent Heteroaromatic Ring System” refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of “parent heteroaromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and the like. “Preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). The application of a therapeutic for preventing or prevention of a disease or disorder is known as ‘prophylaxis.’ In some embodiments, the compounds provided herein provide superior prophylaxis because of lower long term side effects over long time periods. “Salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. “Substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s). Substituent groups useful for substituting saturated carbon atoms in the specified group or radical include, but are not limited to —Ra, halo, —O−, ═O, —ORb, —SRb, —S—, ═S, —NRcRc, ═NRb, ═N—ORb, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N—ORb, —N—NRcRc, —NRbS(O)2Rb, ═N2, —N3, —S(O)2Rb, —S(O)2NRbRb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —OS(O)2NRcNRc, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(O)NRb—ORb—C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(O)NRcRc, —OC(NCN)NRcRc—OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(NCN)ORb, —NRbS(O)2NRcRc, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(S)NRcRc, —NRbC(S)NRbC(O)Ra, —NRbS(O)2ORb, —NRbS(O)2Rb, —NRbC(NCN)NRcRc, —NRbC(NRb)Rband —NRbC(NRb)NRcRc, where Rais independently alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each Rbis independently hydrogen, Ra, substituted alkyl, substituted heteroalkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl and substituted heteroarylalkyl; and each Rcis independently Rbor alternatively, the two Rcs are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl or a cycloheteroalkyl fused with an aryl group which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S. As specific examples, —NRcRcis meant to include —NH2, —NH-alkyl, N-pyrrolidinyl and N-morpholinyl. Similarly, substituent groups useful for substituting unsaturated carbon atoms in the specified group or radical include, but are not limited to, —Ra, halo, —O−, —ORb, —SRb, —S−, —NRcRc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2Rb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —OC(O)NRcRc, —OS(O)2NRcNRc, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, NRbS(O)2ORa, —NRbS(O)2Ra, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rband —NRbC(NRb)NRcRc, where Ra, Rband Rcare as previously defined. Substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, —Ra, —O−, —ORb, —SRb, —S—, —NRcRc, trihalomethyl, —CF3, —CN, —NO, —NO2, —S(O)2Rb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rband —NRbC(NRb)NRcRc, where Ra, Rband Rcare as previously defined. Substituent groups from the above lists useful for substituting other specified groups or atoms will be apparent to those of skill in the art. The substituents used to substitute a specified group can be further substituted, typically with one or more of the same or different groups selected from the various groups specified above. Compounds The present invention provides novel piperdinyl nociceptin receptor ligands useful in the treatment of neurological diseases and conditions where such ligands mediate the negative effects of the condition. Such neurological diseases and conditions include, for example, acute and chronic pain, substance abuse/dependence, alcohol addiction, anxiety, depression, sleep disorders, gastrointestinal disorders, renal disorders, cardiovascular disorders, and Parkinson's disease. In some embodiments, a compound of structural formula (I) is provided: or salts, hydrates or solvates thereof where A is B is hydrogen; or alternatively, A and B are absent and the carbon atom to which they are attached is the carbon atom adjacent to the amide carbonyl atom in R1and R2together with the carbon atoms to which they are attached form aryl, substituted aryl, heteroaryl or substituted heteroaryl; X is hydrogen, —C═NOR4, —C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y is hydrogen, —C═NOR7, —C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; T is ═NR10; =CR11R12—, —NR13R14—, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R3is hydrogen, alkyl, substituted alkyl, aryl substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; provided that R3is not hydrogen or methyl when R1and R2form a phenyl ring and L is R4is hydrogen, alkyl or substituted alkyl; R5is hydrogen, alkyl or substituted alkyl; R6is hydrogen, alkyl, substituted alkyl or OR15; R7is hydrogen, alkyl or substituted alkyl; R8and R9are independently hydrogen, alkyl or substituted alkyl; R10is hydrogen, alkyl, substituted alkyl, —OR16or —NR17R18; R11is hydrogen, alkyl, substituted alkyl, —C(O)R19or —CN; R12is hydrogen, —C(O)R20, or —CN; R13is hydrogen or —C(O)R21; R14is hydrogen or —C(O)R22; provided that both R13and R14are not both hydrogen; R15is hydrogen, alkyl or substituted alkyl R16is hydrogen, alkyl or substituted alkyl; R17is hydrogen or —C(O)R23; R18is hydrogen or —C(O)R24; R19and R20are independently —NR25R26, —OR27, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R21and R22are independently —NR28R29, —OR30, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R23and R24are independently alkyl or substituted alkyl; R25, R26, R27, R28, R29and R30are independently, hydrogen, alkyl or substituted alkyl; and L is (C3-C8) cycloalkyl, (C3-C8) substituted cycloalkyl, (C3-C5) cycloheteroalkyl, (C3-C8) substituted cycloheteroalkyl, In some embodiments, R1and R2together with the carbon atoms to which they are attached form phenyl, substituted phenyl, pyridyl or substituted pyridyl. In some embodiments, L is (C3-C8) cycloalkyl, (C3-C8) substituted cycloalkyl or (C3-C8) cycloheteroalkyl. In other embodiments, L is n is 0, 1 or 2, K is —NR31— or —O— and R31is hydrogen, alkyl or substituted alkyl. In still other embodiments, L is a substituted cyclohexyl group. In still other embodiments, L is wherein Z is alkyl, substituted alkyl aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and U is hydrogen, alkyl or absent. In still other embodiments, Z is alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl. In still other embodiments, Z is and U is hydrogen. In still other embodiments, Z is methyl and U is methyl. In still other embodiments, Z is and U is absent. In some embodiments, A is In other embodiments, R1and R2form phenyl, substituted phenyl, pyridyl or substituted pyridyl. In still other embodiments, a compound of structural formula (II) is provided: where D is —CH— or —N—, R32is alkyl, halo, —OR33, —NHR34, —CF3or —CN; n is an integer between 0 and 4; R33is hydrogen, alkyl, —(CO)NR35R36or —SO2NR37R38; and R34, R35, R36, R37and R38are independently hydrogen or alkyl. In still other embodiments, X is hydrogen, —C═NOR4, —C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl or substituted heteroalkyl; and Y is hydrogen, —C═NOR7, —C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl or substituted heteroalkyl. In still other embodiments, X is hydrogen; and Y is —C═NOR7, —C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl or substituted heteroalkyl. In still other embodiments, X is —C═NOR4, —C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl or substituted heteroalkyl; and Y is hydrogen. In still other embodiments, X is —C═NOR4, —C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl; and Y is —C═NOR7, —C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl or substituted heteroalkyl. In some embodiments, A is In other embodiments, R1and R2form phenyl, substituted phenyl, pyridyl or substituted pyridyl. In still other embodiments, a compound of structural formula (III) is provided: where E is —CH— or —N—, R39is alkyl, halo, —OR40, —NHR41, —CF3or —CN; o is an integer between 0 and 4; R40is hydrogen, alkyl, —(CO)NR42R43or —SO2NR44R45; and R41, R42, R43, R44and R45are independently hydrogen or alkyl. In some embodiments, A and B are absent and the carbon atom to which they are attached is the carbon atom adjacent to the amide carbonyl atom in In other embodiments, R1and R2form phenyl, substituted phenyl, pyridyl or substituted pyridyl. In still other embodiments, a compound of structural Formula (IV) is provided: wherein J is —CH— or —N—, R46is alkyl, halo, —OR47, —NHR48, —CF3or —CN; p is an integer between 0 and 4; R47is hydrogen, alkyl, —(CO)NR49R50, —SO2NR51R52; and R48, R49, R50, R51and R52are independently hydrogen or alkyl. Table 1 illustrates compounds of structural formula (II). In some embodiments, the 1,4-substituents on the cyclohexyl ring are cis to each other. TABLE 1NoStructure*IUPAC NameNMR (300 or 400 MHz) or TLC1(E/Z)-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-2-carbaldehyde oxime1H NMR (CDCl3) δ 10.7 (br, 1H), 8.70 (s, 1H), 7.59 (m, 2H), 7.18 (t, J = 5.7 Hz, 1H), 7.07 (t, J = 5.7 Hz, 1H), 6.83 (s, 1H), 4.89 (m, 1H), 3.24 (d, J = 8.4 Hz, 2H), 2.65 (dq, J = 9.6, 2.1 Hz, 2H), 2.45 (m, 1H), 2.31 (t, J = 8.7 Hz, 2H), 1.56-1.93 (m, 9H), 1.43 (m, 2H), 1.19 (m, 1H), 0.94 (d, J = 4.8 Hz, 6H)2(E/Z)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-2-carbaldehyde O-methyl oxime1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 5.04 (m, 1H), 4.00 (s, 3H), 3.20 (d, J = 11.2 Hz, 2H), 2.57 (dq, J = 12.4, 4.0 Hz, 2H), 2.35 (m, 1H), 2.20 (t, J = 11.2 Hz, 2H), 1.91 (d, J = 10.8 Hz, 2H), 1.79- 1.52 (m, 7H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)31-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-2-yl) methanamine1H NMR (CDCl3) δ 7.64 (d, J = 6.3 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 7.14 (dt, J = 5.4, 0.9 Hz, 1H), 7.06 (dt, J = 5.4, 0.9 Hz, 1H), 6.38 (s, 1H), 4.25 (m, 1H), 4.04 (s, 2H), 3.20 (d, J = 9.0 Hz, 2H), 2.61 (dq, J = 7.2, 1.8 Hz, 2H), 2.36 (m, 1H), 2.24, (t, J = 8.4 Hz, 2H), 1.87 (dd, J = 9.3, 1.5 Hz, 2H), 1.50-1.80 (m, 8H), 1.42 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 4.8 Hz, 6H)41-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)-N- methylmethanamine1H NMR (CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.13 (dt, J = 8.4, 1.4 Hz, 1H), 7.05 (m, 1H), 6.36 (s, 1H), 4.34 (m, 1H), 3.89 (s, 2H), 3.20 (d, J = 11.7 Hz, 2H), 2.62 (m, 2H), 2.49 (s, 3H), 2.36 (m, 1H), 2.22 (t, J = 11.7 Hz, 2H), 1.85 (d, J = 11.7 Hz, 2H), 1.80-1.35 (m, 10H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)5(5-fluoro)-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl) methanamine1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 9.2, 4.0 Hz, 1H), 7.19 (dd, J = 9.2, 2.4 Hz, 1H), 6.88 (td, J = 9.2, 2.4 Hz, 1H), 6.33 (s, 1H), 4.23 (m, 1H), 4.02 (s, 2H), 3.19 (d, J = 11.6 Hz, 2H), 2.55 (dq, J = 12.4, 4.0 Hz, 2H), 2.35 (m, 1H), 2.22 (t, J = 11.6 Hz, 2H), 1.87 (dd, J = 12.4, 2.0 Hz, 2H), 1.77-1.63 (m, 7H), 1.54 (m, 2H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)6(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-5- methyl- 1H-indole-2- yl)methanamine1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 6.96 (dd, J = 8.8, 1.6 Hz, 1H), 6.28 (s, 1H), 4.20 (m, 1H), 4.03 (br, 2H), 3.19 (d, J = 11.6 Hz, 2H), 2.58 (dq, J = 12.4, 4.0 Hz, 2H), 2.43 (s, 3H), 2.35 (m, 1H), 2.23 (t, J = 11.2 Hz, 2H), 1.86 (dd, J = 12.0, 2.0 Hz, 2H), 1.79-1.63 (m, 5H), 1.55 (m, 2H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)72-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)-2- (phenylamino) acetonitrile1H NMR (CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.24 (m, 1H), 7.14 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J = 7.8 Hz, 2H), 5.61 (d, J = 8.7 Hz, 2H), 4.07 (m, 1H), 3.94 (d, J = 8.7 Hz, 1H), 3.15 (m, 2H), 2.61 (m, 2H), 2.29 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H), 1.87 (d, J = 14.0 Hz, 2H), 1.76- 1.30 (m, 8H), 1.13 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H)81-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-2- (pyrrolidin-1- ylmethyl)- 1-H-indole1H NMR (CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 6.9 Hz, 1H), 7.12 (dt, J = 8.1, 1.2 Hz, 1H), 7.04 (dt, J = 7.5, 1.2 Hz, 1H), 6.32 (s, 1H), 4.48 (m, 1H), 3.74 (s, 2H), 3.19 (d, J = 11.7 Hz, 2H), 2.57 (m, 6H), 2.35 (m, 1H), 2.18 (t, J = 12.4 Hz, 2H), 1.86-1.49 (m, 13H), 1.47-1.34 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)91-cyclopropyl-N- (cyclopropylmethyl)-N- ((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-2- yl)methyl) methanamine1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.31 (s, 1H), 4.80 (m, 1H), 3.80 (s, 2H), 3.19 (d, J = 11.6 Hz, 2H), 2.62 (dq, J = 12.4, 4.0 Hz, 2H), 2.39 (d, J = 6.4 Hz, 4H), 2.34 (m, 1H), 2.21 (dt, J = 11.6, 1.6 Hz, 2H), 1.86 (d, J = 12.0 Hz, 2H), 1.78-1.53 (m, 7H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (m, 8H), 0.50 (m, 4H), 0.10 (q, J = 5.6 Hz, 4H)102-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)ethan-1-amine1H NMR (CDCl3) δ NMR (300 J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.09 (m, 2H), 6.28 (s, 1H), 5.4 (br, 2H), 4.10 (m, 1H), 3.29 (d, J = 11.7 Hz, 2H), 3.04 (m, 2H), 2.93 (m, 2H), 2.35 (m, 1H), 2.21 (t, J = 12 Hz, 2H), 1.50-1.88 (m, 11H), 1.4 (m, 2H), 1.15 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)112-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)ethyl sulfamate1H NMR (CDCl3) δ 7.64 (d, J = 6.3 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.15 (t, J = 5.7 Hz, 1H), 7.07 (t, J = 5.7 Hz, 1H), 6.34 (s, 1H), 4.50 (t, J = 5.1 Hz, 2H), 4.13 (m, 1H), 3.28 (t, J = 5.1 Hz, 2H), 3.22 (d, J = 8.4 Hz, 2H), 2.64 (m, 2H), 2.40 (m, 1H), 2.27 (t, J = 8.4 Hz, 2H), 1.84 (d, J = 8.4 Hz, 2H), 1.76 (m, 2H), 1.55-1.70 (m, 3H), 1.41 (m, 2H), 1.26 (m, 2H), 1.17 (m, 1H), 0.92 (d, J = 5.1 Hz, 6H)12N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)acetamide1H NMR (CDCl3) δ 7.54 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.42 (s, 1H), 4.64 (d, J = 5.7 Hz, 2H), 3.17 (m, 2H), 2.61 (m, 2H), 2.09 (m, 4H), 1.78 (d, J = 12.3 Hz, 2H), 1.76-1.50 (m, 10H), 1.42 (m, 2H), 1.19 (m, 1H) 0.94 (d, J = 6.6 Hz, 6H)13N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl) propionamide1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.40 (s, 1H), 5.56 (br, 1H), 4.66 (d, J = 5.6 Hz, 2H), 4.17 (m, 1H), 3.17 (d, J = 11.6 Hz, 2H), 2.62 (dq, J = 12.4, 4.0 Hz, 2H), 2.36 (m, 1H), 2.23 (m, 4H), 1.79-1.51 (m, 9H), 1.41 (m, 2H), 1.19 (m, 4H), 0.92 (d, J = 6.6 Hz, 6H)14N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)pivalamide1H NMR (CDCl3) δ 7.69 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 6.41 (s, 1H), 5.72 (br, 1H), 4.64 (d, J = 5.4 Hz, 2H), 4.13 (m, 1H), 3.16 (d, J = 11.6 Hz, 2H), 2.61 (dq, J = 12.4, 3.6 Hz, 2H), 2.34 (m, 1H), 2.19 (dt, J = 11.6, 1.8 Hz, 2H), 1.82- 1.49 (m, 9H), 1.41 (m, 2H), 1.22 (s, 9H),1.15 (m, 1H) 0.92 (d, J = 6.6 Hz, 6H)15N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl) methanesulfonamide1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 1H), 7.58 (dt, J = 8.0 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.47 (s, 1H), 4.51 (m, 3H), 4.26 (m, 1H), 3.20 (d, J = 11.6 Hz, 2H), 2.96 (s, 3H), 2.61 (dq, J = 12.4, 4.0 Hz, 2H), 2.36 (m, 1H), 2.25 (t, J = 12.0 Hz, 2H), 1.87 (dd, J = 8.0, 2.0 Hz, 2H), 1.77- 1.53 (m, 7H), 1.41 (m, 2H), 1.19-1.12 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)16N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)-4-methyl- benzenesulfonamide1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.28 (s, 1H), 4.41 (t, J = 6.4 Hz, 1H), 4.25 (m, 3H), 3.15 (d, J = 11.6 Hz, 2H), 2.58 (dq, J = 12.4, 4.0 Hz, 2H), 2.47 (s, 3H), 2.35 (m, 1H), 2.20 (t, J = 11.6 Hz, 2H), 1.84 (dd, J = 12.0, 2.0 Hz, 2H), 1.79-1.62 (m, 5H), 1.55 (m, 2H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)17benzyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)carbamate1H NMR (CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.40-7.31 (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.39 (s, 1H), 5.17 (s, 2H), 4.90 (br, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.15 (m, 1H), 3.10 (d, J = 10.0 Hz, 2H), 2.56 (dq, J = 12.1, 3.7 Hz, 2H), 2.30 (m, 1H), 2.11 (t, J = 11.9 Hz, 2H), 1.82-1.33 (m, 12H), 1.15 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H)18benzyl ((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-5- methyl- 1H-indole-2- yl)methyl)carbamate1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 1H), 7.35 (m, 5H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.30 (s, 1H), 5.16 (s, 2H), 4.89 (m, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.12 (m, 1H), 3.08 (d, J = 10.8 Hz, 2H), 2.54 (dq, J = 12.4, 4.0 Hz, 2H), 2.42 (s, 3H), 2.31 (m, 1H), 2.11 (t, J = 11.2 Hz, 2H), 1.78-1.49 (m, 9H), 1.40 (m, 2H), 1.17 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)19benzyl ((5-fluoro-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)carbamate1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 9.2, 4.0 Hz, 1H), 7.36 (m, 5H), 7.18 (dd, J = 9.2, 2.8 Hz, 1H), 6.90 (dt, J = 9.2, 2.8 Hz, 1H), 6.34 (s, 1H), 5.17 (s, 2H), 4.92 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H), 4.14 (m, 1H), 3.09 (d, J = 11.2 Hz, 2H), 2.50 (dq, J = 12.4, 4.0 Hz, 2H), 2.30 (m, 1H), 2.10 (t, J = 11.2 Hz, 2H), 1.79- 1.60 (m, 7H), 1.52 (m, 2H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)20ethyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)carbamate1H NMR (CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.40 (s,1H), 4.79 (br, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.18 (m, 3H), 3.18 (d, J = 12.0 Hz,2H), 2.60 (dq, J = 12.8, 4.1 Hz, 2H), 2.34 (m, 2H), 2.21 (t, J = 12.0 Hz, 2H), 1.88-1.34 (m, 10H), 1.27 (t, J = 7.1 Hz, 3H), 1.18 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)212-amino-N-((1-(1-(cis- 4-isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)-3- methylbutanamide1H NMR (CDCl3) δ 7.68 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.42 (s, 1H), 4.71 (dd, J = 15.1, 6.1 Hz, 1H), 4.57 (dd, J = 15.1, 6.1 Hz, 1H), 3.27 (d, J = 3.7 Hz, 2H), 3.17 (d, J = 11.0 Hz, 2H), 2.60 (m, 2H), 2.40 (m, 2H), 2.19 (m, 2H), 1.88-1.38 (m, 14H), 1.16 (m, 1H), 1.02 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.6 Hz, 6H), 0.85 (d, J = 7.0 Hz, 3H)222-acetamido-N-((1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)-3- methylbutanamide1H NMR (CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.39 (m, 1H), 6.06 (d, J = 9.0 Hz, 1H), 4.68 (dd, J = 15.2, 5.5 Hz, 1H), 4.56 (dd, J = 15.2, 5.4 Hz, 1H), 4.26 (m, 1H), 4.08 (m, 1H), 3.15 (m, 2H), 2.56 (m, 2H), 2.32 (m, 1H), 2.17 (m, 2H), 1.94 (s, 3H), 1.86-1.32 (m, 12H), 1.15 (m, 1H), 1.01- 0.88 (m, 12H)23N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl)furan-3- carboxamide1H NMR (CDCl3) δ 7.94 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 1.8 Hz, 1H), 7.18 (dt, J = 7.2, 1.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 1.8 Hz, 1H), 6.46 (s, 1H), 5.84 (br, 1H), 4.81 (d, J = 5.7 Hz, 2H), 4.22 (m, 1H), 3.13 (d, J = 11.7 Hz, 1H), 2.58 (dt, J = 11.2, 3.3 Hz, 2H), 2.31 (m, 1H), 2.18 (t, J = 11.4 Hz, 12H), 1.83- 1.31 (m, 6H), 1.14 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)24N-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methyl) nicotinamide1H NMR (CDCl3) δ 8.97 (d, J = 1.5 Hz, 1H), 8.75 (dd, J = 4.8, 1.5 Hz, 1H), 8.10 (dt, J = 7.8, 2.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.40 (m, 1H), 7.18 (dt, J = 7.2, 1.2 Hz, 1H), 7.09 (m, 1H), 6.49 (s, 1H), 3.27 (br, 1H), 4.89 (d, J = 5.7 Hz, 2H), 4.24 (m, 1H), 3.14 (d, J = 11.1 Hz, 2H), 2.61 (m, 2H), 2.31 (m, 1H), 2.18 (t, J = 12.0 Hz, 2H), 1.83-1.35 (m, 11H), 1.13 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)252-(cis-4-(4-(2- (hydroxymethyl)-1H- indole-1-yl)piperidin-1- yl)cyclohexyl)propanol- 2-ol1H NMR (CDCl2) δ 7.61 (m, 1H), 7.19 (m, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.45 (s, 1H), 4.81 (d, J = 3.3 Hz, 2H), 4.40 (m, 1H), 3.31 (d, J = 11.1 Hz, 2H), 2.62 (m, 2H), 2.30 (br, 1H), 2.19-1.85 (m, 7H), 1.58 (m, 6H), 1.43 (m, 2H), 1.25 (s, 6H)26(1-(1-(4,4- dimethylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methanol1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.17 (m, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.43 (s, 1H), 4.81 (s, 2H), 4.37 (m, 1H), 3.11 (d, J = 11.6 Hz, 2H), 2.65 (dq, J = 12.4, 4.0 Hz, 2H), 2.44 (dt, J = 11.6, 1.6 Hz, 2H), 2.32 (tt, J = 12.0, 4.0 Hz, 1H), 1.99 (br, 1H), 1.91 (dd, J = 12.0, 2.0 Hz, 2H), 1.69 (m, 2H), 1.48 (m, 4H), 1.23 (dt, J = 13.6, 3.6 Hz, 2H), 0.93 (s, 6H)27(1-(1-(trans- 2,3,3a,4,5,6-hexahydro- 1H-phenalen-1- yl)piperidin-4-yl)-1H- indol-2-yl)methanol1H NMR (CDCl3) δ □ NMR (300 J = 8.1 Hz, 1H), 7.60 (t, J = 8.1 Hz, 2H), 7.20 (q, J = 7.2 Hz, 2H), 7.08 (t, J = 8.1 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.43 (s, 1H), 4.81 (s, 2H), 4.38 (m, 1H), 3.86 (m, 1H), 3.03 (m, 1H), 2.75-2.88 (m, 5H), 2.48 (m, 2H), 2.34 (m, 1H), 1.74-2.10 (m, 9H), 1.35 (m, 2H)28(1-1-(4-propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methanol1H NMR (CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.44 (s, 1H), 4.81 (s, 2H), 4.35 (m, 1H), 3.09 (d, J = 11.6 Hz, 2H), 2.65 (m, 5H), 2.81-2.54 (m, 1H), 2.46 (t, J = 11.6 Hz, 2H), 1.92 (t, J = 12.0 Hz, 4H), 1.69 (m, 8H), 1.32 (dq, J = 12.0, 4.0 Hz, 2H)29(5-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methanol1H NMR (CDCl3) δ 7.41 (dd, J = 6.0, 2.1 Hz, 1H), 6.95 (dt, J = 6.0, 2.1 Hz, 1H), 6.51 (dd, J = 6.9, 3.6 Hz, 1H), 3.91 (d, J = 6.0 Hz, 1H), 3.28 (m, 1H), 2.92 (m, 2H), 2.24 (m, 3H), 2.04 (m, 2H), 1.47-1.73 (m, 8H), 1.38 (m, 2H), 1.13 (m, 1H), 0.88 (d, J = 5.1 Hz, 6H)30(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methanol1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.44 (s, 1H), 4.81 (d, J = 4.8 Hz, 2H), 4.37 (m, 1H), 3.19 (d, J = 11.6 Hz, 2H), 2.61 (dq, J = 12.4, 3.2 Hz, 2H), 2.37 (m, 1H), 2.26 (t, J = 11.6 Hz, 2H), 1.89 (d, J = 12.0 Hz, 2H), 1.70 (m, 5H), 1.55 (m, 2H), 1.40 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.8 Hz, 6H)311-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethan-1-ol1H NMR (CDCl3) δ 7.70 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.46 (s, 1H), 5.07 (br, 1H), 4.46 (m, 1H), 3.19 (d, J = 11.6 Hz, 2H), 2.65 (m, 2H), 2.35 (m, 1H), 2.25 (m, 2H), 1.95-1.50 (m, 13H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)322-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethan-1-ol1H NMR (CDCl3) δ 7.65 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.13 (t, J = 5.4 Hz, 1H), 7.07 (t, J = 5.4 Hz, 1H), 6.33 (s, 1H), 4.14 (m, 1H), 3.94 (t, J = 4.8 Hz, 2H), 3.20 (d, J = 8.7 Hz, 2H), 3.09 (t, J = 4.8 Hz, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.36 (m, 1H), 2.22 (t, J = 8.7 Hz, 2H), 1.51-1.87 (m, 9H), 1.42 (m, 2H), 1.27 (m, 1H), 0.92 (d, J = 4.8 Hz, 6H)332-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethyl acelate1H NMR (CDCl3) δ □ 7.64 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.02-7.15 (m, 2H), 6.29 (s, 1H), 4.38 (t, J = 7.2 Hz, 2H), 4.16 (m, 1H), 3.21 (d, J = 11.7 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.65 (dq, J = 12.6, 3.3 Hz, 2H), 2.38 (m, 1H), 2.26 (dt, J = 11.7, 1.8 Hz, 2H), 2.08 (m, 5H), 1.55-1.88 (m, 7H), 1.40 (m, 2H), 1.17 (m, 1H), 0.91 (d, J = 6.3 Hz, 6H)341-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl acetate1H NMR (CDCl3) δ □ 7.67 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.19 (dt, J = 7.2, 0.9 Hz, 1H), 7.08 (dt, J = 7.2, 0.9 Hz, 1H), 6.54 (s, 1H), 4.13 (m, 1H), 3.20 (d, J = 11.7 Hz, 2H), 2.62 (dq, J = 12.6, 3.3 Hz, 2H), 2.38 (m, 1H), 2.20 (dt, J = 11.7, 1.5 Hz, 2H), 2.08 (s, 3H), 1.50-1.90 (m, 12H), 1.40 (m, 2H), 1.16 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)351-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl pivalate 2-(4-chlorophenyl)-1-1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.56 (s, 1H), 5.25 (s, 2H), 4.17 (m, 1H), 3.31 (d, J = 12.0 Hz, 2H), 2.78 (q, J = 12.0 Hz, 2H), 2.55 (q, J = 6.4 Hz, 1H), 2.32 (t, J = 11.6 Hz, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.80 (m, 2H), 1.64 (m, 5H), 1.43 (m, 2H), 1.22 (s, 9H), 1.20 (m, 1H), 0.92 (d, J = 6.4 Hz, 6H)361-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl valinate1H NMR (CDCl3) δ 7.67 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.57 (s, 1H), 5.32 (d, J = 3.5 Hz, 2H), 4.15 (m, 1H), 3.31 (d, J = 5.0 Hz, 1H), 3.21 (d, J = 9.8 Hz, 2H), 2.62 (m, 1H), 2.33 (m, 1H), 2.18 (t, J = 11.4 Hz, 2H), 2.02 (m, 1H), 1.87 (m, 1H), 1.80-1.35 (m, 13H), 1.17 (m, 1H), 1.00-0.87 (m, 12H)372-(4-chlorophenyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.48 (s, 1H), 4.13 (m, 1H), 3.13 (d, J = 11.6 Hz, 2H), 2.69 (dq, J = 12.4, 4.0 Hz, 2H), 2.30 (sept, J = 3.4 Hz, 1H), 2.05 (dt, J = 11.6, 1.6 Hz, 2H), 1.82 (dd, J = 12.0, 1.6 Hz, 2H), 1.75- 1.60 (m, 5H), 1.50 (m, 2H), 1.39 (m, 2H), 1.21-1.11 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)381-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-5- methyl- 1H-indol-2-yl) methanol1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.8 Hz, 1H), 7.37 (s, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 6.35 (s, 1H), 4.79 (s, 2H), 4.33 (m, 1H), 3.18 (d, J = 11.6 Hz, 2H), 2.60 (dq, J = 12.4, 4.0 Hz, 2H), 2.43 (s, 3H), 2.35 (m, 1H), 2.26 (t, J = 12.4 Hz, 2H), 1.88 (dd, J = 12.4, 2.0 Hz, 2H), 1.78-1.53 (m, 8H), 1.41 (m, 2H), 1.17 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)392-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethyl pivalate1H NMR (CDCl3) δ 7.64 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.08 (m, 2H), 6.30 (s, 1H), 4.37 (t, J = 7.2 Hz, 2H), 4.14 (m, 1H), 3.21 (d, J = 11.6 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.63 (dq, J = 12.0, 3.6 Hz, 2H), 2.36 (m, 1H), 2.25 (t, J = 11.6 Hz, 2H), 1.88-1.52 (m, 1H), 1.42 (m, 2H), 1.22 (s, 9H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)40benzyl ((3- (hydroxymethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)carbamateRf= 0.25 (30:70:3 drops EtOAc:Hexanes:NH4OH (aq.), UV, I2)41benzyl ((3- (hydroxymethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)(methyl) carbamate1H NMR (400 MHz, CDCl3) δ 7.71 (t, J = 7.2 Hz, 2H), 7.43-7.30 (m, 5H), 7.20 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 4.91 (s, 2H), 4.82 (s, 2H), 4.26 (br, 1H), 3.04 d, J = 10.0 Hz, 2H), 2.78 (s, 3H), 2.57 (qd, J = 12.4, 4.0 Hz, 2H), 2.27 (m, 1H), 2.05 (m, 2H), 1.78-1.44 (m, 9H), 1.39 (m, 2H), 1.15 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)42benzyl ((3-((E/Z)- (hydroxyamino)methyl- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)carbamate1H NMR (CDCl3) δ 8.53 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 7.1 Hz, 1H), 7.31 (m, 5H), 7.15 (m, 2H), 5.35 (br, 1H), 5.10 (s, 2H), 1.69 (d, J = 6.3 Hz, 2H), 4.48 (br, 1H), 3.12 (d, J = 11.4 Hz, 2H), 2.65 (q, J = 12.0 Hz, 2H), 2.36 (m, 1H), 2.24 (m, 2H), 1.83-1.47 m, 10H), 1.40 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)43ethyl ((3- (hydroxymethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)carbamate1H NMR (400 MHz, CDCl3) δ 7.69 (t, J = 6.8 Hz, 1H), 7.20 (dt, J = 6.8, 1.2 Hz, 1H), 7.13 (dt, J = 6.8, 1.2 Hz, 1H), 5.04 (br, 1H), 4.90 (s, 2H), 4.62 (d, J = 5.6 Hz, 2H), 4.28-4.08 (m, 3H), 3.20 (d, J = 12.0 Hz, 2H), 2.63 (dq, J = 12.0, 4.0 Hz, 2H), 2.36 (m, 1H), 2.23 (t, J = 8.7 Hz, 1H), 1.87-1.51 (m, 11H), 1.42 (m, 2H), 1.25 (m, 4H), 0.92 (d, J = 6.6 Hz, 6H)44ethyl ((3-((E/Z)- (hydroxyimino) methyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)carbamate1H NMR (400 MHz, CDCl3) δ 8.78 (br, 1H), 8.56 (s, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.14 (m, 2H), 5.30 (br, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.53 (m, 1H), 4.16 (m, 2H), 3.22 (d, J = 11.2 Hz, 2H) , 2.73 (dq, J = 12.4, 4.0, Hz, 2H), 2.40 (m, 3H), 1.73 (m, 11H), 1.41 (m, 2H), 1.21 (m, 3H), 0.91 (d, J = 6.6 Hz, 6H)45N-((3- (hydroxymethyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)acetamide1H NMR (400 MHz, CDCl3) δ 7.68 (t, J = 8.8 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 6.05 (br, 1H), 5.40 (br, 1H), 4.90 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H) 4.27 (m, 1H), 3.17 (d, J = 11.6 Hz, 2H), 2.62 (dq, J = 12.4, 3.6 Hz, 2H), 2.36 (m, 1H), 2.25 (t, J = 11.0 Hz, 2H), 2.01 (s, 2H), 1.96 (s, 3H), 1.80-1.50 (m, 7H), 1.40 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)46N-((3-((E/Z)- (hydroxyimino) methyl)- 1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)acetamide1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.87 (m, 1H), 7.79 (m, 1H) 7.12 (dt, J = 7.0, 3.4 Hz, 2H), 6.11 (br, 1H), 4.75 (d, J = 5.6 Hz, 2H), 4.57 (m, 1H), 3.20 (d, J = 11.2 Hz, 2H), 2.71 (dq, J = 12.4, 4.0 Hz, 2H), 2.38 (m, 3H), 1.88-1.73 (m, 6H), 1.65 (m, 6H), 1.40 (m, 2H), 1.17 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)47N-((3- (hydroxymethyl)- 1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)-4- methylbenzene- sulfonamide1H NMR (CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.1 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 4.90 (br, 1H), 4.71 (s, 2H), 4.31 (m, 3H), 3.15 (d, J = 12.4 Hz, 2H), 2.57 (dq, J = 12.4, 4.0 Hz, 2H), 2.46 (s, 3H), 2.34 (m, 1H), 2.21 (t, J = 12.6 Hz, 2H), 1.85-1.50 (m, 10H), 1.40 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)48N-((3-((E/Z)- (hydroxyimino) methyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)methyl)-4- methylbenzene- sulfonamide1H NMR (CDCl3) δ 8.29 (s, 1H), 7.78 (m, 5H), 7.29 (m, 1H), 7.15 (m, 2H), 5.12 (br, 1H), 4.39 (m, 3H), 3.17 (d, J = 12.4 Hz, 2H), 2.62 (dq, J = 12.4, 4.0 Hz, 2H), 2.42 (m, 4H), 2.28 (t, J = 11.6 Hz, 2H), 1.95-1.55 (m, 10H), 1.43 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)49(2-(aminomethyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 3-yl)methanol1H NMR (CDCl3) δ 7.66 (t, J = 8.7 Hz, 2H), 7.22-7.08 (m, 2H), 4.88 (s, 2H), 4.34 (m, 1H), 4.14 (s, 2H), 3.21 (d, J = 11.7 Hz, 2H), 2.61 (q, J = 11.4 Hz, 2H), 2.38 (m, 1H), 2.25 (t, J = 10.9 Hz, 2H), 1.88 (d, J = 14.5 Hz, 3H), 1.82-1.40 (m, 11H), 1.17 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)501-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-2- ((methylamino) methyl)- 1H-indol-2-yl) methanol1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.15 (m, 1H), 4.87 (s, 2H), 4.34 (m, 1H), 4.00 (s, 2H), 3.20 (d, J = 11.6 Hz, 2H), 2.58 (dq, J = 12.4, 4.0 Hz, 2H), 2.49 (s, 3H), 2.36 (m, 1H), 2.23 (dt, J = 12.0, 2.0 Hz, 2H), 1.85 (dd, J = 12.0. 2.0 Hz, 2H), 1.78-1.51 (m, 9H), 1.41 (m, 2H), 1.17 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)511-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2,3-yl)dimethanol1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.4 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 4.86 (s, 2H), 4.83 (s, 2H), 4.38 (m, 1H), 3.17 (d, J = 11.6 Hz, 2H), 2.59 (q, J = 12.0 Hz, 2H), 2.37 (m, 1H), 2.25 (t, J = 11.0 Hz, 2H), 1.52-1.89 (m, 9H), 1.43 (m, 2H), 1.18 (m, 1H), 0.92 (d, J = 6.4 Hz, 6H)523-(aminomethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 2-yl)methanol1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.88 (s, 2H), 4.30 (m, 1H), 4.12 (s, 2H), 3.19 (d, J = 11.6 Hz, 2H), 2.80 (br, 3H), 2.58 (dq, J = 12.4, 4.0 Hz, 2H), 2.35 (sept, J = 3.6 Hz, 1H), 2.24 (dt, J = 12.0, 2.0 Hz, 2H), 1.88 (dd, J = 12.0, 2.0 Hz, 2H), 1.79-1.50 (m, 7H), 1.41 (m, 2H), 1.15 (m, 1H), 0.92 (d, J = 6.6 Hz,6H)532-(hydroxymethyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 3-carboxamide1H NMR (CDCl3) 7.75 (m, 2H), 7.26 (m, 2H), 5.90 (br, 2H), 5.00 (s, 1H), 4.65 (br, 1H), 4.44 (m, 1H), 3.22 (d, J = 11.6 Hz, 2H), 2.60 (dq, J = 12.0, 4.0 Hz, 2H), 2.36 (m, 1H), 2.25 (t, J = 11.6 Hz, 2H), 1.91 (dd, J = 12.0,2.4 Hz, 2H), 1.64 (m, 8H), 1.41 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)54(E/Z)-2- (hydroxymethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole- 3-carbaldehyde oxime1H NMR (400 MHz, DMSO-d6) δ 10.6 (br, 1H), 8.39 (s, 1H), 8.07 (d, J = 8.0, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.18 (dt, J = 7.2, 1.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 4.74 (s, 2H), 4.45 (m, 1H), 3.14 (d, J = 11.4 Hz, 2H), 2.47- 2.29 (m, 3H), 2.18 (t, J = 8.0 Hz, 2H), 1.82 (dd, J = 12.4, 4.0 Hz, 2H), 1.75-1.33 (m, 10H), 1.12 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H)552-(3-(hydroxymethyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethyl pivalateRf= 0.40 (60:40:3 drops EtOAc:Hexanes:NH4OH (aq.), UV, I2)562-(3-((E/Z)- (hydroxyimido)methyl- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethyl pivalate1H NMR (CDCl3) δ 8.48 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.17 (m, 2H), 4.24 (m, 3H), 3.25 (m, 4H), 2.71 (m, 2H), 2.47-2.23 (m, 3H), 1.93-1.52 (m, 10H), 1.42 (m, 2H), 1.20 (m, J = 5.2 Hz, 10H), 0.92 (d, J = 6.6 Hz, 6H)572-(3-(aminomethyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethyl pivalate1H NMR (CDCl3) δ 7.66 (m, 2H), 7.12 (m, 2H), 4.13 (m, 5H), 3.20 (m, 4H), 2.70 (m, 2H), 2.35 (m, 3H), 1.89-1.50 (m, 11H), 1.42 (m, 2H), 1.22 (s, 9H), 1.16 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)582-(3-(aminomethyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol- 2-yl)ethan-1-ol1H NMR ( DMSO-d6) δ 7.67 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.10 (m, 2H), 4.30 (m, 1H), 4.17 (s, 2H), 3.82 (s, 2H), 3.62 (t, J = 6.0 Hz, 2H), 3.12 (m, 4H), 2.58-2.23 (m, 6H), 1.79-1.32 (m, 11H), 1.14 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H)592-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- methylsulfonamido- methyl)-1H-indol-2-yl) ethyl pivalate1H NMR ( DMSO-d6) δ 7.75 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.24 (m, 2H), 7.09 (t, J = 7.2 Hz, 1H), 5.33 (s, 2H), 4.34 (m, 3H), 4.10 (s, 2H), 2.77 (s, 4H), 2.62 (m, 4H), 1.87 (m, 2H), 1.88-1.58 (m, 8H), 1.40 (m, 2H), 1.15 (m, 10H), 0.89 (d, J = 6.6 Hz, 6H)602-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- methylsulfonamido- methyl)-1H-indol-2- yl)ethan-1-ol1H NMR (CDCl3) δ 7.64 (m, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 4.81 (s, 2H), 4.52 (s, 2H), 4.36 (m, 1H), 3.11 (m, 2H), 2.60 (s, 6H), 2.29 (m, 2H), 1.83-1.40 (m, 13H), 1.18 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H)611-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole1H NMR (CDCl3) δ 7.64 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 6.0 Hz, 1H), 7.26 (m, 1H), 7.20 (t, J = 6.0 Hz, 1H), 7.11 (t, J = 6.0 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 4.23 (m, 1H), 3.20 (d, J = 9.0 Hz, 2H), 2.30 (m, 3H), 2.08 (m, 4H), 1.51-1.78 (m, 7H), 1.40 (m, 2H), 1.17 (m, 1H), 0.9 (d, J = 4.8 Hz, 6H)621-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-3-carboxamide1H NMR (CDCl3) δ □ 8.00 (m, 1H), 7.90 (m, 1H), 7.49 (m, 1H), 7.29 (m, 1H), 5.78 (br, 2H), 4.23 (m, 1H), 3.26 (d, J = 8.7 Hz, 2H), 2.37 (m, 2H), 2.28 (t, J = 8.7 Hz, 2H), 2.10 (m, 4H), 1.75-1.52 (m, 6H), 1.40 (m, 2H), 1.16 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)633-azidomethyl-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole1H NMR (CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.27 (m, 2H), 7.17 (t, J = 6.9 Hz, 1H), 4.54 (s, 2H), 4.19 (m, 1H), 3.21 (d, J = 11.1 Hz, 2H), 2.30 (m, 3H), 2.08 (m, 4H), 1.78-1.51 (m, 7H), 1.40 (m, 2H), 1.15 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)643-(indolin-1- ylmethyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole1H NMR (CDCl3) δ □ 7.70 (d, J = 6.0 Hz, 1H), 7.38 (d, J = 6.3 Hz, 1H), 7.22 (t, J = 5.4 Hz, 2H), 7.11 (t, J = 6.0 Hz, 3H), 6.88 (m, 2H), 4.42 (s, 2H), 4.17 (m, 1H), 3.28 (t, J = 6.3 Hz, 2H), 3.18 (d, J = 9.0 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.37-2.24 (m, 3H), 2.04 (m, 4H), 1.77-1.51 (m, 7H), 1.40 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)651-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolin-1-ylmethyl)- 1H-indole1H NMR (CDCl3) δ 7.70 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 4.17 (m, 1H), 3.84 (s, 2H), 3.19 (d, J = 12.0 Hz, 2H), 2.59 (s, 4H), 2.27 (m, 3H), 2.04 (m, 5H), 1.82-1.48 (m, 12H), 1.40 (m, 2H), 1.15 m, 1H), 0.91 (d, J = 6.6 Hz, 6H)66(R)-1-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)pyrrolin- 3-ol1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 (m, 1H), 7.11 (t, J = 7.2 Hz, 1H), 4.32 (m, 1H), 4 17 (m, 1H), 3.86 (s, 2H), 3.19 (d, J = 12.0 Hz, 2H), 2.93 (m, 1H), 2.74 (dd, J = 10.4, 1.0 Hz, 1H), 2.61 (dd, J = 10.4, 5.2 Hz, 1H), 2.45-1.94 (m, 11H), 1.78-1.51 (m, 7H), 1.41 (m, 2H), 1.15 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)671-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl) methyl)azetidin-3-ol1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6 Hz, 1H), 7.58 (br, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.21 (m, 2H), 7.12 (m, 1H), 4.44 (p, J = 6.0 Hz, 1H), 4.17 (m, 1H), 3.84 (s, 2H), 3.69 (m, 3H), 3.19 (d, J = 12.4 Hz, 2H), 3.03 (m, 2H), 2.29 (m, 3H), 2.12-1.89 (m, 3H), 1.76-1.47 (m, 7H), 1.40 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H)681-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl) methyl)piperidin-1-ol1H NMR (CDCl3) δ 7.71 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.21 (m, 1H), 7.11 (t, J = 7.2 Hz, 1H), 4.16 (m, 1H), 3.78 (m, 3H), 3.19 (d, J = 11.6 Hz, 3H), 2.87 (m, 2H), 2.38-2.20 (m, 4H), 2.15-1.91 (m, 5H), 1.78-1.48 (m, 11H), 1.41 (m, 2H), 1.15 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)691-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)piperidin-4- amineH1NMR (CDCl3): δ 7.70 (dd, J = 2.4, 4.2 Hz, 2 H), 7.53 (dd, J = 2.4, 4.2 Hz, 2 H), 7.4 (br s, 1H), 4.24-4.21 (m, 3H), 3.48 (q, J = 5.1, 10.5 Hz, 4H), 2.08 (s, 14H), 1.69-1.68 (m, 2H), 1.45-1.40 (m, 3H), 1.35-1.29 (m, 4H), 1.20 (t, J = 5.1 Hz, 3H), 0.94-0.88 (m, 6H).702-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)amino) ethan- 1-olH1NMR (CDCl3) δ 7.56 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 6.3 Hz, 1H), 7.18 (t, J = 5.1 Hz, 2H), 7.06 (d, J = 5.7 Hz, 1H), 4.22-4.21 (m, 1H), 3.66 (br s, 1H), 3.22 (s, 1H), 2.79 (s, 1H), 2.32 (br s, 3H), 2.10 (s, 4H), 1.72-1.61 (m, 7H), 1.43-1.32 (m, 2H), 1.26 (s, 2H), 1.15 (s, 1H), 0.89 (d, J = 4.8 Hz, 6H).71N-(((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl) carbamothioyl) benzamideH1NMR (CDCl3): δ 10.81 (s, 1H), 9.05 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.78 (dd, J = 5.7, 13.8 Hz, 1H), 7.69 (d, J = 5.7 Hz, 1H), 7.58 (t, J = 5.4 Hz, 1H), 7.55-7.39 (m, 4H), 7.3 (s, 1H), 7.22-7.14 (m, 1H), 5.01 (d, J = 3.9 Hz, 1H), 4.37-4.34 (m, 1H), 3.55 (d, J = 9 Hz, 2H), 3.0 (br s, 1H), 2.72 (t, J = 8.1, 2H), 2.53 (q, J = 8.4, 9.6 Hz, 2H), 2.18 (d, J = 9.3 Hz, 2H), 1.86 (dd, J = 9.9, 19.5 Hz, 4H), 1.68-1.63 (m, 3H), 1.43 (t, J = 9.6 Hz, 2H), 1.26-1.22 (m, 1H), 0.89 (d, J = 4.8 Hz, 6 H).721-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)thioureaH1NMR (CDCl3): δ 7.61 (br s, 1H), 7.37 (d, J = 6 Hz, 7.24 (S, 2H), 7.11 (t, J = 5.1 Hz, 1H), 6.58 (br s, 1H), 5.82 (s, 2H), 4.88 (br s, 1H), 4.45 (br s, 1H), 4.18 (s, 1H), 3.14 (d, J = 6.9 Hz, 2H), 2.33 (s, 1H), 2.22 (t, J = 9.3 Hz, 2H), 2.02-1.97 (m, 4H), 1.71-1.61 (m, 5H), 1.56-1.54 (m, 2H), 1.42-1.39 (m, 2H), 1.14 (br s, 1H), 0.89 (d, J = 4.8 Hz, 6H).73phenyl (E)-N′-cyano- N-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl) carbamimidateH1NMR (CDCl3): δ 7.66 (d, J = 5.7 Hz, 1H), 7.42 (d, J = 5.7 Hz, 3H), 7.29 (d, J = 6.9 Hz, 2H), 7.27 (s, 2H), 7.13 (dd, J = 5.4, 14.4 Hz, 3H), 6.39 (br s, 1H), 4.81 (s, 2H), 4.65 (d, J = 9 Hz, 2H), 4.24 (br s, 1H), 3.20 (d, J = 8.1 Hz, 2H), 2.28 (dd, J = 10.2, 19.8 Hz, 3H), 2.04 (t, J = 11.4 Hz, 4H), 1.72-1.59 (m, 7H), 1.37 (q, J = 7.2, 9.6 Hz, 2H), 1.16 (br s, 1H), 0.90 (d, J = 4.8 Hz, 6H).74(Z)-2-cyano-1-((1-(1- cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)guanidineH1NMR (CDCl3): δ 7.58 (d, J = 5.4 Hz, 1H), 7.34 (d, J = 6 Hz, 1H), 7.21 (d, J = 5.1 Hz, 3H), 7.09 (t, J = 4.8, 1H), 5.84 (br s, 2H), 4.53 (s, 2H), 4.29 (br s, 1H), 3.63 (s, 2H), 3.32 (d, J = 7.5 Hz, 2H), 2.78 (br s, 1H), 2.63 (br s, 2H), 2.27-2.22 (m, 2H), 1.90 (br s, 4H), 1.70-1.62 (m, 3H), 1.44 (br s, 2H), 1.22 (d, J = 11.7 Hz, 3H), 0.91 (d, J = 4.8 Hz, 6H).75benzyl (2-cyano-(((1- (1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)amino)-2- oxoethyl)carbamateH1NMR (CDCl3): δ 7.59 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 6.3 Hz, 1H), 7.32 (s, 5H), 7.25- 7.22 (m, 2H), 7.11 (t, J = 5.7 Hz, 1H), 6.11 (s, 1H), 5.45 (s, 1H), 5.08 (s, 2H), 4.20-4.18 (m, 1H), 3.85 (d, J = 4.2 Hz, 2H), 3.22 (d, J = 8.7 Hz, 2H), 2.44 (s, 1H), 2.31 (d, J = 7.8 Hz, 2H), 2.09 (t, J = 7.8 Hz, 4H), 1.73 (br s, 2H), 1.68-1.63 (m, 3H), 1.43-1.38 (m, 2H), 1.17- 1.16 (m, 1H), 0.89 (d, J = 4.8 Hz, 6H)762-(ethylamino)-N-((1- (1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)acetamidoH1NMR (CDCl3): δ 7.59 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 4.8 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 5.31 (s, 1H), 4.60 (d, J = 5.4 Hz, 2H), 4.32 (br s, 1H), 3.42-3.36 (m, 4H), 2.71-2.44 (m, 9H), 2.11 (d, J = 11.7 Hz, 2H), 1.88-1.64 (m, 5H), 1.408 (q, J = 10.2, 13.2 Hz, 2H), 1.28-1.20 (m, 1H), 1.07 (t, 6.9 Hz 3H), 0.92 (d, J = 6.3 Hz, 6 H).772-(diethylamino)-N- ((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)acetamidoH1NMR (CDCl3): δ 7.65 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.25-7.21 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 5.18 (d, J = 15 Hz, 1H), 4.23 (br s, 1H), 4.10 (d, J = 15 Hz, 1H), 3.81 (q, J = 5.1, 10.8 Hz, 1H), 3.63 (d, J = 14.4 Hz, 1H), 3.28 (br s, 2H), 2.98 (d, 13.5 Hz, 1H), 2.72-2.64 (m, 1H), 2.39 (br s, 2H), 2.27 (m, 2.20 (m, 2H), 2.13 (br s, 3H), 1.77- 1.68 (m, 6H), 1.46-1.42 (m, 2H), 1.33-1.28 (m, 3H), 1.20-1.1.19 (m, 1H), 1.02 (t, J = 7.2 Hz, 6H), 0.91 (d, J = 6.6 Hz, 6H).78N-((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)methyl)-5- ((oxo-2-phenyl-1λ3- ethylidene)amino) pentanamideH1NMR (CDCl3): δ 7.61 (d, J = 6.0 Hz, 1H), 7.36-7.30 (m, 5H), 7.21 (t, J = 11.4 Hz, 1H), 7.19 (s, 1H), 7.11 (t, J = 11.1 Hz, 1H), 5.7 (br s, 1H), 5.12-5.00 (m, 2H), 4.87 (br s, 1H), 4.58 (d, J = 3.6 Hz, 2H), 4.22-4.21 (m, 1H), 3.30 (d, J = 8.4 Hz, 2H), 3.13 (p, J = 4.8, 12, 17.1 Hz, 2H), 2.61-2.60 (m, 1H), 2.42 (t, J = 8.7 Hz, 2H), 2.28 (t, J = 5.4 Hz, 2H), 2.22 (d, J = 9 Hz, 1H), 2.14 (t, J = 5.4 Hz, 2H), 2.06 (d, 2H), 1.83-1.799 (m, 2H), 1.64 (d, J = 3.9 Hz, 5H), 1.61-1.33 (m, 5H), 1.16 (1H), 0.89 (d, J = 5.1 Hz, 6H).795-amino-N-((1-(1-cis- 4-isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl(methyl)pentanamideH1NMR (CDCl3): δ 7.61 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 5.1 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 5.93 (s, 1H), 4.59 (d, J = 5.1 Hz, 2H), 4.22-4.20 (m, 1H), 3.57 (t, J = 5.4 Hz, 4H), 3.22 (d, J = 11.4 Hz, 2H), 2.56-2.5 (m, 3H), 2.43-2.32 (m, 2H), 2.17 (t, J = 7.5 Hz, 2H), 2.12 (s, 2H), 1.78- 1.51 (m, 11H), 1.45-1.31 (m, 4H), 1.29-1.16- (m, 1H), 0.90 (d, J = 6.6 Hz, 6H).802-amino-5-guanidino- N-((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indolo-3- yl)methyl)pentanamideH1NMR (DMSO-d6): δ 8.32 (s, 2H), 7.72 (br s, 1H), 7.50 (d, J = 6 Hz, 1H), 7.44 (d, J = 6.3 Hz, 1H), 7.41 (s, 1H), 7.08 (t, J = 6 Hz, 1H), 6.95 (t, J = 5.7 Hz, 1H), 4.39 (dd, J = 3.6, 10.8 Hz, 1H), 4.31-4.24 (m, 2H), 3.83 (br s, 1H), 3.066 (br s, 3H), 2.90 (m, 1H), 2.66 (s, 2H), 2.28 (d, J = 13.5, 2H), 2.16 (t, J = 8.4 Hz, 3H), 1.91-1.85 (m, 4H), 1.70 (br, s, 2H), 1.54 (br s, 4H), 1.41-1.35 (m, 4H), 1.14-1.09 (m, 1H), 0.85 (d, J = 4.8 Hz, 6H).81(E/Z)-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-carbaldehyde oxime1H NMR (CDCl3, Major Isomer) δ 10.8 (br, 1H), 8.47 (s, 1H), 7.78 (m, 2H), 7.41 (d, J = 6.0, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 4.31 (m, 1H), 3.30 (d, J = 8.7 Hz, 2H), 2.55 (m, 1H), 2.46 (t, J = 7.8, 2H), 2.23 (m, 3H), 1.86 (m, 2H), 1.60-1.80 (m, 6H), 1.43 (m, 2H), 1.19 (m, 1H), 0.91 (d, J = 5.1, 6H); 1H NMR (300 MHz, CDCl3, Minor Isomer) δ 8.30 (s, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J = 6.0 Hz, 1H), 7.28 (t, J = 5.4 Hz, 1H), 7.20 (t, J = 5.4 Hz, 1H), 4.23 (m, 1H), 3.22 (d, J = 5.7 Hz, 2H), 2.35 (m, 3H), 2.13 (m, 4H), 1.55-1.80 (m, 7H), 1.43 (m, 2H), 1.17 (m, 1H), 0.91 (d, J = 5.1 Hz, 6H)82(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)methanolH1NMR (CDCl3): δ 7.73(d, J = 5.7 Hz, 1H), 7.37 (d, J = 6 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J = 6 Hz, 1H), 7.13 (t, J = 5.4 Hz, 1H), 4.87 (s, 2H), 4.20 (m, 1H), 3.15 (d, 8.7 J = Hz, 2H), 2.33 (br s, 1H), 2.23 (t, J = 8.4 Hz, 2H), 1.98 (dd, J = 9, 18.3 Hz, 4H), 1.73-1.69 (m, 4H), 1.61 (t, J = 4.8 Hz, 2H), 1.58-1.56 (m, δ1H), 1.42-1.39 (m, 2H), 1.26 (br s, 1H), 1.02 (br s, 1H), 0.86 (dd, J = 4.8, 6.9 Hz, 6H).83(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methanamineH1NMR (DMSO-d6): δ 7.58 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 6.3 Hz, 1H), 7.37 (s, 1H), 7.10 (t, J = 5.7 Hz, 1H), 6.98 (t, J = 5.7 Hz, 1H), 4.26-4.25 (m, 1H), 3.86 (s, 1H), 3.16 (s, 2H), 3.077 (d, J = 8.7 Hz, 3H), 2.27 (br s, 1H), 2.18 (t, J = 8.4 Hz, 2H), 1.91-1.86 (m, 4H), 1.71 (br s, 2H), 1.55-1.50 (m, 3H), 1.38 (dd, J = 9.3, 18.3 Hz, 4H), 1.097 (s, 1H), 0.858 (d, J = 5.1 Hz, 6H).841-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)-N,N- dimethylmethanamineH1NMR (CDCl3): δ 7.73 (d, J = 6 Hz, 1H), 7.62 (d, J = 6 Hz, 1H), 7.37 (d, J = 6 Hz, 1H), 7.22 (d, J = 5.1 Hz, 1H), 7.17-7.14 (m, 1H), 5.61-5.43 (m, 6H), 4.87 (s, 1H), 4.65 (d, J = 3.9 Hz, 1H), 4.59 (d, J = 3.6 Hz, 1H), 4.19 (t, J = 5.4 Hz, 1H), 3.21 (d, J = 7.5 Hz, 2H), 2.38-2.30 (m, 3H), 2.18-1.98 (m, 6H), 1.71- 1.60 (m, 5H), 1.43-1.37 (m, 2H), 1.14 (t, J = 3.3 Hz, 1H), 0.89 (d, J = 5.1 Hz, 6H).85N-benzyl-1-(1-(1-cis- 4-isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methanamineH1NMR (CDCl3): δ 7.64-7.61 (m, 1H), 7.37- 7.31 (m, 4H), 7.23-7.18 (m, 3H), 7.12-7.07 (m, 2H), 4.18-4.17 (m, 1H), 4.07 (s, 1H), 4.00 (s, 1H), 3.88 (s, 1H), 3.17 (d, J = 8.4 Hz, 2H), 2.32-2.18 (m, 4H), 2.06-2.07 (m, 5H), 1.69-1.63 (m, 4H), 1.55-1.54 (m, 3H), 1.39 (br s, 2H), 1.71-1.15 (br s, 1H), 0.89 (d, J = 4.8 Hz, 6H).862-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)ethan-1- amine1H NMR (CDCl3) d 7.61 (d, J = 5.7 Hz, 1H), 7.37 (d, J = 6.0 Hz, 1H), 7.21 (t, J = 5.7 Hz, 1H), 7.10 (m, 2H), 4.18 (m, 1H), 3.19 (d, J = 8.7 Hz, 2H), 3.02 (t, J = 5.1 Hz, 2H), 2.91 (t, J = 5.1 Hz, 2H), 2.33 (m, 1H), 2.26 (t, J = 8.7 Hz, 2H), 2.12-2.00 (m, 4H), 1.78-1.36 (m, 11H), 1.15 (m, 1H), 0.90 (d, J = 4.8 Hz, 6H)873-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)propan-1- amine1H NMR (CDCl3) δ, 7.60 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 6.0 Hz, 1H), 7.19 (t, J = 5.4 Hz, 1H), 7.09 (t, J = 5.4 Hz, 1H), 7.04 (s, 1H), 4.17 (m, 1H), 3.18 (d, J = 9.0 Hz, 2H), 2.79 (m, 4H), 2.33 (m, 1H), 2.25 (dt, J = 9.0, 1.8 Hz, 2H), 2.10-1.97 (m, 6H), 1.90 (p, J = 5.4 Hz, 2H), 1.78-1.52 (m, 7H), 1.41 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 4.8 Hz, 6H)882-(5-fluoro-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl-1H- indol-3-yl)ethan-1- amine1H NMR (CDCl3) δ, 7.25 (m, 2H), 7.13 (s, 1H), 6.94 (dt, J = 6.9, 1.8 Hz, 1H), 4.13 (m, 1H), 3.19 (d, J = 8.7 Hz, 2H), 3.00 (t, J = 5.1 Hz, 2H), 2.86 (t, J = 5.1 Hz, 2H), 2.33 (m, 1H), 2.23 (t, J = 8.7 Hz, 2H), 2.10-1.96 (m, 4H), 1.75-1.50 (m, 7H), 1.41 (m, 4H),1.16 (m, 1H), 0.91 (d, J = 5.1 Hz, 6H)893-(5-fluoro-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)propan-1- amine1H NMR (CDCl3) δ, 7.23 (m, 2H), 7.07 (s, 1H), 6.93 (dt, J = 6.9, 1.8 Hz, 1H), 4.12 (m, 1H), 3.18 (d, J = 8.7 Hz, 2H), 2.77 (m, 4H), 2.32 (m, 1H), 2.40 (t, J = 8.7 Hz, 2H), 2.10- 1.96 (m, 4H), 1.83 (p, J = 5.7 Hz, 2H), 1.75- 1.36 (m, 11H), 1.16 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)902-(5-chloro-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)ethan-1- amine1H NMR (CDCl3) δ, 7.56 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 6.3 Hz, 1H), 7.14 (dd, J = 6.6, 1.5 Hz, 1H), 7.06 (s, 1H), 4.12 (m, 1H), 3.18 (d, J = 8.7 Hz, 2H), 2.74 (m, 3H), 2.32 (m, 1H), 2.24 (t, J = 8.7 Hz, 2H), 2.04 (m, 5H), 1.83 (q, J = 5.4 Hz, 1H), 1.75-1.48 (m, 7H), 1.42 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)913-(5-chloro-1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)propan-1- amine1H NMR (CDCl3) δ, 7.54 (m, 1H), 7.24 (d, J = 6.6 Hz, 1H), 7.13 (dd, J = 6.6, 1.5 Hz, 1H), 7.06 (s, 1H), 4.12 (m, 1H), 3.18 (d, J = 8.7 Hz, 2H), 2.76 (m, 3H), 2.33 (m, 1H), 2.24 (t, J = 8.7 Hz, 2H), 2.05 (m, 5H), 1.84 (m, 1H), 1.75-1.50 (m, 10H), 1.41 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)92N-(2-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)acetamide1H NMR (CDCl3) δ, d 7.60 (d, J = 5.7 Hz, 1H), 7.38 (d, J = 6.3 Hz, 1H), 7.23 (t, J = 5.4 Hz, 1H), 7.12 (m, 2H), 5.32 (br, 1H), 4.19 (m, 1H), 3.58 (q, J = 4.8 Hz, 2H), 3.20 (d, J = 8.7 Hz, 2H), 2.97 (t, J = 4.8 Hz, 2H), 2.30 (m, 3H), 2.05 (m, 4H), 1.93 (s, 3H), 1.75- 1.50 (m, 8H), 1.41 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)932-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)ethyl)urea1H NMR (CDCl3) δ, 7.60 (d, J = 6.3 Hz, 1H), 7.37 (d, J = 6.3 Hz, 1H), 7.22 (t, J = 5.4 Hz, 1H), 7.11 (m, 2H), 4.55 (m, 1H), 4.18 (m, 3H), 3.50 (q, J = 4.8 Hz, 2H), 3.18 (d, J = 9.0 Hz, 2H), 2.97 (t, J = 4.8 Hz, 2H), 2.33 (m, 1H), 2.25 (m, 2H), 2.05 (m, 4H), 1.75-1.50 (m, 7H), 1.40 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 5.1 Hz. 6H)94ethyl (2-(1-(1-cis-4- isopropylcyclohexyl) piperidin-1-yl)-1H- indol-3- yl)ethyl)carbamate1H NMR (CDCl3) δ, 7.60 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.22 (m, 1H), 7.11 (m, 2H), 4.70 (br, 1H), 4.13 (m, 3H), 3.49 (m, 2H), 3.20 (m, 2H), 2.97 (J = 6.9 Hz, 2H), 2.29 (m, 2H), 2.05 (m, 4H), 1.75-1.50 (m, 8H), 1.40 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.16 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)951-(2-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)ethyl)thiourea1H NMR (CDCl3) δ, 7.58 (br, 1H), 7.38 (d, J = 6.3 Hz, 1H), 7.23 (t, J = 5.4 Hz, 1H), 7.12 (m, 2H), 6.23 (br, 1H), 5.68 (br, 2H), 4.20 (m, 1H), 3.22 (d, J = 8.4 Hz, 2H), 3.06 (t, J = 5.1 Hz, 2H), 2.45-2.07 (m, 8H), 1.80-1.52 (m, 7H), 1.43 (m, 2H), 1.16 (m, 1H),0.90 (d, J = 5.1 Hz, 6H)961-(3-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)propyl)thiourea1H NMR (CDCl3) δ, 7.56 (d, J = 6.0 Hz, 1H), 7.36 (d, J = 6.0 Hz, 1H), 7.21 (t, J = 5.7 Hz, 1H), 7.10 (m, 2H), 6.26 (br, 1H), 5.66 (br, 2H), 4.17 (m, 1H), 3.19 (m, 3H), 2.85 (t, J = 5.1 Hz, 2H), 2.30 (m, 3H), 2.10-1.94 (m, 6H), 1.77-1.55 (m, 6H), 1.42 (m, 2H), 1.27 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 4.8 Hz, 6H)97(E)-3-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)acrylonitrile1H NMR (CDCl3) δ, 7.77 (d, J = 6.3 Hz, 1H), 7.56-7.42 (m, 2H), 7.44 (d, J = 6.3 Hz, 1H), 7.34-7.25 (m, 2H), 5.74 (d, J = 12.3 Hz, 1H), 4.21 (m, 1H), 3.21 (d, J = 8.7 Hz, 2H), 2.34 (m, 1H), 2.26 (t, J = 8.4 Hz, 2H), 2.12 (m, 2H), 2.02 (m, 2H), 1.75-1.50 (m, 7H), 1.42 (m, 2H), 1.16 (m, 1H), 0.91 (d, J = 4.8 Hz, 6H)98(Z)-3-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)acrylonitrile1H NMR (CDCl3) δ, 8.39 (s, 1H), 7.71 (d, J = 5.7 Hz, 1H), 7.44 (m, 2H), 7.27 (m, 2H), 5.15 (d, J = 8.4 Hz, 1H), 4.26 (m, 1H), 3.22 (d, J = 7.8 Hz, 2H), 2.35 2.22 (m, 3H), 2.14 (m, 4H), 1.75-1.50 (m, 7H), 1.41 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)995-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde oxime1001-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde O-methyl oxime1015-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde O-methyl oxime1021-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde oxime1031-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde O-methyl oxime1041-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b] pyridine-3- carbaldehyde oxime1051-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b] pyridine-3- carbaldehyde O- methyl oxime1061-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde oxime1071-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-5- fluoro-1H-indole-3- carbaldehyde oxime1081-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b] pyridine-3- carbaldehyde oxime1092-(5-fluoro-1-(1-(cis- 4-isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)ethan-1- amine1103-(2-aminoethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-5-ol1113-(2-aminoethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-5-yl sulfamate1122-(5-isopropoxy-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)ethan-1- amine1133-(2-aminoethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-5-yl carbamate1142-(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-amine1152-(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-3-yl)ethan-1- amine1163-(2-aminoethyl)-1-(1- (4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-5-yl sulfamate1172-(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-amine1182-(1-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-5- fluoro- 1H-indol-3-yl)ethan- 1-amine1192-(1-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-amine1203-(2-aminoethyl)-1-(1- (cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-1H- indol-5- yl sulfamate1213-(azetidin-1- ylmethyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-2H- indole1221-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (piperidin-1- ylmethyl)-1H-indole1233-((4,5-dihydro-1H- imidazol-2-yl)methyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indole1241-((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3- yl)methyl)piperidin-2- one1255-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indole1261-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indole1271-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridine1281-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridine1291-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-5- yl sulfamate1301-((1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indole1311-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridine1321-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-5- fluoro-3-(pyrrolidin-1- ylmethyl)-1H-indole1331-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-5- yl carbamate1341-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-5- yl methylcarbamate135(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl carbamate136(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl carbamate137(5-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl carbamate138(5-fluoro-1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl carbamate139(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl carbamate140(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl carbamate1412-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl sulfamate1422-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl sulfamate1432-(5-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl sulfamate1442-(5-fluoro-1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl sulfamate1452-(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl sulfamate1462-(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl sulfamate147N-(2-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl) aminosulfonamide148N-(2-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl)amino- sulfonamide149N-(2-(5-fluoro-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl) aminosulfonamide150N-(2-(5-fluoro-1-(1- (4-propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethyl) aminosulfonamide151N-(2-(1-(1-(4-(propan- 2-ylidene)cyclohexyl) piperidin-4-yl)- 3-(pyrrolidin-1-yl methyl)-1H-indol-2- yl)ethyl) aminosulfonamide152N-(2-(1-(1-(4-(propan- 2-ylidene) cyclohexyl)piperidin- 4-yl)-3-(pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl) aminosulfonamide153N-((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)methane- sulfonamide154N-((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl) methanesulfonamide155N-((5-fluoro-1-(1-(cis- 4-isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl) methanesulfonamide156N-((5-fluoro-1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl) methanesulfonamide157N-((1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl) methanesulfonamide158N-((1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl) methanesulfonamide159N-((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)acetamide160N-((1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl)acetamide161N-((5-fluoro-1-(1-(cis- 4-isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)acetamide162N-((5-fluoro-1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)acetamide163N-((1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)acetamide164N-((1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl)acetamide1652-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethan-1-ol1662-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethan-1-ol1672-(5-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethan-1-ol1682-(5-fluoro-1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethan-1-ol1692-(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)ethan-1-ol1702-(1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-d]pyridin- 2-yl)ethan-1-ol171ethyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)carbamate172ethyl ((1-(1-((1s,4s)-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl)carbamate173ethyl ((5-fluoro-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)carbamate174ethyl ((5-fluoro-1-(1- (4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)carbamate175ethyl ((1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H-indol-2- yl)methyl)carbamate176ethyl ((1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-3- (pyrrolidin-1- ylmethyl)-1H- pyrrolo [2,3-b]pyridin- 2-yl)methyl)carbamate177benzyl ((3- ((hydroxyimino) methyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl)carbamate178benzyl ((5-fluoro-3- ((hydroxyimino) methyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2- yl)methyl)carbamate179benzyl ((3- ((hydroxyimino) methyl)- 1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2- yl)methyl)carbamate180benzyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl)carbamate181benzyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-pyrrolo [2,3-b]pyridin-2- yl)methyl)carbamate182benzyl ((5-fluoro-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl)carbamate183benzyl ((3- ((methoxyimino) methyl)- 1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2- yl)methyl)carbamate184benzyl ((1-(1-(cis-4- (tert-butyl) cyclohexyl)piperidin- 4-yl)-3-((hydroxy- imino)methyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl)carbamate185benzyl ((1-(1-(cis-4- (tert-butyl) cyclohexyl)piperidin- 4-yl)-5-fluoro-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl)carbamate186benzyl ((3- ((hydroxyimino) methyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)methyl)carbamate187benzyl ((5-fluoro-3- ((hydroxyimino) methyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2- yl)methyl)carbamate188N-((3- ((hydroxyimino) methyl)- 1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2- yl)methyl)acetamide189benzyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl)carbamate190benzyl ((1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-pyrrolo [2,3-b]pyridin-2- yl)methyl)carbamate191benzyl ((5-fluoro-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl)carbamate192N-((3- ((methoxyimino) methyl)- 1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2- yl)methyl)acetamide193N-((1-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-5- fluoro- 3-((methoxyimino) methyl)-1H-indol-2- yl)methyl)acetamide1942-(hydroxymethyl)-1- (1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indole-3-carbaldehyde oxime195(5-fluoro-3- ((hydroxyimino) methyl)- 1-(1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methyl carbamate196(5-fluoro-3- ((hydroxyimino) methyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methyl sulfamate197(3-((hydroxyimino) methyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methyl sulfamate198(3-((hydroxyimino) methyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methyl carbamate199(5-fluoro-3- ((hydroxyimino) methyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methyl carbamate200(3-((hydroxyimino) methyl)-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo [2,3-b]pyridin- 2-yl)methyl carbamate201(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-pyrrolo [2,3-b]pyridin-2-yl) methyl carbamate202(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl carbamate203(5-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl carbamate204(5-fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl sulfamate205(1-(1-cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl sulfamate206(5-fluoro-3- ((methoxyimino) methyl)-1-(1-(4- (propan- 2-ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2-yl)methyl carbamate207(1-(1-cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-5- fluoro- 3-((methoxyimino) methyl)-1H-indol-2- yl)methyl sulfamate208(1-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-3- ((methoxyimino) methyl)-1H-indol-2- yl)methyl carbamate209(1-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-3- ((hydroxyimino) methyl)-1H-pyrrolo [2,3-b]pyridin-2-yl) methyl carbamate2102-(3-(aminomethyl)-5- fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethan-1-ol2112-(3-(aminomethyl)-1- (1-(4-propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethan-1-ol212N-((2-(2- hydroxyethyl)-1-(1- (cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-3-yl)methyl) methanesulfonamide2132-(3-(aminomethyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethyl sulfamate2142-(3-(aminomethyl)-1- (1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethyl carbamate2152-(3-(aminomethyl)-5- fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethyl carbamate2162-(5-fluoro-3- (methylsulfonamido- methyl)-1-(1-(4- (propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethyl carbamate2172-(3-(aminomethyl)- 1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl carbamate2182-(3-(aminomethyl)-5- fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethan-1-ol2192-(3-(aminomethyl)-1- (1-(4-(propan-2- ylidene)cyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl carbamate2202-(3-(aminomethyl)-5- fluoro-1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-1H- indol-2-yl)ethyl sulfamate2212-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (methylsulfonamido- methyl)-1H-pyrrolo [2,3-b]pyridin-2-yl) ethyl carbamate2222-(1-(1-(cis-4- isopropylcyclohexyl) piperidin-4-yl)-3- (methylsulfonamido- methyl)-1H-indol-2- yl)ethyl carbamate2232-(3-(methyl- sulfonamidomethyl)- 1-(1-(4-(propan-2- ylidene)cyclohrxyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl carbamate2242-(3-(aminomethyl)-1- (1-(cis-4-(tert-butyl) cyclohexyl)piperidin- 4-yl)-5-fluoro-1H- indol-2-yl)ethan-1-ol2252-(1-(1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-3- (methylsulfonamido- methyl)-1H-indol-2- yl)ethyl carbamate2262-(3-(aminomethyl)-1- (1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-5- fluoro- 1H-indol-2-yl)ethyl sulfamate2272-(3-(aminomethyl)-1- (1-(cis-4-(tert- butyl)cyclohexyl) piperidin-4-yl)-1H- pyrrolo[2,3-b]pyridin- 2-yl)ethyl sulfamate Table 2 illustrates compounds of structural formula (III). In some embodiments, the 1,4-substituents on the cyclohexyl ring are cis to each other. TABLE 2No.Structure*IUPAC NameNMR (300 or 400 MHz)228(Z)-3-(hydroxy- imino)-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one1H NMR (DMSO-d6) δ 13.4 (1H, s), 8.00 (1H, d, J = 9 Hz), 7.40 (1H, t, J = 9 Hz), 7.18 (1H, d, J = 6 Hz), 7.05 (1H, t, J = 6 Hz), 4.00-4.02 (1H, m), 3.06 (2H, d, J = 9 Hz), 2.24-2.36 (3H, m), 2.08 (2H, t, J = 12 Hz), 1.52-1.69 (7H, m), 1.31-1.44 (4H, m), 1.06 (1H, s), 0.85 (6H, d, J = 6 Hz).229(Z)-1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-3-(methoxy- imino)indolin-2- one1H NMR (CDCl3) δ 8.39 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 5.7 Hz, 1H), 7.17 (d, J = 5.7 Hz, 1H), 7.09 (t, J = 5.7 Hz, 1H), 4.39 (s, 3H), 4.30 (m, 1H), 3.17 (d, J = 6.0 Hz, 2H), 2.48-2.32 (m, 3H), 2.21 (m, 2H), 1.78-1.50 (m, 9H), 1.40 (m, 2H), 1.14 (m, 1H), 0.90 (d, 6H)230N′-((Z)-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin- 3-ylidene)aceto- hydrazide1H NMR (CDCl3) δ 12.58 (br, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.35 (t. J = 7.5 Hz, 1H). 7.19 (d. J = 8.1 Hz, 1H), 7.10 (t, J = 11.4 Hz, 2H), 2.42 (m, 5H), 2.20 (m, 3H), 1.80-1.46 (m, 9H), 1.39 (m, 2H), 1.25 (s, 1H), 1.15 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H)231(Z)-3-((3- (aminooxy)pro- poxy)imino)-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one1H NMR (DMSO-d6) δ 7.91 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 5.98 (br, 2H), 4.46 (t, J = 6.3 Hz, 2H), 4.00 (m, 1H), 3.65 (t, J = 6.3 Hz, 2H), 3.07 (d, J = 11.1 Hz, 2H), 2.27 (m, 3H), 2.15-1.92 (m, 4H), 1.74-1.48 (m, 7H), 1.46-1.28 (m, 4H), 1.09 (m, 1H), 0.87 (d, J = 6.6 Hz, 6H)232(Z)-3-((2-hydroxy- ethoxy)imino)- 1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one1H NMR (DMSO-d6) δ 7.96 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 4.85 (t, J = 5.4 Hz, 1H), 4.40 (t, J = 5.4 Hz, 2H), 4.00 (m, 1H), 3.73 (q, J = 5.4 Hz, 2H), 3.05 (d, J = 11.1 Hz, 2H), 2.28 (m, 3H), 2.08 (t, J = 11.4 Hz, 2H), 1.73-1.27 (m, 11H), 1.07 (m, 1H), 0.85 (d, J = 6.6 Hz, 6H)233methyl 2-((Z)-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2- oxoindolin-3- ylidene)acetate1H NMR (CD3OD) δ 8.56 (d, J = 5.7 Hz, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 7.10 (t, J = 5.7 Hz, 1H), 6.78 (s, 1H), 4.40 (m, 1H), 3.87 (s, 3H), 3.70 (m, 2H), 2.90 (m, 2H), 2.14-1.78 (m, 6H), 1.76 (m, 5H), 1.55 (m, 2H), 1.28 (m, 3H), 0.96 (d, J = 4.5 Hz, 6H)2342-((Z)-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2- oxoindolin-3- ylidene)acetamido1H NMR (CDCl3) δ 8.56 (d, J = 5.7 Hz, 1H), 7.32 (m, 1H), 7.10 (m, 1H), 7.04 (t, J = 6.0 Hz, 1H), 6.91 (s, 1H), 5.92 (br, 1H), 5.66 (br, 1H), 4.23 (m, 1H), (d, J = 8.1 Hz, 2H), 2.46-2.28 (m, 3H), 2.20 (t, J = 8.7 Hz, 2H), 1.74-1.48 (m, 10H), 1.39 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)2355-((Z)-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin- 3-ylidene)-4- oxopentanamideNMR (CDCl3) δ 8.69 (d, J = 5.7 Hz, 1H), 7.30 (m, 1H), 7.09 (m, 1H), 7.03 (m, 1H), 6.98 (s, 1H), 5.78 (br, 1H), 5.59 (br, 1H), 4.23 (m, 1H), 3.72 (q, J = 4.2 Hz, 2H), 3.15 (m, 2H), 2.59 (t, J = 4.2 Hz, 2H), 2.45-2.14 (m, 5H), 1.65 (m, 10H), 1.40 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 4.8 Hz, 6H)2362-((Z)-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- ylidene)acetonitrileNMR CDCl3) δ 8.09 (d, J = 5.7 Hz, 1H), 7.40 (t, J = 5.7 Hz, 1H), 7.14 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 5.7 Hz, 1H), 6.31 (s, 1H), 4.20 (m, 1H), 3.15 (d, J = 5.4 Hz, 2H), 2.40 (m, 3H), 2.19 (t, J = 5.4 Hz, 2H), 1.78-1.49 (m, 7H), 1.52 (m, 2H), 1.40 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 5.1 Hz, 6H)237N-(1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)acetamido1H NMR (CD3OD) δ 7.28 (m, 3H), 7.07 (t, J = 7.5 Hz, 1H), 4.99 (s, 1H), 4.40 (m, 1H), 3.70 (m, 2H), 3.22 (m, 4H), 3.01-2.71 (m, 2H), 2.13-1.86 (m, 9H), 1.74 (m, 3H), 1.55 (m, 2H), 1.26 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H)238ethyl (1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)carbamate1H NMR (CD3OD) δ 7.33 (m, 2H), 7.19 (d, J = 8.1 Hz, 1H), 7.11 (q, J = 7.5 Hz, 1H), 4.33 (m, 1H), 4.11 (m, 2H), 3.71 (m, 1H), 3.24 (m, 4H), 3.05- 2.70 (m, 2H), 2.16-1.86 (m, 5H), 1.75 (m, 4H), 1.56 (m, 2H), 1.26 (m, 6H), 0.96 (d, J = 6.6 Hz, 6H)2391-(1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)-3-methylurea1H NMR (CDCl3) δ 7.09 (d, J = 7.2 Hz, 1H), 7.01 (m, 1H), 6.77 (m, 2H), 4.65 (d, J = 4.8 Hz, 1H), 4.26 (m, 1H), 3.13 (m, 2H), 2.70 (m, 3H), 2.40-2.10 (m, 4H), 1.88-1.31 (m, 13H), 1.14 (s, 1H), 0.90 (d, J = 6.6 Hz, 6H)240N-(1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)isobutyramide1H NMR (CDCl3) δ 7.35 (d, J = 7.5 Hz, 1H), 7.27 (m, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 5.96 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 7.5 Hz, 1H), 4.24 (m, 1H), 3.14 (d, J = 10.8 Hz, 2H), 2.52-2.27 (m, 3H), 2.18 (t, J = 11.7 Hz, 2H), 1.80-1.47 (m, 10H), 1.40 (m, 2H), 1.23 (m, 7H), 0.90 (d, 6H)2412-(1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin- 3-yl)acetic acid1H NMR (CDCl3) δ 12.8 (br, 1H), 7.42- 7.18 (m 3H), 6.93 (t, J = 5.4 Hz, 1H), 4.52 (m, 1H), 3.62 (s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 3.10-2.75 (m, 7H), 2.05-1.40 (m, 11H), 1.22 (m, 1H), 0.91 (d, J = 3.9 Hz, 6H)242methyl 2-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin- 3-yl)acetate1H NMR (CD3OD) δ 7.33-7.27 (m, 2H), 7.23 (d, J = 5.7 Hz, 1H), 7.06 (t, J = 5.7 Hz, 1H),4.44 (m, 1H), 3.71 (t, J = 3.9 Hz, 3H), 3.55 (s, 3H), 3.27 (m, 4H), 3.13-2.80 (m, 3H), 2.13-1.91 (m, 6H), 1.77 (m, 3H), 1.56 (t, J = 9.6 Hz, 2H), 1.26 (m, 1H), 0.96 (d, 6H)243ethyl 2-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetate1H NMR (CD3OD) δ 7.30 (d, J = 5.7 Hz, 2H), 7.23 (d, J = 5.7 Hz, 1H),7.06 (t, J = 5.7 Hz, 1H), 4.44 (m, 1H), 4.00 (m, 2H), 3.71 (m, 2H), 3.27 (m, 4H), 3.12-2.30 (m, 4H), 2.12-1.90 (m, 6H), 1.77 (m, 3H), 1.59 (m, 2H), 1.28 (m, 1H), 1.10 (t, J = 5.4 Hz, 3H), 0.96 (d, J = 4.8 Hz, 6H)244isopropyl 2-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetate1H NMR (CD3OD) δ 7.37-7.20 (m, 3H), 7.05 (t, J = 4.8 Hz, 1H), 4.44 (m, 1H),3.70 (m, 3H), 3.27 (m, 4H), 3.10- 2.82 (m, 4H), 2.14-1.90 (m, 6H), 1.77 (m, 3H), 1.56 (m, 2H), 1.27 (m, 1H), 1.07 (t, J = 4.8 Hz, 6H), 0.95 (d, 6H)2452-(1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamido1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.2 Hz, 1H),7.24 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.59 (br, 1H), 5.42 (br, 1H), 4.26 (m, 1H), 3.83 (t, J = 6.4 Hz, 1H), 3.15 (d, J = 11.2 Hz, 2H), 2.91 (dd, J = 15.6, 6.4 Hz, 1H), 2.65 (dd, J = 15.6, 6.4 Hz, 1H), 2.45-2.27 (m, 3H), 2.19 (t, J = 11.6 Hz, 2H), 1.75-1.61 (m, 8H), 1.52 (m, 2H), 1.39 (m, 1H), 1.14 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H)2463-(2-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamido)pro- panamide1H NMR (CD3OD) δ 7.27 (m, 2H), 7.14 (d, J = 6.0 Hz, 1H), 7.05 (t, J = 5.7 Hz, 1H), 4.37 (m, 1H), 3.71 (m, 2H), 3.39-3.20 (m, 5H), 2.96-2.72 (m, 5H), 2.31 (m, 2H), 2.13-1.88 (m, 6H), 1.76 (m, 3H), 1.56 (m, 2H), 1.25 (m, 1H), 0.96 (d, J = 5.1 Hz, 6H)2472-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)-N-methoxy- acetamide1H NMR (400 MHz, CDCl3) δ 8.53 (1H, d, J = δ Hz), 7.31 (1H, td, J = 8, 4 Hz), 7.10 (1H, d, J = 8 Hz), 7.02 (1H, t, J = 8 Hz), 6.83 (1H, s), 4.21-4.26 1H, m), 3.13 (2H, d, J = 6 Hz), 2.29-2.45 (3H, m), 2.18 (2H, t, J = 12 Hz), 1.59- 1.71 (7H, m), 1.56 (9H, s), 1.34-1.52 (4H, m), 1.13 (1H, s), 0.89 (6H, d, J = 8 Hz)2482-(5-fluoro-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)-N-methoxy- acetamide1H NMR (CD3OD) δ 7.16 (dd, J = 8.4, 4.2 Hz, 1H), 7.07 (m, 1H), 4.42 (s, 3H), 3.69 (d, J = 11.4 Hz, 2H), 3.53 (s, 3H), 3.20 (m, 3H), 2.96-2.74 (m, 4H), 2.10- 1.86 (m, 6H), 1.75 (m, 3H), 1.54 (m, 2H), 1.24 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H)2492-(1-(1-(4,4- dimethylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)-N-methoxy- acetamide1H NMR (CDCl3) δ 7.30 (d, J = 7.5 Hz, 1H),7.22 (m, 2H), 7.04 (m, 1H), 5.40 (br, 1H), 4.26 (m, 1H), 3.77 (s, 3H), 3.07 (d, J = 8.1 Hz, 2H), 2.68 (m, 1H), 2.45- 2.25 (m, 5H), 1.68 (m, 6H), 1.45 (m, 4H), 1.23 (m, 2H), 0.90 (s, 6H)250N-hydroxy-2-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamido1H NMR (CDCl3) δ 7.31 (d, J = 7.5 Hz, 2H), 7.17 (m, 1H), 7.04 (t, J = 7.5 Hz, 1H), 4.18 (m, 1H), 3.80 (t, J = 6.6 Hz, 1H), 3.15 (d, J = 10.5 Hz, 2H), 2.80- 2.20 (m, 7H), 1.67 (m, 9H), 1.39 (m, 2H), 1.15 (m, 1H), 0.90 (d, 6H)2512-(1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)-N′-methyl- acetohydrazide1H NMR (400 MHz, CDCl3) δ 7.92 (br, 1H), 7.28 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 4.59 (br, 1H), 4.26 (m, 1H), 3.83 (t, J = 6.4 Hz, 1H), 3.14 (d, J = 10.8 Hz, 2H), 2.82 (dd, J = 15.6, 6.8 Hz, 1H), 2.60 (m, 4H), 2.45- 2.15 (m, 3H), 2.19 (t, J = 11.6 Hz, 2H), 1.78- 1.59 (m, 7H), 1.52 (m, 2H), 1.38 (m, 2H), 1.14 (m, 1H), 0.90 (d, 6H)252N′-acetyl-2- (1-(1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetohydrazide1H NMR (400 MHz, CDCl3) δ 9.71 (br, 1H), 8.83 (br, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 4.26 (m, 1H), 3.83 (t, J = 6.4 Hz, 1H), 3.12 (d, J = 10.4 Hz, 2H), 2.92 (dd, J = 16.0, 6.4 Hz, 1H), 2.73 (dd, J = 16.0, 6.4 Hz, 1H), 2.45-2.27 (m, 3H), 2.17 (t, J = 11.2 Hz, 2H), 2.03 (s, 3H), 1.77-1.46 (m, 9H), 1.38 (m, 1H), 1.13 (m, 2H), 0.90 (d, J = 6.6 Hz, 6H)253N-(benzyloxy)-2- (1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamido1H NMR (CDCl3) δ 9.20 (br, 1H), 7.38 (m, 5H), 7.28 (m, 3H), 7.03 (m, 1H), 4.94 (m, 3H), 4.33 (m, 1H), 3.79 (m, 1H), 3.10 (d, J = 11.1 Hz, 2H), 2.78- 2.45 (m, 4H), 2.33 (t, J = 11.7 Hz, 2H), 1.84-1.48 (m, 9H), 1.36 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H)2543-(2-hydroxyethyl)- 1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one1H NMR (DSMO-d6) δ 10.15 (br, 1H), 7.69 (m, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.32 (d, J = 5.4 Hz, 1H), 7.25 (t, J = 5.4 Hz, 1H), 7.03 (t, J = 5.4 Hz, 1H), 4.51 (m, 1H), 3.60-3.12 (m, 8H), 2.82 (d, J = 6.3 Hz, 2H), 2.03 (m, 1H), 1.91-1.58 (m, 8H), 1.48-1.14 (m, 5H), 0.88 (d, J = 4.8 Hz, 6H)255N-(2-(1-(1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)ethyl)acetamido1H NMR (DSMO-d6) δ 7.88 (s, 1H), 7.36 (d, J = 5.7 Hz, 1H), 7.27 (t, J = 5.7 Hz, 1H), 7.04 (t, J = 5.7 Hz, 1H), 3.50-3.00 (m, 12H), 1.98 (m, 2H), 1.79-1.58 (m, 12H), 1.38 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 4.8 Hz, 6H)256(2S)-2-amino-5- guanidino-N-(2-(1- (1-((1s,4R)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)ethyl)pentanamide1H NMR (CD3OD) δ 7.40 (t, J = 5.7 Hz, 1H), 7.32 (t, J = 5.7 Hz, 1H), 7.20 (d, J = 5.7 Hz, 1H), 7.11 (t, J = 5.7 Hz, 1H), 4.44 (m, 1H), 3.83 (m, 2H), 3.71 (d, J = 8.7 Hz, 2H), 3.56 (m, 1H), 3.40-3.20 (m, 10H), 2.86 (m, 2H), 2.17-1.50 (m, 19H), 1.26 (m, 2H), 0.96 (d, 6H)2571-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-3-((tetra- hydrofuran-3- yl)methyl)indolin- 2-one1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.25-7.15 (m, 2H), 7.01 (m, 2H), 4.29 (m, 1H), 4.10 (m, 1H), 3.91 (m, 1H), 3.83 (m, 1H), 3.75 (m, 1H), 3.63 (m, 1H), 3.50 (t, J = 5.6 Hz, 1H), 3.13 (m, 2H), 2.24-2.05 (m, 6H), 1.97-1.47 (m, 12H), 1.41 (m, 2H), 1.15 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H)2581-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-3-(pyrrolidin- 3-ylmethyl)indolin- 2-one1H NMR (400 MHz, CDCl3) δ 7.26 (m, 1H), 7.18 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 5.36 (br, 1H), 4.28 (m, 1H), 3.69 (br, 2H), 3.42 (q, J = 5.6 Hz, 1H), 3.16- 2.90 (m, 4H), 2.50-2.30 (m, 4H), 2.21 (t, J = 11.2 Hz, 2H), 2.03 (m, 2H), 1.78- 1.33 (m, 11H), 1.22 (d, J = 5.6 Hz, 2H), 1.14 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H)2592-(1-(1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)acetonitrile1H NMR (CDCl3) δ 7.50 (d, J = 5.4 Hz, 1H), 7.33 (t, J = 5.7 Hz, 1H), 7.22 (d, J = 5.7 Hz, 1H), 7.11 (t, J = 5.7 Hz, 1H), 4.25 (m, 1H), 3.64 (dd, J = 6.6, 3.3 Hz, 1H), 3.14 (m, 2H), 3.08 (d, J = 3.3 Hz, 1H), 2.73 (dd, J = 12.6, 6.6 Hz, 1H), 2.48-2.30 (m, 3H), 2.20 (t, J = 8.7 Hz, 2H), 1.78-1.50 (m, 13H), 1.39 (m, 2H), 1.14 (m, 1H), 0.90 (d, J = 4.8 Hz, 6H)260(Z)-5-fluoro-3- (hydroxyimino)- 1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one261(Z)-3-(hydroxy- imino)-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-2-one262(Z)-5-fluoro-3- (hydroxyimino)- 1-(1-(4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-2-one263(Z)-5-bromo-3- (hydroxyimino)- 1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one264(Z)-5-chloro-3- (hydroxyimino)- 1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)indolin-2-one265(Z)-3-(hydroxy- imino)-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindoline- 5-carbonitrile266(Z)-3-(hydroxy- imino)-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 5-yl carbamate267(Z)-1-(1-((1R,5S)- bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 3-(hydroxy- imino)indolin-2- one268(Z)-1-(1-(1R,5S)- bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 5-fluoro-3-(hydroxy- imino)indolin-2- one2692-((Z)-5-fluoro-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- ylidene)acetamide270(Z)-2-(5-fluoro-2- oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin-4- yl)indolin-3- ylidene)acetamide271(Z)-2-(5-cyano-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- ylidene)acetamide272(Z)-2-(1-(1- (bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 2-oxoindolin-3- ylidene)acetamide273(Z)-2-(1-(1- ((6,6-dimethyl- bicyclo[3.1.1]heptan- 2-yl)methyl)piperidin- 4-yl)-2-oxoindolin-3- ylidene)acetamide2742-(2-oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide2752-(5-fluoro-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)acetamide2762-(5-fluoro-2-oxo- 1-(1-(4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide2772-(5-cyano-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamide2782-(5-cyano-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide2792-(1-(1-(((2R)- 6,6-dimethyl- bicyclo[3.1.1]heptan- 2-yl)methyl)piperidin- 4-yl)-2-oxoindolin-3- yl)acetamide2802-(1-(1- (bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 2-oxoindolin-3- yl)acetamide2812-(1-(1- (bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 5-fluoro-2-oxoindolin- 3-yl)acetamide282N-(2-(5-fluoro-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin-3- yl)ethyl)acetamide283N-(2-(2-oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin-4- yl)indolin-3- yl)ethyl)acetamide2842-(2-oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetonitrile2852-(5-fluoro-1-(1- ((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)acetonitrile2862-(5-fluoro-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetonitrile2872-(1-(1-((1R,5S)- bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 2-oxoindolin-3- yl)acetonitrile2882-(1-(1- ((6,6-dimethyl- bicyclo[3.1.1]heptan- 2-yl)methyl)piperidin- 4-yl)-2-oxoindolin-3- yl)acetonitrile2892-(1-(1-((1R,5S)- bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)-5- fluoro-2-oxoindolin-3- yl)acetonitrile290(2S)-2-amino-5- guanidino-N-(2-(2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin-4- yl)indolin-3- yl)ethyl)pentanamide291(2S)-2-amino-N- (2-(5-cyano-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)ethyl)-5- guanidinopentanamide292(2S)-2-amino-N- (2-(5-fluoro-1- (1-((1s,4R)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)ethyl)-5- guanidinopentanamide293(2S)-2-amino-N- (2-(5-cyano-1- (1-((1s,4R)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin-3- yl)ethyl)-5- guanidinopentanamide294N-(2-oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide295N-(5-fluoro-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamide296N-(5-fluoro-2- oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide297N-(5-fluoro-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)isobutyramide298N-(2-oxo-1-(1- (4-(propan- 2-ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)isobutyramide299N-(5-fluoro-2- oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)isobutyramide300N-(5-cyano-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)acetamide301N-(5-cyano-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)isobutyramide302N-(5-cyano-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide303ethyl (2-oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin-4- yl)indolin-3- yl)carbamate304ethyl (5-fluoro-1-(1- ((1s,4s)-4-iso- propylcyclo- hexyl)piperidin-4-yl)- 2-oxoindolin-3- yl)carbamate305ethyl (5-fluoro-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)carbamate306ethyl (5-cyano-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)carbamate307ethyl (5-cyano-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)carbamate308ethyl (1-(1-(((2R)- 6,6-dimethyl- bicyclo[3.1.1]heptan- 2-yl)methyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)carbamate309ethyl (1-(1- (bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 2-oxoindolin-3- yl)carbamate310ethyl (1-(1- (bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 5-fluoro-2-oxoindolin- 3-yl)carbamate311N-methoxy-2- (2-oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide3122-(5-fluoro-2- oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)-N-methoxy- acetamide313N-hydroxy-2- (2-oxo-1-(1-(4- (propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetamide3142-(5-cyano-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)-N-methoxy- acetamide3152-(1-(1-((1R,5S)- bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 2-oxoindolin-3-yl)-N- methoxyacetamide3162-(1-(1-((1R,5S)- bicyclo[3.3.1]nonan- 9-yl)piperidin-4-yl)- 2-oxoindolin-3-yl)-N- hydroxyacetamide3172-(5-bromo-1- (1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin- 3-yl)-N-methoxy- acetamide318N′-methyl-2- (2-oxo-1- (1-(4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetohydrazide3192-(5-fluoro- 1-(1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin-4- yl)-2-oxoindolin-3- yl)-N′-methyl- acetohydrazide3202-(5-bromo-1- (1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxoindolin- 3-yl)-N′-methyl- acetohydrazide321N′-acetyl-2- (2-oxo-1-(1- (4-(propan-2- ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetohydrazide322N′-acetyl-2- (5-fluoro- 1-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2- oxoindolin-3- yl)acetohydrazide323N′-acetyl-2- (5-fluoro-2- oxo-1-(1- (4-(propan- 2-ylidene)cyclo- hexyl)piperidin- 4-yl)indolin-3- yl)acetohydrazide3241-(1-(4-(propan-2- ylidene)cyclo- hexyl)piperidin-4- yl)-3-(pyrrolidin-3- ylmethyl)indolin- 2-one3255-fluoro-1- (1-((1s,4s)- 4-isopropylcyclo- hexyl)piperidin- 4-yl)-3- (pyrrolidin-3- ylmethyl)indolin- 2-one3261-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxo-3- (pyrrolidin-3- ylmethyl)indoline- 5-carbonitrile3271-(1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2-oxo-3- (pyrrolidin-3- ylmethyl)indoline- 5-carboxamide3283-((4,5-dihydro- 1H-imidazol- 2-yl)methyl)-1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin-4- yl)indolin-2-one329isopropyl 2-(1- (1-((1s,4s)-4- isopropylcyclo- hexyl)piperidin- 4-yl)-2- oxoindolin-3- yl)acetimidate Table 3 illustrates compounds of structural formula (IV). In some embodiments, the 1,4-substituents on the cyclohexyl ring are cis to each other. TABLE 3No.Structure*NameNMR (300 Or 400 MHz)3301′-(cis-[1,1′- bi(cyclohexan)]-4- yl)-1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (300 MHz, CDCl3) δ 7.58 (1H, m), 7.34 (1H, t, J = 6 Hz), 7.25, t, J = 6 Hz), 7.15 (1H, d, 6 Hz), 4.51 (2 H, s), 3.0 (4H, m), 2.19 (4H, d, J = 10 Hz), 1.71 (12 H, m), 1.26 (8H, m), 0.82 (3H, m)3311′-(cis-[1,1′- bi(cyclohexan)]-4- yl)-2-methyl-1,2- dihydro-3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (CDCl3) δ, J = 6 Hz), 7.40 (1H, t, J = 6 Hz), 7.25 (1H, t, J = 6 Hz), 7.15 (1H, d, J = 6 Hz), 4.56 (2H, s), 3.82 (2H, m), 3.36 (3H, m), 3.11 (3H, s), 3.03 (1H, m), 2.06 (4H, m), 1.73 (8H, m), 1.26 (8H, m), 0.82 (3H, m)332methyl 2-(1′-(cis- 4-isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)acetate1H NMR (DMSO, d6) δ, J = 6 Hz), 7.40 (1H, t, J = 6 Hz), 7.37 (1H, t, J = 6 Hz), 7.28 (1H, d, J = 6 Hz), 4.64 (2H, s), 4.27 (2H, s), 3.67 (3H, s), 3.5 (4H, m), 3.2 (1H, m), 2.18 (2H, d, J = 8 Hz), 1.83 (4H, m), 1.69 (4H, m), 1.42 (2H, m), 1.15 (1H, m), 0.88 (6H, d, J = 5 Hz)333isopropyl 2-(1′- (cis-4-isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)acetate1H NMR (DMSO, d6) δ, J = 6 Hz), 7.39 (1H, t, J = 6 Hz), 7.33 (1H, t, J = 6 Hz), 7.29 (1H, d, J = 6 Hz), 4.63 (2H, s), 4.13 (2H, s), 3.5 (4H, m), 3.20 (1H, m), 2.17 (2H, d, J = 8 Hz), 1.82 (4H, m), 1.67 (4H, m), 1.39 (11H, s), 1.16 (1H, m), 0.87 (6H, d, J = 5 Hz)3342-(1′-(cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)acetic acid1H NMR (DMSO, d6) δ, J = 6 Hz), 7.38 (1H, t, J = 6 Hz), 7.31 (1H, t, J = 6 Hz), 7.28 (1H, d, J = 6 Hz), 4.62 (2H, s), 4.14 (2H, s), 3.1 (1H, m), 2.3 (2H, m), 2.19 (2H, m), 1.77 (4H, m), 1.67 (4H, m), 1.40 (2H, m), 1.13 (1H, m,), 0.9 (6H, d,)3352-(1′-(cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) acetamide1H NMR (CDCl3) δ, J = 6 Hz), 7.34 (1H, t, J = 6 Hz), 7.25 (1H, t, J = 6 Hz), 7.18 (1H, d, J = 6 Hz), 4.15 (2H, s), 2.85 (4H, m), 2.30 (1H, m), 2.22 (2H, d, J = 8 Hz), 2.05 (2H, m), 1.6 (10H, m), 1.37 (2H, m), 1.12 (1H, m), 0.88 (6H, d, J = 5 Hz)3361′-(cis-4- isopropyl- cyclohexyl)-2- (2-methoxy- ethyl)-1,2- dihydro-3H- spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (DMSO, d6) δ, J = 6 Hz), 7.38 (1H, t, J = 6 Hz), 7.32 (1H, t, J = 6 Hz), 7.29 (1H, d, J = 6 Hz), 4.65 (2H, s), 3.62 (2H, m), 3.48 (4H, m), 3.25 (3H, s), 3.2 (1H, m), 2.39 (3H, m), 2.13 (2H, d, J = 8 Hz), 1.83 (4H, m), 1.70 (4H, m), 1.40 (2H, m), 1.13 (1H, m), 0.9 (6H, d)337tert-butyl 3- (1′-(cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) propanoate1H NMR (DMSO, d6) δ, (1H, t, J = 6 Hz), 7.28 (1H, d, J = 6 Hz), 4.61 (2H, s), 3.64 (2H, m), 3.47 (4H, m), 3.21 (1H, m), 2.4 (3H, m), 2.12 (2H, d, J = 8 Hz), 1.84 (4H, m), 1.69 4H, m), 1.31 (11H, s), 1.57 (1H, m), 0.88 (6H, d, J = 5 Hz)3382-(1′-(cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl acetate1H NMR (DMSO, d6) δ 10.0 (1H, m), 7.46 (1H, d, J = 6 Hz), 7.38 (1H, t, J = 6 Hz), 7.32 (1H, t, J = 6 Hz), 7.30 (1H, d, J = 6 Hz), 4.65 (2H, s), 4.20 (2H, m), 3.70 (2H, m), 3.47 (4H, m), 3.22 (1H, m), 2.15 (2H, d, J = 8 Hz), 1.99 (3H, s), 1.84 (4H, m), 1.68 (4H, m), 1.41 (2H, m), 1.15 (1H, m), 0.88 (6H, d, J = 5 Hz)3392-(1′-(cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) acetonitrile1H NMR (DMSO, d6) δ 7.35 (1H, t, J = 6 Hz), 7.33 (1H, d, J = 6 Hz), 4.74 (2H, s), 4.56 (2H, s), 3.5 (4H, m), 3.22 (1H, m), 2.18 (2H, d, J = 8 Hz), 1.83 (4H, m), 1.69 (4H, m), 1.40 (2H, m), 1.17 (1H, m), 0.88 (6H, d, J = 5 Hz)3402-(2-amino- ethyl)-1′-(cis- 4-isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (DMSO, d6) δ 10.6 (1H, m), 8.06 (3H, m), 7.54 (1H, d, J = 6 Hz), 7.38 (1H, t, J = 6 Hz), 7.32 (1H, t, J = 6 Hz), 7.26 (1H, d, J = 6 Hz), 4.68 (2H, s), 3.68 (2H, m), 3.47 (4H, m), 3.16 (2H, m), 3.03 (2H, m), 2.22 (2H, d, J = 8 Hz), 1.84 (4H, m), 1.68 (4H, m), 1.42 (2H, m), 1.14 (1H, m), 0.88 (6H, d, J = 5 Hz)3411-(2-(1′- (cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)guanidine1H NMR (DMSO, d6) δ, 7.96 (1H, m), = 6 Hz), 7.32 (1H, t, J = 6 Hz), 7.28 (1H, d, J = 6 Hz), 4.68 (2H, s), 3.59 (2H, m), 3.46 (4H, m), 3.17 (1H, m), 2.20 (2H, d, J = 8 Hz), 1.83 (4H, m), 1.60 (4H, m), 1.40 (2H, m), 1.14 (1H, m), 0.88 (6H, d, J = 5 Hz)342(S)-2-amino- 5-guanidino- N-(2-(1′-(cis- 4-isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- ethyl) 2(3H)-yl) pentanamide1H NMR (DMSO, d6) δ, 8.98 (1H, m), 8.29 (3H, m), 7.88 (1H, m), = 6 Hz), 7.32 (1H, t, J = 6 Hz), 7.28 (1H, d, J = 6 Hz), 4.69 (2H, s), 3.82 (1H, m), 3.15 (4H, m), 2.20 (2H, d, J = 8 Hz), 1.86 (3H, m), 1.71 (4H, m), 1.51 (2H, m), 1.41 (2H, m), 1.13 (1H, m), 0.88 (6H, d, J = 5 Hz)343N-(2-(1′- (cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) methane- sulfonamide1H NMR (CDCl3) δ, J = 6 Hz), 7.33 (1H, t, J = 6 Hz), 7.25 (1H, t, J = 6 Hz), 7.19 (1H, d, J = 6 Hz), 5.00 (1H, m), 4.59 (2H, s), 3.70 (2H, m), 3.38 (2H, m), 2.84 (6H, s), 2.30 (1H, m), 2.19 (2H, d, J = 8 Hz), 2.01 (2H, m), 1.65 (8H, m), 1.36 (2H, m), 1.12 (1H, m), 0.88 (6H, d, J = 5 Hz)344N-(2-(1′- (cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) amino- sulfonamide1H NMR (DMSO, d6) δ, (2H, s), 3.5 (4H, = 4 Hz), 2.81 (3H, m), 2.33 (2H, m), 2.23 (2H, m), 2.04 (2H, m), 1.71 (2H, m), 1.59 (6H, m), 1.36 (2H, m), 1.12 (1H, m), 0.87 (6H, d)3452-(1′-(cis- 4-isopropyl- cyclohexyl)-3- oxo-7-phenyl- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) acetamide1H NMR (300 MHz, CDCl3) δ 7.1-7.8 (8H, m), 4.41 (2H, s), 4.59 (2H, s), 4.06 (2H, m), 3.02 (4H, m), 2.9 (4H, m), 2.1 (4H, m), 1.65 (8H, m), 1.36 (2H, m), 1.10 (1H, m), 0.86 (6H, d, J = 5 Hz)3462-(2-amino- ethyl)-1′- (cis-4- isopropyl- cyclohexyl)-7- phenyl-1,2- dihydro-3H- spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (300 MHz, CDCl3) δ 7.85 (1H, d, J = 6 Hz), 7.61 (1H, d, J = 6 Hz), 7.56 (2H, d, J = 6 Hz), 7.45 (2H, t, J = 6 Hz), 7.38 (1H, d, J = 6 Hz), 7.34 (1H, br s), 4.66 (2H, s), 3.77 (2H, m), 3.62 2H, m), 3.40 (2H, m), 3.0 (5H, m), 1.8 (4H, m), 1.44 (2H, m), 1.26 (1H, m), 0.91 (6H, d)3472-(2-amino- ethyl)-7- bromo-1′- (cis-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (300 MHz, CDCl3) δ 7.68 (1H, d, J = 6 Hz), 7.50 (1H, dd, J = 6, 1.2 Hz), 7.29 (1H, d, J = 1.2 Hz), 4.57 (2H, s), 3.74 (2H, m), 3.59 (2H, m), 3.37 (2H, m), 3.09 (1H, m), 2.98 (3H, m), 2.06 (4H, m), 1.71 (4H, m), 1.47 (2H, m), 1.24 (1H, m), 0.90 (6H, d)3487-bromo-1′- (cis-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (300 MHz, CDCl3) δ 7.43 (1H, d, J = 6 Hz), 7.34 (1H, d, J = 6 Hz), 7.31 (1H, br s), 6.04 (1H, m), 4.46 (2H, s), 2.83 (3H, m), 2.32 (1H, m), 2.19 (2H, d, J = 8 Hz), 1.98 (2H, m), 1.63 (8H, m), 1.36 (2H, m), 1.12 (1H, m), 0.88 (6H, d, J = 5 Hz)3491-(2-(1′- (cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)urea1H NMR (CDCl3) δ J = 6 Hz), 7.31 (1H, t, J = 6 Hz), 7.23 (1H, t, J = 6 Hz), 7.12 (1H, d, J = 6 Hz), 6.12 (1H, m), 5.0 (2H, m), 4.64 (2H, s), 3.64 (4H, m), 3.42 (2H, m), 3.27 (2H, m), 2.92 (1H, m), 2.62 (2H, m), 2.32 (2H, d, J = 8 Hz), 1.91 (5H, m), 1.65 (4H, m), 1.36 (2H, m), 1.21 (1H, m), 0.89 (6H, d, J = 5 Hz)3501′-(cis-4- isopropyl- cyclohexyl)-7- methyl-1,2- dihydro-3H- spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (300 MHz, CDCl3) δ 7.39 (1H, d, J = 6 Hz), 7.12 (1H, d, J = 6 Hz), 6.97 (1H, br s), 6.0 (1H, m), 4.44 (2H, s), 3.83 (4H, m), 2.34 (3H, s), 2.19 (2H, d, J = 8 Hz), 2.00 (2H, m), 1.64 (8H, m), 1.36 (2H, m), 1.12 (1H, m), 0.88 (6H, d, J = 5 Hz)3512-(2- hydroxyethyl)- 1′-(cis-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (CDCl3) δ J = 6 Hz), 7.36 (1H, t, J = 6 Hz), 7.53 (1H, t, J = 6 Hz), 7.15 (1H, d, J = 6 Hz), 4.62 (2H, s), 3.86 (2H, m), 3.70 (2H, m), 3.25 (1H, m), 3.12 (2H, m), 2.17 (2H, d, J = 8 Hz), 1.84 (4H, m), 1.66 (4H, m), 1.41 (2H, m), 1.18 (1H, m), 0.89 (6H, d, J = 5 Hz)3521-(2-(1′- (cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)thiourea1H NMR (CDCl3) δ J = 6 Hz), 7.33 (1H, t, J = 6 Hz), 7.26 (1H, t, J = 6 Hz), 7.18 (1H, d, J = 6 Hz), 5.85 (1H, m), 4.62 (2H, s), 3.75 (2H, m), 2.83 (3H, br s), 2.33 (1H, m), 2.18 (2H, m), 2.05 (2H, m), 1.65 (8H, m), 1.37 (2H, m), 1.23 (1H, m), 0.87 (6H, d, J = 5 Hz)353N-(2-(1′- (cis-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) formamide1H NMR (CDCl3) δ), d, J = 8 Hz), 1.61 (11H, m), 1.40 (2H, m), 1.67 (1H, m), 0.88 (6H, d)3542-(2-(benzyl- oxy)ethyl)-1′- (cis-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one1H NMR (DMSO, d6) δ 10.3 (1H, m), 7.44 (1H, d, J = 6 Hz), 7.37 (1H, t, J = 6 Hz), 7.29 (7H, m), 4.67 (2H, s), 4.47 (2H, s), 3.66 (4H, d, J = 17 Hz), 3.05 (1H, m), 2.39 (2H, m), 2.08 (2H, d, J = 8 Hz), 1.83 (2H, m), 1.72 (4H, m), 1.56 (2H, m), 1.38 (2H, m), 1.14 (1H, m), 0.88 (6H, d)355N-(2-(1′- (4,4-dimethyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)amino- sulfonamide1H NMR (CDCl3) δ, 4.56 (2H, s), 3.73 (2H, m), 3.37 (2H, m), 2.90 (3H, m), 2.24 (2H, J = 8 Hz), 2.18 (2H, m), 1.72 (2H, m), 1.48 (4H, m), 1.20 (2H, m), 0.89 (6H, s)3562-(2-amino- ethyl)-1′-(4- (propan-2- ylidene) cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one3572-(2-amino- ethyl)-7- fluoro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one358N-(2-(2- aminoethyl)- 1′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl)acetamide3592-(2-amino- ethyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidine]- 7-carbonitrile3602-(2-amino- ethyl)-7- isopropoxy- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one3612-(2-amino- ethyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate3622-(2-amino- ethyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl carbamate3631-(2-(3-oxo- 1′-(4- (propan-2- ylidene) cyclohexyl)- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) guanidine3641-(2-(7- fluoro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) guanidine3651-(2-(7- chloro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) guanidine3661-(2-(7- hydroxy-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) guanidine367N-(2-(2- guanidino- ethyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl)acetamide3681-(2-(7-cyano- 1′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) guanidine3691-(2-(7- isopropoxy- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) guanidine3702-(2-guanidino- ethyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate3712-(2-guanidino- ethyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl carbamate372N-(2-(3-oxo- 1′-(4-(propan- 2-ylidene) cyclohexyl)- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) methane- sulfonamide373N-(2-(7- fluoro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) methane- sulfonamide374N-(2-(7- chloro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) methane- sulfonamide375N-(1′- ((1s,4s)-4- isopropyl- cyclohexyl)-2- (2-(methyl- sulfonamido) ethyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl)acetamide376N-(2-(7- cyano-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) methane- sulfonamide377N-(2-(7- isopropoxy- 1′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl) methane- sulfonamide3781′-((1s,4s)-4- isopropyl- cyclohexyl)-2- (2-(methyl- sulfonamido) ethyl)-3-oxo- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate3791′-((1s,4s)-4- isopropyl- cyclohexyl)-2- (2-(methyl- sulfonamido) ethyl)-3-oxo- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl carbamate380N-(2-(3-oxo- 1′-(4-(propan- 2-ylidene) cyclohexyl)- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)amino- sulfamide381N-(2-(7- fluoro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)amino- sulfamide382N-(2-(7- chloro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)amino- sulfamide383N-(1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 3-oxo-2-(2- (sulfamoyl- amino)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl)acetamide384N-(2-(7- cyano-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)amino- sulfamide385N-(2-(7- isopropyloxy- 1′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl) ethyl)amino- sulfamide3861′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo-2-(2- (sulfamoyl- amino)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate3871′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo-2-(2- (sulfamoyl- amino)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl carbamate3882-(2-(2- oxopiperidin- 1-yl)ethyl)- 1′-(4-(propan- 2-ylidene) cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one,3897-fluoro- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 2-(2-(2- oxopiperidin- 1-yl)ethyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one3907-chloro- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 2-(2-(2- oxopiperidin- 1-yl)ethyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one391N-(1′-((1s,4s)- 4-isopropyl- cyclohexyl)-3- oxo-2-(2-(2- oxopiperidin- 1-yl)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl)acetamide3921′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2-(2-(2- oxopiperidin- 1-yl)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidine]- 7-carbonitrile3937-isopropoxy- 1′-((1s,4s,)-4- isopropyl- cyclohexyl)- 2-(2-(2- oxopiperidin- 1-yl)ethyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one3941′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2-(2-(2- oxopiperidin- 1-yl)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate3951′-((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2-(2-(2- oxopiperidin- 1-yl)ethyl)- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl carbamate3961′-((1s,4s)-4- isopropyl- cyclohexyl)- 2-(2-(2- oxopiperidin- 1-yl)ethyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one 3973972-((4,5- dihydro-1H- imidazol-2-yl) methyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one3982-((4,5- dihydro-1H- imidazol-2-yl) methyl)-1′- (4-(propan-2- ylidene) cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one3992-((4,5- dihydro-1H- imidazol-2-yl) methyl)-7- fluoro-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one4007-chloro-2- ((4,5-dihydro- 1H-imidazol- 2-yl)methyl)- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one401N-(2-((4,5- dihydro-1H- imidazol-2- yl)methyl)- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl)acetamide4022-((4,5- dihydro-1H- imidazol-2-yl) methyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)-3- oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidine]- 7-carbonitrile4032-((4,5- dihydro-1H- imidazol-2-yl) methyl)-7- isopropoxy- 1′-((1s,4s)-4- isopropyl- cyclohexyl)- 1,2-dihydro- 3H-spiro [isoquinoline- 4,4′-piperidin]- 3-one4042-((4,5- dihydro-1H- imidazol-2-yl) methyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 3-oxo- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate4052-((4,5- dihydro-1H- imidazol-2-yl) methyl)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 3-oxo- 2,3-dihydro- 1H-spiro [isoquinoline- 4,4′-piperidin]- 7-yl carbamate4062-(1′-((1s,4s)- 4-isopropyl- cyclohexyl)-3- oxo-1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4072-(3-oxo- 1′-(4-(propan- 2-ylidene) cyclohexyl)- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4082-(7-fluoro- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4092-(7-chloro- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4102-(7- acetamido- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4112-(7-cyano- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4122-(7- isopropoxy- 1′-((1s,4s)- 4-isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate4131′-((1s,4s)- 4-isopropyl- cyclohexyl)- 2-(2-((methyl- carbamoyl) oxy)ethyl)- 3-oxo-2,3- dihydro-1H- spiro [isoquinoline- 4,4′-piperidin]- 7-yl sulfamate4142-(7- (carbamoyl- oxy)-1′- ((1s,4s)-4- isopropyl- cyclohexyl)- 3-oxo- 1H-spiro [isoquinoline- 4,4′-piperidin]- 2(3H)-yl)ethyl methyl- carbamate Preparation of the Compounds The piperidinyl-containing nociceptin receptor compounds of Formula (I), and the embodiments represented by Formula (II), Formula (III), and Formula (IV) can be synthesized via numerous synthetic routes as may be appreciated by one of ordinary skill in the art. Exemplary synthetic methods for compounds of Formula (II) are shown in Figures 1 through 6 and 10, and described in Examples 1 through 6 and 10 below. Table 1 also provides1H NMR or TLC data for compounds of Formula II. Exemplary synthetic methods for compounds of Formula (III) are shown in Figures 7 and 8 and described in Examples 7 and 8 below. For the compounds of Formula (III), Table 2 provides1H NMR or TLC data for such compounds. An exemplary route to compounds of Formula (IV) is shown in Figure 9 and described in Example 9 below. For the compounds of Formula (IV), Table 3 provides1H NMR data where indicated. Compositions and Methods of Administration The compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders described herein and a vehicle. Vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients. The compositions contain one or more compounds provided herein. The compounds are, in some embodiments, formulated into suitable preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as topical administration, transdermal administration and oral inhalation via nebulizers, pressurized metered dose inhalers and dry powder inhalers. In some embodiments, the compounds described above are formulated into compositions using techniques and procedures well known in the art (see, e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)). In the compositions, effective concentrations of one or more compounds or derivatives thereof is (are) mixed with a suitable vehicle. The compounds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, ion-pairs, hydrates or prodrugs prior to formulation, as described above. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration that treats, leads to prevention, or amelioration of one or more of the symptoms of diseases or disorders described herein. In some embodiments, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of a compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated. The active compound is included in the vehicle in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be predicted empirically by testing the compounds in in vitro and in vivo systems well known to those of skill in the art and then extrapolated therefrom for dosages for humans. Human doses are then typically fine-tuned in clinical trials and titrated to response. The concentration of active compound in the composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders as described herein. In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used such as use of liposomes, prodrugs, complexation/chelation, nanoparticles, or emulsions or tertiary templating. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO), using surfactants or surface modifiers, such as TWEEN®, complexing agents such as cyclodextrin or dissolution by enhanced ionization (i.e. dissolving in aqueous sodium bicarbonate). Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective compositions. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. The compositions are provided for administration to humans and animals in indication appropriate dosage forms, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes/bioerodible strips, tablets or capsules, powders, granules, lozenges, lotions, salves, suppositories, fast melts, transdermal patches or other transdermal application devices/preparations, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or derivatives thereof. The therapeutically active compounds and derivatives thereof are, in some embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required vehicle. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging. Liquid compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional adjuvants in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension, colloidal dispersion, emulsion or liposomal formulation. If desired, the composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions thereof. Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from vehicle or carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 0.4-10%. In certain embodiments, the compositions are lactose-free compositions containing excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions contain active ingredients, a binder/filler, and a lubricant in compatible amounts. Particular lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate. Further provided are anhydrous compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations. Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are generally packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. Oral dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. In certain embodiments, the formulations are solid dosage forms such as for example, capsules or tablets. The tablets, pills, capsules, troches and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an enteric coating; a film coating agent and modified release agent. Examples of binders include microcrystalline cellulose, methyl paraben, polyalkyleneoxides, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidones, sucrose and starch and starch derivatives. Lubricants include talc, starch, magnesium/calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate and advanced coloring or anti-forgery color/opalescent additives known to those skilled in the art. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation or mask unpleasant taste, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Enteric-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Modified release agents include polymers such as the Eudragit® series and cellulose esters. The compound, or derivative thereof, can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2blockers, and diuretics. The active ingredient is a compound or derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included. In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil. Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation. For a solid dosage form, the solution or suspension, in for example, propylene carbonate, vegetable oils or triglycerides, is in some embodiments encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a liquid vehicle, e.g., water, to be easily measured for administration. Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those set forth in U.S. Pat. Nos. RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or polyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates. Other formulations include, but are not limited to, aqueous alcoholic solutions including an acetal. Alcohols used in these formulations are any water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal. Parenteral administration, in some embodiments characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous. If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. Vehicles used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (Tween® 80). A sequestering or chelating agent of metal ions includes EDTA. Carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. The concentration of compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, body surface area and condition of the patient or animal as is known in the art. The unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. Injectables are designed for local and systemic administration. In some embodiments, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.01% w/w up to about 90% w/w or more, in certain embodiments more than 0.1% w/w of the active compound to the treated tissue(s). The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. All controlled-release products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials can be used. In other embodiments, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels. The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, an antioxidant, a buffer and a bulking agent. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose and other suitable agent. The solvent may contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, at about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In some embodiments, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature. Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined. Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. The compounds or derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will, in some embodiments, have mass median geometric diameters of less than 5 microns, in other embodiments less than 10 microns. Oral inhalation formulations of the compounds or derivatives suitable for inhalation include metered dose inhalers, dry powder inhalers and liquid preparations for administration from a nebulizer or metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, a crystalline form of the compounds or derivatives is the preferred physical form of the drug to confer longer product stability. In addition to particle size reduction methods known to those skilled in the art, crystalline particles of the compounds or derivatives can be generated using supercritical fluid processing which offers significant advantages in the production of such particles for inhalation delivery by producing respirable particles of the desired size in a single step. (e.g., International Publication No. WO2005/025506). A controlled particle size for the microcrystals can be selected to ensure that a significant fraction of the compounds or derivatives is deposited in the lung. In some embodiments, these particles have a mass median aerodynamic diameter of about 0.1 to about 10 microns, in other embodiments, about 1 to about 5 microns and still other embodiments, about 1.2 to about 3 microns. Inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane) and provided either alone or as a ratio to match the density of crystal particles of the compounds or derivatives. A ratio is also selected to ensure that the product suspension avoids detrimental sedimentation or cream (which can precipitate irreversible agglomeration) and instead promote a loosely flocculated system, which is easily dispersed when shaken. Loosely fluctuated systems are well regarded to provide optimal stability for pMDI canisters. As a result of the formulation's properties, the formulation contained no ethanol and no surfactants/stabilizing agents. The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other excipients can also be administered. For nasal administration, the preparation may contain an esterified phosphonate compound dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol application. The carrier may contain solubilizing or suspending agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives. Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7.4, with appropriate salts. Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein. Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those of skill in the art. For example, such patches are disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957. For example, dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The weight of a rectal suppository, in one embodiment, is about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same substance and by the same methods as for formulations for oral administration. The compounds provided herein, or derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. In some embodiments, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down phosphatidyl choline and phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. The compounds or derivatives may be packaged as articles of manufacture containing packaging material, a compound or derivative thereof provided herein, which is effective for treatment, prevention or amelioration of one or more symptoms of the diseases or disorders, supra, within the packaging material, and a label that indicates that the compound or composition or derivative thereof, is used for the treatment, prevention or amelioration of one or more symptoms of the diseases or disorders, supra. The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder described herein. Dosages For use to treat or prevent infectious disease, the compounds described herein, or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount. In human therapeutics, the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. The amount of active ingredient in the formulations provided herein, which will be effective in the prevention or treatment of an infectious disease will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the infection, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Exemplary doses of a formulation include milligram or microgram amounts of the active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 micrograms per kilogram to about 5 milligrams per kilogram). In some embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.001 ng/ml to about 50-200 μg/ml. The compositions, in other embodiments, should provide a dosage of from about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 5000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data or subsequent clinical testing. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50as determined in cell culture (i.e., the concentration of test compound that is lethal to 50% of a cell culture), or the IC100as determined in cell culture (i.e., the concentration of compound that is lethal to 100% of a cell culture). Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques that are well known in the art. One of ordinary skill in the art can readily optimize administration to humans based on animal data. Alternatively, initial dosages can be determined from the dosages administered of known agents by comparing the IC50, MIC and/or I100of the specific compound disclosed herein with that of a known agent, and adjusting the initial dosages accordingly. The optimal dosage may be obtained from these initial values by routine optimization In cases of local administration or selective uptake, the effective local concentration compound used may not be related to plasma concentration. One of skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation. Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of compounds can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50(the dose lethal to 50% of the population) or the LD100(the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in subjects. The dosage of the compounds described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (See, e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1). The therapy may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. Methods of Use of the Compounds and Compositions The compounds and compositions described herein can be used in a wide variety of applications to treat or prevent neurological conditions and other disorders in a subject. The methods generally involve administering therapeutically effective amounts of compounds disclosed herein or a pharmaceutical composition thereof to the subject. The compounds and compositions described herein may be used to treat and prevent, for example, pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain, sickle-cell disease pain, acute pain), fibromyalgia, migraine; substance abuse or dependency (e.g., nicotine, cocaine, methamphetamine), alcohol addiction; neurological conditions such as anxiety, depression (e.g., major depressive disorder), post-traumatic stress disorder, mood disorder, affective disorders (e.g. depression and dysthymia; bipolar disorder, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, vertigo, epilepsy, schizophrenia, schizophrenia-related disorder, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, behavior disorder; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia; cognitive impairment, cognitive impairment associated with schizophrenia (CIAS), movement disorders, restless leg syndrome (RLS), multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effect of medications, insomnia, eating disorder, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. Nociceptin receptor compounds can be used to treat or prevent renal disorders and urinary incontinence, including, but not limited to those characterized by inappropriate antidiuretic hormone secretion, imbalances of water retention and/or salt excretion. For example, U.S. Pat. No. 6,869,960 discloses a class of spiropiperidine ORL-1 ligands said to be therapeutic agents for renal disorders. Nociceptin receptor compounds can further be used to treat or prevent cardiovascular disorders including but not limited to systolic hypertension, myocardial infarction, bradycardia, arrhythmias, hypertension, hypotension, thrombosis, anemia, arteriosclerosis and angina pectoris. For example, U.S. Pat. No. 7,241,770 discloses a class of nociceptin agonists said to be therapeutic agents for cardiovascular disorders. Nociceptin receptor compounds can be further used to treat gastrointestinal disorders including but not limited to diarrhea and pain such as that in inflammatory bowel diseases, Crohn's disease, inflammatory bowel syndrome. The compounds disclosed herein may utilize a new, non-dopaminergic target for the treatment of Parkinson's disease (PD) and its associated dysinesias. Several studies have uncovered a pathogenic role of N/OFQ and the NOP receptor in nigrostriatal pathways affected in PD (vide infra). The NOP receptor, a G-protein coupled receptor, is the fourth member of the opioid receptor family, but does not bind known opiates with high affinity (Mollereau et al., FEBS Lett., 1994, 341:33-8). The endogenous ligand for NOP is a 17-amino acid peptide called N/OFQ. N/OFQ has low affinity for the mu, delta, and kappa opioid receptors (Gintzler, et al., Eur. J. Pharmacol., 1997, 325:29-34). The N/OFQ-NOP receptor system is widely expressed in brain cortical and subcortical areas, particularly in striatum, globus pallidus and substantia nigra (SN) neurons. Endogenous N/OFQ contributes to development of PD symptoms and N/OFQ levels are elevated in the SNr following dopamine (DA) cell loss or impairment of DA transmission (Marti, et al., Mov. Disord., 2010, 25:1723-32). Such an increase is also observed in the CSF of PD patients (Marti et al., 2010); ii) NOP receptor antagonists reverse parkinsonian symptoms in neurodegenerative (6-OHDA hemi-lesioned rat, MPTP-treated mouse and macaque) and functional (reserpinized- or haloperidol-treated animals) models of PD iii) genetic deletion of the N/OFQ gene protects mice from the neurotoxic action of MPTP. Mechanistic studies revealed that the antiparkinsonian action of NOP antagonists is accomplished through normalization of the imbalance between excitatory (GLU) and inhibitory (GABA) inputs impinging on nigro-thalamic neurons, generated by striatal DA deafferentation. NOP antagonists also potentiate the symptomatic effect of levodopa. NOP receptor agonists (commercially available SCH221510; Varty et al., J. Pharmaco. Exp. Ther., 2008, 326:672-82) attenuated the expression of abnormal involuntary movements [AIMs, a rodent correlate of levodopa-induced dyskinesias (LID)] in dyskinetic rats and nonhuman primates challenged with L-DOPA, by acting in the striatum where, contrary to SNr, the N/OFQ tone is reduced and NOP receptors are up-regulated following DA cell loss (Marti, M., et al., 2012). This action can be dissociated from the typical motor-inhibiting effects of NOP agonists, since antidyskinetic doses were 100-fold lower than the typical hypo-locomotive doses. From a clinical perspective, NOP receptor antagonists disclosed herein may be useful in treating the symptoms and the neurodegeneration associated with PD, while NOP receptor agonists are effective in treating LID. Genetic deletion of the N/OFQ gene protects mice from the neurotoxic action of MPTP. Mechanistic studies revealed that the antiparkinsonian action of NOP antagonists is accomplished through normalization of the imbalance between excitatory (GLU) and inhibitory (GABA) inputs impinging on nigro-thalamic neurons, generated by striatal DA deafferentation. NOP antagonists also potentiate the symptomatic effect of levodopa. Therefore NOP receptor antagonists may provide symptomatic and neuroprotective benefit in PD patients. On the other hand, NOP receptor agonists have been shown to attenuate the expression of AIMs in dyskinetic rats and nonhuman primates challenged with L-DOPA. Nociceptin receptor agonists are known in the art to block the rewarding properties of several common drugs of abuse such as morphine, cocaine, amphetamines, and alcohol. Administration of NOP ligands suppresses basal and drug-stimulated dopamine release in the reward areas in rodent brain. The inhibitory effect of NOP agonists on drug reward and the inhibition of drug-induced dopamine release in mesolimbic areas in the brain suggest the utility of NOP agonists as drug abuse medications. The compounds descried herein may find use in the treatment of substance abuse disorders and addiction. While other opioid receptors, mu, delta and kappa opioid receptors are historically associated with “opioid analgesia”, the NOP receptor and its agonists and antagonists have only begun to be noticed as possible analgesics, due to emerging data on the antinociceptive efficacies of NOP ligands in rodents and nonhuman primate models of acute pain as well as neuropathic and inflammatory pain (Khroyan et al., Eur. J. Pharmacol., 2009, 610:49-54; Khroyan et al., J. Pharmacol. Exper. Therap., 2011, 339:687-93; Khroyan et al., J. Pharmacol. Exp. Ther., 2007, 320:934-43; Lin and Ko, ACS Chem. Neurosci., 2013, 4:214-24; Toll et al., J. Pharmacol. Exp. Ther., 2009, 331:954-64). The NOP receptor is widely distributed in the central and peripheral nervous systems and in the same pain processing pathways as the other three opioid receptors. However, unlike the opioid receptors, the pharmacology of the NOP receptor in nociception is quite distinct and complex. NOP agonists have been shown to have potent anti-nociceptive potency in rodent models of chronic pain (Khroyan et al., J. Pharmacol. Exper. Therap., 2011, 339:687-93; Sukhtankar et al, J. Pharmacol. Exp. Ther., 2013, 346:11-22). NOP antagonists can potentiate the anti-nociceptive efficacies of morphine in chronic pain (Khroyan et al., Eur. J. Pharmacol., 2009, 610:49-54). NOP agonists which are effective as analgesics do not show any rewarding effects or abuse potential in rodent models, pointing to a possible advantage that NOP agonists may have as non-addicting analgesics over traditional opioids (Khroyan et al., J. Pharmacol. Exper. Ther., 2011, 339:687-93; Toll et al., J. Pharmacol. Exp. Ther., 2009, 331:954-64). The compounds disclosed herein may find use as analgesics (NOP agonists) or adjuncts to opioid pain therapy (NOP antagonists), particularly for chronic, neuropathic as well as inflammatory pain conditions. While all nociceptin receptor ligands have binding affinity for the NOP receptor, they can modulate the “intrinsic activity (functional efficacy)” of the receptor over a spectrum from 0% to a 100%. NOP ligands that have 0% functional efficacy and block the function of the receptor are classified as NOP antagonists. Ligands that have 75-100% functional efficacy and activate the receptor are classified as NOP agonists. Those ligands in between (15-75% functional efficacy) are generally labelled as NOP partial agonists. The binding affinity of NOP ligands as well as their functional efficacy (agonist, partial agonist, antagonist) may be modulated by chemical structure modifications, as shown in our previous studies with various chemical scaffolds (Zaveri et al., J. Med. Chem., 2004, 47:2973-6; Zaveri, et al., AAPS J., 2005, 7:E345-52; Zaveri et al., “Structure-activity relationships of Nociceptin Receptor (NOP) Ligands and the Design of Bifunctional NOP/mu opioid receptor-targeted Ligands”, in Research and Development of Opioid-Related Analgesics, Ko, M. C.; Husbands, S. M., Eds., American Chemical Society, 2013, Chapter 8, pp 145-160). Combination Therapy The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination, or sequentially, with another therapeutic agent. Such other therapeutic agents include those known for treatment, prevention, or amelioration one or more symptoms associated with drug addiction, pain, neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, psychiatric disorders, renal disorders, gastrointestinal disorders, and cardiovascular disorders. It should be understood that any suitable combination of the compounds and pharmaceutical compositions provided herein with one or more of the above therapeutic agents and optionally one or more further pharmacologically active substances are considered to be within the scope of the present disclosure. In some embodiments, the compounds and pharmaceutical compositions provided herein are administered prior to or subsequent to the one or more additional active ingredients. All publications and patents cited herein are incorporated by reference in their entirety. EXAMPLES The starting materials and reagents employed in preparing these compounds were obtained from commercial suppliers such as Sigma-Aldrich (St. Louis, Mo.), Strem Chemicals (Newburyport, Mass.), and AK Scientific (Union City, Calif.).1H NMR spectra were recorded on a Varian Gemini 300 MHz spectrometer (300 MHz and 75 MHz, respectively) and are internally referenced to chloroform at δ 7.27. Data for 1H NMR are reported as follows: chemical shift (6 ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constant (Hz), integration, and assignment. Mass spectra were obtained using a ThermoFinnigan LCQ Duo LC/MS/MS or API 150 EX MS (Applied Biosystems) instrument and an electrospray ionization probe. Thin-layer chromatography was run on Analtech Uniplate silica gel TLC plates. Flash chromatography was carried out using silica gel, Merck grade 9385, 230-400 mesh. Example 1: Synthesis of 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole (61) and 1-(1-((1s, 4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-3-carbaldehyde oxime (81) SCHEME I depicts this synthesis. Scheme I Reagents and Conditions: a) AcOH, sodium triacetoxyborohydride (STAB), MgSO4, DCE, rt (General Procedure A); b) i. TFA, CH2Cl2, ii. 4-isopropyl-cyclohexanone, STAB, AcOH, DCE (General Procedure B, 2 steps); c) MnO2, CH2Cl2; d) POCl3, DMF; and e) NH2OH.HCl, NaOAc.3H2O, EtOH:H2O (2:1), 110° C. General Procedure A: Reductive Amination with N-Boc Piperidone: The aniline substrate (1.00 equiv) and N-Boc-piperidone (1.05-1.50 equiv) were charged into a round bottom flask. 1,2-DCE (0.25M) was added, and the mixture was stirred until both components dissolved. To this solution was added MgSO4(100 wt % of limiting reagent) and glacial AcOH (1.00-2.30 equiv) at ambient temperature, and the solution was stirred for 90 minutes. At this stage, sodium triacetoxyborohydride (STAB) (1.50-2.30 equiv) was added. The reaction was allowed to stir at room temperature and monitored by TLC (EtOAc:Hexanes). After 1-2 days, the reaction was >90% complete by TLC analysis. The reaction was quenched with saturated NaHCO3(aq.) and stirred until the reaction mixture was basic and bubbling had ceased. The biphasic layer was separated and the organic layer was washed 2× with H2O, brine, dried with MgSO4, filtered and concentrated in vacuo to provide a brown oil that was purified via flash chromatography using EtOAc:Hexanes to provide the desired product, which was used directly in the following reaction. t-butyl 4-(indolin-1-yl)piperidine-1-carboxylate (I-1) See General Procedure A: Indoline (10.0 g, 83.9 mmol, 1.00 equiv), N-Boc piperidone (17.6 g, 88.1 mg, 1.05 equiv), AcOH, 4.80 mL, 83.9 mmol, 1.00 equiv), STAB (26.7 g, 12.6 mmol, 1.50). MgSO4was not used in the reaction. The crude oil was purified via flash chromatography using 10:90 EtOAc:Hexanes to provide indoline I-1 (24.3 g, 96% yield).1H NMR (300 MHz, CDCl3) δ 7.06 (t, J=6.0 Hz, 2H), 6.03 (t, J=6.0 Hz, 1H), 6.43 (d, J=6.0 Hz, 1H), 4.25 (m, 2H), 3.52 (m, 1H), 3.35 (t, J=6.3 Hz, 2H), 2.79 (m, 2H), 1.80 (d, J=9.3 Hz, 2H), 1.60 (m, 4H), 1.49 (s, 9H); MS (APCI) m/z: 303.06 [M+H]+. General Procedure B: Boc Removal and Reductive Amination with 4-iPr Cyclohexanone: Step 1. A solution of N-Boc intermediate (1.00 equiv) in CH2Cl2(0.25-0.30M) was cooled to 0° C., and then TFA (6-30 equiv) was added over several minutes. Upon completion of addition, the ice-bath was removed and the reaction was allowed to warm to room temperature and monitored by TLC (EtOAc:Hexanes). After 2 hours, the reaction was complete. The reaction was concentrated in vacuo, followed by the addition of EtOAc, which was consequently removed in vacuo. The oil residue was then dissolved in EtOAc and was stirred as saturated NaHCO3(aq.) was added until the aqueous layer remained basic. The layers were separated, and the aqueous layer was extracted with EtOAc until UV activity in the aqueous layer was minimal (3-8×). The EtOAc layers were combined, washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide the piperidine intermediate. Step 2. The piperidine intermediate from the previous step (1.00 equiv) and 4-iPr-cyclohexanone (1.00-1.50 equiv) were dissolved 1,2-DCE (0.070M). To the reaction was added glacial AcOH (1.00-2.30 equiv), and the reaction was stirred for 20 minutes. After 20 minutes, STAB (1.50-2.30 equiv) was added in 3 portions. An Ar balloon was fitted on top of the reaction, and the reaction was monitored by TLC (MeOH:CH2Cl2:NH4OH (aq.)). After 2-3 days, the reaction was >95% complete; hence, saturated NaHCO3(aq.) was added until the aqueous layer remained basic. At this stage, the layers were separated, and the aqueous layer was extracted 2× with CH2Cl2. The organic layers were combined, and washed 2× with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a crude residue that was purified via flash chromatography using EtOAc:Hexanes:NH4OH (aq.). syn-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)indoline (I-2) See General Procedure B: Step 1. Indoline I-1 (24.4 g, 80.5 mmol, 1.00 eq), TFA (38.0 mL, 496 mmol, 6.20 equiv), CH2Cl2(300 mL, 0.27M). Combined EtOAc layers were dried immediately with MgSO4, and were not washed with water or brine. Obtained a grey solid (13.6 g, 84% yield). Step 2. See General Procedure B: N—H piperidine from the previous step (13.6 g, 67.2 mmol, 1.00 equiv), iPr-cyclohexanone (9.40 g, 67.2 mmol, 1.00 equiv), AcOH (3.85 mL, 67.2 mmol, 1.00 equiv), STAB (21.3 g, 101 mmol, 1.50 equiv). Purified via flash chromatography using 10:90:1.5 EtOAc:Hexanes:NH4OH (aq.) to provide intermediate I-2 as a light-gold oil (33% yield). Rf=0.25 (20:80:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3) δ 7.05 (t, J=5.7 Hz, 2H), 6.60 (J=5.7 Hz, 1H), 6.41 (d, J=5.7 Hz, 1H), 3.37 (m, 3H), 3.10 (d, J=8.7 Hz, 2H), 2.94 (t, J=6.3 Hz, 2H), 2.27 (m, 1H), 2.14 (t, J=8.7 Hz, 2H), 1.54-1.82 (m, 11H), 1.38 (m, 2H), 1.13 (m, 1H), 0.88 (d, J=5.1 Hz, 6H); MS(ESI) m/z: 327.4 [M+H]+. syn-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole (61) Indoline I-2 (4.63 g, 14.2 mmol, 1.00 equiv) was dissolved in 180 mL of CH2Cl2. To this solution was added 4 ÅMS (56.8 g, 4 g/mmol of indoline), followed by MnO2(12.3 g, 142 mmol, 10.0 equiv) and another 20 mL of CH2Cl2. An argon balloon was fitted onto the reaction vessel, and the thick suspension was stirred and monitored by TLC (20:80:3 drops EtOAc:hexanes:NH4OH (aq.)). After 16 hours, the reaction was complete. The mixture was filtered over a large pad of Celite and the remaining solid was washed 5× with CH2Cl2. The filtrate was concentrated in vacuo to provide a crude oil. This material was dissolved in EtOAc, and 10% HCl (aq.) was added with vigorous stirring, which resulted in a white precipitate. The white solid was filtered, and washed 3× with EtOAc, and was then air-dried over 1 hour. The white solid was then suspended in EtOAc, 70% NaHCO3(aq.) was added, and the mixture stirred until >90% of the solid had dissolved. The EtOAc layer was separated, washed with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a thick oil that was purified via flash chromatography using 10:90:1.5 EtOAc:hexanes:NH4OH (aq.) to provide indole 1 as an off-white solid (3.65 g, 79% yield). Rf=0.25 (10:90:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=6.0 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H), 7.26 (m, 1H), 7.20 (t, J=6.0 Hz, 1H), 7.11 (t, J=6.0 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 4.23 (m, 1H), 3.20 (d, J=9.0 Hz, 2H), 2.30 (m, 3H), 2.08 (m, 4H), 1.51-1.78 (m, 7H), 1.40 (m, 2H), 1.17 (m, 1H), 0.9 (d, J=4.8 Hz, 6H); MS(ESI) m/z: 325.4 [M+H]+. syn-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-3-carbaldehyde (I-3) To a stirred solution of 25.0 mL DMF at 0° C. was added POCl3(3.66 mL, 40.0 mmol, 4.00 equiv). The solution was stirred at 0° C. for 15 minutes. At this stage, indole I-3 (3.10 g, 10.0 mmol, 1.00 equiv), was dissolved in 10 mL of DMF with the assistance of heat. The warm solution of indole I-3 was then added to the reaction, and the reaction was rinsed with 5.00 mL of DMF. The reaction was now a red solution, and the reaction was allowed to stir for 15-20 minutes at 0° C. TLC (50:50:3 drops EtOAc:hexanes:NH4OH (aq.)) showed the reaction was complete. The reaction was poured into a saturated NaHCO3(aq.) ice bath, followed by the addition of CH2Cl2. The mixture was stirred vigorously for 30 minutes, upon which the layers were separated, and the aqueous layer was extracted with CH2Cl2until UV activity was minimal (5-6×). The organic layer was then washed 3× with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a dark red oil, which was purified via flash chromatography using 50:50:1.5 EtOAc:hexanes:NH4OH (aq.) to provide aldehyde I-3 as a light-yellow solid (2.15 g, 74% yield). Rf=0.20 (50:50:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 8.33 (m, 1H), 7.89 (s, 1H), 7.43 (m, 1H), 7.33 (m, 2H), 4.29 (m, 1H), 3.28 (d, J=7.8 Hz, 2H), 2.40 (m, 3H), 2.19 (m, 3H), 1.55-1.78 (m, 8H), 1.42 (m, 2H), 1.17 (m, 1H), 0.9 (d, J=5.7 Hz, 6H); MS(ESI) m/z: 353.1 [M+H]+. syn-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-3-carbaldehyde oxime (81) Aldehyde I-3 (2.15 g, 6.10 mmol, 1.00 equiv), NH2OH.HCl (551 mg, 7.93 mmol, 1.30 equiv), and NaOAc.3H2O (1.08 g, 7.93 mmol, 1.30 equiv) were charged into a round bottom flask. Absolute EtOH (20.5 mL) and 10 mL of H2O were added, and the reaction was fitted with a condenser and an Ar balloon on top. The suspension was heated to reflux (ca. 110° C. oil bath) and monitored by TLC (40:60:3 drops EtOAc:hexanes:NH4OH (aq.)). After 2 hours, the reaction was complete. The reaction was allowed to cool to room temperature upon which a white precipitate formed. The mixture was diluted with EtOAc and saturated NaHCO3(aq.), and stirred until the mixture became a biphasic solution. The layers were separated, and the organic layer was washed 2× with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide oxime 2 as a white solid (1.74 g, 78% yield). The two isomers of the oxime are in a ca. 3:2 ratio. Rf=0.50 (top spot), 0.45 (bottom spot) (40:60:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3, Major Isomer) δ10.8(br, 1H), 8.47 (s, 1H), 7.78 (m, 2H), 7.41 (d, J=6.0, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 4.31 (m, 1H), 3.30 (d, J=8.7 Hz, 2H), 2.55 (m, 1H), 2.46 (t, J=7.8, 2H), 2.23 (m, 3H), 1.86 (m, 2H), 1.60-1.80 (m, 6H), 1.43 (m, 2H), 1.19 (m, 1H), 0.91 (d, J=5.1, 6H);1H NMR (300 MHz, CDCl3, Minor Isomer) δ 8.30 (s, 1H), 8.07 (d, J=6.0 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J=6.0 Hz, 1H), 7.28 (t, J=5.4 Hz, 1H), 7.20 (t, J=5.4 Hz, 1H), 4.23 (m, 1H), 3.22 (d, J=5.7 Hz, 2H), 2.35 (m, 3H), 2.13 (m, 4H), 1.55-1.80 (m, 7H), 1.43 (m, 2H), 1.17 (m, 1H), 0.91 (d, J=5.1 Hz, 6H); MS(ESI) m/z: 368.5 [M+H]+. Example 2: Synthesis of Benzyl ((1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methyl)carbamate (17) and (1-(1-((1s, 4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanamine (3) SCHEME II depicts this synthesis. Scheme II Reagents and Conditions: a) i. N-Boc piperidone, AcOH, STAB, MgSO4, DCE, rt (General Procedure A), ii. TFA, CH2Cl2, iii. 4-isopropyl-cyclohexanone, STAB, AcOH, DCE (General Procedure B, 2 steps); b) i. benzyl prop-2-yn-1-ylcarbamate, cat. PdCl2(PPh3)2, catalyst copper(I)iodide (CuI), DMF:iso-Pr2NEt (3:1), ii. cat. Cu(OAc)2, PhMe, reflux (General Procedure C, 2 steps); and c) H2balloon, cat. 10% Pd/C, NH3/MeOH. syn-N-(2-iodophenyl)-1-(4-isopropylcyclohexyl)piperidin-4-amine (I-1) i. See General Procedure A. 2-iodoaniline (15.0 g, 63.3 mmol, 1.00 equiv), N-Boc-piperidone (18.5 g, 95.0 mmol, 1.50 equiv), glacial AcOH (8.40 mL, 146 mmol, 2.30 equiv), STAB (30.9 g, 146 mmol, 2.30 equiv), DCE (250 mL, 0.25M). MgSO4was not used in the reaction. The product was purified via flash chromatography using 5:95 EtOAc:hexanes to provide the desired bicyclic compound as a white solid (75% yield), and was used directly in the following reaction. Rf=0.15 (5:95 EtOAc:Hexanes, UV). ii. See General Procedure B: Step 1. N-Boc piperidine (43.5 g, 0.108 mol, 1.00 equiv), TFA (200 mL, 2.61 mol, 24.0 equiv), CH2Cl2(300 mL, 0.36M). Obtained the N—H piperidine intermediate as a light-tan solid (42.0 g, 128% yield, due to NaTFA), and was used directly in the next step. See General Procedure B: Step 2. N—H piperidine (0.108 mol, 1.00 equiv), 4-iPr-cyclohexanone (22.7 g, 0.162 mol, 1.50 equiv), glacial AcOH (14.2 mL, 0.248 mol, 2.30 equiv), STAB (52.6 g, 0.248 mol, 2.30 equiv), DCE (1.54 L, 0.070M). Compound II-1 was purified via flash chromatography using 6:94:1.5→9:91:1.5 EtOAc:hexanes:NH4OH (aq.) to provide a gold oil. (The syn diastereomer has a higher RFcompared to the anti diastereomer). The purified oil was dissolved in EtOAc and transferred to an Erlenmeyer flask, and then 10% HCl (aq.) was added. Upon addition of the 10% HCl (aq.), a white precipitate formed, and the suspension was stirred for 10 minutes. The white precipitate was then filtered, washed 2× with EtOAc, and then air dried over 1 hour. The white precipitate was then suspended in EtOAc in an erlenmeyer flask, and then saturated NaHCO3(aq.) was added until basic, and then stirred overnight. At this stage, the mixture was now a clear biphasic solution. The layers were separated, and the EtOAc layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide iodoaniline II-1 as a light gold oil (24.0 g, 39% yield over 3 steps). Rf=0.30 (10:90:3 drops EtOAc:hexanes:NH4OH (aq.), UV);1H NMR (CDCl3, 300 MHz) δ 7.65 (dd, J=5.7, 0.9, 1H), 7.184 (t, J=6.0, 1H), 6.58 (d, J=6.0, 1H), 6.41 (dt, J=5.7, 0.9, 1H), 4.12 (d, J=5.7 Hz, 1H), 3.36 (m, 1H), 2.93 (m, 2H), 2.25 (m, 3H), 2.15 (d, J=8.4 Hz, 2H), 1.47-1.74 (m, 8H), 1.38 (m, 2H), 1.13 (m, 1H), 0.89 (d, J=4.8 Hz, 6H); MS(ESI) m/z: 427 [M+H]+. General Procedure C: Sonogashira Coupling and Cyclization: Step 1. Iodoaniline (1.00 equiv) and terminal alkyne (3.00-5.00 equiv) were dissolved in DMF and iPr2NEt (3:1, 0.40 M). PdCl2(PPh3)2(0.0400 equiv) and CuI (0.100 equiv) were added simultaneously to the reaction mixture. An argon balloon with a 3-way adapter was placed on top of the reaction vessel, and the vessel was purged, and then backfilled with argon (repeated 3× total). The reaction was covered with aluminum foil, and allowed to stir overnight at ambient temperature. The reaction was monitored by TLC (EtOAc:hexanes:NH4OH (aq.)). Once complete, the reaction was diluted with EtOAc and H2O and stirred for 10 minutes. The biphasic layers were separated, and the organic layer was washed 2× with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified via flash chromatography, then used without further processing directly in the following reaction. Step 2. The internal alkyne from Step 1 (1.00 equiv) was charged into a round-bottom flask. Cu(OAc)2(0.200-0.400 equiv) was added, followed by PhMe (0.25M). The reaction was fitted with a reflux condenser, followed by an Ar balloon on top of the condenser. The reaction was then heated to reflux and monitored by TLC (30:70:3 drops EtOAc:hexanes:NH4OH (aq.)). After 1-2 hours, TLC showed the reaction was complete. The reaction was allowed to cool to room temperature, EtOAc and H2O were added, and the mixture was stirred for 30 minutes. The mixture was filtered through a pad of Celite, and the Celite pad was washed 3-4× with EtOAc. The layers were separated, and the organic layer was washed 1× with H2O. The water layers were combined, and extracted 1× with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a crude solid. This solid was adsorbed onto silica gel, loaded onto a column, and purified by flash chromatography to provide pure indole intermediate. syn-benzyl((1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methyl)carbamate (17) i. See General Procedure C: Step 1. Iodoaniline II-1 (5.60 g, 13.1 mmol, 1.00 equiv), N-benzyl prop-2-yn-1ylcarbamate (8.69 g, 45.9 mmol, 3.50 equiv), DMF (25.0 mL) and iPr2NEt (8.25 mL), PdCl2(PPh3)2(368 mg, 0.524 mmol, 0.0400 equiv), and CuI (250 mg, 1.31 mmol, 0.100 equiv). Crude product was purified by flash chromatography using 20:80:1.5 to 5:75:1.5 EtOAc:Hexanes:NH4OH (aq.) to provide the desired internal alkyne as a light-yellow solid (6.26 g, 98% yield), which was used directly in the next reaction. Rf=0.25 (25:75:3 drops EtOAc:Hexanes:NH4OH (aq.), UV). See General Procedure C: Step 2. Internal alkyne (6.26 g, 12.8 mmol, 1.00 equiv), Cu(OAc)2(700 mg, 3.85 mmol, 0.300 equiv), and PhMe (51.0 mL, 0.25M). Crude solid was purified by flash chromatography using 15:85:1.5 to 20:80:1.5 to 30:70:1.5 EtOAc:hexanes:NH4OH (aq.) to provide a light-yellow solid. The solid was triturated with a minimal amount of 1:1 EtOAc:hexanes to provide indole 3 as a white solid (64% yield over 2 steps). Rf=0.30 (25:75:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.32 (m, 5H), 7.16 (t, J=8.1 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.38 (s, 1H), 5.17 (s, 2H), 4.90 (br, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.15 (m, 1H), 3.10 (d, J=10.2 Hz, 2H), 2.57 (dq, J=12.6, 3.3 Hz, 2H), 2.31 (m, 1H), 2.10 (t, J=12.6 Hz, 2H), 1.35-1.80 (m, 11H), 1.17 (m, 1H), 0.93 (d, J=6.9 Hz, 6H); MS(ESI) m/z: 488.4 [M+H]+. syn-(1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanamine (3) Indole 17 (2.83 g, 5.80 mmol, 1.00 equiv.) and 10% Pd/C (425 mg, 15% w/w) were suspended in a 7N NH3in MeOH mixture. The reaction vessel was fitted with a H2balloon, and the atmosphere was purged and backfilled with H2, and then repeated (3× total). Over the next 2-3 hours, indole 17 slowly dissolved, and the reaction was monitored by TLC (100:3 drops EtOAc:NH4OH (aq.) After a total of 4 hours, the reaction was complete. The reaction mixture was filtered over a pad of Celite and washed thoroughly with MeOH. The filtrate was concentrated in vacuo, and the crude material was purified via flash chromatography using 0:100:1.5 to 2:98:1.5 MeOH:EtOAc:NH4OH (aq.) to provide diamine 3 as a white solid (2.00 g, 98% yield). Rf=0.35 (5:95:3 drops MeOH:EtOAc:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=6.3 Hz, 1H), 7.56 (d, J=5.4 Hz, 1H), 7.14 (dt, J=5.4, 0.9 Hz, 1H), 7.06 (dt, J=5.4, 0.9 Hz, 1H), 6.38 (s, 1H), 4.25 (m, 1H), 4.04 (s, 2H), 3.20 (d, J=9.0 Hz, 2H), 2.61 (dq, J=7.2, 1.8 Hz, 2H), 2.36 (m, 1H), 2.24, (t, J=8.4 Hz, 2H), 1.87 (dd, J=9.3, 1.5 Hz, 2H), 1.50-1.80 (m, 8H), 1.42 (m, 2H), 1.16 (m, 1H), 0.92 (d, J=4.8 Hz, 6H); MS(ESI) m/z: 354.5 [M+H]+. Example 3: Synthesis of (1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (30) and (E)-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-2-carbaldehyde oxime (1) SCHEME III depicts this synthesis. Scheme III Reagents and Conditions: a) i. terminal alkyne, cat. PdCl2(PPh3)2, cat. CuI, DMF:iPr2NEt (3:1), ii. cat. Cu(OAc)2, PhMe, reflux (General Procedure C, 2 steps); and b) i. MnO2, CH2Cl2, ii. NH2OH.HCl, NaOAc.3H2O, EtOH:H2O (2:1), 110° C. syn-(1-(1-(-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (30) See General Procedure C: Step i. Iodoaniline II-1 (3.97 g, 9.30 mmol, 1.00 equiv), propargyl alcohol (2.61 g, 46.5 mmol, 5.00 equiv.), DMF (17.2 mL) and iPr2NEt (5.8 mL), PdCl2(PPh3)2(261 mg, 0.372 mmol, 0.0400 equiv), and CuI (177 mg, 0.930 mmol, 0.100 equiv). Crude product was purified by flash chromatography using 40:60:1.5 to 50:50:1.5 EtOAc:hexanes:NH4OH (aq.) to provide the desired internal alkyne as a dark-red glue (2.86 g, 87% yield), which was used directly in the next reaction. See General Procedure C: Step 2. Internal alkyne (2.86 g, 8.07 mmol, 1.00 equiv), Cu(OAc)2(440 mg, 2.42 mmol, 0.300 equiv.), and PhMe (32.3 mL, 0.25M). This material (adsorbed onto silica gel) was loaded onto a column and purified by flash chromatography using 25:75:1.5 to 35:65:1.5 EtOAc:hexanes:NH4OH (aq.) to provide a light-yellow solid. The solid was triturated with a minimal amount of 1:1 EtOAc:hexanes to provide indole 30 as a white solid (1.82 g, 56% yield over 2 steps). Rf=0.25 (25:75:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 6.44 (s, 1H), 4.81 (d, J=4.8 Hz, 2H), 4.37 (m, 1H), 3.19 (d, J=11.6 Hz, 2H), 2.61 (dq, J=12.4, 3.2 Hz, 2H), 2.37 (m, 1H), 2.26 (t, J=11.6 Hz, 2H), 1.89 (d, J=12.0 Hz, 2H), 1.70 (m, 5H), 1.55 (m, 2H), 1.40 (m, 2H), 1.16 (m, 1H), 0.92 (d, J=6.8 Hz, 6H); MS(ESI) m/z: 355.27 [M+H]+. syn-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-2-carbaldehyde oxime (1) i. To a solution of indole 30 (1.30 g, 3.67 mmol, 1.00 equiv) in 36.7 mL of CH2Cl2, was added MnO2(3.83 g, 44.0 mmol, 12.0 equiv) at room temperature, and the reaction was allowed to stir overnight. At this stage, TLC (30:70:1.5 EtOAc:hexanes:NH4OH (aq.)) showed the reaction was complete. The reaction was filtered over a pad of Celite, washed 3× with CH2Cl2, and the filtrate was concentrated in vacuo to provide an aldehyde as a glue (1.27 g, 98%). This compound was used directly in the next procedure. ii. The latter aldehyde (1.26 g, 3.57 mmol, 1.00 equiv.), NH2OH.HCl (372 mg, 5.36 mmol, 1.50 equiv), and NaOAc-3H2O (730 mg, 5.36 mmol, 1.50 equiv.) were all charged into a round bottom flask. EtOH (12.0 mL) and H2O (6.00 mL) were then added, and a reflux condenser with an Ar balloon on top was attached to the reaction, and the reaction (a white suspension) was then heated to 110° C. At ca. 50° C., the reaction becomes a light-yellow solution, and at ca. 70-80° C., a white precipitate begins to form. At 110° C., the reaction is now a thick white slurry, and after 10 minutes, TLC (20:80:3 drops EtOAc:hexanes:NH4OH (aq.)) showed the reaction was complete. The reaction was allowed to cool to room temperature, CH2Cl2and saturated NaHCO3(aq.) was added, and the mixture stirred 20 minutes to provide a clear biphasic mixture. The layers were separated, and the aqueous layer was extracted 1× with CH2Cl2. The organic layers were combined, washed 2× with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide to provide a white foam. To this foam was added 2 mL of EtOAc, followed by 10 mL of MeOH, and the suspension was stirred for 10 minutes. The solid was then filtered, and washed 3× with cold MeOH, and dried in vacuo to provide oxime 1 as a white solid (1.10 g, 84% yield). Rf=0.25 (20:80:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (CDCl3, 300 MHz) δ 10.7 (br, 1H), 8.70 (s, 1H), 7.59 (m, 2H), 7.18 (t, J=5.7 Hz, 1H), 7.07 (t, J=5.7 Hz, 1H), 6.83 (s, 1H), 4.89 (m, 1H), 3.24 (d, J=8.4 Hz, 2H), 2.65 (dq, J=9.6, 2.1 Hz, 2H), 2.45 (m, 1H), 2.31 (t, J=8.7 Hz, 2H), 1.56-1.93 (m, 9H), 1.43 (m, 2H), 1.19 (m, 1H), 0.94 (d, J=4.8 Hz, 6H); MS(ESI) m/z: 368.32 [M+H]+. Example 4: Synthesis of 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)ethan-1-ol (32) and 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)ethyl sulfamate (11) SCHEME IV depicts this synthesis. Scheme IV Reagents and Conditions: a) i. terminal alkyne, cat. PdCl2(PPh3)2, cat. CuI, DMF:iso-Pr2NEt (3:1), ii. cat. Cu(OAc)2, PhMe, reflux (General Procedure C, 2 steps), iii. TBAF, THF, and b) ClSO2NH2, CH2Cl2. syn-2-(1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)ethan-1-ol (32) i. See General Procedure C: Step 1. Iodoaniline II-1 (1.60 g, 3.75 mmol, 1.00 equiv), (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (2.41 g, 13.1 mmol, 3.50 equiv), DMF (11.3 mL) and iPr2NEt (3.80 mL), and PdCl2(PPh3)2(105 mg, 0.150 mmol, 0.0400 equiv) and CuI (71.4 mg, 0.375 mmol, 0.100 equiv). The crude oil was purified via flash chromatography using 7:93:1.5 to 10:90:1.5 EtOAc:hexanes:NH4OH (aq.) to provide the desired internal alkyne as a brown oil (1.60 g, 88% yield), and it was used directly in following reaction. See General Procedure C: Step 2. Internal alkyne (1.60 g, 3.31 mmol, 1.00 equiv), Cu(OAc)2(601 mg, 3.31 mmol, 1.00 equiv), and PhMe (13.3 mL, 0.25M). Reaction time was 4 hours. The crude material was purified by flash chromatography using 2:98:1.5 to 6:94.15 to provide the desired indole as a light-yellow oil (1.00 g, 63% yield), and was used directly in the following reaction. ii. To a solution of the previously synthesized indole (1.10 g, 2.28 mmol, 1.00 equiv) in 15.0 mL of THF was added TBAF (1.0 M, 4.55 mL, 2.00 equiv) at room temperature, and the was stirred and monitored by TLC (20:80:3 drops EtOAc:hexanes:NH4OH (aq.)). Once the reaction was complete (ca. 2 hours), the reaction was concentrated in vacuo, and the crude material was flashed using 25:75:1.5 to 50:50:1.5 EtOAc:hexanes:NH4OH (aq.) to provide alcohol 32 as a white solid (792 mg, 94% yield). Rf=0.25 (30:70:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=9.0 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.13 (t, J=5.4 Hz, 1H), 7.07 (t, J=5.4 Hz, 1H), 6.33 (s, 1H), 4.14 (m, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.20 (d, J=8.7 Hz, 2H), 3.09 (t, J=4.8 Hz, 2H), 2.64 (q, J=7.5 Hz, 2H), 2.36 (m, 1H), 2.22 (t, J=8.7 Hz, 2H), 1.51-1.87 (m, 9H), 1.42 (m, 2H), 1.27 (m, 1H), 0.92 (d, J=4.8 Hz, 6H); MS(ESI) m/z: 369.27 [M+H]+. syn-2-(1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)ethyl sulfamate (11) To a solution of alcohol 32 (200 mg, 0.543 mmol, 1.00 equiv) and iPr2NEt (0.946 mL, 5.43 mmol, 10.0 equiv) in 5.00 mL of CH2Cl2, at 0° C., was added a solution (ca. 0.50 M in CH2Cl2) of sulfamoyl chloride (7.00 mL, 3.26 mmol, 6.00 equiv) dropwise to the reaction. The ice bath was removed, and the reaction was stirred for 1 hour. At this time, TLC (40:60:3 drops EtOAc:hexanes:NH4OH (aq.) showed the reaction was complete. The reaction was diluted with EtOAc, followed by the addition of 10% NaHCO3(aq.). A white precipitate formed, which was filtered and washed with EtOAc. The filtrate layers were separated, and the EtOAc layer was washed 2× with H2O, brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was flashed in 40:60:1.5 EtOAc:hexanes:NH4OH (aq.) to provide sulfamate 11 as a white solid (35 mg, 14% yield). Rf=0.25 (40:60:3 drops EtOAc:hexanes:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=6.3 Hz, 1H), 7.54 (d, J=5.7 Hz, 1H), 7.15 (t, J=5.7 Hz, 1H), 7.07 (t, J=5.7 Hz, 1H), 6.34 (s, 1H), 4.50 (t, J=5.1 Hz, 2H), 4.13 (m, 1H), 3.28 (t, J=5.1 Hz, 2H), 3.22 (d, J=8.4 Hz, 2H), 2.64 (m, 2H), 2.40 (m, 1H), 2.27 (t, J=8.4 Hz, 2H), 1.84 (d, J=8.4 Hz, 2H), 1.76 (m, 2H), 1.55-1.70 (m, 3H), 1.41 (m, 2H), 1.26 (m, 2H), 1.17 (m, 1H), 0.92 (d, J=5.1 Hz, 6H); MS(ESI) m/z: 448.3 [M+H]+. Example 5: Synthesis of (5-fluoro-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (29) SCHEME V depicts this synthesis. Scheme V Reagents and Conditions: a) i. N-Boc piperidone, AcOH, STAB, MgSO4, DCE, rt (General Procedure A), ii. TFA, CH2Cl2, iii. 4-iso-Pr-cyclohexanone, STAB, AcOH, DCE (General Procedure B, 2 steps); and b) i. terminal alkyne, cat. PdCl2(PPh3)2, cat. CuI, DMF:iso-Pr2NEt (3:1), ii. cat. Cu(OAc)2, PhMe, reflux (General Procedure C, 2 steps). syn-N-(4-fluoro-2-iodophenyl)-1-(4-isopropylcyclohexyl)piperidin-4-amine (V-1) i. See General Procedure A. 4-fluoro-2-iodoaniline (3.80 g, 16.0 mmol, 1.00 equiv), N-Boc piperidone (4.69 g, 24.0 mmol, 1.50 equiv), MgSO4(3.80 g, 100 wt %), glacial AcOH (2.11 mL, 36.8 mmol, 2.30 equiv), STAB (7.80 g, 36.8 mmol, 2.30 equiv), and DCE (80.0 mL, 0.20M). The crude material was purified via flash chromatography using 12:88 EtOAc:hexanes to provide the desired bicyclic intermediate as a white solid (6.70 g, 99% yield), and was used directly in the next reaction. ii. See General Procedure B: Step 1. N-boc piperidine intermediate (5.00 g, 11.9 mmol, 1.00 equiv), TFA (27.3 mL, 357 mmol, 30.0 equiv), CH2Cl2(60.0 mL, 0.20M). An off-white solid was obtained from the workup (4.94 g, 130%, due to NaTFA) of the reaction described above, and this material was used directly in the next reaction. See General Procedure B: Step 2. N—H piperidine intermediate (11.9 mmol, 1.00 equiv), 4-iPr-cyclohexanone (2.51 g, 17.9 mmol, 1.50 equiv), glacial AcOH (1.57 mL, 27.4 mmol, 2.30 equiv), MgSO4(3.81 g, 100 wt %), STAB (5.81 g, 27.4 mmol, 2.30 equiv), and DCE (150 mL, 0.080M). The crude material was purified via flash chromatography using 10:90:1.5 EtOAc:hexanes:NH4OH (aq.) to provide intermediate V-1 as a dark orange-brown oil (55% yield over 3 steps). Rf=0.25 (20:80:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (CDCl3, 300 MHz) δ 7.41 (dd, J=6.0, 2.1 Hz, 1H), 6.95 (dt, J=6.0, 2.1 Hz, 1H), 6.51 (dd, J=6.9, 3.6 Hz, 1H), 3.91 (d, J=6.0 Hz, 1H), 3.28 (m, 1H), 2.92 (m, 2H), 2.24 (m, 3H), 2.04 (m, 2H), 1.47-1.73 (m, 8H), 1.38 (m, 2H), 1.13 (m, 1H), 0.88 (d, J=5.1 Hz, 6H); MS(ESI) m/z: 445.1 [M+H]+. syn-(5-fluoro-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (29) i. See General Procedure C: Step 1. Intermediate V-1 (600 mg, 1.35 mmol, 1.00 equiv.), propargyl alcohol (378 mg, 6.75 mmol, 5.00 equiv.), DMF (3.12 mL) and iPr2NEt (1.13 mL), and PdCl2(PPh3)2(38.0 mg, 0.0540 mmol, 0.0400 equiv.) and CuI (25.7 mg, 0.135 mmol, 0.100 equiv). The crude material was purified via flash chromatography using 40:60:1.5 EtOAc:hexanes:NH4OH (aq.) to provide the desired internal alkyne as a brown-red oil (440 mg, 87%), which used directly in the next reaction. See General Procedure C: Step 2. Internal alkyne (440 mg, 1.18 mmol, 1.00 equiv), Cu(OAc)2(64.4 mg, 0.354 mmol, 0.300 equiv), and PhMe (4.75 mL, 0.21M). The crude material was purified by flash chromatography using 25:75:1.5 EtOAc:hexanes:NH4OH (aq.) to provide a light-yellow solid. This solid was triturated with EtOAc to provide indole 29 as a white solid (143 mg, 29% yield over 2 steps). Rf=0.20 (25:75:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=9.0, 4.2 Hz, 1H), 7.20 (dd, J=9.3, 2.7 Hz, 1H), 6.92 (dt, J=9.3, 2.7 Hz, 1H), 6.38 (s, 1H), 4.78 (s, 2H), 4.35 (m, 1H), 3.19 (d, J=11.7 Hz, 2H), 2.55 (dq, J=12.6, 3.6 Hz, 2H), 2.35 (m, 1H), 2.26 (dt, J=11.7, 1.8 Hz, 2H), 1.88 (dd, J=12.0, 2.4 Hz, 2H), 1.48-1.79 (m, 9H), 1.40 (m, 2H), 1.15 (m, 1H), 0.91 (d, J=6.6 Hz, 6H); MS(ESI) m/z: 373.4 [M+H]+. Example 6: Synthesis of (1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-2,3-diyl)dimethanol (51) SCHEME VI depicts this synthesis. Scheme VI Reagents and Conditions: a) (t-BuCO)2O, cat. DMAP, (isopropyl)2NEt, CH2Cl2; and b) i. POCl3, DMF, ii. NaBH4, EtOH, iii. NaOH, cat. Bu4NI, THF. syn-(1-(1-(-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methyl pivalate (35) To a solution of alcohol 30 (7.29 g, 20.6 mmol, 1.00 equiv) in CH2Cl2(138 mL, 0.15M), was added DMAP (503 mg, 4.12 mmol, 0.200 equiv) and iPr2NEt (18.4 mL, 103 mmol, 5.00 equiv) at rt. Subsequently, (tBuCO)2O (6.70 mL, 33.0, 1.60 equiv) was added, and the reaction was allowed to stir overnight. TLC (30:70:3 drops EtOAc:Hexanes:NH4OH (aq.)) showed the reaction was complete. The reaction was concentrated in vacuo, and the crude oil was purified via flash chromatography using 5:95:1.5 EtOAc:Hexanes:NH4OH (aq.) to provide 35 as a white solid (8.59 g, 95%). Rf=0.70 (30:70:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 6.56 (s, 1H), 5.25 (s, 2H), 4.17 (m, 1H), 3.31 (d, J=12.0 Hz, 2H), 2.78 (q, J=12.0 Hz, 2H), 2.55 (q, J=6.4 Hz, 1H), 2.32 (t, J=11.6 Hz, 2H), 1.90 (d, J=12.4 Hz, 2H), 1.80 (m, 2H), 1.64 (m, 5H), 1.43 (m, 2H), 1.22 (s, 9H), 1.20 (m, 1H), 0.92 (d, J=6.4 Hz, 6H); MS(ESI) m/z: 439.3 [M+H]+. syn-(1-(1-(-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-2,3-diyl)dimethanol (51) i. POCl3(9.43 mL, 103 mmol, 5.00 equiv) was added to DMF (83.0 mL) at 0° C., and the mixture turned light yellow. Indole 35 (9.00 g, 20.6 mmol, 1.00 equiv) was separately dissolved in 20 mL of DMF with the aid of heat, and then allowed to cool back to RT. After the POCl3solution stirred for 15 minutes at 0° C., the solution of indole 35 was added slowly, forming a red solution. After the addition was complete, the reaction stirred for 40 minutes at 0° C. TLC (20:80:3 drops EtOAc:Hexanes:NH4OH (aq.)) showed the reaction was complete. The reaction was poured into an ice:NaHCO3(sat'd, aq.) slurry, and then EtOAc was added. The mixture stirred vigorously until the mixture warmed to rt, and NaHCO3(sat'd, aq.) was added to ensure a basic pH. The layers were separated, and the aqueous layer was extracted 1× with EtOAc. The EtOAc layers were combined, washed 3× with water, brine, dried with MgSO4, filtered and concentrated in vacuo to provide the aldehyde as a light-yellow solid (9.55 g, 99%), which was used directly in the next step. ii. The aldehyde (9.55 g, 20.5 mmol, 1.00 equiv) was suspended in absolute EtOH (100. mL, 0.20M), and NaBH4(1.55 g, 41.0 mmol, 2.00 equiv) was added in several portions at rt. NOTE: may need to add another 1.00 equiv of NaBH4and a small amount of CH2Cl2to help solubilize the reaction mixture. The reaction was monitored by TLC (40:60:3 drops EtOAc:Hexanes:NH4OH (aq.)), and once complete, the reaction was concentrated in vacuo to ca. 50% volume. EtOAc was added, followed by 50% NaHCO3(aq.), and the mixture stirred until bubbling ceased. The layers were separated, and the EtOAc layer was washed 2× with water, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a foam (9.60 g, quantitative yield), which was taken directly on the next step. iii. The alcohol (9.60 g, 20.5 mmol, 1.00 equiv) was dissolved in THF (130 mL, 0.16M), followed by the addition of Bu4NI (1.51 g, 4.10 mmol, 0.20 equiv). Grounded NaOH powder (8.20 g, 205 mmol, 10.0 equiv) was added at RT, and the reaction stirred for ca. 90 minutes, and a thick white-fluffy precipitate formed. TLC (60:40:3 drops EtOAc:Hexanes:NH4OH (aq.)) showed the reaction was complete. The reaction was diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted 2× with EtOAc, and the EtOAc layers were then combined, washed 2× with water, brine, dried with MgSO4, filtered, and conc'd in vacuo. The crude material was purified via flash chromatography in 60:40:1.5 to 80:20:1.5 to 90:10:1.5 EtOAc:Hexanes:NH4OH (aq.) to provide diol 51 as a white foam (4.70 g, 60%). Rf=0.20 (80:20:3 drops EtOAc:Hexanes:NH4OH (aq.), UV);1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.4 Hz, 2H), 7.20 (t, J=8.4 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 4.86 (s, 2H), 4.83 (s, 2H), 4.38 (m, 1H), 3.17 (d, J=11.6 Hz, 2H), 2.59 (q, J=12.0 Hz, 2H), 2.37 (m, 1H), 2.25 (t, J=11.0 Hz, 2H), 1.52-1.89 (m, 9H), 1.43 (m, 2H), 1.18 (m, 1H), 0.92 (d, J=6.4 Hz, 6H); MS(ESI) m/z: 385.4 [M+H]+. Example 7: Synthesis of (E, Z)-3-(hydroxyimino)-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)indolin-2-one (228) SCHEME VII depicts this synthesis. Scheme VII Reagents and Conditions: a) HCO2NH4, Pd/C, 10%, MeOH, 2 h, 45° C.; b) 4-isopropylcyclohexanone, HOAc, MgSO4, NaBH(OAc)3, DCE, 48 h, rt; c) ceric ammonium nitrate (CAN), MeCN/H2O, 2 h, rt; d) NH2OH.HCl, NaOAc, EtOH/H2O, 20 h, rt. 1-(piperidin-4-yl)-2,3-dihydro-1H-indol-2-one (VII-2) To an ice-chilled solution of 1-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-indol-2-one VII-1 (prepared using a procedure adopted from Forbes (2001) Tetrahedron Letters 2:6943-6945) (25.7 g, 82.6 mmol, 1.00 equiv) in 600 mL MeOH was added ammonium formate (46.9 g, 743 mmol, 9.00 equiv), followed by an ice-chilled slurry of Pd/C, 10% (5.14 g) in 226 mL MeOH. The reaction was outfitted with a reflux condenser, and heated to 45° C. for 2.5 h. The solution was filtered through a pad of Celite and concentrated. Trituration with CH2Cl2/MeOH 90/10 (500 mL total), followed by flash chromatography using CH2Cl2/MeOH/NH4OH 100/0/0 to 79/20/1 as the eluent afforded 15.94 g of the title material in 89% yield, and matched reported values (WO 2002/085357, Sun et al). 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)indoline-2,3-dione (VII-4) To a stirred solution of 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)indolin-2-one (VII-3) (prepared from intermediate VII-2 according to Zaveri et al (2004) Journal of Medicinal Chemistry 47:2973-2976) (3.43 g, 10.1 mmol, 1.00 equiv) in 336 mL MeCN was added CAN (22.1 g, 40.3 mmol, 4.00 equiv) in 17.0 mL H2O, and the reaction was stirred at room temperature for 1 h. The reaction was diluted with CH2Cl2and satd. NaHCO3(aq). The layers were separated, and the aqueous solution was extracted 2× with CH2Cl2. The combined organic layers were filtered through a pad of Celite, washed with satd. NaCl (aq), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using CH2Cl2/MeOH 99/1 to 90/10 to afford 2.73 g of the title material in 76% yield.1H NMR (300 MHz, CDCl3) 7.62 (1H, d, J=5.1 Hz), 7.56 (1H, t, J=6 Hz), 7.20 (1H, d, J=6 Hz), 7.10 (1H, t, J=5.7 Hz), 4.19-4.22 (1H, m), 3.16 (2H, d, J=8.7 Hz), 2.30-2.40 (3H, m), 2.20 (2H, t, J=8.1 Hz), 1.60-1.79 (7H, m), 1.49-1.54 (2H, m), 1.36-1.43 (2H, m), 1.13-1.15 (1H, m), 0.90 (6H, d, J=5.1 Hz). MS(ESI) m/z 355.27 (M+H)+. (E, Z)-3-(hydroxyimino)-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)indolin-2-one (228) To a stirred solution of intermediate VII-4 (500 mg, 1.41 mmol, 1.00 equiv) in EtOH (17.6 mL) was added hydroxylamine HCl (147 mg, 2.12 mmol, 1.50 equiv), followed by NaOAc (231 mg, 2.82 mmol, 2.00 equiv). H2O (2.78 mL) was added to solubilize the reaction, and the reaction was stirred at room temperature for 20 h. The reaction was diluted with CH2Cl2and satd. NaHCO3(aq). The layers were separated, and the aqueous solution was extracted 2× with CH2Cl2. The combined organic layers were washed 2× with H2O, dried over Na2SO4, filtered and concentrated. The reaction was repeated on a 1.12 g scale, and the crude residue of the two runs was combined. The residue was purified by trituration using EtOAc/hexanes 1/1 to afford 1.54 g of the title material in 91% yield.1H NMR (300 MHz, DMSO-d6), 13.4 (1H, s), 8.00 (1H, d, J=9 Hz), 7.40 (1H, t, J=9 Hz), 7.18 (1H, d, J=6 Hz), 7.05 (1H, t, J=6 Hz), 4.00-4.02 (1H, m), 3.06 (2H, d, J=9 Hz), 2.24-2.36 (3H, m), 2.08 (2H, t, J=12 Hz), 1.52-1.69 (7H, m), 1.31-1.44 (4H, m), 1.06 (1H, s), 0.85 (6H, d, J=6 Hz). MS(ESI) m/z 370.3 (M+H)+. Anal. Calcd. for C22H31N3O2.1.00 HCl.0.4 H2O.0.1 CH2Cl2: C, 62.95; H, 7.89; N, 9.97; found: C, 62.61; H, 7.54; N, 9.73. Example 8: Synthesis of 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindolin-3-yl)-N-methoxyacetamide (247) SCHEME VIII depicts this synthesis. Scheme VIII Reagents and Conditions: a) tert-butyl glyoxalate/DMSO, K2CO3, THF, activated mol. sieves, 2 h, 80° C.; b) H2(g), Pd/C, THF, 2 h, rt; c) TFA, CH2Cl2, 1.5 h, rt; d) NH2OCH3.HCl, T3P, diisopropylethylamine, THF, 17 h, rt. tert-butyl 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindolin-3-ylidene)acetate (VIII-1) To a stirred solution of intermediate VII-3 (4.96 g, 14.6 mmol, 1.00 equiv) in THF (146 mL) was added tert-butyl glyoxalate, 34% solution in DMSO (prepared according to Yao et al., Tetrahedron, 2007, 63:10657-10670) (15.2 g, 117 mmol, 8.00 equiv), followed by K2CO3(4.03 g, 29.1 mmol, 2.00 equiv) and activated molecular sieves (50 g). The reaction was outfitted with a reflux condenser and stirred at 80° C. for 2 h. The reaction was allowed to cool to room temperature, filtered, and then diluted with EtOAc, H2O, and minimal NaCl (aq). The layers were separated, and the aqueous solution was extracted 2× with EtOAc. The combined organic layers were washed 2× with NaCl (aq), dried over Na2SO4, filtered and concentrated. The reaction was repeated on a 12.7 g scale, and the crude residue of the two runs was combined. The residue was purified by flash chromatography using hexanes/EtOAc/NH4OH 85/15/0 to 35/64/1 to afford 16.9 g of the title material in 72% yield.1H NMR (400 MHz, CDCl3) 8.53 (1H, d, J=8 Hz), 7.31 (1H, td, J=8, 4 Hz), 7.10 (1H, d, J=8 Hz), 7.02 (1H, t, J=8 Hz), 6.83 (1H, s), 4.21-4.26 (1H, m), 3.13 (2H, d, J=6 Hz), 2.29-2.45 (3H, m), 2.18 (2H, t, J=12 Hz), 1.59-1.71 (7H, m), 1.56 (9H, s), 1.34-1.52 (4H, m), 1.13 (1H, s), 0.89 (6H, d, J=8 Hz). MS(ESI) m/z 453.3 (M+H)+. tert-butyl 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindolin-3-yl)acetate (VIII-2) To a stirred solution of intermediate VIII-1 (3.05 g, 6.74 mmol, 1.00 equiv) in THF (67.0 mL) was added Pd/C, 10% (305 mg). The atmosphere of the reaction was evacuated and replaced with 1 atm H2(g). The reaction was stirred at room temperature for 2 h, filtered through a pad of Celite, and concentrated. The reaction was repeated on 7.00 g and 6.80 g scales, and the crude residue of the three runs was combined. The residue was purified by flash chromatography using hexanes/EtOAc/NH4OH 95/5/0 to 35/64/1 to afford 12.9 g of the title material in 76% yield. MS(ESI) m/z 455.4 (M+H)+.1H NMR (400 MHz, CDCl3) 7.26 (1H, d, J=8 Hz), 7.22 (1H, d, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.00 (1H, t, J=8 Hz), 4.25-4.29 (1H, m), 3.73-3.76 (1H, m), 3.13 (2H, d, J=12 Hz), 2.97 (1H, dd, J=16, 8 Hz), 2.65 (1H, dd, J=16, 8 Hz), 2.28-2.45 (4H, m), 2.18 (2H, t, J=12 Hz), 1.48-1.72 (10H, m), 1.39 (9H, s), 1.12 (1H, s), 0.89 (6H, d, J=8 Hz). 2,2,2-trifluoroacetic acid compound with 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindolin-3-yl)acetic acid (VIII-3) To an ice-chilled solution of intermediate VIII-2 (12.9 g, 28.4 mmol, 1.00 equiv) in CH2Cl2(284 mL) was added TFA (284 mL) portion wise. The reaction was allowed to warm to room temperature, and stirred for 1.5 h. The reaction was concentrated, and azeotroped 5× with toluene to dryness to afford 14.5 g of the title material as a TFA salt in >100% yield. MS(ESI) m/z 399.2 (M+H)+. 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindolin-3-yl)-N-methoxyacetamide (247) To a stirred solution of intermediate VIII-3, 78% free base equivalent (641 mg, 1.25 mmol, 1.00 equiv) in THF (15.7 mL) was added O-methylhydroxylamine HCl (943 mg, 11.29 mmol, 9.00 equiv), followed by DiPEA (3.93 mL, 22.6 mmol, 18.0 equiv), and the reaction was stirred at room temperature for 5 min. Propylphosphonic anhydride solution (T3P®) (2.24 mL, 7.53 mmol, 6.00 equiv) was added, and the reaction was stirred at room temperature for 17 h. The reaction was diluted with EtOAc and H2O. The layers were separated, and the aqueous solution was extracted 2× with EtOAc. The combined organic layers were filtered through a pad of Celite, washed with satd. NaCl(aq), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using [hexanes/EtOAc]/iPrOH/NH4OH 100/0/0 to 94/5/1 to afford 336 mg of the title material in 63% yield.1H NMR (400 MHz, CDCl3) □□□9.79 (1H, s), 7.30 (1H, d, J=8 Hz), 7.26 (1H, d, J=16 Hz), 7.17 (1H, d, J=8 Hz), 7.03-7.06 (1H, m), 4.24 (1H, s), 3.79 (3H, br s), 3.14 (2H, d, J=12 Hz), 2.63-2.70 (2H, m), 2.30-2.43 (3H, m), 2.18 (2H, t, J=12 Hz), 1.59-1.71 (8H, m), 1.48-1.53 (2H, m), 1.35-1.41 (2H, m), 1.14 (1H, s), 0.89 (6H, d, J=8 Hz). MS(ESI) m/z 428.44 (M+H)+. Anal. Calcd. for C25H37N3O3.1.00 HCl.0.9 H2O: C, 62.52; H, 8.35; N, 8.75; found: C, 62.39; H, 8.20; N, 8.66. Example 9: 2-(1′-(cis-4-isopropylcyclohexyl)-3-oxo-1H-spiro[isoquinoline-4,4′-piperidin]-2(3H)-yl)acetonitrile (339); 2-(2-aminoethyl)-1′-(cis-4-isopropylcyclohexyl)-1,2-dihydro-3H-spiro[isoquinoline-4,4′-piperidin]-3-one (340); and N-(2-(1′-(cis-4-isopropylcyclohexyl)-3-oxo-1H-spiro[isoquinoline-4,4′-piperidin]-2(3H)-yl)ethyl)aminosulfonamide (344) SCHEME IX depicts this synthesis. Scheme IX Reagents and Conditions: a) NaH, BrCH2CN, THF, 14 h, rt; b) H2, PtO2hydrate, MeOH, conc. HCl, 50° C., 3 h; c) chlorosulfonyl isocyanate, benzyl alcohol, CH2Cl2, 5° C., then Et3N, CH2Cl2, amine, 14 h, rt; and d) H2, 10% Pd/C, MeOH, NH3, 4 h. 2-(1′-(cis-4-isopropylcyclohexyl)-3-oxo-1H-spiro[isoquinoline-4,4′-piperidin]-2(3H)-yl)acetonitrile (339) To a solution of IX-1 (prepared as described by Mustazza, J. Med. Chem., 2008, 51:1058-1062) (1.65 g, 4.84 mmol) in 40 ml of THF under an argon atmosphere was added in portions 60% NaH in mineral oil (0.969 g, 24.2 mmol) and the mixture was stirred at room temperature for 0.5 h. The mixture was cooled in an ice bath and a solution of bromoacetonitrile (1.74 g, 14.5 mmol) in 20 ml of THF was added drop wise over 0.25 h and allowed to come to room temperature and stirred for 14 h. The mixture was treated with saturated sodium bicarbonate and extracted with ethyl acetate, dried over magnesium sulfate, and evaporated to dryness. Purification by chromatography on silica gel eluting with methanol/ethyl acetate/hexane/ammonium hydroxide (2:49:49:0.1) afforded 1.31 g of 339, 71% yield. A portion of the base was converted to the hydrochloride salt.1H NMR (300 MHz, DMSO, d6) δ 10.2 (1H, m), 7.51 (1H, d, 6 Hz), 7.41 (1H, t, J=6 Hz), 7.35 (1H, t, 6 Hz), 7.34 (1H, d, J=6 Hz), 4.74 (2H, s), 4.56 (2H, s), 3.4-3.5 (4H, m), 3.2 (1H, m), 2.18 (2H, d, J=11 Hz), 1.84 (4H, m), 1.68 (4H, m), 1.41 (2H, m), 1.14 (2H, m), 0.88 (6H, d, J=5 Hz). MS m/z 380 (M+H)+. 2-(2-aminoethyl)-1′-(cis-4-isopropylcyclohexyl)-1,2-dihydro-3H-spiro[isoquinoline-4,4′-piperidin]-3-one (340) To a solution of 339 (1.37 g, 3.61 mmol) dissolved in 30 ml of methanol and 3.3 ml of concentrated hydrochloric acid was added platinum oxide hydrate (178 mg) and stirred under an atmosphere of hydrogen gas at 50° C. for 3 h. The mixture was cooled to room temperature, filtered through Celite, and evaporated to dryness. The residue was purified by chromatography on silica gel eluting with methanol/dichloromethane/ammonium hydroxide (11:89:0.1) which afforded 1.37 g of 340, 90% yield. A portion of the base was converted to the hydrochloride salt.1H NMR (300 MHz, DMSO, d6) δ 10.6 (1H, m), 8.06 (3H, m), 7.54 (1H, d, J=6 Hz), 7.38 (1H, t, 6 Hz), 7.32 (1H, t, J=6 Hz), 7.26 (1H, d, J=6 Hz), 4.68 (2H, s), 3.68 (2H, m), 3.45 (3H, m), 3.18 (2H, m), 3.03 (2H, m), 2.23 (2H, d, J=11 Hz), 1.87 (4H, d, J=8 Hz), 1.67 (3H, m), 1.41 (2H, m), 1.15 (1H, m), 0.88 (6H, d, J=5 Hz). MS m/z 384 (M+H)+. Syn-phenyl(N-(2-(1′-(4-isopropylcyclohexyl)-3-oxo-1H-spiro[isoquinoline-4,4′-piperidin]-2(3H)-yl)ethyl)sulfamoyl)carbamate (IX-2) A solution of chlorosulfonyl isocyanate (0.76 g, 5.4 mmol) in 20 ml of dichloromethane was cooled in an ice bath under an Argon atmosphere and treated with benzyl alcohol (0.58 g, 5.4 mmol). After stirring for 0.25 h, the mixture was added to a solution of IX-2 (1.29 g, 3.36 mmol) in 20 ml of dichloromethane containing triethyl amine (0.68 g, 6.72 mmol) which was cooled in an ice bath under an argon atmosphere. The resultant mixture was stirred at 5° C. for 1 h and then at room temperature for 14 h. The mixture was treated with saturated sodium bicarbonate, extracted with dichloromethane, dried over magnesium sulfate, and evaporated to dryness. Purification by chromatography on silica gel eluting with methanol/dichloromethane/ammonium hydroxide (3:97:0.1) afforded 1.68 g of IX-2, 84% yield.1H NMR (300 MHz, CDCl3) δ 7.28-7.38 (6H, m), 7.11-7.25 (3H, m), 6.94 (1H, m), 5.27 (1H, m), 5.07 (2H, s), 4.31 (1H, m), 3.57 (3H, m), 3.2 (4H, m), 3.0 (1H, m), 2.35 (1H, m), 2.04 (2H, m), 1.87 (5H, m), 1.58 (3H, m), 1.31 (2H, m), 1.18 (1H, m), 0.89 (6H, d, J=5 Hz). MS m/z 597 (M+H)+. N-(2-(1′-(cis-4-isopropylcyclohexyl)-3-oxo-1H-spiro[isoquinoline-4,4′-piperidin]-2(3H)-yl)ethyl)aminosulfonamide (344) To a solution of IX-2 (1.51 g, 2.53 mmol) dissolved in 80 ml of methanol and 10 ml of 7N ammonia in methanol was added 10% Pd/C (150 mg) and stirred under an atmosphere of hydrogen gas for 4 h. The mixture was filtered through Celite and evaporated to dryness. The residue was purified by chromatography eluting with methanol/ethyl acetate/hexane/ammonium hydroxide (14:43:43:0.1) afforded 0.625 g of 344, 40% yield.1H NMR (300 MHz, CDCl3) □ 7.51 (1H, d, J=6 Hz), 7.33 (1H, t, J=6 Hz), 7.25 (1H, t, J=6 Hz), 7.18 (1H, d, J=6 Hz), 5.2 (1H, m), 4.57 (2H, s), 3.74 (2H, t, J=4 Hz), 3.38 (2H, t, J=4 Hz), 2.81 (3H, m), 2.33 (2H, m), 2.23 (2H, m), 2.04 (2H, m), 1.71 (2H, m), 1.59 (6H, m), 1.36 (2H, m), 1.12 (1H, m), 0.87 (6H, d, 5 Hz). MS m/z 463 (M+H)+. A portion of the base was converted to the hydrochloride salt. Anal. (C24H38N4O3S.HCl.H2O) C, H, N. Example 10: Synthesis of 2-(1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-3-yl)ethan-1-amine (86) SCHEME X depicts this synthesis. Scheme X Reagents and Conditions: a) Alkyne X-1, LiCl, K2CO3, cat. Pd(OAc)2, DMF, 100° C.; and b) AcCl, MeOH, room temperature. tert-butyl (2-(1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-2-(triethylsilyl)-1H-indol-3-yl)ethyl)carbamate (X-2) Iodo-aniline II-2 (401 mg, 0940 mmol, 1.00 equiv), alkyne X-1 (320 mg, 1.13 mmol, 1.20 equiv), and LiCl (39.8 mg, 0.940 mmol, 1.00 equiv) were charged into a 100 mL round bottom flask. DMF (13.4 mL, 0.070M) was added, followed by K2CO3(390 mg, 2.82 mmol, 3.00 equiv) and Pd(OAc)2(21.1 mg, 0.0940 mmol, 0.100 equiv). The reaction was fitted with a three-way adapter and an Ar balloon, and then the reaction was purged 3× with vacuum, and backfilled with Ar. The reaction was then heated in an 100° C. oil bath and monitored by TLC (20:80:3 drops EtOAc:Hexanes:NH4OH (aq.)). After ca. 60 minutes, a black color formed in the reaction, and after ca. 80-90 minutes, TLC showed the reaction was complete. The reaction was allowed to cool to room temperature, and then it was diluted with EtOAc and H2O and allowed to stir for 10 minutes. The reaction mixture was then filtered thru a small pad of Celite, and then the layers were separated, and the aqueous layer was extracted 1× with EtOAc. EtOAc layers were combined, washed 2× with H2O, brine, dried with MgSO4, filtered, and conc'd in vacuo to provide a crude material that was purified via flash chromatography using 8:92:1.5 EtOAc:Hexanes:NH4OH (aq.) to provide intermediate X-2 as a white foam (360 mg, 66%). Rf=0.30 (20:80:3 drops EtOAc:Hexanes:NH4OH (aq.), UV, I2, pAA);1H NMR (300 MHz, CDCl3) δ 7.69 (d, J=6.0 Hz, 1H), 7.61 (d, J=6.0 Hz, 1H), 7.16 (t, J=5.7 Hz, 1H), 7.06 (t, J=5.7 Hz, 1H), 4.56 (m, 1H), 4.25 (m, 1H), 3.40 (q, J=4.8 Hz, 2H), 3.21 (d, J=8.7 Hz, 2H), 3.01 (t, J=5.1 Hz, 2H), 2.71 (dq, J=8.7, 2.1 Hz, 2H), 2.35 (m, 1H), 2.15 (t, J=8.7 Hz, 2H), 1.85-1.38 (m, 21H), 1.16 (m, 1H), 1.05-0.90 (m, 20H); MS(ESI) m/z: 467.6 [M+H]+. 2-(1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-3-yl)ethan-1-amine (86) AcCl (806 μL, 11.3 mmol, 6.00 equiv) was added to MeOH (19.0 mL, 0.10M) at 0° C., and the reaction stirred for 5 minutes. Indole X-2 (1.10 g, 1.89 mmol, 1.00 equiv) was then added to the reaction. After 10 minutes of stirring at 0° C., a white slurry had formed. The ice-bath was then removed, and the reaction was allowed to warm to room temperature and was stirred for 4 hours. After 4 hours, TLC (10:90:3 drops iPrOH:CH2Cl2:NH4OH (aq.)) indicated reaction was complete. EtOAc (ca. 50 mL) was added to the stirring reaction, and after several minutes a white precipitate formed. The white precipitate was filtered, washed 3× with cold EtOAc, and dried in vacuo to provide the HCl salt of indole 86. Obtained 665 mg (80%) of the desired salt. Rf=0.10 (10:90:3 drops iPrOH:CH2Cl2:NH4OH (aq.), UV, 12);1H NMR (Freebase) (300 MHz, CDCl3) δ 7.61 (d, J=6.0 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.11 (m, 2H), 4.18 (m, 1H), 3.19 (d, J=8.7 Hz, 2H), 3.03 (t, J=4.8 Hz, 2H), 2.93 (t, J=4.8 Hz, 2H), 2.35 (m, 1H), 2.26 (dt, J=8.4, 1.8 Hz, 2H), 2.07 (m, 6H), 1.78-1.52 (m, 7H), 1.42 (m, 2H), 1.15 (m, 1H), 0.90 (d, J=5.1 Hz, 6H); MS(ESI) m/z: 368.5 [M+H]+. Example 11: In Vitro Characterization of Receptor Binding Affinity at the Nociceptin, Mu and Kappa Opioid Receptors All compounds were tested for their binding affinity at the nociceptin (NOP), mu and kappa opioid receptors as described below. The binding assays are fast and simple, and use Chinese hamster ovary cells transfected with human NOP or opioid receptors. The results of these assays are shown in Tables 4, 5 and 6, which provide ranges of receptor binding affinities at nociceptin and opioid receptors for compounds of Formula (II), Formula (III) and Formula (IV), respectively. Receptor binding affinity at NOP, mu, delta, and kappa receptors was determined using radioligand binding assays, which used the following radioligands: [3H]N/OFQ (for NOP), [3H]DAMGO (for mu opioid receptor), and [3H]U-696593 (for kappa opioid receptor) respectively. IC50values were determined by the curve-fitting program Prism, with Ki values calculated from the formula Ki=IC50/(1+L/Kd), where Kdis the binding affinity of the [3H]-radioligand and L is the concentration of the [3H]-radioligand used. Cell Culture: All receptors were in CHO cells transfected with human receptor cDNA. The cells were grown in Dulbecco's Modified Eagle Medium (DMEM) with 10% fetal bovine serum, in the presence of 0.4 mg/ml G418 and 0.1% penicillin/streptomycin, in 100-mm plastic culture dishes. For binding assays, the cells were scraped off the plate at confluence. Receptor Binding: Binding to cell membranes was conducted in a 96-well format, as described previously by Zaveri, N. T., et al., J. Med. Chem., 2004, 47:2973-2976; Adapa, I. D., et al., Neuropeptides, 1997, 31(5):403-408; and Dooley, C. T., et al., J. Pharmacol. Exp. Ther., 1977, 283(2):735-741. Cells were removed from the plates by scraping with a rubber policeman, homogenized in Tris buffer using a Polytron homogenizer, then centrifuged once and washed by an additional centrifugation at 27,000 g for 15 min. The pellet was resuspended in 50 mM Tris, pH 7.5, and the suspension incubated with [3H]nociceptin, [3H]DAMGO, or [3H]U69593, for binding to NOP, mu-, or kappa-opioid receptors, respectively. The total volume of incubation was 1.0 ml and samples were incubated for 60-120 min at 25° C. The amount of protein in the binding reaction varied from approximately 15 μg to 30 μg. The reaction was terminated by filtration using a Tomtec 96 harvester (Orange, CT) with glass fiber filters. Bound radioactivity was counted on a Pharmacia Biotech beta-plate liquid scintillation counter (Piscataway, N.J.) and expressed in counts per minute. IC50values were determined using at least six concentrations of test compound, and calculated using Graphpad/Prism (ISI, San Diego, Calif.). Kivalues were determined by the method of Cheng and Prusoff (Cheng, Y., et al., Biochem Pharmacol., 1973, 22(23):3099-3108). For the binding affinity for each compound in the Tables below, the values indicated as “A” represent a Ki of less than 15 nM; values indicated as “B” represents a Ki between 15 and 150 nM; values indicated as “C” represent Ki between 150 nM to 5000 nM and values indicated as “D” represent Ki greater than 5000 nM. TABLE 3Receptor Binding Ki(nM) forCompounds of Formula (II)Compound #NOPμκ1ABB2ABC3AAB4AAB5AAB6ABB7ABB8ABB9BBB10AAB11AAB12ABC13ABB14BBC15AAC16BAB17AAB18CBD19ABB20ABC21AAB22AAB23AAB24AAB25BCD26ABB27ABC29ABB30AAB31ABB32ABB33AAC34AAC35ABC36AAB37CCD38CCC39BB—40AAB41AAC42AAC43AAC44ABB45ABC46AAC47ABC48AAB49ABB50ABB51ABB52AAC53ABC54AAC56BB—57AA—58AA—61ACC62BCC63BCC64CC—65ACC66ACD67BDD68BDC69CCC70BCC71CCD72ABC73BCD74BBC75BBC76BCC77BCD78BBC79BC80ACC81ABD82BCD83ABC84BC85CC86ACC87BBC88ABC89BBD90BBC91BBC92BCC93BCC94CCD95BCB96BCC97BCC98BCC TABLE 4Receptor Binding Ki (nM) forCompounds of Formula (III)Cmpound #NOPμκ228ABB229ABC230BBB231CBB232BCB233BCC234ABB235ABC236ABB237ABC238AAB239BCC240A241BCD242AAA243ABB244BBC245AAC246BBD247ABC248ADC249BAC250ABC251ABC252ABB253ABB254AAC255ABC256AAC257ABB258AAB259AAC TABLE 5Receptor Binding Ki (nM) forCompounds of Formula (IV)Compound #NOPμκ330CBC331BCC332BCC333BCC334CCC335BCC336BCC337BBC338BBC339ABC340ABC341ABB342ABB343ABC344AAB345DCC346CCC347AB348BBC349BCC350BCC351ABB352ABB353BBB354ABB355BBC The compounds disclosed herein have selectivity for the NOP receptor over the mu opioid receptor and the kappa opioid receptor that ranges from 1-fold to >10,000-fold. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. | 237,271 |
RE49826 | EXPERIMENTAL Abbreviations and Acronyms MS: mass from mass spectrometry HPLC: high-performance liquid chromatography DMF: dimethylformamide Red-Al solution in toluene: sodium bis(2-methoxyethoxy) aluminium dihydride in toluene THF: tetrahydrofuran Aqu. HCl: aqueous hydrochloric acid DMAP: 4-(dimethylamino)pyridine EXAMPLES Example 1 Methyl 4-bromo-2-methoxybenzoate (XV) 3.06 kg (22.12 mol) of potassium carbonate were initially charged in 3.6 l of acetone and heated to reflux. To this suspension were added 1.2 kg of 4-bromo-2-hydroxybenzoic acid (5.53 mol), suspended in 7.8 l of acetone, and were rinsed in with 0.6 l of acetone. The suspension was heated under reflux for 1 hour (vigorous evolution of gas!). 2.65 kg (21.01 mol) of dimethyl sulphate were then added over 4 hours while boiling. The mixture was subsequently stirred under reflux for 2.5 hours. The solvent was largely distilled off (to the point of stirrability) and 12 l of toluene were added and the residual acetone was then distilled off at 110° C. About 3 l of distillate were distilled off, this being supplemented by addition of a further 3 l of toluene to the mixture. The mixture was allowed to cool to 20° C. and 10.8 l of water were added and vigorously stirred in. The organic phase was separated off and the aqueous phase was extracted once more with 6.1 l of toluene. The combined organic phases were washed with 3 l of saturated sodium chloride solution and the toluene phase is concentrated to about 4 l. Determination of the content by evaporation of a portion resulted in a converted yield of 1.306 kg (96.4% of theory). The solution was used directly in the subsequent stage. HPLC method A: RT about 11.9 min. MS (Elpos): m/z=245 [M+H]+ 1H NMR (400 MHz, CD2Cl2): δ=3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, 1H). Example 2 4-Bromo-2-methoxybenzaldehyde (XIX) 1.936 kg (6.22 mol) of a 65% Red-Al solution in toluene were charged with 1.25 l of toluene at −5° C. To this solution was added 0.66 kg (6.59 mol) of 1-methylpiperazine, which was rinsed in with 150 ml of toluene, keeping the temperature between −7 and −5° C. The mixture was then left to stir at 0° C. for 30 minutes. This solution was then added to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 4 l of toluene, keeping the temperature at −8 to 0° C. After rinsing in twice with 0.7 l of toluene, the mixture was then stirred at 0° C. for 1.5 hours. For the work-up, the solution was added to cold aqueous sulphuric acid at 0° C. (12.5 l of water+1.4 kg of conc. sulphuric acid). The temperature should increase at maximum to 10° C. (slow addition). The pH was adjusted to pH 1, if necessary, by addition of further sulphuric acid. The organic phase was separated off and the aqueous phase was extracted with 7.6 l of toluene. The combined organic phases were washed with 5.1 l of water and then substantially concentrated and the residue taken up in 10 l of DMF. The solution was again concentrated to a volume of about 5 l. Determination of the content by evaporation of a portion resulted in a converted yield of 1.041 kg (94.1% of theory). The solution was used directly in the subsequent stage. HPLC method A: RT about 12.1 min. MS (EIpos): m/z=162 [M+H]+ 1H NMR (CDCl3, 400 MHz): δ=3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10.40 (1H, s) Example 3 4-Formyl-3-methoxybenzonitrile (VI) 719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 l of DMF were charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K4[Fe(CN)6]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate were added. The mixture was stirred at 120° C. for 3 hours. The mixture was left to cool to 20° C. and 5.7 l of water were added to the mixture. The mixture was extracted with 17 l of ethyl acetate and the aqueous phase was washed once more with 17 l of ethyl acetate. The organic phases were combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to about 2 l. The mixture was heated to boiling and 2 l of water were added dropwise. The mixture was allowed to cool to 50° C. and another 2 l of water were added. The mixture was cooled to 3° C. and stirred at this temperature for one hour. The product was filtered off and washed with water (2×1.2 l). The product was dried at 40° C. under vacuum. Yield: 469 g (87% of theory) of a beige solid. HPLC method A: RT about 8.3 min. MS (EIpos): m/z=162 [M+H]+ 1H NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H). Example 4 (2E/2Z)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutanamide (XVI a,b) 1000 g (6204.95 mmol) of 4-formyl-3-methoxybenzonitrile (VI), 721.5 g (7135.7 mmol) of 3-oxobutanamide (XVII), 53 g (620 mmol) of piperidine and 37.3 g (620 mmol) of glacial acetic acid were heated under reflux in 15 l of dichloromethane for 4 hours on a water separator. Subsequently, about 10 l of dichloromethane were distilled off and the mixture was left to cool to room temperature. The mixture was cooled to 0° C. and left to stir for 4 hours, and the product was filtered off and washed twice with 1000 ml each time of cold dichloromethane. The product was dried at 40° C. under vacuum under entraining gas. Yield: 1439.8 g (95.0% of theory) of a yellow solid. HPLC method A: RT about 3.55 min. MS (EIpos): m/z=245 [M+H]+ 1H NMR (500 MHz, DMSO-d6): δ=2.35 (s, 3H), 3.30 (s, 2H), 3.90 (s, 3H), 7.45 (d, 1H), 7.7 (m, 3H), 7.75 (d, 1H), 8.85 (d, 1H) Example 5 4-(4-Cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxamide (XVIII) 2.128 kg (8.712 mol) of (2E/2Z)-2-(4-cyano-2-methoxybenzylidene)-3-oxobutanamide (XVI a,b) were taken up with 29 l of 2-butanol, 1.277 kg (7.92 mol) of 4-amino-5-methylpyridone were added, and then the mixture was heated in a closed stirred tank under elevated pressure at internal temperature 120° C. for 12 h. The mixture was then cooled to 0° C. by means of a gradient over a period of 5 h and then stirred at 0° C. for 3 hours. The product was then filtered off and washed with 2.1 l of cold isopropanol. The product was dried at 60° C. under vacuum. Yield: 2.081 kg (75% of theory based on 4-amino-5-methylpyridone, since this component is used substoichiometrically) of a pale yellow solid. HPLC method A: RT about 3.64 min. MS (EIpos): m/z=351 [M+H]+ 1H H NMR (500 MHz, DMSO-d6): δ=2.00 (s, 3H), 2.10 (s, 3H), 3.78 (s, 3H), 5.22 (s, 1H), 6.65 (s(broad), 1H), 6.85 (s(broad), 1H), 6.91 (s, 1H), 7.11 (d, 1H), 7.28 (d, 1H), 7.35 (s, 1H), 7.52 (s, 1H), 10.61 (s, 1H) Example 5 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) 1.857 kg (5.3 mol) of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxamide (XVIII) and 4.70 kg (29 mol) of triethyl orthoacetate were dissolved in 12.15 l of dimethylacetamide, and 157.5 g of concentrated sulphuric acid were added. The mixture was heated at 115° C. for 1.5 hours and then cooled to 50° C. At 50° C., 12.15 l of water were added dropwise over 30 minutes. After completion of the addition, the mixture was seeded with 10 g of the title compound (XI) and a further 12.15 l of water were added dropwise over 30 minutes at 50° C. The mixture was cooled to 0° C. (gradient, 2 hours) and then stirred at 0° C. for two hours. The product was filtered off, washed twice with 7.7 l each time of water and dried at 50° C. under vacuum. Yield: 1.845 kg (92.0% of theory) of a pale yellow solid. HPLC method B: RT about 10.2 min. MS (EIpos): m/z=433 [M+H]+ 1H NMR (300 MHz, DMSO-d6): δ=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H). Example 6 (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) as a Solution in 40:60 acetonitrile/methanol Enantiomer Separation on an SMB System The feed solution was a solution corresponding to a concentration consisting of 50 g of racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), dissolved in 1 liter of a mixture of 60:40 methanol/acetonitrile. The solution was chromatographed by means of an SMB system on a stationary phase: Chiralpak AS-V, 20 μm. The pressure was 30 bar and a mixture of methanol/acetonitrile 60:40 was used as eluent. 9.00 kg of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) were dissolved in 180 l of a mixture consisting of methanol/acetonitrile 60:40 and chromatographed by means of SMB. After concentrating the product-containing fractions, 69.68 liters of a 6.2% solution (corresponding to 4.32 kg of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I)) were obtained as a solution in acetonitrile/methanol 40:60. Yield: 4.32 kg (48% of theory), as a colourless fraction dissolved in 69.68 liters of acetonitrile/methanol 40:60. Enantiomeric purity: >98.5% e.e. (HPLC, Method D) A sample is concentrated under vacuum and gives: MS (EIpos): m/z=379 [M+H]+ 1H NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H). Example 7 (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Crystallization and Polymorph Adjustment 64.52 liters of a 6.2% solution from Example 6 in a mixture of acetonitrile/methanol 40:60 (corresponding to 4.00 kg of compound 1) were filtered through a filter cartridge (1.2 um) and subsequently sufficiently concentrated at 250 mbar such that the solution was still stirrable. 48 l of ethanol, denatured with toluene, was added and distilled again at 250 mbar up to the limit of stirrability (redistillation in ethanol). A further 48 l of ethanol, denatured with toluene, were added and then distilled off at atmospheric pressure down to a total volume of about 14 l (jacket temperature 98° C.). The mixture was cooled via a gradient (4 hours) to 0° C., stirred at 0° C. for 2 hours and the product filtered off. The product was washed twice with 4 l of cold ethanol each time and then dried at 50° C. under vacuum. Yield: 3.64 kg (91% of theory) of a colourless crystalline powder. Enantiomeric purity: >>99% e.e. (HPLC Method D); retention times/RRT: (4S)-4-(4-cyano-2-me thoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) about 11 min. RRT: 1.00; (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) about 9 min. RRT: 0.82 Purity: >99.8% (HPLC Method B), RT: about 6.7 min. Content: 99.9% (relative to external standard) specific rotation (chloroform, 589 nm, 19.7° C., c=0.38600 g/100 ml): −148.8°. MS (EIpos): m/z=379 [M+H]+ 1H NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H). Melting point: 252° C. (compound of the formula (I) in crystalline form of polymorph I) Physicochemical Characterization of Compound of the Formula (I) in Crystalline Form of Polymorph I Compound of the formula (I) in crystalline form of polymorph I melts at 252° C., ΔH=95-113 Jg−1(heating rate 20 Kmin−1). A depression of the melting point was observed depending on the heating rate. The melting point decreases at a lower heating rate (e.g. 2 Kmin−1) since decomposition occurs. No other phase transitions were observed. A loss of mass of about 0.1% was observed up to a temperature of 175° C. Stability and Moisture Absorption Samples of compound of the formula (I) in crystalline form of polymorph I were stored at 85% and 97% rel. humidity (25° C.). The samples were evaluated after 12 months by DSC, TGA and XRPD. After 12 months, a mass change of <0.1% is observed in both cases. This means that compound of the formula (I) in crystalline form of polymorph I shows no significant absorption of water under these storage conditions. According to DSC, TGA and XRPD, no difference exists in compound of the formula (I) in crystalline form of polymorph I. HPLC Conditions/Methods Method A YMC Hydrosphere C18 150*4.6 mm, 3.0 μm 25° C., 1 ml/min, 270 nm, 4 nm 0′: 70% TFA 0.1%*; 30% acetonitrile 17′: 20% TFA 0.1%*; 80% acetonitrile 18′: 70% TFA 0.1%*; 30% acetonitrile *: TFA in water Method B YMC Hydrosphere C18 150*4.6 mm, 3.0 μm 25° C., 1 ml/min, 255 nm, 6 nm 0′: 90% TFA 0.1%*; 10% acetonitrile 20′: 10% TFA 0.1%*; 90% acetonitrile 18′: 10% TFA 0.1%*; 90% acetonitrile Method C Nucleodur Gravity C18 150*2 mm, 3.0 μm 35° C., 0.22 ml/min, 255 nm, 6 nm Solution A: 0.58 g of ammonium hydrogen phosphate and 0.66 g of ammonium dihydrogen phosphate in 1 l of water (ammonium phosphate buffer pH 7.2) Solution B: acetonitrile 0′: 30% B; 70% A 15′: 80% B; 20% A 25′: 80% B; 20% A Method D Column length: 25 cm Internal diameter: 4.6 mm Packing: Chiralpak IA, 5 μm Reagents: 1. Acetonitrile HPLC grade 2. Methyl tert-butyl ether (MTBE), p.a. Test solution The sample is dissolved at a concentration of 1.0 mg/ml in acetonitrile. (e.g. about 25 mg of sample, weighed accurately, dissolved in acetonitrile to 25.0 ml). Eluent A. acetonitrile B. Methyl tert-butyl ether (MTBE), p.a. Flow rate 0.8 ml/min Column oven temperature 25° C. Detection measurement wavelength: 255 nm Bandwidth: 6 nm Injection volumes 5 μl Mix composition of eluents A and B in ratio by volume of 90:10 Chromatogram run time 30 min Retention times/RRT: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) about 11 min. RRT: 1.00 (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) about 9 min. RRT: 0.82 Measuring Parameters of the X-Ray Diffractometry for the Analysis of the Compound of the Formula (I) in Crystalline Form of Polymorph I Dataset name2429-08a r2Scan axis2Theta-OmegaStart position [°2th.]2.0000End position [°2th.]37.9900Type of divergence slitfixedSize of divergence slit [°]1.0000Measurement temperature [° C.]25Anode materialCuK-alpha1 [Å]1.54060Generator setting35 mA, 45 kVDiffractometer typetransmission diffractometerGoniometer radius [mm]240.00Focus-div. slit gap [mm]91.00Primary beam monochromatoryesSample rotationyesPeak maximum [2 theta]Polymorph I8.511.411.913.414.114.815.015.416.017.218.519.019.820.520.822.122.723.023.123.623.924.624.925.225.626.026.527.127.328.328.528.829.630.130.631.531.932.432.933.133.433.734.534.735.035.836.236.537.237.4 Measuring Conditions for the IR and Raman Spectroscopy for the Measurement of the Compound of the Formula (I) in Crystalline Form of Polymorph I: IR:InstrumentPerkin Elmer Spectrum OneNumber of scans32Resolution4 cm−1TechniqueDiamond ATR unitRaman:InstrumentBruker Raman RFS 100/SNumber of scans64Resolution2-4 cm−1Laser power350 mWLaser wavelength1064 nmBand maximum [cm−1]IR-ATR Polymorph IRaman Polymorph 1347530743416299733662970307429412992292029522836283522312230165916811641165816231606160115721577148514871464144314541383143113621420132714071303138112671355123013411191132511611303112312851093126710321255991122988312228271161810113675910977341031708991671976613967528924505909471875442847346827320810297776186758155746114733723706697670 | 15,675 |
RE49827 | DETAILED DESCRIPTION As used herein, terms such as “typically” are not intended to limit the scope of the claimed invention or to imply that certain features are critical, essential, or even important to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present invention. As used herein, the terms “comprise(s),” “include(s),” “having,” “has,” “contain(s),” and variants thereof, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structure. Any concentration range, percentage range, or ratio range recited herein are to be understood to include concentrations, percentages, or ratios of any integer within that range and fractions thereof, such as one tenth and one hundredth of an integer, unless otherwise indicated. Also, any number range recited herein relating to any physical feature are to be understood to include any integer within the recited range, unless otherwise indicated. It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. For example, “a” polymer refers to one polymer or a mixture comprising two or more polymers. As used herein, the term “dry silicone gel” may refer to a chemically crosslinked polymer having a Si—O backbone and comprising a relatively low amount, or no amount at all, of diluent fluids such as silicone oil or mineral oil. As opposed to carbon-based polymers, the crosslinked silicone polymers of dry silicone gels are based on a Si—O backbone. The characteristics of silicon and oxygen provide crosslinked polymers with their exceptional properties. For example, silicon forms stable tetrahedral structures, and silicon-oxygen bonds are relatively strong which results in dry silicone gels with high temperature resistance. In addition, crosslinked Si—O polymers have a relatively high chain flexibility as well as low rotational energy barrier. The dry silicone gels may be made according to a number of different polymerization reactions. In certain embodiments, the polymerization reaction is a hydrosilylation reaction, also referred to as a hydrosilation reaction. In some embodiments, the hydrosilylation reaction makes use of a platinum catalyst, while other embodiments make use of radicals. In further embodiments, the dry silicone gel is made by a dehydrogenated coupling reaction. In other embodiments, the dry silicone gel is made by a condensation cure RTV reaction. In certain embodiments, the dry silicone gel is made by reacting at least a crosslinker, a chain extender, and a base polymer (e.g., a vinyl-terminated polydimethylsiloxane). In certain embodiments, a catalyst is included to speed up the reaction. In additional embodiments, an inhibitor may be used to slow down the rate of reaction. The components of the dry silicone gels, their resulting properties, and their end-use are described in greater detail below. In certain embodiments, the dry silicone gel is made by an addition cure or platinum cure reaction mechanism. In some embodiments, the mechanism employs the use of a catalyst. By using a catalyst, the activation energy of the reaction is lowered and faster curing times at lower temperatures can be achieved. A schematic overview of the platinum cure reaction mechanism is shown below in (I). For the reaction in (I) to be made possible, two functional groups must react with each other. In certain embodiments, the two functionalities are (1) the Si—H group and (2) the Si-vinyl group. These two functionalities may be provided by: (1) a base polymer, (2) a crosslinker, and (3) a chain extender. Base Polymer In certain embodiments, the Si-vinyl group is provided by a base polymer such as a vinyl terminated polydimethylsiloxane (otherwise referred to as “V-PDMS”), which is shown below in (II). In this example, the base polymer compound comprises a vinyl group at each end of the compound. In certain embodiments, the molecular weight, of the base polymer is controlled through anionic ring-opening polymerization of cyclic siloxanes in the presence of alkali-metal hydroxide of a base that is volatile (e.g., tetramethylammonium silanolate). Endcapping of the PDMS with a vinyl group is needed, so these groups are added to the polymeriztion mixture. V-PDMS together with the chain extender determine the molecular weight between the different crosslink sites. The vinyl-containing base polymer, such as V-PDMS, may have different viscosities that affect the resulting dry silicone gel. In general, a high molecular weight V-PDMS will produce an uncured gel with a higher viscosity. In certain embodiments, a low molecular weight V-PDMS generally improves processability. In other embodiments, the V-PDMS used in the dry silicone gel has a viscosity between approximately 500 and 165,000 cSt (500-165,000 mm2/s), between approximately 1000 cSt and 50,000 cSt (1000-50,000 mm2/s), between approximately 3000 cSt and 7000 cSt (3000-7000 mm2/s), or between approximately 4500 cSt and 5500 cSt (4500-5500 mm2/s). In some embodiments, the vinyl-terminated polydimethylsiloxane has a molecular weight between about 20,000 g/mol and about 50,000 g/mol. In other embodiments, the vinyl-terminated polydimethylsiloxane has a molecular weight between about 50,000 g/mol and about 80,000 g/mol. In yet other embodiments, the vinyl-terminated polydimethylsiloxane has a molecular weight between about 28,000 g/mol and about 72,000 g/mol. In one particular embodiment, the vinyl-terminated polydimethylsiloxane has a molecular weight of approximately 49,500 g/mol. In certain embodiments, the base polymer contains between approximately 1 and 10 mol of vinyl per 500,000 g/mol of V-PDMS. In one embodiment, the base polymer contains approximately 2 mol of vinyl per 200,000 g/mol of V-PDMS (the vinyl end group concentration would be in the order of 10−5). In yet other embodiments, the vinyl content of the V-PDMS is between approximately 0.01 and 0.1 mmol/g, or between approximately 0.036 and 0.07 mmol/g. Crosslinker In certain embodiments, the Si—H end groups for the reaction in (I) may be provided by a crosslinker and/or a chain extender. A crosslinker is capable of forming connections between vinyl-terminated polydimethylsiloxane chains. In certain embodiments, the crosslinker includes electronegative substituents such as alkylsiloxy or chlorine. In one embodiment, the crosslinker comprises four Si—H groups that are capable of forming a connection point between four different vinyl-terminated polydimethylsiloxane chains. In some embodiments, the crosslinker is tetrakis (dimethylsiloxy)silane, shown below in (III). In other embodiments, the crosslinker is methyltris(dimethylsiloxy)silane. Other crosslinkers may also be used. Using higher functional crosslinkers is also possible, but these form less defined polymer structures. Chain Extender In addition to the crosslinker, the Si—H end group may be provided by a chain extender, wherein both ends of the chain extender compound are terminated with a Si—H group. In certain embodiments, the chain extender comprises reactive groups that are compatible and are willing to react with the vinyl groups in the base polymer. Just as for the crosslinker, these groups are Si—H groups that can react in a hydrosilation reaction. The chain extender typically includes two functional groups; however, the chain extender may include three or more functional groups, such that the chain extender functions as a branching agent. The functional groups may be the same as or different than each other. The functional groups may also be the same as or different than the functional groups of the first component and/or the second component. The chain extender may be any chain extender known in the art. In one embodiment, the chain extender is a hydride containing polydimethylsiloxane. In another embodiment, the chain extender is a hydride terminated polydimethylsiloxane, shown below in (IV). In a further embodiment, the chain extender is a hydride terminated polyphenylmethylsiloxane. In another embodiment, the chain extender is a hydride terminated polydiphenylsiloxane. In yet another embodiment, the chain extender is a dihydride containing siloxane. The chain extender may have a high molecular weight or a low molecular weight. The chain extender may also be branched or unbranched. In other embodiments, the chain extender is a high molecular weight polydimethylsiloxane. In other embodiments, the chain extender is a low molecular weight polydimethylsiloxane. In other embodiments, the chain extender is a functionally-terminated silicone such as a silanol terminated, vinyl terminated, and amino terminated polydimethylsiloxane. Such silicones have low tear strength and can be toughened by incorporating fumed silica (SiO2) into the structure. For example, an alkoxy-functionalized siloxane can be included. Suitable alkoxy-functionalized siloxanes include polydiethoxysiloxane, tetraethoxy silane, tetramethoxy silane, and polydimethoxy siloxane. In other embodiments, the chain extender is a fluorosilicone, phenyl silicone, or a branching diethyl silicone. In certain embodiments, by making use of the chain extender molecule, the V-PDMS base polymer can be shorter because the H-PDMS chain extender will extend the V-PDMS base polymer chain in situ between two crosslinker compounds. By using this mechanism, a V-PDMS chain of a shorter length can be applied which leads to lower viscosities and compounds that are easier to work with. Therefore, lower viscosity base polymer compounds can be used unlike a peroxide activated cure reaction mechanism. For example, a peroxide activated cure mechanism makes use of polymer chains with viscosities of approximately 2,000,000 cSt (2,000,000 mm2/s) while in the platinum cure mechanism allows for base polymer chains (V-PDMS) having viscosities of approximately 5,000 cSt (5,000 mm2/s). MFHC and H/V Ratios The amounts of crosslinker and chain extender that provide the hydride component may be varied. In certain embodiments, the amount of hydride in the gel is defined in terms of the mole fraction of hydride present as crosslinker (“MFHC”). For example, when the MFHC value is 0.3 or 30%, this means that 30% of the hydrides present in the system are part of the crosslinker and the remaining 70% of the hydrides are provided by the chain extender. In certain embodiments, the MFHC ratio may be altered to adjust the hardness of the gel (i.e., an increase in the MFHC may increase the hardness). In certain embodiments, the MFHC value is greater than 0.2, 0.3, 0.4, or 0.5. In some embodiments, the MFHC value is between 0.2 and 0.5. In other embodiments, the MFHC value is between 0.3 and 0.4. The overall amount of hydride components in the gel can also vary. The ratio of hydride to vinyl components (provided by the base polymer) can be defined as “H/V.” In other words, H/V is the total moles of hydride (contributions from crosslinker and chain extender) divided by the amount in moles of vinyl from the base polymer (e.g., V-PDMS) present. In certain embodiments, the dry silicone gel has a H/V ratio between 0.5 and 1.0, between 0.6 and 1.0, between 0.7 and 1.0, between 0.8 and 1.0, or between 0.9 and 1.0. If the H/V ratio is greater than 1, this means that there are more hydride groups present in the system than vinyl groups. In theory, the dry silicone gel will have a maximum hardness where the H/V ratio is 1 (this is the theoretical point where all the groups react with each other.) However, in practice this is not always the case and the maximum will be situated in the neighborhood of H/V equals 1. A theoretical representation depicting the relation between hardness of the dry silicone gel and the H/V ratio is shown inFIG.5. In certain embodiments, the region of interest (or “ROI”) for the dry silicone gel comprises slightly less hydrides than vinyl groups (i.e., the H/V is less than but close to 1). This is because gels with H/V values greater than 1 can undergo undesired post-hardening of the gel. With the help of the stoichiometric curve shown inFIG.5, the relationship between the amount of hydride groups and the amount of vinyl can be calculated to get a certain hardness. This value can be used to obtain the different amount of reagents needed to make a gel with the wanted hardness. A schematic overview of the reaction is depicted in (V) below, wherein the crosslinker compounds are represented by “+,” the chain extender compounds are represented by “=,” and the base polymer V-PDMS compounds are represented by “−.” In certain embodiments, the chain extender must always connect two different base polymer compounds, or connect to one base polymer and terminate the chain on the opposite end. Catalyst In certain embodiments, an addition cure catalyst is used to assist in reacting the base polymer, crosslinker, and chain extender. Performing the reaction without using a catalyst is typically a very energy consuming process. Temperatures of 300° C. or even higher are needed in order to avoid the produced gel to have poor and inconsistent mechanical properties. In certain embodiments, the catalyst includes a Group VIII metal. In other embodiments, the catalyst comprises platinum. Platinum catalyst can be prepared according to methods disclosed in the art, e.g., Lewis, Platinum Metals Rev., 1997, 41, (2), 66-75, and U.S. Pat. No. 6,030,919, herein incorporated by reference. In another embodiment, the catalyst is a homogenous catalyst. In other embodiments, the catalyst is a heterogeneous catalyst. Examples of heterogeneous catalysts include platinum coated onto carbon or alumina. In one embodiment, the catalyst is “Karstedt's catalyst.” This is a platinum catalyst made of Pt complexed with divinyltetramethyldisiloxane, shown below in (VI). An advantage of this catalyst is the fact that no heterogeneous reaction is taking place but that the catalyst will form a colloid. An advantage of these catalysts is the fact that only a small amount (ppm level) is needed. This reduces the cost of the polymerization process. In another embodiment, the catalyst may be a rhodium chloride complex, e.g., tris(triphenylphosphine)rhodium chloride (“Wilkinson's catalyst”). Rhodium based catalysts may require higher concentrations and higher reaction temperatures to be successful to a large extent. But poisoning comes together with reactivity; and therefore rhodium based catalysts may be less easily poisoned than platinum catalysts. In yet other embodiments, the catalyst may be a carbonyl derivation of iron, cobalt, and nickel. In one embodiment, the catalyst is dicobaltoctacarbonyl CO2(CO)8. High temperatures (e.g., >60° C.) should be avoided in order to prevent decomposition and deactivation of the catalyst. In comparison to the Pt catalyst, here 10−3M are needed in the case of Pt which is 10−6M or ppm level. Also the reactivity is slowed down by a factor of 5. The catalytic reaction mechanism is a Lewis-mechanism. First, there is a coordination of oxygen to the catalyst in the presence of the crosslinker or chain extender. This step is called the induction period. This gives hydrogen and the platinum colloid. Next, the chain extender or crosslinker will precede the attack of the vinyl group. By doing this, an electrophile complex is formed. The vinyl group (V-PDMS) then will act as a nucleophile. Combining both the vinyl-group of the V-PDMS chain with the crosslinker or chain extender that was bound to the Pt-catalyst gives the silicone product. The hydride is transferred to the second carbon of the vinyl group. The Pt-colloid is than available for reacting a second time. Oxygen can be seen as a co-catalyst because oxygen is not consumed in this reaction and the O—O is not broken in the reaction sequence. Catalysts should be isolated from compounds that can poison, or otherwise harm, the catalyst's performance. For example, amines, thiols, and phosphates can all poison a catalyst such as a platinum containing catalyst. Amines, thiols, and phosphates may form very stable complexes with a catalyst, thereby slowing the reaction or altogether stopping the reaction. Inhibitor In certain embodiments, inhibitors are added in the silicone gel formulation to slow down the curing process. Slowing down the curing process allows more time to work with the polymer mixture during processing, dispensing, and molding. The inhibitor can bind to the catalyst and form a stable complex. By doing this, the Pt catalyst is deactivated. When the complex is activated by adding energy (raising the temperature) the inhibitor will lose its binding for the Pt-catalyst. After this, the Pt-catalyst is in its activated form again and the polymerization reaction can start. The inhibitor may help manipulate the gel before it fully cures and extend the pot life. In certain embodiments, the pot life may be approximately 1 hour at room temperature and 6-8 hours at 3° C. In certain embodiments, the inhibitor comprises two electron-rich groups (alcohol- and allylfunction) forming an acetylenic alcohol. These groups can interact with the catalyst and shield it from other reactive groups. In one embodiment, the inhibitor of a Pt-catalyst is 3,5-Dimethyl-1-hexyn-3-ol, shown below in (VII). Additives In certain embodiments, the dry silicone gel composition may comprise additional common components. For example, the compositions may include additives such as flame retardants, coloring agents, adhesion promoters, stabilizers, fillers, dispersants, flow improvers, plasticizers, slip agents, toughening agents, and combinations thereof. In certain embodiments, the additional additives may include at least one material selected from the group consisting of Dynasylan 40, PDM 1922, Songnox 1024, Kingnox 76, DHT-4A, Kingsorb, pigment, and mixtures thereof. In some embodiments, the additives comprise between 0.1 and 25 wt % of the overall composition, between 0.1 and 5 wt % of the overall composition, between 0.1 and 2 wt % of the overall composition, or between 0.1 and 1 wt % of the overall composition. In some embodiments, the compositions disclosed and by methods disclosed herein comprise a flame retardant. In certain embodiments, the flame retardant is zinc oxide. In some embodiments, the flame retardant comprises between 0.1 and 25 wt % of the overall composition, between 0.1 and 5 wt % of the overall composition, between 0.1 and 2 wt % of the overall composition, or between 0.1 and 1 wt % of the overall composition. In one embodiment, the flame retardant comprises 20 wt % of the overall gel composition. In some embodiments, the compositions disclosed and made by methods disclosed herein contain at least one stabilizer. Stabilizers include antioxidants, acid-scavengers, light and UV absorbers/stabilizers, heat stabilizers, metal deactivators, free radical scavengers, carbon black, and antifungal agents. Making the Dry Silicone Gel In one embodiment, the dry silicone gel is prepared by mixing a first set of components together, mixing a second set of components together, and then mixing the two sets of components together. The first set of components comprises blending the base polymer (e.g., V-PDMS) with the catalyst. The second set of components comprises blending the crosslinker and chain extender. The second set of components may also comprise blending additional base polymer, and in some embodiments, an inhibitor. In some embodiments, the first and/or second set of components may also comprise blending at least one of the additives discussed above. In certain embodiments, the amount of catalyst present in the first set of components is between 0.01-1 wt %, between 0.05-0.1 wt %, or approximately 0.083 wt %. In some embodiments, the remainder of the first set of components is the base polymer. Regarding the second set of components, in certain embodiments, the amount of crosslinker is between 0.1-1 wt %, between 0.2-0.4 wt %, or approximately 0.3 wt %. In certain embodiments, the amount of chain extender in the second set of components is between 0.5-5 wt %, between 1-3 wt %, or between 1.5-2.5 wt %. In some embodiments, the amount of inhibitor in the second set of components is between 0.01-0.1 wt %, between 0.1-0.5 wt %, or approximately 0.04 wt %. In other embodiments, the amount of base polymer in the second set of components is between 95-99.9 wt %, between 96-99 wt %, or between 97-98.5 wt %. In certain embodiments, the amount of combined crosslinker and chain extender in the overall dry silicone gel is between 0.1-5 wt %, between 0.5-2 wt %, between 0.75-1.5 wt %, or approximately 1.25 wt %. The dry silicone gel is then prepared by mixing the first set of components with the second set of components. In one embodiment, the weight ratio of the blend of the first set of components to the second set of components is approximately 1:1. In another embodiment, the weight ratio of the blend is between approximately 47.5:52.5 and 52.5:47.5. Adjusting the ratio slightly can cause large differences in the overall hardness of the dry silicone gel. For example, in certain embodiments, when the ratio is 52.5:47.5 between the first and second set of components (wherein the second set of components comprises V-PDMS, crosslinker, chain extender, and inhibitor), the hardness may be lower than the hardness of the same composition at the 1:1 blending ratio. Additionally, in certain embodiments, when the ratio is 47.5:52.5 between the first and second set of components, the hardness may be greater than hardness of the same composition at the 1:1 blending ratio. In one example, the hardness may be approximately 72 g at the 52.5:47.5 ratio, 140 g at the 1:1 ratio, and about 210 g at the 47.5:52.5 ratio. In other words, a 2.5% variation may affect the hardness of the gel by as much as 70 g. Therefore, the weighing procedure during the preparation of the gel composition needs to be carried out with a high precision. Uses and Properties of the Dry Silicone Gel The dry silicone gels described herein may be used in a number of end uses due to their improved properties, such as improved behavior in mechanical stresses (e.g., vibration and shock) or ability to seal uneven or complicated structures (due to the ability to flow and adapt to the area of the structure). In certain embodiments, the dry silicone gels may be used in an interconnect, cover, or closure system. In particular, the dry silicone gel may be used in a fiber optic closure, electrical sealant, or electrical closure. In some embodiments, the dry silicone gels are used as gel wraps, clamshells, or gel caps. In further embodiments, the dry silicone gels are used in the inside of a residence. In other embodiments, the dry silicone gels are used outside of a residence. Use of the dry silicone gel within a closure or interconnect system may allow for a reduction in the number of components, frame size, or cost over other sealing mechanisms. In certain embodiments, the dry silicone gel is used as a flame retardant sealant. In one embodiment, the dry silicone gel comprises a flame retardant additive (e.g., zinc oxide) in order to function as a flame retardant sealant. In certain embodiments, the dry silicone gel is used in a closure system. In certain embodiments, the closure system comprises a housing, a cable, and a dry silicone gel. In some embodiments, the cable is a LSZH cable. In some embodiment, the system further comprises a connector, and, in some instances, a receptacle or port, therein forming an interconnect system. The interconnect system may comprise a mini input/output connector, data connector, power connector, fiber optic connector, or combination thereof. For example, the interconnect system may comprise a RJ-45 connector system. Non-limiting examples of interconnect systems and components are displayed inFIGS.6,7,8,9a,9b,10a, and10b. The dry silicone gel may be used to create a seal formed by displacement. In other embodiments, the dry silicone gel may be used to create a seal having radial functionality, axial functionality, or a combination thereof. In yet other embodiments, the dry silicone gel may be used to create a seal formed by displacement and having radial and/or axial functionality. FIGS.6,7, and8provide non-limiting examples of radial and axial functionality.FIG.6displays an example of a connection hub having multiple connection receptacles or ports for the cables16within the housings14to be connected.FIG.6displays both radial connection ports10and axial connection ports12.FIG.7displays a connector26; housing18,28; and cable16assembly with radial sealing22.FIG.8displays a connector26; housing32,34; and cable16assembly with axial sealing30, wherein the seal follows the surface of the axial port12. In certain embodiments, the housing may have a knob20that may be pushed inward to engage the latch24on the connector26, allowing the connector to be removed from the port. In certain embodiments, the dry silicone gel may be used to create a seal in a housing assembly having multiple parts. For example, in one embodiment the dry silicone gel may be used in a straight two-piece housing assembly, as shown inFIGS.9a and9b. In another embodiment, the dry silicone gel may be used in an angled two-piece housing assembly, as shown inFIGS.10a and10b. The dry silicone gel may be sealed around the cable16by sliding a smaller diameter gel formation over the cable to create a seal through interference. In other embodiments, the seal may be created by molding the dry silicone gel around the inside of the housing components and then snapping the housing, gel, and cable into place. In some embodiments, the dry silicone gel is used in a closure or interconnect system that is “compatible” with a low smoke zero halogen (LSZH) cable. In certain embodiments, compatibility is measured by subjecting the sample to one or more mechanical or environmental tests to test for certain functional requirements. In some embodiments, compatibility is measured by passing a pressure loss test, tightness test, and/or visual appearance test. In certain embodiments, the dry silicone gel in the closure or interconnect system is compatible where a traditional thermoplastic elastomer gel would fail (as shown and described in the examples and figures). Tightness may be tested under International Electrotechnical Commission (IEC) Test 61300-2-38, Method A and IEC 60068-2-17, Test Qc. In certain embodiments, tightness is tested by immersing the specimen in a water bath and using an internal pressure of 20-40 kPa (0.2-0.4 atm) for 15 minutes. It is important that tightness is measured directly after installing the closure at a temperature of −15° C. or 45° C. It is also important that all the air bubbles present on the outside of the closure are removed. If a continuous stream of air bubbles is observed, this means the specimen is not properly sealed and it will be considered as a failure (i.e., not compatible). Pressure loss may be tested under IEC 61300-2-38, Method B. In certain embodiments, the gel and cable are compatible if the difference in pressure before and after the test is less than 2 kPa (0.02 atm). Visual appearance may be tested under IEC 61330-3-1 by examination of the product with the naked eye for defects that could adversely affect the product performance. The sample may be subjected to various mechanical and/or environmental conditions prior to testing tightness, pressure loss, visual appearance, etc. In certain embodiments, compatibility is determined by subjecting the sample to one or more of the following mechanical tests: axial tension test, flexure test, re-entry test, and torsion test, and/or one or more environmental tests: resistance to aggressive media test, resistance to stress cracking test, salt fog test, temperature cycling test, and waterhead test. In certain embodiments, the sample is subjected to an axial tension test according to IEC 61300-2-4. In this test, the sample may be pressured internally at 20 kPa (0.2 atm) or 40 kPa (0.4 atm) at room temperature and sealed. The base assembly is clamped and a force is applied to each of the extending cables individually. If the sample has an outer diameter of less than or equal to 7 mm, then the amount of force per cable applied is equal to (outer diameter/45 mm)*500 Newtons (“N”). This force is applied for 15 minutes for each cable and built up to the IEC 61300-2-4 test. If the sample has an outer diameter of greater than 7 mm, then the amount of force per cable applied is equal to (outer diameter/45 mm)*1000 N, with a maximum of 1000 N applied. This force is applied for one hour. Internal pressure is then examined for pressure loss. In certain embodiments, the gel and cable are compatible if the pressure loss is less than 2 kPa (0.02 atm). In addition, in certain embodiments, the gel and cable are compatible if the displacement of the cable is less than 3 mm. In other embodiments, the specimens are further subjected to the tightness test, previously described. In other embodiments, compatibility is measured by subjecting the sample to a flexure test according to IEC 61300-2-37. In this test, the samples are subjected to temperatures of −15° C. and 45° C. Samples are pressured internally at 20 kPa or 40 kPa (0.2 atm or 0.4 atm) and sealed. Cables are bent individually at an angle of 30° (or a maximum force application of 500 N) each side of neutral in the same plane. Each bending operation is held for 5 minutes. The cable is returned to its original position and then the procedure is repeated in the opposite direction. After 5 cycles on each cable, the samples are visually inspected by the naked eye for appearance, conditioned at room temperature, and subjected to a tightness test. In some embodiments, the gel and LSZH cable are compatible if the specimen passes the visual appearance test, pressure loss test (i.e., less than 2 kPa (0.02 atm)), and/or tightness test. In another embodiment, compatibility is measured by subjecting the sample to a re-entry test according to IEC 61300-2-33. In certain embodiments, re-entry can be simulated after a certain time of temperature cycling. To complete this test, the closure has to be removed from the cycling room and tested on tightness. After this a reentry test can be done. In this test, a dummy plug or cable is removed from the closure and another cable or dummy plug is added. Then, tightness is measured again. Re-entry is successful if the closure passes the tightness test again. Another mechanical test may be employed to determine compatibility. The sample may be subjected to a torsion test according to IEC 61300-2-5. After completion of the torsion test, the gel and cable may be considered compatible if the sample passes the visual inspection test, pressure loss test, and/or tightness test. In yet other embodiments, compatibility is measured by conducting an environmental test of temperature cycling or accelerated aging under IEC 61300-2-22 and IEC 60068-2-14, Test Nb. In one embodiment, the temperature cycling test is conducted on the cable jacket between the gel blocks by cycling the temperature between −40° C. and 70° C. for 10 days at two cycles between the extreme temperatures per day. In some embodiments, the humidity is uncontrolled, the dwell time is four hours and the transition time is two hours. In certain embodiments, the cable jacket is tested for maintenance of tensile strength, ultimate elongation, tightness, visual appearance, and/or re-entry. Also, in certain embodiments, after the temperature cycling test, tightness of the closures needs to be tested after being conditioned to room temperature for a minimum of 2 hours. Therefore, in certain embodiments, the gel and LSZH cable are compatible if the specimen passes the tightness test. In another embodiment, compatibility is determined by subjecting the sample to a resistance to aggressive media test under EEC 61300-2-34, ISO 1998/I, and EN 590. The sample is considered compatible if it subsequently passes the tightness and/or appearance test. In yet another embodiment, compatibility is determined by subjecting the sample to a resistance to stress cracking test under IEC 61300-2-34. The sample is considered compatible if it subsequently passes the tightness test and/or shows no visible signs of cracking. In other embodiments, compatibility is determined by subjecting the sample to a salt fog test under IEC 61300-2-36 and IEC 60068-2-11, Test Ka. The sample is considered compatible if it subsequently passes the tightness and/or appearance test. In some embodiments, compatibility is determined by subjecting the sample to a waterhead test under IEC 61300-2-23, Method 2. The sample is considered compatible if there is no water ingress. In certain embodiments, the dry silicone gel has measurable properties. For example, in some embodiments, the dry silicone gel has a hardness in the range of 26 to 53 Shore 000 Hardness, or 100 to 300 g, as measured according to methods known in the art. In certain embodiments, the shore hardness gauge is measured according to ISO868 or ASTM D2240. In other embodiments, hardness can be measured on a texture analyzer. For example, a LFRA Texture Analyzer-Brookfield may include a probe assembly fixed to a motor driven, bi-directional load cell. In such a system, the probe is driven vertically into the sample at a pre-set speed and to a pre-set depth. The hardness is the amount of force needed to push the probe into the test sample. In other embodiments, the dry silicone gel has a hardness in the range of 37 to 45 Shore 000, or 160 to 220 g. In yet other embodiments, the silicone gel has a hardness in the range of 38 to 42 Shore 000, or 170 to 200 g. For further example, in some embodiments, the compression set, as measured after 50% strain is applied for 1000 hours at 70° C., has a range between 4% and 20%. In other embodiments, the compression set, as measured after 50% strain is applied for 1000 hours at 70° C., has a range between 10% and 14% when measured according to the modified version of ASTM D395, method B described above. In some embodiments, the gel is compressed with a certain strain or deformation (e.g., in certain embodiments, to 50% of its original size). This causes a certain stress in the material. The stress is now reduced because the material relaxes. In certain embodiments, the stress relaxation of the dry silicone gel has a possible range between 30 and 60% when subjected to a tensile strain or deformation of about 50% of the gel's original size, wherein the stress relaxation is measured after a one minute hold time at 50% strain. In other embodiments, the stress relaxation of the dry silicone gel is between 40% and 60% when subjected to a tensile strain of about 50%. A higher stress relaxation indicates that once a gel is installed in a closure, the gel will require less stress in order for it to seal. In certain embodiments, the dry silicone gel composition has less than 10% oil bleed out over a period of time when the gel is under compression of 120 kPa (1.2 atm) at 60° C. In certain embodiments, oil bleed out is measured on a wire mesh, wherein the oil loss may exit the gel through the mesh. The weight of the gel sample is recorded before and after the pressure has been applied. In some embodiments, the gel has less than 8% oil bleed out over the period of time. In other embodiments, the gel has less than 6% oil bleed out over the period of time. In certain embodiments, the oil loss is measured at 200 hours, 400 hours, 600 hours, 800 hours, 1000 hours, 1200 hours, or 1440 hours (60 days). In certain embodiments, the dry silicone gel has less oil bleed out in comparison to a thermoplastic gel over the same period of time at 120 kPa (1.2 atm) at 60° C. In some embodiments, the dry silicone gel has 40%, 50%, or 60% oil bleed out than the thermoplastic gel at 200 hours, 400 hours, 600 hours, 800 hours, 1000 hours, 1200 hours, or 1500 hours (about 60 days). EXAMPLES Dry silicone gels were synthesized according to the following examples. A first set of components was prepared. To prepare the first set of components, a platinum catalyst complex (Karstedt catalyst, CAS-number 68478-92-2) from Sigma-Aldrich N.V./S.A., Bornem, Belgium, is added to a container. Vinyl-terminated polydimethylsiloxane (CAS-number 68083-19-2) from ABCR GmbH & Co. KG, Karlsruhe, Germany, is combined with the catalyst in a ratio of 100:0.0311. The catalyst is added first, this compound needs to be added to the bottom of the container and make sure no catalyst is splashed onto the sides. After adding the catalyst the V-PDMS can be added by pouring it into the container until about 10 grams from what needs to be weighed out. The last 10 or more grams are added with more precision by the use of a large pipette or syringe. It is best to start mixing at low rpm (100 rpm) and gradually increasing to 500 rpm in 2 minutes. After the 2 minutes mixing, the mixing speed can be increased to 1200-1400 rpm for 3 minutes. To prepare a second set of components, a vinyl-terminated polydimethylsiloxane (CAS-number 68083-19-2) from ABCR GmbH & Co. KG is added to a crosslinker, GELEST SIT 7278.0, a chain extender GELEST DMS-H03, and an inhibitor, ALDRICH 27, 839-4. The crosslinker is added to the container first, because small variations in the added amount can greatly influence the hardness of the gel. If too much is added, this can always be sucked out again. Next, the inhibitor is added to the reaction container. The third component that needs to be weighed out is the chain extender. It is best to start mixing at low rpm (100 rpm). In 2 minutes go to 500 rpm and scrape off the sides of the container with a plastic rod. After this 2 minutes of mixing, the mixing speed can be increased to 1200-1400 rpm for 3 minutes. The first set of components was mixed with the second set of components at 1:1 ratio in a vial. The two sets of components were mixed at 1250 rpm for 2-3 minutes, placed under vacuum for 4-5 minutes, and poured into the desired mold. The resulting molded mixture was placed under vacuum for 3 minutes and then cured for 30 minutes at 90° C. Dry silicone gels were made according to the following Examples 1-6. Example 1Example 2Example 3Example 4Example 5Example 6Wt. %Wt. %Wt. %Wt. %Wt. %Wt. %1st Set ofComponentsGelest99.91799.91799.91799.91799.91799.917DMS-35,vinylCatalyst0.0830.0830.0830.0830.0830.0832nd Set ofComponentsGelest98.07997.63697.59397.50997.46797.439DMS-35,vinylGelest SIT0.3290.2790.2840.2940.2990.3027278.0,crosslinkerGelest1.5522.0452.0832.1572.1942.219DMS-H03,chainextenderAldrich0.0400.0400.0400.0400.0400.04027,839-4,inhibitorHardness40 g75 g95 g145 g180 g205 g While not implemented in these Examples, in certain embodiments, additional additives may be added to the first set of components. In some embodiments, the additional additives may include at least one material selected from the group consisting of Dynasylan 40, PDM 1922, Songnox 1024, Kingnox 76, DHT-4A, Kingsorb, pigment, and mixtures thereof. In some embodiments, the additives comprise between 0.1 and 5 wt %, between 0.1 and 2 wt %, or between 0.1 and 1 wt % of the first set composition. For further example, the first and second sets of components were mixed at 10 ratios from 47.5:52.5 to 52.5:47:5. Dry silicone gels were tested under controlled conditions in a closure system used in underground and aerial applications to repair fiber cables up to 12 fibers. Dry silicone gels were further tested under controlled conditions in a closure system including a fiber organizer and cable closure used in fiber optic cables in above and below-ground environments. In addition, dry silicone gels were tested under controlled conditions in a closure organizer and multi-out system for cables having a small diameter. The dry silicone gels were tested in a number of ways: temperature cycling, re-entry test, French water cycling, cold and hot installations, and kerosene exposure. For temperature cycling experiments, closures including dry silicone gels were exposed to temperatures between −30° C. and +60° C. for 10 days. Humidity was not controlled. The closures were cycled between the high and low temperatures two times a day for ten days. Samples were maintained at the extreme temperatures for four hours during each cycle. For combined temperature cycling tests, dry silicone gels were installed in three closure systems. After installation the closures were tested on tightness and put into temperature cycling. After eight days a re-entry test was performed and after ten days the closures were taken out of cycling, tested on tightness and re-entry. Closures containing the standard thermoplastic gels were also tested. For tightness testing, the closure is immersed in a water bath for 15 minutes and an internal pressure of 20 kPa. If air bubbles are observed, this means the closure is not properly sealed and it will be considered as a failure. For re-entry testing, a dummy plug or cable is removed from the closure and another cable or dummy plug is added. Then, tightness is measured again. Re-entry is successful if the closure passes the tightness test again. In certain embodiments, the dry silicone gel in the closure system is able to pass the tightness and re-entry tests where a traditional thermoplastic elastomer gel would fail (as shown and described in the examples and figures). FIG.1shows the hardness (g) verses stress relaxation (%) of dry silicone gels as measured on a TA-XT2 texture analyzer from Texture Technologies (Westchester County, N.Y.). The squares provide examples of gels that are tight and re-enterable; the red triangles provide examples of gels that fail on tightness and/or re-entry. The solid oval in the bottom left of the graph indicates examples of traditional thermoplastic elastomer gels. The solid oval to the right indicates a specific region for dry silicone gels. Three examples of dry silicone gel are shown within the oval. The dotted oval indicates an extended range of acceptable dry silicone gels. FIG.2shows the stress relaxation (%) versus the compression set (%) of dry silicone gels over 1000 hours at 70° C. The compression set was measured using a modified version of ASTM D395, method B. As opposed to using samples with a diameter of 29 mm a thickness of 12.5 mm, samples were measured having a diameter of 28 mm and thickness of 12 mm. The squares provide examples of gels that are tight and re-enterable; the red triangles provide examples of gels that fail on tightness and/or re-entry. The solid oval on the left of the graph indicates examples of traditional thermoplastic elastomer gels. The solid oval to the lower right indicates a specific region for dry silicone gels. Three examples of dry silicone gel are shown within the oval. The dotted oval indicates an extended range of acceptable dry silicone gels. FIG.3shows the hardness (g) versus the compression set (%) of dry silicone gels over 1000 hours at 70° C. Again, compression set was measured with the modified version of ASTM D395, method B described above. The squares provide examples of gels that are tight and re-enterable; the red triangles provide examples of gels that fail on tightness and/or re-entry. The solid oval on the left of the graph indicates examples of traditional thermoplastic elastomer gels. The solid oval to the lower right indicates a specific region for dry silicone gels. Three examples of dry silicone gel are shown within the oval. The dotted oval indicates an extended range of acceptable dry silicone gels. Oil loss' experiments were also conducted on dry silicone gels with hardness of 140 g, 170 g, and 200 g.FIG.4shows the oil bleed-out of five gels under compression at a pressure of about 120 kPa (about 1.2 atm) and at a temperature of about 60° C. The gels labeled Si H 140, Si H 170, and Si H200 are dry silicone gels having hardnesses of 140 g, 170 g, and 200 g, respectively. The gels labeled L2912 and L2908 are examples of thermoplastic elastomer gels. The silicone gel with a hardness 200 g (Si H200) had the lowest amount of oil loss. After 1,500 hours, about 60 days, the oil loss for these dry silicone gels is between 8 and 10%. For hardness 200 g the oil loss was slightly less than 6%. The oil loss for the L2912 thermoplastic gel is about 16% after 1,500 hours. The data inFIG.4represents a reduction of 50% in oil loss compared to these thermoplastic gel systems. Although examples have been described herein, it should be appreciated that any subsequent arrangement designed to achieve the same or similar purpose may be substituted for the specific examples shown. This disclosure is intended to cover any and all subsequent adaptations or variations of various examples. Combinations of the above examples, and other examples not specifically described herein, may be apparent to those of skill in the art upon reviewing the description. The Abstract is provided with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the foregoing Detailed Description, various features may be grouped together or described in a single example for the purpose of streamlining the disclosure. This disclosure is not to be interpreted as reflecting an intention that the claimed examples require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive subject matter may be directed to less than all of the features of any of the disclosed examples. Thus, the following claims are incorporated into the Detailed Description, with each claim standing on its own as defining separately claimed subject matter. The above disclosed subject matter is to be considered illustrative, and not restrictive, and the appended claims are intended to cover all such modifications, enhancements, and other examples, which fall within the true spirit and scope of the description. Thus, to the maximum extent allowed by law, the scope is to be determined by the broadest permissible interpretation of the following claims and their equivalents, and shall not be restricted or limited by the foregoing detailed description. | 46,617 |
RE49828 | DETAILED DESCRIPTION FIG.2is a simple diagram of an example of a load control system200(e.g., an ultrasonic sensing system) comprising a load control device210(e.g., an ultrasonic sensor) and a remote ultrasonic transmitter230. The load control device210may be adapted to be coupled in series electrical connection between an alternating-current (AC) power source202and an electrical load (e.g., a lighting load204) for controlling the power delivered to the lighting load. For example, the load control device210may be adapted to be wall-mounted in a standard electrical wallbox. The load control device210may be implemented as a table-top load control device. The load control device210may operate as an electronic switch to simply turn on and off the lighting load204. The load control device210may operate as a dimmer switch to adjust the amount of power delivered to the lighting load204and the intensity of the lighting load. The load control device210may be coupled to the neutral side of the AC power source202and/or an earth ground connection. As shown inFIG.2, the load control device210may include two actuators, e.g., an on button212and an off button214, for respectively turning the electrical load on and off. The load control device210may include a single toggle actuator for turning the electrical load on and off, for example, in response to successive actuations. The load control device210may include an intensity adjustment actuator (not shown) to allow for adjustment of the intensity of the lighting load204. The load control device210may include one or more visual indicators (not shown), such as light-emitting diodes (LEDs) arranged in a linear array and illuminated to provide feedback of the intensity of the lighting load204. The load control device210may be configured to raise the intensity of the lighting load204in response to actuations of the upper button (e.g., the on button212) and to lower the intensity of the lighting load204in response to actuations of the lower button (e.g., the off button214). The load control device210may operate as an occupancy sensor to turn the lighting load204on in response to the presence of an occupant in the vicinity of the load control device (e.g., an occupancy condition), or off in response to the absence of the occupant (e.g., a vacancy condition). The load control device210may include an internal ultrasonic occupancy detection circuit operable to transmit and receive ultrasonic waves206via an acoustic grill216(e.g., a vent) for detecting the presence or absence of the occupant. The load control device210may be operable to determine whether an occupancy condition or a vacancy condition is presently occurring in the space in response to the ultrasonic waves received by the ultrasonic occupancy detection circuit, as will be described in greater detail below. The load control device210may operate as a vacancy sensor. When operating as a vacancy sensor, the load control device210may only operate to turn off the lighting load204in response to detecting a vacancy condition in the space. For example, the load control device210would not turn on the lighting load204in response to detecting an occupancy condition. When the load control device210operates as a vacancy sensor, the lighting load204must be turned on manually (e.g., in response to a manual actuation of the on button212). The load control device210may include an internal passive infrared (PIR) occupancy detection circuit for detecting the presence or absence of the occupant, i.e., the load control device210may be a dual-tech occupancy sensor. The load control device210may include a lens218for directing the infrared energy from the occupant to the internal PIR occupancy detection circuit. Examples of occupancy and vacancy sensors having PIR occupancy detection circuits are described in greater detail in commonly-assigned U.S. Pat. No. 8,009,042, issued Aug. 30, 2013, entitled RADIO-FREQUENCY LIGHTING CONTROL SYSTEM WITH OCCUPANCY SENSING, the entire disclosure of which is hereby incorporated by reference. The load control device210may include a microwave detector, or any suitable detector or combination of detectors, for detecting the presence or absence of the occupant. The load control system200may include an electrical outlet220that is coupled in parallel with the AC power source202and has, for example, two electrical receptacles222. The remote ultrasonic transmitter230may be plugged into one of the electrical receptacles222of the electrical outlet220as shown inFIG.2.FIG.3is an example perspective view, andFIG.4is an example left side view of the remote ultrasonic transmitter230. The ultrasonic transmitter230may be operable to transmit ultrasonic waves206via an acoustic grill232(e.g., a vent). The ultrasonic waves206transmitted by the ultrasonic transmitter230may be received by the ultrasonic occupancy detection circuit of the load control device210for improving the ability of the load control device to detect the presence or absence of the occupant, as described herein. The ultrasonic transmitter may have electrical prongs434(e.g., blades) adapted to be plugged into the electrical receptacle222, such that the ultrasonic transmitter230may be powered from the AC power source202. The ultrasonic transmitter230may be battery powered and located at a position distinct from the electrical outlet220. The ultrasonic transmitter230may be powered by an external direct-current (DC) power supply (not shown) plugged into the electrical outlet220, or plugged into a Universal Serial Bus (USB) port on a device capable of supplying power to the ultrasonic transmitter. FIG.5Ais a diagram illustrating ultrasonic waves506,508transmitted by an ultrasonic transmitter510and received by an ultrasonic receiver520located in a single device500(e.g., the load control device200shown inFIG.2). The transmitted ultrasonic waves506are emitted by the ultrasonic transmitter510and are reflected off of an occupant505.FIG.5Bis an example waveform of the received (e.g., reflected) ultrasonic waves508as reflected off of the occupant505. The example waveform of the received ultrasonic waves508shown inFIG.5Bis characterized by a period540of frequency modulation (e.g., a Doppler shift) due to the reflection off of the occupant505. The ultrasonic transmitter510may continuously transmit ultrasonic waves. When ultrasonic waves506reflect off of an occupant505, the ultrasonic waves experience a frequency modulation which the ultrasonic receiver520detects. The load control device may be responsive to the frequency modulation of the received ultrasonic waves that is detected by the ultrasonic receiver520. FIG.6Ais a diagram illustrating ultrasonic waves606transmitted by an ultrasonic transmitter610located in a first device600(e.g., the ultrasonic transmitter230ofFIG.2) and ultrasonic waves608received by an ultrasonic receiver620located in a second device602(e.g., the load control device200ofFIG.2). The ultrasonic transmitter610may continuously transmit ultrasonic waves606. The transmitted ultrasonic waves606may be emitted by the ultrasonic transmitter610. The ultrasonic waves606may be momentarily attenuated by an occupant605. FIG.6Bis an example waveform of the received ultrasonic waves608as attenuated by the occupant605. The example waveform of the received ultrasonic waves608shown inFIG.6Bmay be characterized by a period640of amplitude modulation due to the attenuation by the occupant605. The received ultrasonic waves608may also be characterized by a Doppler shift. FIG.7is a diagram of a room700(e.g., a classroom) illustrating a detection range720of an example ultrasonic sensing system (e.g., the load control system200ofFIG.2). The ultrasonic sensing system installed in the room700may have a wall-mounted ultrasonic sensor710(e.g., the load control device210ofFIG.2) and two ultrasonic transmitters712(e.g., the ultrasonic transmitter230ofFIG.2and/or the ultrasonic transmitter610ofFIG.6A). For example, the wall-mounted ultrasonic sensor710may be mounted in an electrical wallbox and may be coupled in series electrical connection between an AC power source and an electrical load (e.g., the lights of the room700) for turning the electrical load on and off. The wall-mounted ultrasonic sensor710may include an ultrasonic transmitter (e.g., the ultrasonic transmitter510ofFIG.5A) and an ultrasonic receiver (e.g., the ultrasonic receiver520ofFIG.5Aand/or the ultrasonic receiver620ofFIG.6A). The ultrasonic waves transmitted by the ultrasonic transmitter of the wall-mounted ultrasonic sensor710may be reflected off of an occupant of the room700and received by the ultrasonic receiver of the wall-mounted ultrasonic sensor710(e.g., as shown inFIGS.5A and5B). The ultrasonic transmitters712are simple, low-cost devices and operate to transmit the ultrasonic waves. The ultrasonic transmitters712may be spaced about the room700and may be, for example, plugged into electrical outlets in the room. The ultrasonic transmitters712may be located on a surface, such as a tabletop or a chair, or in a wallbox housing a switch for an LED light bulb (e.g., as described with reference toFIG.13). The ultrasonic waves transmitted by the ultrasonic transmitters712may be momentarily attenuated by an occupant of the room700and received by the ultrasonic receiver of the wall-mounted ultrasonic sensor710(e.g., as shown inFIGS.6A and6B). The resulting detection range720of the example ultrasonic sensing system having the wall-mounted ultrasonic sensor710and the two ultrasonic transmitters712may include, for example, substantially all of the area of the room700as shown inFIG.7. Since the ultrasonic transmitters712are simple, low-cost devices, the ultrasonic transmitters allow for an increased detection range (e.g., detection range720) without greatly increasing the total cost of the ultrasonic sensing system since multiple wall-mounted ultrasonic sensors do not need to be installed around the room700. FIG.8is a simplified block diagram of an example load control device800(e.g., the load control device210ofFIG.2and/or the wall-mounted ultrasonic sensor710ofFIG.7). The load control device800may include a first electrical connection (e.g., a hot terminal582) adapted to be coupled to an AC power source (e.g., the AC power source202ofFIG.2) and a second electrical connection (e.g., a load terminal804) adapted to be coupled to an electrical load (e.g., the lighting load204ofFIG.2). The load control device800may include a neutral terminal (not shown) adapted to be coupled to the neutral side of the AC power source and/or an earth ground connection (not shown) adapted to be coupled to earth ground. The load control device800may include a controllably conductive device810coupled in series electrical connection between the hot terminal802and the load terminal804for controlling the power delivered to the electrical load. The controllably conductive device810may include, for example, a relay, a bidirectional semiconductor switch (such as, a triac, a FET in a rectifier bridge, two FETs in anti-series connection, or one or more insulated-gate bipolar junction transistors), or any other suitable switching circuit. The load control device800may include a control circuit820that is coupled to the controllably conductive device810for rendering the controllably conductive device conductive and/or non-conductive to control the power delivered to the electrical load. For example, the control circuit820may include a microcontroller, a programmable logic device (PLD), a microprocessor, an application specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or any suitable processing device, controller, or control circuit. The control circuit820may receive inputs from actuators822(e.g., the on button212and the off button214of the load control device ofFIG.2). The control circuit820may be coupled to a memory (not shown) for storage of the operational characteristics of the load control device800. The memory may be implemented as an external integrated circuit (IC) or as an internal circuit of the control circuit820. A power supply824may generate a first DC supply voltage VCC1(e.g., approximately 3 volts) for powering the control circuit820. The power supply824may generate a second DC supply voltage VCC2(e.g., approximately 12 volts) for powering other circuitry of the load control device800, for example, as described herein. A zero-cross detect circuit826may be coupled between the hot terminal802and the load terminal804. The zero-cross detect circuit826may generate a zero-cross control signal VZC. The zero-cross control signal VZCmay be representative of the zero-crossings of an AC source voltage of the AC power source. A zero-crossing may be defined at the time at which the AC source voltage transitions from positive to negative polarity, at the time at which the AC source voltage transitions from negative to positive polarity, or at the beginning of each half-cycle. The zero-cross control signal VZCmay be received by the control circuit820. The control circuit820may control the controllably conductive device810to be conductive and/or non-conductive at predetermined times relative to the zero-crossing points of the AC source voltage. The load control device800may include a wireless communication circuit828, for example, including a radio-frequency (RF) transceiver coupled to an antenna for transmitting and receiving wireless signals (e.g., RF signals from a remote ultrasonic receiver or a remote ultrasonic transmitter). The communication circuit828may comprise an RF transmitter for transmitting RF signals, an RF receiver for receiving RF signals, or an infrared (IR) transmitter and/or receiver for transmitting and/or receiving IR signals. The wireless communication circuit828may be in electrical communication with the control circuit820of the load control device800, such that one or more wireless signals received from the ultrasonic receiver may cause the load control device to adjust the lighting on or off. The antenna of the wireless communication circuit828may be enclosed in the housing of the load control device800or coupled to the exterior portion of the housing. The control circuit820may be coupled to a low phase-noise oscillator circuit530for setting an internal operating frequency for of the control circuit (e.g. approximately 40 kHz±2 Hz). The low phase-noise oscillator circuit830may include, for example, a Pierce oscillator circuit (as shown inFIG.8) having a crystal832, such as a 40-kHz piezoelectric crystal, e.g., part number CM250C, manufactured by Citizen Crystal. For example, the low phase-noise oscillator circuit830may be characterized by a spectral purity of approximately −60 dBc at 5 Hz from the rated frequency (i.e., 40 kHz±2 Hz). The low phase-noise oscillator circuit830may include an inverter834, two capacitors C835, C836(e.g., each having a capacitance of approximately 12 pF), and two resistors R838, R839(e.g., having resistances of approximately 10 MΩ and 392 kΩ, respectively). The low phase-noise oscillator circuit830may include any suitable external low phase-noise oscillator circuit, or an internal low phase-noise oscillator circuit of the control circuit820. The load control device800may include an ultrasonic sensing circuit840having an ultrasonic transmitting circuit850and an ultrasonic receiving circuit860. The ultrasonic transmitting circuit850may include a drive circuit854(e.g., an H-bridge drive circuit). The drive circuit854may receive the second DC supply voltage VCC2for energizing a piezoelectric element852, for example, in order to transmit ultrasonic waves from the load control device800(e.g., via an acoustic grill, such as the acoustic grill216of the load control device200shown inFIG.2). The control circuit820may drive the drive circuit854with an ultrasonic drive signal VDRIVE, such as a square wave signal having an ultrasonic transmission frequency fOPthat may be equal to the operating frequency fOPof the control circuit (e.g., approximately 40 kHz±2 Hz). Since the operating frequency for of the control circuit820is derived from the low phase-noise oscillator circuit830, the ultrasonic drive signal VDRIVEand the ultrasonic transmission frequency fUSmay be characterized by low phase noise. The ultrasonic receiving circuit860may include a piezoelectric element862. The piezoelectric element862may generate a received ultrasonic input signal VINin response to the received ultrasonic waves (e.g., the received ultrasonic waves shown inFIGS.5B and6B). The input signal VINmay be received by an amplifier864(e.g., a non-linear amplifier). The amplifier864may generate an amplified signal VAMPand may be characterized by a gain of approximately 20 dB. The ultrasonic receiving circuit860may include a rectifier circuit866(e.g., an asynchronous rectifier). The rectifier circuit866may receive the amplified signal VAMPfrom the amplifier circuit864and generate a rectified signal VRECT. For example, the rectifier circuit866may include a diode feeding the parallel combination of a resistor and a capacitor. Since the ultrasonic receiving circuit860of the load control device800may receive some of the unreflected ultrasonic waves transmitted by the ultrasonic transmitting circuit850, the magnitude of the amplified signal VAMPreceived by the rectifier circuit866may be greater than the forward drop of the diode of the rectifier circuit, such that the rectifier circuit may properly generate the rectified signal VRECT. The rectifier circuit866may include a synchronous rectifier as described in commonly-assigned U.S. Pat. No. 8,514,075, issued Aug. 20, 2013, entitled ULTRASONIC RECEIVING CIRCUIT, the entire disclosure of which is hereby incorporated by reference. A filter and amplifier circuit868(e.g., an anti-aliasing filter, such as a bandpass filter) may generate a filtered signal VFILTfrom the rectified signal VRECT. The filter and amplifier circuit868may have a bandwidth of approximately 50-500 Hz. The filter and amplifier868may be characterized by a gain of approximately 60 dB. The control circuit820may receive the filtered signal VFILTfrom the filter and amplifier circuit868. The control circuit820may sample the filtered signal using, for example, an analog-to-digital converter (ADC). The control circuit820is operable to detect the presence of the occupant in the space, for example, if the magnitude of the filtered signal VFILTrises above an upper voltage threshold or falls below a lower voltage threshold. In addition, the control circuit820may be operable to digitally filter the filtered signal VFILTreceived from the filter and amplifier circuit868to provide additional filtering of the signal before determining if the space is occupied or unoccupied. The load control device800may include a passive infrared (PIR) sensing circuit870, e.g., comprising a pyro-electric infrared detector for receiving infrared energy of the occupant through a lens of the load control device (e.g., the lens218of the load control device200shown inFIG.2). The PIR sensing circuit870may generate a PIR sense signal VPIRrepresentative of the magnitude of the received infrared energy. The control circuit820may analyze both the filtered signal VFILTreceived from the ultrasonic receiving circuit860and the PIR sense signal VPIRreceived from the PIR sensing circuit870, for example, to determine if an occupancy condition or a vacancy condition is presently occurring in the space. Examples of PIR sensing circuits are described in greater detail in commonly-assigned U.S. Pat. No. 8,228,184, issued Jul. 24, 2012, entitled BATTERY-POWERED OCCUPANCY SENSOR, the entire disclosure of which is hereby incorporated by reference. FIG.9is a simplified block diagram of an example remote ultrasonic transmitter900(e.g., the remote ultrasonic transmitter230ofFIG.2and/or the ultrasonic transmitters712ofFIG.7). The ultrasonic transmitter900may include a power supply910operable to receive power via electrical connections902,904. The ultrasonic transmitter900may include a power supply910to generate a DC supply voltage VCC(e.g., approximately 12 volts). For example, the electrical connections902,904may have prongs (e.g., the prongs434shown inFIG.4) adapted to be plugged into a receptacle of an electrical outlet for powering the ultrasonic transmitter900from an AC power source. The power supply910may be operable to convert the AC source voltage of the AC power source to the DC supply voltage VCC. The electrical connections902,904may be adapted to be coupled to an external DC power supply for receiving a DC source voltage. The power supply910may be a DC-to-DC converter for converting the DC source voltage to the DC supply voltage VCC. The power supply910may be replaced by one or more batteries. The ultrasonic transmitter900may include a low phase-noise oscillator circuit920, such as for driving an ultrasonic transmitting circuit930. The oscillator circuit920may generate an oscillating signal VOSC(e.g., a square wave) at an ultrasonic transmission frequency fUS(e.g., approximately 40 kHz±2 Hz) for driving the ultrasonic transmitting circuit930. As shown inFIG.9, the oscillator circuit920may comprise, for example, a Pierce oscillator circuit having a crystal922, such as a 40-kHz piezoelectric crystal, e.g., part number CM250C, manufactured by Citizen Crystal. For example, the low phase-noise oscillator circuit920may be characterized by a spectral purity of approximately −60 dBc at 5 Hz from the rated frequency (i.e., 40 kHz±2 Hz). The low phase-noise oscillator circuit920may include an inverter924, two capacitors C925, C926(e.g., each having a capacitance of approximately 12 pF), and two resistors R628, R629(e.g., having resistances of approximately 10 MΩ and 392 kΩ, respectively). The oscillating signal VOSCmay be generated at an output of the oscillator circuit920(e.g., the output of the inverter924). The ultrasonic transmitting circuit930may include a drive circuit932for energizing a piezoelectric element934, for example, to transmit ultrasonic waves from the ultrasonic transmitter900(e.g., through an acoustic grill, such as the acoustic grill232of the ultrasonic transmitter230shown inFIG.2). The drive circuit932may receive the oscillating signal VOSCfrom the oscillator circuit920(e.g., the drive circuit932may be directly driven by the output of the oscillator circuit). The drive circuit932may have a plurality of inverters936that may be coupled to the piezoelectric element934, for example, to generate the ultrasonic waves at the ultrasonic transmission frequency fUS. The piezoelectric element934may be coupled in series with a capacitor938(e.g., having a capacitance of approximately 1 μF). The inverter924of the oscillator circuit920and the inverters936of the ultrasonic transmitter circuit930may be implemented on a single integrated circuit (e.g., part number CD4049UB, manufactured by Texas Instruments), which may be powered by the DC supply voltage VCC. FIG.10is a simple diagram of another example of a load control system1000(e.g., an ultrasonic sensing system) comprising a load control device1010(e.g., an ultrasonic receiver) and a remote ultrasonic transmitter1030(e.g., the ultrasonic transmitter900shown inFIG.9). The load control device1010may be adapted to be coupled in series electrical connection between an AC power source1002and an electrical load (e.g., a lighting load1004) for controlling the power delivered to the lighting load. The remote ultrasonic transmitter1030may be operable to be plugged into a receptacle1022of an electrical outlet1020. The remote ultrasonic transmitter1030may transmit ultrasonic waves1006via an acoustic grill1032at an ultrasonic transmission frequency fUS(e.g., approximately 40 kHz±2 Hz). The load control system1000ofFIG.10may be similar to the load control system200shown inFIG.2. The load control device1010of the load control system1000ofFIG.10may include an ultrasonic occupancy detection circuit having an ultrasonic receiver, such that the load control system1000operates, for example, as shown inFIGS.6A and6B. Because the load control device1010may not have an ultrasonic transmitter and the ultrasonic receiver of the load control device may only receive the ultrasonic waves transmitted by the remote ultrasonic transmitter1030(e.g., ultrasonic waves having small magnitudes), the ultrasonic receiver includes a synchronous rectifier. The synchronous rectifier may be responsive to small signals, as described herein. The ultrasonic receiver of the load control device1010may be operable to receive ultrasonic waves via an acoustic grill1016. The load control device1010may include a PIR occupancy detection circuit operable to detect the presence of an occupant via infrared energy received through a lens1018. The load control device1010may be operable to turn the lighting load1004on and off in response to the ultrasonic occupancy detection circuit and/or the PIR occupancy detection circuit (e.g., as described above with reference to the load control device800ofFIG.8). The load control device1010may have an on button1012and an off button1014to provide manual control of the lighting load1004. FIG.11is a simplified block diagram of a load control device1100(e.g., the load control device1010ofFIG.10). The load control device1100may include a hot terminal1102adapted to be coupled to an AC power source (e.g., the AC power source1002ofFIG.10). The load control device1100may include a load terminal1104adapted to be coupled to an electrical load (e.g., the lighting load1004ofFIG.10). The load control device1100may include a controllably conductive device1110coupled in series electrical connection between the hot terminal1102and the load terminal1104, for example, to control the power delivered to the electrical load. The controllably conductive device1110may comprise, for example, a relay, a bidirectional semiconductor switch (such as, a triac, a FET in a rectifier bridge, two FETs in anti-series connection, or one or more insulated-gate bipolar junction transistors), or any other suitable switching circuit. The load control device1100may include a control circuit1120for controlling the controllably conductive device1110to be conductive and/or non-conductive to control the power delivered to the electrical load. For example, the control circuit1120may have a microcontroller, a programmable logic device (PLD), a microprocessor, an application specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or any suitable processing device, controller, or control circuit. The control circuit1120may receive inputs from actuators1122(e.g., the on button1012and the off button1014of the load control device1010ofFIG.10). The control circuit1120may receive a zero-cross control signal VZCthat may be representative of the zero-crossings of an AC source voltage of the AC power source from a zero-cross detect circuit1126. The control circuit1120may be coupled to an internal or external memory (not shown) for storage of the operational characteristics of the load control device1100. The control circuit1120may be coupled to a low phase-noise oscillator circuit1130(e.g., similar to the low phase-noise oscillator circuit820shown inFIG.8), for example, to set an internal operating frequency fOPof the control circuit (e.g., approximately 40 kHz±2 Hz). A power supply1124may generate a DC supply voltage VCC(e.g., approximately 3 volts) for powering the control circuit1120and/or other low-voltage circuitry of the load control device1100. The load control device1100may have an ultrasonic sensing circuit1140. The ultrasonic sensing circuit1140may include an ultrasonic receiving circuit1160. For example, the ultrasonic sensing circuit1140may include an ultrasonic receiving circuit1160.FIG.12Ashows an example waveform illustrating the operation of the ultrasonic receiving circuit1160when there may be a non-inverted ultrasonic drive signal VDRIVE. FIG.12Bshows an example waveform illustrating the operation of the ultrasonic receiving circuit1160when there may be an inverted ultrasonic drive signal VDR_INV. FIG.12Cshows an example waveform illustrating the operation of the ultrasonic receiving circuit1160when the ultrasonic receiving circuit1160may have received an ultrasonic input signal VINfrom an ultrasonic receiver. FIG.12Dshows an example waveform illustrating the operation of the ultrasonic receiving circuit1160when the ultrasonic receiving circuit1160may have received an amplified signal VAMPfrom the amplified circuit1164. FIG.12Eshows an example waveform illustrating the operation of the ultrasonic receiving circuit1160when the ultrasonic receiving circuit1160may have received a rectified signal VRECTfrom the synchronous rectifier1166. FIG.12Fshows example waveform illustrating the operation of the ultrasonic receiving circuit1160when the space around the load control device1100is vacant. For example,FIG.12Fmay show an example waveform illustrating the operation of the ultrasonic receiving circuit1160when the ultrasonic receiving circuit1160may have received a filtered signal VFILTfrom the bandpass filter1168without an occupant present. FIG.12Gshows an example waveform illustrating the operation of the ultrasonic receiving circuit1160when there is an occupant in the space. For example,FIG.12Gmay show an example waveform illustrating the operation of the ultrasonic receiving circuit1160when the ultrasonic receiving circuit1160may have received a filtered signal VFILTfrom the bandpass filter1168with an occupant present. The ultrasonic receiving circuit1160may have a piezoelectric element1162. The piezoelectric element1162may generate a received ultrasonic input signal VIN, for example, in response to the received ultrasonic waves (e.g., the received ultrasonic waves shown inFIGS.6A and6B). An amplifier circuit1164(e.g., a non-linear amplifier) may receive the input signal VIN. The amplifier circuit1164may generate an amplified signal VAMP(e.g., as shown inFIG.12F). A gain GNL of the amplifier circuit1164may be approximately 11, for example, when the magnitude of the AC component of the input signal VINis small (e.g., less than approximately 1.2 volts), and approximately 2, for example, when the magnitude of the AC component of the input signal VINis large (e.g., greater than approximately 1.2 volts). The ultrasonic receiving circuit1160may include a synchronous rectifier1166(i.e., a lock-in amplifier). The synchronous rectifier1166may be responsive to signals having small magnitudes. The synchronous rectifier1166may receive the amplified signal VAMPfrom the amplifier circuit1164. The synchronous rectifier1166may generate a rectified signal VRECT, for example, as shown inFIG.12E. The control circuit1120may generate a non-inverted ultrasonic drive signal VDRIVE, for example, as shown inFIG.12A. The control circuit1120may generate an inverted ultrasonic drive signal VDR_INV, for example, as shown inFIG.12B) at the operating frequency for of the oscillator circuit1130, which may be approximately equal to an ultrasonic transmission frequency fUSof the received ultrasonic waves (e.g., as transmitted by the ultrasonic transmitter1030shown inFIG.10). The synchronous rectifier1166may receive the non-inverted ultrasonic drive signal VDRIVEand the inverted ultrasonic drive signal VDR_INV, and the synchronous rectifier1166may use these signals to generate the rectified signal VRECT. A filter and amplifier circuit1168(e.g., an anti-aliasing filter, such as a bandpass filter) may generate a filtered signal VFILTfrom the rectified signal VRECTand may have a bandwidth of approximately 50-500 Hz. The filter and amplifier1168may be characterized by a gain of approximately 60 dB. The control circuit1120may be operable to digitally filter the filtered signal VFILTreceived from the bandpass filter1168to provide additional filtering of the signal. The control circuit1120may receive the filtered signal VFILTfrom the bandpass filter1168. The control circuit1120may sample the filtered signal using an ADC. The control circuit1120may be operable to detect the presence of the occupant in the space by comparing the magnitude of the filtered voltage VFILTto an upper voltage threshold VTH+(e.g., approximately 0.25 volts) and a lower voltage threshold VTH−(as shown inFIGS.12F and12G). The synchronous rectifier1166may properly rectify the amplified signal VAMP, and the filtered voltage VFILTmay stay between the upper voltage threshold VTH+and the lower voltage threshold VTH−, for example, when the space is vacant. Since the filtered signal VFILTis biased to approximately one-half of the supply voltage VCC1(i.e., approximately 1.5 volts), the filtered signal VFILTmay have a DC magnitude equal to approximately 1.5 volts and the filtered signal VFILTmay remain between the upper voltage threshold VTH+and the lower voltage threshold VTH−, for example, if the space is vacant (as shown inFIG.12F). If there is an occupant in the space, there may be a Doppler shift in the received ultrasonic waves as compared to the transmitted ultrasonic waves, and the magnitude of the filter voltage VFILTmay rise above the upper voltage threshold VTH+and/or fall below the lower voltage threshold VTH−(e.g., as shown inFIG.12G). The upper voltage threshold VTH+and the lower voltage threshold VTH−may be predetermined fixed values or may be adjustable by the control circuit1120. InFIG.11, the load control device1100may include a passive infrared (PIR) sensing circuit1170, which may, for example, comprise a pyroelectric infrared detector for receiving infrared energy of the occupant through a lens of the load control device (e.g., the lens1018of the load control device1000shown inFIG.10). The PIR sensing circuit1170may generate a PIR sense signal VPIRrepresentative of the magnitude of the received infrared energy. The control circuit1120may be able to analyze both the filtered signal VFILTreceived from the ultrasonic receiving circuit1160and the PIR sense signal VPIRreceived from the PIR sensing circuit1170to determine if an occupancy condition or a vacancy condition is presently occurring in the space. FIG.13is a simple diagram of an example load control system1300(e.g., an ultrasonic sensing system) comprising a wireless ultrasonic sensor1310and a remote ultrasonic transmitter1330(e.g., the ultrasonic transmitter900shown inFIG.9). The wireless ultrasonic sensor1310may be a remote ultrasonic receiver (e.g., the remote ultrasonic receiver1400shown inFIG.14). The remote ultrasonic transmitter1330may be operable to be plugged into a receptacle1322of an electrical outlet1320. The remote ultrasonic transmitter1330may transmit ultrasonic waves1306via an acoustic grill1332at an ultrasonic transmission frequency fUS(e.g., approximately 40 kHz). The wireless ultrasonic sensor1310may be operable to receive the ultrasonic waves1306transmitted by the ultrasonic transmitter1330via an acoustic grill1318. For example, the wireless ultrasonic sensor1310may have an ultrasonic occupancy detection circuit having an ultrasonic receiving circuit (e.g., only an ultrasonic receiving circuit), such that the remote ultrasonic transmitter1330and the wireless ultrasonic sensor1310operate as shown inFIGS.6A and6B. The wireless ultrasonic sensor1310may include an ultrasonic receiving circuit and an ultrasonic transmitting circuit. The ultrasonic receiving circuit of the wireless ultrasonic sensor1310may include a synchronous rectifier (e.g., similar to the synchronous rectifier of the load control device1100shown inFIG.11). The wireless ultrasonic sensor1310(e.g., the ultrasonic receiver1400as shown inFIG.14) may be configured to transmit wireless signals, e.g., radio-frequency (RF) signals1308in response to the received ultrasonic waves1306. For example, the wireless ultrasonic sensor1310may be battery-powered. An example of a battery-powered wireless ultrasonic sensor is described in greater detail in previously-referenced U.S. Pat. No. 8,514,075. The load control system1300may include a remote load control device1340. The remote load control device1340may be coupled in series electrical connection between an AC power source1302and an electrical load (e.g., a lighting load1304), such as for controlling the intensity of the lighting load. The remote load control device1340may be electrically coupled to the neutral side of the AC power source1302or to an earth ground connection. The remote load control device1340may be adapted to be remotely mounted, for example, to a junction box above a ceiling or in an electrical closet, such that the remote load control device is not easily accessible by a user. The remote load control device1340may be configured to control the lighting load1304in response to digital messages transmitted by the wireless ultrasonic sensor1310via the RF signals1308(e.g., in a similar manner as the load control device1100ofFIG.11). The load control system1300may include a wall-mounted load control device responsive to the RF signals1308transmitted by the wireless ultrasonic sensor1310(e.g., a wireless dimmer switch). The load control device1340and remote ultrasonic sensor1310may be located, for example, on a tabletop, a chair, or in a wallbox where a switch for an LED bulb is located. FIG.14is a simplified block diagram of an example remote ultrasonic receiver1400(e.g., the remote ultrasonic sensor1310of the load control system1300ofFIG.13). The ultrasonic receiver1400may include a power supply1410operable to receive power via electrical connections1402,1404. The ultrasonic receiver1400may include a power supply1410to generate a DC supply voltage VCC(e.g., approximately 12 volts). For example, the electrical connections1402,1404may have prongs (e.g., the prongs434shown inFIG.4) adapted to be plugged into a receptacle of an electrical outlet for powering the ultrasonic receiver1400from an AC power source. The power supply1410may be operable to convert the AC source voltage of the AC power source to the DC supply voltage VCC. The electrical connections1402,1404may be adapted to be coupled to an external DC power supply for receiving a DC source voltage. The power supply1410may be a DC-to-DC converter for converting the DC source voltage to the DC supply voltage VCC. The power supply1410may be replaced by one or more batteries. The ultrasonic receiving circuit1460may include a piezoelectric element1462. The piezoelectric element1462may generate a received ultrasonic input signal VINin response to the received ultrasonic waves (e.g., the received ultrasonic waves shown inFIGS.5B and6B). The input signal VINmay be received by an amplifier1464(e.g., a non-linear amplifier). The amplifier1464may generate an amplified signal VAMPand may be characterized by a gain of approximately 20 dB. The ultrasonic receiving circuit1460may include a rectifier circuit1466(e.g., an asynchronous rectifier). The rectifier circuit1466may receive the amplified signal VAMPfrom the amplifier circuit1464and generate a rectified signal VRECT. For example, the rectifier circuit1466may include a diode feeding the parallel combination of a resistor and a capacitor. Since the ultrasonic receiving circuit1460may receive some of the unreflected ultrasonic waves transmitted by an ultrasonic transmitter (e.g., the remote ultrasonic transmitter230ofFIG.2, the ultrasonic transmitters712ofFIG.7, and/or the ultrasonic transmitted900ofFIG.9), the magnitude of the amplified signal VAMPreceived by the rectifier circuit1466may be greater than the forward drop of the diode of the rectifier circuit, such that the rectifier circuit may properly generate the rectified signal VRECT. The rectifier circuit1466may include a synchronous rectifier as described in previously-referenced U.S. Pat. No. 8,514,075. The remote ultrasonic receiver1400may include a control circuit1420. The control circuit1420may include a microcontroller, a programmable logic device (PLD), a microprocessor, an application specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or any suitable processing device, controller, or control circuit. The remote ultrasonic receiver1400may include a wireless communication circuit1422, for example, including a radio-frequency (RF) transceiver coupled to an antenna for transmitting and/or receiving wireless signals (e.g., RF signals). The communication circuit1422may comprise an RF transmitter for transmitting RF signals, an RF receiver for receiving RF signals, or an infrared (IR) transmitter and/or receiver for transmitting and/or receiving IR signals. The wireless communication circuit1422may be in electrical communication with the control circuit1420, such that one or more wireless signals received from the ultrasonic transmitter may cause the ultrasonic receiver1400to transmit signals to a load control device (e.g., such as the remote load control device1340ofFIG.13). The antenna of the wireless communication circuit1422may be enclosed in the housing of remote ultrasonic receiver1400or coupled to the exterior portion of the housing. FIG.15is a simple diagram of an example three-way load control system1500(e.g., an ultrasonic sensing system) comprising first and second load control devices1510A,1510B (e.g., ultrasonic sensors). The first and second load control devices1510A,1510B may be coupled together in series electrical connection between an alternating-current (AC) power source1502and an electrical load (e.g., a lighting load1504). The first and second load control devices1510A,1510B may be installed to replace two single-pole double-throw (SPDT) switches (e.g., three-way switches) of a three-way switching system. As shown inFIG.15, the first and second load control devices1510A,1510B may not be coupled to the neutral side of the AC power source1502. Examples of load control devices for three-way load control systems are described in greater detail in commonly-assigned U.S. Pat. No. 7,847,440, issued Dec. 7, 2010, entitled LOAD CONTROL DEVICE FOR USE WITH LIGHTING CIRCUITS HAVING THREE-WAY SWITCHES, the entire disclosure of which is hereby incorporated by reference. The load control devices1510A,1510B may be coupled to the neutral side of the AC power source1502and/or an earth ground connection. The load control devices1510A,1510B may be similar to the load control devices210,1010shown inFIGS.2and10, respectively. The load control device1510A,1510B may operate together to control the power delivered to the lighting load1504. The load control devices1510A,1510B may be coupled together via a first electrical wire1508and a second electrical wire1509. The first electrical wire1508may conduct a load current from the AC power source1502to the lighting load1504. The second electrical wire1509may allow for communication between the load control devices. The first and second load control devices1510A,1510B may be identical devices (e.g., may have the same electrical circuitry). For example, the first and second load control devices1510A,1510B may have a controllable conductive device coupled in series with the first electrical wire1508for conducting the load current between the AC power source1502and the lighting load1504. The load control devices1510A,1510B may include internal ultrasonic occupancy detection circuits having ultrasonic transmitters and receivers. The load control devices1510A,1510B may transmit and receive ultrasonic waves1506via respective acoustic grills1516A,1516B. The load control devices1510A,1510B may be operable to detect the presence or absence of an occupant in the space surrounding the two load control devices in response to reflected and/or attenuated ultrasonic waves as shown inFIGS.5A-6B. The load control devices1510A,1510B may be operable to communicate with each other via the second electrical wire1509, for example, to determine how to control the lighting load1504in response to detecting the presence or absence of an occupant. For example, the second load control device1510B may establish itself as a master device in the load control system1500. The first load control device1510A may render its controllably conductive device conductive substantially fully conductive. The first load control device1510A may transmit digital messages to the second load control device1510B via the second electrical wire1509in response to detecting the presence or absence of an occupant. The second load control device1510B may control its controllably conductive device to control the power delivered to the lighting load1504in response to its internal ultrasonic occupancy detection circuit and/or the digital messages received from the first load control device1510A. The load control system1500may include one or more ultrasonic transmitters (e.g., the ultrasonic transmitter230shown inFIG.2or the ultrasonic transmitter900shown inFIG.9). The first load control device1510A may include only an ultrasonic transmitter and/or the second load control device1510B may include only an ultrasonic receiver, such that the load control system1500may operate, for example, as shown inFIGS.6A and6B. In addition, the first load control device1510A may operate as the master device of the load control system1500. | 45,396 |
RE49829 | BEST MODE FOR CARRYING OUT THE INVENTION First Embodiment Hereinafter, a memory card100which is a memory device, a host device200, and a memory system1provided with the memory card100and the host device200according to a first embodiment of the present invention will be explained with reference to the accompanying drawings. FIG.1is a schematic view showing a configuration of the memory system1made up of the memory card100and the host device200andFIG.2is a block diagram showing a configuration of a power circuit part of the memory system1. As shown inFIG.1, the memory card100is connectable to the host device200and is an SD memory card (registered trademark) connected to the host device200and used as an external storage device of the host device200. Examples of the host device200include an information processing apparatus including a personal computer that processes various kinds of data such as image data or music data, and a digital camera. The host device200includes an I/O cell209for transmitting/receiving a command signal, response signal, clock signal and data signal, that is, transmission signals to/from the memory card100connected and a host control section251that controls transmission/reception of a transmission signal or the like. The memory card100is provided with a memory section150made up of a non-volatile memory, a memory controller151that controls the memory section150and transmission/reception or the like of a transmission signal, an I/O cell121for inputting/outputting data and a connector152(including pin1to pin9). The memory controller151is connected to the memory section150via a bus of, for example, 8-bit bus width. When the memory card100is attached to the host device200, the connector152is electrically connected to the host device200. Allocation of signal lines to the pin1to pin9included in the connector152is defined in the standard of an SD memory card (registered trademark). That is, data DAT0, DAT1, DAT2and DAT3to transmit and receive a data signal are allocated to pin7, pin8, pin9and pin1respectively. Furthermore, the pin1is also allocated to a card detection signal CD. A command signal CMD and a response signal RES which is a response signal of the memory card100to this command signal are allocated to the pin2. A clock signal CLK is allocated to the pin5. A supply voltage VDD is allocated to the pin4and a grounding voltage VSS1is allocated to the pin3and a grounding voltage VSS2is allocated to the pin6. In the memory card100of the present embodiment, the memory section150is a non-volatile semiconductor memory and made up of a NAND type flash memory. Data or the like sent from the host device200is stored in the memory section150. Furthermore, as shown in FIG,2, the bus that transmits/receives a signal or the like between the memory card100and host device200includes a CLK line111(hereinafter also referred to as a “clock signal line”), a CMD/RES line112(hereinafter also referred to as a “CMD line”), a DAT[3:0] line113and a VDD line (hereinafter also referred to as a “power line”), and a DAT1line, a DAT2line, a CD/DAT3line, a VSS1line and a VSS2line which are not shown. Hereinafter, the DAT0line (hereinafter also referred to as a “data line”) will be explained as an example of the data signal line. Furthermore, the CMD/RES line is also referred to as a command signal line or response signal (RES) line. That is, the command signal line and the response signal line are one and the same signal line. As the operation mode (hereinafter also referred to as a “transfer mode”) of the memory card100which is the SD memory card (registered trademark) during a data transfer, an SD mode and an SPI mode are defined. Furthermore, as the transfer mode of the SD mode, two modes: a 1-bit mode using only the data DAT0and a 4-bit mode using the data DAT0to DAT3are defined. As the transfer mode of the memory card100, in addition to a normal speed mode (NSM) of a normal transfer rate and a high-speed mode (HSM) of a speed doubling that of the NSM, an ultra-high-speed mode (UHSM) of a speed further doubling that of the HSP is defined depending on the transfer clock frequency or the like, As shown inFIG.2, the memory card100of the memory system1has a regulator (VR2)116, which is a first regulator, and the host device200of the memory system1has a regulator (VR1)204which is a second regulator. Therefore, in addition to a data transfer mode whose signal voltage is a standard 3.3 V (hereinafter referred to as a “3.3 V mode”) which is a voltage mode supported by many memory systems1, the memory system1supports a mode in which the supply voltage remains standard 3.3 V and the data transfer signal voltage is set to a lower voltage 1.8 V (hereinafter referred to as a “1.8 V mode”). That is, the memory card100has a multi-drive type first I/O cell121that can transmit and receive a command signal, response signal, clock signal and data signal to/from the host device200at any one signal voltage selected from a first voltage (3.3 V) and a second voltage (1.8 V), which is lower than the first voltage and the first regulator116that can output the first voltage and the second voltage, and the host device200has a multi-drive type second I/O cell209and the second regulator204of specifications similar to those of the memory card100. InFIG.2, a power switch (PSW)201is a switch that turns ON/OFF the supply voltage (VDD) applied to the memory card100. Band gap references (BGR)115and203are reference voltage generation circuits using a potential difference of a band gap. Noise filters (Filter)114and201are not indispensable parts, yet effective in preventing noise from the power line (VDD) and generating more stable reference voltages. The first regulator (VR2)116and the second regulator (VR1)204are regulators that create a 1.8 V voltage from a 3.3 V supply voltage and generate the 1.8 V voltage based on the reference voltages of the BGRs115and203respectively. A third regulator (VR3)122which is a core voltage generation circuit, which is an internal logic circuit, generates a voltage supplied to a random logic section123. The random logic section123is a circuit having the memory controller151shown inFIG.1, ROM and RAM or the like. The host device200may also need a voltage generation circuit for the internal logic, which is however not shown. A comparator (VDCLK)120, which is a first voltage comparison circuit, detects whether or not the voltage of the CLK line is 1.8 V. Furthermore, a comparator (VDCMD/RES)208, which is a second voltage comparison circuit, detects whether or not the voltage of the CMD/RES line is 1.8 V. On the other hand, a comparator119, which is a third voltage comparison circuit or a comparator207, which is a fourth voltage comparison circuit, detects whether or not a 1.8 V voltage is correctly generated from the first regulator (VR2)116or the second regulator (VR1)204respectively. Here, that the second voltage is 1.8 V means that the second voltage falls within a range of 1.65 V to 1.95 V. Furthermore, the comparator that detects whether a voltage is the first voltage or the second voltage is a voltage comparator having a third threshold voltage intermediate between the first voltage and the second voltage, decides on the first voltage when the voltage of the measurement line is higher than the third threshold voltage, and decides on the second voltage when the voltage of the measurement line is lower than the third threshold voltage. When the signal of the bus line is a tri-state, pull-up resistors224and225keep the voltage of each line to 3.3 V or 1.8 V. Furthermore, capacitors118and206accumulate charge to stabilize a predetermined voltage. Next, a signal voltage switching operation of the memory system1will be explained usingFIG.3A,FIG.3BandFIG.4.FIG.3AandFIG.3Bare flowcharts illustrating the signal voltage switching operation of the memory system1andFIG.4is a timing chart of a signal line group (bus) during the signal voltage switching operation of the memory system1. The host device200performs a signal voltage switching operation taking into consideration compatibility with the memory card supporting only the 3.3 V mode. That is, if the host device200applies a 1.8 V signal voltage to the connected memory card from the beginning, the input I/O cell of the memory card supporting only the 3.3 V mode recognizes the applied 1.8 V as an intermediate voltage. Therefore, a large through current may flow through the input I/O cell of the memory card. Therefore, the host device200follows a procedure of sending a signal of 3.3 V signal voltage to the memory card first and switching to the 1.8 V mode only after detecting that the memory card is a memory card that supports the 1.8 V mode through handshake processing which will be described later. Hereinafter, the signal voltage switching operation of the memory system1will be explained following the flowcharts inFIG.3AandFIG.3B. The left side ofFIG.3AandFIG.3Bshows the operation flow of the host device200and the right side shows the operation flow of the memory card100. <Step S10> Memory Card Connected to Host Device The memory card100is connected to the host device200. That is, with the lines111to113making up the bus interface, the I/O cell121of the memory card100and the I/O cell209of the host device200are connected through the command/response signal line, clock signal line and data signal line or the like. <Step S11> CMD8 In the case of the host device200supporting a 1.8 V mode, the host device200inquires whether or not the connected memory card100supports the 1.8 V mode. That is, the host device200issues a command CMD8first (FIG.4: T1). Since a bit requesting the shift to the 1.8 V mode is set in an argument of the CMD8, the command signal CMD8transmitted from this host device200to the memory card100is also a command signal that informs that the signal voltage will be changed from the first voltage (3.3 V) to the second voltage (1.8 V). <Step S12> 1.8 V supported? Upon receiving the command signal CMD8from the host device, the memory card100decides whether or not the memory card100supports the 1.8 V mode. <Step S13> RES 1.8 V Not Supported/RES 1.8 V Supported When the memory card100does not support the 1.8 V mode (step S12: No), the memory card100sends in reply a response signal indicating that the 1.8 V mode is not supported to the host device200. On the other hand, when the memory card100supports the 1.8 V mode (step S12: Yes), the memory card100sends in reply a response signal indicating that the mode will be switched to the 1.8 V mode to the host device200(FIG.4: T2). <Step S14> 1.8 V Supported? Upon receiving a response signal (No) indicating that the 1.8 V mode is not supported from the memory card100, the host device200starts initialization processing in the 3.3 V mode in S33. On the other hand, upon receiving a response signal (Yes) indicating that the 1.8 V mode is supported from the memory card100, the host device200performs processing of mutually sending a next transmission signal based on the contents of the received signal, so-called handshake processing. <Step S15> Drive CMD/RES to 0 V After sending the response signal, the memory card100sets the CMD line to L level (ground level=0 V) (FIG.4: T3). <Step S16> Stop CLK to 0 V, Drive DAT to 0 V The host device200sets the DAT line to L level (ground level: 0 V) (FIG.4: T4), stops clock oscillation and also sets the CLK line to L level (ground level: 0 V) (FIG.4: T5). Any line of the DAT line and CLK line can be driven to L level first. Here, the reason that the CMD line, CLK line and DAT line are set, that is, driven to L level (0 V) is to prevent the respective lines from becoming a tri-state and prevent unstable voltages from being applied. When all unstable voltage is applied to the I/O cell121or the like for a voltage switching period, there is a danger that a through current may flow through the I/O cell121or the like. For this reason, the host device200or memory card100fixes the voltage of the signal line to L level (0 V). <Step S17, step S18> VR1, VR2from 3.3 V to 1.8 V The memory card100switches the regulator VR2so as to generate 1.8 V. Furthermore, the host device200switches the regulator VR1so as to generate 1.8 V. <Step S19, step S20> Timer Set The host device200waits until a predetermined time elapses (FIG.4: T5to T6). Therefore, the timer sets 100 microseconds for example. This is because the host device200needs to wait for the capacitors206and118connected to the regulator VR1and regulator VR2respectively to discharge from a state charged to 3.3 V to a state charged to 1.8 V. It is of course possible to provide a circuit that causes the capacitors206and118to actively discharge, but since the discharge time is a sufficiently short time to human senses, the memory system1is not provided with any discharge circuit. The above described explanation assumes that the waiting time is 100 microseconds, but the waiting time varies depending on the specification of the capacitor206or118and is generally on the order of 10 to 500 microseconds. <Step S21> Drive CLK to 1.8 V-DC The host device200sets the clock signal line at the ground level to 1.8 V for a predetermined time after a lapse of 100 microseconds in the above described example (FIG.4: T6). Here, the host device200applies a 1.8 V DC signal to the clock signal line which normally sends a clock signal. The host device200then informs the memory card100that the 1.8 V signal voltage can be supplied from the regulator VR2. <Step S22> CLK 1.8 V? When a voltage is applied to the clock signal line, the memory card100checks with the comparator120, which is the first voltage comparison circuit, whether or not the signal voltage is 1.8 V. When no 1.8 V voltage is applied to the clock signal line (No), the memory card100does not perform further voltage switching processing and the memory card100stops operating in step S32. <Step S23> Drive CMD/RES to 1.8 V-DC In step S22, when the signal voltage of the clock signal line is confirmed to be 1.8 V (Yes), the memory card100drives the CMD/RES line (response signal line) at the ground level to 1.8 V (FIG.4: T7). Here, the memory card100applies a 1.8 V DC signal to the response signal line which normally sends a RES signal. <Step S24> Timer Set After setting the signal voltage of the clock signal line to 1.8 V, the host device sets the timer. <Step S25> CMD Line 1.8 V? When a voltage is applied to the CMD/RES line, the host device200detects with the comparator (VDCMD/RES)208which is the second voltage comparison circuit whether or not the signal voltage of the CMD/RES signal line is 1.8 V. <Step S26, Step S27> When the 1.8 V voltage has not been applied to the clock signal line (No) even after a lapse of a predetermined time, for example, 100 microseconds, the host device200turns OFF the power switch (PSW)201in step S27and stops the operation of the memory card100. As explained above, when the memory card100or the host device200does not perform the predetermined operation even after a lapse of the predetermined time in the middle of handshake processing in the voltage switching processing, the memory system1of the present embodiment may detect that switching to 1.8 V has not been successfully performed and thereby output an error code or execute initialization processing in a 3.3 V mode. An example thereof will be shown inFIG.5. FIG.5shows a timing chart when the memory card100has not driven the CMD/RES line (response signal line) to 1.8 V in step S23. The host device200applies a 1.8 V voltage to the clock signal line and waits for a response operation from the memory card100, that is, for the response signal line to change from 0 V (ground level) to 1.8 V. However, when the response signal line does not become 1.8 V even after a lapse of a predetermined time (for example, 100 microseconds), the host device200turns OFF the power switch201at T12and stops the supply voltage (VDD) applied to the memory card100. Furthermore, the host device200sets the voltage of the CLK signal line to 0 V. Not only in the case shown inFIG.5, but also in the event of an error in the middle of handshake processing during the voltage switching processing, the host device200sets the voltage of the CLK signal line to 0 V and stops the power supply to the memory card100. <Step S28> CLK Oscillation In step S24, when the signal voltage of the CMD/RES signal line is confirmed to be 1.8 V (Yes), the host device200sends an oscillating clock signal to the clock signal line, in other words, oscillates the clock signal (FIG.4: T8). <Step S29, Step30> Drive DAT to 1.8 V/DAT to Tri-State After clock oscillation starts, the host device200drives the DAT signal line to a 1.8 V voltage for a short time (FIGS.4: T9to T10), sets the DAT signal line to a tri-state. Since the DAT signal line is pulled up at 1.8 V, the voltage level of 1.8 V is maintained. <Step S31, Step32> CLK Oscillated?/CMD/RES to Tri-State Upon receiving the oscillating clock signal from the host device200(Yes), the memory card100sets the CMD/RES line to a tri-state in step S29(FIG.4: T11). Since the CMD/RES line is pulled up at 1.8 V, the 1.8 V voltage level is maintained. When the oscillating clock signal is not applied to the clock signal line (No), the memory card100stops operating in step S35. <Step S33> Both the memory card100and host device200perform initialization processing in the 3.3 V mode and transmits/receives subsequent signals at a 3.3 V signal voltage. <Step S34> Both the memory card100and host device200complete the processing of moving to the 1.8 V mode and transmits/receives subsequent signals at a 1.8 V signal voltage. <Step S35> When the procedure for moving the signal voltage to the 1.8 V mode fails and the memory card100stops, the host device200turns OFF once the power and then sends the 3.3 V signal voltage to the memory card100again and performs initialization processing in the 3.3 V mode without switching to the 1.8 V mode. As explained above, in the memory system1, the memory card100and host device200mutually check signal voltages used through handshake processing and thereby prevent the I/O cell or the like from being damaged. Furthermore, in the memory system1, the memory card100and host device200mutually check the voltage of the output of the regulator116or204, and can thereby improve the reliability of the voltage applied to the signal line. Furthermore, the memory system1defines the handshake processing sequence using the clock signal line and command signal line, and can thereby follow a procedure to safely perform switching from the first voltage (3.3 V) to the second voltage (1.8 V). Even with the memory system1, it remains possible to cause the I/O cell121or209damaged if switching to the 1.8 V mode is frequently performed. Therefore, the memory system1can preferably perform normal processing of switching the signal voltage to the 1.8 V mode only at the first stage before the initialization processing starts. That is, after switching to the 1.8 V mode, the memory system1does not change the voltage mode even if a reset command is issued. In other words, even when a reset command is issued, the memory card100and host device200transmit and receive all signals at the second voltage of 1.8 V, and this state continues until the operation of the memory system1is completed where the supply voltage becomes 0 V. Since the memory system1should not frequently switch the voltage mode, it is possible to maintain stability and reliability by preventing the signal voltage from being changed even by a reset. Next, a protection diode owned by the memory card100and host device200will be explained usingFIG.6.FIG.6is a partial configuration diagram showing partial configurations of the I/O cells121and209of the memory card100and host device200. Any one voltage of 3.3 V and 1.8 V which are the outputs of the regulators204and116is selected and applied to the I/O cells209and121of the host device200and memory card100respectively. Therefore, when the voltage is switched, there may be a time during which the output voltage of the regulator204differs from that of the regulator116. When the output voltage of the regulator204is different from that of the regulator116, a current may flow through an unexpected path and damage the I/O cell121or209or the like. In the host device200and the memory card100, protection diodes232and136are connected to the power lines of a 3.3 V voltage. Therefore, in the host device200and memory card100, a protection diode137or233is not damaged by an applied voltage exceeding 1.8 V even in the 1.8 V mode. That is, the memory card100has the non-volatile memory section150which is connectable to the host device200, the power line VDD114that supplies the first voltage (3.3 V), the first regulator116that can output power of any one voltage selected from the first voltage (3.3 V) and the second voltage (1.8 V) which is lower than the first voltage from the VDD114, the I/O cell121that receives the power supply from the first regulator116and transmits/receives signals to/from the host device200, and the protection diode136connected to an input end of the I/O cell121and an end of the power supply connected to the 3.3 V power line to protect the I/O cell121from an overvoltage, wherein it is possible to perform transmission/reception to/from the host device200with a signal of any one voltage selected from the first voltage (3.3 V) and second voltage (1.8 V). In the memory system1, both the host device200and memory card100have the regulator116or204that can output two voltages, and therefore connecting the protection diode to the regulator output may damage the protection diode. When the signal voltage is set to 1.8 V, the supply voltage itself is generally set to 1.8 V, but since compatibility is taken into consideration in the memory system1, the supply voltage is set to 3.3 V. Therefore, the above described protection diode136is effective in preventing damage to the protection diode in the memory system1. As explained above, the host device200and the memory card100switch the voltage mode only at the stage of connection start. Therefore, the host device200never switches voltages by sending a switch commandFIG.7AandFIG.7Bare diagrams illustrating parameter examples of a switch command for changing the transfer mode in which the host device200performs transmission. The present embodiment has explained the memory system1or the like having an SD memory card (registered trademark) as the memory device for an example, but the present embodiment is also applicable to a memory system having another memory card, memory device, inner memory or the like as long as the memory system has a similar bus structure and can exert operations and effects similar to those of the memory system1or the like. As described above, the memory device or the like of the present invention is as follows. 1. A memory device, host device, memory system, memory device control method, host device control method and memory system control method. 2. The memory device according to 1 above, wherein the memory device includes a memory controller and upon sending the response signal indicating that the signal voltage is switched from the first voltage to the second voltage, the memory controller holds a response signal line to 0 V. 3. The memory device according to 1 or 2 above, wherein the host device includes a host control section and upon receiving through the response signal that the signal voltage is switched from the first voltage to the second voltage, the host control section stops the clock signal and holds the clock signal line and the data signal line to 0 V. 4. The memory device according to any one of 1 to 3 above, wherein voltages detected by the first voltage comparison circuit and the second voltage comparison circuit are voltages of DC currents. 5. The memory device according to any one of I to 4 above, wherein the memory controller and the host control section wait for a predetermined time after starting to switch voltages outputted from the first regulator and the second regulator from the first voltage to the second voltage. 6. The memory device according to any one of 1 to 5 above, further including a third voltage comparison circuit and a fourth voltage comparison circuit that detect that the voltages outputted by the first regulator and the second regulator are the second voltages. 7. The memory device according to any one of 1 to 6 above, wherein the first I/O cell and the second I/O cell include protection diodes that protect the respective I/O cells from an overvoltage. 8. The memory device according to any one of 1 to 7 above, wherein after switching the signal voltage from the first voltage to the second voltage, the memory controller and the host control section transmit and receive the signal at the second voltage until the power is turned OFF. 9. The memory device according to any one of 1 to 8 above, wherein the memory section is a NAND type flash memory. Furthermore, the memory device or the like of the present invention is a memory system having the memory device according to 2 to 8 above, a method of controlling the memory device and a method of controlling the memory system according to 2 to 8 above. Furthermore, the memory device, host device, memory system, memory device control method, host device control method and memory system control method of the present embodiment will be described hereinafter. 1. A memory device connectable to a host device, the memory device including a non-volatile memory section, a first I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the host device via a command signal line, response signal line, clock signal line or data signal line respectively at any one signal voltage selected from a first voltage and a second voltage which is lower than the first voltage, a first regulator that can output the first voltage and the second voltage, and a memory controller that sends, upon receiving the command signal requesting switching of the signal voltage from the first voltage to the second voltage from the host device, information indicating that the signal voltage will be switched to the host device using the response signal, switches a voltage outputted by the first regulator from the first voltage to the second voltage, applies, upon detecting that a clock signal line is at the second voltage, the second voltage to the response signal line at a ground level and starts, upon detecting oscillation of the clock signal, to transmit and receive a signal voltage of the second voltage. 2. The memory device according to 1 above, further including a first voltage comparison circuit that detects that a signal voltage of the clock signal line is the second voltage. 3. A host device to which a memory device having a non-volatile memory section is connectable, the host device including a second I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the memory device via a command signal line, response signal line, clock signal line or data signal line respectively at any one signal voltage selected from a first voltage and a second voltage which is lower than the first voltage, a second regulator that can output the first voltage and the second voltage, and a host control section that sends, when the signal voltage is switched from the first voltage to the second voltage, information indicating that the signal voltage will be switched using the command signal, switches, upon receiving the response signal indicating that the signal voltage can be switched, a voltage outputted by the second regulator from the first voltage to the second voltage, applies the second voltage to the clock signal line at a ground level, oscillates, upon detecting that the response signal line is at the second voltage, the clock signal and starts transmission/reception at a signal voltage of the second voltage. 4. A host device to which a memory device having a non-volatile memory section is connectable, the host device including a second I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the memory device via a command signal line, response signal line, clock signal line or data signal line respectively at any one signal voltage selected from a first voltage and a second voltage which is lower than the first voltage, a second regulator that can output the first voltage and the second voltage, and a host control section that sends, when the signal voltage is switched from the first voltage to the second voltage, information indicating that the signal voltage will be switched using the command signal, turns OFF once the power of the memory device when the response signal indicating that the signal voltage can be switched cannot be received for a predetermined time or upon receiving a response signal indicating that switching is not possible and starts transmission/reception at the first voltage again. 5. The host device according to 3 or 4 above, further including a second voltage comparison circuit that detects that a signal voltage of the response signal line is the second voltage. 6. A memory system including a memory device including a first I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the host device via a command signal line, response signal line, clock signal line or data signal line respectively at any one signal voltage selected from a first voltage and a second voltage which is lower than the first voltage, a first regulator that can output the first voltage and the second voltage, and a memory controller that receives the command signal that requests switching of the signal voltage from the host device including a second I/O cell that can perform transmission/reception to/from the memory device when the signal voltage is switched from the first voltage to the second voltage at any one signal voltage selected from the first voltage and the second voltage and a second regulator that can output the first voltage and the second voltage, sends information indicating that the signal voltage can be switched to the host device using the response signal at the first voltage, switches a voltage outputted by the first regulator from the first voltage to the second voltage, applies, upon detecting that the clock signal line is at the second voltage, the second voltage to the response signal line at a ground level and starts transmission/reception upon detecting that the response signal line is at the second voltage and detecting oscillation of a clock signal from the host device at a signal voltage of the second voltage, and a host device including a second I/O cell that can perform transmission/reception to/from the memory device at any one signal voltage selected from the first voltage and the second voltage, a second regulator that can output the first voltage and the second voltage, and a host control section that sends, when the signal voltage is switched from the first voltage to the second voltage, the command signal requesting switching of the signal voltage to the memory device, receives information indicating that the signal voltage can be switched from the memory device using the response signal at the first voltage, switches a voltage outputted by the second regulator from the first voltage to the second voltage, applies the second voltage to a clock signal line at a ground level and oscillates the clock signal upon detecting that the response signal line is at the second voltage. 7. The memory system according to 6 above, wherein the memory device further includes a first voltage comparison circuit that detects that a signal voltage of the clock signal line is the second voltage and the host device further includes a second voltage comparison circuit that detects that a signal voltage of the response signal line is the second voltage. 8. A method of controlling a memory device connectable to a host device, the memory device including a non-volatile memory section, a first I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the host device via a command signal line, response signal line, clock signal line or data signal line at any one signal voltage selected from a first voltage and a second voltage which is lower than the first voltage, a first regulator that can output the first voltage and the second voltage and a memory controller, the method including a command receiving step of receiving the command signal requesting switching of the signal voltage from the first voltage to the second voltage from the host device, a response signal sending step of sending information indicating that the signal voltage can be switched to the host device using the response signal, a first regulator switching step of switching a voltage outputted by the first regulator from the first voltage to the second voltage, a clock signal line voltage detecting step of detecting that the clock signal line is at the second voltage, a response signal line voltage applying step of applying the second voltage to the response signal line at a ground level, a clock signal oscillation detecting step of detecting oscillation of the clock signal and a transmitting/receiving step of starting transmission/reception at a signal voltage of the second voltage. 9. The method of controlling a memory device according to 8 above, the memory device further including a first voltage comparison circuit that detects that a signal voltage of the clock signal line is the second voltage. 10. A method of controlling a host device to which a memory device having a non-volatile memory section is connectable, the host device including a second I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the memory device via a command signal line, response signal line, clock signal line or data signal line respectively at any one signal voltage selected from a first voltage and a second voltage which is lower than the first voltage and a second regulator that can output the first voltage and the second voltage and a host control section, the method including a command signal sending step of sending, when the signal voltage is switched from the first voltage to the second voltage, information indicating that the signal voltage will be switched using the command signal, a response signal receiving step of receiving the response signal indicating that the signal voltage can be switched, a regulator voltage switching step of switching a voltage outputted by the second regulator from the first voltage to the second voltage, a clock signal line voltage applying step of applying the second voltage to the clock signal line at a ground level, a response signal line voltage detecting step of detecting that the response signal line is at the second voltage, a clock signal oscillation step of oscillating the clock signal and a transmitting/receiving step of starting transmission/reception at a signal voltage of the second voltage. 11. The method of controlling a host device according to 10 above, the host device further including a second voltage comparison circuit that detects that a signal voltage of the response signal line is the second voltage. 12. A method of controlling a memory system including a host device and a memory device connectable to the host device, when the memory device including a non-volatile memory section, a first I/O cell that can transmit and receive a command signal, response signal, clock signal and data signal to/from the host device via a command signal line, response signal line, clock signal line or data signal line respectively at any one signal voltage selected from the first voltage and a second voltage which is lower than the first voltage, a first regulator that can output the first voltage and the second voltage and a memory controller, and the host device including a second I/O cell that can transmit and receive the signal to/from the memory device at the signal voltage selected from the first voltage and the second voltage, a second regulator that can output the first voltage and the second voltage and a host control section switch the signal voltage from the first voltage to the second voltage, the method including a command signal sending step of sending the command signal requesting switching of the signal voltage to the memory device, a response signal sending step of the memory device sending information indicating that the signal voltage can be switched to the host device using the response signal at the first voltage, a regulator voltage switching step of the memory device and the host device switching a voltage outputted by the first regulator and the second regulator from the first voltage to the second voltage, a clock signal line voltage applying step of the host device applying the second voltage to the clock signal line at a ground level, a clock signal line voltage detecting step of the memory device detecting that the clock signal line is at the second voltage, a response signal line voltage applying step of the memory device applying the second voltage to the response signal line at a ground level, a response signal line voltage detecting step of the host device detecting that the response signal line is at the second voltage, a clock signal oscillation step of the host device oscillating the clock signal, a clock signal oscillation detecting step of the memory device detecting oscillation of the clock signal, and a transmitting/receiving step of the memory device and the host device starting transmission/reception at a signal voltage of the second voltage. 13. The method of controlling a memory system according to 12 above, wherein the memory device includes a first voltage comparison circuit that detects that a signal voltage of the clock signal line is the second voltage and the host device includes a second voltage comparison circuit that detects that a signal voltage of the response signal line is the second voltage. 14. A memory device connectable to a host device, including a non-volatile memory section, a memory controller, a power supply that supplies a first voltage, a regulator that can output power of any one voltage selected from the first voltage and a second voltage which is lower than the first voltage from the power supply, an I/O cell that receives a power supply from the regulator, can perform transmission/reception to/from the host device via a command signal line, response signal line, clock signal line or data signal line respectively using a signal of any one voltage selected from the first voltage and the second voltage and a protection diode connected between an input end of the I/O cell and an end of the power supply to protect the I/O cell from an overvoltage. 15. A host device connectable to a memory device having a non-volatile memory section, including a host control section, a power supply that supplies a first voltage, a regulator that can output power of any one voltage selected from the first voltage from the power supply and a second voltage which is lower than the first voltage, an I/O cell that receives a power supply from the regulator, can perform transmission/reception to/from the memory device via a command signal line, response signal line, clock signal line or data signal line using a signal at any one voltage selected from the first voltage and the second voltage and a protection diode connected between an input end of the I/O cell and an end of the power supply to protect the I/O cell from an overvoltage. Second Embodiment Hereinafter, a memory system301having a memory card400which is a memory device, a host device500, a memory card400and a host device500according to a second embodiment of the present invention will be explained with reference to the accompanying drawings. Since the memory system301or the like of the present embodiment is similar to the memory system1or the like according to the first embodiment, the same components will be assigned the same reference numerals and explanations thereof will be omitted. Next, a signal voltage switching operation of the memory system301will be explained usingFIG.8A,FIG.8B,FIG.9andFIG.10.FIG.8AandFIG.8Bare flowcharts illustrating the signal voltage switching operation of the memory system301andFIG.9andFIG.10are timing charts of a signal line group (bus) during the signal voltage switching operation of the memory system301. Hereinafter, the signal voltage switching operation of the memory system301will be explained according to the flowcharts ofFIG.8AandFIG.8B. The left side ofFIG.8AandFIG.8Bshows an operation flow of the host device500and the right side shows an operation flow of the memory card400. <Step S40> to <Step S44> Since these steps are the same as step S10to step S14of the memory system1or the like, explanations thereof will be omitted. <Step S45> Drive CMD/RES to 0 V, Drive DAT to 0 V After sending a response signal, the memory card400sets the CMD line to L level (ground level: 0 V) (FIG.9: T3) and sets the DAT line to L level (ground level=0 V) (FIG.9: T4). Between the CMD/RES line and DAT line, any line can be set to L level first. <Step S46> Stop CLK to 0 V The host device500stops clock oscillation and also sets the CLK line to L level (ground level: 0 V) (FIG.9: T5). <Step S47> to <Step S50> Since these steps are the same as step S17to step S20of the memory system1or the like, explanations thereof will be omitted. <Step S51> CLK Oscillation After a lapse of a predetermined period (e.g., 100 microseconds) in the steps49,50, the host device500sends an oscillating clock signal to a clock signal line, in other words, oscillates a clock signal (FIG.9: T6). The host device500then informs the memory card400that a 1.8 V signal voltage can be supplied from a regulator VR2. <Step S52> CLK Oscillation? The memory card400checks whether or not an H level clock signal of a predetermined voltage is applied to the clock signal line. <Step S53> This step is the same as step S23of the memory system1or the like and therefore explanations thereof will be omitted. <Step S54> CMD/RES to Tri-State The memory card400drives the CMD/RES line to a 1.8 V voltage for only a short time (FIG.9: T7to T8), and then sets the CMD/RES line to a tri-state (FIG.9: T8). Since the CMD/RES line is pulled up at 1.8 V, the voltage level of 1.8 V is maintained. <Step S55, Step56> Drive DAT to 1.8 V/DAT to Tri-State The memory card400drives the DAT signal line to a 1.8 V mode voltage for only a short time (FIG.9: T9to T10), then sets the DAT signal line to a tri-state. Since the DAT signal line is pulled up at 1.8 V, the voltage level of 1.8 V is maintained. <Step S57> Clock Counter Set The host device500sets the clock counter after oscillating the clock signal and then sets a count n to 0. <Step S58, Step S59> The host device500waits until at least 16 clocks are counted. A value equal to or greater than 16 clocks is set as the waiting time. <Step S60> DAT Line 1.8 V? The host device500detects that the DAT signal line is not at a ground level, that is, that a predetermined voltage is applied. Here, the predetermined voltage is 1.8 V. When no voltage is applied to the DAT signal line (No), the host device500turns OFF a power switch (PSW)201in step S61and stops operation of the memory card400. When a voltage is applied to the DAT signal line (Yes), in step S63, the host device500transmits/receives subsequent signals at a 1.8 V signal voltage. Furthermore, the host device500detects that not only the DAT signal line but also the DAT signal line and CMD signal line are not at a ground level, that is, by detecting that a predetermined voltage is applied, it is possible to perform voltage switching processing more safely. Here, the predetermined voltage is 1.8 V. <Step S62> Both the memory card400and the host device500perform initialization processing in a 3.3 V mode and transmits/receives subsequent signals at a 3.3 V signal voltage. <Step S63> Both the memory card400and the host device500complete the processing of moving to the 1.8 V mode and transmits/receives subsequent signals at a 1.8 V signal voltage. When the procedure for moving to the 1.8 V mode signal voltage fails and the memory card400stops, the host device500turns OFF once the power, sends a 3.3 V signal voltage to the memory card400again and performs initialization processing in the 3.3 V mode without switching to the 1.8 V mode. As described above, the memory card400of the memory system301detects the voltage of the oscillation clock signal outputted by the host device500. This eliminates the necessity for a circuit that applies a DC voltage to the clock signal line, which is required in the memory system1. Furthermore, the memory card400sets the DAT line to a tri-state. Despite its simpler configuration, the memory system301of the present embodiment can still exert effects similar to those of the memory system1of the first embodiment. Third Embodiment Hereinafter, a memory card700, which is a memory device, a host device800and a memory system601having the memory card700and the host device800according to a third embodiment of the present invention will be explained. The memory system601or the like of the present embodiment is similar to the memory system301or the like of the second embodiment, and therefore the same components will be assigned the same reference numerals and explanations thereof will be omitted. The memory system601or the like is not provided with the comparators119,120,207,208(seeFIG.2) for confirming that the voltage is a desired voltage, for example, 1.8 V. Therefore, the memory card700checks in step S52inFIG.8Athat the clock signal line is not at a ground level, that is, only the presence/absence of clock oscillation. Furthermore, in step S55inFIG.8B, the host device800only checks whether or not any voltage is applied to the CMD line, that is, whether or not the CMD line is at a ground level. Despite its simpler configuration, the memory system601of the present embodiment can still exert effects similar to those of the memory system1or the like of the first embodiment. Having described the preferred embodiments of the invention referring to the accompanying drawings, it should be understood that the present invention is not limited to those precise embodiments and various changes and modifications thereof could be made by one skilled in the art without departing from the spirit or scope of the invention as defined in the appended claims. The present application is based on Japanese Patent Application No. 2008-72429 filed on Mar. 19, 2008 and Japanese Patent Application No. 2008-99740 filed on Apr. 7, 2008 as the basis for claiming priority, entire disclosure content of which is quoted in the specification of the present application, claims and drawings. | 47,304 |
RE49830 | The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present invention. In the drawings, like reference numerals designate corresponding parts throughout the several views. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Set forth below is a description of what are believed to be the preferred embodiments and/or best examples of the invention claimed. Future and present alternatives and modifications to this preferred embodiment are contemplated. Any alternatives or modifications which make insubstantial changes in function, in purpose, in structure, or in result are intended to be covered by the claims of this patent. Work unit 50, such as table or cabinet 50, may include a work surface 51, such as shown in FIGS. 1, 3 and 4-7.FIG.1shows a preferred embodiment of a pop-up receptacle electrical charger, generally designated by reference numeral100, which preferably as both wireless and hard-wired charging capabilities, for use with various equipment or furniture, such as counter tops, tables, desks or other similar items having work surfaces which the charger can be attached to. Referring toFIG.8, electrical charger/relocatable power tap (RPT)100may generally include a base portion A, a top portion B, and a charging station C located between these portions. Still referring toFIG.8, base portion A may include a fixing ring16with vertical threads16a, allowing ring16to be threadably attached to a work surface. Base portion A may also include a fixing base14with external threads14a, enabling base14to be threadably fastened to fixing ring16, using interdisposed gasket15for waterproofing. Referring to FIGS. 3, 5, 6 and 8, base portion A may include a fixing base 14 with a body having threads 14a, and a fixing ring threadably engaged to base threads 14a. Threads 14a may engage the work piece as shown, with base 14 located above the work piece, and fixing ring 16 located below the work piece and used to secure the charger to the work piece. Data adapter29may be used if it is desired to add internet or phone (wired) to unit100, and may be affixed to the bottom of ring16using column end cover22. Friction plates11and12, and cable tighten plate12, are used to support prop-up spring36. Decorative ring23may be used to enhance the aesthetics of the unit. When the unit is in the down position, rubber sealing gasket26may be pushed flush against the surrounding side of an aperture51a of work surfaces51(e.g.,FIG.5), so that protective cover5provides a liquid-tight seal for wireless charging emitter coil4, such that liquid cannot flow through the work surface aperture and into the bottom portion of the unit. Charging station C may include case1carrying, e.g., a 20-amp GFI (encased by receptacle adaptor9), a 2USB charger13(encased by frame7), and a terminal block6secured to the unit by fasteners34. Terminal block6may be used for the connection of power cables from outside unit100with the cables inside unit100; with this terminal block, when unit100is popped up or pushed down, the power cable inside will not be dragged or become loose. Still referring toFIG.8, locking mechanisms17,27,28, and locking spring21, may be used to lock unit100in its elevated position. When the unit is in its elevated, locked position, if a user pushes down on the top cover (perhaps inadvertently), the unit will not move. However, when column locking part17is first depressed, this depresses spring21, allowing the unit to move down. Locking mechanisms27,28house locking part17, and fix spring21inside. Module adaptor8and blank plate30may be used if it is desired to install another receptacle in this area, so that an extra power receptacle or communication data port may be provided when the unit is in a depressed position. Now referring toFIG.8, locking guide blocks19and prop-up spring31, together with left and right spring plates24,25, constitute the pop-up mechanism for unit100. Spring20a moves within a triangular slot20b of locking mechanism main part20. Locking guide block19constitutes a housing to ensure that spring20a only moves inside the slot or main part20. When a user pushes down on the top cover5, spring20a moves to one side of triangular slot20b of main part20, allowing unit100to pop up; when a user pushes down on cover5again, spring20a moves to another side of triangular slot20b, and the top cover will be locked into a closed state. Top portion B may include fixing base14fixably secured to a top portion of case1, with top cover sealing gasket26interdisposed therein. Wireless charging emitter coil4may be mainly made of enameled copper wire, and may be carried by fixing base3accommodating a PCB board (see parts list for PCB board inFIG.9), as shown. For this purpose, tab4a of coil4may fit within corresponding tab aperture14a of base14. In function, electrical charger100may be powered by a power cord (not shown) connected to charging station C; the power cord may be run down though base portion A and into an outlet (not shown). Whether charger is in a depressed or upright position, the wireless charger may be used by placing an electrical device to be powered on protective cover5; the battery of the device to be powered will then electronically synchronize with emitter coil4for charging. When charger100is in an upright position, exposing charging station C above the work surface, electrical devices may be charged by hard-wire connection to GFI receptacles2of USB charger9. Here is a part list for the preferred embodiment shown, summarizing the parts, and providing exemplary materials and quantities. The part numbers correspond to the reference numerals on the drawings: PARTSDescription and/orNO.Parts NameMaterialQuantity1aluminum caseLocking mechanism1main part220A GFIPC, ABS, copper, etc.13wireless charging emitterPC1fixing base4wireless charging emitter coilenameled copper wire15wireless charging emitterABS1protective cover6terminal blockPC17PUR (pop-up receptacle)PC1single type 45 frame8type 45 size module adaptorsilicon19US type receptacle adaptorPC110left-side friction platePC111right-side friction platePC112cable tighten clipABS113type 45 2 USB chargerPC and others114PUR fixing basePC115Gasketbutadiene-acrylonitrile1rubber16PUR fixing ringPC117column-locking partPC118locking springprop-up spring219locking guide blockstainless steel220locking mechanismlocking mechanism2main partmain part21locking springlocking spring122column end coverPC123down decorative ringSS304124right-side spring platePC125left-side spring platePC126top cover sealing gasketsoft silicone127Upper locking mechanismPC1part28down locking mechanismPC1part29data adaptorPC230blank platePC231prop-up springlocking spring432GB (standard Chinese) wood10screws (type 135, 3.5X8-C)33cross-recessed countersunk2head screws GB234GB cross-screws (type 12M3X16-16, H Type-N)35GB cross-screws (type 22M4X5-5, H Type-N)36friction prop-up springlocking spring237GB cross screws (Type5M3X5-3.35, H Type-C) Preferably, wireless charging emitter4is in the shape of a round coil. It will also be understood that GFI receptacle2or USB charger13may also include a ground fault circuit interrupter (GFCI)-type outlet to prevent electrical shock in wet locations. The above description is not intended to limit the meaning of the words used in the following claims that define the invention. Persons of ordinary skill in the art will understand that a variety of other designs still falling within the scope of the following claims may be envisioned and used. It is contemplated that these additional examples, as well as future modifications in structure, function, or result to that disclosed here, will exist that are not substantial charges to what is claimed here, and that all such insubstantial changes in what is claimed are intended to be covered by the claims. | 7,907 |
RE49831 | DETAILED DESCRIPTION Hereinafter, various embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. The figures are provided to allow those having ordinary skill in the art to understand the scope of the embodiments of the disclosure. The present invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present invention to those skilled in the art. FIG.3is a perspective view of the structure of a semiconductor device according to an embodiment. An insulating layer is not depicted for illustration purposes. As illustrated inFIG.3, the semiconductor device according to the embodiment may include a first source layer S1; one or more second source layers S2formed substantially in the first source layer S1; a plurality of conductive layers formed substantially over the first source layer S1; semiconductor pillars passing through the conductive layers and coupled to the one or more second source layers S2; and a third source layer S3formed substantially in each second source layer S2, and passing through the second source layer S2and coupled to the first source layer S1. In addition, the semiconductor device according to the embodiment may further include memory layers (not illustrated) and bit lines BL. Each of the memory layers may substantially surround outer surfaces of the semiconductor pillars and an outer surface of the second source layer S2. The bit lines BL may be formed substantially over the conductive layers and extend in a second direction II-II′. Each of the bit lines BL may be coupled to the semiconductor pillars that are arranged in the second direction II-II′. Here, at least one of lowermost conductive layers, from the plurality of conductive layers stacked one upon another, may be used as a lower select line LSL, at least one of uppermost conductive layers may be used as an upper select line USL, and the rest of the conductive layers may be used as word lines WL. Each of the first to third source layers S1to S3may comprise of a polysilicon layer doped with impurities or a metal layer. For example, the first and second source layers S1and S2may be formed of polysilicon layers doped with N-type impurities, and the third source layer S3may comprise of a metal layer formed of tungsten. The semiconductor pillars may be used as channel layers CH. For example, each of the semiconductor pillars may be formed of a polysilicon layer not doped with impurities. In addition, the semiconductor pillars may be formed integrally with the second source layer S2. According to the structure of the semiconductor device as described above, strings substantially extend vertically from a substrate. Therefore, pipe transistors may not be provided, which makes it easier to drive the memory device. In addition, as the third source layer S3comprises a metal layer, and the third source layer S3is coupled to the first and second source layers S1and S2, source resistance may be reduced improving the characteristics of the memory device. FIG.4is an exploded perspective view of a source layer structure of the semiconductor device according to an embodiment. As illustrated inFIG.4, the second source layer S2may be formed substantially in the first source layer S1, and the first source layer S1substantially surrounds the side surfaces and the bottom surface of the second source layer S2. In addition, the third source layer S3may be formed substantially in the second source layer S2, and the second source layer S2substantially surrounds a top surface, side surfaces, and the bottom surface of the third source layer S3. Here, the second source layer S2may include one or more first openings OP1that may be formed substantially in the bottom surface thereof and at least one second opening OP2formed substantially in the top surface thereof. Here, the one or more first openings OP1may be in the form of islands and may be arranged at regular intervals. The second opening OP2may be in the form of a line and may overlap with the first openings OP1. The third source layer S3may comprise of a plate layer S3-1and one or more protruding layers S3-2. The plate layer S3-1may be formed substantially in the second source layer S2. The one or more protruding layers S3-2may protrude from a bottom surface of the plate layer S3-1. The one or more protruding layers S3-2may be in the form of islands and be located at positions corresponding to the first openings OP1of the second source layer S2. Therefore, the protruding layers S3-2may protrude through the first openings OP1of the second source layer S2and be directly coupled to the first source layer S1. FIG.5is an exploded perspective view of a source layer structure of the semiconductor device according to an embodiment. As illustrated inFIG.5, the second source layer S2may be formed substantially in the first source layer S1, and the first source layer S1substantially surrounds side surfaces and the bottom surface of the second source layer S2. In addition, the third source layer S3may be formed substantially in the second source layer S2, and the second source layer S2substantially surrounds a top surface, side surfaces, and a bottom surface of the third source layer S3. Here, the second source layer S2may comprise, at least, one first opening OP1that is formed substantially in the bottom surface thereof and at least one second opening OP2that may be formed substantially in the top surface thereof. The first opening OP1may be in the form of a line that substantially crosses the bottom surface of the second source layer S2, and the second opening OP2may be in the form of a line that substantially crosses the top surface of the second source layer S2. In addition, the first opening OP1and the second opening OP2may substantially overlap with each other. The third source layer S3may comprise the plate layer S3-1and at least one protruding layer S3-2. The plate layer S3-1may be formed substantially in the second source layer S2, and the protruding layer S3-2may protrude from a bottom surface of the plate layer S3-1. The protruding layer S3-2may be in the form of a line and may be located at a position corresponding to the first opening OP1of the second source layer S2. Therefore, the protruding layer S3-2may protrude through the first opening OP1of the second source layer S2and be directly coupled to the first source layer S1. FIGS.6A and6B,7A and7B,8A to8D,9A to9D,10A and10B, and11A and11Bare views illustrating a method of manufacturing the semiconductor device according to an embodiment.FIGS.6A to11Aare layout views,FIGS.6B to11Bare cross-sectional views taken along line A-A′,FIGS.8C and9Care cross-sectional views taken along line B-B′, andFIGS.8D and9Dare cross-sectional views taken along line C-C′. As illustrated inFIGS.6A and6B, after an insulating layer12is formed substantially over a substrate11, a first source layer13(S1) may be formed substantially over the insulating layer12. The insulating layer12may electrically insulate the first source layer13from the substrate11. The insulating layer12may comprise an oxide layer. In addition, the first source layer13may be a polysilicon layer doped with impurities. In an example, the first source layer13may comprise a polysilicon layer doped with N type impurities. Subsequently, the first source layer13may be etched to form trenches. Each of the trenches may define a region in which a second source layer and a third source layer may be formed in subsequent processes. For example, each trench may be in the form of an island, a line, or a combination of an island and a line. In the first embodiment, the trench may be shaped like a ladder consisting of line trenches and island trenches that coupe the line trenches. Subsequently, sacrificial layers14may be formed substantially in the trenches. For example, after the sacrificial layers14are formed substantially over the first source layer13in which the trenches may be formed, a planarization process may be performed until a surface of the first source layer13is exposed. As a result, the sacrificial layer14may be formed in each of the trenches. In one example, the sacrificial layer14may comprise a nitride layer (SiN) or a titanium nitride layer (TiN). As illustrated inFIGS.7A and7B, first material layers15and second material layers16may be formed alternately over the first source layer13or13(S1) in which the sacrificial layer14may be formed. The first material layer15may be used to form a conductive layer of a word line, a lower select line, or an upper select line. The second material layer16may be used to separate stacked conductive layers from each other. The thickness of the first material layer15may vary, depending on its purpose. A conductive layer for an upper select line or a lower select line may have substantially the same thickness as a conductive layer for a word line. The first material layer15and the second material layer16may be formed of materials having a high etch selectivity therebetween. In an example, the first material layer15may comprise a conductive layer such as a polysilicon layer, and the second material layer16may comprise an insulating layer such as an oxide layer. In another example, the first material layer15may comprise a conductive layer such as a doped polysilicon layer or a doped amorphous silicon layer, and the second material layer16may be formed of a sacrificial layer such as an undoped polysilicon layer or an undoped amorphous silicon layer. In yet another example, the first material layer15may comprise a sacrificial layer such as a nitride layer, and the second material layer16may comprise an insulating layer such as an oxide layer. In an embodiment, the first material layer15may comprise of a sacrificial layer, and the second material layer16may comprise of an insulating layer. Subsequently, the first material layers15and the second material layers16may be etched to form channel holes, which may be coupled to each of the trenches. For illustration purposes, positions of channel holes may be indicated by dotted lines in the layout view ofFIG.7A, and channel holes formed behind the cross-section taken along the line A-A′ are indicated by dotted lines in the cross-sectional view ofFIG.7B. Here, the channel holes may taper toward the bottom. The channel holes may be arranged in a matrix or they may alternate with each other. In addition, the channel holes may be divided between both sides of each trench in consideration of a position of a first slit to be formed in subsequent processes. In an example, when the trench may be shaped like a ladder, channel holes may be arranged at positions so that they overlap with the line trench. In another example, when the trench is shaped like an island shape, channel holes may be located at both sides of the trench. The number of channel holes coupled to each trench may vary depending on an integration degree of the memory device.FIGS.7A and7Billustrate that a single trench may be coupled to four channel hole arrays. However, a single trench may be coupled to two, six, eight or ten channel hole arrays. Subsequently, after the sacrificial layer14that is located substantially on the bottom surfaces of the channel holes is removed, a memory layer17may be formed substantially along an inner surface of the trench and inner surfaces of the channel holes. The memory layer17may be formed to store data and may comprise of a charge blocking layer, a charge trap layer, and a tunnel insulating layer. The charge trap layer may include a nitride layer, nanodots, and a polysilicon layer. Subsequently, a semiconductor layer18may be formed substantially over the memory layer17. For example, the semiconductor layer18may comprise of a polysilicon layer not doped with impurities. Since the channel holes taper toward the bottom, connecting portions of the trench and the channel holes may be completely sealed before the trench may be entirely filled with the semiconductor layer18. Therefore, empty space may be formed in the trench. In addition, the channel holes may not be entirely filled with the semiconductor layer18, and central portions of the channel holes may remain empty. In this case, an insulating layer19may be formed substantially at the central portion of the semiconductor layer18. As illustrated inFIGS.8A to8D, first slits SL1may pass through each of the trenches. The first slits SL1may be used to form a second source layer and a third source layer. Each of the first slits SL1may be formed between the channel holes and extend to the first source layer13(S1). For example, the first slit SL1may be located substantially at a central portion of the trench, and an end of the first slit SL1may be widened to substantially form an I-shape. In one example, when the trench has a ladder shape, the first slit SL1may overlap with the island trenches. In addition, after the first material layers15, the second material layers16, the memory layer17, and the semiconductor layer18(i.e.,18A(S2) and18B) are etched, a portion of the first source layer13may be etched to a predetermined depth to form the first slit SL1. Here, the memory layer17that may be formed on the bottom surface of each trench may be used as an etch stop layer. As illustrated inFIG.8B, the first slit SL1may be formed to a depth that exposes the surface of the memory layer17formed on the bottom surface of the island trench (cross-section taken along the line A-A′). As illustrated inFIG.8C, the first slit SL1may extend to the first source layer13(S1) only between the island trenches (cross-section taken along the line B-B′). In addition, as illustrated inFIG.8D, the first slit SL1may have unevenness at a bottom surface thereof (cross-section taken along the line C-C′). In another example, in the case where the trench is in the form of an island, after the first material layers15, the second material layers16, the memory layer17, and the semiconductor layer18are etched, a portion of the first source layer13(S1) may be deeply etched to form the first slit SL1. Since the portion of the first source layer13(S1) may be deeply etched after the memory layer17on the bottom surface of the trench is etched, the bottom surface of the first slit SL1not have unevenness. Subsequently, the semiconductor layers18in the trenches may be doped with impurities to form second source layers18A(S2). In one example, the semiconductor layer18in the trench may be doped with N type impurities through the first slit SL1by performing a plasma doping process to thus form the second source layer18A. In another example, an oxide layer doped with impurities may be formed substantially over the semiconductor layer18, and the impurities included in the oxide layer may be diffused into the semiconductor layer18by heat treatment to thus form the second source layer18A. Subsequently, the oxide layer may be removed therefrom. Therefore, a substantially horizontal region of the semiconductor layer18that may be formed in the trench may be used as the second source layer18A, while a substantially vertical region of the semiconductor layer18that passes through the stacked layers, that is, semiconductor pillars18B may used as channel layers. For reference, when subsequent processes that involve high temperatures are performed after the second source layer18A is formed by doping impurities, it may become difficult to control doping concentration because the impurities included in the second source layer18A may be diffused to another layer. However, according to an embodiment, since the second source layer18A may be formed by doping impurities after a process of stacking the first and second material layers15and16, respectively, at relatively high temperatures is completed, doping concentration may be easy to control. As illustrated inFIGS.9A to9D, a third source layer20(S3) may be formed substantially in the second source layer18A(S2) and Substantially under the first slit SL1(seeFIGS.8A-8D). For example, a barrier layer may be formed substantially along an inner surface of the first slit SL1and an inner surface of the trench, in which the second source layer18A is formed, and a metal layer is formed thereon. Subsequently, the barrier layer and the metal layer may be etched except for where they are formed in the first and second source layers13and18A, respectively, to thus form the third source layer20. Here, the barrier layer may be any one of a titanium layer (Ti) and a titanium nitride layer (TiN), or a combination thereof, and the metal layer may be a tungsten layer (W). In addition, when the barrier layer and the metal layer are etched, when a tungsten layer, formed under the first slit SL1, in the first source layer13is disconnected from a tungsten layer, formed in the trench, in the second source layer18A, the tungsten layers may be grown by a selective growth process so as to be re-connected. As described above, when the second source layer18A, the semiconductor pillars18B, and the third source layer20are formed after the memory layer17is formed, the memory layer17may substantially surround an outer surface of the second source layer18A and outer surfaces of the semiconductor pillars18B. Therefore, unlike the related art, the bottom surfaces of the channel holes are not blocked by the memory layer. Thus, the process of etching the memory layer to expose the source layer may not be performed. Subsequently the first slit SL1is substantially filled with an insulating layer21. Here, the insulating layer21may be an oxide layer formed by using High Temperature Oxidation (HTO) or Hugh Density Plasma (HDP) or a flowable oxide layer such as a Spin-On Dielectric SOD (SOD) layer or a polysilazane (PSZ) layer. Subsequently, though not illustrated inFIGS.9A to9D, the first material layers15and the second material layers16that are stacked in slimming regions may be stepwise patterned. For example, a mask pattern may be formed to substantially cover portions of slimming regions and a cell region, and a process of etching the first material layers15and the second material layers16may be repeated by gradually reducing the size of the mask pattern, whereby pad portions may be formed at the conductive layers. The pad portions may be coupled to contact plugs by subsequent processes. As illustrated inFIGS.10A and10B, the first material layers15and the second material layers16may be etched to form second slits SL2-1and SL2-2between the second source layers18A. For example, the second slits SL2-1may be formed at interfaces between memory blocks, and the second slits SL2-2may be formed between the second source layers18A within a single memory block. Here, since the second slits SL2-1formed at interfaces between memory blocks extend to the slimming regions as well as the cell region, each of the second slits SL2-1may have a length greater than a length of each of the second slits SL2-2formed substantially between the second source layers18A. Each of the second slits SL2-2formed substantially between the second source layers18A may have a length greater than, smaller than, or equal to the length of each of the first slits SL1. In addition, though not illustrated inFIGS.10A and10B, the second slits SL2-1may have at least one protrusion that protrudes inside the memory block, and an end of each of the second slits SL2-2formed between the second source layers18A inside the memory block may be expanded into substantially an I-shape. One or more thirds slit SL3may be formed at substantially the same time as the second slits SL2-1and SL2-2are formed. The one or more third slits SL3may be formed substantially in the slimming regions. Here, the third slits SL3may be formed substantially in or around the slimming regions. In addition, the memory device includes the slimming regions at substantially the top and the bottom with the cell region at the center. The third slits SL3may be formed substantially in the slimming regions at either or both of the top and bottom. In addition, when the third slits SL3are formed in slimming regions at the top and bottom, the third slits SL3may be symmetrical or asymmetrical with respect to each other. InFIGS.10A and10B, the third slits SL3are symmetrically formed around the edges of the slimming regions at the top and bottom. Subsequently, the first material layers15exposed to the second slits SL2-1and SL2-2and the third slits SL3may be etched to form first recessed regions. Conductive layers22may be subsequently formed substantially in the first recessed regions. For example, after the conductive layers22are deposited to substantially fill the first recessed regions, the conductive layers22formed along inner walls of the second slits SL2-1and SL2-2may be etched to separate the conductive layers22that substantially fill the first recessed regions from each other. Here, charge blocking layers may be additionally formed in the first recessed regions before the conductive layers22are formed. In addition, air gaps may be formed in the first recessed regions by controlling deposition conditions when the conductive layers22are formed. Subsequently, the second slits SL2-1and SL2-2and the third slits SL3may be substantially filled with an insulating layer23. At this time, air gaps may be formed in the second slits SL2-1and SL2-2. As illustrated inFIGS.11A and11B, first contact plugs CP1may be formed such that the first contact plugs CP1may be coupled to the conductive layers22stacked in the slimming region. In addition, second contact plugs CP2may be formed such that the second contact plugs CP2may be coupled to the first source layer13. In this manner, the semiconductor device may be formed of the semiconductor pillars18B coupled to the second source layer18A(S2) and the first, second, and third source layers13(S1),18A(S2), and20(S3), respectively. As described above, after the memory layer17is formed substantially along the inner surface of the trench and the inner surfaces of the channel holes, the second and third source layers18A(S2) and20(S3), respectively, and the semiconductor pillars18B are formed in the memory layer17. Therefore, an etch process of exposing the source layer on the bottom surfaces of the channel holes may not be performed. Accordingly, manufacturing processes may become easier, and characteristics of the memory device may be improved. Additionally, various changes may be made to the above-described manufacturing processes, depending on the types of the first material layer15and the second material layer16. In particular, the processes subsequent to the formation of the second slits SL2-1and SL2-2may be partly changed. For example, when the first material layers15are formed of conductive layers, and the second material layers16are formed of interlayer insulating layers, the first material layers15exposed to the second slits SL2-1and SL2-2may be silicided after the second slits SL2-1and SL2-2are formed. Subsequently, the second slits SL2-1and SL2-2may be substantially filled with the insulating layer23. In another example, when the first material layers15are formed of conductive layers, and the second material layers16are formed of sacrificial layers, the second material layers16exposed to the second slits SL2-1and SL2-2may be selectively etched to form second recessed regions. Subsequently, the first material layers15exposed to the second slits SL2-1and SL2-2may be silicided, and the second recessed regions and the second slits SL2-1and SL2-2may be substantially filled with the insulating layer23. FIG.12is a layout view of a semiconductor device according to another embodiment. Here, a description of the contents of the embodiment, overlapping with those of the prior embodiment, is omitted. As illustrated inFIG.12, the semiconductor device according to the second embodiment may include at least one of a third slit SL3that may be substantially located in the slimming regions. The third slit SL3may be formed at substantially the same time as the first slits SL1are formed. In this example, the second slits SL2-1and SL2-2may be formed after the third slit SL3is substantially filled with the insulating layer21. The insulating layer21substantially filling the third slit SL3may serve as a support during the process of forming the first recessed regions. Therefore, the insulating layer21may prevent the remaining second material layers16from collapsing during the process of forming the first recessed regions. In addition, the first material layers15, substantially surrounded by the third slit SL3, in the slimming region may not be etched, but may remain. FIG.13is a perspective view of the structure of a semiconductor device according to another embodiment. Here, a description of the contents of this embodiment, overlaps with those of the prior embodiments, and is thus omitted. As illustrated inFIG.13, the semiconductor device according to this embodiment may include an interlayer insulating layer ILD, one or more first source layers S1formed substantially in the interlayer insulating layer ILD, a plurality of conductive layers stacked substantially over the interlayer insulating layer ILD, semiconductor pillars passing through the conductive layers and coupled to the one or more the first source layers S1, and a second source layer S2formed substantially in each of the first source layers S1. In addition, the semiconductor device may further include memory layers (not illustrated) and bit lines BL. Each of the memory layers (not illustrated) may substantially surround an outer surface of the first source layer S1and outer surfaces of the semiconductor pillars. The bit lines BL may be formed substantially over the conductive layers and extend substantially in the second direction II-II′. The semiconductor pillars may be used as the channel layers CH, and the conductive layers may be used as the lower select line LSL, the word lines WL, and the upper select line USL. In addition, the first source layer S1may be formed by doping the semiconductor layer with impurities, and the second source layer S2may be formed of a metal layer. In this case, source resistance may be reduced to improve characteristics of the memory device. InFIG.13, the first source layer S1may completely surround the bottom surface of each second source layer S2. However, a portion of the bottom surface of the second source layer S2may protrude and pass through the first source layer S1. FIG.14is an exploded perspective view of a source layer structure of the semiconductor device according to the above embodiment. As illustrated inFIG.14, the second source layer S2may be formed substantially in the first source layer S1, and the first source layer S1substantially surrounds a top surface, a side surfaces, and a bottom surface of the second source layer S2. Here, the first source layer S1may include at least one opening OP that may be formed substantially in the top surface thereof. The opening OP may be substantially in the form of a line. In addition, though not illustrated inFIG.14, the first source layer S1may further include at least one opening that may be formed substantially in the bottom surface thereof. In this case, the second source layer S2may have a protrusion on the bottom surface thereof, and the protrusion may substantially protrude through the opening OP. FIGS.15A and15Bare cross-sectional views illustrating a method of manufacturing the semiconductor device according to the above embodiment. Here, a description of the contents of the above embodiment, overlapping with those of the other embodiments, is omitted. As illustrated inFIG.15A, after an interlayer insulating layer32is formed substantially over a substrate31, the interlayer insulating layer32may be etched to form trenches. Subsequently, a sacrificial layer (not illustrated) may be formed substantially in each of the trenches. Subsequently, first material layers33and second material layers34may be formed alternately substantially over the interlayer insulating layer32in which the sacrificial layer may be formed. The first material layers33may be used to form conductive layers of word lines, a lower select line, and an upper select line. The second material layers34may be used to separate the stacked conductive layers from each other. In an embodiment, the first material layers33may comprise sacrificial layers, and the second material layers34may comprise insulating layers. Subsequently, the first material layers33and the second material layers34may be etched to form channel holes, which may be coupled to the trench. Subsequently, after the sacrificial layer formed substantially on the bottom surfaces of the channel holes are removed, a memory layer35may be formed substantially along inner surfaces of the channel holes and an inner surface of the trench. Subsequently, after a semiconductor layer is formed substantially over the memory layer35, an insulating layer37may be formed substantially at open central regions in the channel holes. Subsequently, the first slits SL1may be formed substantially between the channel holes such that the first slits SL1may extend to the trench. Here, the memory layer35and the semiconductor layer formed substantially on the bottom surface of the trench may be used as an etch stop layer. Alternatively, the first slits SL1may extend to the interlayer insulating layer32. Subsequently, the semiconductor layers in the trenches may be doped with impurities to form first source layers36A(S1). Here, semiconductor pillars36B, not doped with impurities, may be used as channel layers. As illustrated inFIG.15B, second source layers38(S2) may be formed substantially in the first source layers36A (S1). When the first slits SL1extend to the interlayer insulating layer32, the second source layer38may substantially fill a lower portion of each of the first slits SL1. Subsequently, each first slit SL1may be substantially filled with an insulating layer39. Subsequently, second slits may be formed between the first source layers36A by etching the first material layers33and the second material layers34. Subsequently, the first material layers33exposed in the second slits may be etched to form first recessed regions. Conductive layers40may be subsequently formed substantially in the first recessed regions. The second slits may be substantially filled with an insulating layer41. Subsequently, though not illustrated inFIG.15B, first contact plugs may be formed substantially at slimming regions such that the first contact plugs may be coupled to the conductive layers40. In addition, second contact plugs may be formed such that the second contact plugs may be coupled to the second source layers38(S2). FIGS.16A and16Bare views illustrating the structure of a semiconductor device according to an embodiment whereFIG.16Ais a layout view andFIG.16Bis a cross-sectional view. Referring toFIGS.16A and16B, a semiconductor device according to an embodiment includes a source structure60, a stack ST, channel layers64, and slit insulating layers51to54. The source structure60is located at a lower portion of the stack ST and is coupled to the channel layers64. The source structure60may have a structure described above in relation toFIGS.3to15B. Additionally, the source structure60may be a polysilicon layer or metal layer in the form of a plate, or may have a structure that the polysilicon layers and the metal layers are stacked. The stack ST includes alternately stacked conductive layers61and insulating layers62. Here, at least one upper-most conductive layer61may be an upper select line, at least one lowermost conductive layer61may be a lower select line, and the remaining conductive layers61may be word lines. In addition, the stack ST may include a cell region C and contact regions CT1and CT2. Memory strings may be located in the cell region C, and interconnections for applying biases to the memory strings may be located in the contact regions CT1and CT2. For example, the cell region C may be located between a first contact region CT1and a second contact region CT2. The channel layers64may pass through the stacks ST in a stacking direction to abut onto the source structure60. The channel layers64may have a form in which even a central portion is completely filled or in which the central portion is open. The opened central portion may be filled with insulating patterns65. In addition, memory layers63may be intervened between conductive layers61of the channel layers64. The memory layers63may include at least one of a tunnel insulating layer, a data storing layer, and a charge blocking layer, and the data storing layer may include polysilicon, nitride materials, phase change materials, and nano-dots, etc. The slit insulating layers51to54pass through the stack ST in the stacking direction. The slit insulating layers51to54may completely pass through the stack ST to abut onto the source structure60or may pass through only a portion of the stack ST. For example, the slit insulating layers51to54may pass through all the lower select lines, the word lines, and the upper select lines included in the stack ST, only the lower select lines, only the upper select lines, or pass through only the word lines and the upper select lines. In addition, the slit insulating layers51to54may be located in the cell region C, in the contact regions CT1and CT2, on the boundary between the cell region C and the contact regions CT1and CT2, or may be located across the cell region C and the contact regions CT1and CT2. First slit insulating layers51may be located at the cell region C and may have a form of which at least one end extends. For example, the first slit insulating layers51may be in the form of a line extending in a first direction I-I′ and may have an I-shape in which the widths of ends extend. Second slit insulating layers52may be located at the contact regions CT1and CT2and may have a shape in which at least one end extends. For example, the second slit insulating layers52may be in the form of a line extending in the first direction I-I′ and may have an I-shape in which the widths of ends extend. In addition, the second slit insulating layers52may have shorter lengths than the first slit insulating layers51. Third slit insulating layers53may extend in the first direction I-I′ across the first contact region CT1, the cell region C, and the second contact region CT2, and may be located on the boundaries between adjacent memory blocks. Here, the memory block may be a data deletion unit. The third slit insulating layers53may be in the form of a line with a uniform width or may have a shape in which at least one end extends. Fourth slit insulating layers54may be located at the contact regions CT1and CT2and may be located between the adjacent second slit insulating layers52. The fourth slit insulating layers54may be in the form of islands of which the widths in a second direction II-II′ may be larger than those in the first direction I-I′. In addition, the fourth slit insulating layers54may have the uniform width or may have a shape in which at least one end extends. A method for manufacturing the slit insulating layers51to54will be described briefly as follows. Firstly, a stack in which first material layers and second material layers are alternately stacked is formed and then slits passing through the stack is formed. Then, the first material layers are replaced with third material layers through the slits. At this point, during the process in which the first material layers are replaced with the third material layers, an etching process for separating the stacked third materials from each other and removing the third material layers remaining in the slits may be additionally performed. Then the slit insulating layers51to54are formed in the slits. However, as the aspect ratio of the slit becomes larger, a profile may be modified such that the width of the slit is reduced in a certain level or smaller. In particular, for an end of the slit, the profile may be severely modified and the end may have a sharp shape. In this case, the third material layer remaining at the sharp end of the slit may not be completely removed to cause a bridge. According to an embodiment, in consideration of a degree that the end width of the slit is reduced, ends of the slit insulating layers51to54are extended. In this case, although the slit profile is modified according to the level, a prescribed width may be maintained. FIGS.17A to17Eare views illustrating a structure of a slit insulating layer according to an embodiment. Here,FIG.17Ais a perspective view,FIGS.17B and17Care cross-sectional views of the I-II plane, andFIGS.17D and17Eare cross-sectional views of A of the II-III plane. Referring toFIGS.17A to17E, the slit insulating layer according to an embodiment has a shape in which the end extends. For example, the slit insulating layer includes a main pattern M and at least one protruding pattern P coupled to the main pattern M. Here, the protruding pattern P is to extend the width of the end of the slit insulating layer and is coupled to the end of the main pattern M. For example, the protruding pattern P abuts onto edges E1and E2and/or corners CN of the ends of the main pattern M. The main pattern M includes a first edge E1extending in a first direction I and a second edge E2extending in a second direction II. Here, when the first edge E1has a longer length than the second edge E2and the main pattern M extends in the first direction, the protruding pattern P may protrude from the first edge E1in the second direction II. Accordingly, the slit insulating layer may include the main pattern M extending in the first direction I and the protruding pattern P protruding from the first edge E1in the second direction II. For reference, it is also possible that the second edge E2has a longer length than the first edge E1and the main pattern M extends in the second direction II, and the protruding pattern P may protrude from the second edge E2in the first direction I. In addition, the slit insulating layer may have a structure obtained by combining the above-described. For example, the slit insulating layer may include both the protruding pattern P protruding from the second edge E2in the first direction I and the protruding pattern P protruding from the first edge E1in the second direction II. In the present embodiment, it is illustrated that 4 protruding patterns P are respectively coupled to both ends of the main pattern M, but the number, width, and area, etc. of the protruding patterns P may be variously changed. For example, the protruding patterns P may be coupled to only one end of the main pattern M. The protruding patterns P may be coupled to both sides with the main pattern M intervened therebetween or may be coupled to only one side. The protruding patterns P, which are positioned opposite to each other with the main pattern M intervened therebetween, may have a symmetric form or asymmetric form. In addition, the protruding patterns P may be respectively coupled to corners of the main pattern M or may be coupled to only some of the corners. The protruding pattern P may have a first width W1in the first direction I, the main pattern M may have a third width W3in the second direction II, and the ends of the slit insulating layer may have a second width W2in the second direction II. Here, the end of the slit insulating layer may have a wider width than the main pattern M and may satisfy a condition [W3<W2≤2W3]. In addition, the first width W1of the protruding pattern P and the third pattern W3of the main pattern M may satisfy a condition [0.5*W3≤W1]. For example, the first width W1and the third width W3may have substantially the same value or the first width W1may have a larger value than the third width W3. Here, the term “substantially” means not only that two values are the same but that the two values belong to a range including an error in process. On the other hand, the slit insulating layer may have a structure that the height is larger than the width, namely, a structure having a large aspect ratio. In this case, a cross- sectional area of the lower surface71B of the slit insulating layer is smaller than that of the upper surface71A of the slit insulating layer. Hereinafter, the uppermost portion of the slit insulating layer is defined as a first level L1, the lowermost portion is defined as a fourth level L4, and a description will be provided about a shape change according to the first to fourth levels (where L1>L2>L3>L4). The cross-sectional area of the slit insulating layer may vary according to the levels L1to L4, and may increase or decrease as a result of proceeding from the upper portion to the lower portion. At this point, all cross-sectional areas of the main pattern M and the protruding patterns P may increase or decrease, or only the cross-sectional area of the protruding patterns P may increase or decrease with the cross-sectional area of the main pattern M maintained. Referring toFIG.17A, the cross-sectional area of the slit insulating layer may decrease from the first level L1to the fourth level L4. Referring toFIG.17D, the cross-sectional area of the slit insulating layer may increase from the first level L1to the second level L2, and may decrease from the second level L2to the fourth level L4(See A). Referring toFIG.17E, the cross-sectional area of the slit insulating layer may increase from the first level L1to the second level L2, decrease from the second level L2to the third level L3, and may be maintained substantially the same from the third level L3to the fourth level L4. In addition, the slit insulating layer may vary in shape according to the levels L1to L4. At this point, all the main pattern M and the protruding pattern P vary and only the protruding pattern M may vary with the shape of the main pattern M maintained. As one example, the protruding pattern P of the first level L1may have a polygonal shape having corners, and the protruding pattern P of the second level L2may have a circular or elliptical shape. For another example, the slit insulating layer may include the protruding pattern P from the first level L1to the third level L3and may not include the protruding pattern P at the third level L3or lower. Accordingly, the upper surface71A and the lower surface71B of the slit insulating layer may have different shapes and the lower surface71B may have a narrower cross-sectional area than the upper surface71A. For example, the upper surface71A may include the main pattern M extending in the first direction I-I′ and a protruding pattern P protruding in the second direction II-II′, and the lower surface71B may only include the main pattern M having the uniform width. In this case, the lower surface71B may have the uniform width of a third width W3. FIGS.18A to18Gare layout views illustrating a cross-sectional shape of a slit insulating layer according to an embodiment. Hereinafter, a description of the contents of the above embodiment, overlapping with those of the other embodiments, will be omitted. Referring toFIG.18A, the slit insulating layer1includes a main pattern1A extending in one direction and first and second protruding patterns1B and1C coupled to ends of the main pattern1A. Here, the first protruding patterns1B may abut onto first edges E1of the main pattern1A and the second protruding patterns1C may abut onto second edges E2of the main pattern1A. In this case, corners of the main pattern1A may be enclosed by the first and second protruding patterns1B and1C. In addition, the protruding patterns1B and1C have circular or elliptical cross sections with a prescribed curvature. In this case, the first protruding patterns1B have the longest width W1in a first direction I, the main pattern1A has a third width W3in a second direction II, and the ends of the slit insulating layer1have a second width W2in the second direction II. Here, the second width W2and the third width W3may satisfy a condition [W3<W2≤2W3]. In addition, the first width W1and the third width W3may satisfy a condition [0.5*W3≤W1], and the first width W1and the third width W3may have substantially the same value or the first width W1may have a larger value than the third width W3. Referring toFIG.18B, a slit insulating layer2includes a first main pattern2A, second main patterns2B, and protruding patterns2C. Here, the first main pattern2A includes first edges E11extending in a first direction I and second edges E12extending in a second direction II. The second main patterns2B include first edges E21extending in the first direction I and second edges E22extending in the second direction II. In addition, the second edges E12of the first main pattern2A and the second edges E22of the second main pattern2B abut onto each other. Accordingly, the second main patterns2B intersect with the first main pattern2A and are coupled to the ends of the first main pattern2A. For example, the first main pattern2A and the second main patterns2B are coupled in a T shape, and the ends of the slit insulting layer2have the T shape. In addition, both ends of the slit insulating layer2may have the T shape and, in this case, the slit insulating layer2may have an I-shape. In addition, since the second main patterns2B abut onto the ends of the first main pattern2A, the ends and corners of the first main pattern2A are not exposed. Accordingly, the protruding patterns2C may be coupled only to the ends of the second main pattern2B and may not be coupled to the first main pattern2A. Here, the protruding patterns2C may have a polygonal shape. Referring toFIG.18C, the slit insulating layer3includes a first main pattern3A, second main patterns3B, first protruding patterns3C and second protruding patterns3D. Here, the second main patterns3B intersect with the first main pattern3A and are coupled to the ends of the first main pattern3A. In addition, the first protruding patterns3C are coupled to first edges E31of the second main patterns3B, and the second protruding patterns3D are coupled to second edges E32of the second main patterns3B. Accordingly, corners of the second main patterns3B may be completely enclosed by the first and second protruding patterns3C and3D. Referring toFIG.18D, the slit insulating layer4includes a first main pattern4A, second main patterns4B, first protruding patterns4C and second protruding patterns4D. Here, the second main patterns4B are separated from the outermost ends of the first main pattern4A by a prescribed distance to be coupled to the first main pattern4A, and extends across the first main pattern4A. For example, the first main pattern4A and the second main patterns4B are coupled in a cruciform shape, and the ends of the slit insulting layer4have the cruciform shape. In addition, since the ends of the first main pattern4A and the ends of the second main patterns4B are exposed, the first and second protruding patterns4C and4D are coupled to the ends of the first and second main patterns4A and4B. For example, the first protruding patterns4C are coupled to first edges E41of the first main pattern4A, and the second protruding patterns4D are coupled to second edges E42of the second main pattern4B. The first and second protruding patterns4C and4D may have polygonal shapes. Here, the first protruding patterns4C and the second protruding patterns4D may have substantially the same width or different widths. For example, the first protruding patterns4C, which are located at the outermost ends of the slit insulating layer4, may have a wider width (W11>W12) than the second protruding patterns4D. Referring toFIG.18E, the slit insulating layer5includes a first main pattern5A, second main patterns5B, first protruding patterns5C and second protruding patterns5D. Here, the second main patterns5B extend across the first main pattern5A. For example, the first main pattern5A and the second main patterns5B are coupled in a cruciform shape, and the ends of the slit insulting layer5have the cruciform shape. In addition, the first protruding patterns5C are coupled to the ends of the first main pattern5A and the second protruding patterns5D are coupled to the ends of the second main pattern5B. Here, the first and second protruding patterns5C and5D may have a circular or elliptical shape. Referring toFIG.18F, a slit insulating layer6includes a main pattern6A and protruding patterns6B. Here, the protruding patterns6B are coupled to abut onto first edges E61of the main pattern6A. The protruding patterns6B has a first width W1in a first direction I, the main pattern1A has a third width W3of a second direction II, and the ends of the slit insulating layer6have a second width W2that is the longest in the second direction II. For example, the second width W2and the third width W3may satisfy a condition [W3<W2≤2W3]. In addition, the first width W1and the third width W3may satisfy a condition [0.5*W3≤W1], and the first width W1and the third width W3may have substantially the same value or the first width W1may have a larger value than the third width W3. In addition, at least one edge of the protruding patterns6B may have a stepwise shape. As one example, the slit insulating layer6may have a shape in which the width of the end extends but the width thereof decreases as proceeding to the outermost end. In this case, a fifth width W5of the outermost end may have a smaller value than the second width W2. For another example, the slit insulating layer6may have a shape in which the width of the end extends but the width thereof may decrease as being separated from the outermost end. In addition, the fifth width W5may have substantially the same value as the third width W3of the main pattern6A or may have different values. Referring toFIG.18G, a slit insulating layer7includes a main pattern7A, first protruding patterns7B, and second protruding patterns7C. The first protruding patterns7B are coupled to abut onto first edges E71of the main patterns7A, and the second protruding patterns7C are coupled to abut onto second edges E72of the main pattern7A. The protruding patterns7B have a first width W1in a first direction I, the main pattern7A has a third width W3of a second direction II, and the ends of the slit insulating layer7have a second width W2that is the longest in the second direction II. For example, the second width W2and the third width W3may satisfy a condition [W3<W2≤2W3]. In addition, the first width W1and the third width W3may satisfy a condition [0.5*W3≤W1], and the first width W1and the third width W3may have substantially the same value or the first width W1may have a larger value than the third width W3. In addition, the first and second protruding patterns7B and7C may include at least one curved edge. For example, the first protruding patterns7B may include both the curved edge and a straight line edge, and the second protruding patterns7C may include only the curved edge. In this case, the slit insulating layer7may become to have the curved edges at the outermost ends. On the other hand,FIGS.8A to18Gmay be cross-sectional views at a prescribed level of the slit insulating layer, for example, cross-sectional shapes of an upper surface. According to an embodiment, since element insulating layers have different cross-sectional shapes according to a level, a lower surface of the slit insulating layer may be in the form of a line with a uniform width. FIG.19is a view illustrating the configuration of a memory system according to an embodiment. As illustrated inFIG.19, a memory system100according to an embodiment includes a non-volatile memory device120and a memory controller110. The non-volatile memory device120may have a structure in accordance with the layout as described above. In addition, the non-volatile memory device120may be a multi-chip package including a plurality of flagship memory chips. The memory controller110may be configured to control the non-volatile memory device120and may include an SRAM111, a Central Processing Unit (CPU)112, a host interface (I/F)113, an ECC circuit114and a memory I/F115. The SRAM111may be used as an operating memory of the CPU112. The CPU112may perform an overall control operation for the data exchange of the memory controller110. The host I/F113may include a data exchange protocol of a host that may be coupled to the memory system100. Furthermore, the ECC circuit114may detect and correct errors included in data read out from the non-volatile memory device120. The memory I/F115may interface the memory controller110with the non-volatile memory device120. The memory controller110may further include RCM for storing code data for an interface with the host (i.e., Host). The memory system100constructed as above may be a memory card or a Solid State Disk (SSD) in which the non-volatile memory device120and the controller110may be combined. For example, if the memory system100is an SSD, the memory controller110may communicate with the outside (e.g., a host) through one of various interface protocols, such as USB, MMC, PCI-E, SATA, PATA, SCSI, ESDI, and IDE, etc. FIG.20is a view illustrating the configuration of a computing system according to an embodiment. As illustrated inFIG.20, the computing system200may include a CPU220, RAM230, a user interface240, a modem250, and a memory system210that may be electrically coupled to a system bus260. If the computing system200is a mobile device, the computing system200may further include a battery for supplying an operating voltage to the computing system200. The computing system200may further include application chipsets, a Camera Image Processor (CIS), mobile DRAM, and so on. The memory system210may include a non-volatile memory device212and a memory controller211as described above in connection withFIG.19. The present invention provides a three-dimensional semiconductor device that does not have a pipe transistor. In addition, since a memory surface on bottom surfaces of channel holes are not etched, processes of manufacturing a semiconductor device may become easier, and deterioration of memory cell characteristics caused by damage to the memory layer may be prevented. | 54,622 |
RE49832 | DETAILED DESCRIPTION Embodiments shown in the drawings and described herein provide an actuation system for an articulating bed which may be implemented in a compact vertical space to present a minimum profile for modern bed designs. Referring to the drawings,FIG.1FIGS. 1A and 1Billustrates an exemplary embodiment of an adjustable bed8incorporating the ultra-compact profile actuation system with the articulating elements of the bed in an unarticulated position. As seen inFIGS.1A,1B and2, in the unarticulated position, a frame10carries a translating carriage12having a seat support section14on which a flexible mattress support15is attached. The flexible mattress support and interconnection to the upper body support may be as disclosed in U.S. patent application Ser. No. 13/946,970 having a filing date of Jul. 19, 2013 and entitled ARTICULATING BED WITH FLEXIBLE MATTRESS SUPPORT issued as U.S. Pat. No. 8,910,328 on Dec. 16, 2014 the disclosure of which is incorporated herein by reference. While described herein with respect to a flexible mattress support, rigid support sections for the upper body, seat, thigh support and lower leg support may be employed in alternative embodiments. Carriage12is supported on the frame by a plurality of wheels25engaged in side frame members31. An upper body support section16is actuated by translation of the carriage12toward a head end rail21of the frame. The carriage12is moved with a first actuator13engaged between the carriage and a foot end rail11. Extension of the first actuator13urges the carriage12toward the head end of the bed from a first unarticulated position to a second fully articulated position. Motion of the carriage during a first range initially engages a first set of telescoping rotation struts18, attached at a first end to a rotating axle19and reacting in compression to the translational motion of the carriage, to rotate about the axle19beginning rotation of the upper body section16about hinges17attached to the carriage12as seen inFIG.3. A set of fixed length rotation arms20is carried at a first end by a rotating tube22mounted with wheels23for initial lateral translation in a track24carried within side frame members29, with translation of the carriage in the first range of motion. Upon reaching the extent of the track24at the head end, the fixed length rotation arms20are engaged in compression and with rotation of tube22contribute to the further rotation of the upper body section16. The second end of the telescoping rotation struts18and second end of the fixed length rotation arms20are commonly pinned at rotation points26in frame members27of the upper body support section16for the embodiment shown. As the telescoping rotation struts18approach a vertical orientation, reaction forcestooftranslation of the carriage are fully assumed by the fixed length rotation arms20and the telescoping rotations struts18extend through in a second range of motion of the carriage to fully elevate the upper body support structure as shown inFIG.4. The configuration of the actuating components, namely the actuator13, telescoping rotation struts18and fixed length rotation arms20, allows the actuating components to be masked within a vertical profile29of the frame10and upper body support section16(best seen inFIG.2) with the bed in the first unarticulated position. This allows the minimum profile for the overall frame and articulating structure of the bed desired in modern designs. As shown inFIGS.3and4and best seen inFIG.7, a tension link50is rotatably attached to rotating tube22at a first end and attached to a lateral tube52at a second end. The lateral tube52is attached to a first end of head tilt levers54which rotate about pivot attachments55on upper body support16. The head tilt levers are attached at a second end to head bar56. As the rotating tube22reaches the extent of track24and fixed length rotation arms20are placed in compression during the second range of motion of the carriage12, tension link50causes rotation of the head tilt levers54through lateral tube52thereby urging the head bar56to additionally lift the head of the mattress support15from the upper body support section16. As seen inFIG.5a second actuator30is attached to the foot end of the carriage12at a first rotation point32at a head of the actuator and a second rotation point33at a first end of a first leg36. Upon extension of an actuator rod38, the first leg36is placed in compression to react at a second end at a rotation point34on the carriage20. A second leg40is attached at a first end to the second rotation point33on the actuator and at a second end to a third rotation point41on a thigh support section42. Compression of the first and second legs between rotation point34and rotation point41causes first leg36and second leg40to cooperatively rotate upward. Second leg40is attached at the second end to the third rotation point41on the thigh support section42which rotates about hinges43attached to the carriage12asseeseeninFIG.6. The second actuator30, first leg36and second leg40are also shielded within the vertical profile with the thigh support in an unrotated position (as best seen inFIG.5). Fixed length reaction rods44pivotally attached to the carriage12at rotation point47and flexible mattress support15with brackets48cause relative rotation between the portion45of the flexible mattress support engaged by the thigh support section42and a lower leg support portion46(both shown slightly displaced from contact for clarity of the components). For the embodiment shown, rotation point47is an axle of the foot end wheels25of the carriage12. A distal portion49of the thigh support section42is arcuate to contour the flexible mattress support in the elevated position as seen inFIG.6. Having now described various embodiments of the invention in detail as required by the patent statutes, those skilled in the art will recognize modifications and substitutions to the specific embodiments disclosed herein. Such modifications are within the scope and intent of the present invention as defined in the following claims. | 6,107 |
RE49833 | DETAILED DESCRIPTION OF THE DRAWINGS Reference is made toFIG.1which illustrates a dispenser10incorporating a pump12in accordance with the first embodiment of the present invention. The dispenser10includes a reservoir13containing a fluid14. The reservoir13has a cylindrical upwardly opening neck15and the pump12extends downwardly through the neck15into the reservoir13and is operative to dispense fluid14from the reservoir out a discharge outlet17on the pump12. As shown inFIG.1, the reservoir13is fixedly secured to a countertop16with the neck15extending upwardly through an opening18through the countertop16and being engaged by a threaded collar19to secure the reservoir13to the countertop16underneath the countertop16. The pump12is vertically slidable within the neck15for removal and replacement. With the pump12removed, the reservoir13may be replenished with the fluid14by a user pouring fluid downwardly into the reservoir13through the neck15. This arrangement is useful, for example, in a kitchen or washroom, to provide for dispensing of foamed cleaning fluid by use of the pump12above the top of countertop16from the reservoir13permanently secured below the countertop16, yet with substantial portions of the pump12disposed below the countertop16. The pump12comprises a piston chamber-forming member20, a spring21and a piston-forming element22. As seen inFIG.4, the piston chamber-forming member20extends longitudinally about a central axis23from a lower end24to an upper end25. The piston chamber-forming member20defines a central chamber26therein coaxially about the axis23and within an annular chamber wall27. The piston chamber-forming member20has a liquid inlet28at the lower end24in communication with the liquid14in the reservoir13. As seen only inFIG.1, a hollow dip tube29is coupled to the lower end24of the piston chamber-forming member20by which the liquid inlet28is in communication with fluid14in the reservoir13. Reference is made toFIGS.5and6which show in exploded views components of the piston chamber-forming member20. These components comprise:a housing31;a lower casing assembly100including a lower casing101and a one-way valve102;a first upper casing assembly200comprising a first upper casing201and a first upper annular seal disc203; anda second upper casing assembly300comprising a second upper casing301and a second upper annular seal disc303. In the preferred embodiment, the first upper casing assembly200is identical to the second upper casing assembly300and each may be considered to be an identical modular component, which is advantageous but not necessary as each may be different. The lower casing101extends from the lower end24to an upper end105and defines therein a liquid chamber106and coaxially above the liquid chamber106a lower air chamber107. The lower casing101has a wall108with a cylindrical first lower portion109and a cylindrical second lower portion110. The liquid chamber106is defined within the cylindrical first lower portion109of the wall108. The lower air chamber107is defined within the cylindrical second lower portion110of the wall108. The liquid chamber106has a diameter which is less than the diameter of the lower air chamber107. The wall108includes a radially inwardly extending shoulder111which forms a lower end112of the lower air chamber107. The liquid chamber106opens at an upper end113through the shoulder111coaxially into the lower air chamber107. The wall108extends inwardly as a shoulder114at a lower end115of the liquid chamber106. An opening116through the shoulder114at the lower end115of the liquid chamber106opens via a passageway117to the lower end24. The one-way valve102is secured in a friction-fit relation within the opening116at the lower end115of the liquid chamber106. The one-way valve102has a fluted stem118and a resilient annular disc119extending radially outwardly from the stem118at the upper end of the one-way valve102. The stem118carries axially extended flutes permitting fluid flow axially past the stem118when the one-way valve102is snap-fitted within the opening116. The disc119is resilient and biased such that under its inherent bias a circumferential edge of the disc119engages the shoulder114to prevent fluid flow downwardly from the liquid chamber106to the reservoir13. The disc119is deflectable such that when the pressure in the liquid chamber106is less than the pressure in the reservoir13fluid will flow upwardly past the disc119from the reservoir13into the liquid chamber106. The wall108of the lower casing101at its upper end105defines an inwardly directed annular catch shoulder125with an annular surface directed at least in part axially downwardly. The first upper casing201has a lower end204and an upper end205. The first upper casing201has a wall208with a cylindrical upper portion210defining a first upper air chamber207therein. The wall208includes a radially inwardly extending annular upper shoulder211which forms a lower end212of the first upper air chamber207. An opening216extends through the upper shoulder211. The wall208also includes a radially inwardly extending annular lower shoulder220. An opening221extends through the lower shoulder220. The wall208defines between the upper shoulder211and the lower shoulder220an annular recess223. The opening216through the upper shoulder111has a diameter less than a diameter of the recess223and less than a diameter of the opening221through the lower shoulder220such that the seal disc203which is resilient may be forced downwardly into the recess223past the shoulder214to be received within the recess223against removal. The first upper casing201has an opening224at its upper end205. The wall208of the first upper casing201at its upper end205defines an inwardly directed annular catch shoulder225with an annular surface directed at least in part axially downwardly. The wall208of the first upper casing201carries about its lower end204a radially outwardly extending catching shoulder226with an annular surface directed at least in part axially upwardly. The upper end105of the lower casing101is adapted to engage the lower end204of the first upper casing201in a snap-fit relation with the catch shoulder125of the lower casing101to engage the catching shoulder226of the first upper casing201to resist disengagement. The second upper casing301has a wall308with a cylindrical upper portion310defining a second upper air chamber307therein. The wall308includes a radially inwardly extending annular upper shoulder311which forms a lower end312of the second upper air chamber307. An opening316extends through the upper shoulder311. The wall308also includes a radially inwardly extending annular lower shoulder320. An opening321extends through the lower shoulder320. The wall308defines between the upper shoulder311and the lower shoulder320an annular recess323. The opening316through the upper shoulder311has a diameter less than the diameter of the recess323and less than a diameter of the opening321through the lower shoulder320such that the seal disc303which is resilient may be forced downwardly into the recess323past the shoulder314to be received within the recess323against removal. The wall308of the second upper casing301at its upper end305defines an inwardly directed annular catch shoulder325with an annular surface directed at least in part axially downwardly. The wall308of the second upper casing301carries about the opening324at its lower end304a radially outwardly extending catching shoulder326with an annular surface directed at least in part axially upwardly. The upper end205of the upper air casing201is adapted to engage the lower end304of the second upper casing301in a snap-fit relation with the catch shoulder225of the first upper casing201to engage the catching shoulder326of the second upper casing301to resist disengagement. The housing31comprises a generally cylindrical outer tube401extending coaxially about the axis23. The outer tube401has a lower end404and an upper end405. Proximate the upper end405of the outer tube401, an annular flange406extends radially inwardly from the outer tube401. The annular flange406the supports a cylindrical inner tube407which extends coaxial with the outer tube401about the axis23. The inner tube407has a lower end408and an upper end409. The lower end408of the inner tube407carries a radially outwardly extending catching shoulder426with an annular surface directed at least in part axially upwardly. The upper end305of the second upper air casing301is adapted to engage the lower end408of the inner tube407in a snap-fit relation with the catch shoulder325of the second upper casing301to engage the catching shoulder426of the inner tube407of the housing to resist disengagement. The first annular seal disc203comprises a radially outermost annular ring230from which an annular sealing flange231extends radially inwardly to an annular distal end232. The annular sealing flange231extends from the ring230radially inwardly and axially upwardly to the distal end232. The second annular seal disc303comprises a radially outermost annular ring330from which an annular sealing flange331extends radially inwardly to an annular distal end332. The annular sealing flange331extends from the ring330radially inwardly and axially upwardly to the distal end332. In an assembled piston chamber-forming member20as seen inFIG.4, the lower casing101is secured in a friction-fit relation to the first upper casing201which is secured in a friction-fit relation to the second upper casing301which is secured in a friction-fit relation to the housing31. The one-way valve102is secured in a friction-fit relation to the lower casing101. The first annular seal disc203is snap-fitted into the recess223of the first upper casing201. The second annular seal disc303is secured in a friction-fit relation into the recess323of the second upper casing301. The annular chamber wall27includes the wall108, the wall208and the wall308. The central chamber26includes, axially inline one above the other, the liquid chamber106, the lower air chamber107, the first upper air chamber207and the second upper air chamber307in axial communication with each other via the openings113,221,216,321and316. Reference is made toFIGS.7to11which illustrate the piston-forming element22. As best seen in the exploded views ofFIGS.8and9, the piston-forming element22includes a liquid piston130, a lower air piston150, a first upper air piston250, a second upper air piston350, a foam producing member464, a head41and an outlet tube40. In the first embodiment shown, each of the lower air piston150and the first upper air piston250is identical and each may be considered to be an identical modular component, which is advantageous but not necessary as each may be different. The second upper air piston350is identical to the lower air piston150with the exception that there is no equivalent on the second upper air piston350to the air port162. The second air piston350may be identical to the lower air piston150with the second air piston350having an air port, not shown, identical to the air port162provided that the head41engages the second air piston350in a manner to sealably close the air port on the second air piston350. The lower air piston150has an elongate tubular stem151with a tubular wall152. The stem151of the lower air piston150has a lower end154and an upper end155. The tubular wall152defines a central passageway153longitudinally therethrough from the lower end154to the upper end155open at each end. The lower air piston150carries a first lower air sealing disc156which extends radially outwardly and axially downwardly from the stem151to an annular distal edge157. Proximate the upper end155, a radially outwardly directed surface158of the wall152of the stem151carries a radially outwardly extending catching shoulder159with an annular surface directed, at least in part, axially downwardly. Proximate the lower end154, the stem151carries a socket160with a radially inwardly extending catch shoulder161with an annular surface directed, at least in part, axially upwardly. A first upper air port162is provided on the stem151and extends radially through the wall152of the stem151into the passageway153. The first upper air port162is on the stem151above the lower air sealing disc156. InFIG.8as shown, two such first upper air ports162are provided at diametrically opposed positions on the stem151, however, only one is necessary. The radially outwardly directed surface158of the wall152of the stem151is cylindrical over a cylindrical portion163between the first lower air sealing disc156and the upper end155. The first upper air piston250has an elongate tubular stem251with a tubular wall252. The stem251of the first upper air piston250has a lower end254and an upper end255. The tubular wall252defines a central passageway253longitudinally therethrough from the lower end254to the upper end255open at each end. The first upper air piston250carries a first upper air sealing disc256which extends radially outwardly and axially downwardly from the stem251to an annular distal edge257. Proximate the upper end255, a radially outwardly directed surface258of the wall252of the stem251carries a radially outwardly extending catching shoulder259with an annular surface directed at least in part axially downwardly. Proximate the lower end254, the stem251carries a socket260with radially inwardly extending catch shoulder261with an annular surface directed at least in part axially upwardly. A second upper air port262is provided on the stem251and extends radially through the wall252of the stem251into the passageway253. The second upper air port262is on the stem251above the first upper air sealing disc256. The radially outwardly directed surface258of the wall252of the stem251is cylindrical over a cylindrical portion263between the first upper air sealing disc256and the upper end255. The second upper air piston350has an elongate tubular stem351with a tubular wall352. The stem351of the second upper air piston350has a lower end354and an upper end355. The tubular wall352defines a central passageway353longitudinally therethrough from the lower end354to the upper end355open at each end. The second upper air piston350carries a second upper air sealing disc356which extends radially outwardly and axially downwardly from the stem351to an annular distal edge357. Proximate the upper end355, a radially outwardly directed surface358of the wall352of the stem351carries a radially outwardly extending catching shoulder359with an annular surface directed at least in part axially downwardly. Proximate the lower end354, the stem351carries a socket360with radially inwardly extending catch shoulder361with an annular surface directed at least in part axially upwardly. The radially outwardly directed surface358of the wall352of the stem351is cylindrical over a cylindrical portion363between the second upper air sealing disc356and the upper end355. The upper end155of the lower air piston150is adapted to be secured in a snap-fit relation against removal in the socket260of the first upper air piston250to secure the lower air piston150to the first upper air piston250with the catching shoulder159of the lower air piston150in opposition to the catch shoulder261of the socket260of the first upper air piston250. Similarly, the upper end255of the first upper air piston250is adapted to be secured in a snap-fit relation against removal in the socket360of the second upper air piston350to secure the first upper air piston250to the second upper air piston350with the catching surface259of the first upper air piston250in opposition to the catch shoulder361of the socket360of the second upper air piston350. The liquid piston130has an elongate tubular stem131with a tubular wall132. The stem131of the liquid piston130has a lower end134and an upper end135. The tubular wall132defines a central passageway133longitudinally therethrough from the lower end134to the upper end135. The passageway133is open at the upper end135. The passageway133is closed at the lower end134by an end wall136. Proximate the upper end135, a radially outwardly directed surface137of the wall132of the stem131carries a radially outwardly extending catching shoulder138with an annular surface directed, at least in part, axially downwardly. The upper end135of the liquid piston130is adapted to be secured in a snap-fit relation against removal in the socket160of the lower air piston150to secure the liquid piston130to the lower air piston150with the catching shoulder138of the liquid piston130in opposition to the catch shoulder161of the socket160of the lower air piston150. The liquid piston130carries proximate its lower end134, a radially outwardly extending liquid sealing disc139. The lower liquid piston130carries proximate its lower end134, a radially outwardly extending second lower air sealing disc140spaced axially upwardly from the liquid sealing disc139. A liquid port141is provided on the stem131axially between the liquid sealing disc139and the second lower air sealing disc140. The liquid port141extends radially through the wall132of the stem131into the passageway131. A lower air port142is provided on the stem131above the lower air disc142. The lower air port142extends radially through the wall132of the stem131into the passageway131. Over a cylindrical portion143between lower air port142and the upper end135, the radially outwardly directed surface137of the wall132of the stem131is cylindrical. The head41comprises a top portion42from which an outer tube43extends about the axis23downwardly to an open lower end44. The top portion42has an upper surface46and a lower surface47. An inner tube48extends downwardly from the lower surface47coaxially about the axis23to an open lower end62. Within the inner tube48, a socket49is provided having a catch shoulder50with an annular surface directed, at least in part, axially upwardly. A discharge passageway51is provided within the head41between an opening52coaxially within the socket49at an upper end of the socket49to an opening53directed forwardly. The outlet tube40is a hollow tube with a tube passageway54therethrough from a first end55to a second forward end56providing the discharge outlet17. The outlet tube40is coupled to the top portion42with the first end55secured within the opening53. On the head41, a downwardly opening annular groove57is provided in the lower surface47coaxially between the outer tube43and the inner tube48with a blind upper end58to receive an upper end59of the spring21. On the housing31, an upwardly opening annular groove60is provided coaxially between the outer tube401and the inner tube407with a blind upper end61on the annular flange406to receive a lower end62of the spring21. In the assembled piston-forming element as seen inFIG.7, a passageway63extends therethrough from the lower end135to the discharge outlet17including the central passageways133,153,253and353, the socket49, the discharge passageway51and the tube passageway54. The assembled piston-forming element22has an elongate tubular stem90formed by the stems131,151,251and351with the central passageway63longitudinally therethrough including the passageways133,153,253and353. The passageway63extends from a lower end134of the passageway133to an upper end355of the passageway353. The upper end355of the second upper air piston350is adapted to be secured in a snap-fit relation against removal in the socket49of the head41to secure the second upper air piston350to the head41with the catching surface359of the second upper air piston350in opposition to the catch shoulder50of the socket49of the head41. The foam producing member464is located within the socket49and sandwiched between the upper end of the socket49and the upper end355of the upper air piston350axially upwardly of the upper end355. Air and liquid passing outwardly through the passageway63passes through the foam producing member464to create a foam of air and liquid as, for example, by creating turbulence in the fluids as they pass through the foam producing member464. The foam producing member464may preferably comprise a screen member with suitably sized openings. Reference is made toFIGS.1and2which show the assembled pump12in an extended position with the piston-forming element22engaged with the piston chamber-forming member20. The spring21is in its inherent unbiased position. In use, from the position ofFIGS.1and2, a user manually applies downwardly directed forces to the upper surface46of the top portion42of the head41to axially compress the spring21against its inherent bias and move the piston-forming element22coaxially downwardly along the central axis23relative to the piston chamber-forming member20to the retracted position as shown inFIG.3. The spring21has an inherent bias and from the retracted position ofFIG.3on release of the manual pressure, the spring21will move the piston-forming element22upwardly from the retracted position ofFIG.3to the extended position ofFIG.2. As seen inFIG.5, the outer tube401of the piston chamber-forming member has a radially outwardly extending annular flange427which, as seen inFIG.1, engages the uppermost end of the neck15of the reservoir13to prevent downward movement of the piston chamber-forming member20relative to the countertop16and the reservoir13. A cycle of operation arises in the relevant movement of the piston-forming element22from the extended position ofFIG.2to the retracted position ofFIG.3in a retraction stroke and then from the retracted position ofFIG.3to the extended position ofFIG.2in a withdrawal or extension stroke. In the assembled pump10, as seen inFIGS.2and3, the cylindrical portion263of the stem251of the first upper air piston250passes through the second annular seal disc303with the annular distal end332of the annular sealing flange331engaging the cylindrical portion263of the stem251to form a seal therewith preventing fluid flow therepast axially downwardly. The second upper air sealing disc356of the second upper air piston350engages the radially inwardly directed cylindrical surface of the cylindrical upper portion310of the second upper casing301forming a seal therewith to prevent fluid flow axially upwardly therepast. A second upper air pump370is thereby formed within the second upper casing301between the second upper casing assembly300and the piston forming element22. The second upper air pump370provides a cylindrical second upper air compartment371radially in between the cylindrical upper portion310of the wall308of the second upper casing301and the stem251of the first upper air piston250and axially between the first upper air sealing disc356and the second annular seal disc303. The second upper air port262provides communication between the second upper air compartment371and the passageway253. The volume of the second upper air compartment371varies with relative movement of the piston-forming element22relative to the piston chamber-forming member20with the volume being largest in the extended position ofFIG.2and smallest in the retracted position ofFIG.3. In a retraction stroke in moving from the extended position ofFIG.2to the retracted position ofFIG.3the volume of the second upper air compartment371decreases and fluid therein, typically substantially air, is compressed and forced out of the second upper air port262into the passageway253and hence out the discharge outlet17. In a withdrawal stroke the volume of the second upper air compartment371increases and, fluid is drawn via the discharge outlet17into the passageway253and via the second upper air port262into the second upper air compartment371. In the assembled pump10, as seen inFIGS.2and3, the cylindrical portion163of the stem151of the lower air piston150passes through the first annular seal disc203with the annular distal end232of the annular sealing flange231engaging the cylindrical portion163of the stem151to form a seal therewith preventing fluid flow therepast axially downwardly. The first upper air sealing disc256of the first upper air piston250engages the radially inwardly directed cylindrical surface of the cylindrical upper portion210of the first upper casing201forming a seal therewith to prevent fluid flow axially upwardly therepast. A first upper air pump270is thereby formed within the first upper casing201between the first upper casing assembly200and the piston forming element22. The first upper air pump270provides a cylindrical first upper air compartment271radially in between the cylindrical upper portion210of the wall208of the first upper casing201and the stem151of the lower air piston150and axially between the upper air sealing disc256and the first annular seal disc203. The first upper air port162provides communication between the first upper air compartment271and the passageway153. The volume of the first upper air compartment271varies with relative movement of the piston-forming element22relative to the piston chamber-forming member20with the volume being largest in the extended position ofFIG.2and smallest in the extended position ofFIG.3. In a retraction stroke in moving from the extended position ofFIG.2to the retracted position ofFIG.3the volume of the first upper air compartment271increases and, fluid therein, typically substantially air, is compressed and forced out of the first upper air port162into the passageway153and hence out the discharge outlet17. In a withdrawal stroke the volume of the second upper air compartment271increases and fluid is drawn via the discharge outlet17into the passageway153and via the first upper air port162into the first upper air compartment271. The lower air sealing disc156of the lower air piston150extends radially outwardly to sealably engage with the radially inwardly directed surface of the wall108of the lower casing101in the cylindrical second lower portion110within the lower air chamber107. The second lower air sealing disc140extends radially outwardly to sealably engage the wall108of the lower casing101in the cylindrical first lower portion109within the liquid chamber106. A lower air pump170is defined within the lower casing101between the lower air piston150and the lower casing101. The lower air pump170has an annular lower air compartment171which extends radially between the wall108of the lower casing101and the stem151of the lower air piston150and axially between the first lower air sealing disc156and the second lower air sealing disc140. The lower air port142provides communication between the lower air compartment171and the central passageway133. The lower air compartment171has a volume which varies as the piston-forming element22moved axially relative to the piston chamber-forming member20. The lower air compartment171has a largest volume in the extended position ofFIG.2and a smallest volume in the retracted position ofFIG.3with this volume decreasing with movement of the piston-forming element22axially downwardly since the lower air compartment171is formed within a stepped chamber formed by the lower air chamber107and the lesser diameter liquid chamber106. The liquid sealing disc139extends radially outwardly from the liquid piston130into engagement with the wall108of the lower casing101within the cylindrical first lower portion109of the liquid chamber106. The liquid sealing disc139extends radially outwardly to a distal end145. The liquid sealing disc139extends axially inwardly as it extends radially outwardly to the distal end145as seen inFIG.10. The liquid sealing disc139is resilient adopting an unbiased inherent condition as seen inFIG.10which preferably biases the distal end143of the liquid sealing disc139into the wall108of the cylindrical first lower portion109of the liquid chamber106. The liquid sealing disc139can be deflected against this bias away from the wall108to permit fluid flow upwardly therepast. As seen inFIG.10, the lower air sealing disc140extends radially outwardly to a distal end144which engages the wall108of the lower casing101in the cylindrical first lower portion109forming the liquid chamber106and substantially prevents liquid flow axially upwardly past the lower air sealing disc140. A liquid pump70is formed within the liquid chamber106between the stem131of the liquid piston130and the cylindrical first lower portion109of the lower casing101within the liquid chamber106. The liquid pump70has a liquid compartment71defined within the liquid chamber106between one-way valve102and the lower end134of the liquid piston130. The volume of the liquid compartment71varies with relative movement of the piston-forming element22within the piston chamber-forming member20with the volume being greatest in the extended position ofFIG.2and least in the retracted position ofFIG.3. On movement of the liquid piston130from the extended position ofFIG.2to the retracted position ofFIG.3, the volume of the liquid compartment71reduces compressing liquid within the liquid compartment71closing the one-way valve102to fluid flow downwardly from the liquid compartment71and with the pressure in the liquid compartment71deflecting the liquid sealing disc139for liquid flow upwardly past the liquid sealing disc139into an annular compartment between the annular sealing disc139and the second lower air sealing disc140and via the liquid port141into the central passageway133in a retraction stroke. In a withdrawal stroke, the volume of the liquid compartment71increases reducing the pressure within the liquid compartment71and drawing liquid from the reservoir past the one-way valve102into the liquid compartment71. In the first embodiment illustrated inFIGS.1to11, each of the liquid pump70, the lower air pump170, the first upper air pump270and the second upper air pump370are all in phase such that they, in a retraction stroke, simultaneously discharge fluid from their respective compartments and, in a retraction stroke, simultaneously draw fluid into their respective compartments. Thus, for example, advantageously in a retraction stroke, a unit dosage of liquid is discharged into the passageway63by the liquid pump70and, simultaneously, a volume of air is discharged from each of the air pumps170,270and370so as to provide for the discharge of liquid and air simultaneously through the air forming member464forming foam which is discharged out the discharge outlet17. In a withdrawal stroke, fluid, notably air, is withdrawn from the discharge outlet17through the passageway63and into each of the second upper air compartment371, the first upper air compartment271and lower air compartment171simultaneously with fluid being drawn into the liquid compartment71from the reservoir. Reference is made toFIG.12which illustrates a second embodiment of a pump10in accordance with the present invention which is identical to the pump of the first embodiment, however, with the exception that the second upper air pump370has been eliminated by elimination from the pump10of the first embodiment as seen inFIG.2of the second upper casing assembly300and the first upper air piston250. Reference is made toFIG.13which illustrates a third embodiment of a pump10in accordance with the present invention which is identical to the pump illustrated inFIG.2, however, in which a third upper air pump570is provided by providing a third upper casing assembly500with a third upper casing501and a third upper air piston550which are modular and substantially the same as, respectively, the second upper casing assembly300and the first upper air piston250. A feature of the invention is that the pumps are configured to be made from modular components. The first upper casing assembly200and the second upper casing assembly300are identical in their casings201and301and in their first and second upper annular seal disc203and303. The lower air piston150and the first upper air piston250are identical. The second upper air piston350is identical to the lower air piston150with the exception that there is no equivalent on the second upper air piston350to the air port162. The second air piston350can be identical to the lower air piston150by firstly providing the second air piston350with an air port, not shown, identical to the air port162and, secondly, providing the head41to engage the second air piston350in a manner to sealably close the air port on the second air piston350, as can be accomplished by suitable modification of the socket49of the head41. The use of modular components for the casing assembly and piston for air pumps permits pump arrangements with one, two or three identical upper air pumps to be assembled from modular components as is apparent from a comparison of the embodiments ofFIGS.2,12and13. Each of these embodiments provided have a constant diameter exterior about the upper air pumps. Reference is made toFIG.14which illustrates a fourth embodiment of a piston pump10in accordance with the present invention which is identical to the piston pump as shown inFIG.2but for two exceptions. A first exception is that while inFIG.2the diameter of each of the central passageways133,153,253and353are identical and equal, inFIG.14, the diameter of the passageway63changes varies between the lower end134and the upper end of the central passageway353of the second upper air pump350, with the variation being an increase in diameter as the passageway63extends upwardly. The second exception is that in addition to the foam producing member464within the socket49of the head41, a foam producing member364is provided within the socket360of the second upper air piston350, a foam producing member264is provided within the socket260of the first upper air piston250and a foam producing member164is provided within the socket160of the lower air piston150. In operation of the pump ofFIG.14in a retraction stroke, liquid from the liquid pump70and air from the first air pump170are passed through the foam producing member164to produce at least some foam as a first resultant product which is joined from air from the first upper air pump270and passed through the foam producing member264forming a second resultant foamed product which, together with air from the second upper air pump370, is passed first through the foam producing member364and then through the foam producing member464to produce a final resultant foam product which is delivered to the discharge outlet17. The arrangement ofFIG.14with four foam producing members164,264,364and464provides for successive partial foaming of the air and fluid passing through each of the foam producing members. This is believed to be preferred for providing foam of desired characteristics. The increase in diameter and therefore the relative cross-sectional area of the passageway66axially upwardly can assist in adjusting the relative velocity of the fluid through the passageway66with a relative reduction in velocity compared to velocities which would arise in the arrangement inFIG.2as the fluid extends axially upwardly. Reference is made toFIG.15which illustrates a fifth embodiment in accordance with the present invention which is identical to the embodiment ofFIG.14with the exception that the diameter and therefore the cross-sectional area of the passageway133increases axially upwardly and above the passageway133, the passageway63decreases in diameter and, therefore, the cross-sectional area decreases axially upwardly successively through the central passageways153,253and353. In accordance with the present invention by a selection to use one or more of the foam producing members164,264,354and464, a selection of characteristics for each foam producing member used and a selection of the relative diameter for the passageway63and changes in the diameter along the length of the passageway63, advantageous configurations may be selected having regard to the relative velocity of fluid through the passageway at any location and the relative nature of the foam producing members. For example, it is believed to be desired that the relative opening size through the foam producing member is largest in the lower foam producing member164and the relative opening size is preferably to successively decrease to be smallest in the uppermost foam producing member464. While the embodiments ofFIGS.14and15show four foam producing members164,264,364and464, it is to be understood that, alternatively, only one, two or three such foam producing members may be provided. Reference is made toFIG.16which illustrates a sixth embodiment of a foam pump in accordance with the present invention. InFIG.16, the lower casing101has a liquid chamber106defined within a cylindrical second lower portion109and a cylindrical third lower portion127of a larger diameter than the cylindrical second lower portion109. The liquid sealing disc139is within the enlarged diameter second lower portion109while the lower air sealing disc140is within the lesser diameter cylindrical lower portion109. With movement of the piston-forming element22downwardly in a retraction stroke, the volume of the liquid compartment71between the second lower air sealing disc140and the liquid sealing disc139increases to draw liquid in from the reservoir and, in the withdrawal stroke, the volume in the liquid compartment71decreases deflecting the second lower air sealing disc140radially inwardly and axially upwardly such that liquid flows upwardly past the second lower air sealing disc140into the lower air compartment171. From the lower air compartment171via the lower air port142, liquid and air within the lower air compartment171are urged in a retraction stroke into the passageway63for discharge out the discharge outlet17. In the embodiment ofFIG.16, the liquid pump70is out of phase with the air pumps170,270and370in the sense that in a retraction stroke, each of the air pumps is discharging fluid into the passageway66whereas the liquid pump70is drawing liquid into the liquid compartment71from the reservoir and, in a withdrawal stroke, the liquid pump70is discharging fluid into the lower air compartment171while each of the air pumps170,270and370is drawing air from the atmosphere into their respective air compartments171,271and371. The particular nature of the liquid pump70for use in various embodiments is not limited and the liquid pump70may have valves as illustrated in the embodiment ofFIG.1or a stepped chamber as illustrated inFIG.16and may be in phase or out of phase with each of the air pumps. Each of the air pumps is shown to be coaxially aligned and operate in phase simultaneously. In the preferred embodiment, air which is drawn into each of the air pumps is atmospheric air drawn from the atmosphere via the discharge outlet17. This is not necessary. Various arrangements may be provided for atmospheric air to enter the air compartments in a retraction stroke without passing through the discharge outlet. For example, an arrangement for an air inlet valve could be provided as in the manner disclosed in U.S. Pat. No. 7,337,930 to Ophardt et al, issued Mar. 4, 2008. The embodiments ofFIGS.1to16illustrate arrangements which pump liquid upwardly from the reservoir13, that is, from the lower end24of the piston chamber-forming member20upwardly. Reference is made toFIG.17which illustrates a seventh embodiment in which the pump12pumps liquid downwardly. InFIG.17, similar reference numerals are used to identify equivalent elements inFIGS.1to16. The seventh embodiment ofFIG.17consists of an arrangement in which the pump12is the same as the pump12in the first embodiment ofFIGS.2to11, but with the exceptions that pump12is inverted so that the end24of the piston chamber-forming member20is an upper end, both the head41and the tube40are eliminated, the air piston350is modified to provide the discharge outlet17at a lower end, and the air piston350is modified to carry an engagement flange399for engagement to slide the piston-forming element22relative the piston chamber-forming member20. With the end24in communication with liquid as in a liquid reservoir, such as an inverted bottle, not shown, liquid from the reservoir is dispensed downwardly by the liquid pump70simultaneously with the air pumps170,270and370discharging air to pass with the liquid downwardly through the foam producing member436and out the discharge outlet17. The pump12ofFIG.17may have its housing31extend upwardly into a liquid containing reservoir, however, this is not necessary. As was the case with the pumps of this invention which dispense liquid upwardly, many different configurations of the liquid pump70may be used in downwardly dispensing pumps in substitution of the liquid pump70shown. Downwardly dispensing liquid pumps are known as taught, for example, in U.S. Pat. No. 5,165,577 to Ophardt, issued Nov. 24, 1992, the disclosure of which is incorporated herein by reference. The preferred embodiments illustrate the pumps12as being orientated with the central axis23vertical in each of the embodiments ofFIGS.1to17. This is not necessary. In accordance with the present invention, the central axis23may be orientated to be horizontal or any angle between horizontal and vertical. In the embodiments ofFIGS.1to16, the terms “upper” and “lower” and “above” and “below” are used to describe the various orientations and in the names of elements with as considered axially along the axis relative the direction that fluid is dispensed from a reservoir such that “up” means “outer” and “down” means “inner” as seen inFIGS.1to16. However, inFIG.17, the reverse applies with as considered axially along the axis relative the direction that fluid is dispensed from a reservoir such that “up” means “inner” and “down” means “outer” as seen inFIG.17. In the embodiments ofFIGS.1to16, in referring to the various orientations and elements, the following words have the same meaning and may be substituted:above=axially outwardly ofbelow=axially inwardly ofupper=outerlower=innerdownwardly=axially inwardlyupwardly=axially outwardly. For example, the lower end24may be referred to as the inner end24, and the first upper casing201may be referred to as the first outer casing201. While the invention has been described with reference to preferred embodiments, many variations and modifications may now occur to a person skilled in the art. For a definition of the invention, reference is made to the following claims. | 42,320 |
RE49834 | DETAILED DESCRIPTION OF THE INVENTION Definitions The terms “ameliorate” and “treat” are used interchangeably and both mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein). By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. By “marker” is meant any alteration that is associated with a disease or disorder. For example, any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease or disorder. In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. patent law and can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. The term “compound” as used herein, is also intended to include pharmaceutically acceptable salts, prodrugs, and prodrug salts of a compound of formulae herein. The term also includes any solvates, hydrates, and polymorphs of any of the foregoing. The specific recitation of “prodrug,” “prodrug salt,” “solvate,” “hydrate,” or “polymorph” in certain aspects of the invention described in this application shall not be interpreted as an intended omission of these forms in other aspects of the invention where the term “compound” is used without recitation of these other forms. A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another preferred embodiment, the compound is a pharmaceutically acceptable acid addition salt. As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of the formulae disclosed herein that comprise biohydrolyzable moieties such as amides, esters, carbamates, carbonates, and phosphate analogues. Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed); see also Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”. As used herein and unless otherwise indicated, the term “biohydrolyzable moiety” means a functional group (e.g., amide, ester, carbamate, carbonate, or phosphate analogue, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. A prodrug salt is a compound formed between an acid and a basic group of the prodrug, such as an amino functional group, or a base and an acidic group of the prodrug, such as a carboxyl functional group. In a one embodiment, the prodrug salt is a pharmaceutically acceptable salt. Particularly favored prodrugs and prodrug salts are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. See, e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ.: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189-214. The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups of prodrugs of this invention include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. As used herein, the term “hydrate” means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein, the term “solvate” means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces. As used herein, the term “polymorph” means solid crystalline forms of a compound or complex thereof which may be characterized by physical means such as, for instance, X-ray powder diffraction patterns or infrared spectroscopy. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat, light or moisture), compressibility and density (important in formulation and product manufacturing), hygroscopicity, solubility, and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it. The term “substantially free of other stereoisomers” as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than “X”% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present. Methods of obtaining or synthesizing diastereomers are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates. Other embodiments are those wherein the compound is an isolated compound. The term “at least X % enantiomerically enriched” as used herein means that at least X % of the compound is a single enantiomeric form, wherein X is a number between 0 and 100, inclusive. The term “stable compounds”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents). “Stereoisomer” refers to both enantiomers and diastereomers. As used herein, the term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine. The terms “alk” or “alkyl” refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression “lower alkyl” refers to alkyl groups of 1 to 4 carbon atoms (inclusive). The term “arylalkyl” refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group. The term “alkenyl” refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond. The term “alkoxy” refers to an —O-alkyl radical. The term “alkylenedioxo” refers to a divalent species of the structure —O—R—O—, in which R represents an alkylene. The term “alkynyl” refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond. The term “alkylene” refers to a divalent straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., —(CH2)x—, wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups. The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are —CH═CH—CH═CH—, —CH2—CH═CH—, —CH2—CH═CH—CH2—, —C(CH3)2CH═CH— and —CH(C2H5)—CH═CH—. The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are —C≡C—, —CH2—C≡C—, —CH(CH3)C≡C— and —C≡C—CH(C2H5)CH2—. The terms “cycloalkyl” and “cycloalkenyl” as employed herein includes saturated and partially unsaturated cyclic, respectively, hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons. The terms “Ar” or “aryl” refer to aromatic cyclic groups (for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems) which contain 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene. “Heteroaryl” refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine and carbazole. The terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. The term “heterocyclyl” refers to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclyl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclyl group may be attached at any heteroatom or carbon atom of the ring or ring system. The term “substituents” refers to a group “substituted” on any functional group delineated herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group. Suitable substituents include, without limitation halogen, CN, NO2, OR15, SR15, S(O)2OR15, NR15R16, C1-C2perfluoroalkyl, C1-C2perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR15, C(O)NR15R16, OC(O)NR15R16, NR15C(O)NR15R16, C(NR16)NR15R16, NR15C(NR16)NR15R16, S(O)2NR15R16, R17, C(O)R17, NR15C(O)R17, S(O)R17, S(O)2R17, R16, oxo, C(O)R16, C(O)(CH2)nOH, (CH2)nOR15, (CH2)nC(O)NR15R16, NR15S(O)2R17, where n is independently 0-6 inclusive. Each R15is independently hydrogen, C1-C4alkyl or C3-C6cycloalkyl. Each R16is independently hydrogen, alkenyl, alkynyl, C3-C6cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4alkyl or C1-C4alkyl substituted with C3-C6cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R17is independently C3-C6cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4alkyl or C1-C4alkyl substituted with C3-C6cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4alkyl in each R15, R16and R17can optionally be substituted with halogen, CN, C1-C4alkyl, OH, C1-C4alkoxy, NH2, C1-C4alkylamino, C1-C4dialkylamino, C1-C2perfluoroalkyl, C1-C2perfluoroalkoxy, or 1,2-methylenedioxy. The term “oxo” refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur. The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures, as well as cis and trans geometric isomers. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention. Compounds of the Invention In one aspect, the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein: R1is H, halo, or C1-3alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O)2R′, S(O)2R, and S(O)2NRR′; R2is H, halo, or C1-3alkyl; Cy is C3-7cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O)2R′, S(O)2R, and S(O)2NRR′, wherein R3is C1-3alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O)2R′, S(O)2R, and S(O)2NRR′; R, R′ each is independently H, or C1-3alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. In another aspect Cy can be C5-7cycloalkyl, or 5-7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O)2R′, S(O)2R, and S(O)2NRR′, wherein R3is C1-3alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O)2R′, S(O)2R, and S(O)2NRR′. In another aspect R2can be hydrogen. Representative compounds of the invention are depicted in Table 1. In these examples the stereochemistry at the chiral carbon atoms is independently either RS, R, or S, unless specified. For compounds 4, 7-11, the stereochemistry shows only one of the trans or cis isomers, and the structures of their respective isomers are not shown. The structures depicted herein, including the Table 1 structures, may contain certain —NH—, —NH2(amino) and —OH (hydroxyl) groups where the corresponding hydrogen atom(s) do not explicitly appear; however they are to be read as —NH—, —NH2or —OH as the case may be. In certain structures, a stick bond is drawn and is meant to depict a methyl group. TABLE 11234567891011 Representative compounds of the invention are listed below:trans-4-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b] imidazo[4,5-d]pyridin-1-yl]cyclohexanecarbonitrile (1);trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexanecarbonitrile (2);2-[trans-4-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexyl]acetonitrile (3);2-[(2R,5S)-5-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (4);3-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (5);(R)-4-[2-(1-Hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide (6);2-[(2R,5 S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (7);2-[(2S,5 S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (8),2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d] pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (9),2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d] pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (10),2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d] pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (11). The synthesis of compounds of the formulae herein can be readily effected by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance, herein. Each of the patents, patent applications, and publications, whether in traditional journals or available only through the internet, referred to herein, is incorporated in its entirety by reference. Other approaches to synthesizing compounds of the formulae herein can readily be adapted from references cited herein. Variations of these procedures and their optimization are within the skill of the ordinary practitioner. The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (e.g., R1, R2, R, R′, X, etc.) or not. The suitability of a chemical group in a compound structure for use in synthesis of another compound structure is within the knowledge of one of ordinary skill in the art. Additional methods of synthesizing compounds of the formulae herein and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. The methods described herein may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds herein. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The methods delineated herein contemplate converting compounds of one formula to compounds of another formula. The process of converting refers to one or more chemical transformations, which can be performed in situ, or with isolation of intermediate compounds. The transformations can include reacting the starting compounds or intermediates with additional reagents using techniques and protocols known in the art, including those in the references cited herein. Intermediates can be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography). Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The invention also provides compositions comprising an effective amount of a compound of any of the formulae herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or prodrug, if applicable, of said compound; and an acceptable carrier. Preferably, a composition of this invention is formulated for pharmaceutical use (“a pharmaceutical composition”), wherein the carrier is a pharmaceutically acceptable carrier. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in amounts typically used in medicaments. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch). Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (17th ed. 1985). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product. In certain preferred embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US patents, some of which include, but are not limited to, U.S. Pat. Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethyl cellulose acetate succinate. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia. Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant. The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. See, e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ.: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189-214. Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access. According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers. According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active. In another embodiment, a composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered alone or with a compound of any of the formulae herein. Drugs that could be usefully combined with these compounds include other kinase inhibitors and/or other therapeutic agents for the treatment of the diseases and disorders discussed above. Such agents are described in detail in the art. Preferably, the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from cancer and neoplastic diseases or disorders, or autoimmune and inflammatory diseases or disorders. In another embodiment, the invention provides separate dosage forms of a compound of this invention and a second therapeutic agent that are associated with one another. The term “associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously). In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., (1966) Cancer Chemother Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. An effective amount of a compound of this invention can range from about 0.001 mg/kg to about 500 mg/kg, more preferably 0.01 mg/kg to about 50 mg/kg, more preferably 0.1 mg/kg to about 2.5 mg/kg. Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are entirely incorporated herein by reference. It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation. Methods of Treatment According to another embodiment, the invention provides a method of treating a subject suffering from or susceptible to a disease or disorder or symptom thereof (e.g., those delineated herein) comprising the step of administering to said subject an effective amount of a compound or a composition of this invention. Such diseases are well known in the art and are also disclosed herein. In one aspect, the method of treating involves treatment of a disorder that is mediated by the Jak1 protein kinase. In another aspect, the method of treating involves treatment of a disorder that is mediated primarily by the Jak1 protein kinase, but also to some extent by the Jak2 protein kinase. In another aspect, the invention provides a method of treating a disease in a subject comprising administering to the subject a compound of any of the formulae herein. In another aspect, invention provides a method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of any of the formulae herein. In another aspect, invention provides a method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of any of the formulae herein. In certain embodiments, the disease is mediated by the Jak1 kinase. For example, the condition may be an inflammatory disease/disorder, an autoimmune disease/disorder, such as, but not limited to rheumatoid arthritis (RA), juvenile idiopathic arthritis, osteoarthritis, multiple sclerosis, allergic asthma, chronic obstructive pulmonary disease, bronchitis, experimental allergic encephalomyelitis, Crohn's disease, vasculitis, cardiomyopathy, ankylosing spondylitis (AS), glomerulonephritis, insulin-dependent diabetes, psoriatic arthritis, psoriasis, plaque psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, Castleman disease, neutropenia, endometriosis, autoimmune thyroid disease, sperm and testicular autoimmunity, scleroderma, axonal & neuronal neuropathies, allergic rhinitis, sinusitis, hemolytic anemia, Graves, disease, Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis, myositis, dry eye syndrome, primary biliary cirrhosis, polymyalgia rheumatic, Reiter's syndrome, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome, celiac sprue, myasthenia gravis, Sjogren's Syndrome, alopecia areata, vitiligo, atopic dermatitis, POEMS syndrome, lupus, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), pemphigus vulgris, bullous pemphigoid, chronic fatigue syndrome, organ transplant rejection (e.g., allograft rejection and graft versus host disease), viral diseases such as Epstein Barr virus, Hepatitis C, HIV, HTLV 1, Varicella-Zoster virus, and human papilloma virus, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflext sympathetic dystrophy, algodystrophy, Tietze syndrome, costal athropathy, Mseleni disease, Handigodu disease, fibromyalgia, scleroderma, congentital cartilage malformations, and pulmonary arterial hypertension. Further JAK-associated diseases include inflammation and inflammatory diseases or disorders, Examples include sarcoidosis, inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis, blepharitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lowe respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis and other inflammatory diseases. In another embodiment, the disease is, cancer, a proliferative or other neoplastic disease, such as, but not limited to, breast cancer, Castleman's disease, colon and colorectal cancers, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, glioblastoma, head and neck cancer, Kaposi's sarcoma, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, renal cancer, rectal cancer, small intestine cancer, thyroid cancer, uterine leiomyosarcoma, lymphomas and leukemias such as acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, cutaneous T cell lymphoma, cutaneous B cell lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonoytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD). In some embodiments, the myeloproliferative disorder is post-essential thrombocythemia melofibrosis (Post-ET MF) or post-polycythemia versa myelofibrosis (Post-PV MF), Further JAK-associated diseases include ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest, endotoxin-driven disease state (e.g., complications after bypass surgery of chronic endotoxin states contributing to chronic cardiac failure), anorexia, sclerodermitis, fibrosis, conditions associated with hypoxia or astrogliosis such as diabetic retinopathy, cancer, or neurodegeneration, and other inflammatory disease such as systemic inflammatory response syndrome and septic shock. Other JAK-associated disease include gout and increased prostate size due to, e.g., benign prostate hypertrophy or benign prostatic hyperplasia, as well as bone resorption diseases such as osteoporosis or osteoarthritis, bone resorption diseases associated with: hormonal imbalance and/or hormonal therapy, autoimmune disease (e.g., osseous sarcoidosis). Other examples of JAK-associated diseases or conditions include ameliorating the dermatological side effects of other pharmaceuticals by administration of the compound of the invention. For example, numerous pharmaceutical agents result in unwanted allergic reaction which can manifest as acneiform rash or related dermatitis. Example pharmaceutical agents that have such undesirable side effects include anti-cancer drugs such as gefitinib, cetuximab, erlotinib, and the like. The compounds of the invention may be administered systemically or topically (e.g., localized to the vicinity of the dermatitis) in combination with pharmaceutical agent having the undesirable dermatological side effect. Accordingly, compositions of the invention include topical formulations containing the compound of the invention and a further pharmaceutical agent which can cause dermatitis, skin disorders, or related side effects. In a one embodiment, the method of this invention is used to treat a subject suffering from or susceptible to a disease or condition. Such diseases, disorders or symptoms thereof include, for example, those modulated by the Jak1 protein kinase. The disease or disease symptom can be, for example, rheumatoid arthritis, cancer or proliferation disease or disorder. Methods delineated herein include those wherein the subject is identified as in need of a particular stated treatment. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In yet another embodiment, the compounds of the formulae herein (and compositions thereof) can be used to treat subjects having a disease or disorder who have been treated with and developed resistance to other therapeutic agents. In one aspect, the methods herein include those where a subject resistant to treatment with methotrexate or anti-TNF-alpha therapy. In another embodiment, the invention provides a method of modulating the activity of the Jak1 protein kinase in a cell comprising contacting a cell with one or more compounds of any of the formulae herein. In another embodiment, the above method of treatment comprises the further step of co-administering to said patient one or more second therapeutic agents. The choice of second therapeutic agent may be made from any therapeutic agent known to be useful for indications herein. One or more additional therapeutic may include chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as PI3Kdelta, mTOR, BCR-ABl, FLT-3, RAF and FAK kinase inhibitors, and the like. Additional therapeutic agents include but are not limited to agents for treatment of diseases, disorders or symptoms thereof including for example, (1) agents that modulate human immune system or are anti-inflammatory agents selected from the group consisting of, but not limited to, aspirin, acetaminophen, aminosalicylate, antithymoyte globulin, ciprofloxacin, corticosteroid, cyclosporine, deoxyspergualin, daclizuma, metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam, prednisolone, dexamethasone, anti-inflammatory steroid, methotrexate, chloroquine, azathioprine, hydroxychloroquine, mycophnolate, muromonab-CD3, penicillamine, sulfasalazine, leflunomide, tacrolimus, tocilzumab, anakinra, abatacept, certolizumab pegol, golimumab, rapamycin, vedolizumab, natalizumab, ustekinumab, rituximab, efalizumab, belimumab, etanercept, infliximab, adalimuman, immune modulator (e.g., activator) for CD4+CD25+ regulatory T cells, NSAIDs, analgesics, other non-biological disease-modifying anti-rheumatic drugs (DMARDs) and/or in combination with anti-TNF-alpha biological agents such as TNA antagnoists like chimeric, humanized or human TNF antibodies, adalimumab, infliximab, golimumab, CDP571 and soluble p55 or l75 TNA receptors, derivatives, thereof, etanerceptr pr lenercept (2) anti-cancer and anti-neoplastic agents, antiproliferative agents, antineoplastic agents, antitumor agents, antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents, alkylating-type antineoplastic agents, antibiotic-type antineoplastic agents, or, any other agent typically administered as a primary or adjuvant agent in cancer treatment protocols (e.g., antinausea, antianemia, etc.), including for example, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan, an epothilone, Iressa, Avastin, OSI-774, angiogenesis inhibitors, EGFR inhibitors, MEK inhibitors, VEGFR inhibitors, CDK inhibitors, Her1 and Her2 inhibitors, monoclonal antibodies, proteosome inhibitors such as bortezomib, thalidomide, and revlimid; an apoptotic inducer such as ABT-737. A nucleic acid therapy such as antisense or RNAi; nuclear receptor ligands (e.g., agonists and/or antagonists. All-trans retinoic acid or boxarotene); epigenetic targeting agents such as histone deacetylase inhibitors (e.g., vorinostat), hypomethylating agents (e.g., decitabine), regulators of protein stability such as HSP90 inhibitors, ubiquitin and/or ubiquitin like conjugating or deconjugating molecules. In some embodiments, the additional pharmaceutical agent is selected from IMiDs, an anti-IL-6 agent, an anti-TNF-alpha agent, a hypomethylating agent, and a biologic response modifier (RBM). RBM is generally a substance made from living organisms to treat disease. Examples of RBMs include IL-2, GM-CSF, CSF, monoclonal antibodies such as abciximab, etanercept, infliximab, rituximab, trastuzumab, and high dose ascorbate. The hypomethylating agent is a DNA methyltransferase inhibitor such as 5 azacytidine and decitabine. Examples of IMiDs include thalidomide, lenalidomide, pomalidomide, CC-11006, and CC-10015. In some embodiments, the additional pharmaceutical agents include anti-thymocyte globulin, recombinant human granulocyte colony-stimulating factor (G-CSF), granulocyte-moncyte CSF (GM-CSF), a erythropoiesis-stimulating agent (ESA), and cyclosporine. In some embodiments, the additional therapeutic agent is an additional JAK inhibitor. In some embodiments, the additional JAK inhibitor is tofacitinib, ruxolitinib or baricitinib. In some embodiments, one or more JAK inhibitors of the invention can be used in combination with one or more other cancer therapeutic agents in the treatment of cancer, such as multiple myeloma, and may improve the treatment benefit as compared to the benefit shown by the other cancer therapeutic agents, without exacerbating of their toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma can include, without limition, melphalan, melphalan plus prednisone (MP), doxorubicin, dexamethasone, and bortezomib. Additional agents used in the treatment of multiple myeoloma include BRC-ABL, FLT-3, RAF, MEK, PI3K, mTOR inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the current invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone or other agents may be reversible upon treatment with a JAK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor of the invention where the dexamethasone is administered intermittently as opposed to continuously. In some embodiments, combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplantation or stem cell transplantation. In some embodiments, the additional therapeutic agent is fluocinolone acetonide or remexolone. In some embodiments, the additional therapeutic is a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone. In some embodimennts, the additional therapeutic agent includes Dehydrex, Civamide, sodium hyaluronate, cyclosporine, ARG101, AGR1012, ecabet sodium, gefarnate, 15-(s)-hydroxyeicosatetraenoic acid, cevilemine doxycycline, minocycline, iDestrin, cyclosporine A, oxytetracycline, voclosporin, ARG103, RX-10045, DYN15, rivoglitazone, TB4, OPH-01, PCS101, REV1-31, Lacritin, rebamipide, OT-551, PAI-2, pilocarpine, tacrolimus, pimercrolimus, loteprednol etabonate, rituximan, diquafosol tetrasodium, KLS-0611, dehydroepiandrosterone, anakinra, efalizuma, mycophenolate sodium, etanercept, hydroxychloroquine, NGX267, actemra, or L-asparaginase. In some embodiments, the additional therapeutic agent is an anti-angiogenic agent, cholinergic agent, TRP-1 receptor modulator, a calcium channel blocker, a mucin secretagogue, MUC1 stimulant, a calcineurin inhibitor, a P2Y2 receptor agonist, a muscarinic receptor agonist, and a tetracycline derivative. In some embodimenbts, the additional therapeutic agents include demulcent eye drops, which include, but not limited to, compositions containing polyvinylalchol, hyroxypropyl methylcellulose, glycerin, polyethylene glycol (e.g., PEG400), or carboxymethyl cellose, In some embodiments, the additional therapeutic agent is a mucolytic drug, such as N-acetyl-systeine, which can interact with the mucoproteins and decrease the viscositiy of the tear film. In some embodiments, the additional therapeutic agent includes an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, and anti-allergic agents. Examples of suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin, vanocomycin; tetracyclines; rifampin and its derivatives; cycloserine; beta-lactams; cephalosporins; emphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; dicloenac; flurbiprofen; ketorolac; suprofen; cromolyn; iodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic. The term “co-administered” as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention comprising both a compound of the invention and a second therapeutic agent to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment. Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range. In one embodiment of the invention where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art. In yet another aspect, the invention provides the use of a compound of any of the formulae herein alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above. Another aspect of the invention is a compound of the formulae herein for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof delineated herein. In other aspects, the methods herein include those further comprising monitoring subject response to the treatment administrations. Such monitoring may include periodic sampling of subject tissue, fluids, specimens, cells, proteins, chemical markers, genetic materials, etc. as markers or indicators of the treatment regimen. In other methods, the subject is prescreened or identified as in need of such treatment by assessment for a relevant marker or indicator of suitability for such treatment. In one embodiment, the invention provides a method of monitoring treatment progress. The method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target or cell type delineated herein modulated by a compound herein) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof delineated herein, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof. The level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status. In preferred embodiments, a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre-treatment level of Marker in the subject is determined prior to beginning treatment according to this invention; this pre-treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment. In certain method embodiments, a level of Marker or Marker activity in a subject is determined at least once. Comparison of Marker levels, e.g., to another measurement of Marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful in determining whether therapy according to the invention is having the desired effect, and thereby permitting adjustment of dosage levels as appropriate. Determination of Marker levels may be performed using any suitable sampling/expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first removed from a subject. Examples of suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples containing roots. Other suitable samples would be known to the person skilled in the art. Determination of protein levels and/or mRNA levels (e.g., Marker levels) in the sample can be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA, radiolabelling/assay techniques, blotting/chemiluminescence methods, real-time PCR, and the like. The present invention also provides kits for use to treat diseases, disorders, or symptoms thereof, including those delineated herein. These kits comprise: a) a pharmaceutical composition comprising a compound of any of the formula herein or a pharmaceutically acceptable salt thereof; or a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof, wherein said pharmaceutical composition is in a container; and b) instructions describing a method of using the pharmaceutical composition to treat the disease, disorder, or symptoms thereof, including those delineated herein. The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. Preferably, the container is a blister pack. The kit may additionally comprising information and/or instructions for the physician, pharmacist or subject. Such memory aids include numbers printed on each chamber or division containing a dosage that corresponds with the days of the regimen which the tablets or capsules so specified should be ingested, or days of the week printed on each chamber or division, or a card which contains the same type of information. The compounds delineated herein can be assessed for their biological activity using protocols known in the art, including for example, those delineated herein. Certain of the compounds herein demonstrate unexpectedly superior attributes (e.g., inhibition of P450, metabolic stability, pharmacokinetic properties, etc.) making them superior candidates as potential therapeutic agents. All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, technical data sheets, internet web sites, databases, patents, patent applications, and patent publications. EXAMPLES Example 1: Synthesis of trans-4-[2-[(R)-1-Hydroxyethyl]-1H-furo [3,2-b]imidazo [4,5-d]pyridin-1-yl] cyclohexanecarbonitrile (1) Step 1. A solution of trans-4-(Boc-amino)cyclohexane carboxylic acid (A1-1) (62 g, 0.256 mol, 1.0 eq) in THF (1500 mL) was treated with NMM (64.6 g, 0.64 mol, 2.5 eq) in nitrogen atmosphere. The mixture was cooled to −78° C., and isobutyl chloroformate (33.6 g, 0.33 mol, 1.3 eq) was added dropwise. After stirring at −78° C. for 1 hr, NH3(gas) was bubbled through the mixture for about 20 mins. After that the reaction temperature rose to −30° C., then stirring at −30° C. for 1 hr. The resulting slurry was filtered, washed by water (3*200 mL), and oven dried to give compound A1-2 as white powder (58 g, yield 93.5%). MS-ESI:[M+1]+: 243.1 1H NMR (300 MHz, d6-DMSO): 7.192 (s, 1H), 6.688-6.728 (m, 2H), 3.122-3.147 (m, 1H), 1.92-1.959 (m, 1H), 1.696-1.787 (m, 4H), 1.382 (s, 9H), 1.086-1.358 (m, 4H). Step 2. A solution of compound A1-2 (74 g, 0.306 mol, 1.0 eq) in DCM (1000 mL) was treated with triethylamine (77.2 g, 0.64 mol, 2.5 eq). The mixture was cooled to 0° C. in ice-bath, and TFAA (80.9 g, 0.383 mol, 1.25 eq) was added dropwise. The ice bath was removed after addition and the reaction temperature rose to 20° C., then stirring at 20° C. for 2 hrs, water (300 mL) was added, and then the aqueous phase was extracted twice with DCM. The combined extracts was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A1-3 as white powder (46 g, yield 67.1%). MS-ESI:[M+1]+: 225.1. 1H NMR (300 MHz, CDCl3): 4.397 (m, 1H), 3.467 (m, 1H), 2.381-2.418 (m, 1H), 2.079-2.147 (m, 4H), 1.613-1.757 (m, 2H), 1.454 (s, 9H), 1.114-1.232 (m, 2H). Step 3. To a solution of compound A1-3 (10 g, 44.6 mmol, 1.0 eq) in DCM (50 mL), was added TFA (20 g). The reaction mixture was stirred for 2 hrs at room temperature until TLC showed the reaction was complete, then concentrated under vacuum. Ice-water (30 mL) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/L) to pH 10. Then the aqueous phase was extracted six times with DCM/methanol (10/1). The combined extracts was dried over anhydrous sodium sulfate, concentrated to give compound A1-4 as an off-white solid (5.1 g, yield 91.9%). MS-ESI:[M+1]+: 125.1. 1H NMR (300 MHz, CDCl3): 2.738-2.772 (m, 1H), 2.370-2.421 (m, 1H), 2.115-2.170 (m, 2H), 1.923-1.977 (m, 2H), 1.580-1.694 (m, 2H), 1.075-1.197 (m, 2H) Step 4. In nitrogen atmosphere, to a solution of 2-Bromo-3-hydroxypyridine (A1-5) (225 g, 1.293 mol, 1.0 eq), trimethylsilylacetylene (153.3 g, 1.592 mol, 1.23 eq) in 1,4-dioxane (2500 mL) was added CuI (25 g) and Pd(PPh3)2Cl2(45 g). The reaction mixture was stirred for 30 mins at 25° C., then cooled to 10° C. and triethylamine (363 g, 3.594 mol, 2.78 eq) was added dropwise. After stirring for 4 hrs at 60° C., the solution was cooled and concentrated under vacuum. The residue was added water (2000 mL) and MTBE (200 mL), stirring and filtered. The filtrate was extracted with MTBE (1000 mL*2). The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A1-6 as light brown liquid (150 g, yield 60.7%). GC-MS: 191 (EI) Step 5. To a solution of compound A1-6 (105 g, 0.55 mol, 1.0 eq) in DCM (1000 mL) was added m-chloroperoxybenzoic acid (85%, 230 g, 1.13 mol, 12.06 eq) in portions below 25° C. After stirring overnight at room temperature, saturated sodium bicarbonate solution was added to pH 7-8 in ice-bath. The resulting mixture was filtered, and the filtrate was separate, and was extracted twice with DCM. The combined organic layers was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated to give compound A1-7 as a brown liquid (115 g, yield 100%). Step 6. A solution of compound A1-7 (115 g, 0.55 mol, 1.0 eq) in toluene (400 mL) was added to phosphorus oxychloride (400 mL) in ice-bath below 30° C. The reaction mixture was stirred for 2 hrs at 90° C., cooled to room temperature, and concentrated. The residue was slowly added saturated sodium bicarbonate solution to pH 7-8 below 20° C., and the mixture was extracted twice with MTBE. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A1-8 as a yellow liquid (73 g, yield 58.7%). GC-MS: 225 (EI) Step 7. To a solution of compound A1-8 (73 g, 0.323 mol, 1.0 eq) in THF (400 mL) was added aqueous sodium hydroxide solution (300 mL, 4 mol/L). After stirring for 1 hr at 50° C., the reaction mixture was cooled to room temperature and 1000 mL water was added. The mixture was extracted twice with MTBE. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from ethyl acetate and petroleum ether to give compound A1-9 as an off-white powder (30 g, yield 60.5%). GC-MS: 153 (EI) 1H NMR (300 MHz, CDCl3): 8.485 (d, 1H), 7.945 (d, 1H), 7.312 (d, 1H), 7.079 (d, 1H). Step 8. Compound A1-9 (9.21 g, 60 mmol, 1.0 eq) was dissolved in methanol (150 mL), then water (150 mL) and sodium hydroxide (24 g, 10 eq) were added. After stirring for 1 hr at 50° C., the reaction mixture was cooled to 20° C. and concentrated. The residue was extracted three times with DCM, then the combined organic layers was dried over anhydrous sodium sulfate and concentrated to give compound A1-10 as a yellow liquid (5.5 g, yield 61.5%). MS-ESI:[M+1]+: 150 Step 9. Compound A1-10 (5.5 g, 37 mmol, 1.0 eq) was added to 40% HBr aq (150 mL). The reaction mixture was heated to reflux for 18 hrs, cooled and concentrated. The residue was treated with saturated sodium bicarbonate solution (100 mL) to pH 7-8. After stirring for 20 min, the precipitate was filtered, washed with water, and oven dried to give compound A1-11 as an off-white powder (3.1 g, yield 62%). MS-ESI:[M+1]+: 136 Step 10. In nitrogen atmosphere, a mixture of compound A1-11 (1.68 g, 12.4 mmol, 1.0 eq) in 120 mL DCM was cooled to −5° C., and tetrabutyl-ammonium nitrate (5.17 g, 17 mmol, 1.36 eq) in DCM (30 mL) was added drop wise below 0° C., then TFAA (5.17 g, 20 mmol, 1.6 eq) was added all at once. After addition, the reaction mixture was stirred at −5° C. for 1 hr and then warmed up to 25° C. and stirred for 15 hrs. The solvent was concentrated, and ether (200 mL) was added to the residue, stirred and filtered. Collected filter-cake and saturated sodium bicarbonate solution (100 mL) was added. The mixture was extracted twice with ethyl acetate, then the combined organic layers was dried over anhydrous sodium sulfate and concentrated to give compound A1-12 as a yellow powder (1.37 g, yield 61.4%). MS-ESI:[M+1]+: 181 Step 11. A mixture of compound A1-12 (1.37 g, 7.61 mmol, 1.0 eq) and propionic acid (50 mL) was heated to 110° C., then fuming nitric acid (0.65 mL) was added dropwise at 110° C. to 120° C. After stirring for 30 mins at 125° C. and cooled to room temperature, ether (100 mL) was added, and the solid was filtered, washed with ether and dried under vacuum to give compound A1-13 as yellow a powder (1.2 g, yield 87.6%). MS-ESI:[M+1]+: 181. 1H NMR (300 MHz, d6-DMSO): 13.149 (s, 1H), 9.024 (s, 1H), 8.234 (d, 1H), 6.966 (d, 1H). Step 12. To a solution of compound A1-13 (1.2 g, 6.67 mmol, 1.0 eq) in 1,2-dichloroethane (50 mL), was added phosphorus oxychloride (15 mL) below 20° C., then stirred for 2 hrs at 95° C. in nitrogen atmosphere, cooled to 25° C. and concentrated. The residue was slowly added saturated sodium bicarbonate solution to pH 7-8 below 20° C., and the mixture was extracted twice with MTBE. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A1-14 as a light-yellow powder (0.8 g, yield 60.4%), 1H NMR (300 MHz, CDCl3): 9.250 (s, 1H), 8.189 (d, 1H), 7.191 (d, 1H). Step 13. To a solution of A1-14 (280 mg, 1.41 mmol, 1.0 eq) in n-butanol (20 mL) was added compound A1-4 (290 mg, 2.34 mmol, 1.66 eq) and DIPEA (403 mg, 3.12 mmol, 2.21 eq). The reaction mixture was stirred for 1 hr at 135° C., concentrated and purified by silica gel column chromatography to give A1-15 as a yellow powder (320 mg, yield 79.4%). MS-ESI:[M+1]+: 287.1. 1H NMR (300 MHz, CDCl3): 9.268 (s, 1H), 8.653 (d, 1H), 7.952 (d, 1H), 7.034 (d, 1H), 4.423-4.511 (m, 1H), 2.629-2.723 (m, 1H), 2.241-2.355 (m, 4H), 1.864-1.902 (m, 2H), 1.539-1.578 (m, 2H). Step 14. To a solution of A1-15 (320 mg, 1.12 mmol, 1.0 eq) in methanol (15 mL), was added 10% Pd/C (0.3 g, 50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrates was concentrated under vacuum, and A1-16 was obtained as a yellow oil (286 mg, yield 100%). MS-ESI: [M+1]+: 257.1 Step 15. A solution of (R)-(+)-Lactamide (259 mg, 2.8 mmol, 5.0 eq) and Et3O—BF4 (543 mg, 2.8 mmol, 5.0 eq) in THF (10 mL) was stirred 30 mins at room temperature in nitrogen atmosphere. Then the above solution was added to the mixture of A1-16 (143 mg, 0.56 mmol, 1.0 eq) in ethanol (10 mL). After stirring for 2 hrs at 85° C., the mixture was concentrated, added water and extracted four times with ethyl acetate. The organic phase was discarded and the aqueous phase was treated with saturated sodium bicarbonate solution (100 mL) to pH 8, extracted twice with ethyl acetate. The second organic phases was dried over anhydrous sodium sulfate, concentrated to give the title compound as a light-yellow powder (80 mg, yield 46%). MS-ESI: [M+1]+: 311.4 1H NMR (300 MHz, CDCl3): 9.005 (s, 1H), 7.949 (s, 1H), 7.256 (s, 1H), 5.227-5.290 (m, 1H), 4.766-4.843 (m, 1H), 2.783-2.864 (m, 1H), 2.438-2.527 (m, 4H), 2.068-2.192 (m, 2H), 1.913-2.003 (m, 2H), 1.767-1.846 (d, 3H). Example 2: Synthesis of trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexanecarbonitrile (2) Example 2 was made using the same procedure as Example 1 except that (R)-(+)-Lactamide is replaced by 2-hydroxyacetamide in step 15): 40 mg of title compound as a light-yellow powder, MS-ESI: [M+1]+: 297.4 1H NMR (300 MHz, CDCl3): 9.048 (s, 1H), 7.965 (s, 1H), 7.286 (s, 1H), 5.049 (s, 2H), 4.702-4.813 (m, 1H), 2.753-2.873 (m, 1H), 2.376-2.527 (m, 4H), 2.087-2.226 (m, 2H), 1.872-2.053 (m, 2H). Example 3: Synthesis of 2-[trans-4-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] cyclohexyl] acetonitrile (3) Step 1. In nitrogen atmosphere, to a solution of trans-1,4-cyclohexane-dicarboxylic acid monomethyl ester (A3-1) (100 g, 0.538 mol, 1.0 eq) and triethylamine (57.4 g, 0.568 mol, 1.055 eq) in t-butyl alcohol (1000 mL) was added dropwise diphenylphosphoryl azide (155 g, 0.563 mol, 1.047 eq) at room temperature. The mixture was refluxed over 16 hrs. Upon completion by TLC, the mixture was then cooled and concentrated. Water (1000 mL) was added, and the mixture was extracted three times with MTBE. Then the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A3-2 as an off-white powder (53 g, yield 39.2%). MS-ESI:[M+1]+: 257.1 Step 2. A suspension of LiAlH4(9.0 g, 0.236 mol, 1.12 eq) in THF (500 mL) was cooled to 0° C. in ice-bath, and then added a solution of compound A3-2 (54.3 g, 0.211 mol, 1.0 eq) in THF (200 mL) while keeping the temperature below 10° C. The reaction mixture was stirred overnight at room temperature, and then quenched with sodium sulfate decahydrate (27 g) at 15° C. to 25° C., filtered and the filtrate was concentrated to give compound A3-3 as a white powder (43 g, yield 89%). MS-ESI:[M+1]+: 229.1 Step 3. A mixture of compound A3-3 (11.5 g, 0.05 mol, 1.0 eq) and triethylamine (7.6 g, 0.075 mol, 1.5 eq) in DCM (200 mL), was added methylsufonyl chloride (6.9 g, 0.06 mol, 1.2 eq) dropwise below 10° C. After stirring for 2 hrs at room temperature, water (300 mL) was added. The mixture was extracted twice with ethyl acetate. The combined extracts was washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A3-4 as yellow liquid (16.0 g, yield 100%). MS-ESI:[M+1]+: 307.1 Step 4. To a solution of compound A3-4 (16.0 g, 0.05 mol, 1.0 eq) in DMSO (150 mL) was added sodium cyanide (7.0 g, 0.143 mol, 2.86 eq) in portions below 20° C. After stirring for 5 hrs at 85° C., the mixture was cooled to room temperature, ice-water (500 mL) was added. The mixture was extracted twice with MTBE. The combined extracts was washed three times with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A3-5 as white powder (9.3 g, yield 78%). MS-ESI:[M+1]+: 238.1. 1H NMR (300 MHz, CDCl3): 4.408 (m, 1H), 3.405 (m, 1H), 2.263-2.285 (d, 2H), 2.064-2.096 (m, 2H), 1.457 (s, 9H), 1.122-1.281 (m, 4H). Step 5. To a solution of compound A3-5 (1.1 g, 4.6 mmol, 1.0 eq) in DCM (10 mL) was added TFA (6 g). The reaction mixture was stirred for 2 hrs at room temperature, then concentrated under vacuum. Ice-water (15 mL) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/L) to pH 10. Then the aqueous phase was extracted five times with DCM/methanol (10/1). The combined extracts was dried over anhydrous sodium sulfate, concentrated to give compound A3-6 as a yellow oil (0.55 g, yield 87.7%). MS-ESI:[M+1]+: 138.1. Step 6 to step 8 are the same as step 13 to step 15 in Example 1 except that the amine A1-4 is replaced by A3-6 to make the title compound: 70 mg of light-yellow powder (Yield: 0.565%). MS-ESI: [M+1]+: 325.5 1H NMR (300 MHz, CDCl3): 9.003 (s, 1H), 7.965 (s, 1H), 7.270 (s, 1H), 5.255-5.298 (m, 1H), 4.713-4.795 (m, 1H), 2.439-2.611 (m, 4H), 2.068-2.512 (m, 5H), 1.808-1.829 (d, 3H), 1.452-1.576 (d, 2H). Example 4: Synthesis of 2-[(2R,5S)-5-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (4) Step 1. In a round bottom flask, triethylamine (188 g, 1.86 mol, 1.0 eq) was added dropwise to a stirred solution of di-tert-butyl dicarbonate (162 g, 0.744 mol, 1.2 eq) and compound A4-1 (100 g, 0.62 mol, 1.0 eq) in water (500 mL) and 1,4-dioxane (500 mL). After stirring for 18 hrs at room temperature, the solution was extracted with MTBE (500 mL*2) and the aqueous phase was cooled on ice and carefully acidified to pH 3 by slow addition of 10% citric acid solution. The urethane was then extracted twice with ethyl acetate, and the combined extracts was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give compound A4-2 as clear viscous oil (180 g, yield 100%). MS-ESI:[M+1]+: 262.1 Step 2. A solution of compound A4-2 (40 g, 0.153 mmol, 1.0 eq) in THF (600 mL) was treated with 4-methylmorpholine (17 g, 0.168, 1.1 eq) at room temperature. The resulting mixture was cooled to 0° C. before being treated with isobutyl chloroformate (22.7 g, 0.166 mmol, 1.08 eq) dropwise. The resulting reaction mixture was stirred at 0° C. for an addition 20 mins before being filtered and washed with THF. Then the clear filtrate solution was cooed to 0° C., and treated with a solution of NaBH4(11.2 g, 0.295 mol, 1.93 eq) in water (100 mL). The resulting mixture was stirred overnight at room temperature, and then quenched with an aqueous HCl solution (1.0 mol/L,200 mL) dropwise, The mixture was extracted with ethyl acetate, and the combined extracts was washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A4-3 as a yellow oil (25 g, yield 66%). MS-ESI:[M+1]+: 248.1 Step 3. A solution of compound of A4-3 (25 g, 0.1 mol, 1.0 eq) in toluene (300 mL) and acetic acid (150 mL) was heated to reflux for 5 hrs and then cooled, concentrated under vacuum. The residual was added saturated sodium bicarbonate solution to pH 7-8 in ice-bath. Then the mixture was extracted three times with ethyl acetate, and the combined extracts was washed with brine, dried over anhydrous sodium sulfate, concentrated and recrystallized by ethyl acetate and PE to give compound A4-4 as a white powder (8.0 g, yield 37.2%). GC-MS: 215 Step 4. A solution of tributyl phosphine (72.9 g, 0.36 mol, 1.0 eq) in nitromethane (500 mL), was added dropwise chloroacetonitrile (27.2 g, 0.36 mol, 1.0 eq) in nitrogen atmosphere. The resulting reaction mixture was stirred for 16 hrs at room temperature, then concentrated. The residual oil solidified when a small amount of ethyl acetate was added. The solid was recrystallized by ethyl acetate and DCM to afford compound A4-5 as a white powder (95 g, yield 95%). Step 5. To a solution of dry compound A4-5 (8.3 g, 30 mmol, 3.0 eq) in N,N-dimethylacetamide (30 mL) in nitrogen atmosphere, was added solid Potassium tert-butoxide (3.1 g, 28 mmol, 2.8 eq) in portions at 0° C. The resulting mixture was gradually warmed to 30° C. and stirred for 2 hrs. The resulting ylide solution was then treated with compound A4-4 (2.15 g, 10 mmol, 1.0 eq), and stirred overnight at 70° C. After cooled to room temperature, the resulting slurry was poured into the mixture of ice-water (100 mL) and saturated sodium bicarbonate solution (100 mL). The mixture was extracted twice with ethyl acetate, and the combined extracts was washed three times with brine, dried over anhydrous sodium sulfate, concentrated to give compound A4-6 as yellow oil without purification (7.5 g, yield 100%). MS-ESI:[M+1]+: 239.1 Step 6. To a solution of compound A4-6 (7.5 g, 10 mmol, 1.0 eq) in methanol (200 mL), was added 10% Pd/C (0.5 g,50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrates was concentrated under vacuum, and purified by silica gel column chromatography to give compound A4-7 as off-white powder (1.6 g, yield 66.7%). MS-ESI:[M+1]+: 241.1 Step 7. To a solution of compound A4-7 (1.6 g, 6.67 mmol, 1.0 eq) in DCM (20 mL), was added TFA (10 g, 88.5 mmol, 13.2 eq). The reaction mixture was stirred for 2 hrs at room temperature until TLC showed the reaction was complete, then concentrated under vacuum. Water (20 mL) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/L) to pH 10. Then the aqueous phase was extracted six times with DCM/methanol (10/1). The combined extracts was dried over anhydrous sodium sulfate, concentrated to give compound A4-8 as light-brown oil (950 mg, yield 100%). MS-ESI:[M+1]+: 141.1 Step 8. To a solution of compound A1-14 (prepared as step 4 to 12 in example 1) (600 mg, 3.0 mmol, 1.0 eq) in n-butanol (15 mL), was added compound A4-8 (950 mg, 6.7 mmol, 2.26 eq) and DIPEA (1.36 g, 10.5 mmol, 3.5 eq). The reaction mixture was stirred for 1 hr at 135° C., concentrated and purified by silica gel column chromatography to give compound A4-9 (2R,5S) as light-yellow powder (254 mg, yield 28.0%).MS-ESI: [M+1]+: 303.1. 1H NMR (300 MHz, d6-DMSO): 9.063 (s, 1H), 8.503 (d, 1H), 9.326 (d, 1H), 7.176 (d, 1H), 4.431-4.513 (m, 1H), 4.128-4.156 (m, 1H), 3.633-3.659 (m, 1H), 3.448-3.518 (m, 1H), 2.775-2.841 (m, 2H), 2.205-2.312 (m, 1H), 1.829-1.859 (m, 2H), 1.501-1.521 (m, 1H). Step 9. To a solution of compound A4-9 (254 g, 0.84 mmol, 1.0 eq) in methanol (20 mL), was added 10% Pd/C (0.15 g,50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrates was concentrated under vacuum, and compound A4-10 was obtained as yellow oil (230 mg, yield 100%). MS-ESI:[M+1]+: 273.1 Step 10. A solution of D-Lactamide (388 mg, 4.2 mmol, 5.0 eq) and Et3O—BF4(1.3 g, 6.72 mmol, 8.0 eq) in THF (10 mL) was stirred for 30 mins at room temperature in nitrogen atmosphere. Then the above solution was added to the mixture of compound A4-10 (230 mg, 0.84 mmol, 1.0 eq) in ethanol (10 mL). After stirring for 3 hrs at 85° C. until HPLC showed the reaction was complete, the mixture was concentrated, added water and extracted four times with ethyl acetate. The organic phases was discarded and the aqueous phase was treated with saturated sodium bicarbonate solution to pH 8, extracted twice with ethyl acetate. The second organic phases was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as light-yellow powder (120 mg, yield 43.8%). MS-ESI: [M+1]+: 327.6, 1H NMR (300 MHz, CDCl3): 9.039 (s, 1H), 7.939 (d, 1H), 7.196 (d, 1H), 5.235-5.336 (m, 1H), 4.806-4.973 (m, 1H), 4.403-4.483 (t, 1H), 4.096-6.116 (m, 2H), 2.700-2.807 (m, 4H), 2.105-2.312 (m, 2H), 1.830-1.852 (d, 3H). Example 5: Synthesis of 3-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d] pyridin-1-yl]-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (5) Step 1. To a solution of compound A1-14 (prepared as step 4 to 12 in example 1) (820 mg, 4.13 mmol, 1.0 eq) in n-butanol (15 mL), was added compound A5-3 (1.0 g, 5.37 mmol, 1.3 eq) and DIPEA (1.6 g, 12.4 mmol, 3.0 eq). The reaction mixture was stirred for 1 hr at 135° C., concentrated and purified by silica gel column chromatography to give compound A5-4 as yellow powder (1.32 g, yield 91.8%). MS-ESI:[M+1]+: 349.1 Step 2. To a solution of compound A5-4 (1.32 g, 3.8 mmol, 1.0 eq) in DCM (15 mL), was added a solution of HCl in ethanol (30% w/w) (15 mL). The reaction mixture was stirred for 2 hrs at room temperature until TLC showed the reaction was complete, then concentrated under vacuum. Ice-water (20 mL) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/L) to pH 10. Then the aqueous phase was extracted three times with DCM. The combined extracts was dried over anhydrous sodium sulfate, concentrated to give compound A5-5 as yellow powder (950 mg, yield 100%). MS-ESI:[M+1]+: 249.1 Step 3. A mixture of 2,2,2-trifluoroethylamine (A5-1) (1.21 g, 12.2 mmol, 1.0 eq) and pyridine (2.4 g, 30.5 mmol, 2.5 eq) in DCM (50 mL) was cooled to 0° C., and treated with triphosgene (1.34 g, 4.52 mmol, 0.37 eq) in DCM (50 mL) dropwise below 5° C. After addition, the reaction mixture was stirred at 35° C. for 1 hr and then 25° C. for 2 hrs. The isocyanate (A5-2) solution was used for next step without purification. Step 4. A mixture of compound A5-5 (0.95 g, 3.8 mmol, 1.0 eq) and pyridine (0.45 g, 5.7 mmol, 1.5 eq) in DCM (60 mL) was cooled to 10° C., and treated with the isocyanate (A5-2) solution (12.2 mmol, 3.2 eq) dropwise. The reaction mixture was heated to reflux for 3 h, and then cooled. Saturated sodium bicarbonate solution (200 mL) was added, the mixture was extracted twice with DCM. The combined extracts was washed brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A5-6 as yellow powder (850 mg, yield 60%). MS-ESI:[M+1]+: 374.3 1H NMR (300 MHz, d6-DMSO): 9.282 (s, 1H), 8.718 (d, 1H), 7.962 (d, 1H), 7.024 (d, 1H), 5.165-5.186 (m, 1H), 4.642 (m, 1H), 3.926-4.008 (m, 3H), 3.517-3.675 (m, 3H), 2.502-2.568 (m, 1H), 2.206-2.267 (m, 2H). Step 5. To a solution of compound A5-6 (850 mg, 2.28 mmol, 1.0 eq) in methanol (80 mL), was added 10% Pd/C (0.45 g, 50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrate was concentrated under vacuum, and compound A5-7 was obtained as brown oil (800 mg, yield 100%). MS-ESI:[M+1]+: 344.3 Step 6. A solution of D-Lactamide (1.27 g,13.68 mmol,6.0 eq) and Et3O—BF4 (3.53 g, 18.24 mmol, 8.0 eq) in THF (20 mL) was stirred 30 min at room temperature in nitrogen atmosphere. Then the above solution was added to the mixture of compound A5-7 (800 mg, 2.28 mmol, 1.0 eq) in ethanol (20 mL). After stirring for 5 hrs at 85° C. until HPLC showed the reaction was complete, the mixture was concentrated, added HCl (1 mol/L, 30 mL) and extracted four times with ethyl acetate. The organic phases was discarded and the aqueous phase was treated with saturated sodium bicarbonate solution to pH 8, extracted three times with ethyl acetate. The second organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as light-yellow powder (530 mg, yield 58.5%). MS-ESI:[M−1]: 396.5. 1H NMR (300 MHz, d6-DMSO): 8.931 (s, 1H), 8.338 (d, 1H), 7.276 (d, 1H), 7.007 (m, 1H), 5.889-5.910 (m, 1H), 5.661-5.683 (m, 1H), 5.251-5.273 (m, 2H), 3.652-3.970 (m, 5H), 3.435-3.505 (m, 1H), 2.455-2.712 (m, 2H), 1.672 (d, 3H). Example 6: Synthesis of (R)-4-[2-(1-Hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide (6) The procedures are similar to those in Example 5 to produce the title compound as an off-white powder (21 mg, Yield:6.7%), MS-ESI:[M−1]−:410.6. 1H NMR (300 MHz, CD3OD): 8.862 (s, 1H), 8.046 (d, 1H), 7.150 (d, 1H), 5.152-5.383 (m, 2H), 4.325-4.386 (m, 2H), 3.990-4.022 (m, 2H), 3.110-3.192 (m, 2H), 2.423-2.653 (m, 2H), 1.984-2.117 (m, 2H), 1.793-1.915 (d, 3H). Example 7: Synthesis of 2-[(2R,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (7) Step 1. In nitrogen atmosphere, to a solution of compound A1-14 (500 mg, 2.0 mmol, 1.0 eq) in butyl alcohol (8 mL), were added compound A4-8 (350 mg, 2.5 mmol, 1.0 eq) and DIPEA (403 mg, 8.25 mmol, 3.3 eq). The reaction mixture was stirred 2 hrs at 135° C., then concentrated and purified by silica gel column chromatography to give compound A4-9 as yellow solid (194 mg, yield 25.6%). MS-ESI:[M+1]+: 302.3 Step 2. To a solution of compound A4-9 (97 mg, 1.0 mmol) in methanol (15 mL), was added 10% Pd/C (50 mg, 50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrate was concentrated to give compound A4-10 as yellow oil (535 mg, yield: 100%). MS-ESI: [M+1]+: 272.5 Step 3. A solution of glycolamide (126 mg, 1.6 mmol, 5.0 eq) and Et3O—BF4 (310 mg, 1.6 mmol, 5.0 eq) in THF (10 mL) was stirred 30 mins at room temperature in nitrogen atmosphere. Then the above solution was added to the mixture of compound A4-10 (88 mg, 0.32 mmol, 1.0 eq) in ethanol (10 mL). After stirring 12 hrs at 85° C., the mixture was concentrated, added water and extracted three times with ethyl acetate. The organic phases were discarded and the aqueous phase was treated with saturated sodium bicarbonate solution (100 mL) to pH: 8, then the mixture was extracted twice with ethyl acetate. The second organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as an off-white powder (70 mg, yield: 70%). MS-ESI: [M+1]+: 313.5 1H NMR (300 MHz, CDCl3): 9.00 (s, 1H), 7.95 (d, 1H), 7.26 (d, 1H), 5.27-5.29 (m, 1H), 4.76-4.84 (m, 1H), 2.78-2.86 (m, 1H), 2.43-2.52 (m, 4H), 2.06-2.19 (m, 2H), 1.91-2.00 (m, 2H), 1.76-1.84 (d, 3H). Example 8: Synthesis of 2-[(2S,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (8) Step 1. In nitrogen atmosphere, to a solution of compound A1-14 (500 mg, 2.0 mmol, 1.0 eq) in butyl alcohol (8 mL), were added compound A4-8 (350 mg, 2.5 mmol, 1.0 eq) and DIPEA (403 mg, 8.25 mmol, 3.3 eq). The reaction mixture was stirred 2 hrs at 135° C., then concentrated and purified by silica gel column chromatography to give compound A8-1 as yellow solid (67 mg, yield 8.84%). MS-ESI:[M+1]+: 302.3 Step 2. To a solution of compound A8-1 (67 mg, 1.0 mmol) in methanol (10 mL), was added 10% Pd/C (30 mg, 50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrate was concentrated to give compound A8-2 as yellow oil (60 mg, yield: 100%). MS-ESI: [M+1]+: 272.5 Step 3. A solution of glycolamide (105 mg, 1.33 mmol, 6.0 eq) and Et3O—BF4(258 mg, 1.33 mmol, 6.0 eq) in THF (10 mL) was stirred 30 mins at room temperature in nitrogen atmosphere. Then the above solution was added to the mixture of compound A8-2 (60 mg, 0.221 mmol, 1.0 eq) in ethanol (10 mL). After stirring 12 hrs at 85° C., the mixture was concentrated, added water and extracted three times with ethyl acetate. The organic phases was discarded and the aqueous phase was treated with saturated sodium bicarbonate solution (100 mL) to pH: 8, then the mixture was extracted twice with ethyl acetate. The second organic phases was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as an off-white powder (21 mg, yield: 30.5%). MS-ESI: [M+1]+: 313.5 1H NMR (300 MHz, CD3OD): 8.85 (s, 1H), 8.29 (d, 1H), 7.18 (d, 1H), 4.98 (d, 3H), 4.35-4.42 (m, 2H), 3.95-3.99 (m, 1H), 3.48-3.65 (m, 1H), 3.04-3.11 (m, 1H), 2.67-2.76 (m, 1H), 1.97-2.31 (m, 3H). Example 9: Synthesis of 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d] pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (9) In nitrogen atmosphere, a solution of compound A4-10 (1.1 g, 4.04 mmol, 1.0 eq) and trimethyl ortho-propionate (2.2 mL) in 1,2-dichloroethane (50 mL) was heated to reflux, and then added pyridine hydrochloride (200 mg). The reaction mixture was stirred 2 hrs at 80° C., concentrated, and treated with saturated sodium bicarbonate solution to pH: 8. The mixture was and extracted twice with ethyl acetate. The combined organic phases was dried over anhydrous sodium sulfate, concentrated purified by silica gel column chromatography to give the title compound as a yellow solid (800 mg, yield: 63.8%). MS-ESI: [M+1]+: 311.0 1H NMR (300 MHz, CDCl3): 9.01 (s, 1H), 7.91 (d, 1H), 7.17 (d, 1H), 4.54-4.59 (m, 1H), 4.33-4.38 (t, 1H), 4.05-4.09 (m, 2H), 3.01-3.06 (m, 2H), 2.70-2.83 (m, 3H), 2.15-2.19 (m, 2H), 1.85-1.92 (m, 1H), 1.49-1.54 (t, 3H). Example 10: Synthesis of 2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d] pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (10) In nitrogen atmosphere, to a solution of compound A4-10 (136 mg, 0.5 mmol, 1.0 eq) in trimethyl ortho-formate (5.0 mL), was added formic acid (1.0 mL). The reaction mixture was stirred 1 hr at 80° C., concentrated, and treated with saturated sodium bicarbonate solution (100 mL) to pH: 8. The mixture was and extracted twice with ethyl acetate. The combined organic phases was dried over anhydrous sodium sulfate, concentrated purified by silica gel column chromatography to give the title compound as a yellow solid (400 mg, yield: 28.4%). MS-ESI: [M+1]+: 282.9 1H NMR (300 MHz, CDCl3): 9.10 (s, 1H), 7.94 (s, 1H), 7.92 (d, 1H), 7.19 (d, 1H), 4.76-4.79 (m, 1H), 4.32-4.37 (m, 1H), 3.92-4.03 (m, 2H), 2.71-2.73 (d, 2H), 2.46-2.51 (m, 2H), 2.17-2.21 (m, 1H), 1.89-1.91 (m, 1H). Example 11: Synthesis of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b]imidazo [4,5-d] pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (11) In nitrogen atmosphere, a solution of compound A4-10 (1.0 g, 3.67 mmol, 1.0 eq) and trimethyl ortho-acetate (2.0 mL) in 1,2-dichloroethane (30 mL) was heated to reflux, and then added pyridine hydrochloride (200 mg). The reaction mixture was stirred 2 hrs at 80° C., concentrated, and treated with saturated sodium bicarbonate solution to pH: 8. The mixture was and extracted twice with ethyl acetate. The combined organic phases was dried over anhydrous sodium sulfate, concentrated purified by silica gel column chromatography to give the title compound as yellow solid (500 mg, yield: 46.0%). MS-ESI: [M+1]+: 296.9 1H NMR (300 MHz, CDCl3): 8.98 (s, 1H), 7.91 (d, 1H), 7.16 (d, 1H), 4.54-4.59 (m, 1H), 4.31-4.38 (t, 1H), 4.02-4.09 (m, 2H), 2.71-2.82 (m, 6H), 2.15-2.22 (m, 2H), 1.85-1.92 (m, 1H). Biological Test Example B1: Jak1, 2, 3, Tyk2 Biochemical Assays Assays were performed by Reaction Biology Corp, Malvern, Pa. The procedure is briefly described below. Reagent: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Required cofactors are added individually to each kinase reaction Reaction Procedure: 1. Prepare indicated substrate in freshly prepared Base Reaction Buffer 2. Deliver any required cofactors to the substrate solution above 3. Deliver indicated kinase into the substrate solution and gently mix 4. Deliver compounds in DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), incubate for 20 minutes at room temperature 5. Deliver33P-ATP (specific activity 10 μCi/μl) into the reaction mixture to initiate the reaction. 6. Incubate kinase reaction for 2 hours at room temperature 7. Reactions are spotted onto P81 ion exchange paper 8. Detect kinase activity by filter-binding method. Activities of compounds are summarized below based on the range of IC50: +: >1 μM; ++: 0.1-1 μM; +++: 10-100 nM; ++++: <10 nM; NT: not tested. Examples 3, 4, 7, 9 are potent and selective Jak1 inhibitors. ExampleJak1Jak21++NT2++NT3++++++4++++++5++6++7++++++8+++9++++++11+++++++ Example B2: Human Whole Blood p-STAT3 Assay Materials and Reagents: 1. Whole blood samples from human donors 2. IL-6 (R&D systems; Cat #206-IL) 3. Thrombopoietin (TPO; R&D systems; Cat #288-TP) 4. Red Blood Cell Lysis Buffer (Qiagen, Cat #79217) 5. ELISA kit for pSTAT3 (Invitrogen; Cat # KH00481) Instruments: 1. Centrifuge 2. Envision; absorbance at 450 nm Procedure: 1. 150 μl heparinized blood sample/tube. 2. Compounds at various concentrations is added to the blood, incubate for 10 min at RT (10 doses, 2 replicates for each compound). 3. Add IL-6 (final concentration: 100 ng/ml) or TPO (final conc: 50 ng/ml) to the blood for 15 min. 4. After the stimulation, add 0.6 mL RBC lysis buffer (Qiagen 79217) and mix and rock for 1-2 minutes at room temperature before centrifugation to remove lyzed RBCs. This step may be repeated once if RBCs are not lyzed completely. Harvest the WBCs. 5. Add 200 μl cell lysis buffer, ice 30 min. 6. Centrifuge at 16,000 g, 10 min, 4° C. 7. Transfer the supernatant to a new tube as cell lysate. 8. Run ELISA procedure according to the product instruction of ELIA kit. In these assays, Examples 3, 4 and 7 showed selective inhibition of IL-6 induced STAT3 phosphorylation, but not TPO induced STAT3 phosphorylation as shown below based on the range of IC50: +: >100 μM; ++: 20-100 μM; +++: 5-20 μM; ++++: <5 μM. Example 11 also showed some activity in the TPO induced STAT3 phosphorylation assay. ExampleIL-6TPO3+++++4+++++7+++++11++++++ | 102,228 |
RE49835 | DEFINITIONS Allele: The term “allele” as used herein refers to a genetic variation associated with a gene or a segment of DNA, i.e., one of two or more alternate forms of a DNA sequence occupying the same locus. Amplicon/amplification product/amplified sequence: The terms “amplicon,” “amplification product” and “amplified sequence” are used interchangeably herein and refer to a broad range of techniques for increasing polynucleotide sequences, either linearly or exponentially and can be the product of an amplification reaction. An amplicon can be double-stranded or single-stranded, and can include the separated component strands obtained by denaturing a double-stranded amplification product. In certain embodiments, the amplicon of one amplification cycle can serve as a template in a subsequent amplification cycle. Exemplary amplification techniques include, but are not limited to, PCR or any other method employing a primer extension step. Other nonlimiting examples of amplification include, but are not limited to, ligase detection reaction (LDR) and ligase chain reaction (LCR). Amplification methods can comprise thermal-cycling or can be performed isothermally. In various embodiments, the term “amplification product” and “amplified sequence” includes products from any number of cycles of amplification reactions. Amplify: As used herein, “amplify” refers to the process of enzymatically increasing the amount of a specific nucleotide sequence. This amplification is not limited to but is generally accomplished by PCR. As used herein, “denaturation” refers to the separation of two complementary nucleotide strands from an annealed state. Denaturation can be induced by a number of factors, such as, for example, ionic strength of the buffer, temperature, or chemicals that disrupt base pairing interactions. As used herein, “annealing” refers to the specific interaction between strands of nucleotides wherein the strands bind to one another substantially based on complementarity between the strands as determined by Watson-Crick base pairing. It is not necessary that complementarity be 100% for annealing to occur. As used herein, “extension” refers to the amplification cycle after the primer oligonucleotide and target nucleic acid have annealed to one another, wherein the polymerase enzyme catalyzes primer extension, thereby enabling amplification, using the target nucleic acid as a replication template. Detecting: The terms “detecting” and “detection” are used in a broad sense herein and encompass any technique by which one can determine the presence of or identify a nucleic acid sequence. In some embodiments, detecting comprises quantitating a detectable signal from the nucleic acid, including without limitation, a real-time detection method, such as quantitative PCR (“Q-PCR”). In some embodiments, detecting comprise's determining the sequence of a sequencing product or a family of sequencing products generated using an amplification product as the template; in some embodiments, such detecting comprises obtaining the sequence of a family of sequencing products. In other embodiments detecting can be achieved through measuring the size of a nucleic acid amplification product. Locus-specific allelic DNA size marker: The term “locus-specific allelic DNA size marker” as used herein refers to a nucleic acid size standard for one or more alleles for a particular STR locus or marker. Those of skill in the art may variably refer to this as an “allelic ladder.” The allelic ladder serves as a reference standard and nucleic acid size marker for the amplified alleles from the locus. In some embodiments, the allelic ladder can comprise size standards for the alleles of different STRs. In some embodiments, the allelic ladder can be made of DNA. In some embodiments, the allelic ladder can be made of non-naturally occurring nucleic acid analogs. The different individual size standards within an allelic ladder can, in some embodiments, be labeled with a detectable label, e.g., a fluorophore. In some embodiments, the allelic ladder components are labeled with the same fluorophore. In some embodiments, the allelic ladder components are labeled with different fluorophores. The size standards can be selected to work for a specific pair (or pairs) of oligonucleotides primers. For example, if a first set of primers for marker X with a tetranucleotide repeat produces a 150 base pair amplicon corresponding to allele 1, the corresponding allelic ladder component will serve as a size standard for the 150 base amplicons; while a second pair of primers for marker X produces a 154 base pair amplicon corresponding to allele 2, the corresponding allelic ladder component will serve as a size standard for the 154 base amplicons. Thus different size standards for different size amplicons of the same marker are contemplated. The size standard for a given amplicon derived from a given allele may have nucleic acid base sequence that is the same or different than the nucleic acid base sequence of the amplicon or allele from which the amplicon is derived. For allele analysis in electrophoresis systems the size standard can be selected so as to have the same electropheretic mobility as the amplicon of interest. Alternatively, in some embodiments, the size standard can be selected so as to have different electropheretic mobility than the amplicon of interest, given an understanding of the predicable nature of the difference; the identity of the amplicons could be determined. For allele analysis in mass spectroscopy systems the size standard (weight/charge ratio, not electropheretic mobility) can be selected so as to have the same signal as the amplicon of interest. Alternatively, in some embodiments, the size standard (weight/charge ratio, not electropheretic mobility) can be selected so as to have the different separation properties than the amplicon of interest, given an understanding of the predicable nature of the difference, the identity of the amplicons could be determined. Primer: The term “primer” refers to a polynucleotide (oligonucleotide) and analogs thereof that are capable of selectively hybridizing to a target nucleic acid or “template”, a target region flanking sequence or to a corresponding primer-binding site of an amplification product; and allows the synthesis of a sequence complementary to the corresponding polynucleotide template, flanking sequence or amplification product from the primer's 3′ end. Typically a primer can be between about 10 to 100 nucleotides in length and can provide a point of initiation for template-directed synthesis of a polynucleotide complementary to the template, which can take place in the presence of appropriate enzyme(s), cofactors, substrates such as nucleotides (dNTPs) and the like. Amplification Primer/Oligonucleotide primer: As used herein, the terms “amplification primer” and “oligonucleotide primer” are used interchangeably and refer to an oligonucleotide, capable of annealing to an RNA or DNA region adjacent a target sequence, and serving as an initiation primer for DNA synthesis under suitable conditions well known in the art. Typically, a PCR reaction employs an “amplification primer pair” also referred to as an “oligonucleotide primer pair” including an “upstream” or “forward” primer and a “downstream” or “reverse” primer, which delimit a region of the RNA or DNA to be amplified. A first primer and a second primer may be either a forward or reverse primer and are used interchangeably herein and are not to be limiting. STR Marker/STR Locus: As used herein the terms “STR marker” and “STR locus”, and their plural forms, are used to describe one of a set of marker loci suitable for use in genotyping using the method of the present invention. In particular: “18-3” refers to the STR marker on mouse chromosome 18, corresponding to base pairs 60271556-60271705 (NCBI 38.1 mouse build, corresponding to GenBank Accession # NT_039674.8) (SEQ ID NO: 1) (REPEAT MOTIF: [ATCT]n); “4-2” refers to the STR marker on mouse chromosome 4, corresponding to base pairs 82068280-82068580 (NCBI 38.1 mouse build, corresponding to GenBank Accession # NT_187032.1) (SEQ ID NO: 2) (REPEAT MOTIF: [GATA]n[GATG]n[ATAG]n; “6-7” refers to the STR marker on mouse chromosome 6, corresponding to base pairs 51601265-51601685 (NCBI 38.1 mouse build, corresponding to GenBank Accession # NT_039353.8) (SEQ ID NO: 3) (REPEAT MOTIF: [CTAT]n); “9-2” refers to the STR marker on mouse chromosome 9, corresponding to base pairs 74395400-74395000 (NCBI 38.1 mouse build, GenBank Accession # NT039474.8) (SEQ ID NO: 4) (REPEAT MOTIF: [TAGA]n[AGAT]n); “15-3” refers to the STR marker on mouse chromosome 15, corresponding to base pairs 4930200-4930500 (NCBI 38.1 mouse build, GenBank Accession # NT_039617.8) (SEQ ID NO: 5) (REPEAT MOTIF: [TAGA]n); “6-4” refers to the STR marker on mouse chromosome 6, corresponding to base pairs 142021975-142022270 (NCBI 38.1 mouse build, GenBank Accession # NT_039360.8) (SEQ ID NO: 6) (REPEAT MOTIF: [ATAG]n[ATGA]n[TAGA]n); “12-1” refers to the STR marker on mouse chromosome 12, corresponding to base pairs 38480950-38481170 (NCBI 38.1 mouse build, GenBank Accession # NT_039548.8) (SEQ ID NO: 7) (REPEAT MOTIF: [AGAT]n[GATA]n); “5-5” refers to the STR marker on mouse chromosome 5, corresponding to base pairs 112641540-112641820 (NCBI 38.1 mouse build, GenBank Accession # NT_109320.5) (SEQ ID NO: 8) (REPEAT MOTIF: [TATC]n); and “X-1” refers to the STR marker on mouse chromosome X, corresponding to base pairs 110959842-110960080 (NCBI 38.1 mouse build, GenBank Accession # NT_039706.8) (SEQ ID NO: 9) (REPEAT MOTIF: [ATAG]n[ATGA]n[TAGA]n). Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which these teachings belong. All patents, patent applications, published applications, treatises and other publications referred to herein, both supra and infra, are incorporated by reference in their entirety. If a definition and/or description is set forth herein that is contrary to or otherwise inconsistent with any definition set forth in the patents, patent applications, published applications, and other publications that are herein incorporated by reference, the definition and/or description set forth herein prevails over the definition that is incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present teachings are not entitled to antedate such publication by virtue of prior disclosure. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure relates to a method and kit for mouse cell line authentication. The method and kit disclosed herein target tetranucleotide repeats in the mouse genome including primers that amplify nine mouse short tandem repeat (STR) markers. Based on unique profiles obtained from seventy-two (72) mouse samples, the allele distribution for each short tandem repeat (STR) marker was determined. Correlations between allele fragment length and repeat number were confirmed with sequencing. The STR markers may be stable up to passage forty-five in L929 and NIH3T3 cell lines as there were no significant differences in fragment length in samples of low passage when compared to high passage samples. Primer sets for two human STR markers were incorporated into the multiplex method and kit to facilitate detection of human cell line contaminants. Adoption of this simple method and kit would provide assurance in cell line identity for researchers and cell repositories. The method and kit provide a unique STR profile for each individual mouse sample and can be used to authenticate mouse cell lines. Target STR markers were chosen for each chromosome, including the X and Y chromosomes, by searching for tetranucleotide repeat sequences (AGAT and TCTA) within the mouse genome using the National Center for Biotechnology Information (NCBI) BLAST program Primers were tested to meet three requirements. First, the locus must be present in every sample tested. Second, the locus must contain a tetranucleotide repeat. Third, primers for each marker must amplify products in a functional multiplex. Two markers were located on mouse chromosome six; however, they were 90 megabases (Mb) apart and on opposite arms of the chromosome and were considered unlinked. In humans, markers that are over 50 Mb apart have been considered unlinked. Two well-characterized human STR markers, D8S1106 and D4S2408, may be included in the multiplex kit (sometimes referred to hereinafter as an “assay”). These markers may be used to screen for contamination of mouse cell lines with human or African green monkey cell lines. Both human STR markers can be used to identify human and African green monkey cell lines (e.g., Vero cells). Primer3 software, available online from the Massachusetts Institute of Technology, may be used to design PCR primers to flank the STR regions by inputting the downloaded mouse sequences from the NCBI BLAST program. The parameters for Primer3 were set to target primers with annealing temperatures of 60° C. AUTODIMER™ software was used to assess primer-dimer interactions and hairpin structures of possible primer combinations to be used in the multiplex. Forward primers were labeled with one of the following fluorescent dyes at the 5′ end: 6FAM™ (blue), VIC™ (green), NED™ (yellow), or PET™ (red) (Applied Biosystems, Foster, Calif.). In some cases, an additional guanine base (G) or a “PIGtail” sequence (GTTTCTT) was added to the 5′ end of the unlabeled reverse primers to promote complete adenylation. Referring now toFIG.1, illustrated is a table showing the primers used for STR amplification and their corresponding chromosomal locations. InFIG.1, mouse chromosomal locations, or base pairs (bp), are based on NCBI BLAST 38.1 mouse build. Chromosomal locations for human STR markers D8S1106 and D4S2408 are based on the NCBI 37.3 human build. Primer concentrations in the rightmost column are final concentrations of forward and reverse primers in a 20 μL reaction volume. Primer concentrations were determined empirically based on peak height, DNA concentration and the number of cycles in the PCR program. Based onFIG.1, the exemplary amplification primers are set forth below. In order to specifically amplify the selected STR markers, the following oligonucleotide primer pairs were used, where “F” and “R” correspond to the forward and reverse primers respectively. The PCR is the product expected from amplification of the particular STR locus to which the oligonucleotide pair was directed. 18-3:(SEQ ID NO: 10)F-TCTTTCTCCTTTTGTGTCATGC(SEQ ID NO: 11)R-GTTTCTTGCTAAATAACTAAGCAAGTGAACAGA(SEQ ID NO: 1)Primer4-2:(SEQ ID NO: 12)F-AAGCTTCTCTGGCCATTTGA(SEQ ID NO: 13)R-GTTCATAAACTTCAAGCAATGACA(SEQ ID NO: 2)Primer6-7:(SEQ ID NO: 14)F-AGTCCACCCAGTGCATTCTC(SEQ ID NO: 15)R-GTTTCTTCATGTGGCTGGTATGCTGTT(SEQ ID NO: 3)Primer9-2:(SEQ ID NO: 16)F-GGATTGCCAAGAATTTGAGG(SEQ ID NO: 17)R-GTTTCTTTCCTGAGTTGTGGACAGGGTTA(SEQ ID NO: 4)Primer15-3 :(SEQ ID NO: 18)F-TCTGGGCGTGTCTGTCATAA(SEQ ID NO: 19)R-GTTTCTTTTCTCAGGGAGGAGTGTGCT(SEQ ID NO: 5)Primer6-4:(SEQ ID NO: 20)F-TTTGCAACAGCTCAGTTTCC(SEQ ID NO: 21)R-GTTTCTTAATCGCTGGCAGATCTTAGG(SEQ ID NO: 6)Primer12-1:(SEQ ID NO: 22)F-CAAAATTGTCATTGAACACATGTAA(SEQ ID NO: 23)R-GTTTCTTTCAATGGTCAAGAAATACTGAAGTACAA(SEQ ID NO: 7)Primer5-5:(SEQ ID NO: 24)F-CGTTTTACCTGGCTGACACA(SEQ ID NO: 25)R-GTTTCTTTGGTTTAAAACTCAATACCAAACAA(SEQ ID NO: 8)PrimerX-1:(SEQ ID NO: 26)F-GGATGGATGGATGGATGAAA(SEQ ID NO: 27)R-GTTTCTTAAGGTATATATCAAGATGGCATTATCA(SEQ ID NO: 9)PrimerD8S1106:(SEQ ID NO: 30)F-GTTTACCCCTGCATCATGG(SEQ ID NO: 31)R-GTTTCTTTCAGAATTGCTCATAGTGCAAGA(SEQ ID NO: 28)PrimerD4S2408:(SEQ ID NO: 32)F-TCATTTCCATAGGGTAAGTGAAAA(SEQ ID NO: 33)R-GTTTCTTGCCATGGGGATAAAATCAGA(SEQ ID NO: 29)Primer Genomic mouse DNA samples were obtained from Jackson Laboratories (Bar Harbor, Me., USA). These samples represent 48 common inbred strains used in the scientific community. The DNA included thirty-seven inbred mice DNA samples, one recombinant inbred mouse sample, and ten wild-derived mice DNA samples. DNA from 15 wild-caught mice (courtesy of Dr. Michael Nachman from the University of Arizona, USA) collected in Tucson, Ariz. was used for heterozygosity studies. Genomic DNA from mouse (male and female CD1/ICR), hamster (Syrian golden hamster, Chinese hamster), rat (Fischer, Wistar, Sprague Dawley), gerbil, pig, baboon, rhesus, and cynomolgus monkey were obtained from Zyagen (San Diego, Calif.). TN1 cells (stably transfected green fluorescent protein (GFP) expressing cell line derived from the parent NIH3T3 line) were originally obtained from the American Type Culture Collection, Manassas, Va., in 2003. The following cell lines were obtained from The American Type Culture Collection (ATCC, Manassas, Va.): NIH3T3 (CRL-1658), L-929 (CCL-1), MC3T3-E1 subclone 4 (CRL-2593), RAW 264.7 (TIB-71), M. dunni (CRL-2017), P3X63Ag8.653 (CRL-1580), HK-PEG-1 (CCL-189), Vero (CCL-81), HeLa (CCL-2), and CHO-K1 (CCL-61). DNA was quantified using the SYNERGY™ Mx plate reader and TAKE3™ plate (BioTek, Winooski, Vt., USA) at an absorbance of 260 nm. To study STR marker stability as passage number increased, duplicate 25 cm2tissue culture flasks of L929 cells were carried independently, and one million cells were harvested at passage numbers 2, 4, 9, 14, 19, 22, 26, 29, 31, 37, 41, and 44. Duplicate 25 cm2flasks were also carried for NIH3T3 cells which were carried independently, and one million cells were harvested from passage numbers 5, 7, 10, 15, 20, 23, 26, 32, 35, 40, 43, and 45. PCR amplification was performed on a VERITI™ thermal cycler (Applied Biosystems). The reaction mixture of 20 μL final volume contained 1 ng of mouse DNA (or 5 ng to 10 ng of non-mouse DNA for specificity studies), 1× GENEAMP® PCR Gold buffer (Applied Biosystems), 2 mM MgCl2(Applied Biosystems), 250 μM dNTPs (USB Corporation, Cleveland, Ohio, USA), forward labeled and reverse primers (as shown inFIG.1hereinabove), 1U AMPLITAQ GOLD™ DNA Polymerase (Applied Biosystems), and 0.16 mg/mL non-acetylated BSA (Invitrogen). PCR conditions for the multiplex assay are as follows: denaturation for 11 min at 95° C., amplification for 30 cycles of 45 s at 94° C., 2 min at 59° C., and 1 min at 72° C., followed by an extension for 60 min at 60° C., and a final soak at 25° C. Initial unlabeled primers and their respective PCR products were screened by using gel electrophoresis. PCR products (4 μL) were added to the Lonza 5× loading dye (1 μL), loaded onto a 2.2% agarose Flash Gel (Lonza) and run at 275 V for 5 min. Forward primers generating clean PCR products were ordered with a fluorescent dye at the 5′ end and were tested in monoplex reactions with mouse DNA from Jackson Laboratories, Zyagen, and mouse cell lines. Multiplex reactions were then optimized by varying primer combinations, primer concentrations, DNA concentration, and PCR cycle number. To analyze monoplex and multiplex PCR products, samples were prepared by adding 1 μL of amplified product and 0.3 μL of GENESCAN™ 500 LIZ internal size standard (Applied Biosystems) to 8.7 μL of HI-DI™ formamide (Applied Biosystems) for separation on the 16-capillary ABI 3130×1 Genetic Analyzer (Applied Biosystems). A five dye matrix was established under the G5 filter with dyes 6FAM, VIC, NED, PET, and LIZ. POP-4™ (Applied Biosystems) was used on a 36 cm capillary array (Applied Biosystems) with 1× ACE™ buffer (Amresco, Solon, Ohio, USA). Samples were injected electrokinetically for 10 s at 3 kV. The STR alleles were separated at 15 kV at a run temperature of 60° C. Data from the 3130×1 genetic analyzer was analyzed using the GENEMAPPER™ ID-X v1.1 Software (Applied Biosystems). Bins and panels were created in GENEMAPPER™ ID-X based on fragment length data generated from the fifty-seven mouse profiles using fixed bin allele sizes to determine allele calls. The allele distribution range for the human STR markers (D8S1106 and D4S2408) was previously described and adjustments were made to the size range to take into account the “PIGtail” sequence that was added to the reverse primers. Calibration of repeat number to allele fragment length was determined by DNA sequencing. Multiplex primers were used for sequencing STR markers, except for three loci (18-3, 9-2, and 12-1) where sequencing primers were used. Referring now toFIG.2, illustrated are the forward and reverse primers used to sequence each of the nine STR markers. Also shown inFIG.2are the corresponding annealing temperatures and amplicon sizes for these markers. At least four homozygous samples were sequenced for each STR locus to determine the corresponding number of repeats for each allele. The targeted repeat regions were amplified using 0.15 μM unlabeled forward and reverse primers using the PCR reaction specified herein in connection with PCR amplification with the following thermal cycling program: denaturation for 10 min at 95° C., amplification for 35 cycles of 1 min at 94° C., 1 min at 52-60° C. (annealing temperature specific to individual primers), and 1 min at 72° C., followed by an extension for 45 min at 60° C., and a final soak at 25° C. Samples were treated with 2 μL of EXOSAP-IT® PCR product cleanup (USB Corporation) per 5 μL of PCR product. This product cleanup was used to remove unincorporated primers and deoxyribonucleotide triphosphates (dNTPs) by incubating samples for 90 min at 37° C. followed by 20 min at 80° C. to inactivate the enzymes. Samples were then sent to Eurofins MWG Operon for sequencing using BIGDYE® Terminator v3.1 (Applied Biosystems). Resulting profiles were received after data analysis was performed by Eurofins MWG Operon. Mixture samples containing genomic DNA extracted from NIH3T3, RAW264.7, and HeLa cells were analyzed to assess the capability of the multiplex assay to detect low levels of contamination in NIH3T3 cells. DNA from NIH3T3 and RAW264.7 cells were added to individual reactions with a final concentration of 1 nanogram (ng) of total DNA in the following ratios 1:1, 2:1, 3:1, 5:1, 7:1, 9:1, and 10:1. Reciprocal reactions were also prepared using DNA from RAW264.7 and NIH3T3 cells. The same procedure was repeated using DNA from NIH3T3 and HeLa cells, followed by reciprocal reactions with DNA from HeLa and NIH3T3 cells. PCR amplification and PCR product analysis are described above. The heterozygosity (H) values were calculated by dividing the number of heterozygotes at a locus into the total number of individuals. The probability of identity (PI) was calculated by the summation of the square of the genotype frequencies. The probability of a random match (PM) for a full profile was calculated by multiplying the inverse of each genotype frequency for each marker. The coefficient of inbreeding (F), specifically the fixation in a subpopulation compared to the total population (FST) was determined by subtracting the average heterozygosity of the two subpopulations (wild-caught mice and inbred mice samples) from the total heterozygosity, divided by the total heterozygosity. The mouse primers targeting tetranucleotide repeat markers in the multiplex PCR assay were designed based on the annotated mouse genome from NCBI build 38.1 of Mus musculus origin. Fifty-seven genomic mouse DNA samples were tested using the multiplex assay and the designated allele range was determined for each marker, and fragment lengths were correlated to actual number of repeats using sequence analysis. Referring now toFIG.3, illustrated is a table defining STR fragment length and corresponding repeat number in accordance with the present disclosure. InFIG.4, fragment length in base pairs corresponds to apparent size based on LIZ GENESCAN® 500 size standard. The corresponding number of repeats are each shown just below the fragment length. The corresponding number of repeats was determined by the analysis of 57 mouse DNA samples. The correlation of the allele size and number of repeats was determined based on sequencing data. The mouse samples were selected to represent the genetic diversity of the mouse family tree. To determine the specificity of the multiplex assay, DNA was tested from several different species and subspecies of mice, near neighbors, and non-mouse samples. A panel of 57 mouse genomic DNA samples representing species from M. musculus musculus, M. musculus domesticus, M. musculus molossinus, M. musculus castaneus, M. spretus (Spain), and M. dunni were tested with the multiplex PCR primers to determine assay robustness. Full unique profiles amplified in the designated allele range were obtained from the panel for all but the following samples: CAST/EiJ (M. musculus castaneus), JF1/Ms (M. musculus molossinus), SPRET (M. spretus), and M. dunni cell line. DNA from CAST and JF1 mice resulted in amplicons for each marker. However, the PCR product was outside of the designated allele range for the 18-3 and 6-7 loci, respectively. Sequencing the CAST mouse DNA revealed that this sample has conserved sequence flanking the repeat region. However, fifty-two ATCT repeats were observed at this locus. Thus, twenty-nine more repeats were observed at this locus than in the designated allele range. Because of additional repeats present in the CAST mouse sample, the amplified product appears between STR markers 4-2 and 6-7. All M. musculus molossinus samples resulted in full profiles except for DNA from the JF1 mouse which amplified outside the designated allele range for marker 6-7. The additional thirty-two repeats that JF1 contains at the 6-7 locus may be explained in the origin of Mus musculus molossinus, a natural hybrid of M. m. musculus and M. m. castaneus, the latter shown to deviate from the designated allele range at marker 18-3. DNA from the SPRET mouse (M. spretus) results in amplicons that fall outside the designated allele range for the following loci: 18-3, 4-2, 15-3, and X-1. The SPRET sample was sequenced at the 18-3 locus resulting in sixty-six repeats, eleven of which were GTCT repeats embedded within the defined ATCT repeat for this marker. DNA extracted from the M. dunni cell line does not amplify at the 6-4 STR marker and falls outside the designated allele range for X-1. Further analysis of DNA from M. dunni and SPRET was not continued as their profiles were incomplete using the multiplex assay. Interestingly, CAST and SPRET are mapped together in group 2 in a published mouse family tree. However, full profiles within the allele range are observed for the other members in that group including PERC (M. m. domesticus), MOLG (M. m. molossinus), and MOLF (M. m. molossinus). A panel of rodent and porcine DNA (rat, hamster, gerbil, pig), human cell lines (HeLa, HEPM, SK-BR-3, MCF10A) and nonhuman primate DNA samples (Vero, COS-7, rhesus, baboon, cynomolgus monkey) were tested with the multiplex assay to determine assay specificity. None of these samples resulted in a complete profile using the primers targeting mouse STR markers. DNA from Wistar, Fischer, and Sprague-Dawley rats resulted in a single amplified product in the red dye channel; however, each sample resulted in an amplicon with a fragment length of 219 base pairs. Characteristic stutter peaks associated with polymerase slippage of repeat regions were absent in the rat samples. Lack of stutter peaks and identical amplicon sizes for each rat strain suggests the peak present is most likely a PCR artifact rather than amplification of a repeat region. Amplification products were absent for each mouse STR marker when DNA from human and African green monkey cell lines were tested. However, both cell lines amplified at the human STR markers (D8S1106 and D4S2408) present in the multiplex as expected. No significant amplicons were visible for pig, hamster, or gerbil DNA. SNP assays, commonly used to type mouse strains, are efficient in discriminating between different strains of mice, but may not be ideal in differentiating between cell lines derived from the same substrain. SNPs are mostly bi-allelic markers whereas STR markers typically have greater than five alleles. Using the mouse multiplex assay, unique profiles were obtained for the mouse cell lines listed inFIG.5with the capability of distinguishing between three Balb/c-derived cell lines.FIG.5is a table illustrating the complete genetic profiles of six mouse cell lines in accordance with the present disclosure. InFIG.4, the repeat numbers are listed for each locus. Microvariants are indicated by a decimal point. As shown inFIG.4, there are many conserved alleles between the three Balb/c-derived samples; however, there are sufficient differences resulting in unique profiles for each individual cell line. Two of the Balb/c-derived cell lines, mouse myeloma cells (P3X63Ag8.653) and hybridoma cells (HK-PEG-1), are very similar in their genotype, only varying by one allele at the 9-2 locus. The HK-PEG-f cell line was produced by fusing P3X63Ag8.653 (myeloma cells originating from a BALB/c mouse) with spleen cells from a BALB/c mouse, explaining why they share so many alleles. The myeloma cell line is heterozygous at the 9-2 locus whereas the hybridoma cell line is homozygous. To verify the presence of a null allele at the 9-2 marker, a panel of primers was tested with DNA from the hybridoma cells resulting in amplicons ranging from 132 to 244 base pairs (bp). Homozygote peaks were present in each sample, supporting the findings that these two cell lines differ by one allele at this marker. To test assay sensitivity and determine the lower limits of detection, DNA from NIH3T3, HeLa, and Vero cell lines was diluted from 6 nanograms (ng) to 7.8 picograms (pg). A full profile for NIH3T3 cells was obtained using 62 pg of DNA but resulted in a loss of an allele at one mouse STR markers at 31 pg of DNA. The two human STR markers were also tested and resulted in peaks above the analytical threshold (50 relative fluorescent units) for HeLa and Vero cell lines using 62 and 187 pg of DNA, but resulted in allelic drop-out at 31 and 93 pg of DNA, respectively. In previous studies, higher concentrations of Vero cell DNA (6 ng) were needed to obtain an STR profile using human STR markers when compared to human DNA (0.5-1 ng). This is consistent with the higher concentrations of Vero DNA needed in this study to amplify efficiently using the human STR markers in the multiplex assay. The multiplex assay described herein was designed to detect human or African green monkey cell line contamination of mouse cells by incorporating two human STR markers that amplify outside the designated allele ranges for the nine mouse STR markers. Mixture ratios ranging from 1:1 to 10:1 of NIH3T3 and HeLa DNA were tested to model contamination scenarios. Referring now toFIG.5, illustrated is a genetic profile of the NIH3T3 cell line using the multiplex assay of the present disclosure. An electropherogram depicting a pure NIH3T3 STR profile is shown in thisFIG.7. Referring now toFIG.6, illustrated is a human contaminant detected in the NIH3T3 STR profile. A 1:1 ratio of NIH3T3 and HeLa DNA is shown in thisFIG.8. Even at the lowest dilution of HeLa DNA (90 pg), human STR markers were detected above the analytical threshold. The assay can also be used to detect a mixture of multiple mouse cell lines. Referring now toFIG.7, illustrated is a genetic profile of the RAW 264.7 cell line using the mouse multiplex assay (1 ng DNA). This electropherogram depicts a pure RAW264.7 STR profile. Mixture ratios ranging from 1:1 to 10:1 of NIH3T3 and RAW264.7 DNA were tested and full profiles of both cell lines were present even at the lowest DNA dilution (90 pg). Referring now toFIG.8, illustrated is a mixture of NIH3T3 and RAW 264.7 mouse cell lines detected using the assay described herein.FIG.10shows a 1:1 mixture of the two mouse cell lines. The majority of mouse cell lines are derived from inbred mice resulting in alleles that are mostly homozygous in nature. For example, as shown earlier in connection withFIG.4, the RAW 264.7 mouse cell line is homozygous at each STR marker. Multiple alleles present at each locus could indicate a mixed population of cells. Triallelic patterns have been observed in some human cell lines at a particular locus, which may or may not be equal in intensity. The L929 cell line appears to have three alleles with similar peak height intensities at the 15-3 marker and each allele is four base pairs or one repeat apart. Since most of the mouse samples tested were homozygous for the majority of the markers, a panel of primers targeting the 15-3 locus were tested in monoplex with DNA from L929 cells. The amplicons ranged from 210 to 435 base pairs in length and each resulted in three alleles that were four bases apart with very little peak height imbalance. The evidence supports a true triallelic pattern at the 15-3 marker. Alteration of genetic profiles of some cancer cell lines has been observed previously at high passage numbers. However, other studies show STR stability over high passage numbers in some human cancer cell lines and in African green monkey cell lines. Accordingly, stability may be cell line dependent. To test the stability of the mouse STR markers in this assay, L929 and NIH3T3 cell lines were carried independently and in duplicate flasks up to passage 44 and 45, respectively. Genotypes were determined and standard deviations were calculated for each locus representing the variations in fragment lengths over all passage numbers. The NIH3T3 cell line resulted in the lowest standard deviation values (0.02-0.05) for each locus. The L929 cell line resulted in standard deviations ranging from 0.05 to 0.14. The STR markers with the highest standard deviations in L929 cells are 6-7 (0.14) and 5-5 (0.13). In both the NIH3T3 and L929 cell lines, even the highest standard deviation values did not result in an allele repeat number change indicating stable STR profiles at high passage numbers. The changes in fragment lengths for each marker over the passage period were not significant enough to change the allele calls and the variability in the amplicon sizes fell within the range of the instrument fluctuation. Identical DNA samples were tested on three different days using the same instrument and the variation in fragment length was ±0.3 base pairs. In addition to stability of the STR profile for NIH3T3 cells over time, profile stability was evaluated after transfection procedures. The TN1 cell line, derived from NIH3T3 cells obtained from ATCC in 2003 and engineered to express the gene for green fluorescent protein, was analyzed using the multiplex assay and resulted in identical STR profiles for both TN1 and recently obtained NIH3T3 cells. These data support the findings that the STR markers are stable over time in transfected NIH3T3 cell lines. The mouse multiplex assay described herein can be used to identify cell lines derived from M. musculus musculus and M. musculus domesticus species. The assay is also useful in identifying M. musculus molossinus and M. musculus castaneus species which amplify at each locus, but in some instances failed to fall within the designated allele range for one of the STR markers. This assay may not be suitable for genotyping mouse cell lines derived from M. spretus (amplicons may fall outside the designated allele range for four STR markers) or M. dunni which may fail to amplify at the 6-4 locus. Stability studies show the mouse STR markers are stable with high passage numbers and the STR profiles remain unchanged after transfection procedures in the TN1 cell line. Although the STR markers are stable up through passages 44-45, it may be desirable to genotype samples at low passage numbers. The power of discrimination based on the probability of a random match is 1 in 5.7 million using the nine STR markers in the multiplex assay. The assay described in the present disclosure can be used to identify both human and African green monkey cell line contaminants using the two human STR markers incorporated in the multiplex assay in addition to detecting mixtures of mouse cell lines. The targeted tetranucleotide repeat regions in the mouse genome result in unique individual profiles making this assay more sensitive and specific than those that are currently available. The requirement of cell line authentication is becoming more routine, and this assay provides a reliable method to genotype mouse cell lines. The STR profiles shown in the Table inFIG.9display the allele range for the 9 markers. This data could be used to develop a size reference standard that is a locus-specific allelic ladder. While the specification describes particular embodiments of the present invention, those of ordinary skill can devise variations of the present invention without departing from the inventive concept. | 37,104 |
RE49836 | DETAILED DESCRIPTION OF THE INVENTION As shown inFIG.2, this invention comprises a hanger1for connecting a held or supported member2to a holding or support member3. As shown inFIGS.1and2, in the preferred embodiment of the present invention, the hanger1consists of a seat member4adapted for supporting the held or supported member2. A first side portion5of the seat member4is connected to a lower portion9of a first side member7. An upper portion11of the first side member7is connected to a first back flange13. The first back flange13is adapted to be connected to the supporting member3by one or more fasteners15. A second side portion6of the seat member4is connected to a lower portion10of a second side member8. An upper portion12of the second side member8is connected to a second back flange14. The second back flange14is adapted to be connected to the supporting member3by one or more fasteners15. As shown inFIG.1, in the preferred embodiment, the hanger1consists of a continuous, non-overlapped single seat member4. In the preferred embodiment, the first side member7is integrally connected to a first side edge43of the seat member4. In the preferred embodiment, the second side member8is integrally connected to a second side edge44of the seat member4. As shown inFIG.3, in the preferred embodiment, the lower portion9of the first side member7is formed with an outer face19disposed away from the supported member2and the lower portion9of the first side member7is formed with an inner face17that is disposed toward the supported member2. In the preferred embodiment, the lower portion9of the first side member7is adapted so that at least portions of the inner face17of the lower portion9of the first side member7register with portions of a first side face21of the supported member2. In the preferred embodiment, the lower portion10of the second side member8is formed with an outer face20disposed away from the supported member2and the lower portion10of the second side member8is formed with an inner face18that is disposed toward the supported member2. In the preferred embodiment, the lower portion10of the second side member8is adapted so that at least portions of the inner face18of the lower portion10of the second side member8register with portions of a second side face22of the supported member2. As shown inFIG.1, in the preferred embodiment, openings45are provided in the lower portions9and10of the first and second side members7and8to receive fasteners16for attachment of the hanger1to the carried or supported member2. In the preferred embodiment, the fasteners16for attaching the first and second side members7and8to the supported member2are self-drilling, threaded fasteners. Also, preferably, these fasteners16are each formed with a head46, and when the fasteners16are driven into the supported member2the heads46of the fasteners16abut against the outer faces19and20of the lower portions9and10of the first and second side members7and8and the inner faces17and18of the lower portions9and10of the first and second side members7and8are pulled by the driving of the fasteners16towards the first and second side faces21and22of the supported member2. As shown inFIG.3, in the preferred embodiment, the lower portions9and10of the first and second side members7and8form a generally orthogonal angle with the seat member4, and are generally parallel to each other with the inner faces17and18of the lower portions9and10of the first and second side members7and8disposed towards each other and the outer faces19and20of the lower portions9and10of the first and second side members7and8disposed away from each other. As shown inFIG.1, in the preferred embodiment, the upper portion11of the first side member7is formed with an outer face25disposed away from the supported member2and the upper portion11of the first side member7is formed with an inner face23that is disposed toward the supported member2. In the preferred embodiment, the upper portion11of the first side member7is adapted so that the inner face23of the upper portion11of the first side member7does not register with portions of a first side face21of the supported member2. In the preferred embodiment, the upper portion12of the second side member8is formed with an outer face26disposed away from the supported member2and the upper portion12of the second side member8is formed with an inner face24that is disposed toward the supported member2. In the preferred embodiment, the upper portion12of the second side member8is adapted so that the inner face24of the upper portion12of the second side member8does not register with portions of a second side face22of the supported member2. As is best shown ifFIG.3, in the preferred embodiment, the inner face17of the lower portion9of the first side member7and the inner face23of the upper portion11of the first side member7form a reflex angle27that is greater than 180 degrees that is bounded by said inner face17of the lower portion9of the first side member7, sweeps through said supported member2when it is held by the hanger1and is bounded by the inner face23of the upper portion11of the first side member7. Similarly, in the preferred embodiment, the outer face19of the lower portion9of the first side member7and the outer face25of the upper portion11of the first side member7form an obtuse angle29that is bounded by said outer face19of the lower portion9of the first side member7, sweeps away from the hanger1and is bounded by the outer face25of the upper portion11of the first side member7. As is best shown inFIG.3, in the preferred embodiment, the inner face18of the lower portion10of the second side member8and the inner face24of the upper portion12of the second side member8form a reflex angle28that is greater than 180 degrees and is bounded by said inner face18of the lower portion10of the second side member8, sweeps through said supported member2when it is held by the hanger1and is bounded by the inner face24of the upper portion12of the second side member8. Similarly, in the preferred embodiment, the outer face20of the lower portion10of the second side member8and the outer face26of the upper portion12of the second side member8form an obtuse angle30that is bounded by said outer face20of the lower portion10of the second side member8, sweeps away from the hanger1, and is bounded by the outer face26of the upper portion12of the second side member8. As is best shown inFIG.5, in the preferred embodiment, the first back flange13is formed with an exposed face31and a registration or attachment face33. In the preferred embodiment, when the hanger1is attached to a supporting member3, a substantial portion of the registration face33of the first back flange13is adapted to register with an attachment face47of the supporting member3. In the preferred embodiment, the second back flange14is formed with an exposed face32and a registration or attachment face34. In the preferred embodiment, when the hanger1is attached to a supporting member3, a substantial portion of the registration face34of the second back flange14is adapted to register with the attachment face47of the supporting member3. In the preferred embodiment, openings48are provided in the first and second back flanges13and14to receive fasteners15for attachment of the hanger1to the holding or supporting member3. In the preferred embodiment, the fasteners15for attaching the first and second back flanges13and14to the supported member3are self-drilling, threaded fasteners. Also, preferably, these fasteners15are each formed with a head49, and when the fasteners15are driven into the supporting member3the heads49of the fasteners15abut against the exposed faces31and32of the first and second back flanges13and14and the registration faces33and34of the first and second back flanges13and14are pulled by the driving of the fasteners15towards the attachment face of the supporting member47. As shown inFIG.4, In the preferred embodiment, the first and second back flanges13and14are orthogonally disposed to the upper and lower portions9,10,11and12of the first and second side members7and8. Also, in the preferred embodiment, the exposed face31of the first back flange13and the inner face23of the upper portion H of the first side member7form a right angle35of 90 degrees that is bounded by the inner face23of the upper portion H of the first side member7and is bounded by the exposed face31of the first back flange13. Similarly, in the preferred embodiment, the registration face33of the first back flange13and the outer face25of the upper portion11of the first side member7form an angle37of 270 degrees that is bounded by the outer face25of the upper portion11of the first side member7sweeps through the supporting member3when the hanger1is attached to the supporting member3and is bounded by the registration33face of the first back flange13. Also, in the preferred embodiment, the exposed face32of the second back flange14and the inner face24of the upper portion12of the second side member8form a right angle36of 90 degrees that is bounded by the inner face24of the upper portion12of the second side member8and is bounded by the exposed face32of the second back flange14. Similarly, in the preferred embodiment, the registration face34of the second back flange14and the outer face26of the upper portion12of the second side member8form an angle of 270 degrees that is bounded by the outer face26of the upper portion12of the second side member8sweeps through the supporting member3when the hanger1is attached to the supporting member3and is bounded by the registration face34of the second back flange14. In the preferred embodiment, the first and second back flanges13and14are separate members that are not connected to each other except through their respective connections to the first and second side members7and8which are in turn connected to the seat member4. In the preferred embodiment, the first back flange13is formed with an opposing free edge51, and the second back flange14is formed with an opposing free edge52. In the preferred embodiment the opposing edges51and52of the first and second back flanges13and14are spaced apart from each other. As shown inFIG.2, in the preferred embodiment, the first and second side members7and8extend a substantial distance above the seat member4, providing substantial lateral support to the supported member2. In the preferred embodiment, the upper portions11and12of the first and second side members7and8are separated from and differentiated from the lower portions9and10of the first and second side members7and8by transverse bends39and40in the first and second side members7and8. In the preferred embodiment, these transverse bends39and40in the first and second side members7and8create reflex angles between 190 and 197 degrees between the inner faces17and23and18and24of the upper and lower portions9and11and10and12of the first and second side members7and8. As shown inFIG.3, in the preferred embodiment, the upper portions11and12of the first and second side members7and8extend a substantial distance away from the seat member4and above the transverse bends39and40that separate the upper portions11and12of the first and second side members7and8from the lower portions9and10of the first and second side members7and8. In the preferred embodiment, the portions of the first and second back flanges13and14that are disposed between the upper portions11and12of the first and second side flanges7and8and do not extend above the side flanges7and8are considered the lower portions41and42of the first and second back flanges13and14. In the preferred embodiment, the lower portions41and42of the first and second back flanges13and14between the upper portions11and12of the first and second side members7and8span a width53that is greater than the width54between the lower portions9and10of the first and second side members7and8. In the preferred embodiment, the upper portions11and12of the first and second side members7and8span a maximum selected width53, and the lower portions9and10of the first and second side members7and8span a second width54and the maximum selected width53between the upper portions11and12of the first and second side members7and8is greater than the width54between the lower portions9and10of the first and second side members7and8. In the preferred embodiment, the lower portions41and42of the back flanges13and14do not overlap each other, and the lower portions41and42are adapted to have multiple fasteners15driven through each of them into the supporting member3. In the preferred embodiment, the second back member14is parallel and substantially aligned with the first back member13. In the preferred embodiment, the lower portions41and42of the first and second back flanges13and14are only attached to the first and second side members7and8at the upper portions11and12of the first and second side members7and8above the transverse bend lines39and40. In the preferred embodiment, the lower portions41and42of the first and second back flanges13and14are connected to the upper portions11and12of the first and second side members7and8close to the transverse bends39and40in the first and second side members7and8. Preferably, the hanger1of the present invention is constructed from a single blank member of galvanized sheet steel (7 Gauge G90) without requiring any welding or painting. In the preferred embodiment, the hanger1is formed by bending along substantially straight bend lines and all bends have a radius of one thickness of the metal. In the preferred embodiment, the hanger1is designed for attachment to a vertically elongated member55that is part of the larger supporting member3such as a webbed truss. In the preferred embodiment, the vertically disposed, elongated member is a web member55of the truss. In the preferred embodiment, the vertically disposed, elongated member55of the supporting truss has a selected maximum width56for the receipt of fasteners15for attaching the hanger1to the supporting member. In the preferred embodiment, the first and second back flanges13and14are disposed a selected distance above the seat member4of the hanger1. When the supporting member3is a truss formed with a bottom chord57, a top chord and web members55connecting the top and bottom chords, it is desirable to not connect the hanger1to the bottom chord57of the truss3. In the preferred embodiment of the hanger1which is designed for attaching to a truss3having a bottom chord57from wood having a nominal height of 6″, the first and second back flanges13and14are preferably formed a selected distance above the seat member4and the lowest of the openings48in the first and second back members13and14for receiving a fastener15is disposed above 6″ from the seat member4. In the preferred embodiment the supporting member3and the supported member2are multi-ply girder trusses made from Southern Pine or an equivalent, and the fasteners used are Simpson Strong-Drive SDS ¼×3 fasteners. The minimum width of the vertical web member of the 55 of the supporting member3is nominally 6 inches in width as in a standard 2×6 piece of US lumber. The hanger1of the preferred embodiment is formed on an progressive die with minimal waste of the sheet metal from which the blanks are made by taking a sheet metal blank, bending the first and second side members7and8downwardly from the seat member4, bending the upper portions11and12of the first and second side members7and8upwardly from the lower portions9and10of the first and second side members7and8, and then bending the first and second back members13and14downwardly from the upper portions11and12of the first and second side members7and8. Openings45and48are provided in the hanger1for receiving fasteners15and16at designated points. | 15,758 |
RE49837 | DESCRIPTION OF EMBODIMENTS To make the objectives, technical solutions, and advantages of the embodiments of the present disclosure clearer, the following clearly describes the technical solutions in the embodiments of the present disclosure with reference to the accompanying drawings in the embodiments of the present disclosure. The described embodiments are some but not all of the embodiments of the present disclosure. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present disclosure without creative efforts shall fall within the protection scope of the present disclosure. FIG.1is a flowchart of Embodiment 1 of a method for identifying a device according to the present disclosure. As shown inFIG.1, the method for identifying a device according to this embodiment of the present disclosure may be executed by a control device. The control device may be implemented by using software and/or hardware. The method for identifying a device according to this embodiment includes Step101: The control device generates an identification identifier of a multimedia device according to device description information of the multimedia device, and sends the identification identifier to the multimedia device, so that the multimedia device displays the identification identifier. Step102: The control device acquires the identification identifier displayed by the multimedia device and an appearance image of the multimedia device, and acquires the device description information according to the identification identifier displayed by the multimedia device. Step103: The control device associates the device description information with the appearance image of the multimedia device, so that a user equipment identifies the multimedia device according to the appearance image. In this embodiment, the control device may be an interactive terminal device, such as a mobile phone, a notebook computer, or a tablet computer, that can take photos, can be networked, and supports wireless connection. The multimedia device may be an interactive device, such as a television, sound equipment, or a notebook computer, that can be networked and can output a video or audio. During a specific implementation process, before step101, the control device acquires the device description information and device capability information of the multimedia device; and the control device determines, according to the device description information and the device capability information, that the multimedia device is a video device or an audio device. The control device acquires the device description information of the multimedia device by using the Simple Service Discovery Protocol (SSDP), and there may be two possible cases. One possible case is that, when connected to a network, the control device may send an “ssdp:discover” message to an SSDP port at a specific multicast address, where the message includes a request for acquiring the device description information; and when the multimedia device obtains the message by listening, the multimedia device analyzes the request sent by the control device, and then returns a response with respect to the request sent by the control device, that is, returns the device description information. The other case is that, when connected to a network, the multimedia device sends an “ssdp:alive” message to an SSDP port at a specific multicast address, where the message includes the device description information. The device description information includes a series of general attributes of the multimedia device. The general attributes include a service, a device structure, a device attribute, for example, a UUID, an IP address, and a device type of the multimedia device. A value of a UUID for a same multimedia device is unique at different times. A form of a UUID may be as follows: uuid:d1578360-feb3-1167-1000- 2c27d742936c; a form of an IP address may be as follows: HOST:239.255.255.250:1900; and a form of a device type may be as follows: device:Media Renderer. For a specific form of other device description information, details are not described in this embodiment again After the control device discovers the multimedia device, the control device may invoke a UPnP acquire action (Get ProtrocolInfo( ) action) to acquire the device capability information. A packet of the device capability information that is of the multimedia device and is acquired by the control device may be shown as follows: <SinkProtocolInfo>http-get:*:image/jpeg:DLNA.ORG_PN=JPEG_SM,http-get:*:audio/mpeg:DLNA.ORG_PN=MP3,</SinkProtocolInfo> In the acquired device capability information, image represents an image, jpeg represents a format of an image file, audio represents a sound, and mpeg represents a format of an audio file. Persons skilled in the art may understand that the foregoing format of the packet of the device capability information is merely exemplary, and this embodiment is not limited thereto. The multimedia device may determine, according to the device description information and the device capability information, that the multimedia device is a video device or an audio device. For example, the device type is a media renderer and the device capability information is image/jpeg, it may be determined that the multimedia device is a video device; and if the device capability information is audio/mpeg, it may be determined that the multimedia device is an audio device. In step101, the control device generates an identification identifier of the multimedia device according to device description information of the multimedia device. During a specific implementation process, the control device may generate the identification identifier of the multimedia device according to the device description information of the multimedia device, where the device description information may be a UUID, an IP address, and a device type. The identification identifier may be a picture with a specific color, a two-dimensional code, a sound, a specific shape, or the like. Optionally, the control device generates the identification identifier of the multimedia device according to a UUID and an IP address of the multimedia device in the device description information of the multimedia device. After the identification identifier of the multimedia device is generated, the control device sends the identification identifier to the multimedia device, so that the multimedia device acquires the identification identifier. The control device sends a universal resource identifier (URI) of the identification identifier to the multimedia device, and the multimedia device may acquire the identification identifier according to the URI. In step102, the control device acquires the identification identifier displayed by the multimedia device and an appearance image of the multimedia device, and acquires the device description information according to the identification identifier displayed by the multimedia device. When the multimedia device is a video device, the control device may capture, in a manner of photographing or scanning, an identification identifier played by the video device; and when the multimedia device is an audio device, the control device may acquire, in a manner of recording by a microphone, an identification identifier played by the audio device, and then acquire the device description information according to a picture with a specific color, a two-dimensional code, a sound, a specific shape, or the like. In addition, the multimedia device acquires an appearance image of the multimedia device by using a camera, learns whether the media playback device is a video device or an audio device by means of an image recognition technology, and then learns appearance information such as a brand and a screen size of the multimedia device by analyzing the multimedia device. In step103, the control device associates the device description information with the appearance image of the multimedia device, so that a user equipment identifies the multimedia device according to the appearance image. During a specific implementation process, the device description information may be associated with the appearance image of the multimedia device in a manner of establishing a table, mapping, or binding, and association information is stored on the control device. Optionally, the control device may associate the UUID and the IP address in the device description information with the appearance image. When a user equipment needs to implement media content sharing between electronic devices on a home network, the user equipment may identify and select a multimedia device according to appearance images of multimedia devices displayed on the control device. Because an association relationship exists between an appearance image and device description information, after the user equipment identifies and selects the multimedia device according to the appearance images, the control device may directly acquire device description information of the multimedia device, and then establishes a connection with the multimedia device according to the device description information, thereby implementing media file sharing. In the method for identifying a device according to this embodiment of the present disclosure, a control device generates an identification identifier of a multimedia device according to device description information of the multimedia device, and sends the identification identifier to the multimedia device, so that the multimedia device displays the identification identifier; the control device acquires the identification identifier displayed by the multimedia device and an appearance image of the multimedia device, and acquires the device description information according to the identification identifier displayed by the multimedia device; and the control device associates the device description information with the appearance image of the multimedia device, so that a user equipment identifies the multimedia device according to the appearance image. In this way, a user equipment can correctly identify, only according to the appearance image of the multimedia device, the multimedia device corresponding to the appearance image, thereby improving convenience and correctness of device identification. The following uses several specific embodiments to describe, with respect to the video device and the audio device in the embodiment shown inFIG.1, in detail the method for identifying a device. FIG.2is a flowchart of a process, in Embodiment 1 of a method for identifying a device, for identifying a video device according to the present disclosure. That a multimedia device is a video device is described in detail for description in this embodiment. Specific steps are as follows. Step201: A control device generates an identification identifier of the video device according to a UUID and an IP address of the video device in device description information of the video device, and sends the identification identifier to the video device, so that the video device displays the identification identifier. For a method used by the control device to discover and determine a video device, and a method for acquiring device description information and device capability information, reference may be made to step101, and details are not described herein again in this embodiment. When the multimedia device is a video device, the control device compiles information such as the UUID and the IP address of the video device into a two-dimensional code for the video device. If multiple video devices are discovered on a home network, UUIDs and IP addresses of the video devices are different, and therefore, two-dimensional codes generated for the video devices are also different. Alternatively, the control device may also generate, according to UUIDs and IP addresses of different video devices discovered on the home network, pictures with preset colors for the different video devices. For example, if a video device with a UUID of xx.1xx.xxx.1 and with an IP address of 192.168.xx.1 is acquired by the control device, the control device generates a red picture for the video device; and if a video device with a UUID of xx.1xx.xxx.2 and with an IP address of 192.168.xx.2 is acquired by the control device, the control device generates a blue picture for the video device. The control device generates two-dimensional codes or pictures with preset colors for video devices with different UUIDs and IP addresses. Persons skilled can understand that both the foregoing two-dimensional code and the picture with a preset color are identification identifiers in this embodiment. When the multimedia device is a video playback device, the control device invokes a Set AV Transport URI( ) action command of the video device, where the command carries a URI of a picture with a preset color or a URI of a two-dimensional code, where the picture with a preset color or the two-dimensional code is generated for the video device. After acquiring the URI of the picture with a preset color or the URI of the two-dimensional code, the video device acquires the picture with a preset color or the two-dimensional code by using Hypertext Transfer Protocol (HTTP) GET method call, and displays the picture with a preset color or the two-dimensional code on a screen. Step202: The control device acquires the identification identifier displayed by the video device, acquires the UUID and the IP address according to the identification identifier, and acquires an appearance image of the video device by using a camera. When the multimedia device is a video device, the camera on the control device captures the appearance image of the video playback device, and captures a preset picture or a two-dimensional code picture in a manner of photographing or scanning. When the identification identifier is a two-dimensional code picture, the UUID and the IP address may be directly acquired by parsing. When the identification identifier is a preset picture, the preset picture may be a picture with a preset pattern, or may be a picture with a preset color. If the control device determines that a preset picture played by the video device is consistent with a preset picture generated by the control device, the control device acquires device description information corresponding to the preset picture. The control device determines whether the captured preset picture played by the video device is a preset picture generated by an audio device; and if the captured preset picture played by the video device is a preset picture generated by an audio device, the control device determines that the identification identifier played by the video device is consistent with the identification identifier generated by the control device. In addition, the control device may learn that the multimedia device is a video device according to an appearance image by means of an image recognition technology, and then learns appearance information such as a brand and a screen size of the multimedia device by analyzing the multimedia device. Step203: The control device associates the UUID and the IP address with the appearance image of the video device. After the camera of the control device captures the appearance image of the video device and key information such as the UUID and the IP address of the video device is acquired, the control device matches and associates the appearance image of the video device with the UUID and the IP address. For example, the control device correspondingly binds the appearance image of the video device collected by the video device and a red picture with a corresponding UUID and a corresponding IP address, and the binding information is stored on the control device. A manner for associating device description information with an appearance image in a form of a table may be listed in Table 1. TABLE 1GeneratedAcquiredpicture withpicture withAppearanceUUIDIPpreset colorpreset colorpicturexx.1xx.xxx.1192.168.xx.1RedRedHDTV1xx.1xx.xxx.2192.168.xx.3YellowYellowHDTV1xx.1xx.xxx.3192.168.xx.2BlueBlueHDTV1 By using the method for identifying a device according to this embodiment of the present disclosure, a user equipment can correctly identify, only according to an appearance image of a multimedia device, the multimedia device corresponding to the appearance image, thereby improving convenience and correctness of device identification. FIG.3is a flowchart of a process, in Embodiment 1 of a method for identifying a device, for identifying an audio device according to the present disclosure. That a multimedia device is an audio device is described in detail in this embodiment. Step301: A control device generates an identification identifier of the audio device according to a UUID and an IP address of the audio device in device description information of the audio device, and sends the identification identifier to the audio device, so that the audio device displays the identification identifier. For a method used by the control device to discover and determine an audio device, and a method for acquiring device description information and device capability information, reference may be made to step101, and details are not described herein again in this embodiment. When the multimedia device is an audio device, the control device may generate, according to UUIDs and IP addresses of different audio devices discovered on a home network, preset music for the different video devices. For example, if an audio device with a UUID of xx.1xx.xxx.1 and with an IP address of 192.168.xx.1 is acquired by the control device, the control device generates music A for the audio device. If an audio device with a UUID of xx.1xx.xxx.2 and with an IP address of 192.168.xx.2 is acquired by the control device, the control device generates music B for the audio device. Alternatively, the control device may generate audio files with preset frequencies according to the UUIDs and the IP addresses of the different video devices, for example, the control device generates an audio file with a frequency of 1000 kHz for a device with a UUID of xx.1xx.xxx.1 and with an IP address of 192.168.xx.1, and the control device generates an audio file with a frequency of 2000 kHz for a device with a UUID of xx.1xx.xxx.2 and with an IP address of 192.168.xx.2. Persons skilled in the art can understand that both the foregoing preset music and a sound with a preset frequency are identification identifiers in this embodiment. When the multimedia device is an audio playback device, the control device invokes a Set AV Transport URI( ) action command of the audio device, where the command carries a URI of preset music or a URI of a sound with a preset frequency, where the preset music or the sound with a preset frequency is generated for the audio device. After acquiring the URI of the preset music or the URI of the sound with a preset frequency, the playback device acquires the preset music or the sound with a preset frequency by using HTTP GET, and plays the preset music or the sound with a preset frequency by using sound equipment. Step302: The control device acquires the identification identifier displayed by the audio device, acquires the UUID and the IP address according to the identification identifier, and acquires an appearance image of the audio device by using a camera. When the multimedia device is an audio device, a microphone on the control device collects preset music, or a sound with a preset frequency played by the audio device. For example, the control device generates music A or an audio file with 1000 kilohertz (kHz) for an audio device with a UUID of xx.1xx.xxx.1 and with an IP address of 192.168.xx.1. When a user puts the control device near the audio device, a camera on the control device acquires an appearance image of the audio device, and the microphone captures that what is playing by the audio device is music A or the audio file with 1000 kHz. Then, if the control device determines that the preset music and the sound with a preset frequency played by the audio device is consistent with the preset music and the sound with a preset frequency generated by the control device, the control device acquires device description information corresponding to the preset music and the sound with a preset frequency. The control device determines whether the collected preset music or the sound with a preset frequency played by the audio device is the preset music or the sound with a preset frequency generated by the control device; and if the collected preset music or the sound with a preset frequency played by the audio device is the preset music or the sound with a preset frequency generated by the control device, the control device determines that the identification identifier played by the audio device is consistent with the identification identifier generated by the control device. In addition, the control device learns that the multimedia device is an audio device by means of an image recognition technology, and then learns appearance information such as a brand and a screen size of the multimedia device by analyzing the multimedia device. Step303: The control device associates the UUID and the IP address with the appearance image of the audio device. The control device matches and associates key information, such as the UUID and the IP address of the audio device that are corresponding to the preset music or the sound with a preset frequency, with the appearance image of the audio device collected by the camera of the control device; and the association information is stored on the control device. A manner for associating device description information with an appearance image in a form of a table may be listed in Table 2. TABLE 2GeneratedAcquiredsoundsoundwith presetwith presetAppearanceUUIDIPfrequencyfrequencypicturexx.1xx.xxx.1192.168.xx.1A/1000 kHzA/1000 kHzStereo speaker1xx.1xx.xxx.2192.168.xx.3A/1000 kHzA/1000 kHzStereo speaker2xx.1xx.xxx.3192.168.xx.2A/1000 kHzA/1000 kHzStereo speaker3 By using the method for identifying a device according to this embodiment of the present disclosure, a user equipment can correctly identify, only according to an appearance image of a multimedia device, the multimedia device corresponding to the appearance image, thereby improving convenience and correctness of device identification. FIG.4is a flowchart of Embodiment 2 of a method for identifying a device according to the present disclosure. As shown inFIG.4, the method for identifying a device according to this embodiment of the present disclosure may be executed by a multimedia device. The multimedia device may be implemented by using software and/or hardware. The method for identifying a device according to this embodiment includes Step401: The multimedia device receives an identification identifier of the multimedia device sent by a control device. Step402: The multimedia device displays the identification identifier, so that the control device acquires device description information of the multimedia device according to the identification identifier and associates the device description information with the appearance image, where the identification identifier is generated by the control device according to the device description information of the multimedia device. Optionally, if the multimedia device is a video device, the identification identifier is a preset picture or a two-dimensional code. Optionally, if the multimedia device is an audio device, the identification identifier is preset music, or a sound with a preset frequency. For a specific implementation process of this embodiment, reference may be made to descriptions about the multimedia device shown in the embodiments ofFIG.1toFIG.3, and details are not described herein again in this embodiment. In the method for identifying a device according to this embodiment of the present disclosure, a multimedia device receives an identification identifier of the multimedia device sent by a control device; and the multimedia device displays the identification identifier, so that the control device associates the device description information with the appearance image, which enables a user equipment to identify the multimedia device according to the appearance image. In this way, a user equipment can correctly identify, only according to the appearance image of the multimedia device, the multimedia device corresponding to the appearance image, thereby improving convenience and correctness of device identification. FIG.5is a flowchart of Embodiment 3 of a method for identifying a device according to the present disclosure. The method for identifying a device according to this embodiment is as follows. Step501: A control device acquires device description information and device capability information of a multimedia device. Step502: The control device acquires an appearance image of the multimedia device. Step503: The control device associates the device description information with the appearance image of the multimedia device, so that a user equipment identifies the multimedia device according to the appearance image. In step501, the control device acquires device description information and device capability information of a multimedia device by using the Service Discovery Protocol. The control device may acquire the device description information of the multimedia device by using SSDP, and there may be two possible cases. One possible case is that when connected to a network, the control device may send an “ssdp:discover” message to an SSDP port at a specific multicast address, where the message includes a request for acquiring the device description information; and when the multimedia device obtains the message by listening, the multimedia device analyzes the request sent by the control device, and then returns a response with respect to the request sent by the control device, that is, returns the device description information. The other case is that when connected to a network, the multimedia device sends an “ssdp:alive” message to an SSDP port at a specific multicast address, where the message includes the device description information. After the control device discovers the multimedia device, the control device may invoke a UPnP acquire action (Get ProtocolInfo( ) action) to acquire the device capability information. Optionally, after the control device acquires the device description information of the multimedia device, the method further includes determining, by the control device according to the device description information and the device capability information, that the multimedia device is a video device or an audio device. In step502, the control device acquires an appearance image of the multimedia device. The control device acquires an appearance image of the multimedia device from a network side by using the device description information, and acquires an appearance image of the multimedia device by using a camera; and the control device determines that the appearance image of the multimedia device acquired from the network side by using the device description information is consistent with the appearance image of the multimedia device acquired by using a camera. The control device uses the appearance image of the multimedia device acquired from the network side as an appearance image of the multimedia device, and acquires the appearance image. The control device acquires more detailed device information from the network side by analyzing key information in the device description information. For example, a uniform resource locator (URL) of a product appearance image is acquired from the device description information, and then the control device acquires the appearance image from the network side according to the URL; or, the control device may acquire a portal website of a device manufacturer by analyzing <manufacturer URL> in the device description information, and may acquire a detailed product model by analyzing <model Name> in the device description information. After acquiring a portal website of the manufacturer, the control device may search for more detailed device description information and product description information on the website by using a background program, for example, product parameters such as an appearance image, a brand, a screen size, and a resolution. The control device binds a UUID and an IP address of the multimedia device with the product parameters, such as the appearance image, the brand, and the screen size, of the multimedia device acquired from the network side, and the control device stores binding information. Details may be listed in Table 3. TABLE 3UUIDIPAppearance picture on networkxx.1xx.xxx.1192.168.xx.1Samsung smart TVxx.1xx.xxx.2192.168.xx.3B&W sound equipmentxx.1xx.xxx.3192.168.xx.2Sony high-definition TV The camera on the control device collects an appearance image of a multimedia device that needs to be identified. For example, a user starts the camera on the control device and aligns the camera with a multimedia device in a living room or a bedroom, and the camera collects an appearance image of the multimedia device, such as an appearance image of a television or an appearance image of sound equipment. The control device analyzes the collected appearance image of the multimedia device. The control device can learn, by means of image recognition, whether the appearance image acquired by using a camera by the user is a television or sound equipment. The control device may identify information such as a screen size of the multimedia device by means of an image recognition technology. Details may be listed in Table 4. TABLE 4Photographed appearanceIDpictureASamsung smart TVBB&W sound equipmentCSony high-definition TV The control device performs analysis by means of an image recognition technology; if it is determined that the appearance image of the multimedia device acquired from the network side is consistent with the appearance image acquired by using a camera, the appearance image acquired by using a camera is used as an appearance image; and the appearance image is acquired. Persons skilled in the art may understand that consistency of appearance images not only includes consistency of images, but also includes consistency of device types, brands, and product parameters that are acquired according to the image recognition technology. In step503, the control device associates the device description information with the appearance image. The control device associates the UUID and the IP address in the device description information with the appearance image acquired by using a camera in step502, and stores the association information on the control device. A manner for associating device description information with an appearance image in a form of a table may be listed in Table 5. TABLE 5Appearance picturePhotographedUUIDIPon networkappearance picturexx.1xx.xxx.1192.168.xx.1Samsung smart TVSamsung smart TVxx.1xx.xxx.2192.168.xx.3B&W soundB&W soundequipmentequipmentxx.1xx.xxx.3192.168.xx.2Sony high-definitionSonyTVhigh-definition TV By using the method for identifying a device according to this embodiment of the present disclosure, a user equipment can correctly identify, only according to an appearance image of a multimedia device, the multimedia device corresponding to the appearance image, thereby improving convenience and correctness of device identification. FIG.6is a schematic structural diagram of Embodiment 1 of a control device according to the present disclosure. As shown inFIG.6, a control device60provided in this embodiment of the present disclosure includes a generating module601, a first acquiring module602, a second acquiring module603, and an associating module604. The generating module601is configured to generate an identification identifier of a multimedia device according to device description information of the multimedia device, and send the identification identifier to the multimedia device, so that the multimedia device displays the identification identifier, the first acquiring module602is configured to acquire the identification identifier displayed by the multimedia device and an appearance image of the multimedia device, the second acquiring module603is configured to acquire the device description information according to the identification identifier displayed by the multimedia device, and the associating module604is configured to associate the device description information with the appearance image of the multimedia device, so that a user equipment identifies the multimedia device according to the appearance image. The control device in this embodiment may be used to execute the technical solution of the method embodiment shown inFIG.1. The implementation principles and technical effects are similar and are not described herein again. FIG.7is a schematic structural diagram of Embodiment 2 of a control device according to the present disclosure. As shown inFIG.7, this embodiment of the present disclosure is implemented based on the embodiment ofFIG.6, and details are as follows. Optionally, the second acquiring module603is configured to determine that the identification identifier displayed by the multimedia device is consistent with the identification identifier generated by the control device, and acquire the device description information corresponding to the identification identifier generated by the control device. Optionally, the control device further includes a determining module605configured to, before the identification identifier of the multimedia device is generated according to the device description information of the multimedia device, acquire the device description information and device capability information of the multimedia device, and determine, according to the device description information and the device capability information, that the multimedia device is a video device or an audio device. Optionally, if the multimedia device is a video device, the identification identifier is a preset picture or a two-dimensional code, or if the multimedia device is an audio device, the identification identifier is preset music, or a sound with a preset frequency. Optionally, the generating module601is configured to generate the identification identifier of the multimedia device according to a UUID and an IP address of the multimedia device in the device description information of the multimedia device, and the associating module604is configured to associate the UUID and the IP address with the appearance image of the multimedia device. Optionally, the first acquiring module602is configured to acquire the identification identifier displayed by the multimedia device, and acquire the appearance image of the multimedia device by using a camera. The control device in this embodiment may be used to execute the technical solutions of the foregoing method embodiments. The implementation principles and technical effects are similar and are not described herein again FIG.8is a schematic structural diagram of Embodiment 1 of a multimedia device according to the present disclosure. As shown inFIG.8, a multimedia device70provided in this embodiment of the present disclosure includes a receiving module701and a displaying module702. The receiving module701is configured to receive an identification identifier of the multimedia device sent by a control device, and the displaying module702is configured to display the identification identifier, so that the control device acquires device description information of the multimedia device according to the identification identifier and associates the device description information with the appearance image, where the identification identifier is generated by the control device according to the device description information of the multimedia device. Optionally, if the multimedia device is a video device, the identification identifier is a preset picture or a two-dimensional code, or if the multimedia device is an audio device, the identification identifier is preset music, or a sound with a preset frequency. The multimedia device in this embodiment may be used to execute the technical solution of the method embodiment shown inFIG.4. The implementation principles and technical effects are similar and are not described herein again FIG.9is a schematic structural diagram of Embodiment 3 of a control device according to the present disclosure. As shown inFIG.9, a control device80provided in this embodiment of the present disclosure includes a first acquiring module801, a second acquiring module802, and an associating module803. The first acquiring module801is configured to acquire device description information and device capability information of a multimedia device, the second acquiring module802is configured to acquire an appearance image of the multimedia device, and the associating module 803 is configured to associate the device description information with the appearance image of the multimedia device, so that a user equipment identifies the multimedia device according to the appearance image. The control device in this embodiment may be used to execute the technical solution of the method embodiment shown inFIG.5. The implementation principles and technical effects are similar and are not described herein again FIG.10is a schematic structural diagram of Embodiment 4 of a control device according to the present disclosure. As shown inFIG.10, the control device provided in this embodiment of the present disclosure is implemented based on the embodiment inFIG.9, and details are as follows Optionally, the second acquiring module802is configured to acquire an appearance image of the multimedia device from a network side by using the device description information, and acquire an appearance image of the multimedia device by using a camera, and determine that the appearance image of the multimedia device acquired from the network side by using the device description information is consistent with the appearance image of the multimedia device acquired by using the camera. Optionally, the associating module 803 is configured to associate, by the control device, a UUID and an IP address in the device description information with the appearance image of the multimedia device acquired by using the camera. Optionally, the control device further includes a determining module 804 configured to, after the device description information of the multimedia device is acquired, determine, according to the device description information and the device capability information, that the multimedia device is a video device or an audio device. The control device in this embodiment may be used to execute the technical solutions of the foregoing method embodiments. The implementation principles and technical effects are similar and are not described herein again. Persons of ordinary skill in the art may understand that all or some of the steps of the method embodiments may be implemented by a program instructing relevant hardware. The program may be stored in a computer-readable storage medium. When the program runs, the steps of the method embodiments are performed. The foregoing storage medium includes any medium that can store program code, such as a read-only memory (ROM), a random access memory (RAM), a magnetic disk, or an optical disc. Finally, it should be noted that the foregoing embodiments are merely intended for describing the technical solutions of the present disclosure, but not for limiting the present disclosure. Although the present disclosure is described in detail with reference to the foregoing embodiments, persons of ordinary skill in the art should understand that they may still make modifications to the technical solutions described in the foregoing embodiments or make equivalent replacements to some or all technical features thereof, without departing from the scope of the technical solutions of the embodiments of the present disclosure. | 40,341 |
RE49838 | DETAILED DESCRIPTION The invention will now be described by reference to the preferred embodiments. This does not intend to limit the scope of the present invention, but to exemplify the invention. First Embodiment The knowledge that provides the basis of the technology will be discussed before discussing the first embodiment in specific details. The first embodiment relates to a communication system that performs inter-vehicle communication between terminal apparatuses mounted in vehicles and also performs road-to-vehicle communication from a base station apparatus placed at a traffic intersection or the like to a terminal apparatus. Such a system is referred to as an Intelligent Transport System (ITS). ITS is defined by the standard for 700 Hz band intelligent transport systems (Association of Radio Industries and Businesses). The communication system uses access control called Carrier Sense Multiple Access with Collision Avoidance (CSMA/CA) along with wireless local area network (LAN) that complies with a standard such as IEEE802.11. For this reason, a given radio channel is shared by a plurality of terminal apparatuses. Meanwhile, information in ITS needs to be transmitted to an unspecified number of terminal apparatuses. To transmit information efficiently, the communication system broadcasts a packet signal. In other words, a terminal apparatus broadcasts a packet signal containing information such as vehicle speed or position for inter-vehicle communication. Other terminal apparatuses receive the packet signal and acknowledge, for example, that the broadcasting vehicle is approaching based on the information. The base station apparatus repeatedly defines a frame containing a plurality of subframes in order to reduce interference between road-to-vehicle communication and inter-vehicle communication. For road-to-vehicle communication, the base station apparatus selects one of the plurality of subframes and broadcasts a packet signal containing control information, etc. in a period at the start of the selected subframe. The control information includes information related to a period in which the base station apparatus broadcasts a packet signal (hereinafter, referred to as “road-to-vehicle transmission period”). The terminal apparatus identifies the road-to-vehicle period based on the control information and broadcasts a packet signal using CSMA in a period other than the road-to-vehicle period (hereinafter, referred to as “inter-vehicle transmission period”). As a result, road-to-vehicle communication and inter-vehicle communication are time-division multiplexed. Terminal apparatuses that cannot receive the control information from the base station apparatus, i.e., terminal apparatuses located outside an area formed by the base station apparatus, transmit a packet signal using CSMA irrespective of the frame structure. A description will be given of an outline of the embodiments. When a vehicle decelerates or stops before a red light and then restarts, a large amount of energy is lost. GW driving is proposed in order to reduce energy loss. GW driving is a form of driving designed to achieve smooth traffic flow by controlling the speed of a vehicle so that the vehicle can pass a green light. In GW driving, the vehicle and the infrastructure are coordinated to present the driver with a method of driving capable of reducing energy loss. For example, a packet signal broadcast from a base station apparatus contains traffic signal information. The traffic signal information indicates the timing of a red light or the timing of a green light. The terminal apparatus mounted in the vehicle acquires the traffic signal information by receiving the packet signal. The GW controller of the vehicle derives a speed, etc. to pass a green light at a traffic intersection based on the traffic signal information and the route information from the car navigation system and notifies the driver of the result. In GW driving as described above, the timing of acceleration or deceleration is different from that of normal driving. Drivers of nearby vehicles are not aware of the reason behind such driving. In order to reduce near-end accidents occurring for this reason, the notification device performs the following process. The notification device may be implemented by a standalone hardware device. In this case, it will be assumed that the notification device is implemented as an application of a terminal apparatus by way of example. The terminal apparatus stores information indicating that GW control is in effect in a packet signal and broadcasts the packet signal. Other terminal apparatuses mounted in vehicles behind receive the packet signal and notifies the drivers of the vehicles behind that the vehicle running in front is under GW control. For clarity, a description will be given below of 1. a summary of the communication system for broadcasting a packet signal and then 2. notification of GW control. I. Summary of the Communication System FIG.1shows the structure of a communication system100according to the first embodiment. The illustration is a view from above a given traffic intersection. The communication system100includes a base station apparatus10, a first vehicle12a, a second vehicle12b, a third vehicle12c, a fourth vehicle12d, a fifth vehicle12e, a sixth vehicle12f, a seventh vehicle12g, an eighth vehicle12h, which are generically referred to as vehicles12, and a network202. Although only the first vehicle12a is shown to have a terminal apparatus, the terminal apparatus14is mounted in each vehicle12. An area212is formed around the base station apparatus10and an outlying area214is formed outside the area212. As illustrated, the road that runs in the transversal direction in the figure, i.e., that runs leftward and rightward, and the road that runs in the vertical direction in the figure, i.e., that runs upward and downward, intersect at the center. The top of the figure corresponds to compass “north”, the left side corresponds to compass “west”, the bottom corresponds to compass “south”, and the right side corresponds to compass “east”. The intersection of the two roads represents a “traffic intersection”. The first vehicle12a and the second vehicle12b are traveling from left to right, and the third vehicle12c and the fourth vehicle12d are traveling from right to left. Further, the fifth vehicle12e and the sixth vehicle12f are traveling from top to bottom, and the seventh vehicle12g and the eighth vehicle12h are traveling from bottom to top. In the communication system100, the base station apparatus is fixedly placed at the traffic intersection. The base station apparatus10controls communication between terminal apparatuses. The base station apparatus10repeatedly generates frames each including a plurality of subframes based on a signal received from a Global Positioning System (GPS) satellite (not shown) or a frame formed by another base station apparatus (not shown). The frames are defined such that a road-to-vehicle transmission period can be provided at the start of each subframe. Of a plurality of subframes in a frame, the base station apparatus10selects a subframe in which a road-to-vehicle transmission period is not defined by another base station apparatus10. The base station apparatus10defines a road-to-vehicle transmission period at the start of the selected subframe. The base station apparatus10broadcasts a packet signal during the road-to-vehicle transmission period thus defined. A plurality of packet signals may be broadcast during a road-to-vehicle transmission period. For example, a packet signal includes traffic accident information, traffic jam information, signal information, etc. A packet signal also includes information related to the timing of defining the road-to-vehicle transmission period and control information related to frames. As described above, the terminal apparatus14is mounted on the vehicle12and so is movable. When the terminal apparatus14receives a packet signal from the base station apparatus10, the terminal apparatus14estimates that the terminal apparatus14is located in the area212. While in the area212, the terminal apparatus14generates a frame based on the control information included in the packet signal and, in particular, the information related to the timing of defining the road-to-vehicle transmission period and the information related to frames. As a result, the frame generated in each of the plurality of terminal apparatuses14is synchronized with the frame generated in the base station apparatus10. The terminal apparatus14broadcasts a packet signal in an inter-vehicle transmission period different from the road-to-vehicle transmission period. CSMA/CA is used in the inter-vehicle transmission period. Meanwhile, when the terminal apparatus14estimates that the terminal apparatus14is located in the outlying area214, the terminal apparatus14broadcasts a packet signal by using CSMA/CA irrespective of the frame structure. FIG.2shows the structure of the base station apparatus10. The base station apparatus10includes an antenna20, an RF unit22, a modem unit24, a processing unit26, a controller28, and a network communication unit30. The processing unit26includes a frame definition unit32, a selector34, and a generator36. In a reception process, the RF unit22receives a packet signal from the terminal apparatus14or another base station so apparatus10(not shown) at the antenna20. The RF unit22subjects the radio frequency packet signal thus received to frequency conversion so as to generate a baseband packet signal. Further, the RF unit22outputs the baseband packet signal to the modem unit24. Generally, a baseband packet signal is formed of an in-phase component and a quadrature component. Therefore, two signal lines should be shown. For clear illustration, the figure only shown one signal line. The RF unit22also includes a Low Noise Amplifier (LNA), a mixer, an AGC, and an A/D converter. In a transmission process, the RF unit22subjects the baseband packet signal input from the modem unit24to frequency conversion so as to generate a radio frequency packet signal. Further, the RE unit22transmits the radio frequency packet signal from the antenna20in a road-to-vehicle transmission period. The RF unit22also includes a Power Amplifier (PA), a mixer, and a D/A converter. For example, a radio frequency of 700 MHz is used. In a reception process, the modem unit24subjects the baseband packet signal from the RF unit22to demodulation. Further, the modem unit24outputs the demodulated result to the processing unit26. In a transmission process, the modem unit24subjects data from the processing unit26to modulation. Further, the modem unit24outputs the modulated result to the RF unit22as a baseband packet signal. The communication system100supports the Orthogonal Frequency Division Multiplexing (OFDM) modulation scheme. Therefore, the modem unit24also performs Fast Fourier Transform (FFT) in a reception process and Inverse Fast Fourier Transform (IFFT) in a transmission process. The frame definition unit32receives a signal from a GPS satellite (not shown) and retrieves time information by referring to the received signal. A publicly known technology may be used to retrieve time information so that a description thereof is omitted. The frame definition unit32generates a plurality of frames based on the time information. For example, the frame definition unit32generates 10 “100 msec” frames by dividing a period of “1 sec” into 10 with reference to the timing indicated by the timing information. By repeating the process, frames are repeated. The frame definition unit32may detect control information from the demodulated result and generate frames based on the detected control information. Such a process translates into generating frames synchronized with the timing of frames formed by another base station apparatus10. FIGS.3A-3Dshow the format of a frame defined in the communication system100.FIG.3Ashows a frame structure. A frame is formed by N subframes illustrated as first through N-th subframes. It can be said that a frame is formed by multiplexing subframes available for broadcasting by the terminal apparatus14in multiple time windows. For example, given that the length of a frame is 100 msec and N is equal to 8, subframes each having a length of 12.5 msec are defined. N may be other 8. A description with reference toFIGS.3B-3Dwill be given later. Reference is made back toFIG.2. Of the plurality of subframes included in a frame, the selector34selects a subframe in which a road-to-vehicle transmission period should be defined. To describe it more specifically, the selector34accepts a frame defined by the frame definition unit32. Also, the selector34accepts an instruction related to a selected subframe via an interface (not shown). The selector34selects a subframe designated by the instruction. Aside from this, the selector34may automatically select a subframe. In this process, the selector34may receive a result of demodulation from another base station apparatus10or the terminal apparatus14(not shown) via the RF unit22and the modem unit24. The selector34refers to the input demodulation results and extracts a result of demodulation from another base station apparatus10. The selector34identifies a subframe in which a result of demodulation is not received by identifying a subframe in which a result of demodulation is received. This translates into identifying a subframe in which a road-to-vehicle transmission period is not defined by another base station apparatus10, i.e., identifying an unused subframe. If there are a plurality of unused subframes, the selector34selects one subframe at random. If no unused subframes are available, i.e., if each of the plurality of subframes is used, the selector34acquires reception power corresponding to the result of demodulation and selects a subframe with small reception power in preference to the other subframes. FIG.3Bshows the structure of a frame generated by a first base stations apparatus10a (not shown). The first base station apparatus10a defines a road-to-vehicle transmission period at the start of the first subframe. The first base station apparatus10a also defines an inter-vehicle transmission period to succeed the road-to-vehicle transmission period in the first subframe. An inter-vehicle transmission period is a period in which the terminal apparatus14can broadcast a packet signal. In other words, the first base station apparatus10a defines the frame such that a packet signal can be transmitted in a road-to-vehicle transmission period at the start of the first subframe, and the terminal apparatus14can broadcast a packet signal in the inter-vehicle transmission period provided in the frame in addition to the road-to-vehicle transmission period. Further, the first base station apparatus10a defines only inter-vehicle transmission periods in the second through N-th subframes. FIG.3Cshows the structure of a frame generated by a second base station apparatus10b (not shown). The second base station apparatus10b defines a road-to-vehicle transmission period at the start of the second subframe. The second base station apparatus10b also defines inter-vehicle transmission periods subsequent to the road-to-vehicle transmission period in the second subframe, and in the first subframe, and the third through N-th subframes.FIG.3Dshows the structure of a frame generated by a third base station apparatus10c (not shown). The third base station apparatus10c defines a road-to-vehicle transmission period at the start of the third subframe. The third base station apparatus10c also defines inter-vehicle transmission periods subsequent to the road-to-vehicle transmission period in the third subframe, and in the first subframe, the second subframe, and the fourth through N-th subframes. Thus, the plurality of base station apparatuses10select mutually different subframes and define a road-to-vehicle transmission period at the start of the selected subframe. Reference is made back toFIG.2. The selector34outputs the number of the selected subframe to the generator36. The generator36receives the number of the subframe from the selector34. The generator36defines a road-to-vehicle transmission period in the subframe having the subframe number received and generates a packet signal that should he broadcast in the road-to-vehicle transmission period. If a plurality of packet signals are transmitted in a single road-to-vehicle transmission period, the generator36generates those packet signals. A packet signal is comprised of control information and a payload. The control information includes the number of the subframe in which the road-to-vehicle transmission period is defined. The payload includes, for example, accident information, traffic jam information, and traffic signal information. These data are acquired by the network communication unit30from the network202(not shown) The processing unit26causes the modem unit24and the RF unit22to broadcast the packet signal in the road-to-vehicle transmission period. The controller28controls the process of the base station apparatus10as a whole. The features are implemented in hardware such as a CPU of a computer, a memory, or other LSI's, and in software such as a program loaded into a memory, etc. The figure depicts functional blocks implemented by the cooperation of these elements. Therefore, it will be obvious to those skilled in the art that the functional blocks may be implemented in a variety of manners by hardware only or by a combination of hardware and software. FIG.4shows the structure of the terminal apparatus14mounted in the vehicle12. The terminal apparatus14includes an antenna50, an RF unit52, a modem unit54, a processing unit56, and a controller58. The processing unit56includes a timing identifier60, a transfer determination unit62, an acquisition unit64, a generator66, a user IF unit68, a notification unit70, an application processing unit76, and an application manager78. The timing identifier60includes an extractor72and a carrier sensor74. The antenna50, the RE unit52, and the modem unit54performs processes similar to those of the antenna20, the RE unit22, and the modem unit24ofFIG.2. The difference will be discussed below. In a reception process, the modem unit54and the processing unit56receive a packet signal from another terminal apparatus14or the base station apparatus10(not shown). As described above, the modem unit54and the processing unit56receive a packet signal from the base station apparatus10in a road-to-vehicle transmission period and receive a packet signal from another terminal apparatus14in an inter-vehicle transmission period. If a result of demodulation provided front the modem unit54indicates a packet signal from the base station apparatus10(not shown), the extractor72identifies the timing of a subframe in which a road-to-vehicle transmission period is defined. In this process, the extractor72estimates that the terminal apparatus14is located in the area212ofFIG.1. The extractor72generates a frame based on the timing of the subframe and the content of message header of the packet signal. As a result, the extractor72generates a frame synchronized with the frame formed in the base station apparatus10. If the source of broadcasting of the packet signal is another terminal apparatus14, the extractor72omits the process of generating a synchronized frame. If the terminal apparatus14is located in the area212, the extractor72identifies the road-to-vehicle transmission period in use and then identifies the inter-vehicle transmission periods. The extractor72outputs the tinting of the frame and the subframes and information related to the inter-vehicle transmission periods to the carrier sensor74. Meanwhile, if the extractor72does not receive a packet signal from the base station apparatus10, i.e., if the extractor72does not generate frames synchronized with the base station apparatus10, the extractor72estimates that the terminal apparatus14is located in the outlying area214ofFIG.1. If the terminal apparatus14is located in the outlying area214, the extractor72directs the carrier sensor74to perform carrier sensing unrelated to the frame structure. The carrier sensor74receives the timing of the frame and the subframes and information related to the inter-vehicle transmission periods from the extractor72. The carrier sensor74determines the timing of transmission by initiating CSMA/CA in an inter-vehicle transmission period. This translates into defining a Network Allocation Vector (NAV) in the road-to-vehicle transmission period and performs carrier sensing in periods other than the period in which the NAV is defined. Meanwhile, if carrier sensor74is directed by the extractor72to perform carrier sensing unrelated to the frame structure, the carrier sensor74determines the timing of transmission by performing CSMA/CA, disregarding the frame structure. The carrier sensor74communicates the determined timing of transmission to the modem unit54and the RF unit52so as to cause a packet signal to be broadcast. The transfer determination unit62controls transfer of control information. The transfer determination unit62refers to the control information and extracts information that should he transferred. The transfer determination unit62determines the information that should be transferred based on the extracted information. A description of this process is omitted. The transfer determination unit62outputs the information that should be transferred, i.e., a part of the control information, to the generator66. The generator66receives data from the application manager78and receives a part of the control information from the transfer determination unit62. Data received from the application manager78will be described later. The generator66generates a packet signal by storing a part of the control information thus received in the control information and storing the data in the payload. The processing unit56, the modem unit54, and the RF unit52successively broadcast a plurality of packet signals generated by the generator66. The controller58controls the operation of the terminal apparatus14. The acquisition unit64includes a GPS receiver, a gyroscope, a vehicle speed sensor, etc. (not shown). The acquisition unit64refers to data supplied from these units so as to acquire a position, a direction of travel, a speed of movement, etc. (hereinafter, referred to as “position information”) of the vehicle12(not shown), i.e. the vehicle12in which the terminal apparatus is mounted. The position is denoted by longitude and latitude. A publicly known technology could be used for acquisition so that a description thereof is omitted. The GPS receiver, the gyroscope, the vehicle speed sensor, etc. may be provided outside the terminal apparatus14. The acquisition unit64outputs the position information to the application processing unit76. The application processing unit76can execute a plurality of types of applications. Each application is executed in a plurality of terminal apparatuses14. In other words, the transmitting terminal apparatus14generates data and broadcasts a packet signal storing the data. The receiving terminal apparatus14receives the packet signal and performs a predefined process based on the data included in the packet signal. Therefore, a given application is divided into a process at the transmitting end (hereinafter, referred to as “transmitter application”) and a process at the receiving end (hereinafter, “receiver application”). It should be noted that the transmitter application and the receiver application executed in a given terminal apparatus14need not match. Hereinafter, the transmitter application and the receiver application may generically referred to as applications. The plurality of types of applications are categorized as follows. One category is a common application. A common application is an application to alert the driver of the approach of another vehicle12and is executed in all terminal apparatuses14. The application processing unit76receives position information from the acquisition unit64when executing the transmitter application in the common application. Further, the application processing unit76periodically outputs position information to the application manager78. Meanwhile, in executing the receiver application in the common application, the application processing unit76acquires position information included in a packet signal from another terminal apparatus14from the application manager78. The application processing unit76detect the approach of another vehicle12based on the position information of another terminal apparatus14acquired from the application manager78and the position information received from the acquisition unit64. The application processing unit76causes the notification unit70to notify the driver of the approach of another vehicle12. The notification unit70notifies the driver accordingly via a monitor or a speaker. The second category is a free application. A free application is executed only in a selected terminal apparatus14and not in all of the terminal apparatuses14. A plurality of free applications may be executed simultaneously. Given the above-defined system, the application processing unit76executes a transmitter application in a free application that is allowed to be registered and outputs generated data to the application manager78. Meanwhile, the application processing unit76executes the receiver application by processing the data received from the application manager78as determined by the free application. The application manager78manages a transmitter application by acknowledging an application registration request from the user IF unit68. Subsequently, the application manager78receives a plurality of data items from the application processing unit76and outputs the plurality of data items, which are used to generate a packet signal, to the generator66so as to cause the generator66to generate a packet signal based on the plurality of data items. Meanwhile, the application manager78manages a receiver application by receiving the data stored in a packet signal received by the extractor72. Of the received data, the application manager78outputs the data corresponding to the receiver application executed in the application processing unit76to the application processing unit76. The application manager78discards the other data. To summarize the above, the base station apparatus10and the terminal apparatus14in the communication system100both perform communication at a period of about 10 ms. Road-to-vehicle communication and inter-vehicle communication are time-division multiplexed in order to reduce interference between road-to-vehicle communication and inter-vehicle communication. The base station apparatus10includes the transmission time and information on the road-to-vehicle communication period in a packet signal and notifies the surrounding terminal apparatuses accordingly in order to secure a road-to-vehicle communication period. The terminal apparatus14in the area212transmits a packet signal using CSMA/CA at a point of time outside the road-to-vehicle communication period by establishing time synchronization based on the transmission time received from the base station apparatus10and suspending transmission based on the information on the road-to-vehicle communication period. The payload of inter-vehicle communication is comprised of data for a common application and data for a free application. A description will he given hereinafter of processes in the application processing unit76and the application manager78. To describe how a plurality of applications are processed on the whole, a protocol stack involving the application processing unit76and the application manager78will he used.FIG.5shows a protocol stack in the terminal apparatus14. The application processing unit76and the application manager78in the two top layers are included in the terminal apparatus14at the transmitting end and so perform a process for a transmitter application. The application manager78and the application processing unit76in the two bottom layers are included in the terminal apparatus14at the receiving end and so perform a process for a receiver application. The application processing unit76at the transmitting end executes a plurality of types of applications. It will be assumed that a common application, a first free application, a second free application, and a third free application are executed. The application processing unit76outputs the data corresponding to the respective applications to the application manager78. The application manager78manages applications run in the application processing unit76. Further, the application manager78at the transmitting end receives a plurality of data items from the application processing unit76and aggregates a plurality of data items in order to store them in a single packet signal. The packet signal in which a plurality of data items are aggregated is output from the application manager78. The application manager78at the receiving end receives the packet signal in which the plurality of data items are aggregated. The application manager78extracts the data for the common application included in the packet signal and outputs the extracted data to the application processing unit76. Further, the application manager78managers the free application run in the application processing unit76in the subsequent stage and extracts the data corresponding to the free application that is being run. In this process, the data is extracted by referring to an application ID included in the header for the free application. The application manager78outputs the extracted data to the application processing unit76. Meanwhile, the application manager78discards the remaining data. For example, the third free application is not being run in the application processing unit76in the subsequent stage so that the application manager78discards the data for the third free application. The application processing unit76receives the data from the application manager78and executes the application corresponding to the data. In this process, it will be assumed that the common application, the first free application, the second free application, and the fourth free application are being run. 2. Notification of GW Control A description will now he given of a process performed when GW control of the vehicle12is in effect.FIG.6shows an alternative structure of the communication system100according to the embodiment. For clarity of description, the figure shows only two vehicles, namely, the first vehicle12a and the second vehicle12b traveling from right to left. In other words, the first vehicle12a is traveling in front, followed by the second vehicle12b. In reality, the number of vehicles12may not be two. The first vehicle12a includes a first terminal apparatus14a, a GW controller80, and a navigator86. The second vehicle12b includes a second terminal apparatus14b. This translates into the fact that the first vehicle12a is subject to GW control and the second vehicle12b is not subject to GW control. The first vehicle12a and the second vehicle12b will be generically referred to as vehicles12. The first terminal apparatus14a and the second terminal apparatus14b will be generically referred to as terminal apparatuses14. The navigator86in the first vehicle12a receives the position information from the first terminal apparatus14a and runs mute guidance based on the position information. For this purpose, the navigator86derives a route from the current position of the running vehicle to the destination based on the current position of the running vehicle and the position of the destination. The navigator86may determine the position information by receiving a signal from a GPS satellite (not shown). A publicly known technology may be used to derive a route so that a description thereof is omitted. The navigator86notifies the driver of the route by creating a map image reflecting the derived route and displaying the map image on a monitor. Sound may be output from a speaker so as to provide route guidance. The GW controller80receives the route derived by the navigator86and receives the position information and the signal information from the first terminal apparatus14a. The GW controller80derives a speed that allows the vehicle to pass a plurality fo signals included in the route with the traffic lights turned green. Further, the GW controller80checks for possible turns at traffic intersections along the route. The GW controller80directs the driver to drive the vehicle in a GW mode by displaying the information on the derived speed and the information on possible turns checked. The direction may be provided in sound. The driver drives the vehicle in a GW mode according to the direction. Apart from this, the GW controller80may directly control the driving of the first vehicle12a according to the information on the derived speed and the information on possible turns checked. This translates into automatic driving and a description thereof will be omitted. The first terminal apparatus14a acquires the position information and the traffic signal information by performing the process substantially as already described and outputs the position information and the traffic signal information to the GW controller80and the navigator86. When GW driving is performed by the GW controller80, the first terminal apparatus14a stores information indicating that “GW control is in effect” in a packet signal and broadcasts the packet signal. The packet signal may further include information indicating that “the speed changes” or “the vehicle turns right or left”. A detailed description on the information included in the packet signal will be given later. The function of the first terminal apparatus14a for performing the process described above represents the notification device. The second terminal apparatus14b receives the packet signal from the first terminal apparatus14a. The second terminal apparatus14b extracts the information indicating “GW control is in effect” from the received packet signal and notifies the driver of the information. As a result, the driver of the second vehicle12b knows that the first vehicle12a is being driven in a GW mode. The driver also understands that unexpected acceleration or deceleration of the first vehicle12a is due to GW driving. A similar process is performed when the received packet signal includes information indicating that “the speed changes” or “the vehicle turns right or left”. Accordingly, the driver of the second vehicle12b can know that the change in the speed of the first vehicle12a, or the right or left turn thereof is due to GW driving. FIG.7shows the structure of the application processing unit76. The application processing unit76includes an input unit110and an output unit112. The illustrated structure is related to an application for notifying that GW control is in effect, which is one of the transmitter applications executed in the application processing unit76. The application is a free application and corresponds to the notification device mounted on the vehicle12. The input unit110acquires the information indicating that “GW control is in effect” from the GW controller80(not shown), i.e., acquires the information indicating that the driver's vehicle12is receiving driving assistance. The information is input when the GW controller SO is started. The input unit110also acquires the information indicating that “the speed changes” or “the vehicle turns right or left” from the GW controller80(not shown), i.e., the information indicating that the running condition is changed due to the driving assistance. The information is input when the speed changes, or when the vehicle turns right or left. The speed is defined as changing when a difference between the speed derived by the GW controller80and the current speed is equal to or greater than a threshold value. The input unit110may only receive the information indicating that “GW control is in effect” and not receive the information indicating that “the speed changes” or “the vehicle turns right left”. The output unit112outputs the information indicating that GW control is effect and acquired in the input unit110to the application manager78. Ultimately, the information indicating that GW control is in effect is included in a packet signal and broadcast. As a result, the output unit112outputs notification to other vehicles12in accordance with the information indicating that GW control is in effect. In other words, the output unit112broadcasts the information indicating that the vehicle is receiving GW driving assistance to the vehicles12around. When the input unit110acquires the information indicating that the speed changes or the information indicating that the vehicle turns right or left, the output unit112outputs the information to the application manager78. Ultimately, that information is also included in the packet signal and broadcast. As a result, the output unit112outputs notification to other vehicles12in accordance with the information indicating that the speed changes or the information indicating that the vehicle turns right or left. In other words, the likelihood that the vehicle may be accelerated or decelerated due to the driving assistance it receives is broadcast to the vehicles around. In particular, notification is given before the speed changes, or before the vehicle turns right or left actually. That the speed changes, or the vehicle turns right or left translates into change in the running condition induced by the driving assistance. FIGS.8A-8Cshow the data structure of the data output from the application processing unit76.FIG.8Ashows a case where the data includes information indicating that GW control is in effect and does not include information indicating that the speed changes or the information indicating that the vehicle turns right or left.FIG.8Bshows a case where the data includes information indicating that GW control is in effect and information indicating that the speed changes.FIG.8Cshows a case the data includes information indicating that GW control is in effect and information indicating that the vehicle turns right or left. A description will now be given of the operation of the communication system100configured as described above.FIG.9is a flowchart showing steps of transmitting a packet signal performed by the terminal apparatus14. If the input unit110acquires information indicating that GW control is in effect (Y in S10), the output unit112transmits a packet signal including the information indicating that GW control is in effect (S12). Meanwhile, if the input unit110does not acquire information indicating that GW control is in effect (N in S10), the process is terminated. FIG.10is a flowchart showing alternative steps of transmitting a packet signal performed by the terminal apparatus14. If the input unit110acquires information indicating that the running condition is changed (Y in S20), the output unit112transmits a packet signal including the information indicating a change (S22). Meanwhile, if the input unit110does not acquire information indicating that the running condition is changed (N in S20), the process is terminated. When the vehicle according to the embodiment acquires information indicating that the driver's vehicle is receiving driving assistance, the vehicle outputs notification to other vehicles. Thus, the drivers of the other vehicles can know that the notifying vehicle is receiving driving assistance. Since the drivers of the other vehicles can know that the notifying vehicle is receiving driving assistance, the stress felt by the drivers can be reduced. By reducing the stress, accidents induced by the vehicle receiving driving assistance are reduced. As the information indicating that the speed is increased or decreased, or the information indicating the vehicle turns right or left is acquired, notification is output to other vehicles. Therefore, the drivers of the other vehicles can know that the speed of the notifying vehicle is increased or decreased, or the vehicle turns right or left due to the driving assistance received. Because the notification is given before the running condition is changed, it can be made clear that the notification is output because the speed is increased or decreased, or the vehicle turns right or left due to the driving assistance received by the notifying vehicle. By declaring that the driver is receiving driving assistance and revealing the reason for the behavior or letting the other drivers know the behavior in advance, the other drivers are prevented from feeling uncomfortable. By understanding the driving policy and following that policy, the vehicles around can also benefit from automatic driving assistance of green wave driving assistance indirectly. Second Embodiment Like the first embodiment, the second embodiment also assumes a communication system in which road-to-vehicle communication as well as inter-vehicle communication takes place, and relates to a notification device capable of notifying vehicles around that that acceleration or deceleration, or right or left turn of the notifying vehicle is induced by GW driving. In the second embodiment, as in the first embodiment, the notification device is implemented as an application of a terminal apparatus. The notification device according to the first embodiment knows that the vehicle is driven in a GW mode. The notification device according to the second embodiment determines that the vehicle is being driven in a GW mode on its own. Thus, if a vehicle is being driven in a manner similar to GW driving, the notification device mounted in the vehicle notifies other vehicles that the notifying vehicle is being driven in a GW mode regardless of whether the notifying vehicle is being driven in a GW mode. In other words, a determination is made as to whether the vehicle is being manually (as opposed to automatically) driven in a GW mode. If it is determined that the vehicle is being driven in a GW mode, information indicating that the vehicle is changed by referring to the signal information, etc. is broadcast. The communication system100, the base station apparatus10, and the terminal apparatus14according to the second embodiment are of the same type as those ofFIGS.1,2, and4. The following description concerns a difference. A description of 1. an outline of the communication system will be omitted, and 2. notification of GW control will be described. FIG.11shows the structure of the application processing unit76according to the second embodiment. The application processing unit76includes the input unit110, a determination unit114, and the output unit112. As in the case of the first embodiment, the illustrated structure is related to an application for indicating that GW control is in effect, which is one of the transmitter applications executed in the application processing unit76. The input unit110may or may not acquire the information indicating that “GW control is in effect” from the GW controller80(not shown), i.e., the information indicating that the driver's vehicle12is receiving driving assistance. In other words, the process according to the second embodiment does not depend on whether or not the information indicating that the driver's vehicle12is receiving driving assistance is received. Meanwhile, the input unit110also acquires the information indicating that “the speed changes” or “the vehicle turns right or left” from the GW controller80(not shown), i.e., the information indicating that the running condition is changed due to the driving assistance. The determination unit114receives from the GW controller80the speed derived by the GW controller80. The determination unit114also receives the current speed via the acquisition unit64. The determination unit114derives a cumulative difference between these speed values. If the cumulative value is smaller than a threshold value, the determination unit114determines that the vehicle is being driven in a manner similar to GW driving. In other words, the determination unit114determines whether the running condition of the driver's vehicle12approximates the running condition achieved by driving assistance regardless of whether the information indicating that the driver's vehicle is receiving driving assistance is received or not. If the determination unit114identifies similarity, the output unit112outputs the information indicating that GW control is in effect to the application manager78. In other words, the determination unit114similarly outputs the information as it does when the input unit110receives the information indicating that the driver's vehicle12is receiving driving assistance. When the determination unit114identifies similarity and when the input unit110acquires the information indicating that the speed changes or the information indicating that the vehicle turns right or left, the output unit112also outputs the information to the application manager78. FIG.12is a flowchart showing steps of estimation performed by the application processing unit76. The determination unit114receives the speed under GW control (S30). The determination unit114receives the current speed (S32). If the difference between the speed values is small over a predetermined period (Y in S34), the determination unit114determines that GW control is in effect (S36). If the difference between the speed values is not small (N in S34), step36(S36) is skipped. According to the second embodiment, notification given when the vehicle is receiving driving assistance is similarly given when the vehicle is in a running condition approximating the condition achieved by driving assistance. Therefore, the drivers of other vehicles can know that the notifying vehicle is virtually receiving driving assistance. Further, since the notification is given when the notifying vehicle is virtually in a running condition achieved by driving assistance, the drivers of other vehicles can know that the notifying vehicle is virtually traveling in a GW mode. Third Embodiment Like the foregoing embodiments, the third embodiment also relates to a notification device capable of notifying vehicles around that acceleration or deceleration, or right or left turn of a vehicle is induced by GW driving. Meanwhile, the communication system in which road-to-vehicle communication as well as inter-vehicle communication is performed may or may not be assumed in the third embodiment. The notification device according to the third embodiment gives notification that the vehicle is being driven in a GW mode by flashing the tail lamp, etc. The following description concerns the difference from the foregoing embodiments. FIG.13shows the structure of a notification device82according to the third embodiment. The vehicle12includes the notification device82and a tail lamp84in addition to the GW controller80and the navigator86. The GW controller80and the navigator86are configured similarly as above. When the GW controller80is performing GW driving, the notification device82receives information indicating that “GW control is in effect” and notifies vehicles around that “GW control is in effect” by flashing the tail lamp84. For example, this is done before decreasing the speed. Instead of flashing the tail lamp84, the direction light may he flashed. In other words, an arbitrary state indicator capable of displaying the status may be used instead of the tail lamp84. Still alternatively, the lamp or light may be lighted with brightness different from normal. According to the third embodiment, vehicles around are notified that the vehicle is being driven in a GW mode by the flashing of a lamp, etc. Therefore, the drivers of other vehicles not provided with terminal apparatus can know that the notifying vehicle is being driven in a GW mode. Because the drivers of other vehicles not provided with a terminal apparatus can know that the notifying vehicle is being driven in a GW mode, the likelihood of implementation is increased. Described above is an explanation based on an exemplary embodiment. The embodiment is intended to be illustrative only and it will be obvious to those skilled in the art that various modifications to constituting elements and processes could be developed and that such modifications are also within the scope. In the first and second embodiments, ITS (e.g., ITS compatible with the standard for 700 Hz band intelligent transport systems) is used for communication between the plurality of terminal apparatuses14. However, the example given is non-limiting. For example, the plurality of terminal apparatuses14may communicate with each other according to CSMA/CA as in wireless LAN. According to this variation, flexibility of communication between the plurality of terminal apparatuses14is improved. The first through third embodiments are adapted to assist GW driving. However, the target of driving assistance may be ordinary automatic driving instead of GW driving. According to this variation, the target of driving assistance is extended. In the first embodiment, notification from the output unit112is given before the speed actually changes or before the vehicle actually turns right or left. However, the example given is non-limiting. For example, if the vehicle12is provided with a device for preventing collision, notification may be given when an obstacle is detected and before the vehicle12is braked. According to this variation, notification is given before the vehicle is braked so that a collision accident is prevented from occurring. Combinations of the first through third embodiments will also be useful. According to this variation, the advantages from an arbitrary combinations of the first through third embodiments are obtained. In the embodiments described above, the packet signal may be compatible with the standard for 700 Hz band intelligent transport systems. A summary of one embodiment is as described below. A notification device according to one embodiment is mounted on a vehicle and includes an acquisition unit that acquires information indicating that a driver's vehicle is receiving driving assistance, and an output unit that outputs notification to other vehicles in accordance with the information acquired by the acquisition unit. According to this embodiment, when the information indicating that the driver's vehicle is receiving driving assistance, the driver's vehicle outputs notification to other vehicles. Therefore, the drivers of the other vehicles can know that the notifying vehicle is receiving driving assistance. The acquisition unit may also acquire information indicating that a running condition is changed due to the driving assistance, and the output unit may output notification to the other vehicles when the acquisition unit acquires the information indicating that the running condition is changed due to the driving assistance. In this case, by outputting notification to the other vehicles when the information indicating that the running condition is changed is received, the drivers of the other vehicles can know that the running condition is changed due to the driving assistance. The output unit may output notification to the other vehicles before the running condition is changed, when the acquisition unit receives the information indicating that the running condition is changed due to the driving assistance. In this case, the reason of notification is made clear by outputting notification before the running condition is changed. The notification device may further include a determination unit that determines whether a running condition of the driver's vehicle approximates a running condition achieved by driving assistance, regardless of whether or not the acquisition unit acquires the information indicating that the driver's vehicle is receiving driving assistance. When the determination unit identifies similarity, the output unit may similarly output the information as it does when the acquisition unit acquires the information indicating that the driver's vehicle is receiving driving assistance. In this case, notification is similarly output when the running condition approximates the running condition achieved by driving assistance as it is when the notifying vehicle is receiving driving assistance. Therefore, the drivers of other vehicles can know that the notifying vehicle is virtually receiving driving assistance. The notification device may further include a radio unit that transmits a packet signal including the notification output from the output unit. In this case, notification is issued widely because the notification is included in the packet signal. The notification device may farther include a display unit that lights in accordance with the notification output from the output unit. In this case, by lighting the display unit in accordance with the notification, the notification is directly issued. Another embodiment of the present invention relates to a vehicle. The vehicle has a notification device mounted thereon. The notification device includes an acquisition unit that acquires information indicating that a driver's vehicle is receiving driving assistance, and an output unit that outputs notification to other vehicles in accordance with the information acquired by the acquisition unit. When the vehicle according to the embodiment of the present invention acquires information indicating that the vehicle is receiving driving assistance, the vehicle outputs notification to other vehicles. Thus, the vehicle can let the drivers of the other vehicles know that the notifying vehicle is receiving driving assistance. | 54,088 |
RE49839 | DETAILED DESCRIPTION Hereinafter, embodiment of the present invention are described in detail it is to be noted that the same reference numbers are used throughout the drawings to refer to the same elements. The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of embodiments of the present invention as defined by the claims and their equivalents. It includes various details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skilled in the art will recognize that various changes and modifications of the embodiments of the present invention described herein can be made without departing from the scope and spirit of the present invention. In addition, descriptions of well-known functions and constructions may be omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited their dictionary meanings, but, are merely used to enable a clear and consistent understanding of the present invention. Accordingly, it should be apparent to those skilled in the art that the following description of embodiments of the present invention is provided for illustration purpose only and not for the purpose of limiting the present invention as defined by the appended claims and their equivalents. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component surface” includes reference to one or more of such surfaces. By the term “substantially” it is meant that the recited characteristic, parameter, or value need not be achieved exactly, but that deviations or variations, including for example, tolerances, measurement error, measurement accuracy limitations and other factors known to those of skill in the art, may occur in amounts that do not preclude the effect the characteristic was intended to provide. First, reference will be made toFIGS.1to11, to describe the concept of the wireless charging system to which embodiments of the present invention are applicable. Next, reference will be made toFIGS.12to25, to describe in detail methods for generating a load variation according to various embodiments of the present invention. FIG.1illustrates a wireless charging system. As shown inFIG.1, the wireless charging system includes a wireless power transmitting unit100and one or more wireless power receiving units110-1,110-2, . . . , and110-n. The wireless power transmitting unit100wirelessly transmits power1-1,1-2, . . . , and1-n to the one or more wireless power receiving units110-1,110-2, . . . , and110-n, respectively. The wireless power transmitting unit100wirelessly transmits the power1-1,1-2, . . . , and1-n only to the wireless power receiving units authorized through a preset authentication process. The wireless power transmitting unit100forms wireless connections with the wireless power receiving units110-1,110-2, . . . , and110-n. For example, the wireless power transmitting unit100transmits wireless power to the wireless power receiving units110-1,110-2, . . . , and110-n through electromagnetic waves. The one or more wireless power receiving units110-1,110-2, . . . , and110-n wirelessly receive power from the wireless power transmitting unit100to charge batteries inside the wireless power receiving units110-1,110-2, . . . , and110-n. Further, the one or more wireless power receiving units110-1,110-2, . . . , and110-n transmits messages2-1,2-2, . . . , and2-n including a request for wireless power transmission, information required for reception of wireless power, state information of the wireless power receiving units110-1,110-2, . . . , and110-n and information (that is, control information) for controlling the wireless power transmitting unit100to the wireless power transmitting unit100. Similarly, the wireless power transmitting unit100transmits a message including state information of the wireless power transmitting unit100and information (that is, control information) for controlling the wireless power receiving units110-1,110-2, . . . , and110-n to the wireless power receiving units110-1,110-2, . . . , and110-n. Further, each of the wireless power receiving units110-1,110-2, . . . , and110-n transmits a message indicating a charging state to the wireless power transmitting unit100. The wireless power transmitting unit100includes a display unit such as a display, and displays a state of each of the wireless power receiving units110-1,110-2, and110-n based on the message received from each of the wireless power receiving units110-1,110-2, . . . , and110-n. Further, the wireless power transmitting unit100also displays a time expected to be spent until each of the wireless power receiving units110-1,110-2, . . . , and110-n is completely charged. The wireless power transmitting unit100transmits a control signal (or control message) for disabling a wireless charging function of each of the one or more wireless power receiving units110-1,110-2, . . . , and110-n. The wireless power receiving units having received the disable control signal of the wireless charging function from the wireless power transmitting unit100disable the wireless charging function. FIG.2illustrates a wireless power transmitting unit and a wireless power receiving unit according to an embodiment of the present invention. As illustrated inFIG.2, the wireless power transmitting unit200includes at least a power transmitter211, a controller212, a communication unit213, a display unit214, and a storage unit215. Further, the wireless power receiving unit250includes a power receiver251, a controller252, and a communication unit253. The power transmitter211supplies power which is required by the wireless power transmitting unit200, and wirelessly provides power to the wireless power receiving unit250. The power transmitter211supplies power in an Alternating Current (AC) waveform type, or converts power in a Direct Current (DC) waveform type to the power in the AC waveform type by using an inverter, and then supplies the power in the AC waveform type. The power transmitter211is implemented in a form of an embedded battery or in a form of a power receiving interface so as to receive the power from outside thereof and supply the power to the other components. It will be easily understood by those skilled in the art that the power transmitter211is not limited if it supplies power of constant alternate current waves. The controller212controls overall operations of the wireless power transmitting unit200. The controller212controls overall operations of the wireless power transmitting unit200by using an algorithm, a program, or an application which is required for a control and reads from the storage unit215. The controller212may be implemented in a form of a CPU, a microprocessor, a mini computer and the like. The communication unit213communicates with the wireless power receiving unit250. The communication unit213receives power information from the wireless power receiving unit250. Here, the power information includes at least one of a capacity of the wireless power receiving unit250, a residual amount of the battery, a number of times of charging, an amount of use, a battery capacity, and a proportion of the remaining battery capacity. Further, the communication unit213transmits a signal of controlling a charging function in order to control the charging function of the wireless power receiving unit250. The signal of controlling the charging function may be a control signal for controlling the power receiver251of the wireless power receiving unit250so as to enable or disable the charging function. More specifically, the power information may include information on an insertion of a wireless charging terminal, a transition from a Stand Alone (SA) mode to a Non-Stand Alone (NSA) mode, error state release and the like. The communication unit213receives a signal from another wireless power transmitting unit (not shown) as well as from the wireless power receiving unit250. The controller212displays a state of the wireless power receiving unit250on a display unit214based on the message received from the wireless power receiving unit250through the communication unit213. Further, the controller212also displays a time expected to be spent until the wireless power receiving unit is completely charged on the display unit214. FIG.3is a block diagram illustrating the wireless power transmitting unit200and the wireless power receiving unit250according to an embodiment of the present invention. As illustrated inFIG.3, the wireless power transmitting unit200includes the power transmitter211, the controller/communication unit (Multipoint Control Unit (MCU) & Out-of-band Signaling)212/213, a driver (Power Supply)217, an amplifier (Power Amp)218, and a matching unit (Matching Circuit)216. The wireless power receiving unit250includes the power receiver251, the controller/communication unit252/253, a DC/DC converter255, a switching unit (Switch)256, and a loading unit (Client Device Load)257. The driver217outputs DC power having a preset voltage value. The voltage value of the DC power output by the driver217is controlled by the controller/communication unit212/213. The DC power output from the driver217is output to the amplifier218, which amplifies the DC power by a preset gain. Further, the amplifier218converts DC power to AC power based on a signal input from the controller/communication unit212/213. Accordingly, the amplifier218outputs AC power. The matching unit216performs impedance matching. For example, the matching unit216adjusts impedance viewed from the matching unit216to control output power to be high efficient or high output power. The matching unit216also adjusts impedance based on a control of the controller/communication unit212/213. The matching unit216includes at least one of a coil and a capacitor. The controller/communication unit212/213controls a connection state with at least one of the coil and the capacitor, and accordingly, performs impedance matching. The power transmitter211transmits input AC power to the power receiver251. The power transmitter211and the power receiver251are implemented by resonant circuits having the same resonance frequency. For example, the resonance frequency may be 6.78 MHz. The controller/communication unit212/213communicates with the controller/communication unit252/253of the wireless power receiving unit250, and performs communication (Wireless Fidelity (WiFi), ZigBee, or Bluetooth (BT)/Bluetooth Low Energy (BLE)), for example, with a bidirectional 2.4 GHz frequency. The power receiver251receives charging power. The rectifying unit254rectifies wireless power received by the power receiver251in the form of direct current, and is implemented in a form of bridge diode. The DC/DC converter255converts the rectified electric current into a predetermined gain. For example, the DC/DC converter255converts the rectified electric current so that a voltage of an output end259becomes 5V. Meanwhile, a minimum value and a maximum value of the voltage which can be applied is preset for a front end258of the DC/DC converter255. The switching unit256connects the DC/DC converter255to the loading unit257. The switching unit256is held in an on/off state under a control of the controller252. In a case where the switch256is in the ON state, the loading unit257stores converted electric power which is input from the DC/DC converter255. FIG.4is a flow diagram illustrating operations of the wireless power transmitting unit and the wireless power receiving unit according to an embodiment of the present invention. As illustrated inFIG.4, a wireless power transmitting unit400applies power in operation S401. When the power is applied, the wireless power transmitting unit400configures an environment in operation S402. The wireless power transmitting unit400enters a power saving mode in operation S403. In the power saving mode, the wireless power transmitting unit400applies different types of power beacons for detection according to their own periods, which will be described in more detail with reference toFIG.6. For example, inFIG.4, the wireless power transmitting unit400applies detection power beacons404and405, and the sizes of power values of the detection power beacons404and405may be different. A part or all of the detection power beacons404and405may have power enough to drive the communication unit of the wireless power receiving unit450. For example, the wireless power receiving unit450drives the communication unit by the part or all of the detection power beacons404and405to communicate with the wireless power transmitting unit400. The above state is named a null state in operation S406. The wireless power transmitting unit400detects a load change by an arrangement of the wireless power receiving unit450. The wireless power transmitting unit400enters a low power mode in operation S409. The low power mode will be described in more detail with reference toFIG.6. Meanwhile, the wireless power receiving unit450drives the communication unit based on power received from the wireless power transmitting unit400in operation S409. The wireless power receiving unit450transmits a PTU searching signal to the wireless power transmitting unit400in operation S410. The wireless power receiving unit450transmits the PTU searching signal as an advertisement signal based on a Bluetooth Low Energy (BLE) scheme. The wireless power receiving unit450transmits the PTU searching signal periodically or until a preset time arrive, and receives a response signal from the wireless power transmitting unit400. When receiving the PTU searching signal from the wireless power receiving unit450, the wireless power transmitting unit400transmits a PRU response signal in operation S411. The PRU response signal forms a connection between the wireless power transmitting unit400and the wireless power receiving unit450. The wireless power receiving unit450transmits a PRU static signal in operation S412. The PRU static signal is a signal indicating that the wireless power receiving unit450is making a request for joining the wireless power network managed by the wireless power transmitting unit400. The wireless power transmitting unit400transmits a PTU static signal in operation S413. The PTU static signal transmitted by the wireless power transmitting unit400is a signal indicating a capability of the wireless power transmitting unit400. When the wireless power transmitting unit400and the wireless power receiving unit450transmit and receive the PRU static signal and the PTU static signal, the wireless power receiving unit450periodically transmits a PRU dynamic signal in operations S414and S415. The PRU dynamic signal includes at least one parameter information measured by the wireless power receiving unit450. For example, the PRU dynamic signal may include voltage information of a back end of the rectifier of the wireless power receiving unit450. The state of the wireless power receiving unit450is called a boot state in operation S407. The wireless power transmitting unit400enters a power transmission mode in operation S416and transmits a PRU control signal corresponding to a command signal to allow the wireless power receiving unit450to be charged in operation S417. In the power transmission mode, the wireless power transmitting unit400transmits charging power. The PRU control signal transmitted by the wireless power transmitting unit400includes information enabling/disabling the charging of the wireless power receiving unit450and permission information. The PRU control signal is transmitted whenever a charging state is changed. The PRU control signal is transmitted, for example, every 250 ms, or transmitted when a parameter is changed. The PRU control signal is set to be transmitted within a preset threshold, for example, within one second even though the parameter is not changed. The wireless power receiving unit450changes a configuration according to the PRU control signal and transmits the PRU dynamic signal for reporting the state of the wireless power receiving unit450in operations S418and S419. The PRU dynamic signal transmitted by the wireless power receiving unit450includes at least one of information on a voltage, a current, a state of the wireless power receiving unit, and temperature. The state of the wireless power receiving unit450is called an ON state in operation S421. For example, the PRU dynamic signal has a data structure as shown in Table 1 below. TABLE 1-contFieldoctetsdescriptionuseunitsoptional1defines which optionalmandatoryfieldsfields are populatedVrect2DC voltage at themandatorymVoutput of the rectifierIrect2DC current at themandatorymAoutput of the rectifierVout2voltage at charge/optionalmVbattery portIout2current at charge/optionalmAbattery porttemperature1temperature of PRUoptionalDeg C.from −40° C.Vrect min dyn2The current dynamicoptionalmVminimum rectifiervoltage desiredVrect set dyn2desired VrectoptionalmV(dynamic value)Vrect high dyn2The current dynamicoptionalmVmaximum rectifiervoltage desiredPRU alert1warningsmandatoryBitfieldRFU3undefined As shown in Table 1, the PRU dynamic signal includes one or more fields. The fields include optional field information, voltage information of a back end of the rectifier of the wireless power receiving unit (‘Vrect’), current information of the back end of the rectifier of the wireless power receiving unit (‘Irect’), voltage information of a back end of the DC/DC converter of the wireless power receiving unit (‘Vout’), current information of the back end of the DC/DC converter of the wireless power receiving unit (‘Iout’), temperature information (‘temperature’), minimum voltage value information of the back end of the rectifier of the wireless power receiving unit (‘Vrect min dyn’), optimal voltage value information of the back end of the rectifier of the wireless power receiving unit (‘Vrect set dyn’), maximum voltage value information of the back end of the rectifier of the wireless power receiving unit (‘Vrect high dyn’), alert information (‘PRU alert’) and RFU (Reserved for Future Use). The PRU dynamic signal includes at least one of the above fields. For example, one or more voltage setting values (for example, the minimum voltage value information (Vrect min dyn) of the back end of the rectifier of the wireless power receiving unit, the optimal voltage value information (Vrect set dyn) of the back end of the rectifier of the wireless power receiving unit, and the maximum voltage value information (Vrect high dyn) of the back end of the rectifier of the wireless power receiving unit) determined according to a charging state is inserted into corresponding fields and then transmitted. As described above, the wireless power receiving unit having received the PRU dynamic signal controls a wireless charging voltage to be transmitted to each of the wireless power receiving units with reference to the voltage setting values included in the PRU dynamic signal. For example, the alert information (PRU Alert) has a data structure shown in Table 2 below. TABLE 276543210over-over-over-ChargeTA detectTransitionrestartRFUvoltagecurrenttemperatureCompleterequest Referring to Table 2, the alert information (PRU Alert) includes a bit for a restart request, a bit for a transition, and a bit for detecting an insertion of a Travel Adapter (TA) (TA detect). The TA detect indicates a bit informing of a connection between the wireless power transmitting unit providing wireless charging and a terminal for wired charging by the wireless power receiving unit. The transition indicates a bit informing the wireless power transmitting unit that the wireless power receiving unit is reset before a communication Integrated Circuit (IC) of the wireless power receiving unit is switched from a Stand Alone (SA) mode to a Non Stand Alone (NSA) mode. Lastly, the restart request indicates a bit informing the wireless power receiving unit that the wireless power transmitting unit is ready to restart the charging when the charging is disconnected since the wireless power transmitting unit reduces power due to the generation of an over current state or a over temperature state and then the state is returned to an original state. Further, the alert information (PRU Alert) has a data structure shown in Table 3 below. TABLE 376543210PRUPRUPRUPRUChargeWiredModeModeover-over-over-SelfCompleteChargerTransitionTransitionvoltagecurrenttemperatureProtectionDetectBit 1Bit 0 Referring to Table 3 above, the alert information includes over voltage, over current, over temperature, PRU self protection, charge compete, wired charger detect, mode transition and the like. When the over voltage field is set as “1”, it indicates that a voltage Vrect of the wireless power receiving unit exceeds a limit of the over voltage. Further, the over current and the over temperature may be set in the same way as the over voltage. The PRU self protection indicates that the wireless power receiving unit directly reduces a load of power and thus protects itself. In this event, the wireless power transmitting unit is not required to change a charging state. Bits for a mode transition according to an embodiment of the present invention are set as a value informing the wireless power transmitting unit of a period during which a mode transition process is performed. The bits indicating the mode transition period are expressed as shown in Table 4 below. TABLE 4Value (Bit)Mode Transition Bit Description00No Mode Transition012 s Mode Transition time limit103 s Mode Transition time limit116 s Mode Transition time limit Referring to Table 4 above, “00” indicates that there is no mode transition, “01” indicates that a time required for completing the mode transition is a maximum of two seconds, “10” indicates that a time required for completing the mode transition is a maximum of three seconds, and “11” indicates that a time required for completing the mode transition is a maximum of six seconds. For example, when three seconds or less are spent for completing the mode transition, the mode transition bit is set as “10”. Prior to starting the mode transition process, the wireless power receiving unit may make a restriction such that there is no change in impedance during the mode transition process by changing an input impedance setting to match 1.1 W power draw. Accordingly, the wireless power transmitting unit controls power (ITX_COIL) for the wireless power receiving unit in accordance with the setting, and accordingly, maintain the power (ITX_COIL) for the wireless power receiving unit during the mode transition period. Accordingly, when the mode transition period is set by the mode transition bit, the wireless power transmitting unit maintains the power (ITX_COIL) for the wireless power receiving unit during the mode transition time, for example, three seconds. That is, the wireless power transmitting unit maintains a connection even though a response is not received from the wireless power receiving unit for three seconds. However, after the mode transition time passes, the wireless power receiving unit is considered as a rogue object (foreign substance) and thus power transmission is terminated. Meanwhile, the wireless power receiving unit450detects the generation of errors. The wireless power receiving unit450transmits an alert signal to the wireless power transmitting unit400in operation S420. The alert signal is transmitted as the PRU dynamic signal or the alert signal. For example, the wireless power receiving unit450transmits the PRU alert field of Table 3 reflecting an error state to the wireless power transmitting unit400. Alternatively, the wireless power receiving unit450transmits a single alert signal indicating the error state to the wireless power transmitting unit400. When receiving the alert signal, the wireless power transmitting unit400enters a latch fault mode in operation S422, and the wireless power receiving unit450enters a null state in operation S423. FIG.5is a flowchart illustrating operations of the wireless power transmitting unit and the wireless power receiving unit according to another embodiment of the present invention. A control method ofFIG.5will be described in more detail with reference toFIG.6.FIG.6is a graph on an x axis of a power amount applied by the wireless power transmitting unit according toFIG.5. As illustrated inFIG.5, the wireless power transmitting unit initiates the operation in operation S501. Further, the wireless power transmitting unit resets an initial configuration in operation S503. The wireless power transmitting unit enters a power saving mode in operation S505. The power saving mode corresponds to an interval where the wireless power transmitting unit applies power having different amounts to the power transmitter. For example, the power saving mode may correspond to an interval where the wireless power transmitting unit applies second power601and602and third power611,612,613,614, and615to the power transmitter inFIG.6. The wireless power transmitting unit periodically applies the second power601and602according to a second period. When the wireless power transmitting unit applies the second power601and602, the application continues for a second term. The wireless power transmitting unit periodically applies the third power611,612,613,614, and615according to a third period. When the wireless power transmitting unit applies the third power611,612,613,614, and615, the application continues for a third term. Meanwhile, although it is illustrated that power values of the third power611,612,613,614, and615are different from each other, the power values of the third power611,612,613,614, and615may be different or the same. The wireless power transmitting unit may output the third power611and then output the third power612having the same size of the power amount. As described above, when the wireless power transmitting unit outputs the third power having the same size, the power amount of the third power may have a power amount by which a smallest wireless power receiving unit, for example, a wireless power receiving unit designated as Category 1 can be detected. The wireless power transmitting unit may output the third power611and then output the third power612having a different size of the power amount. As described above, when the wireless power transmitting unit outputs the third power having the different size, the power amount of the third power may be a power amount by which a wireless power receiving unit designated as Category 1 to Category 5 can be detected. For example, when the third power611may have a power amount by which a wireless power receiving unit of Category 5 can be detected, the third power612may have a power amount by which a wireless power receiving unit designated as Category 3 can be detected, and the third power613may have a power amount by which a wireless power receiving unit designated as Category 1 can be detected. Meanwhile, the second power601and602may be a power amount which can drive the wireless power receiving unit. More specifically, the second power601and602may have a power amount which can drive the controller and the communication unit of the wireless power receiving unit. The wireless power transmitting unit applies the second power601and602and the third power611,612,613,614, and615to the power receiver according to a second period and a third period, respectively. When the wireless power receiving unit is arranged on the wireless power transmitting unit, impedance viewed from a point of the wireless power transmitting unit may be changed. The wireless power transmitting unit detects a change in the impedance while the second power601and602and the third power611,612,613,614, and615are applied. For example, the wireless power transmitting unit may detect the change in the impedance while the third power615is applied. Accordingly, referring back toFIG.5, the wireless power transmitting unit detects an object in operation S507. When the object is not detected in operation S507, the wireless power transmitting unit maintains a power saving mode in which different power is periodically applied. When there is a change in the impedance and thus the object is detected in operation S507, the wireless power transmitting unit enters a low power mode in operation S509. The low power mode is a mode in which the wireless power transmitting unit applies driving power having a power amount by which the controller and the communication unit of the wireless power receiving unit can be driven. For example, inFIG.6, the wireless power transmitting unit applies driving power620to the power transmitter. The wireless power receiving unit receives the driving power620to drive the controller and the communication unit. The wireless power receiving unit performs communication with the wireless power transmitting unit according to a predetermined scheme based on the driving power620. For example, the wireless power receiving unit transmits/receives data required for an authentication and joins the wireless power network managed by the wireless power transmitting unit based on the data. However, when a rogue object is arranged instead of the wireless power receiving unit, data transmission/reception cannot be performed. Accordingly, the wireless power transmitting unit determines whether the arranged object is a rogue object in operation S511. For example, when the wireless power transmitting unit does not receive a response from the object within a preset time, the wireless power transmitting unit determines the object as a rogue object. When the object is determined as a rogue object in operation S511, the wireless power transmitting unit enters a latch fault mode. When the object is not determined as a rogue object in operation S511, the wireless power transmitting unit performs a joining operation in operation S519. For example, the wireless power transmitting unit periodically applies first power631to634according to a first period inFIG.6. The wireless power transmitting unit may detect a change in impedance while applying the first power. For example, when the rogue object is withdrawn or removed, the impedance change is detected and the wireless power transmitting unit determines that the rogue object is withdrawn. Alternatively, when the rogue object is not withdrawn, the wireless power transmitting unit does not detect the impedance change and determines that the rogue object is not withdrawn. When the rogue object is not withdrawn, the wireless power transmitting unit outputs at least one of a lamp and a warning sound to inform a user that a state of the wireless power transmitting unit is an error state. Accordingly, the wireless power transmitting unit includes an output unit that outputs at least one of a lamp and a warning sound. When it is determined that the rogue object is not withdrawn in operation S515, the wireless power transmitting unit maintains the latch fault mode in operation S513. When it is determined that the rogue object is withdrawn in operation S515, the wireless power transmitting unit enters the power saving mode again in operation S517. For example, the wireless power transmitting unit applies second power651and652and third power661to665, as shown inFIG.6. As described above, when the rogue object is arranged instead of the wireless power receiving unit, the wireless power transmitting unit enters the latch fault mode. Further, the wireless power transmitting unit determines whether to withdraw the rogue object by the impedance change based on the power applied in the latch fault mode. That is, a condition of the entrance into the latch fault mode in the embodiment ofFIGS.5and6may be the arrangement of the rogue object. Meanwhile, the wireless power transmitting unit may have various latch fault mode entrance conditions as well as the arrangement of the rogue object. For example, the wireless power transmitting unit may be cross-connected with the arranged wireless power receiving unit and may enter the latch fault mode in the above case. Accordingly, when cross-connection is generated, the wireless power transmitting unit is required to return to an initial state and the wireless power receiving unit is required to be withdrawn. The wireless power transmitting unit sets the cross-connection by which the wireless power receiving unit arranged on another wireless power transmitting unit joins the wireless power network as the latch fault mode entrance condition. An operation of the wireless power transmitting unit when the error is generated which includes the cross-connection will be described with reference toFIG.7. FIG.7is a flowchart illustrating a control method of the wireless power transmitting unit according to an embodiment of the present invention. The control method ofFIG.7will be described in more detail with reference toFIG.8.FIG.8is a graph on an x axis of a power amount applied by the wireless power transmitting unit according to the embodiment ofFIG.7. The wireless power transmitting unit initiates the operation in operation S701. Further, the wireless power transmitting unit resets an initial configuration in operation S703. The wireless power transmitting unit enters the power saving mode in operation S705. The power saving mode is an interval where the wireless power transmitting unit applies power having different amounts to the power transmitter. For example, the power saving mode may correspond to an interval where the wireless power transmitting unit applies second power801and802and third power811,812,813,814, and815to the power transmitter inFIG.8. The wireless power transmitting unit periodically applies the second power801and802according to a second period. When the wireless power transmitting unit applies the second power801and802, the application continues for a second term. The wireless power transmitting unit periodically applies the third power811,812,813,814, and815according to a third period. When the wireless power transmitting unit applies the third power811,812,813,814, and815, the application continues for a third term. Meanwhile, although it is illustrated that power values of the third power811,812,813,814, and815are different from each other, the power values of the third power811,812,813,814, and815may be different or the same. The second power801and802is power which can drive the wireless power receiving unit. More specifically, the second power601and602has a power amount which can drive the controller and the communication unit of the wireless power receiving unit. The wireless power transmitting unit applies the second power801and802and the third power811,812,813,814, and815to the power receiver according to a second period and a third period, respectively. When the wireless power receiving unit is arranged on the wireless power transmitting unit, impedance viewed from a point of the wireless power transmitting unit may be changed. The wireless power transmitting unit detects the impedance change while the second power801and802and the third power811,812,813,814, and815are applied. For example, the wireless power transmitting unit may detect the impedance change while the third power815is applied. Accordingly, referring back toFIG.7, the wireless power transmitting unit detects an object in operation S707. When the object is not detected in operation S707, the wireless power transmitting unit maintains the power saving mode in which different power is periodically applied in operation S705. When the impedance is changed and thus the object is detected in operation S707, the wireless power transmitting unit enters the low power mode in operation S709. The low power mode is a mode in which the wireless power transmitting unit applies driving power having a power amount by which the controller and the communication unit of the wireless power receiving unit can be driven. For example, inFIG.8, the wireless power transmitting unit applies driving power820to the power transmitter. The wireless power receiving unit receives the driving power820to drive the controller and the communication unit. The wireless power receiving unit performs communication with the wireless power transmitting unit according to a predetermined scheme based on the driving power820. For example, the wireless power receiving unit transmits/receives data required for an authentication and joins the wireless power network managed by the wireless power transmitting unit based on the data. Thereafter, the wireless power transmitting unit enters the power transmission mode in which charging power is transmitted in operation S711. For example, the wireless power transmitting unit applies charging power821and the charging power is transmitted to the wireless power receiving unit as illustrated inFIG.8. The wireless power transmitting unit determines whether an error is generated in the power transmission mode. The error may be the arrangement of a rogue object on the wireless power transmitting unit, the cross-connection, over voltage, over current, over temperature and the like. The wireless power transmitting unit includes a sensing unit that measures the over voltage, the over current, over temperature and the like. For example, the wireless power transmitting unit may measure a voltage or a current at a reference position. When the measured voltage or current is larger than a threshold, it is determined that conditions of the over voltage or the over current are satisfied. Alternatively, the wireless power transmitting unit includes a temperature sensing means which measures temperature at a reference position of the wireless power transmitting unit. When temperature at the reference position is larger than a threshold, the wireless power transmitting unit determines that a condition of the over temperature is satisfied. When an over voltage, over current, or over temperature state is determined according to a measurement value of the temperature, voltage, or current, the wireless power transmitting unit prevents the over voltage, over current, or over temperature by reducing the wireless charging power by a preset value. At this time, when a voltage value of the reduced wireless charging power is less than a preset minimum value (for example, the minimum voltage value (VRECT MIN DYN) of the back end of the rectifier of the wireless power receiving unit), the wireless charging is interrupted or stopped, so that the voltage setting value is re-controlled according to an embodiment of the present invention. Although it has been illustrated that the error is generated since the rogue object is additionally arranged on the wireless power transmitting unit in the embodiment ofFIG.8, the type of error is not limited thereto and it will be easily understood by those skilled in the art that the wireless power transmitting unit operates through a similar process with respect to the arrangement of the rogue object, the cross-connection, the over voltage, the over current, and the over temperatures. When the error is not generated in operation S713, the wireless power transmitting unit maintains the power transmission mode in operation S711. Meanwhile, when the error is generated in operation S713, the wireless power transmitting unit enters the latch fault mode in operation S715. For example, the wireless power transmitting unit applies first power831to835as illustrated inFIG.8. Further, the wireless power transmitting unit outputs an error generation display including at least one of a lamp and a warning sound during the latch fault mode. When it is determined that the1rogue object is not withdrawn in operation S717, the wireless power transmitting unit maintains the latch fault mode in operation S715. Meanwhile, when it is determined that the rogue object is withdrawn in operation S717, the wireless power transmitting unit enters the power saving mode again in operation S719. For example, the wireless power transmitting unit applies second power851and852and third power861to865ofFIG.8. In the above description, the operation in a case where the error is generated while the wireless power transmitting unit transmits the charging power has been discussed. Hereinafter, an operation in a case where a plurality of wireless power receiving units on the wireless power transmitting unit receives charging power will be described. FIG.9is a flowchart for describing a control method of a wireless power transmitting unit according to an embodiment of the present. The control method ofFIG.9will be described in more detail with reference toFIG.10.FIG.10is a graph on an x axis of an amount of power applied by a wireless power transmitting unit according to the embodiment ofFIG.9. As illustrated inFIG.9, the wireless power transmitting unit transmits charging power to a first wireless power receiving unit in operation S901. Further, the wireless power transmitting unit allows a second wireless power receiving unit to additionally join the wireless power network in operation S903. The wireless power transmitting unit transmits charging power to the second wireless power receiving unit in operation S905. More specifically, the wireless power transmitting unit applies a sum of the charging power required by the first wireless power receiving unit and the second wireless power receiving unit to the power receiver. FIG.10illustrates an embodiment of operations S901to S905. For example, the wireless power transmitting unit maintains the power saving mode in which second power1001and1002and third power1011to1015are applied. Thereafter, the wireless power transmitting unit detects the first wireless power receiving unit and enters the low power mode in which a detection power1020applied to the first wireless power receiving unit to detect is maintained. Next, the wireless power transmitting unit enters the power transmission mode in which first charging power1030is applied. The wireless power transmitting unit detects the second wireless power receiving unit and allows the second wireless power receiving unit to join the wireless power network. Further, the wireless power transmitting unit applies second charging power1040having a power amount corresponding to a sum of power amounts required by the first wireless power receiving unit and the second wireless power receiving unit. Referring back toFIG.9, the wireless power transmitting unit detects error generation in operation S907while charging power is transmitted to both the first and second wireless power receiving units in operation S905. As described above, the error may be the arrangement of the rogue object, the cross-connection, the over voltage, the over current, the over temperature and the like. When the error is not generated in operation S907, the wireless power transmitting unit maintains the application of the second charging power1040. When the error is generated in operation, the wireless power transmitting unit enters the latch fault mode in operation S909. For example, the wireless power transmitting unit applies first power1051to1055according to a first period inFIG.10. The wireless power transmitting unit determines whether both the first wireless power receiving unit and the second wireless power receiving unit are withdrawn in operation S911. For example, the wireless power transmitting unit may detect an impedance change while applying the first power1051to1055. The wireless power transmitting unit determines whether both the first wireless power receiving unit and the second wireless power receiving unit are withdrawn based on whether the impedance is returned to an initial value. When it is determined that both the first wireless power receiving unit and the second wireless power receiving unit are withdrawn in operation S911, the wireless power receiving unit enters the power saving mode in operation S913. For example, the wireless power transmitting unit applies second power1061and1062and third power1071to1075according to a second period and a third period, respectively. As described above, even when the wireless power transmitting unit applies charging power to at least one wireless power receiving unit, the wireless power transmitting unit determines whether the wireless power receiving unit or the rogue object is easily withdrawn when the error is generated. FIG.11is a block diagram of a wireless power transmitting unit and a wireless power receiving unit in a Stand Alone (SA) mode according to an embodiment of the present invention. A wireless power transmitting unit1100includes a communication unit1110, a Power Amplifier (PA)1120, and a resonator1130. A wireless power receiving unit1150includes a communication unit (WPT Communication IC)1151, an Application Processor (AP)1152, a Power Management Integrated Circuit (PMIC)1153, a Wireless Power Integrated Circuit (WPIC)1154, a resonator1155, an InterFace Power Management (IFPM) IC1157, a Travel Adapter (TA)1158, and a battery1159. The communication unit1110may be implemented by WiFi/BlueTooth (BT) Combo IC and communicates with the communication unit1151in a predetermined scheme, for example, a BLE scheme. For example, the communication unit1151of the wireless power receiving unit1150transmits a PRU dynamic signal having the data structure as shown in Table 3 to the communication unit1110of the wireless power transmitting unit1100. As described above, the PRU dynamic signal includes at least one of voltage information, current information, temperature information, and alert information of the wireless power receiving unit1150. Based on the received PRU dynamic signal, a power value output from the power amplifier1120is adjusted. For example, when the over voltage, the over current, and the over temperature are applied to the wireless power receiving unit1150, a power value output from the power amplifier1120is reduced. Further, when a voltage or current of the wireless power receiving unit1150is less than a preset value, a power value output from the power amplifier1120is increased. Charging power from the resonator1130is wirelessly transmitted to the resonator1155. The WPIC1154rectifies the charging power received from the resonator1155and performs DC/DC conversion. The WPIC1154drives the communication unit1151or charges the battery1159by using the converted power. A wired charging terminal is inserted into the travel adapter1158. A wired charging terminal such as 30-pin connector or a Universal Serial Bus (USB) connector is inserted into the travel adapter1158, and the travel adapter1158receives power supplied from an external power source to charge the battery1159. The IFPM1157processes power applied from the wired charging terminal and outputs the processed power to the battery1159and the PMIC1153. The PMIC1153manages wirelessly received power, power received through a wire, and power applied to each of the components of the wireless power receiving unit1150. The AP1152receives power information from the PMIC1153and controls the communication unit1151to transmit the PRU dynamic signal for reporting the power information. The travel adapter1158is connected to a node1156connected to the WPIC1154. When the wired charging connector is inserted into the travel adapter1158, a preset voltage, for example, 5 V may be applied to the node1156. The WPIC1154monitors the voltage applied to the node1156to determine whether the travel adapter is inserted. The AP1152has a stack in a predetermined communication scheme, for example, a WiFi/BT/BLE stack. Accordingly, in communication for the wireless charging, the communication unit1151loads the stack from the AP1152and then communicates with the communication unit1110of the wireless power transmitting unit1100by using a BT or BLE communication scheme based on the stack. However, a state may occur in which data for performing wireless power transmission cannot be fetched from the AP1152since the AP1152is turned off or in which power is lost so that the AP1152cannot remain in an ON state while the data is fetched from a memory within the AP1152. When a residual capacity of the battery1159is less than a minimum power threshold, the AP1152is turned off, and the wireless charging can be performed using some components for the wireless charging within the wireless power receiving unit, for example, the communication unit1151, the WPIC1154, and the resonator1155. A state where the AP1152cannot be turned on is referred to as a dead battery state. Since the AP1152is not driven in the dead battery state, the communication unit1151cannot receive a stack in a predetermined communication scheme, for example, a WiFi/BT/BLE stack from the AP1152. For such a case, some of the stacks in the predetermined communication scheme, for example, the BLE stack, are fetched within the memory1162of the communication unit1151from the AP1152and stored in the memory1162. Accordingly, the communication unit1151communicates with the wireless power transmitting unit1100for the wireless charging by using the stack in the communication scheme stored in the memory1162, that is, a wireless charging protocol. At this time, the communication unit1151includes a memory therewithin, and the BLE stack may be stored in a memory in a form of a ROM in the SA mode. As described above, a mode in which the communication unit1151performs the communication by using the stack of the communication scheme stored in the memory1162is referred to as the SA mode. Accordingly, the communication unit1151manages a charging process based on the BLE stack. FIGS.12and13illustrate impedance in a case where no wireless power receiving unit is put on a wireless power transmitting unit, andFIGS.14and15illustrate impedance in a case where a wireless power receiving unit is put on a wireless power transmitting unit. Referring toFIGS.12to15, a difference between the impedance that is detected when no PRU is put on a PTU and the impedance that is detected when a PRU is put on the PTU should be large, in order for the PTU to more efficiently detect a load variation of the PRU. For example, the PTU may hardly detect a load if a change in power due to a load variation is insignificant even though a resistance varies. In addition, a point at which there is no change in reactance may exist on the PTU. Therefore, in the below-described embodiments of the present invention, a dummy load is added to a PRU as illustrated inFIGS.16and17, and a PTU efficiently detects the PRU by an operation of a dummy load switch capable of turning on/off the connection to the added dummy load. FIG.16is a circuit diagram of a wireless power receiving unit to which a dummy load is added according to an embodiment of the present invention, andFIG.17is a circuit diagram of a wireless power receiving unit to which a dummy load is added according to another embodiment of the present invention. In order to keep a big difference in impedance between a case where no PRU is put on a PTU and another case where a PRU is put on the PTU as in the Smith charts inFIGS.13and15, a dummy load is additionally connected to the circuit of the PRU as illustrated inFIGS.16and17. Referring toFIG.16, the wireless power receiving unit includes a resonator1601, rectifier1602, a DC/DC convertor1603, a controller (or Micro Control Unit (MCU)1604, and the like. The wireless power transmitted by a wireless power transmitting unit is delivered to the wireless power receiving unit through the resonator1601, the rectifier1602and the DC/DC converter1603, and if a load switch1609is in an ON state, power is supplied to a load1610. As illustrated, in the circuit, dummy loads1605and1607are connected in parallel between the resonator1601and the rectifier1602. Dummy load switches1606and1608capable of shorting or opening (e.g., turning on/off) the connection of their associated dummy loads1605and1607are further provided to connection terminals of the dummy loads1605and1607. The dummy load switches1606and1608are turned on/off by a control signal from the controller1604. Therefore, in various wireless charging circumstances, the controller1604generates a desired load variation by switching the dummy load switches1606and1608to an ON or OFF state. For example, if the dummy load switches1606and1608are in the ON state under control of the controller1604, the dummy loads1605and1607are additionally added to the circuit of the wireless power receiving unit, and the wireless power transmitting unit detects a load by detecting a variation in the load of the wireless power receiving unit. Referring toFIG.16, capacitors as AC dummy loads serves as the dummy loads1605and1607. Values (e.g., AC dummy load values) of the AC dummy loads1605and1607may be, for example, 1 nF˜2.2 nF at a frequency of 6.78 MHz. Referring toFIG.17, the wireless power receiving unit includes a resonator1701, a rectifier1702, a DC/DC convertor1703, a controller (or Micro Control Unit (MCU))1704, and the like. As inFIG.16, the wireless power transmitted by a wireless power transmitting unit is delivered to the wireless power receiving unit through the resonator1701, the rectifier1702and the DC/DC converter1703, and if a load switch1707is in the ON state, power is supplied to a load1708. As illustrated, in the circuit, a dummy load1705is connected in parallel between the rectifier1702and the DC/DC converter1703. A dummy load switch1706capable of shorting or opening (e.g., turning on/off) the connection of the dummy load1705is further provided to a connection terminal of the dummy load1705. The dummy load switch1706is turned on/off by a control signal from the controller1704. Therefore, in various wireless charging circumstances, the controller1704generates a desired load variation by switching the dummy load switch1706to the ON or OFF state. For example, if the dummy load switch1706is in the ON state under control of the controller1704, the dummy load1705is additionally added to the circuit of the wireless power receiving unit, and the wireless power transmitting unit detects a load by detecting a variation in the load of the wireless power receiving unit. Referring toFIG.17, a resistor as a DC dummy load serves as the dummy load1705. A value (e.g., DC dummy load value) of the DC dummy load1705may be, for example, 70 Ohms at a frequency of 6.78 MHz. As for the dummy loads, if power is applied to the PRU, the dummy load circuit is opened by switching the dummy load switches to the OFF state, so the dummy loads are not detected by the PTU. In other words, the dummy loads do not affect the impedance measured by the PTU. The dummy load switches may be situated in at least one of the AC dummy load circuit (FIG.16) and the DC dummy load circuit (FIG.17) as illustrated inFIGS.16and17. In accordance with various embodiments of the present invention, if power is applied to the PRU, the dummy load switches are opened. Otherwise, the dummy load switches are opened by a control signal from the MCU, after the MCU is turned on as the power is applied to the PRU. The DC dummy load switch is designed to keep the short state if no power is applied to the PRU. If power is applied to the PRU for a short period of time by a beacon transmitted by the PTU, the dummy load switch is switched from the short state to the open state, allowing the PTU to detect a large load variation. Reference will now be made toFIGS.18to25, to describe examples of detecting a load variation using a dummy load according to various embodiments of the present invention. FIG.18is a flow diagram illustrating a procedure for detecting a load variation according to a first embodiment of the present invention. Referring toFIG.18, upon receiving power from a PTU in operation1803while a dummy load switch is in the ON state in operation1801, a dummy load circuit added to a PRU switches the dummy load switch to the OFF state in operation1805. The power transmitted from the PTU is a short beacon signal. If the dummy load switch is switched to the OFF state, the PTU performs a procedure for charging wireless power, by detecting a load variation of the PRU in operation1807. For example, the PTU performs the wireless power charging procedure with the PRU, by transmitting a long beacon to the PRU in operation1809. FIG.19is a graph illustrating an example of detecting a load variation according to the first embodiment of the present invention. Referring toFIG.19, a PTU monitors a variation in load by periodically generating power for a short period of time. For example, the PTU detects a load variation by transmitting a short beacon signal. If the user puts a PRU on the PTU as illustrated inFIG.14, or puts the PRU in close proximity to a field of the PTU, the dummy load switch added to the PRU is switched from the short state (e.g., 30 to 70 Ohms) to the open state (e.g., 100 Ohms) according to an embodiment of the present invention, generating a variation in load. In accordance with various embodiments of the present invention, if a PRU is put on a PTU while the PTU exists alone, the PTU detects a load given when the dummy load switch is in the short state, before power is sufficiently applied to the PRU, and the PTU detects a load variation at the moment the dummy load switch is switched from the short state to the open state as power is applied to the PRU. As illustrated inFIG.19, upon detecting a variation in load, the PTU drives the controller (e.g., MCU) by applying move power to the PRU. For example, the PTU drives the controller of the PRU by transmitting a long beacon signal. Thereafter, communication between a PTU and a PRU is attempted, and it is determined whether an authenticated device is put on the PTU, for charging. If the authentication is completed, charging begins. FIGS.20and21illustrate an example of detecting a load variation according to a second embodiment of the present invention, andFIGS.22and23illustrate an example of detecting a load variation according to a third embodiment of the present invention. The second and third embodiments of the present invention correspond to methods of controlling the dummy load switch after the controller (e.g., MCU) is turned on (or driven). Referring toFIG.20, upon receiving power from a PTU in operation2003while the dummy load switch is in the ON state in operation2001, a dummy load circuit added to a PRU turns on power of the controller according to the second embodiment of the present invention in operation2005. The controller is driven as the power of the controller is turned on, and the controller varies a load of the PRU by switching the dummy load switch to the OFF state in operation2007. If the dummy load switch is switched to the OFF state, the PTU performs a procedure for charging wireless power, by detecting a load variation of the PRU. Thereafter, the PRU performs the wireless power charging procedure with the PTU by transmitting a message (e.g., advertisement message) to the PTU in operation2009. FIG.21illustrates a method of controlling a dummy load switch after the MCU is turned on according to the second embodiment of the present invention, as described in conjunction withFIG.20. In this method, after the MCU is turned on, the MCU generates a variation in load by generating a control signal for opening the dummy load switch. Next, the PRU transmits a message (e.g., advertisement message) to the PTU. The third embodiment illustrated inFIGS.22and23corresponds to another method of controlling the dummy load switch after the MCU is turned on. In this method, after the MCU is turned on, the PRU transmits a message (e.g., advertisement message) to the PTU, and opens the dummy load switch after the message is transmitted, thereby generating a variation in load. Using the information included in the message that the PRU has transmitted, the PTU determines whether the PRU is a PRU capable of generating a load variation. Referring toFIG.22, upon receiving power from a PTU in operation2203while a dummy load switch is in the ON state in operation2201, a dummy load circuit added to a PRU turns on power of the controller according to the third embodiment of the present invention in operation2205. The controller is driven as the power of the controller is turned on, and the PRU performs the wireless power charging procedure with the PTU by transmitting a message (e.g., advertisement message) to the PTU in operation2207. Thereafter, the controller varies a load of the PRU by switching the dummy load switch to the OFF state in operation2009. If the dummy load switch is switched to the OFF state, the PTU performs the procedure for charging wireless power, by detecting a load variation of the PRU. FIG.23illustrates a method of controlling a dummy load switch after the MCU is turned on according to the third embodiment of the present invention, as described in conjunction withFIG.22. In this method, after the MCU is turned on, the PRU transmits a message (e.g., advertisement message) to the PTU. After transmitting the message, the controller of the PRU generates a variation in load by generating a control signal for opening the dummy load switch. The PTU performs the procedure for charging wireless power by detecting the load variation of the PRU, which is caused by the switching of the dummy load switch of the PRU. FIG.24is a flow diagram illustrating a procedure for detecting a load variation according to a fourth embodiment of the present invention, andFIG.25is a graph illustrating an example of detecting a load variation according to the fourth embodiment of the present invention. Referring toFIG.24, upon occurrence of a circumstance in operation2401, in which cross connection should be checked for a PTU and a PRU, the PTU transmits a time set value to the PRU in operation2403. Upon receiving the time set value from the PTU, the PRU generates a load variation depending on the received time set value. The PRU generates a load variation of the PRU by switching the dummy load switch to the ON or OFF state as described above, in operation2405. The PTU detects the load variation of the PRU, which is caused by the switching of the dummy load switch of the PRU, in operation2407, and determine in operation2409whether the PRU is cross-connected. Referring toFIG.25, a load variation for prevention of cross connection is detected during the low power mode. For example, while a PRU receives power transmitted from a first PTU on which the PRU is actually put, the PRU communicates with a second PTU, or vice versa. This is called cross connection. If cross connection occurs, the system may be unstable. Therefore, in order to determine whether a PTU and a PRU are cross-connected, the PTU, as described above, provides a time set value T to the PRU and determines based thereon whether cross connection has occurred. In other words, if the PRU that has received the time set value T generates a variation in load for the time T, the PTU monitors the variation in load to determine whether the value T that the PTU has sent to the PRU is coincident with the period for which the variation in load has occurred, thereby making it possible to determine whether cross connection has occurred. In order to generate a load variation, the MCU of the PRU performs the above-described operation of turning on/off (e.g., shorting or opening) the dummy load switch, thereby making it possible to artificially generate a variation in load. In addition, the switching operation of turning on/off the dummy load switch may be repeatedly performed as illustrated inFIG.25, allowing the PTU to recognize the switching of the dummy load switch. As is apparent from the foregoing description, an aspect of the present invention provides a method for generating a load variation used for detecting a wireless power receiving unit in a wireless charging network. In other words, in accordance with an embodiment of the present invention, a dummy load is added to a wireless power receiving unit (or PRU), allowing a wireless power transmitting unit (or PTU) to detect a load depending on a change in impedance, making it possible for the PTU to detect a large change impedance. While the present invention has been shown and described with reference to certain embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the appended claims and their equivalents. | 65,022 |
RE49840 | DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS With reference toFIG.1there is shown an embodiment100of a “stationary coil” electrical generator101in communication with a “centred axle” magnet102, and also in communication with at least one or a plurality of focus magnets104“all” combined325electromechanically and utilized as a power source means101&102for an electrical power load105in the form of a ISM band transceiver105for the purpose of powering momentarily, said transceiver105to emit electromagnetic waves of radio frequencies that are modulated with a digital code sequence but not limited to utilization as a power source for an electrical power load in the form of a ISM band transceiver and further can330be utilized for a plurality of power source applications means. With reference toFIG.1Athere is shown the same, but enhanced with enclosure108embodiment100A with a protective enclosure108. Power connexion leads106are connected to said power load105and with this embodiment said power load105is said ISM band transceiver105with attached antennas107. With reference toFIG.2a coil form101with its output power leads106are electrically connected and in communication with said power load105, which in this illustrated embodiment is an ISM band radio transceiver105with associated antenna107C. A spherical “centred axle” magnet102with axles for rotation103is positioned and in communication with the centre of said coil form101. Said axial spherical “centred axle” magnet102is magnetized with its North and South magnetic poles perpendicular to its axle of rotation103, and is at right angles to the coil-wire turns and parallel to the tangent of said coil-wire turns. The magnetic field lines emanating from the North magnetic pole and entering the South magnetic pole of said spherical magnet102will therefore be at right angles to said coil-wire sections that are parallel to said spherical magnet axle103. Upon rotation of said spherical magnet means102about its axle103, said magnetic field (visually assumed and not illustrated) lines cut through said coil form101and induces an electromotive force felt at the output leads106. Said induced electromotive force is varying in intensity and polarity, thus generating an alternating electrical current utilized as a power source. In order to increase the amount of power produced by this action, a focus magnet104or a plurality of focus magnets104are positioned and in communication with said spherical “centred axle” magnet102. Positioning of said focus magnets104are such that said focus magnet(s)104remain stationary with the South magnetic and North magnetic poles field lines that are aligned “inline parallel” to and in communication with said spherical magnet102field lines. This embodiment of the present invention allows for the action of concentration of said spherical magnet fields lines per unit square (area) so that more field lines cut through a coil-wire section thus producing more induced electromotive force (power). The amount of induced electromotive force is directly proportional to the number of lines per unit square (area). InFIG.3said coil-wire form with a Topological “genus of one” means is shown in an exploded view to further explain away the mounting of said spherical magnet102with its axle103that is in communication with recessed molded spherical magnet inset well109and cavity opening110. Said axle103is mounted into a support well111that allows for a smooth movement of said axle103in the process of spherical magnet102rotation. Said rotation is further enhanced, for a minimum frictional mechanical impedance, by a plurality of unitized molded “standoff bearings”112. The overall recessed molded spherical magnet inset well109, is at coil-wire form101centre. Said position of spherical magnet is positioned and recessed midway in coil-wire form but is not limited to any alternative position arrangement method means. Another embodiment feature of the present invention is shown inFIG.4, whereby an alternative to said coil-wire form's recessed molded spherical magnet inset well109ofFIG.3is now embodied and shown inFIG.4with a four sided open cavity113to accommodate and be in communication with a non-spherical magnet means. Said non-spherical four sided “centred axle” magnet inset well113has axle inset wells114with same enhanced rotational molded “standoff bearings” as is shown inFIG.3for said spherical magnet embodiment.FIG.4also shows said focus magnet(s)104coil-wire form insert(s)115that holds stationary in position said focus magnet(s) on said coil-wire form101. Another advantageous embodiment feature of the present invention is shown inFIG.5, whereby said spherical “centred axle” magnet configuration means is replaced a modified model means for a spherical “centred axle” magnet equivalent comprising; a non-magnetic material “centred axle” sphere means with a Topological “genus of one”116and attached sub form non-magnetic material axle means116A. A cavity “through hole”116H exists in said spherical non-magnetic material means and is perpendicular to said non-magnetic material axle means116A. A cylindrical magnet117is inserted in said cavity “through hole”116H and is in communication with non-magnetic material means sphere116, and further said cylindrical magnet117has its North and South magnetic poles at the opposite ends of said cylindrical shape means and thereby has its magnetic field lines of force perpendicular to said axle116A axis. This embodiment of the present invention is implemented to serve as an economic alternative to an intrinsic “all metal” spherical “centred axle” magnet means and should be obvious to anyone steeped in the arts. Another advantageous embodiment feature of the present invention is shown inFIG.6, whereby a “centred axle” wheel118comprised of a non-magnetic material means with a Topological “genus of one” and having a planar plurality of serrations119, whereby said serrations are utilized as an enhancement to rotational momentum, which should be obvious to anyone steeped in the arts. A cylindrical magnet117is inserted in said cavity “through hole”117H and is in communication with non-magnetic material “centred axle” wheel means118, and further said cylindrical magnet117has its North and South magnetic poles at the opposite ends of said cylindrical shape means and thereby has its magnetic field lines of force perpendicular to said axle104axis. This embodiment of the present invention is implemented to serve as an economic alternative to an intrinsic “all metal” serrated “centred axle” wheel magnet means and should be obvious to anyone steeped in the arts. Another advantageous embodiment feature of the present invention is shown inFIG.7, whereby a “centred axle” wheel with a Topological “zeroth genus”120comprised of a non-magnetic material means and having a planar plurality of serrations119, whereby said serrations are utilized as an enhancement to rotational momentum, which should be obvious to anyone steeped in the arts. Adjacent to each serration119is a recessed “blind hole”122, utilized to accommodate an be in communication with an inserted cylindrical magnet means121whose North and South poles are at opposite ends of said cylinder magnet means121, and its magnetic field lines of force are perpendicular to the axle104axis. It should be obvious to anyone steeped in the arts that as said cylinder magnets121are rotated by said “centred axle” wheel120said magnets corresponding magnetic lines of force cut through said aforementioned coil-wire form101as shown inFIG.4. Said “centred axle” serrated wheel is inserted in axle well114and is free to rotate through said four sided opening113. FIG.8illustrates the insertion of said “centred axle” wheel with a Topological “zeroth genus”120with an exploded view of said cylinder magnet means121parallel and tangent to inset well122. Said “centred axle” wheel120is positioned in said four sided cavity opening113, and as said wheel is rotated said plurality of cylinder magnets121move in a continuing circular path, with the perpendicular magnetic lines of force cutting through the coil-wire form and establishing an instant induced voltage for any useful purpose. Said focus magnet inset well(s)115hold stationary said focus magnet(s)104in place. Said “centred axle” serrated wheel120is inserted in axle well114and is free to rotate through said four sided opening113. FIG.9is an exploded multi-view of another advantageous embodiment of the present invention, whereby a “centred axle” wheel118designed with a single “centred through hole” that is perpendicular to said axle103and is of such diameter to accommodate an be in communication with a cylindrical magnet117and where cylindrical magnet117has its North and South poles at the end planes of said cylinder magnet117. As said wheel118is rotated said cylinder magnet117, contained within said “centred through hole,” moves in a continuing circular path, with the perpendicular magnetic lines of force of said cylindrical magnet117cutting through the coil-wire form and establishing an instant induced voltage for any useful purpose. Said focus magnet inset well(s)115hold stationary said focus magnet(s)104in place. Said “centred axle” serrated wheel118is inserted in axle well114and is free to rotate through said four sided opening113. FIG.10graphically illustrates1G the mathematical dot product of said stationary coil-wire form101and said rotational spherical magnet102or “centred axle” wheel118and120shown in previous figures above. The resultant value, which is a scalar quantity that indicates the reference North pole of the associated rotational magnet in question. Vector (A) represents said stationary coil-wire form102and Vector (B) represents the rotated North pole position of either; said all magnetic rare earth (neodymium) spherical magnet102, hybrid spherical magnet of non-magnetic material non-metal (polymer) sphere means116and insert cylinder magnet117, non-magnetic material non-metal (polymer) “centred axle” serrated wheel120and a plurality of insert cylinder magnets121, and non-magnetic material non-metal (polymer) “centred axle” serrated wheel118and insert cylinder magnet117. Further illustrated2G is the dot product of A and B that is C and the cross product of B and C represents the instantaneous value and polarity of the induced voltage from said interaction of a “centred rotating magnetic field” through said stationary coil-wire form101. InFIG.11an exploded view of the embodiment of utilizing a Topological “genus of one” serrated wheel118with a cylinder magnet117that is inserted into and in communication with said “centred through hole”117H that is perpendicular to said axle103, which is an extrusion of serrated wheel118. Said serrated wheel118is inserted into four sided through hole113and is in communication with and free to rotate about its centre axis by axle103, which is inserted into axle well114and is in communication with said axle well114. Said magnetic field lines of cylinder magnet117are concentrated along the pole path of said cylinder magnet117by focus magnet(s)104inserted and in stationary communication focus magnet inset(s)115. FIG.12shows one embodiment of a wireless receiver system200WR that has its electronic circuitry situated internal to enclosure200. The operation of said receiver system200WR is that said receiver system200WR is powered by an AC power line voltage means and operates from either 120 or 240 VAC @50 or 60 hertz. Connexion to said power line means is by plug terminals202that are in communication with a female AC power line receptacle means. Said plug terminal base201that is in communication with plugs202can be removed and replaced with various plug terminals to fit foreign AC receptacles. Any AC load such as lights, motors, fans, or any reasonable AC load is plugged into and in communication with AC receptacle inserts203. Said AC load that is plugged into and in communication with said receptacle203is then under the influence of electrical switching and dimming control of said receiver and electronic switching and dimming circuitry (not shown, but internal to enclosure200) is in communication with said AC load to cause on/off switching and dimming of AC electrical power to load. Said wireless receiver200WR receives its control command function from a remote battery-less and wireless transmitter100A shown inFIG.2. The action causing load control is by rotating any featured method means of; said all magnetic rare earth (neodymium) spherical magnet102, hybrid spherical magnet of non-magnetic material non-metal (polymer) sphere means116and insert cylinder magnet117combination in common communication with all, or said non-magnetic material non-metal (polymer) “centred axle” serrated wheel120and a plurality of insert cylinder magnets121combination in common communication with all, or said non-magnetic material non-metal (polymer) “centred axle” serrated wheel with a Topological “genus of one”118and insert cylinder magnet117combination in common communication with all. An illustration ofFIG.13shows a typical intrinsic magnetic field embodiment102mf surrounding a spherical permanent magnet102. Said magnetic lines of force extend outward from the North magnetic pole and enter the South magnetic pole, whereby said magnetic field lines are concentrated at the pole volume102R. Magnetic field lines of a cylinder magnet will have a similar magnetic line pole path and should be obvious to anyone steeped in the arts that field concentration is greatest at the magnetic poles of any magnet. FIG.14shows a magnetic field embodiment of a spherical permanent magnet102that is under the magnetic influence of an external cylindrical focus magnet104. It should be obvious to anyone steeped in the arts that magnetic field intensity of influence varies to the inverse square of the distance from the magnetic pole in question. At the south pole of said spherical magnet102the field concentration102R is intrinsic. At the opposite pole of spherical magnet102a cylinder magnet104is placed in close proximity of said spherical magnet102and is in commutative magnetic attractive pole communication. The action of placing a focus magnet104in close proximity to said spherical magnet102is to increase the number of magnetic field lines per unit area about a magnetic pole in question. As magnetic field lines (a.k.a. flux lines or flux) are increased, the amount of induced voltage in said coil-wire form101inFIG.2will increase as said spherical magnet102is rotated. Another embodiment of said present invention as shown inFIG.15is for a flat (12 mm thick) wall type battery-less and wireless switch transmitter means300with a smooth wall or carry about enclosure301an having a rocker type flip mechanism means for switching on and off a remote AC electrical load such as a lighting fixture, but not limited to a lighting fixture. Another embodiment inFIG.16is a detailed multi-view of a rocker-rotator method means302in communication with its extruded planar perpendicular axle304that is in communication with and utilizes a soft and flexible polymer flip finger method means303,303B, and303F to initiate and promote rotation of a spherical magnet method means102about its centred axle103axis. Said flexible flip finger base303is in communication with bending notch303B and flip finger303F and upon an operator pushing (pressing) said rocker method means302and its consequent flip movement about its axle304axis, said flip finger303F that is in communication with spherical magnet102will cause a reaction to spherical magnet and initiate rotation of said spherical magnet in a cyclical direction opposite to the push force direction applied to said rocker302; likewise the converse action takes place with the opposite side of said rocker302is pushed. After said flip finger303F ends mechanical communication with said spherical magnet102, said spherical magnet is free to spin for a goodly number of cycles before ceasing rotation due to natural damping frictional forces. This action of said present invention produces enough power from a single flip to generate a voltage level sufficient for several seconds; ample time to power a micro transmitter and send a large amount of encoded digital data to a remote receiver that decodes said data received. Another embodiment inFIG.17shows said rocker302that is in communication with its flip finger base303, its flip finger303F and said flip finger303F is bendable in a forward or backward direction by flexible notch section303B. The embodiment of said rocker means302inFIG.18shows the action of switch activation by pushing the left side of said rocker means302that is in communication with flip finger base303and whose flip finger means303F is in flexible communication with spherical magnet102. Further, pushing the rocker causes a bending around finger notch303B and moves flip finger means303F to move on a leftward position303FL thus establishing a thrust force on said spherical magnet102causing a clockwise rotation of said spherical magnet. Conversely, the embodiment of said rocker means302inFIG.18shows the action of switch activation by pushing the right side of said rocker means302that is in communication with flip finger base303and whose flip finger means303F is in flexible communication with spherical magnet102. Further, pushing the rocker causes a bending around finger notch303B and moves flip finger means303F to move on a rightward position303FR thus establishing a thrust force on said spherical magnet102causing an anticlockwise rotation of said spherical magnet. Another embodiment of the present invention inFIG.19utilizes a rectangular shape coil-wire form400that is of a Topological genus of one, whereby a centred through hole exists for free movement of rotation of a plurality of spherical permanent magnets401, and existing about the side of said rectangular coil-wire form is disposed a dual series plurality of focus magnet means402. Each said focus magnet pair402have their magnetic lines of force in-line and disposed in an attractive state relative to each one of said plurality of spherical permanent magnets401. Another embodiment of the present invention inFIG.20utilizes a rectangular shape coil-wire form500that is of a Topological genus of one, whereby a centred through hole exists for free movement of rotation of a plurality of serrated wheels501, and existing about the side of said rectangular coil-wire form is disposed a dual series plurality of focus magnet means502. Each said focus magnet pair502have their magnetic lines of force in-line and disposed in an attractive state relative to each one of said plurality of serrated wheels that can be of a Topological “zeroth genus” with a plurality of centred blind hole insets on a serrated wheel to accommodate a plurality of cylindrical magnets121. Another embodiment of the present invention inFIG.21utilizes a rectangular shape coil-wire form500that is of a Topological genus of one, whereby a centred through hole exists for free movement of rotation of a plurality of serrated wheels501, and existing about the side of said rectangular coil-wire form is disposed a dual series plurality of focus magnet means502(not visible in drawing). Each said focus magnet pair502(not visible in drawing) have their magnetic lines of force in-line and disposed in an attractive state relative to each one of said plurality of serrated wheels501that can be of a Topological “zeroth genus” with a plurality of centred blind hole insets on a serrated wheel to accommodate a plurality of cylindrical magnets121, or each said focus magnet pair502(not visible in drawing) have their magnetic lines of force in-line and disposed in an attractive state relative to each one of said plurality of serrated wheels501A that can be of a Topological “genus one” and each with a centred through hole on a serrated wheel to accommodate a single cylindrical permanent magnet117. Another embodiment of the present invention inFIG.22where a 360 degrees of freedom rotatable propeller440is in communication with a 360 degrees of freedom rotatable drive shaft430that is in turn in communication with a 360 degrees of freedom rotatable Gaussian spherical form drive gear410having two axles that are supported by two stationary mounting brackets420where at least one axle component is in communication with said drive shaft430and the remaining axle is in communication with mounting bracket420. A separate embodiment associated with the present invention inFIG.23of an axial encapsulation tabbed magnet shell400that is comprised of two halves, where each half shell component has a hollow hemisphere401with a tangent protruding axle means403and a flip tab half402tangent to the hemisphere401and positioned at its outer rim; and when said two halves are combined, they form a complete hollow encapsulation means400for enclosing a spherical permanent magnet. Another embodiment of the present invention inFIG.24illustrates the insertion of said spherical magnet404and is disposed into each half of said hollow hemisphere401with said tangent protruding axle means403and said flip tab half402tangent to the hemisphere401and positioned at its outer rim. Said flip tab halves are locked inline to each other by a plurality of keyed synchronized male nubs405and female nub receptors405. Another embodiment of the present invention inFIG.25shows said magnet enclosure means comprised of two halves of said hollow hemisphere401with said tangent protruding axle means403and said flip tab half402tangent to the hemisphere401and positioned at its outer rim and said coil bobbin406of which a plurality of sufficient enameled copper wire turns are wound around said coil bobbin406to create an electric coil that will generate electrical energy during any movement of magnet enclosure assembly means400that is further disposed into said coil bobbin406. Said magnet enclosure assembly means400has its axle components fitted and disposed in coil bobbin axle wells407and further said enclosure axle component means403are free and unrestricted to rotate within said axle wells407. Another embodiment of the present invention inFIG.26shows said coil bobbin406and its axle wells407for containing a set of axles. Another embodiment of the present invention inFIG.27shows said functional energy harvesting generator that is comprised of spherical magnet enclosed within said enclosure400comprised of hollow spherical cap401with tangent axles403and said flip tab402whereby said magnet enclosure400is inserted and free to rotate within said coil bobbin axle wells407as member to coil bobbin406; for the purpose of generating electrical energy. Another embodiment of the present invention inFIG.28illustrates the flip action of said energy harvesting generator whereby said enclosure400comprised of hollow spherical cap401with tangent axles403and said flip tab402remains moveable (flappable) in a forward and reverse motion, and whereby said motion causes said enclosed spherical magnet to move and with this movement consequently it ambient residual magnetic field. There are disposed a plurality of focus magnets408that are aligned and disposed along the sides of said coil406in such a manner as to have their corresponding magnetic fields aligned inline, and facing North pole to South pole so as to provide a magnetic force field that will keep said magnet enclosure400and consequently its flip tab positioned centre vertical402, but not restricted to centre vertical and is free to flip in an angular forward402A or reverse402B direction and due to the inline attractive magnetic field established by said focus magnets408. This action of said inline focus magnets408with their inherent magnetic fields established a spring action that causes a damped oscillatory motion and consequently a damped alternating current within said coil wire that is wound around said coil bobbin406. Another embodiment of the present invention inFIG.29illustrates two different battery-less, powered by said energy harvesting generators500of ISM ENIGMA, LLC., and International ISM Band wireless electrical remote power switch with said dimming features. Model501is of the configuration model having an indicator LED503, a flip tab control means504, a dimmer potentiometer506with grey scale level graph505. Wherein as flip tab504is moved by a consumer in either an up or down flipping motion, said indicator LED503blinks momentarily indicating that the unit is generating power for its internal ISM Band transmitter that has a single frequency of a possible plurality of designated approved and licensed ISM Band of frequencies for International operation; and dim level that has been set is sent along with a permanent key code that is instantly established upon an initial flip tab504operation. A designated receiver with same key code and frequency receives said ON/OFF information and fixed dime level established by the setting of the transmitter potentiometer, and further said receiver is electrically connected in series with an electrical load such as a lighting fixture, but not limited to a lighting fixture; in general any electrical load within said receiver's power load capabilities that can be a plurality of levels dependent on model type. Model502is of the configuration model having an indicator LED503, a flip tab control means504, and a slide switch507that allows an ON/OFF position and a dimming position. When said slide switch507is in the ON/OFF position, said flip tab504is moved by a consumer in either an up or down flipping motion, said indicator LED503blinks momentarily indicating that the unit is generating power for its internal ISM Band transmitter that has a single frequency of a possible plurality of designated approved and licensed ISM Band of frequencies for International operation; and a permanent key code is instantly established upon an initial flip tab504operation and transmitted. A designated receiver with same key code and frequency is electrically connected in series with an electrical load such as a lighting fixture, but not limited to a lighting fixture; in general any electrical load within said receiver's power load capabilities that can be a plurality of levels dependent on model type. After a light or any designated electrically connected load is turned on, if said slide switch507is moved into its Auto Dim mode position another flick of said flip tab504send a different code via the same single transmitter and frequency to said designated receiver where an auto dimming feature is triggered into operation. Said dimming feature now, is of the type that allows for a continuous slow oscillating of the brightness or power level to increase and decrease periodically, thus giving a consumer time to decide what level is suited for the occasion. Once a level is decided, another flick of said tab cause the dim level to be memorized and constant in said decided level of power or brightness. Any future dimming choices can be made by a consumer simply be re-flicking said flip tab504and observing the slow undulations of brightness levels for a new choice of dimming level. Another embodiment of the present invention inFIG.30illustrates a method means for utilizing said energy harvesting generator of said present invention and in conjunction with another embodiment of an ISM ENIGMA battery-less and wireless electrical switch.FIG.30shows a motor601driven circular array603of a plurality of disk type, but not limited to disk type, magnets605disposed on a disk603that is connected by an axle604to a rotating motor601contained in a motor support means602. Said disk type, but not limited to disk type, magnets605are arranged in a manner so as to allow their corresponding magnetic fields (not illustrated but implied) to be aligned as a North to South pole configuration means that disposes them with an adjacent face up opposite pole alignment. A further corresponding embodiment shown inFIG.31illustrates an operation of positioning an ISM ENIGMA battery-less remote switch606in close proximity to said disk type magnet605array disposed on circular array plate603, whereby as said motor601is rotating and consequently as said circular array plate rotates by its connexion to said motor601disposed on motor axle604. When said ISM ENIGMA battery-less switch603is placed in close proximity to said EH recharger as seen inFIG.30, upon high speed rotation of said recharging array plate603and disposed arrayed disk magnets605their respective magnetic fields are set in motion and cut through said coil bobbin windings contained within said switch enclosure606. This continuous rotating magnet field action continues to induce electrical currents into said coil windings that are electrically connected to a recharging bank of super capacitors that in effect act as a rechargeable battery, and where said super capacitor bank can be utilized through a USB connexion for any outside world recharging purpose such as the recharging of a cell phone, tablet, or laptop computer. It should also be understood by those steeped in the art that this accumulated charge acne be utilized by the switch circuitry itself. | 29,300 |
RE49841 | DETAILED DESCRIPTION The specific details of the single embodiment or variety of30embodiments described herein are to the described system and methods of use. Any specific details of the embodiments are used for demonstration purposes only and not unnecessary limitations or inferences are to be understood therefrom. Before describing in detail exemplary embodiments, it is noted that the embodiments reside primarily in combinations of components related to the system and method. Accordingly, the system components have been represented where appropriate by conventional symbols in the drawings, showing only those specific details that are pertinent to understanding the embodiments of the present disclosure so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein. As used herein, relational terms, such as “first” and “second”, “left” and “right” and the like, may be used solely to distinguish one entity or element from another entity or element without necessarily requiring or implying any physical or logical relationship or order between such entities or elements. Embodiments presented herein relate to an exercise apparatus to strengthen and rehabilitate muscle groups related to proper balance and gait of a human user.FIG.1shows the first rocker board110and second rocker board120. It is understood by one skilled in the arts that each of the first and second rocker board110,120can be non-superimposable mirrored structures of one another to facilitate the human anatomy of the feet and toes. The top surfaces210,220are each dimensioned to support the right and left feet of the user such that the first rocker board110supports the left foot, and the second rocker board120supports the right foot. In some embodiments, a left indicator130and right indicator132are provided to identify proper foot placement to ensure a suitable central axis140is provided. The apertures160is positioned at a suitable angle150which is about 45° from the central axis140. In some embodiments, the suitable angle150can include angles between 35° and 55° from the central axis140such that the angle150corresponds to the anatomical axis of pronation and supination of the foot. The first and second rocker boards110,120are designed to support the weight of a person in many different positions, including standing and squatting positions in addition to any movement in common balancing muscle strengthening exercises. Each of the first and second rocker boards110,120are suitably dimensioned to support a foot and rays of the user such that no portion of the foot or rays is extending past the perimeter of the rocker boards110,120. Suitable materials include wood, metals, and substantially rigid plastic materials. In some embodiments, each rocker board110,120is substantially planar to provide a suitable surface for standing, balancing, or exercising.FIG.2illustrates a plurality of convex rockers200engaged with one of the apertures160such that the convex rockers200protrude from the bottom surface230,240of the rocker boards110,120. Auxiliary convex rockers (not shown) can be provided and releasably engaged with apertures160similarly as described above. During use, the user stands upon the top surface210,220of each rocker board110,120. In some embodiments, two convex rockers200are positioned in parallel to protrude from the bottom surfaces of each rocker board110,120. The two convex rockers200on a rocker board (such as110) are herein referred to as a “set”. In some embodiments, a single convex rocker200is engaged with one or more apertures160. The single convex rocker200can be constructed to support the user during an exercise routine. Referring back toFIG.1, one skilled in the arts will understand that the convex rockers200can be positioned at any combination of apertures160to provide additional exercise routines and altered muscle stimulation. Convex rockers200may be provided as one of a set or kit to provide alternate angles of deflection and increased balancing difficulty. The convex surface250on the rocker plates defines the rate of change of the angle of deflection of the board. The board may be deflected as much as perpendicular, i.e., 45°, to the ground, but for most embodiments, the maximum angle of deflection of the board is between 10° and 35°. In a preferred embodiment, the maximum angle of deflection is between 12° and 16°. The user may increase the difficulty by using convex rockers having a more sharply curved convex surface. Each convex rocker200may be shaped as a semi-circle, semi-sphere, or semi-ovoid member. In an alternate embodiment, each convex rocker200is pivotally engaged with one or more apertures160to provide varying planes of deflection during exercise. FIG.3shows the apparatus10having a base355,365configured to lie atop a substantially flat surface350,360. Each platform310,320is positioned between the corresponding base355,365and the rocker board110,120. Each platform includes sets of recessed channels330dimensioned to receive and retain the convex rockers200and rocker boards110,120connected thereto. The convex rockers200each include a mounting portion340which is insertable into an aperture160to retain the convex rockers200at the bottom surfaces230,240of each rocker board110,120. The apparatus10can be configured to exercise with a single foot (left or right) of the user, or as a set such that both the left and right feet of the user are exercised. The embodiment illustrated inFIG.3can be otherwise shown wherein bases355,365are configured as a single connected component. Further, platforms310,320may also be configured as a single connected component. It will be understood by one skilled in the art that a variety of instability members (illustrated as convex rockers200) can be utilized to promote the strengthening of the anatomy and a proper gait. Instability members can include the convex rockers200shown, in addition to one or more balance domes, one or more rollers, or other suitable instability members. FIG.4illustrates a foot (shown as the user's left foot)400having the first ray (i.e., big toe)405contacting the top surface210of the first rocker board110. The second, third, fourth, and fifth rays (herein referred collectively as407) are positioned at a cutout410to isolate the second, third, fourth, and fifth rays407from contacting the top surface210of the first rocker board110. The cutout410is provided through the entire thickness of the first rocker board110such that thefirst,second, third,andfourthand fifthrays407are unable to sufficiently contact a surface to provide a balancing force. The first ray405resides on the top surface210to provide sufficient force to balance the user atop the rocker board110during use. One skilled in the arts will understand thatFIG.4as shown and described can be readily implemented with the user's right foot and corresponding second rocker board120. Further, each rocker board110,120can be turned upside down to exercise either foot. For example, the first rocker board110can first be used to exercise the left foot by positioning the of convex rockers200on the bottom surface230and placing the foot on the top surface210. The right foot can be exercised by removing the convex rockers200from the bottom surface230and engaging the convex rockers200with the top surface210, while the right foot contacts the bottom surface230of the first rocker board110. Now referring toFIG.5, a user500is shown balancing atop each rocker board110,120. In some embodiments, two convex rockers200(i.e., a set) are positioned in parallel to releasably engage with the first rocker board110, while two convex rockers200(i.e., a second set) are positioned on the second rocker board120such that the convex rockers200on the first rocker board110are perpendicular to the convex rockers200on the second rocker board120. The user500can then stand and balance on the rocker boards110,120while positioning the first ray405having sufficient contact with the top surfaces210,220and isolating the second, third, fourth, and fifth rays407over or partially through the respective cutout410. FIG.6shows the user500standing upon the first rocker board110. An auxiliary exercise device600is shown mounted to an aperture160of the rocker board120. In the illustrated embodiment, the auxiliary exercise device600is a resistance band fastened to the aperture160by looping and tying the exercise band through the aperture160. The exercise band is pulled by the hand of the user to impart an unstable force to the rocker board120. The first ray and foot forcefully balance the user500while the second, third, fourth, and fifth rays of the user500are isolated by the cutout410. Intrinsic and extrinsic muscles are strengthened as the user500engaged in various exercises while using the apparatus10. The user500utilizes the intrinsic and extrinsic muscles in communication with the leg, foot, and first rays to manipulate and stabilize each rocker board110,120during an exercise. The apparatus10allows for users having differing levels of capabilities by providing interchangeable and modular components as part of a set. In one example, the degree of difficulty in balancing on one or more of the rocker boards110,120throughout an exercise by providing a numbering of different convex rockers200having varying shape, size, and radius of curvature. In one example, the diameter of each convex rocker200and height of each convex rocker200may vary between sets of predetermined ranges. One skilled in the arts will recognize various exercise positions, protocols, and techniques that will be useful with the apparatus10. The exercise may not be limited to standing positions, as sitting techniques can be useful, especially in compromised or otherwise rehabilitating users. To provide suitable top surfaces210,220a cover may be provided having favorable grip, feel, softness, tack, or texture to ensure comfort and adequate friction between the foot of the user and the rocker boards110,120. From the foregoing, it will be appreciated that the present invention provides a versatile exercise apparatus having a platform for exercising to which different forms and shapes of instability members and exercise attachments may be detachably mounted so that the person using the apparatus may perform a wide variety of exercises in a number of different exercise positions on the platform. The exercises may be performed on the platform either with or without weights, exercise attachments on the top surface of the platform or other external exercise devices including but not limited to exercise bands, medicine balls, and weights. Many different embodiments have been disclosed herein, in connection with the above description and the drawings. It will be understood that it would be unduly repetitious and obfuscating to literally describe and illustrate every combination and subcombination of these embodiments. Accordingly, all embodiments can be combined in any way and/or combination, and the present specification, including the drawings, shall be construed to constitute a complete written description of all combinations and subcombinations of the embodiments described herein, and of the manner and process of making and using them, and shall support claims to any such combination or subcombination. An equivalent substitution of two or more elements can be made for any one of the elements in the claims below or that a single element can be substituted for two or more elements in a claim. Although elements can be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements from a claimed combination can in some cases be excised from the combination and that the claimed combination can be directed to a subcombination or variation of a subcombination. It will be appreciated by persons skilled in the art that the present embodiment is not limited to what has been particularly shown and described hereinabove. A variety of modifications and variations are possible in light of the above teachings without departing from the following claims. | 12,263 |
RE49842 | DETAILED DESCRIPTION OF ILLUSTRATIVE IMPLEMENTATIONS Reference now should be made to the drawings, in which the same reference numbers are used throughout the different figures to designate the same components. It will be understood that, although the terms first, second, third, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another element. Thus, a first element discussed below could be termed a second element without departing from the teachings of the present disclosure. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms “a”, “an”, and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising” or “includes” and/or “including” when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof. The present disclosure describes a metallic insert which, in some implementations, can be coupled into a rotary actuated mechanism, to flare or swage metallic tube ends. The actuation of the insert, in some implementations, can be performed by “drills” or “screwdrivers” and, as a final result, the insert is capable of creating flares and swages in metallic tubes, especially tubes applied to “split” air conditioning connection systems, refrigeration connection systems, and transportation of liquefied petroleum gas and any other similar tube, being much quicker and more resistant to cracks than conventional technology, due to the heat created by the friction of the insert spinning inside the metallic tube. In embodiments, the insert may provide, to a tube, a flared opening at at least one of the tube's ends, such as, but not limited to, a 45 degree angle. In embodiments, the insert may provide, to a tube, a swaged opening at at least one of the tube's ends, which may allow for the coupling of another tube with the same, or a larger, diameter. In embodiments, the insert may provide, to a tube, a swaging opening with a flared opening, which may allow for the coupling of another tube with the same, or a larger, diameter. Many industrial segments, especially the Heating, Ventilation and Air Conditioning (HVAC) industry, demand tools and equipment to simplify their day to day work, in order to optimize and reduce the production and work times. For example, there is a need to swage and flare metallic tubes of heat exchangers, such as copper tubes and aluminum tubes, to both manufacture condensating and evaporating units for residential, commercial, and industrial applications. It will be understood that, as used herein, “tube” may include pipe or piping having a round, tubular cross section. FIG.1presents an isometric view of a concentric flaring or swaging tool100, according to an implementation. The concentric flaring or swaging tools are characterized by possessing a clamping tool1, to affix the tube, and a flaring or swaging mechanism2. The flaring or swaging mechanism2is compound by a fixing body, to attach the flaring or swaging mechanism2into the clamping tool1, and a thread fuse3, which at one end has a crank5and the other end has a conical tip,4that can be extended into a longer tip for swaging, with a 45 degree angle, to be performed at room temperature. FIG.2presents a bottom view of the alignment between the fuse axis and conical tip axis of the flaring or swaging tool100, according to an implementation. The coupling between the flaring or swaging mechanism2and the thread fuse3is characterized by the concentric alignment between the fuse axis6and the conical tip axis7. During the execution of flare, the contact zone between the conical tip and the tube is given through the whole surface of the cone, at room temperature. FIG.3presents an isometric view of an eccentric flaring tool300, according to an implementation. The eccentric flaring tools are characterized by possessing a clamping tool8, to affix the tube, and a flaring mechanism9. The flaring mechanism9is compound by a fixing body, to attach the flaring mechanism9into the clamping tool8, and a thread fuse10, which at one end has a crank12and the other end has a conical tip11, with a 45 degree angle to be performed at room temperature. FIG.4presents a bottom view of the alignment between the fuse axis and conical tip axis of the eccentric flaring tool300, according to an implementation. The coupling between the flaring mechanism9and the thread fuse10is characterized by the eccentric alignment between the fuse axis13and the conical tip axis14. During the execution of flare, the contact zone between the conical tip and the tube is given through a linear contact with the cone, at room temperature. Conventionally, there are many mechanisms to obtain a swaged or flared tube. In embodiments, the bits may provide the ability to be coupled to a number of drills or screwdrivers. In embodiments, a single flaring bit may provide the ability to create multiple flares in metallic tubes with different diameters without needing to use one or more other bits. In embodiment, the bits do not need to be utilized with any clamping tools or holders during or after operation. In embodiments, the bits may be utilized to perform a flare or swage at a hot temperature in order to avoid material hardening and, subsequently, cracking. In embodiments, the bits may comprise a homogeneous and resistant microstructure due to the high temperature at which the bits may be formed. During an air conditioning installation, especially the split types of air conditioners, at least four flaring are necessary for the installation. The split type air conditioners comprise two units: an indoor unit and an outdoor unit. To connect the outdoor unit and the indoor unit and make the two air conditioner units work together, the use of copper or aluminum tubes is required. Each tube has a different diameter, varying according to the refrigeration capacity of the equipment. As an example, for R-22 air conditioners, 7,000 BTUs/hour and 9,000 BTUs/hour equipment generally requires one ¼″ tube and one ⅜″ tube, while 12,000 BTUs/hour and 18,000 BTUs/hour equipment generally requires one ½″ tube and one ¼″ tube. In embodiments, the rotary inserts600,700,1000,1100,1200inFIGS.6,7,10,11, and12speed up the flaring and swaging processes, by coupling two or more flaring or swaging stages of different diameters into one tool, creating a multiple-stage insert, which means that during installation procedures of equipment, the technician may only need to insert one insert into the drill or screwdriver and perform the four flares/swages for a specific job. Rotary insert600may comprise two-stage flaring bit620. Rotary insert700may comprise two-stage flaring tip720. Rotary insert1000and1100may comprise two-stage swaging tip1020. Rotary insert1200may comprise two-stage swaging tip1220. In embodiments, rotary inserts600,700,1000,1100, and1200comprise shank portion40. In embodiments, rotary inserts600,700,1000,1100, and1200comprise stopper portion50. In embodiments, the rotary insert500,600,700for the flaring of metallic tubes (FIGS.5,6, and7) may perform flares into metallic tubes through the flaring tip's multiple diameter stages and interchangeable system. The inserts, in some implementations, can be coupled into drills (whether the inserts are with a mechanical mandrel or pneumatic mandrel), screwdrivers, etc. Rotary insert500comprises a single-stage flaring tip520that may be used to flare metallic tubes. Rotary insert500further comprises flared bottom portion530that may provide a flare to a metallic tube. Rotary insert500comprises a stopper portion50found between the flared bottom portion530and the single-stage flaring tip520. FIG.5presents a front view of a one-stage flaring tip500, according to an implementation. The flared bottom portion530of the head of the flaring tip500may allow the head to flare a portion of a tube when the tip is inserted into a tube. FIGS.6and7present front and isometric views of rotary inserts600and700according to an implementation. The inserts600,700comprise shank portions40that may be inserted into the mandrel or chuck of a screwdriver or drill. The inserts600,700further comprise two-stage flaring tips620,720comprising two stages of different diameters and a flared bottom portion630, which may fit into the inner diameter of a metallic tube to create a flared end that may properly fit onto the outer diameter of another metallic tube. The inserts600,700further include stopper portions50located between the shank portions40and the flared bottom portions630,730that may allow the user to more easily flare a tube of the appropriate length. In embodiments, the inserts may comprise, but are not limited to having, a cylindrical, hexagonal, or square shank portion630,730with 8 mm of diameter, which may couple with a drill or screwdriver through their mandrels or chuck. The flared bottom portion630of rotary insert600may create a flare that has a smaller opening angle that that of an opening angle of a flare that had been flared by the flared bottom portion730of rotary insert700. FIG.8presents a top profile view of the two-stage flaring tip620of rotary insert600according to an implementation. The flaring tip620comprises a slender body21and smooth rounded edges22, which may diminish the contact surface between the two-stage flaring tip620and the metallic tube. In embodiments, the slender body21and smooth rounded edges22may decrease heat and burr formation that may develop at the front of the flaring tip620during traditional flares. Stopper portion50may be found circumnavigating the two-stage flaring tip620.FIG.8further displays an axis of symmetry850. The length of the flaring tip620may run along the axis of symmetry850. FIG.9presents an isometric view of a rotary insert900according to an implementation. In embodiments, the insert900comprises a one-stage swaging tip920, which may fit into the inner diameter of a metallic tube to create a widened end to properly fit onto the outer diameter of another metallic tube. Stopper portion50may be found below swaging tip920. Shank portion40may be found below stopper portion50. FIG.10presents a front view of a rotary insert1000according to an implementation. In embodiments, the insert includes a swaging tip1020comprising two stages, which means that it comprises a least two different diameters in a single tool, which may fit into the inner diameter of a metallic tube to create a widened end to properly fit onto the outer diameter of another metallic tube. Stopper portion50may be found below swaging tip1020. Shank portion40may be found below stopper portion50. FIGS.11and12present isometric views of rotary insert1000and rotary insert1200according to an implementation. In an embodiment, the rotary insert1000and1200each comprise a swaging tip containing two stages1020,1220, which means, they have at least two different diameters in one single tool, which may fit into the inner diameter of a metallic tube to create a widened end to properly fit onto the outer diameter of another metallic tube. In embodiments, rotary insert1200may be utilized in a tube with a larger diameter that may not allow for swaging from rotary insert1000. In embodiments, rotary insert1200may provide a larger swage to a tube than rotary insert1000. Stopper portions50may be found below swaging tips1020and1220. Shank portions40may be found below stopper portions50. FIG.13presents a top profile view of a two-stage swaging tip1020according to an implementation. The swaging tip1020has a slender body21and smooth rounded edges22, which may diminish the contact surface between the two-stage swaging tip1020and the metallic tube. In embodiments, the slender body21and smooth rounded edges22may decrease heat and burr formation that may develop at the front of the swaging tip1020during the swage. Stopper portion50may be found circumnavigating the two-stage swaging tip1020.FIG.13further displays an axis of symmetry1350. The length of the swaging tip1320may run along the axis of symmetry1350. FIG.14presents an isometric view of a rotary insert1400according to an implementation. In an embodiment, the insert1400may include a one-stage swaging tip1420with three swaging lobes1430,1440,1450, which may fit into the inner diameter of a metallic tube to create a widened end to properly fit onto the outer diameter of another metallic tube. In embodiments, the lobes may comprise an equal angle between them in order to enhance stability while swaging. In embodiments, the three swaging lobes may comprise flared bottom portions, thus making the one-stage swaging tip1420a one-stage flaring tip. In embodiments, the one-stage swaging tip1420may comprise two stages, thus making the one-stage swaging tip1420a two-stage swaging tip. Stopper portion50may be found below swaging tip1420. Shank portion40may be found below stopper portion50. FIG.15presents an isometric view of a tube1500, which a flaring tip or swaging tip may be inserted into, according to an implementation. The metallic tube end1520at this stage has not been flared or swaged by a flaring tip or a swaging tip. FIG.16presents an isometric view of a tube1600that has been flared by a flaring tip, such as, but not limited to flaring tip500, according to an implementation.FIG.16shows the flare shape1620created by a flaring tip. In embodiments, the flare shape1620may comprise an angle ranging between 30° and 60°. FIG.17presents an isometric view of a tube1700that has been swaged by a two-stage swaging tip such as, but not limited to two-stage swaging tip1100and1200, according to an implementation.FIG.17shows the double swaged shape1720created by a swaging tip. In embodiments, the bits may be composed of separate parts that may be connected by any connection method, including but not limited to, screwing, gluing, welding, etc. Whenever a metallic tube is cut, the cutting may create sharp inner edges around the perimeter of the metallic tube due to material deformation and design of the cutting tool. In embodiments, the swaging and flaring tips design may allow for the removal of sharp edges from the tube and may not permit the tube to crack easily. In embodiments, the tips may not require any clamping or holding tool to perform a flare or swage in a metallic tube because the strength required to keep the metallic tube in position is low so a user can keep the tubes in the right position using his hands. The friction and ensuing heat generation (from the rotation of the tips) facilitate the shape formation of the flare or swage, which may increase malleability in the flared or swaged tip of the metallic tube. The lack of hardening in the flared or swaged tip may prevent cracking at the flared or swaged tube end during the assembling of a metallic tube with a valve using a connection nut, which is a recurring problem during any air conditioning installation. FIG.18displays a method1800for flaring a tube. The method1800may comprise spinning1820a rotary insert coupled to one of a drill or screwdriver. The insert may comprise a shank portion comprising a top end, a bottom end, and a body. The insert may further comprise a stopper portion coupled to one of the top end and the bottom end of the shank portion. The stopper portion may comprise a top surface and a bottom surface. The insert may further comprise a tip comprising at least one stage portion coupled to one of the top surface and the bottom surface of the stopper portion along an axis of symmetry. The at least one stage portion may comprise rounded edges. The tip may further comprise a flared bottom portion. The flared bottom portion may be affixed between the stopper portion and the at least one stage portion. At least two edges of the flared bottom portion may slope from the tip to the stopper portion. The method1800may further comprise inserting1840the rotary insert into an interior surface of a tube to cause friction between the tip and an interior surface of the tube, to increase the diameter of at least a portion of the tube, to create a flare, and to increase structural quality of the tube from heat provided to the tube. FIG.19displays a method1900for swaging a tube. The method1900may comprise spinning1920a rotary insert coupled to one of a drill or screwdriver. The insert may comprise a shank portion comprising a top end, a bottom end, and a body. The insert may further comprise a stopper portion coupled to one of the top end and the bottom end of the shank portion. The stopper portion may comprise a top surface and a bottom surface. The insert may further comprise a tip comprising at least one stage portion coupled to one of the top surface and the bottom surface of the stopper portion along an axis of symmetry. The at least one stage portion may comprise rounded edges. The method1900may further comprise inserting1940the rotary insert into an interior surface of a tube to cause friction between the tip and an interior surface of the tube, to increase the diameter of at least a portion of the tube, and to increase structural quality of the tube from heat provided to the tube. In embodiments, the flaring or swaging tips may be handled more easily than traditional flaring or swaging tools. In embodiments, the flaring or swaging tips may save a technician time when completing a job. In embodiments, a rotary insert may be provided. The rotary insert may comprise a shank portion comprising a top end, a bottom end, and a body. The insert may further comprise a stopper portion coupled to one of the top end and the bottom end of the shank portion. The stopper portion may comprise a top surface and a bottom surface. The insert may further comprise a tip comprising at least one stage portion coupled to one of the top surface and the bottom surface of the stopper portion along an axis of symmetry (such as that inFIG.8andFIG.13). The at least one stage portion may comprise rounded edges. In embodiments, a system may be provided. The system may comprise a shank portion comprising a top end, a bottom end, and a body. The insert may further comprise a stopper portion coupled to one of the top end and the bottom end of the shank portion. The stopper portion may comprise a top surface and a bottom surface. The insert may further comprise a tip comprising at least one stage portion coupled to one of the top surface and the bottom surface of the stopper portion along an axis of symmetry (such as that inFIG.8andFIG.13). The at least one stage portion may comprise rounded edges. The system may further comprise a drill engaging at least a portion of the shank portion. In embodiments, each of the at least one stage portion may be different in diameter than each of the other at least one stage portion. In embodiments, the insert may be formed as a single element. In embodiments, the single element insert may be formed using a mold. In embodiments, the insert may be formed from more than one element. For example, the shank portion, the stopper portion, and the tip may be single elements that may be affixed to one another. In embodiments, the separate elements may be welded together. In embodiments, the insert may comprise metal. In embodiments, the insert may comprise ceramic. In embodiments, the tip may further comprise a flared bottom portion. The flared bottom may be affixed between the stopper portion and the at least one stage portion. At least two edges of the flared bottom portion may slope from the tip to the stopper portion. In embodiments, the rounded edges may be equal in diameter. In embodiments, the insert may comprise one stage portion. In embodiments, the insert may comprise two stage portions. For the purposes of this disclosure, the term “insert” may refer to the end of a bit that may be inserted and secured within a drill or screwdriver. For the purposes of this disclosure, the terms “tube” and “pipe” may be synonymous. In embodiments, a flaring or swaging bit may comprise more than two stages. In embodiments, any of the embodiments of a rotary insert may comprise a shank portion40. The shank portion40may be configured to fit within a mandrel, such as, but not limited to, a mandrel in a screwdriver or a drill. In embodiments, any of the embodiments of a rotary insert may comprise a stopper portion50. The stopper portion50may be found between a swaging tip and a shank portion40or (if a flaring bit) between a flared bottom and a shank portion40. The stopper portion50may prevent a flaring or swaging bit from being inserted more than a certain length into a metallic tube. In embodiments, the stopper portion50may comprise a single stage, such as that inFIG.10. In embodiments, the stopper portion50may comprise multiple stages, such as that inFIG.6. In embodiments, the stopper portion50may be a shape other than that of a cylinder such as, but not limited to a rectangular prism, a hexagonal prism, and an octagonal prism. In embodiments, inserts may be formed as a single element. In embodiments, inserts may be formed from more than one element. In embodiments, tubes to be flared or swaged may comprise polymer. In embodiments, tubes to be flared or swaged may comprise wood. For the purposes of this disclosure, the terms “stage” and “stage portion” may be synonymous. In embodiments, the disclosure may provide optimization of the flaring or swaging process and optimization of time for altering metallic tubes for air conditioning installations, altering tubes for refrigeration applications, altering tubes for liquefied petroleum gas systems, or any similar flared or swaged connections. In embodiments, the flaring and swaging bits may improve the final quality of a flare or swage by adding heat through constant friction to a flared or swaged area, which may create a stronger micro structure. Although specific embodiments are illustrated and described herein, it will be appreciated by those of ordinary skill in the art that any arrangement which is calculated to achieve the same purpose can be substituted for the specific embodiments shown. This application is intended to cover any adaptations or variations of the embodiments and disclosure. For example, although described in terminology and terms common to the field referenced hereinabove, one of ordinary skill in the art will appreciate that implementations can be made for other systems, apparatus or methods that provide the required function. In particular, one of ordinary skill in the art will readily appreciate that the names of the methods and apparatus are not intended to limit embodiments or the disclosure. Furthermore, additional methods, steps, and apparatus can be added to the components, functions can be rearranged among the components, and new components to correspond to future enhancements and physical devices used in embodiments can be introduced without departing from the scope of embodiments and the disclosure. One of skill in the art will readily recognize that embodiments are applicable to future systems, apparatus and processes. Terminology used in the present disclosure is intended to include all environments and alternate technologies which provide the same functionality described herein. Inserted herein is text from certified English language translation of the Specification of PCT Application No. PCT/BR2013/00379, filed 30 Sep. 2013 (published as WO 2015/042674 on 2 Apr. 2015), which was incorporated by reference in U.S. patent application Ser. No. 14/947,537, as noted above. References to the FIGS. 5-10 have been amended to refer to FIGS. 20-25. The present invention refers to a metal insert that must be coupled to a rotary drive mechanism, for flanging/widening the ends of metal tubes. The insert drive can be made by using “drills” or “screwdrivers” and, as a final result, it is capable of making flanges in specially applied metal tubes, and “split” type air conditioning system connections, refrigeration systems connections and liquefied petroleum gas transport systems connections and similar, being faster than the current state of the art, due to the heating generated by the rotation of the insert inside the metal tube. Therefore, the insert is intended to form:1) a flange opening at the tube ends at an angle of 45°, or;2) widening of the metal tube for coupling with a tube of the same gauge, or3) widening with the flange opening, for coupling of another metal tube of the same diameter. The industrial sectors, notably the industry and commerce of refrigeration, demand equipment that simplifies, optimizes and reduces production and labor time. As an example, the need for widening and shaping flange in metal tubes of heat exchangers, such as copper tubes and aluminum tubes, for the manufacture of condensing and evaporation units, in home applications, commercial and industrial lines can be highlighted. The present patent application is directly related to patent PI0902047-0 A2, which clearly denotes the characteristics of the connection where flanged tubes are applied. However, it differs in that it refers to the method of obtaining the shape of the flanged tube or, as denoted in patent PI0902047-0 A2 cited above, “angled tube.” Currently, there are several mechanisms of obtaining a flanged tube. However, they are differentials of the object of the present invention:1) the operating tool design;2) application mode, which can be performed using a “drill” or “screwdriver”;3) ability to make, with the same insert, multiple flanges in tubes of different gauges, due to the different diameters in a single insert;4) it does not require a tailstock system, “mordant,” to fix the metal pipe to be flanged;5) the hot formation of the flange, in order to avoid the hardening of the flanged material; and6) the characteristic of the final flange obtained, with its homogeneous and resistant microstructure, due to its formation through a heated medium. Initially, referring to the current state of the art, there are two models of flanging tools present on the market, called a) “conventional flanging tool” and b) “eccentric flanging tool”:a) The conventional flanging tools (FIG. 1) are characterized by having a “mordant” for fixing the tubes (1) and a flanging mechanism, the latter, in turn, comprising a body for fixing the “mordant” (2), a threaded spindle (3), which is coupled to the body, a 45-degree conical tip (4) coupled to one end of the spindle and a drive crank (5) at the other end of the spindle. This system is characterized by the concentric alignment (FIG. 2), between the spindle shaft (6) and the conical tip shaft (7). During the flange execution, the contact zone between the tip and the tube is set through the entire surface of the cone.b) The eccentric flanging tools (FIG. 3) are characterized by having a “mordant” for fixing the tubes (8) and a flanging mechanism, the latter, in turn, comprising a body for fixing the “mordant” (9), a threaded spindle (10), which is coupled to the body, a 45-degree conical tip (11) coupled to one end of the spindle and a drive crank (12) at the other end of the spindle. This system is characterized by the eccentric misalignment (FIG. 4) between the spindle shaft (13) and the conical tip shaft (14). During the flange execution, the contact zone between the tip and the tube is set through a linear contact of the cone. Although both promote the final shape of the flange, the current state of the art requires the use of a “mordant” (tailstock) for shaping the flange. The coupling of the tube to the “mordant” and the flange execution takes a long time to execute because, in the case of split type air conditioning applications, it is necessary, for example, to make a total of four flanges per equipment. That is, two flanges per tube, these tubes being necessarily of two different gauges. In addition, due to their conception, both make the cold tube conformation, hardening the flanged material, incurring the risk of cracks in the flange wall. Referring now to the rotating Insert for flanging and widening of metal tubes, called drill for flanging, it allows the execution of the widening and/or flanging of metal tubes through a system of interchangeable inserts. These inserts can be coupled to drills (whether with a chuck or pneumatic coupling) or even to electric screwdrivers. Insert (FIG. 20) can be subdivided into the following parts:a) A cylindrical body (15), for coupling with a drill or a screwdriver, through chuck.b) A flanging tip (16), to properly fit in the metal tube (FIG. 21) and give to its tip (17) a flanged (18) metal tube shape (FIG. 22) at an angle of approximately 45°. The flanging tip (FIG. 23) can contain one stage (19) or (FIG. 24) more stages (20) to make the flange in one or more tubes without the need to change the insert for another one of different size and gauge. For instance, the same tip can have a diameter of 6.35 mm at the end close to its tip and 12.05 mm at the end closest to the cylindrical body. In addition, it (FIG. 25) has a slim shape (21) and rounded corners (22), reducing only two points the contact with the metal tube, thus reducing friction and the amount of burrs. Therefore, the invention differs from the current state of the art in several aspects. First, because the insert does not need a tailstock (“mordant”) system to perform the flange in the metal tube. Since the strength required to hold the pipe in the working position is low, the user himself can maintain the positioning of the flanged pipe by hands. Second, as it works through a high rotation system, it is present friction and heating generation in the pipe, facilitating the hot shaping of the flange, without hardening in the region of the tube flange. The absence of hardening in the flange region avoids cracking problems during the tightening of the connection, a problem that is recurrent in the current state of the art. Third, the invention allows the presence of one or more gauges within the same insert, with different diameters, reducing the time of flanges execution, especially in the installation of split type air conditioners, being able of flanging different tube sizes using only one single insert. The main objective of the insert in question is, therefore, to optimize the working time, due to its speed and ease of operation and to bring a higher quality result, considering the heating of the tube when flanged with the insert and its best microstructural result with greater strength. Regarding the applicability of the product, the present invention aims to optimize the process and time of a flange in metal tubes for split type air conditioning systems, but it is not restricted to them. It can also be applied in flange type connections, in tubes for refrigeration applications or even in tube connections for systems that use liquefied petroleum gas. | 31,372 |
RE49843 | DETAILED DESCRIPTION Several embodiments of the invention with reference to the appended drawings are now explained. Whenever the shapes, relative positions and other aspects of the parts described in the embodiments are not clearly defined, the scope of the invention is not limited only to the parts shown, which are meant merely for the purpose of illustration. FIG.1is an exploded view of a shaving razor of one embodiment of the invention. Shaving razor100is made up of a handle180, an actuator assembly170, a bridge150and a plurality of blade assemblies102that couple to the bridge150. While three blade assemblies102are shown, more or fewer blade assemblies102are within the scope and contemplation of embodiments of the invention. For example, two, four or five blade assemblies102could be used in various embodiments of the invention. Distal end182(the shaving end) of handle180is formed to receive actuator assembly170. Actuator assembly170is used to drive and control reciprocation of the blade assemblies102. In one embodiment, actuator assembly170includes an armature housing174, an armature176, a pair of bushing containing end caps178and an actuator support172. Armature176has dual shafts184and, in use, applies force to the bridge150to cause reciprocating motion of the blades as described more fully below. As it translates back and forth is applies a force on the bridge150. In one embodiment the armature housing174and armature176uses a voice coil principle to move the shaft184back and forth in a reciprocating motion. In this context, by rapidly changing direction of the magnetic flux in the voice coil, the relative range of motion of the blade assemblies102can be precisely controlled. Armature176resides within armature housing174. The armature housing174then resides within a void defined by distal end182of handle180. Actuator support172is molded to engage distal end182and retain armature housing174within the void. Actuator support172may also be molded to include a leading platform160that extends from a front edge of the actuator support172. Leading platform160resides ahead of the leading blade assembly and does not move responsive to force applied by the actuator assembly170. As used herein, “leading” refers to earlier in position relative to the direction of shaving. Bridge150is molded to have a yoke158that spans between two linkages154on to which blade assemblies102may be installed. The yoke158terminates in an eye at either end. The linkages154are substantially rigid such that they do not bend along the length of the linkage when driven by the actuator assembly170. Linkages154are molded to define a plurality of bores152. The number of bores152in each linkage154is dictated by the number of blade assemblies102desired to be part of the shaving head100. Each blade assembly102includes a pair of posts142that pass through and remain rotatable within the bores152of the linkages154. The importance of this rotatable engagement is detailed further below. Eyes156permit the bridge150to rotatably couple to the post142of one of the blade assemblies102. Thus, the bridge150couples to the linkages154adjacent to at least one of the plurality of bores152. In the shown embodiment, Eyes156couple the bridge to the linkages154adjacent to the center bore152of the three bores152. In an alternative embodiment the eyes might couple the bridge adjacent to any one of the other bores152. Bridge150is formed of a substantially rigid mechanical structure and may be molded of a material such as glass fiber impregnated plastic. Bridge150also defines a handle attachment mechanism162that permits selective coupling of the razor head to handle180and in particular engagement of the yoke by the actuator assembly170and more specifically by actuator shaft184. A release lever181is provided to cause the disengagement of the shaving head from the handle180. While one possible handle arrangement is shown, other shapes and form factors are deemed to be within the scope and contemplation of different embodiments of the invention. In one embodiment, blade assembly102has three primary parts, a razor blade130, a cover120and a base140. The cover120is unitarily molded as a single unit. The blade130has a cutting edge132and defines a plurality of voids134. It is within the scope and contemplation of embodiments of the invention to use blades with more or fewer voids134than shown. If fewer or more pins are used fewer or more voids can be defined. The cover120has formed as part thereof a plurality of deformable pins126that pass through the voids134of the blade130. The cover120also has formed as part thereof end caps124at either longitudinal end of the cover120. In one embodiment, the end caps124have a generally L shaped cross section. In one embodiment, the short leg of the L provides a hard stop that prevents forward movement of the blade130once installed over the pins126. By holding the blade130against the hard stops during manufacture constant cutting edge location is achieved independent of inconsistences that may arise in the manufacture of the blade itself. For example, the relative distance between the cutting edge and the voids may be different between two blades owing to the fact that the edge is typically ground after the voids are punched. Precision molding of the hard stops permits significant tolerance in the blade production including both the edge and the voids without negatively impacting the precision of the finished assembly. The base140is unitarily molded to define a plurality of voids144to receive pins126. Base140may also optionally be molded to define one or more sacrificial electrode pockets to receive sacrificial electrodes190. In one embodiment, the sacrificial electrodes190are aluminum spheres and the pockets are defined to be of a size that the sphere will pressure fit within the pocket. In one embodiment, the sphere has a diameter of 1 mm. Other shapes of sacrificial electrodes are also contemplated including but not limited to rectangular solids, toroids, discs and the like. Other embodiments may have the electrode pockets molded into the cover120, but it is believed that ease of manufacture is enhanced with the electrodes190residing in the base140. Molded as part of base140are a pair of deformable posts142, which during assembly pass through the bores152of linkages154. To assemble blade assembly102, the cover120is held in a fixture and the blade130is inserted such that the pins126pass through the voids134in the blade130. The hard stops124in conjunction with the pins126force the blade into a precise position. The sacrificial electrodes190(if present in the embodiment) are pressure fit into pockets in the base140and the base140is overlaid on the cover-blade combination such that the pins126pass through the voids144in the base140. Pressure is applied to pins126to drive them into the plastic range of the material used such that the pins126are permanently deformed and hold the assembly102together as a unit. Notably, unlike prior art razor assemblies that often relied on heat welding or similar processes, here, no heat processing is required for assembly. The final position of the blade is achieved when the sandwich of the cover, blade and base is compressed. The hard stops124ensure precision and consistency between blade assemblies. While the foregoing blade assemblies102are cost effective and efficient to manufacture, practice of embodiments of the invention are not limited to that particular construction or arrangement. Generally, any individual independent blade assemblies that can be installed on the linkages154could be used. FIG.2is a rear view of the shaving head disconnected from the handle. In the shown embodiment, three independent blade assemblies102-1,102-2and102-3are coupled to linkages154. The linkages154are substantially rigid and couple to the bridge150via eye156that rotatably engages post142. Thus, in the shown embodiment, the bridge150(which in use is driven by the actuator) attaches to the linkages154adjacent to center blade assembly102-2. FIGS.3A-3Bshow a plan view of the razor face of one embodiment of the invention with when no force is applied to the bridge and when the bridge is driven to the left respectively. In this embodiment, three identical blade assemblies102-1,102-2,102-3are coupled to bridge150. As seen inFIG.3A, when no force is applied the three blade assemblies102-1,102-2,102-3are all aligned with a common central axis also shared with the leading platform160. Conversely as shown inFIG.3Bwhen the bridge is driven the maximum distance to the left assembly102-3is displace a distance d to the right of the common central axis, and assemblies102-1and102-2are driven a distance d″ and d′ respectively to the left from the common central axis. The mirror effect occurs when the bridge is driven to the right. In some embodiments, d≠d′≠d″. For example in one embodiment d=0.08 mm, d′=0.10 mm and d″=0.28 mm. In another embodiment d=d′≠d″. For example d=d′=0.10 mm and d″=0.20 mm. As a general matter, the leading blade in a shaving razor performs the majority of the cutting. Accordingly, it is desirable for the leading blade to have the greatest range of motion as that large range improves the cutting efficiency. In some embodiments, the relative motion of the leading blade assembly to the lagging blade assembly is in the range from 0.1 mm to less than 0.5 mm and the relative motion of the middle blade assembly to the either other blade assembly is in the range of 0.05 mm to less than 0.25 mm. While greater movement of the leading assembly has be found to be effective, it should be recognized that is not required. In some embodiments, for example, only two blade assemblies may be used with the pivot point centrally located between them such that each blade assembly experiences substantially equal movement. Other embodiments may have the pivot point located between the leading blade assembly and the middle blade assembly such that the lagging blade assembly experiences the greatest movement (presuming equal distance between the blade assemblies). In another embodiment the pivot point may be located at the middle blade assembly such that it effectively does not move and the leading and lagging blade assemblies reciprocate back and forth. Such an embodiment requires the bridge to apply its force displaced from the pivot point to cause the pivot. FIGS.4A-4Bshow a rear plan view of the razor head in a undriven and driven configuration respectively. As revealed inFIG.4A, the actuator support has molded as part thereof a pair of stops410that, in use, engage the linkages154each to define a pivot point412about which the linkages154pivot when driven by the actuator. In some embodiment the pivot point is defined simply by the abutment of the stop410against the linkage. In other embodiments, a cup, stop pocket or other stop retention feature is molded as part of the linkages154. InFIG.4Ano force is applied, and the blade assemblies share a common central axis as inFIG.3A. InFIG.4B, the bridge150is shown driven to the left. The pivot of the linkage154about the stop410at the pivot point412result in the displacements d to the right for the lagging blade assembly and a displacement of d′ and d″ to the left for the middle and leading blade assemblies respectively. The difference between the displacements d, d′ and d″ are a function of the distance between the pivot point412and the location to which the blade assembly is attached along the linkage154. Thus, if two assemblies are equal distance from the pivot point the relative displacement in opposite directions will be equal. As the relative distance between the pivot point412and the attachment location of the blade assemblies increases, the amplitude of the displacement will increase. In this manner difference amplitudes of reciprocating motion can be created for different blade assemblies of a single shaving head with a single actuator. The posts of the blade assemblies must rotate within the bores to permit the linkage to pivot as describe. In this embodiment d′ is equal to the distance the bridge is driven in one direction. If one draws an axis through the center of the middle bore, the displacement of the center of the leading and lagging bores is a′ and a respectively. Notably, while in the shown embodiment the distance between the middle bore and the other bores is the same, that need not be the case in all embodiment. Where the distance between the bore is different between the bore pairs, a and a′ will generally not be the same. Furthermore, while the pivot point412in some embodiments is defined to be closer to the lagging attachment point (relative to the middle bore) other embodiments define the pivot point centrally between the middle and lagging bore or even closer to the middle bore. All of these geometric changes affect the relative range of reciprocating motion experiences by each blade assembly.FIGS.4C and4Dshow the kinematic scheme consistent with one embodiment of the invention. Shown schematically inFIG.4Cthe razor head is in an initial position. The pivot points are shown. The distances between the pivot point and the lagging, middle, and leading blade assemblies are given by x, y, z respectively.FIG.4Dshow the displacement of a linkage when the bridge is driven to the right. In this example, displacement from the initial position for the lagging, middle and leading balde assemblies are d1, d2and d3respectively. Then, geometrically, d1/x=d2/y=d3/z. Therefore, d1/d2=x/y and d1/d3=x/z. While strictly the pivot of the rigid linkage causes arcuate movement of the blade assemblies, within the actual range of motion the movement of the blade assemblies is substantially linear. This is due to the fact that d1, d2and d3are all <<the radius of the arc of rotation of the linkage. FIG.5is a view of the shaving assembly and handle of one embodiment of the invention. Handle180has a shaft582that may contain power source such as a battery. In one embodiment, a single AAA battery is used. In other embodiments, a rechargeable battery, such as a lithium ion battery, may be employed. In a rechargeable embodiment, a power port584may be provided. In other embodiments, such as wet shave embodiments, the rechargeable battery may be induction charged without an explicit power port. The power source powers the actuator within distal end182of handle180. The actuator then applies force to the shaving head as described above. In the foregoing specification, the embodiments of the invention have been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes can be made thereto without departing from the broader spirit and scope of the invention as set forth in the appended claims. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. | 14,975 |
RE49844 | DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Referring toFIGS.1to3, a surface profiler10according to the invention comprises a frame12which is supported by a front support wheel14and a rear support wheel16. Wheels14,16are spaced apart longitudinally on the frame12and are collinear, for travel along the same line. They are mounted for rotation on axles18,20that are supported on frame12. A suitably strong and lightweight material, such as aluminum, is chosen to minimize the mass of the wheel hubs. A suitable wheel material, such as solid natural rubber, is chosen for durability, to keep wheel mass low and to provide compliance between the frame and the surface to be profiled, i.e. to average out micro-texture, and to reduce vibration from the wheels to the frame and instruments of the profiler. If additional stability is desired, a third wheel may be attached to an arm (not shown) that extends orthogonally from a side of the frame12in order to support the profiler10and prevent it from tipping to the side. Alternatively, the frame12of the profiler may be widened and the third wheel attached directly to the frame. The profiler may comprise a distance measuring unit26to measure the distance that the profiler has travelled. In the embodiment shown, the distance measuring unit is a measuring wheel32attached to an arm28which is pivotally attached30at either end of the frame12. The measuring wheel32drives a shaft which directly couples its rotational motion to an encoder34for generating digital pulses related to the distance traveled. An inclination measuring apparatus, such as inclinometer44, is mounted on the frame12with its measuring axis in the longitudinal direction of the profiler, i.e. along the path of travel. Inclinometer44measures the orientation of the frame12with respect to the horizontal position. If required for a specific application, a second inclinometer45may be provided near the center of the frame12with its measuring axis in the transverse direction, i.e. perpendicular to the path of travel. This embodiment is best illustrated inFIG.11. The vertical distance between the frame and the surface being profiled is is measured with at least two vertical distance apparatuses, which in the preferred embodiment are lasers40,42provided near the center of the frame12, approximately equidistant from the center of the frame12and substantially closer together than the distance between the rotational axes of the wheels18,20. For example, if the distance between the wheels is approximately 250 mm, the distance between the beams of light from the lasers40,42may be approximately 25 mm. The lasers40,42are aligned so that the points of laser beam light projected on the profile are collinear with the points at which the wheels contact the surface being profiled. The lasers40,42may be of any suitable type, such as the point-type, round spot-type, elliptical spot-type or the line-type; a line-type laser is shown inFIG.2, with a characteristic fan shape, but a suitable laser would ultimately be selected depending on the surface profile demands. The LMI™ Selcom™ RoLine™ or Gocator® series of 3D lasers are examples of lasers that are engineered for the challenges of pavement surface profiling and suitable for this application. If the lasers are of the line-type or three dimensional “3D”-type, the line is preferably projected perpendicular to the path being profiled, that is, in the transverse direction. Line lasers are useful for measuring the profile over a region such as the width of a typical automobile tire. Collecting a multiplicity of distance sample data over a region helps to reduce the influence on the accuracy of the data of macrotexture such as rock chips, tining or grinding, either longitudinally or transversely. Generally the laser line width should be several times larger than the largest texture feature, such as the size of rock chips in an aggregate cement paving mixture. The multiple samples collected by the line-type laser in the transverse direction may simply be averaged to a single value, however it is preferable to include only the values that would contact a tire passing over the surface and eliminate, or to bridge over, values that would not contact a tire, such as cracks or other negative going features. Such tire bridging algorithms are known and should be applied to the transverse line laser data. The measuring wheel32is preferably located approximately mid-way between lasers40,42, in order to ensure it measures the same distance travelled as is “seen” by the lasers40,42traversing the profile to be measured. Alternatively, a distance measuring device may be coupled to the rotational axis of either wheel. However it may be necessary to adjust the calculations, as a unit located off-centre may not measure the distance changes observed by the lasers as accurately as would a unit that is placed near the mid-point of the lasers, as best illustrated inFIG.9. Referring again toFIGS.1to3, a handle47is attached to frame12. An operator interface, such as a cabinet46, is secured to the handle47. Cabinet46may comprise any suitable interface means, such as a keyboard, touchscreen and/or display screen, to allow the operator to control the profiler, including seeing and controlling data input, output, system information, communication, and provision of information. If preferred, the cabinet46may be secured with bracket48that is adjustable to allow the operator to see it properly, regardless of the ground angle or the lighting conditions. An enclosure50attached to the frame12contains the operational equipment necessary to operate the profiler. For example, the enclosure50contains the computer and memory58required to acquire and apply the signals and readings obtained from the measuring devices and other apparatus carried on the profiler, including the distance measuring unit26, one or both inclinometers44,45andtothe distance measuring lasers40,42. It may also obtain information from any other sensors that may be provided, such as a temperature sensor43. Enclosure50may also contain batteries52or any other suitable power supply, internal sensors such as a temperature sensor51and battery voltage monitor53, and signal conditioning equipment including amplification and filtering54and an integrated computer hardware interface56containing suitable apparatus such as a real time clock, distance pulse counters, digital input/output and multi-channel 16 bit analog to digital converter. Data acquisition is controlled through the operator interface46. Under control of the computer58the distance is measured using distance measuring unit26which sends electrical pulses representative of the distance traveled to counters on the hardware interface board timer in order to trigger acquisition (i.e. digital conversion and storage) of analog voltages at appropriate distances. The analog voltages from the inclinometers44,45, distance measuring lasers40,42, temperature sensor43, and batteries52are acquired by the multi-channel 16 bit analog to digital converter on the hardware interface board56. Computer58periodically obtains signals from all measuring devices attached to the profiler, preferably substantially simultaneously measuring the total longitudinal distance travelled, the inclination of the frame and the vertical distances seen by the two lasers. This may be most simply done at constant distance intervals ΔD, such as 1 mm. It is important to capture data from all devices at the same instant in order for the algorithm of the method to provide the most accurate profile results. Conveniently the total longitudinal distance travelled is acquired by counting pulses from the optical encoder, while the inclination is obtained from the inclinometer and the two vertical distances are obtained from the lasers by converting voltages from these devices to their corresponding digital forms using an analog to digital converter with multiple analog inputs. Alternatively, instead of constant distance intervals, measurements may be taken at constant time intervals or any other suitable interval. For example, the computer58may use a real time clock to determine when to obtain the measurement signals, namely at intervals of constant time such as 1 msec. Distance change ΔD may be determined by inspection of the distance travelled at each 1 msec interval, although it may not have a constant value from interval to interval, if the speed of the profiler is not constant. Calculations Referring now toFIG.4, the invention uses the following method to produce a mathematical series that accurately represents the surface profile. First, the following constants are acquired: W is the distance between the rotational axes of the wheels, in meters. While W is not used directly in the calculation of the profile elevation series it does define the wavelength at which the inclinometer frequency response rolls off to zero and the lasers take over. The wheels and lasers must be collinear for smooth and accurate transition between inclinometers and lasers. L is the distance between the measuring light beams emitted from the lasers, in meters. The lasers are preferably substantially equidistant from the mid-point of the frame. α is the angle between the frame and the horizontal plane of the earth in radians, as measured by the inclinometer. Lfis the difference between the distance to the surface, as measured by the front laser, and a line SW connecting the points at which the front and rear wheels contact the surface as shown inFIG.4. Lris the difference between the distance to the surface, as measured by the rear laser, and the same line. Lfand Lrare measured in meters. The points where the laser beams contact the surface define a line, labeled inFIG.4as SL. The angle between line SL and line SW is β. θ is the angle between SL, the line connecting the points where the laser beams contact the profile surface, and the X axis, which is the horizontal plane of the earth, meaning that θ=α+β. We can see that: tanβ=((Lf-Lr)L) or inverted: β=tan-1((Lf-Lr)L) There is a continuous elevation profile function ƒ(x) called E(x): y=E(x) For a point P on the profile function E(x) mid-way between the rotational axes of the wheels and mid-way between the lasers, using principles of differential calculus, the slope at point P is: slope=ⅆyⅆx For a right angle triangle having point P at its lower corner, the hypotenuse has the slope of a tangential line intersecting P that forms the angle θ with the horizontal plane of the earth. The slope at point P is given by the angle θ. The mean value theorem states that a point P on the profile between the points of contact of the lasers on the profile must have the same slope as that defined by the points of contact of the lasers on the profile. We estimate that this value occurs at the mid-point between the lasers: slope=sin(θ)sinθ=ⅆyⅆx We see that for a very small incremental change in horizontal distance Δx there will be a corresponding very small change in elevation ΔE according to the profile slope at point P as determined by the angle θ. For very small incremental changes in horizontal distance Δx, for example less than 1 mm, and elevation ΔE: sinθ=ΔEΔx ΔD is the distance travelled by the profiler10along the surface being measured. The distance is preferably measured at or very near the mid-point between the lasers for greatest accuracy. Otherwise, a ΔD error may be introduced wherever the slope at the location of the non-contact sensors differs from the slope at the location of the distance sensor. As an example,FIG.9illustrates a configuration with a measuring unit remote from the midpoint of the profiler frame. Clearly there can be situations where the midpoint profile is horizontal but the remote distance measuring wheel traverses up a bump or down a dip, where the profile has large positive or negative slope. In this example the distance measuring unit26will record a larger value of ΔD than the actual value observed at the mid-point of only ΔD cos ϕ. The opposite may also occur. The ΔD error results in an incorrect calculation of ΔE and an incorrect mathematical series representing the profile elevations. In summary: sinθ=ΔEΔDΔE=ΔDsinθΔE=ΔDsin(α+β)ΔE=ΔDsin(α+tan-1((Lf-Lr)L)) And to build a mathematical series accurately representing the profile from m samples of data, starting at elevation E0, sampled every ΔDndistance interval, the resulting end distance Emmay be defined as follows: Em=E0+∑n=1m(ΔDnsin(∝n+tan-1((Lfn-Lrn)L))) E0may be taken from existing records for the elevation above sea level of the test site. Alternatively, a relative measure may be sufficient for the purposes of the profile data such that E0is set to zero. In order to build the profile at every n distance interval it is necessary to acquire the values ΔDn, αn, Lfnand Lrnfrom the measuring devices. Therefore, at any given point along the profile, the necessary readings are acquired from the distance measuring unit, the inclinometer and the lasers. Note that the lasers may be removed from the apparatus, which would continue to function as an accurate profiler using only αn, therefore making Lfnand Lrn, and consequently βn, equal to zero. The profiler frequency response would roll off toward and become zero at W. Calculating the Profile The data collection process is initiated by the operator, and continues until the operator stops the process. Once stopped, the data collected can be saved to a USB-connected flash drive or other storage device. Also, the operator may perform diagnostics and calculations such as computation of roughness indices such as the IRI. The following process is used to measure the profile. First, a benchmark survey data may be used to establish the local elevation as E0or the starting elevation may simply be set to 0. Then, at suitable time intervals Δt, such as every millisecond, or every incremental distance ΔD, such as every millimeter, a measuring subroutine is initiated, during which the following steps are performed: 1. Acquire all raw data from measuring devices using input hardware interfaces. This step generally involves obtaining information about the angle of the frame12from the inclinometer44and the distance between each of the lasers40,42and the ground. The data is preferably all acquired substantially simultaneously, for example within one millisecond, because using precise geometry and precise measurements at each position of the profiler along the path will increase the accuracy of the surface profile. Measurements from the is measuring devices are preferably conditioned to remove noise and improve quality prior to performing calculations. Analog voltage signals entering the multi-channel analog to digital converter may be provided anti-aliasing filters. “Anti-aliasing” involves the application of passive resistor-capacitor low pass filters to incoming analog signals to limit the frequencies applied to the inputs of analog to digital converters to one-half of the digital sampling frequency, which is known as the Nyquist frequency, to avoid digitization errors. Digital values derived from the analog to digital converter may be digitally filtered using a band pass digital filter that passes only signal frequencies containing useful information. 2. Determine the distance travelled. In the embodiment shown, this is accomplished by accumulating the counts of electrical pulses from the longitudinal distance measuring unit26and dividing by a scaling factor that converts the number of pulses to a distance Dnewtravelled along the profile, in meters. However, any method suitable to accurately obtain and provide the distance travelled by the profiler may be employed. 3. Determine the incremental distance ΔD travelled. This simply uses the formula: ΔD=Dnew−Dold where Doldis the distance travelled and stored during the iteration of the measurement subroutine. ΔD may be as small as approximately 1 mm and may vary depending on speed of the profiler but the method is generally independent of speed. The current distance value Dnewis stored for use at the next measurement interval as Dold. 4. Convert the data acquired into useful values. This step involves scaling digital values from the analog to digital converter to voltages and then to engineering quantities of angles in radians and distances in meters. The value of α obtained from the inclinometer will be in radians. The distance measured by the front laser distance measuring device is Lfand the distance measured by the rear laser is Lr, both being directed vertically downward and perpendicular to the frame. Lfand Lrfrom the distance measuring lasers will be converted to meters. The lasers are normally scaled to produce 0 to 10 volts for 16 to 120 mm of distance, but by simple scaling adjustments consisting of adding an offset and inverting the range, it is possible to obtain values of Lfand Lrthat represent the distances between the points where the lasers strike the surface of the profile (i.e. along line SL) and the line SW, which extends between the points where wheels contact the surface of the profile pavement. Lfand Lrwill have a positive value where the profile is higher than the line SW, and a negative value where the profile is below the line SW. 5. Calculate the nth incremental change in elevation ΔEnUsing the Formula: ΔEn=ΔDnsin(αn+tan-1((Lfn-Lrn)L)) ΔEnis then added to the accumulated elevation series as: En=E0+ΔE1+ΔE2. . . +ΔEn 6. Return to step 1 at the next increment. The mathematical elevation series created captures within the resulting profile all wavelengths from L to the longest wavelengths of interest. At L, the gain of the device becomes zero. Above L, all frequencies are captured without phase shift or distortion with the result that large and small profile features such as bumps, dips and cracks are captured with correct amplitude and longitudinal distance. FIG.6shows how the addition of dual lasers, in this example being lasers spaced about 25 mm apart mounted to a profiler having a wheelbase of about 250 mm, can extend the short wavelength response over the 25 mm-250 mm range, as compared to an otherwise identical profiler using only an inclinometer, that is where β is always zero because of the absence of lasers to derive β. Overall the performance of this configuration of dual laser/inclinometer profiler is smooth and accurate from 25 mm to effectively infinite millimeters, and in particular provides useful information in the region Δ the wheelbase separation distance W, down to laser separation distance L. FIG.7is a more specific example of the results from a profiler to which dual lasers have been added. The profiler, which has the same dimensions as that in theFIG.6example, is now able to measure the shape and amplitude of a bump on the profile having a half cycle sinusoidal shape with width of 160 mm. Without the addition of the dual lasers to the profile calculation, laser-derived angle β would always be zero and would not affect the profile. Using only the inclinometer, the wheels would contact points on the profile, spaced apart by W, tilt the frame and provide the inclinometer slopeaαto calculate the profile. If the slope is positive the calculated profile increases; if the slope is negative the calculated profile decreases; if the slope is zero the elevation remains constant. On a generally horizontal profile, for profile features such as bumps or dips that are shorter than W, the wheels can actually straddle the feature with the result that the calculated profile remains constant while the feature is between the wheels. For this reason the profiler without dual lasers, that is with inclinometer only, is unable to provide a calculated profile that accurately records the height of profile features smaller than W. These calculated profile features will be both lower in height and wider than the actual feature, as shown inFIG.7. The profiler measures the total distance travelled along the surface of the profile, the summation of the ΔDnvalues. This is normally sufficient since the true elevation values are most important and in most cases the D values are adequate for uses of the data. If the total distance travelled along the horizontal plane of the earth (the X axis) is required, then each ΔDnvalue must be multiplied by the corresponding cos(θn) before summing. Specifically: ΔXn=ΔDncos θn Correction and Compensation The measurement of the surface profile is accomplished using a combination of inclinometer measurements and laser measurements. The inclinometer is able to measure profile independently of the laser measurements using the formula: ΔE=ΔD sin(α) However, as shown inFIG.8, when the wavelength λ of any surface feature is equal to or is less than W, the inclinometer alone loses effectiveness, and the profiler is incapable of accurately detecting these features. Where the feature wavelength λ is equal to W, the profiler remains horizontal relative to the plane of the earth at all positions on the profile so the angle α measured by the inclinometer remains constantly at zero, meaning the response gain of the profiler is zero at this wavelength. The use of the lasers therefore extends the wavelength range of the invention into the range of λ between W and L, enabling high resolution measurement of surface features. For features having wavelengths λ between W and L, the combination of inclinometer and lasers work together to measure the profile using the formula: ΔE=ΔDsin(α+tan-1((Lf-Lr)L)) FIG.10is a graph showing the contributions of the inclinometer alone and lasers alone, as compared to using the dual laser and inclinometer combination of the invention. In practice, despite efforts to accurately calibrate and balance the front and rear lasers, it is possible that Lfwill not equal Lrwhen the profiler is placed on a perfectly straight surface with or without tilting relative to the horizontal plane of the earth. Also for very long wavelength sine wave profiles, the distance measuring lasers “see” a straight line and produce no LfLror β signal.FIG.10shows that at 20 times W (5 m where W is 0.25m), the contribution of the lasers to the total profile, or their gain, is nearly zero compared to the inclinometer which is nearly 1.0. At 20 times W, the Lfand Lrsignals will be very small relative to the resolution of the lasers or the analog to digital converters or will be buried in noise inherent in data acquisition systems. This may result in poor performance of the profiler if the long wavelength component of the LfLror β signal is not removed. Therefore it may be necessary to wavelength high pass filter Lfand Lror the term: β=tan-1((Lf-Lr)L) using a high pass digital filter with a cutoff wavelength of approximately 20 times W. This involves filtering in the distance domain (cycles/meter) rather than the frequency domain (cycles/second) and requires the ΔD values to be fairly constant. In this way, even if Lf-Lror β is not exactly equal to zero for a perfectly straight profile, there will be no non-zero value of β that causes the profile elevation to wander and result in large elevation errors at the end of the profile, since the high pass digital filter will make Lfand Lror β equal to zero for very long wavelengths. Filtering out very long wavelengths from the β signal as described requires the wheels and lasers be collinear to ensure the component of the profile contributed by the inclinometer is aligned with the component of the profile contributed by the lasers particularly through the crossover region at 20 times W. A typical inclinometer is basically an accelerometer that responds to the direction of the acceleration of gravity using a pendulum that is balanced to the zero position by a miniature torque motor. The electrical current to the torque motor required to maintain the pendulum in the zero position is proportional to the sine of the angle of inclination and is the source of the voltage signal produced by the inclinometer. Such devices are also sensitive to acceleration of the inclinometer along the sensitive axis, such as may be caused by the operator pushing on the handle of the profiler to start it moving, and pulling on the handle to stop it. The inclinometer will also be sensitive to the normal acceleration and deceleration inherent in the walking motion of the operator. In order to correct this sensitivity, it may be necessary to calculate a compensating signal using high resolution distance information from the optical encoder or other distance measuring device, if the information is available. By differentiating the distance signal D twice, an acceleration signal A can be derived. This differentiation may be performed on the digital representation of distance obtained from the distance measuring unit. By appropriately scaling this acceleration with constant k, an equal and opposite compensation signal can be added to the inclinometer signal i to eliminate this issue. Specifically this is accomplished as follows:dD/dt=velocity VdV/dt=acceleration Aicorrected=iuncorrected−k A In some cases, the longitudinal inclinometer produces an errant signal when tilted in the transverse direction, a characteristic known as cross-axis error. Cross-axis error is caused by misalignment between the axis of the sensing accelerometer element in the longitudinal inclinometer with its enclosure, or misalignment between the enclosure of the inclinometer with the longitudinal axis of the profiler. Either misalignment exposes the sensing accelerometer element to tilting in the transverse direction. As best shown inFIG.11, if a transversely-aligned (or cross-axis) inclinometer45is provided to measure the angle χ between the horizontal plane of the earth and the frame in the transverse direction, it may provide information to correct the longitudinal inclinometer angle α for cross-axis error. The correction is applied to the voltage output from the inclinometer prior to conversion to angle. The longitudinal inclinometer voltage Vαis compensated for cross-axis error as follows. Vαc=Vα+SαtoχxVχ-VχoffsetSχwhere:Vαcis the longitudinal inclinometer voltage, after compensation, in volts;Vαis the longitudinal inclinometer voltage, before compensation, in volts;Sα to χis the longitudinal inclinometer's (or α's) sensitivity to tilting in χ direction in volts/G, determined empirically;Vχis the transverse, or cross-axis, inclinometer voltage in volts;Vχ offsetis the transverse inclinometer voltage output measured when the inclinometer is set horizontal relative to the plane of the earth in volts, determined empirically; andSχis the full range sensitivity of the transverse inclinometer in volts/G. Then the cross-axis compensated angle α is given by: α=sin-1VαcSα where Sαis the full range sensitivity of the longitudinal inclinometer in volts/G. The present invention, given its high accuracy and repeatability, while finding uses in several industries and for many purposes, will be of particular value in both the contract management of new surface construction and as a reference standard for certification of other instruments. The foregoing embodiment of the invention has been described as a rolling/walking profiler, having an operator to physically move the apparatus along the surface being profiled. However, it is also contemplated to provide a motorized drive mechanism for the apparatus, which can move the apparatus along the surface at a controllable speed. In a further alternative, the apparatus may comprise appropriate attachment means by which it can be attached to a motorized vehicle, which will then move the apparatus along the surface to be profiled, such as by towing or pushing. In the foregoing specification, the invention has been described with reference to specific embodiments thereof. However, the scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. | 28,295 |
RE49846 | DETAILED DESCRIPTION OF THE INVENTION With reference toFIG.1, a simplified block diagram of the present CATV MoCA splitter includes an input terminal2for receiving a CATV signal typically having a frequency range of 5 MHz to 1002 MHz, and is connected via an electrically conductive line path or lead30to the input of a 2-way hybrid splitter4. The 2-way hybrid splitter4has a first output connected via an electrically conducted path34to the input of a first diplex filter14, and a second output connected via an electrically conductive path38to an input32of a second 2-way hybrid splitter6. The 2-way hybrid splitter6has a first output connected via an electrically conductive path36to a second diplex filter18, and a second output connected via an electrically conductive path40to a CATV (RF output) terminal7. The first diplex filter14includes a lowpass filter section15for passing CAN signals in the frequency range from 5 MHZ to 1002 MHz for outputting on an electrically conductive path35for connection to a modem terminal8. When a modem (not shown) is connected to the modem terminal8, typically the modem will provide a voltage feed of 12 volts DC that is connected via electrically conductive path35through a resistor10(typically 1 k Ω), to a light emitting diode12, for indicating by its light output connection of a modem to terminal8. Diplex filter14also includes a highpass filter section16for passing MoCA signals having a frequency range 1125 MHz to 1675 MHz, for connection via an electrically conductive path39to a 6-way resistive splitter24. The second diplex filter18includes a lowpass filter section19passing CAN signals having a frequency range of 5 MHZ to 1002 MHz via an electrical conductive path37to a Gateway terminal22. The Gateway terminal22, in one example, may be connected to a Gateway recording and programmable apparatus (not shown). In this example, indicated CATV signals are passed from the Gateway terminal22to the programmable recording apparatus (not shown), MoCA signals having a frequency range of 1125 MHz to 1675 MHz are bidirectionally passed between Gateway terminal22and the Gateway recording device (not shown). MoCA signals, in this example, as previously mentioned, having a frequency range of 1125 MHz to 1675 MHz, are bidirectionally passed between a highpass filter section16diplex filter14via an electrically conductive pass39to a 6-way resistive splitter24. Similarly, the highpass filter section20of diplex filter18is connected via an electrically conductive path41to bidirectionally pass MoCA signals to the 6-way resistive splitter24. However, splitter24is not meant to be limited to a 6-way resistive splitter, and can be configured to provide any desired number of MoCA ports within practical limits. The 6-way resistive splitter24bidirectionally passes MoCA signals via individual electrically conductive paths3,5,7, and9, to MoCA terminals or ports25,26,27, and28, respectively. In this example, individual MoCA clients (not shown) can be individually connected to the ports or terminals25through28, respectively, for permitting each of them to program the Gateway device (not shown) to record desired cable television programs for later viewing. The diplex filters14and18insure that the CATV signals are electrically isolated from the MoCA signals. A typical 2-way hybrid splitter circuit schematic is shown inFIG.2. In this example, the typical hybrid 2-way splitter4(6) includes a matching transformer having a primary winding42with one end individually connected to an electrically conductive path30(32), with the other end of the winding42being connected to ground. The splitter4(6) also includes a secondary winding44having one end individually connected to electrically conductive paths34(36), respectively, and another end connected to electrically conductive paths38(40). In this example, the primary winding42has a turns ratio of 2:5 relative to a center tap43connected between the primary winding42and the secondary winding44. The secondary winding44has a turns ratio of 2:2 relative to the center tap43. A capacitor46is connected between the center tap and ground to match the leakage inductance inherent in the interconnection of the transformer windings42and44. A series circuit of a resistor47and two inductors49and50are connected across the secondary winding44, as shown. Note that the inductors49and50are chokes that modify the phase cancellation at the very high end of the frequency band of signals outputted from either of the splitters14and18. The resistor47, in combination with the chokes49and50sets the phase cancellation between the two output lines from the secondary winding44in order to maximize the electrical isolation therebetween. Note that the value of the capacitor46is typically 1 pF (picofarads), the chokes49and50typically have values of 5 nH (nanohenries), and resistor47a value of 200 ohms. The circuit schematic diagram for a 6-way resistive splitter24for an embodiment of the invention is shown inFIG.3. Six resistors52through57each have one end connected in common as shown. The other end of resistor55is connected to electrically conductive circuit path39to the highpass filter section16of diplex filter14. The other end of resistor52is connected via electrically conductive path41to the highpass filter section20of diplex filter18. The other end of resistor53is connected via electrically conductive path3to MoCA terminal25. The other end of resistor54is connected via electrically circuit path5to MoCA terminal26. The other end of resistor56is connected via electrically conductive path7to MoCA terminal27. The other end of resistor57is connected via electrically conductive path9to MoCA terminal28. A diplex filter circuit schematic diagram, shown inFIG.4, can be used to provide diplex filters14,18, respectively. As shown, each diplex filter14(18) includes a plurality of inductors60through72, and a plurality of capacitors73through88, connected in series and parallel circuit combinations, as shown. Values of the aforesaid inductors and capacitors are selected for obtaining the required lowpass filter frequency range, and highpass filter frequency range, as previously indicated. A circuit schematic diagram for a prototype Gateway splitter developed by the inventors is shown inFIG.5. As will be explained, the circuitry for the prototype design differs in this embodiment from the previously described embodiments of the invention, whereby additional components have been added. More specifically, spark gaps100have been connected individually between input port2, CATV port7, modem port8, Gateway port22, MoCA port25, MoCA port26, MoCA port27, MoCA port28, and ground, respectively. Note that use of the terminology port is meant to be also analogous to a terminal, whereby typically each of the aforesaid ports are coaxial connector ports. Also, as shown, DC blocking capacitors89have been added to 2-way hybrid splitters4,6, diplex filters14,18, and the 6-way resistive splitter24, each of the blocking capacitors89being connected as shown. Each of the 2-way hybrid splitters4and6include two matching capacitors in parallel between the tap offs from primary winding42and secondary winding44and ground, as shown. The lowpass filter sections15and19of diplex filters14,18, respectively, now each further include additional capacitors96and99, and a choke for inductance98, as shown. The highpass filter sections16and20of the diplex filters14,18, respectively, remain identical to the circuitry previously shown inFIG.4. Also note that in the 6-way resistive splitter24, a connection pad60has been included in order to provide a common connection node for all of the resistors of the resistive splitter24. Pad60is large enough to provide a low impedance node via the copper material of the pad providing body capacitance on a dielectric PC Board substrate. If MoCA ports25through28are all terminated to MoCA device ports each having a 75 ohm input impedance, the characteristic impedance at pad or node60will be 21.5 ohms. In this example, as is typical with CATV systems, the impedance at the various ports is 70 ohms. In the 2-way hybrid splitters4and6, the reason that two capacitors46are used in parallel between the ferrite transformer windings42and44is to obtain a more distributed ground connection. The capacitors46provide for canceling small amounts of stray inductance in the interconnection between the ferrite core transformers42and44, for improving high frequency return loss and isolation therebetween. Note further that in the prototype the resistor94of the 2-way hybrid splitters4and6have a value 180 ohms, but can have a resistance range of 150 ohms to 220 ohms depending on the characteristics of the particular ferrite core transformers42,44, at low frequencies between 5 MHz and 50 MHz. Note further that resistors94are connected in series with an inductor (not shown) that is printed on an associated printed circuit board rather than being a discrete component, with the series circuit thereof being connected therebetween capacitors90and92. Capacitors90and92improve isolation and return loss at low frequencies. With further reference to the diplex filters14and18, as shown inFIG.5, note that the lowpass filter sections15and19thereof, respectively, differ from the circuitry ofFIG.4. More specifically, in the prototype circuitry four parallel tank circuits are included in the associated lowpass filter sections15and19, rather than three as shown inFIG.4. The additional parallel tank circuit in each section includes capacitors96and99, and inductor98, for further insuring a frequency roll off above 1.0 GHz, thereby avoiding adding additional inductors to every shunt element. With further reference to the prototype circuit schematic diagram ofFIG.5, values of various of the components utilized will now be given, but are not meant to be limiting. The DC blocking capacitors89each have a value of 2200 (picofarads), and a voltage rating of 50 volts in this example. In the 2-way hybrid splitter circuits4and6, the tapoff43for the ferrite core transformer42is between the second turn and the fifth turn of the seven turns thereof, whereas in the ferrite core transformer44the tapoff43is between the second turn from each end of the four turns included. The capacitors90each have a value of 1000 pf. Capacitors92each have a value of 1000 pf. Capacitors46each have a value of 1 pf. For diplex filters14and18, the inductances60each have a 0.3 mm (millimeter) wire diameter, a 1.5 mm coil diameter, and 2.5 turns. Capacitors73each have a value of 2.0 pf. Capacitors74,78, and96each have a value of 0.75 pf. The inductances65,66,67, and98each have a 0.3 mm wire diameter, 1.7 mm coil diameter, and 2.5 turns, respectively. Capacitors75each have a value of 1.8 pf. The capacitors77and79each have a value of 1.8 pf. Capacitor99has a value of 2.2 pf. Inductor68has a 0.3 mm wire diameter, a 2.0 mm coil diameter, and 2.5 turns. Capacitor99has a value of 2.2 pf. In the highpass filter sections16and20of diplex filters14,18, respectively, capacitor80has a value of 1.2 pf. Capacitors82,86, and87each has a value of 1.8 pf, respectively. Capacitor81has a value of 2.2 pf. Capacitor83has a value of 2.0 pf. Capacitor84has a value of 1.5 pf. Capacitor85has a value of 6.8 pf. Capacitor88has a value of 2.5 pf. Inductor69has a 0.3 mm wire diameter, a 1.5 mm coil diameter, and 2.5 turns. Inductors70,71and72each have a 0.3 mm wire diameter, a 1.7 mm coil diameter, and 2.5 turns, in this example. In the 6-way resistive splitter24, each of the resistors52through57, respectively, has a value of 54 ohms, in this example. Note that none of the component values used in the prototype as given above are meant to be limiting. InFIG.6, a housing102for a Gateway prototype splitter1is shown. The MoCA ports25through28are located at one end of the associated housing102, whereas the input port2, modem port8, RF output port7, and Gateway port22are located at an opposite end of the housing102. Also shown is a terminal104for receiving a ground connection. Screw receptive brackets105are provided for securing the Gateway splitter to a desired seating surface, such as a mounting base within a cavity or enclosure (not shown). In the second embodiment of the invention, as shown inFIG.7, an input port2for receiving a CATV signal is connected via electrically conductive line path31to an input32of the 2-way hybrid splitter6. The 2-way hybrid splitter6outputs are connected as in the embodiment ofFIG.1to the lowpass section19of a diplex filter18, and the CATV port7. Further, as with the embodiment ofFIG.1, the diplex filter18has a connection to a Gateway port22, and to a resistive splitter24, as shown. Relative to the first embodiment of the invention ofFIG.1, in the second embodiment the 2-way hybrid splitter4, diplex filter14, modem port8, resistor10, and LED12have been removed. A third embodiment of the invention is shown inFIG.8. In the third embodiment an input port2for receiving a CATV signal provides for connection thereof via an electrical lead line or conductive path33directly to the lowpass section19diplex filter18. In comparison to the second embodiment of the invention ofFIG.7, in the third embodiment the 2-way hybrid splitter6has been eliminated, which in turn eliminates the provision of a CATV port7, as in the other embodiments. Accordingly, relative to embodiment ofFIG.1, the embodiment ofFIG.7eliminates the provision of allowing a user to connect a modem, but otherwise retains all of the other connections of the first embodiment. The third embodiment of the invention relative to the second embodiment eliminates the provision of a CATV port7, and only provides for a user to have use of MoCA ports, and a Gateway port. Note further that as shown, the resistive splitter24ofFIG.1is a 6-way splitter, whereas the resistive splitter24of the second and third embodiments ofFIGS.7and8is a 5-way resistive splitter. However, it should be understood that the resistive splitter24can be configured to provide any number of MoCA ports within practical limits. Although various embodiments of the invention have been shown and described, they are not meant to be limiting. Those of skill in the art may recognize certain modifications to these embodiments, which modifications are meant to be covered by the spirit and scope of the appended claims. | 14,412 |
RE49847 | DETAILED DESCRIPTION Provided herein are compositions of matter and methods of use for the treatment or prevention of a disease such as cancer using CD20 and/or chimeric antigen receptors (CAR). In one aspect, the invention provides a number of chimeric antigen receptors (CAR) comprising an antibody or antibody fragment engineered for specific binding to a CD20 protein, or CD22 protein or fragments thereof. In one aspect, the invention provides a cell (e.g., T cell or NK cell) engineered to express a CAR, wherein the cell (e.g., “CART”) exhibits an antitumor property. In one aspect a cell is transformed with the CAR and the at least part of the CAR is expressed on the cell surface. In some embodiments, the cell (e.g., T cell or NK cell) is transduced with a viral vector encoding a CAR. In some embodiments, the viral vector is a retroviral vector. In some embodiments, the viral vector is a lentiviral vector. In some such embodiments, the cell may stably express the CAR. In another embodiment, the cell (e.g., T cell or NK cell) is transfected with a nucleic acid, e.g., mRNA, cDNA, DNA, encoding a CAR. In some such embodiments, the cell may transiently express the CAR. In one aspect, the CD20 or CD22 binding domain, e.g., the murine, human or humanized CD20 binding domain, of the CAR is a scFv antibody fragment. In one aspect, such antibody fragments are functional in that they retain the equivalent binding affinity, e.g., they bind the same antigen with comparable efficacy, as the IgG antibody having the same heavy and light chain variable regions. In one aspect such antibody fragments are functional in that they provide a biological response that can include, but is not limited to, activation of an immune response, inhibition of signal-transduction origination from its target antigen, inhibition of kinase activity, and the like, as will be understood by a skilled artisan. In some aspects, the antibodies of the invention are incorporated into a chimeric antigen receptor (CAR). In one aspect, the CAR comprises the polypeptide sequence provided herein as Table 1. In one aspect, the CD20 or CD22 binding domain, e.g., murine, humanized or human CD20 or CD22 binding domain, portion of a CAR of the invention is encoded by a transgene whose sequence has been codon optimized for expression in a mammalian cell. In one aspect, entire CAR construct of the invention is encoded by a transgene whose entire sequence has been codon optimized for expression in a mammalian cell. Codon optimization refers to the discovery that the frequency of occurrence of synonymous codons (i.e., codons that code for the same amino acid) in coding DNA is biased in different species. Such codon degeneracy allows an identical polypeptide to be encoded by a variety of nucleic acid sequences. A variety of codon optimization methods is known in the art, and include, e.g., methods disclosed in at least U.S. Pat. Nos. 5,786,464 and 6,114,148. In one aspect, the antigen binding domain of the CAR comprises a murine (e.g., rat or mouse) antibody or antibody fragment. In one aspect, the antigen binding domain of the CAR comprises a human CD20 or CD22 antibody or antibody fragment. In one aspect, the antigen binding domain of the CAR comprises a humanized CD20 or CD22 antibody or antibody fragment. In one aspect, the antigen binding domain of the CAR comprises a murine CD20 or CD22 antibody fragment comprising an scFv. In one aspect, the antigen binding domain of the CAR comprises human CD20 or CD22 antibody fragment comprising an scFv. In one aspect, the antigen binding domain of the CAR is a human CD20 or CD22 scFv. In one aspect, the antigen binding domain of the CAR comprises a humanized CD20 antibody fragment comprising an scFv. In one aspect, the antigen binding domain of the CAR is a humanized CD20 or CD22 scFv. In one aspect, the CAR20 binding domain comprises the scFv portion provided in SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429. In one aspect, the CAR22 binding domain comprises the scFv protein as set forth in Table 6. Furthermore, the present invention provides CD20 CAR of CD22 CAR compositions and their use in medicaments or methods for treating, among other diseases, cancer or any malignancy or autoimmune diseases involving cells or tissues which express CD20 or CD22. In one aspect, the CAR of the invention can be used to eradicate CD20-expressing or CD22-expressing normal cells, thereby applicable for use as a cellular conditioning therapy prior to cell transplantation. In one aspect, the CD20-expressing or CD22-expressing normal cell is a CD20-expressing or CD22-expressing expressing myeloid progenitor cell and the cell transplantation is a stem cell transplantation. In one aspect, the invention provides a cell (e.g., T cell or NK cell) engineered to express a chimeric antigen receptor (e.g., CART) of the present invention, wherein the cell (e.g., “CART”) exhibits an antitumor property. Accordingly, the invention provides a CD20-CAR that comprises a CD20 binding domain and/or a CD22-CAR that comprises a CD22 binding domain and is engineered into a T cell or NK cell and methods of their use for adoptive therapy. In one aspect, the CD20-CAR or CD22-CAR comprises at least one intracellular domain, e.g., described herein, e.g., selected from the group of a CD137 (4-1BB) signaling domain, a CD28 signaling domain, a CD3zeta signal domain, and any combination thereof. In one aspect, the CD20-CAR or CD22-CAR comprises at least one intracellular signaling domain is from one or more co-stimulatory molecule(s) other than a CD137 (4-1BB) or CD28. Chimeric Antigen Receptor (CAR) The present invention encompasses a recombinant DNA construct comprising sequences encoding a CAR, wherein the CAR comprises an antigen binding domain (e.g., antibody, antibody fragment) that binds specifically to CD20 and/or CD22 or a fragment thereof, e.g., human CD20 or CD22, wherein the sequence of the CD20 or CD22 binding domain (e.g., antibody or antibody fragment) is, e.g., contiguous with and in the same reading frame as a nucleic acid sequence encoding an intracellular signaling domain. The intracellular signaling domain can comprise a costimulatory signaling domain and/or a primary signaling domain, e.g., a zeta chain. The costimulatory signaling domain refers to a portion of the CAR comprising at least a portion of the intracellular domain of a costimulatory molecule. In specific aspects, a CAR construct of the invention comprises a scFv domain selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429, wherein the scFv may be preceded by an optional leader sequence such as provided in SEQ ID NO: 797, and followed by an optional hinge sequence such as provided in SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 815, a transmembrane region such as provided in SEQ ID NO: 801, an intracellular signalling domain that includes SEQ ID NO: 803 or SEQ ID NO: 804 and a CD3 zeta sequence that includes SEQ ID NO: 805 or SEQ ID NO: 807, e.g., wherein the domains are contiguous with and in the same reading frame to form a single fusion protein. Also included in the invention is a nucleic acid sequence that encodes the polypeptide of each of the scFv fragments selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429. In one embodiment, the nucleic acid sequence encoding the CD20 binding domain comprises a sequence selected from a group consisting of SEQ ID NO: 25, SEQ ID NO: 52, SEQ ID NO: 79, SEQ ID NO: 106, SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 187, SEQ ID NO: 214, SEQ ID NO: 241, SEQ ID NO: 268, SEQ ID NO: 295, SEQ ID NO: 322, SEQ ID NO: 349, SEQ ID NO: 376, SEQ ID NO: 403, and SEQ ID NO: 430. In an embodiment, the nucleic acid sequence encoding the CD20 binding domain comprises a sequence as set forth in Table 1. In one embodiment, the nucleic acid sequence encoding the CD22 binding domain comprises a sequence as set forth in Table 6. Further embodiments include a nucleic acid sequence that encodes a polypeptide of Table 1 and/or Table 6. Further embodiments include a nucleic acid sequence that encodes a polypeptide of any of Table 1 and/or Table 6 and each of the domains of SEQ ID NOs: 797, 799, 801, 803, 805, and optionally 818. In one aspect an exemplary CD20CAR constructs comprise an optional leader sequence, an extracellular antigen binding domain, a hinge, a transmembrane domain, and an intracellular stimulatory domain. In one aspect an exemplary CD20CAR or CD22CAR construct comprises an optional leader sequence, an extracellular antigen binding domain, a hinge, a transmembrane domain, an intracellular costimulatory domain and an intracellular stimulatory domain. In some embodiments, full-length CD20 CAR sequences are also provided herein as Table 1. In some embodiments, full-length CD22 CAR sequences are also provided herein as Table 6. An exemplary leader sequence is provided as SEQ ID NO: 797. An exemplary hinge/spacer sequence is provided as SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 816. An exemplary transmembrane domain sequence is provided as SEQ ID NO: 801. An exemplary sequence of the intracellular signaling domain of the 4-1BB protein is provided as SEQ ID NO: 803. An exemplary sequence of the intracellular signaling domain of CD27 is provided as SEQ ID NO: 818. An exemplary CD3zeta domain sequence is provided as SEQ ID NO: 805 or SEQ ID NO: 807. In one aspect, the present invention encompasses a recombinant nucleic acid construct comprising a nucleic acid molecule encoding a CAR, wherein the nucleic acid molecule comprises the nucleic acid sequence encoding a CD20 binding domain, e.g., described herein, e.g., that is contiguous with and in the same reading frame as a nucleic acid sequence encoding an intracellular signaling domain. In one aspect, a CD20 binding domain is selected from SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429. In one aspect, the present invention encompasses a recombinant nucleic acid construct comprising a nucleic acid molecule encoding a CAR, wherein the nucleic acid molecule comprises a nucleic acid sequence encoding a CD20 binding domain, e.g., wherein the sequence is contiguous with and in the same reading frame as the nucleic acid sequence encoding an intracellular signaling domain. An exemplary intracellular signaling domain that can be used in the CAR includes, but is not limited to, one or more intracellular signaling domains of, e.g., CD3-zeta, CD28, 4-1BB, and the like. In some instances, the CAR can comprise any combination of CD3-zeta, CD28, 4-1BB, and the like. In one aspect, the nucleic acid sequence of a CAR construct of the invention is selected from one or more of SEQ ID NO: 25, SEQ ID NO: 52, SEQ ID NO: 79, SEQ ID NO: 106, SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 187, SEQ ID NO: 214, SEQ ID NO: 241, SEQ ID NO: 268, SEQ ID NO: 295, SEQ ID NO: 322, SEQ ID NO: 349, SEQ ID NO: 376, SEQ ID NO: 403, and SEQ ID NO: 430. The nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the nucleic acid of interest can be produced synthetically, rather than cloned. The present invention includes retroviral and lentiviral vector constructs expressing a CAR that can be directly transduced into a cell. The present invention also includes an RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3′ and 5′ untranslated sequence (“UTR”), a 5′ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO: 1093). RNA so produced can efficiently transfect different kinds of cells. In one embodiment, the template includes sequences for the CAR. In an embodiment, an RNA CAR vector is transduced into a T cell or NK cell by electroporation. Antigen Binding Domain In one aspect, the CAR of the invention comprises a target-specific binding element otherwise referred to as an antigen binding domain. The choice of moiety depends upon the type and number of ligands that define the surface of a target cell. For example, the antigen binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state. In one aspect, the CAR-mediated T-cell response can be directed to an antigen of interest by way of engineering an antigen binding domain that specifically binds a desired antigen into the CAR. In one aspect, the portion of the CAR comprising the antigen binding domain comprises an antigen binding domain that targets CD20 or a fragment thereof. In one aspect, the antigen binding domain targets human CD20 or a fragment thereof. In one aspect, the portion of the CAR comprising the antigen binding domain comprises an antigen binding domain that targets CD22 or a fragment thereof. In one aspect, the antigen binding domain targets human CD22 or a fragment thereof. The antigen binding domain can be any domain that binds to the antigen including but not limited to a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a murine antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived nanobody, and to an alternative scaffold known in the art to function as antigen binding domain, such as a recombinant fibronectin domain, and the like. In some instances, it is beneficial for the antigen binding domain to be derived from the same species in which the CAR will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment. In some instances, it is beneficial for the antigen binding domain to be derived from the same species in which the CAR will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment. Thus, in one aspect, the antigen binding domain comprises a human antibody or an antibody fragment. In other instances, the antigen binding domain is derived from a different species (e.g., murine) from that in which the CAR will ultimately be used in (e.g., human). In one embodiment, the CD20 binding domain comprises one or more (e.g., all three) light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3) of a CD20 binding domain described herein, and/or one or more (e.g., all three) heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) of a CD20 binding domain described herein, e.g., a CD20 binding domain comprising one or more, e.g., all three, LCDRs and one or more, e.g., all three, HCDRs. In one embodiment, the CD20 binding domain comprises one or more (e.g., all three) heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) of a CD20 binding domain described herein, e.g., the CD20 binding domain has two variable heavy chain regions, each comprising a HCDR1, a HCDR2 and a HCDR3 described herein. In one embodiment, the LCDR1, LCDR2, and/or LCDR3 comprises (or consists of) an amino acid sequence listed in Table 3. In one embodiment, the HCDR1, HCDR2, and/or HCDR3 comprises (or consists of) an amino acid sequence listed in Table 2. In one embodiment, the CD20 binding domain comprises a light chain variable region described herein (e.g., in Table 5) and/or a heavy chain variable region described herein (e.g., in Table 4). In one embodiment, the CD20 binding domain comprises a heavy chain variable region described herein (e.g., in Table 4), e.g., at least two heavy chain variable regions described herein (e.g., in Table 4). In one embodiment, the CD20 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of Table 1. In an embodiment, the CD20 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided in Table 5, or a sequence with 95-99% identity with an amino acid sequence of Table 5; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 4, or a sequence with 95-99% identity to an amino acid sequence of Table 4. In one embodiment, the CD20 binding domain comprises a sequence selected from a group consisting of SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429, or a sequence with 95-99% identity thereof. In one embodiment, the CD20 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 5, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 4, via a linker, e.g., a linker described herein. In one embodiment, the CD20 binding domain includes a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 3 or 4 (SEQ ID NO: 1089). The light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. A humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference), veneering or resurfacing (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering, 7(6):805-814; and Roguska et al., 1994, PNAS, 91:969-973, each of which is incorporated herein by its entirety by reference), chain shuffling (see, e.g., U.S. Pat. No. 5,565,332, which is incorporated herein in its entirety by reference), and techniques disclosed in, e.g., U.S. Patent Application Publication No. US2005/0042664, U.S. Patent Application Publication No. US2005/0048617, U.S. Pat. Nos. 6,407,213, 5,766,886, International Publication No. WO 9317105, Tan et al., J. Immunol., 169:1119-25 (2002), Caldas et al., Protein Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al., J. Biol. Chem., 272(16):10678-84 (1997), Roguska et al., Protein Eng., 9(10):895-904 (1996), Couto et al., Cancer Res., 55 (23 Supp):5973s-5977s (1995), Couto et al., Cancer Res., 55(8):1717-22 (1995), Sandhu J S, Gene, 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol., 235(3):959-73 (1994), each of which is incorporated herein in its entirety by reference. Often, framework residues in the framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, for example, improve, antigen binding. These framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.) A humanized antibody or antibody fragment has one or more amino acid residues remaining in it from a source that is nonhuman. These nonhuman amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. As provided herein, humanized antibodies or antibody fragments comprise one or more CDRs from nonhuman immunoglobulin molecules and framework regions wherein the amino acid residues comprising the framework are derived completely or mostly from human germline. Multiple techniques for humanization of antibodies or antibody fragments are well-known in the art and can essentially be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody, i.e., CDR-grafting (EP 239,400; PCT Publication No. WO 91/09967; and U.S. Pat. Nos. 4,816,567; 6,331,415; 5,225,539; 5,530,101; 5,585,089; 6,548,640, the contents of which are incorporated herein by reference herein in their entirety). In such humanized antibodies and antibody fragments, substantially less than an intact human variable domain has been substituted by the corresponding sequence from a nonhuman species. Humanized antibodies are often human antibodies in which some CDR residues and possibly some framework (FR) residues are substituted by residues from analogous sites in rodent antibodies. Humanization of antibodies and antibody fragments can also be achieved by veneering or resurfacing (EP 592,106; EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., Protein Engineering, 7(6):805-814 (1994); and Roguska et al., PNAS, 91:969-973 (1994)) or chain shuffling (U.S. Pat. No. 5,565,332), the contents of which are incorporated herein by reference herein in their entirety. The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is to reduce antigenicity. According to the so-called “best-fit” method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences. The human sequence that is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987), the contents of which are incorporated herein by reference herein in their entirety). Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (see, e.g., Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997); Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993), the contents of which are incorporated herein by reference herein in their entirety). In one embodiment, the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence. In some aspects, the portion of a CAR composition of the invention that comprises an antibody fragment is humanized with retention of high affinity for the target antigen and other favorable biological properties. According to one aspect of the invention, humanized antibodies and antibody fragments are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly avaiable and are familiar to those skilled in the art. Computer programs are vaailable that illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind the target antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody or antibody fragment characteristic, such as increased affinity for the target antigen, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. A humanized antibody or antibody fragment may retain a similar antigenic specificity as the original antibody, e.g., in the present invention, the ability to bind human CD20 or a fragment thereof. In some embodiments, a humanized antibody or antibody fragment may have improved affinity and/or specificity of binding to human CD20 or a fragment thereof. In one aspect, the antigen binding domain portion comprises one or more sequence selected from SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429. In one aspect, the CD20 binding domain is characterized by particular functional features or properties of an antibody or antibody fragment. For example, in one aspect, the portion of a CAR composition of the invention that comprises an antigen binding domain specifically binds human CD20 or a fragment thereof. In one aspect, the invention relates to an antigen binding domain comprising an antibody or antibody fragment, wherein the antibody binding domain specifically binds to a CD20 protein or fragment thereof, wherein the antibody or antibody fragment comprises a variable light chain and/or a variable heavy chain that includes an amino acid sequence selected from Table 1. In one aspect, the antigen binding domain comprises an amino acid sequence of a scFv selected from SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429. In certain aspects, the scFv is contiguous with and in the same reading frame as a leader sequence. In one aspect the leader sequence is the polypeptide sequence provided as SEQ ID NO: 797. In one aspect, the CD20 binding domain is a fragment, e.g., a single chain variable fragment (scFv). In one aspect, the CD20 binding domain is a Fv, a Fab, a (Fab′)2, or a bi-functional (e.g. bi-specific) hybrid antibody (e.g., Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)). In one aspect, the antibodies and fragments thereof of the invention binds a CD20 protein or a fragment thereof with wild-type or enhanced affinity. In some instances, a human scFv can be derived from a display library. A display library is a collection of entities; each entity includes an accessible polypeptide component and a recoverable component that encodes or identifies the polypeptide component. The polypeptide component is varied so that different amino acid sequences are represented. The polypeptide component can be of any length, e.g. from three amino acids to over 300 amino acids. A display library entity can include more than one polypeptide component, for example, the two polypeptide chains of a Fab. In one exemplary embodiment, a display library can be used to identify a human CD20 binding domain. In a selection, the polypeptide component of each member of the library is probed with CD20, or a fragment thereof, and if the polypeptide component binds to CD20, the display library member is identified, typically by retention on a support. Retained display library members are recovered from the support and analyzed. The analysis can include amplification and a subsequent selection under similar or dissimilar conditions. For example, positive and negative selections can be alternated. The analysis can also include determining the amino acid sequence of the polypeptide component, i.e., the anti-CD20 binding domain, and purification of the polypeptide component for detailed characterization. A variety of formats can be used for display libraries. Examples include the phage display. In phage display, the protein component is typically covalently linked to a bacteriophage coat protein. The linkage results from translation of a nucleic acid encoding the protein component fused to the coat protein. The linkage can include a flexible peptide linker, a protease site, or an amino acid incorporated as a result of suppression of a stop codon. Phage display is described, for example, in U.S. Pat. No. 5,223,409; Smith (1985) Science 228:1315-1317; WO 92/18619; WO 91/17271; WO 92/20791; WO 92/15679; WO 93/01288; WO 92/01047; WO 92/09690; WO 90/02809; de Haard et al. (1999) J. Biol. Chem 274:18218-30; Hoogenboom et al. (1998) Immunotechnology 4:1-20; Hoogenboom et al. (2000) Immunol Today 2:371-8 and Hoet et al. (2005) Nat Biotechnol. 23(3)344-8. Bacteriophage displaying the protein component can be grown and harvested using standard phage preparatory methods, e.g. PEG precipitation from growth media. After selection of individual display phages, the nucleic acid encoding the selected protein components can be isolated from cells infected with the selected phages or from the phage themselves, after amplification. Individual colonies or plaques can be picked, the nucleic acid isolated and sequenced. Other display formats include cell based display (see, e.g., WO 03/029456), protein-nucleic acid fusions (see, e.g., U.S. Pat. No. 6,207,446), ribosome display (See, e.g., Mattheakis et al. (1994) Proc. Natl. Acad. Sci. USA 91:9022 and Hanes et al. (2000) Nat Biotechnol. 18:1287-92; Hanes et al. (2000) Methods Enzymol. 328:404-30; and Schaffitzel et al. (1999) J Immunol Methods. 231(1-2): 119-35), and E. coli periplasmic display (2005 Nov. 22; PMID: 16337958). In some instances, scFvs can be prepared according to method known in the art (see, for example, Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). ScFv molecules can be produced by linking VH and VL regions together using flexible polypeptide linkers. The scFv molecules comprise a linker (e.g., a Ser-Gly linker) with an optimized length and/or amino acid composition. The linker length can greatly affect how the variable regions of a scFv fold and interact. In fact, if a short polypeptide linker is employed (e.g., between 5-10 amino acids) intrachain folding is prevented. Interchain folding is also required to bring the two variable regions together to form a functional epitope binding site. For examples of linker orientation and size see, e.g., Hollinger et al. 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, U.S. Patent Application Publication Nos. 2005/0100543, 2005/0175606, 2007/0014794, and PCT publication Nos. WO2006/020258 and WO2007/024715, is incorporated herein by reference. An scFv can comprise a linker of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 20, 35, 40, 45, 50, or more amino acid residues between its VL and VH regions. The linker sequence may comprise any naturally occurring amino acid. In some embodiments, the linker sequence comprises amino acids glycine and serine. In another embodiment, the linker sequence comprises sets of glycine and serine repeats such as (Gly4Ser)n (SEQ ID NO: 1090), where n is a positive integer equal to or greater than 1. In one embodiment, the linker can be (Gly4Ser)4(SEQ ID NO: 23) or (Gly4Ser)3(SEQ ID NO: 541). Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies. Stability and Mutations The stability of a CD20 binding domain, e.g., scFv molecules (e.g., soluble scFv) can be evaluated in reference to the biophysical properties (e.g., thermal stability) of a conventional control scFv molecule or a full length antibody. In one embodiment, the human scFv has a thermal stability that is greater than about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10 degrees, about 11 degrees, about 12 degrees, about 13 degrees, about 14 degrees, or about 15 degrees Celsius than a control binding molecule (e.g. a conventional scFv molecule) in the described assays. The improved thermal stability of the CD20 binding domain, e.g., scFv is subsequently conferred to the entire CART20 construct, leading to improved therapeutic properties of the CART20 construct. The thermal stability of the CD20 binding domain, e.g., scFv can be improved by at least about 2° C. or 3° C. as compared to a conventional antibody. In one embodiment, the CD20 binding domain, e.g., scFv has a 1° C. improved thermal stability as compared to a conventional antibody. In another embodiment, the CD20 binding domain, e.g., scFv has a 2° C. improved thermal stability as compared to a conventional antibody. In another embodiment, the scFv has a 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 4, 15° C. improved thermal stability as compared to a conventional antibody. Comparisons can be made, for example, between the scFv molecules disclosed herein and full length antibodies. Thermal stability can be measured using methods known in the art. For example, in one embodiment, Tm can be measured. Methods for measuring Tm and other methods of determining protein stability are described in more detail below. Mutations in scFv alter the stability of the scFv and improve the overall stability of the scFv and the CART20 construct. Stability of a murine, humanized or human scFv is determined using measurements such as Tm, temperature denaturation and temperature aggregation. In one embodiment, the CD20 binding domain, e.g., scFv comprises at least one mutation such that the mutated scFv confers improved stability to the CART20 construct. In another embodiment, the CD20 binding domain, e.g., scFv comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mutations arising from the humanization process such that the mutated scFv confers improved stability to the CART20 construct. Methods of Evaluating Protein Stability The stability of an antigen binding domain may be assessed using, e.g., the methods described below. Such methods allow for the determination of multiple thermal unfolding transitions where the least stable domain either unfolds first or limits the overall stability threshold of a multidomain unit that unfolds cooperatively (e.g., a multidomain protein which exhibits a single unfolding transition). The least stable domain can be identified in a number of additional ways. Mutagenesis can be performed to probe which domain limits the overall stability. Additionally, protease resistance of a multidomain protein can be performed under conditions where the least stable domain is known to be intrinsically unfolded via DSC or other spectroscopic methods (Fontana, et al., (1997) Fold. Des., 2: R17-26; Dimasi et al. (2009) J. Mol. Biol. 393: 672-692). Once the least stable domain is identified, the sequence encoding this domain (or a portion thereof) may be employed as a test sequence in the methods. a) Thermal Stability The thermal stability of the compositions may be analyzed using a number of non-limiting biophysical or biochemical techniques known in the art. In certain embodiments, thermal stability is evaluated by analytical spectroscopy. An exemplary analytical spectroscopy method is Differential Scanning Calorimetry (DSC). DSC employs a calorimeter which is sensitive to the heat absorbances that accompany the unfolding of most proteins or protein domains (see, e.g. Sanchez-Ruiz, et al., Biochemistry, 27: 1648-52, 1988). To determine the thermal stability of a protein, a sample of the protein is inserted into the calorimeter and the temperature is raised until the Fab or scFv unfolds. The temperature at which the protein unfolds is indicative of overall protein stability. Another exemplary analytical spectroscopy method is Circular Dichroism (CD) spectroscopy. CD spectrometry measures the optical activity of a composition as a function of increasing temperature. Circular dichroism (CD) spectroscopy measures differences in the absorption of left-handed polarized light versus right-handed polarized light which arise due to structural asymmetry. A disordered or unfolded structure results in a CD spectrum very different from that of an ordered or folded structure. The CD spectrum reflects the sensitivity of the proteins to the denaturing effects of increasing temperature and is therefore indicative of a protein's thermal stability (see van Mierlo and Steemsma, J. Biotechnol., 79(3):281-98, 2000). Another exemplary analytical spectroscopy method for measuring thermal stability is Fluorescence Emission Spectroscopy (see van Mierlo and Steemsma, supra). Yet another exemplary analytical spectroscopy method for measuring thermal stability is Nuclear Magnetic Resonance (NMR) spectroscopy (see, e.g. van Mierlo and Steemsma, supra). The thermal stability of a composition can be measured biochemically. An exemplary biochemical method for assessing thermal stability is a thermal challenge assay. In a “thermal challenge assay”, a composition is subjected to a range of elevated temperatures for a set period of time. For example, in one embodiment, test scFv molecules or molecules comprising scFv molecules are subject to a range of increasing temperatures, e.g., for 1-1.5 hours. The activity of the protein is then assayed by a relevant biochemical assay. For example, if the protein is a binding protein (e.g. an scFv or scFv-containing polypeptide) the binding activity of the binding protein may be determined by a functional or quantitative ELISA. Such an assay may be done in a high-throughput format and those disclosed in the Examples using E. coli and high throughput screening. A library of CD20 binding domains, e.g., scFv variants may be created using methods known in the art. CD20 binding domains, e.g., scFv expression may be induced and the CD20 binding domains, e.g., scFv may be subjected to thermal challenge. The challenged test samples may be assayed for binding and those CD20 binding domains, e.g., scFvs which are stable may be scaled up and further characterized. Thermal stability is evaluated by measuring the melting temperature (Tm) of a composition using any of the above techniques (e.g. analytical spectroscopy techniques). The melting temperature is the temperature at the midpoint of a thermal transition curve wherein 50% of molecules of a composition are in a folded state (See e.g., Dimasi et al. (2009) J. Mol Biol. 393: 672-692). In one embodiment, Tm values for a CD20 binding domain, e.g., scFv are about 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C., 55° C., 56° C., 57° C., 58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64° C., 65° C., 66° C., 67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., 91° C., 92° C., 93° C., 94° C., 95° C., 96° C., 97° C., 98° C., 99° C., 100° C. In one embodiment, Tm values for an IgG is about 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C., 55° C., 56° C., 57° C., 58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64° C., 65° C., 66° C., 67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., 91° C., 92° C., 93° C., 94° C., 95° C., 96° C., 97° C., 98° C., 99° C., 100° C. In one embodiment, Tm values for an multivalent antibody is about 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C., 55° C., 56° C., 57° C., 58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64° C., 65° C., 66° C., 67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., 91° C., 92° C., 93° C., 94° C., 95° C., 96° C., 97° C., 98° C., 99° C., 100° C. Thermal stability is also evaluated by measuring the specific heat or heat capacity (Cp) of a composition using an analytical calorimetric technique (e.g. DSC). The specific heat of a composition is the energy (e.g. in kcal/mol) is required to rise by 1° C., the temperature of 1 mol of water. As large Cp is a hallmark of a denatured or inactive protein composition. The change in heat capacity (ΔCp) of a composition is measured by determining the specific heat of a composition before and after its thermal transition. Thermal stability may also be evaluated by measuring or determining other parameters of thermodynamic stability including Gibbs free energy of unfolding (ΔG), enthalpy of unfolding (ΔH), or entropy of unfolding (ΔS). One or more of the above biochemical assays (e.g. a thermal challenge assay) are used to determine the temperature (i.e. the TCvalue) at which 50% of the composition retains its activity (e.g. binding activity). In addition, mutations to the CD20 binding domain, e.g., scFv alter the thermal stability of the CD20 binding domain, e.g., scFv compared with the unmutated CD20 binding domain, e.g., scFv. When the murine, humanized or human CD20 binding domain, e.g., scFv is incorporated into a CART20 construct, the CD20 binding domain, e.g., murine, humanized or human scFv confers thermal stability to the overall CD20 CART construct. In one embodiment, the CD20 binding domain, e.g., scFv comprises a single mutation that confers thermal stability to the CD20 binding domain, e.g., scFv. In another embodiment, the CD20 binding domain, e.g., scFv comprises multiple mutations that confer thermal stability to the CD20 binding domain, e.g., scFv. In one embodiment, the multiple mutations in the CD20 binding domain, e.g., scFv have an additive effect on thermal stability of the CD20 binding domain, e.g., scFv. b) % Aggregation The stability of a composition can be determined by measuring its propensity to aggregate. Aggregation can be measured by a number of non-limiting biochemical or biophysical techniques. For example, the aggregation of a composition may be evaluated using chromatography, e.g. Size-Exclusion Chromatography (SEC). SEC separates molecules on the basis of size. A column is filled with semi-solid beads of a polymeric gel that will admit ions and small molecules into their interior but not large ones. When a protein composition is applied to the top of the column, the compact folded proteins (i.e. non-aggregated proteins) are distributed through a larger volume of solvent than is available to the large protein aggregates. Consequently, the large aggregates move more rapidly through the column, and in this way the mixture can be separated or fractionated into its components. Each fraction can be separately quantified (e.g. by light scattering) as it elutes from the gel. Accordingly, the % aggregation of a composition can be determined by comparing the concentration of a fraction with the total concentration of protein applied to the gel. Stable compositions elute from the column as essentially a single fraction and appear as essentially a single peak in the elution profile or chromatogram. c) Binding Affinity The stability of a composition can be assessed by determining its target binding affinity. A wide variety of methods for determining binding affinity are known in the art. An exemplary method for determining binding affinity employs surface plasmon resonance. Surface plasmon resonance is an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Jonsson, U., et al. (1993) Ann. Biol. Clin. 51:19-26; Jonsson, U., i (1991) Biotechniques 11:620-627; Johnson, B., et al. (1995) J. Mol. Recognit. 8:125-131; and Johnnson, B., et al. (1991) Anal. Biochem. 198:268-277. In one aspect, the antigen binding domain of the CAR comprises an amino acid sequence that is homologous to an antigen binding domain amino acid sequence described herein, and the antigen binding domain retains the desired functional properties of the CD20 antibody fragments described herein. In one specific aspect, the CAR composition of the invention comprises an antibody fragment. In a further aspect, that antibody fragment comprises an scFv. In various aspects, the antigen binding domain of the CAR is engineered by modifying one or more amino acids within one or both variable regions (e.g., VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions. In one specific aspect, the CAR composition of the invention comprises an antibody fragment. In a further aspect, that antibody fragment comprises an scFv. It will be understood by one of ordinary skill in the art that the antibody or antibody fragment of the invention may further be modified such that they vary in amino acid sequence (e.g., from wild-type), but not in desired activity. For example, additional nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues may be made to the protein For example, a nonessential amino acid residue in a molecule may be replaced with another amino acid residue from the same side chain family. In another embodiment, a string of amino acids can be replaced with a structurally similar string that differs in order and/or composition of side chain family members, e.g., a conservative substitution, in which an amino acid residue is replaced with an amino acid residue having a similar side chain, may be made. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Percent identity in the context of two or more nucleic acids or polypeptide sequences, refers to two or more sequences that are the same. Two sequences are “substantially identical” if two sequences have a specified percentage of amino acid residues or nucleotides that are the same (e.g., 60% identity, optionally 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists over a region that is at least about 50 nucleotides (or 10 amino acids) in length, or more preferably over a region that is 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch, (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman, (1988) Proc. Nat'l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Brent et al., (2003) Current Protocols in Molecular Biology). Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., (1977) Nuc. Acids Res. 25:3389-3402; and Altschul et al., (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. The percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, (1988) Comput. Appl. Biosci. 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In one aspect, the present invention contemplates modifications of the starting antibody or fragment (e.g., scFv) amino acid sequence that generate functionally equivalent molecules. For example, the VH or VL of a CD20 binding domain, e.g., scFv, comprised in the CAR can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting VH or VL framework region of the CD20 binding domain, e.g., scFv. The present invention contemplates modifications of the entire CAR construct, e.g., modifications in one or more amino acid sequences of the various domains of the CAR construct in order to generate functionally equivalent molecules. The CAR construct can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting CAR construct. Bispecific CARs In an embodiment a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In an embodiment the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment the first and second epitopes overlap. In an embodiment the first and second epitopes do not overlap. In an embodiment the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In an embodiment a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope. In an embodiment the first epitope is located on CD19 and the second epitope is located on CD20, C22, or ROR1. In certain embodiments, the antibody molecule is a multi-specific (e.g., a bispecific or a trispecific) antibody molecule. Protocols for generating bispecific or heterodimeric andibody molecules are known in the art; including but not limited to, for example, the “knob in a hole” approach described in, e.g., U.S. Pat. No. 5,731,168; the electrostatic steering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905 and WO 2010/129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07/110205; Fab arm exchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO 2013/060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described in, e.g., U.S. Pat. No. 4,433,059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or Fabs) from different antibodies through cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described in, e.g., U.S. Pat. No. 4,444,878; trifunctional antibodies, e.g., three Fab' fragments cross-linked through sufthydryl reactive groups, as described in, e.g., U.S. Pat. No. 5,273,743; biosynthetic binding proteins, e.g., pair of scFvs cross-linked through C-terminal tails preferably through disulfide or amine-reactive chemical cross-linking, as described in, e.g., U.S. Pat. No. 5,534,254; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized through leucine zippers (e.g., c-fos and c-jun) that have replaced the constant domain, as described in, e.g., U.S. Pat. No. 5,582,996; bispecific and oligospecific mono- and oligovalent receptors, e.g., VH-CH1 regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody typically with associated light chains, as described in, e.g., U.S. Pat. No. 5,591,828; bispecific DNA-antibody conjugates, e.g., crosslinking of antibodies or Fab fragments through a double stranded piece of DNA, as described in, e.g., U.S. Pat. No. 5,635,602; bispecific fusion proteins, e.g., an expression construct containing two scFvs with a hydrophilic helical peptide linker between them and a full constant region, as described in, e.g., U.S. Pat. No. 5,637,481; multivalent and multispecific binding proteins, e.g., dimer of polypeptides having first domain with binding region of Ig heavy chain variable region, and second domain with binding region of Ig light chain variable region, generally termed diabodies (higher order structures are also encompassed creating for bispecific, trispecific, or tetraspecific molecules, as described in, e.g., U.S. Pat. No. 5,837,242; minibody constructs with linked VL and VH chains further connected with peptide spacers to an antibody hinge region and CH3 region, which can be dimerized to form bispecific/multivalent molecules, as described in, e.g., U.S. Pat. No. 5,837,821; VH and VL domains linked with a short peptide linker (e.g., 5 or 10 amino acids) or no linker at all in either orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described in, e.g., U.S. Pat. No. 5,844,094; String of VH domains (or VL domains in family members) connected by peptide linkages with cross-linkable groups at the C-terminus further associated with VL domains to form a series of FVs (or scFvs), as described in, e.g., U.S. Pat. No. 5,864,019; and single chain binding polypeptides with both a VH and a VL domain linked through a peptide linker are combined into multivalent structures through non-covalent or chemical crosslinking to form, e.g., homobivalent, heterobivalent, trivalent, and tetravalent structures using both scFV or diabody type format, as described in, e.g., U.S. Pat. No. 5,869,620. Additional exemplary multispecific and bispecific molecules and methods of making the same are found, for example, in U.S. Pat. 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The contents of the above-referenced applications are incorporated herein by reference in their entireties. Exemplary Multispecific Molecules In some embodiments, the antibody molecule is a multispecific, e.g., bispecific, antibody molecule comprising one, two, or more binding specificities, e.g., a first binding specificity for a first antigen, e.g., a B-cell epitope, and a second binding specificity for the same or a different antigen, e.g., B cell epitope. In one embodiment, the first and second binding specificity is an antibody molecule, e.g., an antigen binding domain (e.g., a scFv). Within each antibody molecule (e.g., scFv) of a bispecific antibody molecule, the VH can be upstream or downstream of the VL. In some embodiments, the upstream antibody or antibody fragment (e.g., scFv) is arranged with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VL2-VH2, from an N- to C-terminal orientation. In some embodiments, the upstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VH2-VL2, from an N- to C-terminal orientation. In some embodiments, the upstream antibody or antibody fragment (e.g., scFv) is arranged with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VL2-VH2, from an N- to C-terminal orientation. In some embodiments, the upstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VH2-VL2, from an N- to C-terminal orientation. In any of the aforesaid configurations, optionally, a linker is disposed between the two antibodies or antibody fragments or antigen binding domains (e.g., scFvs), e.g., between VH1and VL2if the construct is arranged as VH1-VL1-VL2-VH2; between VH1and VH2if the construct is arranged as VL1-VH1-VH2-VL2; between VH1and VL2if the construct is arranged as VL1-VH1-VL2-VH2; or between VL1and VH2if the construct is arranged as VH1-VL1-VH2VL2. In general, the linker between the two antibody fragments or antigen binding domains, e.g., scFvs, should be long enough to avoid mispairing between the domains of the two scFvs. The linker may be a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In any of the aforesaid configurations, optionally, a linker is disposed between the VL and VH of the first antigen binding domains, e.g., scFv. Optionally, a linker is disposed between the VL and VH of the second antigen binding domains, e.g., scFv. In constructs that have multiple linkers, any two or more of the linkers can be the same or different. Accordingly, in some embodiments, a bispecific CAR comprises VLs, VHs, and optionally one or more linkers in an arrangement as described herein. In some embodiments, each antibody molecule, e.g., each antigen binding domain (e.g., each scFv) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In other embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In certain embodiments, the antibody molecule is a bispecific antibody molecule having a first binding specificity for a first B-cell epitope and a second binding specificity for the same or a different B-cell antigen. For instance, in some embodiments the bispecific antibody molecule has a first binding specificity for CD20 and a second binding specificity for one or more of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In some embodiments the bispecific antibody molecule has a first binding specificity for CD19 and a second binding specificity for CD20. In some embodiments the bispecific antibody molecule has a first binding specificity for CD19 and a second binding specificity for CD22. In one embodiment, the antibody molecule is a bispecific antibody molecule having a binding specificity, e.g., a first and/or second binding specificity, to CD19. In one embodiment, the binding specificity is configured with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domains (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VL2-VH2, from an N- to C-terminal orientation. In one embodiment, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a CTL019 scFv (SEQ ID NO: 765). In some embodiments, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a humanized CD19 scFv, e.g., a humanized CAR2. In some embodiments, the first and/or second binding specificity, to CD19 (e.g., first and/or second scFv to CD19) comprises a linker between the VH and the io VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD19 is configured with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domains (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VH2-VL2, from an N- to C-terminal orientation. In one embodiment, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a CTL019 scFv (SEQ ID NO: 765). In some embodiments, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a humanized CD19 scFv, e.g., a humanized CAR2. In some embodiments, the first and/or second binding specificity, to CD19 (e.g., first and/or second scFv to CD19) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD19 is configured with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment or antigen bindng domain (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VL2-VH2, from an N- to C-terminal orientation. In one embodiment, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a CTL019 scFv (SEQ ID NO: 765). In some embodiments, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a humanized CD19 scFv, e.g., a humanized CAR2. In some embodiments, the first and/or second binding specificity, to CD19 (e.g., first and/or second scFv to CD19) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD19 is configured with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VH2-VL2, from an N- to C-terminal orientation. In one embodiment, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a CTL019 scFv (SEQ ID NO: 765). In some embodiments, the CD19 binding specificity comprises a VH and VL as depicted in Table 11, e.g., a humanized CD19 scFv, e.g., a humanized CAR2. In some embodiments, the first and/or second binding specificity, to CD19 (e.g., first and/or second scFv to CD19) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the antibody molecule is a bispecific antibody molecule having a binding specificity, e.g., a first and/or second binding specificity, to CD20. In one embodiment, the binding specificity is configured with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VL2-VH2, from an N- to C-terminal orientation. In one embodiment, the CD20 binding specificity comprises a VH and VL as depicted in Table 1, e.g., a VH and VL from a C3H2 scFv or a C5H1 scFv. In some embodiments, the first and/or second binding specificity, to CD20 (e.g., first and/or second scFv to CD20) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD20 is configured with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VH2-VL2, from an N- to C-terminal orientation. In one embodiment, the CD20 binding specificity comprises a VH and VL as depicted in Table 1, e.g., a VH and VL from a C3H2 scFv or a C5H1 scFv. In some embodiments, the first and/or second binding specificity, to CD20 (e.g., first and/or second scFv to CD20) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD20 is configured with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VL2-VH2, from an N- to C-terminal orientation. In one embodiment, the CD22 binding specificity comprises a VH and VL as depicted in Table 1, e.g., a VH and VL from a C3H2 scFv or a C5H1 scFv. In some embodiments, the first and/or second binding specificity, to CD20 (e.g., first and/or second scFv to CD20) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD20 is configured with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VH2-VL2, from an N- to C-terminal orientation. In one embodiment, the CD22 binding specificity comprises a VH and VL as depicted in Table 1, e.g., a VH and VL from a C3H2 scFv or a C5H1 scFv. In some embodiments, the first and/or second binding specificity, to CD20 (e.g., first and/or second scFv to CD20) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker. In another embodiment, the antibody molecule is a bispecific antibody molecule having a binding specificity, e.g., a first and/or second binding specificity, to CD22. In one embodiment, the binding specificity is configured with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VL2-VH2, from an N- to C-terminal orientation. In one embodiment, the CD22 binding specificity comprises a VH and VL as depicted in Table 6, e.g., a VH and VL from a CD22-65 or CD22-65KD scFv. In some embodiments, the first and/or second binding specificity, to CD22 (e.g., first and/or second scFv to CD22) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090), e.g., as in the CD22-65s scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084), e.g., as in the CD22-65 scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker, e.g., as in the CD22-65ss scFv. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD22 is configured with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VL1-VH1-VH2-VL2, from an N- to C-terminal orientation. In one embodiment, the CD22 binding specificity comprises a VH and VL as depicted in Table 6, e.g., a VH and VL from a CD22-65 or CD22-65KD scFv. In some embodiments, the first and/or second binding specificity, to CD22 (e.g., first and/or second scFv to CD22) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090), e.g., as in the CD22-65s scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084), e.g., as in the CD22-65 scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker, e.g., as in the CD22-65ss scFv. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD22 is configured with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VL (VL2) upstream of its VH (VH2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VL2-VH2, from an N- to C-terminal orientation. In one embodiment, the CD22 binding specificity comprises a VH and VL as depicted in Table 6, e.g., a VH and VL from a CD22-65 or CD22-65KD scFv. In some embodiments, the first and/or second binding specificity, to CD22 (e.g., first and/or second scFv to CD22) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090), e.g., as in the CD22-65s scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084), e.g., as in the CD22-65 scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker, e.g., as in the CD22-65ss scFv. In another embodiment, the binding specificity, e.g., a first and/or second binding specificity, to CD22 is configured with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment or antigen binding domain (e.g., scFv) is arranged with its VH (VH2) upstream of its VL (VL2), such that the overall bispecific antibody molecule has the arrangement VH1-VL1-VH2-VL2, from an N- to C-terminal orientation. In one embodiment, the CD22 binding specificity comprises a VH and VL as depicted in Table 6, e.g., a VH and VL from a CD22-65 or CD22-65KD scFv. In some embodiments, the first and/or second binding specificity, to CD22 (e.g., first and/or second scFv to CD22) comprises a linker between the VH and the VL regions. In some embodiments, the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090), e.g., as in the CD22-65s scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084), e.g., as in the CD22-65 scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker, e.g., as in the CD22-65ss scFv. In some embodiments, the bispecific antibody molecule comprises a first binding specificity to CD19, e.g., any of the binding specificities to CD19 described herein, and a second binding specificity to CD22, e.g., any of the binding specificities to CD22 as described herein. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In one embodiment, the bispecific antibody molecule comprises a first binding specificity to CD19, e.g., a VL1VH1 binding specificity to CD19, and a second binding specificity to CD22, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD22. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In one embodiment, the bispecific antibody molecule comprises a first binding specificity to CD22, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD22, and a second binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19. In one embodient, the firt and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). Two or more antibody molecules, e.g., as described herein, can be linked providing multispecific antibody molecules, e.g., bi-, tri or more antibody molecules. In some embodiments, any of the aforesaid multispecific, e.g., bispecific, antibody molecules is present in a CAR molecule as described herein. In embodiments, CAR molecule comprises a bispecific CAR comprising a first and second binding specificities, e.g., as described herein (e.g., two antibody molecules, e.g., two scFvs as described herein). In some embodiments, the bispecific CAR comprises two antibody molecules, wherein the first binding specificity, e.g., the first antibody molecule (e.g., the first antigen binding domain, e.g., the first scFv) is closer to the transmembrane domain, also referred to herein as the proximal antibody molecule (e.g., proximal antigen binding domain) and the second binding specificity, e.g., the second antibody molecule (e.g., second antigen binding domain, e.g., the second scFv) is further away from the membrane, also referred to herein as the distal antibody molecule (e.g., the distal antigen binding domain). Thus, from N-to-C-terminus, the CAR molecule comprises a distal binding specificity, e.g., a distal antibody molecule (e.g., a distal antigen binding domain, e.g., a distal scFV or scFv2), optionally, a linker, followed by a proximal binding specificity, e.g., a proximal antibody molecule (e.g., a proximal antigen binding domain, e.g., a proximal scFv or scFv1), optionally via a linker, to a transmembrane domain and an intracellular domain, e.g., as described herein. A schematic of a bispecific CAR configuration is depicted inFIG.27. In some embodiments, CAR molecule comprises a bispecific CAR comprising a first and second binding specificities. In some embodiments, the bispecific CAR comprises a first binding specificity for a B-cell epitope and a second binding specificity for the same or a different B-cell antigen. For instance, in some embodiments, the bispecific CAR molecule has a first binding specificity for CD20 and a second binding specificity for one or more of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In some embodiments the bispecific CAR molecule has a first binding specificity for CD19 and a second binding specificity for CD20. In some embodiments the bispecific CAR molecule has a first binding specificity for CD19 and a second binding specificity for CD22. In some embodiments the bispecific CAR molecule has a first binding specificity for CD22 and a second binding specificity for CD20. In some embodiments, the CAR molecule comprises a proximal or distal binding specificity for CD19, e.g., a CD19 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal binding specificity for CD19, e.g., a CD19 binding specificity as described herein, and a distal binding specificity for CD20, e.g., a CD20 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal binding specificity for CD19, e.g., a CD19 binding specificity as described herein, and a distal binding specificity for CD22, e.g., a CD22 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal binding specificity for CD20, e.g., a CD20 binding specificity as described herein, and a distal binding specificity for CD19, e.g., a CD19 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal binding specificity for CD22, e.g., a CD22 binding specificity as described herein, and a distal binding specificity for CD19, e.g., a CD19 binding specificity as described herein. In some embodiments, the CAR molecule comprises a proximal or distal binding specificity for CD22, e.g., a CD22 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal binding specificity for CD22, e.g., a CD22 binding specificity as described herein, and a distal binding specificity for CD20, e.g., a CD20 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal binding specificity for CD20, e.g., a CD20 binding specificity as described herein, and a distal binding specificity for CD22, e.g., a CD22 binding specificity as described herein. In one embodiment, the CAR molecule comprises a distal to the membrane binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19, and a proximal to the embrane binding specificity to CD22, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD22. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In one embodiment, the CAR molecule comprises a distal to the membrane binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19, optionally, a Gly4-Ser linker (SEQ ID NO: 1090) or a LAEAAAK linker (SEQ ID NO: 1091). In embodiments, the CD22 binding specificity comprises a CD22 VH and VL, wherein the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090), e.g., as in the CD22-65s scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084), e.g., as in the CD22-65 scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker, e.g., as in the CD22-65ss scFv. In one embodiment, the CAR molecule comprises a proximal to the membrane binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19, and a distal to the membrane binding specificity to CD22, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD22. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In one embodiment, the CAR molecule comprises a proximal to the membrane binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19, optionally, a Gly4-Ser linker (SEQ ID NO: 1090) or a LAEAAAK linker (SEQ ID NO: 1091). In embodiments, the CD22 binding specificity comprises a CD22 VH and VL, wherein the linker between the VH and the VL regions is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090), e.g., as in the CD22-65s scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 1084), e.g., as in the CD22-65 scFv. In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the VH and VL regions are connected without a linker, e.g., as in the CD22-65ss scFv. In some embodiments, the CAR molecule comprises a proximal or distal binding specificity for CD20, e.g., a CD20 binding specificity as described herein. In one embodiment, the CAR molecule comprises a distal to the membrane binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19, and a proximal to the membrane binding specificity to CD20, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD20. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In some embodiments, the CAR molecule comprises a proximal or distal binding specificity for CD20, e.g., a CD20 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal to the membrane binding specificity to CD19, e.g., a VL1-VH1 binding specificity to CD19, and a distal to the membrane binding specificity to CD20, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD20. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In some embodiments, the linker consists of the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In one embodiment, the CAR molecule comprises a distal to the membrane binding specificity to CD22, e.g., a VL1-VH1 binding specificity to CD22, and a proximal to the membrane binding specificity to CD20, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD20. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises, e.g., consists of, the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In some embodiments, the CAR molecule comprises a proximal or distal binding specificity for CD20, e.g., a CD20 binding specificity as described herein. In one embodiment, the CAR molecule comprises a proximal to the membrane binding specificity to CD22, e.g., a VL1-VH1 binding specificity to CD22, and a distal to the membrane binding specificity to CD20, e.g., a VL2-VH2 or VH2-VL1 binding specificity to CD20. In one embodiment, the first and second binding specificity are in a contiguous polypeptide chain, e.g., a single chain. In some embodiments, the first and second binding specificities, optionally, comprise a linker as described herein. In some embodiments, the linker is a (Gly4-Ser)nlinker, wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 1089). In some embodiments, the linker is (Gly4-Ser)n, wherein n=1 (SEQ ID NO: 1083), e.g., the linker has the amino acid sequence Gly4-Ser (SEQ ID NO: 1090). In some embodiments, the linker is (Gly4-Ser)n, wherein n=3 (SEQ ID NO: 841). In some embodiments, the linker is (Gly4-Ser)n, wherein n=4 (SEQ ID NO: 23). In some embodiments, the linker comprises the amino acid sequence: LAEAAAK (SEQ ID NO: 1091). In some embodiments, the linker consists of the amino acid sequence: LAEAAAK (SEQ ID NO: 1091) In some embodiments, the CAR molecule further comprises human sequence leader, e.g., a human CD8alpha sequence at the N-terminus. Transmembrane Domain With respect to the transmembrane domain, in various embodiments, a CAR can be designed to comprise a transmembrane domain that is attached to the extracellular domain of the CAR. A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid associated with the extracellular region of the protein from which the transmembrane was derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the extracellular region) and/or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the intracellular region). In one aspect, the transmembrane domain is one that is associated with one of the other domains of the CAR, e.g., in one embodiment, the transmembrane domain may be from the same protein that the signaling domain, costiumlatory domain or the hinge domain is derived from. In another aspect, the transmembrane domain is not derived from the same protein that any other domain of the CAR is derived from. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins, e.g., to minimize interactions with other members of the receptor complex. In one aspect, the transmembrane domain is capable of homodimerization with another CAR on the cell surface of a CAR-expressing cell. In a different aspect the amino acid sequence of the transmembrane domain may be modified or substituted so as to minimize interactions with the binding domains of the native binding partner present in the same CAR-expressing cell. The transmembrane domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In one aspect the transmembrane domain is capable of signaling to the intracellular domain(s) whenever the CAR has bound to a target. A transmembrane domain of particular use in this invention may include at least the transmembrane region(s) of e.g., the alpha, beta or zeta chain of the T-cell receptor, CD22, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 (e.g., CD8 alpha, CD8 beta), CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. In some embodiments, a transmembrane domain may include at least the transmembrane region(s) of, e.g., KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2R beta, IL2R gamma, IL7R α, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp. In some instances, the transmembrane domain can be attached to the extracellular region of the CAR, e.g., the antigen binding domain of the CAR, via a hinge, e.g., a hinge from a human protein. For example, in one embodiment, the hinge can be a human Ig (immunoglobulin) hinge, e.g., an IgG4 hinge, an IgD hinge, a GS linker (e.g., a GS linker described herein), a KIR2DS2 hinge, or a CD8a hinge. In one embodiment, the hinge or spacer comprises (e.g., consists of) the amino acid sequence of SEQ ID NO: 799. In one aspect, the transmembrane domain comprises (e.g., consists of) a transmembrane domain of SEQ ID NO: 801. In one aspect, the hinge or spacer comprises an IgG4 hinge. For example, in one embodiment, the hinge or spacer comprises a hinge of the amino acid sequence SEQ ID NO: 814. In some embodiments, the hinge or spacer comprises a hinge encoded by a nucleic acid sequence of SEQ ID NO: 815. In one aspect, the hinge or spacer comprises an IgD hinge. For example, in one embodiment, the hinge or spacer comprises a hinge of the amino acid sequence SEQ ID NO: 816. In some embodiments, the hinge or spacer comprises a hinge encoded by a nucleic acid sequence of (SEQ ID NO: 817). In one aspect, the transmembrane domain may be recombinant, in which case it will comprise predominantly hydrophobic residues such as leucine and valine. In one aspect a triplet of phenylalanine, tryptophan and valine can be found at each end of a recombinant transmembrane domain. Optionally, a short oligo- or polypeptide linker, between 2 and 10 amino acids in length may form the linkage between the transmembrane domain and the cytoplasmic region of the CAR. A glycine-serine doublet provides a particularly suitable linker. For example, in one aspect, the linker comprises the amino acid sequence of GGGGS (SEQ ID NO: 834). In one aspect, the hinge or spacer comprises a KIR2DS2 hinge. Cytoplasmic Domain The cytoplasmic domain or region of the CAR includes an intracellular signaling domain. An intracellular signaling domain is capable of activation of at least one of the normal effector functions of the immune cell in which the CAR has been introduced. The term “effector function” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. Thus the term “intracellular signaling domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term intracellular signaling domain is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal. Examples of intracellular signaling domains for use in the CAR of the invention include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any recombinant sequence that has the same functional capability. It is known that signals generated through the TCR alone are insufficient for full activation of the T cell and that a secondary and/or costimulatory signal is also required. Thus, T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (secondary cytoplasmic domain, e.g., a costimulatory domain). A primary signaling domain regulates primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs. Examples of ITAM containing primary intracellular signaling domains that are of particular use in the invention include those of CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc Epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. In one embodiment, a CAR of the invention comprises an intracellular signaling domain, e.g., a primary signaling domain of CD3-zeta. In one embodiment, a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain. In one embodiment, a primary signaling domain comprise amodified ITAM-containing promary intrecellular signaling domain, e.g., an optimized and/or truncated ITAM-containing primary intracellular signaling domain. In an embodiment, a primary signaling domain comprises one, two, three, four or more ITAM motifs. Further examples of molecules containing a primary intracellular signaling domain that are of particular use in the invention include those of DAP10, DAP12, and CD32. The intracellular signalling domain of the CAR can comprise the primary signalling domain, e.g., CD3-zeta signaling domain, by itself or it can be combined with any other desired intracellular signaling domain(s) useful in the context of a CAR of the invention. For example, the intracellular signaling domain of the CAR can comprise a primary signalling domain, e.g., CD3 zeta chain portion, and a costimulatory signaling domain. The costimulatory signaling domain refers to a portion of the CAR comprising the intracellular domain of a co stimulatory molecule. A costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligands that is required for an efficient response of lymphocytes to an antigen. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD1, ICOS, lymphocyte function-associated antigen-1 (LFA-1) (CD11a and CD18), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like. For example, CD27 costimulation has been demonstrated to enhance expansion, effector function, and survival of human CART cells in vitro and augments human T cell persistence and antitumor activity in vivo (Song et al. Blood. 2012; 119(3):696-706). Further examples of such costimulatory molecules include NKp44, NKp30, NKp46, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD16a, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, and PAG/Cbp. The intracellular signaling sequences within the cytoplasmic portion of the CAR of the invention may be linked to each other in a random or specified order. Optionally, a short oligo- or polypeptide linker, for example, between 2 and 10 amino acids (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) in length may form the linkage between intracellular signaling sequence. In one embodiment, a glycine-serine doublet can be used as a suitable linker. In one embodiment, a single amino acid, e.g., an alanine, a glycine, can be used as a suitable linker. In one aspect, the intracellular signaling domain is designed to comprise two or more, e.g., 2, 3, 4, 5, or more, costimulatory signaling domains. In an embodiment, the two or more, e.g., 2, 3, 4, 5, or more, costimulatory signaling domains, are separated by a linker molecule, e.g., a linker molecule described herein. In one embodiment, the intracellular signaling domain comprises two costimulatory signaling domains. In some embodiments, the linker molecule is a glycine residue. In some embodiments, the linker is an alanine residue. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of 4-1BB. In one aspect, the signaling domain of 4-1BB is a signaling domain of SEQ ID NO: 803. In one aspect, the signaling domain of CD3-zeta is a signaling domain of SEQ ID NO: 805. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD27. In one aspect, the signaling domain of CD27 comprises an amino acid sequence of SEQ ID NO: 818. In one aspect, the signalling domain of CD27 is encoded by a nucleic acid sequence of SEQ ID NO: 819. In one aspect, the CAR-expressing cell described herein can further comprise a second CAR, e.g., a second CAR that includes a different antigen binding domain, e.g., to the same target (CD20) or a different target (e.g., CD22, CD19, ROR1, CD10, CD33, CLL-1, CD34, CD123, FLT3, CD79b, CD179b, and CD79a). In one embodiment, the second CAR includes an antigen binding domain to a target expressed on acute myeloid leukemia cells, such as, e.g., CD22, CD19, ROR1, CD10, CD33, CLL-1, CD34, CD123, FLT3, CD79b, CD179b, and CD79a. In one embodiment, the CAR-expressing cell comprises a first CAR that targets a first antigen and includes an intracellular signaling domain having a costimulatory signaling domain but not a primary signaling domain, and a second CAR that targets a second, different, antigen and includes an intracellular signaling domain having a primary signaling domain but not a costimulatory signaling domain. While not wishing to be bound by theory, placement of a costimulatory signaling domain, e.g., 4-1BB, CD28, CD27 or OX-40, onto the first CAR, and the primary signaling domain, e.g., CD3 zeta, on the second CAR can limit the CAR activity to cells where both targets are expressed. In one embodiment, the CAR expressing cell comprises a first CD20 CAR that includes a CD20 binding domain, a transmembrane domain and a costimulatory domain and a second CAR that targets an antigen other than CD20 (e.g., an antigen expressed on AML cells, e.g., CD22, CD19, ROR1, CD10, CD33, CLL-1, CD34, CD123, FLT3, CD79b, CD179b, or CD79a) and includes an antigen binding domain, a transmembrane domain and a primary signaling domain. In another embodiment, the CAR expressing cell comprises a first CD20 CAR that includes a CD20 binding domain, a transmembrane domain and a primary signaling domain and a second CAR that targets an antigen other than CD20 (e.g., an antigen expressed on AML cells, e.g., CD22, CD19, ROR1, CD10, CD33, CD123, CLL-1, CD34, FLT3, CD79b, CD179b, or CD79a) and includes an antigen binding domain to the antigen, a transmembrane domain and a costimulatory signaling domain. In one embodiment, the CAR-expressing cell comprises a CD20 CAR described herein and an inhibitory CAR. In one embodiment, the inhibitory CAR comprises an antigen binding domain that binds an antigen found on normal cells but not cancer cells, e.g., normal cells that also express D20. In one embodiment, the inhibitory CAR comprises the antigen binding domain, a transmembrane domain and an intracellular domain of an inhibitory molecule. For example, the intracellular domain of the inhibitory CAR can be an intracellular domain of PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta. In one embodiment, when the CAR-expressing cell comprises two or more different CARs, the antigen binding domains of the different CCARs can be such that the antigen binding domains do not interact with one another. For example, a cell expressing a first and second CAR can have an antigen binding domain of the first CAR, e.g., as a fragment, e.g., an scFv, that does not form an association with the antigen binding domain of the second CAR, e.g., the antigen binding domain of the second CAR is a VHH. In some embodiments, the antigen binding domain comprises a single domain antigen binding (SDAB) molecules include molecules whose complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain variable domains, binding molecules naturally devoid of light chains, single domains derived from conventional 4-chain antibodies, engineered domains and single domain scaffolds other than those derived from antibodies. SDAB molecules may be any of the art, or any future single domain molecules. SDAB molecules may be derived from any species including, but not limited to mouse, human, camel, llama, lamprey, fish, shark, goat, rabbit, and bovine. This term also includes naturally occurring single domain antibody molecules from species other than Camelidae and sharks. In one aspect, an SDAB molecule can be derived from a variable region of the immunoglobulin found in fish, such as, for example, that which is derived from the immunoglobulin isotype known as Novel Antigen Receptor (NAR) found in the serum of shark. Methods of producing single domain molecules derived from a variable region of NAR (“IgNARs”) are described in WO 03/014161 and Streltsov (2005) Protein Sci. 14:2901-2909. According to another aspect, an SDAB molecule is a naturally occurring single domain antigen binding molecule known as heavy chain devoid of light chains. Such single domain molecules are disclosed in WO 9404678 and Hamers-Casterman, C. et al. (1993) Nature 363:446-448, for example. For clarity reasons, this variable domain derived from a heavy chain molecule naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be derived from Camelidae species, for example in camel, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain molecules naturally devoid of light chain; such VHHs are within the scope of the invention. The SDAB molecules can be recombinant, CDR-grafted, humanized, camelized, de-immunized and/or in vitro generated (e.g., selected by phage display). It has also been discovered, that cells having a plurality of chimeric membrane embedded receptors comprising an antigen binding domain that interactions between the antigen binding domain of the receptors can be undesirable, e.g., because it inhibits the ability of one or more of the antigen binding domains to bind its cognate antigen. Accordingly, disclosed herein are cells having a first and a second non-naturally occurring chimeric membrane embedded receptor comprising antigen binding domains that minimize such interactions. Also disclosed herein are nucleic acids encoding a first and a second non-naturally occurring chimeric membrane embedded receptor comprising a antigen binding domains that minimize such interactions, as well as methods of making and using such cells and nucleic acids. In an embodiment the antigen binding domain of one of said first said second non-naturally occurring chimeric membrane embedded receptor, comprises an scFv, and the other comprises a single VH domain, e.g., a camelid, shark, or lamprey single VH domain, or a single VH domain derived from a human or mouse sequence. In some embodiments, the claimed invention comprises a first and second CAR, wherein the antigen binding domain of one of said first CAR said second CAR does not comprise a variable light domain and a variable heavy domain. In some embodiments, the antigen binding domain of one of said first CAR said second CAR is an scFv, and the other is not an scFv. In some embodiments, the antigen binding domain of one of said first CAR said second CAR comprises a single VH domain, e.g., a camelid, shark, or lamprey single VH domain, or a single VH domain derived from a human or mouse sequence. In some embodiments, the antigen binding domain of one of said first CAR said second CAR comprises a nanobody. In some embodiments, the antigen binding domain of one of said first CAR said second CAR comprises a camelid VHH domain. In some embodiments, the antigen binding domain of one of said first CAR said second CAR comprises an scFv, and the other comprises a single VH domain, e.g., a camelid, shark, or lamprey single VH domain, or a single VH domain derived from a human or mouse sequence. In some embodiments, the antigen binding domain of one of said first CAR said second CAR comprises an scFv, and the other comprises a nanobody. In some embodiments, the antigen binding domain of one of said first CAR said second CAR comprises an scFv, and the other comprises a camelid VHH domain. In some embodiments, when present on the surface of a cell, binding of the antigen binding domain of said first CAR to its cognate antigen is not substantially reduced by the presence of said second CAR. In some embodiments, binding of the antigen binding domain of said first CAR to its cognate antigen in the presence of said second CAR is 85%, 90%, 95%, 96%, 97%, 98% or 99% of binding of the antigen binding domain of said first CAR to its cognate antigen in the absence of said second CAR. In some embodiments, when present on the surface of a cell, the antigen binding domains of said first CAR said second CAR, associate with one another less than if both were scFv antigen binding domains. In some embodiments, the antigen binding domains of said first CAR said second CAR, associate with one another 85%, 90%, 95%, 96%, 97%, 98% or 99% less than if both were scFv antigen binding domains. In another aspect, the CAR-expressing cell described herein can further express another agent, e.g., an agent which enhances the activity of a CAR-expressing cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., PD1, can, in some embodiments, decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGF beta. In one embodiment, the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta, or a fragment of any of these (e.g., at least a portion of an extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 41BB, CD27 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD1 or a fragment thereof (e.g., at least a portion of an extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). PD1 is an inhibitory member of the CD28 family of receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B cells, T cells and myeloid cells (Agata et al. 1996 Int. Immunol 8:765-75). Two ligands for PD1, PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD1 (Freeman et a. 2000 J Exp Med 192:1027-34; Latchman et al. 2001 Nat Immunol 2:261-8; Carter et al. 2002 Eur J Immunol 32:634-43). PD-L1 is abundant in human cancers (Dong et al. 2003 J Mol Med 81:281-7; Blank et al. 2005 Cancer Immunol. Immunother 54:307-314; Konishi et al. 2004 Clin Cancer Res 10:5094). Immune suppression can be reversed by inhibiting the local interaction of PD1 with PD-L1. In one embodiment, the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., Programmed Death 1 (PD1), can be fused to a transmembrane domain and intracellular signaling domains such as 41BB and CD3 zeta (also referred to herein as a PD1 CAR). In one embodiment, the PD1 CAR, when used in combinations with a CD20 CAR described herein, improves the persistence of the T cell. In one embodiment, the CAR is a PD1 CAR comprising the extracellular domain of PD1 according to SEQ ID NO: 820. In one embodiment, the PD1 CAR comprises the amino acid sequence of SEQ ID NO: 820. In one embodiment, the agent comprises a nucleic acid sequence encoding the PD1 CAR, e.g., the PD1 CAR described herein. In one embodiment, the nucleic acid sequence for the PD1 CAR is SEQ ID NO: 821. In another aspect, the present invention provides a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells. In some embodiments, the population of CAR-expressing cells comprises a mixture of cells expressing different CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CAR having a CD20 binding domain described herein, and a second cell expressing a CAR having a different CD20 binding domain, e.g., a CD20 binding domain described herein that differs from the CD20 binding domain in the CAR expressed by the first cell. As another example, the population of CAR-expressing cells can include a first cell expressing a CAR that includes a CD20 binding domain, e.g., as described herein, and a second cell expressing a CAR that includes an antigen binding domain to a target other than CD20 (e.g., CD22, CD19, ROR1, CD10, CD33, CD34, CLL-1, CD123, FLT3, CD79b, CD179b, or CD79a). In one embodiment, the population of CAR-expressing cells includes, e.g., a first cell expressing a CAR that includes a primary intracellular signaling domain, and a second cell expressing a CAR that includes a secondary signaling domain, e.g., a costimulatory signaling domain. In another aspect, the present invention provides a population of cells wherein at least one cell in the population expresses a CAR having a CD20 binding domain described herein, and a second cell expressing another agent, e.g., an agent which enhances the activity of a CAR-expressing cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., can, in some embodiments, decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGF beta. In one embodiment, the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta, or a fragment of any of these (e.g., at least a portion of an extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 41BB, CD27 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD1 or a fragment thereof (e.g., at least a portion of the extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). In one aspect, the present invention provides methods comprising administering a population of CAR-expressing cells, e.g., CAR-expressing cells, e.g., a mixture of cells expressing different CARs, in combination with another agent, e.g., a kinase inhibitor, such as a kinase inhibitor described herein. In another aspect, the present invention provides methods comprising administering a population of cells wherein at least one cell in the population expresses a CAR having an anti-cancer associated antigen binding domain as described herein, and a second cell expressing another agent, e.g., an agent which enhances the activity of a CAR-expressing cell, in combination with another agent, e.g., a kinase inhibitor, such as a kinase inhibitor described herein. Regulatable Chimeric Antigen Receptors In some embodiments, a regulatable CAR (RCAR) where the CAR activity can be controlled is desirable to optimize the safety and efficacy of a CAR therapy. There are many ways CAR activities can be regulated. For example, inducible apoptosis using, e.g., a caspase fused to a dimerization domain (see, e.g., Di Stasa et al., N Egnl. J. Med. 2011 Nov. 3; 365(18):1673-1683), can be used as a safety switch in the CAR therapy of the instant invention. In one embodiment, the cells (e.g., T cells or NK cells) expressing a CAR of the present invention further comprise an inducible apoptosis switch, wherein a human caspase (e.g., caspase 9) or a modified version is fused to a modification of the human FKB protein that allows conditional dimerization. In the presence of a small molecule, such as a rapalog (e.g., AP 1903, AP20187), the inducible caspase (e.g., caspase 9) is activated and leads to the rapid apoptosis and death of the cells (e.g., T cells or NK cells) expressing a CAR of the present invention. Examples of a caspase-based inducible apoptosis switch (or one or more aspects of such a switch) have been described in, e.g., US2004040047; US20110286980; US20140255360; W01997031899; W02014151960; W02014164348; W02014197638; W02014197638; all of which are incorporated by reference herein. In an aspect, a RCAR comprises a set of polypeptides, typically two in the simplest embodiments, in which the components of a standard CAR described hrerin, e.g., an antigen binding domain and an intracellular signaling domain, are partitioned on separate polypeptides or members. In some embodiments, the set of polypeptides include a dimerization switch that, upon the presence of a dimerization molecule, can couple the polypeptides to one another, e.g., can couple an antigen binding domain to an intracellular signaling domain. In one embodiment, a CAR of the present invention utilizes a dimerization switch as those described in, e.g., W02014127261, which is incorporated by reference herein. In an aspect, an RCAR comprises two polypeptides or members: 1) an intracellular signaling member comprising an intracellular signaling domain, e.g., a primary intracellular signaling domain described herein, and a first switch domain; 2) an antigen binding member comprising an antigen binding domain, e.g., that targets CD19, as described herein and a second switch domain. Optionally, the RCAR comprises a transmembrane domain described herein. In an embodiment, a transmembrane domain can be disposed on the intracellular signaling member, on the antigen binding member, or on both. (Unless otherwise indicated, when members or elements of an RCAR are described herein, the order can be as provided, but other orders are included as well. In other words, in an embodiment, the order is as set out in the text, but in some embodiments, the order can be different. E.g., the order of elements on one side of a transmembrane region can be different from the example, e.g., the placement of a switch domain relative to a intracellular signaling domain can be different, e.g., reversed). In an embodiment, the first and second switch domains can form an intracellular or an extracellular dimerization switch. In an embodiment, the dimerization switch can be a homodimerization switch, e.g., where the first and second switch domain are the same, or a heterodimerization switch, e.g., where the first and second switch domain are different from one another. In embodiments, an RCAR can comprise a “multi switch.” A multi switch can comprise heterodimerization switch domains or homodimerization switch domains. A multi switch comprises a plurality of, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, switch domains, independently, on a first member, e.g., an antigen binding member, and a second member, e.g., an intracellular signaling member. In an embodiment, the first member can comprise a plurality of first switch domains, e.g., FKBP-based switch domains, and the second member can comprise a plurality of second switch domains, e.g., FRB-based switch domains. In an embodiment, the first member can comprise a first and a second switch domain, e.g., a FKBP-based switch domain and a FRB-based switch domain, and the second member can comprise a first and a second switch domain, e.g., a FKBP-based switch domain and a FRB-based switch domain. In an embodiment, the intracellular signaling member comprises one or more intracellular signaling domains, e.g., a primary intracellular signaling domain and one or more costimulatory signaling domains. In an embodiment, the antigen binding member may comprise one or more intracellular signaling domains, e.g., one or more costimulatory signaling domains. In an embodiment, the antigen binding member comprises a plurality, e.g., 2 or 3 costimulatory signaling domains described herein, e.g., selected from 41BB, CD28, CD27, ICOS, and OX40, and in embodiments, no primary intracellular signaling domain. In an embodiment, the antigen binding member comprises the following costimulatory signaling domains, from the extracellular to intracellular direction: 41BB-CD27; 41BB-CD27; CD27-41BB; 41BB-CD28; CD28-41BB; OX40-CD28; CD28-OX40; CD28-41BB; or 41BB-CD28. In such embodiments, the intracellular binding member comprises a CD3zeta domain. In one such embodiment the RCAR comprises (1) an antigen binding member comprising, an antigen binding domain, a transmembrane domain, and two costimulatory domains and a first switch domain; and (2) an intracellular signaling domain comprising a transmembrane domain or membrane tethering domain and at least one primary intracellular signaling domain, and a second switch domain. An embodiment provides RCARs wherein the antigen binding member is not tethered to the surface of the CAR cell. This allows a cell having an intracellular signaling member to be conveniently paired with one or more antigen binding domains, without transforming the cell with a sequence that encodes the antigen binding member. In such embodiments, the RCAR comprises: 1) an intracellular signaling member comprising: a first switch domain, a transmembrane domain, an intracellular signaling domain, e.g., a primary intracellular signaling domain, and a first switch domain; and 2) an antigen binding member comprising: an antigen binding domain, and a second switch domain, wherein the antigen binding member does not comprise a transmembrane domain or membrane tethering domain, and, optionally, does not comprise an intracellular signaling domain. In some embodiments, the RCAR may further comprise 3) a second antigen binding member comprising: a second antigen binding domain, e.g., a second antigen binding domain that binds a different antigen than is bound by the antigen binding domain; and a second switch domain. Also provided herein are RCARs wherein the antigen binding member comprises bispecific activation and targeting capacity. In this embodiment, the antigen binding member can comprise a plurality, e.g., 2, 3, 4, or 5 antigen binding domains, e.g., scFvs, wherein each antigen binding domain binds to a target antigen, e.g. different antigens or the same antigen, e.g., the same or different epitopes on the same antigen. In an embodiment, the plurality of antigen binding domains are in tandem, and optionally, a linker or hinge region is disposed between each of the antigen binding domains. Suitable linkers and hinge regions are described herein. An embodiment provides RCARs having a configuration that allows switching of proliferation. In this embodiment, the RCAR comprises: 1) an intracellular signaling member comprising: optionally, a transmembrane domain or membrane tethering domain; one or more co-stimulatory signaling domain, e.g., selected from 41BB, CD28, CD27, ICOS, and OX40, and a switch domain; and 2) an antigen binding member comprising: an antigen binding domain, a transmembrane domain, and a primary intracellular signaling domain, e.g., a CD3zeta domain, wherein the antigen binding member does not comprise a switch domain, or does not comprise a switch domain that dimerizes with a switch domain on the intracellular signaling member. In an embodiment, the antigen binding member does not comprise a co-stimulatory signaling domain. In an embodiment, the intracellular signaling member comprises a switch domain from a homodimerization switch. In an embodiment, the intracellular signaling member comprises a first switch domain of a heterodimerization switch and the RCAR comprises a second intracellular signaling member which comprises a second switch domain of the heterodimerization switch. In such embodiments, the second intracellular signaling member comprises the same intracellular signaling domains as the intracellular signaling member. In an embodiment, the dimerization switch is intracellular. In an embodiment, the dimerization switch is extracellular. In any of the RCAR configurations described here, the first and second switch domains comprise a FKBP-FRB based switch as described herein. Also provided herein are cells comprising an RCAR described herein. Any cell that is engineered to express a RCAR can be used as a RCARX cell. In an embodiment the RCARX cell is a T cell, and is referred to as a RCART cell. In an embodiment the RCARX cell is an NK cell, and is referred to as a RCARN cell. Also provided herein are nucleic acids and vectors comprising RCAR encoding sequences. Sequence encoding various elements of an RCAR can be disposed on the same nucleic acid molecule, e.g., the same plasmid or vector, e.g., viral vector, e.g., lentiviral vector. In an embodiment, (i) sequence encoding an antigen binding member and (ii) sequence encoding an intracellular signaling member, can be present on the same nucleic acid, e.g., vector. Production of the corresponding proteins can be achieved, e.g., by the use of separate promoters, or by the use of a bicistronic transcription product (which can result in the production of two proteins by cleavage of a single translation product or by the translation of two separate protein products). In an embodiment, a sequence encoding a cleavable peptide, e.g., a P2A or F2A sequence, is disposed between (i) and (ii). In an embodiment, a sequence encoding an IRES, e.g., an EMCV or EV71 IRES, is disposed between (i) and (ii). In these embodiments, (i) and (ii) are transcribed as a single RNA. In an embodiment, a first promoter is operably linked to (i) and a second promoter is operably linked to (ii), such that (i) and (ii) are transcribed as separate mRNAs. Alternatively, the sequence encoding various elements of an RCAR can be disposed on the different nucleic acid molecules, e.g., different plasmids or vectors, e.g., viral vector, e.g., lentiviral vector. E.g., the (i) sequence encoding an antigen binding member can be present on a first nucleic acid, e.g., a first vector, and the (ii) sequence encoding an intracellular signaling member can be present on the second nucleic acid, e.g., the second vector. Dimerization Switches Dimerization switches can be non-covalent or covalent. In a non-covalent dimerization switch, the dimerization molecule promotes a non-covalent interaction between the switch domains. In a covalent dimerization switch, the dimerization molecule promotes a covalent interaction between the switch domains. In an embodiment, the RCAR comprises a FKBP/FRAP, or FKBP/FRB,-based dimerization switch. FKBP12 (FKBP, or FK506 binding protein) is an abundant cytoplasmic protein that serves as the initial intracellular target for the natural product immunosuppressive drug, rapamycin. Rapamycin binds to FKBP and to the large PI3K homolog FRAP (RAFT, mTOR). FRB is a 93 amino acid portion of FRAP, that is sufficient for binding the FKBP-rapamycin complex (Chen, J., Zheng, X. F., Brown, E. J. & Schreiber, S. L. (1995) Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA 92: 4947-51.) In embodiments, an FKBP/FRAP, e.g., an FKBP/FRB, based switch can use a dimerization molecule, e.g., rapamycin or a rapamycin analog. The amino acid sequence of FKBP is SEQ ID NO: 824. In embodiments, an FKBP switch domain can comprise a fragment of FKBP having the ability to bind with FRB (SEQ ID NO: 825), or a fragment or analog thereof, in the presence of rapamycin or a rapalog. The amino acid sequence of FRB is SEQ ID NO: 826. “FKBP/FRAP, e.g., an FKBP/FRB, based switch” as that term is used herein, refers to a dimerization switch comprising: a first switch domain, which comprises an FKBP fragment or analog thereof having the ability to bind with FRB, or a fragment or analog thereof, in the presence of rapamycin or a rapalog, e.g., RAD001, and has at least 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identity with, or differs by no more than 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 amino acid residues from, the FKBP sequence of SEQ ID NO: 824 or 825; and a second switch domain, which comprises an FRB fragment or analog thereof having the ability to bind with FRB, or a fragment or analog thereof, in the presence of rapamycin or a rapalog, and has at least 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identity with, or differs by no more than 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 amino acid residues from, the FRB sequence of SEQ ID NO: 826. In an embodiment, a RCAR described herein comprises one switch domain comprises amino acid residues disclosed in SEQ ID NO: 824 or 825, and one switch domain comprises amino acid residues disclosed in SEQ ID NO: 826. In embodiments, the FKBP/FRB dimerization switch comprises a modified FRB switch domain that exhibits altered, e.g., enhanced, complex formation between an FRB-based switch domain, e.g., the modified FRB switch domain, a FKBP-based switch domain, and the dimerization molecule, e.g., rapamycin or a rapalogue, e.g., RAD001. In an embodiment, the modified FRB switch domain comprises one or more mutations, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, selected from mutations at amino acid position(s) L2031, E2032, S2035, R2036, F2039, G2040, T2098, W2101, D2102, Y2105, and F2108, where the wild-type amino acid is mutated to any other naturally-occurring amino acid. In an embodiment, a mutant FRB comprises a mutation at E2032, where E2032 is mutated to phenylalanine (E2032F), methionine (E2032M), arginine (E2032R), valine (E2032V), tyrosine (E2032Y), isoleucine (E2032I), e.g., SEQ ID NO: 827, or leucine (E2032L), e.g., SEQ ID NO: 828. In an embodiment, a mutant FRB comprises a mutation at T2098, where T2098 is mutated to phenylalanine (T2098F) or leucine (T2098L), e.g., SEQ ID NO: 829. In an embodiment, a mutant FRB comprises a mutation at E2032 and at T2098, where E2032 is mutated to any amino acid, and where T2098 is mutated to any amino acid, e.g., SEQ ID NO: 830. In an embodiment, a mutant FRB comprises an E20321 and a T2098L mutation, e.g., SEQ ID NO: 831. In an embodiment, a mutant FRB comprises an E2032L and a T2098L mutation, e.g., SEQ ID NO: 832. Other suitable dimerization switches include a GyrB-GyrB based dimerization switch, a Gibberellin-based dimerization switch, a tag/binder dimerization switch, and a halo-tag/snap-tag dimerization switch. Following the guidance provided herein, such switches and relevant dimerization molecules will be apparent to one of ordinary skill. Dimerization Molecule Association between the switch domains is promoted by the dimerization molecule. In the presence of dimerization molecule interaction or association between switch domains allows for signal transduction between a polypeptide associated with, e.g., fused to, a first switch domain, and a polypeptide associated with, e.g., fused to, a second switch domain. In the presence of non-limiting levels of dimerization molecule signal transduction is increased by 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 5, 10, 50, 100 fold, e.g., as measured in a system described herein. Rapamycin and rapamycin analogs (sometimes referred to as rapalogues), e.g., RAD001, can be used as dimerization molecules in a FKBP/FRB-based dimerization switch described herein. In an embodiment the dimerization molecule can be selected from rapamycin (sirolimus), RAD001 (everolimus), zotarolimus, temsirolimus, AP-23573 (ridaforolimus), biolimus and AP21967. Additional rapamycin analogs suitable for use with FKBP/FRB-based dimerization switches are further described in the section entitled “Combination Therapies”, or in the subsection entitled “Exemplary mTOR inhibitors”. Split CAR In some embodiments, the CAR-expressing cell uses a split CAR. The split CAR approach is described in more detail in PCT publications WO2014/055442 and WO2014/055657, incorporated herein by reference. Briefly, a split CAR system comprises a cell expressing a first CAR having a first antigen binding domain and a costimulatory domain (e.g., 4-1BB), and the cell also expresses a second CAR having a second antigen binding domain and an intracellular signaling domain (e.g., CD3 zeta). When the cell encounters the first antigen, the costimulatory domain is activated, and the cell proliferates. When the cell encounters the second antigen, the intracellular signaling domain is activated and cell-killing activity begins. Thus, the CAR-expressing cell is only fully activated in the presence of both antigens. RNA Transfection Disclosed herein are methods for producing an in vitro transcribed RNA CAR. The present invention also includes a CAR encoding RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection can involve in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3′ and 5′ untranslated sequence (“UTR”), a 5′ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO: 1093). RNA so produced can efficiently transfect different kinds of cells. In one aspect, the template includes sequences for the CAR. In one aspect the CD20 CAR is encoded by a messenger RNA (mRNA). In one aspect the mRNA encoding the CD20 CAR is introduced into an immune effector cell, e.g., a T cell or a NK cell, for production of a CAR-expressing cell, e.g., a CART cell or a CAR NK cell. In one embodiment, the in vitro transcribed RNA CAR can be introduced to a cell as a form of transient transfection. The RNA is produced by in vitro transcription using a polymerase chain reaction (PCR)-generated template. DNA of interest from any source can be directly converted by PCR into a template for in vitro mRNA synthesis using appropriate primers and RNA polymerase. The source of the DNA can be, for example, genomic DNA, plasmid DNA, phage DNA, cDNA, synthetic DNA sequence or any other appropriate source of DNA. The desired temple for in vitro transcription is a CAR of the present invention. For example, the template for the RNA CAR comprises an extracellular region comprising a single chain variable domain of an anti-tumor antibody; a hinge region, a transmembrane domain (e.g., a transmembrane domain of CD8a); and a cytoplasmic region that includes an intracellular signaling domain, e.g., comprising the signaling domain of CD3-zeta and the signaling domain of 4-1BB. In one embodiment, the DNA to be used for PCR contains an open reading frame. The DNA can be from a naturally occurring DNA sequence from the genome of an organism. In one embodiment, the nucleic acid can include some or all of the 5′ and/or 3′ untranslated regions (UTRs). The nucleic acid can include exons and introns. In one embodiment, the DNA to be used for PCR is a human nucleic acid sequence. In another embodiment, the DNA to be used for PCR is a human nucleic acid sequence including the 5′ and 3′ UTRs. The DNA can alternatively be an artificial DNA sequence that is not normally expressed in a naturally occurring organism. An exemplary artificial DNA sequence is one that contains portions of genes that are ligated together to form an open reading frame that encodes a fusion protein. The portions of DNA that are ligated together can be from a single organism or from more than one organism. PCR is used to generate a template for in vitro transcription of mRNA which is used for transfection. Methods for performing PCR are well known in the art. Primers for use in PCR are designed to have regions that are substantially complementarity to regions of the DNA to be used as a template for the PCR. “Substantially complementarity,” as used herein, refers to sequences of nucleotides where a majority or all of the bases in the primer sequence are complementarity, or one or more bases are non-complementarity, or mismatched. Substantially complementarity sequences are able to anneal or hybridize with the intended DNA target under annealing conditions used for PCR. The primers can be designed to be substantially complementarity to any portion of the DNA template. For example, the primers can be designed to amplify the portion of a nucleic acid that is normally transcribed in cells (the open reading frame), including 5′ and 3′ UTRs. The primers can also be designed to amplify a portion of a nucleic acid that encodes a particular domain of interest. In one embodiment, the primers are designed to amplify the coding region of a human cDNA, including all or portions of the 5′ and 3′ UTRs. Primers useful for PCR can be generated by synthetic methods that are well known in the art. “Forward primers” are primers that contain a region of nucleotides that are substantially complementarity to nucleotides on the DNA template that are upstream of the DNA sequence that is to be amplified. “Upstream” is used herein to refer to a location 5, to the DNA sequence to be amplified relative to the coding strand. “Reverse primers” are primers that contain a region of nucleotides that are substantially complementarity to a double-stranded DNA template that are downstream of the DNA sequence that is to be amplified. “Downstream” is used herein to refer to a location 3′ to the DNA sequence to be amplified relative to the coding strand. Any DNA polymerase useful for PCR can be used in the methods disclosed herein. The reagents and polymerase are commercially available from a number of sources. Chemical structures with the ability to promote stability and/or translation efficiency may also be used. The RNA preferably has 5′ and 3′ UTRs. In one embodiment, the 5′ UTR is between one and 3000 nucleotides in length. The length of 5′ and 3′ UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5′ and 3′ UTR lengths required to achieve optimal translation efficiency following transfection of the transcribed RNA. The 5′ and 3′ UTRs can be the naturally occurring, endogenous 5′ and 3′ UTRs for the nucleic acid of interest. Alternatively, UTR sequences that are not endogenous to the nucleic acid of interest can be added by incorporating the UTR sequences into the forward and reverse primers or by any other modifications of the template. The use of UTR sequences that are not endogenous to the nucleic acid of interest can be useful for modifying the stability and/or translation efficiency of the RNA. For example, it is known that AU-rich elements in 3′ UTR sequences can decrease the stability of mRNA. Therefore, 3′ UTRs can be selected or designed to increase the stability of the transcribed RNA based on properties of UTRs that are well known in the art. In one embodiment, the 5′ UTR can contain the Kozak sequence of the endogenous nucleic acid. Alternatively, when a 5′ UTR that is not endogenous to the nucleic acid of interest is being added by PCR as described above, a consensus Kozak sequence can be redesigned by adding the 5′ UTR sequence. Kozak sequences can increase the efficiency of translation of some RNA transcripts, but does not appear to be required for all RNAs to enable efficient translation. The requirement for Kozak sequences for many mRNAs is known in the art. In some embodiments, the 5′ UTR can be 5′UTR of an RNA virus whose RNA genome is stable in cells. In some embodiments, various nucleotide analogues can be used in the 3′ or 5′ UTR to impede exonuclease degradation of the mRNA. To enable synthesis of RNA from a DNA template without the need for gene cloning, a promoter of transcription should be attached to the DNA template upstream of the sequence to be transcribed. When a sequence that functions as a promoter for an RNA polymerase is added to the 5′ end of the forward primer, the RNA polymerase promoter becomes incorporated into the PCR product upstream of the open reading frame that is to be transcribed. In one preferred embodiment, the promoter is a T7 polymerase promoter, as described elsewhere herein. Other useful promoters include, but are not limited to, T3 and SP6 RNA polymerase promoters. Consensus nucleic acid sequences for T7, T3 and SP6 promoters are known in the art. In a preferred embodiment, the mRNA has both a cap on the 5′ end and a 3′ poly(A) tail which determine ribosome binding, initiation of translation and stability mRNA in the cell. On a circular DNA template, for instance, plasmid DNA, RNA polymerase produces a long concatameric product which is not suitable for expression in eukaryotic cells. The transcription of plasmid DNA linearized at the end of the 3′ UTR results in normal sized mRNA which is not effective in eukaryotic transfection even if it is polyadenylated after transcription. On a linear DNA template, phage T7 RNA polymerase can extend the 3′ end of the transcript beyond the last base of the template (Schenborn and Mierendorf, Nuc Acids Res., 13:6223-36 (1985); Nacheva and Berzal-Herranz, Eur. J. Biochem., 270:1485-65 (2003). The conventional method of integration of polyA/T stretches into a DNA template is molecular cloning. However polyA/T sequence integrated into plasmid DNA can cause plasmid instability, which is why plasmid DNA templates obtained from bacterial cells are often highly contaminated with deletions and other aberrations. This makes cloning procedures not only laborious and time consuming but often not reliable. That is why a method which allows construction of DNA templates with polyA/T 3′ stretch without cloning highly desirable. The polyA/T segment of the transcriptional DNA template can be produced during PCR by using a reverse primer containing a polyT tail, such as 100 T tail (SEQ ID NO: 1094) (size can be 50-5000 T (SEQ ID NO: 1095)), or after PCR by any other method, including, but not limited to, DNA ligation or in vitro recombination. Poly(A) tails also provide stability to RNAs and reduce their degradation. Generally, the length of a poly(A) tail positively correlates with the stability of the transcribed RNA. In one embodiment, the poly(A) tail is between 100 and 5000 adenosines (SEQ ID NO: 1096). Poly(A) tails of RNAs can be further extended following in vitro transcription with the use of a poly(A) polymerase, such as E. coli polyA polymerase (E-PAP). In one embodiment, increasing the length of a poly(A) tail from 100 nucleotides to between 300 and 400 nucleotides results in about a two-fold increase in the translation efficiency of the RNA. Additionally, the attachment of different chemical groups to the 3′ end can increase mRNA stability. Such attachment can contain modified/artificial nucleotides, aptamers and other compounds. For example, ATP analogs can be incorporated into the poly(A) tail using poly(A) polymerase. ATP analogs can further increase the stability of the RNA. 5′ caps on also provide stability to RNA molecules. In a preferred embodiment, RNAs produced by the methods disclosed herein include a 5′ cap. The 5′ cap is provided using techniques known in the art and described herein (Cougot, et al., Trends in Biochem. Sci., 29:436-444 (2001); Stepinski, et al., RNA, 7:1468-95 (2001); Elango, et al., Biochim. Biophys. Res. Commun., 330:958-966 (2005)). The RNAs produced by the methods disclosed herein can also contain an internal ribosome entry site (IRES) sequence. The IRES sequence may be any viral, chromosomal or artificially designed sequence which initiates capindependent ribosome binding to mRNA and facilitates the initiation of translation. Any solutes suitable for cell electroporation, which can contain factors facilitating cellular permeability and viability such as sugars, peptides, lipids, proteins, antioxidants, and surfactants can be included. RNA can be introduced into target cells using any of a number of different methods, for instance, commercially available methods which include, but are not limited to, electroporation (Amaxa Nucleofector-II (Amaxa Biosystems, Cologne, Germany)), (ECM 830 (BTX) (Harvard Instruments, Boston, Mass.) or the Gene Pulser II (BioRad, Denver, Colo.), Multiporator (Eppendort, Hamburg Germany), cationic liposome mediated transfection using lipofection, polymer encapsulation, peptide mediated transfection, or biolistic particle delivery systems such as “gene guns” (see, for example, Nishikawa, et al. Hum Gene Ther., 12(8):861-70 (2001). Non-Viral Delivery Methods In some aspects, non-viral methods can be used to deliver a nucleic acid encoding a CAR described herein into a cell or tissue or a subject. In some embodiments, the non-viral method includes the use of a transposon (also called a transposable element). In some embodiments, a transposon is a piece of DNA that can insert itself at a location in a genome, for example, a piece of DNA that is capable of self-replicating and inserting its copy into a genome, or a piece of DNA that can be spliced out of a longer nucleic acid and inserted into another place in a genome. For example, a transposon comprises a DNA sequence made up of inverted repeats flanking genes for transposition. Exemplary methods of nucleic acid delivery using a transposon include a Sleeping Beauty transposon system (SBTS) and a piggyBac (PB) transposon system. See, e.g., Aronovich et al. Hum. Mol. Genet. 20.R1 (2011):R14-20; Singh et al. Cancer Res. 15 (2008):2961-2971; Huang et al. Mol. Ther. 16 (2008):580-589; Grabundzija et al. Mol. Ther. 18 (2010):1200-1209; Kebriaei et al. Blood. 122.21 (2013): 166; Williams. Molecular Therapy 16.9 (2008):1515-16; Bell et al. Nat. Protoc. 2.12 (2007):3153-65; and Ding et al. Cell. 122.3 (2005):473-83, all of which are incorporated herein by reference. The SBTS includes two components: 1) a transposon containing a transgene and 2) a source of transposase enzyme. The transposase can transpose the transposon from a carrier plasmid (or other donor DNA) to a target DNA, such as a host cell chromosome/genome. For example, the transposase binds to the carrier plasmid/donor DNA, cuts the transposon (including transgene(s)) out of the plasmid, and inserts it into the genome of the host cell. See, e.g., Aronovich et al. Exemplary transposons include a pT2-based transposon. See, e.g., Grabundzija et al. Nucleic Acids Res. 41.3 (2013): 1829-47; and Singh et al. Cancer Res. 68.8 (2008): 2961-2971, all of which are incorporated herein by reference. Exemplary transposases include a Tc1/mariner-type transposase, e.g., the SB10 transposase or the SB11 transposase (a hyperactive transposase which can be expressed, e.g., from a cytomegalovirus promoter). See, e.g., Aronovich et al.; Kebriaei et al.; and Grabundzija et al., all of which are incorporated herein by reference. Use of the SBTS permits efficient integration and expression of a transgene, e.g., a nucleic acid encoding a CAR described herein. Provided herein are methods of generating a cell, e.g., T cell or NK cell, that stably expresses a CAR described herein, e.g., using a transposon system such as SBTS. In accordance with methods described herein, in some embodiments, one or more nucleic acids, e.g., plasmids, containing the SBTS components are delivered to a cell (e.g., T or NK cell). For example, the nucleic acid(s) are delivered by standard methods of nucleic acid (e.g., plasmid DNA) delivery, e.g., methods described herein, e.g., electroporation, transfection, or lipofection. In some embodiments, the nucleic acid contains a transposon comprising a transgene, e.g., a nucleic acid encoding a CAR described herein. In some embodiments, the nucleic acid contains a transposon comprising a transgene (e.g., a nucleic acid encoding a CAR described herein) as well as a nucleic acid sequence encoding a transposase enzyme. In some embodiments, a system with two nucleic acids is provided, e.g., a dual-plasmid system, e.g., where a first plasmid contains a transposon comprising a transgene, and a second plasmid contains a nucleic acid sequence encoding a transposase enzyme. For example, the first and the second nucleic acids are co-delivered into a host cell. In some embodiments, cells, e.g., T or NK cells, are generated that express a CAR described herein by using a combination of gene insertion using the SBTS and genetic editing using a nuclease (e.g., Zinc finger nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), the CRISPR/Cas system, or engineered meganuclease reengineered homing endonucleases). In some embodiments, use of a non-viral method of delivery permits reprogramming of cells, e.g., T or NK cells, and direct infusion of the cells into a subject. Advantages of non-viral vectors include but are not limited to the ease and relatively low cost of producing sufficient amounts required to meet a patient population, stability during storage, and lack of immunogenicity. Nucleic Acid Constructs Encoding a CAR The present invention also provides nucleic acid molecules encoding one or more CAR constructs described herein. In one aspect, the nucleic acid molecule is provided as a messenger RNA transcript. In one aspect, the nucleic acid molecule is provided as a DNA construct. Accordingly, in one aspect, the invention pertains to an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a CD20 binding domain (e.g., a murine, humanized or human CD20 binding domain), a transmembrane domain, and an intracellular signaling domain comprising a stimulatory domain, e.g., a costimulatory signaling domain and/or a primary signaling domain, e.g., zeta chain. In one embodiment, the CD20 binding domain is a CD20 binding domain described herein, e.g., a CD20 binding domain which comprises a sequence selected from a group consisting of SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429, or a sequence with 95-99% identity thereof. In one embodiment, the transmembrane domain is transmembrane domain of a protein, e.g., described herein, e.g., selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD123, CD134, CD137 and CD154. In one embodiment, the transmembrane domain comprises a sequence of SEQ ID NO: 801, or a sequence with 95-99% identity thereof. In one embodiment, the CD20 binding domain is connected to the transmembrane domain by a hinge region, e.g., a hinge described herein. In one embodiment, the hinge region comprises SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 816, or a sequence with 95-99% identity thereof. In one embodiment, the isolated nucleic acid molecule further comprises a sequence encoding a costimulatory domain. In one embodiment, the costimulatory domain is a functional signaling domain of a protein, e.g., described herein, e.g., selected from the group consisting of OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137). In one embodiment, the costimulatory domain comprises a sequence of SEQ ID NO: 803, or a sequence with 95-99% identity thereof. In one embodiment, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and a functional signaling domain of CD3 zeta. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO: 805 or SEQ ID NO: 806, or a sequence with 95-99% identity thereof, and the sequence of SEQ ID NO: 807 or SEQ ID NO: 808, or a sequence with 95-99% identity thereof, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain. In another aspect, the invention pertains to an isolated nucleic acid molecule encoding a CAR construct comprising a leader sequence of SEQ ID NO: 797, a scFv domain having a sequence selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429 (or a sequence with 95-99% identity thereof), a hinge region of SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 814 (or a sequence with 95-99% identity thereof), a transmembrave domain having a sequence of SEQ ID NO: 801 (or a sequence with 95-99% identity thereof), a 4-1BB costimulatory domain having a sequence of SEQ ID NO: 803 or a CD27 costimulatory domain having a sequence of SEQ ID NO: 818 (or a sequence with 95-99% identity thereof), and a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:805 or SEQ ID NO: 807 (or a sequence with 95-99% identity thereof. In another aspect, the invention pertains to an isolated polypeptide molecule encoded by the nucleic acid molecule. In one embodiment, the isolated polypeptide molecule comprises a sequence selected from the group consisting of SEQ ID NO: 25, SEQ ID NO: 52, SEQ ID NO: 79, SEQ ID NO: 106, SEQ ID NO: 133, SEQ ID NO: 160, SEQ ID NO: 187, SEQ ID NO: 214, SEQ ID NO: 241, SEQ ID NO: 268, SEQ ID NO: 295, SEQ ID NO: 322, SEQ ID NO: 349, SEQ ID NO: 376, SEQ ID NO: 403, and SEQ ID NO: 430, or a sequence with 95-99% identity thereof. In another aspect, the invention pertains to a nucleic acid molecule encoding a chimeric antigen receptor (CAR) molecule that comprises a CD20 binding domain, a transmembrane domain, and an intracellular signaling domain comprising a stimulatory domain, and wherein said CD20 binding domain comprises a sequence selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 51, SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429, or a sequence with 95-99% identity thereof. In one embodiment, the encoded CAR molecule further comprises a sequence encoding a costimulatory domain. In one embodiment, the costimulatory domain is a functional signaling domain of a protein selected from the group consisting of OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18) and 4-1BB (CD137). In one embodiment, the costimulatory domain comprises a sequence of SEQ ID NO: 803. In one embodiment, the transmembrane domain is a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD123, CD134, CD137, CD154, KIR2DS2, OX40, CD2, CD27, LFA-1 (CD11a and CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2R β, IL2R g (Common gamma), IL7R α, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4, (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR and PAG/Cbp. In one embodiment, the transmembrane domain comprises a sequence of SEQ ID NO: 803. In one embodiment, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and a functional signaling domain of zeta. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO: 803 and the sequence of SEQ ID NO: 804, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain. In one embodiment, the CD20 binding domain is connected to the transmembrane domain by a hinge region. In one embodiment, the hinge region comprises SEQ ID NO: 799. In one embodiment, the hinge region comprises SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 816. In another aspect, the invention pertains to an encoded CAR molecule comprising a leader sequence of SEQ ID NO: 797, a scFv domain having a sequence selected from SEQ ID NO: 78, SEQ ID NO: 105, SEQ ID NO: 132, SEQ ID NO: 159, SEQ ID NO: 186, SEQ ID NO: 213, SEQ ID NO: 240, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, SEQ ID NO: 348, SEQ ID NO: 375, SEQ ID NO: 402, and SEQ ID NO: 429, or a sequence with 95-99% identity thereof, a hinge region of SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 816, a transmembrane domain having a sequence of SEQ ID NO: 801, a 4-1BB costimulatory domain having a sequence of SEQ ID NO: 803 or a CD27 costimulatory domain having a sequence of SEQ ID NO: 818, and a CD3 zeta stimulatory domain having a sequence of SEQ ID NO: 805 or SEQ ID NO: 807. The nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the gene of interest can be produced synthetically, rather than cloned. The present invention also provides vectors in which a DNA of the present invention is inserted. Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. In another embodiment, the vector comprising the nucleic acid encoding the desired CAR of the invention is an adenoviral vector (A5/35). In another embodiment, the expression of nucleic acids encoding CARs can be accomplished using of transposons such as sleeping beauty, crisper, CAS9, and zinc finger nucleases. See below June et al. 2009 Nature Reviews Immunology 9.10: 704-716, is incorporated herein by reference. In brief summary, the expression of natural or synthetic nucleic acids encoding CARs is typically achieved by operably linking a nucleic acid encoding the CAR polypeptide or portions thereof to a promoter, and incorporating the construct into an expression vector. The vectors can be suitable for replication and integration eukaryotes. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. The expression constructs of the present invention may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties. In another embodiment, the invention provides a gene therapy vector. The nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. Further, the expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, (e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193). A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In one embodiment, lentivirus vectors are used. Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription. Exemplary promoters include the CMV IE gene, EF-1α, ubiquitin C, or phosphoglycerokinase (PGK) promoters. An example of a promoter that is capable of expressing a CAR transgene in a mammalian T cell is the EF-1 alpha (EF1a) promoter. The native EF1a promoter drives expression of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. The EF1a promoter has been extensively used in mammalian expression plasmids and has been shown to be effective in driving CAR expression from transgenes cloned into a lentiviral vector. See, e.g., Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). In one aspect, the EF1a promoter comprises the sequence provided as SEQ ID NO: 833. Another example of a promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the elongation factor-1α promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the invention should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the invention. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metal-lothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. In order to assess the expression of a CAR polypeptide or portions thereof, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic-resistance genes, such as neo and the like. Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5′ flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription. In one embodiment, the vector can further comprise a nucleic acid encoding a second CAR. In one embodiment, the second CAR includes an antigen binding domain to a target expressed on acute myeloid leukemia cells, such as, e.g., CD22, CD19, ROR1, CD10, CD33, CD34, CLL-1, CD123, FLT3, CD79b, CD179b, or CD79a. In one embodiment, the vector comprises a nucleic acid sequence encoding a first CAR that targets a first antigen and includes an intracellular signaling domain having a costimulatory signaling domain but not a primary signaling domain, and a nucleic acid encoding a second CAR that targets a second, different, antigen and includes an intracellular signaling domain having a primary signaling domain but not a costimulatory signaling domain. In one embodiment, the vector comprises a nucleic acid encoding a first CD20 CAR that includes a CD20 binding domain, a transmembrane domain and a costimulatory domain and a nucleic acid encoding a second CAR that targets an antigen other than CD20 (e.g., an antigen expressed on AML cells, e.g., CD22, CD19, ROR1, CD10, CD33, CD34, CLL-1, CD123, FLT3, CD79b, CD179b, or CD79a) and includes an antigen binding domain, a transmembrane domain and a primary signaling domain. In another embodiment, the vector comprises a nucleic acid encoding a first CD20 CAR that includes a CD20 binding domain, a transmembrane domain and a primary signaling domain and a nucleic acid encoding a second CAR that targets an antigen other than CD20 (e.g., an antigen expressed on AML cells, e.g., CD22, CD19, ROR1, CD10, CD33, CLL-1, CD34, CD123, FLT3, CD79b, CD179b, or CD79a) and includes an antigen binding domain to the antigen, a transmembrane domain and a costimulatory signaling domain. In one embodiment, the vector comprises a nucleic acid encoding a CD20 CAR described herein and a nucleic acid encoding an inhibitory CAR. In one embodiment, the inhibitory CAR comprises an antigen binding domain that binds an antigen found on normal cells but not cancer cells, e.g., normal cells that also express CD20. In one embodiment, the inhibitory CAR comprises the antigen binding domain, a transmembrane domain and an intracellular domain of an inhibitory molecule. For example, the intracellular domain of the inhibitory CAR can be an intracellular domain of PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta. Methods of introducing and expressing genes into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means. Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY). A preferred method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362. Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). Other methods of state-of-the-art targeted delivery of nucleic acids are available, such as delivery of polynucleotides with targeted nanoparticles or other suitable submicron sized delivery system. In the case where a non-viral delivery system is utilized, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid/DNA or lipid/expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes. Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine “DMPC”) can be obtained from Sigma, St. Louis, Mo.; dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories (Plainview, N.Y.); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, Ala.). Stock solutions of lipids in chloroform or chloroform/methanol can be stored at about −20° C. Chloroform is used as the only solvent since it is more readily evaporated than methanol. “Liposome” is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh et al., 1991 Glycobiology 5: 505-10). However, compositions that have different structures in solution than the normal vesicular structure are also encompassed. For example, the lipids may assume a micellar structure or merely exist as nonuniform aggregates of lipid molecules. Also contemplated are lipofectamine-nucleic acid complexes. Regardless of the method used to introduce exogenous nucleic acids into a host cell or otherwise expose a cell to the inhibitor of the present invention, in order to confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention. The present invention further provides a vector comprising a CAR encoding nucleic acid molecule. In one aspect, a CAR vector can be directly transduced into a cell, e.g., a T cell or NK cell. In one aspect, the vector is a cloning or expression vector, e.g., a vector including, but not limited to, one or more plasmids (e.g., expression plasmids, cloning vectors, minicircles, minivectors, double minute chromosomes), retroviral and lentiviral vector constructs. In one aspect, the vector is capable of expressing the CAR construct in mammalian T cells or NK cells. In one aspect, the mammalian T cell is a human T cell. Sources of Cells Prior to expansion and genetic modification or other modification, a source of cells, e.g., T cells or natural killer (NK) cells, can be obtained from a subject. The term “subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals). Examples of subject include humans, monkeys, chimpanzees, dogs, cats, mice, rats, and transgenic species thereof. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain aspects of the present invention disclosure, immune effector cells, e.g., T cells, can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll™ separation. In one preferred aspect, cells from the circulating blood of an individual are obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In one aspect, the cells collected by apheresis may be washed to remove the plasma fraction and, optionally, to place the cells in an appropriate buffer or media for subsequent processing steps. In one aspect of the invention, the cells are washed with phosphate buffered saline (PBS). In an alternative aspect, the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. Initial activation steps in the absence of calcium can lead to magnified activation. As those of ordinary skill in the art would readily appreciate a washing step may be accomplished by methods known to those in the art, such as by using a semi-automated “flow-through” centrifuge (for example, the Cobe 2991 cell processor, the Baxter CytoMate, or the Haemonetics Cell Saver 5) according to the manufacturer's instructions. After washing, the cells may be resuspended in a variety of biocompatible buffers, such as, for example, Ca-free, Mg-free PBS, PlasmaLyte A, or other saline solution with or without buffer. Alternatively, the undesirable components of the apheresis sample may be removed and the cells directly resuspended in culture media. In one aspect, T cells are isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL™ gradient or by counterflow centrifugal elutriation. The methods described herein can include, e.g., selection of a specific subpopulation of immune effector cells, e.g., T cells, that are a T regulatory cell-depleted population, CD25+ depleted cells, using, e.g., a negative selection technique, e.g., described herein. Preferably, the population of T regulatory depleted cells contains less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of CD25+ cells. In one embodiment, T regulatory cells, e.g., CD25+ T cells, are removed from the population using an anti-C25 antibody, or fragment thereof, or a CD25-binding ligand, IL-2. In one embodiment, the anti-CD25 antibody, or fragment thereof, or CD25-binding ligand is conjugated to a substrate, e.g., a bead, or is otherwise coated on a substrate, e.g., a bead. In one embodiment, the anti-CD25 antibody, or fragment thereof, is conjugated to a substrate as described herein. In one embodiment, the T regulatory cells, e.g., CD25+ T cells, are removed from the population using CD25 depletion reagent from Militenyi™. In one embodiment, the ratio of cells to CD25 depletion reagent is 1e7 cells to 20 uL, or 1e7 cells to 15 uL, or 1e7 cells to 10 uL, or 1e7 cells to 5 uL, or 1e7 cells to 2.5 uL, or 1e7 cells to 1.25 uL. In one embodiment, the population of immune effector cells to be depleted includes about 6×109CD25+ T cells. In other aspects, the population of immune effector cells to be depleted include about 1×109to 1×1010CD25+ T cell, and any integer value in between. In one embodimen, the esulting population T regulator y depleted cells has 2×109T regulatory cells, e.g., CD25+ cells, or less (e.g., 1×109, 5×108, 1×108, 5×107, 1×107, or less CD25+ cells). In one embodiment, the T regulatory cells, e.g., CD25+ cells, are removed from the population using the CliniMAC system with a depletion tubing set, such as, e.g., tubing 162-01. In one embodiment, the CliniMAC system is run on a depletion setting such as, e.g., DEPLETION2.1. The methods described herein can include more than one selection step, e.g., more than one depletion step. Enrichment of a T cell population by negative selection can be accomplished, e.g., with a combination of antibodies directed to surface markers unique to the negatively selected cells. One method is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected. For example, to enrich for CD4+ cells by negative selection, a monoclonal antibody cocktail can include antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8. The methods described herein can further include removing cells from the population which express a tumor antigen, e.g., a tumor antigen that does not comprise CD25, e.g., CD19, CD30, CD38, CD123, CD20, CD14 or CD11b, to thereby provide a population of T regulatory depleted, e.g., CD25+ depleted, and tumor antigen depleted cells that are suitable for expression of a CAR, e.g., a CAR described herein. In one embodiment, tumor antigen expressing cells are removed simultaneously with the T regulatory, e.g., CD25+ cells. For example, an anti-C25 antibody, or fragment thereof, and an anti-tumor antigen antibody, or fragment thereof, can be attached to the same substrate, e.g., bead, which can be used to remove the cells or an anti-CD25 antibody, or fragment thereof, or the anti-tumor antigen antibody, or fragment thereof, can be attached to separate beads, a mixture of which can be used to remove the cells. In some embodiments, the removal of T regulatory cells, e.g., CD25+ cells, and the removal of the tumor antigen expressing cells is sequential, and can occur, e.g., in either order. Also provided are methods that include removing cells from the population which express a check point inhibitor, e.g., a check point inhibitor described herein, e.g., one or more of PD1+ cells, LAG3+ cells, and TIM3+ cells, to thereby provide a population of T regulatory depleted, e.g., CD25+ depleted cells, and check point inhibitor depleted cells, e.g., PD1+, LAG3+ and/or TIM3+ depleted cells. Exemplary check point inhibitors include B7-H1, B&-1, CD160, P1H, 2B4, PD1, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, TIGIT, CTLA-4, BTLA and LAIR1. In one embodiment, check point inhibitor expressing cells are removed simultaneously with the T regulatory, e.g., CD25+ cells. For example, an anti-C25 antibody, or fragment thereof, and an anti-check point inhibitor antibody, or fragment thereof, can be attached to the same bead which can be used to remove the cells, or an anti-CD25 antibody, or fragment thereof, and the anti-check point inhibitor antibody, or fragment there, can be attached to separate beads, a mixture of which can be used to remove the cells. In some embodiments, the removal of T regulatory cells, e.g., CD25+ cells, and the removal of the check point inhibitor expressing cells is sequential, and can occur, e.g., in either order. Methods described herein can include a positive selection step. For example, T cells can be isolated by incubation with anti-CD3/anti-CD28 (e.g., 3×28)-conjugated beads, such as DYNABEADS® M-450 CD3/CD28 T, for a time period sufficient for positive selection of the desired T cells. In one aspect, the time period is about 30 minuites. In a further aspect, the time period ranges from 30 minutes to 36 hours or longer and all integer values there between. In a further aspect, the time period is at least 1, 2, 3, 4, 5, or 6 hours. In yet another preferred aspect, the time period is 10 to 24 hours. In one aspect, the incubation time period is 24 hours. Longer incubation times may be used to isolate T cells in any situation where there are few T cells as compared to other cell types, such in isolating tumor infiltrating lymphocytes (TIL) from tumor tissue or from immunocompromised individuals. Further, use of longer incubation times can increase the efficiency of capture of CD8+ T cells. Thus, by simply shortening or lengthening the time T cells are allowed to bind to the CD3/CD28 beads and/or by increasing or decreasing the ratio of beads to T cells (as described further herein), subpopulations of T cells can be preferentially selected for or against at culture initiation or at other time points during the process. Additionally, by increasing or decreasing the ratio of anti-CD3 and/or anti-CD28 antibodies on the beads or other surface, subpopulations of T cells can be preferentially selected for or against at culture initiation or at other desired time points. In one embodiment, a T cell population can be selected that expresses one or more of IFN-γ, TNFα, IL-17A, IL-2, IL-3, IL-4, GM-CSF, IL-10, IL-13, granzyme B, and perforin, or other appropriate molecules, e.g., other cytokines. Methods for screening for cell expression can be determined, e.g., by the methods described in PCT Publication No.: WO 2013/126712. For isolation of a desired population of cells by positive or negative selection, the concentration of cells and surface (e.g., particles such as beads) can be varied. In certain aspects, it may be desirable to significantly decrease the volume in which beads and cells are mixed together (e.g., increase the concentration of cells), to ensure maximum contact of cells and beads. For example, in one aspect, a concentration of about 10 billion cells/ml, 9 billion/ml, 8 billion/ml, 7 billion/ml, 6 billion/ml, or 5 billion/ml is used. In one aspect, a concentration of 1 billion cells/ml is used. In one aspect, a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/ml is used. In further aspects, concentrations of 125 or 150 million cells/ml can be used. Using high concentrations can result in increased cell yield, cell activation, and cell expansion. Further, use of high cell concentrations allows more efficient capture of cells that may weakly express target antigens of interest, such as CD28-negative T cells, or from samples where there are many tumor cells present (e.g., leukemic blood, tumor tissue, etc.). Such populations of cells may have therapeutic value and would be desirable to obtain. For example, using high concentration of cells allows more efficient selection of CD8+ T cells that normally have weaker CD28 expression. In a related aspect, it may be desirable to use lower concentrations of cells. By significantly diluting the mixture of T cells and surface (e.g., particles such as beads), interactions between the particles and cells is minimized This selects for cells that express high amounts of desired antigens to be bound to the particles. For example, CD4+ T cells express higher levels of CD28 and are more efficiently captured than CD8+ T cells in dilute concentrations. In one aspect, the concentration of cells used is 5×10e6/ml. In other aspects, the concentration used can be from about 1×105/ml to 1×106/ml, and any integer value in between. In other aspects, the cells may be incubated on a rotator for varying lengths of time at varying speeds at either 2-10° C. or at room temperature. T cells for stimulation can also be frozen after a washing step. Wishing not to be bound by theory, the freeze and subsequent thaw step provides a more uniform product by removing granulocytes and to some extent monocytes in the cell population. After the washing step that removes plasma and platelets, the cells may be suspended in a freezing solution. While many freezing solutions and parameters are known in the art and will be useful in this context, one method involves using PBS containing 20% DMSO and 8% human serum albumin, or culture media containing 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin and 7.5% DMSO, or 31.25% Plasmalyte-A, 31.25% Dextrose 5%, 0.45% NaCl, 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin, and 7.5% DMSO or other suitable cell freezing media containing for example, Hespan and PlasmaLyte A, the cells then are frozen to −80° C. at a rate of 10 per minute and stored in the vapor phase of a liquid nitrogen storage tank. Other methods of controlled freezing may be used as well as uncontrolled freezing immediately at −20° C. or in liquid nitrogen. In certain aspects, cryopreserved cells are thawed and washed as described herein and allowed to rest for one hour at room temperature prior to activation using the methods of the present invention. Also contemplated in the context of the invention is the collection of blood samples or apheresis product from a subject at a time period prior to when the expanded cells as described herein might be needed. As such, the source of the cells to be expanded can be collected at any time point necessary, and desired cells, such as T cells, isolated and frozen for later use in immune effector cell therapy for any number of diseases or conditions that would benefit from immune effector cell therapy, such as those described herein. In one aspect a blood sample or an apheresis is taken from a generally healthy subject. In certain aspects, a blood sample or an apheresis is taken from a generally healthy subject who is at risk of developing a disease, but who has not yet developed a disease, and the cells of interest are isolated and frozen for later use. In certain aspects, the T cells may be expanded, frozen, and used at a later time. In certain aspects, samples are collected from a patient shortly after diagnosis of a particular disease as described herein but prior to any treatments. In a further aspect, the cells are isolated from a blood sample or an apheresis from a subject prior to any number of relevant treatment modalities, including but not limited to treatment with agents such as natalizumab, efalizumab, antiviral agents, chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAM-PATH, anti-CD3 antibodies, cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, and irradiation. In a further aspect of the present invention, T cells are obtained from a patient directly following treatment that leaves the subject with functional T cells. In this regard, it has been observed that following certain cancer treatments, in particular treatments with drugs that damage the immune system, shortly after treatment during the period when patients would normally be recovering from the treatment, the quality of T cells obtained may be optimal or improved for their ability to expand ex vivo. Likewise, following ex vivo manipulation using the methods described herein, these cells may be in a preferred state for enhanced engraftment and in vivo expansion. Thus, it is contemplated within the context of the present invention to collect blood cells, including T cells, dendritic cells, or other cells of the hematopoietic lineage, during this recovery phase. Further, in certain aspects, mobilization (for example, mobilization with GM-CSF) and conditioning regimens can be used to create a condition in a subject wherein repopulation, recirculation, regeneration, and/or expansion of particular cell types is favored, especially during a defined window of time following therapy. Illustrative cell types include T cells, B cells, dendritic cells, and other cells of the immune system. In one embodiment, the immune effector cells expressing a CAR molecule, e.g., a CAR molecule described herein, are obtained from a subject that has received a low, immune enhancing dose of an mTOR inhibitor. In an embodiment, the population of immune effector cells, e.g., T cells or NK cells, to be engineered to express a CAR, are harvested after a sufficient time, or after sufficient dosing of the low, immune enhancing, dose of an mTOR inhibitor, such that the level of PD1 negative immune effector cells, e.g., T cells or NK cells, or the ratio of PD1 negative immune effector cells, e.g., T cells/NK cells/PD1 positive immune effector cells, e.g., T cells or NK cells, in the subject or harvested from the subject has been, at least transiently, increased. In some embodiments, population of immune effector cells, e.g., T cells or NK cells, which have, or will be engineered to express a CAR, can be treated ex vivo by contact with an amount of an mTOR inhibitor that increases the number of PD1 negative immune effector cells, e.g., T cells or increases the ratio of PD1 negative immune effector cells, e.g., T cells/NK cells/PD1 positive immune effector cells, e.g., T cells or NK cells. In one embodiment, a T cell population is diaglycerol kinase (DGK)-deficient. DGK-deficient cells include cells that do not express DGK RNA or protein, or have reduced or inhibited DGK activity. DGK-deficient cells can be generated by genetic approaches, e.g., administering RNA-interfering agents, e.g., siRNA, shRNA, miRNA, to reduce or prevent DGK expression. Alternatively, DGK-deficient cells can be generated by treatment with DGK inhibitors described herein. In one embodiment, a T cell population is Ikaros-deficient. Ikaros-deficient cells include cells that do not express Ikaros RNA or protein, or have reduced or inhibited Ikaros activity, Ikaros-deficient cells can be generated by genetic approaches, e.g., administering RNA-interfering agents, e.g., siRNA, shRNA, miRNA, to reduce or prevent Ikaros expression. Alternatively, Ikaros-deficient cells can be generated by treatment with Ikaros inhibitors, e.g., lenalidomide. In embodiments, a T cell population is DGK-deficient and Ikaros-deficient, e.g., does not express DGK and Ikaros, or has reduced or inhibited DGK and Ikaros activity. Such DGK and Ikaros-deficient cells can be generated by any of the methods described herein. In an embodiment, the NK cells are obtained from the subject. In another embodiment, the NK cells are an NK cell line, e.g., NK-92 cell line (Conkwest). Allogenic CART In embodiments described herein, the immune effector cell can be an allogenic immune effector cell, e.g., T cell or NK cell. For example, the cell can be an allogenic T cell, e.g., an allogenic T cell lacking expression of a functional T cell receptor (TCR) and/or human leukocyte antigen (HLA), e.g., HLA class I and/or HLA class II. A T cell lacking a functional TCR can be, e.g., engineered such that it does not express any functional TCR on its surface, engineered such that it does not express one or more subunits that comprise a functional TCR or engineered such that it produces very little functional TCR on its surface. Alternatively, the T cell can express a substantially impaired TCR, e.g., by expression of mutated or truncated forms of one or more of the subunits of the TCR. The term “substantially impaired TCR” means that this TCR will not elicit an adverse immune reaction in a host. Such cells can be created throughout the use of one or more gene editing systems as described herein. In embodiments, the gene editing system targets a sequence encoding a component of the TCR, for example a sequence in the TCR alpha constant chain gene (TRAC) or its regulatory elements. In embodiments, the gene editing system targets a sequence encoding a component of the TCR, for example a sequence in the TCR beta constant chain gene (TRBC) or its regulatory elements. A T cell described herein can be, e.g., engineered such that it does not express a functional HLA on its surface. For example, a T cell described herein, can be engineered such that cell surface expression HLA, e.g., HLA class 1 and/or HLA class II, is downregulated. Such cells can be created through the use of one or more gene editing systems as described herein. In embodiments, the gene editing system targets a sequence encoding a component of one or more HLA molecules. In embodiments, the gene editing system targets a sequence encoding a factor which affects the expression of one or more HLA molecules. In embodiments, the gene editing system targets a regulator of MHC class I expression, for example a sequence encoding beta-2 microglobulin (B2M). In embodiments, the gene editing system targets a sequence encoding a regulator of MHC class II molecule expression, for example, CIITA. In embodiments, gene editing systems targeting both a regulator of MHC class I expression (for example, B2M) and a regulator of MHC class II molecule expression (e.g., CIITA) are introduced into the cells, such that at least MHC class I molecule and at least one MHC class II molecule expression is downregulated. In some embodiments, the T cell can lack a functional TCR and a functional HLA, e.g., HLA class I and/or HLA class II. Modified T cells that lack expression of a functional TCR and/or HLA can be obtained by any suitable means, including a knock out or knock down of one or more subunit of TCR or HLA. For example, the T cell can include a knock down of TCR and/or HLA using siRNA, shRNA, clustered regularly interspaced short palindromic repeats (CRISPR) transcription-activator like effector nuclease (TALEN), or zinc finger endonuclease (ZFN). In some embodiments, the allogeneic cell can be a cell which does not express or expresses at low levels an inhibitory molecule, e.g. by any method described herein. For example, the cell can be a cell that does not express or expresses at low levels an inhibitory molecule, e.g., that can decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGF beta. Inhibition of an inhibitory molecule, e.g., by inhibition at the DNA, RNA or protein level, can optimize a CAR-expressing cell performance. In embodiments, an inhibitory nucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., an siRNA or shRNA, a clustered regularly interspaced short palindromic repeats (CRISPR), a transcription-activator like effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), e.g., as described herein, can be used. siRNA and shRNA to Inhibit, e.g., TCR or HLA In some embodiments, TCR expression and/or HLA expression can be inhibited using siRNA or shRNA that targets a nucleic acid encoding a TCR and/or HLA in a T cell. Expression of siRNA and shRNAs in T cells can be achieved using any conventional expression system, e.g., such as a lentiviral expression system. Exemplary shRNAs that downregulate expression of components of the TCR are described, e.g., in US Publication No.: 2012/0321667. Exemplary siRNA and shRNA that downregulate expression of HLA class I and/or HLA class II genes are described, e.g., in U.S. publication No.: US 2007/0036773. CRISPR to Inhibit, e.g., TCR or HLA “CRISPR” or “CRISPR to TCR and/or HLA” or “CRISPR to inhibit TCR and/or HLA” as used herein refers to a set of clustered regularly interspaced short palindromic repeats, or a system comprising such a set of repeats. “Cas”, as used herein, refers to a CRISPR-associated protein. A “CRISPR/Cas” system refers to a system derived from CRISPR and Cas which can be used to silence or mutate a TCR and/or HLA gene. Naturally-occurring CRISPR/Cas systems are found in approximately 40% of sequenced eubacteria genomes and 90% of sequenced archaea. Grissa et al. (2007) BMC Bioinformatics 8: 172. This system is a type of prokaryotic immune system that confers resistance to foreign genetic elements such as plasmids and phages and provides a form of acquired immunity. Barrangou et al. (2007) Science 315: 1709-1712; Marragini et al. (2008) Science 322: 1843-1845. The CRISPR/Cas system has been modified for use in gene editing (silencing, enhancing or changing specific genes) in eukaryotes such as mice or primates. Wiedenheft et al. (2012) Nature 482: 331-8. This is accomplished by introducing into the eukaryotic cell a plasmid containing a specifically designed CRISPR and one or more appropriate Cas. The CRISPR sequence, sometimes called a CRISPR locus, comprises alternating repeats and spacers. In a naturally-occurring CRISPR, the spacers usually comprise sequences foreign to the bacterium such as a plasmid or phage sequence; in the TCR and/or HLA CRISPR/Cas system, the spacers are derived from the TCR or HLA gene sequence. RNA from the CRISPR locus is constitutively expressed and processed by Cas proteins into small RNAs. These comprise a spacer flanked by a repeat sequence. The RNAs guide other Cas proteins to silence exogenous genetic elements at the RNA or DNA level. Horvath et al. (2010) Science 327: 167-170; Makarova et al. (2006) Biology Direct 1: 7. The spacers thus serve as templates for RNA molecules, analogously to siRNAs. Pennisi (2013) Science 341: 833-836. As these naturally occur in many different types of bacteria, the exact arrangements of the CRISPR and structure, function and number of Cas genes and their product differ somewhat from species to species. Haft et al. (2005) PLoS Comput. Biol. 1: e60; Kunin et al. (2007) Genome Biol. 8: R61; Mojica et al. (2005) J. Mol. Evol. 60: 174-182; Bolotin et al. (2005) Microbiol. 151: 2551-2561; Pourcel et al. (2005) Microbiol. 151: 653-663; and Stern et al. (2010) Trends. Genet. 28: 335-340. For example, the Cse (Cas subtype, E. coli) proteins (e.g., CasA) form a functional complex, Cascade, that processes CRISPR RNA transcripts into spacer-repeat units that Cascade retains. Brouns et al. (2008) Science 321: 960-964. In other prokaryotes, Cas6 processes the CRISPR transcript. The CRISPR-based phage inactivation in E. coli requires Cascade and Cas3, but not Cas1 or Cas2. The Cmr (Cas RAMP module) proteins in Pyrococcus furiosus and other prokaryotes form a functional complex with small CRISPR RNAs that recognizes and cleaves complementarity target RNAs. A simpler CRISPR system relies on the protein Cas9, which is a nuclease with two active cutting sites, one for each strand of the double helix. Combining Cas9 and modified CRISPR locus RNA can be used in a system for gene editing. Pennisi (2013) Science 341: 833-836. The CRISPR/Cas system can thus be used to edit a TCR and/or HLA gene (adding or deleting one or more base pairs), or introducing a premature stop which thus decreases expression of a target gene or chromosomal sequence such as a TCR and/or HLA. The CRISPR/Cas system can alternatively be used like RNA interference, turning off TCR and/or HLA gene in a reversible fashion. In a mammalian cell, for example, the RNA can guide the Cas protein, e.g., a Cas protein lacking nuclease activity (e.g., dCas9), to a TCR and/or HLA promoter, sterically blocking RNA polymerases. Artificial CRISPR/Cas systems can be generated which inhibit, for example, TCR and/or HLA, using technology known in the art, e.g., that described in U.S. Publication No. 20140068797. CRISPR systems which may be useful in the inventions described herein include those described in, for example, PCT application publication W02017/093969, the contents of which are incorporated herein by reference in their entirety. TALEN to Inhibit, e.g., TCR and/or HLA “TALEN” or “TALEN to HLA and/or TCR” or “TALEN to inhibit HLA and/or TCR” refers to a transcription activator-like effector nuclease, an artificial nuclease which can be used to edit the HLA and/or TCR gene. TALENs are produced artificially by fusing a TAL effector DNA binding domain to a DNA cleavage domain. Transcription activator-like effects (TALEs) can be engiveered to bind any desired DNA sequence, including a portion of the HLA or TCR gene. By combining an engineered TALE with a DNA cleavage domain, a restriction enzyme can be produced which is specific to any desired DNA sequence, including a HLA or TCR sequence. These can then be introduced into a cell, wherein they can be used for genome editing. Boch (2011) Nature Biotech. 29: 135-6; and Boch et al. (2009) Science 326: 1509-12; Moscou et al. (2009) Science 326: 3501. TALEs are proteins secreted by Xanthomonas bacteria. The DNA binding domain contains a repeated, highly conserved 33-34 amino acid sequence, with the exception of the 12th and 13th amino acids. These two positions are highly variable, showing a strong correlation with specific nucleotide recognition. They can thus be engineered to bind to a desired DNA sequence. To produce a TALEN, a TALE protein is fused to a nuclease (N), which is a wild-type or mutated Fokl endonuclease. Several mutations to Fold have been made for its use in TALENs; these, for example, improve cleavage specificity or activity. Cermak et al. (2011) Nucl. Acids Res. 39: e82; Miller et al. (2011) Nature Biotech. 29: 143-8; Hockemeyer et al. (2011) Nature Biotech. 29: 731-734; Wood et al. (2011) Science 333: 307; Doyon et al. (2010) Nature Methods 8: 74-79; Szczepek et al. (2007) Nature Biotech. 25: 786-793; and Guo et al. (2010) J. Mol. Biol. 200: 96. The FokI domain functions as a dimer, requiring two constructs with unique DNA binding domains for sites in the target genome with proper orientation and spacing. Both the number of amino acid residues between the TALE DNA binding domain and the FokI cleavage domain and the number of bases between the two individual TALEN binding sites appear to be important parameters for achieving high levels of activity. Miller et al. (2011) Nature Biotech. 29: 143-8. A HLA or TCR TALEN can be used inside a cell to produce a double-stranded break (DSB). A mutation can be introduced at the break site if the repair mechanisms improperly repair the break via non-homologous end joining. For example, improper repair may introduce a frame shift mutation. Alternatively, foreign DNA can be introduced into the cell along with the TALEN; depending on the sequences of the foreign DNA and chromosomal sequence, this process can be used to correct a defect in the HLA or TCR gene or introduce such a defect into a wt HLA or TCR gene, thus decreasing expression of HLA or TCR. TALENs specific to sequences in HLA or TCR can be constructed using any method known in the art, including various schemes using modular components. Zhang et al. (2011) Nature Biotech. 29: 149-53; Geibler et al. (2011) PLoS ONE 6: e19509. Zinc Finger Nuclease to Inhibit, e.g., HLA and/or TCR “ZFN” or “Zinc Finger Nuclease” or “ZFN to HLA and/or TCR” or “ZFN to inhibit HLA and/or TCR” refer to a zinc finger nuclease, an artificial nuclease which can be used to edit the HLA and/or TCR gene. Like a TALEN, a ZFN comprises a Fokl nuclease domain (or derivative thereof) fused to a DNA-binding domain. In the case of a ZFN, the DNA-binding domain comprises one or more zinc fingers. Carroll et al. (2011) Genetics Society of America 188: 773-782; and Kim et al. (1996) Proc. Natl. Acad. Sci. USA 93: 1156-1160. A zinc finger is a small protein structural motif stabilized by one or more zinc ions. A zinc finger can comprise, for example, Cys2His2, and can recognize an approximately 3-bp sequence. Various zinc fingers of known specificity can be combined to produce multi-finger polypeptides which recognize about 6, 9, 12, 15 or 18-bp sequences. Various selection and modular assembly techniques are available to generate zinc fingers (and combinations thereof) recognizing specific sequences, including phage display, yeast one-hybrid systems, bacterial one-hybrid and two-hybrid systems, and mammalian cells. Like a TALEN, a ZFN must dimerize to cleave DNA. Thus, a pair of ZFNs are required to target non-palindromic DNA sites. The two individual ZFNs must bind opposite strands of the DNA with their nucleases properly spaced apart. Bitinaite et al. (1998) Proc. Natl. Acad. Sci. USA 95: 10570-5. Also like a TALEN, a ZFN can create a double-stranded break in the DNA, which can create a frame-shift mutation if improperly repaired, leading to a decrease in the expression and amount of HLA and/or TCR in a cell. ZFNs can also be used with homologous recombination to mutate in the HLA or TCR gene. ZFNs specific to sequences in HLA AND/OR TCR can be constructed using any method known in the art. Cathomen et al. (2008) Mol. Ther. 16: 1200-7; and Guo et al. (2010) J. Mol. Biol. 400: 96. Activation and Expansion of Immune Effector Cells (e.g., T Cells) Immune effector cells such as T cells may be activated and expanded generally using methods as described, for example, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No. 20060121005. Generally, invention population of immune effector cells may be expanded by contact with a surface having attached thereto an agent that stimulates a CD3/TCR complex associated signal and a ligand that stimulates a costimulatory molecule on the surface of the T cells. In particular, T cell populations may be stimulated as described herein, such as by contact with an anti-CD3 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore. For co-stimulation of an accessory molecule on the surface of the T cells, a ligand that binds the accessory molecule is used. For example, a population of T cells can be contacted with an anti-CD3 antibody and an anti-CD28 antibody, under conditions appropriate for stimulating proliferation of the T cells. To stimulate proliferation of either CD4+ T cells or CD8+ T cells, an anti-CD3 antibody and an anti-CD28 antibody. Examples of an anti-CD28 antibody include 9.3, B-T3, XR-CD28 (Diaclone, Besancon, France) can be used as can other methods commonly known in the art (Berg et al., Transplant Proc. 30(8):3975-3977, 1998; Haanen et al., J. Exp. Med. 190(9):13191328, 1999; Garland et al., J. Immunol Meth. 227(1-2):53-63, 1999). In certain aspects, the primary stimulatory signal and the costimulatory signal for the T cell may be provided by different protocols. For example, the agents providing each signal may be in solution or coupled to a surface. When coupled to a surface, the agents may be coupled to the same surface (i.e., in “cis” formation) or to separate surfaces (i.e., in “trans” formation). Alternatively, one agent may be coupled to a surface and the other agent in solution. In one aspect, the agent providing the costimulatory signal is bound to a cell surface and the agent providing the primary activation signal is in solution or coupled to a surface. In certain aspects, both agents can be in solution. In one aspect, the agents may be in soluble form, and then cross-linked to a surface, such as a cell expressing Fc receptors or an antibody or other binding agent which will bind to the agents. In this regard, see for example, U.S. Patent Application Publication Nos. 20040101519 and 20060034810 for artificial antigen presenting cells (aAPCs) that are contemplated for use in activating and expanding T cells in the present invention. In one aspect, the two agents are immobilized on beads, either on the same bead, i.e., “cis,” or to separate beads, i.e., “trans.” By way of example, the agent providing the primary activation signal is an anti-CD3 antibody or an antigen-binding fragment thereof and the agent providing the costimulatory signal is an anti-CD28 antibody or antigen-binding fragment thereof; and both agents are co-immobilized to the same bead in equivalent molecular amounts. In one aspect, a 1:1 ratio of each antibody bound to the beads for CD4+ T cell expansion and T cell growth is used. In certain aspects of the present invention, a ratio of anti CD3:CD28 antibodies bound to the beads is used such that an increase in T cell expansion is observed as compared to the expansion observed using a ratio of 1:1. In one particular aspect an increase of from about 1 to about 3 fold is observed as compared to the expansion observed using a ratio of 1:1. In one aspect, the ratio of CD3:CD28 antibody bound to the beads ranges from 100:1 to 1:100 and all integer values there between. In one aspect of the present invention, more anti-CD28 antibody is bound to the particles than anti-CD3 antibody, i.e., the ratio of CD3:CD28 is less than one. In certain aspects of the invention, the ratio of anti CD28 antibody to anti CD3 antibody bound to the beads is greater than 2:1. In one particular aspect, a 1:100 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:75 CD3:CD28 ratio of antibody bound to beads is used. In a further aspect, a 1:50 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:30 CD3:CD28 ratio of antibody bound to beads is used. In one preferred aspect, a 1:10 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:3 CD3:CD28 ratio of antibody bound to the beads is used. In yet one aspect, a 3:1 CD3:CD28 ratio of antibody bound to the beads is used. Ratios of particles to cells from 1:500 to 500:1 and any integer values in between may be used to stimulate T cells or other target cells. As those of ordinary skill in the art can readily appreciate, the ratio of particles to cells may depend on particle size relative to the target cell. For example, small sized beads could only bind a few cells, while larger beads could bind many. In certain aspects the ratio of cells to particles ranges from 1:100 to 100:1 and any integer values in-between and in further aspects the ratio comprises 1:9 to 9:1 and any integer values in between, can also be used to stimulate T cells. The ratio of anti-CD3- and anti-CD28-coupled particles to T cells that result in T cell stimulation can vary as noted above, however certain preferred values include 1:100, 1:50, 1:40, 1:30, 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, and 15:1 with one preferred ratio being at least 1:1 particles per T cell. In one aspect, a ratio of particles to cells of 1:1 or less is used. In one particular aspect, a preferred particle: cell ratio is 1:5. In further aspects, the ratio of particles to cells can be varied depending on the day of stimulation. For example, in one aspect, the ratio of particles to cells is from 1:1 to 10:1 on the first day and additional particles are added to the cells every day or every other day thereafter for up to 10 days, at final ratios of from 1:1 to 1:10 (based on cell counts on the day of addition). In one particular aspect, the ratio of particles to cells is 1:1 on the first day of stimulation and adjusted to 1:5 on the third and fifth days of stimulation. In one aspect, particles are added on a daily or every other day basis to a final ratio of 1:1 on the first day, and 1:5 on the third and fifth days of stimulation. In one aspect, the ratio of particles to cells is 2:1 on the first day of stimulation and adjusted to 1:10 on the third and fifth days of stimulation. In one aspect, particles are added on a daily or every other day basis to a final ratio of 1:1 on the first day, and 1:10 on the third and fifth days of stimulation. One of skill in the art will appreciate that a variety of other ratios may be suitable for use in the present invention. In particular, ratios will vary depending on particle size and on cell size and type. In one aspect, the most typical ratios for use are in the neighborhood of 1:1, 2:1 and 3:1 on the first day. In further aspects of the present invention, the cells, such as T cells, are combined with agent-coated beads, the beads and the cells are subsequently separated, and then the cells are cultured. In an alternative aspect, prior to culture, the agent-coated beads and cells are not separated but are cultured together. In a further aspect, the beads and cells are first concentrated by application of a force, such as a magnetic force, resulting in increased ligation of cell surface markers, thereby inducing cell stimulation. By way of example, cell surface proteins may be ligated by allowing paramagnetic beads to which anti-CD3 and anti-CD28 are attached (3×28 beads) to contact the T cells. In one aspect the cells (for example, 104to 109T cells) and beads (for example, DYNABEADS® M-450 CD3/CD28 T paramagnetic beads at a ratio of 1:1) are combined in a buffer, for example PBS (without divalent cations such as, calcium and magnesium). Again, those of ordinary skill in the art can readily appreciate any cell concentration may be used. For example, the target cell may be very rare in the sample and comprise only 0.01% of the sample or the entire sample (i.e., 100%) may comprise the target cell of interest. Accordingly, any cell number is within the context of the present invention. In certain aspects, it may be desirable to significantly decrease the volume in which particles and cells are mixed together (i.e., increase the concentration of cells), to ensure maximum contact of cells and particles. For example, in one aspect, a concentration of about 10 billion cells/ml, 9 billion/ml, 8 billion/ml, 7 billion/ml, 6 billion/ml, or 5 billion/ml is used. In one aspect, greater than 100 million cells/ml is used. In a further aspect, a concentration of cells of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells/ml is used. In yet one aspect, a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/ml is used. In further aspects, concentrations of 125 or 150 million cells/ml can be used. Using high concentrations can result in increased cell yield, cell activation, and cell expansion. Further, use of high cell concentrations allows more efficient capture of cells that may weakly express target antigens of interest, such as CD28-negative T cells. Such populations of cells may have therapeutic value and would be desirable to obtain in certain aspects. For example, using high concentration of cells allows more efficient selection of CD8+ T cells that normally have weaker CD28 expression. In one embodiment, cells transduced with a nucleic acid encoding a CAR, e.g., a CAR described herein, are expanded, e.g., by a method described herein. In one embodiment, the cells are expanded in culture for a period of several hours (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 18, 21 hours) to about 14 days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days). In one embodiment, the cells are expanded for a period of 4 to 9 days. In one embodiment, the cells are expanded for a period of 8 days or less, e.g., 7, 6 or 5 days. In one embodiment, the cells, e.g., a CD19 CAR, CD20 CAR, CD22 CAR, or ROR1 CAR cell described herein, are expanded in culture for 5 days, and the resulting cells are more potent than the same cells expanded in culture for 9 days under the same culture conditions. Potency can be defined, e.g., by various T cell functions, e.g. proliferation, target cell killing, cytokine production, activation, migration, or combinations thereof. In one embodiment, the cells, e.g., a CD19 CAR cell described herein, expanded for 5 days show at least a one, two, three or four fold increase in cells doublings upon antigen stimulation as compared to the same cells expanded in culture for 9 days under the same culture conditions. In one embodiment, the cells, e.g., the cells expressing a CD19 CAR, CD20 CAR, CD22 CAR, or ROR1 CAR described herein, are expanded in culture for 5 days, and the resulting cells exhibit higher proinflammatory cytokine production, e.g., IFN-γ and/or GM-CSF levels, as compared to the same cells expanded in culture for 9 days under the same culture conditions. In one embodiment, the cells, e.g., a CD19 CAR, CD20 CAR, CD22 CAR, or ROR1 CAR cell described herein, expanded for 5 days show at least a one, two, three, four, five, ten fold or more increase in pg/ml of proinflammatory cytokine production, e.g., IFN-γ and/or GM-CSF levels, as compared to the same cells expanded in culture for 9 days under the same culture conditions. In one aspect of the present invention, the mixture may be cultured for several hours (about 3 hours) to about 14 days or any hourly integer value in between. In one aspect, the mixture may be cultured for 21 days. In one aspect of the invention the beads and the T cells are cultured together for about eight days. In one aspect, the beads and T cells are cultured together for 2-3 days. Several cycles of stimulation may also be desired such that culture time of T cells can be 60 days or more. Conditions appropriate for T cell culture include an appropriate media (e.g., Minimal Essential Media or RPMI Media 1640 or, X-vivo 15, (Lonza)) that may contain factors necessary for proliferation and viability, including serum (e.g., fetal bovine or human serum), interleukin-2 (IL-2), insulin, IFN-γ, IL-4, IL-7, GM-CSF, IL-10, IL-12, IL-15, TGFβ, and TNF-α or any other additives for the growth of cells known to the skilled artisan. Other additives for the growth of cells include, but are not limited to, surfactant, plasmanate, and reducing agents such as N-acetyl-cysteine and 2-mercaptoethanol. Media can include RPMI 1640, AIM-V, DMEM, MEM, α-MEM, F-12, X-Vivo 15, and X-Vivo 20, Optimizer, with added amino acids, sodium pyruvate, and vitamins, either serum-free or supplemented with an appropriate amount of serum (or plasma) or a defined set of hormones, and/or an amount of cytokine(s) sufficient for the growth and expansion of T cells. Antibiotics, e.g., penicillin and streptomycin, are included only in experimental cultures, not in cultures of cells that are to be infused into a subject. The target cells are maintained under conditions necessary to support growth, for example, an appropriate temperature (e.g., 37° C.) and atmosphere (e.g., air plus 5% CO2). In one embodiment, the cells are expanded in an appropriate media (e.g., media described herein) that includes one or more interleukin that result in at least a 200-fold (e.g., 200-fold, 250-fold, 300-fold, 350-fold) increase in cells over a 14 day expansion period, e.g., as measured by a method described herein such as flow cytometry. In one embodiment, the cells are expanded in the presence IL-15 and/or IL-7 (e.g., IL-15 and IL-7). T cells that have been exposed to varied stimulation times may exhibit different characteristics. For example, typical blood or apheresed peripheral blood mononuclear cell products have a helper T cell population (TH, CD4+ ) that is greater than the cytotoxic or suppressor T cell population (TC, CD8+ ). Ex vivo expansion of T cells by stimulating CD3 and CD28 receptors produces a population of T cells that prior to about days 8-9 consists predominately of TH cells, while after about days 8-9, the population of T cells comprises an increasingly greater population of TC cells. Accordingly, depending on the purpose of treatment, infusing a subject with a T cell population comprising predominately of TH cells may be advantageous. Similarly, if an antigen-specific subset of TC cells has been isolated it may be beneficial to expand this subset to a greater degree. Further, in addition to CD4 and CD8 markers, other phenotypic markers vary significantly, but in large part, reproducibly during the course of the cell expansion process. Thus, such reproducibility enables the ability to tailor an activated T cell product for specific purposes. Once a CAR, e.g., CD20 CAR, is constructed, various assays can be used to evaluate the activity of the molecule, such as but not limited to, the ability to expand T cells following antigen stimulation, sustain T cell expansion in the absence of re-stimulation, and anti-cancer activities in appropriate in vitro and animal models. Assays to evaluate the effects of a CAR, e.g., CD20 CAR, are described in further detail below. Western blot analysis of CAR expression in primary T cells can be used to detect the presence of monomers and dimers. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Very briefly, T cells (1:1 mixture of CD4+ and CD8+T cells) expressing the CARs are expanded in vitro for more than 10 days followed by lysis and SDS-PAGE under reducing conditions. CARs containing the full length TCR-ζ cytoplasmic domain and the endogenous TCR-ζ chain are detected by western blotting using an antibody to the TCR-ζ chain. The same T cell subsets are used for SDS-PAGE analysis under non-reducing conditions to permit evaluation of covalent dimer formation. In vitro expansion of CAR+T cells following antigen stimulation can be measured by flow cytometry. For example, a mixture of CD4+and CD8+T cells are stimulated with αCD3/αCD28 aAPCs followed by transduction with lentiviral vectors expressing GFP under the control of the promoters to be analyzed. Exemplary promoters include the CMV IE gene, EF-1α, ubiquitin C, or phosphoglycerokinase (PGK) promoters. GFP fluorescence is evaluated on day 6 of culture in the CD4+and/or CD8+T cell subsets by flow cytometry. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Alternatively, a mixture of CD4+and CD8+T cells are stimulated with αCD3/αCD28 coated magnetic beads on day 0, and transduced with CAR on day 1 using a bicistronic lentiviral vector expressing CAR along with eGFP using a 2A ribosomal skipping sequence. Cultures are re-stimulated with either CD19+K562 cells (K562-CD19), wild-type K562 cells (K562 wild type) or K562 cells expressing hCD32 and 4-1BBL in the presence of antiCD3 and anti-CD28 antibody (K562-BBL-3/28) following washing. Exogenous IL-2 is added to the cultures every other day at 100 IU/ml. GFP+T cells are enumerated by flow cytometry using bead-based counting. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Similar assays can be performed using anti-CD20 T cells (see, e.g. Gill et al Blood 2014; 123:2343) or with anti-CD20 CAR T cells. Sustained CAR+T cell expansion in the absence of re-stimulation can also be measured. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Briefly, mean T cell volume (fl) is measured on day 8 of culture using a Coulter Multisizer III particle counter, a Nexcelom Cellometer Vision, or Millipore Scepter following stimulation with αCD3/αCD28 coated magnetic beads on day 0, and transduction with the indicated CAR on day 1. Animal models can also be used to measure a CART activity. For example, xenograft model using human CD19-specific CAR+T cells to treat a primary human pre-B ALL in immunodeficient mice can be used. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Very briefly, after establishment of ALL, mice are randomized as to treatment groups. Different numbers of αCD19-ζ and αCD19-BB-ζ engineered T cells are coinjected at a 1:1 ratio into NOD-SCID-γ−/−mice bearing B-ALL. The number of copies of αCD19-ζ and αCD19-BB-ζ vector in spleen DNA from mice is evaluated at various times following T cell injection. Animals are assessed for leukemia at weekly intervals. Peripheral blood CD19+B-ALL blast cell counts are measured in mice that are injected with αCD19-ζ CAR+T cells or mock-transduced T cells. Survival curves for the groups are compared using the log-rank test. In addition, absolute peripheral blood CD4+and CD8+T cell counts 4 weeks following T cell injection in NOD-SCID-γ−/−mice can also be analyzed. Mice are injected with leukemic cells and 3 weeks later are injected with T cells engineered to express CAR by a bicistronic lentiviral vector that encodes the CAR linked to eGFP. T cells are normalized to 45-50% input GFP+T cells by mixing with mock-transduced cells prior to injection, and confirmed by flow cytometry. Animals are assessed for leukemia at 1-week intervals. Survival curves for the CAR+T cell groups are compared using the log-rank text. Similar experiments can be done with CD20 CARTs. Dose dependent CAR treatment response can be evaluated. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). For example, peripheral blood is obtained 35-70 days after establishing leukemia in mice injected on day 21 with CAR T cells, an equivalent number of mock-transduced T cells, or no T cells. Mice from each group are randomly bled for determination of peripheral blood CD19+ALL blast counts and then killed on days 35 and 49. The remaining animals are evaluated on days 57 and 70. Similar experiments can be done with CD20 CARTs. Assessment of cell proliferation and cytokine production has been previously described, e.g., at Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Briefly, assessment of CAR-mediated proliferation is performed in microtiter plates by mixing washed T cells with K562 cells expressing CD19 (K19) or CD32 and CD137 (KT32-BBL) for a final T-cell:K562 ratio of 2:1. K562 cells are irradiated with gamma-radiation prior to use. Anti-CD3 (clone OKT3) and anti-CD28 (clone 9.3) monoclonal antibodies are added to cultures with KT32-BBL cells to serve as a positive control for stimulating T-cell proliferation since these signals support long-term CD8+T cell expansion ex vivo. T cells are enumerated in cultures using CountBright™ fluorescent beads (Invitrogen, Carlsbad, Calif) and flow cytometry as described by the manufacturer. CAR+T cells are identified by GFP expression using T cells that are engineered with eGFP-2A linked CAR-expressing lentiviral vectors. For CAR+ T cells not expressing GFP, the CAR+ T cells are detected with biotinylated recombinant CD19 protein and a secondary avidin-PE conjugate. CD4+ and CD8+expression on T cells are also simultaneously detected with specific monoclonal antibodies (BD Biosciences). Cytokine measurements are performed on supernatants collected 24 hours following re-stimulation using the human TH1/TH2 cytokine cytometric bead array kit (BD Biosciences, San Diego, Calif) according the manufacturer's instructions or using a Luminex 30-plex kit (Invitrogen). Fluorescence is assessed using a BD Fortessa flow cytometer, and data is analyzed according to the manufacturer's instructions. Similar experiments can be done with CD20 CARTs. Cytotoxicity can be assessed by a standard 51Cr-release assay. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Briefly, target cells (K562 lines and primary pro-B-ALL cells) are loaded with 51Cr (as NaCrO4, New England Nuclear, Boston, Mass.) at 37° C. for 2 hours with frequent agitation, washed twice in complete RPMI and plated into microtiter plates. Effector T cells are mixed with target cells in the wells in complete RPMI at varying ratios of effector cell:target cell (E:T). Additional wells containing media only (spontaneous release, SR) or a 1% solution of triton-X 100 detergent (total release, TR) are also prepared. After 4 hours of incubation at 37° C., supernatant from each well is harvested. Released 51Cr is then measured using a gamma particle counter (Packard Instrument Co., Waltham, Mass.). Each condition is performed in at least triplicate, and the percentage of lysis is calculated using the formula: % Lysis=(ER−SR)/(TR−SR), where ER represents the average 51Cr released for each experimental condition. Imaging technologies can be used to evaluate specific trafficking and proliferation of CARs in tumor-bearing animal models. Such assays have been described, for example, in Barrett et al., Human Gene Therapy 22:1575-1586 (2011). Briefly, NOD/SCID/γc−/−(NSG) mice are injected IV with Nalm-6 cells followed 7 days later with T cells 4 hour after electroporation with the CAR constructs. The T cells are stably transfected with a lentiviral construct to express firefly luciferase, and mice are imaged for bioluminescence. Alternatively, therapeutic efficacy and specificity of a single injection of CAR+T cells in Nalm-6 xenograft model can be measured as the following: NSG mice are injected with Nalm-6 transduced to stably express firefly luciferase, followed by a single tail-vein injection of T cells electroporated with a CAR 7 days later. Animals are imaged at various time points post injection. For example, photon-density heat maps of firefly luciferasepositive leukemia in representative mice at day 5 (2 days before treatment) and day 8 (24 hr post CAR+PBLs) can be generated. Other assays, including those described in the Example section herein as well as those that are known in the art can also be used to evaluate the CD20 CAR or CD22 CAR constructs disclosed herein. Therapeutic Application CD20-, CD19-, and/or CD22-Associated Diseases and/or Disorders The present invention provides, among other things, compositions and methods for treating a cancer or a disease associated with expression of CD20, CD19 and/or CD22 or condition associated with cells which express CD20, CD19 and/or CD22. In some embodiments, the cancer or disease includes, e.g., a proliferative disease such as a cancer or malignancy or a precancerous condition such as a myelodysplasia, a myelodysplastic syndrome or a preleukemia; or a noncancer related indication associated with cells which express CD20, CD19 and/or CD22. In one aspect, a cancer or disease associated with expression of CD20 is a hematological cancer. In one aspect, a hematological cancer includes but is not limited to a B-cell malignancy. In one aspect, the hematological cancer is a leukemia or a lymphoma. In one aspect, a cancer, e.g., a cancer associated with expression of CD20, CD19 and/or CD22, includes cancers and malignancies including, but not limited to, e.g., one or more acute leukemias including but not limited to B-cell acutelymphoidlymphoblasticleukemia (BALL), T-cell acutelymphoidlymphoblasticleukemia (TALL), small lymphocyticleukemialymphoma(SLL), acutelymphoidlymphoblasticleukemia (ALL); one or more chronic leukemias including but not limited to chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to mantle cell lymphoma (MCL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” (which is a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells). In some embodiments, to the disease associated with CD20, CD19and/or CD22 expression includes, but not limited to, atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD20, CD19 and/or CD22, and any combination thereof Non-cancer related indications associated with expression of CD20 may also be included. Non-cancer related indications associated with expression of CD20 include, but are not limited to, e.g., autoimmune disease, (e.g., lupus, rheumatoid arthritis, multiple sclerosis autoimmune hemolytic anemia, pure red cell aplasia, idopathic thromocytopenic prupura, Evans snydrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome, anti-NMDA receptor encephalitis and Devic's disease, Graves' ophthalmopathy, and autoimmune pancreatitis), inflammatory disorders (allergy and asthma) and transplantation. In one aspect, the invention provides methods for treating a disease associated with CD20, CD19 and/or CD22 expression. In one aspect, the invention provides methods for treating a disease wherein part of the tumor is negative for CD20, CD19 and/or CD22 and part of the tumor is positive for CD20, CD19 and/or CD22. For example, the CAR of the invention is useful for treating subjects that have undergone treatment for a disease associated with expression of CD20, CD19 and/or CD22, wherein the subject that has undergone treatment related to expression of CD20, CD19 and/or CD22 exhibits a disease associated with expression of CD20, CD19 and/or CD22. In one aspect, the invention pertains to a vector comprising CAR as described herein operably linked to promoter for expression in mammalian T cells or NK cells. In one aspect, the invention provides a recombinant T cell expressing the CAR for use in treating CD20-, CD19- and/or CD22-expressing tumors, wherein the recombinant T cell expressing the CD20 CAR, CD19 CAR or CD22 CAR is termed a CD20 CART, CD19 CART or CD22 CART, respectively. In one aspect, the CD19 CART or CD22 CART of the invention is capable of contacting a tumor cell with at least one CD20 CAR, CD19 CAR or CD22 CAR of the invention expressed on its surface such that the CART targets the tumor cell and growth of the tumor is inhibited. In one aspect, the invention pertains to a method of inhibiting growth of a CD20-CD19- and/or CD22-expressing tumor cell, comprising contacting the tumor cell with a CD20 CD19- and/or CD22-CAR T cell or a CD20 CD19and/or CD22-CAR-expressing NK cell of the present invention such that the CAR-expressing cell is activated in response to the antigen and targets the cancer cell, wherein the growth of the tumor is inhibited. In one aspect, the invention pertains to a method of treating cancer in a subject. The method comprises administering to the subject a CD20, CD19- and/or CD22-CAR-expressing cell of the present invention such that the cancer is treated in the subject. An example of a cancer that is treatable by the CD20, CD19- and/or CD22-CAR-expressing cell of the invention is a cancer associated with expression of CD20. An example of a cancer that is treatable by the CD20, CD19- and/or CD22-CAR-expressing cell of the invention includes but is not limited to a hematological cancer described herein. The invention includes a type of cellular therapy where cells are genetically modified to express a chimeric antigen receptor (CAR) and the CAR-expressing cell is infused to a recipient in need thereof. The infused cell is able to kill tumor cells in the recipient. Unlike antibody therapies, CAR-modified cells are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control. In various aspects, the T cells administered to the patient, or their progeny, persist in the patient for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen month, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty-one months, twenty-two months, twenty-three months, two years, three years, four years, or five years after administration of the cell to the patient. The invention also includes a type of cellular therapy where immune effector cells, e.g., NK cells or T cells are modified, e.g., by in vitro transcribed RNA, to transiently express a chimeric antigen receptor (CAR) and the CAR-expressing (e.g., CART or CAR-expressing NK) cell is infused to a recipient in need thereof. The infused cell is able to kill cancer cells in the recipient. Thus, in various aspects, the CAR-expressing cells, e.g., T or NK cells, administered to the patient, is present for less than one month, e.g., three weeks, two weeks, one week, after administration of the CAR-expressing cell, e.g., T or NK cell, to the patient. Without wishing to be bound by any particular theory, the anti-tumor immunity response elicited by the CAR-modified T cells or NK cells may be an active or a passive immune response, or alternatively may be due to a direct vs indirect immune response. In one aspect, the CAR transduced T cells or NK cells exhibit specific proinflammatory cytokine secretion and potent cytolytic activity in response to human cancer cells expressing CD20, resist soluble CD20 inhibition, mediate bystander killing and mediate regression of an established human tumor. For example, antigen-less tumor cells within a heterogeneous field of CD20-expressing tumor may be susceptible to indirect destruction by CD20-redirected T cells or NK cells that has previously reacted against adjacent antigen-positive cancer cells. In one aspect, the CAR-modified cells of the invention, e.g., fully human CAR-expressing cells, may be a type of vaccine for ex vivo immunization and/or in vivo therapy in a mammal. In one aspect, the mammal is a human. With respect to ex vivo immunization, at least one of the following occurs in vitro prior to administering the cell into a mammal: i) expansion of the cells, ii) introducing a nucleic acid encoding a CAR to the cells or iii) cryopreservation of the cells. Ex vivo procedures are well known in the art and are discussed more fully below. Briefly, cells are isolated from a mammal (e.g., a human) and genetically modified (i.e., transduced or transfected in vitro) with a vector expressing a CAR disclosed herein. The CAR-modified cell can be administered to a mammalian recipient to provide a therapeutic benefit. The mammalian recipient may be a human and the CAR-modified cell can be autologous with respect to the recipient. Alternatively, the cells can be allogeneic, syngeneic or xenogeneic with respect to the recipient. The procedure for ex vivo expansion of hematopoietic stem and progenitor cells is described in U.S. Pat. No. 5,199,942, incorporated herein by reference, can be applied to the cells of the present invention. Other suitable methods are known in the art, therefore the present invention is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of T cells comprises: (1) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo. In addition to the cellular growth factors described in U.S. Pat. No. 5,199,942, other factors such as flt3-L, IL-1, IL-3 and c-kit ligand, can be used for culturing and expansion of the cells. In addition to using a cell-based vaccine in terms of ex vivo immunization, the present invention also provides compositions and methods for in vivo immunization to elicit an immune response directed against an antigen in a patient. Generally, the cells activated and expanded as described herein may be utilized in the treatment and prevention of diseases that arise in individuals who are immunocompromised. In particular, the CAR-modified cells of the invention are used in the treatment of diseases, disorders and conditions associated with expression of CD20. In certain aspects, the cells of the invention are used in the treatment of patients at risk for developing diseases, disorders and conditions associated with expression of CD20. Thus, the present invention provides methods for the treatment or prevention of diseases, disorders and conditions associated with expression of CD20 comprising administering to a subject in need thereof, a therapeutically effective amount of the CAR-modified cells of the invention. In one aspect the CAR-expressing cells of the inventions may be used to treat a proliferative disease such as a cancer or malignancy or is a precancerous condition such as a myelodysplasia, a myelodysplastic syndrome or a preleukemia. In one aspect, a cancer associated with expression of CD20 is a hematological cancer preleukemia, hyperproliferative disorder, hyperplasia or a dysplasia, which is characterized by abnormal growth of cells. In one aspect, the CAR-expressing cells of the invention are used to treat a cancer, wherein the cancer is a hematological cancer. Hematological cancer conditions are the types of cancer such as leukemia and malignant lymphoproliferative conditions that affect blood, bone marrow and the lymphatic system. Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia can be further classified as acute myelogenous leukemia (AML) and acutelymphoidlymphoblasticleukemia (ALL). Chronic leukemia includes chronic myelogenous leukemia (CML) and chroniclymphoidlymphocyticleukemia (CLL). Other related conditions include myelodysplastic syndromes (MDS, formerly known as “preleukemia”) which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells and risk of transformation to AML. Lymphoma is a group of blood cell tumors that develop from lymphocytes. Exemplary lymphomas include no-nHodgkin lymphoma and Hodgkin lymphoma. In one aspect, the compositions and CAR-expressing cells of the present invention are particularly useful for treating B cell malignancies, such as non-Hodgkin lymphomas, e.g., DLBCL, Follicular lymphoma, or CLL. Non-Hodgkin lymphoma (NHL) is a group of cancers of lymphocytes, formed from either B or T cells. NHLs occur at any age and are often characterized by lymph nodes that are larger than normal, weight loss, and fever. Different types of NHLs are categorized as aggressive (fast-growing) and indolent (slow-growing) types. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. Examples of T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are typically B-cell non-Hodgkin lymphomas. See, e.g., Maloney. NEJM. 366.21 (2012):2008-16. Diffuse large B-cell lymphoma (DLBCL) is a form of NHL that develops from B cells. DLBCL is an aggressive lymphoma that can arise in lymph nodes or outside of the lymphatic system, e.g., in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Three variants of cellular morphology are commonly observed in DLBCL: centroblastic, immunoblastic, and anaplastic. Centroblastic morphology is most common and has the appearance of medium-to-large-sized lymphocytes with minimal cytoplasm. There are several subtypes of DLBCL. For example, primary central nervous system lymphoma is a type of DLBCL that only affects the brain is called and is treated differently than DLBCL that affects areas outside of the brain. Another type of DLBCL is primary mediastinal B-cell lymphoma, which often occurs in younger patients and grows rapidly in the chest. Symptoms of DLBCL include a painless rapid swelling in the neck, armpit, or groin, which is caused by enlarged lymph nodes. For some subjects, the swelling may be painful. Other symptoms of DLBCL include night sweats, unexplained fevers, and weight loss. Although most patients with DLBCL are adults, this disease sometimes occurs in children. Treatment for DLBCL includes chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide), antibodies (e.g., Rituxan), radiation, or stem cell transplants. Follicular lymphoma a type of non-Hodgkin lymphoma and is a lymphoma of follicle center B-cells (centrocytes and centroblasts), which has at least a partially follicular pattern. Follicular lymphoma cells express the B-cell markers CD10, CD19, CD20, and CD22. Follicular lymphoma cells are commonly negative for CD5. Morphologically, a follicular lymphoma tumor is made up of follicles containing a mixture of centrocytes (also called cleaved follicle center cells or small cells) and centroblasts (also called large noncleaved follicle center cells or large cells). The follicles are surrounded by non-malignant cells, mostly T-cells. The follicles contain predominantly centrocytes with a minority of centroblasts. The World Health Organization (WHO) morphologically grades the disease as follows: grade 1 (<5 centroblasts per high-power field (hpf); grade 2 (6-15 centroblasts/hpf); grade 3 (>15 centroblasts/hpf). Grade 3 is further subdivided into the following grades: grade 3A (centrocytes still present); grade 3B (the follicles consist almost entirely of centroblasts). Treatment of follicular lymphoma includes chemotherapy, e.g., alkyating agents, nucleoside analogs, anthracycline-containing regimens, e.g., a combination therapy called CHOP-cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone, antibodies (e.g., rituximab), radioimmunotherapy, and hematopoietic stem cell transplantation. CLL is a B-cell malignancy characterized by neoplastic cell proliferation and accumulation in bone morrow, blood, lymph nodes, and the spleen. The median age at time of diagnosis of CLL is about 65 years. Current treatments include chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Sometimes symptoms are treated surgically (e.g., splenectomy removal of enlarged spleen) or by radiation therapy (e.g., de-bulking swollen lymph nodes). Chemotherapeutic agents to treat CLL include, e.g., fludarabine, 2-chlorodeoxyadenosine (cladribine), chlorambucil, vincristine, pentostatin, cyclophosphamide, alemtuzumab (Campath-1H), doxorubicin, and prednisone. Biological therapy for CLL includes antibodies, e.g., alemtuzumab, rituximab, and ofatumumab; as well as tyrosine kinase inhibitor therapies. A number of criteria can be used to classify stage of CLL, e.g., the Rai or Binet system. The Rai system describes CLL has having five stages: stage 0 where only lymphocytosis is present; stage I where lymphadenopathy is present; stage II where splenomegaly, lymphadenopathy, or both are present; stage III where anemia, organomegaly, or both are present (progression is defined by weight loss, fatigue, fever, massive organomegaly, and a rapidly increasing lymphocyte count); and stage IV where anemia, thrombocytopenia, organomegaly, or a combination thereof are present. Under the Binet staging system, there are three categories: stage A where lymphocytosis is present and less than three lymph nodes are enlarged (this stage is inclusive of all Rai stage 0 patients, one-half of RAI stage I patients, and one-third of Rai stage II patients); stage B where three or more lymph nodes are involved; and stage C wherein anemia or thrombocytopenia, or both are present. These classification systems can be combined with measurements of mutation of the immunoglobulin genes to provide a more accurate characterization of the state of the disease. The presence of mutated immunoglobulin genes correlates to improved prognosis. In another embodiment, the CAR-expressing cells of the present invention are used to treat cancers or leukemias, e.g., with leukemia stem cells. For example, the leukemia stem cells are CD34+/CD38−leukemia cells. The present invention provides, among other things, compositions and methods for treating cancer. In one aspect, the cancer is a hematologic cancer including but is not limited to one or more acute leukemias including but not limited to B-cell acutelymphoidlymphoblasticleukemia (BALL), T-cell acutelymphoidlymphoblasticleukemia (TALL), small lymphocyticleukemialymphoma(SLL), acutelymphoidlymphoblasticleukemia (ALL); one or more chronic leukemias including but not limited to chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to mantle cell lymphoma (MCL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” which is a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells, and to disease associated with CD20 expression include, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD20; and any combination thereof. The CAR-modified cells of the present invention may be administered either alone, or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2 or other cytokines or cell populations. In another aspect, the CAR-expressing cells of the invention may be used for treatment of a subject previously treated with a CD19 CAR-expressing cell. In some embodiments, the CAR-expressing cell of the invention is administered post-relapse of a cancer or other condition previously treated with CD19 CAR-expressing cell. In some embodiments, the cancer or other condition is CD19 expressing. In some embodiments, the cancer or other condition is CD20 expressing. In some embodiments, the cancer or other condition is CD19 and CD20 expressing. In some embodiments, the cancer or other condition has not previously been responsive to CD19 CAR-expressing cell. In some embodiments, the subject cancer or other condition is responsive to treatment with CD19 CAR-expressing cell. In some embodiments, the cancer or other condition was more responsive to treatment with CD19 CAR-expressing cell than it is presently. In some embodiments, the cancer or other condition was responsive to treatment with CD19 CAR-expressing cell. In some embodiments, the cancer or other condition was responsive to treatment with CD19 CAR-expressing cell and is no longer responsive to CD19 CAR-expressing cell. In some embodiments, CD19 CAR-expressing cell and CD20 CAR-expressing cell (e.g., as described herein) are administered concurrently. In some embodiments, CD19 CAR-expressing cell and CD20 CAR-expressing cell (e.g., as described herein) are administered concurrently due to a reduction or loss of responsiveness to CD19 CAR-expressing cell. In some embodiments, CD19 CAR-expressing cell therapy has been discontinued. In some embodiments, CD19 CAR therapy has been discontinued due to a reduction or loss of responsiveness to CD19 CAR-expressing cell. In some embodiments, CD19 CAR-expressing cell and CD22 CAR-expressing cell (e.g., as described herein) are administered concurrently. In some embodiments, CD19 CAR-expressing cell and CD22 CAR-expressing cell (e.g., as described herein) are administered concurrently due to a reduction or loss of responsiveness to CD19 CAR-expressing cell. In some embodiments, CD19 CAR-expressing cell therapy has been discontinued. In some embodiments, CD19 CAR therapy has been discontinued due to a reduction or loss of responsiveness to CD19 CAR-expressing cell. In some embodiments, CD22 CAR-expressing cell and CD20 CAR-expressing cell (e.g., as described herein) are administered concurrently. In some embodiments, CD22 CAR-expressing cell and CD20 CAR-expressing cell (e.g., as described herein) are administered concurrently due to a reduction or loss of responsiveness to CD22 CAR-expressing cell. In some embodiments, CD22 CAR-expressing cell therapy has been discontinued. In some embodiments, CD22 CAR therapy has been discontinued due to a reduction or loss of responsiveness to CD22 CAR-expressing cell. In some embodiments, CD22 CAR-expressing cell and CD20 CAR-expressing cell (e.g., as described herein) are administered concurrently. In some embodiments, CD22 CAR-expressing cell and CD20 CAR-expressing cell (e.g., as described herein) are administered concurrently due to a reduction or loss of responsiveness to CD20 CAR-expressing cell. In some embodiments, CD20 CAR-expressing cell therapy has been discontinued. In some embodiments, CD20 CAR therapy has been discontinued due to a reduction or loss of responsiveness to CD20 CAR-expressing cell. The present invention also provides methods for inhibiting the proliferation or reducing a CD20-expressing cell population, the methods comprising contacting a population of cells comprising a CD20-expressing cell with a CD20 CAR-expressing cell of the invention that binds to the CD20-expressing cell. In a specific aspect, the present invention provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD20, the methods comprising contacting the CD20-expressing cancer cell population with a CD20 CAR-expressing cell of the invention that binds to the CD20-expressing cell. In one aspect, the present invention provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD20, the methods comprising contacting the CD20-expressing cancer cell population with a CD20 CAR-expressing cell of the invention that binds to the CD20-expressing cell. In certain aspects, the CD20 CAR-expressing cell of the invention reduces the quantity, number, amount or percentage of cells and/or cancer cells by at least 25%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 95%, or at least 99% in a subject with or animal model for B-cell malignancy or another cancer associated with CD20-expressing cells relative to a negative control. In one aspect, the subject is a human. The present invention also provides methods for preventing, treating and/or managing a disease associated with CD20-expressing cells (e.g., a hematologic cancer or atypical cancer expressing CD20), the methods comprising administering to a subject in need a CD20 CAR-expressing cell of the invention that binds to the CD20-expressing cell. In one aspect, the subject is a human. Non-limiting examples of disorders associated with CD20-expressing cells include autoimmune diseases, (e.g., lupus, rheumatoid arthritis, multiple sclerosis autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome, anti-NMDA receptor encephalitis and Devic's disease, Graves' ophthalmopathy, and autoimmune pancreatitis), inflammatory disorders (allergy and asthma), transplantation, and cancers (such as hematological cancers or atypical cancers expressing CD20). The present invention also provides methods for preventing, treating and/or managing a disease associated with CD20-expressing cells, the methods comprising administering to a subject in need a CD20 CAR-expressing cell of the invention that binds to the CD20-expressing cell. In one aspect, the subject is a human. The present invention provides methods for preventing relapse of cancer associated with CD20-expressing cells, the methods comprising administering to a subject in need thereof a CD20 CAR-expressing cell of the invention that binds to the CD20-expressing cell. In one aspect, the methods comprise administering to the subject in need thereof an effective amount of a CD20 CAR-expressing cell described herein that binds to the CD20-expressing cell in combination with an effective amount of another therapy. In some embodiments, the CD20 expressing cell expresses CD19, CD123, FLT-3, ROR-1, CD79b, CD179b, CD79a, CD10, CD34, and/or CD22. In certain embodiments, the CD20 expressing cell expresses CD19. In some embodiments, the CD20-expressing cell does not express CD19. In some embodiments, the subject is a non-responder to CD19 CAR therapy. In some embodiments, the subject is a partial responder to CD19 CAR therapy. In some embodiments, the subject is a complete responder to CD19 CAR therapy. In some embodiments, the subject is a non-relapser to CD19 CAR therapy. In some embodiments, the subject is a relapser to CD19 CAR therapy. In some embodiments, a cancer or other condition that was previously responsive to treatment with CD19 CAR-expressing cells does not express CD19. In some embodiments, a cancer or other condition that was previously responsive to treatment with CD19 CAR-expressing cells has a 10%, 20%, 30%, 40%, 50% or more reduction in CD19 expression levels relative to when the cancer or other condition was responsive to treatment with CD19 CAR-expressing cells. In some embodiments, a cancer or other condition that was previously responsive to treatment with CD19 CAR-expressing cells expresses CD22 and/or CD123. In some embodiments, the CD20 CAR-expressing cell of the invention is administered post-relapse of a cancer or other condition previously treated with CD19 CAR-expressing cell. In some embodiments, a CD19 CAR-expressing cell and a CD20 CAR-expressing cell are administered concurrently, as described herein. Bone Marrow Ablation In one aspect, the present invention provides compositions and methods for bone marrow ablation. For example, in one aspect, the invention provides compositions and methods for eradication of at least a portion of existing bone marrow in a subject. It is described herein that, in certain instances, the CD20-expressing cells comprising a CD20 CAR of the present invention eradicates CD20 positive bone marrow myeloid progenitor cells. In one aspect, the invention provides a method of bone marrow ablation comprising administering a CD20 CAR-expressing cell of the invention to a subject in need of bone marrow ablation. For example, the present method may be used to eradicate some or all of the existing bone marrow of a subject having a disease or disorder in which bone marrow transplantation or bone marrow reconditioning is a beneficial treatment strategy. In one aspect, the bone marrow ablation method of the invention, comprising the administration of a CD20 CAR-expressing cell described elsewhere herein, is performed in a subject prior to bone marrow transplantation. Thus, in one aspect, the method of the invention provides a cellular conditioning regimen prior to bone marrow or stem cell transplantation. In one aspect, bone marrow transplantation comprises transplantation of a stem cell. The bone marrow transplantation may comprise transplantation of autologous or allogeneic cells. The present invention provides a method of treating a disease or disorder comprising administering a CD20-expressing cell of the invention to eradicate at least a portion of existing bone marrow. The method may be used as at least a portion of a treatment regimen for treating any disease or disorder where bone marrow transplantation is beneficial. That is, the present method may be used in any subject in need of a bone marrow transplant. In one aspect, bone marrow ablation comprising administration of a CD20-expressing cell is useful in the treatment of AML. In certain aspects, bone marrow ablation by way of the present method is useful in treating a hematological cancer, a solid tumor, a hematologic disease, a metabolic disorder, HIV, HTLV, a lysosomal storage disorder, and an immunodeficiency. Compositions and methods disclosed herein may be used to eradicate at least a portion of existing bone marrow to treat hematological cancers including, but not limited to cancers described herein, e.g., leukemia, lymphoma, myeloma, ALL, AML, CLL, CML, Hodgkin lymphoma, Non-Hodgkin lymphoma (e.g., DLBCL or follicular lymphoma), and multiple myeloma. Compositions and methods disclosed herein may be used to treat hematologic diseases including, but not limited to myelodysplasia, anemia, paroxysmal nocturnal hemoglobinuria, aplastic anemia, acquired pure red cell anemia, Diamon-Blackfan anemia, Fanconi anemia, cytopenia, amegakaryotic thrombocytopenia, myeloproliferative disorders, polycythemia vera, essential thrombocytosis, myelofibrosis, hemoglobinopathies, sickle cell disease, β thalassemia major, among others. In one aspect, the present invention provides a method of treating cancer comprising bone marrow conditioning, where at least a portion of bone marrow of the subject is eradicated by the CD20 CAR-expressing cell of the invention. For example, in certain instances, the bone marrow of the subject comprises a malignant precursor cell that can be targeted and eliminated by the activity of the CD20 CAR-expressing cell. In one aspect, a bone marrow conditioning therapy comprises administering a bone marrow or stem cell transplant to the subject following the eradication of native bone marrow. In one aspect, the bone marrow reconditioning therapy is combined with one or more other anti-cancer therapies, including, but not limited to anti-tumor CAR therapies, chemotherapy, radiation, and the like. In one aspect, eradication of the administered CD20 CAR-expressing cell may be required prior to infusion of bone marrow or stem cell transplant. Eradication of the CD20 CAR-expressing cell may be accomplished using any suitable strategy or treatment, including, but not limited to, use of a suicide gene, limited CAR persistence using RNA encoded CARs, or anti-T cell modalities including antibodies or chemotherapy. CD22 Associated Diseases and/or Disorders The present disclosure provides, among other things, compositions and methods for treating a disease associated with expression of CD22 or condition associated with cells which express CD22 including, e.g., a proliferative disease such as a cancer or malignancy or a precancerous condition; or a noncancer related indication associated with cells which express CD22. In one aspect, a cancer associated with expression of CD22 is a hematological cancer. In one aspect, a hematological cancer includes but is not limited to a B-cell malignancy. In one aspect, the hematological cancer is a leukemia or a lymphoma. In one aspect, a cancer associated with expression of CD22 includes cancers and malignancies including, but not limited to, e.g., one or more acute leukemias including but not limited to B-cell acutelymphoidlymphoblasticleukemia (BALL), T-cell acutelymphoidlymphoblasticleukemia (TALL), small lymphocyticleukemialymphoma(SLL), acutelymphoidlymphoblasticleukemia (ALL); one or more chronic leukemias including but not limited to chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to mantle cell lymphoma (MCL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, Marginal zone lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia. In another embodiment, the disease associated with CD22 expression includes, but not limited to, atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD22; and any combination thereof. Non-cancer related indications associated with expression of CD22 may also be included. Non-cancer related indications associated with expression of CD22 include, but are not limited to, e.g., autoimmune disease, (e.g., lupus, rheumatoid arthritis, multiple sclerosis autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome, anti-NMDA receptor encephalitis and Devic's disease, Graves' ophthalmopathy, and autoimmune pancreatitis), inflammatory disorders (allergy and asthma) and solid-organ or hematopoietic cell transplantation. In one aspect, the disclosure provides methods for treating a disease associated with CD22 expression. In one aspect, the disclosure provides methods for treating a disease wherein part of the tumor is negative for CD22 and part of the tumor is positive for CD22. For example, the CAR of the disclosure is useful for treating subjects that have undergone treatment for a disease associated with expression of CD22, wherein the subject that has undergone treatment related to expression of CD22 exhibits a disease associated with expression of CD22. In one aspect, the disclosure pertains to a vector comprising CD22 CAR operably linked to promoter for expression in mammalian cells (e.g., T cells or NK cells). In one aspect, the disclosure provides a recombinant T cell expressing the CD22 CAR for use in treating CD22-expressing tumors, wherein the recombinant T cell expressing the CD22 CAR is termed a CD22 CART. In one aspect, the CD22 CART or CD22 CAR expressing NK cell of the disclosure is capable of contacting a tumor cell with at least one CD22 CAR of the disclosure expressed on its surface such that the CART or CD22 CAR expressing NK cell targets the tumor cell and growth of the tumor is inhibited. In one aspect, the disclosure pertains to a method of inhibiting growth of a CD22-expressing tumor cell, comprising contacting the tumor cell with a CD22 CAR cell (e.g., T cell or NK cell) of the present disclosure such that the CART is activated in response to the antigen and targets the cancer cell, wherein the growth of the tumor is inhibited. In one aspect, the disclosure pertains to a method of treating cancer in a subject. The method comprises administering to the subject a CD22 CAR expressing cell (e.g., T cell or NK cell) of the present disclosure such that the cancer is treated in the subject. An example of a cancer that is treatable by the CD22 CAR expressing cell (e.g., T cell or NK cell) of the disclosure is a cancer associated with expression of CD22. An example of a cancer that is treatable by the CD22 CAR expressing cell (e.g., T cell or NK cell) of the disclosure includes but is not limited to a hematological cancer described herein. The disclosure includes a type of cellular therapy where cells (e.g., T cells or NK cells) are genetically modified to express a chimeric antigen receptor (CAR) and the CAR expressing cell (e.g., T cell or NK cells) is infused to a recipient in need thereof. The infused cell is able to kill tumor cells in the recipient. Unlike antibody therapies, CAR-modified cells (e.g., T cells or NK cells) are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control. In various aspects, the cells (e.g., T cells or NK cells) administered to the patient, or their progeny, persist in the patient for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen month, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty-one months, twenty-two months, twenty-three months, two years, three years, four years, or five years after administration of the T cell to the patient. The disclosure also includes a type of cellular therapy where immune effector cells, e.g., NK cells or T cells are modified, e.g., by in vitro transcribed RNA, to transiently express a chimeric antigen receptor (CAR) and the CAR-expressing (e.g., CART or CAR expressing NK cell) cell is infused to a recipient in need thereof. The infused cell is able to kill cancer cells in the recipient. Thus, in various aspects, the CAR-expressing cells, e.g., T cells or NK cells, are administered to the patient, is present for less than one month, e.g., three weeks, two weeks, one week, after administration of the CAR-expressing cell, e.g., T cells or NK cell, to the patient. Without wishing to be bound by any particular theory, the anti-tumor immunity response elicited by the CAR-modified cells (e.g., T cells or NK cells) may be an active or a passive immune response, or alternatively may be due to a direct vs indirect immune response. In one aspect, the CAR transduced cells (e.g., T cells or NK cells) exhibit specific proinflammatory cytokine secretion and potent cytolytic activity in response to human cancer cells expressing CD22, resist soluble CD22 inhibition, mediate bystander killing and mediate regression of an established human tumor. For example, antigen-less tumor cells within a heterogeneous field of CD22-expressing tumor may be susceptible to indirect destruction by CD22-redirected T cells that has previously reacted against adjacent antigen-positive cancer cells. In one aspect, the CAR-modified cells (e.g., T cells or NK cells) of the disclosure, e.g., fully human CAR-expressing cells, may be a type of vaccine for ex vivo immunization and/or in vivo therapy in a mammal. In one aspect, the mammal is a human. With respect to ex vivo immunization, at least one of the following occurs in vitro prior to administering the cell into a mammal: i) expansion of the cells, ii) introducing a nucleic acid encoding a CAR to the cells or iii) cryopreservation of the cells. Ex vivo procedures are well known in the art and are discussed more fully below. Briefly, cells are isolated from a mammal (e.g., a human) and genetically modified (i.e., transduced or transfected in vitro) with a vector expressing a CAR disclosed herein. The CAR-modified cell can be administered to a mammalian recipient to provide a therapeutic benefit. The mammalian recipient may be a human and the CAR-modified cell can be autologous with respect to the recipient. Alternatively, the cells can be allogeneic, syngeneic or xenogeneic with respect to the recipient. The procedure for ex vivo expansion of hematopoietic stem and progenitor cells is described in U.S. Pat. No. 5,199,942, incorporated herein by reference, can be applied to the cells of the present disclosure. Other suitable methods are known in the art, therefore the present disclosure is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of T cells comprises: (1) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo. In addition to the cellular growth factors described in U.S. Pat. No. 5,199,942, other factors such as flt3-L, IL-1, IL-3 and c-kit ligand, can be used for culturing and expansion of the cells. In addition to using a cell-based vaccine in terms of ex vivo immunization, the present disclosure also provides compositions and methods for in vivo immunization to elicit an immune response directed against an antigen in a patient. Generally, the cells activated and expanded as described herein may be utilized in the treatment and prevention of diseases that arise in individuals who are immunocompromised. In particular, the CAR-modified cells (e.g., T cells or NK cells) of the disclosure are used in the treatment of diseases, disorders and conditions associated with expression of CD22. In certain aspects, the cells of the disclosure are used in the treatment of patients at risk for developing diseases, disorders and conditions associated with expression of CD22. Thus, the present disclosure provides methods for the treatment or prevention of diseases, disorders and conditions associated with expression of CD22 comprising administering to a subject in need thereof, a therapeutically effective amount of the CAR-modified cells (e.g., T cells or NK cells) of the disclosure. In one aspect the CAR expressing cells of the disclosures may be used to treat a proliferative disease such as a cancer or malignancy or is a precancerous condition. In one aspect, a cancer associated with expression of CD22 is a hematological cancer preleukemia, hyperproliferative disorder, hyperplasia or a dysplasia, which is characterized by abnormal growth of cells. In one aspect, the CAR expressing cells of the disclosure are used to treat a cancer, wherein the cancer is a hematological cancer. Hematological cancer conditions are the types of cancer such as leukemia and malignant lymphoproliferative conditions that affect blood, bone marrow and the lymphatic system. Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia can be further classified as acute myelogenous leukemia (AML) and acutelymphoidlymphoblasticleukemia (ALL). Chronic leukemia includes chronic myelogenous leukemia (CML) and chroniclymphoidlymphocyticleukemia (CLL). Other related conditions include myelodysplastic syndromes (MDS, formerly known as “preleukemia”) which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells and risk of transformation to AML. Lymphoma is a group of blood cell tumors that develop from lymphocytes. Exemplary lymphomas include non-Hodgkin lymphoma and Hodgkin lymphoma. In one aspect, the compositions and CART cells or CAR expressing NK cells of the present disclosure are particularly useful for treating B cell malignancies, such as non-Hodgkin lymphomas, e.g., DLBCL, Follicular lymphoma, or CLL. Non-Hodgkin lymphoma (NHL) is a group of cancers of lymphocytes, formed from either B or T cells. NHLs occur at any age and are often characterized by lymph nodes that are larger than normal, weight loss, and fever. Different types of NHLs are categorized as aggressive (fast-growing) and indolent (slow-growing) types. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. Examples of T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are typically B-cell non-Hodgkin lymphomas. See, e.g., Maloney. NEJM. 366.21 (2012):2008-16. Diffuse large B-cell lymphoma (DLBCL) is a form of NHL that develops from B cells. DLBCL is an aggressive lymphoma that can arise in lymph nodes or outside of the lymphatic system, e.g., in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Three variants of cellular morphology are commonly observed in DLBCL: centroblastic, immunoblastic, and anaplastic. Centroblastic morphology is most common and has the appearance of medium-to-large-sized lymphocytes with minimal cytoplasm. There are several subtypes of DLBCL. For example, primary central nervous system lymphoma is a type of DLBCL that only affects the brain is called and is treated differently than DLBCL that affects areas outside of the brain. Another type of DLBCL is primary mediastinal B-cell lymphoma, which often occurs in younger patients and grows rapidly in the chest. Symptoms of DLBCL include a painless rapid swelling in the neck, armpit, or groin, which is caused by enlarged lymph nodes. For some subjects, the swelling may be painful. Other symptoms of DLBCL include night sweats, unexplained fevers, and weight loss. Although most patients with DLBCL are adults, this disease sometimes occurs in children. Treatment for DLBCL includes chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide), antibodies (e.g., Rituxan), radiation, or stem cell transplants. Follicular lymphoma a type of non-Hodgkin lymphoma and is a lymphoma of follicle center B-cells (centrocytes and centroblasts), which has at least a partially follicular pattern. Follicular lymphoma cells express the B-cell markers CD10, CD19, CD20, and CD22. Follicular lymphoma cells are commonly negative for CD5. Morphologically, a follicular lymphoma tumor is made up of follicles containing a mixture of centrocytes (also called cleaved follicle center cells or small cells) and centroblasts (also called large noncleaved follicle center cells or large cells). The follicles are surrounded by non-malignant cells, mostly T-cells. The follicles contain predominantly centrocytes with a minority of centroblasts. The World Health Organization (WHO) morphologically grades the disease as follows: grade 1 (<5 centroblasts per high-power field (hpf); grade 2 (6-15 centroblasts/hpf); grade 3 (>15 centroblasts/hpf). Grade 3 is further subdivided into the following grades: grade 3A (centrocytes still present); grade 3B (the follicles consist almost entirely of centroblasts). Treatment of follicular lymphoma includes chemotherapy, e.g., alkyating agents, nucleoside analogs, anthracycline-containing regimens, e.g., a combination therapy called CHOP-cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone, antibodies (e.g., rituximab), radioimmunotherapy, and hematopoietic stem cell transplantation. CLL is a B-cell malignancy characterized by neoplastic cell proliferation and accumulation in bone morrow, blood, lymph nodes, and the spleen. The median age at time of diagnosis of CLL is about 65 years. Current treatments include chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Sometimes symptoms are treated surgically (e.g., splenectomy removal of enlarged spleen) or by radiation therapy (e.g., de-bulking swollen lymph nodes). Chemotherapeutic agents to treat CLL include, e.g., fludarabine, 2-chlorodeoxyadenosine (cladribine), chlorambucil, vincristine, pentostatin, cyclophosphamide, alemtuzumab (Campath-1H), doxorubicin, and prednisone. Biological therapy for CLL includes antibodies, e.g., alemtuzumab, rituximab, and ofatumumab; as well as tyrosine kinase inhibitor therapies. A number of criteria can be used to classify stage of CLL, e.g., the Rai or Binet system. The Rai system describes CLL has having five stages: stage 0 where only lymphocytosis is present; stage I where lymphadenopathy is present; stage II where splenomegaly, lymphadenopathy, or both are present; stage III where anemia, organomegaly, or both are present (progression is defined by weight loss, fatigue, fever, massive organomegaly, and a rapidly increasing lymphocyte count); and stage IV where anemia, thrombocytopenia, organomegaly, or a combination thereof are present. Under the Binet staging system, there are three categories: stage A where lymphocytosis is present and less than three lymph nodes are enlarged (this stage is inclusive of all Rai stage 0 patients, one-half of Rai stage I patients, and one-third of Rai stage II patients); stage B where three or more lymph nodes are involved; and stage C wherein anemia or thrombocytopenia, or both are present. These classification systems can be combined with measurements of mutation of the immunoglobulin genes to provide a more accurate characterization of the state of the disease. The presence of mutated immunoglobulin genes correlates to improved prognosis. In another embodiment, the CAR expressing cells of the present disclosure are used to treat cancers or leukemias, e.g., with leukemia stem cells. For example, the leukemia stem cells are CD34+/CD38−leukemia cells. The present disclosure provides, among other things, compositions and methods for treating cancer. In one aspect, the cancer is a hematologic cancer including but is not limited to one or more acute leukemias including but not limited to B-cell acutelymphoidlymphoblasticleukemia (BALL), T-cell acutelymphoidlymphoblasticleukemia (TALL), small lymphocyticleukemialymphoma(SLL), acutelymphoidlymphoblasticleukemia (ALL); one or more chronic leukemias including but not limited chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to mantle cell lymphoma (MCL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, Marginal zone lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and to disease associated with CD22 expression include, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD22; and any combination thereof. The CAR-modified cells of the present disclosure may be administered either alone, or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2 or other cytokines or cell populations. The present disclosure also methods for inhibiting the proliferation or reducing a CD22-expressing cell population, the methods comprising contacting a population of cells comprising a CD22-expressing cell with a CD22 CAR expressing cell of the disclosure that binds to the CD22-expressing cell. In a specific aspect, the present disclosure provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD22, the methods comprising contacting the CD22-expressing cancer cell population with a CD22 CAR expressing cell of the disclosure that binds to the CD22-expressing cell. In one aspect, the present disclosure provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD22, the methods comprising contacting the CD22-expressing cancer cell population with a CD22 CART of the disclosure that binds to the CD22-expressing cell. In certain aspects, the CD22 CAR expressing cell of the disclosure reduces the quantity, number, amount or percentage of cells and/or cancer cells by at least 25%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 95%, or at least 99% in a subject with or animal model for B-cell malignancy or another cancer associated with CD22-expressing cells relative to a negative control. In one aspect, the subject is a human. The present disclosure also provides methods for preventing, treating and/or managing a disease associated with CD22-expressing cells (e.g., a hematologic cancer or atypical cancer expressing CD22), the methods comprising administering to a subject in need a CD22 CAR expressing cell of the disclosure that binds to the CD22-expressing cell. In one aspect, the subject is a human. Non-limiting examples of disorders associated with CD22-expressing cells include autoimmune diseases, (e.g., lupus, rheumatoid arthritis, multiple sclerosis autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome, anti-NMDA receptor encephalitis and Devic's disease, Graves' ophthalmopathy, and autoimmune pancreatitis), inflammatory disorders (allergy and asthma), transplantation, and cancers (such as hematological cancers or atypical cancers expressing CD22). The present disclosure also provides methods for preventing, treating and/or managing a disease associated with CD22-expressing cells, the methods comprising administering to a subject in need a CD22 CAR expressing cell of the disclosure that binds to the CD22-expressing cell. In one aspect, the subject is a human. The present disclosure provides methods for preventing relapse of cancer associated with CD22-expressing cells, the methods comprising administering to a subject in need thereof a CD22 CAR expressing cell of the disclosure that binds to the CD22-expressing cell. In one aspect, the methods comprise administering to the subject in need thereof an effective amount of a CD22 CAR expressing cell described herein that binds to the CD22-expressing cell in combination with an effective amount of another therapy. In some embodiments, the CD22 expressing cell expresses CD19, CD123, FLT-3, ROR-1, CD79b, CD179b, CD79a, CD10, CD34, and/or CD20. In certain embodiments, the CD22 expressing cell expresses CD19. In some embodiments, the CD22-expressing cell does not express CD19. In some embodiments, the subject is a non-responder to CD19 CAR therapy. In some embodiments, the subject is a partial responder to CD19 CAR therapy. In some embodiments, the subject is a complete responder to CD19 CAR therapy. In some embodiments, the subject is a non-relapser to CD19 CAR therapy. In some embodiments, the subject is a partial relapser to CD19 CAR therapy. In some embodiments, the subject is a complete relapser to CD19 CAR therapy. In some embodiments, a cancer or other condition that was previously responsive to treatment with CD19 CAR-expressing cells does not express CD19. In some embodiments, a cancer or other condition that was previously responsive to treatment with CD19 CAR-expressing cells has a 10%, 20%, 30%, 40%, 50% or more reduction in CD19 expression levels relative to when the cancer or other condition was responsive to treatment with CD19 CAR-expressing cells. In some embodiments, a cancer or other condition that was previously responsive to treatment with CD19 CAR-expressing cells expresses CD22 and/or CD123. In some embodiments, the CD22 CAR-expressing cell of the disclosure is administered post-relapse of a cancer or other condition previously treated with CD19 CAR-expressing cell. In some embodiments, a CD19 CAR-expressing cell and a CD22 CAR-expressing cell are administered concurrently, as described herein. CD19 CART Cells for Use in Treating Multiple Myeloma Even with current regimens of chemotherapy, targeted therapies, and autologous stem cell transplant, myeloma is considered an incurable disease. In one study (not disclosed), treatment of multiple myeloma (MM) with autologous T cells directed to CD19 with a chimeric antigen receptor (lentivirus/CD19:4-1BB:CD3zeta; also known as “CART19” or CTL019) is described. This example demonstrates that CD19-directed CAR therapies have the potential to establish deep, long-term durable remissions based on targeting the myeloma stem cell and/or tumor cells that express very low (undetectable by most methods) levels of CD19. CAR19 T Cell Therapy for Hodgkin Lymphoma CAR19 T cell therapy can also be used to treat Hodgkin lymphoma (HL). Hodgkin lymphoma is characterized by the presence of malignant Hodgkin Reed-Sternberg (HRS) cells that are derived from clonal germinal center B cells. There are several factors that indicate the therapeutic efficacy of CAR19 T cell therapy for HL. CD19 staining of HL tumors shows CD19-expressing (CD19+) cells within the tumor and tumor microenvironment. A study has shown that a clonal B cell population (CD20+CD27+ALDH+) that expresses CD19 is responsible for the generation and maintenance of Hodgkin lymphoma cell lines, and also circulates in the blood of most HL patients (Jones et al., Blood, 2009, 113(23):5920-5926). This clonal B cell population has also been suggested to give rise to or contribute to the generation of the malignant HRS cells. Thus, CART19 therapy would deplete this B cell population that contributes to tumorigenesis or maintenance of tumor cells. Another study showed that B cell depletion retards solid tumor growth in multiple murine models (Kim et al., J Immunotherapy, 2008, 31(5):446-57). In support of the idea that depletion of B cells in the HL tumor microenvironment results in some anti-tumor effect, current therapies, such as rituxan, are being clinically tested for targeting and depletion of tumoral B cells in HL (Younes et al., Blood, 2012, 119(18):4123-8). De novo carcinogenesis related to chronic inflammation has also been shown to be B-cell dependent (de Visser, et al., Cancer Cell, 2005, 7(5):411-23). The results from these studies indicate that targeting of the B cell population, particularly in the HL tumor microenvironment, would be useful for treating HL, by reducing or inhibiting disease progression or tumor growth. Non-Responder Subset of CLL Patients Exhibit Increased Expression of Immune Checkpoint Inhibitor Molecules In one study (data not published), CART19 cells from clinical manufacture from 34 CLL patients were assessed for expression of immune checkpoint inhibitor molecules, such as PD-1, LAG3, and TIM3. The response of this cohort to CART19 was known and hence a correlation between response and biomarker expression patterns could be assessed. Effects of mTOR Inhibition on Immunosenescence in the Elderly The efficacy of mTOR inhibition on immunosenescence is described, e.g., in Example 1 of International Application WO/2015/073644, and the entirety of the application is herein incorporated by reference. Enhancement of Immune Response to Vaccine in Elderly Subjects The efficacy of mTOR inhibition on enhancing an immune response is described, e.g., in Example 2 of International Application WO/2015/073644, and the entirety of the application is herein incorporated by reference. Low dose mTOR inhibition increases energy and exercise; The effect of mTOR inhibition on energy and exercise is described, e.g., in Example 3 of 20 International Application WO/2015/073644, and the entirety of the application is erein incorporated by reference. P70 S6 Kinase Inhibition with RAD001 The effect of mTOR inhibition on P70 S6 kinase inhibition is described, e.g., in Example 4 of International Application WO/2015/073644, and the entirety of the application is herein incorporated by reference. Exogenous IL-7 Enhances the Function of CAR T Cells After adoptive transfer of CAR T cells, some patients experience limited persistence of the CART cells, which can result in suboptimal levels of anti-tumor activity. In this example, the effects of administration of exogenous human IL-7 is assessed in mouse xenograft models where an initial suboptimal response to CAR T cells has been observed. Combination Therapies A CAR-expressing cell described herein may be used in combination with other known agents and therapies. Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In some embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. A CAR-expressing cell described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the CAR-expressing cell described herein can be administered first, and the additional agent can be administered second, or the order of administration can be reversed. The CAR therapy and/or other therapeutic agents, procedures or modalities can be administered during periods of active disorder, or during a period of remission or less active disease. The CAR therapy can be administered before the other treatment, concurrently with the treatment, post-treatment, or during remission of the disorder. When administered in combination, the CAR therapy and the additional agent (e.g., second or third agent), or all, can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually, e.g., as a monotherapy. In certain embodiments, the administered amount or dosage of the CAR therapy, the additional agent (e.g., second or third agent), or all, is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy. In some embodiments, the amount or dosage of the CAR therapy, the additional agent (e.g., second or third agent), or all, that results in a desired effect (e.g., treatment of cancer) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect. In further aspects, a CAR-expressing cell described herein may be used in a treatment regimen in combination with surgery, cytokines, radiation, or chemotherapy such as cytoxan, fludarabine, histone deacetylase inhibitors, demethylating agents, or peptide vaccine, such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971. In certain instances, compounds of the present invention are combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof. General Chemotherapeutic agents considered for use in combination therapies include anastrozole (ARIMIDEX®), bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan (MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®), carmustine (BICNU®), chlorambucil (LEUKERAN®), cisplatin (PLATINOL®), cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-DOME®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (CERUBIDINE®), daunorubicin citrate liposome injection (DAUNOXOME®), dexamethasone, docetaxel (TAXOTERE®), doxorubicin hydrochloride (ADRIAMYCIN®, RUBEX®), etoposide (VEPESID®), fludarabine phosphate (FLUDARA®), 5-fluorouracil (ADRUCIL®, EFUDEX®), flutamide (EULEXIN®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (HYDREA®), Idarubicin (IDAMYCIN®), ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine (PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®), mylotarg, paclitaxel (TAXOL®), nabpaclitaxel (ABRAXANE®), phoenix (Yttrium90/MXDTPA), pentostatin, polifeprosan 20 with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®), teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®), topotecan hydrochloride for injection (HYCAMPTIN®), vinblastine (VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®). Anti-cancer agents of particular interest for combinations with the compounds of the present invention include: antitumor antibiotics; tyrosine kinase inhibitors; alkylating agents; anti-microtubule or anti-mitotic agents; or oncolytic viruses. Exemplary tyrosine kinase inhibitors include but are not limited to Erlotinib hydrochloride (TARCEVA®); Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (SUTENT®); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in U.S. Pat. No. 6,780,996); Dasatinib (SPRYCEL®); Pazopanib (VOTRIENT®); Sorafenib (NEXAVAR®); Zactima (ZD6474); and Imatinib or Imatinib mesylate (GILVEC® and GLEEVEC®). Exemplary alkylating agents include, without limitation, Oxaliplatin (ELOXATIN®); Temozolomide (TEMODAR® and TEMODAL®); Dactinomycin (also known as actinomycin-D, COSMEGEN®); Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, ALKERAN®); Altretamine (also known as hexamethylmelamine (HMM), HEXALEN®); Carmustine (BICNU®); Bendamustine (TREANDA®); Busulfan (BUSULFEX® and MYLERAN®); Carboplatin (PARAPLATIN®); Lomustine (also known as CCNU, CEENU®); Cisplatin (also known as CDDP, PLATINOL® and PLATINOL®-AQ); Chlorambucil (LEUKERAN®); Cyclophosphamide (CYTOXAN® and NEOSAR®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-DOME®); Altretamine (also known as hexamethylmelamine (HMM), HEXALEN®); Ifosfamide (IFEX®); Prednumustine; Procarbazine (MATULANE®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, MUSTARGEN®); Streptozocin (ZANOSAR®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, THIOPLEX®); Cyclophosphamide (ENDOXAN®, CYTOXAN®, NEOSAR®, PROCYTOX®, REVIMMUNE®); and Bendamustine HCl (TREANDA®). Exemplary anti-tumor antibiotics include, e.g., Doxorubicin (ADRIAMYCIN® and RUBEX®); Bleomycin (LENOXANE®); Daunorubicin (dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, CERUBIDINE®); Daunorubicin liposomal (daunorubicin citrate liposome, DAUNOXOME®); Mitoxantrone (DHAD, NOVANTRONE®); Epirubicin (ELLENCE™); Idarubicin (IDAMYCIN®, IDAMYCIN PFS®); Mitomycin C (MUTAMYCIN®); Geldanamycin; Herbimycin; Ravidomycin; and Desacetylravidomycin. Exemplary anti-microtubule or anti-mitotic agents include, without limitation, Vinca Alkaloids (such as Vinorelbine tartrate (NAVELBINE®), Vincristine (ONCOVIN®), and Vindesine (ELDISINE®); Taxanes (such as paclitaxel and docetaxel); and Estramustine (EMCYL® or ESTRACYT®). In some embodiments, a CAR-expressing cell described herein is administered in combination with an oncolytic virus. In embodiments, oncolytic viruses are capable of selectively replicating in and triggering the death of or slowing the growth of a cancer cell. In some cases, oncolytic viruses have no effect or a minimal effect on non-cancer cells. An oncolytic virus includes but is not limited to an oncolytic adenovirus, oncolytic Herpes Simplex Viruses, oncolytic retrovirus, oncolytic parvovirus, oncolytic vaccinia virus, oncolytic Sinbis virus, oncolytic influenza virus, or oncolytic RNA virus (e.g., oncolytic reovirus, oncolytic Newcastle Disease Virus (NDV), oncolytic measles virus, or oncolytic vesicular stomatitis virus (VSV)). In some embodiments, the oncolytic virus is a virus, e.g., recombinant oncolytic virus, described in US2010/0178684 A1, which is incorporated herein by reference in its entirety. In some embodiments, a recombinant oncolytic virus comprises a nucleic acid sequence (e.g., heterologous nucleic acid sequence) encoding an inhibitor of an immune or inflammatory response, e.g., as described in US2010/0178684 A1, incorporated herein by reference in its entirety. In embodiments, the recombinant oncolytic virus, e.g., oncolytic NDV, comprises a pro-apoptotic protein (e.g., apoptin), a cytokine (e.g., GM-CSF, interferon-gamma, interleukin-2 (IL-2), tumor necrosis factor-alpha), an immunoglobulin (e.g., an antibody against ED-B fibronectin), tumor associated antigen, a bispecific adapter protein (e.g., bispecific antibody or antibody fragment directed against NDV HN protein and a T cell co-stimulatory receptor, such as CD3 or CD28; or fusion protein between human IL-2 and single chain antibody directed against NDV HN protein). See, e.g., Zamarin et al. Future Microbiol. 7.3 (2012):347-67, incorporated herein by reference in its entirety. In some embodiments, the oncolytic virus is a chimeric oncolytic NDV described in U.S. Pat. No. 8,591,881 B2, US 2012/0122185 A1, or US 2014/0271677 A1, each of which is incorporated herein by reference in their entireties. In some embodiments, the oncolytic virus comprises a conditionally replicative adenovirus (CRAd), which is designed to replicate exclusively in cancer cells. See, e.g., Alemany et al. Nature Biotechnol. 18(2000):723-27. In some embodiments, an oncolytic adenovirus comprises one described in Table 1 on page 725 of Alemany et al., incorporated herein by reference in its entirety. Exemplary oncolytic viruses include but are not limited to the following: Group B Oncolytic Adenovirus (ColoAdl) (PsiOxus Therapeutics Ltd.) (see, e.g., Clinical Trial Identifier: NCT02053220); ONCOS-102 (previously called CGTG-102), which is an adenovirus comprising granulocyte-macrophage colony stimulating factor (GM-CSF) (Oncos Therapeutics) (see, e.g., Clinical Trial Identifier: NCT01598129); VCN-01, which is a genetically modified oncolytic human adenovirus encoding human PH20 hyaluronidase (VCN Biosciences, S. L.) (see, e.g., Clinical Trial Identifiers: NCT02045602 and NCT02045589); Conditionally Replicative Adenovirus ICOVIR-5, which is a virus derived from wild-type human adenovirus serotype 5 (Had5) that has been modified to selectively replicate in cancer cells with a deregulated retinoblastoma/E2F pathway (Institut Catalá d'Oncologia) (see, e.g., Clinical Trial Identifier: NCT01864759); Celyvir, which comprises bone marrow-derived autologous mesenchymal stem cells (MSCs) infected with ICOVIR5, an oncolytic adenovirus (Hospital Infantil Universitario Niño Jesus, Madrid, Spain/Ramon Alemany) (see, e.g., Clinical Trial Identifier: NCT01844661); CG0070, which is a conditionally replicating oncolytic serotype 5 adenovirus (Ad5) in which human E2F-1 promoter drives expression of the essential E1a viral genes, thereby restricting viral replication and cytotoxicity to Rb pathway-defective tumor cells (Cold Genesys, Inc.) (see, e.g., Clinical Trial Identifier: NCT02143804); or DNX-2401 (formerly named Delta-24-RGD), which is an adenovirus that has been engineered to replicate selectively in retinoblastoma (Rb)-pathway deficient cells and to infect cells that express certain RGD-binding integrins more efficiently (Clinica Universidad de Navarra, Universidad de Navarra/DNAtrix, Inc.) (see, e.g., Clinical Trial Identifier: NCT01956734). In some embodiments, an oncolytic virus described herein is administering by injection, e.g., subcutaneous, intraarterial, intravenous, intramuscular, intrathecal, or intraperitoneal injection. In embodiments, an oncolytic virus described herein is administered intratumorally, transderwally, transmucosally, orally, intranasally, or via pulmonary administration. In some embodiments, a CAR-expressing cell described herein is administered in combination with (e.g., prior to, simultaneously with, and/or subsequent to) a second CD20 inhibitor, e.g., a CD20 antibody or a CD20 antibody drug conjugate. Exemplary CD20 antibodies include but are not limited to Rituximab (RIUXAN® and MABTHERA®); Tositumomab (BEXXAR®); and Ofatumumab (ARZERRA®). Exemplary CD20 antibody drug conjugates include but are not limited to Ibritumomab tiuxetan (ZEVALIN®); and Tositumomab. In one embodiment, a CAR expressing cell described herein are administered to a subject in combination with a molecule targeting GITR and/or modulating GITR functions, such as a GITR agonist and/or a GITR antibody that depletes regulatory T cells (Tregs). In one embodiment, the GITR binding molecules and/or molecules modulating GITR functions (e.g., GITR agonist and/or Treg depleting GITR antibodies) are administered prior to the CAR-expressing cell. For example, in one embodiment, the GITR agonist can be administered prior to apheresis of the cells. In one embodiment, the subject has CLL. Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) such as, e.g., a GITR fusion protein described in U.S. Pat. No. 6,111,090, European Patent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat. Nos. 7,812,135, 8,388,967, 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683, PCT Publication No. WO 2013/039954, PCT Publication No.: W02005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.: WO2005/055808, PCT Publication No.: WO99/40196, PCT Publication No.: WO2001/03720, PCT Publication No.: WO99/20758, PCT Publication No.: WO2006/083289, PCT Publication No.: WO 2005/115451, U.S. Pat. No. 7,618,632, and PCT Publication No.: WO 2011/051726. In one embodiment, a CAR expressing cell described herein is administered to a subject in combination with an mTOR inhibitor, e.g., an mTOR inhibitor described herein, e.g., a rapalog such as everolimus. In one embodiment, the mTOR inhibitor is administered prior to the CAR-expressing cell. For example, in one embodiment, the mTOR inhibitor can be administered prior to apheresis of the cells. In one embodiment, a CAR expressing cell described herein is administered to a subject in combination with a GITR agonist, e.g., a GITR agonist described herein. In one embodiment, the GITR agonist is administered prior to the CAR-expressing cell, e.g., CD20 CAR-expressing cells. For example, in one embodiment, the GITR agonist can be administered prior to apheresis of the cells. In one embodiment, a CAR expressing cell described herein is administered to a subject in combination with a protein tyrosine phosphatase inhibitor, e.g., a protein tyrosine phosphatase inhibitor described herein. In one embodiment, the protein tyrosine phosphatase inhibitor is an SHP-1 inhibitor, e.g., an SHP-1 inhibitor described herein, such as, e.g., sodium stibogluconate. In one embodiment, the protein tyrosine phosphatase inhibitor is an SHP-2 inhibitor. In one embodiment, a CAR-expressing cell described herein can be used in combination with a kinase inhibitor. In an embodiment this approach can be used to optimize the performance of CAR cells described herein in the subject. While not wishing to be bound by theory, it is believed that, in an embodiment, the performance of endogenous, non-modified immune effector cells, e.g., T cells or NK cells, is improved. While not wishing to be bound by theory, it is believed that, in an embodiment, the performance of a CD20 CAR expressing cell is improved. In some embodiments, cells, e.g., T cells or NK cells, which have, or will be engineered to express a CAR, can be treated ex vivo by contact with an amount of an mTOR inhibitor that increases the number of PD1 negative immune effector cells, e.g., T cells/NK cells or increases the ratio of PD1 negative immune effector cells, e.g., T cells/NK cells/PD1 positive immune effector cells, e.g., T cells or NK cells. In an embodiment, administration of a low, immune enhancing, dose of an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, or a catalytic inhibitor, is initiated prior to administration of an CAR expressing cell described herein, e.g., T cells or NK cells. In an embodiment, the CAR cells are administered after a sufficient time, or sufficient dosing, of an mTOR inhibitor, such that the level of PD1 negative immune effector cells, e.g., T cells/NK cells, or the ratio of PD1 negative immune effector cells, e.g., T cells/NK cells/PD1 positive immune effector cells, e.g., T cells or NK cells, has been, at least transiently, increased. In an embodiment, the cell, e.g., T cell or NK cell, to be engineered to express a CAR, is harvested after a sufficient time, or after sufficient dosing of the low, immune enhancing, dose of an mTOR inhibitor, such that the level of PD1 negative immune effector cells, e.g., T cells or NK cells, or the ratio of PD1 negative immune effector cells, e.g., T cells/NK cells/PD1 positive immune effector cells, e.g., T cells or NK cells, in the subject or harvested from the subject has been, at least transiently, increased. In some embodiments, the mTOR inhibitor is administered for an amount of time sufficient to decrease the proportion of PD-1 positive T cells, increase the proportion of PD-1 negative T cells, or increase the ratio of PD-1 negative T cells/PD-1 positive T cells, in the peripheral blood of the subject, or in a preparation of T cells isolated from the subject. In some embodiments, the dose of an mTOR inhibitor is associated with mTOR inhibitor of at least 5 but no more than 90%, e.g., as measured by p70 S6K inhibition. In some some embodiments, the dose of an mTOR inhibitor is associated with mTOR inhibition of at least 10% but no more than 40%, e.g., as measured by p70 S6K inhibition. In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., a CDK4 inhibitor described herein, e.g., a CD4/6 inhibitor, such as, e.g., 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (also referred to as palbociclib or PD0332991). In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., a BTK inhibitor described herein, such as, e.g., ibrutinib. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., an mTOR inhibitor described herein, such as, e.g., rapamycin, a rapamycin analog, OSI-027. The mTOR inhibitor can be, e.g., an mTORC1 inhibitor and/or an mTORC2 inhibitor, e.g., an mTORC1 inhibitor and/or mTORC2 inhibitor described herein. In one embodiment, the kinase inhibitor is a MNK inhibitor, e.g., a MNK inhibitor described herein, such as, e.g., 4-amino-5-(4-fluoroanilino)-pyrazolo[3,4-d]pyrimidine. The MNK inhibitor can be, e.g., a MNK1a, MNK1b, MNK2a and/or MNK2b inhibitor. In one embodiment, the kinase inhibitor is a DGK inhibitor, e.g., a DGK inhibitor described herein, such as, e.g., DGKinh1 (D5919) or DGKinh2 (D5794). In one embodiment, the kinase inhibitor is a CDK4 inhibitor selected from aloisine A; flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone; crizotinib (PF-02341066; 2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1 -methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF265); indisulam (E7070); roscovitine (CYC202); palbociclib (PD0332991); dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS 387032); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054); 5-[3-(4,6-difluoro -1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519); 4-[2-methyl-1-(1 -methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438); and XL281 (BMS908662). In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., palbociclib (PD0332991), and the palbociclib is administered at a dose of about 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg (e.g., 75 mg, 100 mg or 125 mg) daily for a period of time, e.g., daily for 14-21 days of a 28 day cycle, or daily for 7-12 days of a 21 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of palbociclib are administered. In one embodiment, the kinase inhibitor is a BTK inhibitor selected from ibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13. In one emboiment, the kinase inhibitor is a BTK inbibitor, e.g., ibrutinib (PCI-32765), and the ibrutinib is administered as a dose of about 250 mg, 400 mg, 350 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg (e.g., 250 mg, 420 mg or 560 mg) daily for a period of time, e.g., daily for 21 day cycle, or daily for 28 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of ibrutinib are administered. In one embodiment, the kinase inhibitor is an mTOR inhibitor selected from temsirolimus; ridaforolimus (1R,2R, 4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R, 23S, 24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669; everolimus (RAD001); rapamycin (AY22989); simapimod; (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl) methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502); and N2-[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl) morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-(SEQ ID NO: 1103), inner salt (SF1126); and XL765. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., rapamycin, and the rapamycin is administered at a dose of about 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg (e.g., 6 mg) daily for a period of time, e.g., daily for 21 day cycle, or daily for 28 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of rapamycin are administered. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., everolimus and the everolimus is administered at a dose of about 2 mg, 2.5 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg (e.g., 10 mg) daily for a period of time, e.g., daily for 28 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of everolimus are administered. In one embodiment, the kinase inhibitor is an MNK inhibitor selected from CGP052088; 4-amino-3-(p-fluorophenylamino)-pyrazolo [3,4-d]pyrimidine (CGP57380); cercosporamide; ETC-1780445-2; and 4-amino-5-(4-fluoroanilino)-pyrazolo [3,4-d]pyrimidine. Drugs that inhibit either the calcium dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit the p70S6 kinase that is important for growth factor induced signaling (rapamycin). (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5:763-773, 1993) can also be used. In a further aspect, the cell compositions of the present invention may be administered to a patient in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, and/or antibodies such as OKT3 or CAMPATH. In one aspect, the cell compositions of the present invention are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan. For example, in one embodiment, subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, following the transplant, subjects receive an infusion of the expanded immune cells of the present invention. In an additional embodiment, expanded cells are administered before or following surgery. Some patients may experience allergic reactions to the compounds of the present invention and/or other anti-cancer agent(s) during or after administration; therefore, anti-allergic agents are often administered to minimize the risk of an allergic reaction. Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., DECADRON®), eclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames ALA-CORT®, hydrocortisone phosphate, SOLUCORTEF®, HYDROCORT ACETATE® and LANACORT®), prednisolone (sold under the tradenames DELTACORTEL®, ORAPRED®, PEDIAPRED® and PRELONE®), prednisone (sold under the tradenames DELTASONE®, LIQUID RED®, METICORTEN® and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the tradenames DURALONE®, MEDRALONE®, MEDROL®, M PREDNISOL® and SOLU-MEDROL®); antihistamines, such as diphenhydramine (e.g., BENADRYL®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists, albuterol (e.g., PROVENTIL®), and terbutaline (BRETHINE®). Some patients may experience nausea during and after administration of the compound of the present invention and/or other anti-cancer agent(s); therefore, anti-emetics are used in preventing nausea (upper stomach) and vomiting. Suitable anti-emetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®. dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and ZUNRISA®), and combinations thereof. Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable. Common over-the-counter analgesics, such Tylenol®, are often used. However, opioid analgesic drugs such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain. In an effort to protect normal cells from treatment toxicity and to limit organ toxicities, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy. Suitable cytoprotective agents include Amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). The above-mentioned compounds, which can be used in combination with a compound of the present invention, can be prepared and administered as described in the art, such as in the documents cited above. In one embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention (e.g., a compound of the present invention) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anti-cancer agents. In one embodiment, the present invention provides methods of treating human or animal subjects suffering from a cellular proliferative disease, such as cancer. The present invention provides methods of treating a human or animal subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present invention (e.g., a compound of the present invention) or a pharmaceutically acceptable salt thereof, either alone or in combination with other anti-cancer agents. In particular, compositions will either be formulated together as a combination therapeutic or administered separately. In combination therapy, the compound of the present invention and other anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. In a preferred embodiment, the compound of the present invention and the other anti-cancer agent(s) is generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The compound of the present invention and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug. In another aspect of the present invention, kits that include one or more compound of the present invention and a combination partner as disclosed herein are provided. Representative kits include (a) a compound of the present invention or a pharmaceutically acceptable salt thereof, (b) at least one combination partner, e.g., as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration. A compound of the present invention may also be used to advantage in combination with known therapeutic processes, for example, the administration of hormones or especially radiation. A compound of the present invention may in particular be used as a radiosensitizers, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. In one embodiment, the subject can be administered an agent which reduces or ameliorates a side effect associated with the administration of a CAR-expressing cell. Side effects associated with the administration of a CAR-expressing cell include, but are not limited to CRS, and hemophagocytic lymphohistiocytosis (HLH), also termed Macrophage Activation Syndrome (MAS). Symptoms of CRS include high fevers, nausea, transient hypotension, hypoxia, and the like. CRS may include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, and headache. CRS may include clinical skin signs and symptoms such as rash. CRS may include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea. CRS may include clinical respiratory signs and symptoms such as tachypnea and hypoxemia. CRS may include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardac output (early) and potentially diminished cardiac output (late). CRS may include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding. CRS may include clinical renal signs and symptoms such as azotemia. CRS may include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. CRS may include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dymetria, altered gait, and seizures. Accordingly, the methods described herein can comprise administering a CAR-expressing cell described herein to a subject and further administering one or more agents to manage elevated levels of a soluble factor resulting from treatment with a CAR-expressing cell. In one embodiment, the soluble factor elevated in the subject is one or more of IFN-γ, TNFα, IL-2 and IL-6. In an embodiment, the factor elevated in the subject is one or more of IL-1, GM-CSF, IL-10, IL-8, IL-5 and fraktalkine. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof. Examples of such agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFα, and an inhibitor of IL-6. An example of a TNFα inhibitor is an anti-TNFα antibody molecule such as, infliximab, adalimumab, certolizumab pegol, and golimumab. Another example of a TNFα inhibitor is a fusion protein such as entanercept. Small molecule inhibitor of TNFα include, but are not limited to, xanthine derivatives (e.g. pentoxifylline) and bupropion. An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toc), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301, and FM101. In one embodiment, the anti-IL-6 antibody molecule is tocilizumab. An example of an IL-1R based inhibitor is anakinra. In some embodiment, the subject is administered a corticosteroid, such as, e.g., methylprednisolone, hydrocortisone, among others. In some embodiments, the subject is administered a vasopressor, such as, e.g., norepinephrine, dopamine, phenylephrine, epinephrine, vasopressin, or a combination thereof. In an embodiment, the subject can be administered an antipyretic agent. In an embodiment, the subject can be administered an analgesic agent. In one embodiment, the subject can be administered an agent which enhances the activity of a CAR-expressing cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., Programmed Death 1 (PD1), can, in some embodiments, decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGF beta. Inhibition of an inhibitory molecule, e.g., by inhibition at the DNA, RNA or protein level, can optimize a CAR-expressing cell performance. In embodiments, an inhibitory nucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., an siRNA or shRNA, or a clustered regularly interspaced short palindromic repeats (CRISPR), a transcription-activator like effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), can be used to inhibit expression of an inhibitory molecule in the CAR-expressing cell. In an embodiment the inhibitor is an shRNA. In an embodiment, the inhibitory molecule is inhibited within a CAR-expressing cell. In these embodiments, a dsRNA molecule that inhibits expression of the inhibitory molecule is linked to the nucleic acid that encodes a component, e.g., all of the components, of the CAR. In one embodiment, the inhibitor of an inhibitory signal can be, e.g., an antibody or antibody fragment that binds to an inhibitory molecule. For example, the agent can be an antibody or antibody fragment that binds to PD1, PD-L1, PD-L2 or CTLA4 (e.g., ipilimumab (also referred to as MDX-010 and MDX-101, and marketed as YERVOY®; Bristol-Myers Squibb; Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206).). In an embodiment, the agent is an antibody or antibody fragment that binds to TIM3. In an embodiment, the agent is an antibody or antibody fragment that binds to LAG3. In an embodiment, the agent is an antibody or antibody fragment that binds to CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5). PD1 is an inhibitory member of the CD28 family of receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD1 is expressed on activated B cells, T cells and myeloid cells (Agata et al. 1996 Int. Immunol 8:765-75). Two ligands for PD1, PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD1 (Freeman et a. 2000 J Exp Med 192:1027-34; Latchman et al. 2001 Nat Immunol 2:261-8; Carter et al. 2002 Eur J Immunol 32:634-43). PD-L1 is abundant in human cancers (Dong et al. 2003 J Mol Med 81:281-7; Blank et al. 2005 Cancer Immunol. Immunother 54:307-314; Konishi et al. 2004 Clin Cancer Res 10:5094). Immune suppression can be reversed by inhibiting the local interaction of PD1 with PD-L. Antibodies, antibody fragments, and other inhibitors of PD1, PD-L1 and PD-L2 are available in the art and may be used combination with a CD20 CAR described herein. For example, nivolumab (also referred to as BMS-936558 or MDX1106; Bristol-Myers Squibb) is a fully human IgG4 monoclonal antibody which specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in U.S. Pat. No. 8,008,449 and W02006/121168. Pidilizumab (CT-011; Cure Tech) is a humanized IgGlk monoclonal antibody that binds to PD1Pidilizumab and other humanized anti-PD1 monoclonal antibodies are disclosed in WO2009/101611. Pembrolizumab (formerly known as lambrolizumab, and also referred to as Keytruda, MK03475; Merck) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab and other humanized anti-PD1 antibodies are disclosed in U.S. Pat. No. 8,354,509 and WO2009/114335. MEDI4736 (Medimmune) is a human monoclonal antibody that binds to PDL1, and inhibits interaction of the ligand with PD1. MDPL3280A (Genentech/Roche) is a human Fc optimized IgG1 monoclonal antibody that binds to PD-L. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Pat. No. 7,943,743 and U.S Publication No.: 20120039906. Other anti-PD-L1 binding agents include YW243.55.570 (heavy and light chain variable regions are shown in SEQ ID NOs: 20 and 21 in WO2010/077634) and MDX-1 105 (also referred to as BMS-936559, and, e.g., anti-PD-L1 binding agents disclosed in WO2007/005874). AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1. Other anti-PD1 antibodies include AMP 514 (Amplimmune), among others, e.g., anti-PD1 antibodies disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649. TIM3 (T cell immunoglobulin-3) also negatively regulates T cell function, particularly in IFN-g-secreting CD4+ T helper 1 and CD8+T cytotoxic 1 cells, and plays a critical role in T cell exhaustion. Inhibition of the interaction between TIM3 and its ligands, e.g., galectin-9 (Ga19), phosphotidylserine (PS), and HMGB1, can increase immune response. Antibodies, antibody fragments, and other inhibitors of TIM3 and its ligands are available in the art and may be used combination with a CAR, e.g., CD20 CAR described herein. For example, antibodies, antibody fragments, small molecules, or peptide inhibitors that target TIM3 binds to the IgV domain of TIM3 to inhibit interaction with its ligands. Antibodies and peptides that inhibit TIM3 are disclosed in W02013/006490 and US20100247521. Other anti-TIM3 antibodies include humanized versions of RMT3-23 (disclosed in Ngiow et al., 2011, Cancer Res, 71:3540-3551), and clone 8B.2C12 (disclosed in Monney et al., 2002, Nature, 415:536-541). Bi-specific antibodies that inhibit TIM3 and PD-1 are disclosed in US20130156774. In some embodiments, the agent which enhances the activity of a CAR-expressing cell is a CEACAM inhibitor (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor). In one embodiment, the inhibitor of CEACAM is an anti-CEACAM antibody molecule. Exemplary antiCEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 WO 2014/059251 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552. In some embodiments, the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 Sep. 2; 5(9). pii: e12529 (DOI:10:1371/journal.pone.0021146), or crossreacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618. Without wishing to be bound by theory, carcinoembryonic antigen cell adhesion molecules (CEACAM), such as CEACAM-1 and CEACAM-5, are believed to mediate, at least in part, inhibition of an anti-tumor immune response (see e.g., Markel et al. J Immunol. 2002 Mar. 15; 168(6): 2803-10; Markel et al. J Immunol. 2006 Nov. 1; 177(9): 6062-71; Markel et al. Immunology. 2009 February; 126(2): 186-200; Markel et al. Cancer Immunol Immunother. 2010 February; 59(2):215-30; Ortenberg et al. Mol Cancer Ther. 2012 June; 11(6):1300-10; Stern et al. J Immunol. 2005 Jun. 1; 174(11):6692-701; Zheng et al. PLoS One. 2010 Sep. 2; 5(9). pii: e12529). For example, CEACAM-1 has been described as a heterophilic ligand for TIM-3 and as playing a role in TIM-3-mediated T cell tolerance and exhaustion (see e.g., WO 2014/022332; Huang, et al. (2014) Nature doi:10.1038/nature13848). In embodiments, co-blockade of CEACAM-1 and TIM-3 has been shown to enhance an anti-tumor immune response in xenograft colorectal cancer models (see e.g., WO 2014/022332; Huang, et al. (2014), supra). In some embodiments, co-blockade of CEACAM-1 and PD-1 reduce T cell tolerance as described, e.g., in WO 2014/059251. Thus, CEACAM inhibitors can be used with the other immunomodulators described herein (e.g., anti-PD-1 and/or anti-TIM-3 inhibitors) to enhance an immune response against a cancer, e.g., a melanoma, a lung cancer (e.g., NSCLC), a bladder cancer, a colon cancer an ovarian cancer, and other cancers as described herein. LAG3 (lymphocyte activation gene-3 or CD223) is a cell surface molecule expressed on activated T cells and B cells that has been shown to play a role in CD8+ T cell exhaustion. Antibodies, antibody fragments, and other inhibitors of LAG3 and its ligands are available in the art and may be used combination with a CAR, e.g., a CD20 CAR described herein. For example, BMS-986016 (Bristol-Myers Squib) is a monoclonal antibody that targets LAG3. IMP701 (Immutep) is an antagonist LAG3 antibody and IMP731 (Immutep and GlaxoSmithKline) is a depleting LAG3 antibody. Other LAG3 inhibitors include IMP321 (Immutep), which is a recombinant fusion protein of a soluble portion of LAG3 and Ig that binds to MHC class II molecules and activates antigen presenting cells (APC). Other antibodies are disclosed, e.g., in WO2010/019570. In some embodiments, the agent which enhances the activity of a CAR-expressing cell can be, e.g., a fusion protein comprising a first domain and a second domain, wherein the first domain is an inhibitory molecule, or fragment thereof, and the second domain is a polypeptide that is associated with a positive signal, e.g., a polypeptide comprising an intracellular signaling domain as described herein. In some embodiments, the polypeptide that is associated with a positive signal can include a costimulatory domain of CD28, CD27, ICOS, e.g., an intracellular signaling domain of CD28, CD27 and/or ICOS, and/or a primary signaling domain, e.g., of CD3 zeta, e.g., described herein. In one embodiment, the fusion protein is expressed by the same cell that expressed the CAR. In another embodiment, the fusion protein is expressed by a cell, e.g., a T cell or NK cell that does not express a CD20 CAR. In one embodiment, the agent which enhances activity of a CAR-expressing cell described herein is miR-17-92. Combination with a Low Dose of an mTOR Inhibitor In one embodiment, the cells expressing a CAR molecule, e.g., a CAR molecule described herein, are administered in combination with a low, immune enhancing dose of an mTOR inhibitor. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 90%, at least 10 but no more than 90%, at least 15, but no more than 90%, at least 20 but no more than 90%, at least 30 but no more than 90%, at least 40 but no more than 90%, at least 50 but no more than 90%, at least 60 but no more than 90%, or at least 70 but no more than 90%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 80%, at least 10 but no more than 80%, at least 15, but no more than 80%, at least 20 but no more than 80%, at least 30 but no more than 80%, at least 40 but no more than 80%, at least 50 but no more than 80%, or at least 60 but no more than 80%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 70%, at least 10 but no more than 70%, at least 15, but no more than 70%, at least 20 but no more than 70%, at least 30 but no more than 70%, at least 40 but no more than 70%, or at least 50 but no more than 70%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 60%, at least 10 but no more than 60%, at least 15, but no more than 60%, at least 20 but no more than 60%, at least 30 but no more than 60%, or at least 40 but no more than 60%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 50%, at least 10 but no more than 50%, at least 15, but no more than 50%, at least 20 but no more than 50%, at least 30 but no more than 50%, or at least 40 but no more than 50%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 40%, at least 10 but no more than 40%, at least 15, but no more than 40%, at least 20 but no more than 40%, at least 30 but no more than 40%, or at least 35 but no more than 40%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 30%, at least 10 but no more than 30%, at least 15, but no more than 30%, at least 20 but no more than 30%, or at least 25 but no more than 30%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 1, 2, 3, 4 or 5 but no more than 20%, at least 1, 2, 3, 4 or 5 but no more than 30%, at least 1, 2, 3, 4 or 5, but no more than 35, at least 1, 2, 3, 4 or 5 but no more than 40%, or at least 1, 2, 3, 4 or 5 but no more than 45%. In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 1, 2, 3, 4 or 5 but no more than 90%. As is discussed herein, the extent of mTOR inhibition can be expressed as the extent of P70 S6 kinase inhibition, e.g., the extent of mTOR inhibition can be determined by the level of decrease in P70 S6 kinase activity, e.g., by the decrease in phosphorylation of a P70 S6 kinase substrate. The level of mTOR inhibition can be evaluated by a method described herein, e.g. by the Boulay assay, or measurement of phosphorylated S6 levels by western blot. Exemplary mTOR Inhibitors As used herein, the term “mTOR inhibitor” refers to a compound or ligand, or a pharmaceutically acceptable salt thereof, which inhibits the mTOR kinase in a cell. In an embodiment an mTOR inhibitor is an allosteric inhibitor. In an embodiment an mTOR inhibitor is a catalytic inhibitor. Allosteric mTOR inhibitors include the neutral tricyclic compound rapamycin (sirolimus), rapamycin-related compounds, that is compounds having structural and functional similarity to rapamycin including, e.g., rapamycin derivatives, rapamycin analogs (also referred to as rapalogs) and other macrolide compounds that inhibit mTOR activity. Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus having the structure shown in Formula A. See, e.g., McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat. No. 3,929,992. There are various numbering schemes proposed for rapamycin. To avoid confusion, when specific rapamycin analogs are named herein, the names are given with reference to rapamycin using the numbering scheme of formula A. Rapamycin analogs useful in the invention are, for example, O-substituted analogs in which the hydroxyl group on the cyclohexyl ring of rapamycin is replaced by OR1in which R1is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl, or aminoalkyl; e.g. RAD001, also known as, everolimus as described in U.S. Pat. No. 5,665,772 and WO94/09010 the contents of which are incorporated by reference. Other suitable rapamycin analogs include those substituted at the 26- or 28-position. The rapamycin analog may be an epimer of an analog mentioned above, particularly an epimer of an analog substituted in position 40, 28 or 26, and may optionally be further hydrogenated, e.g. as described in U.S. Pat. No. 6,015,815, WO95/14023 and WO99/15530 the contents of which are incorporated by reference, e.g. ABT578 also known as zotarolimus or a rapamycin analog described in U.S. Pat. No. 7,091,213, WO98/02441 and WO01/14387 the contents of which are incorporated by reference, e.g. AP23573 also known as ridaforolimus. Examples of rapamycin analogs suitable for use in the present invention from U.S. Pat. No. 5,665,772 include, but are not limited to, 40-O-benzyl-rapamycin, 40-O-(4′-hydroxymethyl)benzyl-rapamycin, 40-O-[4′-(1,2-dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl-rapamycin, 40-O-[3′-(2,2-dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin, (2′E,4′S)-40-O-(4′,5′-dihydroxypent-2′-en-1′yl)-rapamycin, 40-O-(2-hydroxy)ethoxycarbonylmethylrapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-(6-hydroxy)hexylrapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(35)-2,2-dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxyprop-1-yl]-rapamycin, 40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2-nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-methyl -N′ -piperazinyl)acetoxy]ethyl -rapamycin, 39-O-desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(2-aminoethyl)-rapamycin, 40-O-(2-acetaminoethyl)-rapamycin, 40-O-(2-nicotinamidoethyl)-rapamycin, 40-O-(2-(N-methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-tolylsulfonamidoethyl)-rapamycin and 40-O-[2-(4′,5′-dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin. Other rapamycin analogs useful in the present invention are analogs where the hydroxyl group on the cyclohexyl ring of rapamycin and/or the hydroxy group at the 28 position is replaced with an hydroxyester group are known, for example, rapamycin analogs found in U.S. RE44,768, e.g. temsirolimus. Other rapamycin analogs useful in the preset invention include those wherein the methoxy group at the 16 position is replaced with another substituent, preferably (optionally hydroxy-substituted) alkynyloxy, benzyl, orthomethoxybenzyl or chlorobenzyl and/or wherein the mexthoxy group at the 39 position is deleted together with the 39 carbon so that the cyclohexyl ring of rapamycin becomes a cyclopentyl ring lacking the 39 position methyoxy group; e.g. as described in WO95/16691 and WO96/41807 the contents of which are incorporated by reference. The analogs can be further modified such that the hydroxy at the 40-position of rapamycin is alkylated and/or the 32-carbonyl is reduced. Rapamycin analogs from WO95/16691 include, but are not limited to, 16-demethoxy-16-(pent-2-ynyl)oxy-rapamycin, 16-demethoxy-16-(but-2-ynyl)oxy-rapamycin, 16-demethoxy-16-(propargyl)oxy-rapamycin, 16-demethoxy-16-(4-hydroxy-but-2-ynyl)oxy-rapamycin, 16-demethoxy-16-benzyloxy-40-O-(2-hydroxyethyl)-rapamycin, 16-demethoxy-16-benzyloxy-rapamycin, 16-demethoxy-16-ortho-methoxybenzyl-rapamycin, 16-demethoxy-40-O-(2-methoxyethyl)-16-pent-2-ynyl)oxyrapamycin, 39-demethoxy-40-desoxy-39-formyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-hydroxymethyl-42nor-rapamycin, 39-demethoxy-40-desoxy-39-carboxy-42nor-rapamycin, 39-demethoxy-40-desoxy-39-(4methylpiperazin-1-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-(morpholin-4-yl)carbonyl-42nor-rapamycin, 39-demethoxy-40-desoxy-39-[N-methyl, N-(2-pyridin-2-yl-ethyl)]carbamoyl-42-nor-rapamycin and 39-demethoxy-40-desoxy-39-(p-toluenesulfonylhydrazonomethyl)-42-nor-rapamycin. Rapamycin analogs from WO96/41807 include, but are not limited to, 32-deoxo-rapamycin, 16-O-pent-2-ynyl-32-deoxo-rapamycin, 16-O-pent-2-ynyl-32-deoxo-40-O-(2-hydroxy-ethyl)-rapamycin, 16-O-pent-2-ynyl-32-(S)-dihydro40-O-(2-hydroxyethyl)-rapamycin, 32(S)-dihydro-40-O-(2methoxy)ethyl-rapamycin and 32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin. Another suitable rapamycin analog is umirolimus as described in US2005/0101624 the contents of which are incorporated by reference. RAD001, otherwise known as everolimus (AFINITOR®), has the chemical name (1R,9S,12S,15R,16E,18R, 19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo [30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. Further examples of allosteric mTOR inhibitors include sirolimus (rapamycin, AY-22989), 40[-3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (also called temsirolimus or CCI-779) and ridaforolimus (AP-23573/MK-8669). Other examples of allosteric mTor inhibitors include zotarolimus (ABT578) and umirolimus. Alternatively or additionally, catalytic, ATP-competitive mTOR inhibitors have been found to target the mTOR kinase domain directly and target both mTORC1 and mTORC2. These are also more effective inhibitors of mTORC1 than such allosteric mTOR inhibitors as rapamycin, because they modulate rapamycin-resistant mTORC1 outputs such as 4EBP1-T37/46 phosphorylation and capdependent translation. Catalytic inhibitors include: BEZ235 or 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5- c]quinolin-1-yl)-phenyl]propionitrile, or the monotosylate salt form. the synthesis of BEZ235 is described in WO2006/122806; CCG168 (otherwise known as AZD-8055, Chresta, C. M., et al., Cancer Res, 2010, 70(1), 288-298) which has the chemical name {5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol; 3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide (WO09104019); 3-(2-aminobenzo[d]oxazol-5-yl)-1-isopropyl-1H-pyrazolo [3,4-d]pyrimidin-4-amine (WO10051043 and WO2012023184); A N-(3-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxaline-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide (WO07044729 and WO12006552); PKI-587 (Venkatesan, A. M., J. Med. Chem., 2010, 53, 2636-2645) which has the chemical name 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl]urea; GSK-2126458 (ACS Med. Chem. Lett., 2010, 1, 39-43) which has the chemical name 2,4-difluoro-N-{2-methoxy-5[-4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide; 5-(9-isopropyl-8-methyl-2-morpholino-9H-purin-6-yl)pyrimidin-2-amine (WO10114484); (E)-N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-(6- (2 -cyanopropan-2 -yl)pyridin-3 -yl)-3-methyl-H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (WO12007926). Further examples of catalytic mTOR inhibitors include 8-(6-methoxy-pyridin-3 -yl)-3 -methyl-1-(4-piperazin-1-yl-3trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (WO2006/122806) and Ku-0063794 (Garcia-Martinez J M, et al., Biochem J., 2009, 421(1), 29-42. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR).) WYE-354 is another example of a catalytic mTor inhibitor (Yu K, et al. (2009). Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin. Cancer Res. 69(15): 6232-6240). mTOR inhibitors useful according to the present invention also include prodrugs, derivatives, pharmaceutically acceptable salts, or analogs thereof of any of the foregoing. mTOR inhibitors, such as RAD001, may be formulated for delivery based on well-established methods in the art based on the particular dosages described herein. In particular, U.S. Pat. No. 6,004,973 (incorporated herein by reference) provides examples of formulations useable with the mTOR inhibitors described herein. Evaluation of mTOR Inhibition mTOR phosphorylates the kinase P70 S6, thereby activating P70 S6 kinase and allowing it to phosphorylate its substrate. The extent of mTOR inhibition can be expressed as the extent of P70 S6 kinase inhibition, e.g., the extent of mTOR inhibition can be determined by the level of decrease in P70 S6 kinase activity, e.g., by the decrease in phosphorylation of a P70 S6 kinase substrate. One can determine the level of mTOR inhibition, by measuring P70 S6 kinase activity (the ability of P70 S6 kinase to phosphorylate a substrate), in the absence of inhibitor, e.g., prior to administration of inhibitor, and in the presence of inhibitor, or after the administration of inhibitor. The level of inhibition of P70 S6 kinase gives the level of mTOR inhibition. Thus, if P70 S6 kinase is inhibited by 40%, mTOR activity, as measured by P70 S6 kinase activity, is inhibited by 40%. The extent or level of inhibition referred to herein is the average level of inhibition over the dosage interval. By way of example, if the inhibitor is given once per week, the level of inhibition is given by the average level of inhibition over that interval, namely a week. Boulay et al., Cancer Res, 2004, 64:252-61, hereby incorporated by reference, teaches an assay that can be used to assess the level of mTOR inhibition (referred to herein as the Boulay assay). In an embodiment, the assay relies on the measurement of P70 S6 kinase activity from biological samples before and after administration of an mTOR inhibitor, e.g., RAD001. Samples can be taken at preselected times after treatment with an mTOR inhibitor, e.g., 24, 48, and 72 hours after treatment. Biological samples, e.g., from skin or peripheral blood mononuclear cells (PBMCs) can be used. Total protein extracts are prepared from the samples. P70 S6 kinase is isolated from the protein extracts by immunoprecipitation using an antibody that specifically recognizes the P70 S6 kinase. Activity of the isolated P70 S6 kinase can be measured in an in vitro kinase assay. The isolated kinase can be incubated with 40S ribosomal subunit substrates (which is an endogenous substrate of P70 S6 kinase) and gamma-32P under conditions that allow phosphorylation of the substrate. Then the reaction mixture can be resolved on an SDS-PAGE gel, and32P signal analyzed using a PhosphorImager. A32P signal corresponding to the size of the 40S ribosomal subunit indicates phosphorylated substrate and the activity of P70 S6 kinase. Increases and decreases in kinase activity can be calculated by quantifying the area and intensity of the32P signal of the phosphorylated substrate (e.g., using ImageQuant, Molecular Dynamics), assigning arbitrary unit values to the quantified signal, and comparing the values from after administration with values from before administration or with a reference value. For example, percent inhibition of kinase activity can be calculated with the following formula: 1-(value obtained after administration/value obtained before administration)×100. As described above, the extent or level of inhibition referred to herein is the average level of inhibition over the dosage interval. Methods for the evaluation of kinase activity, e.g., P70 S6 kinase activity, are also provided in U.S. Pat. No. 7,727,950, hereby incorporated by reference. The level of mTOR inhibition can also be evaluated by a change in the ration of PD1 negative to PD1 positive T cells. T cells from peripheral blood can be identified as PD1 negative or positive by art-known methods. Low-Dose mTOR Inhibitors Methods described herein use low, immune enhancing, dose mTOR inhibitors, doses of mTOR inhibitors, e.g., allosteric mTOR inhibitors, including rapalogs such as RAD001. In contrast, levels of inhibitor that fully or near fully inhibit the mTOR pathway are immunosuppressive and are used, e.g., to prevent organ transplant rejection. In addition, high doses of rapalogs that fully inhibit mTOR also inhibit tumor cell growth and are used to treat a variety of cancers (See, e.g., Antineoplastic effects of mammalian target of rapamycine inhibitors. Salvadori M. World J Transplant. 2012 Oct. 24; 2(5):74-83; Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition. Finn R S. Liver Cancer. 2012 November; 1(3-4):247-256; Emerging Signaling Pathways in Hepatocellular Carcinoma. Moeini A, Cornella H, Villanueva A. Liver Cancer. 2012 September; 1(2):83-93; Targeted cancer therapy—Are the days of systemic chemotherapy numbered?Joo W D, Visintin I, Mor G. Maturitas. 2013 September 20; Role of natural and adaptive immunity in renal cell carcinoma response to VEGFR-TKIs and mTOR inhibitor. Santoni M, Berardi R, Amantini C, Burattini L, Santini D, Santoni G, Cascinu S. Int J Cancer. 2013 Oct. 2). The present invention is based, at least in part, on the surprising finding that doses of mTOR inhibitors well below those used in current clinical settings had a superior effect in increasing an immune response in a subject and increasing the ratio of PD-1 negative T cells/PD-1 positive T cells. It was surprising that low doses of mTOR inhibitors, producing only partial inhibition of mTOR activity, were able to effectively improve immune responses in human subjects and increase the ratio of PD-1 negative T cells/PD-1 positive T cells. Alternatively, or in addition, without wishing to be bound by any theory, it is believed that low, a low, immuni enhancing, dose of an mTOR inhibitor can increase naive T cell numbers, e.g., at least transiently, e.g., as compared to a non-treated subject. Alternatively or additionally, again while not wishing to be bound by theory, it is believed that treatment with an mTOR inhibitor after a sufficient amount of time or sufficient dosing results in one or more of the following: an increase in the expression of one or more of the following markers: CD62LhighCD127high, CD27+, and BCL2, e.g., on memory T cells, e.g., memory T cell precursors; a decrease in the expression of KLRG1, e.g., on memory T cells, e.g., memory T cell precursors; and an increase in the number of memory T cell precursors, e.g., cells with any one or combination of the following characteristics: increased CD62Lhigh, increased CD127highincreased CD27+, decreased KLRG1, and increased BCL2; and wherein any of the changes described above occurs, e.g., at least transiently, e.g., as compared to a non-treated subject (Araki, K et al. (2009) Nature 460:108-112). Memory T cell precursors are memory T cells that are early in the differentiation program. For example, memory T cells have one or more of the following characteristics: increased CD62Lhighincreased CD127high, increased CD27+, decreased KLRG1, and/or increased BCL2. In an embodiment, the invention relates to a composition, or dosage form, of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., a rapalog, rapamycin, or RAD001, or a catalytic mTOR inhibitor, which, when administered on a selected dosing regimen, e.g., once daily or once weekly, is associated with: a level of mTOR inhibition that is not associated with complete, or significant immune suppression, but is associated with enhancement of the immune response. An mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., a rapalog, rapamycin, or RAD001, or a catalytic mTOR inhibitor, can be provided in a sustained release formulation. Any of the compositions or unit dosage forms described herein can be provided in a sustained release formulation. In some embodiments, a sustained release formulation will have lower bioavailability than an immediate release formulation. E.g., in embodiments, to attain a similar therapeutic effect of an immediate release formation a sustained release formulation will have from about 2 to about 5, about 2.5 to about 3.5, or about 3 times the amount of inhibitor provided in the immediate release formulation. In an embodiment, immediate release forms, e.g., of RAD001, typically used for one administration per week, having 0.1 to 20, 0.5 to 10, 2.5 to 7.5, 3 to 6, or about 5, mgs per unit dosage form, are provided. For once per week administrations, these immediate release formulations correspond to sustained release forms, having, respectively, 0.3 to 60, 1.5 to 30, 7.5 to 22.5, 9 to 18, or about 15 mgs of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., rapamycin or RAD001. In embodiments both forms are administered on a once/week basis. In an embodiment, immediate release forms, e.g., of RAD001, typically used for one administration per day, having 0.005 to 1.5, 0.01 to 1.5, 0.1 to 1.5, 0.2 to 1.5, 0.3 to 1.5, 0.4 to 1.5, 0.5 to 1.5, 0.6 to 1.5, 0.7 to 1.5, 0.8 to 1.5, 1.0 to 1.5, 0.3 to 0.6, or about 0.5 mgs per unit dosage form, are provided. For once per day administrations, these immediate release forms correspond to sustained release forms, having, respectively, 0.015 to 4.5, 0.03 to 4.5, 0.3 to 4.5, 0.6 to 4.5, 0.9 to 4.5, 1.2 to 4.5, 1.5 to 4.5, 1.8 to 4.5, 2.1 to 4.5, 2.4 to 4.5, 3.0 to 4.5, 0.9 to 1.8, or about 1.5 mgs of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., rapamycin or RAD001. For once per week administrations, these immediate release forms correspond to sustained release forms, having, respectively, 0.1 to 30, 0.2 to 30, 2 to 30, 4 to 30, 6 to 30, 8 to 30, 10 to 30, 1.2 to 30, 14 to 30, 16 to 30, 20 to 30, 6 to 12, or about 10 mgs of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., rapamycin or RAD001. In an embodiment, immediate release forms, e.g., of RAD001, typically used for one administration per day, having 0.01 to 1.0 mgs per unit dosage form, are provided. For once per day administrations, these immediate release forms correspond to sustained release forms, having, respectively, 0.03 to 3 mgs of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., rapamycin or RAD001. For once per week administrations, these immediate release forms correspond to sustained release forms, having, respectively, 0.2 to 20 mgs of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., rapamycin or RAD001. In an embodiment, immediate release forms, e.g., of RAD001, typically used for one administration per week, having 0.5 to 5.0 mgs per unit dosage form, are provided. For once per week administrations, these immediate release forms correspond to sustained release forms, having, respectively, 1.5 to 15 mgs of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., rapamycin or RAD001. As described above, one target of the mTOR pathway is the P70 S6 kinase. Thus, doses of mTOR inhibitors which are useful in the methods and compositions described herein are those which are sufficient to achieve no greater than 80% inhibition of P70 S6 kinase activity relative to the activity of the P70 S6 kinase in the absence of an mTOR inhibitor, e.g., as measured by an assay described herein, e.g., the Boulay assay. In a further aspect, the invention provides an amount of an mTOR inhibitor sufficient to achieve no greater than 38% inhibition of P70 S6 kinase activity relative to P70 S6 kinase activity in the absence of an mTOR inhibitor. In one aspect the dose of mTOR inhibitor useful in the methods and compositions of the invention is sufficient to achieve, e.g., when administered to a human subject, 90+/−5% (i.e., 85-95%), 89+/−5%, 88+/−5%, 87+/−5%, 86+/−5%, 85+/−5%, 84+/−5%, 83+/−5%, 82+/−5%, 81+/−5%, 80+/−5%, 79+/−5%, 78+/−5%, 77+/−5%, 76+/−5%, 75+/−5%, 74+/−5%, 73+/−5%, 72+/−5%, 71+/−5%, 70+/−5%, 69+/−5%, 68+/−5%, 67+/−5%, 66+/−5%, 65+/−5%, 64+/−5%, 63+/−5%, 62+/−5%, 61+/−5%, 60+/−5%, 59+/−5%, 58+/−5%, 57+/−5%, 56+/−5%, 55+/−5%, 54+/−5%, 54+/−5%, 53+/−5%, 52+/−5%, 51+/−5%, 50+/−5%, 49+/−5%, 48+/−5%, 47+/−5%, 46+/−5%, 45+/−5%, 44+/−5%, 43+/−5%, 42+/−5%, 41+/−5%, 40+/−5%, 39+/−5%, 38+/−5%, 37+/−5%, 36+/−5%, 35+/−5%, 34+/−5%, 33+/−5%, 32+/−5%, 31+/−5%, 30+/−5%, 29+/−5%, 28+/−5%, 27+/−5%, 26+/5−%, 25+/−5%, 24+/−5%, 23+/−5%, 22+/−5%, 21+/−5%, 20+/−5%, 19+/−5%, 18+/−5%, 17+/−5%, 16+/−5%, 15+/5−%, 14+/−5%, 13+/−5%, 12+/−5%, 11+/−5%, or 10+/−5%, inhibition of P70 S6 kinase activity, e.g., as measured by an assay described herein, e.g., the Boulay assay. P70 S6 kinase activity in a subject may be measured using methods known in the art, such as, for example, according to the methods described in U.S. Pat. No. 7,727,950, by immunoblot analysis of phosphoP70 S6K levels and/or phosphoP70 S6 levels or by in vitro kinase activity assays. As used herein, the term “about” in reference to a dose of mTOR inhibitor refers to up to a +/−10% variability in the amount of mTOR inhibitor, but can include no variability around the stated dose. In some embodiments, the invention provides methods comprising administering to a subject an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, at a dosage within a target trough level. In some embodiments, the trough level is significantly lower than trough levels associated with dosing regimens used in organ transplant and cancer patients. In an embodiment mTOR inhibitor, e.g., RAD001, or rapamycin, is administered to result in a trough level that is less than ½, ¼, 1/10, or 1/20 of the trough level that results in immunosuppression or an anticancer effect. In an embodiment mTOR inhibitor, e.g., RAD001, or rapamycin, is administered to result in a trough level that is less than ½, ¼, 1/10, or 1/20 of the trough level provided on the FDA approved packaging insert for use in immunosuppression or an anticancer indications. In an embodiment a method disclosed herein comprises administering to a subject an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, at a dosage that provides a target trough level of 0.1 to 10 ng/ml, 0.1 to 5 ng/ml, 0.1 to 3 ng/ml, 0.1 to 2 ng/ml, or 0.1 to 1 ng/ml. In an embodiment a method disclosed herein comprises administering to a subject an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, at a dosage that provides a target trough level of 0.2 to 10 ng/ml, 0.2 to 5 ng/ml, 0.2 to 3 ng/ml, 0.2 to 2 ng/ml, or 0.2 to 1 ng/ml. In an embodiment a method disclosed herein comprises administering to a subject an mTOR inhibitor, e.g. an, allosteric inhibitor, e.g., RAD001, at a dosage that provides a target trough level of 0.3 to 10 ng/ml, 0.3 to 5 ng/ml, 0.3 to 3 ng/ml, 0.3 to 2 ng/ml, or 0.3 to 1 ng/ml. In an embodiment a method disclosed herein comprises administering to a subject an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, at a dosage that provides a target trough level of 0.4 to 10 ng/ml, 0.4 to 5 ng/ml, 0.4 to 3 ng/ml, 0.4 to 2 ng/ml, or 0.4 to 1 ng/ml. In an embodiment a method disclosed herein comprises administering to a subject an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, at a dosage that provides a target trough level of 0.5 to 10 ng/ml, 0.5 to 5 ng/ml, 0.5 to 3 ng/ml, 0.5 to 2 ng/ml, or 0.5 to 1 ng/ml. In an embodiment a method disclosed herein comprises administering to a subject an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, at a dosage that provides a target trough level of 1 to 10 ng/ml, 1 to 5 ng/ml, 1 to 3 ng/ml, or 1 to 2 ng/ml. As used herein, the term “trough level” refers to the concentration of a drug in plasma just before the next dose, or the minimum drug concentration between two doses. In some embodiments, a target trough level of RAD001 is in a range of between about 0.1 and 4.9 ng/ml. In an embodiment, the target trough level is below 3 ng/ml, e.g., is between 0.3 or less and 3 ng/ml. In an embodiment, the target trough level is below 3 ng/ml, e.g., is between 0.3 or less and 1 ng/ml. In a further aspect, the invention can utilize an mTOR inhibitor other than RAD001 in an amount that is associated with a target trough level that is bioequivalent to the specified target trough level for RAD001. In an embodiment, the target trough level for an mTOR inhibitor other than RAD001, is a level that gives the same level of mTOR inhibition (e.g., as measured by a method described herein, e.g., the inhibition of P70 S6) as does a trough level of RAD001 described herein. Pharmaceutical Compositions: mTOR Inhibitors In one aspect, the present invention relates to pharmaceutical compositions comprising an mTOR inhibitor, e.g., an mTOR inhibitor as described herein, formulated for use in combination with CAR cells described herein. In some embodiments, the mTOR inhibitor is formulated for administration in combination with an additional, e.g., as described herein. In general, compounds of the invention will be administered in therapeutically effective amounts as described above via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. The pharmaceutical formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (e.g., an mTOR inhibitor or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described herein. The mTOR inhibitor is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product. Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Where an mTOR inhibitor is administered in combination with (either simultaneously with or separately from) another agent as described herein, in one aspect, both components can be administered by the same route (e.g., parenterally). Alternatively, another agent may be administered by a different route relative to the mTOR inhibitor. For example, an mTOR inhibitor may be administered orally and the other agent may be administered parenterally. Sustained Release mTOR inhibitors, e.g., allosteric mTOR inhibitors or catalytic mTOR inhibitors, disclosed herein can be provided as pharmaceutical formulations in form of oral solid dosage forms comprising an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001, which satisfy product stability requirements and/or have favorable pharmacokinetic properties over the immediate release (IR) tablets, such as reduced average plasma peak concentrations, reduced interand intra-patient variability in the extent of drug absorption and in the plasma peak concentration, reduced Cmax/Cminratio and/or reduced food effects. Provided pharmaceutical formulations may allow for more precise dose adjustment and/or reduce frequency of adverse events thus providing safer treatments for patients with an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001. In some embodiments, the present disclosure provides stable extended release formulations of an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001, which are multi-particulate systems and may have functional layers and coatings. The term “extended release, multi-particulate formulation as used herein refers to a formulation which enables release of an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001, over an extended period of time e.g. over at least 1, 2, 3, 4, 5 or 6 hours. The extended release formulation may contain matrices and coatings made of special excipients, e.g., as described herein, which are formulated in a manner as to make the active ingredient available over an extended period of time following ingestion. The term “extended release” can be interchangeably used with the terms “sustained release” (SR) or “prolonged release”. The term “extended release” relates to a pharmaceutical formulation that does not release active drug substance immediately after oral dosing but over an extended in accordance with the definition in the pharmacopoeias Ph. Eur. (7thedition) monograph for tablets and capsules and USP general chapter <1151> for pharmaceutical dosage forms. The term “Immediate Release” (IR) as used herein refers to a pharmaceutical formulation which releases 85% of the active drug substance within less than 60 minutes in accordance with the definition of “Guidance for Industry: “Dissolution Testing of Immediate Release Solid Oral Dosage Forms” (FDA CDER, 1997). In some embodiments, the term “immediate release” means release of a drug, e.g., an mTOR inhibitor, e.g., everolimus from tablets within the time of 30 minutes, e.g., as measured in the dissolution assay described herein. Stable extended release formulations of an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001, can be characterized by an in-vitro release profile using assays known in the art, such as a dissolution assay as described herein: a dissolution vessel filled with 900 mL phosphate buffer pH 6.8 containing sodium dodecyl sulfate 0.2% at 37° C. and the dissolution is performed using a paddle method at 75 rpm according to USP by according to USP testing monograph 711, and Ph. Eur. testing monograph 2.9.3. respectively. In some embodiments, stable extended release formulations of an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001, release the mTOR inhibitor in the in-vitro release assay according to following release specifications: 0.5 h: <45%, or <40, e.g., <30% 1 h: 20-80%, e.g., 30-60% 2 h: >50%, or >70%, e.g., >75% 3 h: >60%, or >65%, e.g., >85%, e.g., >90%. In some embodiments, stable extended release formulations of an mTOR inhibitor disclosed herein, e.g., rapamycin or RAD001, release 50% of the mTOR inhibitor not earlier than 45, 60, 75, 90, 105 min or 120 min in the in-vitro dissolution assay. ROR1 Inhibitors Also provided herein are ROR1 inhibitors and combination therapies, e.g., combinations of a CD20 CAR-expressing cell described herein with a ROR1 inhibitor. ROR1 inhibitors include but are not limited to anti-ROR1 CAR-expressing cells, e.g. CARTs, and anti-ROR antibodies (e.g., an anti-ROR1 mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-ROR1 inhibitors can be used to treat a disease described herein. An exemplary anti-ROR1 inhibitor is described in Hudecek, et al. Clin. Cancer Res. 19.12 (2013):3153-64, incorporated herein by reference. For example, an anti-ROR1 inhibitor includes the anti-ROR1 CARTs described in Hudecek et al. (for example, generated as described in Hudecek et al. at page 3155, first full paragraph, incorporated herein by reference). In other examples, an anti-ROR1 inhibitor includes an antibody or fragment thereof comprising the VH and/or VL sequences of the 2A2 and R12 anti-ROR1 monoclonal antibodies described in Hudecek et al. at paragraph bridging pages 3154-55; Baskar et al. MAbs 4(2012):34961; and Yang et al. PLoS ONE 6(2011):e21018, incorporated herein by reference. In some embodiments, a ROR1 inhibitor includes an antibody or fragment thereof (e.g., single chain variable fragment (scFv)) that targets ROR1, including those described in US 2013/0101607, e.g., SEQ ID NOs: 1 or 2 of US 2013/0101607, incorporated herein by reference. In some embodiments, anti-ROR1 antibody fragments (e.g., scFvs) are conjugated or fused to a biologically active molecule, e.g., to form a chimeric antigen receptor (CAR) that directs immune cells, e.g., T cells or NK cells, to respond to ROR1-expressing cells. In some embodiments, an exemplary ROR1 inhibitor includes an anti-ROR1 monoclonal antibody called UC-961 (Cirmtuzumab). See, e.g., Clinical Trial Identifier No. NCT02222688. Cirmtuzumab can be used to treat cancers, such as chronic lymphocytic leukemia (CLL), ovarian cancer, and melanoma. See, e.g., Hojjat-Farsangi et al. PLoS One. 8(4): e61167; and NCT02222688. In some embodiments, cirmtuzumab is administered intravenously, e.g., as an intravenous infusion. For example, each infusion provides about 700-7000 μg (e.g., 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1500, 1500-2000, 2000-2500, 2500-3000, 3000-3500, 3500-4000, 4000-4500, 4500-5000, 5000-5500, 5500-6000, 6000-6500, or 6500-7000 μg) of cirmtuzumab. In some embodiments, cirmtuzumab is administered at a dose of 10-100 μg/kg body weight, e.g., 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, or 95-100 μg/kg body weight. In one embodiment, cirmtuzumab is administered at a starting dose of 15 μg/kg body weight. In some embodiments, cirmtuzumab is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. For example, cirmtuzumab is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, cirmtuzumab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, cirmtuzumab is administered at a dose and dosing interval described herein for a total of at least 2 doses per treatment cycle (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some embodiments, the anti-ROR1 antibody is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a ROR1 inhibitor includes an anti-ROR1 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-ROR1 CAR construct or encoded by a ROR1 binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-ROR1 CAR-expressing cell, e.g., CART is a generated by engineering a ROR1-CAR (that comprises a ROR1 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and ROR1 CARs. For example, in one embodiment, the population of CAR-expressing cell can include a first cell expressing a CD20 CAR and a second cell expressing a ROR1 CAR. In one embodiment, the population of CAR-expressing cells includes, e.g., a first cell expressing a CAR (e.g., a CD19 CAR, a ROR1 CAR, a CD20 CAR, or a CD22 CAR) that includes a primary intracellular signaling domain, and a second cell expressing a CAR (e.g., a CD19 CAR, a ROR1 CAR, a CD20 CAR, or a CD22 CAR)) that includes a secondary signaling domain. CD22 Inhibitors Provided herein are CD22 inhibitors and combination therapies, e.g., combinations of CD22 inhibitors with a CAR-expressing cell described herein (e.g., a CD20 CAR-epressing cell described herein). In one embodiment, the CD22 inhibitor is a CD22 inhibitor described herein. The CD22 inhibitor can be, e.g., an anti-CD22 antibody (e.g., an anti-CD22 mono- or bispecific antibody) or a CD22 CART, such as described in Table 6. In some embodiments the anti-CD22 antibody is conjugated or otherwise bound to a therapeutic agent. Exemplary therapeutic agents include, e.g., microtubule disrupting agents (e.g., monomethyl auristatin E) and toxins (e.g., diphtheria toxin or Pseudomonas exotoxin-A, ricin). In an embodiment, the anti-CD22 antibody is an anti-CD22 monoclonal antibody-MMAE conjugate (e.g., DCDT2980S). In an embodiment, the antibody is a scFv of an anti-CD22 antibody, e.g., a scFv of antibody RFB4. This scFv can be fused to all of or a fragment of Pseudomonas exotoxin-A (e.g., BL22). In an embodiment, the antibody is a humanized anti-CD22 monoclonal antibody (e.g., epratuzumab). In an embodiment, the antibody or fragment thereof comprises the Fv portion of an anti-CD22 antibody, which is optionally covalently fused to all or a fragment or (e.g., a 38 KDa fragment of) Pseudomonas exotoxin-A (e.g., moxetumomab pasudotox). In an embodiment, the anti-CD22 antibody is an anti-CD19/CD22 bispecific antibody, optionally conjugated to a toxin. For instance, in one embodiment, the anti-CD22 antibody comprises an anti-CD19/CD22 bispecific portion, (e.g., two scFv ligands, recognizing human CD19 and CD22) optionally linked to all of or a portion of diphtheria toxin (DT), e.g., first 389 amino acids of diphtheria toxin (DT), DT 390, e.g., a ligand-directed toxin such as DT2219ARL). In another embodiment, the bispecific portion (e.g., anti-CD19/anti-CD22) is linked to a toxin such as deglycosylated ricin A chain (e.g., Combotox). In one embodiment, the anti-CD22 antibody is selected from an anti-CD19/CD22 bispecific ligand-directed toxin (e.g., two scFv ligands, recognizing human CD19 and CD22, linked to the first 389 amino acids of diphtheria toxin (DT), DT 390, e.g., DT2219ARL); anti-CD22 monoclonal antibody-MMAE conjugate (e.g., DCDT2980S); scFv of an anti-CD22 antibody RFB4 fused to a fragment of Pseudomonas exotoxin-A (e.g., BL22); deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 (e.g., Combotox); humanized anti-CD22 monoclonal antibody (e.g., epratuzumab); or the Fv portion of an anti-CD22 antibody covalently fused to a 38 KDa fragment of Pseudomonas exotoxin-A (e.g., moxetumomab pasudotox). In one embodiment, the anti-CD22 antibody is an anti-CD19/CD22 bispecific ligand-directed toxin (e.g., DT2219ARL) and the anti-CD19/CD22 bispecific ligand-directed toxin is administered at a dose of about 1μg/kg, 2 μg/kg, 3 μg/kg, 4 μg/kg, 5μg/kg, 6μg/kg, 7 μg/kg, 8 μg/kg, 9 μg/kg, 10 μg/kg, 11 μg/kg, 12 μg/kg, 13 μg/kg, 14 μg/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 40 μg/kg, 60 μg/kg, 80 μg/kg, 100 μg/kg, 120 μg/kg, 140 μg/kg, 160 μg/kg, 180 μg/kg, 200 μg/kg, 220 μg/kg, 250 μg/kg, 300 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 600 μg/kg, 700 μg/kg, 800 μg/kg, 900 μg/kg, 1 mg·kg (e.g., 30 μg/kg, 40 μg/kg, 60 μg/kg, or 80 μg/kg) for a period of time, e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more days. In some embodiments, the anti-CD19/CD22 bispecific ligand-directed toxin is administered via intravenous infusion. In one embodiment, the anti-CD22 antibody is BL22 and BL22 is administered at a dose of about 1 μg/kg, 2 μg/kg, 3 μg/kg, 4 μg/kg, 5 μg/kg, 6μg/kg, 7μg/kg, 8 μg/kg, 9 μg/kg, 10 μg/kg, 11 μg/kg, 12 μg/kg, 13 μg/kg, 14 μg/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 40 μg/kg, 60 μg/kg, 80 μg/kg, 100 μg/kg, 120 μg/kg, 140 μg/kg, 160 μg/kg, 180 μg/kg, 200 μg/kg, 220 μg/kg, 250 μg/kg, 300 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 600 μg/kg, 700 μg/kg, 800 μg/kg, 900 μg/kg, 1 mg·kg (e.g., 3 μg/kg, 30 μg/kg, 40 μg/kg, or 50 μg/kg) for a period of time, e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more days. In some embodiments, BL22 is administered daily, every other day, every third, day, or every fourth day for a period of time, e.g., for a 4 day cycle, a 6 day cycle, an 8 day cycle, a 10 day cycle, a 12 day cycle, or a 14 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of BL22 are administered. In some embodiments, BL22 is administered via intravenous infusion. In one embodiment, the anti-CD22 antibody is a deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 (e.g., Combotox) and the deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 is administered at a dose of about 500 μg/m2, 600 μg/m2, 700 g/m2, 800 μg/m2, 900 μg/m2, 1 mg/m2, 2 mg/m2, 3 mg/m2, 4 mg/m2, 5 mg/m2, 6 mg/m2, or 7 mg/m2for a period of time, e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more days. In some embodiments, the deglycosylated ricin A chain-conjugated antiCD19/anti-CD22 is administered daily, every other day, every third, day, or every fourth day for a period of time, e.g., for a 4 day cycle, a 6 day cycle, an 8 day cycle, a 10 day cycle, a 12 day cycle, or a 14 day cycle (e.g., every other day for 6 days). In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of the deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 are administered. In some embodiments, the deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 is administered via intravenous infusion. In one embodiment, the anti-CD22 antibody is a humanized anti-CD22 monoclonal antibody (e.g., epratuzumab) and the humanized anti-CD22 monoclonal antibody is administered at a dose of about 10 mg/m2/week, 20 mg/m2/week, 50 mg/m2/week, 100 mg/m2/week, 120 mg/m2/week, 140 mg/m2/week, 160 mg/m2/week, 180 mg/m2/week, 200 mg/m2/week, 220 mg/m2/week, 250 mg/m2/week, 260 mg/m2/week, 270 mg/m2/week, 280 mg/m2/week, 290 mg/m2/week, 300 mg/m2/week, 305 mg/m2/week, 310 mg/m2/week, 320 mg/m2/week, 325 mg/m2/week, 330 mg/m2/week, 335 mg/m2/week, 340 mg/m2/week, 345 mg/m2/week, 350 mg/m2/week, 355 mg/m2/week, 360 mg/m2/week, 365 mg/m2/week, 370 mg/m2/week, 375 mg/m2/week, 380 mg/m2/week, 385 mg/m2/week, 390 mg/m2/week, 400 mg/m2/week, 410 mg/m2/week, 420 mg/m2/week, 430 mg/m2/week, 440 mg/m2/week, 450 mg/m2/week, 460 mg/m2/week, 470 mg/m2/week, 480 mg/m2/week, 490 mg/m2/week, 500 mg/m2/week, 600 mg/m2/week, 700 mg/m2/week, 800 mg/m2/week, 900 mg/m2/week, 1 g/m2/week, or 2 g/m2/week (e.g., 360 mg/m2/week or 480 mg/m2/week) for a period of time, e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks. In some embodiments a first dose is lower than subsequent doses (e.g. a first dose of 360 mg/m2/week followed by subsequent doses of 370 mg/m2/week). In some embodiments, the humanized anti-CD22 monoclonal antibody is administered via intravenous infusion. In one embodiment, the anti-CD22 antibody is moxetumomab pasudotox and moxetumomab pasudotox is administered at a dose of about 1 μg/kg, 2 μg/kg, 3μg/kg, 4 g/kg, 5 μg/kg, 6 μg/kg, 7 μg/kg, 8 μg/kg, 9 μg/kg, 10 μg/kg, 11 μg/kg, 12 μg/kg, 13 μg/kg, 14 g/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 40 μg/kg, 60 μg/kg, 80 μg/kg, 100 μg/kg, 120 g/kg, 140 μg/kg, 160 μg/kg, 180 μg/kg, 200 μg/kg, 220 μg/kg, 250 μg/kg, 300 μg/kg, 350 g/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg (e.g., 5 μg/kg, 10 μg/kg, 20 μg/kg, 30 μg/kg, 40 g/kg, or 50 μg/kg) a period of time, e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more days. In some embodiments, the moxetumomab pasudotox is administered daily, every other day, every third, day, or every fourth day for a period of time, e.g., for a 4 day cycle, a 6 day cycle, an 8 day cycle, a 10 day cycle, a 12 day cycle, or a 14 day cycle (e.g., every other day for 6 days). In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of the moxetumomab pasudotox are administered. In some embodiments, the moxetumomab pasudotox is administered via intravenous infusion. In one embodiment, the CD22 inhibitor includes a CD22 CAR-expressing cell, e.g., a CD22 CART, or e.g., a CD22-CAR that comprises a CD22 binding domain and is engineered into a cell (e.g., T cell or NK cell) for administration in combination with CD20 CART, and methods of their use for adoptive therapy. In some embodiments, the CD22 inhibitor includes a cell expressing a CD22 CAR construct or encoded by a CD22 CAR comprising a scFv, CDRs, or VH and VL chains. For example, a CD22 CAR-expressing cell, e.g., CART, is generated by engineering a CD22-CAR (that comprises a CD22 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein, e.g., a CD20 CART described herein. In another aspect, the present invention provides a population of CAR-expressing cells, e.g., CAR-expressing cell, comprising a mixture of cells expressing CD20 CARs and CD22 CARs. For example, in one embodiment, the population of CAR-expressing cell can include a first cell expressing a CD20 CAR and a second cell expressing a CD22 CAR. In one embodiment, the population of CAR-expressing cells includes, e.g., a first cell expressing a CAR (e.g., a CD20 CAR or CD22 CAR) that includes a primary intracellular signaling domain, and a second cell expressing a CAR (e.g., a CD20 CAR or CD22 CAR) that includes a secondary signaling domain. In one embodiment, CD20 CAR comprise or consist of sequences according to Table 1. In one embodiment, CD22 CAR comprise or consist of sequences according to Table 6. CD19 Inhibitors Provided herein are CD19 inhibitors and combination therapies, e.g., combinations of CD19 inhibitors with a CAR-expressing cell described herein (e.g., a CD20 CAR-expressing cell described herein or a CD22 CAR-expressing cell described herein). A CD19 inhibitor includes but is not limited to a CD19 CAR-expressing cell, e.g., a CD19 CAR-expressing cell, or an anti-CD19 antibody (e.g., an anti-CD19 mono- or bispecific antibody, which may comprise or consist of sequences according to Table 11) or a fragment or conjugate thereof. In an embodiment, the CD19 inhibitor is administered in combination with a CD20, CD22, or ROR1 inhibitor, e.g., a CD20, CD22, or ROR1 CAR-expressing cell, e.g., a CAR-expressing cell described herein. Exemplary anti-CD19 antibodies or fragments or conjugates thereof include but are not limited to blinatumomab, SAR3419 (Sanofi), MEDI-551 (MedImmune LLC), Combotox, DT2219ARL (Masonic Cancer Center), MOR-208 (also called XmAb-5574; MorphoSys), XmAb-5871 (Xencor), MDX-1342 (Bristol-Myers Squibb), SGN-CD19A (Seattle Genetics), and AFM11 (Aimed Therapeutics). See, e.g., Hammer. MAbs. 4.5 (2012): 571-77. In some aspects, the anti-CD19 antibody or fragment or conjugate thereof comprises blinatomomab. Blinatomomab is a bispecific antibody comprised of two scFvs-one that binds to CD19 and one that binds to CD3. Blinatomomab directs T cells to attack cancer cells. See, e.g., Hammer et al.; Clinical Trial Identifier No. NCT00274742 and NCT01209286. In some embodiments, blinatomomab can be used to treat NHL (e.g., DLBCL) or ALL. In some embodiments, blinatomomab is administered intravenously, e.g., as an intravenous infusion. In some embodiments, blinatomomab is administered at a dose of about 0.5 to 120 μg/m2/24 hours, e.g., about 0.5-1 μg/m2/24 hours, 1-5 μg/m2/24 hours, 5-15 μg/m2/24 hours, 15-30 μg/m2/24 hours, 30-60 μg/m2/24 hours, or 60-120 μg/m2/24 hours. In some embodiments, blinatomomab is administered at a dosing interval of at least 4 days, e.g., 4, 7, 14, 21, 28, 35 days, or more. For example, blinatomomab is administered at a dosing interval of at least 0.5 weeks, e.g., 0.5, 1, 2, 3, 4, 5, 6, 7, 8 weeks, or more. In some embodiments, blinatomomab is administered via a continuous intravenous infusion over 2-8 weeks per cycle, e.g., over 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 weeks per cycle. In some embodiments, blinatomomab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, or greater. For example, blinatomomab is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more doses per treatment cycle). In some aspects, the anti-CD19 antibody comprises MEDI-551. MEDI-551 is a humanized anti-CD19 antibody with a Fc engineered to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). See, e.g., Hammer et al.; and Clinical Trial Identifier No. NCT01957579. In some embodiments, MEDI-551 can be used to treat B cell malignancies (e.g., NHL, CLL, DLBCL, and multiple myeloma), multiple sclerosis, and scleroderma. In some embodiments, MEDI-551 is administered intravenously, e.g., as an intravenous infusion. In some cases, MEDI-551 is administered at a dose of about 0.5-12 mg/kg, e.g., 0.5-1 mg/kg, 1-2 mg/kg, 2-4 mg/kg, 4-8 mg/kg, or 8-12 mg/kg. In some embodiments, MEDI-551 is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, MEDI-551 is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. In some embodiments, MEDI-551 is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, MEDI-551 is administered at a dose and dosing interval described herein for a total of at least 2 doses per treatment cycle (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD19 antibody or fragment or conjugate thereof comprises Combotox. Combotox is a mixture of immunotoxins that bind to CD19 and CD22. The immunotoxins are made up of scFv antibody fragments fused to a deglycosylated ricin A chain. See, e.g., Hammer et al.; and Herrera et al. J. Pediatr. Hematol. Oncol. 31.12 (2009):936-41; Schindler et al. Br. J. Haematol. 154.4 (2011):471-6. In some embodiments, Combotox can be used to treat B cell leukemia, e.g., ALL. In some embodiments, Combotox is administered intravenously, e.g., as an intravenous infusion. In some cases, Combotox is administered at a dose of about 1-10 mg/m2, e.g., about 1-2 mg/m2, 2-3 mg/m2, 3-4 mg/m2, 4-5 mg/m2, or 5-6 mg/m2, 6-7 mg/m2, 7-8 mg/m2, 8-9 mg/m2, or 9-10 mg/m2. In some embodiments, Combotox is administered at a dosing interval of at least 2 days, e.g., 2, 3, 4, 5, 6, 7, 14, 21, 28, 35 days, or more. In some embodiments, Combotox is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, Combotox is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD19 antibody or fragment or conjugate thereof comprises DT2219ARL. DT2219ARL is a bispecific immunotoxin targeting CD19 and CD22, comprising two scFvs and a truncated diphtheria toxin. See, e.g., Hammer et al.; and Clinical Trial Identifier No. NCT00889408. In some embodiments, DT2219ARL can be used to treat B cell malignancies, e.g., B cell leukemias and lymphomas. In some embodiments, DT2219ARL is administered intravenously, e.g., as an intravenous infusion. In some embodiments, DT2219ARL is administered at a dose of about 20-100 μg/kg, e.g., about 20-40 μg/kg, 40-60 μg/kg, 60-80 μg/kg, or 80-100 μg/kg. In some embodiments, DT2219ARL is administered at a dosing interval of at least 2 days, e.g., 2, 3, 4, 5, 6, 7, 14, 21, 28, 35 days, or more. In some embodiments, DT2219ARL is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, DT2219ARL is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD19 antibody or fragment or conjugate thereof comprises SGN-CD19A. SGN-CD19A is an antibody-drug conjugate (ADC) comprised of an anti-CD19 humanized monoclonal antibody linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin F (MMAF). See, e.g., Hammer et al.; and Clinical Trial Identifier Nos. NCT01786096 and NCT01786135. In some embodiments, SGN-CD19A can be used to treat B-cell ALL, NHL (e.g., DLBCL, mantle cell lymphoma, or follicular lymphoma), Burkitt lymphoma or leukemia, or B-lineage lymphoblastic lymphoma (B-LBL). In some embodiments, SGN-CD19A is administered intravenously, e.g., as an intravenous infusion. In some embodiments, SGN-CD19A is administered at a dose of about 0.1-10 mg/kg, e.g., about 0.1-0.3 mg/kg, 0.3-0.6 mg/kg, 0.6-1 mg/kg, 1-2 mg/kg, 2-3 mg/kg, 3-4 mg/kg, 4-5 mg/kg, 5-6 mg/kg, 6-7 mg/kg, 7-8 mg/kg, 8-9 mg/kg, or 9-10 mg/kg. In some embodiments, SGN-CD19A is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. For example, SGN-CD19A is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, SGN-CD19A is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, SGN-CD19A is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD19 antibody comprises MOR-208 (also called XmAb-5574). MOR-208 is an Fc-engineered anti-CD19 humanized monoclonal antibody with enhanced FcγRIIIA binding, which results in improved ADCC activity. See, e.g., ClinicalTrials.gov Identifier Nos. NCT01685008, NCT01685021, NCT02005289, and NCT01161511; Hammer et al.; Woyach et al. Blood 124.24 (2014). In some embodiments, MOR-208 can be used to treat NHL (e.g., FL, MCL, DLBCL), CLL, small lymphocytic lymphoma, prolymphocytic leukemia, or B-cell Acute Lymphoblastic Leukemia (B-ALL). In some embodiments, MOR-208 is administered intravenously, e.g., as an intravenous infusion. In some embodiments, MOR-208 is administered at a dose of about 0.3 to 12 mg/kg, e.g., about 0.3-0.5 mg/kg, 0.5-1 mg/kg, 1-2 mg/kg, 2-4 mg/kg, 3-6 mg/kg, 6-9 mg/kg, or 9-12 mg/kg. In some embodiments, MOR-208 is administered at a dosing interval of at least 2 days, e.g., 2, 3, 4, 5, 6, 7, 14, 21, 28, 35 days, or more. For example, MOR-208 is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, MOR-208 is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, MOR-208 is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspect, the anti-CD19 antibody or fragment or conjugate thereof comprises SAR3419. SAR3419 is an anti-CD19 antibody-drug conjugate (ADC) comprising an anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivative via a cleavable linker. See, e.g., Younes et al. J. Clin. Oncol. 30.2 (2012): 2776-82; Hammer et al.; Clinical Trial Identifier No. NCT00549185; and Blanc et al. Clin Cancer Res. 2011; 17:6448-58. In some embodiments, SAR3419 can be used to treat NHL (diffuse large B-cell lymphoma (DLBCL) and follicular small cleaved cell lymphoma) or B-cell ALL. In some embodiments, SAR3419 is administered intravenously, e.g., as an intravenous infusion. In some embodiments, SAR3419 is administered at a dose of about 10-270 mg/m2, e.g., about 10-25 mg/m2, 25-50 mg/m2, 50-75 mg/m2, 75-100 mg/m2, 100-125 mg/m2, 125-150 mg/m2, 150-175 mg/m2, 175-200 mg/m2, 200-225 mg/m2, 225-250 mg/m2, or 250-270 mg/m2. In some embodiments, SAR3419 is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. For example, SAR3419 is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, SAR3419 is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, SAR3419 is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD19 antibody comprises XmAb-5871. XmAb-5871 is an Fc-engineered, humanized anti-CD19 antibody. In some embodiments, XmAb-5871 can be used to treat autoimmune diseases, such as lupus. See, e.g., Hammer et al. In some aspects, the anti-CD19 antibody comprises MDX-1342, which is a human Fc-engineered anti-CD19 antibody with enhanced ADCC. In some embodiments, MDX-1342 can be used to treat CLL and rheumatoid arthritis. See, e.g., Hammer et al. In some aspects, the anti-CD19 antibody comprises AFM11. AFM11 is a bispecific antibody that targets CD19 and CD3. In some embodiments, AFM11 can be used to treat NHL (e.g., DLBCL), ALL, or CLL. See, e.g., Hammer et al.; and Clinical Trial Identifier No. NCT02106091. In some embodiments, AFM11 is administered as an intravenous infusion. In some embodiments, an anti-CD19 antibody described herein is conjugated or otherwise bound to a therapeutic agent, e.g., a chemotherapeutic agent (e.g., a chemotherapeutic agent described herein), peptide vaccine (such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971), immunosuppressive agent (e.g., an immunosuppressive agent described herein), or immunoablative agent (e.g., an immunoablative agent described herein), e.g., cyclosporin, azathioprine, methotrexate, mycophenolate, FK506, CAMPATH, anti-CD3 antibody, cytoxin, fludarabine, rapamycin, mycophenolic acid, steroid, FR901228, or cytokine. In some embodiments, a CD19 inhibitor includes an anti-CD19 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD19 CAR construct. In an embodiment, the anti-CD19 CAR construct comprises a murine scFv sequence. For example, the anti-CD19 CAR construct comprising a murine scFv sequence is the CAR19 construct provided in PCT publication W02012/079000; a CAR19 construct provided in U.S. Pat. No. 7,446,190; a CAR19 construct provided in WO2014/031687; or a CAR19 construct provided in GenBank Accession No. HM852952 and provided herein as SEQ ID NO: 223. In one embodiment, the anti-CD19 binding domain is a scFv described in WO2012/079000. In one embodiment, the anti-CD19 binding domain is a scFv described in U.S. Pat. No. 7,446,190. In one embodiment, the anti-CD19 binding domain is a scFv described in WO2014/031687. In one embodiment, the anti-CD19 binding domain is a scFv described in GenBank Accession No. HM852952, or a sequence at least 95%, e.g., 95-99%, identical thereto. In an embodiment, the anti-CD19 binding domain is part of a CAR construct provided in PCT publication WO2012/079000. In an embodiment, the anti-CD19 binding domain is part of a CAR construct provided in U.S. Pat. No. 7,446,190. In an embodiment, the anti-CD19 binding domain is part of a CAR construct provided in WO2014/031687. In an embodiment, the anti-CD19 binding domain is part of a CAR construct provided in GenBank Accession No. HM852952. In some cases, the anti-CD19 antigen binding domain of the CAR is a scFv antibody fragment that is humanized compared to the murine sequence of the scFv from which it is derived. For example, the anti-CD19 antigen binding domain of the CAR is a humanized scFv antibody fragment, e.g., as described in PCT publication WO2014/153270, incorporated herein by reference. In an embodiment, the anti-CD19 binding domain comprises at least one (e.g., 2, 3, 4, 5, or 6) sequence from Table 11. For example, an anti-CD19 CAR-expressing cell, e.g., CART, is a generated by engineering a CD19-CAR (that comprises a CD19 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CAR-expressing cell, comprising a mixture of cells expressing CD20 CARs and CD19 CARs. For example, in one embodiment, the population of CAR-expressing cell can include a first cell expressing a CD20 CAR and a second cell expressing a CD19 CAR. CD123 Inhibitors CD123 is also called the alpha-chain of the interleukin-3 receptor (IL-3RA). The IL-3 receptor (IL-3R) is a heterodimer composed of alpha and beta chains. IL-3R is a membrane receptor. The IL-3Rα chain is a glycoprotein of 360 amino acid residues. Abnormalities of CD123 are frequently observed in some leukemic disorders. CD123 is overexpressed in multiple hematologic malignancies, e.g., acute myeloid and B-lymphoid leukemias, blastic plasmocytoid dendritic neoplasms (BPDCN) and hairy cell leukemia. Provided herein are CD123 inhibitors and combination therapies. CD123 inhibitors include but are not limited to small molecules, recombinant proteins, anti-CD123 CAR-expressing cells, e.g. CARTs, and anti-CD123 antibodies (e.g., an anti-CD123 mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-CD123 inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the CD123 inhibitor is administered in combination with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In one embodiment, the CD123 inhibitor is a recombinant protein, e.g., comprising the natural ligand (or a fragment) of the CD123 receptor. For example, the recombinant protein is SL-401 (also called DT388IL3; University of Texas Southwestern Medical Center), which is a fusion protein comprising human IL-3 fused to a truncated diphtheria toxin. See, e.g., Testa et al. Biomark Res. 2014; 2: 4; and Clinical Trial Identifier No. NCT00397579. In another embodiment, the CD123 inhibitor is an anti-CD123 antibody or fragment thereof. In one embodiment, the anti-CD123 antibody or fragment thereof comprises a monoclonal antibody, e.g., a monospecific or bispecific antibody or fragment thereof. For example, the anti-CD123 antibody or fragment thereof comprises CSL360 (CSL Limited). CSL360 is a recombinant chimeric monoclonal antibody that binds to CD123. In some embodiments, CSL360 is administered intravenously, e.g., by intravenous infusion. For example, CSL360 is administered at a dose of 0.1-10 mg/kg, e.g., 0.1-0.5 mg/kg, 0.5-1 mg/kg, 1-5 mg/kg, or 5-10 mg/kg. See, e.g., Clinical Trial Identifier No. NCT01632852; and Testa et al. In another embodiment, the CD123 antibody or fragment thereof comprises CSL362 (CSL Limited). CSL362 is a humanized monoclonal antibody that targets the CD123 and is optimized for enhanced activation of antibody dependent cell-mediated cytotoxicity (ADCC). In some embodiments, CSL362 is administered intravenously, e.g., by intravenous infusion. In some examples, CSL362 is administered at a dose of 0.1-12 mg/kg, 0.1-0.2 mg/kg, 0.2-0.5 mg/kg, 0.5-1 mg/kg, 1-6 mg/kg, or 6-12 mg/kg. See, e.g., Clinical Trial Identifier No. NCT01632852. In one embodiment, the CD123 antibody or fragment thereof comprises a bispecific antibody, e.g., MGD006 (MacroGenics). MGD006 is a bispecific antibody that targets CD123 and CD3. See, e.g., Clinical Trial Identifier No. NCT02152956. In some embodiments, the CD123 inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a CD123 inhibitor includes an anti-CD123 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD123 CAR construct or encoded by a CD123 binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-CD123 CAR-expressing cell, e.g., CART is a generated by engineering a CD123-CAR (that comprises a CD123 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. In an embodiment, the anti-CD123 CAR construct comprises a scFv sequence, e.g., a scFv sequence provided in US 2014/0322212 A1, incorporated herein by reference. In one embodiment, the anti-CD123 binding domain is a scFv described in US 2014/0322212 A1. In an embodiment, the anti-CD123 binding domain is part of a CAR construct provided in US 2014/0322212 A1. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and CD123 CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a CD123 CAR. CD10 Inhibitors Cluster of differentiation 10 (CD10) is also called Neprilysin, membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), and common acute lymphoblastic leukemia antigen (CALLA). CD10 is an enzyme encoded by the membrane metallo-endopeptidase (MME) gene. CD10 is expressed on leukemic cells of pre-B phenotype and is a common acute lymphocytic leukemia antigen. Also provided herein are CD10 inhibitors and combination therapies. CD10 inhibitors include but are not limited to small molecules, recombinant proteins, anti-CD10 CAR-expressing cells, e.g. CARTs, and anti-CD10 antibodies (e.g., an anti-CD10 mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-CD10 inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the CD10 inhibitor is administered in combination with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In an embodiment, the CD10 inhibitor comprises a small molecule, such as sacubitril (Novartis), valsartan/sacubritril (Novartis), omapatrilat (Bristol-Myers Squibb), RB-101, UK-414,495 (Pfizer), or a pharmaceutically acceptable salt or a derivative thereof. In an embodiment, the CD10 inhibitor comprises sacubitril (AHU-377; Novartis) (4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid), or a pharmaceutically acceptable salt or a derivative thereof The structure of sacubitril is shown below. In another embodiment, the CD10 inhibitor comprises valsartan/sacubritril (LCZ696; Novartis) or a pharmaceutically acceptable salt or a derivative thereof. Valsartan/sacubritril is a combination drug comprising a 1:1 mixture of valsartan and sacubitril. The structure of valsartan ((S)-3-methyl-2-(N-{[2′-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid) is shown below. In an embodiment, the CD10 inhibitor comprises omapatrilat (Bristol-Myers Squibb) ((4S,7S,10aS)-5-oxo-4-{[(2S)-3-phenyl-2-sulfanylpropanoyl]amino}-2,3,4,7,8,9,10,10a-octahydropyrido [6,1-b][1,3]thiazepine-7-carboxylic acid), or a pharmaceutically acceptable salt or a derivative thereof. The structure of omapatrilat is shown below. In an embodiment, the CD10 inhibitor comprises RB-101 (benzyl N-(3-{[(2S)-2-amino-4-(methylthio)butyl]dithio}-2-benzylpropanoyl)-L-phenylalaninate), or a pharmaceutical acceptable salt or a derivative thereof. The structure of RB-101 is shown below. In an embodiment, the CD10 inhibitor comprises UK-414,495 (Pfizer) ((R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl)carbamoyl]cyclopentyl}methyl)valeric acid), or a pharmaceutically acceptable salt or a derivative thereof. The structure of UK-414,495 is shown below. In some embodiments, the CD10 inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a CD10 inhibitor includes an anti-CD10 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD10 CAR construct or encoded by a CD10 binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-CD10 CAR-expressing cell, e.g., CART is a generated by engineering a CD10-CAR (that comprises a CD10 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and CD10 CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a CD10 CAR. CD34 Inhibitors Cluster of differentiation 34 (CD34) is also called hematopoietic progenitor cell antigen CD34 and is a cell surface glycoprotein that functions as a cell-cell adhesion factor. CD34 is sometimes expressed on some cancers/tumors, e.g., alveolar soft part sarcoma, preB-ALL, AML, AML-M7, dermatofibrosarcoma protuberans, gastrointestinal stromal tumors, giant cell fibroblastoma, granulocytic sarcoma, Kaposi's sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, mengingeal hemangiopericytomas, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma. Also provided herein are CD34 inhibitors and combination therapies. CD34 inhibitors include but are not limited to small molecules, recombinant proteins, anti-CD34 CAR-expressing cells, e.g. CARTs, and anti-CD34 antibodies (e.g., an anti-CD34 mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-CD34 inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the CD34 inhibitor is administered in combination with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In an embodiment, the CD34 inhibitor comprises a monoclonal antibody or fragment thereof that targets CD34 or an immunoliposome comprising an anti-CD34 monoclonal antibody or fragment thereof. In an embodiment, the CD34 inhibitor comprises an antibody or fragment thereof, e.g., the My-10 monoclonal antibody or an immunoliposome comprising the My-10 monoclonal antibody, as described in Mercadal et al. Biochim. Biophys. Acta. 1371.1 (1998):17-23. In some embodiments, the CD34 inhibitor comprises an immunoliposome containing a cancer drug, e.g., doxorubicin, that is targeted to CD34-expressing cells, as described in Carrion et al. Life Sci. 75.3 (2004):313-28. In an embodiment, the CD34 inhibitor comprises a monoclonal antibody against CD34 as described in Maleki et al. Hum. Antibodies. 22(2013):1-8. In another embodiment, the CD34 inhibitor comprises a monoclonal antibody that targets CD34, as described in Maleki et al. Cell J. 16.3 (2014):361-66. In some embodiments, the CD34 inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a CD34 inhibitor includes an anti-CD34 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD34 CAR construct or encoded by a CD34 binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-CD34 CAR-expressing cell, e.g., CART is a generated by engineering a CD34-CAR (that comprises a CD34 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and CD34 CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a CD34 CAR. FLT-3 Inhibitors Fms-like tyrosine kinase 3 (FLT-3), also called Cluster of differentiation antigen 135 (CD135), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2), is a receptor tyrosine kinase. FLT-3 is a cytokine receptor for the ligand, cytokine Flt3 ligand (FLT3L). FLT-3 is expressed on the surface of many hematopoietic progenitor cells and is important for lymphocyte development. The FLT3 gene is commonly mutated in leukemia, e.g., acute myeloid leukemia (AML). Also provided herein are FLT-3 inhibitors and combination therapies. FLT-3 inhibitors include but are not limited to small molecules, recombinant proteins, anti-FLT-3 CAR-expressing cells, e.g. CARTs, and anti-FLT-3 antibodies (e.g., an anti-FLT-3 mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-FLT-3 inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the FLT-3 inhibitor is administered in combinatiion with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In some embodiments, the FLT-3 inhibitor comprises a small molecule, such as quizartinib (Ambit Biosciences), midostaurin (Technische Universitat Dresden), sorafenib (Bayer and Onyx Pharmaceuticals), sunitinib (Pfizer), lestaurtinib (Cephalon), or a pharmaceutically acceptable salt or derivative thereof. In some embodiments, the FLT-3 inhibitor comprises quizartinib (AC220; Ambit Biosciences) or a pharmaceutically acceptable salt or a derivative thereof. Quizartinib is a small molecule receptor tyrosine kinase inhibitor. The structure of quizartinib (1-(5-(tert-Butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea) is shown below. In some embodiments, the FLT-3 inhibitor comprises midostaurin is (PKC412; Technische Universitat Dresden) or a pharmaceutically acceptable salt or a derivative thereof. Midostaurin is a protein kinase inhibitor that is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus. The structure of midostaurin ((9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methyl-amino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonine-1-one) is shown below. In some embodiments, midostaurin is administered orally, e.g., at a dose of about 25-200 mg, e.g., about 25-50 mg, 50-100 mg, 100-150 mg, or 150-200 mg. For example, midostaurin is administered, e.g., orally, at a dose of about 25-200 mg twice daily, e.g., about 25-50 mg, 50-100 mg, 100-150 mg, or 150-200 mg twice daily. See, e.g., Clinical Trial Identifier No. NCT01830361. In an embodiment, the FLT-3 inhibitor comprises sorafenib (Bayer and Onyx Pharmaceuticals) or a pharmaceutically acceptable salt or a derivative thereof. Sorafenib is a small molecular inhibitor of multiple tyrosine protein kinases (e.g., VEGFR and PDGFR), Raf kinases (e.g., C-Raf and B-Raf), and some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf, and mutant B-Raf). See, e.g., labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf. The structure of sorafenib (4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide) is shown below. In some embodiments, the FLT-3 inhibitor comprises sunitinib (previously known as SU11248; Pfizer) or a pharmaceutically acceptable salt or derivative thereof. Sunitinib is a small molecule oral drug that inhibits multiple receptor tyrosine kinases, including FLT3. Sunitinib has been approved by the Food and Drug Administration (FDA) for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). The structure of sunitinib (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1-H-pyrrole-3-carboxamide) is shown below. In some embodiments, the FLT-3 inhibitor comprises lestaurtinib (CEP-701; Cephalon) or a pharmaceutically acceptable salt or derivative thereof. Lestaurtinib is a tyrosine kinase inhibitor that is structurally related to staurosporine. The structure of lestaurtinib ((9S,10S,12R)-2,3,9,10,11,12-Hexahydro-10-hydroxy-10-(hydroxymethyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′--kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one) is shown below. In some embodiments, lestaurtinib is administered orally, e.g., at a dose of about 40-100 mg twice a day, e.g., about 40-60 mg, 50-70 mg, 60-80 mg, 70-90 mg, or 80-100 mg twice a day. See, e.g., Clinical Trial Identifier No. NCT00079482; or NCT00030186. In some embodiments, the FLT-3 inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a FLT-3 inhibitor includes an anti-FLT-3 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-FLT-3 CAR construct or encoded by a FLT-3 binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-FLT-3 CAR-expressing cell, e.g., CART is a generated by engineering a FLT-3-CAR (that comprises a FLT-3 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and FLT-3 CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a FLT-3 CAR. CD79b Inhibitors CD79b is also called immunoglobulin-associated beta, which is a component of the B lymphocyte antigen receptor multimeric complex. CD79b forms a heterodimer with another accessory protein called CD79a (immunoglobulin-associated alpha), and the heterodimer complexes with surface immunoglobulins on B cells. CD79b is important for the assembly of and surface expression of the B lymphocyte antigen receptor. CD79b and CD79a are important for pre-B-cell and B-cell development. Mutations and aberrant CD79b expression occurs in many B-CLL cells and may be correlated with the loss of surface expression and/or defective signaling of B lymphocyte antigen receptor in B-CLL. See, e.g., Thompson et al. Blood 90.4 (1997):1387-94. In some cases, overexpression of a mutant form or splice variant of CD79b has been correlated with diminished B lymphocyte antigen receptor in B-CLL and other lymphoid malignancies. See, e.g., Cragg et al. Blood 100.9 (2002): 3068-76. Provided herein are CD79b inhibitors and combination therapies. CD79b inhibitors include but are not limited to small molecules, recombinant proteins, anti-CD79b CAR-expressing cells, e.g. CARTs, and anti-CD79b antibodies (e.g., an anti-CD79b mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-CD79b inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the CD79b inhibitor is administered in combination with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In an embodiment, the CD79b inhibitor is an anti-CD79b antibody or fragment thereof. In one embodiment, the anti-79b antibody or fragment thereof comprises a monoclonal antibody, e.g., a monospecific or bispecific antibody or fragment thereof. For example, the anti-CD79b antibody or fragment thereof comprises polatuzumab vedotin (Roche), an anti-CD79b antibody drug conjugate. In embodiments, polatuzumab vedotin is used to treat a cancer, e.g., NHL, e.g., follicular lymphoma or DLBCL, e.g., relapsed or refractory follicular lymphoma or DLBCL. See, e.g., NCT02257567. In embodiments, the anti-CD79b antibody or fragment thereof comprises MGD010 (MacroGenics), which is a bispecific antibody comprising components that bind to CD32B and D79B. See, e.g., NCT02376036. In some embodiments, the CD79b inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a CD79b inhibitor includes an anti-CD79b CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD79b CAR construct or encoded by a CD79b binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-CD79b CAR-expressing cell, e.g., CART is a generated by engineering a CD79b-CAR (that comprises a CD79b binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and CD79b CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a CD79b CAR. CD79a Inhibitors CD79a is also called immunoglobulin-associated alpha. CD79a heterodimerizes with CD79b to form a component of the B lymphocyte antigen receptor multimeric complex. CD79a is expressed in many hematological cancers, e.g., acute leukemias (e.g., AML), B-cell Lymphomas, and Myelomas. Provided herein are CD79a inhibitors and combination therapies. CD79a inhibitors include but are not limited to small molecules, recombinant proteins, anti-CD79a CAR-expressing cells, e.g. CARTs, and anti-CD79a antibodies (e.g., an anti-CD79a mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-CD79a inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the CD79a inhibitor is administered in combination with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In an embodiment, the CD79a inhibitor is an anti-CD79a antibody or fragment thereof. In one embodiment, the anti-CD79a antibody or fragment thereof comprises a monoclonal antibody, e.g., a monospecific or bispecific antibody or fragment thereof. For example, the anti-CD79a antibody or fragment thereof comprises an anti-CD79a antibody or fragment thereof described in Polson et al. Blood 110.2 (2007):616-23, incorporated herein by reference. For example, the anti-CD79a antibody or fragment thereof comprises the 7H7, 15E4, or 16C11 antibody or fragment thereof described in Polson et al. See Id. In some embodiments, the CD79a inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a CD79a inhibitor includes an anti-CD79a CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD79a CAR construct or encoded by a CD79a binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-CD79a CAR-expressing cell, e.g., CART is a generated by engineering a CD79a-CAR (that comprises a CD79a binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and CD79a CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a CD79a CAR. CD179b Inhibitors CD179b is also called immunoglobulin lambda-like polypeptide 1 (IGLL1). CD179b is a subunit of a heterodimeric light chain that complexes with a membrane-bound Ig mu heavy chain. Together, the light chain and heavy chain form the preB cell receptor. Mutations in CD179b have been correlated with B cell deficiency and agammaglobulinemia. CD179b is expressed in some cancer cells, e.g., precursor B-cell lymphoblastic lymphoma cells. Provided herein are CD179b inhibitors and combination therapies. CD179b inhibitors include but are not limited to small molecules, recombinant proteins, anti-CD179b CAR-expressing cells, e.g. CARTs, and anti-CD179b antibodies (e.g., an anti-CD179b mono- or bispecific antibody) and fragments thereof. In some embodiments, anti-CD179b inhibitors can be used to treat a B-cell malignancy described herein. In an embodiment, the CD179b inhibitor is administered in combination with a CD20 inhibitor, e.g., a CD20 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. In an embodiment, the CD179b inhibitor is an anti-CD179b antibody or fragment thereof. In one embodiment, the anti-179b antibody or fragment thereof comprises a monoclonal antibody, e.g., a monospecific or bispecific antibody or fragment thereof. In some embodiments, the CD179b inhibitor is conjugated or otherwise bound to a therapeutic agent. In some embodiments, a CD179b inhibitor includes an anti-CD179b CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD179b CAR construct or encoded by a CD179b binding CAR comprising a scFv, CDRs, or VH and VL chains. For example, an anti-CD179b CAR-expressing cell, e.g., CART is a generated by engineering a CD179b-CAR (that comprises a CD179b binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, comprising a mixture of cells expressing CD20 CARs and CD179b CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CD20 CAR and a second cell expressing a CD179b CAR. CD20 Inhibitors Provided herein are CD20 inhibitors and combination therapies, e.g., one or more CD20 inhibitors. In some embodiments, the methods and compositions (e.g., CD20 CAR-expressing cells) described herein further include a second CD20 inhibitor. For example, a CD20 CAR-expressing cell described herein is administered in combination with a second CD20 inhibitor. A CD20 inhibitor includes but is not limited to a CD20 CAR-expressing cell, e.g., a CD20 CART cell, a CD20 CAR-expressing NK cell, or an antiCD20 antibody (e.g., an anti-CD20 mono- or bispecific antibody) or a fragment thereof. In one embodiment, the second CD20 inhibitor is an anti-CD20 antibody or fragment thereof. In an embodiment, the antibody is a monospecific antibody, and in another embodiment, the antibody is a bispecific antibody. In an embodiment, the CD20 inhibitor is a chimeric mouse/human monoclonal antibody, e.g., rituximab. In an embodiment, the CD20 inhibitor is a human monoclonal antibody such as ofatumumab. In an embodiment, the CD20 inhibitor is a humanized antibody such as ocrelizumab, veltuzumab, obinutuzumab, ocaratuzumab, or PRO131921 (Genentech). In an embodiment, the CD20 inhibitor is a fusion protein comprising a portion of an anti-CD20 antibody, such as TRU-015 (Trubion Pharmaceuticals). For example, the anti-CD20 antibody is chosen from rituximab, ofatumumab, ocrelizumab, veltuzumab, obinutuzumab, TRU-015 (Trubion Pharmaceuticals), ocaratuzumab, or Pro131921 (Genentech). See, e.g., Lim et al. Haematologica. 95.1 (2010):135-43. In some embodiments, the anti-CD20 antibody comprises rituximab. Rituximab is a chimeric mouse/human monoclonal antibody IgG1 kappa that binds to CD20 and causes cytolysis of a CD20 expressing cell, e.g., as described in www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s53111bl.pdf. In some embodiments, rituximab is administered intravenously, e.g., as an intravenous infusion. For example, each infusion provides about 500-2000 mg (e.g., about 500-550, 550-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1100, 1100-1200, 1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1800-1900, or 1900-2000 mg) of rituximab. In some embodiments, rituximab is administered at a dose of 150 mg/m2, to 750 mg/m2, e.g., about 150-175 mg/m2, 175-200 mg/m2, 200-225 mg/m2, 225-250 mg/m2, 250-300 mg/m2, 300-325 mg/m2, 325-350 mg/m2, 350-375 mg/m2, 375-400 mg/m2, 400-425 mg/m2, 425-450 mg/m2, 450-475 mg/m2, 475-500 mg/m2, 500-525 mg/m2, 525-550 mg/m2, 550-575 mg/m2, 575-600 mg/m2, 600-625 mg/m2, 625-650 mg/m2, 650-675 mg/m2, or 675-700 mg/m2, where m2indicates the body surface area of the subject. In some embodiments, rituximab is administered at a dosing interval of at least 4 days, e.g., 4, 7, 14, 21, 28, 35 days, or more. For example, rituximab is administered at a dosing interval of at least 0.5 weeks, e.g., 0.5, 1, 2, 3, 4, 5, 6, 7, 8 weeks, or more. In some embodiments, rituximab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, or greater. For example, rituximab is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more doses per treatment cycle). In some aspects, the anti-CD20 antibody comprises ofatumumab. Ofatumumab is an anti-CD20 IgGlκ human monoclonal antibody with a molecular weight of approximately 149 kDa. For example, ofatumumab is generated using transgenic mouse and hybridoma technology and is expressed and purified from a recombinant murine cell line (NS0). See, e.g., www.accessdata.fda.gov/drugsatfda_docs/label/2009/1253261bl.pdf; and Clinical Trial Identifier number NCT01363128, NCT01515176, NCT01626352, and NCT01397591. In some embodiments, ofatumumab is administered as an intravenous infusion. For example, each infusion provides about 150-3000 mg (e.g., about 150-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, 550-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1200, 1200-1400, 1400-1600, 1600-1800, 1800-2000, 2000-2200, 2200-2400, 2400-2600, 2600-2800, or 2800-3000 mg) of ofatumumab. In some embodiments, ofatumumab is administered at a dosing interval of at least 4 days, e.g., 4, 7, 14, 21, 28, 35 days, or more. For example, ofatumumab is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, ofatumumab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, ofatumumab is administered at a dose and dosing interval described herein for a total of at least 2 doses per treatment cycle (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD20 antibody comprises ocrelizumab. Ocrelizumab is a humanized anti-CD20 monoclonal antibody, e.g., as described in Clinical Trials Identifier Nos. NCT00077870, NCT01412333, NCT00779220, NCT00673920, NCT01194570, and Kappos et al. Lancet. 19.378 (2011):1779-87. In some embodiments, ocrelizumab is administered as an intravenous infusion. For example, each infusion provides about 50-2000 mg (e.g., about 50-100, 100-150, 150-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, 550-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1100, 1100-1200, 1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1800-1900, or 1900-2000 mg) of ocrelizumab. In some embodiments, ocrelizumab is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. For example, ocrelizumab is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, ocrelizumab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, ocrelizumab is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD20 antibody comprises veltuzumab. Veltuzumab is a humanized monoclonal antibody against CD20. See, e.g., Clinical Trial Identifier No. NCT00547066, NCT00546793, NCT01101581, and Goldenberg et al. Leuk Lymphoma. 51(5)(2010):747-55. In some embodiments, veltuzumab is administered subcutaneously or intravenously, e.g., as an intravenous infusion. In some embodiments, veltuzumab is administered at a dose of 50-800 mg/m2, e.g., about 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250, 250-275, 275-300, 300-325, 325-350, 350-375, 375-400, 400-425, 425-450, 450-475, 475-500, 500-525, 525-550, 550-575, 575-600, 600-625, 625-650, 650-675, 675-700, 700-725, 725-750, 750-775, or 775-800 mg/m2. In some embodiments, a dose of 50-400 mg, e.g., 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg of veltuzumab is administered. In some embodiments, veltuzumab is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. For example, veltuzumab is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, veltuzumab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, veltuzumab is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD20 antibody comprises GA101. GA101 (also called obinutuzumab or R05072759) is a humanized and glyco-engineered anti-CD20 monoclonal antibody. See, e.g., Robak. Curr. Opin. Investig. Drugs. 10.6 (2009):588-96; Clinical Trial Identifier Numbers: NCT01995669, NCT01889797, NCT02229422, and NCT01414205; and www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s0001bl.pdf. In some embodiments, GA101 is administered intravenously, e.g., as an intravenous infusion. For example, each infusion provides about 100-3000 mg (e.g., about 100-150, 150-200, 200-250, 250-500, 300-350, 350-400, 400-450, 450-500, 500-550, 550-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1200, 1200-1400, 1400-1600, 1600-1800, 1800-2000, 2000-2200, 2200-2400, 2400-2600, 2600-2800, or 2800-3000 mg) of GA101. In some embodiments, GA101 is administered at a dosing interval of at least 7 days, e.g., 7, 14, 21, 28, 35 days, or more. For example, GA101 is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. For example, GA101 is administered at a dosing interval of at least 1 month, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, GA101 is administered at a dosing interval of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments, GA101 is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, GA101 is administered at a dose and dosing interval described herein for a total of at least 2 doses per treatment cycle (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). In some aspects, the anti-CD20 antibody comprises AME-133v. AME-133v (also called LY2469298 or ocaratuzumab) is a humanized IgG1 monoclonal antibody against CD20 with increased affinity for the FcγRIIIa receptor and an enhanced antibody dependent cellular cytotoxicity (ADCC) activity compared with rituximab. See, e.g., Robak et al. BioDrugs 25.1 (2011):13-25; and Forero-Torres et al. Clin Cancer Res. 18.5 (2012):1395-403. In some aspects, the anti-CD20 antibody comprises PRO131921. PRO131921 is a humanized anti-CD20 monoclonal antibody engineered to have better binding to FcγRIIIa and enhanced ADCC compared with rituximab. See, e.g., Robak et al. BioDrugs 25.1 (2011):13-25; and Casulo et al. Clin Immunol. 154.1 (2014):37-46; Clinical Trial Identifier No. NCT00452127. In some embodiments, PRO131921 is administered intravenously, e.g., as an intravenous infusion. In some embodiments, PRO131921 is administered at a dose of 15 mg/m2to 1000 mg/m2, e.g., about 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, 95-100, 100-125, 125-150, 150-175, 175-200, 200-226, 225-250, 250-300, 300-325, 325-350, 350-375, 375-400, 400-425, 425-450, 450-475, 475-500, 500-525, 525-550, 550-575, 575-600, 600-625, 625-650, 650-675, 675-700, 700-725, 725-750, 750-775, 775-800, 800-825, 825-850, 850-875, 875-900, 900-925, 925-950, 950-975, or 975-1000 mg/m2, where m2indicates the body surface area of the subject. In some aspects, the anti-CD20 antibody comprises TRU-015. TRU-015 is an anti-CD20 fusion protein derived from domains of an antibody against CD20. TRU-015 is smaller than monoclonal antibodies, but retains Fc-mediated effector functions. See, e.g., Robak et al. BioDrugs 25.1 (2011):13-25. TRU-015 contains an anti-CD20 single-chain variable fragment (scFv) linked to human IgG1 hinge, CH2, and CH3 domains but lacks CH1 and CL domains. In some cases, TRU-015 is administered intravenously, e.g., as an intravenous infusion. In some embodiments, TRU-015 is administered at a dose of 0.01-30 mg/kg, e.g., 0.01-0.015, 0.015-0.05, 0.05-0.15, 0.15-0.5, 0.5-1, 1-1.5, 1.5-2.5, 2.5-5, 5-10, 10-15, 15-20, 20-25, or 25-30 mg/kg body weight. In some embodiments, TRU-015 is administered at a dosing interval of at least 1 day, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days apart. See, e.g., Burge et al. Clin Ther. 30.10 (2008):1806-16. In some embodiments, an anti-CD20 antibody described herein is conjugated or otherwise bound to a therapeutic agent, e.g., a chemotherapeutic agent (e.g., a chemotherapeutic agent described herein, e.g., cytoxan, fludarabine, histone deacetylase inhibitor, demethylating agent, peptide vaccine, anti-tumor antibiotic, tyrosine kinase inhibitor, alkylating agent, anti-microtubule or anti-mitotic agent, CD20 antibody, or CD20 antibody drug conjugate described herein), anti-allergic agent, anti-nausea agent (or anti-emetic), pain reliever, or cytoprotective agent described herein. In one embodiment, the antigen binding domain CAR (e.g., a CD19, ROR1, CD20, CD22, CD123, CD10, CD34, FLT-3, CD79b, CD179b, or CD79a antigen binding domain) comprises an scFv portion, e.g., a human, humanized, or murine scFv portion. The scFv may be preceded by an optional leader sequence such as provided in SEQ ID NO: 797, and followed by an optional hinge sequence such as provided in SEQ ID NO: 799 or SEQ ID NO: 814 or SEQ ID NO: 816, a transmembrane region such as provided in SEQ ID NO: 801, an intracellular signaling domain that includes SEQ ID NO: 803 and a CD3 zeta sequence that includes SEQ ID NO: 805 or SEQ ID NO: 807, e.g., wherein the domains are contiguous with and in the same reading frame to form a single fusion protein. In some embodiments, the present disclosure encompasses a recombinant nucleic acid construct comprising a nucleic acid molecule encoding a CAR (e.g., a CD19 CAR, a ROR1 CAR, a CD20 CAR, a CD22 CAR, a CD123 CAR, a CD10 CAR, a CD34 CAR, a FLT-3 CAR, a CD79b CAR, a CD179b CAR, or a CD79a CAR), wherein the nucleic acid molecule comprises the nucleic acid sequence encoding an antigen binding domain, e.g., described herein, e.g., that is contiguous with and in the same reading frame as a nucleic acid sequence encoding an intracellular signaling domain. n exemplary intracellular signaling domain that can be used in the CAR includes, but is not limited to, one or more intracellular signaling domains of, e.g., CD3-zeta, CD28, 4-1BB, and the like. In some instances, the CAR can comprise any combination of CD3-zeta, CD28, 4-1BB, and the like. In one embodiment, the antigen binding domain (e.g., a CD19, ROR1, CD20, CD22, CD123, CD10, CD34, FLT-3, CD79b, CD179b, or CD79a antigen binding domain) is characterized by particular functional features or properties of an antibody or antibody fragment. For example, in one embodiment, the portion of a CAR composition of the invention that comprises an antigen binding domain specifically binds a human B-cell antigen (e.g., CD19, ROR1, CD20, CD22, CD123, CD10, CD34, FLT-3, CD79b, CD179b, or CD79a) or a fragment thereof. In certain embodiments, the scFv is contiguous with and in the same reading frame as a leader sequence. In one aspect the leader sequence is the polypeptide sequence provided as SEQ ID NO: 797. In one embodiment, the antigen binding domain is a fragment, e.g., a single chain variable fragment (scFv). In one embodiment, the antigen binding domain is a Fv, a Fab, a (Fab′)2, or a bi-functional (e.g. bi-specific) hybrid antibody (e.g., Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)). In one aspect, the antibodies and fragments thereof of the invention binds a B-cell protein or a fragment thereof with wild-type or enhanced affinity. In some instances, a human scFv can be derived from a display library. In one embodiment, the antigen binding domain, e.g., scFv comprises at least one mutation such that the mutated scFv confers improved stability to the CAR construct. In another embodiment, the antigen binding domain, e.g., scFv comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mutations arising from, e.g., the humanization process such that the mutated scFv confers improved stability to the CAR construct. In one embodiment, the population of CAR-expressing cells includes, e.g., a first cell expressing a CAR (e.g., a CD19 CAR, a ROR1 CAR, a CD20 CAR, a CD22 CAR, a CD123 CAR, a CD10 CAR, a CD34 CAR, a FLT-3 CAR, a CD79b CAR, a CD179b CAR, or a CD79a CAR) that includes a primary intracellular signaling domain, and a second cell expressing a CAR (e.g., a CD19 CAR, a ROR1 CAR, a CD20 CAR, a CD22 CAR, a CD123 CAR, a CD10 CAR, a CD34 CAR, a FLT-3 CAR, a CD79b CAR, a CD179b CAR, or a CD79a CAR) that includes a secondary signaling domain. In some embodiments, a first and second CAR molecules are expressed in different cells, e.g., a first and second cells. In some embodiments, a first and second CAR molecules are expressed in the same cell, e.g., the same immune effector cell. In one embodiment, the first CAR molecule is a CD19 CAR and the second CAR molecule is a CD22. In one embodiment, the first CAR molecule is a CD19 CAR and the second CAR molecule is a CD20. In one embodiment, the first CAR molecule is a CD20 CAR and the second CAR molecule is a CD22. In some embodiments, the same cell or a different cell expresses two CARs (e.g., a CD19 CAR and a CD20 CAR described herein; a CD19 CAR and a CD22 CAR described herein; a CD20 CAR described herein and a CD22 CAR described herein; or more than two CARs, e.g., a CD22 CAR described herein, a CD20 CAR described herein and a CD19 CAR described herein. In some embodiments, nucleic acid encoding the more than one CAR molecules can be introduced into the cell on a single vector, for example with a 2A or IRES site disposed between the nucleic acid encoding the first and second CAR molecules, or can be introduced via more than one vector, for example, a first vector comprising nucleic acid sequence encoding a first CAR and a second vector comprising nucleic acid sequence encoding a second CAR. Pharmaceutical Compositions and Treatments Pharmaceutical compositions of the present invention may comprise a CAR-expressing cell, e.g., a plurality of CAR-expressing cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives. Compositions of the present invention are in one aspect formulated for intravenous administration. Pharmaceutical compositions of the present invention may be administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient's disease, although appropriate dosages may be determined by clinical trials. In one embodiment, the pharmaceutical composition is substantially free of, e.g., there are no detectable levels of a contaminant, e.g., selected from the group consisting of endotoxin, mycoplasma, replication competent lentivirus (RCL), p24, VSV-G nucleic acid, HIV gag, residual anti-CD3/anti-CD28 coated beads, mouse antibodies, pooled human serum, bovine serum albumin, bovine serum, culture media components, vector packaging cell or plasmid components, a bacterium and a fungus. In one embodiment, the bacterium is at least one selected from the group consisting of Alcaligenes faecalis, Candida albicans, Escherichia coli, Haemophilus influenza, Neisseria meningitides, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumonia, and Streptococcus pyogenes group A. When “an immunologically effective amount,” “an anti-tumor effective amount,” “a tumor-inhibiting effective amount,” or “therapeutic amount” is indicated, the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). In some embodiments, a pharmaceutical composition comprising the cells, e.g., T cells or NK cells described herein may be administered at a dosage of 104to 109cells/kg body weight, in some instances 105to 106cells/kg body weight, including all integer values within those ranges. In some embodiments, the cells, e.g., T cells or NK cells described herein may be administered at 3×104, 1×106, 3×106, or 1×107cells/kg body weight. The cell compositions may also be administered multiple times at these dosages. The cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med. 319:1676, 1988). In certain aspects, it may be desired to administer activated cells, e.g., T cells or NK cells, to a subject and then subsequently redraw blood (or have an apheresis performed), activate the cells therefrom according to the present invention, and reinfuse the patient with these activated and expanded cells. This process can be carried out multiple times every few weeks. In certain aspects, cells, e.g., T cells or NK cells, can be activated from blood draws of from 10 cc to 400 cc. In certain aspects, cells, e.g., T cells or NK cells, are activated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc, 80 cc, 90 cc, or 100 cc. The administration of the subject compositions may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The compositions described herein may be administered to a patient trans arterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally. In one aspect, the cell compositions, e.g., T cell or NK cell compositions, of the present invention are administered to a patient by intradermal or subcutaneous injection. In one aspect, the cell compositions, e.g., T cell or NK cell compositions, of the present invention are administered by i.v. injection. The compositions of cells, e.g., T cell or NK cell compositions, may be injected directly into a tumor, lymph node, or site of infection. In a particular exemplary aspect, subjects may undergo leukapheresis, wherein leukocytes are collected, enriched, or depleted ex vivo to select and/or isolate the cells of interest, e.g., T or NK cells. These cell isolates, e.g., T cell or NK cell isolates, may be expanded by methods known in the art and treated such that one or more CAR constructs of the invention may be introduced, thereby creating a CAR-expressing cell, e.g., CAR T cell or CAR-expressing NK cell, of the invention. Subjects in need thereof may subsequently undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain aspects, following or concurrent with the transplant, subjects receive an infusion of the expanded CAR-expressing cells of the present invention. In an additional aspect, expanded cells are administered before or following surgery. In embodiments, lymphodepletion is performed on a subject, e.g., prior to administering one or more cells that express a CAR described herein, e.g., a CD20-binding CAR described herein. In embodiments, the lymphodepletion comprises administering one or more of melphalan, cytoxan, cyclophosphamide, and fludarabine. The dosage of the above treatments to be administered to a patient will vary with the precise nature of the condition being treated and the recipient of the treatment. The scaline of dosages for human administration can be performed according to art-accepted practices. The dose for a therapeutic, e.g., an antibody, e.g., CAMPATH, for example, may generally be, e.g., in the range 1 to about 100 mg for an adult patient, e.g., administered daily for a period between 1 and 30 days. A suitable daily dose is 1 to 10 mg per day although in some instances larger doses of up to 40 mg per day may be used (described in U.S. Pat. No. 6,120,766). In one embodiment, the CAR is introduced into cells, e.g., T cells or NK cells, e.g., using in vitro transcription, and the subject (e.g., human) receives an initial administration of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells of the invention, and one or more subsequent administrations of the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells of the invention, wherein the one or more subsequent administrations are administered less than 15 days, e.g., 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 days after the previous administration. In one embodiment, more than one administration of the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells of the invention are administered to the subject (e.g., human) per week, e.g., 2, 3, or 4 administrations of the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells of the invention are administered per week. In one embodiment, the subject (e.g., human subject) receives more than one administration of the CAR-expressing cells, e.g., CAR T cells per week or CAR-expressing NK cells (e.g., 2, 3 or 4 administrations per week) (also referred to herein as a cycle), followed by a week of no CAR-expressing cells, e.g., CAR T cell administrations or CAR-expressing NK cell administrations, and then one or more additional administration of the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells (e.g., more than one administration of the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells, per week) is administered to the subject. In another embodiment, the subject (e.g., human subject) receives more than one cycle of CAR-expressing cells, e.g., CART cells or CAR-expressing NK cells, and the time between each cycle is less than 10, 9, 8, 7, 6, 5, 4, or 3 days. In one embodiment, the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells, are administered every other day for 3 administrations per week. In one embodiment, the CAR-expressing cells, e.g., CAR T cells or CAR-expressing NK cells of the invention, are administered for at least two, three, four, five, six, seven, eight or more weeks. In some embodiments, subjects may be adult subjects (i.e., 18 years of age and older). In certain embodiments, subjects may be between 1 and 30 years of age. In some embodiments, the subjects are 16 years of age or older. In certain embodiments, the subjects are between 16 and 30 years of age. In some embodiments, the subjects are child subjects (i.e., between 1 and 18 years of age). In one aspect, CAR-expressing cells, e.g., CD20 CARTs, are generated using lentiviral viral vectors, such as lentivirus. CAR-expressing cells, e.g., CARTs, generated that way will have stable CAR expression. In one aspect, CAR-expressing cells, e.g., CARTs, transiently express CAR vectors for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days after transduction. Transient expression of CARs can be effected by RNA CAR vector delivery. In one aspect, the CAR RNA is transduced into the cell, e.g., NK cell or T cell, by electroporation. A potential issue that can arise in patients being treated using transiently expressing CAR T cells or CAR-expressing NK cells (particularly with murine scFv bearing CAR-expressing cells) is anaphylaxis after multiple treatments. Without being bound by this theory, it is believed that such an anaphylactic response might be caused by a patient developing humoral anti-CAR response, i.e., anti-CAR antibodies having an anti-IgE isotype. It is thought that a patient's antibody producing cells undergo a class switch from IgG isotype (that does not cause anaphylaxis) to IgE isotype when there is a ten to fourteen day break in exposure to antigen. If a patient is at high risk of generating an anti-CAR antibody response during the course of transient CAR therapy (such as those generated by RNA transductions), CART infusion breaks should not last more than ten to fourteen days. Biopolymer Delivery Methods In some embodiments, one or more CAR-expressing cells as disclosed herein can be administered or delivered to the subject via a biopolymer scaffold, e.g., a biopolymer implant. Biopolymer scaffolds can support or enhance the delivery, expansion, and/or dispersion of the CAR-expressing cells described herein. A biopolymer scaffold comprises a biocompatible (e.g., does not substantially induce an inflammatory or immune response) and/or a biodegradable polymer that can be naturally occurring or synthetic. Examples of suitable biopolymers include, but are not limited to, agar, agarose, alginate, alginate/calcium phosphate cement (CPC), beta-galactosidase (β-GAL), (1,2,3,4,6-pentaacetyl a-D-galactose), cellulose, chitin, chitosan, collagen, elastin, gelatin, hyaluronic acid collagen, hydroxyapatite, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), poly(lactide), poly(caprolactone) (PCL), poly(lactide-co-glycolide) (PLG), polyethylene oxide (PEO), poly(lactic-co-glycolic acid) (PLGA), polypropylene oxide (PPO), polyvinyl alcohol) (PVA), silk, soy protein, and soy protein isolate, alone or in combination with any other polymer composition, in any concentration and in any ratio. The biopolymer can be augmented or modified with adhesion- or migration-promoting molecules, e.g., collagen-mimetic peptides that bind to the collagen receptor of lymphocytes, and/or stimulatory molecules to enhance the delivery, expansion, or function, e.g., anti-cancer activity, of the cells to be delivered. The biopolymer scaffold can be an injectable, e.g., a gel or a semi-solid, or a solid composition. In some embodiments, CAR-expressing cells described herein are seeded onto the biopolymer scaffold prior to delivery to the subject. In embodiments, the biopolymer scaffold further comprises one or more additional therapeutic agents described herein (e.g., another CAR-expressing cell, an antibody, or a small molecule) or agents that enhance the activity of a CAR-expressing cell, e.g., incorporated or conjugated to the biopolymers of the scaffold. In embodiments, the biopolymer scaffold is injected, e.g., intratumorally, or surgically implanted at the tumor or within a proximity of the tumor sufficient to mediate an anti-tumor effect. Additional examples of biopolymer compositions and methods for their delivery are described in Stephan et al., Nature Biotechnology, 2015, 33:97-101; and W02014/110591. CD20 CAR Constructs Sequences useful for practicing the invention are disclosed in Table 1, Table 6, Table 11 and Table 14. Throughout the text of this application, should there be a discrepancy between the text of the specification (e.g., Table 1) and the sequence listing, the text of the specification shall prevail. Anti-CD20 single chain variable fragments were isolated. See Table 1. Anti-CD20 ScFvs were cloned into lentiviral CAR expression vectors comprising the CD3zeta chain and the 4-1BB costimulatory molecule. See Table 14. The cloning method is further described in the Example section. The sequences of the CD20 CARs are provided below in Table 1. Each full CAR amino acid sequence in Table 1 includes an optional signal peptide sequence of 21 amino acids corresponding to the amino acid sequence: MALPVTALLLPLALLLHAARP (SEQ ID NO: 1080). Each full CAR nucleotide sequence in Table 1 includes an optional nucleotide signal peptide sequence corresponding to the first 63 nucleotides corresponding to the nucleotide sequence: TABLE 1CD20 CAR ConstructsSEQ IDNUMBERAb regionSequenceCD20-C3H2SEQ ID NO:HCDR1NYNLH136 (Kabat)SEQ ID NO:HCDR2AIYPGNYDTSYNQKFKG137 (Kabat)SEQ ID NO:HCDR3VDFGHSRYWYFDV138 (Kabat)SEQ ID NO:HCDR1GYTFTNY139 (Chothia)SEQ ID NO:HCDR2YPGNYD140 (Chothia)SEQ ID NO:HCDR3VDFGHSRYWYFDV141 (Chothia)SEQ ID NO:HCDR1GYTFTNYN142 (IMGT)SEQ ID NO:HCDR2IYPGNYDT143 (IMGT)SEQ ID NO:HCDR3ARVDFGHSRYWYFDV144 (IMGT)SEQ ID NO: 926HCDR1GYTFTNYNLH(CombinedChothia andKabat)SEQ ID NO: 927HCDR2AIYPGNYDTSYNQKFKG(CombinedChothia andKabat)SEQ ID NO: 928HCDR3VDFGHSRYWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYNL145HWVRQAPGQGLEWMGAIYPGNYDTSYNQKFKGRVTMTADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCCGGTGCAGAAGTC146AAGAAACCTGGAGCATCCGTGAAAGTGTCTTGCAAAGCCTCCGGCTACACCTTCACCAACTACAACCTCCATTGGGTCAGACAGGCCCCCGGACAAGGACTCGAATGGATGGGAGCGATCTACCCGGGAAACTACGACACCAGCTACAACCAGAAGTTCAAGGGCCGCGTGACTATGACCGCCGATAAGAGCACCTCCACCGCCTACATGGAACTGTCCTCGCTGAGGTCCGAGGACACTGCGGTGTACTACTGCGCCCGCGTGGACTTCGGACACTCACGGTATTGGTACTTCGACGTCTGGGGACAGGGCACTACCGTGACCGTGTCGAGCSEQ ID NO:LCDR1RATSSVSSMN147 (Kabat)SEQ ID NO:LCDR2ATSNLAS148 (Kabat)SEQ ID NO:LCDR3QQWTFNPPT149 (Kabat)SEQ ID NO:LCDR1TSSVSS150 (Chothia)SEQ ID NO:LCDR2ATS151 (Chothia)SEQ ID NO:LCDR3WTFNPP152 (Chothia)SEQ ID NO:LCDR1SSVSS153 (IMGT)SEQ ID NO:LCDR2ATS154 (IMGT)SEQ ID NO:LCDR3QQWTFNPPT155 (IMGT)SEQ ID NO: 929LCDR1RATSSVSSMN(CombinedChothia andKabat)SEQ ID NO: 930LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 931LCDR3QQWTFNPPT(CombinedChothia andKabat)SEQ ID NO:VLDIQLTQSPSFLSASVGDRVTITCRATSSVSSMNWYQ156QKPGKAPKPLIHATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWTFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGATATCCAGCTGACTCAGTCCCCGTCATTCCTGT157CCGCCTCCGTGGGAGACAGAGTGACCATCACCTGTCGGGCCACTTCCTCCGTGTCAAGCATGAACTGGTATCAGCAGAAGCCCGGGAAGGCCCCAAAGCCGCTGATTCACGCGACGTCCAACCTGGCTTCCGGCGTGCCGAGCCGGTTCTCCGGCTCGGGGAGCGGGACTGAGTACACCCTGACTATTTCCTCGCTTCAACCCGAGGACTTTGCTACCTACTACTGCCAACAGTGGACCTTCAATCCTCCGACATTCGGACAGGGTACCAAGTTGGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS158SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYNL159linker-VL)HWVRQAPGQGLEWMGAIYPGNYDTSYNQKFKGRVTMTADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRATSSVSSMNWYQQKPGKAPKPLIHATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWTFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAGTCCGGTGCAGAAGTCAAG160(VH-linker-AAACCTGGAGCATCCGTGAAAGTGTCTTGCAAAGCCTVL)CCGGCTACACCTTCACCAACTACAACCTCCATTGGGTCAGACAGGCCCCCGGACAAGGACTCGAATGGATGGGAGCGATCTACCCGGGAAACTACGACACCAGCTACAACCAGAAGTTCAAGGGCCGCGTGACTATGACCGCCGATAAGAGCACCTCCACCGCCTACATGGAACTGTCCTCGCTGAGGTCCGAGGACACTGCGGTGTACTACTGCGCCCGCGTGGACTTCGGACACTCACGGTATTGGTACTTCGACGTCTGGGGACAGGGCACTACCGTGACCGTGTCGAGCGGCGGAGGAGGTTCGGGAGGGGGCGGATCAGGGGGCGGCGGCAGCGGTGGAGGGGGCTCGGATATCCAGCTGACTCAGTCCCCGTCATTCCTGTCCGCCTCCGTGGGAGACAGAGTGACCATCACCTGTCGGGCCACTTCCTCCGTGTCAAGCATGAACTGGTATCAGCAGAAGCCCGGGAAGGCCCCAAAGCCGCTGATTCACGCGACGTCCAACCTGGCTTCCGGCGTGCCGAGCCGGTTCTCCGGCTCGGGGAGCGGGACTGAGTACACCCTGACTATTTCCTCGCTTCAACCCGAGGACTTTGCTACCTACTACTGCCAACAGTGGACCTTCAATCCTCCGACATTCGGACAGGGTACCAAGTTGGAAATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK161amino acidPGASVKVSCKASGYTFTNYNLHWVRQAPGQGLEsequenceWMGAIYPGNYDTSYNQKFKGRVTMTADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRATSSVSSMNWYQQKPGKAPKPLIHATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWTFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC162nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAACCTGGAGCATCCGTGAAAGTGTCTTGCAAAGCCTCCGGCTACACCTTCACCAACTACAACCTCCATTGGGTCAGACAGGCCCCCGGACAAGGACTCGAATGGATGGGAGCGATCTACCCGGGAAACTACGACACCAGCTACAACCAGAAGTTCAAGGGCCGCGTGACTATGACCGCCGATAAGAGCACCTCCACCGCCTACATGGAACTGTCCTCGCTGAGGTCCGAGGACACTGCGGTGTACTACTGCGCCCGCGTGGACTTCGGACACTCACGGTATTGGTACTTCGACGTCTGGGGACAGGGCACTACCGTGACCGTGTCGAGCGGCGGAGGAGGTTCGGGAGGGGGCGGATCAGGGGGCGGCGGCAGCGGTGGAGGGGGCTCGGATATCCAGCTGACTCAGTCCCCGTCATTCCTGTCCGCCTCCGTGGGAGACAGAGTGACCATCACCTGTCGGGCCACTTCCTCCGTGTCAAGCATGAACTGGTATCAGCAGAAGCCCGGGAAGGCCCCAAAGCCGCTGATTCACGCGACGTCCAACCTGGCTTCCGGCGTGCCGAGCCGGTTCTCCGGCTCGGGGAGCGGGACTGAGTACACCCTGACTATTTCCTCGCTTCAACCCGAGGACTTTGCTACCTACTACTGCCAACAGTGGACCTTCAATCCTCCGACATTCGGACAGGGTACCAAGTTGGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C5H1SEQ ID NO:HCDR1SYNMH217 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYNPKFKG218 (Kabat)SEQ ID NO:HCDR3SYFYGSSSWYFDV219 (Kabat)SEQ ID NO:HCDR1GYTFTSY220 (Chothia)SEQ ID NO:HCDR2YPGNGD221 (Chothia)SEQ ID NO:HCDR3SYFYGSSSWYFDV222 (Chothia)SEQ ID NO:HCDR1GYTFTSYN223 (IMGT)SEQ ID NO:HCDR2IYPGNGDT224 (IMGT)SEQ ID NO:HCDR3ARSYFYGSSSWYFDV225 (IMGT)SEQ ID NO: 941HCDR1GYTFTSYNMH(CombinedChothia andKabat)SEQ ID NO: 942HCDR2AIYPGNGDTSYNPKFKG(CombinedChothia andKabat)SEQ ID NO: 943HCDR3SYFYGSSSWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNM226HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTMTADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAGCTCGTCCAGTCCGGTGCAGAAGTC227AAGAAACCCGGTGCTTCAGTGAAAGTGTCCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTCCGCCAAGCCCCGGGCCAGGGACTCGAATGGATGGGAGCCATCTACCCTGGCAACGGGGACACCTCATACAACCCTAAGTTCAAGGGCAGAGTGACCATGACTGCGGACAAGTCCACTAGAACAGCGTACATGGAGCTGAGCAGCCTGCGGTCCGAGGATACTGCCGTGTACTACTGCGCCCGCTCCTACTTCTACGGAAGCTCGTCGTGGTACTTCGATGTCTGGGGACAGGGCACCACTGTGACTGTGTCCTCCSEQ ID NO:LCDR1RASSSVSSMH228 (Kabat)SEQ ID NO:LCDR2ATSNLAS229 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT230 (Kabat)SEQ ID NO:LCDR1SSSVSS231 (Chothia)SEQ ID NO:LCDR2ATS232 (Chothia)SEQ ID NO:LCDR3WIFNPP233 (Chothia)SEQ ID NO:LCDR1SSVSS234 (IMGT)SEQ ID NO:LCDR2ATS235 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT236 (IMGT)SEQ ID NO: 944LCDR1RASSSVSSMH(CombinedChothia andKabat)SEQ ID NO: 945LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 988LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLEIVLTQSPATLSLSPGERATLSCRASSSVSSMHWYQ237QKPGQAPRPLIFATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA VLGAAATTGTGCTGACTCAGAGCCCCGCCACCCTGA238GCTTGTCCCCCGGGGAAAGGGCAACGCTGTCATGCCGCGCCTCGTCATCCGTGTCCTCCATGCATTGGTACCAGCAGAAGCCGGGACAGGCCCCTCGGCCGCTGATCTTCGCCACCTCCAATCTCGCTTCCGGCATTCCGGCCCGGTTCTCGGGAAGCGGGTCGGGGACCGACTATACCCTGACCATCTCTAGCCTTGAACCTGAGGACGCCGCGGTGTACTATTGTCAACAGTGGATCTTTAACCCCCCAACCTTCGGTGGAGGCACCAAAGTGGAGATTAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS239SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNM240linker-VL)HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTMTADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSSMHWYQQKPGQAPRPLIFATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA scFvCAAGTGCAGCTCGTCCAGTCCGGTGCAGAAGTCAAG241(VH-linker-AAACCCGGTGCTTCAGTGAAAGTGTCCTGCAAGGCCTVL)CCGGTTACACCTTCACCTCCTACAACATGCACTGGGTCCGCCAAGCCCCGGGCCAGGGACTCGAATGGATGGGAGCCATCTACCCTGGCAACGGGGACACCTCATACAACCCTAAGTTCAAGGGCAGAGTGACCATGACTGCGGACAAGTCCACTAGAACAGCGTACATGGAGCTGAGCAGCCTGCGGTCCGAGGATACTGCCGTGTACTACTGCGCCCGCTCCTACTTCTACGGAAGCTCGTCGTGGTACTTCGATGTCTGGGGACAGGGCACCACTGTGACTGTGTCCTCCGGTGGCGGAGGCTCGGGCGGAGGCGGAAGCGGCGGCGGGGGATCGGGAGGAGGAGGGTCCGAAATTGTGCTGACTCAGAGCCCCGCCACCCTGAGCTTGTCCCCCGGGGAAAGGGCAACGCTGTCATGCCGCGCCTCGTCATCCGTGTCCTCCATGCATTGGTACCAGCAGAAGCCGGGACAGGCCCCTCGGCCGCTGATCTTCGCCACCTCCAATCTCGCTTCCGGCATTCCGGCCCGGTTCTCGGGAAGCGGGTCGGGGACCGACTATACCCTGACCATCTCTAGCCTTGAACCTGAGGACGCCGCGGTGTACTATTGTCAACAGTGGATCTTTAACCCCCCAACCTTCGGTGGAGGCACCAAAGTGGAGATTAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK242amino acidPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEsequenceWMGAIYPGNGDTSYNPKFKGRVTMTADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSSMHWYQQKPGQAPRPLIFATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWIFNPPTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC243nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceGCAGCTCGTCCAGTCCGGTGCAGAAGTCAAGAAACCCGGTGCTTCAGTGAAAGTGTCCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTCCGCCAAGCCCCGGGCCAGGGACTCGAATGGATGGGAGCCATCTACCCTGGCAACGGGGACACCTCATACAACCCTAAGTTCAAGGGCAGAGTGACCATGACTGCGGACAAGTCCACTAGAACAGCGTACATGGAGCTGAGCAGCCTGCGGTCCGAGGATACTGCCGTGTACTACTGCGCCCGCTCCTACTTCTACGGAAGCTCGTCGTGGTACTTCGATGTCTGGGGACAGGGCACCACTGTGACTGTGTCCTCCGGTGGCGGAGGCTCGGGCGGAGGCGGAAGCGGCGGCGGGGGATCGGGAGGAGGAGGGTCCGAAATTGTGCTGACTCAGAGCCCCGCCACCCTGAGCTTGTCCCCCGGGGAAAGGGCAACGCTGTCATGCCGCGCCTCGTCATCCGTGTCCTCCATGCATTGGTACCAGCAGAAGCCGGGACAGGCCCCTCGGCCGCTGATCTTCGCCACCTCCAATCTCGCTTCCGGCATTCCGGCCCGGTTCTCGGGAAGCGGGTCGGGGACCGACTATACCCTGACCATCTCTAGCCTTGAACCTGAGGACGCCGCGGTGTACTATTGTCAACAGTGGATCTTTAACCCCCCAACCTTCGGTGGAGGCACCAAAGTGGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C2H1SEQ ID NO: 1HCDR1NYWMH(Kabat)SEQ ID NO: 2HCDR2FITPTTGYPEYNQKFKD(Kabat)SEQ ID NO: 3HCDR3RKVGKGVYYALDY(Kabat)SEQ ID NO: 4HCDR1GYTFTNY(Chothia)SEQ ID NO: 5HCDR2TPTTGY(Chothia)SEQ ID NO: 6HCDR3RKVGKGVYYALDY(Chothia)SEQ ID NO: 7HCDR1GYTFTNYW(IMGT)SEQ ID NO: 8HCDR2ITPTTGYP(IMGT)SEQ ID NO: 9HCDR3ARRKVGKGVYYALDY(IMGT)SEQ ID NO: 896HCDR1GYTFTNYWMH(CombinedChothia andKabat)SEQ ID NO: 897HCDR2FITPTTGYPEYNQKFKD(CombinedChothia andKabat)SEQ ID NO: 898HCDR3RKVGKGVYYALDY(CombinedChothia andKabat)SEQ ID NO: 10VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSSEQ ID NO: 11DNA VHCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAACCAGGCGCATCCGTGAAAGTCTCCTGCAAAGCCTCCGGCTACACATTCACTAACTATTGGATGCATTGGGTGCGCCAGGCCCCGGGACAGGGGCTGGAGTGGATGGGGTTCATTACCCCTACCACCGGCTACCCTGAGTACAACCAGAAGTTCAAGGATAGGGTCACCATGACCGCTGACAAGTCCACCTCCACCGCGTACATGGAACTGTCATCGCTCCGGTCCGAGGATACCGCGGTGTACTACTGCGCCCGGAGAAAAGTCGGAAAGGGAGTGTATTACGCCTTGGACTACTGGGGACAGGGGACTACCGTGACCGTGTCGAGCSEQ ID NO: 12LCDR1RASGNIHNYLA(Kabat)SEQ ID NO: 13LCDR2NTKTLAD(Kabat)SEQ ID NO: 14LCDR3QHFWSSPWT(Kabat)SEQ ID NO: 15LCDR1SGNIHNY(Chothia)SEQ ID NO: 16LCDR2NTK(Chothia)SEQ ID NO: 17LCDR3FWSSPW(Chothia)SEQ ID NO: 18LCDR1GNIHNY(IMGT)SEQ ID NO: 19LCDR2NTK(IMGT)SEQ ID NO: 20LCDR3QHFWSSPWT(IMGT)SEQ ID NO: 899LCDR1RASGNIHNYLA(CombinedChothia andKabat)SEQ ID NO: 900LCDR2NTKTLAD(CombinedChothia andKabat)SEQ ID NO: 901LCDR3QHFWSSPWT(CombinedChothia andKabat)SEQ ID NO: 21VLDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKVPKLLIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO: 22DNA VLGACATCCAGATGACCCAGTCCCCGTCAAGCCTTAGCGCCTCCGTGGGCGACCGCGTGACCATTACTTGTCGGGCGTCGGGAAACATCCACAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAGGTCCCCAAGCTGCTGATCTACAATACCAAGACTCTGGCCGACGGAGTGCCTTCCCGCTTTTCCGGTTCGGGAAGCGGGACTGACTACACCCTGACTATCTCCTCGCTGCAACCCGAAGATGTGGCTACGTACTACTGCCAGCACTTCTGGTCCTCTCCCTGGACCTTCGGCGGTGGCACTAAGGTCGAGATTAAGSEQ ID NO: 23LinkerGGGGSGGGGSGGGGSGGGGSSEQ ID NO: 24scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWlinker-VL)MHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKVPKLLIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO: 25DNA scFvCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTCAAG(VH-linker-AAACCAGGCGCATCCGTGAAAGTCTCCTGCAAAGCCVL)TCCGGCTACACATTCACTAACTATTGGATGCATTGGGTGCGCCAGGCCCCGGGACAGGGGCTGGAGTGGATGGGGTTCATTACCCCTACCACCGGCTACCCTGAGTACAACCAGAAGTTCAAGGATAGGGTCACCATGACCGCTGACAAGTCCACCTCCACCGCGTACATGGAACTGTCATCGCTCCGGTCCGAGGATACCGCGGTGTACTACTGCGCCCGGAGAAAAGTCGGAAAGGGAGTGTATTACGCCTTGGACTACTGGGGACAGGGGACTACCGTGACCGTGTCGAGCGGTGGAGGCGGCTCCGGCGGAGGAGGAAGCGGGGGAGGCGGTTCAGGGGGCGGAGGAAGCGACATCCAGATGACCCAGTCCCCGTCAAGCCTTAGCGCCTCCGTGGGCGACCGCGTGACCATTACTTGTCGGGCGTCGGGAAACATCCACAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAGGTCCCCAAGCTGCTGATCTACAATACCAAGACTCTGGCCGACGGAGTGCCTTCCCGCTTTTCCGGTTCGGGAAGCGGGACTGACTACACCCTGACTATCTCCTCGCTGCAACCCGAAGATGTGGCTACGTACTACTGCCAGCACTTCTGGTCCTCTCCCTGGACCTTCGGCGGTGGCACTAAGGTCGAGATTAAGSEQ ID NO: 26Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKKamino acidPGASVKVSCKASGYTFTNYWMHWVRQAPGQGLEsequenceWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKVPKLLIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQHFWSSPWTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 27Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCnucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceGCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAACCAGGCGCATCCGTGAAAGTCTCCTGCAAAGCCTCCGGCTACACATTCACTAACTATTGGATGCATTGGGTGCGCCAGGCCCCGGGACAGGGGCTGGAGTGGATGGGGTTCATTACCCCTACCACCGGCTACCCTGAGTACAACCAGAAGTTCAAGGATAGGGTCACCATGACCGCTGACAAGTCCACCTCCACCGCGTACATGGAACTGTCATCGCTCCGGTCCGAGGATACCGCGGTGTACTACTGCGCCCGGAGAAAAGTCGGAAAGGGAGTGTATTACGCCTTGGACTACTGGGGACAGGGGACTACCGTGACCGTGTCGAGCGGTGGAGGCGGCTCCGGCGGAGGAGGAAGCGGGGGAGGCGGTTCAGGGGGCGGAGGAAGCGACATCCAGATGACCCAGTCCCCGTCAAGCCTTAGCGCCTCCGTGGGCGACCGCGTGACCATTACTTGTCGGGCGTCGGGAAACATCCACAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAGGTCCCCAAGCTGCTGATCTACAATACCAAGACTCTGGCCGACGGAGTGCCTTCCCGCTTTTCCGGTTCGGGAAGCGGGACTGACTACACCCTGACTATCTCCTCGCTGCAACCCGAAGATGTGGCTACGTACTACTGCCAGCACTTCTGGTCCTCTCCCTGGACCTTCGGCGGTGGCACTAAGGTCGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C2H2SEQ ID NO: 28HCDR1NYWMH(Kabat)SEQ ID NO: 29HCDR2FITPTTGYPEYNQKFKD(Kabat)SEQ ID NO: 30HCDR3RKVGKGVYYALDY(Kabat)SEQ ID NO: 31HCDR1GYTFTNY(Chothia)SEQ ID NO: 32HCDR2TPTTGY(Chothia)SEQ ID NO: 33HCDR3RKVGKGVYYALDY(Chothia)SEQ ID NO: 34HCDR1GYTFTNYW(IMGT)SEQ ID NO: 35HCDR2ITPTTGYP(IMGT)SEQ ID NO: 36HCDR3ARRKVGKGVYYALDY(IMGT)SEQ ID NO: 902HCDR1GYTFTNYWMH(CombinedChothia andKabat)SEQ ID NO: 903HCDR2FITPTTGYPEYNQKFKD(CombinedChothia andKabat)SEQ ID NO: 904HCDR3RKVGKGVYYALDY(CombinedChothia andKabat)SEQ ID NO: 37VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWMHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSSEQ ID NO: 38DNA VHCAAGTCCAACTCGTCCAATCAGGAGCAGAAGTCAAGAAGCCCGGAAGCTCTGTCAAAGTGTCCTGCAAGGCCTCCGGTTACACCTTCACCAACTATTGGATGCACTGGGTCAGACAGGCCCCGGGACAGGGCTTGGAATGGATGGGTTTCATCACTCCAACCACCGGTTACCCGGAGTACAACCAGAAGTTTAAGGACCGCGTGACCATTACTGCCGACAAGTCCACGAGCACCGCTTACATGGAACTTAGCAGCCTGCGGTCCGAGGACACTGCCGTGTATTACTGCGCGCGGAGGAAGGTCGGAAAGGGAGTGTACTACGCACTGGACTACTGGGGCCAGGGAACCACCGTGACTGTGTCCTCCSEQ ID NO: 39LCDR1RASGNIHNYLA(Kabat)SEQ ID NO: 40LCDR2NTKTLAD(Kabat)SEQ ID NO: 41LCDR3QHFWSSPWT(Kabat)SEQ ID NO: 42LCDR1SGNIHNY(Chothia)SEQ ID NO: 43LCDR2NTK(Chothia)SEQ ID NO: 44LCDR3FWSSPW(Chothia)SEQ ID NO: 45LCDR1GNIHNY(IMGT)SEQ ID NO: 46LCDR2NTK(IMGT)SEQ ID NO: 47LCDR3QHFWSSPWT(IMGT)SEQ ID NO: 905LCDR1RASGNIHNYLA(CombinedChothia andKabat)SEQ ID NO: 906LCDR2NTKTLAD(CombinedChothia andKabat)SEQ ID NO: 907LCDR3QHFWSSPWT(CombinedChothia andKabat)SEQ ID NO: 48VLDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKVPKLLIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO: 49DNA VLGATATTCAGATGACCCAGTCCCCTTCATCCCTGAGCGCCTCAGTGGGCGATAGAGTGACCATCACTTGTCGCGCCTCGGGCAATATCCACAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAAGTGCCTAAGCTGCTGATCTACAACACTAAGACCCTGGCGGATGGAGTGCCCAGCCGGTTCTCCGGCTCCGGCAGCGGCACAGACTACACCCTCACCATCTCCTCGCTGCAACCAGAGGACGTGGCTACCTACTACTGCCAGCATTTCTGGTCGTCCCCCTGGACTTTCGGAGGGGGGACCAAAGTGGAGATTAAGSEQ ID NO: 50LinkerGGGGSGGGGSGGGGSGGGGSSEQ ID NO: 51scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWlinker-VL)MHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKVPKLLIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO: 52DNA scFvCAAGTCCAACTCGTCCAATCAGGAGCAGAAGTCAAG(VH-linker-AAGCCCGGAAGCTCTGTCAAAGTGTCCTGCAAGGCCTVL)CCGGTTACACCTTCACCAACTATTGGATGCACTGGGTCAGACAGGCCCCGGGACAGGGCTTGGAATGGATGGGTTTCATCACTCCAACCACCGGTTACCCGGAGTACAACCAGAAGTTTAAGGACCGCGTGACCATTACTGCCGACAAGTCCACGAGCACCGCTTACATGGAACTTAGCAGCCTGCGGTCCGAGGACACTGCCGTGTATTACTGCGCGCGGAGGAAGGTCGGAAAGGGAGTGTACTACGCACTGGACTACTGGGGCCAGGGAACCACCGTGACTGTGTCCTCCGGTGGCGGAGGGTCGGGAGGGGGGGGCTCGGGAGGAGGAGGGTCCGGGGGCGGTGGCTCAGATATTCAGATGACCCAGTCCCCTTCATCCCTGAGCGCCTCAGTGGGCGATAGAGTGACCATCACTTGTCGCGCCTCGGGCAATATCCACAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAAGTGCCTAAGCTGCTGATCTACAACACTAAGACCCTGGCGGATGGAGTGCCCAGCCGGTTCTCCGGCTCCGGCAGCGGCACAGACTACACCCTCACCATCTCCTCGCTGCAACCAGAGGACGTGGCTACCTACTACTGCCAGCATTTCTGGTCGTCCCCCTGGACTTTCGGAGGGGGGACCAAAGTGGAGATTAAGSEQ ID NO: 53Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKKamino acidPGSSVKVSCKASGYTFTNYWMHWVRQAPGQGLEsequenceWMGFITPTTGYPEYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKVPKLLIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQHFWSSPWTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 54Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCnucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAATCAGGAGCAGAAGTCAAGAAGCCCGGAAGCTCTGTCAAAGTGTCCTGCAAGGCCTCCGGTTACACCTTCACCAACTATTGGATGCACTGGGTCAGACAGGCCCCGGGACAGGGCTTGGAATGGATGGGTTTCATCACTCCAACCACCGGTTACCCGGAGTACAACCAGAAGTTTAAGGACCGCGTGACCATTACTGCCGACAAGTCCACGAGCACCGCTTACATGGAACTTAGCAGCCTGCGGTCCGAGGACACTGCCGTGTATTACTGCGCGCGGAGGAAGGTCGGAAAGGGAGTGTACTACGCACTGGACTACTGGGGCCAGGGAACCACCGTGACTGTGTCCTCCGGTGGCGGAGGGTCGGGAGGGGGGGGCTCGGGAGGAGGAGGGTCCGGGGGCGGTGGCTCAGATATTCAGATGACCCAGTCCCCTTCATCCCTGAGCGCCTCAGTGGGCGATAGAGTGACCATCACTTGTCGCGCCTCGGGCAATATCCACAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAAGTGCCTAAGCTGCTGATCTACAACACTAAGACCCTGGCGGATGGAGTGCCCAGCCGGTTCTCCGGCTCCGGCAGCGGCACAGACTACACCCTCACCATCTCCTCGCTGCAACCAGAGGACGTGGCTACCTACTACTGCCAGCATTTCTGGTCGTCCCCCTGGACTTTCGGAGGGGGGACCAAAGTGGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C2H3SEQ ID NO: 55HCDR1NYWMH(Kabat)SEQ ID NO: 56HCDR2FITPTTGYPEYNQKFKD(Kabat)SEQ ID NO: 57HCDR3RKVGKGVYYALDY(Kabat)SEQ ID NO: 58HCDR1GYTFTNY(Chothia)SEQ ID NO: 59HCDR2TPTTGY(Chothia)SEQ ID NO: 60HCDR3RKVGKGVYYALDY(Chothia)SEQ ID NO: 61HCDR1GYTFTNYW(IMGT)SEQ ID NO: 62HCDR2ITPTTGYP(IMGT)SEQ ID NO: 63HCDR3ARRKVGKGVYYALDY(IMGT)SEQ ID NO: 908HCDR1GYTFTNYWMH(CombinedChothia andKabat)SEQ ID NO: 909HCDR2FITPTTGYPEYNQKFKD(CombinedChothia andKabat)SEQ ID NO: 910HCDR3RKVGKGVYYALDY(CombinedChothia andKabat)SEQ ID NO: 64VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSSEQ ID NO: 65DNA VHCAAGTCCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAACCCGGAGCTTCCGTGAAAGTGTCCTGCAAAGCCTCCGGTTACACCTTTACGAACTACTGGATGCATTGGGTGCGCCAGGCCCCGGGACAGGGGCTGGAATGGATGGGCTTCATTACCCCCACCACCGGATACCCCGAGTACAATCAGAAGTTCAAGGACCGGGTCACCATGACCGCCGACAAGTCAACCTCTACTGCTTACATGGAGCTGTCCAGCCTGCGGTCGGAAGATACCGCCGTGTATTACTGCGCGAGAAGGAAAGTCGGAAAGGGAGTGTACTATGCCCTGGACTACTGGGGACAGGGGACCACTGTGACTGTGTCAAGCSEQ ID NO: 66LCDR1RASGNIHNYLA(Kabat)SEQ ID NO: 67LCDR2NTKTLAD(Kabat)SEQ ID NO: 68LCDR3QHFWSSPWT(Kabat)SEQ ID NO: 69LCDR1SGNIHNY(Chothia)SEQ ID NO: 70LCDR2NTK(Chothia)SEQ ID NO: 71LCDR3FWSSPW(Chothia)SEQ ID NO: 72LCDR1GNIHNY(IMGT)SEQ ID NO: 73LCDR2NTK(IMGT)SEQ ID NO: 74LCDR3QHFWSSPWT(IMGT)SEQ ID NO: 911LCDR1RASGNIHNYLA(CombinedChothia andKabat)SEQ ID NO: 912LCDR2NTKTLAD(CombinedChothia andKabat)SEQ ID NO: 913LCDR3QHFWSSPWT(CombinedChothia andKabat)SEQ ID NO: 75VLAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAWYQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO: 76DNA VLGCGATCCGCATGACCCAGAGCCCGTTCTCCCTGTCCGCGTCCGTGGGGGACCGCGTGACTATCACGTGTCGGGCCTCCGGGAACATCCACAACTACCTCGCATGGTACCAGCAGAAGCCGGCCAAGGCCCCTAAGTTGTTCATCTACAACACCAAGACTCTTGCCGACGGAGTGCCGTCCCGGTTTAGCGGAAGCGGTTCCGGCACCGACTACACCCTGACTATCTCGAGCCTGCAACCAGAAGATTTCGCCACTTACTACTGCCAGCACTTCTGGTCGTCCCCTTGGACATTCGGCGGCGGCACCAAGGTCGAGATTAAGSEQ ID NO: 77LinkerGGGGSGGGGSGGGGSGGGGSSEQ ID NO: 78scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWlinker-VL)MHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAWYQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO: 79DNA scFvCAAGTCCAACTCGTCCAGTCCGGTGCAGAAGTCAAG(VH-linker-AAACCCGGAGCTTCCGTGAAAGTGTCCTGCAAAGCCTVL)CCGGTTACACCTTTACGAACTACTGGATGCATTGGGTGCGCCAGGCCCCGGGACAGGGGCTGGAATGGATGGGCTTCATTACCCCCACCACCGGATACCCCGAGTACAATCAGAAGTTCAAGGACCGGGTCACCATGACCGCCGACAAGTCAACCTCTACTGCTTACATGGAGCTGTCCAGCCTGCGGTCGGAAGATACCGCCGTGTATTACTGCGCGAGAAGGAAAGTCGGAAAGGGAGTGTACTATGCCCTGGACTACTGGGGACAGGGGACCACTGTGACTGTGTCAAGCGGAGGCGGAGGCTCGGGGGGCGGAGGTTCGGGCGGAGGAGGATCAGGGGGCGGCGGTTCCGCGATCCGCATGACCCAGAGCCCGTTCTCCCTGTCCGCGTCCGTGGGGGACCGCGTGACTATCACGTGTCGGGCCTCCGGGAACATCCACAACTACCTCGCATGGTACCAGCAGAAGCCGGCCAAGGCCCCTAAGTTGTTCATCTACAACACCAAGACTCTTGCCGACGGAGTGCCGTCCCGGTTTAGCGGAAGCGGTTCCGGCACCGACTACACCCTGACTATCTCGAGCCTGCAACCAGAAGATTTCGCCACTTACTACTGCCAGCACTTCTGGTCGTCCCCTTGGACATTCGGCGGCGGCACCAAGGTCGAGATTAAGSEQ ID NO: 80Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKKamino acidPGASVKVSCKASGYTFTNYWMHWVRQAPGQGLEsequenceWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAWYQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 81Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCnucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAACCCGGAGCTTCCGTGAAAGTGTCCTGCAAAGCCTCCGGTTACACCTTTACGAACTACTGGATGCATTGGGTGCGCCAGGCCCCGGGACAGGGGCTGGAATGGATGGGCTTCATTACCCCCACCACCGGATACCCCGAGTACAATCAGAAGTTCAAGGACCGGGTCACCATGACCGCCGACAAGTCAACCTCTACTGCTTACATGGAGCTGTCCAGCCTGCGGTCGGAAGATACCGCCGTGTATTACTGCGCGAGAAGGAAAGTCGGAAAGGGAGTGTACTATGCCCTGGACTACTGGGGACAGGGGACCACTGTGACTGTGTCAAGCGGAGGCGGAGGCTCGGGGGGCGGAGGTTCGGGCGGAGGAGGATCAGGGGGCGGCGGTTCCGCGATCCGCATGACCCAGAGCCCGTTCTCCCTGTCCGCGTCCGTGGGGGACCGCGTGACTATCACGTGTCGGGCCTCCGGGAACATCCACAACTACCTCGCATGGTACCAGCAGAAGCCGGCCAAGGCCCCTAAGTTGTTCATCTACAACACCAAGACTCTTGCCGACGGAGTGCCGTCCCGGTTTAGCGGAAGCGGTTCCGGCACCGACTACACCCTGACTATCTCGAGCCTGCAACCAGAAGATTTCGCCACTTACTACTGCCAGCACTTCTGGTCGTCCCCTTGGACATTCGGCGGCGGCACCAAGGTCGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C2H4SEQ ID NO: 82HCDR1NYWMH(Kabat)SEQ ID NO: 83HCDR2FITPTTGYPEYNQKFKD(Kabat)SEQ ID NO: 84HCDR3RKVGKGVYYALDY(Kabat)SEQ ID NO: 85HCDR1GYTFTNY(Chothia)SEQ ID NO: 86HCDR2TPTTGY(Chothia)SEQ ID NO: 87HCDR3RKVGKGVYYALDY(Chothia)SEQ ID NO: 88HCDR1GYTFTNYW(IMGT)SEQ ID NO: 89HCDR2ITPTTGYP(IMGT)SEQ ID NO: 90HCDR3ARRKVGKGVYYALDY(IMGT)SEQ ID NO: 914HCDR1GYTFTNYWMH(CombinedChothia andKabat)SEQ ID NO: 915HCDR2FITPTTGYPEYNQKFKD(CombinedChothia andKabat)SEQ ID NO: 916HCDR3RKVGKGVYYALDY(CombinedChothia andKabat)SEQ ID NO: 91VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWMHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSSEQ ID NO: 92DNA VHCAAGTCCAACTCGTCCAAAGCGGTGCAGAAGTCAAGAAGCCCGGTTCCTCCGTGAAAGTGTCCTGCAAAGCCTCGGGCTACACCTTCACTAATTACTGGATGCATTGGGTCCGCCAGGCGCCCGGACAGGGATTGGAATGGATGGGGTTCATCACGCCGACCACCGGATACCCGGAGTACAACCAGAAGTTCAAGGACAGAGTGACCATTACCGCCGATAAGTCCACCTCCACCGCTTACATGGAGCTCTCCTCACTGCGGTCCGAAGATACAGCCGTGTACTATTGTGCTCGCCGGAAAGTCGGAAAGGGAGTGTACTACGCCCTGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCGSEQ ID NO: 93LCDR1RASGNIHNYLA(Kabat)SEQ ID NO: 94LCDR2NTKTLAD(Kabat)SEQ ID NO: 95LCDR3QHFWSSPWT(Kabat)SEQ ID NO: 96LCDR1SGNIHNY(Chothia)SEQ ID NO: 97LCDR2NTK(Chothia)SEQ ID NO: 98LCDR3FWSSPW(Chothia)SEQ ID NO: 99LCDR1GNIHNY(IMGT)SEQ ID NO:LCDR2NTK100 (IMGT)SEQ ID NO:LCDR3QHFWSSPWT101 (IMGT)SEQ ID NO: 917LCDR1RASGNIHNYLA(CombinedChothia andKabat)SEQ ID NO: 918LCDR2NTKTLAD(CombinedChothia andKabat)SEQ ID NO: 919LCDR3QHFWSSPWT(CombinedChothia andKabat)SEQ ID NO:VLAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAW102YQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO:DNA VLGCCATTAGGATGACTCAGTCCCCTTTCTCCCTCT103CCGCGAGCGTGGGCGACCGCGTGACGATCACTTGCCGGGCCTCGGGGAACATTCACAACTACCTGGCCTGGTACCAGCAGAAGCCGGCCAAGGCCCCTAAGCTGTTCATCTACAACACCAAGACCCTTGCGGACGGAGTGCCATCGAGATTTTCCGGCTCGGGCTCTGGGACCGATTACACTCTGACTATCTCAAGCCTGCAACCTGAGGACTTCGCCACTTACTACTGCCAGCACTTCTGGAGCAGCCCCTGGACTTTCGGTGGCGGGACCAAGGTCGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS104SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYW105linker-VL)MHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAWYQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAAAGCGGTGCAGAAGTCAAG106(VH-linker-AAGCCCGGTTCCTCCGTGAAAGTGTCCTGCAAAGCCTVL)CGGGCTACACCTTCACTAATTACTGGATGCATTGGGTCCGCCAGGCGCCCGGACAGGGATTGGAATGGATGGGGTTCATCACGCCGACCACCGGATACCCGGAGTACAACCAGAAGTTCAAGGACAGAGTGACCATTACCGCCGATAAGTCCACCTCCACCGCTTACATGGAGCTCTCCTCACTGCGGTCCGAAGATACAGCCGTGTACTATTGTGCTCGCCGGAAAGTCGGAAAGGGAGTGTACTACGCCCTGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCGGGAGGAGGGGGTTCGGGCGGAGGCGGCTCCGGTGGAGGCGGAAGCGGAGGGGGCGGATCAGCCATTAGGATGACTCAGTCCCCTTTCTCCCTCTCCGCGAGCGTGGGCGACCGCGTGACGATCACTTGCCGGGCCTCGGGGAACATTCACAACTACCTGGCCTGGTACCAGCAGAAGCCGGCCAAGGCCCCTAAGCTGTTCATCTACAACACCAAGACCCTTGCGGACGGAGTGCCATCGAGATTTTCCGGCTCGGGCTCTGGGACCGATTACACTCTGACTATCTCAAGCCTGCAACCTGAGGACTTCGCCACTTACTACTGCCAGCACTTCTGGAGCAGCCCCTGGACTTTCGGTGGCGGGACCAAGGTCGAAATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK107amino acidPGSSVKVSCKASGYTFTNYWMHWVRQAPGQGLEsequenceWMGFITPTTGYPEYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAWYQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC108nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAAAGCGGTGCAGAAGTCAAGAAGCCCGGTTCCTCCGTGAAAGTGTCCTGCAAAGCCTCGGGCTACACCTTCACTAATTACTGGATGCATTGGGTCCGCCAGGCGCCCGGACAGGGATTGGAATGGATGGGGTTCATCACGCCGACCACCGGATACCCGGAGTACAACCAGAAGTTCAAGGACAGAGTGACCATTACCGCCGATAAGTCCACCTCCACCGCTTACATGGAGCTCTCCTCACTGCGGTCCGAAGATACAGCCGTGTACTATTGTGCTCGCCGGAAAGTCGGAAAGGGAGTGTACTACGCCCTGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCGGGAGGAGGGGGTTCGGGCGGAGGCGGCTCCGGTGGAGGCGGAAGCGGAGGGGGCGGATCAGCCATTAGGATGACTCAGTCCCCTTTCTCCCTCTCCGCGAGCGTGGGCGACCGCGTGACGATCACTTGCCGGGCCTCGGGGAACATTCACAACTACCTGGCCTGGTACCAGCAGAAGCCGGCCAAGGCCCCTAAGCTGTTCATCTACAACACCAAGACCCTTGCGGACGGAGTGCCATCGAGATTTTCCGGCTCGGGCTCTGGGACCGATTACACTCTGACTATCTCAAGCCTGCAACCTGAGGACTTCGCCACTTACTACTGCCAGCACTTCTGGAGCAGCCCCTGGACTTTCGGTGGCGGGACCAAGGTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C3H1SEQ ID NO:HCDR1NYNLH109 (Kabat)SEQ ID NO:HCDR2AIYPGNYDTSYNQKFKG110 (Kabat)SEQ ID NO:HCDR3VDFGHSRYWYFDV111 (Kabat)SEQ ID NO:HCDR1GYTFTNY112 (Chothia)SEQ ID NO:HCDR2YPGNYD113 (Chothia)SEQ ID NO:HCDR3VDFGHSRYWYFDV114 (Chothia)SEQ ID NO:HCDR1GYTFTNYN115 (IMGT)SEQ ID NO:HCDR2IYPGNYDT116 (IMGT)SEQ ID NO:HCDR3ARVDFGHSRYWYFDV117 (IMGT)SEQ ID NO: 920HCDR1GYTFTNYNLH(CombinedChothia andKabat)SEQ ID NO: 921HCDR2AIYPGNYDTSYNQKFKG(CombinedChothia andKabat)SEQ ID NO: 922HCDR3VDFGHSRYWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYNL118HWVRQAPGQGLEWMGAIYPGNYDTSYNQKFKGRVTMTADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAATCCGGTGCAGAAGTC119AAGAAACCCGGTGCATCCGTGAAAGTGTCATGCAAAGCCTCCGGGTACACCTTCACTAACTACAACCTCCACTGGGTCCGCCAGGCCCCGGGACAGGGACTGGAGTGGATGGGGGCCATCTACCCGGGAAACTACGACACTTCATACAACCAGAAGTTCAAGGGCAGAGTGACCATGACTGCCGACAAGAGCACATCGACCGCCTACATGGAACTCAGCTCCCTGCGCTCCGAGGATACTGCCGTCTACTACTGTGCCCGGGTGGACTTCGGCCACTCCCGGTATTGGTATTTCGATGTCTGGGGACAGGGAACCACCGTGACTGTGTCCAGCSEQ ID NO:LCDR1RATSSVSSMN120 (Kabat)SEQ ID NO:LCDR2ATSNLAS121 (Kabat)SEQ ID NO:LCDR3QQWTFNPPT122 (Kabat)SEQ ID NO:LCDR1TSSVSS123 (Chothia)SEQ ID NO:LCDR2ATS124 (Chothia)SEQ ID NO:LCDR3WTFNPP125 (Chothia)SEQ ID NO:LCDR1SSVSS126 (IMGT)SEQ ID NO:LCDR2ATS127 (IMGT)SEQ ID NO:LCDR3QQWTFNPPT128 (IMGT)SEQ ID NO: 923LCDR1RATSSVSSMN(CombinedChothia andKabat)SEQ ID NO: 924LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 925LCDR3QQWTFNPPT(CombinedChothia andKabat)SEQ ID NO:VLEIVLTQSPATLSLSPGERATLSCRATSSVSSMNWYQ129QKPGQAPRPLIHATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWTFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGAAATCGTGCTGACCCAGTCCCCTGCGACTCTGA130GCCTGAGCCCTGGGGAACGCGCCACTTTGTCATGCCGGGCCACCTCCTCCGTGTCCTCCATGAACTGGTACCAGCAGAAGCCCGGACAGGCTCCGCGGCCGCTGATCCATGCCACCTCCAACCTGGCCAGCGGCATTCCCGCGAGGTTTTCCGGCTCGGGCTCTGGTACCGACTACACCCTGACCATCTCGAGCCTTGAGCCAGAAGATGCTGCGGTGTACTACTGCCAACAGTGGACCTTCAATCCGCCTACGTTCGGACAGGGGACCAAGCTGGAGATTAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS131SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYNL132linker-VL)HWVRQAPGQGLEWMGAIYPGNYDTSYNQKFKGRVTMTADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRATSSVSSMNWYQQKPGQAPRPLIHATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWTFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAATCCGGTGCAGAAGTCAAG133(VH-linker-AAACCCGGTGCATCCGTGAAAGTGTCATGCAAAGCCVL)TCCGGGTACACCTTCACTAACTACAACCTCCACTGGGTCCGCCAGGCCCCGGGACAGGGACTGGAGTGGATGGGGGCCATCTACCCGGGAAACTACGACACTTCATACAACCAGAAGTTCAAGGGCAGAGTGACCATGACTGCCGACAAGAGCACATCGACCGCCTACATGGAACTCAGCTCCCTGCGCTCCGAGGATACTGCCGTCTACTACTGTGCCCGGGTGGACTTCGGCCACTCCCGGTATTGGTATTTCGATGTCTGGGGACAGGGAACCACCGTGACTGTGTCCAGCGGGGGCGGAGGATCGGGTGGCGGAGGTTCGGGGGGAGGAGGATCAGGCGGCGGCGGATCGGAAATCGTGCTGACCCAGTCCCCTGCGACTCTGAGCCTGAGCCCTGGGGAACGCGCCACTTTGTCATGCCGGGCCACCTCCTCCGTGTCCTCCATGAACTGGTACCAGCAGAAGCCCGGACAGGCTCCGCGGCCGCTGATCCATGCCACCTCCAACCTGGCCAGCGGCATTCCCGCGAGGTTTTCCGGCTCGGGCTCTGGTACCGACTACACCCTGACCATCTCGAGCCTTGAGCCAGAAGATGCTGCGGTGTACTACTGCCAACAGTGGACCTTCAATCCGCCTACGTTCGGACAGGGGACCAAGCTGGAGATTAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK134amino acidPGASVKVSCKASGYTFTNYNLHWVRQAPGQGLEsequenceWMGAIYPGNYDTSYNQKFKGRVTMTADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRATSSVSSMNWYQQKPGQAPRPLIHATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWTFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC135nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAATCCGGTGCAGAAGTCAAGAAACCCGGTGCATCCGTGAAAGTGTCATGCAAAGCCTCCGGGTACACCTTCACTAACTACAACCTCCACTGGGTCCGCCAGGCCCCGGGACAGGGACTGGAGTGGATGGGGGCCATCTACCCGGGAAACTACGACACTTCATACAACCAGAAGTTCAAGGGCAGAGTGACCATGACTGCCGACAAGAGCACATCGACCGCCTACATGGAACTCAGCTCCCTGCGCTCCGAGGATACTGCCGTCTACTACTGTGCCCGGGTGGACTTCGGCCACTCCCGGTATTGGTATTTCGATGTCTGGGGACAGGGAACCACCGTGACTGTGTCCAGCGGGGGCGGAGGATCGGGTGGCGGAGGTTCGGGGGGAGGAGGATCAGGCGGCGGCGGATCGGAAATCGTGCTGACCCAGTCCCCTGCGACTCTGAGCCTGAGCCCTGGGGAACGCGCCACTTTGTCATGCCGGGCCACCTCCTCCGTGTCCTCCATGAACTGGTACCAGCAGAAGCCCGGACAGGCTCCGCGGCCGCTGATCCATGCCACCTCCAACCTGGCCAGCGGCATTCCCGCGAGGTTTTCCGGCTCGGGCTCTGGTACCGACTACACCCTGACCATCTCGAGCCTTGAGCCAGAAGATGCTGCGGTGTACTACTGCCAACAGTGGACCTTCAATCCGCCTACGTTCGGACAGGGGACCAAGCTGGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C3H3SEQ ID NO:HCDR1NYNLH163 (Kabat)SEQ ID NO:HCDR2AIYPGNYDTSYNQKFKG164 (Kabat)SEQ ID NO:HCDR3VDFGHSRYWYFDV165 (Kabat)SEQ ID NO:HCDR1GYTFTNY166 (Chothia)SEQ ID NO:HCDR2YPGNYD167 (Chothia)SEQ ID NO:HCDR3VDFGHSRYWYFDV168 (Chothia)SEQ ID NO:HCDR1GYTFTNYN169 (IMGT)SEQ ID NO:HCDR2IYPGNYDT170 (IMGT)SEQ ID NO:HCDR3ARVDFGHSRYWYFDV171 (IMGT)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYW172MHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCGGGAGCAGAAGTC173AAGAAGCCCGGATCATCCGTGAAAGTGTCCTGCAAAGCCTCAGGCTACACCTTTACCAACTACAACTTGCACTGGGTCAGACAGGCCCCGGGACAGGGCCTGGAGTGGATGGGCGCCATCTACCCCGGAAACTATGACACCTCGTACAACCAGAAGTTCAAGGGTCGCGTGACTATCACGGCTGACAAGTCCACTAGCACCGCGTACATGGAACTTTCCTCACTGCGGTCCGAGGATACTGCGGTGTACTACTGCGCCCGGGTGGACTTCGGACACTCGAGATATTGGTACTTCGATGTCTGGGGACAGGGGACCACCGTGACTGTGTCCTCCSEQ ID NO:LCDR1RATSSVSSMN174 (Kabat)SEQ ID NO:LCDR2ATSNLAS175 (Kabat)SEQ ID NO:LCDR3QQWTFNPPT176 (Kabat)SEQ ID NO:LCDR1TSSVSS177 (Chothia)SEQ ID NO:LCDR2ATS178 (Chothia)SEQ ID NO:LCDR3WTFNPP179 (Chothia)SEQ ID NO:LCDR1SSVSS180 (IMGT)SEQ ID NO:LCDR2ATS181 (IMGT)SEQ ID NO:LCDR3QQWTFNPPT182 (IMGT)SEQ ID NO: 932LCDR1RATSSVSSMN(CombinedChothia andKabat)SEQ ID NO: 933LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 934LCDR3QQWTFNPPT(CombinedChothia andKabat)SEQ ID NO:VLAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAW183YQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO:DNA VLGAAATTGTGCTGACCCAGTCTCCCGCAACCCTGT184CCCTGAGCCCTGGAGAGCGCGCCACCCTGTCCTGCCGGGCCACATCCTCCGTGTCGTCCATGAACTGGTACCAGCAGAAGCCCGGCCAAGCCCCGAGGCCTCTGATTCATGCTACCTCAAATCTGGCCAGCGGAATCCCGGCGCGCTTCTCCGGCTCGGGCAGCGGTACTGACTACACTCTCACCATCTCGTCCCTCGAACCGGAGGACGCCGCCGTCTACTACTGTCAGCAGTGGACCTTCAACCCACCTACTTTCGGACAAGGGACCAAGCTGGAGATCAAGSEQ ID NO:LinkerGGGSGGGGSGGGGSGGGGS185SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYW186linker-VL)MHWVRQAPGQGLEWMGFITPTTGYPEYNQKFKDRVTMTADKSTSTAYMELSSLRSEDTAVYYCARRKVGKGVYYALDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSAIRMTQSPFSLSASVGDRVTITCRASGNIHNYLAWYQQKPAKAPKLFIYNTKTLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPWTFGGGTKVEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAGTCGGGAGCAGAAGTCAAG187(VH-linker-AAGCCCGGATCATCCGTGAAAGTGTCCTGCAAAGCCTVL)CAGGCTACACCTTTACCAACTACAACTTGCACTGGGTCAGACAGGCCCCGGGACAGGGCCTGGAGTGGATGGGCGCCATCTACCCCGGAAACTATGACACCTCGTACAACCAGAAGTTCAAGGGTCGCGTGACTATCACGGCTGACAAGTCCACTAGCACCGCGTACATGGAACTTTCCTCACTGCGGTCCGAGGATACTGCGGTGTACTACTGCGCCCGGGTGGACTTCGGACACTCGAGATATTGGTACTTCGATGTCTGGGGACAGGGGACCACCGTGACTGTGTCCTCCGGGGGCGGTGGCAGCGGGGGAGGCGGAAGCGGCGGAGGGGGTTCCGGGGGTGGAGGAAGCGAAATTGTGCTGACCCAGTCTCCCGCAACCCTGTCCCTGAGCCCTGGAGAGCGCGCCACCCTGTCCTGCCGGGCCACATCCTCCGTGTCGTCCATGAACTGGTACCAGCAGAAGCCCGGCCAAGCCCCGAGGCCTCTGATTCATGCTACCTCAAATCTGGCCAGCGGAATCCCGGCGCGCTTCTCCGGCTCGGGCAGCGGTACTGACTACACTCTCACCATCTCGTCCCTCGAACCGGAGGACGCCGCCGTCTACTACTGTCAGCAGTGGACCTTCAACCCACCTACTTTCGGACAAGGGACCAAGCTGGAGATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK188amino acidPGSSVKVSCKASGYTFTNYNLHWVRQAPGQGLEWsequenceMGAIYPGNYDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRATSSVSSMNWYQQKPGQAPRPLIHATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWTFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC189nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAGTCGGGAGCAGAAGTCAAGAAGCCCGGATCATCCGTGAAAGTGTCCTGCAAAGCCTCAGGCTACACCTTTACCAACTACAACTTGCACTGGGTCAGACAGGCCCCGGGACAGGGCCTGGAGTGGATGGGCGCCATCTACCCCGGAAACTATGACACCTCGTACAACCAGAAGTTCAAGGGTCGCGTGACTATCACGGCTGACAAGTCCACTAGCACCGCGTACATGGAACTTTCCTCACTGCGGTCCGAGGATACTGCGGTGTACTACTGCGCCCGGGTGGACTTCGGACACTCGAGATATTGGTACTTCGATGTCTGGGGACAGGGGACCACCGTGACTGTGTCCTCCGGGGGCGGTGGCAGCGGGGGAGGCGGAAGCGGCGGAGGGGGTTCCGGGGGTGGAGGAAGCGAAATTGTGCTGACCCAGTCTCCCGCAACCCTGTCCCTGAGCCCTGGAGAGCGCGCCACCCTGTCCTGCCGGGCCACATCCTCCGTGTCGTCCATGAACTGGTACCAGCAGAAGCCCGGCCAAGCCCCGAGGCCTCTGATTCATGCTACCTCAAATCTGGCCAGCGGAATCCCGGCGCGCTTCTCCGGCTCGGGCAGCGGTACTGACTACACTCTCACCATCTCGTCCCTCGAACCGGAGGACGCCGCCGTCTACTACTGTCAGCAGTGGACCTTCAACCCACCTACTTTCGGACAAGGGACCAAGCTGGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C3H4SEQ ID NO:HCDR1NYNLH190 (Kabat)SEQ ID NO:HCDR2AIYPGNYDTSYNQKFKG191 (Kabat)SEQ ID NO:HCDR3VDFGHSRYWYFDV192 (Kabat)SEQ ID NO:HCDR1GYTFTNY193 (Chothia)SEQ ID NO:HCDR2YPGNYD194 (Chothia)SEQ ID NO:HCDR3VDFGHSRYWYFDV195 (Chothia)SEQ ID NO:HCDR1GYTFTNYN196 (IMGT)SEQ ID NO:HCDR2IYPGNYDT197 (IMGT)SEQ ID NO:HCDR3ARVDFGHSRYWYFDV198 (IMGT)SEQ ID NO: 935HCDR1GYTFTNYNLH(CombinedChothia andKabat)SEQ ID NO: 936HCDR2AIYPGNYDTSYNQKFKG(CombinedChothia andKabat)SEQ ID NO: 937HCDR3VDFGHSRYWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYNL199HWVRQAPGQGLEWMGAIYPGNYDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCGGGAGCAGAAGTC200AAGAAGCCCGGATCATCCGTGAAAGTGTCCTGCAAAGCCTCAGGCTACACCTTTACCAACTACAACTTGCACTGGGTCAGACAGGCCCCGGGACAGGGCCTGGAGTGGATGGGCGCCATCTACCCCGGAAACTATGACACCTCGTACAACCAGAAGTTCAAGGGTCGCGTGACTATCACGGCTGACAAGTCCACTAGCACCGCGTACATGGAACTTTCCTCACTGCGGTCCGAGGATACTGCGGTGTACTACTGCGCCCGGGTGGACTTCGGACACTCGAGATATTGGTACTTCGATGTCTGGGGACAGGGGACCACCGTGACTGTGTCCTCCSEQ ID NO:LCDR1RATSSVSSMN201 (Kabat)SEQ ID NO:LCDR2ATSNLAS202 (Kabat)SEQ ID NO:LCDR3QQWTFNPPT203 (Kabat)SEQ ID NO:LCDR1TSSVSS204 (Chothia)SEQ ID NO:LCDR2ATS205 (Chothia)SEQ ID NO:LCDR3WTFNPP206 (Chothia)SEQ ID NO:LCDR1SSVSS207 (IMGT)SEQ ID NO:LCDR2ATS208 (IMGT)SEQ ID NO:LCDR3QQWTFNPPT209 (IMGT)SEQ ID NO: 938LCDR1RATSSVSSMN(CombinedChothia andKabat)SEQ ID NO: 939LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 940LCDR3QQWTFNPPT(CombinedChothia andKabat)SEQ ID NO:VLEIVLTQSPATLSLSPGERATLSCRATSSVSSMNWYQ210QKPGQAPRPLIHATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWTFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGAAATTGTGCTGACCCAGTCTCCCGCAACCCTGT211CCCTGAGCCCTGGAGAGCGCGCCACCCTGTCCTGCCGGGCCACATCCTCCGTGTCGTCCATGAACTGGTACCAGCAGAAGCCCGGCCAAGCCCCGAGGCCTCTGATTCATGCTACCTCAAATCTGGCCAGCGGAATCCCGGCGCGCTTCTCCGGCTCGGGCAGCGGTACTGACTACACTCTCACCATCTCGTCCCTCGAACCGGAGGACGCCGCCGTCTACTACTGTCAGCAGTGGACCTTCAACCCACCTACTTTCGGACAAGGGACCAAGCTGGAGATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS212SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYNL213linker-VL)HWVRQAPGQGLEWMGAIYPGNYDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRATSSVSSMNWYQQKPGQAPRPLIHATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWTFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAATCCGGCGCAGAAGTCAAG214(VH-linker-AAACCAGGATCGTCCGTGAAAGTGTCCTGCAAGGCGVL)TCCGGGTACACCTTCACTAATTACAACCTCCACTGGGTCAGACAGGCCCCAGGACAGGGCCTGGAATGGATGGGCGCCATCTACCCTGGAAACTACGATACCTCGTACAACCAGAAGTTCAAGGGCCGCGTGACTATTACCGCCGACAAGAGCACCTCCACCGCCTATATGGAACTGTCGTCCCTGCGGTCCGAGGACACTGCCGTGTACTACTGTGCAAGGGTGGACTTCGGTCACTCCCGGTATTGGTACTTCGACGTCTGGGGACAGGGGACCACTGTGACCGTGTCGTCGGGAGGCGGTGGAAGCGGCGGTGGCGGAAGCGGAGGCGGCGGATCAGGGGGCGGAGGAAGCGACATTCAGCTTACCCAGTCACCGTCCTTCCTGAGCGCCTCCGTGGGAGATCGCGTGACCATCACATGCCGCGCCACTTCCTCGGTGTCCTCCATGAACTGGTACCAGCAGAAGCCCGGAAAGGCTCCTAAGCCTCTGATCCATGCGACCTCCAACTTGGCTTCCGGGGTGCCGTCACGGTTCAGCGGCAGCGGTTCAGGAACTGAGTACACCCTGACTATTAGCTCTCTCCAACCCGAGGACTTCGCCACCTACTACTGCCAGCAGTGGACCTTCAACCCGCCCACGTTTGGGCAGGGTACCAAGCTGGAGATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK215amino acidPGSSVKVSCKASGYTFTNYNLHWVRQAPGQGLEWsequenceMGAIYPGNYDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARVDFGHSRYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRATSSVSSMNWYQQKPGKAPKPLIHATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWTFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC216nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAATCCGGCGCAGAAGTCAAGAAACCAGGATCGTCCGTGAAAGTGTCCTGCAAGGCGTCCGGGTACACCTTCACTAATTACAACCTCCACTGGGTCAGACAGGCCCCAGGACAGGGCCTGGAATGGATGGGCGCCATCTACCCTGGAAACTACGATACCTCGTACAACCAGAAGTTCAAGGGCCGCGTGACTATTACCGCCGACAAGAGCACCTCCACCGCCTATATGGAACTGTCGTCCCTGCGGTCCGAGGACACTGCCGTGTACTACTGTGCAAGGGTGGACTTCGGTCACTCCCGGTATTGGTACTTCGACGTCTGGGGACAGGGGACCACTGTGACCGTGTCGTCGGGAGGCGGTGGAAGCGGCGGTGGCGGAAGCGGAGGCGGCGGATCAGGGGGCGGAGGAAGCGACATTCAGCTTACCCAGTCACCGTCCTTCCTGAGCGCCTCCGTGGGAGATCGCGTGACCATCACATGCCGCGCCACTTCCTCGGTGTCCTCCATGAACTGGTACCAGCAGAAGCCCGGAAAGGCTCCTAAGCCTCTGATCCATGCGACCTCCAACTTGGCTTCCGGGGTGCCGTCACGGTTCAGCGGCAGCGGTTCAGGAACTGAGTACACCCTGACTATTAGCTCTCTCCAACCCGAGGACTTCGCCACCTACTACTGCCAGCAGTGGACCTTCAACCCGCCCACGTTTGGGCAGGGTACCAAGCTGGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C5H2SEQ ID NO:HCDR1SYNMH244 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYNPKFKG245 (Kabat)SEQ ID NO:HCDR3SYFYGSSSWYFDV246 (Kabat)SEQ ID NO:HCDR1GYTFTSY247 (Chothia)SEQ ID NO:HCDR2YPGNGD248 (Chothia)SEQ ID NO:HCDR3SYFYGSSSWYFDV249 (Chothia)SEQ ID NO:HCDR1GYTFTSYN250 (IMGT)SEQ ID NO:HCDR2IYPGNGDT251 (IMGT)SEQ ID NO:HCDR3ARSYFYGSSSWYFDV252 (IMGT)SEQ ID NO: 946HCDR1GYTFTSYNMH(CombinedChothia andKabat)SEQ ID NO: 947HCDR2AIYPGNGDTSYNPKFKG(CombinedChothia andKabat)SEQ ID NO: 948HCDR3SYFYGSSSWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNM253HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTMTADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCAGGAGCAGAAGTC254AAGAAACCTGGAGCTTCCGTGAAAGTGTCGTGCAAGGCCTCCGGCTACACCTTCACCTCTTACAACATGCACTGGGTCAGACAGGCCCCTGGTCAAGGACTGGAATGGATGGGAGCGATCTACCCGGGCAACGGAGACACTTCGTACAACCCCAAGTTCAAGGGACGGGTCACTATGACCGCCGATAAGAGCACGCGCACCGCGTACATGGAACTGAGCAGCCTGCGCTCCGAGGACACTGCCGTGTATTACTGCGCGAGGAGCTACTTCTACGGATCATCGTCGTGGTACTTCGACGTCTGGGGCCAGGGCACCACCGTGACCGTGTCATCCSEQ ID NO:LCDR1RASSSVSSMH255 (Kabat)SEQ ID NO:LCDR2ATSNLAS256 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT257 (Kabat)SEQ ID NO:LCDR1SSSVSS258 (Chothia)SEQ ID NO:LCDR2ATS259 (Chothia)SEQ ID NO:LCDR3WIFNPP260 (Chothia)SEQ ID NO:LCDR1SSVSS261 (IMGT)SEQ ID NO:LCDR2ATS262 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT263 (IMGT)SEQ ID NO: 949LCDR1RASSSVSSMH(CombinedChothia andKabat)SEQ ID NO: 950LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 951LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLDIQLTQSPSFLSASVGDRVTITCRASSSVSSMHWYQ264QKPGKAPKPLIFATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA VLGATATTCAGCTGACCCAGAGCCCGTCATTCCTGT265CCGCCTCCGTGGGAGACAGAGTGACCATCACTTGTCGGGCCAGCTCCTCGGTGTCCTCCATGCATTGGTATCAGCAGAAGCCTGGGAAGGCTCCCAAGCCCCTCATCTTCGCCACATCAAATCTTGCCTCCGGGGTGCCAAGCCGGTTCTCCGGGAGCGGCTCCGGTACTGAGTACACTCTGACCATTTCCTCCTTGCAACCCGAGGACTTTGCCACCTACTACTGCCAGCAGTGGATCTTTAACCCGCCGACCTTCGGAGGAGGAACCAAAGTGGAGATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS266SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNM267linker-VL)HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTMTADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVSSMHWYQQKPGKAPKPLIFATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAGTCAGGAGCAGAAGTCAAG268(VH-linker-AAACCTGGAGCTTCCGTGAAAGTGTCGTGCAAGGCCTVL)CCGGCTACACCTTCACCTCTTACAACATGCACTGGGTCAGACAGGCCCCTGGTCAAGGACTGGAATGGATGGGAGCGATCTACCCGGGCAACGGAGACACTTCGTACAACCCCAAGTTCAAGGGACGGGTCACTATGACCGCCGATAAGAGCACGCGCACCGCGTACATGGAACTGAGCAGCCTGCGCTCCGAGGACACTGCCGTGTATTACTGCGCGAGGAGCTACTTCTACGGATCATCGTCGTGGTACTTCGACGTCTGGGGCCAGGGCACCACCGTGACCGTGTCATCCGGTGGCGGAGGATCGGGGGGCGGAGGAAGCGGCGGGGGGGGCTCCGGCGGTGGAGGCTCGGATATTCAGCTGACCCAGAGCCCGTCATTCCTGTCCGCCTCCGTGGGAGACAGAGTGACCATCACTTGTCGGGCCAGCTCCTCGGTGTCCTCCATGCATTGGTATCAGCAGAAGCCTGGGAAGGCTCCCAAGCCCCTCATCTTCGCCACATCAAATCTTGCCTCCGGGGTGCCAAGCCGGTTCTCCGGGAGCGGCTCCGGTACTGAGTACACTCTGACCATTTCCTCCTTGCAACCCGAGGACTTTGCCACCTACTACTGCCAGCAGTGGATCTTTAACCCGCCGACCTTCGGAGGAGGAACCAAAGTGGAGATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK269amino acidPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEsequenceWMGAIYPGNGDTSYNPKFKGRVTMTADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVSSMHWYQQKPGKAPKPLIFATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC270nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAGTCAGGAGCAGAAGTCAAGAAACCTGGAGCTTCCGTGAAAGTGTCGTGCAAGGCCTCCGGCTACACCTTCACCTCTTACAACATGCACTGGGTCAGACAGGCCCCTGGTCAAGGACTGGAATGGATGGGAGCGATCTACCCGGGCAACGGAGACACTTCGTACAACCCCAAGTTCAAGGGACGGGTCACTATGACCGCCGATAAGAGCACGCGCACCGCGTACATGGAACTGAGCAGCCTGCGCTCCGAGGACACTGCCGTGTATTACTGCGCGAGGAGCTACTTCTACGGATCATCGTCGTGGTACTTCGACGTCTGGGGCCAGGGCACCACCGTGACCGTGTCATCCGGTGGCGGAGGATCGGGGGGCGGAGGAAGCGGCGGGGGGGGCTCCGGCGGTGGAGGCTCGGATATTCAGCTGACCCAGAGCCCGTCATTCCTGTCCGCCTCCGTGGGAGACAGAGTGACCATCACTTGTCGGGCCAGCTCCTCGGTGTCCTCCATGCATTGGTATCAGCAGAAGCCTGGGAAGGCTCCCAAGCCCCTCATCTTCGCCACATCAAATCTTGCCTCCGGGGTGCCAAGCCGGTTCTCCGGGAGCGGCTCCGGTACTGAGTACACTCTGACCATTTCCTCCTTGCAACCCGAGGACTTTGCCACCTACTACTGCCAGCAGTGGATCTTTAACCCGCCGACCTTCGGAGGAGGAACCAAAGTGGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C5H3SEQ ID NO:HCDR1SYNMH271 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYNPKFKG272 (Kabat)SEQ ID NO:HCDR3SYFYGSSSWYFDV273 (Kabat)SEQ ID NO:HCDR1GYTFTSY274 (Chothia)SEQ ID NO:HCDR2YPGNGD275 (Chothia)SEQ ID NO:HCDR3SYFYGSSSWYFDV276 (Chothia)SEQ ID NO:HCDR1GYTFTSYN277 (IMGT)SEQ ID NO:HCDR2IYPGNGDT278 (IMGT)SEQ ID NO:HCDR3ARSYFYGSSSWYFDV279 (IMGT)SEQ ID NO: 952HCDR1GYTFTSYNMH(CombinedChothia andKabat)SEQ ID NO: 953HCDR2AIYPGNGDTSYNPKFKG(CombinedChothia andKabat)SEQ ID NO: 954HCDR3SYFYGSSSWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNM280HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTITADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTC281AAGAAGCCTGGTTCATCGGTGAAAGTGTCCTGCAAAGCGTCGGGCTACACCTTCACCTCGTACAACATGCACTGGGTCCGCCAGGCCCCCGGACAAGGACTGGAATGGATGGGTGCTATCTACCCCGGAAACGGAGATACCAGCTACAACCCCAAGTTCAAGGGACGCGTGACCATTACTGCCGACAAGTCCACAAGAACCGCCTACATGGAACTGTCCAGCCTGAGATCCGAGGACACTGCGGTGTACTACTGTGCGAGGTCCTACTTCTACGGGTCCTCCTCTTGGTACTTCGACGTCTGGGGACAGGGCACTACTGTGACCGTGTCCAGCSEQ ID NO:LCDR1RASSSVSSMH282 (Kabat)SEQ ID NO:LCDR2ATSNLAS283 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT284 (Kabat)SEQ ID NO:LCDR1SSSVSS285 (Chothia)SEQ ID NO:LCDR2ATS286 (Chothia)SEQ ID NO:LCDR3WIFNPP287 (Chothia)SEQ ID NO:LCDR1SSVSS288 (IMGT)SEQ ID NO:LCDR2ATS289 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT290 (IMGT)SEQ ID NO: 955LCDR1RASSSVSSMH(CombinedChothia andKabat)SEQ ID NO: 956LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 957LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLEIVLTQSPATLSLSPGERATLSCRASSSVSSMHWYQ291QKPGQAPRPLIFATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA VLGAGATCGTGCTGACGCAGTCGCCGGCCACCCTG292AGCCTTTCACCGGGAGAACGCGCCACTCTGTCATGCCGGGCCAGCAGCTCCGTGTCCTCCATGCATTGGTACCAGCAGAAGCCGGGGCAGGCCCCGCGGCCTCTCATCTTCGCCACCTCCAATCTGGCCTCCGGCATCCCTGCTCGGTTTAGCGGAAGCGGCAGCGGAACTGACTATACCTTGACCATCTCCTCGCTGGAACCAGAGGATGCAGCCGTGTACTATTGCCAGCAGTGGATCTTCAACCCGCCAACCTTCGGCGGCGGCACCAAGGTCGAGATTAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS293SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNM294linker-VL)HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTITADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSSMHWYQQKPGQAPRPLIFATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA scFvCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTCAAG295(VH-linker-AAGCCTGGTTCATCGGTGAAAGTGTCCTGCAAAGCGTVL)CGGGCTACACCTTCACCTCGTACAACATGCACTGGGTCCGCCAGGCCCCCGGACAAGGACTGGAATGGATGGGTGCTATCTACCCCGGAAACGGAGATACCAGCTACAACCCCAAGTTCAAGGGACGCGTGACCATTACTGCCGACAAGTCCACAAGAACCGCCTACATGGAACTGTCCAGCCTGAGATCCGAGGACACTGCGGTGTACTACTGTGCGAGGTCCTACTTCTACGGGTCCTCCTCTTGGTACTTCGACGTCTGGGGACAGGGCACTACTGTGACCGTGTCCAGCGGGGGAGGCGGTAGCGGGGGGGGTGGATCGGGCGGCGGCGGATCAGGAGGAGGAGGGTCCGAGATCGTGCTGACGCAGTCGCCGGCCACCCTGAGCCTTTCACCGGGAGAACGCGCCACTCTGTCATGCCGGGCCAGCAGCTCCGTGTCCTCCATGCATTGGTACCAGCAGAAGCCGGGGCAGGCCCCGCGGCCTCTCATCTTCGCCACCTCCAATCTGGCCTCCGGCATCCCTGCTCGGTTTAGCGGAAGCGGCAGCGGAACTGACTATACCTTGACCATCTCCTCGCTGGAACCAGAGGATGCAGCCGTGTACTATTGCCAGCAGTGGATCTTCAACCCGCCAACCTTCGGCGGCGGCACCAAGGTCGAGATTAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK296amino acidPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEsequenceWMGAIYPGNGDTSYNPKFKGRVTITADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSSMHWYQQKPGQAPRPLIFATSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWIFNPPTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC297nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceGCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAGCCTGGTTCATCGGTGAAAGTGTCCTGCAAAGCGTCGGGCTACACCTTCACCTCGTACAACATGCACTGGGTCCGCCAGGCCCCCGGACAAGGACTGGAATGGATGGGTGCTATCTACCCCGGAAACGGAGATACCAGCTACAACCCCAAGTTCAAGGGACGCGTGACCATTACTGCCGACAAGTCCACAAGAACCGCCTACATGGAACTGTCCAGCCTGAGATCCGAGGACACTGCGGTGTACTACTGTGCGAGGTCCTACTTCTACGGGTCCTCCTCTTGGTACTTCGACGTCTGGGGACAGGGCACTACTGTGACCGTGTCCAGCGGGGGAGGCGGTAGCGGGGGGGGTGGATCGGGCGGCGGCGGATCAGGAGGAGGAGGGTCCGAGATCGTGCTGACGCAGTCGCCGGCCACCCTGAGCCTTTCACCGGGAGAACGCGCCACTCTGTCATGCCGGGCCAGCAGCTCCGTGTCCTCCATGCATTGGTACCAGCAGAAGCCGGGGCAGGCCCCGCGGCCTCTCATCTTCGCCACCTCCAATCTGGCCTCCGGCATCCCTGCTCGGTTTAGCGGAAGCGGCAGCGGAACTGACTATACCTTGACCATCTCCTCGCTGGAACCAGAGGATGCAGCCGTGTACTATTGCCAGCAGTGGATCTTCAACCCGCCAACCTTCGGCGGCGGCACCAAGGTCGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C5H4SEQ ID NO:HCDR1SYNMH298 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYNPKFKG299 (Kabat)SEQ ID NO:HCDR3SYFYGSSSWYFDV300 (Kabat)SEQ ID NO:HCDR1GYTFTSY301 (Chothia)SEQ ID NO:HCDR2YPGNGD302 (Chothia)SEQ ID NO:HCDR3SYFYGSSSWYFDV303 (Chothia)SEQ ID NO:HCDR1GYTFTSYN304 (IMGT)SEQ ID NO:HCDR2IYPGNGDT305 (IMGT)SEQ ID NO:HCDR3ARSYFYGSSSWYFDV306 (IMGT)SEQ ID NO: 958HCDR1GYTFTSYNMH(CombinedChothia andKabat)SEQ ID NO: 959HCDR2AIYPGNGDTSYNPKFKG(CombinedChothia andKabat)SEQ ID NO: 960HCDR3SYFYGSSSWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNM307HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTITADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTC308AAGAAGCCAGGTTCCTCGGTGAAAGTGTCCTGCAAAGCCTCGGGTTACACCTTCACCTCGTACAATATGCACTGGGTCCGCCAAGCTCCGGGACAAGGCCTGGAATGGATGGGAGCGATCTACCCCGGAAACGGCGACACGTCCTACAACCCGAAGTTCAAGGGAAGAGTGACCATCACCGCCGACAAGTCCACCCGCACCGCGTACATGGAGCTTAGCAGCCTGCGGAGCGAGGACACTGCCGTGTATTACTGCGCCCGGTCCTACTTCTATGGATCATCCTCGTGGTACTTCGATGTCTGGGGCCAGGGGACCACCGTGACCGTGTCCAGCSEQ ID NO:LCDR1RASSSVSSMH309 (Kabat)SEQ ID NO:LCDR2ATSNLAS310 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT311 (Kabat)SEQ ID NO:LCDR1SSSVSS312 (Chothia)SEQ ID NO:LCDR2ATS313 (Chothia)SEQ ID NO:LCDR3WIFNPP314 (Chothia)SEQ ID NO:LCDR1SSVSS315 (IMGT)SEQ ID NO:LCDR2ATS316 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT317 (IMGT)SEQ ID NO: 961LCDR1RASSSVSSMH(CombinedChothia andKabat)SEQ ID NO: 962LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 963LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLDIQLTQSPSFLSASVGDRVTITCRASSSVSSMHWYQ318QKPGKAPKPLIFATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA VLGATATCCAGCTGACCCAGAGCCCTTCCTTCCTGT319CCGCTTCCGTGGGAGACAGAGTCACTATTACTTGTCGGGCCTCCTCATCCGTGTCATCCATGCACTGGTACCAGCAGAAGCCGGGAAAGGCCCCAAAGCCCTTGATCTTTGCCACTTCCAACCTGGCATCCGGCGTGCCCTCGAGGTTCTCCGGGAGCGGTTCAGGGACCGAGTACACTCTGACCATTAGCAGCCTCCAGCCTGAGGACTTTGCCACCTACTACTGCCAGCAGTGGATTTTCAACCCGCCTACATTCGGAGGGGGCACTAAGGTCGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS320SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNM321linker-VL)HWVRQAPGQGLEWMGAIYPGNGDTSYNPKFKGRVTITADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVSSMHWYQQKPGKAPKPLIFATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGGGTKVEIKSEQ ID NO:DNA scFvCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTCAAG322(VH-linker-AAGCCAGGTTCCTCGGTGAAAGTGTCCTGCAAAGCCTVL)CGGGTTACACCTTCACCTCGTACAATATGCACTGGGTCCGCCAAGCTCCGGGACAAGGCCTGGAATGGATGGGAGCGATCTACCCCGGAAACGGCGACACGTCCTACAACCCGAAGTTCAAGGGAAGAGTGACCATCACCGCCGACAAGTCCACCCGCACCGCGTACATGGAGCTTAGCAGCCTGCGGAGCGAGGACACTGCCGTGTATTACTGCGCCCGGTCCTACTTCTATGGATCATCCTCGTGGTACTTCGATGTCTGGGGCCAGGGGACCACCGTGACCGTGTCCAGCGGTGGCGGAGGCAGCGGCGGAGGAGGGTCTGGAGGAGGCGGCTCGGGGGGAGGGGGCTCGGATATCCAGCTGACCCAGAGCCCTTCCTTCCTGTCCGCTTCCGTGGGAGACAGAGTCACTATTACTTGTCGGGCCTCCTCATCCGTGTCATCCATGCACTGGTACCAGCAGAAGCCGGGAAAGGCCCCAAAGCCCTTGATCTTTGCCACTTCCAACCTGGCATCCGGCGTGCCCTCGAGGTTCTCCGGGAGCGGTTCAGGGACCGAGTACACTCTGACCATTAGCAGCCTCCAGCCTGAGGACTTTGCCACCTACTACTGCCAGCAGTGGATTTTCAACCCGCCTACATTCGGAGGGGGCACTAAGGTCGAAATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK323amino acidPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEsequenceWMGAIYPGNGDTSYNPKFKGRVTITADKSTRTAYMELSSLRSEDTAVYYCARSYFYGSSSWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVSSMHWYQQKPGKAPKPLIFATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC324nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceGCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAGCCAGGTTCCTCGGTGAAAGTGTCCTGCAAAGCCTCGGGTTACACCTTCACCTCGTACAATATGCACTGGGTCCGCCAAGCTCCGGGACAAGGCCTGGAATGGATGGGAGCGATCTACCCCGGAAACGGCGACACGTCCTACAACCCGAAGTTCAAGGGAAGAGTGACCATCACCGCCGACAAGTCCACCCGCACCGCGTACATGGAGCTTAGCAGCCTGCGGAGCGAGGACACTGCCGTGTATTACTGCGCCCGGTCCTACTTCTATGGATCATCCTCGTGGTACTTCGATGTCTGGGGCCAGGGGACCACCGTGACCGTGTCCAGCGGTGGCGGAGGCAGCGGCGGAGGAGGGTCTGGAGGAGGCGGCTCGGGGGGAGGGGGCTCGGATATCCAGCTGACCCAGAGCCCTTCCTTCCTGTCCGCTTCCGTGGGAGACAGAGTCACTATTACTTGTCGGGCCTCCTCATCCGTGTCATCCATGCACTGGTACCAGCAGAAGCCGGGAAAGGCCCCAAAGCCCTTGATCTTTGCCACTTCCAACCTGGCATCCGGCGTGCCCTCGAGGTTCTCCGGGAGCGGTTCAGGGACCGAGTACACTCTGACCATTAGCAGCCTCCAGCCTGAGGACTTTGCCACCTACTACTGCCAGCAGTGGATTTTCAACCCGCCTACATTCGGAGGGGGCACTAAGGTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C8H1SEQ ID NO:HCDR1RYNMH325 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYSQKFKG326 (Kabat)SEQ ID NO:HCDR3SFFYGSSDWYFDV327 (Kabat)SEQ ID NO:HCDR1GYTFTRY328 (Chothia)SEQ ID NO:HCDR2YPGNGD329 (Chothia)SEQ ID NO:HCDR3SFFYGSSDWYFDV330 (Chothia)SEQ ID NO:HCDR1GYTFTRYN331 (IMGT)SEQ ID NO:HCDR2IYPGNGDT332 (IMGT)SEQ ID NO:HCDR3ARSFFYGSSDWYFDV333 (IMGT)SEQ ID NO: 964HCDR1GYTFTRYNMH(CombinedChothia andKabat)SEQ ID NO: 965HCDR2AIYPGNGDTSYSQKFKG(CombinedChothia andKabat)SEQ ID NO: 966HCDR3SFFYGSSDWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYNM334HWVRQAPGQRLEWMGAIYPGNGDTSYSQKFKGRVTITADKSASTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCAGGAGCAGAAGTC335AAGAAACCAGGAGCATCCGTGAAAGTGTCGTGCAAAGCCTCTGGCTACACCTTCACCCGGTACAACATGCACTGGGTCAGACAGGCCCCGGGACAGCGGCTCGAGTGGATGGGTGCCATCTACCCCGGCAACGGGGACACCTCCTACTCCCAAAAGTTCAAGGGTCGCGTGACCATCACGGCGGATAAGTCGGCCAGCACTGCGTACATGGAATTGTCATCCCTGCGCTCCGAGGATACCGCCGTGTATTACTGCGCGCGGTCCTTCTTCTACGGCTCCTCCGATTGGTACTTCGACGTCTGGGGACAGGGAACTACCGTGACCGTGTCCTCCSEQ ID NO:LCDR1RASSSVNNMH336 (Kabat)SEQ ID NO:LCDR2ATSNLAS337 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT338 (Kabat)SEQ ID NO:LCDR1SSSVNN339 (Chothia)SEQ ID NO:LCDR2ATS340 (Chothia)SEQ ID NO:LCDR3WIFNPP341 (Chothia)SEQ ID NO:LCDR1SSVNN342 (IMGT)SEQ ID NO:LCDR2ATS343 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT344 (IMGT)SEQ ID NO: 967LCDR1RASSSVNNMH(CombinedChothia andKabat)SEQ ID NO: 968LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 969LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLEIVLTQSPDFQSVTPKEKVTITCRASSSVNNMHWY345QQKPDQSPKPLIYATSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGAAATCGTGCTGACTCAGTCGCCGGACTTCCAAA346GCGTGACCCCAAAGGAGAAGGTCACCATCACCTGTAGAGCCTCATCGTCCGTGAACAATATGCACTGGTACCAGCAGAAGCCGGACCAGTCCCCTAAGCCCCTGATCTACGCCACTTCCAACCTGGCCTCCGGCGTGCCGTCGAGGTTCAGCGGCTCGGGCAGCGGGACCGACTACACCCTGACCATCAACAGCCTTGAAGCTGAGGACGCCGCTACCTACTACTGCCAGCAGTGGATTTTCAACCCTCCCACATTTGGACAGGGCACTAAGCTGGAGATTAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS347SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYNM348linker-VL)HWVRQAPGQRLEWMGAIYPGNGDTSYSQKFKGRVTITADKSASTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDFQSVTPKEKVTITCRASSSVNNMHWYQQKPDQSPKPLIYATSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAGTCAGGAGCAGAAGTCAAG349(VH-linker-AAACCAGGAGCATCCGTGAAAGTGTCGTGCAAAGCCVL)TCTGGCTACACCTTCACCCGGTACAACATGCACTGGGTCAGACAGGCCCCGGGACAGCGGCTCGAGTGGATGGGTGCCATCTACCCCGGCAACGGGGACACCTCCTACTCCCAAAAGTTCAAGGGTCGCGTGACCATCACGGCGGATAAGTCGGCCAGCACTGCGTACATGGAATTGTCATCCCTGCGCTCCGAGGATACCGCCGTGTATTACTGCGCGCGGTCCTTCTTCTACGGCTCCTCCGATTGGTACTTCGACGTCTGGGGACAGGGAACTACCGTGACCGTGTCCTCCGGGGGTGGCGGGAGCGGAGGGGGCGGAAGCGGGGGTGGAGGATCAGGAGGCGGAGGCTCCGAAATCGTGCTGACTCAGTCGCCGGACTTCCAAAGCGTGACCCCAAAGGAGAAGGTCACCATCACCTGTAGAGCCTCATCGTCCGTGAACAATATGCACTGGTACCAGCAGAAGCCGGACCAGTCCCCTAAGCCCCTGATCTACGCCACTTCCAACCTGGCCTCCGGCGTGCCGTCGAGGTTCAGCGGCTCGGGCAGCGGGACCGACTACACCCTGACCATCAACAGCCTTGAAGCTGAGGACGCCGCTACCTACTACTGCCAGCAGTGGATTTTCAACCCTCCCACATTTGGACAGGGCACTAAGCTGGAGATTAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK350amino acidPGASVKVSCKASGYTFTRYNMHWVRQAPGQRLEsequenceWMGAIYPGNGDTSYSQKFKGRVTITADKSASTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDFQSVTPKEKVTITCRASSSVNNMHWYQQKPDQSPKPLIYATSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQWIFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC351nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAGTCAGGAGCAGAAGTCAAGAAACCAGGAGCATCCGTGAAAGTGTCGTGCAAAGCCTCTGGCTACACCTTCACCCGGTACAACATGCACTGGGTCAGACAGGCCCCGGGACAGCGGCTCGAGTGGATGGGTGCCATCTACCCCGGCAACGGGGACACCTCCTACTCCCAAAAGTTCAAGGGTCGCGTGACCATCACGGCGGATAAGTCGGCCAGCACTGCGTACATGGAATTGTCATCCCTGCGCTCCGAGGATACCGCCGTGTATTACTGCGCGCGGTCCTTCTTCTACGGCTCCTCCGATTGGTACTTCGACGTCTGGGGACAGGGAACTACCGTGACCGTGTCCTCCGGGGGTGGCGGGAGCGGAGGGGGCGGAAGCGGGGGTGGAGGATCAGGAGGCGGAGGCTCCGAAATCGTGCTGACTCAGTCGCCGGACTTCCAAAGCGTGACCCCAAAGGAGAAGGTCACCATCACCTGTAGAGCCTCATCGTCCGTGAACAATATGCACTGGTACCAGCAGAAGCCGGACCAGTCCCCTAAGCCCCTGATCTACGCCACTTCCAACCTGGCCTCCGGCGTGCCGTCGAGGTTCAGCGGCTCGGGCAGCGGGACCGACTACACCCTGACCATCAACAGCCTTGAAGCTGAGGACGCCGCTACCTACTACTGCCAGCAGTGGATTTTCAACCCTCCCACATTTGGACAGGGCACTAAGCTGGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C8H2SEQ ID NO:HCDR1RYNMH352 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYSQKFKG353 (Kabat)SEQ ID NO:HCDR3SFFYGSSDWYFDV354 (Kabat)SEQ ID NO:HCDR1GYTFTRY355 (Chothia)SEQ ID NO:HCDR2YPGNGD356 (Chothia)SEQ ID NO:HCDR3SFFYGSSDWYFDV357 (Chothia)SEQ ID NO:HCDR1GYTFTRYN358 (IMGT)SEQ ID NO:HCDR2IYPGNGDT359 (IMGT)SEQ ID NO:HCDR3ARSFFYGSSDWYFDV360 (IMGT)SEQ ID NO: 970HCDR1GYTFTRYNMH(CombinedChothia andKabat)SEQ ID NO: 971HCDR2AIYPGNGDTSYSQKFKG(CombinedChothia andKabat)SEQ ID NO: 972HCDR3SFFYGSSDWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYNM361HWVRQAPGQRLEWMGAIYPGNGDTSYSQKFKGRVTITADKSASTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAACTCGTCCAATCCGGCGCGGAAGTC362AAAAAGCCTGGAGCCTCCGTCAAAGTGTCCTGCAAGGCCTCCGGTTACACTTTCACTCGCTACAACATGCATTGGGTGCGGCAGGCCCCGGGACAGCGCCTGGAATGGATGGGCGCAATCTACCCCGGCAACGGAGACACCTCCTATTCCCAAAAGTTCAAGGGAAGGGTCACAATCACGGCCGACAAGAGCGCCTCAACTGCCTACATGGAGCTGAGCAGCCTCAGATCCGAAGATACCGCGGTGTACTACTGCGCCCGGAGCTTCTTCTACGGTTCGTCTGATTGGTACTTTGACGTCTGGGGCCAGGGAACCACCGTGACCGTGTCGTCCSEQ ID NO:LCDR1RASSSVNNMH363 (Kabat)SEQ ID NO:LCDR2ATSNLAS364 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT365 (Kabat)SEQ ID NO:LCDR1SSSVNN366 (Chothia)SEQ ID NO:LCDR2ATS367 (Chothia)SEQ ID NO:LCDR3WIFNPP368 (Chothia)SEQ ID NO:LCDR1SSVNN369 (IMGT)SEQ ID NO:LCDR2ATS370 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT371 (IMGT)SEQ ID NO: 973LCDR1RASSSVNNMH(CombinedChothia andKabat)SEQ ID NO: 974LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 975LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLDIQLTQSPSFLSASVGDRVTITCRASSSVNNMHWY372QQKPGKAPKPLIYATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGACATCCAGCTTACCCAGTCGCCATCATTCCTGT373CCGCATCAGTGGGTGATCGCGTGACCATTACCTGTCGGGCGTCCTCCTCCGTGAACAACATGCACTGGTACCAGCAGAAGCCGGGGAAGGCTCCCAAGCCTCTGATCTACGCCACTAGCAATTTGGCCAGCGGCGTGCCTTCGAGATTCTCGGGGTCGGGCTCAGGAACCGAGTATACCCTGACCATTTCCTCCCTCCAACCGGAGGACTTTGCTACTTACTACTGCCAGCAGTGGATTTTCAACCCCCCGACTTTCGGACAGGGCACCAAGCTGGAAATCAAGSEQ IDLinkerGGGGSGGGGSGGGGSGGGGSNO: 374SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYNM375linker-VL)HWVRQAPGQRLEWMGAIYPGNGDTSYSQKFKGRVTITADKSASTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVNNMHWYQQKPGKAPKPLIYATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTGCAACTCGTCCAATCCGGCGCGGAAGTCAAA376(VH-linker-AAGCCTGGAGCCTCCGTCAAAGTGTCCTGCAAGGCCTVL)CCGGTTACACTTTCACTCGCTACAACATGCATTGGGTGCGGCAGGCCCCGGGACAGCGCCTGGAATGGATGGGCGCAATCTACCCCGGCAACGGAGACACCTCCTATTCCCAAAAGTTCAAGGGAAGGGTCACAATCACGGCCGACAAGAGCGCCTCAACTGCCTACATGGAGCTGAGCAGCCTCAGATCCGAAGATACCGCGGTGTACTACTGCGCCCGGAGCTTCTTCTACGGTTCGTCTGATTGGTACTTTGACGTCTGGGGCCAGGGAACCACCGTGACCGTGTCGTCCGGTGGCGGAGGGAGCGGTGGAGGAGGCTCCGGGGGAGGAGGCAGCGGCGGGGGAGGCAGCGACATCCAGCTTACCCAGTCGCCATCATTCCTGTCCGCATCAGTGGGTGATCGCGTGACCATTACCTGTCGGGCGTCCTCCTCCGTGAACAACATGCACTGGTACCAGCAGAAGCCGGGGAAGGCTCCCAAGCCTCTGATCTACGCCACTAGCAATTTGGCCAGCGGCGTGCCTTCGAGATTCTCGGGGTCGGGCTCAGGAACCGAGTATACCCTGACCATTTCCTCCCTCCAACCGGAGGACTTTGCTACTTACTACTGCCAGCAGTGGATTTTCAACCCCCCGACTTTCGGACAGGGCACCAAGCTGGAAATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK377amino acidPGASVKVSCKASGYTFTRYNMHWVRQAPGQRLEsequenceWMGAIYPGNGDTSYSQKFKGRVTITADKSASTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVNNMHWYQQKPGKAPKPLIYATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC378nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceGCAACTCGTCCAATCCGGCGCGGAAGTCAAAAAGCCTGGAGCCTCCGTCAAAGTGTCCTGCAAGGCCTCCGGTTACACTTTCACTCGCTACAACATGCATTGGGTGCGGCAGGCCCCGGGACAGCGCCTGGAATGGATGGGCGCAATCTACCCCGGCAACGGAGACACCTCCTATTCCCAAAAGTTCAAGGGAAGGGTCACAATCACGGCCGACAAGAGCGCCTCAACTGCCTACATGGAGCTGAGCAGCCTCAGATCCGAAGATACCGCGGTGTACTACTGCGCCCGGAGCTTCTTCTACGGTTCGTCTGATTGGTACTTTGACGTCTGGGGCCAGGGAACCACCGTGACCGTGTCGTCCGGTGGCGGAGGGAGCGGTGGAGGAGGCTCCGGGGGAGGAGGCAGCGGCGGGGGAGGCAGCGACATCCAGCTTACCCAGTCGCCATCATTCCTGTCCGCATCAGTGGGTGATCGCGTGACCATTACCTGTCGGGCGTCCTCCTCCGTGAACAACATGCACTGGTACCAGCAGAAGCCGGGGAAGGCTCCCAAGCCTCTGATCTACGCCACTAGCAATTTGGCCAGCGGCGTGCCTTCGAGATTCTCGGGGTCGGGCTCAGGAACCGAGTATACCCTGACCATTTCCTCCCTCCAACCGGAGGACTTTGCTACTTACTACTGCCAGCAGTGGATTTTCAACCCCCCGACTTTCGGACAGGGCACCAAGCTGGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C8H3SEQ ID NO:HCDR1RYNMH379 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYSQKFKG380 (Kabat)SEQ ID NO:HCDR3SFFYGSSDWYFDV381 (Kabat)SEQ ID NO:HCDR1GYTFTRY382 (Chothia)SEQ ID NO:HCDR2YPGNGD383 (Chothia)SEQ ID NO:HCDR3SFFYGSSDWYFDV384 (Chothia)SEQ ID NO:HCDR1GYTFTRYN385 (IMGT)SEQ ID NO:HCDR2IYPGNGDT386 (IMGT)SEQ ID NO:HCDR3ARSFFYGSSDWYFDV387 (IMGT)SEQ ID NO: 976HCDR1GYTFTRYNMH(CombinedChothia andKabat)SEQ ID NO: 977HCDR2AIYPGNGDTSYSQKFKG(CombinedChothia andKabat)SEQ ID NO: 978HCDR3SFFYGSSDWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTRYNM388HWVRQAPGQGLEWMGAIYPGNGDTSYSQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTC389AAGAAGCCTGGTTCCTCCGTGAAAGTGTCCTGCAAAGCGTCTGGCTACACCTTCACCCGGTACAATATGCACTGGGTCAGACAGGCGCCCGGACAGGGCCTGGAGTGGATGGGGGCCATCTACCCTGGGAACGGCGACACTAGCTACTCCCAAAAGTTCAAGGGCCGCGTGACGATTACCGCCGACAAGTCAACCAGCACTGCCTATATGGAGCTGAGCTCGCTTCGGAGCGAAGATACCGCCGTGTACTACTGCGCTCGGAGCTTCTTCTACGGGTCCTCGGATTGGTACTTCGACGTCTGGGGCCAGGGGACTACTGTGACCGTGTCCTCCSEQ ID NO:LCDR1RASSSVNNMH390 (Kabat)SEQ ID NO:LCDR2ATSNLAS391 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT392 (Kabat)SEQ ID NO:LCDR1SSSVNN393 (Chothia)SEQ ID NO:LCDR2ATS394 (Chothia)SEQ ID NO:LCDR3WIFNPP395 (Chothia)SEQ ID NO:LCDR1SSVNN396 (IMGT)SEQ ID NO:LCDR2ATS397 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT398 (IMGT)SEQ ID NO: 979LCDR1RASSSVNNMH(CombinedChothia andKabat)SEQ ID NO: 980LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 981LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLEIVLTQSPDFQSVTPKEKVTITCRASSSVNNMHWY399QQKPDQSPKPLIYATSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGAAATCGTGCTGACCCAGTCCCCGGACTTTCAGT400CAGTGACTCCCAAGGAGAAGGTCACCATTACTTGTCGCGCCTCCTCCTCGGTGAACAACATGCACTGGTACCAGCAGAAGCCGGACCAGTCCCCGAAGCCCCTGATCTATGCTACCTCCAACTTGGCGTCCGGCGTGCCGTCAAGGTTCAGCGGATCGGGTTCCGGGACAGACTACACCCTGACTATTAACTCACTCGAGGCCGAGGATGCCGCCACCTACTACTGCCAGCAGTGGATCTTCAACCCTCCAACCTTCGGACAAGGAACCAAGCTGGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS401SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTRYNM402linker-VL)HWVRQAPGQGLEWMGAIYPGNGDTSYSQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDFQSVTPKEKVTITCRASSSVNNMHWYQQKPDQSPKPLIYATSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTGCAACTCGTCCAGTCCGGTGCAGAAGTCAAG403(VH-linker-AAGCCTGGTTCCTCCGTGAAAGTGTCCTGCAAAGCGTVL)CTGGCTACACCTTCACCCGGTACAATATGCACTGGGTCAGACAGGCGCCCGGACAGGGCCTGGAGTGGATGGGGGCCATCTACCCTGGGAACGGCGACACTAGCTACTCCCAAAAGTTCAAGGGCCGCGTGACGATTACCGCCGACAAGTCAACCAGCACTGCCTATATGGAGCTGAGCTCGCTTCGGAGCGAAGATACCGCCGTGTACTACTGCGCTCGGAGCTTCTTCTACGGGTCCTCGGATTGGTACTTCGACGTCTGGGGCCAGGGGACTACTGTGACCGTGTCCTCCGGGGGAGGAGGATCGGGCGGAGGCGGTTCGGGAGGCGGCGGAAGCGGAGGCGGAGGTTCAGAAATCGTGCTGACCCAGTCCCCGGACTTTCAGTCAGTGACTCCCAAGGAGAAGGTCACCATTACTTGTCGCGCCTCCTCCTCGGTGAACAACATGCACTGGTACCAGCAGAAGCCGGACCAGTCCCCGAAGCCCCTGATCTATGCTACCTCCAACTTGGCGTCCGGCGTGCCGTCAAGGTTCAGCGGATCGGGTTCCGGGACAGACTACACCCTGACTATTAACTCACTCGAGGCCGAGGATGCCGCCACCTACTACTGCCAGCAGTGGATCTTCAACCCTCCAACCTTCGGACAAGGAACCAAGCTGGAAATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK404amino acidPGSSVKVSCKASGYTFTRYNMHWVRQAPGQGLEsequenceWMGAIYPGNGDTSYSQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPDFQSVTPKEKVTITCRASSSVNNMHWYQQKPDQSPKPLIYATSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQWIFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC405nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceGCAACTCGTCCAGTCCGGTGCAGAAGTCAAGAAGCCTGGTTCCTCCGTGAAAGTGTCCTGCAAAGCGTCTGGCTACACCTTCACCCGGTACAATATGCACTGGGTCAGACAGGCGCCCGGACAGGGCCTGGAGTGGATGGGGGCCATCTACCCTGGGAACGGCGACACTAGCTACTCCCAAAAGTTCAAGGGCCGCGTGACGATTACCGCCGACAAGTCAACCAGCACTGCCTATATGGAGCTGAGCTCGCTTCGGAGCGAAGATACCGCCGTGTACTACTGCGCTCGGAGCTTCTTCTACGGGTCCTCGGATTGGTACTTCGACGTCTGGGGCCAGGGGACTACTGTGACCGTGTCCTCCGGGGGAGGAGGATCGGGCGGAGGCGGTTCGGGAGGCGGCGGAAGCGGAGGCGGAGGTTCAGAAATCGTGCTGACCCAGTCCCCGGACTTTCAGTCAGTGACTCCCAAGGAGAAGGTCACCATTACTTGTCGCGCCTCCTCCTCGGTGAACAACATGCACTGGTACCAGCAGAAGCCGGACCAGTCCCCGAAGCCCCTGATCTATGCTACCTCCAACTTGGCGTCCGGCGTGCCGTCAAGGTTCAGCGGATCGGGTTCCGGGACAGACTACACCCTGACTATTAACTCACTCGAGGCCGAGGATGCCGCCACCTACTACTGCCAGCAGTGGATCTTCAACCCTCCAACCTTCGGACAAGGAACCAAGCTGGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C8H4SEQ ID NO:HCDR1RYNMH406 (Kabat)SEQ ID NO:HCDR2AIYPGNGDTSYSQKFKG407 (Kabat)SEQ ID NO:HCDR3SFFYGSSDWYFDV408 (Kabat)SEQ ID NO:HCDR1GYTFTRY409 (Chothia)SEQ ID NO:HCDR2YPGNGD410 (Chothia)SEQ ID NO:HCDR3SFFYGSSDWYFDV411 (Chothia)SEQ ID NO:HCDR1GYTFTRYN412 (IMGT)SEQ ID NO:HCDR2IYPGNGDT413 (IMGT)SEQ ID NO:HCDR3ARSFFYGSSDWYFDV414 (IMGT)SEQ ID NO: 982HCDR1GYTFTRYNMH(CombinedChothia andKabat)SEQ ID NO: 983HCDR2AIYPGNGDTSYSQKFKG(CombinedChothia andKabat)SEQ ID NO: 984HCDR3SFFYGSSDWYFDV(CombinedChothia andKabat)SEQ ID NO:VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTRYNM415HWVRQAPGQGLEWMGAIYPGNGDTSYSQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCTGGCGCAGAAGTC416AAGAAGCCCGGAAGCTCCGTGAAAGTGTCCTGCAAAGCGTCGGGTTACACTTTCACCCGGTACAACATGCACTGGGTCAGACAGGCCCCTGGACAAGGACTGGAGTGGATGGGTGCCATCTACCCTGGAAACGGAGATACCTCCTACTCCCAAAAGTTCAAGGGGAGAGTGACCATTACCGCCGACAAGTCAACTTCCACCGCTTACATGGAGCTCAGCTCCCTGCGGTCCGAAGATACTGCGGTGTACTATTGCGCTCGCTCATTTTTCTACGGCTCATCGGATTGGTACTTCGACGTCTGGGGACAGGGAACTACCGTGACCGTGTCCTCGSEQ ID NO:LCDR1RASSSVNNMH417 (Kabat)SEQ ID NO:LCDR2ATSNLAS418 (Kabat)SEQ ID NO:LCDR3QQWIFNPPT419 (Kabat)SEQ ID NO:LCDR1SSSVNN420 (Chothia)SEQ ID NO:LCDR2ATS421 (Chothia)SEQ ID NO:LCDR3WIFNPP422 (Chothia)SEQ ID NO:LCDR1SSVNN423 (IMGT)SEQ ID NO:LCDR2ATS424 (IMGT)SEQ ID NO:LCDR3QQWIFNPPT425 (IMGT)SEQ ID NO: 985LCDR1RASSSVNNMH(CombinedChothia andKabat)SEQ ID NO: 986LCDR2ATSNLAS(CombinedChothia andKabat)SEQ ID NO: 987LCDR3QQWIFNPPT(CombinedChothia andKabat)SEQ ID NO:VLDIQLTQSPSFLSASVGDRVTITCRASSSVNNMHWY426QQKPGKAPKPLIYATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA VLGACATCCAGCTGACTCAGTCCCCGTCCTTCCTGT427CCGCCTCCGTGGGGGACCGCGTGACGATTACTTGTCGGGCCTCCTCATCCGTGAACAACATGCATTGGTACCAGCAGAAGCCAGGAAAGGCACCGAAGCCGCTTATCTATGCCACCTCGAATCTGGCCAGCGGAGTGCCTTCGAGGTTTAGCGGCTCCGGCTCCGGCACCGAGTACACTTTGACCATTAGCAGCCTCCAGCCGGAGGACTTCGCCACATACTACTGCCAGCAGTGGATCTTCAACCCCCCCACCTTCGGCCAAGGAACCAAGCTGGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS428SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGSSVKVSCKASGYTFTRYNM429linker-VL)HWVRQAPGQGLEWMGAIYPGNGDTSYSQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVNNMHWYQQKPGKAPKPLIYATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGQGTKLEIKSEQ ID NO:DNA scFvCAAGTCCAACTCGTCCAGTCTGGCGCAGAAGTC430(VH-linker-AAGAAGCCCGGAAGCTCCGTGAAAGTGTCCTGCVL)AAAGCGTCGGGTTACACTTTCACCCGGTACAACATGCACTGGGTCAGACAGGCCCCTGGACAAGGACTGGAGTGGATGGGTGCCATCTACCCTGGAAACGGAGATACCTCCTACTCCCAAAAGTTCAAGGGGAGAGTGACCATTACCGCCGACAAGTCAACTTCCACCGCTTACATGGAGCTCAGCTCCCTGCGGTCCGAAGATACTGCGGTGTACTATTGCGCTCGCTCATTTTTCTACGGCTCATCGGATTGGTACTTCGACGTCTGGGGACAGGGAACTACCGTGACCGTGTCCTCGGGGGGAGGAGGATCGGGCGGAGGCGGTTCGGGAGGCGGCGGAAGCGGAGGCGGAGGTTCAGACATCCAGCTGACTCAGTCCCCGTCCTTCCTGTCCGCCTCCGTGGGGGACCGCGTGACGATTACTTGTCGGGCCTCCTCATCCGTGAACAACATGCATTGGTACCAGCAGAAGCCAGGAAAGGCACCGAAGCCGCTTATCTATGCCACCTCGAATCTGGCCAGCGGAGTGCCTTCGAGGTTTAGCGGCTCCGGCTCCGGCACCGAGTACACTTTGACCATTAGCAGCCTCCAGCCGGAGGACTTCGCCACATACTACTGCCAGCAGTGGATCTTCAACCCCCCCACCTTCGGCCAAGGAACCAAGCTGGAAATCAAGSEQ ID NO:Full CARMALPVTALLLPLALLLHAARPQVQLVQSGAEVKK431amino acidPGSSVKVSCKASGYTFTRYNMHWVRQAPGQGLEsequenceWMGAIYPGNGDTSYSQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSFFYGSSDWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCRASSSVNNMHWYQQKPGKAPKPLIYATSNLASGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQWIFNPPTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full CARATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC432nucleic acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCCAAGTsequenceCCAACTCGTCCAGTCTGGCGCAGAAGTCAAGAAGCCCGGAAGCTCCGTGAAAGTGTCCTGCAAAGCGTCGGGTTACACTTTCACCCGGTACAACATGCACTGGGTCAGACAGGCCCCTGGACAAGGACTGGAGTGGATGGGTGCCATCTACCCTGGAAACGGAGATACCTCCTACTCCCAAAAGTTCAAGGGGAGAGTGACCATTACCGCCGACAAGTCAACTTCCACCGCTTACATGGAGCTCAGCTCCCTGCGGTCCGAAGATACTGCGGTGTACTATTGCGCTCGCTCATTTTTCTACGGCTCATCGGATTGGTACTTCGACGTCTGGGGACAGGGAACTACCGTGACCGTGTCCTCGGGGGGAGGGGGGAGCGGCGGAGGGGGCTCGGGCGGTGGAGGAAGCGGAGGCGGCGGTTCGGACATCCAGCTGACTCAGTCCCCGTCCTTCCTGTCCGCCTCCGTGGGGGACCGCGTGACGATTACTTGTCGGGCCTCCTCATCCGTGAACAACATGCATTGGTACCAGCAGAAGCCAGGAAAGGCACCGAAGCCGCTTATCTATGCCACCTCGAATCTGGCCAGCGGAGTGCCTTCGAGGTTTAGCGGCTCCGGCTCCGGCACCGAGTACACTTTGACCATTAGCAGCCTCCAGCCGGAGGACTTCGCCACATACTACTGCCAGCAGTGGATCTTCAACCCCCCCACCTTCGGCCAAGGAACCAAGCTGGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD20-C2SEQ ID NO:VHQVHLQQSGAELAKPGASVKMSCKASGYTFTNYW433MHWVKQRPGQGLEWIGFITPTTGYPEYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARRKVGKGVYYALDYWGQGTSVTVSSSEQ ID NO:DNA VHCAAGTGCATCTGCAGCAGTCGGGGGCCGAACTG434GCAAAGCCAGGCGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGGTACACCTTCACCAACTACTGGATGCACTGGGTCAAGCAGCGCCCGGGCCAGGGACTCGAGTGGATCGGGTTCATCACGCCGACTACCGGCTACCCGGAGTATAACCAGAAGTTCAAGGACAAGGCCACTCTGACTGCCGACAAGTCCTCGTCTACCGCGTACATGCAACTGTCCTCACTGACTTCGGAGGATTCCGCTGTGTACTACTGCGCGCGGAGGAAAGTCGGAAAGGGAGTGTACTATGCCCTGGACTACTGGGGCCAGGGTACCAGCGTCACTGTGTCCTCCSEQ ID NO:VLDILMTQSPASLSASVGETVTITCRASGNIHNYLAWY435QQKQGNSPQLLVYNTKTLADGVPSRFSGSGSGTQYSLKINSLQTEDFGTYYCQHFWSSPWTFGGGTKLEIKSEQ ID NO:DNA VLGACATTCTGATGACCCAGTCCCCTGCATCACTCT436CCGCGTCCGTGGGAGAAACCGTGACCATCACGTGTAGAGCCTCCGGCAACATCCACAACTACCTGGCCTGGTACCAGCAGAAGCAGGGAAACTCGCCCCAACTGCTTGTGTACAACACCAAGACCTTGGCTGACGGAGTGCCTTCCCGGTTCTCGGGTTCGGGATCAGGCACACAGTACTCCCTGAAAATCAATAGCCTCCAGACCGAAGATTTTGGAACCTACTACTGCCAACACTTCTGGAGCTCCCCCTGGACTTTCGGAGGCGGTACCAAGCTCGAGATTAAGCD20-C3SEQ ID NO:VHQVQLQQPGAELVKPGASVKMSCKASGYTFTNYNL437HWVKQTPGQGLEWIGAIYPGNYDTSYNQKFKGKATLTADKSSSTAYMLLSSLTSEDSAVYFCARVDFGHSRYWYFDVWGAGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAGCTGCAGCAGCCTGGTGCCGAGCTC438GTGAAGCCGGGAGCGTCCGTGAAGATGAGCTGCAAAGCCTCGGGCTACACCTTCACCAATTACAACTTGCATTGGGTCAAGCAGACCCCGGGCCAGGGCCTCGAATGGATCGGAGCGATCTACCCCGGGAACTACGATACTAGCTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGATAAGTCCTCATCCACCGCCTACATGCTGCTGTCCTCGCTGACTTCCGAGGACTCCGCTGTGTACTTCTGCGCCCGCGTGGACTTCGGACACAGCAGATATTGGTATTTTGACGTCTGGGGCGCCGGGACTACCGTGACTGTGTCGTCCSEQ ID NO:VLQIVLSQSPAILSASPGEKVTMTCRATSSVSSMNWY439QQKPGSFPRPWIHATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWTFNPPTFGAGAKLELKSEQ ID NO:DNA VLCAAATTGTCCTGAGCCAGAGCCCGGCTATCCTGT440CCGCCTCACCGGGCGAAAAGGTCACCATGACTTGTCGGGCCACTTCCTCCGTGTCATCCATGAACTGGTACCAGCAGAAGCCTGGCAGCTTCCCTCGGCCATGGATTCACGCCACGTCAAACCTGGCATCGGGAGTGCCCGCAAGGTTCTCCGGGTCCGGCAGCGGAACATCCTACTCCCTCACCATCTCGCGCGTGGAAGCGGAGGACGCTGCCACCTACTACTGCCAACAGTGGACCTTCAACCCCCCCACCTTTGGAGCGGGAGCCAAGCTGGAACTTAAGCD20-C5SEQ ID NO:VHQVQLQQPGAELVKPGASVKMSCKASGYTFTSYNM441HWVKQTPGQGLEWIGAIYPGNGDTSYNPKFKGKATLTADKSSRTAYIHLSSLTSEDSVVYYCARSYFYGSSSWYFDVWGAGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAGCTGCAGCAGCCGGGAGCAGAGCTC442GTGAAGCCTGGAGCCTCAGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTCAAGCAGACCCCCGGACAAGGCCTGGAATGGATCGGCGCCATCTACCCGGGAAACGGGGACACCTCCTATAACCCCAAGTTCAAGGGAAAAGCAACCCTGACCGCGGACAAGTCCAGCAGAACTGCCTACATCCATCTTTCCTCGCTGACGTCCGAGGATTCCGTGGTGTACTACTGTGCCCGCTCCTACTTCTACGGGTCATCCTCGTGGTACTTCGATGTCTGGGGCGCTGGAACCACCGTGACTGTGTCCTCCSEQ ID NO:VLQIILSQSPAILSASPGEKVTLTCRASSSVSSMHWYQ443QKPGSSPKPWIFATSNLASGVPARFTGSGSGTSYSLTISRVEAEDAATYYCQQWIFNPPTFGGGTSLEIKSEQ ID NO:DNA VLCAGATCATTCTGAGCCAGAGCCCGGCCATTCTGT444CTGCCTCGCCTGGAGAAAAAGTCACCCTCACTTGCCGGGCCAGCTCCTCCGTGTCCTCAATGCACTGGTACCAGCAGAAGCCTGGCTCAAGCCCGAAGCCCTGGATCTTCGCCACCTCCAATCTGGCGTCAGGAGTGCCCGCGAGGTTCACTGGATCGGGGTCCGGCACATCGTATTCGCTCACCATTTCCCGGGTGGAGGCCGAGGACGCCGCTACTTACTACTGCCAACAGTGGATCTTCAACCCACCGACCTTTGGCGGAGGGACTTCCTTGGAAATCAAGCD20-C6SEQ ID NO:VHQIQLVQSGPELKKPGETVKISCKTSGYTFTSHGINW445VKQAPRKGLKWMGWINTYTGEPTYGDDFKGRFAFSLETSARTAYLQINNLKNEDTATYFCARYGNYEEPYAMDYWGQGTSVTVSSSEQ ID NO:DNA VHCAAATTCAGCTGGTGCAGTCGGGACCTGAGCTC446AAGAAGCCCGGAGAAACCGTGAAGATCTCCTGCAAGACTTCCGGGTACACTTTTACTTCCCACGGCATCAACTGGGTCAAGCAGGCACCAAGGAAGGGGCTTAAGTGGATGGGCTGGATTAACACCTACACCGGCGAACCCACCTATGGCGATGACTTCAAAGGACGGTTCGCGTTCTCCCTCGAAACCTCAGCAAGAACCGCGTATTTGCAAATCAACAACCTGAAGAACGAGGACACCGCCACCTACTTCTGCGCCCGCTACGGAAATTACGAGGAACCTTACGCTATGGACTACTGGGGCCAGGGCACTTCCGTGACTGTGTCGTCCSEQ ID NO:VLQIVLSQSPAILSASPGEKVTMTCRATSSVSSMNWY447QQKPGSFPRPWIHATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWTFNPPTFGAGAKLELKSEQ ID NO:DNA VLCAGATCGTGCTGAGCCAGAGCCCCGCCATCCTG448AGCGCTTCCCCGGGAGAAAAGGTCACCATGACTTGCCGGGCCACTAGCAGCGTGTCCTCCATGAACTGGTACCAGCAGAAGCCGGGCTCCTTCCCTCGCCCCTGGATTCATGCCACCTCAAACCTGGCCAGCGGAGTGCCAGCCAGATTCTCGGGATCTGGATCGGGGACGTCCTACTCCCTCACCATCTCGCGGGTGGAGGCCGAAGATGCCGCCACATACTACTGTCAACAGTGGACCTTCAACCCGCCGACCTTTGGAGCGGGGGCCAAGCTGGAGCTGAAACD20-C7SEQ ID NO:VHQVQLQQPGAELVKPGASVKMSCKASGYTFTSYNI449HWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSTTAFIHFSSLTSEDSVVYYCARSYFYGSDSWYFDVWGAGTTVTVSSSEQ ID NO:DNA VHCAAGTGCAGCTTCAGCAGCCTGGGGCCGAACTC450GTGAAGCCAGGAGCCTCCGTGAAGATGTCATGCAAAGCCTCCGGCTACACTTTTACCTCCTACAACATTCATTGGGTCAAGCAGACACCTGGCCAGGGCCTGGAATGGATTGGTGCAATCTACCCGGGCAACGGAGACACCTCGTACAACCAGAAGTTTAAGGGGAAGGCCACCCTGACCGCGGACAAGTCAAGCACTACCGCGTTCATTCACTTCTCGTCCTTGACCTCCGAGGATAGCGTGGTGTACTACTGCGCCCGCTCCTATTTCTACGGCTCCGATTCGTGGTACTTCGACGTCTGGGGAGCCGGAACTACCGTGACCGTGTCCTCCSEQ ID NO:VLQIILSQSPAILSASPGEKVTLTCRASSGVPSLHWYQQ451KPGSSPKPWIFATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWIFNPPTFGGGTSLEIKSEQ ID NO:DNA VLCAAATCATCCTGAGCCAGAGCCCGGCCATCCTGT452CGGCTTCACCCGGGGAAAAGGTCACGCTGACTTGCCGGGCCTCCTCCGGCGTGCCAAGCCTCCACTGGTACCAGCAAAAGCCTGGCTCGTCCCCCAAACCCTGGATTTTCGCCACCTCCAACCTGGCTAGCGGAGTGCCGGCCAGATTCTCGGGTTCCGGGTCCGGCACCAGCTATTCTCTCACCATCTCCCGGGTCGAGGCGGAGGACGCAGCGACTTACTACTGTCAACAGTGGATCTTCAATCCGCCCACCTTCGGCGGAGGAACTTCCCTGGAAATCAAGCD20-C8SEQ ID NO:VHQVQLLQPGAELVKPGASVKMSCKASGYTFTRYNM453HWVKQTPGQGLEWIGAIYPGNGDTSYSQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSFFYGSSDWYFDVWGAGTTVSVSSSEQ ID NO:DNA VHCAAGTGCAGCTGCTGCAGCCCGGAGCCGAACTC454GTGAAGCCGGGCGCATCCGTGAAAATGAGCTGCAAGGCGTCCGGTTACACCTTCACTCGCTACAACATGCACTGGGTCAAGCAGACCCCTGGACAAGGCCTGGAGTGGATTGGTGCTATCTACCCGGGAAACGGAGACACTAGCTACTCGCAGAAATTCAAGGGAAAGGCCACGCTGACCGCCGATAAGTCCTCCTCCACTGCCTACATGCAACTCAGCTCACTGACCTCAGAGGACTCGGCCGTGTACTACTGCGCGAGGTCCTTCTTCTACGGGTCCTCGGATTGGTACTTCGACGTCTGGGGCGCCGGTACCACCGTGTCCGTGTCATCCSEQ ID NO:VLQIVLSQSPAILSTSPGEKVTLTCRASSSVNNMHWYQ455QKPGSSPKPWIYATSNLASGVPSRFSGSGSGTSYSLTISRVEAEDAATYYCQQWIFNPPTFGAGTKLELKSEQ ID NO:DNA VLCAGATCGTGCTGAGCCAGTCCCCGGCGATTCTGT456CCACCTCGCCTGGGGAAAAGGTCACCCTGACATGTAGAGCCTCCTCCTCCGTGAACAATATGCATTGGTATCAGCAGAAGCCAGGATCAAGCCCCAAGCCCTGGATCTATGCCACTTCGAACCTTGCCTCTGGAGTGCCCTCACGGTTCTCCGGCTCGGGATCGGGGACCAGCTACAGCTTGACTATCTCCCGGGTGGAGGCTGAGGACGCCGCAACCTACTACTGCCAGCAATGGATCTTCAACCCTCCGACTTTTGGGGCCGGAACCAAGCTGGAACTCAAGCD20-3mSEQ ID NO:VHQVQLVESGGGVVQPGRSLRLSCAASGFTFRDYYM457AWVRQAPGKGLEWVASISYEGNPYYGDSVKGRFTISRDNAKSTLYLQMSSLRAEDTAVYYCARHDHNNVDWFAYWGQGTLVTVSEQ ID NO:DNA VHCAAGTGCAGTTGGTGGAATCAGGAGGAGGTGTC458GTGCAACCAGGAAGATCATTGAGGCTCTCATGCGCCGCCAGCGGATTCACCTTTCGGGATTACTACATGGCCTGGGTCCGCCAGGCCCCGGGGAAGGGACTGGAATGGGTGGCATCCATCTCGTACGAAGGGAACCCCTACTATGGGGACTCCGTGAAGGGACGGTTCACCATCTCCCGGGACAACGCCAAGTCCACCCTGTACCTTCAAATGTCCTCGCTGAGGGCGGAGGATACTGCTGTCTACTACTGTGCCCGCCACGACCATAACAACGTGGACTGGTTCGCCTACTGGGGCCAGGGAACCCTCGTCACCGTGTCCTCGSEQ ID NO:VLDIVMTQTPLSLSVTPGQPVSMSCKSSQSLLYSENKK459NYLAWYLQKPGQSPQLLIFWASTRESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQYYNFPTFGQGTKLEIKSEQ ID NO:DNA VLGACATTGTGATGACGCAGACTCCCCTGTCGCTCT460CCGTGACCCCTGGCCAGCCCGTGTCGATGTCGTGCAAGAGCTCCCAGTCCCTGCTGTATTCCGAGAACAAGAAGAATTACCTTGCGTGGTACCTCCAGAAGCCGGGGCAGAGCCCGCAGCTGCTGATTTTCTGGGCGTCCACTAGAGAGTCTGGAGTGCCTGACCGGTTTAGCGGAAGCGGCTCCGGTACTGATTTCACCCTGAAAATCTCGCGCGTGGAAGCTGAGGACGTGGGCGTGTACTACTGCCAGCAGTACTACAACTTCCCTACTTTCGGACAAGGAACCAAGCTGGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS461SEQ ID NO:scFv (VH-QVQLVESGGGVVQPGRSLRLSCAASGFTFRDYYM462linker-VL)AWVRQAPGKGLEWVASISYEGNPYYGDSVKGRFTISRDNAKSTLYLQMSSLRAEDTAVYYCARHDHNNVDWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTPLSLSVTPGQPVSMSCKSSQSLLYSENKKNYLAWYLQKPGQSPQLLIFWASTRESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQYYNFPTFGQGTKLEIKCD20-3JSEQ ID NO:VHQVQLVQSGAEVKKPGASVKVSCKASGFTFRDYYM463AWVRQAPGQRLEWMGSISYEGNPYYGDSVKGRVTITRDNSASTLYMELSSLRSEDTAVYYCARHDHNNVDWFAYWGQGTLVTVSSSEQ ID NO:DNA VHCAAGTCCAACTCGTCCAGTCCGGTGCAGAAGTC464AAGAAACCAGGAGCTTCCGTGAAAGTGTCGTGCAAAGCTTCAGGCTTCACCTTCCGCGACTATTACATGGCCTGGGTCCGCCAAGCGCCCGGACAGCGGCTGGAGTGGATGGGGTCCATTTCCTACGAGGGGAACCCCTACTATGGAGATTCCGTGAAGGGCAGAGTGACGATCACTCGGGATAACTCCGCCTCCACTCTCTACATGGAACTGTCCTCGCTTCGGAGCGAAGATACCGCGGTGTACTACTGCGCCCGCCACGACCATAACAACGTGGACTGGTTCGCCTACTGGGGACAGGGGACCCTCGTGACCGTGTCCTCTSEQ ID NO:VLDIQMTQSPSSLSASVGDRVTITCKSSQSLLYSENKK465NYLAWYQQKPGKVPKLLIFWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYYNFPTFGQGTKLEIKSEQ ID NO:DNA VLGACATTCAGATGACCCAGTCCCCGAGCTCGCTGT466CCGCCTCCGTGGGAGACAGAGTGACAATCACTTGCAAGAGCAGCCAGTCACTGTTGTACTCCGAGAACAAGAAGAACTACCTCGCCTGGTACCAGCAGAAGCCGGGAAAGGTCCCTAAGCTGCTGATCTTCTGGGCCAGCACTAGGGAGTCGGGAGTGCCGTCACGGTTCAGCGGATCGGGATCGGGTACCGACTTCACCCTGACTATCTCCTCCCTGCAACCTGAGGACGTGGCCACCTACTACTGTCAGCAGTACTACAATTTTCCCACCTTCGGCCAGGGTACCAAGCTGGAAATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS467SEQ ID NO:scFv (VH-QVQLVQSGAEVKKPGASVKVSCKASGFTFRDYYM468linker-VL)AWVRQAPGQRLEWMGSISYEGNPYYGDSVKGRVTITRDNSASTLYMELSSLRSEDTAVYYCARHDHNNVDWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSQSLLYSENKKNYLAWYQQKPGKVPKLLIFWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYYNFPTFGQGTKLEIKCD20-3H5k1SEQ ID NO:VHEVQLVQSGAEVKKPGESLKISCKGSGFTFRDYYMA469WVRQMPGKGLEWMGSISYEGNPYYGDSVKGQVTISRDNSISTLYLQWSSLKASDTAMYYCARHDHNNVDWFAYWGQGTLVTVSSSEQ ID NO:DNA VHGAAGTCCAACTGGTGCAGTCAGGAGCAGAAGTC470AAAAAACCAGGAGAAAGCCTCAAGATCAGCTGCAAGGGCTCGGGTTTCACCTTCCGGGACTACTATATGGCCTGGGTCAGACAGATGCCGGGAAAGGGACTGGAATGGATGGGGTCAATCAGCTACGAGGGCAACCCCTACTACGGAGACTCCGTGAAGGGACAGGTCACAATCTCCCGGGACAACTCGATTTCCACTCTGTATCTGCAATGGAGCTCCCTCAAGGCCTCCGACACTGCGATGTACTACTGTGCGCGGCATGACCACAACAATGTGGATTGGTTCGCCTACTGGGGACAGGGAACCCTCGTGACCGTGTCCAGCSEQ ID NO:VLDIQMTQSPSSLSASVGDRVTITCKSSQSLLYSENKK471NYLAWYQQKPGKVPKLLIFWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYYNFPTFGQGTKLEIKSEQ ID NO:DNA VLGATATCCAAATGACCCAGTCGCCCTCCTCACTCT472CCGCCTCCGTGGGAGATCGCGTGACCATTACTTGCAAGAGCTCGCAGTCCCTGCTGTACTCCGAGAACAAGAAGAACTACTTGGCCTGGTACCAGCAGAAGCCCGGCAAAGTGCCGAAGCTGCTTATCTTTTGGGCCTCGACCAGGGAAAGCGGAGTGCCGTCACGCTTCTCCGGCTCCGGGTCTGGCACCGACTTCACTCTGACTATTTCCTCCCTGCAACCTGAGGACGTGGCTACCTACTACTGCCAGCAGTACTACAACTTCCCTACCTTCGGCCAAGGGACGAAGCTGGAGATCAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS473SEQ ID NO:scFv (VH-EVQLVQSGAEVKKPGESLKISCKGSGFTFRDYYMA474linker-VL)WVRQMPGKGLEWMGSISYEGNPYYGDSVKGQVTISRDNSISTLYLQWSSLKASDTAMYYCARHDHNNVDWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSQSLLYSENKKNYLAWYQQKPGKVPKLLIFWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYYNFPTFGQGTKLEIKCD20-3H5k3SEQ ID NO:VHEVQLVQSGAEVKKPGESLKISCKGSGFTFRDYYMA475WVRQMPGKGLEWMGSISYEGNPYYGDSVKGQVTISRDNSISTLYLQWSSLKASDTAMYYCARHDHNNVDWFAYWGQGTLVTVSSSEQ ID NO:DNA VHGAAGTGCAGTTGGTCCAATCAGGCGCAGAAGTG476AAGAAACCCGGAGAATCATTGAAGATTTCGTGCAAAGGAAGCGGGTTCACATTCCGCGATTACTACATGGCGTGGGTCAGACAGATGCCGGGAAAGGGACTCGAGTGGATGGGGTCCATCAGCTACGAAGGAAACCCTTACTACGGGGACTCCGTGAAGGGCCAGGTCACCATCTCCCGCGACAACTCAATCTCCACTCTGTATCTGCAATGGTCGAGCCTCAAGGCCTCTGATACTGCGATGTACTACTGCGCTCGGCATGACCACAACAACGTGGACTGGTTCGCTTACTGGGGACAGGGTACCCTTGTGACCGTGTCCTCCSEQ ID NO:VLEIVMTQSPATLSLSPGERATLSCKSSQSLLYSENKK477NYLAWYQQKPGQAPRLLIFWASTRESGIPARFSGSGSGTDFTLTISSLQPEDLAVYYCQQYYNFPTFGQGTKLEIKSEQ ID NO:DNA VLGAGATCGTGATGACTCAGTCCCCTGCCACCCTCT478CGCTGTCCCCCGGGGAGAGGGCCACGCTGTCCTGCAAGAGCTCCCAGTCACTGCTGTATTCCGAAAACAAGAAGAACTACCTCGCCTGGTACCAACAGAAGCCGGGACAGGCCCCGCGGCTTCTGATCTTCTGGGCCTCCACTCGGGAGTCCGGCATTCCGGCCCGCTTCTCCGGCTCGGGGAGCGGAACTGACTTCACCCTGACCATCAGCAGCCTGCAGCCAGAGGACCTCGCAGTGTACTACTGTCAACAGTACTACAATTTCCCCACCTTTGGCCAGGGTACCAAGCTGGAGATTAAGSEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS479SEQ ID NO:scFv (VH-EVQLVQSGAEVKKPGESLKISCKGSGFTFRDYYMA480linker-VL)WVRQMPGKGLEWMGSISYEGNPYYGDSVKGQVTISRDNSISTLYLQWSSLKASDTAMYYCARHDHNNVDWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCKSSQSLLYSENKKNYLAWYQQKPGQAPRLLIFWASTRESGIPARFSGSGSGTDFTLTISSLQPEDLAVYYCQQYYNFPTFGQGTKLEIKCD20-OfaSEQ ID NO: 481HCDR1DYAMH(Kabat)SEQ ID NO: 482HCDR2TISWNSGSIGYADSVKG(Kabat)SEQ ID NO: 483HCDR3DIQYGNYYYGMDV(Kabat)SEQ ID NO: 484HCDR1GFTFNDY(Chothia)SEQ ID NO: 485HCDR2SWNSGS(Chothia)SEQ ID NO: 486HCDR3DIQYGNYYYGMDV(Chothia)SEQ ID NO: 487HCDR1GFTFNDYA(IMGT)SEQ ID NO: 488HCDR2ISWNSGSI(IMGT)SEQ ID NO: 489HCDR3AKDIQYGNYYYGMDV(IMGT)SEQ ID NO: 490VHEVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWNSGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTVSSSEQ ID NO: 491DNA VHGAGGTGCAGCTGGTCGAGTCGGGGGGAGGATTGGTGCAGCCGGGCAGAAGCCTGCGGCTCTCATGTGCCGCCTCCGGCTTCACCTTTAACGACTACGCAATGCACTGGGTCAGACAGGCTCCTGGGAAGGGCCTGGAATGGGTGTCCACCATTTCCTGGAACTCCGGGAGCATCGGCTACGCTGACTCCGTGAAGGGCCGCTTCACGATTAGCCGCGATAACGCGAAAAAGAGCCTGTACCTCCAAATGAACTCCCTGCGGGCCGAAGATACCGCCCTTTACTACTGCGCGAAGGACATTCAGTATGGAAACTACTACTACGGAATGGACGTCTGGGGACAGGGGACCACAGTGACCGTGTCAAGCSEQ ID NO: 492LCDR1RASQSVSSYLA(Kabat)SEQ ID NO: 493LCDR2DASNRAT(Kabat)SEQ ID NO: 494LCDR3QQRSNWPIT(Kabat)SEQ ID NO: 495LCDR1SQSVSSY(Chothia)SEQ ID NO: 496LCDR2DAS(Chothia)SEQ ID NO: 497LCDR3RSNWPI(Chothia)SEQ ID NO: 498LCDR1QSVSSY(IMGT)SEQ ID NO: 499LCDR2DAS(IMGT)SEQ ID NO: 500LCDR3QQRSNWPIT(IMGT)SEQ ID NO: 501VLEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKSEQ ID NO: 502DNA VLGAAATCGTGCTGACCCAGAGCCCAGCCACTTTGTCACTGTCCCCCGGCGAAAGAGCCACTCTGTCCTGCCGGGCATCGCAGTCCGTGTCGTCCTACCTGGCCTGGTACCAGCAAAAGCCCGGACAAGCCCCTCGCCTTCTCATCTACGACGCCTCCAATCGCGCGACCGGAATCCCGGCCAGGTTCTCCGGGAGCGGTTCAGGCACTGACTTCACCCTGACCATCTCGTCCCTGGAGCCGGAGGATTTCGCCGTGTATTACTGCCAGCAGCGGTCCAACTGGCCCATCACCTTCGGCCAAGGGACTCGGCTCGAAATCAAGSEQ ID NO: 503LinkerGGGGSGGGGSGGGGSGGGGSSEQ ID NO: 504scFv (VH-EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVlinker-VL)RQAPGKGLEWVSTISWNSGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKSEQ ID NO: 505DNA scFvGAGGTGCAGCTGGTCGAGTCGGGGGGAGGATTGGTG(VH-linker-CAGCCGGGCAGAAGCCTGCGGCTCTCATGTGCCGCCTVL)CCGGCTTCACCTTTAACGACTACGCAATGCACTGGGTCAGACAGGCTCCTGGGAAGGGCCTGGAATGGGTGTCCACCATTTCCTGGAACTCCGGGAGCATCGGCTACGCTGACTCCGTGAAGGGCCGCTTCACGATTAGCCGCGATAACGCGAAAAAGAGCCTGTACCTCCAAATGAACTCCCTGCGGGCCGAAGATACCGCCCTTTACTACTGCGCGAAGGACATTCAGTATGGAAACTACTACTACGGAATGGACGTCTGGGGACAGGGGACCACAGTGACCGTGTCAAGCGGCGGTGGAGGATCTGGCGGAGGAGGTTCCGGTGGCGGTGGATCGGGAGGGGGAGGATCGGAAATCGTGCTGACCCAGAGCCCAGCCACTTTGTCACTGTCCCCCGGCGAAAGAGCCACTCTGTCCTGCCGGGCATCGCAGTCCGTGTCGTCCTACCTGGCCTGGTACCAGCAAAAGCCCGGACAAGCCCCTCGCCTTCTCATCTACGACGCCTCCAATCGCGCGACCGGAATCCCGGCCAGGTTCTCCGGGAGCGGTTCAGGCACTGACTTCACCCTGACCATCTCGTCCCTGGAGCCGGAGGATTTCGCCGTGTATTACTGCCAGCAGCGGTCCAACTGGCCCATCACCTTCGGCCAAGGGACTCGGCTCGAAATCAAGCD20-3SEQ ID NO:VHEVQLVESGGGLVQPGRSLKLSCAASGFTFRDYYMAWV506RQAPKKGLEWVASISYEGNPYYGDSVKGRFTISRNNAKSTLYLQMNSLRSEDTATYYCARHDHNNVDWFAYWGQGTLVTVSSSEQ ID NO:DNA VH507SEQ ID NO:VLDIVMTQTPSSQAVSAGEKVTMSCKSSQSLLYSENKKNY508LAWYQQKPGQSPKLLIFWASTRESGVPDRFIGSGSGTDFTLTISSVQAEDLAVYYCQQYYNFPTFGSGTKLEIKSEQ ID NO:DNA VL509SEQ ID NO:LinkerGGGGSGGGGSGGGGSGGGGS510SEQ ID NO:scFv (VH-EVQLVESGGGLVQPGRSLKLSCAASGFTFRDYYMAWV511linker-VL)RQAPKKGLEWVASISYEGNPYYGDSVKGRFTISRNNAKSTLYLQMNSLRSEDTATYYCARHDHNNVDWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTPSSQAVSAGEKVTMSCKSSQSLLYSENKKNYLAWYQQKPGQSPKLLIFWASTRESGVPDRFIGSGSGTDFTLTISSVQAEDLAVYYCQQYYNFPTFGSGTKLEIKCD20-8aBBzSEQ ID NO:VHEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHW512VKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSSEQ ID NO:DNA VHGAGGTGCAACTGCAGCAGTCAGGAGCAGAACTGGTC513AAGCCGGGCGCATCCGTCAAGATGAGCTGCAAGGCCTCAGGATACACCTTCACTTCATACAACATGCACTGGGTCAAGCAGACGCCTGGGCAGGGGCTGGAGTGGATCGGTGCCATCTACCCCGGAAACGGCGACACCTCCTACAACCAGAAGTTCAAGGGAAAGGCCACCCTCACCGCTGATAAGTCCAGCAGCACCGCCTACATGCAACTGTCGTCCCTGACTTCGGAGGACAGCGCTGACTACTATTGCGCCCGCTCTAATTACTACGGTTCCTCCTACTGGTTCTTCGACGTGTGGGGCGCGGGTACCACTGTGACTGTCTCCAGCSEQ ID NO:VLDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKK514PGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKSEQ ID NO:DNA VLGACATCGTGCTCACTCAGTCGCCCGCCATTCTGAGCG515CTAGCCCCGGCGAAAAGGTCACCATGACCTGTAGAGCGTCATCCTCGGTGAACTACATGGACTGGTACCAGAAGAAGCCGGGATCGAGCCCTAAGCCATGGATCTACGCCACATCCAATCTGGCGTCCGGCGTGCCGGCCCGGTTCAGCGGGAGCGGCTCAGGCACCTCCTATTCCCTCACCATCTCGAGAGTGGAGGCTGAGGATGCAGCCACGTACTACTGTCAGCAGTGGTCGTTCAACCCCCCAACCTTTGGTGGTGGAACCAAGCTGGAAATCAAGSEQ ID NO:LinkerGSTSGGGSGGGSGGGGSS516SEQ ID NO:scFv (VH-DIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKK517linker-VL)PGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKGSTSGGGSGGGSGGGGSSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSSEQ ID NO:DNA scFvGACATCGTGCTCACTCAGTCGCCCGCCATTCTGAGCG518(VH-linker-CTAGCCCCGGCGAAAAGGTCACCATGACCTGTAGAGVL)CGTCATCCTCGGTGAACTACATGGACTGGTACCAGAAGAAGCCGGGATCGAGCCCTAAGCCATGGATCTACGCCACATCCAATCTGGCGTCCGGCGTGCCGGCCCGGTTCAGCGGGAGCGGCTCAGGCACCTCCTATTCCCTCACCATCTCGAGAGTGGAGGCTGAGGATGCAGCCACGTACTACTGTCAGCAGTGGTCGTTCAACCCCCCAACCTTTGGTGGTGGAACCAAGCTGGAAATCAAGGGAAGCACCTCCGGCGGAGGTTCCGGAGGAGGGTCCGGAGGCGGAGGCAGCTCCGAGGTGCAACTGCAGCAGTCAGGAGCAGAACTGGTCAAGCCGGGCGCATCCGTCAAGATGAGCTGCAAGGCCTCAGGATACACCTTCACTTCATACAACATGCACTGGGTCAAGCAGACGCCTGGGCAGGGGCTGGAGTGGATCGGTGCCATCTACCCCGGAAACGGCGACACCTCCTACAACCAGAAGTTCAAGGGAAAGGCCACCCTCACCGCTGATAAGTCCAGCAGCACCGCCTACATGCAACTGTCGTCCCTGACTTCGGAGGACAGCGCTGACTACTATTGCGCCCGCTCTAATTACTACGGTTCCTCCTACTGGTTCTTCGACGTGTGGGGCGCGGGTACCACTGTGACTGTCTCCAGC An overview of the sequences identifications of CDR (Kabat) sequences of the CD20 scFv domains of Table 1 are shown in Table 2 for the heavy chain variable domains and in Table 3 for the light chain variable domains. The SEQ ID NO's refer to those found in Table 1. TABLE 2Heavy Chain Variable Domain CDR (Kabat) SEQ ID NO's of CD20antibody moleculesCandidateHCDR1HCDR2HCDR3CD20-C3H2136137138CD20-C5H1217218219CD20-C2H1123CD20-C2H2282930CD20-C2H3555657CD20-C2H4828384CD20-C3H1109110111CD20-C3H3163164165CD20-C3H4190191192CD20-C5H2244245246CD20-C5H3271272273CD20-C5H4298299300CD20-C8H1325326327CD20-C8H2352353354CD20-C8H3379380381CD20-C8H4406407408 TABLE 3Light Chain Variable Domain CDR (Kabat) SEQ ID NO's of CD20Antibody MoleculesCandidateLCDR1LCDR2LCDR3CD20-C3H2147148149CD20-C5H1228229230CD20-C2H1121314CD20-C2H2394041CD20-C2H3666768CD20-C2H4939495CD20-C3H1120121122CD20-C3H3174175176CD20-C3H4201202203CD20-C5H2255256257CD20-C5H3282283284CD20-C5H4309310311CD20-C8H1336337338CD20-C8H2363364365CD20-C8H3390391392CD20-C8H4417418419 TABLE 4Heavy Chain Variable Region SEQ ID NO's of CD20 antibody moleculesHeavy ChainCandidateVariable regionCD20-C3H2145CD20-C5H1226CD20-C2H110CD20-C2H237CD20-C2H364CD20-C2H491CD20-C3H1118CD20-C3H3172CD20-C3H4199CD20-C5H2253CD20-C5H3280CD20-C5H4307CD20-C8H1334CD20-C8H2361CD20-C8H3388CD20-C8H4415 TABLE 5Light Chain Variable Region SEQ ID NO's of CD20 antibody moleculesLight ChainCandidateVariable regionCD20-C3H2156CD20-C5H1237CD20-C2H121CD20-C2H248CD20-C2H375CD20-C2H4102CD20-C3H1129CD20-C3H3183CD20-C3H4210CD20-C5H2264CD20-C5H3291CD20-C5H4318CD20-C8H1345CD20-C8H2372CD20-C8H3399CD20-C8H4426 The CAR scFv fragments were then cloned into lentiviral vectors to create a full length CAR construct in a single coding frame, and using the EF1 alpha promoter for expression (SEQ ID NO: 833). The cloning method is further described in the Examples. The order in which the VL and VH domains appear in the scFv was varied (i.e., VL-VH, or VH-VL orientation), and where either three or four copies of the “G4S” subunit (SEQ ID NO: 1083), in which each subunit comprises the sequence GGGGS (SEQ ID NO: 834) (e.g., (G4S)3(SEQ ID NO: 1084) or (G4S)4(SEQ ID NO: 1086)), connect the variable domains to create the entirety of the scFv domain, as shown e.g. in Table 1. CD22 CAR Constructs Anti-CD22 single chain variable fragments were isolated. See Table 6. Anti-CD22 ScFvs were cloned into lentiviral CAR expression vectors comprising the CD3zeta chain and the 4-1BB costimulatory molecule. The cloning method is further described in the Example section. The sequences of the CD22 CARs are provided below in Table 6. TABLE 6CD22 CAR ConstructsSEQ IDNUMBERAb regionSequenceCD22-65s, ssor KDSEQ ID NO:LinkerGGGGS834CD22-65sscFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTSEQ ID NO:linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRG835of CD22-RVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRL65sQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALT(linkerQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQshown byHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLitalics andTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLunderline)CD22-65ssscFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTSEQ ID NO:VL) ofWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRG836CD22-65ssRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRL(no linkerQDGNSWSDAFDVWGQGTMVTVSSQSALTQPASASbetweenGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPVH-VL)KLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLCD22-65sKDscFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTSEQ ID NO:linker-VL)WNWIRKSPSRGLEWLGRTYHRSTWYDDYASSVRG837of CD22-65sKDRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQDHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLSEQ ID NO:VH ofEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDT839CD22-65sKDWNWIRKSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:VL ofQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVS840CD22-65sKDWYQDHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLCD22-57SEQ ID NO:HCDR1NNNAAWN519 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYNDYVGSVKS520 (Kabat)SEQ ID NO:HCDR3ETDYGDYGAFDI521 (Kabat)SEQ ID NO:HCDR1GDSVSNNNA522 (Chothia)SEQ ID NO:HCDR2YHRSTWY523 (Chothia)SEQ ID NO:HCDR3ETDYGDYGAFDI524 (Chothia)SEQ ID NO:HCDR1GDSVSNNNAA525 (IMGT)SEQ ID NO:HCDR2TYHRSTWYN526 (IMGT)SEQ ID NO:HCDR3ARETDYGDYGAFDI527 (IMGT)SEQ ID NO:HCDR1GDSVSNNNAAWN1100 (CombinedChothia andKabat)SEQ ID NO: 989HCDR2RTYHRSTWYNDYVGSVKS(CombinedChothia andKabat)SEQ ID NO: 990HCDR3ETDYGDYGAFDI(CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSVSNNNAA528WNWIRQSPSRGLEWLGRTYHRSTWYNDYVGSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARETDYGDYGAFDIWGQGTTVTVSSSEQ ID NO:DNA VHGAAGTCCAATTGCAACAATCAGGTCCCGGACTC529GTGAAACCTTCCCAAACCCTCTCCCTCACTTGCGCGATCAGCGGAGACTCCGTGTCCAACAACAATGCTGCCTGGAACTGGATTAGGCAGAGCCCTTCAAGAGGACTGGAATGGCTGGGACGGACTTACCACCGCTCCACCTGGTACAACGATTACGTGGGGTCCGTCAAGTCCCGGATCACCATTAACCCGGACACTTCCAAGAATCAGTTCAGCCTGCAACTTAACAGCGTGACTCCCGAGGATACCGCCGTGTACTACTGTGCCCGGGAAACCGACTACGGGGATTACGGAGCCTTCGACATCTGGGGACAGGGAACCACCGTGACCGTGTCCTCGSEQ ID NO:LCDR1TGSRNDIGAYESVS530 (Kabat)SEQ ID NO:LCDR2GVNNRPS531 (Kabat)SEQ ID NO:LCDR3SSHTTTSTLYV532 (Kabat)SEQ ID NO:LCDR1SRNDIGAYES533 (Chothia)SEQ ID NO:LCDR2GVN534 (Chothia)SEQ ID NO:LCDR3HTTTSTLY535 (Chothia)SEQ ID NO:LCDR1RNDIGAYES536 (IMGT)SEQ ID NO:LCDR2GVN537 (IMGT)SEQ ID NO:LCDR3SSHTTTSTLYV538 (IMGT)SEQ ID NO: 991LCDR1TGSRNDIGAYESVS(CombinedChothia andKabat)SEQ ID NO: 992LCDR2GVNNRPS(CombinedChothia andKabat)SEQ ID NO: 993LCDR3SSHTTTSTLYV(CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGSRNDIGAYESVS539WYQQHPGNAPKLIIHGVNNRPSGVFDRFSVSQSGNTASLTISGLQAEDEADYYCSSHTTTSTLYVFGTGTKVTVLSEQ ID NO:DNA VLCAGTCGGCCCTGACTCAGCCGGCCTCCGTGTCCG540GAAGCCCGGGCCAGTCCATCACCATTTCGTGCACTGGGTCGCGCAACGACATCGGCGCCTACGAATCCGTGTCGTGGTACCAGCAGCACCCCGGCAACGCCCCGAAGCTGATCATCCATGGCGTCAACAACAGACCATCCGGAGTGTTCGACCGGTTCAGCGTGTCCCAGTCGGGAAACACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAGGCTGACTATTACTGCTCCTCACACACCACCACCTCTACGCTCTATGTGTTTGGGACTGGCACCAAGGTCACAGTGCTGGGASEQ ID NO:LinkerGGGGSGGGGSGGGGS541SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSVSNNNAA542linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYNDYVGSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARETDYGDYGAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGSRNDIGAYESVSWYQQHPGNAPKLIIHGVNNRPSGVFDRFSVSQSGNTASLTISGLQAEDEADYYCSSHTTTSTLYVFGTGTKVTVLSEQ ID NO:DNA scFvGAAGTCCAATTGCAACAATCAGGTCCCGGACTCGTG543(VH-linker-AAACCTTCCCAAACCCTCTCCCTCACTTGCGCGATCAVL)GCGGAGACTCCGTGTCCAACAACAATGCTGCCTGGAACTGGATTAGGCAGAGCCCTTCAAGAGGACTGGAATGGCTGGGACGGACTTACCACCGCTCCACCTGGTACAACGATTACGTGGGGTCCGTCAAGTCCCGGATCACCATTAACCCGGACACTTCCAAGAATCAGTTCAGCCTGCAACTTAACAGCGTGACTCCCGAGGATACCGCCGTGTACTACTGTGCCCGGGAAACCGACTACGGGGATTACGGAGCCTTCGACATCTGGGGACAGGGAACCACCGTGACCGTGTCCTCGGGCGGTGGTGGTTCGGGCGGCGGGGGATCAGGGGGCGGAGGAAGCCAGTCGGCCCTGACTCAGCCGGCCTCCGTGTCCGGAAGCCCGGGCCAGTCCATCACCATTTCGTGCACTGGGTCGCGCAACGACATCGGCGCCTACGAATCCGTGTCGTGGTACCAGCAGCACCCCGGCAACGCCCCGAAGCTGATCATCCATGGCGTCAACAACAGACCATCCGGAGTGTTCGACCGGTTCAGCGTGTCCCAGTCGGGAAACACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAGGCTGACTATTACTGCTCCTCACACACCACCACCTCTACGCTCTATGTGTTTGGGACTGGCACCAAGGTCACAGTGCTGGGACD22-58SEQ ID NO:HCDR1SNSAAWN544 (Kabat)SEQ ID NO:HCDR2RTFYRSKWYNDYAVSVKG545 (Kabat)SEQ ID NO:HCDR3GDYYYGLDV546 (Kabat)SEQ ID NO:HCDR1GDSVSSNSA547 (Chothia)SEQ ID NO:HCDR2FYRSKWY548 (Chothia)SEQ ID NO:HCDR3GDYYYGLDV549 (Chothia)SEQ ID NO:HCDR1GDSVSSNSAA550 (IMGT)SEQ ID NO:HCDR2TFYRSKWYN551 (IMGT)SEQ ID NO:HCDR3AGGDYYYGLDV552 (IMGT)SEQ ID NO: 994HCDR1GDSVSSNSAAWN(CombinedChothia andKabat)SEQ ID NO: 995HCDR2RTFYRSKWYNDYAVSVKG(CombinedChothia andKabat)SEQ ID NO: 996HCDR3GDYYYGLDV(CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVNPSQTLSITCAISGDSVSSNSAAW553NWIRQSPSRGLEWLGRTFYRSKWYNDYAVSVKGRITISPDTSKNQFSLQLNSVTPEDTAVYYCAGGDYYYGLDVWGQGTTVTVSSSEQ ID NO:DNA VHGAAGTCCAGTTGCAACAGTCAGGTCCCGGCCTC554GTCAACCCATCCCAAACCCTTTCCATTACCTGTGCCATTAGCGGGGACAGCGTGTCCTCCAACTCGGCCGCTTGGAACTGGATCAGACAGAGCCCCAGCCGGGGTCTGGAGTGGCTGGGACGGACCTTCTACCGCTCAAAGTGGTACAACGACTACGCGGTGTCCGTGAAGGGAAGGATTACCATCTCCCCGGATACATCGAAGAATCAGTTCTCCCTGCAACTGAACTCTGTGACCCCTGAGGATACCGCCGTGTACTACTGCGCGGGAGGAGACTACTACTATGGGCTGGACGTCTGGGGCCAGGGAACCACCGTGACTGTGTCAAGCSEQ ID NO:LCDR1TGSSSDVGGYNSVS555 (Kabat)SEQ ID NO:LCDR2EVINRPS556 (Kabat)SEQ ID NO:LCDR3SSYTSSSTYV557 (Kabat)SEQ ID NO:LCDR1SSSDVGGYNS558 (Chothia)SEQ ID NO:LCDR2EVI559 (Chothia)SEQ ID NO:LCDR3YTSSSTY560 (Chothia)SEQ ID NO:LCDR1SSDVGGYNS561 (IMGT)SEQ ID NO:LCDR2EVI562 (IMGT)SEQ ID NO:LCDR3SSYTSSSTYV563 (IMGT)SEQ ID NO: 997LCDR1TGSSSDVGGYNSVS(CombinedChothia andKabat)SEQ ID NO: 998LCDR2EVINRPS(CombinedChothia andKabat)SEQ ID NO: 999LCDR3SSYTSSSTYV(CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGSSSDVGGYNSVS564WYQQHPGKAPKLMIYEVINRPSGVSHRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTYVFGTGTKVTVLSEQ ID NO:DNA VLCAGAGCGCCCTGACCCAGCCGGCCAGCGTGTCC565GGGTCGCCGGGCCAGTCGATCACCATCAGCTGCACTGGGTCATCCTCCGACGTGGGAGGCTACAACTCCGTGTCGTGGTACCAGCAGCACCCGGGGAAGGCTCCTAAGCTGATGATCTACGAAGTGATCAACCGGCCCTCCGGAGTCTCGCATCGCTTTTCCGGTTCAAAGTCCGGAAACACGGCCTCCCTGACCATCTCCGGACTCCAAGCCGAGGATGAAGCAGACTATTACTGCTCCTCGTACACTAGCTCATCCACTTACGTGTTCGGAACTGGCACCAAAGTCACTGTGCTCSEQ ID NO:LinkerGGGGSGGGGSGGGGS566SEQ ID NO:scFv (VH-EVQLQQSGPGLVNPSQTLSITCAISGDSVSSNSAAW567linker-VL)NWIRQSPSRGLEWLGRTFYRSKWYNDYAVSVKGRITISPDTSKNQFSLQLNSVTPEDTAVYYCAGGDYYYGLDVWGQGTTVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGSSSDVGGYNSVSWYQQHPGKAPKLMIYEVINRPSGVSHRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTYVFGTGTKVTVLSEQ ID NO:DNA scFvGAAGTCCAGTTGCAACAGTCAGGTCCCGGCCTCGTCA568(VH-linker-ACCCATCCCAAACCCTTTCCATTACCTGTGCCATTAGVL)CGGGGACAGCGTGTCCTCCAACTCGGCCGCTTGGAACTGGATCAGACAGAGCCCCAGCCGGGGTCTGGAGTGGCTGGGACGGACCTTCTACCGCTCAAAGTGGTACAACGACTACGCGGTGTCCGTGAAGGGAAGGATTACCATCTCCCCGGATACATCGAAGAATCAGTTCTCCCTGCAACTGAACTCTGTGACCCCTGAGGATACCGCCGTGTACTACTGCGCGGGAGGAGACTACTACTATGGGCTGGACGTCTGGGGCCAGGGAACCACCGTGACTGTGTCAAGCGGAGGGGGCGGCTCCGGTGGAGGAGGCTCGGGTGGCGGCGGAAGCCAGAGCGCCCTGACCCAGCCGGCCAGCGTGTCCGGGTCGCCGGGCCAGTCGATCACCATCAGCTGCACTGGGTCATCCTCCGACGTGGGAGGCTACAACTCCGTGTCGTGGTACCAGCAGCACCCGGGGAAGGCTCCTAAGCTGATGATCTACGAAGTGATCAACCGGCCCTCCGGAGTCTCGCATCGCTTTTCCGGTTCAAAGTCCGGAAACACGGCCTCCCTGACCATCTCCGGACTCCAAGCCGAGGATGAAGCAGACTATTACTGCTCCTCGTACACTAGCTCATCCACTTACGTGTTCGGAACTGGCACCAAAGTCACTGTGCTCCD22-59SEQ ID NO:HCDR1SNSDTWN569 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG570 (Kabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV571 (Kabat)SEQ ID NO:HCDR1GDSVLSNSD572 (Chothia)SEQ ID NO:HCDR2YHRSTWY573 (Chothia)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV574 (Chothia)SEQ ID NO:HCDR1GDSVLSNSDT575 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD576 (IMGT)SEQ ID NO:HCDR3ARDRLQDGNSWSDAFDV577 (IMGT)SEQ ID NO:HCDR1GDSVLSNSDTWN1000 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1001 (CombinedChothia andKabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV1002 (CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT578WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCG579TCAAGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCCGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCSEQ ID NO:LCDR1TGSSSDIGGFNYVS580 (Kabat)SEQ ID NO:LCDR2EVTNRPS581 (Kabat)SEQ ID NO:LCDR3SSYASGSPLYV582 (Kabat)SEQ ID NO:LCDR1SSSDIGGFNY583 (Chothia)SEQ ID NO:LCDR2EVT584 (Chothia)SEQ ID NO:LCDR3YASGSPLY585 (Chothia)SEQ ID NO:LCDR1SSDIGGFNY586 (IMGT)SEQ ID NO:LCDR2EVT587 (IMGT)SEQ ID NO:LCDR3SSYASGSPLYV588 (IMGT)SEQ ID NO:LCDR1TGSSSDIGGFNYVS1003 (CombinedChothia andKabat)SEQ ID NO:LCDR2EVTNRPS1004 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYASGSPLYV1005 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGSSSDIGGFNYVSW589YQQHAGEAPKLMIYEVTNRPSGVSDRFSGSKSDNTASLTISGLQAEDEADYYCSSYASGSPLYVFGTGTKVTVLSEQ ID NO:DNA VLCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCG590GATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCTCATCGTCCGACATTGGAGGTTTTAACTACGTGTCGTGGTACCAGCAGCATGCAGGAGAAGCCCCGAAGCTCATGATCTACGAAGTGACCAACCGGCCTTCGGGGGTGTCAGACAGATTCTCGGGCTCCAAGTCCGACAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACGCTTCGGGCTCCCCTCTGTACGTGTTCGGCACTGGGACCAAAGTCACCGTGCTCSEQ ID NO:LinkerGGGGSGGGGSGGGGS591SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT592linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGSSSDIGGFNYVSWYQQHAGEAPKLMIYEVTNRPSGVSDRFSGSKSDNTASLTISGLQAEDEADYYCSSYASGSPLYVFGTGTKVTVLSEQ ID NO:DNA scFvGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCGTCA593(VH-linker-AGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCVL)CGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCGGGGGGGGCGGATCAGGCGGCGGTGGCTCCGGAGGAGGGGGTTCCCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCGGATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCTCATCGTCCGACATTGGAGGTTTTAACTACGTGTCGTGGTACCAGCAGCATGCAGGAGAAGCCCCGAAGCTCATGATCTACGAAGTGACCAACCGGCCTTCGGGGGTGTCAGACAGATTCTCGGGCTCCAAGTCCGACAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACGCTTCGGGCTCCCCTCTGTACGTGTTCGGCACTGGGACCAAAGTCACCGTGCTCCD22-60SEQ ID NO:HCDR1SNSDTWN594 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG595 (Kabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV596 (Kabat)SEQ ID NO:HCDR1GDSVLSNSD597 (Chothia)SEQ ID NO:HCDR2YHRSTWY598 (Chothia)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV599 (Chothia)SEQ ID NO:HCDR1GDSVLSNSDT600 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD601 (IMGT)SEQ ID NO:HCDR3ARDRLQDGNSWSDAFDV602 (IMGT)SEQ ID NO:HCDR1GDSVLSNSDTWN1006 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1007 (CombinedChothia andKabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV1008 (CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT603WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCG604TCAAGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCCGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCSEQ ID NO:LCDR1TGTSSDIGGYNYVS605 (Kabat)SEQ ID NO:LCDR2EVSNRPS606 (Kabat)SEQ ID NO:LCDR3SSYTSSSTLYV607 (Kabat)SEQ ID NO:LCDR1TSSDIGGYNY608 (Chothia)SEQ ID NO:LCDR2EVS609 (Chothia)SEQ ID NO:LCDR3YTSSSTLY610 (Chothia)SEQ ID NO:LCDR1SSDIGGYNY611 (IMGT)SEQ ID NO:LCDR2EVS612 (IMGT)SEQ ID NO:LCDR3SSYTSSSTLYV613 (IMGT)SEQ ID NO:LCDR1TGTSSDIGGYNYVS1009 (CombinedChothia andKabat)SEQ ID NO:LCDR2EVSNRPS1010 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYTSSSTLYV1011 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITFSCTGTSSDIGGYNYVS614WYQQHPGKAPKLMIYEVSNRPSGVSNRFSGTKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTKLTVLSEQ ID NO:DNA VLCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCG615GATCACCGGGACAGTCGATCACGTTTTCCTGCACTGGCACCTCGTCCGACATCGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGAAGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCACCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACGTGTTCGGCACTGGGACCAAACTTACCGTGCTCSEQ ID NO:LinkerGGGGSGGGGSGSGGS616SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT617linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGSGGSQSALTQPASVSGSPGQSITFSCTGTSSDIGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGTKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTKLTVLSEQ ID NO:DNA scFvGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCGTCA618(VH-linker-AGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCVL)CGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCGGGGGGGGCGGATCAGGCGGCGGTGGCTCCGGATCGGGGGGTTCCCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCGGATCACCGGGACAGTCGATCACGTTTTCCTGCACTGGCACCTCGTCCGACATCGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGAAGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCACCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACGTGTTCGGCACTGGGACCAAACTTACCGTGCTCCD22-61SEQ ID NO:HCDR1SNSDTWN619 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG620 (Kabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV621 (Kabat)SEQ ID NO:HCDR1GDSVLSNSD622 (Chothia)SEQ ID NO:HCDR2YHRSTWY623 (Chothia)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV624 (Chothia)SEQ ID NO:HCDR1GDSVLSNSDT625 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD626 (IMGT)SEQ ID NO:HCDR3ARDRLQDGNSWSDAFDV627 (IMGT)SEQ ID NO:HCDR1GDSVLSNSDTWN1012 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1013 (CombinedChothia andKabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV1014 (CombinedChothia andKabat)SEQ ID NO:VHQVQLQESGPGLVKPSQTLSLTCAISGDSVLSNSDT628WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHCAAGTCCAATTGCAAGAATCCGGTCCTGGCCTCG629TCAAGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCCGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCSEQ ID NO:LCDR1TGTSSDVGGYNYVS630 (Kabat)SEQ ID NO:LCDR2EVSNRPS631 (Kabat)SEQ ID NO:LCDR3SSYTSSSTLYV632 (Kabat)SEQ ID NO:LCDR1TSSDVGGYNY633 (Chothia)SEQ ID NO:LCDR2EVS634 (Chothia)SEQ ID NO:LCDR3YTSSSTLY635 (Chothia)SEQ ID NO:LCDR1SSDVGGYNY636 (IMGT)SEQ ID NO:LCDR2EVS637 (IMGT)SEQ ID NO:LCDR3SSYTSSSTLYV638 (IMGT)SEQ ID NO:LCDR1TGTSSDVGGYNYVS1015 (CombinedChothia andKabat)SEQ ID NO:LCDR2EVSNRPS1016 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYTSSSTLYV1017 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVS639WYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTKVTVLSEQ ID NO:DNA VLCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCG640GATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCACCTCGTCCGACGTGGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGAAGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCTCCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACGTGTTCGGCACTGGGACCAAAGTCACCGTGCTCSEQ ID NO:LinkerGGGGSGGGGSGSGGS641SEQ ID NO:scFv (VH-QVQLQESGPGLVKPSQTLSLTCAISGDSVLSNSDT642linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGSGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTKVTVLSEQ ID NO:DNA scFvCAAGTCCAATTGCAAGAATCCGGTCCTGGCCTCGTCA643(VH-linker-AGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCVL)CGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCGGGGGGGGCGGATCAGGCGGCGGTGGCTCCGGATCGGGGGGTTCCCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCGGATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCACCTCGTCCGACGTGGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGAAGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCTCCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACGTGTTCGGCACTGGGACCAAAGTCACCGTGCTCCD22-62SEQ ID NO:HCDR1SNSDTWN644 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG645 (Kabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV646 (Kabat)SEQ ID NO:HCDR1GDSVLSNSD647 (Chothia)SEQ ID NO:HCDR2YHRSTWY648 (Chothia)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV649 (Chothia)SEQ ID NO:HCDR1GDSVLSNSDT650 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD651 (IMGT)SEQ ID NO:HCDR3ARDRLQDGNSWSDAFDV652 (IMGT)SEQ ID NO:HCDR1GDSVLSNSDTWN1018 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1019 (CombinedChothia andKabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV1020 (CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT653WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCG654TCAAGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCCGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCSEQ ID NO:LCDR1TGTSSDVGGYNYVS655 (Kabat)SEQ ID NO:LCDR2DVSNRPS656 (Kabat)SEQ ID NO:LCDR3SSYTSSSTLYV657 (Kabat)SEQ ID NO:LCDR1TSSDVGGYNY658 (Chothia)SEQ ID NO:LCDR2DVS659 (Chothia)SEQ ID NO:LCDR3YTSSSTLY660 (Chothia)SEQ ID NO:LCDR1SSDVGGYNY661 (IMGT)SEQ ID NO:LCDR2DVS662 (IMGT)SEQ ID NO:LCDR3SSYTSSSTLYV663 (IMGT)SEQ ID NO:LCDR1TGTSSDVGGYNYVS1021 (CombinedChothia andKabat)SEQ ID NO:LCDR2DVSNRPS1022 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYTSSSTLYV1023 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVS664WYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTKVTVLSEQ ID NO:DNA VLCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCG665GATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCACCTCGTCCGACGTGGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGACGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCTCCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACGTGTTCGGCACTGGGACCAAAGTCACCGTGCTCSEQ ID NO:LinkerGGGGSGGGGSGGGGS666SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT667linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTKVTVLSEQ ID NO:DNA scFvGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCGTCA668(VH-linker-AGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCVL)CGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCGGGGGGGGCGGATCAGGCGGCGGTGGCTCCGGAGGAGGGGGTTCCCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCGGATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCACCTCGTCCGACGTGGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGACGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCTCCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACGTGTTCGGCACTGGGACCAAAGTCACCGTGCTCCD22-63SEQ ID NO:HCDR1SNSDTWN669 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG670 (Kabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV671 (Kabat)SEQ ID NO:HCDR1GDSVLSNSD672 (Chothia)SEQ ID NO:HCDR2YHRSTWY673 (Chothia)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV674 (Chothia)SEQ ID NO:HCDR1GDSVLSNSDT675 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD676 (IMGT)SEQ ID NO:HCDR3ARDRLQDGNSWSDAFDV677 (IMGT)SEQ ID NO:HCDR1GDSVLSNSDTWN1024 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1025 (CombinedChothia andKabat)SEQ ID NO:HCDR3DRLQDGNSWSDAFDV1026 (CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT678WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCG679TCAAGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCCGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCSEQ ID NO:LCDR1TGTSSDVGGYNYVS680 (Kabat)SEQ ID NO:LCDR2EVSNRPS681 (Kabat)SEQ ID NO:LCDR3SSYTSSSTLYI682 (Kabat)SEQ ID NO:LCDR1TSSDVGGYNY683 (Chothia)SEQ ID NO:LCDR2EVS684 (Chothia)SEQ ID NO:LCDR3YTSSSTLY685 (Chothia)SEQ ID NO:LCDR1SSDVGGYNY686 (IMGT)SEQ ID NO:LCDR2EVS687 (IMGT)SEQ ID NO:LCDR3SSYTSSSTLYI688 (IMGT)SEQ ID NO:LCDR1TGTSSDVGGYNYVS1027 (CombinedChothia andKabat)SEQ ID NO:LCDR2EVSNRPS1028 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYTSSSTLYI1029 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVS689WYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYIFGTGTKVTVLSEQ ID NO:DNA VLCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCG690GATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCACCTCGTCCGACGTGGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGAAGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCTCCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACATTTTCGGCACTGGGACCAAAGTCACCGTGCTCSEQ ID NO:LinkerGGGGSGGGGSGGGGS691SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSVLSNSDT692linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARDRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYIFGTGTKVTVLSEQ ID NO:DNA scFvGAAGTCCAATTGCAACAGTCCGGTCCTGGCCTCGTCA693(VH-linker-AGCCCTCCCAAACCCTCTCCCTGACTTGCGCCATCTCVL)CGGGGATTCCGTGCTGAGCAACTCCGACACCTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGCCTGGAGTGGCTGGGCAGGACCTACCACCGGAGCACTTGGTACGACGACTACGCCAGCTCCGTGCGCGGACGCGTGTCAATCAATGTGGACACCTCCAAGAACCAGTACAGCCTGCAACTTAACGCTGTGACTCCCGAGGATACTGGAGTGTACTATTGTGCCCGCGACCGGCTGCAGGATGGAAACAGCTGGTCCGATGCCTTCGATGTCTGGGGACAGGGTACCATGGTCACAGTGTCCAGCGGGGGGGGCGGATCAGGCGGCGGTGGCTCCGGAGGAGGGGGTTCCCAGTCCGCGCTGACCCAGCCCGCCTCTGTGTCCGGATCACCGGGACAGTCGATCACGATCTCCTGCACTGGCACCTCGTCCGACGTGGGAGGTTACAACTACGTGTCGTGGTACCAGCAGCATCCAGGAAAGGCCCCGAAGCTCATGATCTACGAAGTGTCAAACCGGCCTTCGGGGGTGTCAAACAGATTCTCGGGCTCCAAGTCCGGAAATACCGCATCCCTGACCATTAGCGGCCTGCAGGCGGAGGACGAAGCCGACTACTATTGCTCCTCGTACACCTCGAGCTCCACTCTGTACATTTTCGGCACTGGGACCAAAGTCACCGTGCTCCD22-64SEQ ID NO:HCDR1SNSDTWN694 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG695 (Kabat)SEQ ID NO:HCDR3VRLQDGNSWSDAFDV696 (Kabat)SEQ ID NO:HCDR1GDSVLSNSD697 (Chothia)SEQ ID NO:HCDR2YHRSTWY698 (Chothia)SEQ ID NO:HCDR3VRLQDGNSWSDAFDV699 (Chothia)SEQ ID NO:HCDR1GDSVLSNSDT700 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD701 (IMGT)SEQ ID NO:HCDR3ARVRLQDGNSWSDAFDV702 (IMGT)SEQ ID NO:HCDR1GDSVLSNSDTWN1030 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1031 (CombinedChothia andKabat)SEQ ID NO:HCDR3VRLQDGNSWSDAFDV1032 (CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLPLTCAISGDSVLSNSDT703WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHGAAGTGCAGCTTCAACAATCAGGACCCGGACTC704GTCAAACCATCGCAGACCCTCCCTCTCACTTGCGCCATCTCCGGGGACTCCGTGCTGTCCAACTCCGACACTTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGATTGGAATGGCTGGGAAGGACCTATCACCGGTCCACTTGGTACGACGATTACGCCTCGTCCGTGCGCGGTCGGGTGTCCATCAACGTGGACACCTCCAAGAACCAGTACTCCCTGCAACTGAACGCCGTGACCCCTGAGGACACTGGGGTGTACTACTGTGCGAGAGTGCGGCTGCAGGATGGGAACTCTTGGTCCGACGCCTTCGATGTCTGGGGCCAGGGCACCATGGTCACTGTGTCATCCSEQ ID NO:LCDR1TGTSSDVGGYNYVS705 (Kabat)SEQ ID NO:LCDR2DVSNRPS706 (Kabat)SEQ ID NO:LCDR3SSYTSSSTLYV707 (Kabat)SEQ ID NO:LCDR1TSSDVGGYNY708 (Chothia)SEQ ID NO:LCDR2DVS709 (Chothia)SEQ ID NO:LCDR3YTSSSTLY710 (Chothia)SEQ ID NO:LCDR1SSDVGGYNY711 (IMGT)SEQ ID NO:LCDR2DVS712 (IMGT)SEQ ID NO:LCDR3SSYTSSSTLYV713 (IMGT)SEQ ID NO:LCDR1TGTSSDVGGYNYVS1033 (CombinedChothia andKabat)SEQ ID NO:LCDR2DVSNRPS1034 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYTSSSTLYV1035 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVS714WYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLSEQ ID NO:DNA VLCAGTCGGCACTGACCCAGCCTGCCTCAGCCTCCG715GGAGCCCGGGACAGTCCGTGACCATTTCCTGCACCGGGACCTCCTCCGACGTGGGAGGCTACAACTACGTGTCATGGTACCAGCAGCACCCCGGAAAGGCACCGAAGCTGATGATCTACGACGTGTCCAACCGCCCGAGCGGGGTGTCAAATCGCTTCTCGGGCTCGAAGTCGGGAAACACAGCGAGCCTGACGATCTCGGGACTGCAAGCCGAAGATGAGGCTGACTACTACTGCTCGTCCTACACTAGCTCCAGCACCCTCTACGTGTTCGGTACTGGTACCCAGCTGACCGTCCTGSEQ ID NO:LinkerGGGGSGGGGSGGGGP716SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLPLTCAISGDSVLSNSDT717linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGPQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLSEQ ID NO:DNA scFvGAAGTGCAGCTTCAACAATCAGGACCCGGACTCGTC718(VH-linker-AAACCATCGCAGACCCTCCCTCTCACTTGCGCCATCTVL)CCGGGGACTCCGTGCTGTCCAACTCCGACACTTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGATTGGAATGGCTGGGAAGGACCTATCACCGGTCCACTTGGTACGACGATTACGCCTCGTCCGTGCGCGGTCGGGTGTCCATCAACGTGGACACCTCCAAGAACCAGTACTCCCTGCAACTGAACGCCGTGACCCCTGAGGACACTGGGGTGTACTACTGTGCGAGAGTGCGGCTGCAGGATGGGAACTCTTGGTCCGACGCCTTCGATGTCTGGGGCCAGGGCACCATGGTCACTGTGTCATCCGGCGGTGGTGGCAGCGGCGGAGGCGGCAGCGGAGGCGGAGGACCCCAGTCGGCACTGACCCAGCCTGCCTCAGCCTCCGGGAGCCCGGGACAGTCCGTGACCATTTCCTGCACCGGGACCTCCTCCGACGTGGGAGGCTACAACTACGTGTCATGGTACCAGCAGCACCCCGGAAAGGCACCGAAGCTGATGATCTACGACGTGTCCAACCGCCCGAGCGGGGTGTCAAATCGCTTCTCGGGCTCGAAGTCGGGAAACACAGCGAGCCTGACGATCTCGGGACTGCAAGCCGAAGATGAGGCTGACTACTACTGCTCGTCCTACACTAGCTCCAGCACCCTCTACGTGTTCGGTACTGGTACCCAGCTGACCGTCCTGCD22-65SEQ ID NO:HCDR1SNSDTWN719 (Kabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG720 (Kabat)SEQ ID NO:HCDR3VRLQDGNSWSDAFDV721 (Kabat)SEQ ID NO:HCDR1GDSMLSNSD722 (Chothia)SEQ ID NO:HCDR2YHRSTWY723 (Chothia)SEQ ID NO:HCDR3VRLQDGNSWSDAFDV724 (Chothia)SEQ ID NO:HCDR1GDSMLSNSDT725 (IMGT)SEQ ID NO:HCDR2TYHRSTWYD726 (IMGT)SEQ ID NO:HCDR3ARVRLQDGNSWSDAFDV727 (IMGT)SEQ ID NO:HCDR1GDSMLSNSDTWN1036 (CombinedChothia andKabat)SEQ ID NO:HCDR2RTYHRSTWYDDYASSVRG1037 (CombinedChothia andKabat)SEQ ID NO:HCDR3VRLQDGNSWSDAFDV1038 (CombinedChothia andKabat)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDT728WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO:DNA VHGAAGTGCAGCTTCAACAATCAGGACCCGGACTC729GTCAAACCATCGCAGACCCTCAGCCTCACTTGCGCCATCTCCGGGGACTCCATGCTGTCCAACTCCGACACTTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGATTGGAATGGCTGGGAAGGACCTATCACCGGTCCACTTGGTACGACGATTACGCCTCGTCCGTGCGCGGTCGGGTGTCCATCAACGTGGACACCTCCAAGAACCAGTACTCCCTGCAACTGAACGCCGTGACCCCTGAGGACACTGGGGTGTACTACTGTGCGAGAGTGCGGCTGCAGGATGGGAACTCTTGGTCCGACGCCTTCGATGTCTGGGGCCAGGGCACCATGGTCACTGTGTCATCCSEQ ID NO:LCDR1TGTSSDVGGYNYVS730 (Kabat)SEQ ID NO:LCDR2DVSNRPS731 (Kabat)SEQ ID NO:LCDR3SSYTSSSTLYV732 (Kabat)SEQ ID NO:LCDR1TSSDVGGYNY733 (Chothia)SEQ ID NO:LCDR2DVS734 (Chothia)SEQ ID NO:LCDR3YTSSSTLY735 (Chothia)SEQ ID NO:LCDR1SSDVGGYNY736 (IMGT)SEQ ID NO:LCDR2DVS737 (IMGT)SEQ ID NO:LCDR3SSYTSSSTLYV738 (IMGT)SEQ ID NO:LCDR1TGTSSDVGGYNYVS1039 (CombinedChothia andKabat)SEQ ID NO:LCDR2DVSNRPS1040 (CombinedChothia andKabat)SEQ ID NO:LCDR3SSYTSSSTLYV1041 (CombinedChothia andKabat)SEQ ID NO:VLQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVS739WYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLSEQ ID NO:DNA VLCAGTCGGCACTGACCCAGCCTGCCTCAGCCTCCG740GGAGCCCGGGACAGTCCGTGACCATTTCCTGCACCGGGACCTCCTCCGACGTGGGAGGCTACAACTACGTGTCATGGTACCAGCAGCACCCCGGAAAGGCACCGAAGCTGATGATCTACGACGTGTCCAACCGCCCGAGCGGGGTGTCAAATCGCTTCTCGGGCTCGAAGTCGGGAAACACAGCGAGCCTGACGATCTCGGGACTGCAAGCCGAAGATGAGGCTGACTACTACTGCTCGTCCTACACTAGCTCCAGCACCCTCTACGTGTTCGGTACTGGTACCCAGCTGACCGTCCTGSEQ ID NO:LinkerGGGGSGGGGSGGGGS741SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDT742linker-VL)WNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLSEQ ID NO:DNA scFvGAAGTGCAGCTTCAACAATCAGGACCCGGACTCGTC743(VH-linker-AAACCATCGCAGACCCTCAGCCTCACTTGCGCCATCTVL)CCGGGGACTCCATGCTGTCCAACTCCGACACTTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGATTGGAATGGCTGGGAAGGACCTATCACCGGTCCACTTGGTACGACGATTACGCCTCGTCCGTGCGCGGTCGGGTGTCCATCAACGTGGACACCTCCAAGAACCAGTACTCCCTGCAACTGAACGCCGTGACCCCTGAGGACACTGGGGTGTACTACTGTGCGAGAGTGCGGCTGCAGGATGGGAACTCTTGGTCCGACGCCTTCGATGTCTGGGGCCAGGGCACCATGGTCACTGTGTCATCCGGCGGTGGTGGCAGCGGCGGAGGCGGCAGCGGAGGCGGAGGAAGCCAGTCGGCACTGACCCAGCCTGCCTCAGCCTCCGGGAGCCCGGGACAGTCCGTGACCATTTCCTGCACCGGGACCTCCTCCGACGTGGGAGGCTACAACTACGTGTCATGGTACCAGCAGCACCCCGGAAAGGCACCGAAGCTGATGATCTACGACGTGTCCAACCGCCCGAGCGGGGTGTCAAATCGCTTCTCGGGCTCGAAGTCGGGAAACACAGCGAGCCTGACGATCTCGGGACTGCAAGCCGAAGATGAGGCTGACTACTACTGCTCGTCCTACACTAGCTCCAGCACCCTCTACGTGTTCGGTACTGGTACCCAGCTGACCGTCCTGSEQ ID NO:Full aminoMALPVTALLLPLALLLHAARPEVQLQQSGPGLVKP744acidSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWsequenceLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:Full nucleicATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGC745acidTGGCTCTTCTGCTCCACGCCGCTCGGCCCGAAGTsequenceGCAGCTTCAACAATCAGGACCCGGACTCGTCAAACCATCGCAGACCCTCAGCCTCACTTGCGCCATCTCCGGGGACTCCATGCTGTCCAACTCCGACACTTGGAACTGGATTCGGCAGAGCCCGTCCAGAGGATTGGAATGGCTGGGAAGGACCTATCACCGGTCCACTTGGTACGACGATTACGCCTCGTCCGTGCGCGGTCGGGTGTCCATCAACGTGGACACCTCCAAGAACCAGTACTCCCTGCAACTGAACGCCGTGACCCCTGAGGACACTGGGGTGTACTACTGTGCGAGAGTGCGGCTGCAGGATGGGAACTCTTGGTCCGACGCCTTCGATGTCTGGGGCCAGGGCACCATGGTCACTGTGTCATCCGGCGGTGGTGGCAGCGGCGGAGGCGGCAGCGGAGGCGGAGGAAGCCAGTCGGCACTGACCCAGCCTGCCTCAGCCTCCGGGAGCCCGGGACAGTCCGTGACCATTTCCTGCACCGGGACCTCCTCCGACGTGGGAGGCTACAACTACGTGTCATGGTACCAGCAGCACCCCGGAAAGGCACCGAAGCTGATGATCTACGACGTGTCCAACCGCCCGAGCGGGGTGTCAAATCGCTTCTCGGGCTCGAAGTCGGGAAACACAGCGAGCCTGACGATCTCGGGACTGCAAGCCGAAGATGAGGCTGACTACTACTGCTCGTCCTACACTAGCTCCAGCACCCTCTACGTGTTCGGTACTGGTACCCAGCTGACCGTCCTGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGCD22-53SEQ ID NO:HCDR1SNSAAWN746 (Kabat)SEQ ID NO:HCDR2RTYYRSKWYSDYAVSVKS747 (Kabat)SEQ ID NO:HCDR3DPYDFWSGYPDAFDI748 (Kabat)SEQ ID NO:HCDR1GDSVSSNSA749 (Chothia)SEQ ID NO:HCDR2YYRSKWY750 (Chothia)SEQ ID NO:HCDR3DPYDFWSGYPDAFDI751 (Chothia)SEQ ID NO:VHEVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAA752WNWIRQSPSRGLEWLGRTYYRSKWYSDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDPYDFWSGYPDAFDIWGQGTMVTVSSSEQ ID NO:DNA VHGAGGTACAGCTGCAGCAGTCAGGTCCAGGACTG753GTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATAGTGATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGATCCTTACGATTTTTGGAGTGGTTATCCTGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCASEQ ID NO:LCDR1TGTSSDVGGYNYVS754 (Kabat)SEQ ID NO:LCDR2EVNNRPS755 (Kabat)SEQ ID NO:LCDR3SSYTSGRTLYV756 (Kabat)SEQ ID NO:LCDR1TSSDVGGYNY757 (Chothia)SEQ ID NO:LCDR2EVN758 (Chothia)SEQ ID NO:LCDR3YTSGRTLY759 (Chothia)SEQ ID NO:VLQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVS760WYQQHPGKAPKVIISEVNNRPSGVSHRFSGSKSGNTASLTISGLQAEDEADYFCSSYTSGRTLYVFGTGSKVTVLGSEQ ID NO:DNA VLCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTG761GGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTACAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAGGTCATAATTTCTGAGGTCAATAATCGGCCCTCAGGGGTTTCTCATCGCTTCTCTGGGTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTTCTGCAGCTCATATACAAGTGGCAGGACTCTTTATGTCTTCGGAACTGGGAGCAAGGTCACCGTCCTAGGTSEQ ID NO:LinkerGGGGSGGGGSGGGGS762SEQ ID NO:scFv (VH-EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAA763linker-VL)WNWIRQSPSRGLEWLGRTYYRSKWYSDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDPYDFWSGYPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKVIISEVNNRPSGVSHRFSGSKSGNTASLTISGLQAEDEADYFCSSYTSGRTLYVFGTGSKVTVLG An overview of the sequences identifications of CDR (Kabat) sequences of the CD22 scFv domains of Table 6 are shown in Table 7 for the heavy chain variable domains and in Table 8 for the light chain variable domains. The SEQ ID NO's refer to those found in Table 6. TABLE 7Heavy Chain Variable Domain CDR (Kabat) SEQ ID NO's of CD22antibody moleculesCandidateHCDR1HCDR2HCDR3CD22-57519520521CD22-58544545546CD22-59569570571CD22-60594595596CD22-61619620621CD22-62644645646CD22-63669670671CD22-64694695696CD22-65719720721 TABLE 8Light Chain Variable Domain CDR (Kabat) of CD22 Antibody MoleculesCandidateLCDR1LCDR2LCDR3CD22-57530531532CD22-58555556557CD22-59580581582CD22-60605606607CD22-61630631632CD22-62655656657CD22-63680681682CD22-64705706707CD22-65730731732 TABLE 9Heavy Chain Variable Regions of CD22 antibody moleculesHeavy ChainCandidateVariable regionCD22-57528CD22-58553CD22-59578CD22-60603CD22-61628CD22-62653CD22-63678CD22-64703CD22-65728 TABLE 10Light Chain Variable Regions of CD22 antibody moleculesLight ChainCandidateVariable regionCD22-57539CD22-58564CD22-59589CD22-60614CD22-61639CD22-62664CD22-63689CD22-64714CD22-65739 In some embodiments, the CD22 CAR comprises a short Gly-Ser linker (e.g., GGGGS linker (SEQ ID NO: 1083)) between the VH and VL sequences in the scFv as depicted in Construct CD22-65s, e.g., in Table 6. In some embodiments, the CD22 CAR does not have a linker sequence between the VH and VL sequences in the scFv as depicted in Construct CD22-65ss, e.g., in Table 6. In yet another embodiment, the CD22 CAR comprises one or more mutations relative to the amino acid sequence of CD22-65s, e.g., one or more mutations in the FR region of the VH and/or VL. In one embodiment, the CD22 CAR comprises a mutation at amino acid 41 of the VH region CD22-65s (e.g., a substitution of Q at position 41 of the VH of CD22-65s, e.g., for K); and/or a mutation of amino acid 40 of the VL of CD22-65s (e.g., a substitution of Q at position 40 of the VL of CD22-65s, e.g., for D). In one embodiment, the CD22CAR comprises the amino acid sequence of CD22-65sKD depicted below. An alignment of the CD22-65s and CD22-65sKD is depicted below (The alignment below dicloses SEQ ID NOS 1101-1102, respectively, in order of appearance). CD22-65sKD1EVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRKSPSRGLEWL50||||||||||||||||||||||||||||||||||||||||;|||||||||CD22-65s1EVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWL50CD22-65sKD51GRTYERSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCA100||||||||||||||||||||||||||||||||||||||||||||||||||CD22-65s51GRTYERSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCA100CD22-65sKD101RVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSV150||||||||||||||||||||||||||||||||||||||||||||||||||CD22-65s101RVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSV150CD22-65sKD151TISCTGTSSDVGGYNYVSWYQDHPGKAPKLMIYDVSNRPSGVSNRFSGSK200|||||||||||||||||||||.||||||||||||||||||||||||||||CD22-65s151TISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK200CD22-65sKD201SGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVL243|||||||||||||||||||||||||||||||||||||||||||CD22-65s201SGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVL243 CD19 CAR Constructs In one embodiment, an antigen binding domain against CD19 of the CAR construct is an antigen binding portion, e.g., CDRs of a CAR (e.g., CD19 CAR), antibody or antigen-binding fragment thereof described in, e.g., PCT publication WO2012/079000; PCT publication WO2014/153270; Kochenderfer, J. N. et al., J. Immunother. 32 (7), 689-702 (2009); Kochenderfer, J. N., et al., Blood, 116 (20), 4099-4102 (2010); PCT publication WO2014/031687; Bejcek, Cancer Research, 55, 2346-2351, 1995; or U.S. Pat. No. 7,446,190, each of which is hereby incorporated by reference in its entirety. In one embodiment, the CD19 CAR comprises an amino acid sequence provided as SEQ ID NO: 12 in PCT publication WO2012/079000. In embodiment, the amino acid sequence is (SEQ ID NO: 1097)(MALPVTALLLPLALLLHAARP)diqmtqttsslsaslgdrvtiscrasqdiskylnwyqqkpdgtvklliyhtsrlhsgvpsrfsgsgsgtdysltisnleqediatyfcqqgntlpytfgggtkleitggggsggggsggggsevklqesgpglvapsqslsvtctvsgvslpdygvswirqpprkglewlgviwgsettyynsalksrltiikdnsksqvflkmnslqtddtaiyycakhyyyggsyamdywgqgtsvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr, or a sequence substantially homologous thereto. The optional sequence of the signal peptide is shown in capital letters and parenthesis. In one embodiment, the amino acid sequence is: (SEQ ID NO: 1098)diqmtqttsslsaslgdrvtiscrasqdiskylnwyqqkpdgtvklliyhtsrlhsgvpsrfsgsgsgtdysltisnleqediatyfcqqgntlpytfgggtkleitggggsggggsggggsevklqesgpglvapsqslsvtctvsgvslpdygvswirqpprkglewlgviwgsettyynsalksrltiikdnsksqvflkmnslqtddtaiyycakhyyyggsyamdywgqgtsvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr, or a sequence substantially homologous thereto. In one embodiment, the CD19 CAR has the USAN designation TISAGENLECLEUCEL-T. In embodiments, CTL019 is made by a gene modification of T cells is mediated by stable insertion via transduction with a self-inactivating, replication deficient Lentiviral (LV) vector containing the CTL019 transgene under the control of the EF-1 alpha promoter. CTL019 can be a mixture of transgene positive and negative T cells that are delivered to the subject on the basis of percent transgene positive T cells. In some embodiments, the CD19 CAR comprises an antigen binding domain (e.g., a humanized antigen binding domain) according to Table 3 of WO2014/153270, incorporated herein by reference. Humanization of murine CD19 antibody is desired for the clinical setting, where the mouse-specific residues may induce a human-anti-mouse antigen (HAMA) response in patients who receive CART19 treatment, i.e., treatment with T cells transduced with the CAR19 construct. The production, characterization, and efficacy of humanized CD19 CAR sequences is described in International Application WO2014/153270 which is herein incorporated by reference in its entirety, including Examples 1-5 (p. 115-159), for instance Tables 3, 4, and 5 (p. 125-147). In one embodiment, the CD19 CAR includes a CAR molecule, or an antigen binding domain (e.g., a humanized antigen binding domain) according to Table 3 of WO2014/153270, incorporated herein by reference. The amino acid and nucleotide sequences encoding the CD19 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2014/153270. In embodiments, the CD19 CAR, or antigen binding domain, comprises an amino acid, or has a nucleotide sequence shown in WO2014/153270 incorporated herein by reference, or a sequence substantially identical to any of the aforesaid sequences (e.g., at least 85%, 90%, 95% or more identical to any of the aforesaid sequences). In some embodiments, CD19 CAR constructs are described in PCT publication WO 2012/079000, incorporated herein by reference, and the amino acid sequence of the murine CD19 CAR and scFv constructs are shown in Table 11 below, or a sequence substantially identical to any of the aforesaid sequences (e.g., at least 85%, 90%, 95% or more identical to any of the sequences described herein). TABLE 11CD19 CAR ConstructsSEQ IDNUMBERRegionSequenceCTL019SEQ ID NO:CTL019 FullMALPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGD764amino acidRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHsequenceSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:CTL019 FullATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTG1042nucleotideGCCTTGCTGCTCCACGCCGCCAGGCCGGACATCCAGsequenceATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTAGTAAATATTTAAATTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTACCATACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAGATCACAGGTGGCGGTGGCTCGGGCGGTGGTGGGTCGGGTGGCGGCGGATCTGAGGTGAAACTGCAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCATTACCCGACTATGGTGTAAGCTGGATTCGCCAGCCTCCACGAAAGGGTCTGGAGTGGCTGGGAGTAATATGGGGTAGTGAAACCACATACTATAATTCAGCTCTCAAATCCAGACTGACCATCATCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATTTACTACTGTGCCAAACATTATTACTACGGTGGTAGCTATGCTATGGACTACTGGGGCCAAGGAACCTCAGTCACCGTCTCCTCAACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCSEQ ID NO:CTL019 scFvDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ765domainKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSmCAR1SEQ ID NO:mCAR1 scFvQVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNW766VKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVTGGGSGGGSGGGSGGGSELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFCQYNRYPYTSFFFTKLEIKRRSSEQ ID NO:mCAR1 FullQVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNW767amino acidVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTAsequenceDKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVTGGGSGGGSGGGSGGGSELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFCQYNRYPYTSFFFTKLEIKRRSKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRmCAR2SEQ ID NO:mCAR2 scFvDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ768KPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESEQ ID NO:mCAR2DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ769amino acidKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNsequenceLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRLSEQ ID NO:mCAR2 fullDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ770amino acidKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNsequenceLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRLEGGGEGRGSLLTCGDVEENPGPRMLLLVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMmCAR3SEQ ID NO:mCAR3 scFvDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ771KPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSSEQ ID NO:mCAR3 fullDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ772amino acidKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNsequenceLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSSJ25-C1SEQ ID NO:SSJ25-C1QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNW1043VH sequenceVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVTSEQ ID NO:SSJ25-C1 VLELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWY1044QQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRSHumanizedCAR1SEQ ID NO:CAR1 scFvEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ1045domainKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO:CAR 1-Full-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1046aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR2SEQ ID NO:CAR2 scFvEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ1047domain-aaKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSL(Linker isQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGunderlined)GSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO:CAR2 scFvatggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcg1048domain-ntgcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagccaccaccatcatcaccatcaccatSEQ ID NO:CAR 2-Full-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1049aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:CAR 2-Full-atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcg1050ntgcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggSEQ ID NO:CAR2-MALPVTALLLPLALLLHAARPeivmtqspatlslspgeratlscrasqd1051Soluble scFv-iskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltissaalqpedfavyfcqqgntlpytfgqgtkleikggggsggggsggggsqvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgsettyyqsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgqgtlvtvsshhhhhhhhHumanizedCAR3SEQ ID NO:CAR3 scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIR1052domainQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKSEQ ID NO:CAR 3-Full-MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSE1053aaTLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR4SEQ ID NO:CAR4 scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIR1054domainQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKSEQ ID NO:CAR 4-Full-MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSE1055aaTLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR5SEQ ID NO:CAR5 scFvEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ1056domainKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO:CAR 5-Full-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1057aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR6SEQ ID NO:CAR6EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ1058scFv domainKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO:CAR6-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1059Full-aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR7SEQ ID NO:CAR7 scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIR1060domainQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKSEQ ID NO:CAR 7 Full-MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSE1061aaTLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR8SEQ ID NO:CAR8 scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIR1062domainQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKSEQ ID NO:CAR 8-Full-MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSE1063aaTLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR9SEQ ID NO:CAR9 scFvEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ1064domainKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO:CAR 9-Full-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1065aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR10SEQ ID NO:CAR10 scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIR1066domainQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKSEQ ID NO:CAR 10 Full-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1067aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR11SEQ ID NO:CAR11 scFvEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ1068domainKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO:CAR 11 Full-MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSE1069aaTLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRHumanizedCAR12SEQ ID NO:CAR12QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIR1070scFv domainQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKSEQ ID NO:CAR 12-MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGE1071Full-aaRATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRMurineCART19SEQ ID NO:HCDR1DYGVS773(Kabat)SEQ ID NO:HCDR2VIWGSETTYYNSALKS774(Kabat)SEQ ID NO:HCDR3HYYYGGSYAMDY775(Kabat)SEQ ID NO:LCDR1RASQDISKYLN776(Kabat)SEQ ID NO:LCDR2HTSRLHS777(Kabat)SEQ ID NO:LCDR3QQGNTLPYT778(Kabat)HumanizedCART19 aSEQ ID NO:HCDR1DYGVS779(Kabat)SEQ ID NO:HCDR2VIWGSETTYYSSSLKS780(Kabat)SEQ ID NO:HCDR3HYYYGGSYAMDY781(Kabat)SEQ ID NO:LCDR1RASQDISKYLN782(Kabat)SEQ ID NO:LCDR2HTSRLHS783(Kabat)SEQ ID NO:LCDR3QQGNTLPYT784(Kabat)HumanizedCART19 bSEQ ID NO:HCDR1DYGVS785(Kabat)SEQ ID NO:HCDR2VIWGSETTYYQSSLKS786(Kabat)SEQ ID NO:HCDR3HYYYGGSYAMDY787(Kabat)SEQ ID NO:LCDR1RASQDISKYLN788(Kabat)SEQ ID NO:LCDR2HTSRLHS789(Kabat)SEQ ID NO:LCDR3QQGNTLPYT790(Kabat)HumanizedCART19 cSEQ ID NO:HCDR1DYGVS791(Kabat)SEQ ID NO:HCDR2VIWGSETTYYNSSLKS792(Kabat)SEQ ID NO:HCDR3HYYYGGSYAMDY793(Kabat)SEQ ID NO:LCDR1RASQDISKYLN794(Kabat)SEQ ID NO:LCDR2HTSRLHS795(Kabat)SEQ ID NO:LCDR3QQGNTLPYT796(Kabat) CD19 CAR constructs containing humanized anti-CD19 scFv domains are described in PCT publication WO 2014/153270, incorporated herein by reference. The sequences of murine and humanized CDR sequences of the anti-CD19 scFv domains are shown in Table 12 for the heavy chain variable domains and in Table 13 for the light chain variable domains. The SEQ ID NO's refer to those found in Table 11. In some embodiments, the HCDR1 of a murine or humanized CD19 binding domain is GVSLPDYGVS (SEQ ID NO: 1099). TABLE 12Heavy Chain Variable Domain CDR (Kabat) SEQ ID NO'sof CD19 AntibodiesCandidateHCDR1HCDR2HCDR3murine_CART19773774775humanized_CART19 a779780781humanized_CART19 b785786787humanized_CART19 c791792793 TABLE 13Light Chain Variable Domain CDR (Kabat) SEQ ID NO's ofCD19 AntibodiesCandidateLCDR1LCDR2LCDR3murine_CART19776777778humanized_CART19 a782783784humanized_CART19 b788789790humanized_CART19 c794795796 General CAR Sequences Sequences useful for generating CARs are provided below in Table 14. TABLE 14Sequences of CAR componentsSEQ IDNUMBERRegionSequenceSEQ ID NO:Leader amino acidMALPVTALLLPLALLLHAARP797sequenceSEQ ID NO:Leader nucleic acidATGGCCCTCCCTGTCACCGCCCTGCTGCTTCC798sequenceGCTGGCTCTTCTGCTCCACGCCGCTCGGCCCSEQ ID NO:CD8 hinge aminoTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGA799acid sequenceVHTRGLDFACDSEQ ID NO:CD8 hinge nucleicACCACGACGCCAGCGCCGCGACCACCAACA800acid sequenceCCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATSEQ ID NO:CD8IYIWAPLAGTCGVLLLSLVITLYC801transmembraneregion (amino acidsequence)SEQ ID NO:CD8ATCTACATTTGGGCCCCTCTGGCTGGTACTTG802transmembraneCGGGGTCCTGCTGCTTTCACTCGTGATCACTC(nucleic acidTTTACTGTsequence)SEQ ID NO:CD8 TransmembraneATCTACATCTGGGCGCCCTTGGCCGGGACTTGTG1072(nucleic acidGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACsequence)TGCSEQ ID NO:4-1BB IntracellularKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP803domain (aminoEEEEGGCELacid sequence)SEQ ID NO:4-1BB IntracellularAAGCGCGGTCGGAAGAAGCTGCTGTACATCT804domain (nucleicTTAAGCAACCCTTCATGAGGCCTGTGCAGACacid sequence)TACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGSEQ ID NO:4-1BB intracellularAAACGGGGCAGAAAGAAACTCCTGTATATATTC1073domain (nucleic acidAAACAACCATTTATGAGACCAGTACAAACTACTCsequence)AAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGSEQ ID NO:CD3 zeta domainRVKFSRSADAPAYKQGQNQLYNELNLGRREE805(amino acidYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELsequence)QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:CD3 zeta (nucleicCGCGTGAAATTCAGCCGCAGCGCAGATGCTC806acid sequence)CAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGGSEQ ID NO:CD3-zeta (na)AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCC1074(Q/K mutant)GCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCSEQ ID NO:CD3 zeta domainRVKFSRSADAPAYQQGQNQLYNELNLGRREE807(amino acidYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELsequence; NCBIQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLReferenceSTATKDTYDALHMQALPPRSequenceNM_000734.3)SEQ ID NO:CD3 zeta (nucleicAGAGTGAAGTTCAGCAGGAGCGCAGACGCC808acid sequence;CCCGCGTACCAGCAGGGCCAGAACCAGCTCTNCBI ReferenceATAACGAGCTCAATCTAGGACGAAGAGAGGSequenceAGTACGATGTTTTGGACAAGAGACGTGGCCGNM_000734.3)GGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCSEQ ID NO:CD28 DOMAINRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAP809(AMINO ACIDPRDFAAYRSSEQUENCE)SEQ ID NO:CD28 DOMAINAGGAGTAAGAGGAGCAGGCTCCTGCACAGT810(NUCLEIC ACIDGACTACATGAACATGACTCCCCGCCGCCCCGSEQUENCE)GGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCSEQ ID NO:WILD-TYPETKKKYSSSVHDPNGEYMFMRAVNTAKKSRLT811ICOS DOMAINDVTL(AMINO ACIDSEQUENCE)SEQ ID NO:WILD-TYPEACAAAAAAGAAGTATTCATCCAGTGTGCACG812ICOS DOMAINACCCTAACGGTGAATACATGTTCATGAGAGC(NUCLEOTIDEAGTGAACACAGCCAAAAAATCCAGACTCACSEQUENCE)AGATGTGACCCTASEQ ID NO:Y TO F MUTANTTKKKYSSSVHDPNGEFMFMRAVNTAKKSRLT813ICOS DOMAINDVTL(AMINO ACIDSEQUENCE)SEQ ID NO:IgG4 Hinge (aminoESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM814acid sequence)ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMSEQ ID NO:IgG4 HingeGAGAGCAAGTACGGCCCTCCCTGCCCCCCTT815(nucleic acidGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGsequence)CGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATGSEQ ID NO:IgD hinge (aminoRWPESPKAQASSVPTAQPQAEGSLAKATTAPA816acid sequence)TTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDHSEQ ID NO:IgD hinge (nucleicAGGTGGCCCGAAAGTCCCAAGGCCCAGGCA817acid sequence)TCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATTSEQ ID NO:CD27 signallingQRRKYRSNKGESPVEPAEPCRYSCPREEEGSTI818domain (aminoPIQEDYRKPEPACSPacid)SEQ ID NO:CD27 signallingAGGAGTAAGAGGAGCAGGCTCCTGCACAGT819domain (nucleicGACTACATGAACATGACTCCCCGCCGCCCCGacid sequence)GGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCSEQ ID NO:ExtracellularPGWFLDSPDRPWNPPTFSPALLVVTEGDNATF820domain of PD1TCSFSNTSESFVLNWYRMSPSNQTDKLAAFPE(amino acidDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRsequence)NDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVSEQ ID NO:ExtracellularCCCGGATGGTTTCTGGACTCTCCGGATCGCC821domain of PD1CGTGGAATCCCCCAACCTTCTCACCGGCACT(nucleic acidCTTGGTTGTGACTGAGGGCGATAATGCGACCsequence)TTCACGTGCTCGTTCTCCAACACCTCCGAATCATTCGTGCTGAACTGGTACCGCATGAGCCCGTCAAACCAGACCGACAAGCTCGCCGCGTTTCCGGAAGATCGGTCGCAACCGGGACAGGATTGTCGGTTCCGCGTGACTCAACTGCCGAATGGCAGAGACTTCCACATGAGCGTGGTCCGCGCTAGGCGAAACGACTCCGGGACCTACCTGTGCGGAGCCATCTCGCTGGCGCCTAAGGCCCAAATCAAAGAGAGCTTGAGGGCCGAACTGAGAGTGACCGAGCGCAGAGCTGAGGTGCCAACTGCACATCCATCCCCATCGCCTCGGCCTGCGGGGCAGTTTCAGACCCTGGTCSEQ ID NO:PD1 CAR aminoPGWFLDSPDRPWNPPTFSPALLVVTEGDNATF822acid sequenceTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO:PD1 CAR (nucleicCCCGGATGGTTTCTGGACTCTCCGGATCGCC823acid sequence)CGTGGAATCCCCCAACCTTCTCACCGGCACTCTTGGTTGTGACTGAGGGCGATAATGCGACCTTCACGTGCTCGTTCTCCAACACCTCCGAATCATTCGTGCTGAACTGGTACCGCATGAGCCCGTCAAACCAGACCGACAAGCTCGCCGCGTTTCCGGAAGATCGGTCGCAACCGGGACAGGATTGTCGGTTCCGCGTGACTCAACTGCCGAATGGCAGAGACTTCCACATGAGCGTGGTCCGCGCTAGGCGAAACGACTCCGGGACCTACCTGTGCGGAGCCATCTCGCTGGCGCCTAAGGCCCAAATCAAAGAGAGCTTGAGGGCCGAACTGAGAGTGACCGAGCGCAGAGCTGAGGTGCCAACTGCACATCCATCCCCATCGCCTCGGCCTGCGGGGCAGTTTCAGACCCTGGTCACGACCACTCCGGCGCCGCGCCCACCGACTCCGGCCCCAACTATCGCGAGCCAGCCCCTGTCGCTGAGGCCGGAAGCATGCCGCCCTGCCGCCGGAGGTGCTGTGCATACCCGGGGATTGGACTTCGCATGCGACATCTACATTTGGGCTCCTCTCGCCGGAACTTGTGGCGTGCTCCTTCTGTCCCTGGTCATCACCCTGTACTGCAAGCGGGGTCGGAAAAAGCTTCTGTACATTTTCAAGCAGCCCTTCATGAGGCCCGTGCAAACCACCCAGGAGGAGGACGGTTGCTCCTGCCGGTTCCCCGAAGAGGAAGAAGGAGGTTGCGAGCTGCGCGTGAAGTTCTCCCGGAGCGCCGACGCCCCCGCCTATAAGCAGGGCCAGAACCAGCTGTACAACGAACTGAACCTGGGACGGCGGGAAGAGTACGATGTGCTGGACAAGCGGCGCGGCCGGGACCCCGAAATGGGCGGGAAGCCTAGAAGAAAGAACCCTCAGGAAGGCCTGTATAACGAGCTGCAGAAGGACAAGATGGCCGAGGCCTACTCCGAAATTGGGATGAAGGGAGAGCGGCGGAGGGGAAAGGGGCACGACGGCCTGTACCAAGGACTGTCCACCGCCACCAAGGACACATACGATGCCCTGCACATGCAGGCCCTTCCCCCTCGCFKBPSEQ ID NO:FKBP full aminoDVPDYASLGGPSSPKKKRKVSRGVQVETISPG824acid sequenceDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLETSYSEQ ID NO:FKBP fragmentVQVETISPGDGRTFPKRGQTCVVHYTGMLEDG825amino acidKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAsequenceQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLETSSEQ ID NO:FRBILWHEMWHEGLEEASRLYFGERNVKGMFEVL826EPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKFRBmutantsSEQ ID NO:E2032I mutantILWHEMWHEGLIEASRLYFGERNVKGMFEVLE827PLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKTSSEQ ID NO:E2032L mutantILWHEMWHEGLLEASRLYFGERNVKGMFEVL828EPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKTSSEQ ID NO:T2098L mutantILWHEMWHEGLEEASRLYFGERNVKGMFEVL829EPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVFRRISKTSSEQ ID NO:E2032, T2098ILWHEMWHEGLXEASRLYFGERNVKGMFEVL830mutantEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLXQAWDLYYHVFRRISKTSSEQ ID NO:E2032I, T2098LILWHEMWHEGLIEASRLYFGERNVKGMFEVLE831mutantPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVFRRISKTSSEQ ID NO:E2032L, T2098LILWHEMWHEGLLEASRLYFGERNVKGMFEVL832mutantEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVFRRISKTSEF1 alphapromoterSEQ ID NO:EF1 alphaCGTGAGGCTCCGGTGCCCGTCAGTGGGCAGA833promoter nucleicGCGCACATCGCCCACAGTCCCCGAGAAGTTGacid sequenceGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGALinkerSEQ ID NO:G4S subunitGGGGS834SEQ ID NO:LinkerLAEAAAK838 CD19 and CD22 Tandem CAR Constructs Tandem CARs comprising two distinct scFvs that target CD19 and CD22 were generated. The generated anti-CD19 scFv and anti-CD22 scFv constructs included two different linkers: LAEAAAK (SEQ ID NO: 838) and GGGGS (SEQ ID NO: 1083). The generation and evaluation of the tandem CARs is further described in Example 13. The sequences of the single CARs targeting CD22 and CD19 are provided below in Table 15. TABLE 15Amino acid and nucleic acid sequences of single CARs targeting CD22 and CD19.CD19/CD22 CARSEQ ID NO:ConstructSequenceSEQ ID NO: 844Construct 171atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcttggcagaagccgccgcgaaagaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctgggggcggtggatcgggtggcgggggttcggggggcggcggctctcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 845Construct 171MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 846Construct 172atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcggagggggagggagtgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctgggggcggtggatcgggtggcgggggttcggggggcggcggctctcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 847Construct 172MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINTVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR*SEQ ID NO: 848Construct 173atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcttggcagaagccgccgcgaaagaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggcggaggaggctcccagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 849Construct 173MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 850Construct 174atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcggagggggagggagtgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggcggaggaggctcccagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 851Construct 174MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 852Construct 177atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcttggcagaagccgccgcgaaacagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctggggggcggtggatcgggtggcgggggttcggggggcggcggctctgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 853Construct 177MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSFQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSGGGGSGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR*SEQ ID NO: 854Construct 178atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcggagggggagggagtcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctggggggcggtggatcgggtggcgggggttcggggggcggcggctctgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 855Construct 178MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSGGGGSGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 856Construct 179atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcttggcagaagccgccgcgaaacagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgggcggaggaggctccgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 857Construct 179MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 895Construct 180atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaaattgtgatgacccagtcasequence)cccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcggagggggagggagtcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgggcggaggaggctccgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 858Construct 180MALPVTALLLPLALLLHAARPEIVMTQ(amino acidSPATLSLSPGERATLSCRASQDISKYLNsequence)WYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR*SEQ ID NO: 859Construct 181atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaagtgcagcttcaacaatcasequence)ggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctgggggcggtggatcgggtggcgggggttcggggggcggcggctctcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgttggcagaagccgccgcgaaagaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 860Construct 181MALPVTALLLPLALLLHAARPEVQLQ(amino acidQSGPGLVKPSQTLSLTCAISGDSMLSNSsequence)DTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 861Construct 182atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaagtgcagcttcaacaatcasequence)ggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctgggggcggtggatcgggtggcgggggttcggggggcggcggctctcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgggagggggagggagtgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 862Construct 182MALPVTALLLPLALLLHAARPEVQLQ(amino acidQSGPGLVKPSQTLSLTCAISGDSMLSNSsequence)DTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 863Construct 183atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaagtgcagcttcaacaatcasequence)ggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggcggaggaggctcccagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgttggcagaagccgccgcgaaagaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 864Construct 183MALPVTALLLPLALLLHAARPEVQLQ(amino acidQSGPGLVKPSQTLSLTCAISGDSMLSNSsequence)DTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 865Construct 184atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccgaagtgcagcttcaacaatcasequence)ggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggcggaggaggctcccagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgggagggggagggagtgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 866Construct 184MALPVTALLLPLALLLHAARPEVQLQ(amino acidQSGPGLVKPSQTLSLTCAISGDSMLSNSsequence)DTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSQSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 867Construct 185atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggccccagtccgctcttacccaaccgsequence)gcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctggggggcggtggatcgggtggcgggggttcggggggcggcggctctgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctttggcagaagccgccgcgaaagaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 868Construct 185MALPVTALLLPLALLLHAARPQSALTQ(amino acidPASASGSPGQSVTISCTGTSSDVGGYNsequence)YVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSGGGGSGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 869Construct 186atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggccccagtccgctcttacccaaccgsequence)gcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctggggggcggtggatcgggtggcgggggttcggggggcggcggctctgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggagggggagggagtgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 870Construct 186MALPVTALLLPLALLLHAARPQSALTQ(amino acidPASASGSPGQSVTISCTGTSSDVGGYNsequence)YVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSGGGGSGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 871Construct 187atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggccccagtccgctcttacccaaccgsequence)gcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgggcggaggaggctccgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctttggcagaagccgccgcgaaagaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 872Construct 187MALPVTALLLPLALLLHAARPQSALTQ(amino acidPASASGSPGQSVTISCTGTSSDVGGYNsequence)YVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSEQ ID NO: 873Construct 188atggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggccccagtccgctcttacccaaccgsequence)gcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgggcggaggaggctccgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggagggggagggagtgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctaccagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 874Construct 188MALPVTALLLPLALLLHAARPQSALTQ(amino acidPASASGSPGQSVTISCTGTSSDVGGYNsequence)YVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLGGGGSEVQLQQSGPGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR*CD19/CD22 CARSEQ ID NO:ComponentSequenceSEQ ID NO: 875Linker (amino acidGGGGSsequence)SEQ ID NO: 876Alternative linkerLAEAAAK(amino acidsequence)SEQ ID NO: 877Signal peptideatggccctccctgtcaccgccctgctgcttccgctggctcttc(nucleic acidtgctccacgccgctcggcccsequence)SEQ ID NO: 878Signal peptideMALPVTALLLPLALLLHAARP(amino acidsequence)SEQ ID NO: 879CD19 scFv(nucleicgaaattgtgatgacccagtcacccgccactcttagcctttcacacid sequence)ccggtgagcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattggtatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggctccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccctcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaagggaacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggaggtggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaagggtctggaatggattggagtgatttggggctctgagactacttactaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattactattatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgtccagcSEQ ID NO: 880CD19 scFV(aminoEIVMTQSPATLSLSPGERATLSCRASQDacid sequence; linkerISKYLNWYQQKPGQAPRLLIYHTSRLHshown by italics andSGIPARFSGSGSGTDYTLTISSLQPEDFAunderline)VYFCQQGNTLPYTFGQGTKLEIKQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSSEQ ID NO: 881CD22 scFv ingaagtgcagcttcaacaatcaggaccaggactcgtcaaaccheavy/lightatcacagaccctctccctcacatgtgccatctccggggactcorientation (nucleiccatgttgagcaattccgacacttggaattggattagacaaagcacid sequence)ccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctgggggcggtggatcgggtggcgggggttcggggggcggcggctctcagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgSEQ ID NO: 882CD22 scFv inEVQLQQSGPGLVKPSQTLSLTCAISGDSheavy/lightMLSNSDTWNWIRQSPSRGLEWLGRTYorientation (aminoHRSTWYDDYASSVRGRVSINVDTSKNacid sequence; linkerQYSLQLNAVTPEDTGVYYCARVRLQDshown by italics andGNSWSDAFDVWGQGTMVTVSSunderline)QSALTQPASASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGTGTQLTVLSEQ ID NO: 883CD22 scFv ingaagtgcagcttcaacaatcaggaccaggactcgtcaaaccheavy/lightatcacagaccctctccctcacatgtgccatctccggggactcorientation withcatgttgagcaattccgacacttggaattggattagacaaagcshorter (GGGGSccgtcccggggtctggaatggttgggacgcacctaccaccg(SEQ ID NO: 1083))gtctacttggtacgacgactacgcgtcatccgtgcggggaalinker betweengagtgtccatcaacgtggacacctccaagaaccagtacagcheavy/light chainsctgcagcttaatgccgtgactcctgaggatacgggcgtctac(nucleic acidtactgcgcccgcgtccgcctgcaagacgggaacagctggasequence)gcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctggcggaggaggctcccagtccgctcttacccaaccggcctcagcctcggggagccccggccagagcgtgaccatttcctgcaccggcacttcatccgacgtgggcggctacaactacgtgtcctggtaccaacagcacccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctgSEQ ID NO: 884CD22 scFv inEVQLQQSGPGLVKPSQTLSLTCAISGDSheavy/lightMLSNSDTWNWIRQSPSRGLEWLGRTYorientation withHRSTWYDDYASSVRGRVSINVDTSKNshorter (GGGGS)QYSLQLNAVTPEDTGVYYCARVRLQD(SEQ ID NO: 1083)GNSWSDAFDVWGQGTMVTVSSlinker betweenQSALTQPASASGSPGQSVTISCTGTSSheavy/light chainsDVGGYNYVSWYQQHPGKAPKLMIYD(amino acidVSNRPSGVSNRFSGSKSGNTASLTISGLsequence; linkerQAEDEADYYCSSYTSSSTLYVFGTGTQshown by italics andLTVLunderline)SEQ ID NO: 885CD22 scFV incagtccgctcttacccaaccggcctcagcctcggggagccclight/heavycggccagagcgtgaccatttcctgcaccggcacttcatccgorientation (nucleicacgtgggcggctacaactacgtgtcctggtaccaacagcacacid sequence)ccgggaaaggcccccaagctcatgatctacgacgtgtccaacaggccctcgggagtgtccaaccggttctcgggttcgaaatcgggaaacacagccagcctgaccatcagcggactgcaggctgaagatgaagccgactactactgctcctcctacacctcgtcatccacgctctacgtgttcggcactggaactcagctgactgtgctggggggcggtggatcgggtggcgggggttcggggggcggcggctctgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctSEQ ID NO: 886CD22 scFV inQSALTQPASASGSPGQSVTISCTGTSSDlight/heavyVGGYNYVSWYQQHPGKAPKLMIYDVorientation (aminoSNRPSGVSNRFSGSKSGNTASLTISGLQacid sequence; linkerAEDEADYYCSSYTSSSTLYVFGTGTQLshown by italics andTVLEVQLQQSGunderline)PGLVKPSQTLSLTCAISGDSMLSNSDTWNWIRQSPSRGLEWLGRTYHRSTWYDDYASSVRGRVSINVDTSKNQYSLQLNAVTPEDTGVYYCARVRLQDGNSWSDAFDVWGQGTMVTVSSSEQ ID NO: 887CD22 scFv incagtccgctcttacccaaccggcctcagcctcggggagccclight/heavycggccagagcgtgaccatttcctgcaccggcacttcatccgorientation withacgtgggcggctacaactacgtgtcctggtaccaacagcacshorter linkerccgggaaaggcccccaagctcatgatctacgacgtgtccaa(GGGGS (SEQ IDcaggccctcgggagtgtccaaccggttctcgggttcgaaatNO: 1083)) betweencgggaaacacagccagcctgaccatcagcggactgcagglight and heavyctgaagatgaagccgactactactgctcctcctacacctcgtcchains (nucleic acidatccacgctctacgtgttcggcactggaactcagctgactgtsequence)gctgggcggaggaggctccgaagtgcagcttcaacaatcaggaccaggactcgtcaaaccatcacagaccctctccctcacatgtgccatctccggggactccatgttgagcaattccgacacttggaattggattagacaaagcccgtcccggggtctggaatggttgggacgcacctaccaccggtctacttggtacgacgactacgcgtcatccgtgcggggaagagtgtccatcaacgtggacacctccaagaaccagtacagcctgcagcttaatgccgtgactcctgaggatacgggcgtctactactgcgcccgcgtccgcctgcaagacgggaacagctggagcgatgcattcgatgtctggggccagggaactatggtcaccgtgtcgtctSEQ ID NO: 888CD22 scFv inQSALTQPASASGSPGQSVTISCTGTSSDlight/heavyVGGYNYVSWYQQHPGKAPKLMIYDVorientation withSNRPSGVSNRFSGSKSGNTASLTISGLQshorter linkerAEDEADYYCSSYTSSSTLYVFGTGTQL(GGGGS (SEQ IDTVLEVQLQQSGPGLVKPSQTLSNO: 1083)) betweenLTCAISGDSMLSNSDTWNWIRQSPSRGlight and heavyLEWLGRTYHRSTWYDDYASSVRGRVSchains (amino acidINVDTSKNQYSLQLNAVTPEDTGVYYsequence; linkerCARVRLQDGNSWSDAFDVWGQGTMVshown by italics andTVSSunderline)SEQ ID NO: 889Hinge andaccactaccccagcaccgaggccacccaccccggctcctatransmembraneccatcgcctcccagcctctgtccctgcgtccggaggcatgtadomain (nucleic acidgacccgcagctggtggggccgtgcatacccggggtcttgasequence)cttcgcctgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtSEQ ID NO: 890Hinge andTTTPAPRPPTPAPTIASQPLSLRPEACRPtransmembraneAAGGAVHTRGLDFACDIYIWAPLAGTdomain (amino acidCGVLLLSLVITLYCsequence)SEQ ID NO: 8914-1BB (nucleic acidaagcgcggtcggaagaagctgctgtacatctttaagcaaccsequence)cttcatgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactgSEQ ID NO: 8924-1BB (amino acidKRGRKKLLYIFKQPFMRPVQTTQEEDGsequence)CSCRFPEEEEGGCELSEQ ID NO: 893CD3zeta (nucleiccgcgtgaaattcagccgcagcgcagatgctccagcctaccaacid sequence)gcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctcggtaaSEQ ID NO: 894CD3zeta (aminoRVKFSRSADAPAYQQGQNQLYNELNLacid sequence)GRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR* EXAMPLES The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples specifically point out various aspects of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. Example 1: Generation of Mouse Anti-Human CD20 Monoclonal Antibodies A panel of monoclonal antibodies to human CD20 target has been generated and selected by a cell-based immunization approach (Proetzel G, Ebersbach H and Zhang C., Methods Mol Biol, 901:1-10, 2012). Human CD20 was transfected and expressed on the surface of 300-19 cells, a mouse pre-B cell line. The CD20-transfected 300-19 cells were used as antigens for the immunization of mice and for the subsequent screening of specific hybridoma antibodies after cell fusion. Animal immunization and sample collection were carried out according to the IACUC-approved standard animal use protocols (12 NBC 059). Briefly, female Balb/c VAF mice at the age of 5-6 weeks (Charles River Laboratories) were immunized with human CD20-transfected 300-19 cells. The mice were subcutaneously immunized for 4 times with approximately 5×106cells in 100 μL of phosphate-buffered saline (PBS) per animal. The injection was performed every 2-3 weeks to develop immune responses in the animals. Three days before cell fusion for the hybridoma generation, the mice were intraperitoneally boosted with the same dose of cell-based antigens, and were euthanized for the spleen collection under sterilized surgical conditions on the day of cell fusion. Spleens from the immunized mice were used for preparation of single cell suspension in RPMI-1640 medium. The spleen cells were pelleted and washed twice with RPMI-1640 medium. For cell fusions to generate hybridoma clones, the splenocytes were mixed and fused with murine myeloma P3X63Ag8.653 cells (Kearney J. F. et al., 1979. J. Immunol., 123:1548-1550) using polyethylene glycol-1500 as fusogen according to our standard fusion protocols (Zhang C., Methods Mol. Biol. 901:117-135, 2012). Following cell fusions and centrifugation, the cells were suspended in complete RPMI-1640 culture medium (200 mL/spleen) containing hypoxanthine-aminopterin-thymidine (HAT) supplement (Sigma H-0262), and were plated into 96-well flat-bottom plates (Corning-Costar 3596) at 200 μL of cell suspension per well. Following incubation at 37° C., 5% CO2for 3-4 days, 100 μL of culture supernatant were removed from each well of the plates and replaced with an equal volume of complete RPMI-1640 culture medium containing hypoxanthine-thymidine (HT) supplement (Sigma H-0137). The plates continued to be incubated in an atmosphere of 5% CO2at 37° C. until hybridoma clones had grown large enough colonies for antibody screening. Hybridoma Screening, Subcloning and Selection On week 2 post-fusion when hybridoma cells had grown to be half-confluent in the plate wells and the culture supernatant had changed to an orange color, hybridoma supernatants were sampled from the culture plates for antibody screening by immunofluorescence flow cytometry. For primary screening, hybridoma supernatants were analyzed by flow cytometry using human CD20-transfected 300-19 cells versus non-transfected 300-19 cells. Briefly, human CD20-transfected 300-19 cells or the non-transfected cells were respectively incubated with 50 μL of hybridoma supernatant, followed by labeling with fluorescein-AffiniPure Fab fragment goat anti-mouse IgG (H+L) conjugate and analyzed by flow cytometry with Becton Dickinson FACSCalibur in an automatic mode. By flow cytometric analysis, hybridoma clones that reacted with human CD20-transfected 300-19 cells but not with non-transfected 300-19 cells were identified and selected from culture plates. The desired hybridoma clones were expanded in T12 plates for further characterization. Hybridoma clone of interest was subcloned by limiting dilution and by picking single colonies with a Cellavista imaging system to attain a monoclonal population that produces a CD20- specific antibody. The selected hybridoma subclones were expanded in T12 plates and frozen for cryopreservation or used for monoclonal antibody production. The isotype of specific monoclonal antibodies derived from hybridoma clones was tested by using commercially-available isotyping reagents to determine the antibody property. On the basis of screening results, a panel of 19 human CD20-specific hybridoma clones was identified and selected from the immunization of mice with human CD20 antigen (data not shown). The hybridoma antibodies were further tested on human tumor tissues or cell lines to identify the top clones for antibody sequencing and humanization based on its binding profile and biological property. Example 2: Humanization of Mouse scFv The top clones were humanized according standard methods, well known to a person skilled in the art (Jones et al., Nature, 321: 522-525, 1986; Reichmann et al., Nature, 332: 323-329, 1988; Presta, Curr. Op. Struct. Biol., 2: 593-596, 1992). The antigen-binding site comprises the complementarity determining retions (CDRs) and positions outside the CDR, i.e., in the framework region of the variable domains (VL and VH) that directly or indirectly affect binding. Framework residues that may directly affect binding can, for example, be found in the so called “outer” loop region located between CDR2 and CDR3. Residues that indirectly affect binding are for example found at so called Vernier Zones (Foote and Winter 1992). They are thought to support CDR conformation. Those positions outside the CDRs were taken into account when choosing a suitable acceptor framework to minimize the number of deviations of the final humanized antibody to the human germline acceptor sequence in the framework regions. Example 3: Analysis and In Vitro Activity of Humanized Anti-CD20 scFv Bearing CARTs Humanized, murine single chain variable fragments (scFv) specific for CD20, generated as described in the examples above, were cloned into lentiviral CAR expression vectors comprising the CD3zeta chain and the 4-1BB stimulatory molecules; CD20-C2H1, -C2H2, -C2H3, -C2H4, -C3H1, -C3H2, -C3H3, -C3H4, -C5H1, -C5H2, -C5H3, -C5H4, -C8H1, -C8H2, -C8H3, and -C8H4. A rat scFv-derived CAR CD20-3 and its humanized derivatives -CD20-3m, -3J, -3H5k1, and -3H5k3 as well as the CD20-8aBBz CAR, based on the scFv of a published CAR (Jensen et al., Mol. Ther., 2000, incorporated here by reference), were included as controls. In addition, a CAR was constructed, which was based on the variable regions of the Ofatumumab monoclonal antibody (CD20-Ofa) (CAS registry number: 679818-59-8, Drug bank accession number: DB06650). All the CD20 CARs are set forth in Table 1. The optimal constructs were selected based on the quantity and quality of the effector T cell responses of these CD20 CAR-transduced T cells (“CD20 CART” or “CD20 CART cells”) in response to CD20 expressing (“CD20+” or “CD20 positive”) targets. Effector T cell responses include, but are not limited to, cellular expansion, proliferation, doubling, cytokine production and target cell killing or cytolytic activity (degranulation). Generation of CD20 CAR Lentivirus Humanized scFv encoding lentiviral transfer vectors were used to produce the genomic material packaged into the VSVg pseudotyped lentiviral particles. Lentiviral transfer vector DNA encoding the CAR was mixed with the three packaging components VSVg, gag/pol and rev in combination with lipofectamine reagent to transfect Lenti-X 293T cells (Clontech), followed by medium replacement 12-18 h later. 30 hours after medium change, the media is collected, filtered and stored at −80° C. Alternatively, lentivirus encoding for CD20 CARs was generated in an automated, small scale fashion in 96-well plates, where virus-containing supernatant was used fresh, without freezing, for the transduction of a Jurkat T cell reporter cell line. Generation of CD20 CAR JNL Cells The Jurkat NFAT Luciferase (JNL) reporter cell line is based on the acute T cell leukemia line Jurkat (RRID: CVCL_0367). The line was modified to express luciferase under control of the Nuclear Factor of Activated T cells (NFAT) response element. For the transduction with CD20 CARs, 10,000 JNL cells/well of a 96-well plate were transduced with 50 μl of fresh, 45 m-filtered virus-containing supernatant. The plates were spun for 3 min at 2000 rpm and cultured for 4 days. Evaluating Efficacy of CD20 CAR-Redirected JNL Cells To evaluate the functional ability of CD20 CARs to activate JNL cells, they were co-cultured with target cancer cells to read out their activation by quantifying luciferase expression. The humanized scFv-based CARs CD2O-C2H1, -C2H2, -C2H3, -C2H4, -C3H1, -C3H2, -C3H3, -C3H4, -C5H1, -C5H2, -C5H3, -C5H4, -C8H1, -C8H2, -C8H3, and -C8H4, were compared to CD20-8aBBz and CD20-3, -3m, -3J, -3H5k3, and -3H5k1. The control CARs CD20-3 and CD20-8aBBz were used in all assays to compare assay variation and/or act as a control. The EGFRvIII CART cells (CAR 2174, Johnson et al., Science Translational Medicine 2015) were used as non-targeting control. JNL CART cells were co-cultured with the Burkitt's lymphoma line Raji (RRID: CVCL_0511) and the diffuse large B cell lymphoma (DLBCL) lines Pfeiffer (RRID: CVCL_3326), HBL-1 (RRID: CVCL_4213) and TMD8 (RRID: CVCL_A442); K562 (RRID: CVCL_0004), a chronic myelogenous leukemia (CML) cell line, served as CD20-negative control. Co-cultures were set up in 384-well plates at effector-to-target (E:T) ratios of 4:1, 2:1, 1:1 and 0.5:1 and incubated for 24 h, after which the expression of luciferase by the activated JNL CAR T cells was quantified by britelite plus Reporter Gene Assay System (PerkinElmer, Waltham, Mass.). The amount of light emitted from each well (Luminescence) was a direct read-out of JNL activation by the respective CAR. All four CD20-positive target cell lines demonstrate activation of all humanized CD20 CARs (FIG.1A-D). Humanization of the murine scFvs did not lead to loss in binding to CD20. Some of the humanized scFvs, which were fused to the transmembrane and signaling domains of the CARs, seem to have improved the efficacy of CARs to activate JNL T cells. These were CD20-C2H1, -C2H3, -C5H1, -C5H2, and -C8H3. None of the humanized mouse CARs showed activation by the CD20-negative line K562 (FIG.1E). Generation of CD20 CAR T Cells Based on the results in the JNL reporter assay described above, the following CARs were chosen for analysis of efficacy in primary T cells: CD02-C2H1, -C2H3, -C3H2, -C3H3, -C5H1, -C5H2, and -C8H2. Additionally, CD20-Ofa and the controls CD20-8aBBz and CD20-3H5k3 were added. CD20 CAR T cells were generated by starting with blood from healthy apheresed donors whose naïve T cells were obtained by negative selection for T cells, CD4+ and CD8+ lymphocytes. These cells were activated by the addition of CD3/CD28 beads (DYNABEADS® Human T-Expander CD3/CD28, Thermo Fisher Scientific) at a ratio of 1:3 (T cell to bead) in T cell medium (RPMI-1640, 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine, 1× Penicillin/Streptomycin, 100 μM non-essential amino acids, 1 mM Sodium Pyruvate, 10 mM Hepes, and 55 μM 2-mercaptoethanol). T cells were cultured at 0.5×106T cells in 1 mL medium per well of a 24-well plate at 37° C., 5% CO2. After 24 hours, when T cells were blasting, 0.5 mL of non-concentrated, or smaller volumes of concentrated viral supernatant were added; T cells were transduced at a multiplicity of infection (MOI) of 5. T cells began to divide in a logarithmic growth pattern, which was monitored by measuring the cell counts per mL, and T cells were diluted in fresh medium every two days. T cells began to rest down after approximately 10 days; the combination of slowing growth rate and reduced T cell size (approaching 350 fL) determines the state for T cells to be cryopreserved for later analysis. All CD20 CAR T cells were produced in research grade (i.e., not clinical grade) manufacturing conditions. Before cryopreserving, the percentage of cells transduced (expressing the CD20-specific CAR on the cell surface) was determined by flow cytometric analysis on a FACS Fortessa (BD). The viral transduction showed comparable expression levels, indicating similar transduction efficiency (percent cells transduced,FIG.2) as well as surface expression of the respective CARs (mean fluorescence intensity, MFI); with the CD20-Ofa CAR showing lowest expression levels (MFI 1370 versus 2200 to 4420). The cell counts of the CAR T cell cultures indicated that there is no detectable negative effect of the human scFv bearing CAR-CD20 on the cells ability to expand normally when compared to the untransduced T cells (“UTD”). Evaluating Efficacy of CD20 CAR-Redirected T Cells. To evaluate the functional abilities of CD20 CAR T cells, the cells, generated as described above, were thawed, counted and co-cultured with target cancer cells to read out their killing capabilities, secretion of cytokine as well as proliferation. In addition to the humanized scFv bearing CARs CD20-C2H1, -C2H3, -C3H2, -C3H3, -C5H1, -C5H2, and -C8H2 the CD20-Ofa CAR as well as the controls CD20-8aBBz and CD20-3H5k3 were used as controls. The EGFRvIII CAR and non-transduced T cells (UTD) were used as non-targeting T cells controls. To measure cytokine production of CD20 CAR T cells in response to CD20-expressing target cells, CAR T cells were co-cultured with the Burkitt's lymphoma line Raji and the diffuse large B cell lymphoma (DLBCL) lines Pfeiffer, HBL-1 and TMD8; K562, a chronic myelogenous leukemia (CML) cell line, served as CD20-negative control. Cells were cultured at an effector:target ratio of 1:1 and 25,000 cells per well of a 96-well plate for 24 h, after which the media was removed for cytokine analysis using the V-PLEX Human IFN-γ Kit (Meso Scale Diagnostics, Rockville, Md.) for cytokine quantification. Data shows that most humanized mouse CD20 CARTs as well as the CD20-8aBBz, CD20-Ofa and CD20-3H5k3 CARTs produced IFN-γ when cultured with CD20-positive target cell lines Raji, Pfeiffer, HBL1 and TMD8 (FIGS.3Aand B). CD2O-C3H2 and -C3H3 were the highest cytokine producers with levels similar or higher than CD20-8aBBz. Levels of cytokine produced by CD20 CARTs after exposure to the control K562 cells were non-detectable (FIGS.3Aand B), indicating no unspecific activation by CD20 CARs. Conclusions All humanized CD20-specific CARs tested here were expressed on the cell surface of primary human T cells similarly well. CD20-C2H1, -C2H3, -C3H2, -C3H3, -C5H1, -C5H2, and -C8H2 were expressed similarly to the controls CD20-8aBBz and CD20-3H5k; only CD20-Ofa showed lower levels of expression. In the JNL T cell reporter assay, all CD20 CAR T cells showed similar, CD20-specific reactivity. CD20-C3H2 and CD20-C3H3 showed slightly better or at least equal function as compared to CD20-8aBBz with regard to IFN-γ production by primary human T cells. Overall, the transfer of CD20 CARs induced anti-CD20 reactivity but no off-target function was detected as controlled with the CD20-negative cell line K562. Example 4: Analysis and In Vitro Activity of Human Anti-CD22 scFv Bearing CARTs Single chain variable fragments for anti-CD22 antibodies were cloned into lentiviral CAR expression vectors comprising the CD3zeta chain and the 4-1BB stimulatory molecules; CD22-57, CD22-58, CD22-59, CD22-60, CD22-61, CD22-62, CD22-63, CD22-64, and CD22-65 were compared to CD22-53. All the CD22 CARs are set forth in Table 6. The optimal constructs were selected based on the quantity and quality of the effector T cell responses of these CD22 CAR-transduced T cells (“CD22 CART” or “CD22 CAR T cells”) in response to CD22 expressing (“CD22+”) targets. Effector T cell responses include, but are not limited to, cellular expansion, proliferation, doubling, cytokine production and target cell killing or cytolytic activity (degranulation). Generation of CD22 CAR T Cells Human scFv encoding lentiviral transfer vectors were used to produce the genomic material packaged into the VSVg pseudotyped lentiviral particles. Lentiviral transfer vector DNA encoding the CAR was mixed with the three packaging components VSVg, gag/pol and rev in combination with lipofectamine reagent to transfect Lenti-X 293T cells (Clontech), followed by medium replacement 12-18 h later. 30 hours after medium change, the media is collected, filtered and stored at −80° C. CD22 CAR T cells were generated by starting with blood from healthy apheresed donors whose nave T cells were obtained by negative selection for T cells, CD4+ and CD8+ lymphocytes. These cells were activated by the addition of CD3/CD28 beads (DYNABEADS® Human T-Expander CD3/CD28, Thermo Fisher Scientific) at a ratio of 1:3 (T cell to bead) in T cell medium (RPMI1640, 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine, 1× Penicillin/Streptomycin, 100 μM non-essential amino acids, 1 mM Sodium Pyruvate, 10 mM Hepes, and 55 μM 2-mercaptoethanol) at 37° C., 5% CO2. T cells were cultured at 0.5×106T cells in 1 mL medium per well of a 24-well plate. After 24 hours, when T cells were blasting, 0.5 mL of non-concentrated, or smaller volumes of concentrated viral supernatant were added; T cells were transduced at a multiplicity of infection (MOI) of 5. T cells began to divide in a logarithmic growth pattern, which is monitored by measuring the cell counts per mL, and T cells are diluted in fresh medium every two days. As the T cells began to rest down after approximately 10 days, the logarithmic growth wanes. The combination of slowing growth rate and reduced T cell size (approaching 350 fL) determines the state for T cells to be cryopreserved for later analysis. All CD22 CAR T cells were produced in research grade (i.e., not clinical grade) manufacturing conditions. Before cryopreserving, the percentage of cells transduced (expressing the CD22-specific CAR on the cell surface) were determined by flow cytometric analysis on a FACS Fortessa (BD). The viral transduction showed comparable expression levels, indicating similar transduction efficiency (percent cells transduced,FIG.4) as well as surface expression of the respective CARs (mean fluorescence intensity, MFI). Only CD22-58 showed lower expression levels (MFI=5,700, compared to >20,000 for other CARs). The cell counts of the CAR T cell cultures indicate that there is no detectable negative effect of the human scFv bearing CAR-CD22 on the cells ability to expand normally when compared to the untransduced T cells (“UTD”). Evaluating Efficacy of CD22 CAR-Redirected T Cells. To evaluate the functional abilities of CD22 CAR T cells, the cells, generated as described above, were thawed, counted and co-cultured with target cancer cells to read out their killing capabilities, secretion of cytokine as well as proliferation. In addition to the human scFv bearing CARs CD22-57, CD22-58, CD22-59, CD22-60, CD22-61, CD22-62, CD22-63, CD22-64, and CD22-65, the CAR CD22-53 was used as a control. The control CAR CD22-53 was used in all assays to compare assay variation and/or act as a control. The EGFRvIII CAR and non-transduced T cells (UTD) were used as non-targeting T cells controls. T cell killing was directed toward the acute lymphoblastic leukemia (ALL) lines Nalm6 (RRID: CVCL_0092) and SEM (RRID: CVCL_0095); K562 (RRID: CVCL_0004), a chronic myelogenous leukemia (CML) cell line served as CD22-negative control. All cell lines were transduced to express luciferase as a reporter for cell viability/killing. The cytolytic activities of CD22 CARTs were measured at a titration of effector:target cell ratios (E:T) of 20:1, 10:1, 5:1, 2.5:1, 1.25:1 0.63:1 and 0.31:1. Assays were initiated by mixing the respective number of T cells with a constant number of targets cells (25,000 cells per well of a 96-well plate). After 20 hours, remaining cells in the wells were lysed by addition of Bright-Glo™ Luciferase Assay System (Promega Corp., Madison, Wis.) reagent, to quantify the remaining cells in each well. “% Killing” was calculated in relation to wells containing target cells alone. The data show that transduction with the CD22 CART encoding lentiviruses transfers anti-CD22 killing activity to T cells (Nalm6 (FIG.5A) and SEM (FIG.5B)). UTD and EGFRvIII CAR-expressing T cells show background killing only. Similarly, none of the CD22 CARs show killing of the CD22-negative control line K562 (FIG.5C). CD22-64 and CD22-65 showed highest killing of both Nalm6 and SEM target cell lines. To measure cytokine production of CD22 CAR T cells in response to CD22-expressing target cells, CAR T cells were co-cultured with the ALL line SEM; K562, a CML line, served as CD22-negative control. Cells were cultured at an effector:target ratio of 1:1 and 25,000 cells per well of a 96-well plate for 24 h, after which the media was removed for cytokine analysis using the V-PLEX Human IFN-γ Kit (Meso Scale Diagnostics, Rockville, Md.) for cytokine quantification. Data shows that most new CD22 CARTs as well as the CD22-53 CARTs produced IFN-γ when cultured SEM (FIG.6A). CD22-63, -64 and -65 were the highest cytokine producers. Levels of cytokine produced by CD22 CARTs after exposure to the control K562 cells were low (FIG.6B), indicating no unspecific effects by CD22 CARs. In the last T cell efficacy assay, the proliferative capacity of the CD22 CART cells was assessed. Again, thawed CAR T cells we co-cultured with the ALL line SEM, while K562, a CML line, served as CD22-negative control. Target cell lines were irradiated prior to co-culture to prevent overgrowth of the wells, they were then cultured at an effector: target ratio of 1:1 and 30,000 cells per well of a 96-well plate for 4 days. Additional controls were CD3/CD28 beads (positive control, DYNABEADS® Human T-Expander CD3/CD28, Thermo Fisher Scientific) as well as medium alone (negative control). Cells were stained on day 4 with anti-CD3 antibody as well as soluble CD22-Fc to detect CAR expression. Prior to acquisition on the BD Fortessa, 20 μl of CountBright™ Absolute Counting Beads (Thermo Fisher Scientific) were added to each sample for quantitative analysis of cell numbers.FIG.7Ashows the number of CD3+ T cells per 3000 counting beads, whileFIG.7Bshows the number of CD3+ CAR+ CARTs per 3000 counting beads, as determined by binding of CD22-Fc. The data shows strongest CD22-induced proliferation of CD22-64, -65 as well as the control CD22-53 CAR T cells, followed by CD22-63. None of the CARTs showed proliferation in response to the CD22-negative line K562 nor due to any cell intrinsic stimulation of the CARs e.g. by aggregation. Conclusions Most CD22-specific CARs were expressed on the cell surface of primary human T cells similarly well: CD22-57, CD22-59, CD22-60, CD22-61, CD22-62, CD22-63, CD22-64, and CD22-65 were comparable to reference CARs CD22-53; only CD22-58 showed lower levels of expression. In T cell functional assays, CD22-57 and -58 were the least functional CARs, while CD22-64 and -65 were equally (IFN-γ production and proliferation) or more functional (killing) as compared to CD22-53. Overall, the transfer of CD22 CARs induced anti-CD22 reactivity but no off-target function was detected. Example 5: CD22 CART in ALL Anti-tumor activity of a set of CD22 CAR T cells was assessed in vivo in a NALM6 xenograft model. CAR T cells with CAR constructs CD22-60, CD22-63, and CD22-65 were evaluated versus positive control (CD22-53 and CD19) and mock CAR T cells (EGFRvIII). Materials and Methods Cell Line: NALM6 (RRID: CVCL_0092) is a human leukemia cell line that was derived from the peripheral blood of a 19-year-old man with acute lymphoblastic leukemia (ALL) in relapse in 1976. Cells were grown in RMPI medium containing 10% fetal bovine serum. This cell line grows in suspension in tissue culture flasks. This cell line persists and expands in mice when implanted intravenously. The NALM6 cells have been modified to express luciferase, so that that tumor cell growth can also be monitored by imaging the mice. Mice: 6 week old NSG (NOD.Cg-PrkdcscidI12rgtm1Wjl/SzJ) mice were received from the Jackson Laboratory (stock number 005557). Animals were allowed to acclimate in the Novartis NIBR animal facility for at least 3 days prior to experimentation. Animals were handled in accordance with Novartis ACUC regulations and guidelines. Electronic transponders for animal identification were implanted on the left flank one day prior to tumor implantation. Tumor Implantation: NALM6 cells in logarithmic growth phase were harvested and washed in 50 ml falcon tubes at 1200 rpm for 5 minutes, once in growth media and then two times in cold sterile PBS. The cells were resuspended in PBS at a concentration of 5×106per ml, placed on ice, and immediately injected in mice. Cancer cells were injected intravenously in 200 μl through the caudal vein. The NALM6 model endogenously expresses CD22 and thus, can be used to test the in vivo efficacy of CD22-directed CAR T cells. This model grows well when implanted intravenously in mice and can be imaged for tumor burden measurements. Upon injection of 1×106cancer cells in PBS, the tumors establish and can be accurately measured within 3 days. Baseline measurements are 4-6×10{circumflex over ( )}5 photons/second (p/s). Within 7 days the mean bioluminescence measurement is 2-4×10{circumflex over ( )}6 p/s and untreated tumors reach endpoint measurement (2-3×10{circumflex over ( )}9) by 21-26 days. Anti-tumor activities of therapeutic agents are often tested once tumors are fully engrafted. Thus, there is a large window with this model during which the anti-tumor activity of the CAR T cells can be observed. CAR T Cell Dosing: Mice were dosed with 5×106CART cells (12.3×106total T cells) 7 days after tumor implantation. Cells were partially thawed in a 37° C. water bath and then completely thawed by the addition of 1 ml of warmed growth media to the tube containing the cells. The thawed cells were transferred to a 50 ml falcon tube and adjusted to a final volume of 12 ml with growth media. The cells were washed twice and spun at 300 g for 10 minutes and then counted by hemocytometer. T cells were then resuspended at a concentration of 61.7×106cells per ml in cold PBS and kept on ice until the mice were dosed. The mice were injected intravenously via the tail vein with 200 μl of the T cells for a dose of 5×106CAR T cells (12.3×106total T cells) per mouse. 5 mice per group were either treated with 200 μl of PBS alone (PBS), T cells transduced with a mock EGFRvIII CAR, CD19 CAR T cells, CD22-53 CAR T cells, as well as the novel CD22-60, CD22-63, or CD22-65 CAR T cells. All cells were prepared from the same donor in parallel. Animal Monitoring: The health status of the mice was monitored daily, including twice weekly body weight measurements. The percent change in body weight was calculated as (BWcurrent-BWinitial)/BWinitial)×100%. Tumors were monitored 2 times weekly by imaging the mice. Results The anti-tumor activity of CD22 CAR T cells was assessed in a B-cell acute lymphoblastic leukemia xenograft model (Luo et al., Cancer Research 1989). Following tumor cell implantation on day 0, tumor bearing mice were randomized into treatment groups and were administered 5×106CAR T cells (12.3×106total T cells) intravenously via the lateral tail vein on day 7 after tumor implantation. Tumor growth and animal health were monitored until animals achieved endpoint. The mice which received PBS or the mock EGFRvIII CAR T cells were euthanized on days 23 and 30, respectively, when tumors were causing decreased hind leg mobility. All other groups were euthanized on day 43. The mean bioluminescence for all treatment groups is plotted inFIG.8. The PBS treatment group, which did not receive any T cells, demonstrates baseline NALM6 tumor growth kinetics in intravenously injected NSG mice. The EGFRvIII treatment group received T cells transduced with a control CAR. These cells serve as a T cell control to show the non-specific response of human donor T cells in this model. Both the PBS and the mock treatment groups demonstrated continuous tumor progression throughout this study. The EGFRvIII group shows a slight slower tumor growth, due to the background activity of the donor T cells. CD22-60, CD22-63, as well as CD22-53 all show significantly slower tumor growth when compared to EGFRvIII. CD22-65 shows tumor regression and is comparable to the positive control CD19. Discussion This study demonstrated that the CD22-specific CAR T cells CD22-65 are capable of leading to the regression of NALM6 tumors. While the other constructs showed a slowing of tumor growth, none were as complete or as durable as the effects of CD22-65. Example 6: Comparative Analysis of In Vitro Activity of Anti-CD20 and Anti-CD22 scFv Bearing Carts To compare the activity of CD22 or CD20 targeting CAR T cells in vitro, the control CAR T cells CD20-3 and CD22-53 were generated as described in Examples 3 and 4, respectively. Co-cultures of CAR T cells and cancer cell lines were conducted as described in Examples 3 and 4. Activation of CAR T cells was measured by means of IFN-γ secretion (FIG.9). Interestingly, the CD20-3 CAR lead to more cytokine secretion when cultured with the Burkitt's lymphoma line Raji (FIG.9A) and the DLBCL line Pfeiffer (FIG.9B), as compared to the CD22-53 CAR T cells. Inversely, the ALL line SEM stimulated CD22-53 to a greater extend as compared to CD20-3, albeit at an overall lower level (FIG.9C). This comparison demonstrated the general response of both CD20 and CD22 CARs to B cell malignancies in general. The bias in CAR T activation correlated with the levels of CD20 and CD22 expression on the respective target cell lines. Example 7: In Vivo Activity of CARTs Bearing Humanized Anti-CD20 scFvs Anti-tumor activity of a set of CD20 CAR T cells was assessed in vivo in a TMD8 xenograft model. CAR T cells with CAR constructs CD20-C3H2, CD20-C5H1, CD20-3H5k3, CD20-Ofa, and CD20-8aBBZ were evaluated. CD20-C3H2, CD20-C5H1, CD20-3H5k3 CARs are based on humanized mouse (C3H2 and C5H1) and rat (3H5k3) CD20-specific scFvs. CD20-8aBBZ is based on a published CD20-targeting CAR (Jensen et al., Mol. Ther., 2000, incorporated herein by reference). Cell Lines: TMD8 (RRID: CVCL_A442) is a human diffuse large B-cell lymphoma (DLBCL) cell line of the activated B-cell (ABC) subtype. Cells were grown grow in suspension in MEM medium containing 10% fetal bovine serum, 1×HEPES, Pen/Strep, L-Glut, and NEAA. TMD8 persist and grows in mice when implanted sub-cutaneously (s.c.). Mice: 6 week old NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) mice were received from the Jackson Laboratory (stock number 005557). Animals were allowed to acclimate in the Novartis NIBR animal facility for at least 3 days prior to experimentation. Animals were handled in accordance with Novartis ACUC regulations and guidelines. Electronic transponders for animal identification were implanted on the left flank one day prior to tumor implantation. Tumor Implantation: Cells in logarithmic growth phase were harvested and washed in 50 ml falcon tubes at 1200 rpm for 5 minutes, once in growth media and then twice in cold sterile PBS. Cells were resuspended in PBS at a concentration of 25×106per ml, placed on ice, and injected in mice. Cancer cells were injected s.c. in 200 μl. The TMD8 model endogenously expresses CD20 and thus, can be used to test the efficacy of CD20-directed CAR T cells in vivo. This model grows well when implanted s.c. in mice, which can be measured by caliper measurements. Upon injection of 5×106cancer cells, the tumors establish and can be accurately measured within 3-4 days. Tumor volumes were determined by caliper measurement (2-3 times per week) and calculated as follows: TumorVolume=(max(tumorX,tumorY)*min(tumorX,tumorY){circumflex over ( )}2*π)/6 Within 9 days the tumor volume measurement was 200 mm3and untreated tumors reach endpoint measurement (>1200 m3) by 15-18 days. Anti-tumor activities of therapeutic agents are often tested once tumors are fully engrafted. Thus, there is a suitable window with this model during which the anti-tumor activity of CAR T cells can be observed. CAR T Cell Dosing: Mice were dosed 9 days after tumor implantation, with 3×106CAR T cells. Cells were partially thawed in a 37° C. water bath and then completely thawed by the addition of 1 ml of warmed growth media. The thawed cells were transferred to a 50 ml falcon tube and adjusted to a final volume of 12 ml with growth media. The cells were washed twice and spun at 300 g for 10 minutes and then counted by hemocytometer. T cells were then resuspended at respective concentrations in cold PBS and kept on ice until the mice were dosed. The CARTs were injected intravenously via the tail vein in 200 al, for a dose of 3×106CART cells. 5 mice per group were either treated with 200 μl of PBS alone (PBS), EGFRvIII-specific, mock CAR T cells as well as CD20-C3H2, CD20-C5H1, CD20-3H5k3, CD20-Ofa, and CD20-8aBBZ. All cells were prepared from the same donor in parallel. Animal Monitoring: The health status of the mice was monitored daily, including twice weekly body weight measurements. The percent change in body weight was calculated as (BWcurrent—BWinitial)/(BWinitial)×100%. The anti-tumor activity of CD20 CAR T cells was assessed in a DLBCL leukemia xenograft model (FIG.11). Following tumor cell implantation, tumor bearing mice were randomized into treatment groups and CAR T cells were administered intravenously via the lateral tail vein on day 9 after tumor implantation. Tumor growth and animal health were monitored until animals achieved endpoint. Mice in the negative control groups, which received PBS or the mock EGFRvIII-specific CAR T cells were euthanized on day 17. Also the groups which received CD20-Ofa and CD20-3H5k3 showed no efficacy of the respective CARTs and were euthanized on day 17. The other groups were euthanized on day 24. The PBS treatment group, which did not receive any T cells, demonstrates baseline TMD8 tumor growth kinetics. The EGFRvIII treatment group received mock CAR-transduced T cells and served as a T cell control to show the non-specific response of human donor T cells in this model. Both the PBS and EGFRvIII treatment groups demonstrated continuous tumor progression throughout this study. CD20-Ofa and CD20-3H5k3 showed similar growth kinetics, suggesting no anti-tumor efficacy by these CARTs. CD20-C3H2, CD20-C5H1, and the control CD20-8aBBZ CAR T cells all showed significantly slower tumor growth, with the strongest and fastest regression seen for CD20-C3H2, followed by CD22-C5H1. This study demonstrated that the CD20-specific CAR T cells CD22-C3H2 and CD22-C5H1 are capable of leading to the regression of TMD8 tumors. The efficacy was superior to CD20-8aBBZ, the published benchmark CAR. Example 8: In Vitro Activity of CARTs Bearing Human Anti-CD22 scFv with Short Linkers Genes encoding for single chain variable fragments for anti-CD22 antibodies (CD22-65, CD22-65s, positive control CD22 CAR m971 (m971), and m971s) were cloned into lentiviral CAR expression vectors with the CD3zeta chain and 4-1BB stimulatory molecules: The CD3zeta chain was either wildtype (Zwt) or carried a Q65K mutation (Zmut). The constructs were ranked based on the effector T cell responses of these CD22 CAR-transduced T cells (“CD22 CART” or “CD22 CAR T cells”) in response to CD22 expressing (“CD22+”) targets. Effector T cell responses include, but are not limited to, cellular expansion, proliferation, doubling, cytokine production and target cell killing or cytolytic activity (degranulation). Generation of CD22 CAR T Cells: Human scFv encoding lentiviral transfer vectors were used to produce the genomic material packaged into the VSVg pseudotyped lentiviral particles. Lentiviral transfer vector DNA encoding the CAR was mixed with the three packaging components VSVg, gag/pol and rev in combination with lipofectamine reagent to transfect Lenti-X 293T cells (Clontech), followed by medium replacement 12-18 h later. 30 hours after medium change, the media is collected, filtered and stored at −80° C. CD22 CAR T cells were generated by starting with blood from healthy apheresed donors whose T cells were enriched by negative selection of T cells, CD4+ and CD8+ lymphocytes (Pan T cell isolation, Miltenyi). T cells were activated by the addition of CD3/CD28 beads (DYNABEADS® Human T-Expander CD3/CD28, ThermoFisher Scientific) at a ratio of 1:3 (T cell to bead) in T cell medium (RPMI1640, 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine, 1× Penicillin/Streptomycin, 100 μM non-essential amino acids, 1 mM Sodium Pyruvate, 10 mM Hepes, and 55 μM 2-mercaptoethanol) at 37° C., 5% CO2. T cells were cultured at 0.5×106 T cells in 1 mL medium per well of a 24-well plate. After 24 hours, when T cells were blasting, non-concentrated or concentrated viral supernatant was added; T cells were transduced at a multiplicity of infection (MOI) of 5. T cells began to proliferate, which is monitored by measuring the cell concentration (as counts per mL), and T cells are diluted in fresh T cell medium every two days. As the T cells began to rest down after approximately 10 days, the logarithmic growth wanes. The combination of slowing growth rate and reduced T cell size (approaching 350 fL) determines the state for T cells to be cryopreserved for later analysis. All CD22 CAR T cells were produced under research grade (i.e., not clinical grade) manufacturing conditions. Before cryopreserving, the percentage of cells transduced (expressing the CD22-specific CAR on the cell surface) were determined by flow cytometric analysis on a FACS Fortessa (BD) (FIG.12). The viral transduction showed comparable expression levels, indicating similar transduction efficiency as well as surface expression of the respective CARs. The cell counts of the CAR T cell cultures indicate that there is no detectable negative effect of the human CD22 CARs on the cells' ability to expand normally when compared to the untransduced T cells (“UTD”). Evaluating Potency of CD22 CAR-Redirected T Cells: To evaluate the functional abilities of CD22 CAR T cells, the cells, generated as described above, were thawed, counted and co-cultured with cancer cells to read out their killing capabilities, secretion of cytokine as well as proliferation. Human scFv bearing CARs CD22-65_Zmut, CD22-65_Zwt, CD22-65s_Zwt, m971_Zmut, and m971s_Zmut were used and compared to a CD19 CAR as well as non-transduced T cells (UTD), which were used as non-targeting T cells control. T cell killing was directed towards the acute lymphoblastic leukemia (ALL) lines Nalm6 (RRID: CVCL_0092) and SEM (RRID: CVCL_0095); K562 (RRID: CVCL_0004), a chronic myelogenous leukemia (CML) cell line served as CD22-negative/low control. All cell lines were transduced to express luciferase as a reporter for cell viability/killing. The cytolytic activities of CD22 CARTs were measured at a titration of effector:target cell ratios (E:T) of 10:1, 5:1, 2.5:1, 1.25:1 0.63:1 and 0.31:1. Assays were initiated by mixing the respective number of T cells with a constant number of targets cells (25,000 cells per well of a 96-well plate). After 20 hours, remaining cells in the wells were lysed by addition of Bright-Glo™ Luciferase Assay System (Promega) reagent, to quantify the remaining Luc-expressing cancer cells in each well. “% Killing” was calculated in relation to wells containing target cells alone (0%, maximal Luc signal). The data show that transduction with the CD22 CART encoding lentiviruses transfers andi-CD22 killing activityy to T cells in Nalm6 (FIG.13A)) and SEM (FIG.13B)), UTD T cells show background killing only. Similarly, none of the CD22 CARs show killing of the CD22-negative control line K562 (FIG.13C). All CARs showed high killing of both Nalm6 and SEM target cell lines, with m971s_Zmut, CD22-65s_Zwt and CD22-65_Zwt being the top 3. To measure cytokine production of CD22 CAR T cells in response to CD22-expressing target cells, CAR T cells were co-cultured with the same ALL lines as above plus K562, serving as CD22-negative/low control. Cells were cultured at an effector:target ratio of 1:1 and 25,000 cells per well of a 96-well plate for 24 h, after which the media was removed for cytokine analysis using the V-PLEX Human IFN-γ Kit (Meso Scale Diagnostics). These data show that all CD22 CARTs as well as the CD19 CARTs produced IFN-γ when cultured with Nalm6 or SEM (FIG.14). m971s_Zmut, CD22-65s_Zwt and CD22-65_Zwt were the highest cytokine producers. Levels of cytokine produced by CD22 CARTs after exposure to the control K562 cells were low, indicating no unspecific effects by CD22 CARs. In the last T cell efficacy assay, the proliferative capacity of the CD22 CAR T cells was assessed. Again, thawed CAR T cells we co-cultured with the ALL lines Nalm6 and SEM. CARTs were stained with CellTracer Violet dye (Thermo-Fisher Scientific) and target cell lines were irradiated prior to co-culture to prevent overgrowth in the wells. They were then cultured at an effector:target ratio of 1:1 and 30,000 cells per well in a 96-well plate for 4 days. On day 4, cells were stained with anti-CD3 antibody as well as soluble CD22-Fc to detect CAR expression. From the intensity of the violet dye of all CD3+ T cells; the lower the fluorescence, the stronger the proliferation, as each cell division of the T cells leads to retention of half the fluorescence in each daughter cell (FIG.15A). Non-divided cells show high fluorescence as seen for UTD. The cell proliferation is quantified and reported as “Division Index” using FlowJo software (FIG.15B). Here, CD22-65s_Zwt was among the best proliferating CARTs in response to Nalm6 and showed the highest proliferation in response to SEM and. All CD22-specific CARs in this experiment were expressed on the cell surface of primary human T cells similarly well: CD22-65_Zmut, CD22-65_Zwt, CD22-65s_Zwt, m971_Zmut, and m971s_Zmut. While all CD22 CARTs showed efficacy in T cell functional assays, m971s_Zmut, CD22-65s_Zwt and CD22-65_Zwt were the top 3 CARTs in all 3 assays. Overall, the transfer of CD22 CARs induced anti-CD22 reactivity but no off-target function was detected. Example 9: In Vivo Activity of CARTs Bearing Human Anti-CD22 scFv with Short Linkers Anti-tumor activity of a set of CD22 CAR T cells was assessed in vivo in a NALM6 and a SEM xenograft model. CAR T cells with CAR constructs CD22-65_Zmut, CD22-65_Zwt, CD22-65s_Zwt, m971_Zmut, and m971s_Zmut were evaluated. Cell Lines: Both Nalm6 (RRID: CVCL_0092) and SEM (RRID: CVCL_0095) are human acute lymphoblastic leukemia (ALL) cell lines. Cells were grown in RMPI medium containing 10% fetal bovine serum and both grow in suspension. Both cell lines persist and expand in mice when implanted intravenously. Cells have been modified to express luciferase, so that that tumor cell growth can also be monitored by imaging the mice after they have been injected with the substrate Luciferin. Mice: 6 week old NSG (NOD.Cg-PrkdcscidIl2rgtml Wjl/SzJ) mice were received from the Jackson Laboratory (stock number 005557). Animals were allowed to acclimate in the Novartis NIBR animal facility for at least 3 days prior to experimentation. Animals were handled in accordance with Novartis ACUC regulations and guidelines. Electronic transponders for animal identification were implanted on the left flank one day prior to tumor implantation. Tumor Implantation: Cells in logarithmic growth phase were harvested and washed in 50 ml falcon tubes at 1200 rpm for 5 minutes, once in growth media and then twice in cold sterile PBS. Cells were resuspended in PBS at a concentration of 5×106 per ml, placed on ice, and injected in mice. Cancer cells were injected intravenously in 200 μl through the caudal vein. Both, the Nalm6 and SEM models endogenously express CD22 and thus, can be used to test the efficacy of CD22-directed CAR T cells in vivo. These models grow well when implanted intravenously in mice, which can be imaged for tumor burden measurements. Upon injection of 1×106 cancer cells, the tumors establish and can be accurately measured within 3 days. Baseline measurements are 4-6×105 photons/second (p/s). Within 7 days the mean bioluminescence measurement is 2-4×106 p/s and untreated tumors reach endpoint measurement (2-3×109) by 21-26 days. Anti-tumor activities of therapeutic agents are often tested once tumors are fully engrafted. Thus, there is a large window with these models during which the anti-tumor activity of CAR T cells can be observed. CAR T Cell Dosing: Mice were dosed 7 days after tumor implantation, with 1×106 CART cells for the treatment of Nalm6 and 3×106 CAR T cells for the treatment of SEM. Cells were partially thawed in a 37° C. water bath and then completely thawed by the addition of 1 ml of warmed growth media. The thawed cells were transferred to a 50 ml falcon tube and adjusted to a final volume of 12 ml with growth media. The cells were washed twice and spun at 300 g for 10 minutes and then counted by hemocytometer. T cells were then resuspended at respective concentrations in cold PBS and kept on ice until the mice were dosed. The CARTs were injected intravenously via the tail vein in 200 al, for a dose of 1 or 3×106 CAR T cells for Nalm6 and SEM bearing mice, respectively. 5 mice per group were either treated with 200 μl of PBS alone (PBS), non-transduced T cells (UTD), CD19 CAR T cells, as well as the novel CD22-65_Zmut, CD22-65_Zwt, CD22-65s_Zwt, m971_Zmut, or m971s_Zmut CAR T cells. All cells were prepared from the same donor in parallel. Animal Monitoring: The health status of the mice was monitored daily, including twice weekly body weight measurements. The percent change in body weight was calculated as (BWcurrent-BWinitial)/(BWinitial)×100%. Tumors were monitored 2 times weekly by imaging the mice. The anti-tumor activity of CD22 CAR T cells was assessed in two B-cell acute lymphoblastic leukemia xenograft models. Following tumor cell implantation on day 0, tumor bearing mice were randomized into treatment groups and CAR T cells were administered intravenously via the lateral tail vein on day 7 after tumor implantation. Tumor growth and animal health were monitored until animals achieved endpoint. In the Nalm6 model, mice which received PBS or UTDT cells were euthanized on day 22, when tumors were causing decreased hind leg mobility. All other groups were euthanized on day 40. The PBS treatment group, which did not receive any T cells, demonstrates baseline Nalm6 tumor growth kinetics in intravenously injected NSG mice. The UTD treatment group received non-transduced T cells and served as a T cell control to show the non-specific response of human donor T cells in this model. Both the PBS and UTD treatment groups demonstrated continuous tumor progression throughout this study. CD22-65_Zmut, CD22-65_Zwt, CD22-65s_Zwt, m971_Zmut, and m971s_Zmut CAR T cells all showed significantly slower tumor growth. CD22-65s_Zwt and m971_Zmut showed complete tumor regression as indicated from mean bioluminescence (FIG.16). In the SEM model, mice which received PBS or UTD T cells were euthanized on day 27, when tumors were causing decreased hind leg mobility. All other groups were euthanized on day 45. The PBS treatment group, which did not receive any T cells, demonstrates baseline SEM tumor growth kinetics in intravenously injected NSG mice. The UTD treatment group received non-transduced T cells and served as a T cell control to show the non-specific response of human donor T cells in this model. Both the PBS and UTD treatment groups demonstrated continuous tumor progression throughout this study. CD22-65_Zmut, CD22-65_Zwt, CD22-65s_Zwt, m971_Zmut, m971s_Zmut, and CD19 CAR T cells all showed significantly slower tumor growth. CD19 CARTs showed fastest tumor regression, followed by CD22-65s_Zwt and m971s_Zmut (FIG.17A). Bioluminescence curves were also generated for single mice in the respective groups, highlighting the stronger efficacy of both CD22-65s_Zwt and m971s_Zmut as compared to the CAR variants with the longer linkers within the scFv (CD22-65_Zwt and m971_Zmut, respectively (FIG.17B). This study demonstrated that the CD22-specific CAR T cells CD22-65s_Zwt are capable of leading to the regression of both NALM6 and SEM tumors. The efficacy was comparable to m971 CAR variants and higher as compared to the CD22-65 variants with the long linker. Example 10: Clinical Efficacy of Anti-CD22 CAR T Cells for B-Cell Acute Lymphoblastic Leukemia Correlates with scFv Linker Length and can be Predicted Using a Xenograft Model Patients and Methods: An anti-CD22 CAR (“CD22 CAR”) including a longer linker (4×(GGGGS) (SEQ ID NO: 1086); LL) compared to anti-CD22 CAR including a short linker (1×(GGGGS) (SEQ ID NO: 1083); SL) between the light and heavy chains of the scFv was generated (FIG.18). The CD22 CAR LL construct was tested in two pilot clinical trials in adults (NCT02588456) and children with r/r-ALL (NCT02650414). CART22LLT cells were generated using lentiviral transduction. The protocol-specified CART22 dose was 2×106-1×107cells/kg for pediatric patients <50 kg and 1-5×108for pediatric patients >50 kg and adult patients, infused after lymphodepleting chemotherapy. Patient characteristics are described in Table 16. TABLE 16Patient characteristics of patients infused with CART22LLT cells.Pediatric ALL (n = 6)CharacteristicValue (range, %)Adult ALL (n = 3)Age median (range)14 years (4-25)47 years (28-64)Gender (%)3 M (50%)/3 F (50%)2 M (66.6%)/1 F (33.3%)Race5 caucasian/1 asian3 caucasianPrior allogeneic⅚ (83.3%)⅓ (33.3%)transplantation (%)Prior blinatumomab or⅚ (83.3%) CART19⅓ (33.3%) CART19CART19 (%)⅙ (16.6%) blinatumomab3/3 (100%) blinatumomabBM blast pre CART2277.5% (0.6-95)95% (0-97)% (range)⅚ (83.3%) CD19− relapse⅓ (33.3%) CD19− relapse⅙ (16.6%) CD19+ relapse⅔ (66.6%) CD19+ relapseCART22 dose3.55 × 108(3.96 × 107-5 × 108)2 × 108(5 × 107-5 × 108)median (range)CAR expression36.4% (15-49.7)25.8% (25-30) For the adult trial, 5 patients were screened, 4 enrolled (1 patient withdrew consent) and 3 infused (1 manufacturing failure). For the pediatric trial, 9 patients were screened, 8 enrolled (1 screen failure) and 6 infused (two patients were not infused for disease progression). For the preclinical studies, CART22LLand CART22SLwere generated and tested in vivo using xenograft models. NSG mice were engrafted with either a luciferase+ standard B-ALL cell line (NALM6) or primary B-ALL cells obtained from a patient relapsing after CART19 (CHP110R). Additionally, 2-photon imaging was used to study the in vivo behavior and immune synapse formation and flow cytometry to asses T cell activation. CART22 cells were successfully manufactured for 10 out of 12 patients. In the adult cohort, 3/3 patients developed CRS (gr.1-3) and no neurotoxicity was observed; in the pediatric cohort out of 5 evaluable patients (1 discontinued for lineage switch to AML on pre-infusion marrow), 3/5 developed cytokine-release syndrome (CRS) (all grade 2) and 1 patient had encephalopathy (gr.1). CART22 cells were expanded in the PB with median peak of 1977 (18-40314) copies/ug DNA at day 11-18. In an adult patient who had previously received CART19, a second CART19 re-expansion was observed following CART22 expansion (FIG.19). At day 28 in the adult cohort, the patient who was infused in morphologic CR remained in CR, while the other two had no response (NR). In the pediatric cohort, two out of five patients were in CR, one patient was in partial remission (PR) that then converted to CR with incomplete recovery at 2 months, and two had NR. No CD22-negative leukemia progression was observed. A direct comparison of the two different CAR22 constructs (CART22Sand CART22SL) was then performed. In xenograft models, CART22SLsignificantly outperformed CART22LL (FIG.20) with improved overall survival. Moreover, CART22SLshowed higher in vivo proliferation at day 17 (FIG.21). Mechanistically, intravital 2-photon imaging showed that CART22SLestablished more protracted T cell:leukemia interactions than did CART22L, suggesting the establishment of productive synapses (FIG.22). Moreover, in vivo at 24 hrs higher T cell activation (CD69, PD-1) was observed in CART22SLfrom the BM of NALM-6bearing mice. Although feasible and with manageable toxicity, CART22LLled to modest clinical responses for patients with r/r B-ALL. Preclinical evaluation allowed us to conclude that shortening the linker by 15 amino acids significantly increases the anti-leukemia activity of CART22, possibly by leading to more effective interactions between T cells and their targets. Finally, with the caveats of cross-trial comparison, these data suggest that xenograft models can predict the clinical efficacy of CART products and validate the use of In vivo models for lead candidate selection. Example 11: In Vitro Activity of CARTs Bearing Human Anti-CD22 scFv with Linker Variants Genes encoding for single chain variable fragments for anti-CD22 antibodies were cloned into lentiviral CAR expression vectors with the CD3zeta chain and 4-1BB stimulatory molecules. The following anti-CD22 CAR constructs were evaluated: CD22-65_Zwt, CD22-65s_Zwt (short 1×(GGGGS) linker (SEQ ID NO: 1083); SEQ ID NO: 835), CD22-65ss_Zwt (no linker between the VH and VL regions; SEQ ID NO: 836), CD22-65sLH_Zwt (short 1×(GGGGS) linker (SEQ ID NO: 1083) with the VL region oriented at the N-terminus and the VH region oriented at the C-terminus), CD22-65sKD_Zwt (short 1×(GGGGS) linker (SEQ ID NO: 1083) and mutations in the FR regions of the VH and VL regions; SEQ ID NO: 837), and CD22m971s_Zmut (control) were evaluated. Except for CD22-65sLH_Zwt, all anti-CD22 CAR constructs have the VH region oriented at the N-terminus. The CD3zeta chain was either wildtype (Zwt) or carried a Q65K mutation (Zmut). The constructs were ranked based on the effector T cell responses of these CD22 CAR-transduced T cells (“CD22 CART” or “CD22 CART cells”) in response to CD22 expressing (“CD22+”) targets. Effector T cell responses include, but are not limited to, cellular expansion, proliferation, doubling, cytokine production and target cell killing or cytolytic activity (degranulation). Generation of CD22 CAR T Cells: Human scFv encoding lentiviral transfer vectors were used to produce the genomic material packaged into the VSVg pseudotyped lentiviral particles. Lentiviral transfer vector DNA encoding the CAR was mixed with the three packaging components VSVg, gag/pol and rev in combination with lipofectamine reagent to transfect Lenti-X 293T cells (Clontech), followed by medium replacement 12-18h later. 30 hours after medium change, the media is collected, filtered and stored at −80° C. CD22 CAR T cells were generated by starting with blood from healthy apheresed donors whose T cells were enriched by negative selection of T cells, CD4+ and CD8+ lymphocytes (Pan T cell isolation, Miltenyi). T cells were activated by the addition of CD3/CD28 beads (DYNABEADS® Human T-Expander CD3/CD28, ThermoFisher Scientific) at a ratio of 1:3 (T cell to bead) in T cell medium (RPMI1640, 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine, 1× Penicillin/Streptomycin, 100 μM non-essential amino acids, 1 mM Sodium Pyruvate, 10 mM Hepes, and 55 μM 2-mercaptoethanol) at 37° C., 5% CO2. T cells were cultured at 0.5×106T cells in 1 mL medium per well of a 24-well plate. After 24 hours, when T cells were blasting, non-concentrated or concentrated viral supernatant was added; T cells were transduced at a multiplicity of infection (MOI) of 5. T cells began to proliferate, which is monitored by measuring the cell concentration (as counts per mL), and T cells are diluted in fresh T cell medium every two days. As the T cells began to rest down after approximately 10 days, the logarithmic growth wanes. The combination of slowing growth rate and reduced T cell size (approaching 350 fL) determines the state for T cells to be cryopreserved for later analysis. All CD22 CAR T cells were produced under research grade (i.e., not clinical grade) manufacturing conditions. Before cryopreserving, the percentage of cells transduced (expressing the CD22-specific CAR on the cell surface) were determined by flow cytometric analysis on a FACS Fortessa (BD) (FIG.23). The viral transduction showed comparable expression levels, indicating similar transduction efficiency as well as surface expression of the respective CARs. The cell counts of the CAR T cell cultures indicate that there is no detectable negative effect of the human CD22 CARs on the cells' ability to expand normally when compared to the untransduced T cells (“UTD”). Evaluating Potency of CD22 CAR-Redirected T Cells: To evaluate the functional abilities of CD22 CAR T cells, the cells, generated as described above, were thawed, counted and co-cultured with cancer cells to read out their killing capabilities and secretion of cytokine. Human scFv bearing CARs CD22-65_Zwt, CD22-65s_Zwt, CD22-65ss_Zwt, CD22-65sLH_Zwt, CD22-65sKD_Zwt, and CD22-m971s_Zmut were compared and EGFRvIII CAR T cells as well as non-transduced T cells (UTD) were used as non-targeting T cells control. T cell killing was directed towards the acute lymphoblastic leukemia (ALL) lines Nalm6 (RRID: CVCL_0092) and SEM (RRID: CVCL_0095). Both cell lines were transduced to express luciferase as a reporter for cell viability/killing. The cytolytic activities of CD22 CARTs were measured at a titration of effector:target cell ratios (E:T) of 10:1, 5:1, 2.5:1, 1.25:1 0.63:1 and 0.31:1. Assays were initiated by mixing the respective number of T cells with a constant number of targets cells (25,000 cells per well of a 96-well plate). After 20 hours, remaining cells in the wells were lysed by addition of Bright-Glo™ Luciferase Assay System (Promega) reagent, to quantify the remaining Luc-expressing cancer cells in each well. “% Killing” was calculated in relation to wells containing target cells alone (0%, maximal Luc signal). The data show that transduction with the CD22 CART encoding lentiviruses transfers anti-CD22 killing activity to T cells (Nalm6 and SEM (FIGS.24A-B)). UTD and EGFRvIII CAR T cells show background killing only. All CARs except CD22-65sLH_Zwt showed high killing of both Nalm6 and SEM target cell lines. To measure cytokine production of CD22 CAR T cells in reponse to CD22-expressing target cells, CAR T cells were co-cultured with the same ALL lines as above. Cells were cultured at an effector:target ratio of 1:1 and 25,000 cells per well of a 96-well plate for 24 h, after which the media was removed for cytokine analysis using the V-PLEX Human IFN-γ Kit (Meso Scale Diagnostics). These data show that all CD22 CARTs, except CD22-65sLH_Zwt, produced IFN-γ when cultured Nalm6 or SEM (FIG.25). All CD22-specific CARs in this experiment were expressed on the cell surface of primary human T cells similarly well: CD22-65_Zwt, CD22-65s_Zwt, CD22-65ss_Zwt, CD22-65sLH_Zwt, CD22-65sKD_Zwt, and CD22-m971s_Zmut. Additionally, all CD22 CARTs showed efficacy in T cell functional assays, except for CD22-65sLH_Zwt. clp Example 12: In Vivo Activity of CARTs Bearing Human Anti-CD22 scFv with Linker Variants Anti-tumor activity of a set of CD22 CAR T cells was assessed in vivo in a NALM6 xenograft model. CAR T cells with CAR constructs CD22-65_Zwt, CD22-65s_Zwt, CD22-65ss_Zwt, CD22-65sLH_Zwt, CD22-65sKD_Zwt, and CD22-m971s_Zmut (control) were evaluated. Cell Line: Nalm6 (RRID: CVCL_0092) is a human acute lymphoblastic leukemia (ALL) cell line. Cells were grown in RMPI medium containing 10% fetal bovine serum and both grow in suspension. Cells persist and expand in mice when implanted intravenously. Cells have been modified to express luciferase, so that that tumor cell growth can also be monitored by imaging the mice after they have been injected with the substrate Luciferin. Mice: 6 week old NSG (NOD.Cg-PrkdecscidI12rgtm1Wjl/SzJ) mice were received from the Jackson Laboratory (stock number 005557). Animals were allowed to acclimate in the Novartis NIBR animal facility for at least 3 days prior to experimentation. Animals were handled in accordance with Novartis ACUC regulations and guidelines. Electronic transponders for animal identification were implanted on the left flank one day prior to tumor implantation. Tumor Implantation: Cells in logarithmic growth phase were harvested and washed in 50 ml falcon tubes at 1200 rpm for 5 minutes, once in growth media and then twice in cold sterile PBS. Cells were resuspended in PBS at a concentration of 5×106per ml, placed on ice, and injected inl through the caudal vein. Nalm6 cells endogenously express CD22 and thus, can be used to test the efficacy of CD22-directed CAR T cells in vivo. This model grows well when implanted intravenously in mice, which can be imaged for tumor burden measurements. Upon injection of 1×106cancer cells, the tumors establish and can be accurately measured within 3 days. Baseline measurements are 4-6×105photons/second (p/s). Within 7 days the mean bioluminescence measurement is 2-4×106p/s and untreated tumors reach endpoint measurement (2-3×109) by 20-30 days. Anti-tumor activities of therapeutic agents are often tested once tumors are fully engrafted. Thus, there is a large window with these models during which the anti-tumor activity of CAR T cells can be observed. CAR T Cell Dosing: Mice were dosed 7 days after tumor implantation, with 1×106CART cells for the treatment of Nalm6. Cells were partially thawed in a 37° C. water bath and then completely thawed by the addition of 1 ml of warmed growth media. The thawed cells were transferred to a 50 ml falcon tube and adjusted to a final volume of 12 ml with growth media. The cells were washed twice and spun at 300 g for 10 minutes and then counted by hemocytometer. T cells were then resuspended at respective concentrations in cold PBS and kept on ice until the mice were dosed. The CARTs were injected intravenously via the tail vein in 200 al, for a dose of 1×106CART cells. 5 mice per group were either treated with 200 μl of PBS alone (PBS), EGFRvIII-transduced T cells, as well as the novel CD22-65_Zwt, CD22-65s_Zwt, CD22-65ss_Zwt, CD22-65sLH_Zwt, CD22-65sKD_Zwt, and CD22-m971s_Zmut CAR T cells. All cells were prepared from the same donor in parallel. Animal Monitoring: The health status of the mice was monitored daily, including twice weekly body weight measurements. The percent change in body weight was calculated as (BWcurrent−BWinitial)/(BWinitial)×100%. Tumors were monitored 2 times weekly by imaging the mice. The anti-tumor activity of CD22 CAR T cells was assessed in a B-cell acute lymphoblastic leukemia xenograft model. Following tumor cell implantation on day 0, tumor bearing mice were randomized into treatment groups and CAR T cells were administered intravenously via the lateral tail vein on day 7 after tumor implantation. Tumor growth and animal health were monitored until animals achieved endpoint. In this Nalm6 model, mice which received PBS or EGFRvIII T cells were euthanized on day 23, when tumors were causing decreased hind leg mobility. All other groups were euthanized on day 37. The mean bioluminescence for all treatment groups was then determined (FIG.26). The PBS treatment group, which did not receive any T cells, demonstrates baseline Nalm6 tumor growth kinetics in intravenously injected NSG mice. The EGFRvIII treatment group received mock-transduced T cells and served as a T cell control to show the non-specific response of human donor T cells in this model. Both the PBS and UTD treatment groups demonstrated continuous tumor progression throughout this study. CD22-65_Zwt, CD22-65s_Zwt, CD22-65ss_Zwt, CD22-65sKD_Zwt, and CD22-m971s_Zmut CAR T cells all showed significantly slower tumor growth. CD22-65s_Zwt, CD22-65ss_Zwt showed the strongest response. These data demonstrate that the CD22-specific CAR T cells CD22-65s_Zwt and CD22-65ss_Zwt are capable of strongly inhibiting the growth of NALM6 cancer at a low dose of 1×106CART cells. The efficacy was superior to the control m971 CAR. Example 13: Generation, Expression, and Antigen Activation of CARTs Including Tandem Anti-CD19 and Anti-CD22 scFVs To test whether a single CART cell functionalized with two distinct scFVs can be activated by either of the antigens that the CART recognizes, CARTs comprising two distinct scFVs linked together were generated with scFVs targeting CD19 and CD22 (Tables 15 and 17 andFIG.27). These constructs differ in the position of the anti-CD19 recognition moiety relative to the T cell membrane (proximal or distal: closer or distant from the T cell membrane, respectively). The generated constructs explore two different linkers connecting the two scFVs: LAEAAAK (SEQ ID NO: 1091) and GGGGS (SEQ ID NO: 1083). The LAEAAAK (SEQ ID NO: 1091) is a more rigid linker, while the GGGGS linker (SEQ ID NO: 1083) is a more flexible linker. The impact of the orientation of the light (L) and heavy (H) chains within the anti-CD22 scFV activation was also investigated. The anti-CD19 scFV was oriented as L/H (in a N- to C-terminus orientation) in all of the constructs. Two linkers connecting the H and L chains within the anti-CD22 scFV: GGGGSGGGGSGGGGS (SEQ ID NO: 1084) and GGGGS (SEQ ID NO: 1083) were also explored (annotated as “sh” in Tables 17 and 18). Control constructs engineered with the individual scFVs (anti-CD19 or anti-CD22) were also generated (Table 18). TABLE 17Constructs generated in the context of a single CART targeting CD22and CD19. (Table discloses SEQ ID NOS 1091, 1083, 1091, 1083,1091, 1083, 1091 and 1083, respectively, in order of appearance)DistalLinkerProximalH/LL/HαCD19LAEA3KαCD22CG#c171CG#c177αCD19G4SαCD22CG#c172CG#c178αCD19LAEA3KαCD22shCG#c173CG#c179αCD19G4SαCD22shCG#c174CG#c180αCD22LAEA3KαCD19CG#c181CG#c185αCD22G4SαCD19CG#c182CG#c186αCD22shLAEA3KαCD19CG#c183CG#c187αCD22shG4SαCD19CG#c184CG#c188 TABLE 18CAR construct controls generated to target CD19 or CD20.H/LL/HαCD22CAR22-65CG#c175αCD22shCG#c170CG#c176αCD19CAR19 Evaluation of CAR Expression: The sequences encoding the constructs listed in Tables 17 and 18 were cloned into a lentiviral backbone vector. All of the constructs comprised the leader sequence of the human CD8alpha at their N-terminus, which is expected to be cleaved co-translationally and excluded in the final protein product. Transgene expression was driven by the EF1alpha promoter. The resulting DNAs were used to transfect HEK-293 cells for viral production. Exemplary viral titers are shown in Table 19. Viral titers were determined based on surface expression of the various constructs in SupT1 cells, by FACS using two distinct staining reagents. An anti-idiotype antibody recognizing the scFv directed to CD19 and CD22-FC for staining the scFV directed to CD22 were used. Staining was performed individually. TABLE 19viral titers obtained for some constructs tested in the context ofCD19- and CD22- targetingSampleCD19 anti-ID Titer (TU/ml)CD22-Fc (TU/ml)c1712.18E+062.51E+06c1723.29E+059.43E+05c1732.78E+057.34E+05c1748.82E+051.95E+06c1811.99E+062.54E+06c1821.01E+062.53E+06c1832.26E+061.85E+06c1842.24E+062.81E+06c1851.80E+071.99E+07c1869.49E+061.92E+07c1871.64E+071.76E+07c1883.44E+074.84E+07c1700.00E+006.18E+07c1750.00E+002.73E+06c1760.00E+007.84E+06CAR22-65 Long0.00E+002.60E+07CAR198.16E+070.00E+00 For each construct, the viral titers obtained with the two staining reagents were averaged and the viruses were evaluated for their ability to transduce JNL cells. The Jurkat cells were previously transduced with a NFAT-Luciferase reporter construct. A multiplicity of infection of 3 was used. The percent cells positive for CAR in JNLs following transduction with the indicated constructs was determined (FIG.28). CAR expression was determined 7 days post-transduction by FACS using the same staining reagents for checking expression of CAR in infected SupT1 cells. Staining was performed individually with no co-addition of the two reagents to avoid hindrance. These data show that the scFVs across the different constructs were detected at the cell surface, indicating expression and trafficking to the cell surface for the constructs targeting both CD19 and CD22. Use of a staining reagent that is the antigen itself (CD22-Fc) indicates that the scFV directed to CD22 acquired a correctly folded structure, which is compatible with recognition of the antigen within the CD22 protein. This result was observed whether the anti-CD22 scFV arm was engineered upstream or downstream of the antiCD19 scFV arm. Evaluation of CAR Activation: To evaluate whether a CAR comprising two distinct scFVs can be activated by either of the targeted antigens, we co-cultured the untransduced (UTD) and transduced JNLs with target cell lines expressing either CD19 (K562-CD19) or CD22 (K562-CD22). When the CAR recognized the CD19 or CD22 antigen, CAR engagement resulted in downstream NFAT activation. The NFAT-luciferase reporter in the JNL cells provided a measure to read out CAR activation. The expression levels of CD19 and CD22 in the different target cell lines is shown (FIG.29). The level of NFAT-induced luciferase as a measure of CAR activity is shown (FIG.30). The number of JNL cells added to the assay was normalized to the lowest expression of CAR, based on the data shown inFIG.28. All of the constructs comprising two scFVs, one against CD19 and another against CD22, were activated by both targets, regardless of the orientation of the scFV relative to the T cell membrane. The monoCARs were activated only by the antigen that its scFV recognizes (CD19 or CD22). EQUIVALENTS The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific aspects, it is apparent that other aspects and variations of this invention may be devised by others skilled in the art without departing from the true spitir and scope of the invention. The appended claims are intended to be construed to include allsuch aspect and equivalent variations. SEQUENCE LISTING The patent contains a lengthy “Sequence Listing” section. A copy of the “Sequence Listing” is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US10525083B2). An electronic copy of the “Sequence Listing” will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3). | 776,442 |
RE49848 | DETAILED DESCRIPTION OF THE INVENTION FIG.1ashows a system300for trans-dermal delivery of doses of a medicament, comprising a delivery device100to be placed in dermal contact with a patient. The delivery device100comprises a reservoir101for holding a medicament to be delivered, a trans-dermal injection element102for delivering doses of the medicament to the patient, a control unit120for controlling the delivery of the medicament when activated. The system300further comprises a separate hand-held drive device200temporarily placed in proximity of the delivery device100, the drive device200comprising an activation unit220for activating the control unit120of the delivery device100. The drive device200in correspondence of the activation unit220is shaped as to form a complementary cavity221into which the delivery device100comprising the control unit120substantially fits. The drive device200further comprises all the elements needed for operation and control, e.g. a processor230, other electronic components (not shown) such as a memory, a printed circuit board, wires, etc. . . . a battery240, a port250for recharging and/or for connecting to other devices, e.g. a computer, e.g. for exchanging data, buttons or switches260located on the housing of the device, visual and/or Braille-like screens, e.g. an LCD270, alert or warning lights (not shown). FIG.1bis the same asFIG.1aexcept that the delivery device100further comprises a pump110for pumping the medicament from the reservoir101to the trans-dermal injection element102. FIG.2shows a pump rotor111connected to the pump110located in the delivery device100transforming rotational force into pumping force when rotating around an axis112. The pump rotor111presents a saw-like or gear-like edge113. FIGS.3to11depict preferred embodiments of the control unit120. FIG.3shows a primary rotor130connected to the pump rotor111via a gear mechanism, adapted to transfer rotational force to the pump rotor111. The pump rotor111fits with a certain tolerance into a cavity131at the bottom of the primary rotor130. The primary rotor130and the pump rotor111thus have approximately the same axis of rotation112, i.e. they are concentrically arranged. The primary rotor130comprises a pin132parallel to the axis of rotation112, which fits into a cavity (not shown). The primary rotor130works as a stabilization element wherein it is allowed to incline its axis within a tolerance range without causing an inclination of the axis of the pump rotor111. In this way the moment of tilt of the pump rotor is minimized, that is inclinations of the axis112during rotation are minimized. The pin132could be attached directly to the pump rotor111. The primary rotor130comprises also a series of permanent magnets133arranged according to a specific magnetic configuration. Magnets133could have been disposed also on the primary rotor111. FIG.4shows a variant of the embodiment ofFIG.3wherein a compartment134carved in the housing of the delivery device100and designed to fit the footprint of the primary rotor130is part of the stabilization element. This could be used together with the pin132. FIG.5shows part of a control unit120wherein a primary rotor130is locked by a safe-lock mechanism140. The safe-lock mechanism140prevents the primary rotor130to rotate until unlocked. The safe-lock mechanism140thus eliminates the risk of external interferences, i.e. that medicament is pumped when not required. The safe-lock mechanism140has the form of L-shaped pivotable arms, designed as a clamp, which can assume either of two positions, a tight position (as shown in the figure) when it is in a locked status and an enlarged position when it is in an unlocked status (not shown). The safe-lock mechanism140is designed to fit at one extremity between the teeth of a saw-like edge135of the primary rotor130and is made of a rigid but flexible elastic material capable of being stretched and to return to its original position afterwards. The safe-lock mechanism140comprises permanent magnets141. Also shown inFIG.5is a directional element142, which allows the primary rotor130to rotate in one direction only when unlocked. The directional element142is an inclined flexible elastic tongue fitting between the teeth of the saw-like edge135of the primary rotor130. FIG.6shows the pump110connected to an axial pump element150locked by a safe-lock mechanism140. The axial pump element150is directly attached to the pump110and is adapted to transform axial force into pumping force. Disposed on the axial pump element is a magnet133. The safe-lock mechanism140is similar to that shown inFIG.5. In this case, it prevents the axial pump element150to move up and/or down until unlocked. FIG.7shows a secondary rotor160and a primary rotor130having different axis of rotation115and112respectively, while the primary rotor130and the pump rotor111have the same axis of rotation112. The secondary rotor160has here the function to change the magnitude of the torque on the primary rotor130and hence on the pump rotor111by means of a gear mechanism162. The secondary rotor160comprises a series of permanent magnets133and is capable of transferring rotational force to the primary rotor130, which in turn is capable of transferring rotational force to the pump rotor111. The primary rotor130is locked by a safe-lock mechanism140, which acts as a brake on the primary rotor130until unlocked. The safe lock mechanism140may be unlocked analogously toFIGS.5and6magnetically or electronically, e.g. powered by an induced electric current. FIG.8ais a perspective view of an embodiment comprising a mainspring170located between a primary rotor130and a secondary rotor160. The secondary rotor160comprises a series of permanent magnets133arranged according to a specific magnetic configuration. The secondary rotor160is locked by a safe-lock mechanism140similar to that shown inFIG.5. The safe-lock mechanism140fits at one extremity between the teeth of a saw-like frame161of the secondary rotor160and prevents the secondary rotor160to rotate until unlocked. A second safe-lock mechanism (not shown) may lock the primary rotor130while the secondary rotor160is unlocked and allowed to rotate. A directional element142allows the secondary rotor160to rotate in one direction only when unlocked. Rotation of the secondary rotor160in one direction has in this case the function to load the mainspring170. Once the mainspring170is loaded the drive device200may be removed as rotational force is transferred now to the primary rotor130by the mainspring170while returning to its previous status. The mainspring170may be differently loaded according to the dose to be delivered. FIG.8bis a bottom view of the embodiment ofFIG.8awherein the secondary rotor160has been made transparent for clarity. The pump rotor111, the primary rotor130and the secondary rotor160are concentrically arranged with the mainspring170located between the secondary rotor160and the primary rotor130. The primary rotor130could have been in place of the secondary rotor130and the mainspring170could have been located between the primary rotor130and the pump rotor111. FIG.9shows a pump rotor111designed to engage with an axial pump element150and to transform rotational force into axial force upon activation. The pump rotor111and the axial pump element150are not connected to each other, i.e. the pump rotor111may be allowed to rotate but eventual rotational force applied to the pump rotor111is not transferred to the axial pump element150and transformed into axial force, until the separate hand-held drive device200comprising the activation unit220is temporarily placed in proximity of the delivery device100. Thus the separation of the pump rotor111and the axial pump element150has the same function of a safe-lock mechanism140. Unlocking the safe-lock mechanism here means moving the pump rotor111in axial direction in order to engage with the axial pump element150. In particular, a gear element114of the pump rotor111is engaged with a gear element151of the axial pump element150. The pump rotor111comprises a series of permanent magnets133,136arranged according to a specific magnetic configuration. The axial pump element150is here the plunger of a syringe-like reservoir (not shown), comprising the medicament to be delivered. A spring138allows the pump rotor111to disengage and return to its original locked status once the drive device200is no longer in proximity of the delivery device100. Using a similar mechanism and with reference toFIG.3one can imagine a primary rotor130, which needs to move in the axial direction in order to be engaged with the pump rotor111. FIG.10shows another example wherein the pump rotor111needs to be pulled in the axial direction out of its locked position137before freedom to rotate is provided. FIG.11shows a coil180integrated in the delivery device100. A specific magnetic field generated by the activation unit220when the drive device200is placed in proximity of the delivery device100induces a specific current, e.g. modulated, in the coil180, which provides electrical power for unlocking the safe-lock mechanism140for a specific period of time. FIG.12shows a reservoir101comprising an array of blisters103disposed on a base rotor104, each blister103containing a fraction of dose of medicament to be delivered and being connected by a microfluidic channel105to the trans-dermal injection element102. The base rotor104is capable of rotating, at least partially when a new dose is required. The control unit comprises a safe-lock mechanism (not shown) preventing the base rotor104to rotate until unlocked and an axial pump element (not shown) transforming axial force into pumping force by pressing on the blisters103one at a time. Instead of a rotating base rotor104a rotating axial pump element (not shown) could be used as well. Instead of an array of blisters103a single larger pouch (not shown) could be used as well. FIG.13shows the elements of an activation unit220comprised in the drive device200. The design of the activation unit220may vary in order to adapt to different control units120. The activation unit220ofFIG.13is for example suitable for a control unit as shown inFIGS.5to8. In particular, the activation unit220comprises an unlocking element221for unlocking the at least one safe-lock mechanism140of the control unit120when the hand-held drive device200is placed in proximity of the delivery device100. The unlocking element221comprises permanent magnets223symmetrically arranged. This symmetry may be convenient in order to avoid dependency on the angle with which the hand-held drive device200is placed in proximity of the delivery device100. An electromagnet could have also been used. The magnetic field generated by the unlocking element221, which may be specific, is the key for unlocking the safe-lock mechanism140. The activation unit220further comprises a drive unit222providing rotational force and/or axial force to any one or more elements selected from the group of a base rotor104, a pump rotor111, a primary rotor130, a secondary rotor160, an axial pump element150when the hand-held drive device200is placed in proximity of the delivery device100. The drive unit222comprises a drive rotor230connected to a motor240via a belt252, the drive rotor230comprising a series of magnets231. An electromagnet could have also been used. FIG.14shows a different embodiment of an activation unit220wherein the magnets231comprised in the drive rotor230are differently arranged. The drive rotor230comprises also another magnet232at the center, which acts as unlocking element221for a safe-lock mechanism like that described e.g. in relation toFIGS.9and10. FIG.15shows still another embodiment of an activation unit comprising a magnet232at the center and acting as unlocking element221similarly to that shown inFIG.14. As a drive unit222a series of electromagnets represented by coils233are used instead. FIG.16toFIG.18bshow the elements of a delivery device100according a preferred embodiment and are to be seen together.FIG.16is an exploded view showing most of the elements of the delivery device100.FIG.17aandFIG.17bshow the interaction between some of the elements of the delivery device100ofFIG.16, wherein inFIG.17ashows the safe-lock mechanism in a locked status andFIG.17bshows the safe-lock mechanism in an unlocked status.FIG.18aandFIG.18bshow the interaction between some other elements of the delivery device100ofFIG.16not visible inFIG.17aandFIG.17b. The embodiment shown in these figures is similar in principle to that shown inFIG.9. The reservoir155is a syringe for containing the medicament to be delivered. A plunger-like axial pump element consisting of a first axial pump element153and a second axial pump element150transforms axial force into pumping force for pushing the medicament out of the syringe via opening157fluidically connected to trans-dermal injection element102(not shown). A second opening156may be used, e.g. to introduce the medicament into the syringe155. The first axial pump element153comprises o-rings154for achieving a fluid-tight sealing with the inner walls of syringe155. The first axial pump element153is disconnected from the second axial pump element150before introducing the medicament into then syringe. Particularly, the first axial pump element153is close to a first end of the syringe155in proximity of the openings156,157and is pushed towards second axial pump element150by the medicament being introduced into the syringe155, until engaging with the second axial pump element150by fitting head169of the second axial pump element150into cavity171of the first axial pump element153. The syringe155is closed at the second open end with a cap159secured at the inner walls of the syringe155so that it is not allowed to rotate. The cap comprises a hole in the center and a tooth (not shown) protruding towards the center. The second axial pump element150may pass through the hole of the cap159. The second axial pump element150comprises a gear element151and a groove158, into which the tooth of the cap159fits. In this way the second axial pump element150may move axially into the syringe155through the hole of the cap159but may not rotate, due to the groove158being aligned with the tooth of the cap159. The second axial pump element150fits into the body of pump rotor111and is connected via the gear element151with a first internal gear element114of the pump rotor111. The pump rotor111is designed to transform rotational force into axial force by pushing upon rotation the second axial pump element150in axial direction, which in turn pushes the first axial pump element153. A primary rotor130is connected via gear element174with a second external gear element173of the pump rotor111. The primary rotor130is designed to transfer rotational force to pump rotor111upon activation. The pump rotor111may rotate and transform rotational force into axial force only if the primary rotor130is allowed to rotate. The primary rotor150is however locked by a safe-lock mechanism140and is not allowed to rotate until a separate hand-held drive device200is placed in proximity of the delivery device and only when a dose of medicament is required, the drive device200comprising an activation unit220for activating the control unit120of the delivery device100, the activation unit220comprising an unlocking element221to provide energy for unlocking the safe-lock mechanism140and a drive unit222to provide energy for the primary rotor130to rotate. The safe-lock mechanism140comprises a locking element165comprising teeth166. The locking element165is designed to be functionally coupled to primary rotor130so that primary rotor130may rotate only together with locking element165. This is achieved by matching recesses172of the locking element165with protrusions167on the primary rotor130. A spring138located between the locking element165and the primary rotor130pushes the locking element165against the inner walls of the housing190of the delivery device100, wherein similar protruding teeth168prevent the locking element165and thus the primary rotor130to rotate. A spring138like that shown inFIG.16may be more suitable than a spring138like that shown inFIG.17aandFIG.17b. The spring type has been changed inFIG.17aandFIG.17bfor illustration purpose only, wherein also the distance between the locking element165and the primary rotor130has been exaggerated for better clarity. During operation, the locking element165is normally not allowed to go over the upper level of protrusions167on the primary rotor130. The primary rotor130comprises also two permanent magnets133. Another magnet136is placed above the locking element165. The safe-lock mechanism140comprises in this case the locking element165with teeth166, the spring138, the magnet136and teeth168of the housing190. The control unit120comprises the primary rotor130, the pump rotor111, the second axial pump element150, the first axial pump element153, the cap159, and the safe-lock mechanism140. When a dose of medicament is required a separate hand-held drive device200comprising an activation unit220similar to that shown inFIG.14orFIG.15is placed in proximity of the delivery device100and a command is given to activate the control unit120to delivery specifically the dose of medicament needed. The drive device200comprises an activation unit220for activating the control unit120of the delivery device100. The activation unit220comprises an unlocking element221, the unlocking element221comprising a magnet232to interact specifically with magnet136, so that the magnetic force overcomes the force provided by the spring138and the locking element is pushed downwards towards the primary rotor130, thus freeing the locking element165from teeth168and unlocking the control unit120. At the same time the drive unit222of the drive device200, comprising magnets231with a specific magnetic configuration matching the polarity of the magnets133on the primary rotor130provides to the primary rotor130the exact amount of energy to rotate, which is transformed via pump rotor111into the exact axial force required to deliver the correct dose of medicament. As soon as the requested dose has been delivered, the drive unit222stops to provide energy to the primary rotor130, which stops rotating. The hand-held device sends a feedback signal, e.g. visual, vibrational, acoustic, to inform the user that it is possible to remove the hand-held device200from the delivery device100. The safe-lock mechanism140is then locked again, thus locking the control unit120. The combined effect of the unlocking element221and the drive unit222on the combined elements of the control unit120makes the activation of the control unit120specific as a key. FIG.19shows a hand-held drive device200wherein part of the housing has been removed to show some of the elements inside. Particularly a Hall sensor280and an encoder290are shown. The Hall sensor is capable of detecting the fluctuation of the magnetic field induced by the magnets133when the primary rotor130rotates and thus enables the verification that the correct amount of energy has been transferred to the control unit120and transformed into pumping force and delivery of the correct dose of medicament. In this case, the drive device200comprises an activation unit similar to that ofFIG.14and the encoder290is used to verify the rotational movement of the drive unit222. The data from the hall sensor280and the encoder290may be compared for further verification. Of course numerous variations of the described embodiments are possible without departing from the scope of the invention. | 19,680 |
RE49849 | DETAILED DESCRIPTION The term “starting material”, as used herein, means halopropanes or halopropenes which react with hydrogen fluoride (HF) and chlorine (Cl2) in a reaction zone in the embodiments of this invention. As indicated above, for certain processes of this invention the starting material is selected from the group consisting of halopropanes of the formula CX3CH2CH2X, halopropenes of the formula CX3CH═CH2and halopropenes of the formula CX2═CHCH2X, wherein each X is independently selected from the group consisting of F and Cl; and for certain other processes of this invention the starting material is selected from the group consisting of halopropenes of the formula CX3CH═CH2and halopropenes of the formula CX2═CHCH2X, wherein each X is independently selected from the group consisting of F and Cl. The processes of this invention use a molar ratio of HF to the total amount of starting material that is at least stoichiometric. The stoichiometric ratio is determined by subtracting the weighted average of the number of fluorine substituents in the starting material(s) from the weighted average of the number of fluorine substituents in the desired product(s). For example, for producing a C3H3F5isomer from C3H4Cl4, the stoichiometric ratio of HF to C3H4Cl4is 5:1. As another example, for producing a 1:1 mixture of HFC-245cb to HFC-1234yf from CF3CH═CH2, the stoichiometric ratio of HF to CF3CH═CH2is 1.5:1. Certain compounds produced by the processes of this invention may exist as one of two configurational isomers. For example, HFC-1234ze and HCFC-1233zd may each exist as E- or Z-isomers. As used herein HFC-1234ze refers to the isomers, E-HFC-1234ze or Z-HFC-1234ze, as well as any combinations or mixtures of such isomers; and HCFC-1233zd as used herein refers to the isomers, E-HCFC-1233zd or Z-HCFC-1233zd, as well as any combinations or mixtures of such isomers. As indicated above, the present invention provides a process that involves producing a product mixture comprising at least one product compound selected from the group consisting of HFC-245cb, HFC-1234yf and HCFC-1233xf using at least one starting material selected from the group consisting of halopropanes of the formula CX3CH2CH2X, halopropenes of the formula CX3CH═CH2and halopropenes of the formula CX2═CHCH2X. Of note are embodiments of this process wherein HFC-1234yf is recovered. Additional HFC-1234yf may be obtained by dehydrofluorination of HFC-245cb from the product mixture. Also of note are embodiments of this process wherein HCFC-1233xf from the product mixture is fluorinated to produce at least one of HFC-1234yf and HFC-245cb. The product mixture may also comprise HFC-1234ze. The HFC-1234ze may be recovered. The product mixture may further comprise HCFC-1233zd. HFC-1234ze and HFC-245fa may also be obtained by fluorination of HCFC-1233zd from the product mixture. The product mixture may also comprise HFC-245fa. The HFC-245fa may be recovered. The HFC-245fa may also be dehydrofluorinated to produce HFC-1234ze. The product mixture may further comprise HFC-1234ze. A mixture of HFC-245cb and HFC-1234ze may be recovered and further reacted with HF in the liquid phase under fluorination conditions in the presence of a fluorination catalyst to produce a mixture comprising HFC-245fa and HFC-245cb. Alternatively, a mixture of HFC-245cb and HFC-1234ze may be recovered and further reacted under dehydrofluorination conditions in the presence of a dehydrofluorination catalyst to produce a mixture comprising HFC-1234ze and HFC-1234yf. HFC-245fa, HFC-1234ze and/or HCFC-1233zd may also be present in the product mixture. HFC-245cb, HFC-1234yf, and HCFC-1233xf from the product mixture together with HFC-245fa (if present), HFC-1234ze (if present) and HCFC-1233zd (if present) may be further reacted with HF in the liquid phase under fluorination conditions in the presence of a fluorination catalyst to produce a mixture comprising HFC-245fa and HFC-245cb. The HFC-245fa and HFC-245cb from the mixture may be dehydrofluorinated (individually or as a mixture) to produce both HFC-1234ze and HFC-1234yf which may be recovered. See for example, U.S. Patent Application Publication US2006/0106263(A1), which is hereby incorporated herein by reference. HCFC-1233zd and HFC-245fa may also be present in the product mixture; and HCFC-1233xf, HCFC-1233zd, and HFC-245fa from the product mixture may be further reacted with HF in the liquid phase under fluorination conditions in the presence of a fluorination catalyst to produce a mixture comprising CF3CH2CHF2and CF3CF2CH3. As indicated above, the present invention also provides a process that involves producing a product mixture comprising HFC-245fa, HFC-1234ze, and HCFC-1233zd using at least one starting material selected from the group consisting of halopropenes of the formula CX3CH═CH2and halopropenes of the formula CX2═CHCH2X. Of note are embodiments of the process wherein HFC-1234ze is recovered. Additional HFC-1234ze may be obtained by dehydrofluorination of HFC-245fa from the product mixture. Also of note are embodiments of this process wherein HCFC-1233zd from the product mixture is fluorinated to produce at least one of HFC-1234ze and HFC-245fa. Also of note are processes wherein HFC-245fa is recovered. Also of note are processes wherein the product mixture further comprises HFC-1234yf and wherein HFC-1234yf from the product mixture is recovered. The product mixture may further comprise HFC-245cb. A mixture of HFC-245cb and HFC-1234ze may be recovered and further reacted with HF in the liquid phase under fluorination conditions in the presence of a fluorination catalyst to produce a mixture comprising HFC-245fa and HFC-245cb. Alternatively, a mixture of HFC-245cb and HFC-1234ze may be recovered and further reacted under dehydrofluorination conditions in the presence of a dehydrofluorination catalyst to produce a mixture comprising HFC-1234ze and HFC-1234yf. HFC-245cb, HFC-1234yf and/or HCFC-1233xf may also be present in the product mixture. HFC-245fa, HFC-1234ze and HCFC-1233zd from the product mixture together with HFC-245cb (if present), HFC-1234yf (if present) and HCFC-1233xf (if present) may be further reacted with HF in the liquid phase under fluorination conditions in the presence of a fluorination catalyst to produce a mixture comprising HFC-245fa and HFC-245cb. The HFC-245fa and HFC-245cb from the mixture may be dehydrofluorinated (individually or as a mixture) to produce both HFC-1234ze and HFC-1234yf which may be recovered. See for example, U. S. Patent Application Publication US200610106263(A1). HCFC-1233xf may also be present in the product mixture; and HCFC-1233xf, HCFC-1233zd, and HFC-245fa from the product mixture may be further reacted with HF in the liquid phase under fluorination conditions in the presence of a fluorination catalyst to produce a mixture comprising CF3CH2CHF2and CF3CF2CH3. Suitable halopropane starting materials of the formula CX3CH2CH2X include CF3CH2CH2F (HFC-254fb), CF3CH2CH2Cl (HCFC-253fb), CClF2CH2CH2Cl (HCFC-252fc), CCl2FCH2CH2Cl(HCFC-251fb) and CCl3CH2CH2Cl (HCC-250fb). Preferred is HCC-250fb. Suitable halopropene starting materials of the formula CX3CH═CH2include CF3CH═CH2(HFC-1243zf), CClF2CH═CH2(HCFC-1242zf), CCl2FCH═CH2(HCFC-1241zf), and CCl3CH═CH2(HCC-1240zf). Preferred is HFC-1243zf. Suitable halopropene starting materials of the formula CX2═CHCH2X include CCl2═CHCH2Cl (HCC-1240za). HCC-250fb is a readily available starting material that can be prepared by the reaction of ethylene with carbon tetrachloride as disclosed in International Patent Application No. WO 97/05089, which is incorporated herein by reference. HCC-250fb may be converted to HFC-1243zf by reaction with HF in vapor phase as disclosed in U.S. Pat. No. 6,329,559, which is incorporated herein by reference. HCC-1240za may be prepared by reaction of 1,1,1,3-tetrachloropropane with ferric chloride as disclosed by Fujimori, et. al. in Japanese Kokai 49066613. The reaction may be carried out in the liquid or vapor phase. For liquid phase embodiments of the invention, the reaction of starting materials with HF and Cl2may be conducted in a liquid-phase reactor operating in batch, semi-batch, semi-continuous, or continuous modes. In the batch mode, starting materials, Cl2, and HF are combined in an autoclave or other suitable reaction vessel and heated to the desired temperature. Preferably, this reaction is carried out in semi-batch mode by feeding Cl2to a liquid-phase reactor containing HF and starting materials or by feeding starting materials and Cl2to a liquid-phase reactor containing HF, or by feeding Cl2to a mixture containing HF and reaction products formed by initially heating starting materials and HF. Alternatively, HF and Cl2may be fed to a liquid-phase reactor containing a mixture of starting materials and reaction products formed by reacting HF, Cl2, and starting materials. In another embodiment of the liquid-phase process, HF, Cl2, and starting materials may be fed concurrently in the desired stoichiometric ratio to the reactor containing a mixture of HF and reaction products formed by reacting HF, Cl2, and starting materials. Suitable temperatures for the reaction of HF and Cl2with starting materials in the liquid-phase reactor are from about 80° C. to about 180° C., preferably from about 100° C. to about 150° C. Higher temperatures typically result in greater conversion of the starting materials. A suitable molar ratio of HF to total amount of starting materials fed to the liquid-phase reactor is at least stoichiometric and is typically from about 5:1 to about 100:1. Of note are embodiments wherein the molar ratio of HF to starting material is from about 8:1 to about 50:1. A suitable molar ratio of Cl2to total amount of starting materials fed to the liquid-phase reactor is from about 1:1 to about 2:1. The reactor pressure in the liquid-phase process is not critical and in batch reactions is usually the autogenous pressure of the system at the reaction temperature. The pressure of the system increases as hydrogen chloride is formed by replacement of hydrogen substituents by chlorine, and by replacement of chlorine substituents by fluorine in the starting materials and intermediate reaction products. In a continuous process it is possible to set the pressure of the reactor in such a way that the lower boiling products of the reaction, such as HCl, CF3CF═CH2, E/Z-CF3CH═CHF, and CF3CF2CH3, are vented from the reactor, optionally through a packed column or condenser. In this manner, higher boiling intermediates remain in the reactor and the volatile products are removed. Typical reactor pressures are from about 20 psig (239 kPa) to about 1,000 psig (6,994 kPa). In embodiments of the invention in which the reaction is conducted using a liquid-phase process, catalysts which may be used include carbon, AlF3, BF3, FeCl3-aFa(where a=0 to 3), FeX3supported on carbon, SbCl3-aFa, AsF3, MCl5-bFb(where b=0 to 5 and M=Sb, Nb, Ta, or Mo), and M′Cl4-cFc(where c=0 to 4, and M′=Sn, Ti, Zr, or Hf). Preferred catalysts for the liquid phase process are MCl5-bFb(where b=0 to 5 and M=Sb, Nb, or Ta). Preferably, the reaction of HF and Cl2with starting materials is carried out in the vapor phase. Typically a heated reactor is used. A number of reactor configurations are possible including horizontal or vertical orientation of the reactor as well as the sequence of reaction of the starting materials with HF and Cl2. In one embodiment of the invention, the starting materials may be initially vaporized and fed to the reactor as gases. In another embodiment of the invention, starting materials may be contacted with HF, optionally in the presence of Cl2, in a pre-reactor prior to reaction in the vapor-phase reactor. The pre-reactor may be empty, but is preferably filled with a suitable packing such as Monel™ or Hastelloy™ nickel alloy turnings or wool, or other material inert to HCl and HF which allows efficient mixing of starting materials and HF vapor. Suitable temperatures for the pre-reactor for this embodiment of the invention are from about 80° C. to about 250° C., preferably from about 100° C. to about 200° C. Temperatures greater than about 100° C. result in some conversion of the starting materials to compounds having a higher degree of fluorination. Higher temperatures result in greater conversion of the starting materials entering the reactor and a greater degree of fluorination in the converted compounds. Under these conditions, for example, a mixture of HF, Cl2, and HCC-250fb is converted to a mixture containing predominantly HFC-1243zf and HCFC-243db (CF3CHClCH2Cl) and a mixture of HF, Cl2, and HFC-1243zf is converted to a mixture containing predominantly HCFC-243db and HCFC-244db (CF3CHClCH2F). The degree of fluorination reflects the number of fluorine substituents that replace chlorine substituents in the starting materials and their chlorinated products. For example, HCFC-253fb represents a higher degree of fluorination than HCC-250fb and HFC-1243zf represents a higher degree of fluorination than HCC-1240zf. The molar ratio of HF to the total amount of starting material(s) in the pre-reactor is typically from about the stoichiometric ratio of HF to the total amount of starting material to about 50:1. Preferably, the molar ratio of HF to the total amount of starting material in the pre-reactor is from about twice the stoichiometric ratio of HF to the total amount of starting material to about 30:1. In one embodiment of the invention, the preferred molar ratio of HF to the total amount of starting materials is present in the pre-reactor, and no additional amount of HF is added to the vapor-phase reaction zone. In another embodiment of the invention, the starting materials may be contacted with Cl2in a pre-reactor, optionally in the presence of HF, prior to reaction in the vapor-phase reactor. Suitable temperatures for the pre-reactor for this embodiment of the invention are from about 80° C. to about 250° C., preferably from about 100° C. to about 200° C. Under these conditions, at least a portion of CX3CH2CH2X is converted to CX3CHClCH2X, at least a portion of CX3CH═CH2is converted to CX3CHClCH2Cl, and at least a portion of CX2═CHCH2X is converted to CX2ClCHClCH2X. Higher temperatures typically result in a higher degree of halogenation of the starting material. The degree of halogenation reflects the total number of halogen substituents (chlorine plus fluorine) in a halopropane and/or halopropene product. For example, HFC-245cb has a higher degree of halogenation (i.e., 5) than does HCC-250fb (i.e., 4); and HFC-1234yf has a higher degree of halogenation (i.e., 4) than does HFC-1243zf (i.e., 3). The preferred degree of halogenation in the halopropane products in the process of this invention is five. The preferred degree of halogenation of halopropene products in the process of this invention is four. The molar ratio of Cl2to the total amount of the starting materials is typically from about 0.5:1 to about 2:1. Preferably the molar ratio of Cl2to the total amount of the starting materials is from about 1.1:1 to about 1:1. In a preferred embodiment of the invention, the starting materials are vaporized, optionally in the presence of HF, and fed to a pre-reactor or to a vapor-phase reactor along with HF and Cl2. Suitable temperatures for the vapor-phase reaction of this invention are from about 120° C. to about 500° C. Temperatures of from about 250° C. to about 350° C. favor the formation of HFC-1234yf and HFC-245cb. Temperatures of from about 350° C. to about 450° C. favor the formation of HFC-1234ze, HFC-245fa, and HCFC-1233zd. At temperatures of from about 250° C. to about 450° C., some HCFC-1233xf is also produced. Higher temperatures result in greater conversion of starting materials and higher degrees of fluorination and halogenation in the converted compounds. Suitable reactor pressures for the vapor-phase reactor may be from about 1 to about 30 atmospheres. A pressure of about 15 to about 25 atmospheres may be advantageously employed to facilitate separation of HCl from other reaction products, and the suitable reaction time may vary from about 1 to about 120 seconds, preferably from about 5 to about 60 seconds. The molar ratio of HF to the total amount of starting material(s) for the vapor-phase reaction is typically from about the stoichiometric ratio of HF to the total amount of starting material to about 50:1 and preferably from about 10:1 to about 30:1. Preferably a catalyst is used in the reaction zone for the vapor-phase reaction of HF and Cl2with starting materials. Chlorofluorination catalysts which may be used in the vapor phase reaction of the invention include carbon; graphite; alumina; fluorided alumina; aluminum fluoride; alumina supported on carbon; aluminum fluoride supported on carbon; fluorided alumina supported on carbon; magnesium fluoride supported on aluminum fluoride; metals (including elemental metals, metal oxides, metal halides, and/or other metal salts); metals supported on aluminum fluoride; metals supported on fluorided alumina; metals supported on alumina; and metals supported on carbon; mixtures of metals. Suitable metals for use as catalysts (optionally supported on alumina, aluminum fluoride, fluorided alumina, or carbon) include chromium, iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, platinum, manganese, rhenium, scandium, yttrium, lanthanum, titanium, zirconium, and hafnium, copper, silver, gold, zinc, and/or metals having an atomic number of 58 through 71 (i.e., the lanthanide metals). Preferably when used on a support, the total metal content of the catalyst will be from about 0.1 to about 20 percent by weight based on the total weight of the catalyst; typically from about 0.1 to about 10 percent by weight based on the total weight of the catalyst. Suitable chlorofluorination catalysts for the vapor-phase reactions in this invention include chromium-containing catalysts including chromium(III) oxide (Cr2O3); Cr2O3with other metals such as magnesium halides or zinc halides supported on Cr2O3; chromium(III) halides supported on carbon; mixtures of chromium and magnesium (including elemental metals, metal oxides, metal halides, and/or other metal salts) optionally supported on graphite; and mixtures of chromium and other metals (including elemental metals, metal oxides, metal halides, and/or other metal salts) optionally supported on graphite, alumina, or aluminum halides such as aluminum fluoride. Chromium-containing catalysts are well known in the art. They may be prepared by either precipitation methods or impregnation methods as generally described by Satterfield on pages 87-112 in Heterogeneous Catalysis in Industrial Practice, 2ndedition (McGraw-Hill, New York, 1991). Of note are chlorofluorination catalysts that comprise at least one chromium-containing component selected from the group consisting of crystalline alpha-chromium oxide where from about 0.05 atom % to about 6 atom % of the chromium atoms in the alpha-chromium oxide lattice are replaced by trivalent cobalt atoms, and crystalline alpha-chromium oxide where from about 0.05 atom % to about 6 atom % of the chromium atoms in the alpha-chromium oxide lattice are replaced by trivalent cobalt atoms which has been treated with a fluorinating agent. These catalysts, including their preparation, have been disclosed in U. S. Patent Application Publication US2005/0228202 which is incorporated herein by reference in its entirety. Optionally, the metal-containing catalysts described above can be pretreated with HF. This pretreatment can be accomplished, for example, by placing the metal-containing catalyst in a suitable container, and thereafter, passing HF over the metal-containing catalyst. In one embodiment of this invention, such container can be the reactor used to perform the chlorofluorination reaction in this invention. Typically, the pretreatment time is from about 15 to about 300 minutes, and the pretreatment temperature is from about 200° C. to about 450° C. In one embodiment of this invention, the product mixture comprises HFC-245cb, HFC-245fa, HFC-1234yf, HFC-1234ze, HCFC-1233zd and HCFC-1233xf. Halopropane by-products that may be formed in the chlorofluorination reactions of this invention having higher degrees of halogenation and/or fluorination than pentafluoropropanes include CF3CCl2CF3(CFC-216aa), CF3CClFCClF2(CFC-216ba), CF3CClFCF3(CFC-217ba), CF3CF2CClF2(CFC-217ca), CF3CHFCF3(HFC-227ea), CF3CF2CHF2(HFC-227ca), CF3CClFCHF2(HCFC-226ba), CF3CF2CHClF (HCFC-226ca), CF3CHClCF3(HCFC-226da), CF3CCl2CHF2(HCFC-225aa), CF3CClFCHClF (HCFC-225ba), CF3CF2CHCl2(HCFC-225ca), CF3CCl2CClF2(CFC-215aa), CF3CClFCCl2F (CFC-215bb), CF3CCl2CCl2F (HCFC-214ab), CF3CCl2CHClF (HCFC-224aa), and CF3CClFCHCl2(HCFC-224ba). Halopropene by-products that may be formed in the chlorofluorination reactions of this invention having a higher degree of halogenation than tetrafluoropropenes include CF3CCl═CHCl (HCFC-1223xd). In cases where the product mixture produced by the processes of this invention comprises (i) product compounds HFC-245cb, HFC-245fa, HFC-1234yf, HFC-1234ze, HCFC-1233zd and HCFC-1233xf, (ii) HF, HCl, and Cl2, (iii) higher boiling by-products such as CF3CHClCH2Cl, CF3CHClCH2F and (iv) chlorinated by-products such as C3HCl3F4, C3HCl2F5, C3HClF6, C3Cl3F5, and C3Cl2F6, the separation steps (a) through (e) may be employed to recover the product compounds from such a product mixture. In separation step (a), the product mixture may be delivered to a distillation column to separate HCl and Cl2from the product mixture. In separation step (b), the product mixture from separation step (a) may be delivered to one or more distillation columns to separate the azeotropic composition of HFC-1234yf and HF from the rest of the product mixture. The recovered azeotropic composition of HFC-1234yf and HF may be further separated into individual components by using procedures similar to those described in U. S. Patent Application Publication US2006/0106263(A1). In separation step (c), the product mixture from separation step (b) may be delivered to one or more distillation columns in which HF, HFC-245cb, HFC-1234ze, HCFC-1233xf, HCFC-1233zd, and HFC-245fa are recovered from the top of the distillation column, and the higher boiling by-products such as CF3CHClCH2Cl, CF3CHClCH2F and the chlorinated by-products such as C3HCl3F4, C3HCl2F5, C3HClF6, C3Cl3F5, and C3Cl2F6are removed from the bottom of the distillation column. The higher boiling by-products such as CF3CHClCH2Cl and CF3CHClCH2F may be further separated from the chlorinated by-products, e.g. by distillation, and may be recycled back to the vapor-phase chlorofluorination reactor. In separation step (d), the product mixture comprising HF, HFC-245cb, HFC-1234ze, HCFC-1233xf, HCFC-1233zd and HFC-245fa, which is recovered from the top of the distillation column in separation step (c), may be delivered to one or more distillation columns to recover the azeotropic composition of HFC-245cb/HF and the azeotropic composition of HFC-1234ze/HF from the top of the distillation column. The recovered HFC-245cb/HF and HFC-1234ze/HF azeotropic compositions may then be further separated into individual components by using procedures similar to those described in U.S. Patent Application Publication US2006/0106263(A1). In separation step (e), the product mixture comprising HCFC-1233xf, HCFC-1233zd and HFC-245fa and any HF recovered from the bottom of the distillation column in separation step (d) may be delivered to a distillation column to separate the HCFC-1233xf, HCFC-1233zd and HFC-245fa. The HCFC-1233xf can be fluorinated to produce at least one of HFC-245cb and HFC-1234yf. The HCFC-1233zd can be fluorinated to produce at least one of HFC-245fa and HFC-1234ze. As indicated above, in certain embodiments of this invention, the mixture of HF, HFC-245cb and HFC-1234ze, made according to the process of the invention is contacted with additional HF in a liquid-phase fluorination reactor, optionally in the presence of a liquid-phase fluorination catalyst to give a mixture of HF, HFC-245cb and HFC-245fa. The mixture of HF, HFC-245cb, and HFC-245fa is then separated into the individual components by using procedures similar to those described in U.S. Patent Application Publication US200610106263(A1). Suitable fluorination catalysts for these embodiments may be selected from those described for the liquid-phase embodiment of the chlorofluorination reactor described herein. The mole ratio of HF to HFC-245cb and HFC-1234ze in these embodiments is typically from about 5:1 to about 100:1, and is preferably from about 10:1 to about 40:1 based on the amount of HFC-1234ze in the mixture. Suitable temperatures for these embodiments of the invention are within the range of from about 30° C. to about 180° C., preferably from about 50° C. to about 150° C. Suitable reactor pressures for these embodiments are usually the autogenous pressures at the reactor temperatures. The pressure may be in the range of from about 1 to about 30 atmospheres. As indicated above, in certain embodiments of this invention, a mixture of HF, HFC-245cb and HFC-1234ze, made according to the processes of this invention, may be delivered to a reaction zone containing a dehydrofluorination catalyst (optionally after removal of the HF). Conditions in the reaction zone are chosen to be suitable for conversion of HFC-245cb to HFC-1234yf. The products leaving the reactor, comprising HFC-1234ze and HFC-1234yf are separated by techniques known to the art. Catalysts suitable for these embodiments of the invention and suitable operating conditions are disclosed in U.S. Pat. No. 5,396,000 the teachings of which are herein incorporated by reference. Preferably, the dehydrofluorination catalyst comprises aluminum fluoride or fluorided alumina or trivalent chromium oxide. Reaction temperatures suitable for these embodiments are from about 150° C. to about 500° C. Contact times in the reaction zone for these embodiments are typically from about 1 second to about 500 seconds. As indicated above, in certain embodiments of this invention, a mixture of HCFC-1233xf, HCFC-1233zd, and HFC-245fa made according to the process of the invention, is reacted with HF in a liquid-phase fluorination reactor in the presence of a liquid-phase fluorination catalyst to give a mixture of HF, HFC-245cb and HFC-245fa. The conditions of the fluorination are similar to those described for the mixture of HFC-1234ze and HFC-245cb above. The mixture of HF, HFC-245cb, and HFC-245fa is then optionally delivered to a distillation column to separate the two pentafluoropropanes and azeotropic HF by using procedures similar to those described in U.S. Patent Application Publication US2006/0106263(A1). As noted above, HFC-245cb, made according to the processes of this invention, may be dehydrofluorinated to produce HFC-1234yf, and HFC-245fa, made according to the processes of this invention, may be dehydrofluorinated to produce HFC-1234ze. Typical dehydrofluorination reaction conditions and dehydrofluorination catalysts are disclosed in U.S. Pat. No. 5,396,000, which is herein incorporated by reference. Dehydrofluorination reaction temperatures suitable for this invention are from about 150° C. to about 500° C.; however, higher temperature are desirable for the dehydrofluorination of HFC-245cb. Suitable contact times for these dehydrofluorinations are from about 1 second to about 500 seconds. Preferably, the dehydrofluorination catalyst comprises at least one catalyst selected from the group consisting of aluminum fluoride, fluorided alumina, and trivalent chromium oxide. As indicated above, in certain embodiments of this invention, a mixture of HFC-245cb, HFC-1234yf, HFC-1234ze, HCFC-1233xf, HCFC-1233zd, and HFC-245fa that are present in the product mixtures made according to the processes of the invention, is reacted with HF in a liquid-phase fluorination reactor in the presence of a liquid-phase fluorination catalyst. The conditions of the fluorination are similar to those described for the mixture of HFC-1234ze and HFC-245cb above. The fluorination catalysts for the above liquid-phase embodiments of the invention may be selected from those described for the liquid-phase embodiment the chlorofluorination reactor described herein. The amount of HF required for the liquid-phase reaction is determined by the total amount of HFC-1234yf, HFC-1234ze, HCFC-1233xf, and HCFC-1233zd, present in the mixture. The mole ratio of HF to the sum of the moles of HFC-1234yf, HFC-1234ze, HCFC-1233xf, and E/Z-HCFC-1233zd is typically from about the stoichiometric amount (between 1:1 to 2:1) to about 100:1, and is preferably from about 8:1 to about 50:1. Suitable temperatures for these embodiments of the invention are typically within the range of from about 30° C. to about 180° C., preferably from about 50° C. to about 150° C. The resulting mixture of pentafluoropropanes (i.e, HFC-245cb and HFC-245fa) may be then be freed of HF and recovered as individual compounds by techniques known to the art. The reactor, distillation columns, and their associated feed lines, effluent lines, and associated units used in applying the process of this invention should be constructed of materials resistant to hydrogen fluoride and hydrogen chloride. Typical materials of construction, well-known to the fluorination art, include stainless steels, in particular of the austenitic type, the well-known high nickel alloys, such as Monel™ nickel-copper alloys, Hastelloy™ nickel-based alloys and, Inconel™ nickel-chromium alloys, and copper-clad steel. Without further elaboration, it is believed that one skilled in the art can, using the description herein, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and do not constrain the remainder of the disclosure in any way whatsoever. EXAMPLES Preparation of 98% Chromium/2% Cobalt Catalyst A solution of 784.30 g Cr(NO3)3[9(H2O)] (1.96 moles) and 11.64 g Co(NO3)2[6(H2O)] (0.040 mole) was prepared in 2000 mL of deionized water. The solution was treated dropwise with 950 mL of 7.4M aqueous ammonia until the pH reached about 8.5. The slurry was stirred overnight at room temperature and then evaporated to dryness in air at 110-120° C. The dried catalyst was then calcined in air at 400° C. for 24 hours prior to use. General Procedure for Product Analysis The following general procedure is illustrative of the method used for analyzing the products of fluorination reactions. Part of the total reactor effluent was sampled on-line for organic product analysis using a gas chromatograph equipped a mass selective detector (GC/MS). The gas chromatography utilized a 20 ft. (6.1 m) long×⅛ in. (0.32 cm) diameter tube containing Krytox® perfluorinated polyether on an inert carbon support. The helium flow was 30 mL/min (5.0×10−7m3/sec). Gas chromatographic conditions were 60° C. for an initial hold period of three minutes followed by temperature programming to 200° C. at a rate of 6° C./minute. LEGEND215aa is CClF2Cl2CF3216aa is CF3CCl2CF3216ba is CClF2CClFCF3217ba is CF3CClFCF3217ca is CClF2CF2CF3224aa is CF3CCl2CHClF224ba is CF3CClFCHCl2225aa is CHF2Cl2CF3225ba is CHClFCClFCF3226ba is CF3CClFCHF2226ca is CF3CF2CHClF226da is CF3CHClCF3227ca is CF3CF2CHF2233ab is CF3CCl2CH2Cl235da is CF3CHClCHF2236fa is CF3CH2CF3243db is CF3CHClCH2Cl244db is CF3CHClCH2F245cb is CF3CF2CH3245fa is CF3CH2CHF21223xd is E- and Z-CF3CCl═CHCl1233xf is CF3CCl═CH21233zd is E- and Z-CHCl═CHCF31234ze is E- and Z-CHF═CHCF31234yf is CH2═CFCF31243zf is CH2═CHCF3 Examples 1-6 Chlorofluorination of CF3CH═CH2 The 98% chromium/2% cobalt catalyst prepared above (21.4 g, 15 mL, −12 to +20 mesh, (1.68 to 0.84 mm)) was placed in a ⅝″ (1.58 cm) diameter Inconel™ nickel alloy reactor tube heated in a fluidized sand bath. The catalyst was pre-fluorinated by treatment with HF as follows. The catalyst was heated from 45° C. to 175° C. in a flow of nitrogen (50 cc/min) over the course of about 1.5 h. HF was then admitted to the reactor at a flow rate of 50 cc/min for 1.3 h at a temperature of 175° C. The reactor nitrogen flow was decreased to 20 cc/min and the HF flow increased to 80 cc/min; this flow was maintained for 0.3 h. The reactor temperature was then gradually increased to 400° C. over 1 h. After this period, the HF and nitrogen flow was stopped and the reactor brought to the desired operating temperature. A flow of HF vapor, CF3CH═CH2, and Cl2then started through the reactor. Part of the reactor effluent was analyzed by on line GC/MS. The results of the chlorofluorination of CF3CH═CH2over the 98/2 Cr/Co catalyst at various operating temperatures and indicated molar ratios of HF, CF3CH═CH2, and Cl2are shown in Table 1; analytical data is given in units of GC area %. The nominal catalyst bed volume was 15 cc; the contact time (CT) was 15 seconds. Examples 1 and 2 were carried out in the absence of the catalyst. TABLE 1Chlorofluorination of HFC-1243zf(Part A)Ex. No.HF/1243/Cl2RatioT, ° C.1243zf243db244db1234yf245cb1233xf110/1/41403.054.29.85.701.42a10/1/114031.346.211.82.801.53b10/1/13005.9005.922.230.74c10/1/4325000000510/1/13509.10011.311.325.2610/1/137512.80011.66.320.6(Part B)Ex. No.HF/1243/Cl2RatioT, ° C.1233zd1234ze245fa1223xd233ab226ba227ca110/1/41407.7——1.06.3002a10/1/11401.4——01.3003b10/1/13004.12.11.320.20004c10/1/43250000023.813.9510/1/135012.44.71.918.100.20610/1/137517.66.52.316.100.20a243db and 244db confirmed by1H and19F NMR.b245cb and 1233xf confirmed by1H and19F NMR.cAdditional major products were 215aa, 216aa, 216ba, 225aa, 225ba, 226ca, 226da | 33,956 |
RE49850 | DETAILED DESCRIPTION The present applicant has now identified a new class of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives suitable for use in the prevention and/or treatment of proliferative cell diseases and conditions including cancers, which possess desirable biological activity (eg the compounds may inhibit cell proliferation by inhibiting the activity of CDK4 and/or CDK6). In a first aspect, the present invention provides a compound of formula I shown below: wherein:z represents an optional bond such that the bond between N and the adjacent carbon atom can be a single or double bond;R1, R2, R3, R4, R5, R6, and R7are each independently selected from the group consisting of H, alkyl, alkyl-R10, aryl, aryl-R10, aralkyl, aralkyl-R11, halogen, NO2, CN, CF3, OH, O-alkyl, COR10, COOR10, O-aryl, O—R10, NH2, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), NH—R10, N—(R10)(R11),)N-(alkyl)(R10), N-(aryl)(R10), SH-alkyl, SH-aryl, S-(alkyl)2, S-(aryl)2, S-(alkyl)(aryl), SH—R10, S—(R10)(R11), S-(alkyl)(R10), S-(aryl)(R10), COOH, CONH2, CONH-alkyl, CONH-aryl, CON-(alkyl)(R10), CON(aryl)(R10), CONH—R10, CON—(R10)(R11), SO3H, SO2-alkyl, SO2-alkyl-R10, SO2-aryl, SO2-aryl-R10, SO2NH2, SO2NH—R10, SO2N—(R10)(R11), CF3, CO-alkyl, CO-alkyl-R10, CO-aryl, CO-aryl-R10and R12,wherein said alkyl, aryl and aralkyl groups may be optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH2, COOH, CONH2and CF3,and wherein when bond z is absent, R1is taken together with R8and is ═O or ═S;R8is together with R1═O or ═S when bond z is absent, or is not present when bond z is present;R9is H, alkyl, aryl or heterocyclic group when bond z is absent, or is not present when bond z is present; andR10, R11and R12are independently selected from water solubilising groups;or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the compounds of formula I may preferably comprise at least one water solubilising group R10, R11or R12. That is, in such embodiments, the compound is as defined above in paragraph [0018] with the proviso that said compound comprises at least one of said R10, R11and R12groups. The present applicant has found that notwithstanding the addition of such solubilising group(s), the compounds possess desirable biological activity (eg by inhibiting the activity of CDK4 and/or CDK6). The presence of at least one water solubilising group may enhance in vivo absorption and oral bioavailability. The compounds of formula I have been found to possess anti-proliferative activity and are therefore considered to be of use in the treatment of proliferative cell diseases and conditions such as cancer, leukaemia, lymphoma and other diseases and conditions associated with uncontrolled cell proliferation (or, in other words, requires control of the cell cycle) such as, for example, some cardiovascular diseases or conditions such as restenosis and cardiomyopathy, some auto-immune diseases such as glomerulonephritis and rheumatoid arthritis, dermatological conditions such as psoriasis, and fungal or parasitic disorders. As used herein, an anti-proliferative effect within the scope of the present invention may be demonstrated by the ability to inhibit cell proliferation in an in vitro whole cell assay. These assays, including methods for their performance, are described in more detail in the examples provided hereinafter. The compounds of formula I may inhibit any of the steps or stages in the cell cycle, for example, formation of the nuclear envelope, exit from the quiescent phase of the cell cycle (G0), G1 progression, chromosome decondensation, nuclear envelope breakdown, START, initiation of DNA replication, progression of DNA replication, termination of DNA replication, centrosome duplication, G2 progression, activation of mitotic or meiotic functions, chromosome condensation, centrosome separation, microtubule nucleation, spindle formation and function, interactions with microtubule motor proteins, chromatid separation and segregation, inactivation of mitotic functions, formation of contractile ring, and cytokinesis functions. In particular, the compounds of formula I may influence certain gene functions such as chromatin binding, formation of replication complexes, replication licensing, phosphorylation or other secondary modification activity, proteolytic degradation, microtubule binding, actin binding, septin binding, microtubule organising centre nucleation activity and binding to components of cell cycle signalling pathways. Thus, in a second aspect, the present invention provides the use of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof, for treating cancer or another proliferative cell disease or condition. In a third aspect, the present invention provides a method of treating cancer or another proliferative cell disease or condition in a subject, the method comprising administering to said subject a therapeutically effective amount of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and/or excipient. In a fourth aspect, the present invention provides the use of a compound as defined in the first aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for treating cancer or another proliferative cell disease or condition. In a fifth aspect, the present invention provides a pharmaceutical composition or medicament comprising a compound as defined in the first aspect and a pharmaceutically acceptable carrier, diluent and/or excipient. In a sixth aspect, the present invention provides a method for modulating protein kinase activity in a cell, comprising introducing to or contacting said cell with an effective amount of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof. In this specification, a number of terms are used which are well known to those skilled in the art. Nevertheless, for the purposes of clarity, a number of these terms are hereinafter defined. As used herein, the term “treating” includes prophylaxis as well as the alleviation of established symptoms of a condition. As such, the act of “treating” a disease or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the disease or condition developing in a subject afflicted with or predisposed to the disease or condition; (2) inhibiting the disease or condition (ie arresting, reducing or delaying the development of the disease or condition or a relapse thereof (in case of a maintenance treatment) or at least one clinical or subclinical symptom thereof and (3) relieving or attenuating the disease or condition (ie causing regression of the disease or condition or at least one of its clinical or subclinical symptoms). As used herein, the term “alkyl” includes both straight chain and branched alkyl groups having from 1 to 8 carbon atoms (eg methyl, ethyl propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc). As used herein, the term “aryl” refers to a substituted (mono- or poly-) or unsubstituted monoaromatic or polyaromatic group, wherein said polyaromatic group may be fused or unfused. The term therefore includes groups having from 6 to 10 carbon atoms (eg phenyl, naphthyl etc). It is also to be understood that the term “aryl” is synonymous with the term “aromatic”. As used herein, the term “aralkyl” is used as a conjunction of the terms alkyl and aryl as defined above. As used herein, the tern “alicyclic” refers to a cyclic aliphatic group. The term “aliphatic” takes its normal meaning in the art and includes non-aromatic groups such as alkanes, alkenes and alkynes and substituted derivatives thereof. The term “halogen” refers to fluoro, chloro, bromo and iodo. As used herein, the term “heterocyclic” refers to a saturated or unsaturated cyclic group comprising one or more heteroatoms in the ring. The term “derivative” as used herein, includes any chemical modification of an entity. Illustrative of such chemical modifications is the replacement of hydrogen by a halogen group, an alkyl group, an acyl group or an amino group. As used herein, the phrase “manufacture of a medicament” includes the use of one or more of the compounds of formula I directly as the medicament or in any stage of the manufacture of a medicament comprising one or more of the compounds of formula I. Some of the compounds of formula I may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are encompassed within the scope of the present invention. The isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods known to those skilled in the art. The term “pharmaceutically acceptable salt” as used herein, refers to salts that retain the desired biological activity of the compounds of formula I, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic and arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, Pa. 1995. In the case of compounds of formula I that are solid, it will be understood by those skilled in the art that the compounds (or pharmaceutically acceptable salts, solvates or prodrugs thereof) may exist in different crystalline or polymorphic forms, all of which are encompassed within the scope of the present invention. “Prodrug” means a compound that undergoes conversion to a compound of formula I within a biological system, usually by metabolic means (eg by hydrolysis, reduction or oxidation). For example, an ester prodrug of a compound of formula I containing a hydroxyl group may be convertible by hydrolysis in vivo to the compound of formula I. Suitable esters of the compounds of formula I containing a hydroxyl group may be, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates. As another example, an ester prodrug of a compound of formula I containing a carboxy group may be convertible by hydrolysis in vivo to the compound of formula I. Examples of ester prodrugs include those described by Leinweber F J, Drug Metab Rev 18:379-439 (1987). Similarly, an acyl prodrug of a compound of formula I containing an amino group may be convertible by hydrolysis in vivo to the compound of formula I. Examples of prodrugs for these and other functional groups, including amines, are provided in Prodrugs: challenges and rewards, Valentino J Stella (ed), Springer, 2007. The term “therapeutically effective amount” or “effective amount” is an amount sufficient to effect beneficial or desired clinical results. A therapeutically effective amount can be administered in one or more administrations. Typically, a therapeutically effective amount is sufficient for treating a disease or condition or otherwise to palliate, ameliorate, stabilise, reverse, slow or delay the progression of a disease or condition such as, for example, cancer or another proliferative cell disease or condition. By way of example only, a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may comprise between about 0.1 and about 250 mg/kg body weight per day, more preferably between about 0.1 and about 100 mg/kg body weight per day and, still more preferably between about 0.1 and about 25 mg/kg body weight per day. However, notwithstanding the above, it will be understood by those skilled in the art that the therapeutically effective amount may vary and depend upon a variety of factors including the activity of the particular compound (or salt, solvate or prodrug thereof), the metabolic stability and length of action of the particular compound (or salt, solvate or prodrug thereof), the age, body weight, sex, health, route and time of administration, rate of excretion of the particular compound (or salt, solvate or prodrug thereof), and the severity of, for example, the cancer or other proliferative cell disease or condition to be treated. The compounds of formula I, and pharmaceutically acceptable salts, solvates and prodrugs thereof, are capable of inhibiting protein kinases, especially CDKs and may show higher selectivity (to inhibit) CDK4 and/or CDK6 over other protein kinases. As mentioned above, CDK4 and CDK6 promote cancer cell proliferation. As such, the compounds of formula I, and pharmaceutically acceptable salts, solvates and prodrugs thereof, which are believed to inhibit CDK4 and/or CDK6, have utility in both in vitro and in vivo applications (eg in vitro cell-based assays) and as the basis of a therapeutic method of treating cancer or another proliferative cell disease or condition in a subject. The compounds of formula I bear a thiazole group attached to the pyrimidine ring through one of the ring carbon atoms (particularly, the carbon at position 4). The compounds of formula I may bear at least one water solubilising group (eg provided by R10, R11and/or R12). The term “water solubilising group” will be well understood by those skilled in the art as referring to any polar functional group which either ionises or is capable of forming hydrogen bonds with water molecules to increase the water solubility of the compound (ie relative to the water solubility of the corresponding compound lacking the water solubilising group). Examples of suitable water solubilising groups and methods and considerations for their introduction are described in, for example, Fundamentals of Medicinal Chemistry by Gareth Thomas (publisher: John Wiley & Sons). Preferably, where present, R10and R11are independently selected from water solubilising groups of the group consisting of:(i) mono-, di- and poly-hydroxylated alicyclic groups, di- or poly-hydroxylated aliphatic or aryl groups, N-, O- and/or S-containing heterocyclic groups substituted with one or more hydroxyl or amino groups, aliphatic and aryl groups comprising one or more carboxamide, sulfoxide, sulfone or sulfonamide groups, and halogenated alkylcarbonyl groups; andii) COOH, SO3H, OSO3H, PO3H2and OPO3H2. Preferably, where present, R12is selected from water solubilising groups of the group consisting of:(i) mono-, di- and poly-hydroxylated alicyclic groups, di- or poly-hydroxylated aliphatic or aryl groups; N-, O- and/or S-containing heterocyclic groups substituted with one or more hydroxyl or amino groups, aliphatic and aryl groups comprising one or more carboxamide, sulfoxide, sulfone or sulfonamide groups; and halogenated alkylcarbonyl groups;(ii) COOH, SO3H, OSO3H, PO3H2and OPO3H2;(iii) NHCO(CH2)m[NHCO(CH2)m′]p[NHCO(CH2)m″]qY and NHCO(CH2)tNH(CH2)tY wherein p and q are each independently selected from integers 0 or 1, and m, m′, m″, t and ′ are each independently selected from integers 1 to 10, and Y is selected from:(a) alicyclic, aryl and heterocyclic groups comprising one or more O—, S— or N— heteroatoms, which may further comprise an alkyl bridge (eg a —CH2— or —CH2CH2— bridge),(b) alicyclic groups comprising one or more of —O—, NH2, —NH—, ═N—, quaternary amine salt, and amidine, and(c) morpholine, piperazine or 1,4-diazepane groups, each of which may be optionally substituted by one or more substituents selected from SO2-alkyl, alkyl optionally substituted by one or more OH groups, CO-alkyl, aralkyl, COO-alkyl, and an ether group optionally substituted by one or more OH groups;(iv) (CH2)nNR13COR14, (CH2)n′NR13SO2R14and SO2R15, wherein R13is selected from H and alkyl, R14and R15are each independently selected from alkyl groups optionally comprising one or more heteroatoms and/or optionally substituted with one or more substituents independently selected from OH, NH2, halogen and NO2, and n and n′ are each independently selected from integers 0, 1, 2 and 3;(v) ether and polyether groups optionally substituted with one or more OH groups or one or more Y groups, wherein Y is as defined above at (iii);(vi) (CH2)rNH2, wherein r is selected from integers 0, 1, 2 and 3;(vii) (CH2)r′OH, wherein r′ is selected from integers 0, 1, 2 and 3;(viii) (CH2)n″NR16COR17, wherein R16is H or alkyl, n″ is selected from integers 0, 1, 2 and 3, and R17is an aryl group optionally substituted with one or more substituents selected from halogen, NO2, OH, alkoxy, NH2, COOH, CONH2and CF3; and(ix) SO2NR18R19, wherein R18and R19are each independently selected from H, alkyl and aryl, with the proviso that at least one of R18and R19is other than H, or R18and R19together form a cyclic group optionally comprising one or more heteroatoms selected from N, O and S, and wherein said alkyl, aryl or cyclic group is optionally substituted by one or more substituents selected from halogen, NO2, OH, alkoxy, NH2, COOH, CONH, and CF3. In some embodiments, the compound is of the formula II shown below: wherein R1, R2, R3, R4, R5, R6and R7are as defined above for formula I. In some embodiments, the compound is of the formula III shown below: wherein R2, R3, R4, R5, R6and R7are as defined above for formula I, R8is together with R1is ═O or ═S, and R9is H, alkyl (eg a C1-6alkyl or, preferably, a C1-3alkyl such as methyl, ethyl and cyclopentyl), aryl or heterocyclic group. In some embodiments, R1is H, alkyl (eg a C1-6alkyl or, preferably, a C1-3alkyl such as methyl, ethyl and C(CH3)2), aryl, NH-alkyl (eg a NH—C1-6alkyl such as NH(C5H9) (ie NH-cyclopentyl) or, preferably, a NH—C1-3alkyl such as NH—CH3), N(alkyl)2(eg a N(C1-6alkyl)2such as N(C5H9)2or a N(C1-3alkyl)2such as N(CH3)2), NH-aryl, N-(alkyl)(aryl), SH-alkyl (eg a SH—C1-6alkyl or, preferably, a SH—C1-3alkyl such as SHCH3and SHC(CH3)) or R12. Where R1is R12, preferably R12is a mono-, di- or poly-hydroxylated alicyclic group, or an N-, O- and/or S-containing heterocyclic group substituted with one or more hydroxyl or amino group. In some embodiments, R2is H, alkyl (eg a C1-6alkyl or, preferably, a C1-3alkyl such as methyl and ethyl), aryl, CN, CF3, NH2, NH-alkyl (eg a NH—C1-6alkyl such as NH(C5H9) or, preferably, a NH—C1-3alkyl such as NH—CH3), N-(alkyl)2(eg a N(C1-6alkyl)2such as N(C5H9)2or a N(C1-3alkyl)2such as N(CH3)2), N-(alkyl)(aryl) or R12. Where R2is R12, preferably R12is a mono-, di- or poly-hydroxylated alicyclic group, or an N-, O- and/or S-containing heterocyclic group substituted with one or more hydroxyl or amino group. In some embodiments, R3is H, alkyl (eg a C1-6alkyl or, preferably, a C1-3alkyl such as methyl or ethyl), CN, or halogen (preferably F). In some embodiments, R4is H, O-alkyl (preferably, a C1-6alkoxy or, more preferably, a C1-3alkoxy such as methoxy or ethoxy) or halogen (preferably F). In some embodiments, at least one of R5and R6, but preferably R5, is R12wherein R12is preferably an N-, O- and/or S-containing heterocyclic group substituted with one or more hydroxyl, amino or alkoxy (eg —COCH3) group. Preferably, the heteroatom(s) is/are N. In some embodiments, where at least one of R5and R6is R12, R12is preferably selected from the following: Optionally, the R12substituents shown in the preceding paragraph [0055] may further comprise an alkyl bridge (eg a —CH2— or —CH2CH— bridge) to the carbon atom at position 4/5 of the pyridine/phenyl ring. Where R5is R12, R6is preferably H. Vice versa, where R6is R12, R5is preferably H. In some embodiments, R7is H. In some embodiments, R5is R12and R2, R3, R4, R6and R7are each independently selected from H, alkyl (eg a C1-6alkyl or, preferably, a C1-3alkyl), aryl, alicyclic, heterocyclic, halogen, NO2, CN, CF3, OH, O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy such as methoxy or ethoxy), NH2, NH-alkyl (eg a NH—C1-6alkyl such as NH(C5H9) or, preferably, a NH—C1-3alkyl such as NH—CH3) and N-(alkyl)2(eg a N(C1-6alkyl)2such as N(C5H9)2or a N(C1-3alkyl)2such as N(CH3)2). In some embodiments, the compound is of formula II and R5is R12, R1is alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl such as methyl and ethyl), NH(alkyl) (eg a NH—C1-6alkyl or, preferably, a NH—C1-3alkyl), N(alkyl)2(eg a N(C1-6alkyl) such as N(C5H9)2or a N(C1-3alkyl)2such as N(CH3)2), NH(aryl), O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy), S-alkyl (eg a S—C1-6alkyl or a S—C1-3alkyl) and NH2, and R2, R3, R4, R6and R7are each independently selected from H, alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl), halogen, CN, CF3, O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy), NH2and NH-alkyl (eg a NH—C1-6alkyl or, preferably, a NH—C1-3alkyl). In some embodiments, the compound is of formula II and R5is R12, R1is alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl such as methyl and ethyl), NH(alkyl) (eg a NH—C1-6alkyl or, preferably, a NH—C1-3alkyl), N(alkyl)2(eg a N(C1-6alkyl) or, more preferably, a N(C1-3alkyl)2) NH(aryl), O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy), S-alkyl (eg a S—C1-6alkyl or a S—C1-3alkyl) and NH2, R3is selected from H, alkyl, halogen and CN, and R2, R4, R6and R7are each independently selected from H, alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl), halogen, CN, CF3, O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy), NH2and NH-alkyl (eg a NH—C1-6alkyl or, preferably, a NH—C1-3alkyl). In some embodiments, the compound is of formula III and R5is R12, and R2, R3, R4, R6and R7are each independently selected from H, alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl), halogen, CN, CF3, O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy), NH2and NH-alkyl (eg a NH—C1-6alkyl or, preferably, a NH—C1-3alkyl). In some embodiments, the compound is of formula III and R5is R12, R3is selected from H, alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl), halogen and CN, and R2, R4, R6and R7are each independently selected from H, alkyl (eg a C1-6alkyl such as cyclopentyl or a C1-3alkyl), halogen, CN, CF3, O-alkyl (eg a C1-6alkoxy or, more preferably, a C1-3alkoxy), NH2, and NH-alkyl (eg a NH—C1-6alkyl or, preferably, a NH—C1-3alkyl). In some preferred embodiments, the compounds of the present invention exhibit anti-proliferative activity in human cell lines, as measured by a standard cytotoxicity assay. Preferably, the compound exhibits an IC50value of less than 5 μM, even more preferably less than 1 μM as measured by the cell viability (MTT proliferation) assay described in Example 2 hereinafter. More preferably still, the compound exhibits an IC50value of less than 0.5 μM. In some preferred embodiments, the compounds of the present invention inhibit one or more protein kinases, as measured by any standard assay well known to those skilled in the art. Preferably, the compound exhibits an IC50value of less than 1 μM or less than 0.5 μM as measured by the kinase assay described in Example 2 hereinafter, more preferably still less than 0.1 μM. Particular examples of compounds according to the first aspect are shown in Table 1 below. TABLE 1Chemical structure of selected compounds of the present inventionNo.StructureNameMass1.1-(4-(6-((4-(2,4-dimethylthiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one409.52.4-(2,4-dimethylthiazol-5-yl)-N-(5-(piperazin-1- yl)pyridin-2-yl)pyrimidin-2-amine367.53.4-(2,4-dimethylthiazol-5-yl)-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine381.54.4-(2,4-dimethylthiazol-5-yl)-2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidine-5-carbonitrile392.55.4-(2,4-dimethylthiazol-5-yl)-2-((5-(4- methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidine- 5-carbonitrile406.56.2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)-4- (2,4-dimethylthiazol-5-yl)pyrimidine-5-carbonitrile434.57.4-(2-ethyl-4-methylthiazol-5-yl)-N-(5-(piperazin-1- yl)pyridin-2-yl)pyrimidin-2-amine381.58.4-(2-ethyl-4-methylthiazol-5-yl)-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine395.59.4-(2-ethyl-4-methylthiazol-5-yl)-N-(5-(4- ethylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine409.610.1-(4-(6-((4-(2-ethyl-4-methylthiazol-5-yl)pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one423.511.1-(4-(6-((5-chloro-4-(2-ethyl-4-methylthiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one458.012.4-(2-Ethyl-4-methylthiazol-5-yl)-N-(5- morpholinopyridin-2-yl)pyrimidin-2-amine382.513.4-(2-isopropyl-4-methylthiazol-5-yl)-N-(5- (piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine395.514.4-(2-isopropyl-4-methylthiazol-5-yl)-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine409.615.N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-4-(2- isopropyl-4-methylthiazol-5-yl)pyrimidin-2-amine423.616.1-(4-(6-((4-(2-isopropyl-4-methylthiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one437.617.4-(2-isopropyl-4-methylthiazol-5-yl)-N-(5- morpholinopyridin-2-yl)pyrimidin-2-amine396.518.N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-4- (2-isopropyl-4-methylthiazol-5-yl)pyrimidin-2-amine437.619.4-(2-methoxy-4-methylthiazol-5-yl)-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine397.520.4-(4-methyl-2-(methylthio)thiazol-5-yl)-N-(5-(4- piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine399.521.4-(4-methyl-2-(methylthio)thiazol-5-yl)-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine413.622.1-(4-(6-((4-(4-methyl-2-(methylthio)thiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one441.623.4-(2-(isopropylthio)-4-methylthiazol-5-yl)-N-(5- (piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine427.624.4-(2-(isopropylthio)-4-methylthiazol-5-yl)-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine441.625.1-(4-(6-((4-(2-(isopropylthio)-4-methylthiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one469.626.N,4-dimethyl-5-(2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)thiazol-2-amine382.527.4-(4-methyl-2-(methylamino)thiazol-5-yl)-2-((5- (piperazin-1-yl)pyridin-2-yl)amino)pyrimidine-5- carbonitrile407.528.5-(5-fluoro-2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine400.529.N,4-dimethyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine396.530.4-(4-methyl-2-(methylamino)thiazol-5-yl)-2-((5-(4- methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidine- 5-carbonitrile421.531.5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine414.532.5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine428.533.1-(4-(6-((4-(4-methyl-2-(methylamino)thiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one424.534.2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)-4- (4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine- 5-carbonitrile449.535.1-(4-(6-((5-fluoro-4-(4-methyl-2- (methylamino)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one442.536.N,4-dimethyl-5-(2-((5-morpholinopyridin-2- yl)amino)pyrimidin-4-yl)thiazol-2-amine383.537.4-(4-methyl-2-(methylamino)thiazol-5-yl)-2-((5- morpholinopyridin-2-yl)amino)pyrimidine-5- carbonitrile408.538.5-(5-fluoro-2-((5-morpholinopyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine401.539.5-(2-((5-(4-benzylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine472.640.2-((5-(4-benzylpiperazin-1-yl)pyridin-2-yl)amino)-4- (4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine- 5-carbonitrile497.641.5-(2-((4-(4-benzylpiperazin-1- yl)phenyl)amino)pyrimidin-4-yl)-N,4- dimethylthiazol-2-amine471.642.2-((4-(4-benzylpiperazin-1-yl)phenyl)amino)-4-(4- methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5- carbonitrile496.643.N,N,4-trimethyl-5-(2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)thiazol-2-amine396.544.5-(5-fluoro-2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2- amine414.545.N,N,4-trimethyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine410.546.5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2- amine428.547.5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2- yl)amino)-5-fluoropyrimidin-4-yl)-N,4- dimethylthiazol-2-amine442.648.1-(4-(6-((4-(2-(dimethylamino)-4-methylthiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one438.649.1-(4-(6-((4-(2-(dimethylamino)-4-methylthiazol-5- yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3- yl)piperazin-1-yl)ethan-1-one456.550.5-(5-fluoro-2-((5-morpholinopyridin-2- yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2- amine415.551.5-(5-fluoro-2-((5-(piperidin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine399.552.5-(5-fluoro-2-((5-(4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4- dimethylthiazol-2-amine478.653.5-(2-((5-(1,4-diazepan-1-yl)pyridin-2-yl)amino)-5- fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine414.554.5-(5-fluoro-2-(pyridin-2-ylamino)pyrimidin-4-yl)- N,4-dimethylthiazol-2-amine316.455.N-isopropyl-4-methyl-5-(2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine410.556.N-isopropyl-4-methyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine424.657.1-(4-(6-((4-(2-(isopropylamino)-4-methylthiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)ethan-1-one452.658.N-isopropyl-4-methyl-5-(2-((5-morpholinopyridin-2- yl)amino)pyrimidin-4-yl)thiazol-2-amine411.559.5-(2-((5-(1,4-diazepan-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N-isopropyl-4- methylthiazol-2-amine424.660.N-cyclopentyl-4-methyl-5-(2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine436.661.N-cyclopentyl-5-(5-fluoro-2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4- methylthiazol-2-amine454.662.N-cyclopentyl-5-(2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol- 2-amine490.663.N-cyclopentyl-4-methyl-5-(2-((5-(4-methylpiperazin- 1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine450.664.N-cyclopentyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4- (trifluoromethyl)thiazol-2-amine468.665.N-cyclopentyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4- (trifluoromethyl)thiazol-2-amine504.666.N-cyclopentyl-5-(2-((5-(4-ethylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4- methylthiazol-2-amine464.667.N-cyclopentyl-5-(2-((5-(4-ethylpiperazin-1- yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4- methylthiazol-2-amine482.668.1-(4-(6-((4-(2-(cyclopentylamino)-4- (trifluoromethyl)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one478.669.1-(4-(6-((4-(2-(cyclopentylamino)-4- (trifluoromethyl)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one496.670.1-(4-(6-((4-(2-(cyclopentylamino)-4- (trifluoromethyl)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one532.671.N-cyclopentyl-4-methyl-5-(2-((5-morpholinopyridin- 2-yl)amino)pyrimidin-4-yl)thiazol-2-amine437.672.N-cyclopentyl-5-(2-((5-morpholinopyridin-2- yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol- 2-amine455.673.N-cyclopentyl-5-(2-((5-morpholinopyridin-2- yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol- 2-amine491.574.5-(2-((5-(4-aminopiperidin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N-cyclopentyl-4- methylthiazol-2-amine450.675.N-cyclopentyl-4-methyl-5-(2-((5-(piperidin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine435.676.5-(2-((5-(1,4-diazepan-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N-cyclopentyl-4- methylthiazol-2-amine450.677.N-cyclopentyl-4-methyl-5-(2-(pyridin-2- ylamino)pyrimidin-4-yl)thiazol-2-amine514.778.N-cyclopentyl-4-methyl-5-(2-(pyridin-2- ylamino)pyrimidin-4-yl)thiazol-2-amine352.579.4-(6-((4-(2-(cyclopentylamino)-4- (trifluoromethyl)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-1-carbaldehyde518.680.N-cyclopentyl-5-(5-fluoro-2-((5-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine496.781.N-cyclopentyl-5-(5-fluoro-2-((5-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine468.682.N-cyclopentyl-5-(5-fluoro-2-((5-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine532.683.N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4- yl)-4-methylthiazol-2-amine478.784.N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4- yl)-4-methylthiazol-2-amine496.685.N-cyclopentyl-N,4-dimethyl-5-(2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine450.686.N-cyclopentyl-N,4-dimethyl-5-(2-((5-(4- methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin- 4-yl)thiazol-2-amine464.687.1-(4-(6-((4-(2-(cyclopentyl(methyl)amino)-4- methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazin-1-yl)ethan-1-one492.688.N,N-dicyclopentyl-4-methyl-5-(2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2- amine504.789.4-methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N-phenylthiazol-2-amine444.690.4-methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N-phenylthiazol-2-amine458.691.N,4-dimethyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N- phenylthiazol-2-amine472.692.4-methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one383.593.3,4-dimethyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)- one397.594.3-ethyl-4-methyl-5-(2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)- one411.595.5-(2-((5-(4-acetylpiperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-4-methylthiazol-2(3H)-one411.596.3-cyclopentyl-4-methyl-5-(2-((5-(piperazin-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)- one437.697.4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one369.499.2-(4-(6-((5-fluoro-4-(4-methyl-2- (methylamino)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-ol444.5100.8-(6-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol- 5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-1,8- diazaspiro[4.5]decan-2-one468.6101.2-(2-(4-(6-((5-fluoro-4-(4-methyl-2- (methylamino)thiazol-5-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethan-1- ol488.6102.1-(2-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol- 5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)-2-hydroxyethan-1-one429.5103.1-(2-((4-(2-(cyclopentylamino)-4-methylthiazol-5- yl)-5-fluoropyrimidin-2-yl)amino)-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)-2-hydroxyethan-1-one483.6104.2-(4-(6-((4-(2-(cyclopentylamino)-4-methylthiazol-5- yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3- yl)piperazin-1-yl)ethan-1-ol498.6105.8-(6-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol- 5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-1,8- diazaspiro[4.5]decan-2-one468.6106.5-(5-fluoro-2-((5-(4- ((methylsulfonyl)methyl)piperidin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine491.6107.5-(5-fluoro-2-((5-(4- ((methylsulfonyl)methyl)piperidin-1-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2- amine458.5108.1-(4-(6-((4-(2-(cyclopentylamino)-4-methylthiazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1- yl)-2-hydroxyethan-1-one494.6 The compounds (and pharmaceutically acceptable salts, solvates and prodrugs thereof) may be administered in combination with one or more additional agent(s) for the treatment of cancer or another proliferative disease or condition. For example, the compounds may be used in combination with other anti-cancer agents in order to inhibit more than one cancer signalling pathway simultaneously so as to make cancer cells more susceptible to anti-cancer therapies (eg treatments with other anti-cancer agents, chemotherapy, radiotherapy or a combination thereof). As such, the compounds of formula I may be used in combination with one or more of the following categories of anti-cancer agents:other anti-proliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (eg cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (eg gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, fludarabine and hydroxyurea); antitumour antibiotics (eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (eg vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids including taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (eg epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);cytostatic agents such as antioestrogens (eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (eg bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (eg goserelin, leuprorelin and buserelin), progestogens (eg megestrol acetate), aromatase inhibitors (eg as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;anti-invasion agents (eg c-Src kinase family inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Publication No WO 01/94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib) and bosutinib (SKI-606)), and metalloproteinase inhibitors including marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase;inhibitors of growth factor function (eg growth factor antibodies and growth factor receptor antibodies such as the anti-erbB2 antibody trastuzumab (Herceptintm™), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab (Erbitux, C225) and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp 11-29). Such inhibitors also include tyrosine kinase inhibitors such as inhibitors of the epidermal growth factor family (eg EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (eg Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors including sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, PIt3 kinase inhibitors, CSF-IR kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (eg AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK9 inhibitors;antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (eg the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within International Patent Publication No WO 00/47212), compounds such as those disclosed in International Patent Publication Nos WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds that work by other mechanisms (eg linomide, inhibitors of integrin a vb3 function and angiostatin);vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Publication Nos WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;an endothelin receptor antagonist such as zibotentan (ZD4054) or atrasentan;antisense therapies such as those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; andimmunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Where used in combination with other anti-cancer agents, a compound of the present invention and the other anti-cancer agent can be administered in the same pharmaceutical composition or in separate pharmaceutical compositions. If administered in separate pharmaceutical compositions, the compound and the other anti-cancer agent may be administered simultaneously or sequentially in any order (eg within seconds or minutes or even hours (eg 2 to 48 hours)). The present invention is typically applied to the treatment of cancer or another proliferative cell disease or condition in a human subject. However, the subject may also be selected from, for example, livestock animals (eg cows, horses, pigs, sheep and goats), companion animals (eg dogs and cats) and exotic animals (eg non-human primates, tigers, elephants etc). Cancers and other proliferative cell diseases and conditions that may be treated in accordance with the present invention include biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer; choriocarcinoma, colonic cancer, endometrial cancer, oesophageal cancer, gastric cancer, haematological neoplasms (including acute lymphocytic leukemia (ALL)), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML), acute myeloid leukaemia (AML), multiple myeloma, AIDS-associated leukemias and adult T-cell leukemia lymphoma, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, lymphomas (including Hodgkin's disease and lymphocytic lymphomas), neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells, and mesenchymal cells), pancreatic cancer, prostate cancer, colorectal cancer, sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basocellular cancer, and squamous cell cancer), testicular cancer (including germinal tumours such as seminoma, non-seminoma teratomas, and choriocarcinomas), stromal tumours, germ cell tumours, thyroid cancer (including thyroid adenocarcinoma and medullar carcinoma), and renal cancer (including adenocarcinoma and Wilms' tumour). In some embodiments, the compounds of the present invention are used to treat cancers characterised by over-expression of CDK4 and/or cyclin D including, for example, lung cancer (Wu et al. J Transl Med 9:38 (2011)), breast cancer (An et al., Am J Pathol 154(1):113-118 (1999)), cancers of the central nervous system (CNS) and colorectal cancer (Ikeda et al., Jap J Clin Med 54(4):1054-1059 (1996)). CDK4 and/or cyclin Dover-expression may be determined by, for example, assessing the amount of mRNA encoding CDK4 and/or cyclin D in a suitable sample using any of the techniques well known to those skilled in the art (eg quantitative amplification techniques such as qPCR). In some embodiments, the compounds of the present invention are used to treat cancers characterised by over-expression of CDK6 and/or cyclin D including, for example, T-cell acute lymphoblastic leukemia (ALL), colorectal cancer and medullablastoma (reviewed in Tadesse et al., Cell Cycle. 14(20):3220-30, 2015). CDK6 and/or cyclin Dover-expression may be determined by, for example, assessing the amount of mRNA encoding CDK6 and/or cyclin D in a suitable sample using any of the techniques well known to those skilled in the art (eg quantitative amplification techniques such as qPCR). The compounds of the present invention may be formulated into a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent and/or excipient. Examples of suitable carriers and diluents are well known to those skilled in the art, and are described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1995. Examples of suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the Handbook of Pharmaceutical Excipients, 2ndEdition, (1994), Edited by A Wade and P J Weller. Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water. The choice of carrier, diluent and/or excipient may be made with regard to the intended route of administration and standard pharmaceutical practice. A pharmaceutical composition comprising a compound of the present invention may further comprise any suitable binders, lubricants, suspending agents, coating agents and solubilising agents. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Preservatives, stabilising agents, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Anti-oxidants and suspending agents may be also used. A pharmaceutical composition comprising a compound of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration. For oral administration, particular use may be made of compressed tablets, pills, tablets, gellules, drops, and capsules. For other forms of administration, a pharmaceutical composition may comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions. A pharmaceutical composition comprising a compound of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders. A pharmaceutical composition may be formulated in unit dosage form (ie in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose). The compounds of the present invention may be provided as a pharmaceutically acceptable salt including, for example, suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al., J Pharm Sci 66:1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids (eg sulfuric acid, phosphoric acid or hydrohalic acids), with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (eg by halogen), such as acetic acid, with saturated or unsaturated dicarboxylic acids (eg oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic acid), with hydroxycarboxylic acids (eg ascorbic, glycolic, lactic, malic, tartaric or citric acid), with amino acids (eg aspartic or glutamic acid), with benzoic acid, or with organic sulfonic acids (eg (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted by, for example, halogen) such as methane- or p-toluene sulfonic acid). The compounds of the present invention may be provided in their various crystalline forms, polymorphic forms and (an)hydrous forms. In this regard, it is well known to those skilled in the art that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation from the solvents used in the synthetic preparation of such compounds. The present invention further provides a method of synthesising a compound according to the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof. With regard to the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare starting materials, it will be understood by those skilled in the art that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be readily selected. Moreover, it will be understood by those skilled in the art that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the examples hereinafter. Alternatively, necessary starting materials may be obtainable by analogous procedures to those illustrated which are within the ordinary skill of those skilled in the art. Further, it will be appreciated that during the synthesis of the compounds, in the processes described below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. Those skilled in the art will readily recognise when such protection is required, and how such protecting groups may be put in place, and later removed. Examples of protecting groups are described in, for example, Protective Groups in Organic Synthesis by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method well known to those skilled in the art as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxyl, it may be desirable to protect the group in some of the reactions mentioned herein. The compounds of the present invention may be prepared by, for example, the general synthetic methodologies described in International Patent Publication No WO 2013/156780, which is herein incorporated by reference. In a further of the present invention, a method of synthesising a compound of the present invention (or a pharmaceutically acceptable salt, solvate or prodrug thereof) is provided wherein the method comprises:a) reacting a compound of formula IV: whereinz represents an optional bond such that the bond between N and the adjacent carbon atom can be a single or double bond; andR1, R2, R3, R8and R9are as defined in the first aspect; with a compound of formula V: wherein R4, R5, R6and R7are as defined in the first aspect; and if necessaryb) removing any protecting groups present, and/or forming a pharmaceutically acceptable salt, solvate or prodrug thereof. The coupling reaction between the compound of formula IV and formula V may take place in the presence of a suitable solvent or solvent mixture. Those skilled in the art will be able to readily select a suitable solvent or solvent mixture for use in this reaction. Examples of suitable solvents include alcohols, acetonitrile, halogenated solvents, etc. In addition, those skilled in the art will be able to select appropriate reaction conditions to use in the coupling reaction between the compound of formula IV and formula V. However, typically, the reaction will be carried out in anhydrous conditions and in the presence of an inert atmosphere, such as argon or nitrogen. The reaction may also be carried out an elevated temperature, such as, for example, within the range of 80 to 180 C for a suitable time period of, for example, 20 minutes to 48 hours. Suitably, the reaction is carried out under microwave heating, for example, at 80 to 180 C for 20 minutes to 1.5 hour. The resultant compound can be isolated and purified using techniques well known to those skilled in the art. The method of synthesising a compound of the present invention (or a pharmaceutically acceptable salt, solvate or prodrug thereof) may further comprise:c) subjecting the compound of formula I to a salt exchange (particularly in situations where the compound is formed as a mixture of different salt forms). The salt exchange may comprise immobilising the compound on a suitable solid support or resin, and eluting the compound with an appropriate acid to yield salt of the compound of formula I (II or III). An example of a particularly suitable method for synthesising a compound of the present invention is shown as Scheme 1 below. wherein the general reaction conditions are: (a) DMF-DMA or Bredereck's reagent, reflux; (b) Select Fluor, MeOH; (c) Et3N, HgCl2, DCM; (d) TFA/DCM (1:1), reflux; (e) A, B, NaOH, 2-methoxyethanol, microwave and (f) Pd2dba3, xantphose, t-BuONa, dioxane, microwave. The invention is hereinafter described with reference to the following, non-limiting examples and accompanying figures. EXAMPLES Example 1 Synthesis General 1H and13C NMR spectra were recorded at 300 K on a Bruker AVANCE III 500 spectrometer (1H at 500 MHz and13C NMR at 125 MHz).1H and13C NMR spectra were referenced to1H signals of residual non-deuterated solvents (or tetramethylsilane) and13C signals of the deuterated solvents respectively. High resolution mass spectra were recorded on an AB SCIEX TripleTOF® 5600 mass spectrometer, and ionization of all samples was carried out using ESI. The purity of compounds was determined by analytical HPLC, and was greater than 95%. Analytic HPLC was carried out on a Shimadzu Prominence UFLC (UltraFast Liquid Chromatograph) system with a CBM-20A communications bus module, a DGU-20A5Rdegassing unit, an LC-20AD liquid chromatograph pump, an SIL-20AHTautosampler, an SPD-M20A photo diode array detector, a CTO-20A column oven and a Phenomenex Kinetex 5 u C18 100A 250 mm×4.60 mm column using Method A (gradient 5 to 95% MeOH containing 0.1% FA over 7 min, followed by 95% MeOH containing 0.1% FA over 13 min at a flow rate of 1 mL/min), Method B (gradient 5 to 95% MeCN containing 0.1% FA over 7 min followed by 95% MeCN containing 0.1% FA over 13 min, at a flow rate of 1 mL/min). 1-(4-(6-((4-(2,4-Dimethylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (1) To a solution of acetylpiperazine (5.00 g, 39.0 mmol) and 5-bromo-2-nitropyridine (5.00 g, 24.6 mmol) in DMSO (10 mL) was added triethylamine (10.2 mL, 73.9 mmol). The reaction mixture was heated at 120° C. for 16 h, cooled down to room temperature and triturated with EtOAc. The formed solid was filtered and washed with EtOAc (10 mL) and H2O (30 mL) to give the first portion of 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethan-1-one as a yellow solid. The filtrate and washing were combined and extracted with DCM (3×100mL). The organic extracts were combined, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give the second portion of 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethan-1-one.1H NMR (CDCl3) δ 2.16 (s, 3H), 3.47 (t, 2H, J 5.5), 3.52 (t, 2H, J 5.5), 3.71 (t, 2H, J 5.5), 3.83 (t, 2H, 5.5), 7.23 (dd, 1H, J 9.5 & 3.0), 8.14 (d, 1H, 3.0), 8.20 (d, 1H, J 9.0). HRMS (ESI) 251.1130 ([M+H]+); calcd. for C11H15N4O3+([M+H]+) 251.1139. To a suspension of 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethan-1-one (2.51 g, 10.0 mmol) in MeOH (200 mL) was added 10% Pd/C (107 mg, 0.100 mmol, 1 mol %). The reaction mixture was bubbled with H2at room temperature for 5 h and filtered through a pad of Celite®. The solids were washed with MeOH (50 mL). The filtrate and washing were combined and concentrated under reduced pressure and in vacuo to give 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethan-1-one as a brownish solid (2.20 g, 100%), which was used in the next step without purification. HRMS (ESI): m/z 221.1390 [M+H]+; calcd. for C11H17N4O+[M+H]+221.1397. To a solution of 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethan-1-one (2.21 g, 10.0 mmol), N′,N′-bis-Boc-S-methylisothiourea (3.50 g, 12.0 mmol) and triethylamine (4.90 mL, 35.1 mmol) in DCM (100 mL) on an ice bath was added HgCl2(5.45 g, 20.1 mmol). After stirring on an ice bath for 0.5 h, the reaction mixture was warmed to room temperature, stirred for 12 h and filtered through a pad of Celite®. The solids were washed with DCM (50 mL). The filtrate and washing were combined and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM:MeOH=95:5 ramping to 90:10) to give 1-acetyl-4-(6-(2,3-bis(tert-butoxyearbonyl)guanidino)pyridin-3-yl)piperazine as a light yellow solid (3.82 g, 82%).1H NMR (CDCl3) δ 1.53 (s, 18 H), 2.14 (s, 3H), 3.13 (t, 2H, J 5.5), 3.18 (t, 2H, J 5.5), 3.63 (t, 2H, J 5.5), 3.78 (t, 2H, J 5.5), 7.29 (dd, 1H, J 9.0 & 3.0), 7.87 (d, 1H, J 7.5), 7.99 (d, 1H, J 2.5), 10.90 (br s, 1H) 11.58 (br s, 1H). HRMS (ESI): m/z 463.2668 [M+H]+; calcd. for C22H35N6O5+[M+H]+463.2663. To a solution of 1-acetyl-4-(6-(2,3-bis(tert-butoxycarbonyl)guanidino)pyridin-3-yl)piperazine (724 mg, 1.56 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was heated at reflux for 16 h and concentrated under reduced pressure. The residue was redissolved MeOH (50 mL), and a suspension of excess Ambersep®, 900 resin (hydroxide form, pre-swelled with H2O for 30 min and MeOH for 30 min) in MeOH (50 mL) was added. The mixture was stirred at room temperature overnight and filtered, and the solid was washed with MeOH (50 mL). The filtrate and washing were combined and concentrated under reduced pressure to give 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine as a beige solid (410 mg, 100%), which was directly used in the next step without further purification. MS (ESI): m/z 263.2 [M−TFA+H]+. To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (1.08 g, 4.00 mmol) and (E)-3-(dimethylamino)-1-(2,4-dimethylthiazol-5-yl)prop-2-en-1-one (420 mg, 2.00 mmol) in 2-methoxy ethanol (6 mL) was added NaOH (160 mg, 4.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=92:8) and recrystallised with DCM and hexane to give compound 1 as a yellow solid (100 mg, 12%).1H NMR (CDCl3) δ 2.09 (s, 3H), 2.64 (s, 3H), 2.65 (s, 3H), 3.20 (m, 4H), 3.58 (t, 2H, J 5.0), 3.74 (t, 2H, J 5.0), 6.91 (d, 1H, J 5.5), 7.31 (dd, 1H, J 9.0 & 3.0), 7.98 (d, 1H, J 2.5), 8.14 (s, 1H), 8.25 (d, 1H, J 9.0), 8.42 (s, 1H, J 5.5).13C NMR (CDCl3) δ 18.3, 19.6, 21.5, 41.4, 46.3, 50.2, 50.5, 109.4, 113.2, 127.4, 131.4, 137.5, 142.5, 146.9, 152.6, 158.7, 159.0, 159.1, 167.1, 169.1. HRMS (ESI): m/z 410.1763 [M+H]+; calcd. for C20H24N7OS+[M+H]+410.1758 Anal. RP-HPLC Method A: tR8.22 min, purity>99%, Method B: tR2.81 min, purity>99%. 4-(2,4-Dimethylthiazol-5-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (2) To a suspension of 1 (71.0 mg, 0.17 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH)=90:10:1) to give 2 as a yellow solid (49 mg, 77%).1H NMR (DMSO-d6) δ 2.63 (s, 3H), 2.65 (s, 3H), 3.11 (t, 4H, J 5.5), 3.26 (t, 4H, J 4.5), 7.11 (d, 1H, J 5.0), 7.49 (dd, 1H, J 9.0 & 3.0), 8.05 (d, 1H, J 3.0), 8.10 (d, 1H, J 9.0), 8.53 (d, 1H, J 5.5), 9.70 (br, 1H). HRMS (ESI): m/z 368.1653 [M+H]+; calcd. for C18H22N7S+[M+H]+368.1652 Anal. RP-HPLC Method A: tR8.00 min, purity>98%, Method B: tR2.88 min, purity>96%. The following compounds were synthesised by an analogous route. 4-(2,4-dimethylthiazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (3) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2,4-dimethylthiazol-5-yl)prop-2-en-1-one (210 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=92:8) and recrystallised with DCM and hexane to give 2 as a yellow solid (119 mg, 31%). m.p. 183-184° C.1H NMR (CDCl3) δ 2.36 (s, 3H), 2.60 (t, 4H, J 5.0), 2.70 (s, 3H), 2.71 (s, 3H), 3.19 (t, 4H, J 5.0), 6.95 (d, 1H, J 5.0), 7.37 (dd, 1H, J 9.0 & 3.0), 8.05 (d, 1H, J 2.5), 8.23 (br, 1H), 8.27 (d, 1H, J 9.0), 8.48 (d, 1H, J 5.0). HRMS (ESI): m/z 382.1788 [M+H]+; calcd. for C19H24N7S+[M+H]+382.1808. Anal. RP-HPLC Method A: tR8.54 min, purity>99%, Method B: tR3.23 min, purity>99%. 4-(2,4-Dimethylthiazol-5-yl)-2-((5-(piperazin-1-yl) pyridin-2-yl) amino) pyrimidine-5-carbonitrile (4) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and (E)-3-(dimethylamino)-2-(2,4-dimethylthiazole-5-carbonyl)acrylonitrile (235 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) and recrystallised with DCM and hexane to give 4 as a yellow solid (90 mg, 23%). m.p. 110-113° C.1H NMR (DMSO-d6) δ 2.91 (s, 4H, thiazole-CH3& piperazine-NH), 3.11 (s, 3H), 3.27 (t, 4H, J 4.5), 3.48 (t, 4H, J 4.0), 7.84 (dd, 1H, J 9.0 & 3.0), 8.31 (d, 1H, J 9.0), 8.48 (d, 1H, J 2.0) , 9.33 (s, 1H), 11.13 (s, 1H). HRMS (ESI): m/z 393.1597[M+H]+; calcd. for C19H21N8S+[M+H]+393.1604. Anal. RP-HPLC Method A: tR9.18 min, purity>95%; Method B: tR7.68 min, purity>96%. 4-(2,4-Dimethylthiazol-5-yl)-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidine-5-carbonitrile (5) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-2-(2,4-dimethylthiazole-5-carbonyl)acrylonitrile (235 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) and recrystallised with MeOH to give 5 as a brown solid (114 mg, 28%). m.p. 112-114° C.1H NMR (CDCl3) (δ 2.37 (s, 3H), 2.60 (t, 4H, J 5.0), 2.63 (s, 3H), 2.76 (s, 3H), 3.21 (t, 4H, J 5.0), 7.33 (dd, 1H, J 9.0 & 3.0), 8.13 (s, 1H), 8.20 (d, 1H, J 9.0), 8.76 (s, 1H), 8.76 (s, 1H). HRMS (ESI): m/z 407.1772 [M+H]+; calcd. for C19H21N8S+[M+H]+407.1761. Anal. RP-HPLC Method A: tR9.58 min, purity 100%; Method B: tR8.18 min, purity 100%. 2-((5-(4-Acetylpiperazin-1-yl) pyridin-2-yl) amino)-4-(2, 4-dimethylthiazol-5-yl) pyrimidine-5-carbonitrile (6) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-3-(dimethylamino)-2-(2,4-dimethylthiazole-5-carbonyl)acrylonitrile (235 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) and recrystallised with DCM and hexane to give 6 as a yellow solid (150 mg, 34%). m.p. 99-101° C.1H NMR (DMSO-d6) (δ 1.79 (s, 3H), 2.25 (s, 3H), 2.45 (s, 3H), 2.85 (d, 2H, J 4.0), 2.92 (s, 2H), 3.33 (d, 4H, J 4.0), 7.22 (dd, 1H, J 9.0 & 3.0), 7.67 (d, 1H, J 9.0), 7.85 (d, 1H, J 2.5), 8.68 (s, 1H), 10.47 (s, 1H). HRMS (ESI): m/z 435.1700 [M+H]+; calcd. for C22H29N8S+[M+H]+435.1710. Anal. RP-HPLC Method A: tR10.92 min, purity>97%; Method B: tR8.69 min, purity>96%. 4-(2-Ethyl-4-methylthiazol-5-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (7) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-ethyl-4-methylthiazol-5-yl)prop-2-en-1-one (224 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=91:9) and recrystallised with MeOH to give 7 as a yellow solid (35 mg, 9%).1H NMR (DMSO-d6) δ 1.32 (t, 3H, J 7.5), 2.65 (s, 3H), 2.98 (q, 2H, J 7.5), 3.26 (t, 4H, J 2.5), 3.34 (app s, 4H), 7.13 (d, 1H, J 5.0), 7.52 (dd, 1H, J 9.5 & 3.5), 8.07 (d, 1H, J 3.0),), 8.11 (d, 1H, J 9.0), 8.53 (d, 1H, J 5.5), 8.66 (s, 1H), 9.65 (s, 1H). HRMS (ESI): m/z 382.1810 [M+H]+; calcd. for C19H24N7S+[M+H]+382.1808. Anal. RP-HPLC Method A: tR12.55 min, purity>99%; Method B: tR3.71 min, purity>98%. 4-(2-Ethyl -4-methylthiazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (8) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-ethyl-4-methylthiazol-5-yl)prop-2-en-1-one (224 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=91:9) and recrystallised with MeOH to give 8 as a yellow solid (50 mg, 13%). 1H NMR (CDCl3) δ 1.41 (t, 3H, J 7.5), 2.34 (s, 3H), 2.58 (t, 4H, J 5.0), 2.69 (s, 3H), 3.00 (q, 2H, J 7.5), 3.18 (t, 4H, J 5.0), 6.93 (d, 1H, J 5.0), 7.35 (dd, 1H, J 9.0 & 3.0), 8.12 (d, 1H, J 3.0), ), 8.28 (d, 1H, J 9.0), 8.52 (d, 1H, J 5.5), 8.97 (s, 1 H). HRMS (ESI): m/z 396.1980 [M+H]+; calcd. for C19H24N7S+[M+H]+396.1965. Anal. RP-HPLC Method A: tR12.58 min, purity>99%; Method B: tR3.86 min, purity>96%. 4-(2-Ethyl-4-methylthiazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (9) To a mixture of crude 1-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (497 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-ethyl-4-methylthiazol-5-yl)prop-2-en-1-one (224 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) and recrystallised with MeOH to give 9 as a yellow solid (51 mg, 13%).1H NMR (CDCl3) δ 1.13 (t, 3H, J 7.5) 1.42 (t, 3H, J 7.5), 2.49 (q, 2H, J 7.0), 2.63 (t, 4H, J 5.0), 2.70 (s, 3H), 3.02 (q, 2H, J 8.03), 3.20 (t, 4H, J 5.0), 6.95 (d, 1H, J 5.0), 7.36 (dd, 1H, J 9.0 & 3.0), 8.07 (d, 1H, J 3.0), ), 8.28 (d, 1H, J 9.5), 8.40 (s, 1H), 8.49 (d, 1H, J 5.5). HRMS (ESI): m/z 410.2129 [M+H]+; calcd. for C21H28N7S+[M+H]+410.2121. Anal. RP-HPLC Method A: tR12.61 min, purity>99%; Method B: tR3.82 min, purity>94%. 1-(4-(6-((4-(2-Ethyl-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (10) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-ethyl-4-methylthiazol-5-yl)prop-2-en-1-one (224 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) and recrystallised with MeOH to give 10 as a yellow solid (175 mg, 41%).1H NMR (CDCl3) (δ 1.43 (t, 3H, J 7.5), 2.15 (s, 3H), 2.71 (d, 3H, J 2.5), 3.03 (q, 2H, J 8.0), 3.12 (t, 2H, J 5.0), 3.15 (t, 2H, J 5.0), 3.65 (s, 6H), 3.80 (t, 2H, J 5.0), 3.78 (t, 2H, J 5.0), 6.98 (d, J 5.5, 1H), 7.37 (dd, 1H, J 9.0 & 3.0), 8.03 (d, 1H, J 3.0), 8.05 (s, 1H), 8.32 (d, 1H, J 9.0), 8.48 (d, J 5.5, 1H). HRMS (ESI): m/z 424.1932 [M+H]+; calcd. for C21H26N7OS+[M+H]+424.1914. Method A: tR14.52 min, purity 100%; Method B: tR10.33 min, purity 100%. 1-(4-(6-((5-Chloro-4-(2-ethyl-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (11) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-2-chloro-3-(dimethylamino)-1-(2-ethyl-4-methylthiazol-5-yl)prop-2-en-1-one (259 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) and recrystallised with MeOH to give 11 as yellow solid (30 mg, 7%). 1H NMR (CDCl3) δ 1.44 (t, 3H, J 7.5), 2.15 (s, 3H), 2.54 (s, 3H), 3.05 (q, 2H, J 7.5), 3.10 (t, 2H, J 5.0), 3.13 (t, 2H, J 5.0), 3.64 (t, 2H, J 4.5), 3.79 (t, 2H, J 5.0), 7.32 (dd, 1H, J 9.0 & 3.0), 8.03 (d, 1H, J 2.5), 8.22 (d, 1H, J 9.0), 8.31 (d, J 5.5, 1H), 8.49 (s, 1H, NH). HRMS (ESI): m/z 458.1525 [M+H]+; calcd. for C21H25ClN7OS+[M+H]+458.1524. Anal. RP-HPLC Method A: tR11.26 min, purity>99%; Method B: tR8.76 min, purity>98%. 4-(2-Ethyl-4-methylthiazol-5-yl)-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine (12) To a mixture of crude 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (442 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-ethyl-4-methylthiazol-5-yl)prop-2-en-1-one (224 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) and recrystallised with MeOH to give 12 as a yellow solid (61 mg, 16%).1H NMR (CDCl3) δ 1.43 (t, 3H, J 7.5), 2.71 (d, 3H, J 2.5), 3.03 (q, 2H, J 7.5), 3.14 (t, 4H, J 5.0), 3.89 (t, 4H, J 5.0), 6.97 (d, J 5.0, 1H), 7.35 (dd, 1H, J 9.0 & 3.0), 7.99 (s, 1H), 8.02 (d, 1H, J 2.5), 8.30 (d, 1H, J 9.0), 8.47 (d, J 5.5, 1H). HRMS (ESI): m/z 383.1656 [M+H]+; calcd. for C19H23N6OS+[M+H]+383.1649. Anal. RP-HPLC Method A: tR14.71 min, purity>98%; Method B: tR10.48 min, purity>97%. 4-(2-lsopropyl-4-methylthiazol-5-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (13) To a suspension of N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-4-(2-isopropyl-4-methylthiazol-5-yl)pyrimidin-2-amine (150 mg, 0.34 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH)=90:10:1) to give 13 as a yellow solid (108 mg, 80%). RF(DCM:MeOH=9:1+10 drops of 32% aqueous ammonia) 0.10.1H NMR (CDCl3) δ 1.43 (d, 6H, J 7.0), 1.65 (br, 1H), 2.71 (s, 3H), 3.07 (t, 4H, 2.0), 3.11 (t, 4H, J 3.0), 3.30 (m, 1H), 6.96 (d, 1H, J 5.5), 7.36 (dd, 1H, J 9.0 & 3.0), 7.97 (s, 1H), 8.02 (d, 1H, J 3.0), 8.28 (d, 1H, J 9.0), 8.46 (d, 1H, J 5.5). HRMS (ESI): m/z 396.1961 [M+H]+; calcd. for C20H26N7S+[M+H]+396.1965. Anal. RP-HPLC Method A: tR9.08 min, purity>98%; Method B: tR7.44 min, purity 100%. 4-(2-Isopropyl-4-methylthi azol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (14) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-isopropyl-4-methylthiazol-5-yl)prop-2-en-1-one (238 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) and recrystallised with MeOH to give 14 as a yellow solid (200 mg, 48.9).1HNMR (DMSO-d6) δ 1.34 (d, 6H, J 7), 2.21 (s, 1H), 2.45 (t, 4H, J 5), 2.63 (s, 3H), 3.11 (t, 4H, J 4.5), 3.25 (m, 1H), 7.09 (d, 1H, J 5.5), 7.44 (dd, 1H, J 9.5 & 3.0), 8.01 (d, 1H, J 3.0), 8.07 (d, 1H, J 9.5), 8.52 (d, 1H, J 5.5), 9.66 (s, 1H). HRMS (ESI): m/z 410.121 [M+H]+; calcd. for C21H28N7S+[M+H]+410.2121. Anal. RP-HPLC Method A: tR9.14 min, purity>97%; Method B: tR7.53 min, purity 100%. N-(5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)-4-(2-isopropyl-4-methylthiazol-5-yl)pyrimidin-2-amine (15) To a mixture of crude 1-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (496.6 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-isopropyl-4-methylthiazol-5-yl)prop-2-en-1-one (238 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=93:7) to give 15 as a light yellow solid (178 mg, 42%).1H NMR (CDCl3)δ 1.14 (t, 3H, J 7.0), 1.43 (d, 6H, J 7.0), 2.50 (q, 3H, J 7.0), 2.64 (t, 4H, J 5.0), 2.71 (s, 3H), 3.20 (t, 4H, J 5.0), 3.30 (m, 1H), 6.96 (d, 1H, J 5.5), 7.36 (dd, 1H, J 9.5 & 3.0), 8.05 (d, 1H, J 2.5), 8.17 (s, 1H), 8.33 (d, 1H, J 9.5), 8.47 (d, 1H, J 5.5). HRMS (ESI): m/z 424.2298 [M+H]+; calcd. for C22H30N7S+[M+H]+424.2278. Anal. RP-HPLC Method A: tR9.18 min, purity>99%; Method B: tR7.15 min, purity>98%. 1-(4-(6-((4-(2-Isopropyl-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (16) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (L)-3-(dimethylamino)-1-(2-isopropyl-4-methylthiazol-5-yl)prop-2-en-1-one (238 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=93:7) to give 16 as a yellow solid (360 mg, 42%).1H NMR (DMSO-d6) δ 1.41 (d, 6H, J 7), 2.13 (s, 1H), 2.9 (s, 3H), 3.11 (app m, 4H), 3.28 (m, 1H), 3.62 (t, 2H, J 5.0), 3.78 (t, 2H, J 5.0), 6.96 (d, 1H, J 5.5), 7.35 (dd, 1H, J 9.5 & 3.0), 8.14 (d, 1H, J 2.5), 8.33 (d, 1H, J 9.5), 8.55 (d, 1H, J 5.0), 9.24 (s, 1H). HRMS (ESI): m/z 438.2088 [M+H]+; calcd. for C22H28N7OS+[M+H]+438.2071. Anal. RP-HPLC Method A: tR10.50 min, purity>98%; Method B: tR8.45 min, purity>98%. 4-(2-lsopropyl-4-methylthiazol-5-yl)-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine (17) To a mixture of crude 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (331.7 mg, 1.50 mmol) and (E)-3-(dimethylamino)-1-(2-isopropyl-4-methylthiazol-5-yl)prop-2-en-1-one (238 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (60.0 mg, 1.50 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=97:3) to give 17 as a white solid (238 mg, 60%).1H NMR (CDCl3) δ 1.43 (d, 6H, J 7.0), 2.71 (s, 3H), 3.14 (t, 4H, J 5.0), 3.32 (m, 1H), 3.89 (t, 4H, J 5.0), 6.97 (d, 1H, J 5.0), 7.35 (dd, 1H, J 9.0 & 3.0), 8.09 (d, 1H, J 3.0), 8.10 (s, 1H), 8.31 (d, 1H, J 9), 8.46 (d, 1H, J 5.0). HRMS (ESI): m/z 397.1797 [M+H]+; calcd. for C20H25N6OS+[M+H]+397.1805. Anal. RP-HPLC Method A: tR10.97 min, purity>99%; Method B: tR8.68 min, purity 100%. N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(2-isopropyl-4-methylthiazol-5-yl)pyrimidin-2-amine (18) To a mixture of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (341 mg, 1.20 mmol) and 4-(2-isopropyl-4-methylthiazol-5-yl)pyrimidin-2-amine (234.3 mg, 1.00 mmol) in dioxane (3 mL) were added Pd2dba3(45.8 mg, 0.05 mmol), xantphose (57.9 mg, 0.1 mmol) and t-BuONa (144.2 mg, 1.50 mmol). The reaction mixture was heated at 150° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=98:2) to give 18 as a white solid (210 mg, 48%).1H NMR (DMSO-d6) δ 0.97 (t, 3H, J 7.5), 1.36 (d, 6H, J 7.0), 2.28 (q, 2H, J 7.5), 2.36 (s br, 8H), 2.67 (s, 3H), 3.24-3.30 (m, 1H), 3.42 (s, 1H), 7.17 (d, 1H, J 5.5), 7.70 (dd, 1H, J 8.5 & 2.0), 8.20 (d, 1H, J 2.0), 8.22 (d, 1H, J 8.5), 8.58 (d, 2H, J 5.5), 9.92 (s, 1H). HRMS (ESI): m/z 438.2435 [M+H]+; calcd. for C23H32N7S+[M+H]+438.2434. Anal. RP-HPLC Method A: tR9.43 min, purity>97%; Method B: tR8.66 min, purity>98%. 4-(2-Methoxy-4-methylthi azol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (19) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (374 mg, 1.60 mmol) and (E)-3-(dimethylamino)-1-(2-methoxy-4-methylthiazol-5-yl)prop-2-en-1-one (183 mg, 0.80 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (64.0 mg, 1.60 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 19 as a yellow solid (52 mg, 13%). m.p. 190-192° C.1H NMR (CDCl3) 2.37 (s, 3H), 2.58 (s, 3H), 2.60 (t, 4H, J 5.0), 3.19 (t, 4H, J 5.0), 3.37 (s, 3H), 6.73 (d, 1H, J 5.0), 7.34 (dd, 1H, J 9.0 & 3.0), 7.97 (s, 1H), 8.01 (d, 1H, J 3.0), 8.21 (d, 1H, J 9.0), 9.40 (d, 1H, J 5.0). HRMS (ESI): m/z 398.1779 [M+H]+; calcd. for C19H24N7OS+[M+H]+398.1758. Anal. RP-HPLC Method A: tR8.36 min, purity>97%; Method B: tR3.59 min, purity>99%. 4-(4-Methyl-2-(methylthio)thiazol-5-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (20) To a suspension of 1-(4-(6-((4-(4-Methyl-2-(methylthio)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (100 mg, 0.23 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to DCM:MeOH: NH4OH)=90:10:1) to give 20 as a yellow solid (77 mg, 85%).1H NMR (DMSO-d6) δ 2.64 (s, 3H), 2.74 (s, 3H), 3.23 (t, 2H, J 5.5), 3.36 (app s, 4H), 7.12 (d, 1H, J 5.5), 7.54 (dd, 1H, J 9.0 & 3.0), 8.06 (d, 1H, J 3.0), 8.08 (d, 1H, J 9.0), 8.53 (s, 1H, J 5.5), 8.82 (s, 1H), 9.69 (s, 1H). HRMS (ESI): m/z 400.1390 [M+H]+; calcd. for C18H22N7S2+[M+H]+400.1373 Anal. RP-HPLC Method A: tR8.85 min, purity>98%, Method B: tR7.44 min, purity>99%. 4-(4-Methyl-2-(methylthio)thiazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (21) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(4-methyl-2-(methylthio)thiazol-5-yl)prop-2-en-1-one (242 mg, 1.00 mmol) in acetonitrile (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 21 as a yellow solid (200 mg, 48%). m.p. 206-207° C.1H NMR (CDCl3) 2.37 (s, 3H), 2.61 (t, 4H, J 5.0), 2.69 (s, 3H), 2.73 (s, 3H), 3.19 (t, 4H, J 5.0), 6.93 (d, 1H, J 5.0), 7.36 (dd, 1H, J 9.0 & 3.0), 8.05 (d, 1H, J 3.0), 8.20 (s, 1H), 8.24 (d, 1H, J 9.0), 8.46 (d, 1H, J 5.0). HRMS (ESI): m/z 414.1552 [M+H]+; calcd. for C19H24N7S2+[M+H]+414.1529. Anal. RP-HPLC Method A: tR9.36 min, purity>99%; Method B: tR7.83 min, purity>99%. 1-(4-(6-((4-(4-Methyl-2-(methylthio)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (22) To a mixture of crude to a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(4-methyl-2-(methylthio)thiazol-5-yl)prop-2-en-1-one (242 mg, 1.00 mmol) in acetonitrile (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) to give 22 as a yellow solid (141 mg, 32%).1H NMR (CDCl3) δ 2.15 (s, 3H), 2.69 (s, 3H), 2.73 (s, 3H), 3.13 (app m, 4H), 3.64 (t, 2H, J 5.0), 3.80 (t, 2H, J 5.0), 6.95 (d, 1H, J 5.5), 7.37 (dd, 1H, J 9.0 & 3.0), 8.08 (d, 1H, J 3.0), 8.29 (d, 1H, J 9.0), 8.49 (s, 1H, J 5.0), 8.53 (s, 1H). HRMS (ESI): m/z 442.1478 [M+H]+; calcd. for C20H24N7OS2+[M+H]+442.1486 Anal. RP-HPLC Method A: tR8.23 min, purity>97%, Method B: tR2.81 min, purity 100%. 4-(2-(Isopropylthio)-4-methylthiazol-5-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (23) To a suspension of 1-(4-(6-((4-(2-(isopropylthio)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (100 mg, 0.21 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH)=90:10:1) to give 23 as a yellow solid (82 mg, 90%).1H NMR (CDCl3) 1.47 (s, 3H), 1.48 (s, 3H), 2. 7 (s, 3H), 3.06 (t, 4H, J 4.5), 3.13 (t, 4H, J 5.0), 3.89 (m, 1H), 6.94 (d, 1H, J 5.0), 7.36 (dd, 1H, J 9.0 & 3.0), 8.03 (d, 1H, J 3.0), 8.04 (s, 1H), 8.25 (d, 1H, J 9.0) 8.46 (d, 1H, J 5.0). HRMS (ESI): m/z 428.1696 [1M+H]+; calcd. for C20H26N7S2+[M+H]+428.1686. Anal. RP-HPLC Method A: tR9.86 min, purity>93%; Method B: tR7.96 min, purity>96%. 4-(2-(Isopropylthio)-4-methylthiazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (24) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.0 mmol) and (E)-3-(dimethylamino)-1-(2-(isopropylthio)-4-methylthiazol-5-yl)prop-2-en-1-one (270 mg, 1.00 mmol) in acetonitrile (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 24 as a yellow solid (97 mg, 22%). m.p. 198-200° C.1H NMR (CDCl3) 1.46 (s, 3H), 1.47 (s, 3H), 2.37 (s, 3H), 2.61 (t, 4H, J 5.0), 2.69 (s, 3H), 3.19 (t, 4H, J 5.0), 3.88 (m, 1H), 6.93 (d, 1H, J 5.0), 7.36 (dd, 1H, J 9.0 & 3.0), 8.08 (s, 1H), 8.25 (d, 1H, J 9.0), 8.49 (d, 1H, J 5.0), 8.62 (s, 1H). HRMS (ESI): m/z 442.1865 [M+H]+; calcd. for C21H28N7S2+[M+H]+442.1842. Anal. RP-HPLC Method A: tR10.34 min, purity>96%; Method B: tR8.36 min, purity>98%. 1-(4-(6-(4-(2-(Isopropylthio)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (25) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(2-(isopropylthio)-4-methylthiazol-5-yl)prop-2-en-1-one (270 mg, 1.00 mmol) in acetonitrile (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 25 as a yellow solid (193 mg, 41%).1H NMR (CDCl3) δ 1.47 (s, 3H), 1.48 (s, 3H), 2.15 (s, 3H), 2.70 (s, 3H), 3.13 (app m, 4H), 3.65 (t, 2H, J 5.0), 3.80 (t, 2H, J 5.0), 3.89 (m, 1H), 6.95 (d, 1H, J 5.5), 7.37 (dd, 1H, J 9.0 & 3.0), 8.05 (d, 1H, J 3.0), 8.29 (app br d, 2H), 8.48 (d, 1H, J 5.0). HRMS (ESI): m/z 470.1787 [M+H]+; calcd. for C22H28N7OS2+[M+H]+470.1791 Anal. RP-HPLC Method A: tR8.23 min, purity>93%, Method B: tR2.81 min, purity>95%. N,4-Dimethyl-5-(2-((5-piperazin-1-yl)pyridine-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (26) To a solution of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (264 mg, 1.20 mmol) in 2-methoxyethanol (4 mL) were added (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (225 mg, 1.00 mmol) and NaOH (82.0 mg, 2.40 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, chloroform ramping to chloroform:MeOH=91:9 with consecutive addition of 32% aqueous ammonia, up to 10%). The solid was washed with DCM and MeOH, then filtered to give 26 as a pale yellow solid (94.0 mg, 24%).1H NMR (DMSO-d6) δ 2.47 (s, 3H), 2.83 (t, 4H, J 5.0), 2.87 (d, 3H, J 4.5), 3.01 (t, 4H, J 5.0), 6.91 (d, 1H, J 5.5), 7.38 (dd, 1H, J 9.0 & 3.0), 7.97 (d, 1H, J 3.0), 8.04-8.07 (m, 2H), 8.33 (d, 1H, J 4.0), 9.25 (s, 1H). MS (ESI): m/z 383.1674 [M+H]+; calcd. for C18H23N8S+[M+H]+383.1761. Anal. RP-HPLC Method A: tR8.37 min, purity>99%; Method B: tR7.10 min, purity>99%. 4-(4-Methyl-2-(methylamino)thiazol-5-yl)-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidine-5-carbonitrile (27) To a solution of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (264 mg, 1.20 mmol) in 2-methoxyethanol (4 mL) were added tert-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (350 mg, 1.00 mmol) and NaOH (82.0 mg, 2.40 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, chloroform ramping to chloroform:MeOH=91:9 with consecutive addition of 32% aqueous ammonia, up to 3 mL). The solid was washed with DCM and MeOH, and then filtered to give 27 as a pale yellow solid (131 mg, 32%).1H NMR (DMSO-d6) δ 2.41 (s, 3H), 2.88-2.89 (m, 7H), 3.07 (t, 4H, J 5.5), 7.41 (dd, 1H, J 9.0 & 3.0), 7.88 (d, 1H, J 9.0), 8.03 (d, 1H, J 3.0), 8.26 (q, 1H, J 4.5), 8.75 (s, 1H), 10.30 (s, 1H). MS (ESI): m/z 408.1660 [M+H]+; calcd. for C19H22N9S+[M+H]+408.1713. 5-(5-Fluoro-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (28) To a suspension of 1-(4-(6-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (200 mg, 0.45 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to EtOAc:MeOH:NH4OH)=90:10:1) to give 28 as a yellow solid (140 mg, 77%).1H NMR (DMSO-d6) δ 2.47 (d, 3H, J 2.0), 2.83 (t, 4H, J 4.5), 2.87 (d, 3H, J 4.5), 3.00 (t, 4H, J 5.0), 7.37 (dd, 1H, J 9.0 & 2.5), 7.94 (d, 1H, J 9.0), 7.96 (d, 1H, J 3.0), 8.11 (app d, 1H, J 4.5), 8.41 (d, 1H, J 3.0), 9.48 (s, 1H). HRMS (ESI): m/z 401.1678 [M+H]+; calcd. for C18H22FN8S+[M+H]+401.1667. Anal. RP-HPLC Method A: tR8.14 min, purity>95%; Method B: tR2.80 min, purity 100%. N,4-Dimethyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridine-2-yl)amino)pyridine-4-yl)thiazol-2-amine (29) To a solution of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (200 mg, 0.854 mmol) in 2-methoxyethanol (4.0 mL) was added (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one and NaOH (58.1 mg, 1.71 mmol). The reaction mixture was heated at 160° C. for 30 min, cooled down to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=91:9) and washed with DCM and MeOH to give 29 as a pale yellow solid (91.0 mg, 27%,).1H NMR (DMSO-d6) δ 2.22 (s, 3H), 2.45-2.47 (m, 7H), 2.87 (d, 3H, J 4.5), 3.11 (t, 4H, J 5.0), 6.91 (d, 1H, J 5.5), 7.40 (dd, 1H, J 9.0 & 3.0), 7.99 (d, 1H, J 3.0), 8.06-8.08 (m, 2H), 8.33 (d, 1H, J 5.5), 9.24 (s, 1H). MS (ESI): m/z 397.1958 [M+H]+; calcd. for C20H25N7S+[M+H]+397.1917.Anal. RP-HPLC Method A: tR8.27 min, purity>90%; Method B: tR7.09 min, purity>94%. 4-(4-Methyl-2-(methylamino)thiazol-5-yl)-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidine-5-carbonitrile (30) To a solution of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) in 2-methoxyethanol (4 mL) were added tert-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (350 mg, 1.00 mmol) and NaOH (136 mg, 4.00 mmol). The reaction mixture was heated at 180° C. for 60 min, cooled down to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=91:9) and washed with DCM and MeOH, to give 30 as a pale yellow solid (363 mg, 43%).1H NMR (DMSO-d6) δ 2.43 (s, 3H), 2.74 (s, 3H), 2.89 (d, 4H, J 5.0),3.17 (d, 4H, J 5.0),7.50 (dd, 1H, J 9.0 & 3.0), 7.93 (d, 1H, J 9.0), 8.11 (d, 1H, J 3.0), 8.28 (d, 1H, J 4.5), 8.77 (s, 1H), 10.39 (s, 1H). MS (ESI): m/z 422.1808 [M+H]+; calcd. for C20H24N9S+[M+H]+422.1870.Anal. RP-HPLC Method A: tR8.72 min, purity>99%; Method B: tR7.36 min, purity>99%. 5-(5-Fluoro-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (31) To a solution of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 60 min, cooled down to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=92:8:1) and washed with DCM and MeOH, to give 31 as a reddish brown solid (124 mg, 30%).1H NMR (DMSO-d6) δ 2.22 (s, 3H), 2.45 (t, 4H, J 4.5), 2.47 (app d, 3H, J 2), 2.87 (d, 3H, J 5), 3.10 (t, 4H, J 5), 7.40 (dd, 1H, J 9.0 & 3.0), 7.95 (d, 1H, J 9.0), 7.97 (d, 1H, J 3.0), 8.11 (q, 1H, J 4.5), 8.42 (d, 1H, J 3.5), 9.53 (s, 1H). HRMS (ESI): m/z 415.1846 [M+H]+; calcd. for C19H24FN8S+[M+H]+415.1823. Anal. RP-HPLC Method A: tR8.09 min, purity>95%; Method B: tR2.83 min, purity 99%. 5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (32) To a solution of crude 1-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (496.6 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 60 min, cooled down to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 32 as a yellow solid (146 mg, 34%).1H NMR (DMSO-d6) δ 1.03 (t, 3H, J 7.0), 2.36 (q, 3H, J 7.0), 2.48 (app d, 3H, J 2.0), 2.50 (br, 4H), 2.87 (d, 3H, J 5.0), 3.10 (t, 4H, J 5.0), 7.39 (dd, 1H, J 9.0 & 3.0), 7.96 (d, 1H, J 9.0), 7.99 (d, 1H, J 3.0), 8.13 (q, 1H, J 4.5), 8.43 (d, 1H, J 3.5), 9.55 (s, 1H). HRMS (ESI): m/z 429.1982 [M+H]+; calcd. for C20H26FN8S+[M+H]+429.1980. Anal. RP-HPLC Method A: tR8.30 min, purity 100%; Method B: tR2.80 min, purity 100%. 1-(4-(6-((4-(4-Methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (33) To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (525 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (225 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10+0.5 ml of 32% ammonia) to give 33 as a yellow solid (100 mg, 24%).1H NMR (CDCl3) δ 2.15 (s, 3H), 2.56 (s, 3H), 3.05 (s, 3H), 3.10 (t, 2H, J 4.5), 3.14 (t, 2H, J 4.5), 3.64 (t, 2H, J 4.5), 3.79 (t, 2H, J 4.5), 5.73 (s, 1H), 6.88 (d, 1H, J 5.5), 7.35 (dd, 1H, J 9.0 & 2.5), 7.89 (s, 1H), 8.01 (d, 1H, J 2.0), 8.31 (d, 1H, J 9.0), 8.35 (d, 1H, J 5.0). HRMS (ESI): m/z 425.1878 [M+H]+; calcd. for C20H25N8OS+[M+H]+425.1867. Anal. RP-HPLC Method A: tR9.92 min, purity 100%; Method B: tR8.00 min, purity 100%. 2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5-carbonitrile (34) To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (315 mg, 1.20 mmol) in 2-methoxyethanol (4 mL) were added tort-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (350 mg, 1.00 mmol) and NaOH (82.0 mg, 2.40 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10 with consecutive addition of 32% aqueous ammonia, up to 3%). The solid was washed with DCM and McOH, then filtered to give 34 as a pale yellow solid (157 mg, 35%).1H NMR (DMSO-d6) δ 2.04 (s, 3H), 2.40 (s, 3H), 2.87 (s, 3H), 3.10 (t, 2H, J 5.0), 3.16 (t, 2H, J 5.0), 3.58 (t, 4H, J 5.0), 7.46 (dd, 1H, J 9.5 & 3.0), 7.90 (d, 1H, J 9.0), 8.06 (d, 1H, J 3.0), 8.26 (q, 1H, J 3.0), 8.75 (s, 1H), 10.33 (s, 1H). HRMS (ESI): m/z 450.1844 [M+H]+; calcd. for C21H24N9OS+[M+H]+450.1819. Anal. RP-HPLC Method A: tR10.34 min, purity>97%; Method B: tR8.769 min, purity>98%. 1-(4-(6-((5-Fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (35) To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (1.08 g, 2.06 mmol) in 2-methoxyethanol (6 mL) were added (E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (500 mg, 2.06 mmol) and NaOH (164.4 mg, 4.11 mmol). The reaction mixture was heated at 180° C. for 150 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10 with consecutive addition of 32% aqueous ammonia, up to 1%). The solid was washed with DCM and MeOH, then filtered to give 35 as a reddish brown solid (400 mg, 44%).1H NMR (DMSO-d6) δ 2.04 (s, 3H,), 2.47 (d, 3H, J 2.5), 2.87 (d, 3H, J 4.5), 3.05 (t, 2H, J 5.0), 3.11 (t, 2H, J 5.0), 3.58 (app q, 4H, J 6.0), 7.43 (dd, 1H, J 9.0 & 3.0), 7.98 (d, 1H, J 9.0), 8.02 (d, 1H, J 3.0), 8.12 (q, 1H, J 4.5), 8.43 (d, 1H, J 3.5), 9.59 (s, 1H). HRMS (ESI) m/z 443.1800 [M+H]+; calcd. for C20H24FN8OS+[M+H]+443.1772. Anal. RP-HPLC Method A: tR9.75 min, purity>95%; Method B: tR7.77 min, purity>95%. N,4-dimethyl-5-(2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)thiazole-2-amine (36) To a solution of crude 1-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (266 mg, 1.20 mmol) in 2-methoxyethanol (4 mL) were added (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (225 mg, 1.00 mmol) and NaOH (82.0 mg, 2.40 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4). The solid was washed with DCM and MeOH, and then filtered to give 36 as a pale yellow solid (69.0 mg, 18%).1H NMR, DMSO-d6) δ 2.47 (s, 3H), 2.86 (d, 2H, J 5.0), 3.08 (t, 4H, J 5.0), 3.74 (t, 4H, J 5.0), 6.92 (d, 1H, J 5.0), 7.41 (dd, 1H, J 9.0 &3.0), 7.99 (d, 1H, J 3.0), 8.06 (q, 1H, J 5.0 & 4.5), 8.08 (d, 1H, J 9.0), 8.33 (d, 1H, J 5.0), 9.26 (s, 1H). MS (ESI): m/z 384.1674 [M+H]+; calcd. for C18H21N7OS+[M+H]+384.1601.Anal. RP-HPLC Method A: tR10.08 min, purity>99%; Method B: tR7.98 min, purity>99%. 4-(4-Methyl-2-(methylamino)thiazol-5-yl)-2-((5-morpholinopyridin-2-yl)amino)pyrimidine-5-carbonitrile (37) To a solution of crude 1-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (222 mg, 1.00 mmol) in 2-methoxyethanol (4 mL) were added tert-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (350 mg, 1.00 mmol) and NaOH (68.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=97:3), washed with DCM and MeOH, then filtered to give 37 as a pale yellow solid (126 mg, 31%).1H NMR (DMSO-d6) δ 2.42 (s, 3H), 2.89 (d, 3H, J 4.5), 3.12 (t, 4H, J 5.0), 3.75 (t, 4H, J 5.0), 7.42 (dd, 1H, J 9.0 & 3.0), 7.93 (d, 1H, J 9.0), 8.04 (d, 1H, J 3.0), 8.23 (dd, 1H, J 9.0 & 4.5), 8.73 (s, 1H), 10.28 (s, 1H). HRMS (ESI): m/z 409.1549 [M+H]+; calcd. for C19H20N8OS+[M+H]+409.1554.Anal. RP-HPLC Method A: tR10.88 min, purity>98%; Method B: tR8.60 min, purity>97%. 5-(5-Fluoro-2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (38) To a solution of crude 1-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (332 mg, 1.5 mmol) in 2-methoxyethanol (4 mL) were added (E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (60.0 mg, 1.5 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 38 as a purple solid (138 mg, 34%).1H NMR (DMSO-d6) δ 2.48 (d, 3H, J 2.0), 2.87 (d, 3H, J 4.5), 3.08 (t, 4H, J 5), 3.75 (t, 4H, J 5.0), 7.39 (dd, 1H, J 9.0 & 3.0), 7.97 (d, 1H, J 9.0), 7.99 (d, 1H, J 3.0), 8.12 (q, 1H, J 4.5), 8.42 (d, 1H, J 3.5), 9.52 (s, 1H). HRMS (ESI): m/z 402.1524 [M+H]+; calcd. for C18H21FN7OS+[M+H]+402.1507. Anal. RP-HPLC Method A: tR9.95 min, purity 100%; Method B: tR7.97 min, purity 100%. 5-(2-((5-(4-Benzylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (39) To a solution of crude 1-(5-(4-benzylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate trifluoroacetate (640 mg, ≤0.999 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(Dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (390 mg, 1.20 mmol) and NaOH (80.0 mg, 2.03 mmol). The reaction mixture was heated at 140° C. under microwave irradiation for 45 min, cooled down to room temperature and filtered. The solids were washed with MeOH (15 mL) and DCM (30 mL), and purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) to give 39 as a yellow solid (64.0 mg, 14%, an overall yield for two steps). m.p. 275-276° C.1H NMR (DMSO-d6) δ 2.46 (s, 3H), 2.52 (t, 4H, J 4.0), 2.86 (d, 3H, J 4.0), 3.12 (t, 4H, J 3.6), 3.53 (s, 2H), 6.91 (d, 1H, J 4.4), 7.24-7.28 (m, 1H), 7.33-7.36 (m, 4H), 7.38 (dd, 1H, J 7.2 & 2.4), 7.96 (d, 1H, J 2.4), 8.03 (q, 1H, J 4.0), 8.06 (d, 1H, J 7.6), 8.32 (d, 1H, J 4.4), 9.18 (s, 1H). HRMS (ESI): 473.2252 ([M+H]+); calcd. for C25H29N8S+([M+H]+) 473.2230. Anal. RP-HPLC Method A: tR7.51 min, purity>99%; Method B: tR6.26 min, purity>99%. 2-((5-(4-Benzylpiperazin-1-yl)pyridin-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5-carbonitrile (40) To a solution of crude 1-(5-(4-benzylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (640 mg, ≤0.999 mmol) in 2-methoxyethanol (3 mL) were added teat-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (350 mg, 0.999 mmol) and NaOH (80.0 mg, 2.03 mmol). The reaction mixture was heated at 140° C. under microwave irradiation for 45 min, cooled down to room temperature and filtered. The solids were washed with MeOH (15 mL) and DCM (30 mL), and purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) to give 40 as a yellow solid (177 mg, 36%, an overall yield for two steps and calculated based on 6). m.p. 255-256° C.1H NMR (DMSO-d6) δ 2.40 (s, 3H), 2.51 (t, 4H, J 3.6), 2.87 (d, 3H, J 3.2), 3.14 (t, 4H, J 3.6), 3.51 (s, 2H), 7.23-7.28 (m, 1H), 7.32-7.35 (m, 4H), 7.40 (dd, 1H, J 7.2 & 2.4), 7.87 (d, 1H, J 7.2), 8.03 (d, 1H, J 2.4), 8.23 (q, 1H, J 3.2), 8.73 (s, 1H), 10.29 (s, 1H). HRMS (ESI): 498.2188 [M+H]+; calcd. for C26H28N9S+[M+H]+498.2183. Anal. RP-HPLC Method A: tR8.38 min, purity>95%; Method B: tR6.75 min, purity>96%. 5-(2-((4-(4-Benzylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (41). To a solution of crude 1-(4-(4-benzylpiperazin-1-yl)phenyl)guanidine trifluoroacetate (530 mg, ≤1.71 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (200 mg, 0.888 mmol) and NaOH (73.0 mg, 1.82 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 30 min, cooled down to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) to give 41 as a yellow solid (60.0 mg, 14%). m.p. 212-213° C. 1H NMR (DMSO-d6) δ 2.44 (s, 3H), 2.50 (t, 4H, J 4.0), 2.85 (d, 3H, J 3.6), 3.05 (t, 4H, J 4.0), 3.51 (s, 2H), 6.81 (d, 1H, J 4.4), 6.85 (d, 2H, J 7.6), 7.23-7.29 (m, 1H), 7.31-7.35 (m, 4H), 7.57 (d, 2H, J 7.2), 7.98 (q, 1H, J 4.0), 8.26 (d, 1H, J 4.4), 9.13 (s, 1H). HRMS (ESI): 472.2295 [M+H]+; calcd. for C26H30N7S+[M+H]+472.2278. Anal. RP-HPLC Method A: tR8.11 min, purity>99%; Method B: tR6.62 min, purity>99%. 2-((4-(4-Benzylpiperazin-1-yl)phenyl)amino)-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5-carbonitrile (42) To a solution of crude 1-(4-(4-benzylpiperazin-1-yl)phenyl)guanidine trifluoroacetate (353 mg, ≤1.14 mmol) in 2-methoxyethanol (3 mL) were added tort-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (200 mg, 0.571 mmol) and NaOH (45.7 mg, 1.14 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 30 min, cooled down to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:EtOAc=1:3) and recrystallized with DCM and MeOH to give 42 as a yellow solid (80.0 mg, 28%). m.p. 220-221° C.1H NMR (DMSO-d6) δ 2.34 (s, 3H), 2.50 (t, 4H, J 4.0), 2.86 (d, 3H, J 3.6), 3.08 (t, 4H, J 4.0), 3.51 (s, 2H), 6.89 (d, 2H, J 7.2), 7.23-7.29 (m, 1H), 7.31-7.35 (m, 4H), 7.48 (d, 2H, J 6.4), 8.17 (q, 1H, J 3.6), 8.67 (d, 1H, J 4.0), 10.03 (s, 1H). HRMS (ESI): 497.2206 [M+H]+; calcd. for C27H29N8S+[M+H]+1497.2230. Anal. RP-HPLC Method A: tR8.36 min, purity>96%; Method B: tR10.18 min, purity>95%. N,N,4-Trimethyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (43) To a suspension of 1-(4-(6-((4-(2-(Dimethylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (100 mg, 0.23 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to EtOAc:MeOH:NH4OH)=90:10:1) to give 43 as a yellow solid (83 mg, 92%). m.p. 210-211° C.1H NMR (DMSO-d6) δ 1.74 (br, 1H), 2.57 (s, 3H), 3.06 (t, 4H, J 5.5), 3.11 (t, 4H, J 3.5), 3.18 (s, 6H2), 6.84 (d, 1H, J 5.5), 7.33 (dd, 1H, J 9.0 & 3.0), 7.79 (s, 1H), 7.99 (d, 1H, J 3.0), 8.28 (d, 1H, J 9.5), 8.31 (d, 1H, J 5.5). HRMS (ESI): m/z 397.1925 [M+H]+; calcd. for C19H25N8S+[M+H]+397.1917. Anal. RP-HPLC Method A: tR8.39 min, purity>95%; Method B: tR7.42 min, purity 100%. 5-(5-Fluoro-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2-amine (44) To a suspension of 1-(4-(6-((4-(2-(dimethylamino)-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (100 mg, 0.22 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=90:10:1) to give 44 as a yellow solid (45.4 mg, 50%).1H NMR (CDCl3) δ 2.58 (d, 3H, J 2.0,), 3.05 (t, 4H, J 6.0), 3.09 (t, 4H, J 6.0), 3.17 (s, 6H), 7.30 (dd, 1H, J 9.0 & 3.0), 7.98 (br s, 1H), 8.00 (s, 1H), 8.19 (d, 1H, J 9.0), 8.23 (d, 1H, J 1.5). HRMS (ESI): m/z 415.1821 [M+H]+; calcd. for C19H24FN8S+[M+H]+415.1823. Anal. RP-HPLC Method A: tR9.00 min, purity>98%; Method B: tR7.30 min, purity>99%. N,N,4-trimethyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (45) To a solution of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(dimethylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (239 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10 with constant addition of 0.5 ml of 32% ammonia) to give 45 as a yellow solid (40.0 mg, 10%).1H NMR (CDCl3) δ 2.36 (s, 3H), 2.57 (s, 3H), 2.59 (t, 4H, J 5.0), 3.17 (br s, 10H), 6.84 (d, 1H, J 5.5), 7.33 (dd, 1H, J 9.0 & 3.0), 7.96 (s, 1H), 8.02 (d, 1H, J 3.0), 8.28 (d, 1H, J 9.0), 8.33 (d, 1H, J 5.5). HRMS (ESI): m/z 411.2048 [M+H]+; calcd. for C20H27N8S+[M+H]+411.2074. Anal. RP-HPLC Method A: tR8.77 min, purity>99%; Method B: tR3.24 min, purity>95% 5-(5-Fluoro-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2-amine (46) To a solution of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(dimethylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (257 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5 with constant addition of 0.5 ml of 32% ammonia) to give 46 as a reddish brown solid (61.0 mg, 14%).1H NMR (CDCl3) δ 2.36 (s, 3H), 2.57 (d, 3H, J 2.5), 2.59 (t, 4H, J 5.0), 3.17 (s, 10H), 7.30 (dd, 1H, J 9.0 & 3.0), 8.33 (d, 1H, J 2.0), 8.18 (d, 1H, J 9.0), 8.23 (d, 1H, J 3.5). HRMS (ESI): m/z 429.1981 [M+H]+; calcd. for C20H26FN8S [M+H]+429.1980. Anal. RP-HPLC Method A: tR8.99 min, purity>96%; Method B: tR7.30 min, purity>98%. 5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (47) To a solution of crude 1-(5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added ((E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10 with constant addition of 0.5 ml of 32% ammonia) to give 47 as a brown solid (76 mg, 17.2%).1H NMR (DMSO-d6) δ 1.50 (q, 2H, J 11.0), 1.84 (d, 3H, J 11.0), 2.21 (s, 7H), 2.47 (s, 3H, thiazole-CH3), 2.64 (t, 2H, J 11.0), 2.86 (t, 3H, J 3.5), 3.63 (d, 1H, J 11.0), 7.39 (app d, 1H, J 7.0), 7.92 (d, 1H, J 9.0), 7.98 (s, 1H), 8.10(1H, J 4.0), 8.41 (s, 1H), 9.43 (s, 1H). HRMS (ESI): m/z 443.2136 [M+H]+; calcd. for C21H28FN8S+[M+H]+443.2133. Anal. RP-HPLC Method A: tR9.12 min, purity>95%; Method B: tR2.84 min, >99%. 1-(4-(6-((4-(2-(Dimethylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (48) To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (525 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(dimethylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (239 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, EtOAc ramping to PE:EtOAc=100%) to give 48 as a yellow solid (100 mg, 10%). m.p. 234-235° C.1H NMR (CDCl3) δ 2.12 (s, 3H), 2.55 (s, 3H), 3.08 (t, 2H, J 5.0), 3.11 (t, 2H, J 5.0), 3.15 (s, 6H), 3.61 (t, 2H, J 5.0), 3.77 (t, 2H, J 4.5), 6.83 (d, 1H, J 5.5), 7.32 (dd, 1H, J 9.0 & 3.0), 8.08 (d, 1H, J 3.0), 8.32 (d, 1H, J 9.0), 8.37 (d, 1H, J 5.5), 8.73 (s, 1H). HRMS (ESI): m/z 439.2040 [M+H]′; calcd. for C21H27N8OS+[M+H]+439.2023. Anal. RP-HPLC Method A: tR10.06 min, purity>97%; Method B: tR8.62 min, purity>96% 1-(4-(6-((4-(2-(Dimethylamino)-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (49) To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (525 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(dimethylamino)-4-methylthiazol-5-yl)-2-fluoroprop-2-en-1-one (257 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5 with constant addition of 0.5 ml of 32% ammonia) to give 49 as a reddish brown solid (148 mg, 32%).1H NMR (CDCl3) δ 2.14 (s, 3H), 2.57 (d, 3H, J 2.5), 3.08 (t, 2H, J 10.0), 3.11 (t, 2H, J 10.0), 3.17 (s, 6H), 3.63 (t, 2H, J 10.0), 3.78 (t, 2H, J 10.0), 7.31 (dd, 1H, J 9.0 & 3.0), 8.04 (d, 1H, J 3.0), 8.23 (d, 1H, J 9.0), 8.25 (app d, J 3.0, 1H), 8.31 (s, 1H, NH). HRMS (ESI): m/z 457.1925 [M+H]+; calcd. for C21H26FNOS+[M+H]+457.1929. Anal. RP-HPLC Method A: tR10.43 min, purity>95%; Method B: tR8.29 min, purity>95%. 5-(5-Fluoro-2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2-amine (50) To a solution of crude 1-(5-morpholinopyridin-2-yl) guanidine trifluoroacetate trifluoroacetate (443 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(dimethylamino)-4-methylthiazol-5-yl)-2-fluoroprop-2-en-1-one (257 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5 with constant addition of 0.5 ml of 32% ammonia) to give 50 as a reddish brown solid (166 mg, 40%).1H NMR (CDCl3) δ 2.58 (s, 3H), 3.11 (t, 4H, J 5.0), 3.17 (s, 6H), 3.89 (t, 4H, J 4.5), 7.29 (dd, 1H, J 9.0 & 2.5), 8.01 (d, 1H, J 3.0), 8.05 (s, 1H), 8.21 (d, 1H, J 9.0), 8.23 (d, 1H, J 3.5). HRMS (ESI): m/z 416.1665 [M+H]+; calcd. for C19H23FN7OS+[M+H]+416.1663. Anal. RP-HPLC Method A: tit10.60 min, purity>95%; Method B: tR8.52 min, purity>97%. 5-(5-fluoro-2-((5-(piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-di methylthiazol-2-amine (51) To a solution of crude 1-(5-(piperidin-1-yl)pyridin-2-yl)guanidine (439 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added ((E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 51 as a reddish brown solid (66 mg, 17%).1H NMR (DMSO-d6) δ 1.52 (m, 2H), 1.63 (m, 4H), 2.47 (s, 3H), 2.87 (d, 3H, J 5.0), 3.07 (t, 4H, J 5.0), 7.38 (dd, 1H, J 9.0 & 2.5), 7.93 (d, 1H, J 9.0), 7.97 (d, 1H, J 2.5), 8.10 (d, 1H, J 5.0), 8.41 (d, 1H, J 3.5), 9.45 (s, 1H). HRMS (ESI): m/z 400.1710 [M+H]+; calcd. for C19H23FN7S+[M+H]+400.1714. Anal. RP-HPLC Method A: tR12.08 min, purity>95%; Method B: tR8.70 min, >98%. 5-(5-fluoro-2-((5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (52) To a solution of crude 1-(5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)guanidine (596 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added ((E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 52 as a reddish brown solid (29 mg, 6%).1H NMR (DMSO-d6) δ 2.88 (d, 3H, J 4.5), 2.94 (s, 3H), 3.23 (t, 4H, J 5.0), 3.27 (t, 4H, J 5.5), 3.33 (s, 3H), 7.52 (app d, 1H, J 8.0), 7.6 (d, 1H, J 9.0), 8.02 (d, 1H, J 2.5), 8.15 (d, 1H, J 4.5), 8.44 (d, 1H, J 3.5), 9.69 (s, 1H). HRMS (ESI): m/z 479.1441 [M+H]+; calcd. for C19H24FN8O2S+[M+H]+479.1442. Anal. RP-HPLC Method A: 10.60 min, purity>94%; Method B: tR8.08 min, >97%. 5-(2-((5-(1,4-diazepan-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (53) To a solution of crude 1-(5-(1,4-diazepan-1-yl)pyridin-2-yl)guanidine di(2,2,2-trifluoroacetate) (469 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added ((E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 53 as an orange solid (40 mg, 10%).1H NMR (DMSO-d6) δ 1.75-1.80 (m, 2H), 2.45 (d, 3H, 1 2.0), 2.62 (t, 2H, J 6.0), 2.85 (t, 2H, J 5.5), 3.45 (t, 2H, J 5.0),3.53 (t, 2H, J 6.0), 7.13 (dd, 1H, J 9.0 & 3.0), 7.78 (s, 1H), 7.79 (d, 1H, J 4.5), 8.08(q, 1H, J 4.5), 8.37 (d, 1H, J 3.5), 9.21 (s, 1H). HRMS (ESI): m/z 415.1821 [M+H]+; calcd. for C19H24FN8S+[M+H]+415.1823. Anal. RP-HPLCMethod A: tR8.72 min, purity>98%; Method B: tR2.84 min, 100%. 5-(5-fluoro-2-(pyridin-2-ylamino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (54) To a solution of crude 1-(pyridin-2-yl)guanidine 2,2,2-trifluoroacetate (409 mg, 3.00 mmol) in 2-methoxyethanol (8 mL) were added ((L)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (487 mg, 2.00 mmol) and NaOH (160 mg, 4.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=98:2) to give 54 as an orange solid (70 mg, 22%).1H NMR (DMSO-d6) 2.89 (d, 3H, J 4.5), 3.34 (s, 1H), 6.99 (m, 2H), 7.75 (t, 1H, J 7.5), 8.14 (m, 2H), 8.29 (d, 1H, J 3.0), 8.50 (d, 1H, J 3.0), 9.79 (s, 1H). HRMS (ESI): m/z 317.0989 [M+H]+; calcd. for C14H14FN6S+[M+H]+317.0979. Anal. RP-HPLC Method A: tr10.45 min, purity>97%; Method B: tR9.24 min, purity>98%. N-isopropyl-4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (55) To a suspension of 1-(4-(6-((4-(2-(isopropylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (143 mg, 0.32 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=90:10:1) to give 55 as a yellow solid (120 mg, 92%,).1H NMR (DMSO-d6) δ 1.19 (d, 6H, J 6.5, CH(CH3)2), 2.46 (s, 3H), 2.87 (t, 4H, J 5.0), 3.03 (t, 4H, J 5.5), 3.80-3.87 (m, 1H, CH), 6.90 (d, 1H, J 5.5), 7.37 (dd, 1H, J 9.0 & 3.0), 8.00 (d, 1H, J 3.0), 8.05 (d, 2H, J 7.5), 8.08 (d, 1H, J 9.0), 8.33 (d, 1H, J 5.5), 9.29 (s, 1H). HRMS (ESI): m/z 411.2072 [M+H]+; calcd. for C20H27N8S+[M+H]+411.2074.Anal. RP-HPLC Method A: tR8.43 min, purity>96%; Method B: tR7.61 min, purity 99%. N-isopropyl-4-methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (56) To a solution of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(isopropylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (253 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 56 as a yellow solid (131 mg, 31%).1H NMR (DMSO-d6) δ 1.19 (d, 6H, J 6.5,), 2.22 (s, 3H), 2.46 (s br, 7H), 3.11 (t, 4H, J 5.0), 3.81-3.85 (m, 1H), 6.90 (d, 1H, J 5.5), 7.38 (dd, 1H, J 9.0 & 3.0), 8.00 (d, 1H, J 3.0), 8.04 (d, 2H, J 7.5), 8.08 (d, 1H, J 9.0), 8.34 (d, 1H, J 5.5), 9.32 (s, 1H). HRMS (ESI): m/z 425.2235 [M+H]+; calcd. for C21H29N8S+[M+H]+425.2230.Anal. RP-HPLC Method A: tR8.563 min, purity 100%; Method B: tR7.73 min, purity 100%. 1-(4-(6-((4-(2-(isopropylamino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (57) To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (525 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(isopropylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (253 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) to give 57 as an orange solid (80 mg, 18%,).1H NMR (DMSO-d6) δ 1.19 (d, 6H, J 6.5), 2.05 (s, 3H), 2.46 (s, 3H), 3.06 (t, 2H, J 5.0), 3.13 (t, 2H, J 5.0), 3.59 (q, 4H, J 5.5), 3.81-3.85 (m, 1H), 6.91 (d, 1H, J 5.5), 7.40 (dd, 1H, J 9.0 & 3.0), 8.02 (d, 1H, J 3.0), 8.05 (m, 2H, J 7.5), 8.10 (d, 1H, J 9.0), 8.33 (d, 1H, J 5.5), 9.31 (s, 1H). HRMS (ESI): m/z 453.2187 [M+H]+; calcd. for C22H29N8OS+[M+H]+453.2180. Anal. RP-HPLC Method A: tR10.03 min, purity 100%; Method B: tR8.85 min, purity>99%. N-isopropyl-4-methyl-5-(2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (58) To a solution of crude 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (443 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(isopropylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (253 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) to give 58 as a yellow solid (200 mg, 48%,).1H NMR (DMSO-d6) δ 1.19 (d, 6H, J 6.5), 2.45 (s, 3H), 3.09 (t, 4H, J 4.0), 3.76 (t, 4H, J 4.0), 3.81-3.85 (m, 1H), 6.90 (d, 1H, J 5.5), 7.39 (dd, 1H, J 9.0 & 3.0), 7.01 (d, 1H, J 2.5), 8.05 (d, 2H, J 7.5), 8.10 (d, 1H, J 9.0), 8.34 (d, 1H, J 5.5), 9.33 (s, 1H). HRMS (ESI): m/z 412.1912 [M+H]+; calcd. for C20H26N7OS+[M+H]+412.1914.Anal. RP-HPLC Method A: tR10.21 min, purity 100%; Method B: tR9.08 min, purity>99%. 5-(2-((5-(1,4-diazepan-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N-isopropyl-4-methylthiazol-2-amine (59) To a solution of crude 1-(5-(1,4-diazepan-1-yl)pyridin-2-yl)guanidine di(2,2,2-trifluoroacetate) (469 mg, 2.00 mmol) in 2-methoxyethanol (3 mL) were added (E)-3-(dimethylamino)-1-(2-(isopropylamino)-4-methylthiazol-5-yl)prop-2-en-1-one (253 mg, 1.00 mmol) and NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h min under microwave irradiation, cooled down to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 59 as an range solid (114 mg, 34%).1H NMR (DMSO-d6) δ 1.19 (d, 6H, J 6.5), 2.04-2.09 (m, 2H), 2.47 (s, 3H), 3.16 (s, 1H, J 5.5), 3.27 (s, 2H, J 5.0), 3.50 (d, 2H, J 6.0), 3.70 (t, 2H, J 5.0), 3.80-3.86 (m, 1H), 6.87 (d, 1H, J 5.5), 7.24 (dd, 1H, J 9.0 & 3.0), 7.89 (d, 1H, J 3.0), 8.03 (d, 2H, J 5.5), 8.05 (d, 1H, J 4.0), 8.31 (d, 1H, J 5.5), 8.75 (s, 1H). 9.15 (s, 1H). HRMS (ESI): m/z 425.2231 [M+H]+; calcd. for C21H29N8S+[M+H]+425.2230 Anal. RP-HPLC Method A: tR8.48 min, purity>95%; Method B: tR7.69 min, >98%. N-Cyclopentyl-4-methyl-5-(2-((5-(piperazin-1-yl) pyridin-2-yl) amino) pyrimidin-4-yl) thiazol-2-amine (60) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=92:8) and recrystallised with DCM and MeOH to give 60 as a dark yellow solid (70.0 mg, 16%). m.p. 210-213° C.1H NMR (DMSO-d6) 1.49-1.68 (m, 7H), 1.89-1.94 (m, 2H), 2.46 (s, 3H), 2.85 (t, 4H, J 4.5), 3.02 (t, 4H, J 5.0), 3.98 (m, 1H), 6.90 (d, 1H, J 5.5), 7.36 (dd, 1H, J 9.0 & 3.0), 7.98 (d, 1H, J 3.0), 8.07 (d, 1H, J 9.0), 8.18 (d, 1H, J 7.0), 8.33 (d, 1H, J 5.5), 9.33 (s, 1H). HRMS (ESI): m/z 437.2222 [M+H]+; calcd. for C22H29N8S+[M+H]+437.2230. Anal. RP-HPLC Method A: tR10.10 min, purity>99%; Method B: tR7.78 min, purity>99%. N-cyclopentyl-5-(5-fluoro-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (61) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and ((E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxyethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=90:10:1) to give 61 as a yellow solid (101 mg, 22%).1H NMR (DMSO-d6) 1.54-1.57 (m, 4H), 1.66-1.69 (m, 2H), 1.92-1.95 (m, 2H), 2.47 (s, 3H), 3.26 (t, 4H, J 2.5), 3.31 (t, 4H, J 2.5), 3.95 (m, 1H, cyclopentane-CH), 7.46 (dd, 1H, J 9.0 & 3.0), 8.00 (d, 1H, J 9.0), 8.05 (d, 1H, J 3.0), 8.25 (d, 1H, J 7.0), 8.42 (d, 1H, J 3.5), 8.84 (d, 1H, J 3.5), 9.57 (s, 1H). HRMS (ESI): m/z 455.2139 [M+H]+; calcd. for C22H28FN8S+[M+H]+455.2136. Anal. RP-HPLC Method A: tR9.55 min, purity 100%; Method B: tR7.86 min, purity 100%. N-cyclopentyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol-2-amine (62) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-(trifluoromethyl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (333 mg, 1.00 mmol) in 2-methoxyethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=90:10:1) to give 62 as an orange solid (260 mg, 53%).1H NMR (DMSO-d6) δ 1.50-1.59 (m, 4H), 1.65-1.70 (m, 2H), 1.92-1.97 (m, 2H), 2.26 (s, 1H), 2.84 (t, 4H, J 5.0), 3.02 (t, 4H, J 5.0), 3.96 (m, 1H), 6.96 (d, 1H, J 6.0), 7.37 (dd, 1H, J 9.0 & 3.0), 7.98 (d, 1H, J 4.0), 7.99 (d, 1H, J 1.0), 8.50 (d, 1H, J 5.5), 8.59 (d, 1H, J 6.5), 9.59 (s, 1H,). HRMS (ESI): m/z 491.1952 [M+H]+; calcd. for C22H26F3N8S+[M+H]+491.1948. Anal. RP-HPLC Method A: tR10.31 min, purity 100%; Method B: tR8.30 min, >98%. N-Cyclopentyl-4-methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (63) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=93:7) and recrystallised with DCM and MeOH to give 63 as a yellow solid (100 mg, 22%). m.p. 202-205° C.1H NMR (CDCl3) δ 1.51-1.71 (m, 6H), 1.99-2.05 (m, 2H), 2.35 (s, 3H), 2.48 (s, 3H), 2.62 (t, 4H, J 5.0), 3.14 (t, 4H, J 5.0), 3.79 (br, 1H),), 6.03 (br, 1H), 6.78 (d, 1H, J 5.0), 7.27 (dd, 1H, J 9.0 & 3.0), 7.96 (d, 1H, J 3.0), 8.10 (s, 1H), 8.21 (d, 1H, J 9.0), 8.29 (d, 1H, J 5.0). HRMS (ESI): m/z 451.2396 [M+H]+; calcd. for C23H31N8S+[M+H]+451.2387. Anal. RP-HPLC Method A: tR9.56 min, purity>99%; Method B: tR9.50 min, purity>98%. N-cyclopentyl-5-(5-fluoro-24(5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (64) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (234 mg, 1.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (148 mg, 0.50 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (40.0 mg, 1.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=94:6:0.5) and recrystallised with Et2O to give 64 as a dark brown solid (100 mg, 5%). m.p. 207-209° C.1H NMR (CDCl3) δ 1.52-1.79 (m, 6H), 1.06-2.12 (m, 2H), 2.38 (s, 3H), 2.55 (s, 3H), 2.63 (t, 4H, J 5.0), 3.18 (t, 4H, J 5.0), 3.84 (m, 1H), 5.56 (d, J 6.0, 1H), 7.31 (dd, 1H, J 9.0 & 3.0), 7.82 (s, 1H), 7.99 (d, 1H, J 3.0), 8.18 (d, 1H, J 9.0), 8.23 (d, 1H, J 3.5). HRMS (ESI): m/z 469.2287 [M+H]+; calcd. for C23H30N8S+[M+H]+469.2293. Anal. RP-HPLC Method A: tR10.37 min, purity>97%; Method B: tR8.42 min, purity>98%. N-cyclopentyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol-2-amine (65) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-(trifluoromethyl)thiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (148 mg, 0.50 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 65 as a brown solid (30 mg, 6%).1H NMR (DMSO-d6) δ 1.56-1.59 (m, 4H), 1.67-1.69 (m, 2H), 1.93-1.97 (m, 2H), 2.21 (s, 1H), 2.46 (t, 4H, J 5.0), 3.12 (t, 4H, J 5.0), 3.96 (m, 1H), 6.96 (d, 1H, J 6.0), 7.39 (dd, 1H, J 9.0 & 3.0), 8.00 (d, 1H, J 9.0), 8.01 (d, 1H, J 3.0), 8.50 (d, 1H, J 5.5), 8.59 (d, 1H, J 7.0), 9.62(s, 1H). HRMS (ESI): m/z 505.2103 [M+H]+; calcd. for C23H28F3N8S+[M+H]+505.2104. Anal. RP-HPLC Method A: tR10.49 min, purity 96%; Method B: tR9.46 min, >97%. N-Cyclopentyl-5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (66) To a mixture of crude 1-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (496 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) and recrystallised from MeOH to give 66 as a yellow solid (117 mg, 25%).1H NMR (CDCl3) δ 1.14 (t, 3H, J 7.0), 1.56-1.76 (m, 6H), 2.06-2.12 (m, 2H), 2.49 (q, 2H, J 7.5), 2.54 (s, 3H), 2.64 (s, 3H), 3.19 (t, 4H, J 4.5), 3.14 (t, 4H, J 5.0), 3.86 (app s, 1H), 5.77 (s, 1H), 6.84 (d, 1H, J 5.0), 7.34 (dd, 1H, J 9.0 & 3.0), 7.94 (d, 1H, J 3.0), 7.94 (s, 1H), 8.01 (d, 1H, J 3.0), 8.26 (d, 1H, J 9.0), 8.33 (d, 1H, J 5.5). HRMS (EST): m/z 465.2541 [M+H]+; calcd. for C24H33N8S+[M+H]+465.2543. Anal. RP-HPLC Method A: tR13.24 min, purity>98%; Method B: tR8.96 min, purity 100%. N-cyclopentyl-5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine (67) To a mixture of crude 1-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (497 mg, 2.00 mmol) and ((E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=95:5) to give 67 as a yellow solid (74 mg, 15%).1H NMR (DMSO-d6) δ 1.03 (t, 3H, J 7.0), 1.50-1.57 (m, 4H), 1.66-1.69 (m, 2H), 1.90-1.95 (in, 2H), 2.37 (q, 2H, J 7.0), 2.46 (d, 3H, J 2.5), 3.11 (t, 4H, J 5.0), 3.32 (s, 4H), 3.96 (app s, 1H), 7.39 (dd, 1H, J 9.0 & 3.0), 7.94 (d, 1H, J 9.0), 7.97 (d, 1H, J 3.0), 8.23 (d, 1H, J 7.0), 8.40 (d, 1H, J 3.5), 9.44 (s, 1H). HRMS (ESI): m/z 483.2442 [M+H ]+; calcd. for C24H32FN8S+[M+H]+483.2449. Anal. RP-HPLC Method A: tR9.78 min, purity>98%; Method B: tR7.88 min, purity 100%. 1-(4-(6-((4-(2-(Cyclopentylamino)-4-methylthiazol-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) ethan-1-one (68) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by using chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 68 as a light yellow solid (153 mg, 32%). m.p. 207-210° C.1H NMR (CDCl3) δ 1.57-1.75 (m, 6H), 2.05-2.11 (m, 2H), 2.14 (s, 3H), 2.54 (s, 3H), 3.08-3.14 (m, 4H), 3.63 (t, 2H, J 5.0), 3.79 (t, 2H, J 5.0), 3.87 (m, 1H), 5.70 (s, 1H), 6.86 (d, 1H, J 5.0), 7.33 (dd, 1H, J 9.0 & 3.0), 8.03 (d, 1H, J 2.0), 8.19 (br s, 1H,), 8.31 (d, 1H, J 9.0), 8.35 (d, 1H, J 5.0). HRMS (ESI): m/z 479.2340 [M+H]+; calcd. for C24H31N8OS+[M+H]+479.2336 Anal. RP-HPLC Method A: tR10.86 min, purity>99%.; Method B: tR8.51 min, purity>98%. 1-(4-(6-((4-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (69) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by using chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 69 as a light yellow solid (153 mg, 32%). Yellow solid (53 mg, 11%).1H NMR (DMSO-d6) δ 1.51-1.75 (m, 4H), 1.66-1.68 (m, 2H), 1.92-1.95 (m, 2H), 2.04 (s, 3H), 2.47 (d, 3H, J 2.0), 3.06 (t, 2H, J 5.0), 3.12 (t, 2H, J 5.0), 3.58 (t, 4H, J 5.0), 3.96 (t, 1H), 7.43 (dd, 1H, J 9.0 & 3.0), 7.98 (d, 1H, J 9.0), 8.01 (d, 1H, J 3.0), 8.24 (d, 1H, J 7.0), 8.42 (d, 1H, J 3.5), 9.51 (br s, 1H). HRMS (ESI): m/z 497.2245 [M+H]+; calcd. for C24H30FN8OS+[M+H]+497.2242 Anal. RP-HPLC Method A: tR11.02 min, purity>97%.; Method B: tR9.91 min, purity>96%. 1-(4-(6-((4-(2-(cyclopentylamino)-4-(trifluoromethyl)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (70) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-(trifluoromethyl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (333 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by using chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) to give 70 as a brown solid (50 mg, 9%).1H NMR (DMSO-d6) δ 1.53-1.59 (m, 4H), 1.67-1.69 (m, 2H,), 1.94-1.97 (m, 2H), 2.05 (s, 3H), 3.08 (t, 2H, J 4.5), 3.14 (t, 2H, J 4.5), 3.59 (app d, 4H, J 4.5), 3.95 (m, 1H), 6.97 (d, 1H, J 5.0), 7.43 (dd, 1H, J 9.0 & 3.0), 8.02 (s, 1H), 8.04 (d, 1H, J 3.0), 8.50 (d, 1H, J 5.5), 8.59 (d, 1H, J 6.5), 9.66 (s, 1H). HRMS (ESI): m/z 533.2053 [M+H]+; calcd. for C24H27F3N8OS+[M+H]+533.2058. Anal. RP-HPLC Method A: tR12.56 min, purity>97%; Method B: tR9.39 min, >95%. N-cyclopentyl-4-methyl-5-(2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (71) To a mixture of crude 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (442 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) and recrystallised with Et2O to give 71 as a dark brown solid (130 mg, 30%). m.p. 262-263° C.1H NMR (CDCl3) δ 1.57-1.74 (m, 6H), 2.06-2.12 (m, 2H), 2.55 (s, 3H), 3.13 (t, 4H, J 4.5), 3.88 (t, 4H, J 4.5), 5.67 (d, J 4.5, 1H), 6.85 (d, 1H, J 5.5), 7.32 (dd, 1H, J 9.0 & 3.0), 8.02 (d, 1H, J 3.0), 8.16 (s, 1H), 8.30 (d, 1H, J 9.5), 8.35 (d, 1H, J 5.5). HRMS (ESI): m/z 438.2088[M+H]+; calcd. for C22H28N7OS+[M+H]+438.2071. Anal. RP-HPLC Method A: tR10.92 min, purity 100%; Method B: tR9.51 min, purity>99%. N-cyclopentyl-5-(2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol-2-amine (72) To a mixture of crude 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (442 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) and recrystallised with DCM and MeOH to give 72 as a brown solid (120 mg, 26%).1H NMR (DMSO-d6) δ 1.50-1.57 (m, 4H), 1.66-1.69 (m, 2H), 1.90-1.95 (m, 2H), 2.47 (d, 1H, J 2.5), 3.09 (t, 4H, J 5.0), 3.75 (t, 4H, J 5.0), 3.96 (m, 1H), 7.42 (dd, 1H, J 9.0 & 3.0), 7.96 (d, 1H, J 9.0), 7.98 (d, 1H, J 3.0), 8.24 (d, 1H, J 7.0), 8.41 (d, 1H, J 7.0), 9.52(s, 1H). HRMS (ESI): m/z 456.1976 [M+H]+; calcd. for C22H25F3N7OS+[M+H]+456.1967. Anal. RP-HPLC Method A: tR11.28 min, purity 96%; Method B: tR8.93 min, 100%. N-cyclop entyl-5-(2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yI)-4-(trifluoromethyl)thiazol-2-amine (73) To a mixture of crude 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (442 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-(trifluoromethyl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one(333 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, PE ramping to PE:EtOAc=60:40) to give 73 as an orange solid (200 mg, 41%).1H NMR (DMSO-d6) δ 1.52-1.59 (m, 4H), 1.64-1.69 (m, 2H), 1.92-1.99 (m, 2H), 3.09 (t, 4H, J 4.5), 3.75 (t, 4H, J 4.5), 3.95 (m, 1H), 6.97 (d, 1H, J 5.0), 7.41 (dd, 1H, J 9.0 & 3.0), 8.01 (s, 1H), 8.02 (d, 1H, J 2.5), 8.51(d, 1H, J 5.5), 8.59 (d, 1H, J 6.5), 9.64 (s, 1H). HRMS (ESI): m/z 492.1786 [M+H]+; calcd. for C22H24F3N7OS+[M+H]+498.1788. Anal. RP-HPLC Method A: tR12.90 min, purity>97%; Method B: tR9.69 min, >99%. 5-(2-((5-(4-Aminopiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (74) To a mixture of crude 1-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (702 mg, 3.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (558 mg, 2.00 mmol) in 2-methoxy ethanol (5 mL) was added NaOH (160.0 mg, 4.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 2 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:MH4OH=90:10:1) and recrystallised with n-hexane and DCM to give 74 as a dark yellow solid (90 mg, 10%). m.p. 185-186° C.1H NMR (CDCl3) δ 1.50-1.77 (m, 10H), 1.95 (d, 2H, J 10.5), 2.07-2.13 (m, 2H), 2.54 (s, 3H), 2.75-2.85 (m, 3H), 3.53-3.56 (m, 2H), 3.85-3.91 (m, 1H), 5.43 (d, J 5.0, 1H), 6.84 (d, 1H, J 5.5), 7.34 (dd, 1H, J 9.0 & 3.0), 7.75 (s, 1H), 8.00 (d, 1H, J 3.0), 8.25 (d, 1H, J 9.0), 8.32 (d, 1H, J 5.5). HRMS (ESI): m/z 451.2415 [M+H]+; calcd. for C23H31N8S+[M+H]+451.2387. Anal. RP-HPLC Method A: tR9.34 min, purity>95%; Method B: tR8.06 min, purity>95%. N-cyclopentyl-4-methyl-5-(2-((5-(piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (75) To a mixture of crude 1-(5-(piperidin-1-yl)pyridin-2-yl)guanidine (439 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=92:8) and recrystallised with DCM and MeOH to give 75 as yellow solid (250 mg, 57%).1H NMR (DMSO-d6) δ 1.53 (s br, 6H), 1.64 (s br, 6H), 1.93 (s br, 2H), 2.46 (s, 3H), 3.07 (t, 4H, J 10.0), 3.98 (s br, H), 6.89 (d, 1H, J 5.0), 7.37 (app d, 1H, J 9.0), 7.99 (s, 1H), 8.06 (d, 1H, J 9.0), 8.18 (s, 1H), 8.33 (d, 1H, J 5.0), 9.26 (s, 1H). HRMS (ESI): m/z 436.2280 [M+H]+; calcd. for C23H30N7S+[M+H]+436.2278. Anal. RP-HPLC Method A: tR12.08 min, purity>99%; Method B: tR9.36 min, >99%. N-cyclopentyl-4-methyl-5-(2-(pyridin-2-ylamino)pyrimidin-4-yl)thiazol-2-amine (78) To a mixture of crude 1-(pyridin-2-yl)guanidine 2,2,2-trifluoroacetate (272 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=97:3) to give 78 as an orange solid (150 mg, 43%).1H NMR (DMSO-d6) 1.50-1.57 (m, 4H), 1.66-1.69 (m, 2H), 1.91-1.95 (m, 2H), 2.48 (s, 3H), 3.98 (m, 1H), 6.99 (m, 2H), 7.74 (m, 1H), 8.23 (d, 1H, J 7.0), 8.26 (d, 1H, J 8.5), 8.29 (m, 1H), 8.39 (d, 1H, J 5.5), 9.59 (s, 1H). HRMS (ESI): m/z 353.1555 [M+H]+; calcd. for C18H21N6S+[M+H]+353.1543. Anal. RP-HPLC Method A: tR10.45 min, purity>97%; Method B: tR9.24 min, purity>98%. 4-(6-((4-(2-(cyclopentylamino)-4-(trifluoromethyl)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carbaldehyde (79) Compound 79 was obtained as beige solid (25 mg, 7%) by-product in the process of synthesising and purifying N-cyclopentyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)thiazol-2-amine.1H NMR (DMSO-d6) δ 1.53-1.59 (m, 4H), 1.67-1.69 (m, 2H), 1.94-1.97 (m, 2H), 3.08 (t, 2H,15.0), 3.14 (t, 2H, J 5.0), 3.59 (m, 4H), 3.96 (m, 1H), 6.97 (d, 1H, J 4.5), 7.45 (dd, 1H, J 9.0 & 3.0), 8.03 (d, 1H, J 9.0), 8.05 (d, 1H, J 3.0), 8.09 (s, 1H), 8.50 (d, 1H, J 5.5), 8.59 (d, 1H, J 7.0), 9.67 (s, 1H). HRMS (ESI): m/z 519.1897 [M+H]+; calcd. for C23H26F3N8OS+[M+H]+519.1906. Anal. RP-HPLC Method A: tR11.57 min, purity>91%; Method B: tR9.39 min, >95%. N-cyclopentyl-5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine (80) To a mixture of crude 1-(5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (524 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=90:10:1) to give 80 as yellow solid (134 mg, 27%).1H NMR (DMSO-d6) δ 1.49-1.56 (m, 6H), 1.64-1.70 (m, 2H), 1.84 (d, 3H, J 11.5), 1.90-1.96 (m, 2H), 2.20 (s, 7H), 2.46 (s, 3H), 2.65 (t, 2H, J 11.0), 3.63 (d, 1H, J 12.0), 3.92-3.99 (m, 1H), 7.39 (dd, 1H, J 9.0 & 3.0), 7.93 (d, 1H, J 9.0), 7.98 (d, 1H, J 2.5), 8.23(1H, J 7.0), 8.40 (d, 1H, J 3.0), 9.41 (s, 1H). HRMS (ESI): m/z 497.2608 [M+H]+; calcd. for C25H34FN8S+[M+H]+497.2606. Anal. RP-HPLC Method A: tR9.81 min, purity>95%; Method B: tR8.75 min, >99%. 5-(2-((5-(1,4-diazepan-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (81) To a mixture of crude 1-(5-(1,4-diazepan-1-yl)pyridin-2-yl)guanidine di(2,2,2-trifluoroacetate) (469 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) to give 81 as a yellow solid (100 mg, 21%).1H NMR (DMSO-d6) δ 1.49-1.59 (m, 4H), 1.64-1.72 (m, 2H), 1.92-1.95 (m, 2H), 2.05-2.09 (m, 2H), 2.47 (d, 3H, J 2.0), 2.55 (s, 1H), 3.16 (s br, 2H), 3.27 (d, 2H, J 4.0), 3.70 (t, 2H, J 5.0), 3.94-3.98 (m, 1H), 7.32 (dd, 1H, J 9.0 & 3.0), 7.87 (d, 1H, J 2.5), 7.89 (d, 1H, J 3.0), 8.27 (d, 1H, J 7.0), 8.40 (d, 1H, J 3.5), 8.9 (s br, 1H), 9.54 (s, 1H). HRMS (ESI): m/z 469.2297 [M+H]+; calcd. for C23H30FN8S+[M+H]+469.2293. Anal. RP-HPLC Method A: tR9.53 min, purity>97%; Method B: tR8.53 min, 100%. N-cyclopentyl-5-(5-fluoro-2-((5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (82) To a mixture of crude 1-(5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)guanidine (596 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) to give 82 as yellow solid (53 mg, 10%).1H NMR (DMSO-d6) 1.51-1.57 (m, 4H), 1.66-1.68 (m, 2H), 1.91-1.95 (m, 2H), 2.47 (s, 3H), 2.94 (s, 3H), 3.22 (t, 4H, J 5.0), 3.26 (t, 4H, J 5.0), 3.95-3.97 (m, 1H), 7.46 (dd, 1H, J 9.0 & 2.5), 7.98 (d, 1H, J 9.0), 8.02 (d, 1H, J 2.5), 8.24 (d, 1H, J 7.0), 8.42 (d, 1H, J 3.5), 9.57 (s, 1H). HRMS (ESI): m/z 533.1916 [M+H]+; calcd. for C23H30FN8O2S2+[M+H]+533.1912. Anal. RP-HPLC Method A: tR10.96 min, purity>99%; Method B: tR10.25 min, purity>98%. N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (83) To a solution of 5-(2-aminopyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (275 mg, 1.00 mmol) in dioxane (3 mL) were added 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (341 mg, 1.2 mmol), Pd2dba3(45.8 mg, 0.05 mmol), xantphose (58 mg, 0.1 mmol) and t-BuONa (144 mg, 1.5 mmol) and heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=9:1:0.3) and recrystallised with DCM and MeOH to give 83 as a white solid (200 mg, 42%).1H NMR (CDCl3) δ 1.09 (t, 3H, J 7.0), 1.58-1.76 (m, 6H), 2.08-2.14 (m, 2H), 2.43 (q, 2H, J 7.0, CH2CH3), 2.55 (s br, 11H), 3.48 (s, 2H), 3.86-3.92 (m, 1H), 5.42 (d, 2H, J 7.0), 6.90(d, 1H, J 5.5), 7.68 (dd, 1H, J 9.0 & 2.5), 7.89 (s, 1H), 8.19 (d, 1H, J 2.0), 8.35-8.38 (m, 2H). HRMS (ESI): m/z 479.2703 [M+H]+; calcd. for C25H35N8S+[M+H]+479.2700. Anal. RP-HPLC Method A: tR9.89 min, purity>96%; Method B: tR8.66 min, purity>96%. N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine (84) To a solution of 5-(2-amino-5-fluoropyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (200 mg, 0.68 mmol) in dioxane (3 mL) were added 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (233 mg, 0.82 mmol), Pd2dba3 (31 mg, 0.034 mmol), xantphose (41 mg, 0.07 mmol) and t-BuONa (98 mg, 1.02 mmol) and heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=93:7) to give 84 as an orange solid (100 mg, 29%).1H NMR (DMSO-d6) δ 0.99 (t, 3H, J 7.0), 1.49-1.59 (m, 4H), 1.64-1.72 (m, 2H), 1.90-1.97 (m, 2H), 2.38 (s br, 10H), 2.48 (d, 3H, J 2.5), 3.42 (s, 2H), 3.95-3.98 (m, 1H), 7.64 (dd, 1H, J 8.5 & 2.0), 8.10 (d, 1H, J 8.5), 8.16 (d, 1H, J 2.0), 8.27 (d, 1H, J 7.0), 8.46 (d, 1H, J 3.5), 9.77 (s, 1H). HRMS (ESI): m/z 497.2601 [M+H]+; calcd. for C25H34FN8S+[M+H]+497.2606. Anal. RP-HPLC Method A: tR9.89 min, purity>96%; Method B: tR8.66 min, purity>96%. N-Cyclopentyl-N,4-dimethyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (85) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (319 mg, 1.45 mmol) and (E)-1-(2-(cyclopentyl(methyl)amino)-4-methylthiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (250 mg, 0.85 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (68.0 mg, 1.70 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=93:7) and recrystallised with hexane to give 85 as a reddish brown solid (113 mg, 25%). m.p. 166-169° C.1H NMR (CDCl3) δ 1.58-1.79 (m, 6H), 1.96-2.02 (m, 2H), 2.11 (br, 1H), 2.56 (s, 3H), 3.01 (s, 3H), 3.06 (t, 4H, J 6.), 3.10 (t, 4H, J 6.0), 4.55 (m, 1H), 6.82 (d, 1H, J 5.5), 7.32 (dd, 1H, J 9.0 & 3.0), 8.02 (d, 1H, J 3.0), 8.13 (br, 1H), 8.28 (d, 1H, J 9.0), 8.32 (d, 1H, J 5.5). HRMS (ESI): m/z 451.2387 [M+H]+; calcd. for C23H31N8S+[M+H]+451 2387. Anal. RP-HPLC Method A: tR10.28 min, purity>95%; Method B: tR8.69 min, purity>95%. N-Cyclopentyl-N,4-dimethyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (86) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-1-(2-(cyclopentyl(methyl)amino)-4-methylthiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (293 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=93:7:0.5) and recrystallised with MeOH to give 86 as a yellow solid (149 mg, 32%). m.p. 169-170° C.1H NMR (CDCl3) δ 1.65-1.76 (m, 6H), 1.99-2.02 (m, 2H), 2.56 (s, 3H), 2.75 (s, 3H), 2.75 (s, 3H), 3.16 (br, 4H), 3.47 (t, 4H, J 5.0), 4.58 (m, 1H), 6.86 (d, 1H, J 5.5), 7.36 (dd, 1H, J 9.0 & 3.0), 8.05 (d, 1H, J 3.0), 8.07 (s, 1H), 8.32 (d, 1H, J 5.5), 8.35 (d, 1H, J 9.0). HRMS (ESI): m/z 465.2530 [M+H]+; calcd. for C24H33N8S+[M+H]+465.2543. Anal. RP-HPLC Method A: tR10.15 mm, purity>96%; Method B: tR8.47 min, purity>96%. 1-(4-(6-((4-(2-(Cyclopentyl(methyl)amino)-4-methylthiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one (87) To a mixture of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (525 mg, 2.00 mmol) and (E)-1-(2-(cyclopentyl(methyl)amino)-4-methylthiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (293 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=96:4) and recrystallised with Et2O to give 87 as a yellow solid (300 mg, 61%). m.p. 153-154° C.1H NMR (CDCl3) δ 1.61-1.76 (m, 6H), 1.97-2.02 (m, 2H), 2.15 (s, 3H), 2.57 (s, 3H), 3.01 (s, 3H), 3.09 (t, 2H, J 5.0), 3.13 (t, 2H, J 5.0), 3.63 (t, 2H, J 5.0), 3.79 (t, 2H, J 5.0), 4.56 (m, 1H), 6.85 (d, 1H, J 5.5), 7.34 (dd, 1H, J 9.0 & 3.0), 7.93 (s, 1H), 8.00 (d, 1H, J 3.0), 8.31 (s, 1H), 8.32 (d, 1H, J 5.0). HRMS (ESI): m/z 493.2482 [M+H]+; calcd. for C25H33N8OS+[M+H]+493.2493. Anal. RP-HPLC Method A: tR11.55 min, purity>96%; Method B: tR9.57 min, purity>96%. N,N-Dicyclopentyl-4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (88) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and (E)-1-(2-(Dicyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino) prop-2-en-1-one (200 mg, 0.58 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 2 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:10) and recrystallised with DCM and MeOH to give 88 yellow solid (60 mg, 21%).1H NMR (CDCl3) 1.53-1.59 (m, 8H), 1.74-1.76 (m, 4H), 1.85-1.89 (m, 2H), 1.91-1.98 (m, 2H), 2.42-2.47 (m, 1H), 2.58 (s, 3H), 3.05 (t, 4H, J 3.0), 3.10 (t, 4H, J 3.0), 3.41-3.44 (m, 1H), 4.47-4.54 (m, 1H), 6.61 (d, 1H, J 5.5), 7.32 (dd, 1H, J 9.0 & 3.0), 7.70 (s, 1H), 7.98 (d, 1H, J 3.0), 8.25 (d, 1H, J 9.0), 8.28 (d, 1H, J 5.5). HRMS (ESI): m/z 505.2873 [M+H]+; calcd. for C27H37N8S+[M+H]+505.2856. Anal. RP-HPLC Method A: tR8.57 min, purity>98%; Method B: tR7.33 min, purity>96%. 4-Methyl-N-phenyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (89) To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(4-methyl-2-(phenylamino)thiazol-5-yl)prop-2-en-1-one (287 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=90:10:0.5) to give 89 as a light yellow solid (178 mg, 40%). m.p. 228-230° C.1H NMR (DMSO-d6) δ 2.58 (s, 4H), 2.86 (t, 4H, J 4.5), 3.03 (t, 4H, J 4), 7.00 (m, 2H), 7.35 (m, 3H), 7.65 (d, 2H, J 8.0), 8.00 (d, 1H, J 2.5), 8.06 (d, 1H, J 9.0), 8.41 (d, 1H, J 5.0), 9.46 (s, 1H), 10.53 (s, 1H). HRMS (ESI): m/z 445.1918 [M+H]+; calcd. for C23H25N8S+[M+H]+445.1917. Anal. RP-HPLC Method A: tR10.01 min, purity 100%; Method B: tR8.17 min, purity 100%. 4-Methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N-phenylthiazol-2-amine (90) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(4-methyl-2-(phenylamino)thiazol-5-yl)prop-2-en-1-one (287 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=90:8) and recrystallised with DCM to give 90 as a light yellow (220 mg, 48%). mp. 210-211° C.1H NMR (DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 3.12 (br, 4H), 3.38 (t, 4H), 7.00 (m, 2H), 7.37 (m, 3H), 7.65 (d, 2H, J 8.0), 8.01 (d, 1H, J 2.0), 8.07 (d, 1H, J 9.0), 8.41 (d, 1H, J 5.0), 9.46 (s, 1H), 10.54 (s, 1H). HRMS (ESI): m/z 459.2063 [M+H]+; calcd. for C24H27N8S+[M+H]+459.2074. Anal. RP-HPLC Method A: tR9.93 min, purity 100%; Method B: tR9.17 min, purity 100%. N,4-Dimethyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N-phenylthiazol-2-amine (91) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-3-(dimethylamino)-1-(4-methyl-2-(methyl(phenyl)amino)thiazol-5-yl)prop-2-en-1-one (301 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave' irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=92:8) and recrystallised with hexane to give 91 as a reddish brown solid (184 mg, 39%). m.p. 212-215° C.1H NMR (CDCl3) δ 2.36 (s, 3H), 2.59 (app br, 7H), 3.14 (t, 4H, J 5.0), 3.57 (s, 3H), 6.80 (d, 1H, J 5.5), 7.19 (dd, 1H, J 9.0 & 3.0), 7.32 (m, 1H), 7.44 (m, 4H), 8.00 (d, 1H, J 3.0), 8.04 (s, 1H), 8.16 (d, 1H, J 9.0), 8.32 (d, 1H, J 5.5). HRMS (ESI): m/z 473.2220 [M+H]+; calcd. for C25H29N8S+[M+H]+473.2230. Anal. RP-HPLC Method A: tR9.57 min, purity>98%; Method B: tR7.90 min, purity>98%. 4-Methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one (92) Compound 92 was obtained as a grey solid (31 mg, 10%) by-product in the process of synthesising and purifying 4-(2-Methoxy-4-methylthiazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine. m.p. 228-230° C.1H NMR (DMSO-d6) 2.23 (s, 3H), 2.42 (s, 3H), 2.47 (t, 4H, J 4.5), 3.12 (t, 4H, J 4.5), 6.90 (d, 1H, J 5.0), 7.45 (dd, 1H, J 9.0 & 3.0), 7.99 (d, 1H, J 3.0), 8.02 (d, 1H, J 9.0), 8.41 (d, 1H, J 5.0), 9.53 (s, 1H). HRMS (ESI): m/z 384.1596 [M+H]+; calcd. for C18H22N7OS+[M+H]+384.1601. Anal. RP-HPLC Method A: tR8.59 min, purity>97%; Method B: tR3.59 min, purity>99%. 3,4-Dimethyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one (93) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-5-(3-(dimethylamino)acryloyl)-3,4-dimethylthiazol-2(3H)-one (226 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH:NH4OH=94:6:0.5) and recrystallised with hexane to give 93 as a yellow solid (72 mg, 18%). m.p. 243-244° C.1H NMR (CDCl3) 2.37 (s, 3H), 2.59 (s, 3H), 2.61 (t, 4H, J 4.0), 3.19 (t, 4H, J 4.0), 3.37 (s, 3H), 6.73 (d, 1H, J 5.0), 7.34 (dd, 1H, J 9.0 & 3.0), 7.87 (s, 1H), 8.00 (d, 1H, J 3.0), 8.21 (d, 1H, J 9.0), 8.406 (d, 1H, J 5.0). HRMS (ESI): m/z 398.1769 [M+H]+; calcd. for C19H24N7OS+[M+H]+398.1758. Anal. RP-HPLC Method A: tR8.25 min, purity 100%; Method B: tR3.31 min, purity 100%. 3-Ethyl-4-methyl-5-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one (94) To a mixture of crude 1-(5-(4-methylpiperazin-1-yl)pyridine-2-yl)guanidine trifluoroacetate (468 mg, 2.00 mmol) and (E)-5-(3-(dimethylamino)acryloyl)-3-ethyl-4-methylthiazol-2(3H)-one (240 mg, 1.00 mmol) in 2-methoxy ethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM ramping to DCM:MeOH=94:6) to give 94 as a yellow solid (108 mg, 26%). m.p. 181-182° C.1H NMR (CDCl3) 1.31 (t, 3H, J 7.0), 2.37 (s, 3H), 2.59 (s, 3H), 2.61 (t, 4H, J 5.0), 3.19 (t, 4H, J 5.0), 3.87 (q, 3H, J 7.0), 6.73 (d, 1H, J 5.0), 7.34 (dd, 1H, J 9.0 & 3.0), 8.03 (s, 1H), 8.22 (s, 1H), 8.22 (d, 1H, J 9.0), 8.40 (d, 1H, J 5.0). HRMS (ESI): m/z 412.1888 [M+H]+; calcd. for C20H26N7OS+[M+H]+412.1914. Anal. RP-HPLC Method A: tR8.36 mm, purity>99%; Method B: tR3.23 mm, purity>95%. 5-(2-((5-(4-Acetylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2(3H)-one (95) Compound 95 was obtained as a brown solid (30 mg, 7%) by-product in the process of synthesising and purifying 1-(4-(6-((4-(4-methyl-2-(methylthio)thiazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-one.1H NMR (DMSO-16) 2.04 (s, 3H), 2.42 (s, 3H), 3.07 (t, 2H, J 5.0), 3.14 (t, 2H, J 5.0), 3.58 (app m, 4H), 6.91 (d, 1H, J 5.5), 7.50 (dd, 1H, J 9.0 & 3.0), 8.02 (d, 1H, J 3.0), 8.05 (d, 1H, J 9.0), 8.42 (d, 1H, J 5.0), 9.56 (s, 1H). HRMS (ESI): m/z 412.1560 [M+H]+; calcd. for C19H22N7O2S+[M+H]+412.1550. Anal. RP-HPLC Method A: tR9.03 min, purity>99%; Method B: tR7.58 min, purity 100%. 3-Cyclopentyl-4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one (96) To a suspension of 5-(2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3-cyclopentyl-4-methylthiazol-2(3H)-one (100 mg, 0.21 mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by FlashMaster Personal chromatography (silica gel, DCM ramping to DCM:MeOH)=9:1) to give 96 as a yellow solid (73 mg, 80%).1H NMR (CDCl3) δ 1.61-1.64 (m, 2H), 1.90-1.99 (m, 4H), 2.26-2.30 (m, 2H), 2.58 (s, 3H), 3.07 (t, 4H, J 2.5), 3.11 (t, 4H, J 3.0), 4.43 (m, 1H), 6.70 (d, 1H, J 5.5), 7.34 (dd, 1H, J 9.0 & 3.0), 7.90 (s, 1H), 8.00 (d, 1H, J 3.0), 8.22 (d, 1H, J 9.0), 8.39 (d, 1H, J 5.5). HRMS (ESI): m/z 438.2073 [M+H]+; calcd. for C22H28N7OS+[M+H]+438.2071 Anal. RP-HPLC Method A: tR13.52 min, purity>94%, Method B: tR10.0 min, purity>99%. 4-Methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2(3H)-one (97) To a suspension of 5-(2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2(3H)-one (50 mg, 0.13mmol) in methanol HCl (32%, 3 mL) was added and reflexed overnight. The reaction mixture was concentrated and purified by FlashMaster Personal chromatography (silica gel, DCM ramping to DCM:MeOH:NH.4OH)=9:1:1) to give 97 as a grey solid (41 mg, 91%).1H NMR (DMSO-d6) 2.42 (s, 3H), 3.00 (t, 4H, J 5.0), 3.16 (t, 4H, J 5.0), 6.91 (d, 1H, J 5.5), 7.47 (dd, 1H, J 9.0 & 3.0), 8.01 (d, 1H, J 3.0), 8.04 (d, 1H, J 9.0), 8.41 (d, 1H, J 5.5), 9.54 (s, 1H). HRMS (ESI): m/z 370.1433 [M+H]+; calcd. for C17H20N7OS+[M+H]+370 1445. Anal. RP-HPLC Method A: tR7.42 min, purity>97%; Method B: tR3.59 min, purity>99%. Example 2 Biological Activity Kinase Assays Eurofins Pharma Discovery or Reaction Biology Corporation Kinase Profiler services were used to measure inhibition of CDKs and other kinases by radiometric assay. Inhibition of CDK4/D1, CDK6/D3 and CDK9/T1 were also determined in-house using ADP Glo Kinase assays (Promega Corporation, Madison, USA). Briefly, the kinase reaction for CDK4/D1 and CDK6/D3 was performed with kinase reaction buffer (40 nM Tris base pH 7.5, 20 mM MgCl2, 0.4 mM DTT), 0.1 mg/ml BSA and RB-CTF substrate (retinoblastoma protein1 C-terminal fraction). For CDK9/CyclinT1, the kinase reaction was performed with standard assay buffer and Kinase Dilution Buffer and RBER-IRStide substrate. Serial dilutions of 1:3 were prepared for test compounds for 10 concentrations (from 10 μM to 0.5 nM). The kinase reactions were started by addition of ATP, incubated for 40 min at 37° C. and then stopped by adding 10 μL of ADP Glo reagent. After incubation at room temperature in the dark for 40 min, 20 μL of kinase detection reagent was added per well and incubated for 40 min. Luminescence was measured using an EnVision Multilabel plate reader (PerkinElmer, Buckinghamshire, UK). Positive and negative controls were perfonned in the presence and absence of CDK kinases, respectively. Half-maximal inhibition (IC50) values were calculated using a 4-parameter logistic non-linear regression model with Graphpad prism (Version 6.0). Apparent inhibition constants (Ki) values were calculated from Km(ATP) and IC50values for the respective kinases. The results are shown in Table 2. Cell Viability Assay Compounds from Example 1 were subjected to a standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and resazurin assays on solid tumour cell lines and leukemia cell lines, respectively, as previously reported (Wang S et al., J Med Chem 47:1662-1675, 2004 and Diab S. et al. CheMedChem 9:962-972, 2014). Compound concentrations required to inhibit 50% of cell growth (GI50) were calculated using non-linear regression analysis. The results are shown in Tables 3 and 4. Cell Cycle Analysis and Apoptosis Cell cycle analysis and apoptosis studies were performed as described previously (Diab S. et al. CheMedChem 9:962-972, 2014; Teo T., et al. Cancer Letters, 357(2):612-623, 2015). Briefly, human acute myeloid leukaemia MV4-11 cells (1×105) were seeded and incubated overnight at 37° C. and 5% CO2. Cells were centrifuged at 300×g for 5 min upon treatment with inhibitor. Cell pellets were collected and fixed with 70% ethanol on ice for 15 min, followed by centrifugation at 300×g for 5 min. The collected pellets were incubated with staining solution (50 μg/mL PI, 0.1 mg/mL ribonuclease A, 0.05% Triton X-100) at 37° C. for an hour and analysed with Gallios flow cytometer. 1×105of the remaining cells were then used in an apoptotic assay with Annexin V-FITC Apoptosis Detection Kit. The samples were analysed by FACS within one hour of staining. Data were analysed using Kaluza v1.2. In an example shown inFIG.1, MV4-11 cells were treated with compound 60 for 24 hat the concentrations shown. It was found that compound 60 arrested cells in the G1 phase of the cell-cycle in a dose-dependent manner, confirming its inhibitory activity against cellular CDK4/6. Treatment of cancer cells with compounds resulted in apoptosis as represented by the sum of early (annexin-V+/PI−) and late (annexin-V+/PI+) apoptosis. A representative example is shown inFIG.2. Example 3 Pharmacokinetics For pharmacokinetic measurements, healthy male adult Balb/C mice (weighing 20-25 g) or Wistar Rat (weighing 250-350 g) were split into weight matched groups of 3 per group. Compound was administered IV (2 mg/kg for mice, 5 mg/kg for rats) via the tail vein or by oral gavage (20 mg/kg). Blood samples were collected from animals by jugular vein cannula (rats) or under anaesthesia by cardiac puncture (mice) at time zero and at intervals up to 24 h. Harvested blood was centrifuged at 7000×G for 2 minutes, and the plasma aspirated and frozen at −20° C. until analysis. Quantitative analysis of compound in plasma was carried out using LC-MS/MS methods. Pharmacokinetic data derived using Phoenix WinNonlin 6.4® non-compartmental analysis. Oral bioavailability (% F) was calculated by taking the ratio of dose-normalised AUC values from oral versus parenteral (IV) dosing. Pharmacokinetic profiles of example compounds are shown in Table 5. TABLE 2Inhibition of cyclin-dependant kinasesCDK inhibition Ki(μM) or % remaining enzymatic activity at 10 μMCompoundCDK1BCDK 2ACDK4D1CDK6D3CDK7HCDK9T11>5>50.0810.590>5>52>5>50.0550.245>5>53>51.9350.0300.170>5>54>5>50.0310.117>52.0375>5>50.0700.027>5>56>5>50.1190.201>5>57>51.710.0590.237>5>58>51.820.0240.980>5>59>51.800.0101.670>5>510>5>50.290ND*>5>511>5>50.250ND>5>512>52.340.180ND>5>5133.7400.2410.0110.030>5>5143.4100.2870.0100.029>54.180153.0950.4650.0050.025>5>5164.8500.2460.0620.209>5>5171.4400.0600.0010.0044.6901.72518>50.7750.0280.394>5>1019>53.6450.3100.935>54.76420>50.7200.0050.020>54.53021>52.7000.0070.042>5>522>54.7600.1901.95586%80%23>50.1800.0300.200>5>5243.9900.1800.0010.015>54.61025>50.0750.0050.020>5>526>50.8890.0060.114>52.8502756%34%0.0010.04039%11%281.3600.2360.0040.032>50.784293.2050.6500.0050.050>51.8203066%36%0.0040.03243%9%31>50.3650.0020.010>51.90532>50.6650.0050.020>52.925333.1010.3100.5783.032>5>534>54.4660.0040.030>5>5351.8200.1780.0170.046>54.07036>50.4590.0200.610>5>537>50.2010.0040.064>5>5383.3150.1000.0050.030>5>539>5>50.1692.710>5>540>5>50.0160.036>50.999410.1330.0370.0060.2250.0670.117420.0890.0170.0010.0360.1010.03443>50.9030.0210.056>5>544>50.3350.0040.040>5>545>51.4300.0300.154>5>546>51.390.0020.055>54.3647>53.3350.0020.279>5>548>50.9760.0870.234>5>549>51.040.0240.366>5>550>50.0690.044ND>5>551NDND>5NDNDND520.5800.0760.0370.297>5>5532.3700.2060.0030.032>53.03754NDND>5NDNDND553.1400.2400.0050.0110.7752.420563.8150.3990.0030.0150.7600.773572.6950.2000.0210.1054.3853.71758>50.1270.0410.082>5>559>50.8000.0160.0281.1600.92560>5>50.0010.0341.1080.220612.2350.2560.0030.0070.7900.787620.2200.0220.0080.0020.1940.258632.6750.2060.0020.0090.8650.180642.3300.1030.0010.0032.0200.505650.2410.0220.0010.0030.1890.831663.020.3550.0020.0110.7800.14167>50.3490.0020.0060.685>5683.2520.7760.0060.0933.4530.28669>50.2280.0340.023>54.990700.2970.0140.0040.0062.615>571>52.9400.0050.029>5>5724.3500.1040.0060.020>5>573>50.1540.0080.011>5>5741.2300.1810.0030.1331.1870.17375>5>50.0700.257>5>5764.0700.2780.0010.0080.2820.508771.1000.0770.0070.0552.6401.32178——0.570——>5790.3450.0150.0110.0071.900>580>51.1500.0010.031>51.09181>50.4170.0140.0100.8150.67982>50.3480.0390.101>5>583>50.4160.0060.0090.2111.98484>50.6200.0030.0140.6303.570851.3900.1740.0020.0103.201.80186>50.4760.0020.010>51.800873.1700.1210.0100.031>5>588>15>50.0710.539>5>5892.040>50.0050.0661.6600.43690>5>50.0190.485>5>591>51.0400.0260.100>52.009251%61%0.0270.15524%0.9509371%77%0.2550.91552%0.840943.6601.3400.0330.3201.2601.5809555%40%ND25%68%17%9663%61%ND11%22%15%9758%54%ND12%24%3% TABLE 3Anti-proliferative activity (72 h, GI50μM) of example compoundsCompound No.MV4-11MDA-MB-45311.099 ± 0.345>1021.021 ± 0.007>1030.053 ± 0.0030.378 ± 0.02940.296 ± 0.2871.973 ± 0.40450.500 ± 0.2470.914 ± 0.09862.129 ± 0.969>1070.606 ± 0.1503.860 ± 0.22080.750 ± 0.2463.009 ± 0.70590.591 ± 0.0833.320 ± 0.576105.372 ± 1.685>1011>10>10125.294 ± 0.811>10130.029 ± 0.0190.703 ± 0.071140.596 ± 0.231>10150.063 ± 0.0260.542 ± 0.065160.457 ± 0.122>10170.649 ± 0.0241.054 ± 0.203180.418 ± 0.0230.166 ± 0.117193.518 ± 1.044>10200.671 ± 0.0913.137 ± 0.173210.456 ± 0.0667.156 ± 0.886222.511 ± 0.432>10230.073 ± 0.0250.461 ± 0.059240.066 ± 0.0194.877 ± 0.214250.537 ± 0.1170.514 ± 0.050260.259 ± 0.241—270.014 ± 0.006—280.012 ± 0.0030.248 ± 0.044290.297 ± 0.0610.544 ± 0.078300.056 ± 0.004—310.011 ± 0.0040.381 ± 0.096320.065 ± 0.0020.528 ± 0.046330.154 ± 0.0745.840 ± 0.279340.174 ± 0.0220.813 ± 0.022350.035 ± 0.0044.912 ± 0.432360.643 ± 0.018—370.465 ± 0.129—380.069 ± 0.0055.407 ± 0.8013945.90 ± 2.520—400.084 ± 0.008—410.038 ± 0.006—420.037 ± 0.006—430.011 ± 0.0210.894 ± 0.091440.048 ± 0.0040.237 ± 0.044450.092 ± 0.0042.102 ± 0.787460.073 ± 0.0100.638 ± 0.042470.107 ± 0.0220.349 ± 0.036480.537 ± 0.1334.718 ± 0.715490.208 ± 0.0302.369 ± 0.026504.675 ± 0.2985.358 ± 0.501510.606 ± 0.0380.463 ± 0.075520.425 ± 0.0730.660 ± 0.092530.080 ± 0.0130.362 ± 0.003542.158 ± 0.4312.941 ± 0.507550.093 ± 0.0100.031 ± 0.002560.075 ± 0.0050.618 ± 0.193572.071 ± 0.3210.344 ± 0.126580.032 ± 0.0030.115 ± 0.024590.255 ± 0.0850.938 ± 0.068600.023 ± 0.0240.070 ± 0.013610.053 ± 0.0040.780 ± 0.598620.002 ± 0.0010.081 ± 0.039630.009 ± 0.0000.130 ± 0.011640.073 ± 0.0280.202 ± 0.030650.001 ± 0.0010.420 ± 0.120660.009 ± 0.0010.287 ± 0.070670.013 ± 0.0020.066 ± 0.019680.024 ± 0.0280.591 ± 0.256690.015 ± 0.0028.107 ± 1.147700.012 ± 0.0010.077 ± 0.001710.335 ± 0.1843.683 ± 0.285720.290 ± 0.0621.437 ± 0.304730.069 ± 0.0130.415 ± 0.103740.022 ± 0.0020.055 ± 0.012750.191 ± 0.0297.035 ± 0.710760.029 ± 0.0020.102 ± 0.117770.176 ± 0.0090.215 ± 0.052780.300 ± 0.0354.379 ± 0.691790.004 ± 0.0010.336 ± 0.188800.454 ± 0.0400.356 ± 0.024810.029 ± 0.0020.083 ± 0.009822.628 ± 0.5822.813 ± 0.089830.019 ± 0.0030.004 ± 0.002840.010 ± 0.0020.622 ± 0.208850.285 ± 0.0410.402 ± 0.006860.020 ± 0.0153.360 ± 0.286870.328 ± 0.0076.864 ± 0.798880.714 ± 0.1790.373 ± 0.117890.056 ± 0.0110.279 ± 0.044900.508 ± 0.0420.494 ± 0.081910.421 ± 0.0440.150 ± 0.029920.752 ± 0.0333.327 ± 0.864933.725 ± 0.357>10941.829 ± 0.194>10952.238 ± 0.043>10960.792 ± 0.0742.858 ± 0.988971.512 ± 0.802>10 TABLE 4Antiproliferative activity (72 h, GI50μM) of representative compounds.LeukemiaOvarianMedulloblastomaCompoundKG-1MOLM-13A2780D458D28390.047 ± 0.0150.293 ± 0.028———29——0.282 ± 0.0580.326 ± 0.0290.335 ± 0.09731——0.094 ± 0.0010.645 ± 0.0970.489 ± 0.022340.112 ± 0.0450.408 ± 0.025———460.005 ± 0.0040.098 ± 0.012———470.006 ± 0.0010.076 ± 0.008———60——0.081 ± 0.0010.321 ± 0.0680.124 ± 0.02064——0.056 ± 0.0070.457 ± 0.1710.077 ± 0.00686——0.072 ± 0.0200.617 ± 0.1120.358 ± 0.100 TABLE 5Pharmacokinetic properties of representativecompounds 60, 71, and 34Compounds (po, 20 mg/kg in rat)Pharmacokinetic parameter60a7171b34Cmax (μM)0.51.41.60.6AUC (μM · hr)6.615.95.910.2t1/2(hr)16.42.85.04.6Oral bioavailability (F %)512710039a40 mg/kg in rat,b10 mg/kg in mice. Throughout the specification and the claims that follow, unless the context requires otherwise, the words “comprise” and “include” and variations such as “comprising” and “including” will be understood to imply the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement of any form of suggestion that such prior art forms part of the common general knowledge. It will be appreciated by those skilled in the art that the invention is not restricted in its use to the particular application described. Neither is the present invention restricted in its preferred embodiment with regard to the particular elements and/or features described or depicted herein. It will be appreciated that the invention is not limited to the embodiment or embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the scope of the invention as set forth and defined by the following claims. Please note that the following claims are provisional claims only, and are provided as examples of possible claims and are not intended to limit the scope of what may be claimed in any future patent applications based on the present application. Integers may be added to or omitted from the example claims at a later date so as to further define or re-define the invention. | 175,018 |
RE49851 | The present invention will be further illustrated hereinafter in connection with specific Examples. It should be understood that these Examples are only used to illustrate the present invention by the way of examples without limiting the scope thereof. In the following Examples, the experimental methods without specifying conditions are generally performed according to conventional conditions or based on the conditions recommended by the manufacturer. The parts and percentages are the parts and percentages by weight respectively, unless otherwise specified. DETAILED DESCRIPTION OF THE INVENTION 1. Preparation Examples of the Compounds of the Present Invention Intermediate 1a: N2-methyl-N2-[2-(dimethylamino)ethyl]-6-methoxy-3-nitropyridin-2,5-diamine hydrochloride Step 1: Synthesis of 6-chloro-2-methoxy-3-nitropyridine To a 250 mL three-necked flask were added 2,6-dichloro-3-nitropyridine (11.58 g, 60 mmol), 150 ml tetrahydrofuranand methanol (1.92 g, 60 mmol). The mixture was cooled to 0° C. To the mixture was added in batch 60% sodium hydride (2.4 g, 60 mmol). The resulting mixture was stirred at 0° C. for 1 hour, warmed up slowly to room temperature, and continued to stir for 1 hour. To the reaction mixture was added 100 ml ethyl acetate. The reaction mixture was washed successively with water (50 ml×2) and saturated brine (50 ml). The organic phase was dried with anhydrous sodium sulfate, filtered, evaporated under a reduced pressure to remove the solvent, purified by silica gel column chromatography (petroleum ether:ethyl acetate=30:1) to produce 7.3 g of a product with a yield of 64%. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.15 (s, 3H). Step 2: Synthesis of 6-chloro-2-methoxypyridin-3-amine To a 100 mL single-necked flask were added 6-chloro-2-methoxy-3-nitropyridine (2.0 g, 10.6 mmol), ammonia chloride (2.8 g, 53.0 mmol) and 80 ml of a mixed solvent of ethanol and water (volume ratio=3:1). To the mixture was added in batch a reduced iron powders (3.0 g, 53.0 mmol). The mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and filtered through diatomite. 150 ml ethyl acetate and 120 ml saturated sodium chloride were added to the filtrate. An organic layer was separated and dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure to produce a brown solid (1.6 g) with a yield of 95%. MS m/z: 159 [M+1]. Step 3: Synthesis of N-(6-chloro-2-methoxypyridin-3-yl)acetamide To a 250 mL single-necked flask were added 6-chloro-2-methoxypyridin-3-amine (1.6 g, 10.1 mmol), diisopropylethylamine (2.6 ml, 15.1 mmol) and 100 ml dichloromethane. The mixture was cooled to 5° C. in an ice bath. Acetyl chloride (0.86 ml, 12.1 mmol) was added. The reaction continued for 1.25 hours. The reaction mixture was washed successively with 80 ml water, 80 ml 1N hydrochloric acid and 80 ml saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness under a reduced pressure to produce 1.9 g of a brown solid with a yield of 94%. MS m/z: 201 [M+1]. Step 4: Synthesis of N-(6-chloro-2-methoxy-5-nitropyridin-3-yl)acetamide To a 100 mL single-necked flask were added N-(6-chloro-2-methoxypyridin-3-yl)acetamide (1.9 g, 9.47 mmol) and 20 ml trifluoroacetic anhydride. The mixture was cooled in an ice-salt bath to −10° C. Fuming nitric acid (0.4 ml, 9.47 mmol) was dropwisely added while the temperature was controlled to below −5° C. After the completion of dropwise addition, the reaction continued in an ice-salt bath for 1.25 hours. The reaction mixture was slowly added to crushed ice. A solid precipitated and was filtered. The resulting crude product was dried at 60° C., and added to ethyl acetate to form a slurry. 1.5 g of an beige solid was obtained with a yield of 65%. MS m/z: 244 [M−1]. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.17 (s, 1H), 4.06 (s, 3H), 2.17 (s, 3H). Step 5: Synthesis of N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-nitropyridin-3-yl}acetamide hydrochloride To a 100 mL single-necked flask were added N-(6-chloro-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 4.1 mmol), 30 ml acetonitrile and N,N,N′-trimethylethylenediamine (0.6 g, 6.1 mmol). The mixture was reacted at 80° C. for 3 hours. The reaction mixture was concentrated under a reduced pressure to about ⅓ of the original volume. 50 ml ethyl acetate was added. The mixture was stirred for several minutes, a solid precipitated and was filtered to produce 1.1 g of an beige solid with a yield of 87%. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.53 (s, 1H), 8.73 (s, 1H), 4.05 (s, 5H), 3.41 3.36 (m, 2H), 2.83 (s, 3H), 2.80 (s, 6H), 2.07 (s, 3H). Step 6: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-methoxy-3-nitropyridin-2,5-diamine hydrochloride To a 50 mL single-necked flask were added N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-nitropyridin-3-yl}acetamide (600 mg, 1.93 mmol), 15 ml methanol and 0.3 ml concentrated hydrochloric acid. The mixture was reacted at 60° C. overnight. The reaction mixture was evaporated to dryness under a reduced pressure. 100 ml dichloromethane and 80 ml saturated sodium bicarbonate were added. The resulting mixture was stirred until no bubble produced. An organic layer was separated and dried with anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (dichloromelhanemethanol=10:1) to produce 400 mg of a brown solid. MS m/z: 270 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.16 (s, 1H), 4.06-4.02 (m, 5H), 3.38 (br s, 2H), 2.83 (s, 3H), 2.80 (s, 3H), 2.79 (s, 3H). Intermediate 1b: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-3-nitropyridin-2,5-diamine Step 1: Synthesis of 6-chloro-2-isopropyloxy-3-nitropyridine The compound was synthesized in the same manner as those in Step 1 of Intermediate 1a. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 5.50 (kept, J=6.2 Hz, 1H), 1.43 (d, J=6.2 Hz, 6H). Step 2: Synthesis of 6-chloro-2-isopropyloxypyridin-3-amine The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 74%. MS m/z: 187 [M+1], 189. Step 3: Synthesis of N-(6-chloro-2-isopropyloxypyridin-3-yl)acetamide The compound was synthesized in the same manner as those in Step 3 of Intermediate 1a with a yield of 83%. MS m/z: 229 [M+1], 231. Step 4: Synthesis of N-(6-chloro-2-isopropyloxy-5-nitropyridin-3-yl)acetamide The compound was synthesized in the same manner as those in Step 4 of Intermediate 1a with a yield of 33%. MS m/z: 272 [M−1]. Step 5: Synthesis of N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide To a 500 mL single-necked flask were added N-(6-chloro-2-isopropyloxy-5-nitropyridin-3-yl)acetamide (15 g, 54.8 mmol), 150 ml acetonitrile, N,N,N′-trimethylethylenediamine (7.28 g, 71.3 mmol) and potassium carbonate (15.15 g, 110 mmol). The mixture was reacted at 80° C. overnight. The reaction mixture was cooled to room temperature, and filtered. The filtrate was evaporated to dryness under a reduced pressure to produce 18.6 g of a product with a yield of 100%. MS m/z: 340 [M+1]. Step 6: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 6 of Intermediate 1a with a yield of 38%. MS m/z: 298 [M+1]. Intermediate 1c: N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-3-nitropyridin-2,5-diamine Step 1: Synthesis of 6-chloro-2-(2,2,2-trifluoroethoxyl)-3-nitropyridine The compound was synthesized in the same manner as those in Step 1 of Intermediate 1a with a yield of 80%. Step 2: Synthesis of 6-chloro-2-(2,2,2-trifluoroethoxyl)pyridin-3-amine The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 83%. Step 3: Synthesis of N-[6-chloro-2-(2,2,2-trifuoroethoxyl)pyridin-3-yl]acetamide The compound was synthesized in the same manner as those in Step 3 of Intermediate 1a with a yield of 71%. MS m/z: 269 [M+1], 271. Step 4: Synthesis of N-[6-chloro-2-(2,2,2-trifluoroethoxyl)-5-nitropyridin-3-yl]acetamide The compound was synthesized in the same manner as those in Step 4 of Intermediate 1a with a yield of 53%. MS m/z: 314 [M+1], 316. 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 7.63 (s, 1H), 4.93 (q, J=8.2 Hz, 2H), 2.30 (s, 3H). Step 5: Synthesis of N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-(2,2,2-trifluoroethoxyl)-5-nitropyridin-3-yl}acetamide To a 25 mL single-necked flask were added N-[6-chloro-2-(2,2,2-trifluoroethoxyl)]-5-nitropyridin-3-ypacetamide (626 mg, 2 mmol), 10 ml acetonitrile, N,N,N′-trimethylethylenediamine (224 mg, 2.2 mmol) and potassium carbonate (138 mg, 4 mmol). The mixture was stirred at room temperature overnight. To the reaction mixture was added 100 ml ethyl acetate. The resulting mixture was washed with 20 ml water, dried with anhydrous sodium sulfate, and evaporated under a reduced pressure to remove the solvent to produce 710 mg of a product with a yield of 94%. MS m/z: 380 [M+1]. Step 6: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 6 of Intermediate 1a with a yield of 100%. MS m/z: 338 [M+1]. Intermediate 1d: tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate Step 1: Synthesis of N-tert-butoxycarbonyl-N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide To a 500 mL single-necked flask were added N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide (18.6 g, 54.8 mmol), 4-dimethylaminopyridine (0.67 g, 5.48 mmol), 150 ml acetonitrile and di-tert-butyl dicarbonate (59.8 g, 274 mmol). The mixture was reacted at 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature, was evaporated to dryness under a reduced pressure, and purified by silica gel column chromatography (dichloromethane methanol=10:1) to produce 24 g of a product with a yield of 100%. Step 2: Synthesis of tert-butyl {6-({[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}carbamate To a 500 mL single-necked flask were added N-tertbutoxycarbonyl-N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide (24 g, 54.6 mmol) and 240 ml methanol. The mixture was cooled to 0° C. Sodium methoxide (2.95 g, 54.6 nunol) was added. The mixture was slowly warmed up to room temperature and reacted overnight. The reaction mixture was concentrated under a reduced pressure. The residue was dissolved in 300 ml ethyl acetate, and washed with 100 ml water. The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness under a reduced pressure to produce 18 g of a product with a yield of 83%. Step 3: Synthesis of tert-butyl {5-amino-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 97%. MS m/z: 368 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.44 (s, 1H), 6.74 (br s, 2H), 5.09-4.96 (m, 1H), 3.29 (t, J=5.8 Hz, 2H), 3.19 (t, J=5.7 Hz, 2H), 2.70 (s, 6H), 2.56 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=6.2 Hz, 6H). Step 4: Synthesis of tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}-carbamate To a 500 ml three-necked flask were added tert-butyl {5-amino-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate (9 g, 24.49 mmol), trimethylamine (6.83 ml, 49.0 mmol) and 250 ml dichloromethane. The reaction mixture was cooled in an ice-water bath to below 5° C. Acryloyl chloride (2.1 ml, 25.7 mmol) was dropwisely added. The resulting mixture was continued to react for 1 hour. The reaction mixture was washed successively with 150 ml saturated sodium bicarbonate solution and 150 ml saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure to produce 5 g of a product with a yield of 48%. MS m/z: 422 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 6.44 (dd, J=17.0, 10.1 Hz, 1H), 6.22 (dd, J=17.0, 1.9 Hz, IH), 5.74 (dd, J=10.1, 1.9 Hz, 1H), 5.22-5.13 (m, 1H), 3.09 (t, J=6.5 Hz, 2H), 2.77 (s, 3H), 2.41 (t, J=6.5 Hz, 2H), 2.18 (s, 6H), 1.45 (s, 9H), 1.31 (d, J=6.2 Hz, 6H). Intermediate 1e: tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-(2,2,2-trifluoroethoxyl)pyridin-3-yl}carbamate The compound was synthesized in the same manner as those in Step 1 of Intermediate 1d with a yield of 99%. MS m/z: 480 [M+1]. Step 2: Synthesis of tert-butyl {6- f[2-(dimethylamino)ethyl](methypamino}-2-(2,2,2-trifluoroethoxyl)-5-nitropyridin-3-ylIcarbamate The compound was synthesized in the same manner as those in Step 2 of Intermediate 1d with a yield of 88%. MS m/z: 438 [M+1]. Step 3: Synthesis of tert-butyl {5-amino-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-(2,2,2-trifluoroethoxyl)pyridin-3-yl}carbamate The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 76%. MS m/z: 408 [M+1]. Step 4: Synthesis of tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl0amino}-2-(2,2,2-trifluoroethoxyl)pyridin-3-yl}carbamate The compound was synthesized in the same manner as those in Step 4 of Intermediate 1d with a yield of 62%. MS m/z: 462 [M+1]. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 9.35 (s, 1H), 6.61 (s, 1H), 6.46 (dd, J=16.9, 1.7 Hz, 1H), 6.39-6.25 (m, 1H), 5.70 (dd, J=10.0, 1.8 Hz, 1H), 4.76 (q, J=8.5 Hz, 2H), 2.96 (s, 2H), 2.71 (s, 3H), 2.42 (s, 2H), 2.34 (s, 6H), 1.53 (s, 9H). Intermediate 2a: 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole To a 500 mL single-necked flask were added 2,4-dichloropyrimidine (14.9 g, 100 mmol), 1-methyl-1H-indole (13 g, 100 mmol), 200 ml 1,2-diclaloroethane and aluminium chloride (13.9 g, 120 mmol). The mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature in an ice bath. 120 ml methanol and 400 ml water were added to quench the reaction. A solid precipitated and was filtered. The filter cake was washed with methanol, and dried in vacuum to produce 17.2 g of a product with a yield of 71%. MS m/z: 244 [M+1], 246. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.42 (dd, J=7.0, 1.5 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H), 7.33-7.26 (m, 2H), 3.90 (d, J=5.2 Hz, 3-H). Intermediate 2b: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 87%. MS m/z: 278[M+1], 279, 280. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.74 (s, 1H), 8.56 (dd, J=7.3, 1.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.39-7.34 (m, 1H), 7.34-7.29 (m, 1H), 3.97 (s, 3H). Intermediate 2c: 3-(2-chloropyrimidin-4-yl)-1-methyl-5-fluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 29%. MS m/z: 262 [M+1], 264. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.10 (dd, J=10.3, 2.5 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.60 (dd, J=8.9, 4.6 Hz, 1H), 7.17 (td, J=9.1, 2.6 Hz, 1H), 3.90 (s, 3H). Intermediate 2d: 3-(2-chloropyrimidin-4-yl)-1-methyl-6-fluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 262 [M+1], 264. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.39 (dd, J=8.8, 5.6 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.47 (dd, J=9.9, 2.3 Hz, 1H), 7.14 (td, J=9.6, 2.4 Hz, 1H), 3.86 (s, 3H). Intermediate 2e: 3-(2-chloropyrimidin-4-yl)-1-methyl-5,6-difluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 280 [M+1], 282. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=5.5 Hz, 1H), 8.52 (s, 1H), 8.22 (dd, J=11.7, 8.2 Hz, 1H), 7.79 (d, J=5.5 Hz, 1H), 7.73 (dd, J=11.2, 7.0 Hz, 1H), 3.86 (s, 3H). Intermediate 2f: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-6-fluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 296 [M+1], 297, 298. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=8.9, 5.5 Hz, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.17 7.07 (m, 2H), 3.90 (s, 3H). Intermediate 2g: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-5,6-difluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 314 [M+1], 315, 316. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.77 (s, 1H), 8.39 (dd, J=12.1, 8.3 Hz, 1H), 7.83 (dd, J=11.0, 7.1 Hz, 1H), 3.94 (s, 3H). Intennediate 2h: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-5-fluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 296 [M+1], 297, 298. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.46 (s, 1H), 8.46-8.42 (m, 1H), 7.34 (dd, J=8.9, 4.4 Hz, 1H), 7.14 (td, J=8.9, 2.6 Hz, 1H), 3.94 (s, 3H). Intermediate 2i: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 73%. MS m/z: 262 [M+1], 264. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=3.7 Hz, 1H), 8.54 (dd, J=7.2, 1.2 Hz, 1H), 8.39 (d, J=3.0 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.41-7.30 (m, 2H), 3.96 (s, 3H). Intermediate 2j: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-5-fluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 77%. MS m/z: 280 [M+1], 282. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=3.5 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H), 8.20 (dd, J=10.3, 2.5 Hz, 1H), 7.66 (dd, J=8.9, 4.5 Hz, 1H), 7.30-7.16 (m, 1H), 3.96 (s, 3H). Intermediate 2k: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-5,6-difluoro-1H-indole The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 298 [M+1], 300. 1H NMR (400 MHz, CDCl3) δ 8.56 (dd, J=11.4, 8.1 Hz, 1H), 8.36 (d, J=3.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.19 (dd, J=10.1, 6.6 Hz, 1H), 3.90 (s, 3H). Intermediate 2l: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrropyrrolo[2,3-b]pyridine Step 1: Synthesis of 3-bromo-1-p-tosyl-1H-pyrropyrrolo[2,3-b]pyridine To a 250 mL three-necked flask were added 3-bromo-1H-pyrropyrrolo[2,3-b]pyridine (4.0 g, 20.3 mmol) and 80 ml tetrahydrofuran. The mixture was cooled to below 5° C. in an ice-water bath. 60% of sodium hydride (1.3 g, 32.5 mmol) was added. The mixture was stirred for 15 minutes. p-Toluensulfonyl chloride (4.1 g, 21.3 mmol) was added. The reaction continued for 15 minutes. 150 ml water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (150 ml). The organic layer was evaporated to dryness under a reduced pressure to produce a brown solid, which was added to petroleum ether to form a shiny, and a brown solid (5 g) was obtained with a yield of 70%. MS m/z: 351 [M+1], 353. Step 2: Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1-p-tosyl-1H-pyrropyrrolo[2,3-b]pyridine To a 100 mL single-necked flask were added 3-bromo-1-p-tosyl-1H-pyrropyrrolo[2,3-b]pyridine (2.0 g, 5.7 mmol), bis(pinacolato)diboron (1.9 g, 7.4 mmol), potassium acetate (1.7 g, 17.1 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (0.21 g, 0.285 mmol) and 25 ml dioxane with atmosphere replaced by argon. The mixture was reacted at 85° C. for 6.5 hours. LC-MS monitoring showed the starting materials were depleted. To the reaction mixture was added 2,4,5-trichloropyrimidine (1.3 g, 7.0 mmol), 5 ml 2N sodium carbonate solution and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (0.37 g, 0.50 mmol) with atmosphere replaced by argon. The reaction continued at 85° C. overnight. The reaction mixture was diluted with 150 ml ethyl acetate, and washed with 150 ml water. The aqueous phase was extracted with dichloromethane (120 ml×3). The organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1). The product was added to a mixed solvent of petroleum ether and ethyl acetate (volume ratio=2:1) to form a slurry, and 1.0 g of an off-white solid was obtained with a yield of 42%. MS m/z: 419 [M+1], 421. Step 3: Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1H-pyrropyrrolo[2,3-b]pyridine To a 100 mL single-necked flask were added 3-(2,5-dichloropyrimidin-4-yl)-1-p-tosyl-1H-pyrropyrrolo[2,3-b]pyridine (0.95 g, 2.3 mmol) and 30 ml tetrahydrofuran. Under stirring, tetrabutylammonium fluoride (1.2 g, 4.6 mmol) was added. The mixture was reacted at room temperature for 20 minutes. To the reaction mixture was added 100 ml ethyl acetate. The reaction mixture was washed with 100 ml water. The organic phase was dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure. The residue was added to 20 ml of a mixed solvent of petroleum ether and ethyl acetate (volume ratio=4:1) to form a slurry. The slurry was filtered by suction to produce 500 mg of an off-white solid with a yield of 83%. MS m/z: 265 [M+1]. Step 4: Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrropyrrolo[2,3-b]pyridine To a 50 ml three-necked flask were added 3-(2,5-dichloropyrimidin-4-yl)-1H-pyrropyrrolo[2,3-b]pyridine (480 mg, 1.8 mmol) and 15 ml N,N-dimethylformamide. The resulting mixture was cooled to 5° C. under an ice-water bath. 60% of sodium hydride (145 mg, 3.6 mmol) was added. The mixture was stirred for 10 minutes, and methyl iodide (0.12 ml, 1.9 mmol) was added thereto. The resulting mixture was stirred at 5° C. for 15 minutes. The reaction mixture was poured to ice-water, and a solid precipitated and was filtered by suction. The filter cake was dried to produce 450 mg ofanabeige solid with a yield of 89%. MS m/z: 265 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.81 (dd, J=8.0, 1.6 Hz, 1H), 8.78 (s, 1H), 8.44 (dd, J=4.7, 1.6 Hz, 1H), 7.38 (dd, J=8.0, 4.7 Hz, 1H), 3.97 (s, 3H). Intermediate 2m: 5-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-pyrropyrrolo[2,3-b]pyridine The compound was synthesized in the same manner as those in Step 2 of Intermediate 21 with a yield of 50%. MS m/z: 279 [M+1]. 1HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.75 (d, J=2.1 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 7.68 (d, J=3.5 Hz, 1H), 6.66 (d, J=3.5 Hz, 1H), 3.90 (s, 3H). Intermediate 2n: 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine To a three-necked flask were added 2,4,5-trichloropyrimidine (2.0 g, 10.9 mmol), 1-methyl-4-pyrazole-bis(pinacolato)diboron (1.75 g, 8.4 mmol), 8.4 ml 2N sodium carbonate solution, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (0.61 g, 0.84 mmol) and 30 ml dioxane with atmosphere replaced by argon. The mixture was stirred at 80° C. overnight. To the reaction mixture was added 150 ml ethyl acetate, washed successively with 150 ml water and 100 ml saturated sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated to dryness under a reduced pressure to produce a earth yellow solid (1.6 g) with a yield of 83%. MS m/z: 229 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 3.96 (s, 3H). Intermediate 2o: 2,5-dichloro-2′-methoxy-4,5′-bipyrimidine The compound was synthesized in the same manner as those in Intermediate 2n with a yield of 70%. MS m/z: 257 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 9.05 (s, 1H), 4.04 (s, 3H). Intermediate 2p: 2,5-dichloro-2′-amino-4,5′-bipyrimidine The compound was synthesized in the same manner as those in Intermediate 2n with a yield of 44%. MS m/z: 242 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.84 (s, 2H), 7.52 (s, 2H). Example 1: N-{2-{[2-(dimethylamino)ethyl] (methy)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5[5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine To a 50 mL single-necked flask were added N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-3-nitropyridin-2,5-diamine (490 mg, 1.65 mmol), 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (550 mg, 1.98 mmol), tris(dibenzylideneacetone)dipalladium (226 mg, 0.2475 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (286 mg, 0.495 mmol), potassium phosphate (874 mg, 4.125 mmol) and 15 ml dioxane. Under the nitrogen protection, the mixture was reacted at 100° C. overnight. The reaction mixture was filtered with diatomite. The filtrate was evaporated to dryness under a reduced pressure, purified by silica gel column chromatography (dichloromethane:methanol=50:1) to produce 480 mg of a product with a yield of 54%. MS in/z: 539 [M+1]. Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine To a 50 mL single-necked flask were added N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine (480 mg, 0.892 mmol), ammonia chloride (48 mg, 0.897 mmol) and 12 ml of a mixed solvent of ethanol and water (volume ratio=3:1). To the mixture was added in batch a reduced iron powders (240 mg, 4.26 mmol). The mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and filtered through diatomite. The filtrate was evaporated to dryness under a reduced pressure, dissolved in dichloromethane, and washed with a saturated sodium carbonate solution. The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under a reduced pressure, and subjected to a preparative TLC separation (dichloromethane:ethyl acetate:methanol=5:5:1) to produce 96 mg of a product with a yield of 43%. MS m/z: 509 [M+1]. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide To a 50 ml single-necked flask were added N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine (196 mg, 0.385 mmol) and 10 ml dichloromethane. The reaction mixture was cooled in an ice-water bath. 0.5 N of a solution of acryloyl chloride in dichloromethane (0.8 ml, 0.4 mmol) and triethylamine (0.15 ml, 1.08 mmol) were added. The mixture was reacted at room temperature for 0.5 hour. To the reaction mixture was added a suitable amount of water. The dichloromethane layer was separated, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and purified by preparative TLC separation (dichloromethane:ethyl acetate:methano=5:5:1) to produce 130 mg of a pale-yellow solid with a yield of 60%. MS m/z: 563 [M+1], 565. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.36 (s, 1H), 8.39 (s, 1H), 8.38-8.33 (m, 1H), 8.29 (s, 1H), 7.40 (s, 1H), 7.38-7.33 (m, 1H), 7.33-7.27 (m, 2H), 7.06 (dd, J=16.9, 10.2 Hz, 1H), 6.39 (d, J=16.9 Hz, 1H), 5.70 (d, J=10.2 Hz, 1H), 5.29-5.20 (m, 1H), 3.90 (s, 3H), 3.51-3.46 (m, 2H), 3.09 (br s, 2H), 2.77 (s, 3H), 2.75 (s, 6H), 1.38 (d, J=6.2 Hz, 6H). Example 2: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 100%. Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropylory-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine N2-methyl-N2-[2(dimethylamino)ethyl]-6-isopropyloxy-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine (200 mg, 0.397 mmol) was dissolved in 12 ml methanol. 35 mg platinum dioxide was added and hydrogen was introduced. The resulting mixture was stirred at room temperature for 1.5 hour, and filtered. The filtrate was concentrated under a reduced pressure, and subjected to a preparative TLC seperation (dichloromethane:ethyl acetate:methanol=9:1:1) to produce 50 mg of a product with a yield of 27%. MS m/z: 475 [M+1]. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 45%. MS m/z: 529 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 9.73 (s, 1H), 8.88 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 8.11-8.03 (m, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.42-7.40 (m, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.30 (d, J=3.7 Hz, 1H), 7.24 (d, J=5.3 Hz, 1H), 6.50 (dd, J=16.9, 1.9 Hz, 1H), 5.76 (dd, J=10.2, 1.9 Hz, 1H), 5.32-5.21 (m, 1H), 3.99 (s, 3H), 3.52 (br s, 2H), 3.11 (br s, 2H), 2.81 (d, J=2.5 Hz, 9H), 1.39 (d, J=6.2 Hz, 6H). Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 86%. MS m/z: 545 [M+1]. Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine The compound was synthesized in the same manner as those in Step 2 of Example 2 with a yield of 56%. MS m/z: 515 [M+1]. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 23%. MS m/z: 569 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.27 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.28 (t, J=8.5 Hz, 2H), 8.18 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.29-7.14 (m, 3H), 6.98 (s, 1H), 6.28 (d, J=17.1 Hz, 1H), 5.76 (d, J=10.4 Hz, 1H), 5.00 (q, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.61 (s, 2H), 3.28 (s, 2H), 2.80 (s, 3H), 2.73 (s, 6H). Example 4: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{5chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 86%. Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine The compound was synthesized in the same manner as those in Step 2 of Example 1 with a yield of 65%. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 15%. MS m/z: 603 [M+1], 605. 1H NMR (400 MHz, CDCl3) δ 11.68 (br s, 1H), 9.77 (s, 1H), 9.48 (s, 1H), 8.42 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.33 (s, 1H), 7.40-7.37 (m, 2H), 7.32 (dd, J=6.7, 3.0 Hz, 2H), 7.12 (dd, J=16.8, 10.2 Hz, 1H), 6.43 (dd, J=16.9, 1.8 Hz, 1H), 5.72 (dd, J=10.2, 1.8 Hz, 1H), 4.83 (q, J=8.4 Hz, 2H), 3.93 (s, 3H), 3.60 (s, 2H), 3.17 (s, 2H), 2.86 (s, 3H), 2.85 (s, 6H). Example 5: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2(dimethylamino)ethyl]-6-isopropyloxy-N5-[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 57%. MS m/z: 523. Step 2: Synthesis of N2-methyl-N2-[2(dimethylamino)ethyl]-6-isopropyloxy-N5-[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine The compound was synthesized in the same manner as those in Step 2 of Example 1 with a yield of 64%. MS m/z: 493 [M+1]. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methy)amino}-6-isopropyloxy-5-{[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 45%. MS m/z: 547 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 9.80 (s, 1H), 8.93 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 7.71 (d, J=9.7 Hz, 1H), 7.49 (s, 1H), 7.32 (dd, J=8.8, 4.4 Hz, 1H), 7.20-6.98 (m, 3H), 6.48 (d, J=16.8 Hz, 1H), 5.76 (d, J=10.5 Hz, 1H), 5.31-5.25 (m, 1H), 3.99 (s, 3H), 3.43 (br s, 2H), 2.98 (br s, 2H), 2.71 (s, 6H), 1.39 (d, J=6.1 Hz, 6H). Example 6: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 28%. MS m/z: 541. Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine The compound was synthesized in the same manner as those in Step 2 of Example 1 with a yield of 64%. MS m/z: 511 [M+1]. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3 -yl}acrylamide The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 38%. MS m/z: 565 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 9.70 (s, 1H), 8.82 (s, 1H), 8.39 (d, J=4.9 Hz, 1H), 7.88-7.74 (m, 1H), 7.50 (s, 1H), 7.25 (dd, J=16.2, 9.7 Hz, 1H), 7.20-7.13 (m, 1H), 7.05 (d, J=5.0 Hz, 1H), 6.47 (d, J=16.5 Hz, 1H), 5.76 (d, J=10.3 Hz, 1H), 5.31-5.21 (n, 1H), 3.94 (s, 3H), 3.54 (s, 2H), 3.13 (s, 2H), 2.82 (s, 6H), 1.39 (d, J=5.9 Hz, 6H). Example 7: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-6-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide To a 25 ml three-necked flask were added tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate (160 mg, 0.38 mmol), 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1-methyl-1H-indole (112 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (112 mg, 0.59 mmol), 4 ml 2-amyl alcohol and 2 ml N-methylpyrrolidone. Under the nitrogen protection, the mixture was reacted at 120° C. overnight. The mixture was cooled to room temperature and poured into 50 ml water. A solid precipitated and was filtered. The solid was dissolved in 20 ml dichloromethane, washed successively with 10 ml saturated sodium bicarbonate solution and 10 ml water, dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure, and subjected to a preparative TLC seperation (dichloromethane:methanol=10:1). 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 9.46 (s, 1H), 8.43 (s, 1H), 8.32-8.28 (m, 2H), 7.40 (s, 1H), 7.08-7.03 (m, 2H), 7.00-6.86 (m, 1H), 6.45-6.38 (m, 1H), 5.73 (d, J=10.2 Hz, 1H), 5.31-5.23 (m, 1H), 3.88 (s, 3H), 3.45 (s, 2H), 2.99 (s, 2H), 2.80 (s, 3H), 2.73 (s, 6H), 1.39 (d, J=6.2 Hz, 6H). Example 8: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7 with a yield of 8%. MS m/z: 599 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 8.25 8.15 (n, 1H), 8.11 (s, 1H), 7.68 (dd, J=11.1, 7.0 Hz, 1H), 6.83-6.64 (m, 1H), 6.21 (d, J=16.5 Hz, 1H), 5.73 (d, J=11.9 Hz, 1H), 5.21 5.13 (m, 1H), 3.89 (s, 3H), 3.36 (s, 4H), 2.80 (s, 3H), 2.56 (s, 6H), 1.18 (d, J=6.1 Hz, 6H). Example 9: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]atnino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7 with a yield of 10%. MS m/z: 581 [M+1]. 1H NMR (400 MHz, MeOD) δ 8.48 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 8.02 (dd, J=10.6, 2.4 Hz, 1H), 7.44 (dd, J=8.9, 4.4 Hz, 1H), 7.03 (td, J=9.0, 2.5 Hz, 1H), 6.47 (dd, J=17.0, 9.3 Hz, 1H), 6.40 (dd, J=17.0, 2.5 Hz, 1H), 5.82 (dd, J=9.3, 2.5 Hz, 1H), 5.39-5.28 (m, 1H), 3.91 (s, 3H), 3.74 (t, J=5.7 Hz, 2H), 3.32 (t, J=5.9 Hz, 2H), 2.89 (s, 6H), 2.80 (s, 3H), 1.37 (d, J=6.2 Hz, 6H). Example 10: N-{-2-{[2-(dimethylamino)ethyl](methy)amino}-6-isopropyloxy-5-{5-fluoro-[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7 with a yield of 9%. MS m/z: 565 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.45 (s, 1H), 8.35 (d, J=3.9 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J=10.2 Hz, 1H), 7.55 (dd, J=8.9, 4.6 Hz, 1H), 7.11 (td, J=9.1, 2.6 Hz, 1H), 6.90 (s, 1H), 6.23 (dd, J=17.1, 1.9 Hz, 1H), 5.72 (dd, J=10.2, 1.9 Hz, 1H), 5.26-5.12 (m, 1H), 3.92 (s, 3H), 3.53 (s, 2H), 3.24 (s, 2H), 2.77 (s, 3H), 2.71 (s, 6H), 1.21 (d, J=6.2 Hz, 6H). Example 11: N-{2-{[2-(dimethylamino)ethyl](methy)amino}-6-isopropyloxy-5-{5-fluoro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7 with a yield of 7%. MS m/z: 547 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.47 8.32 (m, 3H), 8.23 (d, J=2.8 Hz, 1H), 8.19 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 6.88 (dd, J=16.9, 10.3 Hz, 1H), 6.23 (dd, J=17.1, 1.8 Hz, 1H), 5.72 (dd, J=10.2, 1.7 Hz, 1H), 5.27-5.15 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.57 (s, 2H), 3.28 (s, 2H), 2.76 (s, 6H), 1.26 (d, J=6.2 Hz, 6H). Example 12: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-fluoro-[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7. MS m/z: 583 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.47 (s, 1H), 8.29 (d, J=3.4 Hz, 2H), 8.23 (dd, J=11.8, 8.2 Hz, 1H), 7.33 (s, 1H), 7.14 (dd, J=10.3, 6.7 Hz, 2H), 6.41 (dd, J=16.9, 1.8 Hz, 1H), 5.73 (dd, J=10.2, 1.8 Hz, 1H), 5.31-5.23 (m, 1H), 3.90 (s, 3H), 3.55 (s, 2H), 3.13 (s, 2H), 2.83 (s, 9H), 1.40 (d, J=6.2 Hz, 6H). Example 13: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-6-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylaimide The compound was prepared in the same manner as those in Example 7 with a yield of 15%. MS m/z: 547 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 9.76 (s, 1H), 8.82 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 7.98 (dd, J=8.7, 5.2 Hz, 1H), 7.47 (s, 1H), 7.16 (d, J=5.3 Hz, 1H), 7.08 (dd, J=9.6, 2.3 Hz, 1H), 7.03 (dd, J=9.1, 2.2 Hz, 1H), 6.49 (dd, J=16.9, 2.0 Hz, 1H), 5.77 (dd, J=10.2, 2.0 Hz, 1H), 5.27 (hept, J=6.2 Hz, 1H), 3.94 (s, 3H), 3.52 (s, 2H), 3.10 (s, 2H), 2.82 (s, 3H), 2.80 (s, 6H), 1.39 (d, J=6.2 Hz, 6H). Example 14: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{5-fluoro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7. MS m/z: 587 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 9.53 (s, 1H), 8.52-8.44 (m, 1H), 8.28 (d, J=3.7 Hz, 1H), 8.21 (s, 1H), 7.38 (dd, J=8.1, 4.9 Hz, 1H), 7.33 (dd, 1=6.0, 3.3 Hz, 2H), 7.19 (dd, J=16.9, 10.3 Hz, 1H), 6.43 (dd, J=16.9, 1.5 Hz, 1H), 5.74 (dd, J=10.3, 1.5 Hz, 1H), 4.83 (q, J=8.5 Hz, 2H), 3.93 (s, 3H), 3.56 (t, J=5.1 Hz, 2H), 3.15 (t, J=5.1 Hz, 2H), 2.85 (s, 3H), 2.81 (s, 6H). Example 15: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7. MS m/z: 587 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 2H), 8.83 (s, 1H), 8.40 (d, J=5.3 Hz, 1H), 7.71 (dd, J=10.2, 2.1 Hz, 1H), 7.41 (s, 1H), 7.31 (dd, J=8.9, 4.5 Hz, 1H), 7.13 (d, J=5.3 Hz, 2H), 7.03 (td, J=9.0, 2.3 Hz, 1H), 6.49 (dd, J=16.9, 1.8 Hz, 1H), 5.78 (dd, J=10.2, 1.8 Hz, 1H), 4.83 (q, J=8.5 Hz, 2H), 3.97 (s, 3H), 3.49 (s, 2H), 3.05 (s, 2H), 2.83 (s, 3H), 2.75 (s, 6H). Example 16: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide methanesulfonate To N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide (56 mg, 0.1 mmol) were added 2 ml acetone, 0.4 ml water, and methanesulfonic acid (6.5 μl, 0.1 mmol). The mixture was heated at 50° C. to be completely dissolved, and evaporated to dryness under a reduced pressure. Acetonitrile was added, and the resulting mixture was again evaporated to dryness under a reduced pressure. Acetone was added to the residue, and the resulting mixture was ultrasonically treated and filtered. The filter cake was dried to produce 40 mg of a yellow solid with a yield of 61%. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.88 (s, 1H), 8.63 (s, 2H), 8.40 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.25 (s, 1H), 7.10 (s, 1H), 6.88-6.70 (m, 1H), 6.26 (d, J=16.8 Hz, 1H), 5.75 (d, J=8.6 Hz, 1H), 5.18 (br s, 1H), 3.92 (s, 3H), 3.46 (s, 2H), 3.31 (s, 2H), 2.79 (s, 9H), 2.38 (s, 3H), 1.32-1.12 (m, 6H). Example 17: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide methanesulfonate The compound was synthesized in the substantially same manner as those in Example 16. Ethyl acetate was added to the final crude product. The mixture was ultrasonically treated and filtered to produce a product with a yield of 43%. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.95 (s, 1H), 8.90 (s, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1B), 7.69 (dd, J=11.1, 7.0 Hz, 1H), 6.84 (dd, J=17.0, 10.2 Hz, 1H), 6.23 (dd, J=17.1, 1.7 Hz, 1H), 5.73 (dd, J=10.3, 1.7 Hz, 1H), 5.17 (hept, J=6.1 Hz, 1H), 3.90 (s, 3H), 3.61 (t, J=5.6 Hz, 2H), 3.32 (d, J=5.5 Hz, 2H), 2.79 (s, 6H), 2.78 (s, 3H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H). Example 18: N-{2-{[2-(dimethylamino)ethyl] (methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide methanesulfonate The compound was synthesized in the substantially same manner as those in Example 16. Ethyl acetate was added to the final crude product. The mixture was ultrasonically treated and filtered to produce a product with a yield of 96%. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 2H), 8.82 (s, 1H), 8.26-8.11 (m, 3H), 7.81 (dd, J=10.6, 6.9 Hz, 1B), 7.40 (d, J=6.6 Hz, 1H), 6.82 (dd, J=16.9, 10.3 Hz, 11H), 6.27 (d, J=17.0 Hz, 1H), 5.78 (d, J=10.1 Hz, 1H), 5.25-5.19 (m, 1H), 3.91 (s, 3H), 3.68 (d, J=5.5 Hz, 2H), 3.35 (d, J=5.5 Hz, 2H), 2.86 (s, 3H), 2.82 (s, 3H), 2.80 (s, 3H), 2.36 (s, 3H), 1.21 (d, J=6.1 Hz, 6H). Example 19: N-{2-{[2-(dimethylamino)ethyl](methy)amino}-6-isopropyloxy-5-{[5-chloro-4-(1-methyl-1H-pyrropyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[5-chloro-4-(1-methyl-1H-pyrropyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 46%. MS m/z: 540. Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-isopropyloxy-N5-[5-chloro-4-(1-methyl-1H-pyrropyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine The compound was synthesized in the same manner as those in Step 2 of Example 1 with a yield of 37%. MS m/z: 510 [M+1]. Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5- {[5-chloro-4-(1-methyl-1H-pyrropyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 52%. MS m/z: 564 [M+1]. 1H NMR (400 MHz, MeOD) δ 8.70 (dd, J=8.0, 1.0 Hz, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.29 (dd, J=4.7, 1.5 Hz, 1H), 7.14 (dd, J=8.0, 4.8 Hz, 1H), 6.48 (dd, J=16.9, 2.6 Hz, 1H), 6.42 (dd, J=16.9, 9.2 Hz, 1H), 5.86 (dd, J=9.2, 2.6 Hz, 1H), 5.38-5.32 (m, 1H), 3.97 (s, 3H), 3.74 (t, J=5.7 Hz, 2H), 3.33 (t, J=5.7 Hz, 2H), 2.90 (s, 6H), 2.80 (s, 3H), 1.41 (d, J=6.2 Hz, 6H). Example 20: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-4-(1-methyl-1H-pyrropyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7. MS m/z: 564 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.55 (s, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 8.50 (s, 1H), 7.52 (s, 1H), 7.24 (d, J=3.5 Hz, 1H), 7.14 (dd, J=16.9, 10.2 Hz, 1H), 6.63 (d, J=3.5 Hz, 1H), 6.54 (dd, J=16.9, 1.9 Hz, 1H), 5.77 (dd, 1=10.2, 1.9 Hz, 1H), 5.26 (hept, J=6.2 Hz, 1H), 3.94 (s, 3H), 3.52 (t, J=5.2 Hz, 2H), 3.11 (t, J=5.2 Hz, 2H), 2.81 (s, 3H), 2.79 (s, 3H), 1.38 (d, 1=6.2 Hz, 6H). Example 21: N-{2-{[2-(dimethylamino)ethyl](methy)amino}-6-isopropyloxy-5-{[5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7 with a yield of 8%. MS m/z: 514 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 9.55 (s, 1H), 9.12 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 7.48 (s, 1H), 6.50 (dd, J=17.0, 2.0 Hz, 1H), 5.77 (dd, J=10.0, 2.0 Hz, 1H), 5.30 5.22 (m, 1H), 4.08 (s, 3H), 3.57 (s, 2H), 3.16 (s, 2H), 2.83 (s, 9H), 1.39 (d, J=6.2 Hz, 6H). Example 22: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-2′-methoxy-(4,5′-bipyrimidine)-2-yl]amino}pyridin-3-yl}acrylamide The compound was synthesized in the same manner as those in Example 7. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.50 (s, 1H), 9.27 (s, 2H), 8.51 (s, 1H), 7.52 (s, 1H), 7.17-7.03 (m, 1H), 6.57 (d, J=16.9 Hz, 1H), 5.76 (d, J=12.0 Hz, 1H), 5.31-5.23 (m, 1H), 4.13 (s, 3H), 3.54 (s, 2H), 3.12 (s, 2H), 2.83 (s, 3H), 2.81 (s, 6H), 1.40 (d, J=6.2 Hz, 6H). Example 23: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-2′-amino-(4,5′-bipyrimidine)-2-yl]amino}pyridin-3-yl}acrylamide The compound was prepared in the same manner as those in Example 7 with a yield of 8%. MS m/z: 527 [M+1]. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 9.43 (s, 1H), 9.09 (s, 2H), 8.45 (s, 1H), 7.48 (s, 1H), 7.02 (s, 1H), 6.52 (dd, J=16.9, 1.8 Hz, 1H), 5.75 (dd, J=10.3, 1.8 Hz, IH), 5.61 (s, 2H), 5.26 (hept, J=6.2 Hz, 1H), 3.47 (br s, 2H), 3.05 (br s, 2H), 2.81 (s, 3H), 2.76 (s, 6H), 1.39 (d, J=6.2 Hz, 6H). II. Examples of the Activity Test of the Present Compounds Test Example 1: Proliferation Inhibition Effects on Human Skin Cancer Cell (A431, Wild-Type EGFR), Human Lung Cancer Cell (HCC827, EGFR Exon 19 Deletion Activating Mutation), Human Lung Cancer Cell (H1975, EGFR L858R/T790M Resistant Mutation) Cells in the logarithmic phase were inoculated to 96-well culture plates (cell density: 5000/well, cell suspension: 180 μl/well), and cultured at 37° C. under 5% CO2for 24 hours. After the culturing, the cells adhered to the well walls. Each of compounds was dissolved in DMSO in advance to formulate a 10 nM stock solution. Upon testing, the stock solution was diluted with complete medium to 10 times the target concentration in another 96-cell plate. And then the compound was added at 20 μl/cell in the 96-well plate in which the cells were inoculated, i.e. the target concentration could be reached. The well for each concentration was triplicated, and the blank control was established. Cells continued to be cultured at 37° C. under 5% CO2for 72 hours. After the termination of culturing, 50 μl pre-cooled (4° C.) 50% trichloroacetic acid, i.e., TCA was added to each of wells (final concentration=10%), and was placed at 4° C. for 1 hour to fix the cells. The resulting matter was washed with purified water for at least 5 times, and dried naturally in air or at 60° C. in an oven. 4 mg/ml Sulforhodamine B (SRB) solution prepared by 1% glacial acetic acid/purified water was added at 100 μl/well to each well so as to stain for 1 hour at room temperature. The supernatant was discarded. The residue was washed with 1% acetic acid for at least 5 times to remove the non-specifically binding, and dried for use. To each well was added 150 μl of 10 mM Tris-HCl solution for dissolving the contents therein. The OD value was measured at a wavelength of 510 nm, and the inhibition rate was calculated based on the collected data. The result was shown in Table 1. TABLE 1HCC827H1975A431IC50(nM)IC50(nM)IC50(nM)AZD92913.805.4370.43Example 1 compound2.155.64140.5Example 2 compound4.225.54195.5Example 3 compound1.342.28224.2Example 4 compound1.926.15163.7Example 5 compound2.584.83181.4Example 6 compound2.365.20337.8Example 7 compound1.4016.68307.0Example 8 compound5.988.40375.4Example 9 compound1.1712.58697.2Example 10 compound2.625.32208.9Example 11 compound2.237.22210.3Example 12 compound0.969.01338.6Example 13 compound2.625.33208.9Example 14 compound0.775.17241.8Example 15 compound0.696.28337.4Example 16 compound1.455.43273.4Example 17 compound5.567.63375.4Example 18 compound2.245.07341.3Example 19 compound2.622.56208.9Example 20 compound8.9742.35800.7Example 21 compound142.418.55369.8Example 22 compound33.3037.982765Example 23 compound3.0830.701145Note:AZD9291 was prepared according to Example 28 of WO 2013/014448 A1 The test results showed that the compounds of the present invention had a strong proliferation inhibition effect on human lung cancer cell (HCC827, EGFR Exon 19 deletion activating mutation) and human lung cancer cell (H1975, EGFR L858R/T790M resistant mutation), a relatively weak proliferation inhibition effect on human skin cancer cell (A431, wild-type EGFR), that is to say, the compounds of the present invention had a good selectivity. Test Example 2: Inhibition Effect on the Growth of Subcutaneously Transplanted Tumors of Human Lung Cancer H1975-Bearing Nude Mice The Inhibition effect of the compound of Example 3 of the present invention and AZD9291 on subcutaneously transplanted tumors of human lung cancer H1975-bearing nude mice and the corresponding safety were observed. Cell cultivation: H1975 was placed in a RPMI-1640 medium containing 10% FBS, and cultivated in a temperature-constant incubator containing 5% CO2at 37° C. The cells in exponential growth phase were collected and counted for inoculation. Test animals: 15 BALB/c nude mices, 15 males and 0 female, 6 weeks old, 18-20 g, commercially available from Shanghai Lab. Animal Research Center Three test groups were established: 0.5% sodium carboxymethylcellucose solvent control group, the groups of the compound of Example 3 at 25 mg/kg and the groups of AZD9291 at 25 mg/kg, respectively. Experimental method: human lung cancer H1975 cell strain (5×106/each mouse) was inoculated to nude mice subcutaneously at the right side of the back thereof. Each mouse was inoculated with 0.1 ml, and the tumor growth was observed regularly. After the tumors grew to 100-150 mm3on average, the mice were divided into groups randomly according to the tumor size and the mouse weight. The compound of Example 3 and AZD9291 were administered by intragastric administration in the dosage of 25 mg/kg, and solvent control groups were administered with equal amount of solvent by intragastric administration, wherein the administration was performed once per day for a continuous period of 12 days. During the entire experimental process, the mouse weight and the tumor size were measured twice per week, so as to observe whether or not the toxic reaction occurs. The tumor volume is calculated as follows: Tumor volume (mm3)=0.5×(Tumor major diameterx Tumor minor diameter2) The tumor growth curves of three experimental groups are shown inFIG.1, and the mice's weight growth curves are shown inFIG.2. The results show that the compounds of the present invention have a good inhibition effect on the growth of subcutaneously transplanted tumors of human lung cancer H1975-bearing nude mice, while having little effect on the weights of nude mice, and showing a good safety. All of the literatures mentioned herein are incorporated into the present application by reference. It should be also noted that, upon reading the above mentioned contents of the present application, a person skilled in the art can modify, change or amend the present invention without departing from the spirits of the present invention, and these equivalents are also within the scope as defined by the claims appended in the present application. | 53,846 |
RE49852 | DETAILED DESCRIPTION In the attached drawings, like reference numerals designate corresponding elements throughout. Reference is first made toFIGS.1A-1C and1E-4Dto describe an embodiment of a flame simulating assembly in accordance with the invention indicated generally by the reference numeral20. In one embodiment, the flame simulating assembly20(FIGS.1C,1E) preferably includes one or more light sources22(FIGS.1B,1C) for producing light, and a screen24to which the light from the light source22is directed, to provide a number of images26of flickering flames thereon (FIG.1E), as will be described. Preferably, and as can be seen inFIG.1B, the flame simulating assembly20also includes a rotatable flicker element32. In one embodiment, the flicker element32preferably includes an elongate rod34defined by an axis36thereof (FIGS.2B,4B) about which the rod is rotatable, and a number of paddle elements38located in respective predetermined locations on the rod34(FIGS.1B,1C,2A,2B), as will also be described. It is preferred that each of the paddle elements38includes one or more body portions40having one or more reflective surfaces42thereon (FIGS.3A-3D). Preferably, each of the reflective surfaces42includes a central region44that is substantially centrally located on the reflective surfaces42and a perimeter region46at least partially located around the central region44. As will also be described, the perimeter region46substantially defines a perimeter plane “PR” (FIGS.3B,3E, and5A-5D). The paddle elements38are located to position the perimeter plane “PR” substantially parallel to the axis36, for intermittently reflecting the light from the light source22from the reflective surfaces42to predetermined regions47on the screen24respectively (FIG.1E) as the flicker element32rotates about the axis36, to provide the image of flickering flames on the screen24. The flicker element32preferably positions the paddle elements38in respective preselected positions relative to the light source22to locate the reflective surfaces42on the respective paddle elements38to reflect the light from the light source22to the screen24intermittently as the flicker element32rotates about the axis36, to provide the images26of flickering flames on the respective predetermined regions47on the screen24. As can be seen inFIGS.3B and3E, the central region44preferably is substantially non-planar and the perimeter region46is at least partially planar, to cause the light reflected therefrom to the screen24as the flicker element32rotates to have varying intensity at the respective predetermined regions on the screen, as will also be described. In one embodiment, the flame simulating assembly20preferably additionally includes a flame effect element48that has one or more apertures50. It is preferred that the flame effect element48is positioned to permit the light reflected from the paddle elements38as the flicker element32rotates to pass through the aperture(s)50, to provide the images26of flickering flames on a rear side51of the screen24. As can be seen inFIG.1C, in one embodiment, it is preferred that the light from the light source22is reflected to a rear side51of the screen. In one embodiment, the screen24preferably is at least partially transparent, so that the images26are viewable by an observer88observing a front side52of the screen24(FIGS.1C,1E). Those skilled in the art would appreciate that, in an alternative embodiment (not shown), the light from the light source may be reflected directly onto a front surface of the screen. Preferably, the paddle elements38are located in a number of respective paddle element groups80. Each paddle element group80preferably is located so that the light reflected by the paddle elements38in each paddle element group80respectively is directed to a selected one of the predetermined regions47on the screen24. In one embodiment, as can be seen inFIGS.1C and1E, the predetermined region47for each paddle element group80preferably is a relative small area of the screen24. It will be understood that, in operation, the images of flames provided by a particular paddle element group80generally (intermittently) occupy substantially all of the predetermined region47for that paddle element group80. InFIG.1E, for clarity of illustration, only four predetermined regions47are shown. Also, for clarity of illustration, the images of flames26are shown as occupying the respective predetermined regions47. Preferably, each of the paddle elements38in each of the paddle element groups80is positioned to locate the body portions40thereof in predetermined radial positions relative to the body portions of the other paddle elements in the paddle element group therefor. Preferably, the respective body portions40of the paddle elements38in each of the paddle groups80are positioned substantially at 45° radially relative to the respective body portions40of the paddle elements38adjacent thereto in the paddle element group80therefor, for reflection of the light from the light source22toward the selected one of the predetermined regions on the screen24for the paddle element group thereof when the rod34is rotated. It will be understood that the body portions40of the paddle elements38in any selected paddle element group80may be positioned radially relative to each other in any desired relationship. In one embodiment, illustrated inFIG.2B, the paddle element group80preferably includes four paddle elements. In the paddle element group80illustrated inFIG.2B, the body portions are radially positioned at 45° relative to the body portions that are adjacent thereto. When the flicker element is rotated at an appropriate rotation speed, this arrangement appears to provide images of flames that flicker realistically. Those skilled in the art would appreciate that any suitable arrangement of the paddle elements in each paddle element group80may be used. As noted above, the rate of rotation of the flicker element preferably is taken into account when determining the arrangement of the paddle elements in the respective paddle element groups. Preferably, and as can be seen inFIGS.3A-3E, the body portion40includes a first side54and an opposed second side56thereof, and at least a selected one of the first and second sides54,56includes the reflective surface42. For clarity of illustration, inFIGS.5A-5D, the central region and the perimeter region on the first side54are identified by reference numerals44′ and46′ respectively, and the central region and the perimeter region on the second side56are identified by reference numerals44″ and46″ respectively. In one embodiment, the central region44′ on the first side54preferably is at least partially convex relative to the perimeter region46′ on the first side54, and the central region44″ on the second side56is at least partially concave relative to the perimeter region46″ on the second side56. As can be seen inFIGS.3A-3E, in one embodiment, each of the paddle elements38preferably includes two body portions (identified by reference numerals40A,40B for convenience) connected by a bridge portion58. Preferably, the bridge portion58includes an inner connector60and a pair of outer connectors62,64generally located on opposite sides of the inner connector60. As can be seen inFIG.3B, the body portions40A,40B preferably are at least partially defined by respective perimeters “P1”, “P2”. It is preferred that the outlines of the body portions40A,40B (i.e., as defined by the perimeters “P1”. “P2”) are substantially the same, i.e., they are mirror images of each other. For example, in one embodiment, the central region44on the first side54preferably is at least partially convex relative to the perimeter region46adjacent thereto, and the central region44on the second side56preferably is at least partially concave relative to the perimeter region46adjacent thereto (FIGS.3B,3E). When the paddle elements38are mounted on the rod34, the paddle elements38preferably are subjected to tension as a result, and this causes the paddle elements38to be formed so that they have the central regions44that are bent or curved, to provide the non-planar regions. However, the perimeter regions, which are located around the respective central regions, preferably remain substantially planar after the paddle element38thereof is subjected to tension as aforesaid. As will be described, the differences between the central region44and the perimeter region46result in differences in the light that is reflected from these two different regions of the reflective surface42. Those skilled in the art would appreciate that the paddle elements38may be formed of any suitable materials, and that the central region44, and the perimeter region46, may be formed in any suitable way. It is preferred that the paddle elements38include, or are made of, material that is highly reflective, i.e., adapted for specular reflection. As will also be described, it is also preferred that the paddle element38is made of material that is resilient and flexible. For example, it has been found that the paddle elements38may be made of reflective Mylar®, preferably from sheets that are approximately 7 mil (0.007 inch, or approximately 0.1778 mm) thick. It will be understood that the paddle element38preferably is formed by cutting the paddle element38out of a sheet of suitable material, e.g., reflective Mylar®. Also, it is preferred that the outer connectors62,64and the inner connector60are at least partially defined by cuts65,66that partially separate the respective outer connectors62,64and the inner connector60(FIG.3A). Alternatively, the paddle elements38and/or the body portions may be formed using any other suitable methods and materials. For example, the paddle elements and/or the body portions thereof may be formed using injection molding. It will be understood that the body portions40A,40B and the bridge portion58may have any suitable size, shape or form. In one embodiment, and as can be seen inFIG.3A, the body portions40A,40B preferably each have generally rounded sides and pointed or peaked outer ends Q1, Q2. The paddle element38preferably narrows at the bridge portion58. Those skilled in the art would appreciate that the paddle element preferably is relatively small. For example, the body portion's width “W” from side to side may be a maximum of about 0.625 inch (approximately 1.59 cm), and the length “L” from the central connector56to the outer end may be a maximum of about 0.75 inch (approximately 1.91 cm) (FIG.3A). In one embodiment, each of the body portions40A,40B preferably are approximately the same size and shape. It is also preferred that the inner connector60is integrally formed with the body portions40A,40B. The outer connectors62,64preferably are also integrally formed with the body portions40A,40B. In each paddle element38, the inner connector60and the outer connectors62,64preferably are separated only by the respective cuts65,66therebetween, in the bridge portion58. As can be seen inFIG.3B, the inner connector60preferably extends between its first and second ends67,68, where the inner connector60is integrally joined with the respective body portions40A,40B. Because of the cuts65,66, the inner connector's central portion70may be moved outwardly, i.e., away from the outer connectors62,64(FIG.3A). Such outward movement would be, for example, generally in the direction schematically indicated inFIG.3Cby arrow “A”. As can be seen inFIG.3C, when the central portion70is moved outwardly from the outer connectors62,64, an opening or space72is defined between the central portion70and the inner connectors62,64. The paddle elements38may be positioned on the rod34, and attached to the rod34, in any suitable manner. In one embodiment, it is preferred that the rod34is inserted into the space72between the inner connector60and the outer connectors62,64that is formed when the central portion70of the inner connector60is moved outwardly. That is, the rod34is moved in a generally axial direction into the space72. After the rod34is positioned as desired relative to the paddle element38, the inner connector60is released to engage the rod34, as will be described. The paddle element38is secured to the rod34due to the tension to which the paddle element38is subjected as a result. Specifically, and as will be described, the inner connector60is urged against one side of the rod34, and the outer connectors62,64are simultaneously urged against an opposite side of the rod34. This mounting arrangement is illustrated inFIGS.3B-3E. As noted above, the paddle element38preferably is formed out of a substantially flat sheet of material, e.g., the reflective Mylar® referred to above, that is relatively thin. Those skilled in the art would be aware of other suitable materials. Preferably, if the paddle element is formed out of a flat sheet of material, the material out of which the paddle element38is formed is resilient and flexible, however, the paddle element may be formed in various ways, out of any suitable material(s). It will be understood that, when the central connector's central portion70is moved outwardly (i.e., in the direction indicated by arrow “A” inFIG.3C), the inner connector60is also subjected to tension, as is most of the paddle element38. When the inner connector's central portion70is pulled outwardly, each of the body portions40A,40B pivots inwardly about the outer connectors62,64of the bridge portion58. As a result, the body portions40A,40B are pivoted toward each other, as indicated by arrows “T1” and “T2” inFIG.3C. As noted above, when the central portion70is moved outwardly, the opening72is thereby defined between the inner connector60and the outer connectors62,64, in which the rod34may be positioned. For instance, the rod34may be moved axially into the opening72. It will be understood that, inFIG.3C, the rod34is shown positioned in the opening72. As can be seen inFIG.4C, the outer connectors62,64are urged against the rod34(i.e., also in the direction indicated by arrow “A” inFIG.3C) when the inner connector60is moved outwardly and the rod34is positioned in the open space72. In one embodiment, each of the paddle elements38preferably is positioned at a predetermined location therefor on the rod34. It is preferred that, when the rod34is positioned in the opening72so that a selected paddle element38is proximal to the predetermined location therefor, the inner connector60is released to allow the central portion70of the inner connector60to engage the rod34at the predetermined location for the selected paddle element38. Preferably, when the inner connector60is urged against one side of the rod34, the outer connectors62,64also are urged against the other (opposite) side of the rod34, due to the resilience of the paddle element38. As noted above, it is preferred that the paddle element38is resilient and flexible. Accordingly, in one embodiment, when the rod34is partially located in the space72and the inner connector60is released after it has been pulled outwardly, the inner connector60moves inwardly (i.e., in the direction indicated by arrow “B” inFIG.3D) to engage the rod34. Due to the resilience of the material of which the paddle element38is made, the central portion70of the inner connector60is urged against the rod34, after the central portion70is released. Also, the outer connectors62,64remain engaged, and are urged against the rod34(i.e., in the direction indicated by arrow “C” inFIG.3D) when the inner connector60is released. When the inner connector60and the outer connectors62,64engage the rod34as aforesaid, the selected paddle element38is mounted on the rod34in the predetermined location therefor. From the foregoing, it can be seen that, once the paddle element38is mounted on the rod34in the predetermined location therefor, the inner connector60is urged against one side of the rod34, and the outer connectors62,64are urged against the opposite side of the rod34. In this way, the paddle element38is relatively securely held in its predetermined location on the rod34. It will be understood that the above-described process of mounting the paddle element38on the rod34, at the predetermined location therefor, may be accomplished using any suitable means. However, those skilled in the art would appreciate that the paddle element38preferably is manually mounted onto the rod34in the predetermined location therefor, i.e., the paddle element38preferably is manipulated to provide the space72, the rod34is axially moved so that the paddle element is proximal to its predetermined location on the rod34, and then the paddle element is manually released, to engage the rod at the predetermined location therefor. From the foregoing, it can be seen that when the paddle element38is mounted on the rod34(FIGS.3B,3D, and3E), the rod34prevents the paddle element38from returning to its original, substantially planar, profile (FIG.3A). Accordingly, because the paddle element38is formed from a sheet of substantially planar material (FIG.3A) and is resilient, when the paddle element38is mounted on the rod34, the paddle element38is subjected to tension, which tension keeps the paddle element38mounted on the rod34. In particular, and as can be seen inFIG.3D, the central portion70of the inner connector60is held outwardly, in an extended position away from the outer connectors62,64, when the central portion70is released to engage the rod34. Because it is connected to the body portions40A,40B via the ends67,68of the inner connector60, when the central portion70is pulled outwardly away from the outer connectors62,64, the body portions40A,40B are also subjected to tension. The ends67,68are integrally formed with the body portions40A,40B and are located at the central region44of each body portion40A,40B. Because the body portions40A,40B are relatively thin and flexible, the central regions44of the body portions40A,40B tend to buckle or warp, as they are urged or pulled generally toward the rod34by the inner connector60. Due to the resilience of the paddle element38and because the rod34prevents the paddle element38from returning to its planar profile, the inner connector60and the outer connectors62,64securely engage the rod34to hold the paddle element38thereof in the predetermined location therefor. Those skilled in the art would appreciate that the rod34may have any suitable form, and may be made of any suitable materials. The rod34preferably is made of a suitable metal or alloy, e.g., a suitable steel. Alternatively, the rod34may be made of any suitable plastic or composite material(s). In one embodiment, the rod34preferably includes one or more main portions74thereof. In one embodiment, the main portions74preferably are generally cylindrical and elongate (FIGS.2A,2B,4A,4B). Preferably, the main portions74are coaxial with the axis36of the rod34. It is also preferred that the rod34includes any suitable means for positioning the paddle elements38in the predetermined locations therefor on the rod34. In one embodiment, the rod34preferably includes a number of detents76formed for positioning the paddle elements38in the respective predetermined locations therefor. As can be seen inFIGS.4A and4B, the detents76preferably are formed in a number of detent groups78and the paddle elements38mounted thereon comprise respective paddle element groups80. The detent groups78preferably are spaced apart from each other along the rod34at preselected distances “D” (FIG.4A), as will be described. As noted above, the paddle elements38preferably are located in predetermined locations on the rod34to reflect the light from the light source(s)22to the screen24, to provide the images of flickering flames26thereon. As is also noted above, the paddle elements38preferably are located on the rod34by respective detents76, which preferably are formed in the detent groups78. It will be understood that the respective detent groups78may include any suitable number of detents76, i.e., the paddle element groups80may include any suitable number of paddle elements38. In one embodiment, each paddle element group80preferably includes four paddle elements38. It is also preferred that the bridge portion58of each paddle element38in the paddle element group80respectively engages a selected one of the detents76in the detent group78therefor, to position each paddle element38in a predetermined radial position on the rod34relative to the other paddle elements38in the paddle element group80therefor. Accordingly, and as noted above, the detent groups78preferably are respectively positioned along the rod34to substantially align the paddle element groups80respectively mounted thereon with respective selected ones of the apertures50in the flame effect element48. For each respective paddle element group80, the light from the light source22therefor is intermittently reflected from the body portions of the paddle elements thereof through the respective aperture therefor to the predetermined region on the screen for the paddle element group80, where the light provides the images of flames. It is also preferred that the flame simulating assembly20includes a number of light sources22, and each of the individual light sources is respectively positioned to substantially direct the light therefrom to a selected one of the paddle element groups80. Those skilled in the art would appreciate that any suitable light source(s) may be used. For instance, the flame simulating assembly20may include a number of light-emitting diodes (“LEDs”), and each of the LEDs preferably are located to direct the light therefrom toward respective paddle element groups80, from which the light is reflected to the respective apertures50. Accordingly, it is preferred that the individual LEDs are located generally proximal to respective apertures50in the flame effect element48. As is known, the light generated by LEDs is relatively focused. As a result, the light generated by each of the LED light sources22preferably is relatively narrowly focused. Preferably, each of the light sources22is respectively positioned so that the light generated thereby is directed substantially toward the paddle element group80positioned to reflect the light toward the aperture50selected therefor. It will be understood that more than one light source22may be positioned to direct light therefrom to the paddle element group80to the selected aperture50therefor. For example, in one embodiment, relatively high-powered LEDs may be used. An example of a suitable high-powered LED is a one-watt LED. It has been found that a single high-powered LED may be used for each respective paddle element group80. Alternatively, LEDs that are not high-powered may be used. Those skilled in the art would appreciate that a number of such LEDs may be positioned for use with each paddle element group respectively. Those skilled in the art would also appreciate that the light produced from the light source(s), and reflected from the reflective surfaces, is the sum of the light in each case. As can be seen inFIG.1B, for example, each of the light sources22illustrated is positioned adjacent to a selected paddle element group80, for transmission of the light from each light source22to the paddle element group80therefor. Each of the paddle element groups80is positioned to direct the light from the light source22adjacent thereto through the aperture50that is proximal to the paddle element group80. From the foregoing, it can be seen that the locations of the detent groups78on the rod34, and the positioning of such locations relative to the flame effect element48when the flicker element32is installed in a preselected position therefor relative to the flame effect element48, are predetermined. As noted above, the detent groups78are spaced apart on the rod34so that, when the paddle elements38are mounted on the rod34to form the respective paddle element groups80and the flicker element32is positioned in the preselected position therefor relative to the flame effect element48, the paddle element groups80preferably are substantially aligned respectively with the apertures50in the flame effect element48. In one embodiment, for instance, each detent group78preferably is spaced apart from the detent group(s) adjacent thereto by a preselected distance “D” (FIG.4A). Those skilled in the art would appreciate that the spacings “D” between respective detents may not necessarily be the same distance in each case. InFIG.4B, the four detents in the detent group78illustrated therein are identified by the reference numerals76A-76D, for clarity of illustration. As noted above, in one embodiment, each of the paddle elements38preferably is positioned at approximately 45° radially relative to the paddle elements38immediately adjacent thereto in the paddle element group80thereof respectively. Because of the radial positioning of the paddle elements38in each of the paddle element groups80relative to the other paddle elements28thereof, the light from the light source(s)22is reflected thereby through the aperture48therefor toward the screen24at preselected intervals when the rod34is rotated. When the flicker element32is rotated, this radial arrangement of the paddle elements in each of the paddle groups80provides flame images at intervals so that the flame images26simulate a flickering flame. As noted above, when the flame simulating assembly20is energized, each of the paddle elements38is moving, i.e., rotated about the axis36as the light from the light source(s)22is reflected from the reflective surfaces42of the respective paddle elements. Because each reflective surface42includes non-planar and planar surfaces, the light reflected therefrom towards the aperture50also flickers, i.e., the direction and intensity of the reflected light vary as long as the paddle element moves while the light is reflected therefrom. The rod34may be rotated at any suitable rate, for example, between 10 rpm and 25 rpm. Those skilled in the art would appreciate that the detents76may be formed in any suitable manner. Preferably, each of the detents76includes one or more first regions82and one or more second regions83for engagement with the inner connector60and the outer connectors62,64respectively. In one embodiment, and as can be seen inFIGS.4A-4C, the first region82preferably is substantially planar. It is also preferred that the first region82of each detent78in each respective detent group78is located at a predetermined position located radially relative to each other (FIG.4B), as noted above. In this way, the first region82of the detent78radially locates the paddle element38on it, in a preselected position relative to the other paddle elements38in the paddle element group80therefor. Preferably, the planar first regions82are located at 45° radially relative to the one or more first regions82in the same detent group that are adjacent thereto. As can be seen inFIG.4D, in one embodiment, the detent76preferably also includes the second region83positioned substantially opposite to the first (planar) region82. Those skilled in the art would appreciate that the second region83may have any suitable form. Preferably, the second region83forms a central ridge that includes an outer surface84. In one embodiment, the central ridge83preferably locates the outer surface84thereof so that the outer surface84is at least partially substantially aligned with an outer surface85of the main portion74of the rod34(FIG.4B). Alternatively, in another embodiment, the outer surface84extends outwardly, beyond the outer surface85of the substantially cylindrical main portion74. In one embodiment, each of the substantially planar regions82of the respective detents76A-76D preferably is positioned at approximately 45° relative to the detents that are positioned adjacent thereto. For example, as shown inFIG.4B, the planar region82of the detent76A preferably is positioned to define a radial angle of approximately 45° relative to the planar region82of the detent76B. As can be seen inFIGS.2A,2B, and3D, once the paddle element38is mounted on the detent76, the inner connector60preferably engages the region82of the selected detent, and the center region70of the inner connector60tends to be somewhat flattened as a result. The center region70of the inner connector60accordingly positions the paddle element38in a predetermined radial position, determined by the radial position of the region82. As noted above, it is preferred that the predetermined radial position of the paddle element38is in relation to the paddle element(s) adjacent thereto, i.e., the body portions40of adjacent paddle elements are located at approximately 45° relative to each other. Preferably, the light passing through the aperture50to the screen24is shaped by the aperture50. As can be seen inFIGS.1A and1B, the apertures50preferably are shaped to provide images of flames26(FIG.1E) viewable by the observer88positioned to view the front surface90of the screen24(FIG.1C). In particular, it will be understood that each of the light sources22and each of the paddle element groups80are positioned to direct the light from the light sources22through a selected aperture50to form the flame image26. Although the images26may to an extent overlap at their lower ends so as to simulate a real fire, the respective images26are for the most part formed only by the respective apertures therefore, and the light sources22and the paddle element groups80respectively associated with such apertures50. For instance, the light from the light source(s)22that is directed to the flicker element32is schematically represented by arrow “M” inFIG.1C. The light that is reflected by the paddle elements38toward the aperture50is schematically represented by arrow “N” inFIG.1C. For convenience, the paddle elements illustrated inFIG.2Bare identified by reference numerals38A-38D. It will be understood that the respective positions of the paddle elements38A-38D preferably are determined by the planar region82of each detent76on which they are respectively mounted. As can be seen inFIGS.3B and3E, it is preferred that the central region44of each of the body portions40A,40B of the paddle element38is generally convex on the first side54thereof (FIG.3B) and generally concave on the second side56thereof (FIG.3E). For clarity of illustration, the convex central regions44are identified by reference letter “J” inFIG.3B, and the concave central regions52are identified by reference letter “K” inFIG.3E. Due to the convex and concave regions, the body portions40A,40B are formed to have generally cupped shapes, i.e., they are non-planar, once the paddle element38is mounted on the rod34. It will be understood that the extent of the convexity and concavity of the central regions44is somewhat exaggerated inFIGS.3B and3E and5A-5D. Also, the convexity and concavity of the central regions44is not shown inFIGS.2A,2B,3C, and3Dfor clarity of illustration. In use, as described below, the light forming the images26generally appears to vary in intensity within the images26. This variation in intensity enhances the realistic effect provided by the assembly20, as such variation is similar to variations in light intensity observable in flames in a real wood or coal fire, or a fire consuming other combustible materials. It is believed that the variation in light intensity within the image26is due, at least in part, to the cupped shapes of the body portions40A,40B. Part of the light reflected from a body portion40is reflected from the (substantially planar) perimeter regions46, and another part of the light reflected from such body portion40is reflected from the convex or concave region “J” or “K”, as the case may be. It will be understood that, as the flicker element32is rotated, the intensity of the light reflected by each body portion40and directed to the screen24to form the image of flames varies. This is thought to be because the light from the light source is directed to the moving (i.e., rotating) body portion, causing the light to be reflected, at least in part, sequentially from the substantially planar region and the non-planar central region. As can be seen inFIG.5A, on the first side54of the body portion40A, the central region44′ is somewhat convex. When the paddle element38is in the position shown inFIG.5A, the light from the light source is at least partially directed to the slightly convex central region44′, and is reflected from the central region44′ toward the aperture (not shown inFIG.5A). It will be understood that light is also reflected from the perimeter region46′ that is transversely proximal to the central region44′, however, such reflected light is omitted for clarity of illustration. The light from the light source is schematically represented by the arrow “M1”, and the light reflected from the central region44′is schematically represented by the arrow “N1”. It will also be understood that the reflected light “N1” is directed through the aperture50to the screen24(not shown inFIGS.5A-5D). InFIG.5B, the rod has rotated in the direction indicated by arrow “W” so that the paddle element is in a different position relative to the light source22. In this position, the light is reflected off the substantially planar perimeter region46′. The light from the light source is schematically represented by the arrow “M2”, and the reflected light is schematically represented by the arrow “N2”. Because the light is reflected from the substantially planar surface46′, rather than the convex surface44′, the light reflected from the perimeter region46′ as projected onto the screen24would have a slightly different intensity than the light reflected from the central region44′. InFIG.5C, the paddle element38is shown after it has been rotated further in the direction indicated by the arrow “W”, the second side56of the body portion40B is exposed to the light from the light source22. In this position, light is at least partially reflected from the central region44″, the light being represented by the arrows “M3” and “N3”. The central region44″ on the second side56is concave. It will be understood that light is also reflected, at this point, from the perimeter region46″, however, such reflected light is omitted for clarity of illustration. InFIG.5D, the paddle element38is shown as having been rotated further in the direction indicated by the arrow “W” (relative to the position thereof illustrated in FIG. SC), so that the light from the light source22is at least partially reflected from the substantially planar perimeter region46″. The light reflected from the perimeter region46″ is schematically represented by the arrow “N4”. In this situation also, because the light is reflected from the substantially planar surface46″, rather than the concave surface44″, the light reflected from the perimeter region46″ as projected onto the screen24would have a slightly different intensity than the light reflected from the central region44″. It will also be understood that, as described above, the flicker element preferably includes a number of paddle elements positioned proximal to each other, in the paddle element group. The other paddle elements on the rod are omitted fromFIGS.5A-5Dfor clarity of illustration. As noted above, the paddle elements38preferably are mounted on the rod34to form the paddle element groups80, which are associated with the respective apertures50. It is believed that the radial positioning of the paddle elements38in each group80, to an extent, also causes the realistic variation in light intensity in the image26due to the different reflective surfaces of the body portions40A,40B being used to reflect the light from the light source(s)22in turn as the flicker element32is rotated about the rod's axis36. For example, inFIG.6A, a top view of the situation illustrated inFIG.5Ais provided. The light from the light source22is represented by the arrow “M1”, and it is reflected from the central region44′. The light reflected from the central region44′ toward the screen24is represented by the arrow “N1”. For clarity of illustration, the point on the central region44′ at which the light from the light source22is reflected toward the screen24is identified as “X”. As can be seen inFIG.6A, the light that is reflected from the central region44′ produces an image of flames, or part thereof, at a point identified as “Y” on the screen. InFIG.6B, a top view of the situation illustrated inFIG.5Bis provided. The light from the light source22is represented by the arrow “M2” and the light reflected from the perimeter region46′ is schematically represented by the arrow “N2”. The light is shown as being reflected from a point “V” on the perimeter region46′. As illustrated inFIG.6B, the light that is reflected from the perimeter region46′ is directed substantially orthogonally to the axis36of the rod34, and intersects the screen at a point identified for clarity of illustration as “Z”. FromFIGS.6A and6B, it can be seen that the different shapes of the central region44(i.e., non-planar) and the perimeter region46(i.e., substantially planar) result in the light from the light source22being reflected in slightly different directions toward the screen24as the rod34rotates. For clarity of illustration, the extent to which the locations “Y” and “Z” are different is exaggerated. It will be understood that a number of elements of the flame simulating assembly20are omitted fromFIGS.6A and6B, also for clarity of illustration. It will also be understood that the light reflected from the other central region44″, as illustrated inFIG.5C, is also directed to a location on the screen that is other than the location on the screen to which the light reflected from the perimeter region46″ is directed. Another benefit that is believed to result from the arrangement of the elements of the assembly20is the virtual elimination of incidental partially transverse flashes of light on the screen24. This benefit is believed to be due to the generally consistent positioning of the paddle elements38relative to the screen24, i.e., because the paddle elements38are positioned by the respective detents76in the respective predetermined positions therefor. As described above, and as illustrated inFIG.1C, the rod34preferably is positioned so that its axis36is substantially parallel to the screen24. The light from the light source is directed toward the body portions40A,40B in a direction that is substantially orthogonal to the axis, and aligned with the aperture therefor. It is believed that the elimination of the incidental partially transverse flashes of light is due to this arrangement, and the manner in which each paddle element is secured in position on each detent respectively. As can be seen, for instance, inFIG.1C, the flame simulating assembly20preferably also includes a simulated fuel bed92. Those skilled in the art would appreciate that the simulated fuel bed92may be formed in any suitable manner, and made of any suitable materials. In one embodiment, the simulated fuel bed92preferably includes one or more simulated fuel elements94supported by a platform96. Those skilled in the art would also appreciate that the elements94may be made of any suitable material(s). The simulated fuel elements94preferably are at least partially light-transmitting. Preferably, the simulated fuel elements94are at least partially translucent, and/or at least partially transparent. In one embodiment, it is preferred that the elements94are, for example, pieces of cut glass. Alternatively, the fuel elements94may be made of acrylic. The fuel elements94preferably are formed into any suitable shape(s). In one embodiment, the fuel elements94preferably are formed to be multi-faceted. The fuel elements94preferably are located by a support element96that positions at least some of the fuel elements94adjacent to the screen24. In an alternative embodiment, a flame simulating assembly120of the invention preferably includes a screen124and a simulated fuel bed192located in front of a screen124thereof (FIG.1D). The simulated fuel bed192includes a number of simulated fuel elements194, e.g., pieces of cut glass. As can be seen inFIG.1D, the screen124preferably defines a gap198therein. As can also be seen inFIG.1D, in this embodiment, the light from the light source124preferably is reflected from the flicker element32through the gap198, as schematically represented by arrow “L” inFIG.1D. It has been found that light directed through the gap198enhances the overall simulation effect. Such light illuminates or enters the simulated fuel elements194in the region immediately in front of the screen124. This causes the simulated fuel elements194that are proximal to the front surface190of the screen124to appear to be illuminated from within by a flickering light, e.g., as if by a real fire. The invention also includes a method of providing images of flames that includes the following. The light sources22for producing light, the screen24, and the rotatable flicker element32including the rod34defined by the axis36thereof and a number of the paddle elements38mounted in respective preselected positions on the rod, are provided, as described above. As noted above, in one embodiment, each paddle element38includes one or more body portions with one or more reflective surfaces42thereon, and the reflective surfaces preferably are formed to include the substantially planar region46substantially defining the perimeter plane “PR” and the non-planar region44. The paddle elements are located to position the perimeter planes “PR” thereof substantially parallel to the axis36. The screen24is provided for displaying a number of images of flames26thereon. The rod is located so that the axis thereof is substantially parallel to the screen, to locate the reflective surfaces intermittently in the path of the light from the light source22, for reflecting the light from the light source to the screen as the flicker element rotates relative to the screen. The flicker element is rotated about the axis. When the flicker element is rotating, the light from the light source is directed to the reflective surface intermittently, to intermittently provide a first reflected light reflected from the planar region and a second reflected light reflected from the non-planar region to the screen to provide the images of flames. The images26include respective portions thereof formed by the first reflected light and the second reflected light respectively, the first reflected light having a different intensity on the screen relative to the second reflected light. It will be understood that, in the foregoing description, the references to “first reflected light” and “second reflected light” are intended only to distinguish the light reflected from the planar region from the light that is reflected from the non-planar region. Those skilled in the art would appreciate that the light may be reflected simultaneously, or virtually simultaneously, from these regions. The fluctuations in the reflected light are, in part, the result of the differences in the regions of the reflective surfaces42, as illustrated schematically inFIGS.5A-5D, and as described above. In addition, the light that is reflected from the flicker element fluctuates in intensity because of the gaps between the paddle elements, i.e., each paddle element reflects the light only intermittently as the flicker element rotates. It is also preferred that the invention provides a method of forming the flicker element. The elongate rod is provided, with the detents formed on the rod. Each detent includes one or more of the substantially planar surfaces. The paddle elements are provided, and each paddle element is bent at the bridge portion thereof to define the space72between the inner connector and the pair of outer connectors thereof. The rod is inserted into the space72to locate the planar surface of the detent76for engagement with the inner connector. The inner connector is released to permit resilient pivoting movement of the body portions about the bridge portion, to urge the inner connector against the planar region for positioning the paddle element in the preselected position therefor on the rod. Alternative embodiments of the invention are illustrated inFIGS.7A-10B. In one embodiment, the flame simulating assembly220of the invention preferably includes one or more light sources222(FIG.7B) for producing light, a screen224to which the light from the light source222is directed, to provide a plurality of images226of flickering flames thereon (FIG.7A), and a rotatable flicker element232(FIG.7C). It is preferred that the flicker element232includes an elongate rod234defined by an axis236thereof about which the rod234is rotatable, and a number of paddle elements238located in respective predetermined locations on the rod234(FIG.7C). As will be described, each of the paddle elements238preferably includes one or more body portions240having one or more reflective surfaces242thereon. Preferably, and as shown inFIG.8B, the reflective surface242includes a central region244and a perimeter region246at least partially located around the central region244, the perimeter region246at least partially defining a perimeter plane “2PR”. It is also preferred that the paddle elements238are located in the respective predetermined locations therefor to position the perimeter plane “2PR” substantially perpendicular to the axis236, for intermittently reflecting the light from the light source222from the reflective surface242to predetermined regions245on the screen224respectively (FIGS.7A,7B) as the flicker element232rotates about the axis236, to provide the images of flickering flames on the screen224. Preferably, because the central region244is substantially non-planar and the perimeter region is at least partially planar, the light reflected therefrom to the screen224as the flicker element232rotates has varying intensity at the respective predetermined regions on the screen224. As will also be described, it is also preferred that the perimeter region246includes one or more middle parts247and one or more side parts249(FIG.7C). As shown inFIG.7, the middle part247preferably is at least partially defined by one or more channels253partially separating the middle part247and the side part(s)249. As will also be described, the middle part and the side part(s) preferably are formed to reflect the light from the light source so as to provide a realistic flame effect. It will be understood that the middle part and the side part(s) as illustrated are exemplary, and that they may have any suitable configuration. In one embodiment, the side parts preferably include a first side part249A and a second side part249B (FIG.8A). Also, the one or more channels preferably include first and second channels253A,253B (FIG.8A). In the embodiment illustrated, e.g., inFIG.8A, the middle part247is at least partially defined by the first and second channels253A,253B, the first channel253A being located between the middle part247and the first side part249A, and the second channel253B being located between the middle part247and the second side part249B. Preferably, the perimeter region246includes base regions257A,257B that are adjacent to the side parts249A,249B respectively (FIGS.8A,8B). In the embodiments illustrated inFIGS.7A-10B, it is preferred that the paddle elements238are mounted on the rod234so as to be substantially equally spaced apart from each other, as will be described. Preferably, when mounted on the rod, the respective body portions240of the paddle elements238are positioned substantially at 45° radially relative to the respective body portions240of the paddle elements238that are positioned on the rod234adjacent thereto, for reflection of the light from the light source222toward the predetermined regions on the screen224when the rod234is rotated. It will be understood that the body portions240of the paddle elements238may be positioned radially relative to each other in any desired relationship. As will be described, the rod234preferably includes a rod body274coaxial with the axis236and a number of mounting elements276located at predetermined positions along the rod body274. Preferably, the mounting elements are located on the rod body for positioning the paddle elements in the respective predetermined locations therefor. It is also preferred that the mounting elements are spaced substantially equidistant apart from each other along the rod body. The rate of rotation of the flicker element232preferably is taken into account when determining the arrangement of the paddle elements relative to each other along the rod234. Preferably, and as can be seen inFIGS.8A-8E, the body portion240includes a first side254and an opposed second side256thereof, and at least a selected one of the first and second sides254,256includes the reflective surface242. It is preferred that each of the first and second sides254,256includes reflective surfaces. For clarity of illustration, inFIGS.9A-9D, the central region and the perimeter region on the first side254are identified by reference numerals244′ and246′ respectively, and the central region and the perimeter region on the second side256are identified by reference numerals244″ and246″ respectively. In one embodiment, the central region244′ on the first side254preferably is at least partially convex relative to the perimeter region246′ on the first side254, and the central region244″ on the second side256is at least partially concave relative to the perimeter region246″ on the second side256. For clarity of illustration, the convex central region244is identified by the reference numeral “2J” inFIG.8B, and the concave central region is identified by the reference numeral “2K” inFIG.8E. It will be understood that the convex central region “2J” is convex relative to the perimeter plane “2PR”. Similarly, it will be understood that the concave central region “2K” is concave relative to the perimeter plane “2PR”. As can also be seen inFIGS.8A-8E, in one embodiment, each of the paddle elements238preferably includes two body portions (identified by reference numerals240A,240B for convenience) connected by a bridge portion258. Preferably, the bridge portion258includes an inner connector260and a pair of outer connectors262,264generally located on opposite sides of the inner connector260(FIG.8A). As can be seen inFIG.8B, the body portions240A,240B preferably are at least partially defined by respective perimeters “2P1”, “2P2”. It is preferred that the outlines of the body portions240A,240B (i.e., as defined by the perimeters “2P1”, “2P2”) are substantially the same, i.e., they are mirror images of each other. The base regions257A,257B of the perimeter region249preferably extend to the bridge portion258(FIGS.8A,8B). As will be described, when the paddle element238is mounted on the rod234, the base regions257A,257B tend to define the perimeter plane “2PR”. Other parts of the perimeter region246may be bent so that they are not in the perimeter plane “2PR”. When the paddle elements238are mounted on the rod234, the paddle elements238preferably are subjected to tension as a result, and this causes the paddle elements238to be formed so that they have the central regions244that are bent or curved, to provide the non-planar regions. However, the base regions257A,257B, which are located adjacent to the bridge portion258, preferably remain at least partially substantially planar after the paddle element238thereof is subjected to tension when mounted on the rod234, as aforesaid. As will be described, the differences between the central region244and the perimeter region246result in differences in the light from the light source that is reflected from these two different regions of the reflective surface242to the screen224. Similarly, differences among the middle part247, the side parts249A,249B, the central region244, and the base regions257A,257B result in differences in the light from the light source that is reflected therefrom to the screen224. These differences have been found to provide a realistic flame effect on the screen224, which simulates the flames of a fire. Those skilled in the art would appreciate that the paddle elements238may be formed of any suitable materials, and that the central region244, and the perimeter region246, may be formed in any suitable way. It is preferred that the paddle elements238include, or are made of, material that is highly reflective, i.e., adapted for specular reflection. As will also be described, it is also preferred that the paddle element238is made of material that is resilient and flexible. Those skilled in the art would be aware of suitable materials: For example, it has been found that the paddle elements238may be made of reflective Mylar®, preferably from sheets that are approximately 7 mil (0.007 inch, or approximately 0.1778 mm) thick. In one embodiment, the paddle element238preferably is formed by cutting the paddle element238out of a sheet of suitably flexible material, e.g., reflective Mylar®. Also, it is preferred that the outer connectors262,264and the inner connector260are at least partially defined by cuts265,266that partially separate the outer connectors262,264from the inner connector260respectively (FIG.8A). It is also preferred that the channels253A,253B are formed by cutting material out of the sheet of suitable material. Those skilled in the art would appreciate that the channels253A,253B may be cut after the basic outline of the body portions240A,240B has been formed. Alternatively, the paddle elements238and/or the features thereof may be formed using any other suitable methods and materials, as would be appreciated by those skilled in the art. For example, the paddle elements and/or the body portions thereof may be formed using injection molding. It will be understood that the body portions240A,240B and the bridge portion258may have any suitable size, shape or form. In one embodiment, and as can be seen inFIG.8A, the body portions240A,240B preferably each have generally rounded sides and pointed or peaked tips or outer ends “2Q1”, “2Q2”, interrupted by the channels253A,253B. The paddle element238preferably narrows at the bridge portion258. Those skilled in the art would appreciate that the paddle element preferably is relatively small. For example, the body portion's width “2W” from side to side may be a maximum of about 0.625 inch (approximately 1.59 cm), and the length “2L” from the central connector256to the outer end may be a maximum of about 0.75 inch (approximately 1.91 cm) (FIG.8A). In one embodiment, each of the body portions240A,240B preferably are approximately the same size and shape. It is also preferred that the inner connector260is integrally formed with the body portions240A,240B. The outer connectors262,264preferably are also integrally formed with the body portions240A,240B. In each paddle element238, the inner connector260and the outer connectors262,264preferably are separated only by the respective cuts265,266therebetween, in the bridge portion258(FIG.8A). As can be seen inFIG.8A, the inner connector260preferably extends between its first and second ends267,268, where the inner connector260is integrally joined with the respective body portions240A,240B. Because of the cuts265,266, the inner connector's central portion270may be moved outwardly, i.e., away from the outer connectors262,264(FIG.8A). Such outward movement would be, for example, generally in the direction schematically indicated inFIG.8Cby arrow “2A”. As can be seen inFIG.8C, when the central portion270is moved outwardly from the outer connectors262,264, an opening or space272is defined between the central portion270and the inner connectors262,264. Preferably, the paddle element is mounted on the rod as follows. When the paddle element238is to be mounted on the rod234, the paddle element238is first compressed, or bent. The tips “2Q1”, “2Q2” of the respective body portions240A,240B are moved toward each other. This causes the body portions240A,240B to pivot toward each other, as indicated by arrows “2T1”, “2T2”. As noted above, at the same time, the central portion270is moved or bent outwardly, to define the opening272. The rod234is positioned in the opening272, and while the paddle element238is compressed (so as to hold the opening272open), the paddle element238and/or the rod234is/are moved relative to each other until the paddle element238is positioned at a selected one of the mounting elements276, to locate the paddle element238in a preselected position therefor on the rod234, relative to the other paddle elements. When the paddle element238is located at its preselected position on the rod234, the paddle element238preferably is released (i.e., the tips “2Q1”, “2Q2” of the body portions240A,240B are allowed to move away from each other), and the central portion270is allowed to engage the mounting element276. The inner connector260is allowed to move in the direction indicated by arrow “2B” inFIG.8D. Also, and as can be seen inFIGS.8A,8B, and8E, the outer connectors262,264engage adjacent parts of the rod body274, and are urged in the direction indicated by arrow “2C” inFIG.8D, to locate the paddle element238in its preselected position. From the foregoing, it can be seen that, once the paddle element238is mounted on the rod234in the predetermined location therefor, the inner connector260is urged against one side of the rod234, and the outer connectors262,264are urged against the opposite side of the rod234. In this way, the paddle element238is relatively securely held in its predetermined location on the rod234, i.e., spaced apart from the paddle elements mounted adjacent thereto. When the paddle element238is located in its preselected position, it is subjected to tension, and consequently the central region244is puckered, or curved or bent, to form the central regions244. In turn, because the middle part247and the central region244are joined at a connector part255, the middle part247may at this point become bent or raised relative to the side parts, due to the curvature of the central region244(FIG.8B). As a result, the middle part247may be non-coplanar with the perimeter plane “2PR”. In the same way, when the central regions244are formed, the side parts249A,249B may also be bent due to the connection of the side parts249A,249B with the central regions244at the connectors259A,259B respectively (FIG.8B). As noted above, the paddle element238may be cut out of a relatively thin sheet of flexible plastic with a suitable (reflective) finish. It will be understood that a suitable material is a flexible, resilient material, i.e., preferably a material capable of substantially elastic deformation, and very little plastic deformation. Accordingly, when the tips “2Q1”, “2Q2” of the body portions are moved toward each other, to form the opening272, the deformation of the paddle element238is substantially an elastic deformation. That is, due to the flexibility of the material and because the extent of deformation is limited (i.e., the tips are only moved together to a limited extent), the material is not substantially elastically deformed. Because of this, when the pressure urging the tips “2Q1”, “2Q2” of the body portions together is released, the tips of the body portions are urged apart from each other, because the paddle element238has a tendency to resiliently return to its generally planar, original, configuration. It will be understood that the middle part247and the two side parts249A,249B may be positioned relative to each other in various ways. When the paddle element238is mounted on the rod234, the paddle element238is subjected to tension, and the tension may cause one or more of the middle part247and the side parts249A,249B to bend relative to each other, and/or relative to the base regions257A,257B. It will be understood that, due to the connection of the base regions257A,257B to the bridge portion258, the base regions257A,257B remain relatively planar after the paddle element238has been mounted on the rod234. Accordingly, in at least a selected one of the paddle elements238, the first and second side parts249A,249B are substantially coplanar relative to each other. As will be described, this can be seen, e.g., inFIGS.9A-9D. Also, in at least a selected one of the paddle elements, the middle part247preferably is non-planar (FIGS.8B,8E). As will be described, the effect resulting from mounting the paddle element238on the rod234may include bending one or more of the middle part and the side parts so that one or more of them may be bent somewhat, i.e., they may not be planar after mounting. Also, due to the tensions to which the paddle element238is subjected, even if the middle part and one or more of the side parts are substantially planar, the middle part and/or the side parts may be located in non-coplanar locations relative to each other after mounting. Based on the foregoing, those skilled in the art would appreciate that, in at least a selected one of the paddle elements, the middle part247preferably is non-coplanar with the side parts249A,249B. In another embodiment, in at least a selected one of the paddle elements238, the side parts249A,249B and the middle part247preferably are non-coplanar (FIG.9E). In an alternative embodiment, in at least a selected one of the paddle elements238, the middle part247and the side part(s) preferably are substantially coplanar (FIG.9F). Those skilled in the art would appreciate that the mounting elements276are formed in order to locate the respective paddle elements238relative to each other in their respective predetermined positions and retain the paddle elements therein. It would also be appreciated by those skilled in the art that the mounting elements may be formed in any suitable manner. In one embodiment, each mounting element276preferably includes one or more first region282formed for engagement with the inner connector260, to position the paddle elements238in the respective predetermined locations therefor (FIG.8D). It is preferred that the first region282is substantially planar (FIG.8D). Preferably, the first region282of each mounting element276is located at a predetermined position located radially relative to each other mounting element276adjacent thereto, for positioning the paddle elements238in the respective predetermined locations therefor (FIG.7C). The mounting element276preferably also includes a second section283thereof that may be partially engaged by the side connectors262,264when the paddle element238is mounted on the mounting element276(FIGS.8D,8E). In use, the light source is energized. and the flicker element is rotated about the rod's axis. When the flicker element is rotating, the light from the light source is directed to the reflective surface intermittently, to intermittently provide a first reflected light reflected from the middle part247, a second reflected light reflected from the side part(s)249A,249B, and a third reflected light reflected from the non-planar region244to the screen to provide the images of flames on the screen. The images of flames226include respective portions thereof formed by the first reflected light and the second reflected light and the third reflected light, the first reflected light and the second reflected light having a different intensity on the screen relative to the third reflected light (FIGS.10A,10B). It will be understood that the light from the light source222is reflected from all parts of the reflective surface242. For instance, the light is also reflected from the base regions257A,257B toward the screen224as the flicker element is rotated, when the base regions257A,257B are appropriately positioned. As can be seen inFIGS.8B and8E, it is preferred that the central region244of each of the body portions240A,240B of the paddle element238is generally convex on the first side254thereof (FIG.8B) and generally concave on the second side256thereof (FIG.8E). Due to the convex and concave regions, the body portions240A,240B are formed to have generally cupped shapes, i.e., they are non-planar, once the paddle element238is mounted on the rod234. It will be understood that the extent of the convexity and concavity of the central regions244is somewhat exaggerated as illustrated inFIGS.8B and8E and9A-9D. Also, the convexity and concavity of the central regions244is not shown inFIGS.7C,8C, and8Dfor clarity of illustration. In use, as described below, the light forming the images226generally appears to vary in intensity within the images226. This variation in intensity enhances the realistic effect provided by the assembly220, as such variation is similar to variations in light intensity observable in flames in a real wood or coal fire, or a fire consuming other combustible materials. It is believed that the variation in light intensity within the image226is due, at least in part, to the cupped shapes of the body portions240A,240B. The intermittent nature of the reflection of the light from the flicker element232also contributes to the seemingly random fluctuations in the reflected light intensity. As will be described, it is also believed that the variation in light intensity within the images is also partly due to the forms of the middle part247and the side parts249A,249B. The different positioning of the middle part247and the side parts249A,249B relative to the perimeter plane “2PR” is also believed to cause variations in light intensity within the images of flames226. As noted above, part of the light from the light source222reflected from a body portion240is reflected from the (substantially planar) base regions257A,257B, and another part of the light reflected from such body portion240is reflected from the convex or concave region “2J” or “2K”, as the case may be. Additional light is reflected from the middle part247and the side parts249A,249B. It will be understood that, as the flicker element232is rotated, the intensity of the light that is reflected by each body portion240and directed to the screen224to form the image of flames varies. This is thought to be because the light from the light source222is directed to the moving (i.e., rotating) body portion, causing the light to be reflected, at least in part, sequentially from the substantially planar base regions257A,257B, the non-planar central region244, and the middle part247and the side parts249A,249B. As can be seen inFIG.7B, in one embodiment, the flame simulating assembly220preferably includes a flame effect element248located along the path of the light from the light source that is reflected from the flicker element232toward the screen224. Preferably, the flame effect element248includes one or more apertures therein through which the reflected light is directed, for forming the light received on the screen into flame-like shapes or configurations. InFIG.7B, the light from the light source222is schematically represented by arrow “2M”, and the light reflected from one of the paddle elements238to the predetermined region245on the screen224is schematically represented by arrow “2N”. InFIGS.9A-9D, the middle part247is shown as being bent so that it is non-coplanar with the perimeter plane “2PR”. As illustrated inFIGS.9A-9D, the side parts are coplanar with the perimeter plane “2PR”. Other arrangements are illustrated inFIGS.9E and9F. The flicker element232is rotated in the direction indicated by the arrow “H”. As can be seen inFIG.9A, on the first side254of the body portion240A, the central region244′ is somewhat convex. When the paddle element238is in the position shown inFIG.9A, the light from the light source is at least partially directed to the slightly convex central region244′, and is reflected from the central region244′ toward the screen via the aperture(s) of the flame effect element248(not shown inFIG.9A). It will be understood that the light is also reflected from the base regions257A,257B, however, such reflected light is omitted for clarity of illustration. InFIG.9A, the light from the light source is schematically represented by the arrow “2M1”, and the light reflected from the central region244′ is schematically represented by the arrow “2N1”. The light from the light source222that is directed to the middle part247is also schematically represented by the arrow “F1”, and the light reflected from the middle part247is schematically represented by the arrow “G1”. It will also be understood that the reflected light “2N1” and “G1” is directed through the aperture(s) of the flame effect element to the screen224(not shown inFIGS.9A-9D). The light that is reflected from the side parts is also omitted fromFIG.9A, for clarity of illustration. InFIG.9B, the rod234has rotated in the direction indicated by arrow “H” so that the paddle element238is in a different position (i.e., relative to its position illustrated inFIG.9A) in respect of the light source222. InFIG.9B, the light from the light source222is schematically represented by the arrow “2M2”, and the reflected light is schematically represented by the arrow “2N2”. The light represented by the arrow “2M2” is shown as being reflected from one or both of the side parts249A,249B. Because some of the light is reflected from the substantially planar side parts249A,249B, rather than the convex surface244′, the light reflected from the side parts249A,249B as projected onto the screen224would have a slightly different intensity than the light reflected from the central region244′. The light from the light source that is directed to the middle part247is also schematically represented by the arrow “F2”, and the light reflected from the middle part247is schematically represented by the arrow “G2”. Due to the different positioning of the middle part247relative to the side parts249A,249B, the light reflected from the middle part247is directed toward a different location on the screen. InFIG.9C, the paddle element238is shown after it has been rotated further in the direction indicated by the arrow “H”. InFIG.9C, the second side256of the body portion240B is exposed to the light from the light source222. In this position, the light is also at least partially reflected from the central region244″, the light being represented by the arrows “2M3” and “2N3”. The central region244″ on the second side256is concave. It will be understood that light is also reflected, at this point, from the base regions257A,257B, however, such reflected light is omitted for clarity of illustration. The light from the light source222that is directed to the middle part247is also schematically represented by the arrow “F3”, and the light reflected from the middle part247is schematically represented by the arrow “G3”. Due to the different positioning of the middle part247relative to the base regions257A,257B, the light reflected from the middle part247is directed toward a different location on the screen. InFIG.9D, the paddle element238is shown as having been rotated further in the direction indicated by the arrow “H” (relative to the position thereof illustrated inFIG.9C), so that the light from the light source222is at least partially reflected from the substantially planar perimeter region246″. The light reflected from the base regions257A,257B is schematically represented by the arrow “2N4”. In this situation also, because the light is reflected from the substantially planar side parts249A,249B, rather than the concave surface244″, the light reflected from the side parts249A,249B as directed onto the screen224would have a slightly different intensity than the light reflected from the central region244″. The light from the light source222that is directed to the middle part247is also schematically represented by the arrow “F4”, and the light reflected from the middle part247is schematically represented by the arrow “G4”. Due to the different positioning of the middle part247relative to the side parts249A,249B, the light reflected from the middle part247is directed toward a different location on the screen. As noted above, the positions of the side parts249A,249B and the middle part247relative to each other may vary, depending on how the paddle element238bends when it is mounted on the mounting element. InFIG.9E, on one of the body portions, the side parts and the middle part are shown as being non-coplanar with each other. The middle part and the two side parts are identified for convenience by reference numerals247′,249A′, and249B′ respectively. As noted above, the middle part and the side parts may be substantially coplanar. This situation is illustrated inFIG.9F, where only one side part is identified by reference numeral249A″ for convenience. It will be understood that the middle part and the other side part are not identified inFIG.9Ffor clarity of illustration. It will also be understood that, as described above, the flicker element preferably includes a number of paddle elements positioned along the rod body. The other paddle elements on the rod are omitted fromFIGS.9A-9Ffor clarity of illustration. In addition, the locations of the middle part and the side parts relative to each other are exaggerated inFIG.9Efor clarity of illustration. It is believed that the radial positioning of the paddle elements238relative to each other, to an extent, also causes the realistic variation in light intensity in the image226due to the different reflective surfaces of the body portions240A,240B being located to reflect the light from the light source(s)222in turn as the flicker element232is rotated about the rod's axis236. For example, inFIG.10A. a top view of the situation illustrated inFIG.9Ais provided. The light from the light source222is represented by the arrow “2M1”, and as illustrated, it is reflected from the central region244′. The light reflected from the central region244′ toward the screen224is represented by the arrow “2N1”. For clarity of illustration, the point on the central region244′ at which the light from the light source222is reflected toward the screen224is identified as “2X”. As can be seen inFIG.10A, the light that is reflected from the central region244′ produces an image of flames, or part thereof, at a point identified as “2Y” on the screen. InFIG.10B, a top view of the situation illustrated inFIG.9Bis provided. As can be seen inFIGS.9A and9B, inFIG.9B, the rod has rotated about its axis from the position illustrated inFIG.9A. The light from the light source222is represented by the arrow “2M2” and the light reflected from the middle part247is schematically represented by the arrow “2N2”. The light is shown as being reflected from a point “2V” on the middle part247. As illustrated inFIG.10B, the light that is reflected from the perimeter region246′ is directed substantially orthogonally to the axis236of the rod234, and intersects the screen at a point identified for clarity of illustration as “2Z”. InFIG.10B, the light is schematically illustrated as being reflected from the middle part247. As noted above, the form (i.e., planar or not) and position of the middle part (i.e., relative to the side parts) after mounting on the rod may vary from one paddle element to another. It will be understood that the middle element247is shown as being substantially planar inFIG.10Bfor clarity of illustration. FromFIGS.10A and10B, it can be seen that the different shapes of the central region244(i.e., non-planar) and the middle part247may result in the light from the light source222being reflected in slightly different directions toward the screen224as the rod234rotates. For clarity of illustration, the extent to which the locations “2Y” and “2Z” on the screen are different is exaggerated. It will be understood that a number of elements of the flame simulating assembly220are omitted fromFIGS.10A and10B, also for clarity of illustration. It will also be understood that the light reflected from the other central region244″, as illustrated inFIG.9C, is also directed to a location on the screen that is other than the location on the screen to which the light reflected from the other side of the middle part247is directed. Another benefit that is believed to result from the arrangement of the elements of the assembly220is the virtual elimination of incidental partially transverse flashes of light on the screen224. This benefit is believed to be due to the generally consistent positioning of the paddle elements238relative to the screen224, i.e., because the paddle elements238are positioned by the respective mounting elements276in the respective predetermined positions therefor. It will be understood that the rod234preferably is positioned so that its axis236is substantially parallel to the screen224. The light from the light source is directed toward the body portions240A,240B in a direction that is substantially orthogonal to the axis236, and aligned with an aperture in the flame effect element. It is believed that the elimination of the incidental partially transverse flashes of light is due to this arrangement, and the manner in which each paddle element is secured in position on each mounting element respectively. As can be seen, for instance, inFIGS.7A and7B, the flame simulating assembly220preferably also includes a simulated fuel bed292. Those skilled in the art would appreciate that the simulated fuel bed292may be formed in any suitable manner, and made of any suitable materials. In one embodiment, the simulated fuel bed292preferably includes one or more simulated fuel elements294supported by a platform296. Those skilled in the art would also appreciate that the elements294may be made of any suitable material(s). The simulated fuel elements294preferably are at least partially light-transmitting. Preferably, the simulated fuel elements294are at least partially translucent, and/or at least partially transparent. In one embodiment, it is preferred that the elements294are, for example, pieces of cut glass. Alternatively, the fuel elements294may be made of acrylic. The fuel elements294preferably are formed into any suitable shape(s). The fuel elements294preferably are located by the platform or support element296that positions at least some of the fuel elements294adjacent to the screen224. The fluctuations in the light that is reflected toward the screen are, in part, the result of the differences in forms and positioning of the parts and regions of the reflective surfaces242, as illustrated schematically inFIGS.9A-9F, and as described above. In addition, the light that is reflected from the flicker element fluctuates in intensity because of the gaps between the paddle elements, i.e., each paddle element reflects the light only intermittently as the flicker element rotates. Those skilled in the art would appreciate that, although the embodiments of methods of the invention as described above indicate that steps of the methods are to be performed in a sequence, certain of the steps may alternatively be performed in alternative sequences. For instance, in the method of providing images of flames, the elements of the flame simulating assembly generally may be provided in any suitable order. It will be appreciated by those skilled in the art that the invention can take many forms, and that such forms are within the scope of the invention as claimed. The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole. | 79,843 |
RE49853 | Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION Reconciling disparate records from across different databases can be computationally burdensome to the extent that many desirable database operations are precluded across large and complex databases. For example, in the health care field, a variety of epidemiological studies would reveal links between disparate events. These problems are particularly acute in that the underlying databases may be de-identified in order to satisfy medical privacy concerns. Further, the size of the databases, which can include complex coding for complex and disparate diagnoses may make establishing links between different events even more computationally intensive as a specified item may be compared against countless other items, diagnoses, stimuli, and conditions. These operations are further complicated by different data sources that are formatted in different conventions and with varying degrees of completeness. Further, databases may be constantly updated with large volumes of new information. Thus, newly-received records must be reconciled with and compared to existing records and databases in order to ascertain new trends and real-time information. The problem is particularly acute where longitudinal data associated with a de-identified label is reconciled between two different data sources with two different time sequences that describe different and sometimes unrelated activity. In order to perform the requisite correlation between the two different data sources, the data must be formatted in a manner that facilitates ready comparison of two different data points from each of the data sources. Once rapid comparison of disparate sources can be relied upon, an organization, such as a Patient Safety Organization (PSO) can act in reliance upon the identified correlations and work to address the correlations and derived identifications. For example, one such correlation may be associated with a breach in the desired activity (e.g., a standard of care). A medical administrator then may work to identify these deviations as fault or alarm conditions and take corrective action in real-time. Note that the deviations need not formally be relative to some regulatory standard (e.g., the standard of care). Instead, the deviation may exist relative to desired behavior (e.g., an internal hospital policy). Based on the architecture and organization described above, a variety of configurations may be used to facilitate analysis of patent records organized longitudinally according to a first timeline relative to another source of data organized according to a second timeline. In one configuration, this disclosure generally describes a system and a method for timely providing notifications of treatments to a patient population, and the reaction to notifications. There may be significant problems in determining an impact of a notification about a treatment provided to a patient on a receipt of the treatment by the patient as, in healthcare, treatments generally do not immediately follow notifications of treatments. For example, a patient may not get a prescription without a doctor, the doctor may recommend other lifestyle changes, other treatments, order tests, etc. before prescribing the patient a drug, the patient then may need to go to the pharmacy to get the prescribed drug. Additionally, the patient may need to have insurance or some other way to supplement the expense of the prescribed drug before making the purchase. Additionally, in healthcare, patient information generally must be anonymized. As described in this description, treatment may refer to medical events such as seeing a doctor, receiving a prescription, receiving prescribed drugs from a pharmacy or undergoing an operation. Accordingly, in some implementations, de-identified longitudinal medical records may be collected from data servers at medical service providers that record filled prescription information, medical operations, doctor visits, or other medical events for patients. The information may generally include records of different anonymized patients, where each record identifies one or more treatments received by the anonymized patient, the one or more times the treatments were received by the anonymized patient, and an identifier that uniquely distinguishes the anonymized patient from other anonymized patients. The identifier may refer to a de-identified patient, which may also be referred to as an anonymized patient. The de-identification means no identity information, such as name, address, birth date, or social security information, is available in the recorded information. Instead, each patient is referenced by an anonymous tag that is specific to the patient. Accordingly, an anonymized patient may be a patient for which the patient's identity cannot be determined but is distinguishable from other anonymized patients. Generally, the anonymous tag is doubly encrypted using a key specific to a data supplier (such as a data server at a pharmacy) and another key specific to a longitudinal database. Additionally, notification data may be collected from data servers of notification providers that record notifications provided to recipients. A notification may include text, one or more images, one or more videos, or one or more audio identifying a treatment. The notifications may be placed in various locations, e.g., on websites or in mobile applications. For example, a first type of notification may be provided with an image on a first website, and a second type of notification may be provided with text on a second website. The notification data may include notification records that each identify a type of notification provided, a time the notification was received, and the recipient of the notification. Interestingly, relationships between the patients of the medical data and recipients of the notification data may be identified and time relationships between when patients received a treatment and when the patients received a notification regarding the treatment may be determined. The time relationships may then be used to determine impacts of the notifications on the patients receiving the treatment. The impacts of the notifications may be used to forecast a future effect of various types of notification, and a plan for providing notifications in the feature may be determined based on the forecast. FIG.1Aillustrates an example system100for obtaining de-identified longitudinal medical records. The medical records may include treatment data in the form of prescription data. The prescription may include a pharmaceutical product such as a prescription drug approved by a regulatory agency, such as the Federal Drug Administration (FDA), the European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory Agency (MHRA). The pharmaceutical product can also include approved medical devices. The prescriptions may be filled at multiple sites, such as pharmacies104A to104G. These sites can cover a geographic region, for example, a region in a particular country. These sites may also be located globally, for example, the North American continent, or the European Union. Prescription data for each participant patient may be collected from each pharmacy store. In one example, a pharmacy database may collect prescription data from all pharmacy stores on a daily basis. The pharmacy database includes non-volatile data storage devices. Each pharmacy store may house its own data server in communication with the pharmacy database to transfer prescription data on a daily basis. The prescription data records the information about a particular prescription when the prescription was filled. As disclosed herein, the prescription data for each participant patient, as recorded at the pharmacy store at the time of filling, is de-identified such that the data does not include information capable of identifying the particular participant patient. Examples of such identifying information include: patient's name, patient's insurance identification number, patient's Medicare/Medicaid identification number, patient's social security number, patient driver's license number, etc. In some implementations, such identifying information may be converted by a one-way hash-function to generate an alpha-numerical string. The alpha-numerical string conceals the identity of the individual participant patient, thereby maintaining confidentiality of the data as the data is being reported, for example, daily from the sites104A to104G to the central server102. There, data corresponding to the same participant patient may be linked by virtue of the matching alpha-numerical string. Thus, data for the same participant patient may be longitudinally tracked for each individual, without compromising confidentiality of the individual patients, even though the patient can fill the prescription at various stores and the patient can receive a prescription for a healthcare product from various healthcare professionals. Additionally or alternatively, the de-identified longitudinal medical records may include other forms of data. For example, the de-identified longitudinal medical records may include data describing operations performed on a patient and when the operations were performed, when a patient made a visit to a particular doctor, when a doctor performed a diagnosis on a patient, and other events. In these instances, the sites may be medical service providers that include pharmacy stores and other types of medical service providers, e.g., doctor's offices or hospitals. FIG.1Billustrates an example work flow110for collecting data of patient recipients from data servers at various medical service providers and longitudinally tracking the medical record of each individual patient recipient over time. Data114A-114G may correspond to prescription data reported from each pharmacy store. In some implementations, data114-114G may be reported from data servers at each pharmacy store on a daily basis, for example, at the end of business data local time. Data114A-114G remain de-identified to preserve confidentiality, as disclosed herein. In this illustrated work flow, each pharmacy store may employ the same one-way hashing function to anonymize data records of each patient. As a result, reported prescription data114A-114G, as received at central server102to update database112, include the same de-anonymized key for prescription records from the same patient, even if the patient may move to another pharmacy store, another healthcare professional, or another healthcare provider (e.g., health insurance carrier, pharmacy insurance carrier). The central server102may match prescription data records from the same patient recipient to update database112, which contains data records reported earlier for the same patient recipient. In some implementations, however, the de-identified data may be further encrypted before the data is reported to central server102to update database112. For illustration, data114A-114G may be encrypted using a symmetric encryption key specific to each pharmacy store. The symmetric encryption key may only be known to the pharmacy store and central server102. Thus, only the participant site can encrypt the de-identified data with the symmetric key and only the central server102can decrypt the encrypted de-identified data with the particular symmetric key. In another illustration, a public-key infrastructure (PKI) may be used such that the reported data may be encrypted with the public key of the central server102so that only the central server102can decrypt using its private key. In other illustrations, the central server102and pharmacies104A-104G may exchange messages using the PKI to establish an agreed-on symmetric key. As discussed above, the data114A-114G may correspond to other data besides prescription data. For example, the data114A-114G may describe operations performed on a patient and when the operations were performed, when a patient made a visit to a particular doctor, when a doctor performed a diagnosis on a patient, and other events received from medical service providers that include pharmacy stores and other types of medical service providers, e.g., doctor's offices or hospitals. FIG.1Cillustrates an example linkage of daily reported medical data for the patient recipients based on matching anonymized tags. As illustrated, the daily received prescription data (for example, data114B from pharmacy104B) correspond to patient recipients. The de-identification process allows such prescription data to remain anonymous. In some implementations, the de-identified data from the same patient may be linked at central server102. As illustrated, data are received on different days for the patient recipients. For example, on time point N, de-identified prescription data121A to121C may be received. Likewise, on time point N+1, de-identified prescription data122A to122C are received. Similarly, on time point N+2, de-identified data123A to123C may be received. These de-identified prescription data correspond to different patient recipients. Based on matching tags, such as matching de-identified alpha-numerical strings, the de-identified prescription data from each patient recipient may be linked and hence the prescription activity of a particular patient recipient can be longitudinally tracked. In some implementations, the matching tags may include graphic representations as well as alpha-numerical strings. The graphic representations are also de-identified to remove personally identifiable information of the participant patient. In some instances, the alpha-numerical strings or graphical representations may be tags to the actual prescription data record, which may be referred to as part of the metadata. In other instances, the alpha-numerical strings or graphical representations may be embedded to the actual prescription data record itself. In still other instances, the alpha-numerical strings or graphical representations may be part of the metadata and embedded in the actual prescription data record. The implementations of both the tag and the embedding may further deter alterations or modifications of the data records being reported from each participant site. When the received daily data records are linked with earlier data records of the same patient recipients, database112may be updated. The updated database may allow a variety of data analytics to be generated, revealing the interesting insights of prescription usage pattern for each patient recipient as well as the statistical prescription pattern of each healthcare professional, as discussed below. As discussed above, the de-identified prescription data121A to121C may correspond to other de-identified data besides prescription data. For example, the de-identified data may describe operations performed on a patient and when the operations were performed, when a patient made a visit to a particular doctor, when a doctor performed a diagnosis on a patient, and other events. FIG.2illustrates an example of a block diagram of a system200for providing timely notification of treatments. The system200may include a relationship identifier230that identifies relationships between de-identified longitudinal medical records and notification data, a time decay model generator240that determines an impact model based on the relationships, a treatment impact attribution engine250that determines an impact of notifications on a treatment being received, a treatment trend prediction engine260that determines an initial forecast for the anonymized patients based on the determined impacts, a projection engine270that determines a projected forecast for potential patients from the initial forecast, and an optimization engine280that determines a notification plan based on the projected forecast. In more detail, the relationship identifier230may identify relationships between patients anonymously identified by the de-identified longitudinal medical records210and recipients of identified by the notification data220. As described above, the de-identified longitudinal medical records210may be collected from data servers at medical service providers that record filled prescription information, medical operations, doctor visits, or other medical events for patients. The information may generally include records of different anonymized patients, where each record identifies one or more treatments received by the anonymized patient, the one or more times the treatments were received by the anonymized patient, and an identifier that uniquely distinguishes the anonymized patient from other anonymized patients. The notification data220may be collected from data servers of notification providers that record notifications provided to recipients. The notification data may include notification records that each identify a type of notification provided, a time the notification was received, and the recipient of the notification. The relationship identifier230may obtain the de-identified longitudinal medical records210and the notification data220, and identify relationships between anonymized patients and recipients based on identifying, from the de-identified longitudinal medical records, anonymized patients that received the treatment, identifying, from the notification data, notifications for the treatment that were received by the recipients, and determining, for each of the identified notifications that were received by the recipients, whether the recipient is an anonymized patient identified as having received the treatment. For example, the relationship identifier230may identify from a medical record that an anonymized patient identified as “ad978zfvd3426oiu90” received a particular treatment, identify from the notification data that a recipient identified as “ad978zfvd3426oiu90” received a notification for the particular treatment, and that the identifiers both have the value “ad978zfvd3426oiu90.” In some implementations, the relationship identifier230may, one or more of, determine whether notification records are for notifications for other treatments and determine to ignore those notifications or determine whether treatments indicated by the medical records are for other treatments and determine to ignore those indications in the medical records. Additionally or alternatively, the relationship identifier230may determine that the identifiers match. For example, the relationship identifier230may determine that the identifier of an anonymized patient in a medical record indicates demographics of the anonymized patient, that are insufficiently detailed to identify the anonymized patient, match demographics indicated by the identifier of a recipient in a notification record. The time decay model generator240may determine an impact model based on the relationships determined by the relationship identifier230. The impact model may represent an impact of a notification on a treatment being received based on a time relationship between when a treatment was received by a patient and a notification was received by a recipient corresponding to the patient. For example, the time decay model generator240may determine an impact model that models an impact of 66% for a notification received fifteen days before a treatment is received and an impact of 33% for a notification received thirty days before a treatment is received. In some implementations, the impact model may include a model that is exponentially decayed from time when the notification was initially provided to a patient to a time the treatment was received by the patient. For example, the time decay model generator240may determine coefficients for an exponential function that receives as an input a time relationship and outputs an impact. In some implementations, the impact model may be specific to notification type. For example, the time decay model generator240may generate an impact model that provides different impacts for the same time relationship for notifications of different types. In some other implementations, the impact model may not be specific to notification type. For example, the time decay model generator240may generate an impact model that provides the same impact for the same time relationship for notifications of the same type. The time decay model generator240may determine the impact model based on determining time relationships between times when treatments were received by anonymized patients and times when notifications were received by recipients corresponding to the anonymized patients, determining associations between one or more time relationships for notifications received by the anonymized patients, and determining the impact model from the determined associations between the time relationships. For example, the time decay model generator240may determine from the medical records210that anonymized patient “ad978zfvd3426oiu90” fulfilled a prescription for “Drug X” on Jul. 23, 2015, from the notification data220that a recipient determined to correspond to anonymized patient “ad978zfvd3426oiu90” received a notification regarding “Drug X” on Jul. 8, 2015, and as result, determine a time relationship of fifteen days, determine from the notification data220that a recipient determined to correspond to anonymized patient “ad978zfvd3426oiu90” received a notification regarding “Drug X” on Jun. 23, 2015, and as result, determine a time relationship of thirty days, determine that both notifications were received by anonymized patient “ad978zfvd3426oiu90,” and in response, determine that the time relationship of thirty days and fifteen days for anonymized patient “ad978zfvd3426oiu90” are both associated with anonymized patient “ad978zfvd3426oiu90” receiving the treatment. In another example, the time decay model generator240may determine from the medical records210that anonymized patient “oinj32o908twvc2” fulfilled a prescription for “Drug X” on Jul. 1, 2015 and from the notification data220and determined relationships that a recipient corresponding to anonymized patient “oinj32o908twvc2” received a notification regarding “Drug X” on Jun. 1, 2015, and as result, determine a time relationship of thirty days. From the associations between time relationships, the time decay model generator240may determine the impact model. For example, the time decay model generator240may use machine-learning, e.g., Least Absolute Shrinkage and Selection Operator (LASSO), Cox Proportional Hazard (CPH) model, ensemble learning by random survival forest (RSF), with the de-identified longitudinal medical records210, the notification data220, and the determined time relationships to determine coefficients of an exponential function. The time decay model generator240may use random survival forest by randomly under sampling patients indicated by the medical records210that were not treated with the particular treatment, combine the under sampled data with the data of anonymized patients indicated by the medical records210that were treated with the particular treatment, apply random survival forest to derive an impact of a notification each day to the treatment being received, e.g., scores of impact of a notification each day to treatment being received may be generated, repeating these steps, e.g., for 50,000, 100,000 or some other number of times, and average the impacts, and then fitting a curve to impact decay over time based on the averaged impacts. The treatment impact attribution engine250may determine an impact of notifications on a treatment being received based on the impact model determined by the time decay model generator240. In particular, the treatment impact attribution engine250may attribute an impact of different types of notifications indicated by the notification data220over all anonymized patients identified by the medical records210and time based on the impact model. For example for each type of notification, the treatment impact attribution engine250may sum an impact of the type of notification on each anonymized patient indicated by the medical records210receiving the treatment based on the impact model. From the attribution, the treatment impact attribution engine250may determine different impacts of different types of notifications. For example, the treatment impact attribution engine250may determine that a particular type of notification has twice as much impact as another type of notification, i.e., results in twice as many patients receiving a treatment. The treatment trend prediction engine260may determine an initial forecast model based on the impacts determined by the treatment impact attribution engine. For example, the treatment trend prediction engine260may determine an initial forecast model that models a number of patients identified in the medical records210that would receive a treatment based on a number of each type of notification provided. A forecast model may store, for each type of notification, a notification type label that is indicative of a relationship between a number of patients receiving a treatment and a number of recipients receiving notifications for the treatment. For example, a first notification type label for a first type of notification may reflect how a number of patients estimated to receive a treatment increases as a number of recipients of a notification of the first type of notification for that treatment increases and a second notification type label for a second type of notification may reflect how a number of patients estimated to receive a treatment increases as a number of recipients of a notification of the second type of notification for that treatment increases. The treatment trend prediction engine260may determine the initial forecast model based on fitting the model to the number of treatments received indicated by the medical records210and the notifications provided indicated by the notification data220. For example, the treatment trend prediction engine260may determine an initial forecast model that scales an impact of notifications of all types by an amount so that a number of patients forecasted to receive a treatment best matches the number of patients that actually received the treatment as indicated by the medical records210and the notification records220. The treatment trend prediction engine260may determine the initial forecast model as a sigmoid function considering the diminishing effect of number of notifications received by recipients on number of patients that receive a treatment. The treatment trend prediction engine260may generate more accurate initial forecast models as the amount of data increases across time. For example, at nine weeks data up to 100,000 notifications may be available, at thirteen weeks, data up to 150,000 notifications may be available, and at eighteen weeks data up to 200,000 notifications may be available, and the treatment trend prediction engine260may fit the initial forecast model to match the data. The projection engine270may determine a projected forecast for potential patients from the initial forecast determined by the treatment trend prediction engine260. For example, the projection engine270may project an initial forecast determined from a subset of patients with indicated by the medical records210to a set of all patients indicated by the medical records210, then project from the set of all patients indicated by the medical records210to all recipients of notifications indicated by the notification data220, and then project from all recipients of the notifications indicated by the notification data220to all potential recipients of the notification. The subset of patients of the initial forecast may be patients that have prescription drug activity within a predetermined number of months, e.g., the last three, six, twelve, or another number of months. The projection engine270may project forecasts from a first group to a second group based on scaling on characteristics of the groups. For example, the projection engine270may determine that the initial forecast is prepared for a set of one hundred patients where 40% have high blood pressure, and that the medical records210for all one thousand patients have 20% with high blood pressure, and in response, modify the initial forecast by a factor of five. The optimization engine280may determine a notification plan based on the projected forecast. For example, the optimization engine280may determine to provide one million of a particular type of notification and two million of another type of notification to increase a forecasted number of treatments. The optimization engine280may determine the notification plan based on notification constraints290. The notification constraints290may include specifications of one or more of a budget, notification types available, notifications provided so far, notifications allocated, a minimum number of notifications for each type, a maximum number of notifications of each type, a remaining number of notifications to provide for each type, a cost for each type of notification, an available budget for each type of notification, or a total budget for a type of notification. For example, the notification constraints290may specify that a total of one million is available for notifications, three types of notifications are available, a first type of notification costs fourteen dollars per million provided, a second type of notification costs eighteen dollars per million provided, and a third type of notification costs sixteen dollars per million provided, and in response, based on the projected forecast model, the optimization engine280may determine to allocate two hundred thousand dollars to the first type of notification, five hundred thousand dollars to the second type of notification, and three hundred thousand dollars to the third type of notification. The optimization engine280may receive the notification constraints from a user. For example, the optimization engine280may provide a graphical user interface for a user to input the notification constraints and change the notification constraints, and in response may update the notification plan and display the updated notification plan to the user through the graphical user interface. In some implementations, the optimization engine280may receive indications of events and in response update a notification plan. For example, the optimization engine280may receive an indication that a flu epidemic is spreading, and in response, may determine to increase a number of allocations of a particular type of notification and decrease a number of allocations of another type of notification. The optimization engine280may then schedule the notifications based on the forecast model. For example, the optimization engine280may cause the system100to provide notifications to recipients based on the notification plan. In another example, the optimization engine280may provide the notification plan to a notification provider for the notification provider to provide notifications in accordance with the notification plan. FIG.3illustrates an example of a flow chart300for providing timely notifications of treatments. Initially, de-identified longitudinal medical records are received (310). For example, the relationship identifier230may receive de-identified longitudinal medical records from a database of a medical server provider. Before, after, or in parallel, notification data is received (320). For example, the relationship identifier230may receive notification data from a database of a notification provider. Thereafter, relationships between the medical records and the notification data may be identified (330). For example, the relationships identifier230may determine that a particular medical record indicates that an anonymized patient received a particular treatment, determine that a particular notification record indicates that a recipient received a notification for the particular treatment, and determine that the particular medical record has an identifier, that refers to an anonymized patient, that is the same identifier representing a recipient that is associated with the particular notification record. Thereafter, time relationships between when treatments were received and notification were received may be determined (340). For example, the time decay model generator240may determine that sixty days based between when a recipient received a notification of a treatment and an anonymized patient corresponding to the recipient received the treatment. Next, associations between one or more time relationships may be determined (350). For example, the time decay model generator240may determine the time relationships that are notifications for treatments provided to the same recipient before the recipient received the treatment. Next, an impact model representing an impact of a notification on a treatment being received based on the determined associations between the time relationships may be generated (360). For example, the time decay model generator240may generate the impact model that is exponentially decayed from time when the notification was initially provided to a patient to a time the treatment was received by the patient. Next, the impact of notifications on the treatments being received may be determined based on the impact model and the determined time relationships (370). For example, the treatment impact attribution engine250may determine the impact that a notification received sixty days before a treatment had on the treatment being received based on the impact model and that the notification was received sixty days before the treatment was received. Thereafter, a forecast model may be determined based on the impacts (380). For example, the treatment trend prediction engine260may determine an initial forecast model for a set of patients based on the impacts and the projection engine270may project the initial forecast model to all potential notification recipients. Next, a plan for timely notifying may be determined based on the forecast model (390). For example, the optimization engine280may receive the forecast model and notification constraints specified by a user indicating types of notifications available and constraints on providing the notifications, and in response, determine a notification plan indicating how many of each type of notification should be provided. FIG.4illustrates an example timeline400of notifications being provided and a treatment being received. The timeline400may show time passing from left to right versus impact. The timeline400shows how as notifications are provided earlier from when a treatment is received, an impact of the notification decreases. For example, notification type A is provided most earliest from when a treatment is received and is associated with a lowest impact, notification type B is provided second most earliest from when a treatment is received and is associated with a second lowest impact, notification type C is provided third most earliest from when a treatment is received and is associated with a third lowest impact, and notification type D is provided least earliest from when a treatment is received and is associated with a highest impact. FIG.5illustrates an example graph500of an impact of a notification with a time relationship between a notification and treatment. The x-axis represents a time relationship that increases from left to right and the y-axis represents an impact that increases from bottom to top. As shown in the graph500, as the time relationship between when a notification is provided and a treatment is received increases, the impact decreases. FIG.6illustrates a timeline600of notifications and impacts. The timeline600shows how lower impacts are associated with notifications with greater time relationships. For example, notification type A that has the greatest time relationship is associated with an impact of 5%, notification type B which has a second greatest time relationship is associated with an impact of 15%, notification type C which has a third greatest time relationship is associated with an impact of 30%, and notification type D which has a least time relationship is associated with an impact of 50%. FIG.7illustrates an example graph700output of forecast model of number of treatments with number of notifications. The forecast model may be generated so that the graph700is fitted to numbers of notification provided indicated by notification data and numbers of treatments received indicated by the medical records. FIG.8illustrates an example user interface for receiving notification constraints for determining a plan for timely providing notifications. As shown inFIG.8, the user interface may enable users to view and specify types of notifications differentiated by channel, e.g., display, audio, video, or some other channel, site providing the notification, e.g., publishers A-E, and placement of the notification, e.g., where on a site the notification may be provided. The user interface may further enable users to view and specify budgets for each type of notification, a total budget, minimum and maximum notifications to provide for each type of notification, and cost for each type of notification. FIGS.9and10illustrate example plans900,1000for timely providing notifications. As shown, the plans may indicate a number of each type of notification to provide to increase a number of patients receiving a treatment. The plans may further indicate an estimated budget used, an estimated number of notifications that will be used, and an estimated number of treatments that will be received, and differences from a previous plan. Implementations of the subject matter and the functional operations described in this specification can be implemented in digital electronic circuitry, in tangibly-implemented computer software or firmware, in computer hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. Implementations of the subject matter described in this specification can be implemented as one or more computer programs, i.e., one or more modules of computer program instructions encoded on a tangible non-transitory program carrier for execution by, or to control the operation of, data processing apparatus. The computer storage medium can be a machine-readable storage device, a machine-readable storage substrate, a random or serial access memory device, or a combination of one or more of them. The term “data processing apparatus” refers to data processing hardware and encompasses all kinds of apparatus, devices, and machines for processing data, including, by way of example, a programmable processor, a computer, or multiple processors or computers. The apparatus can also be or further include special purpose logic circuitry, e.g., a central processing unit (CPU), a FPGA (field programmable gate array), or an ASIC (application-specific integrated circuit). In some implementations, the data processing apparatus and/or special purpose logic circuitry may be hardware-based and/or software-based. The apparatus can optionally include code that creates an execution environment for computer programs, e.g., code that constitutes processor firmware, a protocol stack, a database management system, an operating system, or a combination of one or more of them. The present disclosure contemplates the use of data processing apparatuses with or without conventional operating systems, for example Linux, UNIX, Windows, Mac OS, Android, iOS or any other suitable conventional operating system. A computer program, which may also be referred to or described as a program, software, a software application, a module, a software module, a script, or code, can be written in any form of programming language, including compiled or interpreted languages, or declarative or procedural languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program may, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data, e.g., one or more scripts stored in a markup language document, in a single file dedicated to the program in question, or in multiple coordinated files, e.g., files that store one or more modules, sub-programs, or portions of code. A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network. While portions of the programs illustrated in the various figures are shown as individual modules that implement the various features and functionality through various objects, methods, or other processes, the programs may instead include a number of sub-modules, third party services, components, libraries, and such, as appropriate. Conversely, the features and functionality of various components can be combined into single components as appropriate. The processes and logic flows described in this specification can be performed by one or more programmable computers executing one or more computer programs to perform functions by operating on input data and generating output. The processes and logic flows can also be performed by, and apparatus can also be implemented as, special purpose logic circuitry, e.g., a central processing unit (CPU), a FPGA (field programmable gate array), or an ASIC (application-specific integrated circuit). Computers suitable for the execution of a computer program include, by way of example, can be based on general or special purpose microprocessors or both, or any other kind of central processing unit. Generally, a central processing unit will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of a computer are a central processing unit for performing or executing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks. However, a computer need not have such devices. Moreover, a computer can be embedded in another device, e.g., a mobile telephone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a Global Positioning System (GPS) receiver, or a portable storage device, e.g., a universal serial bus (USB) flash drive, to name just a few. Computer-readable media (transitory or non-transitory, as appropriate) suitable for storing computer program instructions and data include all forms of non-volatile memory, media and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices; magnetic disks, e.g., internal hard disks or removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks. The memory may store various objects or data, including caches, classes, frameworks, applications, backup data, jobs, web pages, web page templates, database tables, repositories storing business and/or dynamic information, and any other appropriate information including any parameters, variables, algorithms, instructions, rules, constraints, or references thereto. Additionally, the memory may include any other appropriate data, such as logs, policies, security or access data, reporting files, as well as others. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry. To provide for interaction with a user, implementations of the subject matter described in this specification can be implemented on a computer having a display device, e.g., a CRT (cathode ray tube), LCD (liquid crystal display), or plasma monitor, for displaying information to the user and a keyboard and a pointing device, e.g., a mouse or a trackball, by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be any form of sensory feedback, e.g., visual feedback, auditory feedback, or tactile feedback; and input from the user can be received in any form, including acoustic, speech, or tactile input. In addition, a computer can interact with a user by sending documents to and receiving documents from a device that is used by the user; for example, by sending web pages to a web browser on a user's client device in response to requests received from the web browser. The term “graphical user interface,” or GUI, may be used in the singular or the plural to describe one or more graphical user interfaces and each of the displays of a particular graphical user interface. Therefore, a GUI may represent any graphical user interface, including but not limited to, a web browser, a touch screen, or a command line interface (CLI) that processes information and efficiently presents the information results to the user. In general, a GUI may include a plurality of user interface (UI) elements, some or all associated with a web browser, such as interactive fields, pull-down lists, and buttons operable by the business suite user. These and other UI elements may be related to or represent the functions of the web browser. Implementations of the subject matter described in this specification can be implemented in a computing system that includes a back-end component, e.g., as a data server, or that includes a middleware component, e.g., an application server, or that includes a front-end component, e.g., a client computer having a graphical user interface or a Web browser through which a user can interact with an implementation of the subject matter described in this specification, or any combination of one or more such back-end, middleware, or front-end components. The components of the system can be interconnected by any form or medium of digital data communication, e.g., a communication network. Examples of communication networks include a local area network (LAN), a wide area network (WAN), e.g., the Internet, and a wireless local area network (WLAN). The computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. While this specification contains many specific implementation details, these should not be construed as limitations on the scope of any invention or on the scope of what may be claimed, but rather as descriptions of features that may be specific to particular implementations of particular inventions. Certain features that are described in this specification in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub-combinations. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be helpful. Moreover, the separation of various system modules and components in the implementations described above should not be understood as requiring such separation in all implementations, and it should be understood that the described program components and systems can generally be integrated together in a single software product or packaged into multiple software products. Particular implementations of the subject matter have been described. Other implementations, alterations, and permutations of the described implementations are within the scope of the following claims as will be apparent to those skilled in the art. For example, the actions recited in the claims can be performed in a different order and still achieve desirable results. Accordingly, the above description of example implementations does not define or constrain this disclosure. Other changes, substitutions, and alterations are also possible without departing from the spirit and scope of this disclosure. | 49,260 |
RE49854 | DETAILED DESCRIPTION OF THE INVENTION As shown in the exemplary drawings wherein like reference numerals indicate like or corresponding elements among the figures, example embodiments of a system and method according to the present invention are described below in detail. It is to be understood, however, that the present invention may be embodied in various forms. For example, although described herein as pertaining to minimizing static leakage of an integrated circuit, aspects of the invention may be practiced on circuitry not embodied within an integrated circuit. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure, method, process or manner. FIG.1is a block diagram of an integrated circuit100embodying a system for minimizing static leakage, in accordance with an example embodiment. The integrated circuit100is any electronic device that is instantiated into silicon and/or similar manufacturing materials. One example of the integrated circuit100is a system-on-a-chip. The integrated circuit100includes multiple intellectual property (IP) units, which are blocks of circuitry performing specific functions. It will be appreciated that functions of the integrated circuit100described herein may be performed by a single integrated circuit100or may be partitioned among several integrated circuits100. The exemplary integrated circuit100ofFIG.1includes a central processor unit (CPU)105, one or more power islands110, one or more power island managers120, and one or more leakage manager systems130. WhileFIG.1depicts one power island110and one power island manager120for the sake of simplicity, other embodiments of the integrated circuit100may include any number of power islands110, power island managers120, and leakage manager systems130. In such embodiments, some of the power islands110may comprise different circuitry with respect to other power islands110. The power island110and the power island manager120are further described in copending U.S. patent application Ser. No. 10/840,893, entitled “Managing Power on Integrated Circuits Using Power Islands,” filed May 7, 2004. The power island110is any section, delineation, partition, or division of the integrated circuit100in which power consumption is controlled. In some embodiments, multiple power islands110are delineated based on geographical factors of the integrated circuit100. In some embodiments, multiple power islands110are delineated based on functional IP units of the integrated circuit100. In some embodiments, the power island110comprises sub-islands of power to provide further specificity in controlling power in the integrated circuit100. In some embodiments, each of multiple power islands110includes power control circuitry to control power within the power island110. The power island manager120is any circuitry, device, or system to determine a target power level for one of the power islands110, determine an action to change a consumption power level of the one of the power islands110to the target power level, and perform the action to change the consumption power level of the one of the power islands110to the target power level. The power island manager120can thus dynamically change the power consumption of the power islands110based on the needs and operation of the integrated circuit100. The target power level is a desired, calculated, or specified power consumption of the power islands110. The power island manager120may be a hierarchy or group of power island managers120. WhileFIG.1depicts one leakage manager system130coupled to one power island manager120for the sake of simplicity, some embodiments comprise a plurality of leakage manager systems130. In certain embodiments including a plurality of leakage manager systems130, each of the leakage manager systems130is coupled to one of a plurality of power island managers120. In some embodiments, functions of the leakage manager system130are distributed. In some embodiments, a single leakage manager system130is coupled to one or more power island managers120. It will be appreciated that principles of the invention may apply to a circuit without power islands110or power island managers120. The power island110includes one or more logic gates115. In an embodiment without the power island110, the logic gate115may comprise any logic gate of the integrated circuit100. The logic gate115of the exemplary embodiment comprises any logic circuitry such as an inverter, a NAND, NOR, exclusive-OR, and exclusive-NOR gate, as well as a storage cells such as a flip-flop and a latch. The logic gate115may comprise higher-level Boolean logic, including combinations of individual logic gates. The logic gate115may be powered down to a “sleep mode” in conjunction with a sleep transistor (not shown), as described further herein. To minimize static leakage of the logic gate115, the leakage manager system130generates a negative voltage150to be applied to the sleep transistor. Applying the negative voltage150to a gate of an NMOS sleep transistor coupled between the logic gate115and ground may reduce the static leakage of the logic gate115. The leakage manager system130receives a negative voltage enable signal140and subsequently generates and transmits the negative voltage150to the power island110. The negative voltage enable signal140may include other signals in addition to the negative voltage enable signal140. The leakage manager system130determines whether to adjust the negative voltage150. Based on the determination, the leakage manager system130adjusts the negative voltage150, as described further herein. Adjusting the negative voltage150applied to the sleep transistor minimizes static leakage of the logic gate115. For example, static leakage varies based on parameters such as operating temperature, voltage fluctuations, and manufacturing variations. Therefore, application of a fixed negative voltage to the sleep transistor does not optimally minimize the static leakage of the logic gate115. Furthermore, generating the negative voltage150“on chip” reduces component requirements external to the integrated circuit100. An alternative to reduce the static leakage of the logic gate115comprises multiple threshold voltage CMOS, in which one or more high threshold transistors are inserted in series with a low threshold logic gate115. Switching the high threshold transistor “off” reduces the static leakage of the logic gate115. However, the high threshold transistor requires extra manufacturing process steps for the integrated circuit100and slows down the speed of the logic gate115as compared to nominal threshold transistors. Providing the negative voltage150to a low threshold NMOS sleep transistor advantageously eliminates a requirement to provide high threshold sleep transistor, thereby reducing processing steps needed to manufacture the integrated circuit100. FIG.2is an illustration of a sleep transistor210for minimizing static leakage of the logic gate115ofFIG.1, in accordance with an example embodiment. In some embodiments, the sleep transistor210comprises an NMOS transistor cascaded in series with the logic gate (e.g., inverter)115. Static leakage of the logic gate115passes through the sleep transistor210as a drain-source current (depicted as Id) and/or as a drain-gate current (depicted as Ig). The static leakage of the logic gate115equals Id+Igthrough the sleep transistor210. The negative voltage (SLPB)150applied to the sleep transistor210may be used to control the static leakage of the logic gate115by regulating the drain-source current and the drain-gate current of the sleep transistor210. FIG.3is an illustration of a graph of static leakage of the logic gate115ofFIG.2, for a range of negative voltage at the gate of the sleep transistor210, in accordance with an example embodiment. As the negative voltage (SLPB)150applied to the gate of the sleep transistor210becomes increasingly negative, the drain-source current Idof the sleep transistor210decreases. However, as the magnitude of the negative voltage150increases beyond a minimum leakage point A, for example to point B, the drain-gate current Igof the sleep transistor210exceeds the drain-source current Id. As a result, the static leakage of the logic gate115increases. Accordingly, adjusting the negative voltage150to approximately V(A), corresponding to a substantial equality between the drain-source current Idand the drain-gate current Igat the minimum leakage point A, minimizes static leakage in the logic gate115. FIG.4is a block diagram of the leakage manager system130for minimizing static leakage of the logic gate115by application of the negative voltage of to the sleep transistor210ofFIG.2, in accordance with an example embodiment. The leakage manager system130comprises an adaptive leakage controller (ALC)410, a negative voltage regulator420, and a charge pump430. The charge pump430generates the negative voltage150(SLPB). The ALC410determines whether to adjust the negative voltage150. The ALC410generates a signal (depicted as CTRL) depending on the determination. The negative voltage regulator420adjusts the negative voltage150depending on the CTRL signal. As described further herein, the negative voltage regulator420of one embodiment generates an enable (EN) signal to the charge pump430to enable the charge pump430to increase the magnitude of the negative voltage150(i.e., to make the negative voltage150more negative). If the EN signal is low, an alternating signal from an oscillator425to the charge pump430is disabled, preventing the charge pump430from increasing the magnitude of the negative voltage150. Alternatively, if the EN signal is high, the alternating signal from the oscillator425is enabled so that the charge pump430will increase the magnitude of the negative voltage150. Because the negative voltage regulator420toggles the EN signal on or off depending on whether the ALC410determines to adjust the negative voltage150, the leakage manager system130maintains the negative voltage150at a particular negative voltage to minimize static leakage of the logic gate115. FIG.5is an illustration of a method to minimize the static leakage of the logic gate115ofFIG.2, in accordance with an example embodiment. At step500, the CPU105(FIG.1) enters sleep mode. At step510, the charge pump430(FIG.4) generates the negative voltage150. At step515, the charge pump430applies the negative voltage150to the sleep transistor210(FIG.2). At step520, the ALC410(FIG.4) may monitor one or more parameters of the sleep transistor210corresponding to the static leakage of the logic gate115. The ALC410may monitor the sleep transistor210directly, or may monitor one or more emulated sleep transistors, as described further with respect toFIGS.6-8. At step530, the ALC410determines whether to adjust the negative voltage150to minimize static leakage. If the ALC410determines to adjust the negative voltage150, the ALC410generates the CTRL signal to the negative voltage regulator420(FIG.4). At step540, the negative voltage regulator420adjusts the negative voltage150based on the CTRL signal. In one embodiment, the negative voltage regulator420continuously adjusts the negative voltage150. In another embodiment, the negative voltage regulator420periodically adjusts the negative voltage150. The leakage manager system130adjusts the negative voltage150to minimize the static leakage of the logic gate115, even if the static leakage varies due to effects such as temperature variation, voltage fluctuation, or manufacturing process variation. The leakage manager system130may advantageously be wholly integrated into the integrated circuit100, obviating components external to the integrated circuit100to generate the negative voltage150. Further, the leakage manager system130may advantageously be utilized in the integrated circuit100comprising single threshold transistor logic, so that manufacturing of the integrated circuit100is simplified. FIGS.6-10illustrate further detail of embodiments of the leakage manager system130ofFIG.4. FIG.6is an illustration of the adaptive leakage controller (ALC)410ofFIG.4, in accordance with an example embodiment. The ALC410of this embodiment comprises a first emulated sleep transistor610, a second emulated sleep transistor620, a differential (operational) amplifier630, bias transistors640, and a voltage offset transistor650. It will be appreciated that the ALC410of this embodiment comprises analog circuitry to continuously determine whether to adjust the negative voltage150ofFIG.4. It will also be appreciated that althoughFIG.6depicts the bias transistors640as PMOS transistors with gate connected to drain to provide a resistive voltage drop across the bias transistors640, the bias transistors640may comprise resistors. In the exemplary embodiment with PMOS bias transistors640, matching between the several bias transistors640ensures substantially identical operation of the bias transistors640. The voltage offset transistor650of the exemplary embodiment similarly comprises a PMOS transistor with gate connected to drain to provide a resistive voltage drop across the voltage offset transistor650. Alternatively, the voltage offset transistor650may comprise a resistor. InFIG.6, the negative voltage150(SLPB) is applied to a gate of the first emulated sleep transistor610. The negative voltage150correspondingly produces a first current through the first emulated sleep transistor610. The first current may comprise drain-gate current and/or drain-source current. The first current through the first emulated sleep transistor610is in proportion to the static leakage of the logic gate115. The first current creates a first voltage drop across the bias transistors (resistances)640at a drain of the first emulated sleep transistor610. The first voltage drop is sensed at a negative input of the differential amplifier630. With respect to the second emulated sleep transistor620, the resistance of the voltage offset transistor650reduces the magnitude of the negative voltage150(SLPB) by a voltage offset. A gate of the second emulated sleep transistor620receives the negative voltage150plus the voltage offset. The negative voltage150plus the voltage offset produces a second current through the second emulated sleep transistor620. The second current may comprise drain-gate current and/or drain-source current. The second current creates a second voltage drop across the bias transistors (resistors)640at a drain of the second emulated sleep transistor620. The second voltage drop is sensed at a positive input of the differential amplifier630. In operation, the gate of the second emulated sleep transistor620operates at a slight voltage offset as compared to the gate of the first emulated sleep transistor610, because of the voltage offset transistor650. Referring toFIG.3, the voltage offset may be represented by the voltage offset between points A and B, or V(B)-V(A). As a result of the voltage offset, the minimum leakage point A may be detected by adjusting the negative voltage150so that I(B) is substantially equal to I(A). It will be appreciated that operating parameters of the voltage offset transistor650influence the magnitude of the voltage offset. The operating parameters may be based on such considerations as noise on the negative voltage150, for example. In principle of operation with respect toFIG.3, if the magnitude of the negative voltage150produces a first current I(B) in the first emulated sleep transistor610corresponding to point B, and the negative voltage150plus the voltage offset produces a second current I(A) in the second emulated sleep transistor620corresponding to point A, then the differential amplifier630will generate the CTRL signal so that the magnitude of the negative voltage150will be adjusted until I(A) substantially equals I(B). Alternatively, if the negative voltage150is such that the first emulated sleep transistor610and the second emulated sleep transistor620produce substantially equal currents, so that I(A)=I(B), then the differential amplifier630will maintain the present value of the CTRL signal. The resulting operating point will be a negative voltage which is offset from the ideal operating point by a value equal to one half the voltage offset produced by the current though the voltage offset transistor650. If gate leakage is negligible, there may be no inflection in the leakage vs. gate voltage curve ofFIG.3. In this case, the CTRL signal will decrease to its minimum value, causing the charge pump430(FIG.4) to operate at its most negative voltage. In conjunction with the negative voltage regulator420ofFIG.9, the ALC410of this embodiment advantageously minimizes static leakage of the logic gate115by continuously controlling the negative voltage150to approximately the minimum leakage point A ofFIG.3. FIG.7is an illustration of the ALC410ofFIG.4, in accordance with an alternative example embodiment. The ALC410of this embodiment comprises a charging transistor710, a capacitor715, an emulated sleep transistor720, a comparator730, a counter740, and a register750. The charging transistor710is switched by a controller (not shown) to charge the capacitor715to a positive supply voltage (e.g., VDD). The controller may also switch the charging transistor710so that the capacitor715, once charged, may discharge through the emulated sleep transistor720. The comparator730, the counter740, and the register750comprise a control circuit to measure a time needed to discharge the capacitor715to a predetermined value VREF. A state logic machine (not shown) coupled to the register750may compare values stored in the register750, as described with respect toFIG.8. In this embodiment of the ALC410, the maximum discharge time for the capacitor715corresponding to the lowest value of static leakage is used to generate a digital value for the CTRL signal to the negative voltage regulator420(FIG.4). The ALC410periodically updates the CTRL signal if the ALC410determines to adjust the negative voltage150. The operation of the ALC410of this embodiment is described with respect toFIG.8. FIG.8is an illustration of a method for minimizing static leakage of the logic gate115ofFIG.2, in accordance with the embodiment of the ALC410ofFIG.7. In overview, the method comprises charging the capacitor715to the positive supply voltage VDD, discharging the capacitor at a rate in proportion to the static leakage of the logic gate115via the emulated sleep transistor720, and adjusting the negative voltage150to minimize the rate of discharge of the capacitor715. The negative voltage150that corresponds to minimum current through the emulated sleep transistor720(i.e., minimum static leakage) minimizes the discharge rate of the capacitor715and maximizes the time to discharge the capacitor715. At step805, the CTRL signal is initialized to its minimum value. Setting the CTRL signal to its minimum value directs the negative voltage regulator420to drive the magnitude of the sleep signal SLPB150to its minimum value. At step810, the controller switches the charging transistor710so that the capacitor715is charged to VDD. At step815, the charging transistor710is switched off so that the capacitor715may discharge through the emulated sleep transistor720. At step820, the reference voltage VREF is set to a constant voltage which is less than VDD(e.g. VDD/2). At step825, the comparator730generates an output to the counter740after the capacitor715discharges to VREF. The counter740determines a time required to discharge the capacitor715to VREF. The register750stores a count (i.e., time) of the counter740. At step827, the CTRL signal is incremented by one bit. At step830, the controller switches the charging transistor710so that the capacitor715is again charged to VDD. At step840, the charging transistor710is switched off. At step860, the comparator730generates an output to the counter740after the capacitor715discharges to VREF. The counter740determines the time required to discharge the capacitor715with the new value of the CTRL signal and the corresponding SLPB signal. At step870, the state logic machine compares the value of the register750for the current pass through steps830-860(i.e., the time required to discharge the capacitor715to VREF for the new value of the CTRL signal and the SLPB signal) to the value of the register750for the previous pass through steps830-860. If the value of the register750for the current pass did not decrease relative to the value of the register750for the previous pass, then the new value of the CTRL signal corresponds to a lower value of static leakage through the emulated sleep transistor720. In this case, the method returns to step827to further increment the CTRL signal and measure the time required to discharge the capacitor715. Alternatively, at step870, if the time required to discharge the capacitor715decreased in the current pass, corresponding to a higher value of static leakage through the emulated sleep transistor720, then the previously stored value of the register750corresponds to the lowest value of static leakage through the emulated sleep transistor720. The value of the CTRL signal corresponding to minimal static leakage is used to control the negative voltage regulator420to generate the appropriate setting for the negative voltage150. One advantage of the embodiment of the digital ALC410ofFIGS.7-8is that the CTRL signal comprises a digital signal. The digital CTRL signal may be routed via the control signal140to multiple leakage managers130ofFIG.1. For example, because silicon is an excellent thermal conductor, it may be advantageous to utilize a single digital ALC410with leakage managers130and power island managers120. Each of the multiple power island managers120of this embodiment comprise the negative voltage regulator420and the charge pump430, so that the functions of the leakage controller system130may be distributed as needed across the integrated circuit100. FIG.9is an illustration of the negative voltage regulator420ofFIG.4for minimizing static leakage of the logic gate115, in accordance with an example embodiment. The negative voltage regulator420includes an interface to receive the negative voltage150, a first voltage divider905, a second voltage divider915, and a comparator920. In one embodiment, the first voltage divider905comprises a series of stacked PMOS transistors (not shown) with bulk tied to source. It will be appreciated, for example, that a series of three equivalent stacked PMOS transistors with bulk tied to source provide a divide-by-3 voltage divider in the first voltage divider905. It will further be appreciated that the first voltage divider905may comprise any ratio of division. The first voltage divider905provides a fixed voltage reference (e.g., point C) with respect to a positive voltage source (e.g., VDD). The fixed voltage reference of this embodiment is coupled to a negative terminal of the comparator920. Similarly, a series of three equivalent stacked PMOS transistors with bulk tied to source provide a divide-by-3 voltage divider in the fixed resistances of the second voltage divider915. It will be appreciated that the second voltage divider915may comprise any ratio of division. The second voltage divider915of this embodiment is coupled to a positive terminal of the comparator920. In an embodiment in conjunction with the analog CTRL signal generated by the ALC410ofFIG.6, a variable resistor910of the second voltage divider915allows the second voltage divider915to generate a variable voltage reference (e.g., point D) depending on the negative voltage150and a received signal (CTRL) generated by the ALC410. The variable resistor910may comprise a transistor circuit. Depending on the CTRL signal, the variable resistor910varies between high impedance and low impedance. In conjunction with the digital ALC410ofFIGS.7-8, the variable resistor910of the second voltage divider915comprises a switched resistor network controlled by the digital CTRL signal. The variable resistor910of this embodiment may comprise two or more switched resistors. The variable resistor910may also comprise two or more PMOS transistors with bulk tied to source. In operation, the negative voltage regulator420adjusts the negative voltage150depending on a comparison between the fixed voltage reference (point C) and the variable voltage reference (point D). The comparator920may generate an enable (EN) signal to enable the charge pump430(FIGS.4) to increase the magnitude of the negative voltage150. If the EN signal is low, the alternating signal from the oscillator425(FIG.4) to the charge pump430is disabled, preventing the charge pump430from increasing the magnitude of the negative voltage150. If the EN signal is high, the alternating signal from the oscillator425is enabled to that the charge pump430will increase the magnitude of the negative voltage150. Therefore, depending on the CTRL signal from the ALC410, the comparator920will control the charge pump430to increase the magnitude of the negative voltage150or allow it to decrease. FIG.10is an illustration of the charge pump430ofFIG.4for minimizing static leakage, in accordance with various embodiments of the invention. The charge pump430may receive and function to increase the magnitude of the SLPB signal150(as discussed inFIG.4). The output of the charge pump430may be VSS(seeFIG.10) which, in various embodiments, functions as the SLPB signal150to be applied to the sleep transistor and/or the power island110. The charge pump430may also receive alternating signals from the oscillator425as either the INP signal or the INN signal (in some embodiments, the INN signal is an inverted (i.e., a complement of the) INP signal). Further, the charge pump430may receive an EN signal (discussed inFIG.4) which may enable and/or disable the charge pump430. The EN signal may be received by the charge pump430as the SLP signal (seeFIG.10). The charge pump430comprises two interfaces for voltage (e.g., VDDline1002and VSSline1004), an input for an alternating signal (i.e., an INP line1006), an input for an inverted alternating signal (i.e., an INN line1008), an inverter1010, a pump capacitor1012, capacitances1014and1016, a cross-coupled pass gate1018and1020, PMOS transistors1022and1024, node1026, an SLP line1028, an inverter1030, and an SLPB line1032. The cross-coupled pass gate1018may comprise two PMOS transistors1038and1040. The cross-coupled pass gate1020may comprise two PMOS transistors1042and11044. The inverter1010may comprise a NMOS transistor1034and a PMOS transistor1036. In example embodiments, the capacitance1014is electrically coupled to INP line1006and the capacitance1016is electrically coupled to the INN line1008. The capacitance1014and1016may comprise a capacitor such as a metal-metal capacitor. In other embodiments, the capacitance1014and1016may comprise PMOS capacitances (e.g., varactors). Alternately, the capacitance1014and1016may comprise similar or different components. Those skilled in the art will appreciate that the capacitance1014and1016may be many different components comprising capacitances. In various embodiments, the capacitances1014and1016function to smooth out transients from the INP signals and the INN signals, respectively. The gate of PMOS transistors1022and1024may be electrically coupled to the capacitance1014and1016, respectively. The PMOS transistor1022and PMOS transistor1024may be electrically coupled to the pump capacitor1012. The PMOS transistor1022may also be electrically coupled to the NMOS transistor1034within inverter1010as well as the VSSline1004, the gate of the PMOS transistor1038in the cross coupled pass gate1018, and the gate of the PMOS transistor1044in the cross coupled pass gate1020. PMOS transistor1024may be coupled to SLPB line1032. In various embodiments, the substrates of PMOS transistor1022and1024are electrically coupled to node1026. The output of the inverter1010is electrically coupled to the pump capacitor1012. The drain of PMOS transistor1036is coupled to the source of NMOS transistor1034as well as the pump capacitor1012. The INP line1006is electrically coupled to the gates of both the PMOS transistor1036and the NMOS transistor1034(e.g., the INP line1006is electrically coupled to the input of the inverter1010). The cross-coupled pass gate1018may comprise two PMOS transistors1038and1040. In one example, the PMOS transistor1038is electrically coupled to the capacitance1014, the gate of PMOS transistor1022, the PMOS transistor1040, and the gate of PMOS transistor1042in the cross-coupled pass gate1020. The substrate and drain of PMOS transistor1038may be electrically coupled to the substrate and drain of the PMOS transistor1040as well as the node1026. The gate of PMOS transistor1040is electrically coupled to the PMOS transistors1042and1044as well as the capacitance1016and the gate of PMOS transistor1024. The cross-coupled pass gate1020may comprise two PMOS transistors1042and1044. In one example, the substrate of the PMOS transistor1042is electrically coupled to the substrate of PMOS transistor1044and the node1026. The PMOS transistor1042and the PMOS transistor1044are electrically coupled to the node1026. The cross-coupled pass gate1018of this embodiment may be capacitively coupled to the alternating signal (the INP signal) from the oscillator425(FIG.4). The cross-coupled pass gate1020may be capacitively coupled to a complement of the alternating signal (the INN signal) from the oscillator425. The VSS(over the VSSline1004) may supply negative voltage to the sleep transistor210to control the static leakage of the logic gate115ofFIG.2. The VDDline1002, VSSline1004, INP line1006, INN line1008, and SLPB line1032, and SLP line1028may comprise wires, traces, or any conductive material configured to function as an electrical medium. The INP line1006may be coupled with the oscillator425which may generate an alternating signal (i.e., the INP signal). The INN line1008may be coupled with an inverter configured to invert the alternating signal (i.e., the INP signal) to generate a complement of the alternating signal. It will be appreciated by those skilled in the art that, in some embodiments, the INN line1008receives an alternating signal and the INP line1006receives the complement of the alternating signal. There may be many ways to generate the alternating signal and/or the complement of the alternating signal. Further, the SLPB line1032may receive the sleep signal from the leakage manager system130. In various embodiments, the sleep signal is a negative voltage signal and the SLPB line1032is a negative voltage line. The SLP line1028may receive the SLP signal (e.g., the enable (EN) signal) from the negative voltage regulator420. There may be many ways in which the SLP signal may be generated. Further, the SLP signal may be generated in such a way as to make the inversion of the signal either optional or unnecessary (i.e., the inverter1030may be optional). In various embodiments, the alternating signal (INP signal) and the complement of the alternating signal (INN signal) may each comprise two states discussed herein including “high” and “low.” Those skilled in the art will appreciate that the “high” signal is “high” when compared to the “low” state of the signal and is not “high” or “low” in comparison with another standard. In one example, the high state is 1 volt and the low state is 0 or −1 volts. As used herein, the high state is referred to as “high” and the low state is referred to as “low.” In various embodiments, when the INP signal is low (or goes low), the charge within the pump capacitor1012is released through the VSSsignal (via VSSline1004). In one example, the INP signal is received over the INP line1006by the gates of the inverter1010(i.e., the gate of the PMOS transistor1036and the gate of the NMOS transistor1034). When the INP signal is low (or goes to low), the VDDsignal may pass through from the source of the PMOS transistor1036to the pump capacitor1012. Similarly, the INP signal is received by capacitance1014and, subsequently, the gate of PMOS transistor1022. As a result, the charge of the pump capacitor1012may be released through the PMOS transistor1022and out through the VSSline1004. The alternate of the INP signal, the INN signal, which is high (or goes to high), is coupled to the capacitance1016over the INN line1008. The gate of PMOS transistor1024may receive the high signal from the capacitance1016. As a result, the PMOS transistor1024may decouple the SLPB line1032from the pump capacitor1012. When the INP signal is high (or goes high), the pump capacitor1012is charged (i.e., the capacitor is charged by receiving the VSSsignal and the SLPB signal). When the INP signal is high (or goes to high), the PMOS transistor1036no longer allows the pump capacitor1012to receive the VDDsignal. The gate of NMOS transistor1034receives the INP signal over the INP line1006which subsequently allows the pump capacitor1012to receive the VSSsignal from VSSline1004(the INP signal (i.e., high or going to high) is received by the gate of the PMOS transistor1022which prevents the VSSsignal from flowing through the PMOS transistor1022). The alternate of the INP signal, the INN signal (i.e., which is low or goes to low) is received by the gate of PMOS transistor1024which subsequently allows the SLPB signal (via the SLPB line1032) to be received by the pump capacitor1012thereby allowing the pump capacitor1012to charge. In some embodiments, the node1026is simply tied to ground. In other embodiments, the node1026is not tied to ground, but is coupled to the SLP signal. In one example, the SLP signal (via the SLP line1028) is electrically coupled to the input of inverter1060, the output of which is coupled to the node1026. The inverter1030may be activated on exiting the sleep mode to prevent a power supply that generates VDDfrom being shorted to ground through the PMOS transistors1022and1024, and may ensure that any P-N junctions in the wells are not forward biased. In various embodiments, there is no current flow from the PMOS transistors to the substrate, since the substrate may be at an equal or higher potential than the source and drain of the PMOS transistors. In one example, current flow from the PMOS transistors to the substrate is avoided in order to compete against forward biased diodes for current flow. In another example, to ensure that no P-N junctions in the wells of the PMOS transistors are forward biased, the inverter1030may output a complement of the activated SLP signal to drive the node1026to 0 V. The SLP signal may disable the charge pump430. In one example, the SLP signal (e.g., the EN signal inFIG.4) goes low. The node1026receives the SLP signal via the SLP line1028over the inverter1030, and, as such, the node1026may receive a signal in a “high” state. The node1026electrically couples the high signal to the body of PMOS transistors1022,1038,1040,1042,1044, and1024. As a result, the PMOS transistors1022,1038,1040,1042,1044, and1024do not allow current flow (e.g., are disabled) thereby disabling the charge pump430. Those skilled in art will appreciate that when either the INP signal or the INN signal is high (or goes to high), the signal may electrically couple to the node1026, in various embodiments. In one example, the INP signal is high and the INN signal is low. The low signal (via the INN line1008and the capacitance1016) is received at the gate of PMOS transistor1040which may allow the high INP signal to flow through the PMOS transistor1040to the node1026. In another example, the INN signal is high and the INP signal is low. The low signal (via the INP line1006and the capacitance1014) is received at the gate of PMOS transistor1042which may allow the high INN signal to flow through the PMOS transistor1042to the node1026. In various embodiments, the alternating connectivity of high signals with the node1026allows the high signal current to drain at ground when ground is coupled to node1026. Alternatively, the alternating connectivity of high signals with the node1026may electrically couple with the SLP line1028. In one example, the alternating high signals received by the body of PMOS transistors1022,1038,1040,1042,1044, and1024(via node1026) prevent leakage from the pump capacitor1012or prevents the VDDsignal from coupling to ground. In another example, the alternating high signal over the node1026may reduce the voltage required by the SLP signal to sufficiently bias the bodies (i.e., substrates) of the PMOS transistors1022,1038,1040,1042,1044, and1024in order to disable the charge pump430. While one skilled in the art should be able to implement and gain the benefits of the charge pump430if provided with only the circuits and diagrams ofFIGS.1-10, charging and discharging of the pump capacitor1012will now be described so that functional aspects of other example embodiments of the invention, that are clear from the drawings, may be explained in words that confirm what is shown in the drawings. With reference toFIGS.4and10, in some example embodiments, the INP signal becomes ‘0’ and the INN signal becomes ‘1’ in response to the rising edge of the oscillator425. Due to the INP signal becoming ‘0’, a voltage drop exists across the capacitance1014, so the gate of the first PMOS transistor1022and the gate of the transistor1042is at ‘−1’. The cross-coupled pass gate1020is conducting while a negative voltage is applied at the gate of the transistor1042. The first PMOS transistor1022is also conducting as the negative voltage is applied at the gate of the first PMOS transistor1022. While the first PMOS transistor1022is on, the pump capacitor1012is discharging through the VSSline1004. Due to the INN signal becoming ‘1’, there may be a positive voltage at the capacitance1016because this terminal receives the INN signal. With a ‘1’ at the first terminal of the capacitance1016, there is a ‘0’ at the second terminal of the capacitance1016. In various embodiments, the gate of the PMOS transistor1040and the second terminal of the capacitance1016share the same node, so the PMOS transistor1040is non-conducting because the gate-to-source voltage difference (VGS) is greater than the threshold voltage (VT). As a result, the cross-coupled pass gate1018is non-conducting during the discharging phase. Further, the PMOS transistor1024will be off during the discharging phase. As a result, charging of the pump capacitor1012does not occur during the discharging phase. Next is the falling edge of the oscillator425. In response, the INP signal may go from ‘0’ to ‘1’, and, consequently, the first and second terminals of the capacitance1014go from ‘0’ and ‘1’, respectively, to ‘−1’ and ‘0’, respectively. The cross-coupled pass gate1020becomes non-conducting because VGSof the transistor1042will rise above VT(i.e. the transistor1042will become non-conducting). Also in response to the falling edge of the oscillator425, the INN signal goes from ‘1’ to ‘0’, and consequently the first and second terminals of the capacitance1016go from ‘1’ to ‘0’ and ‘0’ to ‘−1’, respectively. So the node shared by the second terminal of the capacitance1016, the gate of the second PMOS transistor1024and the gate of the PMOS transistor1040will be at ‘−1’. The cross-coupled pass gate1018will be conducting while a negative voltage is applied at the gate of the PMOS transistor1040. The second PMOS transistor1024is also conducting during this period of time, as the negative voltage is also applied at the gate of the second PMOS transistor1024. While the second PMOS transistor1024is on, the pump capacitor1012is charging. The PMOS transistor1022may be off during the above-described charging phase, so, in the illustrated example embodiment, discharging of the pump capacitor1012does not occur during the charging phase. With reference now toFIGS.4-10, it will be understood that the leakage manager system130, comprising the adaptive leakage controller410, the negative voltage regulator420, and the charge pump430, minimizes the static leakage of the logic gate115, even if the static leakage varies due to effects such as temperature variation, voltage fluctuation, or manufacturing process variation. The leakage manager system130may be wholly integrated into the integrated circuit100, obviating components external to the integrated circuit100. Further, the leakage manager system130may advantageously be utilized in the integrated circuit100comprising single threshold transistor logic, simplifying manufacturing of the integrated circuit100. Modification of the previously described charge pump430to make it suitable for operation in different voltage ranges is contemplated. For example, a higher voltage (for instance, +2V) at the high end of the voltage operation range may be possible by customizing the circuit by switching the INN signal and the INP signal as well as using some bigger circuit components such as, for instance, bigger capacitors. The components, type of components, and number of components identified inFIG.10are illustrative. For example, in some embodiments, the charge pump430may not comprise the PMOS transistor1044and the PMOS transistor1038. Further, the inverter1030and SLP signal may be optional (e.g., the inverter1030and SLP signal may be replaced with a ground or a wire coupled to ground). Further, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those of skill in the art upon review of this disclosure. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims along with their full scope of equivalents. | 42,103 |
RE49855 | DETAILED DESCRIPTION OF EMBODIMENTS Example embodiments of the present disclosure enable operation of carrier aggregation. Embodiments of the technology disclosed herein may be employed in the technical field of multicarrier communication systems. The following Acronyms are used throughout the present disclosure: ASIC application-specific integrated circuit BPSK binary phase shift keying CA carrier aggregation CSI channel state information CDMA code division multiple access CSS common search space CPLD complex programmable logic devices CC component carrier DL downlink DCI downlink control information DC dual connectivity EPC evolved packet core E-UTRAN evolved-universal terrestrial radio access network FPGA field programmable gate arrays FDD frequency division multiplexing HDL hardware description languages HARQ hybrid automatic repeat request IE information element LAA licensed assisted access LTE long term evolution MCG master cell group MeNB master evolved node B MIB master information block MAC media access control MAC media access control MME mobility management entity NAS non-access stratum OFDM orthogonal frequency division multiplexing PDCP packet data convergence protocol PDU packet data unit PHY physical PDCCH physical downlink control channel PHICH physical HARQ indicator channel PUCCH physical uplink control channel PUSCH physical uplink shared channel PCell primary cell PCell primary cell PCC primary component carrier PSCell primary secondary cell pTAG primary timing advance group QAM quadrature amplitude modulation QPSK quadrature phase shift keying RBG Resource Block Groups RLC radio link control RRC radio resource control RA random access RB resource blocks SCC secondary component carrier SCell secondary cell Scell secondary cells SCG secondary cell group SeNB secondary evolved node B sTAGs secondary timing advance group SDU service data unit S-GW serving gateway SRB signaling radio bearer SC-OFDM single carrier-OFDM SFN system frame number SIB system information block TAI tracking area identifier TAT time alignment timer TDD time division duplexing TDMA time division multiple access TA timing advance TAG timing advance group TB transport block UL uplink UE user equipment VHDL VHSIC hardware description language Example embodiments of the disclosure may be implemented using various physical layer modulation and transmission mechanisms. Example transmission mechanisms may include, but are not limited to: CDMA, OFDM, TDMA, Wavelet technologies, and/or the like. Hybrid transmission mechanisms such as TDMA/CDMA, and OFDM/CDMA may also be employed. Various modulation schemes may be applied for signal transmission in the physical layer. Examples of modulation schemes include, but are not limited to: phase, amplitude, code, a combination of these, and/or the like. An example radio transmission method may implement QAM using BPSK, QPSK, 16-QAM, 64-QAM, 256-QAM, and/or the like. Physical radio transmission may be enhanced by dynamically or semi-dynamically changing the modulation and coding scheme depending on transmission requirements and radio conditions. FIG.1is a diagram depicting example sets of OFDM subcarriers as per an aspect of an embodiment of the present disclosure. As illustrated in this example, arrow(s) in the diagram may depict a subcarrier in a multicarrier OFDM system. The OFDM system may use technology such as OFDM technology, DFTS-OFDM, SC-OFDM technology, or the like. For example, arrow101shows a subcarrier transmitting information symbols.FIG.1is for illustration purposes, and a typical multicarrier OFDM system may include more subcarriers in a carrier. For example, the number of subcarriers in a carrier may be in the range of 10 to 10,000 subcarriers.FIG.1shows two guard bands106and107in a transmission band. As illustrated inFIG.1, guard band106is between subcarriers103and subcarriers104. The example set of subcarriers A102includes subcarriers103and subcarriers104.FIG.1also illustrates an example set of subcarriers B105. As illustrated, there is no guard band between any two subcarriers in the example set of subcarriers B105. Carriers in a multicarrier OFDM communication system may be contiguous carriers, non-contiguous carriers, or a combination of both contiguous and non-contiguous carriers. FIG.2is a diagram depicting an example transmission time and reception time for two carriers as per an aspect of an embodiment of the present disclosure. A multicarrier OFDM communication system may include one or more carriers, for example, ranging from 1 to 10 carriers. Carrier A204and carrier B205may have the same or different timing structures. AlthoughFIG.2shows two synchronized carriers, carrier A204and carrier B205may or may not be synchronized with each other. Different radio frame structures may be supported for FDD and TDD duplex mechanisms.FIG.2shows an example FDD frame timing. Downlink and uplink transmissions may be organized into radio frames201. In this example, the radio frame duration is 10 msec. Other frame durations, for example, in the range of 1 to 100 msec may also be supported. In this example, each10ms radio frame201may be divided into ten equally sized subframes202. Other subframe durations such as 0.5 msec, 1 msec, 2 msec, and 5 msec may also be supported. Subframe(s) may consist of two or more slots (for example, slots206and207). For the example of FDD, 10 subframes may be available for downlink transmission and 10 subframes may be available for uplink transmissions in each 10 ms interval. Uplink and downlink transmissions may be separated in the frequency domain. Slot(s) may include a plurality of OFDM symbols203. The number of OFDM symbols203in a slot206may depend on the cyclic prefix length and subcarrier spacing. FIG.3is a diagram depicting OFDM radio resources as per an aspect of an embodiment of the present disclosure. The resource grid structure in time304and frequency305is illustrated inFIG.3. The quantity of downlink subcarriers or RBs (in this example 6 to 100 RBs) may depend, at least in part, on the downlink transmission bandwidth306configured in the cell. The smallest radio resource unit may be called a resource element (e.g.301). Resource elements may be grouped into resource blocks (e.g.302). Resource blocks may be grouped into larger radio resources called Resource Block Groups (RBG) (e.g.303). The transmitted signal in slot206may be described by one or several resource grids of a plurality of subcarriers and a plurality of OFDM symbols. Resource blocks may be used to describe the mapping of certain physical channels to resource elements. Other pre-defined groupings of physical resource elements may be implemented in the system depending on the radio technology. For example, 24 subcarriers may be grouped as a radio block for a duration of 5 msec. In an illustrative example, a resource block may correspond to one slot in the time domain and 180 kHz in the frequency domain (for 15 KHz subcarrier bandwidth and 12 subcarriers). FIG.5A,FIG.5B,FIG.5CandFIG.5Dare example diagrams for uplink and downlink signal transmission as per an aspect of an embodiment of the present disclosure.FIG.5Ashows an example uplink physical channel. The baseband signal representing the physical uplink shared channel may perform the following processes. These functions are illustrated as examples and it is anticipated that other mechanisms may be implemented in various embodiments. The functions may comprise scrambling, modulation of scrambled bits to generate complex-valued symbols, mapping of the complex-valued modulation symbols onto one or several transmission layers, transform precoding to generate complex-valued symbols, precoding of the complex-valued symbols, mapping of precoded complex-valued symbols to resource elements, generation of complex-valued time-domain DFTS-OFDM/SC-TDMA signal for each antenna port, and/or the like. Example modulation and up-conversion to the carrier frequency of the complex-valued DFTS-OFDM/SC-TDMA baseband signal for each antenna port and/or the complex-valued PRACH baseband signal is shown inFIG.5B. Filtering may be employed prior to transmission. An example structure for Downlink Transmissions is shown inFIG.5C. The baseband signal representing a downlink physical channel may perform the following processes. These functions are illustrated as examples and it is anticipated that other mechanisms may be implemented in various embodiments. The functions include scrambling of coded bits in each of the codewords to be transmitted on a physical channel; modulation of scrambled bits to generate complex-valued modulation symbols; mapping of the complex-valued modulation symbols onto one or several transmission layers; precoding of the complex-valued modulation symbols on each layer for transmission on the antenna ports; mapping of complex-valued modulation symbols for each antenna port to resource elements; generation of complex-valued time-domain OFDM signal for each antenna port, and/or the like. Example modulation and up-conversion to the carrier frequency of the complex-valued OFDM baseband signal for each antenna port is shown inFIG.5D. Filtering may be employed prior to transmission. FIG.4is an example block diagram of a base station401and a wireless device406, as per an aspect of an embodiment of the present disclosure. A communication network400may include at least one base station401and at least one wireless device406. The base station401may include at least one communication interface402, at least one processor403, and at least one set of program code instructions405stored in non-transitory memory404and executable by the at least one processor403. The wireless device406may include at least one communication interface407, at least one processor408, and at least one set of program code instructions410stored in non-transitory memory409and executable by the at least one processor408. Communication interface402in base station401may be configured to engage in communication with communication interface407in wireless device406via a communication path that includes at least one wireless link411. Wireless link411may be a bi-directional link. Communication interface407in wireless device406may also be configured to engage in a communication with communication interface402in base station401. Base station401and wireless device406may be configured to send and receive data over wireless link411using multiple frequency carriers. According to aspects of an embodiments, transceiver(s) may be employed. A transceiver is a device that includes both a transmitter and receiver. Transceivers may be employed in devices such as wireless devices, base stations, relay nodes, and/or the like. Example embodiments for radio technology implemented in communication interface402,407and wireless link411are illustrated areFIG.1,FIG.2,FIG.3,FIG.5, and associated text. An interface may be a hardware interface, a firmware interface, a software interface, and/or a combination thereof. The hardware interface may include connectors, wires, electronic devices such as drivers, amplifiers, and/or the like. A software interface may include code stored in a memory device to implement protocol(s), protocol layers, communication drivers, device drivers, combinations thereof, and/or the like. A firmware interface may include a combination of embedded hardware and code stored in and/or in communication with a memory device to implement connections, electronic device operations, protocol(s), protocol layers, communication drivers, device drivers, hardware operations, combinations thereof, and/or the like. The term configured may relate to the capacity of a device whether the device is in an operational or non-operational state. Configured may also refer to specific settings in a device that effect the operational characteristics of the device whether the device is in an operational or non-operational state. In other words, the hardware, software, firmware, registers, memory values, and/or the like may be “configured” within a device, whether the device is in an operational or nonoperational state, to provide the device with specific characteristics. Terms such as “a control message to cause in a device” may mean that a control message has parameters that may be used to configure specific characteristics in the device, whether the device is in an operational or non-operational state. According to various aspects of an embodiment, an LTE network may include a multitude of base stations, providing a user plane PDCP/RLC/MAC/PHY and control plane (RRC) protocol terminations towards the wireless device. The base station(s) may be interconnected with other base station(s) (for example, interconnected employing an X2 interface). Base stations may also be connected employing, for example, an S1 interface to an EPC. For example, base stations may be interconnected to the MME employing the S1-MME interface and to the S-G) employing the S1-U interface. The S1 interface may support a many-to-many relation between MMEs/Serving Gateways and base stations. A base station may include many sectors for example: 1, 2, 3, 4, or 6 sectors. Abase station may include many cells, for example, ranging from 1 to 50 cells or more. A cell may be categorized, for example, as a primary cell or secondary cell. At RRC connection establishment/re-establishment/handover, one serving cell may provide the NAS (non-access stratum) mobility information (e.g. TAI), and at RRC connection re-establishment/handover, one serving cell may provide the security input. This cell may be referred to as the Primary Cell (PCell). In the downlink, the carrier corresponding to the PCell may be the Downlink Primary Component Carrier (DL PCC), while in the uplink, the carrier corresponding to the PCell may be the Uplink Primary Component Carrier (UL PCC). Depending on wireless device capabilities, Secondary Cells (SCells) may be configured to form together with the PCell a set of serving cells. In the downlink, the carrier corresponding to an SCell may be a Downlink Secondary Component Carrier (DL SCC), while in the uplink, it may be an Uplink Secondary Component Carrier (UL SCC). An SCell may or may not have an uplink carrier. A cell, comprising a downlink carrier and optionally an uplink carrier, may be assigned a physical cell ID and a cell index. A carrier (downlink or uplink) may belong to only one cell. The cell ID or Cell index may also identify the downlink carrier or uplink carrier of the cell (depending on the context it is used). In the specification, cell ID may be equally referred to a carrier ID, and cell index may be referred to carrier index. In implementation, the physical cell ID or cell index may be assigned to a cell. A cell ID may be determined using a synchronization signal transmitted on a downlink carrier. A cell index may be determined using RRC messages. For example, when the specification refers to a first physical cell ID for a first downlink carrier, the specification may mean the first physical cell ID is for a cell comprising the first downlink carrier. The same concept may apply, for example, to carrier activation. When the specification indicates that a first carrier is activated, the specification may also mean that the cell comprising the first carrier is activated. Embodiments may be configured to operate as needed. The disclosed mechanism may be performed when certain criteria are met, for example, in a wireless device, a base station, a radio environment, a network, a combination of the above, and/or the like. Example criteria may be based, at least in part, on for example, traffic load, initial system set up, packet sizes, traffic characteristics, a combination of the above, and/or the like. When the one or more criteria are met, various example embodiments may be applied. Therefore, it may be possible to implement example embodiments that selectively implement disclosed protocols. A base station may communicate with a mix of wireless devices. Wireless devices may support multiple technologies, and/or multiple releases of the same technology. Wireless devices may have some specific capability(ies) depending on its wireless device category and/or capability(ies). A base station may comprise multiple sectors. When this disclosure refers to a base station communicating with a plurality of wireless devices, this disclosure may refer to a subset of the total wireless devices in a coverage area. This disclosure may refer to, for example, a plurality of wireless devices of a given LTE release with a given capability and in a given sector of the base station. The plurality of wireless devices in this disclosure may refer to a selected plurality of wireless devices, and/or a subset of total wireless devices in a coverage area which perform according to disclosed methods, and/or the like. There may be a plurality of wireless devices in a coverage area that may not comply with the disclosed methods, for example, because those wireless devices perform based on older releases of LTE technology. FIG.6andFIG.7are example diagrams for protocol structure with CA and DC as per an aspect of an embodiment of the present disclosure. E-UTRAN may support Dual Connectivity (DC) operation whereby a multiple RX/TX UE in RRC_CONNECTED may be configured to utilize radio resources provided by two schedulers located in two eNBs connected via a non-ideal backhaul over the X2 interface. eNBs involved in DC for a certain UE may assume two different roles: an eNB may either act as an MeNB or as an SeNB. In DC a UE may be connected to one MeNB and one SeNB. Mechanisms implemented in DC may be extended to cover more than two eNBs.FIG.7illustrates one example structure for the UE side MAC entities when a Master Cell Group (MCG) and a Secondary Cell Group (SCG) are configured, and it may not restrict implementation. Media Broadcast Multicast Service (MBMS) reception is not shown in this figure for simplicity. In DC, the radio protocol architecture that a particular bearer uses may depend on how the bearer is setup. Three alternatives may exist, an MCG bearer, an SCG bearer and a split bearer as shown inFIG.6. RRC may be located in MeNB and SRBs may be configured as a MCG bearer type and may use the radio resources of the MeNB. DC may also be described as having at least one bearer configured to use radio resources provided by the SeNB. DC may or may not be configured/implemented in example embodiments of the disclosure. In the case of DC, the UE may be configured with two MAC entities: one MAC entity for MeNB, and one MAC entity for SeNB. In DC, the configured set of serving cells for a UE may comprise two subsets: the Master Cell Group (MCG) containing the serving cells of the MeNB, and the Secondary Cell Group (SCG) containing the serving cells of the SeNB. For a SCG, one or more of the following may be applied. At least one cell in the SCG may have a configured UL CC and one of them, named PSCell (or PCell of SCG, or sometimes called PCell), may be configured with PUCCH resources. When the SCG is configured, there may be at least one SCG bearer or one Split bearer. Upon detection of a physical layer problem or a random access problem on a PSCell, or the maximum number of RLC retransmissions has been reached associated with the SCG, or upon detection of an access problem on a PSCell during a SCG addition or a SCG change: a RRC connection re-establishment procedure may not be triggered, UL transmissions towards cells of the SCG may be stopped, and a MeNB may be informed by the UE of a SCG failure type. For split bearer, the DL data transfer over the MeNB may be maintained. The RLC AM bearer may be configured for the split bearer. Like a PCell, a PSCell may not be de-activated. A PSCell may be changed with a SCG change (for example, with a security key change and a RACH procedure), and/or neither a direct bearer type change between a Split bearer and a SCG bearer nor simultaneous configuration of a SCG and a Split bearer may be supported. With respect to the interaction between a MeNB and a SeNB, one or more of the following principles may be applied. The MeNB may maintain the RRM measurement configuration of the UE and may, (for example, based on received measurement reports or traffic conditions or bearer types), decide to ask a SeNB to provide additional resources (serving cells) for a UE. Upon receiving a request from the MeNB, a SeNB may create a container that may result in the configuration of additional serving cells for the UE (or decide that it has no resource available to do so). For UE capability coordination, the MeNB may provide (part of) the AS configuration and the UE capabilities to the SeNB. The MeNB and the SeNB may exchange information about a UE configuration by employing RRC containers (inter-node messages) carried in X2 messages. The SeNB may initiate a reconfiguration of its existing serving cells (for example, a PUCCH towards the SeNB). The SeNB may decide which cell is the PSCell within the SCG. The MeNB may not change the content of the RRC configuration provided by the SeNB. In the case of a SCG addition and a SCG SCell addition, the MeNB may provide the latest measurement results for the SCG cell(s). Both a MeNB and a SeNB may know the SFN and subframe offset of each other by OAM, (for example, for the purpose of DRX alignment and identification of a measurement gap). In an example, when adding a new SCG SCell, dedicated RRC signaling may be used for sending required system information of the cell as for CA, except for the SFN acquired from a MIB of the PSCell of a SCG. In an example, serving cells may be grouped in a TA group (TAG). Serving cells in one TAG may use the same timing reference. For a given TAG, user equipment (UE) may use at least one downlink carrier as a timing reference. For a given TAG, a UE may synchronize uplink subframe and frame transmission timing of uplink carriers belonging to the same TAG. In an example, serving cells having an uplink to which the same TA applies may correspond to serving cells hosted by the same receiver. A UE supporting multiple TAs may support two or more TA groups. One TA group may contain the PCell and may be called a primary TAG (pTAG). In a multiple TAG configuration, at least one TA group may not contain the PCell and may be called a secondary TAG (sTAG). In an example, carriers within the same TA group may use the same TA value and/or the same timing reference. When DC is configured, cells belonging to a cell group (MCG or SCG) may be grouped into multiple TAGs including a pTAG and one or more sTAGs. FIG.8shows example TAG configurations as per an aspect of an embodiment of the present disclosure. In Example 1, pTAG comprises a PCell, and an sTAG comprises SCell1. In Example 2, a pTAG comprises a PCell and SCell1, and an sTAG comprises SCell2 and SCell3. In Example 3, pTAG comprises PCell and SCell1, and an sTAG1 includes SCell2 and SCell3, and sTAG2 comprises SCell4. Up to four TAGs may be supported in a cell group (MCG or SCG) and other example TAG configurations may also be provided. In various examples in this disclosure, example mechanisms are described for a pTAG and an sTAG. Some of the example mechanisms may be applied to configurations with multiple sTAGs. In an example, an eNB may initiate an RA procedure via a PDCCH order for an activated SCell. This PDCCH order may be sent on a scheduling cell of this SCell. When cross carrier scheduling is configured for a cell, the scheduling cell may be different than the cell that is employed for preamble transmission, and the PDCCH order may include an SCell index. At least a non-contention based RA procedure may be supported for SCell(s) assigned to sTAG(s). FIG.9is an example message flow in a random access process in a secondary TAG as per an aspect of an embodiment of the present disclosure. An eNB transmits an activation command600to activate an SCell. A preamble602(Msg1) may be sent by a UE in response to a PDCCH order601on an SCell belonging to an sTAG. In an example embodiment, preamble transmission for SCells may be controlled by the network using PDCCH format 1A. Msg2 message603(RAR: random access response) in response to the preamble transmission on the SCell may be addressed to RA-RNTI in a PCell common search space (CSS). Uplink packets604may be transmitted on the SCell in which the preamble was transmitted. According to an embodiment, initial timing alignment may be achieved through a random access procedure. This may involve a UE transmitting a random access preamble and an eNB responding with an initial TA command NTA (amount of timing advance) within a random access response window. The start of the random access preamble may be aligned with the start of a corresponding uplink subframe at the UE assuming NTA-0. The eNB may estimate the uplink timing from the random access preamble transmitted by the UE. The TA command may be derived by the eNB based on the estimation of the difference between the desired UL timing and the actual UL timing. The UE may determine the initial uplink transmission timing relative to the corresponding downlink of the sTAG on which the preamble is transmitted. The mapping of a serving cell to a TAG may be configured by a serving eNB with RRC signaling. The mechanism for TAG configuration and reconfiguration may be based on RRC signaling. According to various aspects of an embodiment, when an eNB performs an SCell addition configuration, the related TAG configuration may be configured for the SCell. In an example embodiment, an eNB may modify the TAG configuration of an SCell by removing (releasing) the SCell and adding(configuring) a new SCell (with the same physical cell ID and frequency) with an updated TAG ID. The new SCell with the updated TAG ID may initially be inactive subsequent to being assigned the updated TAG ID. The eNB may activate the updated new SCell and start scheduling packets on the activated SCell. In an example implementation, it may not be possible to change the TAG associated with an SCell, but rather, the SCell may need to be removed and a new SCell may need to be added with another TAG. For example, if there is a need to move an SCell from an sTAG to a pTAG, at least one RRC message, (for example, at least one RRC reconfiguration message), may be send to the UE to reconfigure TAG configurations by releasing the SCell and then configuring the SCell as a part of the pTAG. When an SCell is added/configured without a TAG index, the SCell may be explicitly assigned to the pTAG. The PCell may not change its TA group and may be a member of the pTAG. The purpose of an RRC connection reconfiguration procedure may be to modify an RRC connection, (for example, to establish, modify and/or release RBs, to perform handover, to setup, modify, and/or release measurements, to add, modify, and/or release SCells). If the received RRC Connection Reconfiguration message includes the sCellToReleaseList, the UE may perform an SCell release. If the received RRC Connection Reconfiguration message includes the sCellToAddModList, the UE may perform SCell additions or modification. In LTE Release-10 and Release-11 CA, a PUCCH may only be transmitted on the PCell (PSCell) to an eNB. In LTE-Release 12 and earlier, a UE may transmit PUCCH information on one cell (PCell or PSCell) to a given eNB. As the number of CA capable UEs and also the number of aggregated carriers increase, the number of PUCCHs and also the PUCCH payload size may increase. Accommodating the PUCCH transmissions on the PCell may lead to a high PUCCH load on the PCell. A PUCCH on an SCell may be introduced to offload the PUCCH resource from the PCell. More than one PUCCH may be configured for example, a PUCCH on a PCell and another PUCCH on an SCell. In the example embodiments, one, two or more cells may be configured with PUCCH resources for transmitting CSI/ACK/NACK to a base station. Cells may be grouped into multiple PUCCH groups, and one or more cell within a group may be configured with a PUCCH. In an example configuration, one SCell may belong to one PUCCH group. SCells with a configured PUCCH transmitted to a base station may be called a PUCCH SCell, and a cell group with a common PUCCH resource transmitted to the same base station may be called a PUCCH group. In an example embodiment, a MAC entity may have a configurable timer timeAlignmentTimer per TAG. The timeAlignmentTimer may be used to control how long the MAC entity considers the Serving Cells belonging to the associated TAG to be uplink time aligned. The MAC entity may, when a Timing Advance Command MAC control element is received, apply the Timing Advance Command for the indicated TAG; start or restart the timeAlignmentTimer associated with the indicated TAG. The MAC entity may, when a Timing Advance Command is received in a Random Access Response message for a serving cell belonging to a TAG and/orif the Random Access Preamble was not selected by the MAC entity, apply the Timing Advance Command for this TAG and start or restart the timeAlignmentTimer associated with this TAG. Otherwise, if the timeAlignmentTimer associated with this TAG is not running, the Timing Advance Command for this TAG may be applied and the timeAlignmentTimer associated with this TAG started. When the contention resolution is considered not successful, a timeAlignmentTimer associated with this TAG may be stopped. Otherwise, the MAC entity may ignore the received Timing Advance Command In example embodiments, a timer is running once it is started, until it is stopped or until it expires; otherwise it may not be running A timer can be started if it is not running or restarted if it is running. For example, a timer may be started or restarted from its initial value. Example embodiments of the disclosure may enable operation of multi-carrier communications. Other example embodiments may comprise a non-transitory tangible computer readable media comprising instructions executable by one or more processors to cause operation of multi-carrier communications. Yet other example embodiments may comprise an article of manufacture that comprises a non-transitory tangible computer readable machine-accessible medium having instructions encoded thereon for enabling programmable hardware to cause a device (e.g. wireless communicator, UE, base station, etc.) to enable operation of multi-carrier communications. The device may include processors, memory, interfaces, and/or the like. Other example embodiments may comprise communication networks comprising devices such as base stations, wireless devices (or user equipment: UE), servers, switches, antennas, and/or the like. The amount of data traffic carried over cellular networks is expected to increase for many years to come. The number of users/devices is increasing and each user/device accesses an increasing number and variety of services, e.g. video delivery, large files, images. This may require not only high capacity in the network, but also provisioning very high data rates to meet customers' expectations on interactivity and responsiveness. More spectrum may therefore needed for cellular operators to meet the increasing demand. Considering user expectations of high data rates along with seamless mobility, it may be beneficial that more spectrum be made available for deploying macro cells as well as small cells for cellular systems. Striving to meet the market demands, there has been increasing interest from operators in deploying some complementary access utilizing unlicensed spectrum to meet the traffic growth. This is exemplified by the large number of operator-deployed Wi-Fi networks and the 3GPP standardization of LTE/WLAN interworking solutions. This interest indicates that unlicensed spectrum, when present, may be an effective complement to licensed spectrum for cellular operators to help addressing the traffic explosion in some scenarios, such as hotspot areas. LAA may offer an alternative for operators to make use of unlicensed spectrum while managing one radio network, thus offering new possibilities for optimizing the network's efficiency. In an example embodiment, Listen-before-talk (clear channel assessment) may be implemented for transmission in an LAA cell. In a listen-before-talk (LBT) procedure, equipment may apply a clear channel assessment (CCA) check before using the channel. For example, the CCA may utilize at least energy detection to determine the presence or absence of other signals on a channel in order to determine if a channel is occupied or clear, respectively. For example, European and Japanese regulations mandate the usage of LBT in the unlicensed bands. Apart from regulatory requirements, carrier sensing via LBT may be one way for fair sharing of the unlicensed spectrum. In an example embodiment, discontinuous transmission on an unlicensed carrier with limited maximum transmission duration may be enabled. Some of these functions may be supported by one or more signals to be transmitted from the beginning of a discontinuous LAA downlink transmission. Channel reservation may be enabled by the transmission of signals, by an LAA node, after gaining channel access via a successful LBT operation, so that other nodes that receive the transmitted signal with energy above a certain threshold sense the channel to be occupied. Functions that may need to be supported by one or more signals for LAA operation with discontinuous downlink transmission may include one or more of the following: detection of the LAA downlink transmission (including cell identification) by UEs, time & frequency synchronization of UEs, and/or the like. In an example embodiment, a DL LAA design may employ subframe boundary alignment according to LTE-A carrier aggregation timing relationships across serving cells aggregated by CA. This may not imply that the eNB transmissions can start only at the subframe boundary. LAA may support transmitting PDSCH when not all OFDM symbols are available for transmission in a subframe according to LBT. Delivery of necessary control information for the PDSCH may also be supported. An LBT procedure may be employed for fair and friendly coexistence of LAA with other operators and technologies operating in an unlicensed spectrum. LBT procedures on a node attempting to transmit on a carrier in an unlicensed spectrum may require the node to perform a clear channel assessment to determine if the channel is free for use. An LBT procedure may involve at least energy detection to determine if the channel is being used. For example, regulatory requirements in some regions, for example, in Europe, may specify an energy detection threshold such that if a node receives energy greater than this threshold, the node assumes that the channel is not free. While nodes may follow such regulatory requirements, a node may optionally use a lower threshold for energy detection than that specified by regulatory requirements. In an example, LAA may employ a mechanism to adaptively change the energy detection threshold. For example, LAA may employ a mechanism to adaptively lower the energy detection threshold from an upper bound. Adaptation mechanism(s) may not preclude static or semi-static setting of the threshold. In an example a Category 4 LBT mechanism or other type of LBT mechanisms may be implemented. Various example LBT mechanisms may be implemented. In an example, for some signals, in some implementation scenarios, in some situations, and/or in some frequencies, no LBT procedure may performed by the transmitting entity. In an example, Category 2 (for example, LBT without random back-off) may be implemented. The duration of time that the channel is sensed to be idle before the transmitting entity transmits may be deterministic. In an example, Category 3 (for example, LBT with random back-off with a contention window of fixed size) may be implemented. The LBT procedure may have the following procedure as one of its components. The transmitting entity may draw a random number N within a contention window. The size of the contention window may be specified by the minimum and maximum value of N. The size of the contention window may be fixed. The random number N may be employed in the LBT procedure to determine the duration of time that the channel is sensed to be idle before the transmitting entity transmits on the channel. In an example, Category 4 (for example, LBT with random back-off with a contention window of variable size) may be implemented. The transmitting entity may draw a random number N within a contention window. The size of the contention window may be specified by a minimum and maximum value of N. The transmitting entity may vary the size of the contention window when drawing the random number N. The random number N may be employed in the LBT procedure to determine the duration of time that the channel is sensed to be idle before the transmitting entity transmits on the channel. LAA may employ uplink LBT at the UE. The UL LBT scheme may be different from the DL LBT scheme (for example, by using different LBT mechanisms or parameters), since the LAA UL may be based on scheduled access which affects a UE's channel contention opportunities. Other considerations motivating a different UL LBT scheme include, but are not limited to, multiplexing of multiple UEs in a single subframe. In an example, a DL transmission burst may be a continuous transmission from a DL transmitting node with no transmission immediately before or after from the same node on the same CC. A UL transmission burst from a UE perspective may be a continuous transmission from a UE with no transmission immediately before or after from the same UE on the same CC. In an example, a UL transmission burst may be defined from a UE perspective. In an example, a UL transmission burst may be defined from an eNB perspective. In an example, in case of an eNB operating DL+UL LAA over the same unlicensed carrier, DL transmission burst(s) and UL transmission burst(s) on LAA may be scheduled in a TDM manner over the same unlicensed carrier. For example, an instant in time may be part of a DL transmission burst or an UL transmission burst. In an example embodiment, in an unlicensed cell, a downlink burst may be started in a subframe. When an eNB accesses the channel, the eNB may transmit for a duration of one or more subframes. The duration may depend on a maximum configured burst duration in an eNB, the data available for transmission, and/or eNB scheduling algorithm.FIG.10shows an example downlink burst in an unlicensed (e.g. licensed assisted access) cell. The maximum configured burst duration in the example embodiment may be configured in the eNB. An eNB may transmit the maximum configured burst duration to a UE employing an RRC configuration message. The wireless device may receive from a base station at least one message (for example, an RRC) comprising configuration parameters of a plurality of cells. The plurality of cells may comprise at least one cell of a first type (e.g. license cell) and at least one cell of a second type (e.g. unlicensed cell, an LAA cell). The configuration parameters of a cell may, for example, comprise configuration parameters for physical channels, (for example, a ePDCCH, PDSCH, PUSCH, PUCCH and/or the like). The wireless device may determine transmission powers for one or more uplink channels. The wireless device may transmit uplink signals via at least one uplink channel based on the determined transmission powers. In an example embodiments, LTE transmission time may include frames, and a frame may include many subframes. The size of various time domain fields in the time domain may be expressed as a number of time units TS=1/(15000×2048) seconds. Downlink, uplink and sidelink transmissions may be organized into radio frames with Tf=30720×TS=10 ms duration. In an example LTE implementation, at least three radio frame structures may be supported: Type 1, applicable to FDD, Type 2, applicable to TDD, Type 3, applicable to LAA secondary cell operation. LAA secondary cell operation applies to frame structure type 3. Transmissions in multiple cells may be aggregated where one or more secondary cells may be used in addition to the primary cell. In case of multi-cell aggregation, different frame structures may be used in the different serving cells. Frame structure type 1 may be applicable to both full duplex and half duplex FDD. A radio frame is Tf=307200·TS=10 ms long and may comprise 20 slots of length Tslot=15360 TS=0.5 ms numbered from 0 to 19. A subframe may include two consecutive slots where subframe i comprises of slots 2i and 2i+1. For FDD, 10 subframes are available for downlink transmission and 10 subframes are available for uplink transmissions in a 10 ms interval. Uplink and downlink transmissions are separated in the frequency domain. In half-duplex FDD operation, the UE may not transmit and receive at the same time while there may not be such restrictions in full-duplex FDD. Frame structure type 2 may be applicable to TDD. A radio frame of length Tf=307200·TS=10 ms may comprise of two half-frames of length 153600·TS=5 ms A half-frame may comprise five subframes of length 30720 TS=1 ms. A subframe/may comprise two slots, 2i and 2i+1, of length Tslot=15360 TS=0.5 ms. The uplink-downlink configuration in a cell may vary between frames and controls in which subframes uplink or downlink transmissions may take place in the current frame. The uplink-downlink configuration in the current frame is obtained via control signaling. An example subframe in a radio frame, “may be a downlink subframe reserved for downlink transmissions, may be an uplink subframe reserved for uplink transmissions or may be a special subframe with the three fields DwPTS, GP and UpPTS. The length of DwPTS and UpPTS are subject to the total length of DwPTS, GP and UpPTS being equal to 30720 TS=1 ms. Uplink-downlink configurations with both 5 ms and 10 ms downlink-to-uplink switch-point periodicity may be supported. In case of 5 ms downlink-to-uplink switch-point periodicity, the special subframe may exist in both half-frames. In case of 10 ms downlink-to-uplink switch-point periodicity, the special subframe may exist in the first half-frame. Subframes 0 and 5 and DwPTS may be reserved for downlink transmission. UpPTS and the subframe immediately following the special subframe may be reserved for uplink transmission. In an example, in case multiple cells are aggregated, the UE may assume that the guard period of the special subframe in the cells using frame structure Type 2 have an overlap of at least 1456·TS. In an example, in case multiple cells with different uplink-downlink configurations in the current radio frame are aggregated and the UE is not capable of simultaneous reception and transmission in the aggregated cells, the following constraints may apply. if the subframe in the primary cell is a downlink subframe, the UE may not transmit any signal or channel on a secondary cell in the same subframe. If the subframe in the primary cell is an uplink subframe, the UE may not be expected to receive any downlink transmissions on a secondary cell in the same subframe. If the subframe in the primary cell is a special subframe and the same subframe in a secondary cell is a downlink subframe, the UE may not be expected to receive PDSCH/EPDCCH/PMCH/PRS transmissions in the secondary cell in the same subframe, and the UE may not be expected to receive any other signals on the secondary cell in OFDM symbols that overlaps with the guard period or UpPTS in the primary cell. Frame structure type 3 may be applicable to LAA secondary cell operation with normal cyclic prefix. A radio frame is Tf=307200·TS=10 ms long and comprises of 20 slots of length Tslot=15360·TS=0.5 ms numbered from 0 to 19. A subframe may comprise as two consecutive slots where subframe i comprises slots 2i and 2i+1. The 10 subframes within a radio frame are available for downlink transmissions. Downlink transmissions occupy one or more consecutive subframes, starting anywhere within a subframe and ending with the last subframe either fully occupied or following one of the DwPTS durations. Subframes may be available for uplink transmission when LAA uplink is supported. FIG.12shows an example 2-stage triggered grant with trigger A and trigger B. In an example embodiment, DCI 0A/4A/0B/4B may include a bit to indicate whether an UL grant is a triggered grant or not. If it is a triggered grant, the UE may transmit after receiving a 1 bit trigger in the PDCCH DCI scrambled with CC-RNTI in a subframe received after the subframe carrying the trigger. The timing between the 2nd trigger transmitted in subframe N and an earliest UL transmission may be a UE capability, if the earliest UL transmission is before subframe N+4 (e.g. UE capability signalling between transmission in subframe N+1 and N+2 and N+3). DCI 0A/4A/0B/4B may comprise one or more fields indicating resource block assignment, modulation and coding scheme, RV, HARQ information, transmit power control command, trigger A, and/or other physical layer parameters. DCI format 1C is used for example for LAA common information. The DCI format 1C in an LAA cell may comprise subframe configuration for an LAA cell—j bits (e.g., j=4) indicating a number of symbols. DCI format 1C may further comprise other information. DCI format 1C may further comprise, for example, k-bits (e.g. k=5) to indicate combinations of offset and burst duration. In an example, a code points may include {offset, duration} combinations as follows: combinations of {{1, 2, 3, 4, 6}, {1, 2, 3, 4, 5, 6}}, Reserved, no signalling of burst and offset. The format of the bits may be defined according to a pre-defined table. DCI format 1C may further comprise PUSCH trigger field (e.g. 1 bit) to indicate a trigger for a two-stage grant. For example, value 1 may indicate a trigger B and value 0 may indicate no trigger B. Reserved information bits may be added until the size is equal to that of format 1C used for very compact scheduling of one PDSCH code-word. In an example, if a serving cell is an LAA Scell, the UE may receive PDCCH with DCI CRC scrambled by CC-RNTI on the LAA SCell. In an example, the DCI CRC scrambled by CC-RNTI may be transmitted in the common search space of an LAA cell. Example PDCCH procedures are described here. In an example, a control region of a serving cell may comprise of a set of CCEs, numbered from 0 to NCCE,k−1 according, where NCCE,kmay be the total number of CCEs in the control region of subframe k. The UE may monitor a set of PDCCH candidates on one or more activated serving cells as configured by higher layer signalling for control information, where monitoring implies attempting to decode the PDCCHs in the set according to monitored DCI formats. A BL/CE UE may not be required to monitor PDCCH. In an example, the set of PDCCH candidates to monitor are defined in terms of search spaces, where a search space Sk(L)at aggregation level L∈{1, 2, 4, 8} is defined by a set of PDCCH candidates. For a serving cell on which PDCCH is monitored, the CCEs corresponding to PDCCH candidate m of the search space Sk(L)are given by L{(Yk+m′)mod └NCCE,k/L┘}+i, where Ykis defined below, i=0, . . . , L−1. For the common search space m′=m. For the PDCCH UE specific search space, for the serving cell on which PDCCH is monitored, if the monitoring UE is configured with carrier indicator field then m′=m+M(L)·nCIwherein nCIis the carrier indicator field value, else if the monitoring UE is not configured with carrier indicator field then m′=m, where m=0, . . . , M(L)−1. M(L)is the number of PDCCH candidates to monitor in the given search space. In an example, if a UE is configured with higher layer parameter cif-InSchedulingCell, the carrier indicator field value corresponds to cif-InSchedulingCell, otherwise, the carrier indicator field value is the same as ServCellIndex. The UE may monitor one common search space in a non-DRX subframe at aggregation levels 4 and 8 on the primary cell. A UE may monitor common search space on a cell to decode the PDCCHs necessary to receive MBMS on that cell when configured by higher layers. In an example, if a UE is not configured for EPDCCH monitoring, and if the UE is not configured with a carrier indicator field, then the UE may monitor one PDCCH UE-specific search space at aggregation levels 1, 2, 4, 8 on an activated serving cell in every non-DRX subframe. If a UE is not configured for EPDCCH monitoring, and if the UE is configured with a carrier indicator field, then the UE may monitor one or more UE-specific search spaces at aggregation levels 1, 2, 4, 8 on one or more activated serving cells as configured by higher layer signalling in every non-DRX subframe. In an example, if a UE is configured for EPDCCH monitoring on a serving cell, and if that serving cell is activated, and if the UE is not configured with a carrier indicator field, then the UE may monitor one PDCCH UE-specific search space at aggregation levels 1, 2, 4, 8 on that serving cell in non-DRX subframes where EPDCCH is not monitored on that serving cell. If a UE is configured for EPDCCH monitoring on a serving cell, and if that serving cell is activated, and if the UE is configured with a carrier indicator field, then the UE may monitor one or more PDCCH UE-specific search spaces at aggregation levels 1, 2, 4, 8 on that serving cell as configured by higher layer signalling in non-DRX subframes where EPDCCH is not monitored on that serving cell. The common and PDCCH UE-specific search spaces on the primary cell may overlap. In an example, a UE configured with a carrier indicator field associated with monitoring PDCCH on serving cell c may monitor PDCCH configured with carrier indicator field and with CRC scrambled by C-RNTI in the PDCCH UE specific search space of serving cell c. A UE configured with the carrier indicator field associated with monitoring PDCCH on the primary cell may monitor PDCCH configured with carrier indicator field and with CRC scrambled by SPS C-RNTI in the PDCCH UE specific search space of the primary cell. The UE may monitor the common search space for PDCCH without carrier indicator field. In an example, for the serving cell on which PDCCH is monitored, if the UE is not configured with a carrier indicator field, it may monitor the PDCCH UE specific search space for PDCCH without carrier indicator field, if the UE is configured with a carrier indicator field it may monitor the PDCCH UE specific search space for PDCCH with carrier indicator field. If the UE is not configured with a LAA Scell, the UE is not expected to monitor the PDCCH of a secondary cell if it is configured to monitor PDCCH with carrier indicator field corresponding to that secondary cell in another serving cell. In an example, if the UE is configured with a LAA Scell, the UE is not expected to monitor the PDCCH UE specific space of the LAA SCell if it is configured to monitor PDCCH with carrier indicator field corresponding to that LAA Scell in another serving cell, where the UE is not expected to be configured to monitor PDCCH with carrier indicator field in an LAA Scell; and where the UE is not expected to be scheduled with PDSCH starting in the second slot in a subframe in an LAA Scell if the UE is configured to monitor PDCCH with carrier indicator field corresponding to that LAA Scell in another serving cell. In an example, for the serving cell on which PDCCH is monitored, the UE may monitor PDCCH candidates at least for the same serving cell. A UE configured to monitor PDCCH candidates with CRC scrambled by C-RNTI or SPS C-RNTI with a common payload size and with the same first CCE index nCCEbut with different sets of DCI information fields in the common search space and/or PDCCH UE specific search space. In an example, a UE configured to monitor PDCCH candidates in a given serving cell with a given DCI format size with CIF, and CRC scrambled by C-RNTI, where the PDCCH candidates may have one or more possible values of CIF for the given DCI format size, may assume that a PDCCH candidate with the given DCI format size may be transmitted in the given serving cell in any PDCCH UE specific search space corresponding to any of the possible values of CIF for the given DCI format size. In an example, if a serving cell is an LAA Scell, the UE may receive PDCCH with DCI CRC scrambled by CC-RNTI on the LAA Scell. The DCI formats that the UE may monitor depend on the configured transmission mode of a serving cell. Example subframe configuration for Frame Structure Type 3 are described here. If a UE detects PDCCH with DCI CRC scrambled by CC-RNTI in subframe n−1 or subframe n of a LAA Scell, the UE may assume the configuration of occupied OFDM symbols in subframe n of the LAA Scell according to the Subframe configuration for LAA field in the detected DCI in subframe n−1 or subframe n. In an example, the Subframe configuration for LAA field indicates the configuration of occupied OFDM symbols (e.g., OFDM symbols used for transmission of downlink physical channels and/or physical signals) in current and/or next subframe according to a predefined table. If the configuration of occupied OFDM symbols for subframe n is indicated by the Subframe configuration for LAA field in both subframe n−1 and subframe n, the UE may assume that the same configuration of occupied OFDM symbols is indicated in both subframe n−1 and subframe n. In an example, if a UE detects PDCCH with DCI CRC scrambled by CC-RNTI in subframe n, and the UE does not detect PDCCH with DCI CRC scrambled by CC-RNTI in subframe n−1, and if the number of occupied OFDM symbols for subframe n indicated by the Subframe configuration for LAA field in subframe n is less than 14, the UE is not required to receive any other physical channels in subframe n. In an example, if a UE does not detect PDCCH with DCI CRC scrambled by CC-RNTI containing Subframe Configuration for LAA field set to other than ‘1110’ and ‘1111’ in subframe n and the UE does not detect PDCCH with DCI CRC scrambled by CC-RNTI containing Subframe Configuration for LAA field set to other than ‘1110’ and ‘1111’ in subframe n−1, the UE is not required to use subframe n for updating CSI measurement. In an example, the UE may detect PDCCH with DCI CRC scrambled by CC-RNTI by monitoring the following PDCCH candidates according to DCI Format 1C: one PDCCH candidate at aggregation level L=4 with the CCEs corresponding to the PDCCH candidate given by CCEs numbered 0, 1, 2, 3; one PDCCH candidate at aggregation level L=8 with the CCEs corresponding to the PDCCH candidate given by CCEs numbered 0, 1, 2, 3, 4, 5, 6, 7. In an example, if a serving cell is an LAA Scell, and if the higher layer parameter subframeStartPosition for the Scell indicates ‘s07’, and if the UE detects PDCCH/EPDCCH intended for the UE starting in the second slot of a subframe, the UE may assume that OFDM symbols in the first slot of the subframe are not occupied, and OFDM symbols in the second slot of the subframe are occupied. If subframe n is a subframe in which OFDM symbols in the first slot are not occupied, the UE may assume that the OFDM symbols are occupied in subframe n+1. In an example embodiment, a field in DCI format 0A/4A/0B/4B for the triggered grant, e.g. 4-bit SF timing, may be reused to signal to the UE a subframe for transmission after reception of the trigger. When a UE receives a trigger in subframe N, the UE may be allowed to start transmission in subframe N+X+Y. 2 bits are reused to indicate X. X={0, 1, 2, 3} may be indicated to the UE reusing two bits in the DCI. Y may be given by the UL burst offset in the C-PDCCH DCI scrambled by CC-RNTI (e.g. in the same subframe where the trigger is transmitted). The UE may receive signalling in the first DCI 0A/4A/0B/4B grant indicating the number of subframes after which the grant becomes invalid. The initial grant may become invalid if M ms after the initial grant, no valid trigger has been received, e.g. M={8, 12, 16, 20}. In an example, a UE may follow the LBT type indicated by the UL grant. In an example embodiment, C(common)-PDCCH may indicate a pair of values (UL burst duration, offset). UL burst duration may be a number of consecutive UL subframes belonging to the same channel occupancy. Offset may be the number of subframes to the start of indicated UL burst from the start of the subframe carrying the C-PDCCH. In an example embodiment, an LBT procedure may be switched to an LBT based on 25 us CCA for any UL subframe from the subframe in which C-PDCCH was received up to and including subframes until the end of the signalled UL burst duration, for which the eNB had already indicated to perform Category 4 LBT. In an example, a UE may not switch to 25 us CCA if part of a set of contiguously scheduled subframes without gap appears in the UL burst indication. The UE may not be required to receive any DL signals/channels in a subframe indicated to be a UL subframe on the carrier. In an example, 5 bits may be employed to indicate combinations of offset and burst duration. Example code points include {offset, duration} combinations as follows: combinations of {{1, 2, 3, 4, 6}, {1, 2, 3, 4, 5, 6}}, Reserved, no signalling of burst and offset. The format of the bits may be defined according to a pre-defined table. In an example embodiment, resource block assignment field in DCI 0A/4A/0B/4B may be 6 bits. In an example, the 64 code points indicated by the 6 bits may include the legacy RIV for contiguous interlace allocation except the code points for the allocation of 7 contiguous interlaces (70 PRBs). This set of code points may include 51 values. Additional code points may be defined for allocation of interlaces as follows: 0, 1, 5, 6; 2, 3, 4, 7, 8, 9; 0, 5; 1, 6; 2, 7; 3, 8; 4, 9; 1, 2, 3, 4, 6, 7, 8, 9. Remaining code points may be reserved. In an example, the Activation/Deactivation MAC control element of one octet may be identified by a MAC PDU subheader with LCID 11000.FIG.11shows example Activation/Deactivation MAC control elements. The Activation/Deactivation MAC control element may have a fixed size and may comprise of a single octet containing seven C-fields and one R-field. Example Activation/Deactivation MAC control element with one octet is shown inFIG.11. The Activation/Deactivation MAC control element may have a fixed size and may comprise of four octets containing 31 C-fields and one R-field. Example Activation/Deactivation MAC control element of four octets is shown inFIG.11. In an example, for the case with no serving cell with a serving cell index (ServCellIndex) larger than 7, Activation/Deactivation MAC control element of one octet may be applied, otherwise Activation/Deactivation MAC control element of four octets may be applied. The fields in an Activation/Deactivation MAC control element may be interpreted as follows. Ci: if there is an SCell configured with SCellIndex i, this field may indicate the activation/deactivation status of the SCell with SCellIndex i, else the MAC entity may ignore the Ci field. The Ci field may be set to “1” to indicate that the SCell with SCellIndex i is activated. The Ci field is set to “0” to indicate that the SCell with SCellIndex i is deactivated. R: Reserved bit, set to “0”. In an example, if the MAC entity is configured with one or more SCells, the network may activate and deactivate the configured SCells. The SpCell may remain activated. The network may activate and deactivate the SCell(s) by sending the Activation/Deactivation MAC control element. In example, the MAC entity may maintain a sCellDeactivationTimer timer for a configured SCell. sCellDeactivationTimer may be disabled for the SCell configured with PUCCH, if any. In example, the MAC entity may deactivate the associated SCell upon its expiry. In an example, the same initial timer value may apply to each instance of the sCellDeactivationTimer and it is configured by RRC. The configured SCells may be initially deactivated upon addition and after a handover. The configured SCG SCells are initially deactivated after a SCG change. The MAC entity may for each TTI and for a configured SCell perform the following: if the MAC entity receives an Activation/Deactivation MAC control element in this TTI activating the SCell, the MAC entity may in the TTI according to a predefined timing, activate the SCell. A UE may operate the following for an activated SCell including: SRS transmissions on the SCell; CQI/PMI/RI/PTI/CRI reporting for the SCell; PDCCH monitoring on the SCell; PDCCH monitoring for the SCell; PUCCH transmissions on the SCell, if configured. If the MAC entity receives an Activation/Deactivation MAC control element in this TTI activating the SCell, the UE may start or restart the sCellDeactivationTimer associated with the SCell and may trigger PHR. If the MAC entity receives an Activation/Deactivation MAC control element in this TTI deactivating the SCell or if the sCellDeactivationTimer associated with the activated SCell expires in this TTI, in the TTI according to a predefined timing, the UE may deactivate the SCell; stop the sCellDeactivationTimer associated with the SCell; flush HARQ buffers associated with the SCell. In an example embodiment, if the SCell is deactivated: the UE may not transmit SRS on the SCell; not report CQI/PMI/RI/PTI/CRI for the SCell; not transmit on UL-SCH on the SCell; not transmit on RACH on the SCell; not monitor the PDCCH on the SCell; not monitor the PDCCH for the Cell; and/or not transmit PUCCH on the SCell. When SCell is deactivated, the ongoing random access procedure on the SCell, if any, is aborted. In an example embodiment, the sCellDeactivationTimer for a cell may be disabled and there may be no need to manage sCellDeactivationTimer for the cell and the cell may be activated or deactivated employing A/D MAC CE. In an example, when a single stage grant is configured, if PDCCH on the activated SCell indicates an uplink grant or downlink assignment; or if PDCCH on the Serving Cell scheduling the activated SCell indicates an uplink grant or a downlink assignment for the activated SCell: the UE/eNB may restart the sCellDeactivationTimer associated with the SCell. In an example embodiment, an eNB may transmit one or more RRC messages comprising one or more parameters (IEs). The one or more parameters may comprise configuration parameters of one or more licensed cells and one or more unlicensed cells (e.g. LAA cells). The one or more parameters may comprise a sCellDeactivationTimer value. For example, sCellDeactivationTimer ENUMERATED {rf2, rf4, rf8, rf16, rf32, rf64, rf128, spare} OPTIONAL. SCell deactivation timer value may be in number of radio frames. For example, value rf4 corresponds to 4 radio frames, value rf8 corresponds to 8 radio frames and so on. In an example, E-UTRAN may configure the field if the UE is configured with one or more SCells other than the PSCell and PUCCH SCell. If the field is absent, the UE may delete any existing value for this field and assume the value to be set to infinity. In an example, the same value may apply for each SCell of a Cell Group (e.g. MCG or SCG) (the associated functionality is performed independently for each SCell). Field sCellDeactivationTimer may not apply to an SCell, when the for the sCellDeactivationTimer is disabled for the SCell (e.g. PUCCH SCell and/or other SCells). A UE may Support UL/DL Scheduling Combinations: Self-scheduling on DL and cross-carrier scheduling on UL. The UE to monitor for DCI formats scheduling PUSCH of a single eLAA Scell on one UL licensed-band scheduling cell, e.g. DCI formats 0A/0B, Formats 4A/4B (e.g if configured for TM2). The UE may monitor for DCI formats scheduling LAA PDSCH on the LAA SCell, e.g. DCI formats 1A/1B/1D/1/2A/2/2B/2C/2D. In legacy RRC mechanisms, when cross carrier scheduling is configured by RRC for an SCell, the scheduling cell schedules both downlink and uplink (if configured) grants for the scheduled cell. In an example, the RRC signaling and cross carrier scheduling may be enhanced. RRC signaling may configure self-scheduling for DL and cross-carrier scheduling for UL, for example for an LAA cell. For example, a new parameter in the cross-carrier scheduling configuration parameters may indicate whether the cross-carrier scheduling is for both downlink scheduling and uplink scheduling or is for uplink scheduling (and DL is self-scheduled). In an example, a licensed cell may be configured for cross-carrier scheduling an unlicensed (e.g. LAA) cell. The IE CrossCarrierSchedulingConfig may used to specify the configuration when the cross carrier scheduling is used in a cell. In an example, the IE CrossCarrierScheduling Config may comprise cif-Presence, schedulingCellId, and pdsch-Start. In an example, the IE CrossCarrierSchedulingConfig may comprise cif-Presence, schedulingCellId, pdsch-Start, and cif-InSchedulingCell. In an example, cif-Presence may be used to indicate whether carrier indicator field is present (value true) or not (value false) in PDCCH/EPDCCH DCI formats. In an example, pdsch-Start field may indicate the starting OFDM symbol of PDSCH for the concerned SCell. In an example, values 1, 2, 3 are applicable when dl-Bandwidth for the concerned SCell is greater than 10 resource blocks, values 2, 3, 4 are applicable when dl-Bandwidth for the concerned SCell is less than or equal to 10 resource blocks. In an example, cif-InSchedulingCell field may indicate the CIF value used in the scheduling cell to indicate this cell. In an example, schedulingCellId field may indicates which cell signals the downlink allocations and/or uplink grants, if applicable, for the concerned SCell. In case the UE is configured with DC, the scheduling cell is part of the same cell group (e.g. MCG or SCG) as the scheduled. In an example, an IE in IE CrossCarrierSchedulingConfig of an RRC message may indicate self-scheduling on DL and cross-carrier scheduling on UL (for example for an LAA cell). In an example, an IE in IE CrossCarrierSchedulingConfig of an RRC message may indicate cross-carrier scheduling on both downlink and uplink. Implementation of legacy deactivation timer and carrier activation status management when cross carrier scheduling is configured may result in inefficiencies and additional constraints. For example, implementation of existing mechanisms may result in keeping a carrier activated, while its scheduling cell is deactivated. In some scenarios, implementation of current mechanisms may result in constraining a carrier to only downlink and/or uplink transmissions. Example embodiments enhances deactivation timer and carrier activation status management and improves battery power consumption and scheduling efficiency when carrier aggregation is implemented, for example, when carrier aggregation is implemented in unlicensed cells (e.g. employing LAA cells) or when carrier aggregation is implemented along with implementation of two stage grants and/or cross carrier scheduling. In an example implementation, RRC signaling may configure self-scheduling on DL and cross-carrier scheduling on UL, for example for an LAA cell. In an example embodiment, when a UE receives DL scheduling grant on the LAA cell for the LAA cell, the UE may restart sCellDeactivationTimer associated with the LAA Cell. The UE may not restart sCellDeactivationTimer associated with the UL scheduling Cell because a DL grant is received on the LAA cell. In an example embodiment, when a UE receives UL scheduling grant for the LAA cell on a scheduling cell, the UE may restart sCellDeactivationTimer associated with the LAA cell and the scheduling cell.FIG.13shows an example sCellDeactivationTimer management. In an example, when RRC signaling configure self-scheduling on DL of an LAA cell and cross-carrier scheduling on UL using a scheduling cell, for example for the LAA cell. The sCellDeactivationTimer of the scheduling cell may be restarted when an uplink grant is received for the LAA Cell. The sCellDeactivationTimer of the scheduling cell may not be restarted when an uplink grant is received for the LAA Cell. The sCellDeactivationTimer of the LAA cell is restarted when an uplink grant or downlink grant is received for the LAA cell. In an example, sCellDeactivationTimer of the scheduling cell may be expired, when the sCellDeactivationTimer timer of the LAA cell is still running. For example, when the UE receives many downlink grants on the LAA cell, but does not receive any uplink grant on the scheduling cell and the PDDCH of the scheduling cell does not carry grants for a period of time (enough that sCellDeactivationTimer of the scheduling cell expires). In an example embodiment, when an LAA cell, configured with cross-carrier scheduling, is activated, the UE may monitor PDCCH for DL transmissions and UE may monitor PDDCH for the UL transmissions only if the scheduling cell is activated. This process may improve the receiver efficiency, since PDCCH monitoring for UL transmission on the scheduling cell requires maintaining the status of the scheduling cell activated even if there is no uplink grant on the PDCCH of the scheduling cell for a relatively long period (compared with sCellDeactivationTimer). In the example scenario, the LAA can be scheduled for downlink but not uplink. When uplink scheduling is required, the eNB may transmit a A/D MAC CE and activate the scheduling cell. A UE may operate the following for an activated SCell including: SRS transmissions on the SCell (if SRS configured); CQI/PMI/RI/PTI/CRI reporting for the SCell; PDCCH monitoring on the SCell; PDCCH monitoring for the SCell if the scheduling cell is activated; PUCCH transmissions on the SCell, (if PUCCH configured). In an example embodiment, the scheduling cell of an LAA may be deactivated, while the LAA cell is still activated. The UE may not monitor for uplink grants for transmission of UL TBs on the LAA cell. The UE may monitor for downlink grants for transmission of DL TBs on the LAA cell. In an example embodiment, an enhanced process may be implemented to further stop other uplink transmissions such as SRS and/or PRACH on the LAA cell when the scheduling cell of the LAA cell is deactivated. The UE may not transmit SRS on the LAA Cell; not transmit on UL-SCH on the LAA Cell; not transmit on RACH on the LAA Cell; not monitor the PDCCH on the scheduling Cell for the LAA cell; and/or not transmit PUCCH on the LAA Cell when the scheduling cell is deactivated. In an example, the UE may report CQI/PMI/RI/PTI/CRI for the LAA Cell and/or monitor the PDCCH on the LAA Cell when the scheduling cell is deactivated. This deactivation mechanism may maintain a different deactivation for uplink compared with downlink. Uplink may be deactivated when the scheduling cell is deactivated. In some scenarios downlink may maintain activation status while uplink is deactivated. In an example, both uplink and downlink may be deactivated, for example, when the deactivation timer for the LAA cell is expired. In an example embodiment, when the scheduling cell of an LAA cell is deactivated, the eNB/UE may consider self-scheduling for uplink transmissions on an LAA cell. Cross carrier for the LAA cell is configured and activated when the scheduling cell is activated, otherwise, the UE/eNB may employ self-scheduling for uplink and downlink. In an example implementation, RRC signaling may configure self-scheduling on DL and cross-carrier scheduling on UL, for example for an LAA cell. In an example embodiment, when the UE receives DL scheduling grant on the LAA cell for the LAA cell, the UE may restart sCellDeactivationTimer associated with the LAA Cell and the scheduling Cell. Even though, PDCCH on the scheduling cell does not indicate a grant, the sCellDeactivationTimer for the scheduling cell is restarted to maintain the activation status as long as LAA cell is activated. In an example embodiment, when the UE receives UL scheduling grant for the LAA cell on the scheduling cell, the UE may restart sCellDeactivationTimer associated with the LAA cell and the scheduling cell.FIG.14shows an example sCellDeactivationTimer management. When an example embodiment is implemented, sCellDeactivationTimer of the scheduling cell may not expire, when the sCellDeactivationTimer timer of the LAA cell is still running. For example, when the UE receives many downlink grants on the LAA cell, but does not receive any uplink grant on the scheduling cell and the PDDCH of the scheduling cell does not carry grants for a period of time, the scheduling cell activation status may be maintained. This process may increase battery power consumption in the UE, since the UE needs to monitor PDCCH on both scheduling cell and the LAA cell. This process enhances the scheduling flexibility for the LAA cell and reduces MAC signalling overhead. In an example embodiment, when an LAA cell is activated, the UE may monitor PDCCH for both DL and UL grants and is able to transmit and receive TBs on the LAA cell. The same activation status is maintained for both downlink and uplink. In an example embodiment, a UE may maintain the activation status of the scheduling cell as long as at least one LAA cell that is configured for cross carrier scheduling by the scheduling cell is activated. In an example, when sCellDeactivationTimer of the scheduling cell expires, the MAC entity may check whether any of the LAA cells being scheduled is still activated. If at least one LAA cell is activated, the MAC may restart the sCellDeactivationTimer, and/or maintain the activation status of the scheduling cell. Other example timer management mechanisms may be implemented to maintain the activation status of the scheduling cell as activated as long as at least one LAA cell (configured being scheduled by the scheduling cell) is activated. In an example embodiment, when an LAA cell configured with cross-carrier scheduling is activated, the UE may monitor PDCCH on the LAA cell for DL transmissions and UE may monitor PDDCH for the UL transmissions on the scheduling cell. This process may improve the receiver flexibility, since the UE may maintain the status of the scheduling cell activated even if there is no uplink grant on the PDCCH of the scheduling cell for a relatively long period (compared with sCellDeactivationTimer). When an LAA status is activated, the UE may receive or transmit TBs on the LAA cell. In an example embodiment, the scheduling cell of an LAA may not be deactivated, while the LAA cell is still activated. In an example implementation, RRC signaling may configure self-scheduling on DL and cross-carrier scheduling on UL, for example for an LAA cell. When the current sCellDeactivationTimer management is implemented, when the UE receives DL scheduling grant on the LAA cell for the LAA cell, the UE may restart sCellDeactivationTimer associated with the LAA Cell. The UE may not restart sCellDeactivationTimer associated with the UL scheduling Cell because a DL grant is received on the LAA cell. In an example embodiment, when the UE receives UL scheduling grant for the LAA cell on a scheduling cell, the UE may restart sCellDeactivationTimer associated with the LAA cell and the scheduling cell. In an example, sCellDeactivationTimer of the scheduling cell may be expired, when the sCellDeactivationTimer timer of the LAA cell is still running. For example, when the UE receives many downlink grants on the LAA cell, but does not receive any uplink grant on the scheduling cell and the PDDCH of the scheduling cell does not carry grants for a period of time (enough that sCellDeactivationTimer of the scheduling cell expires). There is a need to enhance activation and deactivation mechanism so that a scheduling cell is not deactivated as long as the LAA cell is activated. In an example embodiment, the deactivation timer for the scheduling cell is disabled. In an example, the deactivation timer for the scheduling cell is disabled whenever a scheduling cell is configured to schedule an LAA cell. For example, when a licensed cell is configured to schedule uplink TBs on an unlicensed cell, the deactivation timer of the licensed cell may be disabled. An eNB may transmit one or more RRC messages configuring cells and cross carrier scheduling. In an example, one or more RRC messages may comprise a parameter indicating that the sCellDeactivationTimer for a scheduling cell is disabled. In an example, the scheduling cell may be activated or deactivated by A/C MAC CE. An eNB may activate or deactivate the scheduling cell by transmitting a A/C MAC CE comprising a field indicating activation or deactivation of the scheduling cell. This process may increase eNB MAC signalling, but may enhance scheduling flexibility by maintaining uplink scheduling cell activated as long as the LAA cell is activated. In an example embodiment, when an LAA cell configured with cross-carrier scheduling is activated, the UE may monitor PDCCH for DL transmissions and UE may monitor PDDCH for the UL transmissions on the scheduling cell. This process may improve the receiver flexibility, since the UE/eNB may maintain the status of the scheduling cell activated even if there is no uplink grant on the PDCCH of the scheduling cell for a relatively long period (compared with sCellDeactivationTimer). When an LAA status is activated, the UE may receive or transmit TBs on the LAA cell. In an example embodiment, eNB may not deactivate the scheduling cell of an LAA cell, while the LAA cell is still activated. If the scheduling cell is deactivated (e.g. by A/D MAC CE), the UE may not monitor PDCCH on the scheduling cell for uplink grants on the LAA cell. The UE may monitor PDCCH on the LAA cell for downlink grants, when LAA cell is activated. According to various embodiments, a device (such as, for example, a wireless device, off-network wireless device, a base station, and/or the like), may comprise one or more processors and memory. The memory may store instructions that, when executed by the one or more processors, cause the device to perform a series of actions. Embodiments of example actions are illustrated in the accompanying figures and specification. Features from various embodiments may be combined to create yet further embodiments. FIG.15is an example flow diagram as per an aspect of an embodiment of the present disclosure. A wireless device may receive at least one radio resource control (RRC) message at1510. The RRC message may comprise configuration parameters of a plurality of cells comprising a first cell and a second cell. The configuration parameters may comprise: at least one deactivation timer value for a first deactivation timer of the first cell and a second deactivation timer of the second cell, and at least one cross carrier scheduling parameter indicating a configuration of cross carrier scheduling. A first control channel of the first cell may carry downlink scheduling information for packets received by the wireless device via a downlink data channel of the first cell. A second control channel of the second cell may carry uplink scheduling information for second packets transmitted by the wireless device via an uplink data channel of the first cell. At1520, a first downlink control information (DCI) for uplink transmission on the first cell may be received. At1530, the first deactivation timer and the second deactivation timer may be restarted in response to the first DCI. At1540, a second DCI for downlink transmission on the first cell may be received. At1550, the first deactivation timer and not the second deactivation timer may be restarted in response to the second DCI. At1560, the first cell may be deactivated in response to the first deactivation timer expiring. At1570, the second cell may be deactivated in response to the second deactivation timer expiring. According to an embodiment, the first DCI may comprise: a first field indicating an uplink resource block assignment, and a first trigger field indicating that the first DCI is triggered in response to a trigger. According to an embodiment, the first cell may be a licensed assisted access (LAA) cell. According to an embodiment, the second cell may be a licensed cell. According to an embodiment, the first DCI may indicate a modulation and coding scheme for transmission of one or more transport blocks. According to an embodiment, the wireless device may further receive, via a common search space of a control channel of the first cell, a third DCI comprising a second trigger field indicating a second trigger, when the first DCI indicates that the first DCI is a triggered DCI. According to an embodiment, the first DCI may comprise a field indicating a time interval during which a trigger is received. According to an embodiment, the wireless device may further a media access control control element (MAC CE) indicating activation of the first cell, and start the first deactivation timer in response to receiving the MAC CE. According to an embodiment, the first DCI may comprise: a first field indicating an uplink resource block assignment, and a first trigger field indicating that the first DCI is triggered in response to a second trigger. FIG.16is an example flow diagram as per an aspect of an embodiment of the present disclosure. A base station may transmit at least one radio resource control (RRC) message at1610. The RRC message may comprise configuration parameters of a plurality of cells comprising a first cell and a second cell. The configuration parameters may comprise at least one deactivation timer value for a first deactivation timer of the first cell and a second deactivation timer of the second cell; and at least one cross carrier scheduling parameter indicating a configuration of cross carrier scheduling. A first control channel of the first cell may carry downlink scheduling information for packets received by the wireless device via a downlink data channel of the first cell. A second control channel of the second cell may carry uplink scheduling information for second packets transmitted by the wireless device via an uplink data channel of the first cell. At1620, the base station may transmit a first downlink control information (DCI) for uplink transmission on the first cell. At1630, the first deactivation timer and the second deactivation timer may be restarted in response to the first DCI. At1640, the base station may transmit a second DCI for downlink transmission on the first cell. At1650, the first deactivation timer and not the second deactivation timer may be restarted in response to the second DCI. At1660, a status of the first cell may be deactivated in response to the first deactivation timer expiring. At1670, a status of the second cell may be deactivated in response to the second deactivation timer expiring. According to an embodiment, the first DCI may comprise: a first field indicating an uplink resource block assignment; and a first trigger field indicating that the first DCI is triggered in response to a trigger. According to an embodiment, the first cell may be a licensed assisted access (LAA) cell. According to an embodiment, the second cell may be a licensed cell. FIG.17is an example flow diagram as per an aspect of an embodiment of the present disclosure. A wireless device may receive at least one radio resource control (RRC) message at1710. The RRC message may comprise configuration parameters of a plurality of cells. The configuration parameters may comprise: at least one deactivation timer value for a first deactivation timer of a first cell and a second deactivation timer of a second cell, and at least one scheduling parameter. A first control channel of the first cell may carry downlink scheduling information for packets received by the wireless device via a downlink data channel of the first cell. At1720, a first downlink control information (DCI) for uplink transmission on the first cell may be received via a first control channel of first cell. At1730, the first deactivation timer and the second deactivation timer may be restarted in response to the first DCI. At1740, the first cell may be deactivated in response to the first deactivation timer expiring. At1750, the second cell may be deactivated in response to the second deactivation timer expiring. According to an embodiment, the wireless device may further receive, via a second control channel of the second cell, a second DCI for uplink transmission on the first cell; and restart the first deactivation timer and the second deactivation timer in response to the second DCI. According to an embodiment, the second control channel of the second cell may carry uplink scheduling information for second packets transmitted by the wireless device via an uplink data channel of the first cell. FIG.18is an example flow diagram as per an aspect of an embodiment of the present disclosure. A wireless device may receive at least one radio resource control (RRC) message at1810. The RRC message may comprise configuration parameters of a plurality of cells. The configuration parameters may comprise: at least one deactivation timer value, and at least one cross carrier scheduling parameter indicating a configuration of cross carrier scheduling. A first control channel of a first cell may carry downlink scheduling information for packets received by the wireless device via a downlink data channel of the first cell. A second control channel of a second cell may carry uplink scheduling information for second packets transmitted by the wireless device via an uplink data channel of the first cell. At1820, a deactivation timer for the second cell may be disabled in response to the configuration parameters comprising the at least one cross carrier scheduling parameter. At1830, the wireless device may receive, via a first control channel of first cell, a first downlink control information (DCI) for downlink transmission on the first cell. At1840, the wireless device may receive one or more transport blocks employing the first DCI. In this specification, “a” and “an” and similar phrases are to be interpreted as “at least one” and “one or more.” In this specification, the term “may” is to be interpreted as “may, for example.” In other words, the term “may” is indicative that the phrase following the term “may” is an example of one of a multitude of suitable possibilities that may, or may not, be employed to one or more of the various embodiments. If A and B are sets and every element of A is also an element of B, A is called a subset of B. In this specification, only non-empty sets and subsets are considered. For example, possible subsets of B={cell1, cell2} are: {cell1}, {cell2}, and {cell1, cell2}. In this specification, parameters (Information elements: IEs) may comprise one or more objects, and each of those objects may comprise one or more other objects. For example, if parameter (IE) N comprises parameter (IE) M, and parameter (IE) M comprises parameter (IE) K, and parameter (IE) K comprises parameter (information element) J, then, for example, N comprises K, and N comprises J. In an example embodiment, when one or more messages comprise a plurality of parameters, it implies that a parameter in the plurality of parameters is in at least one of the one or more messages, but does not have to be in each of the one or more messages. Many of the elements described in the disclosed embodiments may be implemented as modules. A module is defined here as an isolatable element that performs a defined function and has a defined interface to other elements. The modules described in this disclosure may be implemented in hardware, software in combination with hardware, firmware, wetware (i.e hardware with a biological element) or a combination thereof, all of which are behaviorally equivalent. For example, modules may be implemented as a software routine written in a computer language configured to be executed by a hardware machine (such as C, C++, Fortran, Java, Basic, Matlab or the like) or a modeling/simulation program such as Simulink, Stateflow, GNU Octave, or LabVIEWMathScript. Additionally, it may be possible to implement modules using physical hardware that incorporates discrete or programmable analog, digital and/or quantum hardware. Examples of programmable hardware comprise: computers, microcontrollers, microprocessors, application-specific integrated circuits (ASICs); field programmable gate arrays (FPGAs); and complex programmable logic devices (CPLDs). Computers, microcontrollers and microprocessors are programmed using languages such as assembly, C, C++ or the like. FPGAs, ASICs and CPLDs are often programmed using hardware description languages (HDL) such as VHSIC hardware description language (VHDL) or Verilog that configure connections between internal hardware modules with lesser functionality on a programmable device. Finally, it needs to be emphasized that the above mentioned technologies are often used in combination to achieve the result of a functional module. The disclosure of this patent document incorporates material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, for the limited purposes required by law, but otherwise reserves all copyright rights whatsoever. While various embodiments have been described above, it should be understood that they have been presented by way of example, and not limitation. It will be apparent to persons skilled in the relevant art(s) that various changes in form and detail can be made therein without departing from the spirit and scope. In fact, after reading the above description, it will be apparent to one skilled in the relevant art(s) how to implement alternative embodiments. Thus, the present embodiments should not be limited by any of the above described exemplary embodiments. In particular, it should be noted that, for example purposes, the above explanation has focused on the example(s) using LAA communication systems. However, one skilled in the art will recognize that embodiments of the disclosure may also be implemented in a system comprising one or more TDD cells (e.g. frame structure2and/or frame structure1). The disclosed methods and systems may be implemented in wireless or wireline systems. The features of various embodiments presented in this disclosure may be combined. One or many features (method or system) of one embodiment may be implemented in other embodiments. Only a limited number of example combinations are shown to indicate to one skilled in the art the possibility of features that may be combined in various embodiments to create enhanced transmission and reception systems and methods. In addition, it should be understood that any figures which highlight the functionality and advantages, are presented for example purposes only. The disclosed architecture is sufficiently flexible and configurable, such that it may be utilized in ways other than that shown. For example, the actions listed in any flowchart may be re-ordered or only optionally used in some embodiments. Further, the purpose of the Abstract of the Disclosure is to enable the U.S. Patent and Trademark Office and the public generally, and especially the scientists, engineers and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The Abstract of the Disclosure is not intended to be limiting as to the scope in any way. Finally, it is the applicant's intent that only claims that include the express language “means for” or “step for” be interpreted under 35 U.S.C. 112. Claims that do not expressly include the phrase “means for” or “step for” are not to be interpreted under 35 U.S.C. 112. | 92,517 |
RE49856 | DESCRIPTION In general, grooves of golf club heads and methods to manufacture grooves of golf club heads are described herein. Golf equipment related to the methods, apparatus, and/or articles of manufacture described herein may be conforming or non-conforming to the rules of golf at any particular time. Further, the figures provided herein are for illustrative purposes, and one or more of the figures may not be depicted to scale. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. In the examples ofFIG.1, a putter100is shown. Although grooves for a putter100are described herein, the apparatus, methods, and articles of manufacture described herein may be applicable other types of club head (e.g., a driver-type club head, a fairway wood-type club head, a hybrid-type club head, an iron-type club head, etc.). For example, grooves for iron-type club heads are described in detail in U.S. Patent Application Publication US 2010/0035702, filed Aug. 5, 2009, the entire disclosure of which is expressly incorporated by reference. Accordingly, any reference made herein to a putter may include any type of golf club. The putter100includes a putter head102having a putter face110. The putter face110may be generally planar. The putter face110includes a ball striking face112that may be generally on the same plane as the putter face110or slightly projected outward from the putter face110. The ball striking face112may be the same size or smaller (as shown inFIG.1) than the putter face110. The ball striking face112may be a region on the putter face110that is generally used to strike a golf ball (not shown). However, an individual may also strike a ball with a section of the putter face110that is outside the ball striking face112. The ball striking face112may be a continuous or integral part of the putter face110or formed as an insert that is attached to the putter face110. Such an insert may be constructed from the same material or different materials as the putter face110and then be attached to the putter face110. The ball striking face112may include one or more grooves, generally shown as grooves120, and one or more land portions170. For example, the ball striking face112is shown to have twelve grooves, generally shown as122,124,126,128,130,132,134,136,138,140,142, and144. The grooves120may be generally referred to with a single reference number such as120. However, when specifically describing one of the grooves on the ball striking face112, the reference number for that specific groove may be used. Two adjacent grooves may be separated by a land portion170. A land portion170between each groove120and an adjacent groove120may have the same or different width as a land portion170between another pair of adjacent grooves120. The land portions170may also define the top surface of the ball striking face112. In general, two or more of the grooves120may be parallel to each other. For example, the grooves122and124may be parallel to each other. However, the grooves120may be oriented relative to each other in any manner. For example, any of the grooves120may be diagonally, vertically and/or horizontally oriented. As shown in the example ofFIG.2, one or more of the grooves120may be substantially linear and generally parallel to an adjacent groove120and extend between a toe end180and a heel end190of the putter face110. As described in detail below, the depth, length, width, a horizontal cross-sectional shape, and/or a vertical cross-sectional shape of the grooves120may linearly, nonlinearly, in regular or irregular step-wise intervals, arcuately and/or according to one or more geometric shapes increase, decrease and/or vary from the toe end180to the heel end190and/or from a top rail182to a sole192of the putter head102. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. Referring toFIG.2, the ball striking face112is shown having grooves122-144. The ball striking face112may be an integral part of the putter face110such as to be co-manufactured with the putter face110. Alternatively, the ball striking face112may be an insert that is attached to the putter face110. Each of the grooves120may extend from the toe end180to the heel end190to define a corresponding length193(only the length193of groove144is shown inFIG.2). The lengths193of some or all of the grooves120may vary in a direction from the top rail182to the sole192so that each groove120may generally conform to the shape of the perimeter of the ball striking face112. For example, the length of the grooves may increase from near the top rail182to a center184of the ball striking face112and decrease from the center184to near the sole192. The center184may be a geometric center of the ball striking face112. Alternatively, the center184may represent an inertial or weight related center of the ball striking face112. However, the center184may be generally defined by a region of the ball striking face112that typically strikes the ball. As shown inFIG.1, the length193of the grooves120may be similar. In other examples, such as the example shown inFIG.2, the length193of the grooves may decrease from near the top rail182to the center184and decrease from near the sole192to the center184. Thus, any groove length arranged on the ball striking face112is within the scope of the disclosure. In another example shown inFIG.3, a ball striking face212may include grooves220(shown specifically as grooves222-244). The ball striking face212may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face212, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.4shows a schematic view of the groove232andFIG.5shows a horizontal cross section of the groove232taken at section line5-5ofFIG.3. The groove232is shown to be divided into horizontally spanning regions, generally shown as regions271-275, which are visually defined inFIGS.3and4by vertical boundary lines. The horizontal regions271-275may define variations in the horizontal cross-sectional profile of the groove232from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove may refer to any property of the groove along the length293of the groove, such as length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.3-7, the grooves220include a first vertical wall250and a second vertical wall252that define the length293of the grooves220. Each of the grooves220has a bottom surface254which defines a depth of the groove220. The depth of each groove may vary from the first wall250to the second wall252according to the cross-sectional profile of the groove220in the regions271-275. Each groove220also includes a first horizontal wall256and a second horizontal wall258that define the vertical boundaries of the groove220. The distance between the first horizontal wall256and the second horizontal wall258defines a width280of the groove220. The width280may vary from the first vertical wall250to the second vertical wall252as shown in the examples ofFIGS.38-45, where a groove may have a length590, a first width594, a second width595and/or a third width596. In the example ofFIGS.3-7, however, the first horizontal wall256and the second horizontal wall258are generally parallel to define a generally constant width280. Referring toFIG.5, the bottom surface254at the region271is downwardly sloped or curved to define a first depth282at the boundary between regions271and272. The bottom surface254in the region272transitions with a steeper downward curve from the first depth282to a second depth284at the boundary between regions272and273. If the bottom surface254is flat in the region273, the second depth284may generally define the greatest depth of the groove232. However, if the bottom surface254is not flat, the greatest depth of the groove232may be defined in another part of the region273. Any of the grooves220may be symmetric about the vertical axis y. Accordingly, the shape of the groove220on each side of the y axis may mirror the shape of the groove232on the other side of the y axis. However, any of the grooves220may be asymmetric. The regions271and275define shallow portions of the groove232and the region273defines the deeper center portion of the groove232. The deepest part of any of the grooves220may be at the center of the groove220. The regions272and274facilitate transition of the bottom surface254from the depth282to the depth284. Referring toFIGS.3and5, the general cross-sectional profile of each of the grooves220may remain generally similar from the top rail182to the sole190. However, the cross-sectional profile including lengths, widths and/or depths of the regions271-275of each of the grooves220may progressively vary from the top rail182to the sole192. InFIGS.6and7, the horizontal cross sections of the grooves238and244, respectively, are shown. For example, the regions271-275of the groove238are smaller in length than the regions271-275of the groove232, respectively. Similarly, the regions271-275of the groove244are smaller in length than the regions271-275of the groove238, respectively. In another example, the regions271-275of the groove238may have smaller depths than the regions271-275of the groove232, respectively. Similarly, the regions271-275of the groove244may have smaller depths than the regions271-275of the groove238, respectively. The progressive increase in the length, depth and/or width of the regions271-275of the grooves222-232from the top rail182to generally the center of the ball striking face212and/or the decrease in the size of the regions271-275of the grooves232-244from generally the center of the ball striking face212to the sole192forms a central strike zone260(shown inFIG.3), which may resemble the shape of a golf ball when viewed by an individual in an address position. The approximate visual representation of a golf ball can assist an individual with lining up the ball striking face212with the ball. The regions273, which define the deepest parts of the grooves220may be larger in length at the center of the ball striking face212and progressively reduce in length toward the top rail182and the sole192. Similarly, the transition regions272and274may have the greatest length at the center of the ball striking face212and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions271-275may vary depending on the location of the grooves220on the ball striking face212, the depth of similar regions for each groove220may be similar or different. For example, the greatest depth of the groove232may be similar to the greatest depth of the groove244. Alternatively, the depth of the grooves222-244may vary based on the location of the groove220relative to ball striking face212. Alternatively yet, the depths of the grooves222-244may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include more or less horizontal regions. In another example shown inFIG.8, a ball striking face312includes grooves320(shown specifically as grooves322-344). The ball striking face312may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face312, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.9shows a schematic view of the groove332andFIG.10shows a horizontal cross section of the groove332taken at section line10-10ofFIG.8. The groove332is shown to be divided into horizontally spanning regions371-375, which are visually defined inFIGS.8and9by vertical boundary lines. The horizontal regions371-375may define variations in the horizontal cross-sectional profile of the groove332from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove may refer to any property of the groove along the length393of the groove, such as length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.8-12, the grooves320include a first vertical wall350and a second vertical wall352that define the length393of the grooves320. Each of the grooves320has a bottom surface354which defines a depth of the groove320. The depth of each groove may vary from the first wall350to the second wall352according to the cross-sectional profile of the groove320in the regions371-375. Each groove320also includes a first horizontal wall356and a second horizontal wall358that define the vertical boundaries of the groove320. The distance between the first horizontal wall356and the second horizontal wall358defines a width380of the groove320. The width380may vary from the first vertical wall350to the second vertical wall352as shown in the examples ofFIGS.38-45. In the example ofFIGS.8-12, however, the first horizontal wall256and the second horizontal wall258are generally parallel to define a generally constant width380. Referring toFIG.10, the bottom surface354at the region371may be generally flat and/or slightly sloped to define a first depth382at the boundary between371and372. The bottom surface354in the region372transitions with a step downward from the first depth382to a second depth384at the boundary between the regions372and373. The bottom surface354in the region372may be generally flat and/or slightly sloped such that the groove320has a generally uniform depth384in the region372. The bottom surface354in the region372transitions with a step downward from the second depth384to a third depth386. The bottom surface354in the region373may be generally flat or slightly sloped such that the groove320has a generally uniform depth386in the region373. Any of the grooves320may be symmetric about the vertical axis y. Accordingly, the shape of the groove320on each side of the y axis mirrors the shape of the groove320on the other side of the y axis. However, any of the grooves320may be asymmetric. The depth386represents the greatest depth of the grooves320. Referring toFIGS.10-12, the general cross-sectional profile of the grooves320may remain generally similar from the top rail182to the sole190. However, the cross-sectional profile including the lengths, widths and/or the depths of the regions371-375of each of the grooves320may progressively vary from the top rail182to the sole192. InFIGS.11and12, the horizontal cross sections of the grooves338and344, respectively, are shown. For example, the regions371-375of the groove338are smaller in length than the regions371-375of the groove332, respectively. Similarly, the regions371-375of the groove344are smaller in length than the regions371-375of the groove338, respectively. In another example, the regions371-375of the groove338may have smaller depths than the regions371-375of the groove332, respectively. Similarly, the regions371-275of the groove344may have smaller depths than the regions371-375of the groove338, respectively. The progressive increase in the length, depth and/or width of the regions371-375of the grooves322-332from the top rail182to the center of the ball striking face312and/or the decrease in the size of the regions371-375of the grooves332-344form the center of the ball striking face312to the sole192forms a central strike zone360(shown inFIG.8), which may discretely resemble the shape of a golf ball when viewed by an individual in an address position. The approximate visual representation of a golf ball can assist an individual with lining up the ball striking face312with the ball. The regions373, which define the deepest parts of the grooves360may be larger in length at the center of the ball striking face312and progressively reduce in length toward the top rail182and the sole192. Similarly, the transition regions372and374may have the greatest length at the center of the ball striking face312and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions371-375vary depending on the location of the grooves320on the ball striking face312, the depth of similar regions for each groove320may be similar or different. For example, the greatest depth of the groove344may be similar to the greatest depth of the groove332. Alternatively, the depth of the grooves322-344may vary based on the location of grooves320on the ball striking face312. Alternatively yet, the depths of the grooves322-344may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include more or less horizontal regions. In another example shown inFIG.13, a ball striking face412includes grooves420(shown specifically as grooves422-444). The ball striking face412may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face412, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.14shows a schematic view of the groove432andFIG.15shows a horizontal cross section of the groove432taken at section line15-15ofFIG.13. The groove432is shown to be divided into horizontally spanning regions471and472, which are visually defined inFIGS.13and14by the boundary lines of the groove432and a vertical line at the center of the groove432. The horizontal regions471and472may define variations in the horizontal cross-sectional profiles of the groove432from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove refers to any property of the groove along the length493of the groove, such as length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.13-17, the grooves420include a first vertical wall450and a second vertical wall452that define the length493of the grooves420. Each of the grooves420has a bottom surface454which defines a depth of the groove420. The depth of each groove may vary from the first wall450to the second wall452according to the cross-sectional profile of the groove420in the regions471and472. Each groove420also includes a first horizontal wall456and a second horizontal wall458that define the vertical boundaries of the groove420. The distance between the first horizontal wall456and the second horizontal wall458defines a width480of the groove420. The width480may vary from the first vertical wall450to the second vertical wall452as shown in the examples ofFIGS.38-45. In the example ofFIGS.13-17, however, the first horizontal wall456and the second horizontal wall458are generally parallel to define a generally constant width480. Referring toFIG.15, the bottom surface454at the region471has a linear profile and is downwardly sloped. The grooves450are symmetric about the center vertical axis y. Accordingly, the bottom surface454at the region472has a similar linear profile and is similarly downwardly sloped as the bottom surface454at the region471. Accordingly, the depth of the grooves420gradually increase from a depth482at the first wall452and second wall454to a depth484at the center of the grooves420. The depth484represents the deepest part of the grooves420, which may be at the center of the groove420. Referring toFIGS.15-17, the general cross-sectional profile of the grooves420may remain generally similar from the top rail182to the sole190. However, the cross-sectional profile including the lengths and/or the depths of the regions471and472of each of the grooves420may progressively vary from the top rail182to the sole192. For example, the regions471and472of the groove438are smaller in length than the regions471and472of the groove332, respectively. Similarly, the regions471and471of the groove444are smaller in length than the regions471and472of the groove438, respectively. In another example, the regions471and472of the groove438may have smaller depths than the regions471and472of the groove432, respectively. Similarly, the regions471and472of the groove444may have smaller depths than the regions471and472of the groove438, respectively. The progressive increase in the length, depth and/or width of the regions471and472of the grooves422-432from the top rail182to the center of the ball striking face412and/or the decrease in the size of the regions471and472of the grooves432-444form the center of the ball striking face412to the sole192forms a central strike zone460(shown inFIG.13). The regions471and472may have the greatest length at the center of the ball striking face412and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions471and472vary depending on the location of the grooves420on the ball striking face412, the depth of similar regions for each groove420may be similar or different. For example, the greatest depth of the groove444may be similar to the greatest depth of the groove432. Alternatively, the depth of the grooves422-444may vary based on the location of grooves420on the ball striking face412. Alternatively yet, the depths of the grooves422-444may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include more or less horizontal regions. In another example shown inFIG.18, a ball striking face512includes grooves520(shown specifically as grooves522-544). The ball striking face512may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face512, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.19shows a schematic view of the groove532andFIG.20shows a horizontal cross section of the groove532taken at section line20-20ofFIG.18. The groove532is shown to be divided into horizontally spanning regions571and572, which are visually defined inFIGS.18and19by the boundary lines of the groove532and a vertical line at the center of the groove532. The horizontal regions571and572may define variations in the horizontal cross-sectional profiles of the groove532from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove refers to any property of the groove along the length593of the groove, such as a length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.18-22, the grooves520include a first vertical wall550and a second vertical wall552that define the length593of the grooves520. Each of the grooves520has a bottom surface554which defines a depth of the groove520. The depth of each groove may vary from the first wall550to the second wall552according to the cross-sectional profile of the groove520in the regions571and572. Each groove520also includes a first horizontal wall556and a second horizontal wall558that define the vertical boundaries of the groove520. The distance between the first horizontal wall556and the second horizontal wall558defines a width580of the groove520. The width580may vary from the first vertical wall550to the second vertical wall552as shown in the examples ofFIGS.38-45. In the example ofFIGS.18-22, however, the first horizontal wall556and the second horizontal wall558are generally parallel to define a generally constant width580. Referring toFIG.20, the bottom surface554at the region571has a linear profile and is downwardly sloped. The bottom surface554in the region572also has a linear profile and is downwardly sloped. However, because the second wall552is longer than the first wall550, the bottom surface554in the region572has a smaller slope than the bottom surface554in the region571. Accordingly, the grooves550of this example are asymmetric about the vertical center axis y. Thus, the grooves250have a first depth582defined by the first wall550, a second depth584defined by the second wall552and a center depth586, which is gradually reached from the depths582and584according to the downwardly sloped bottom surface554of the regions571and572, respectively. The center depth586may be the depth of the deepest part of the groove520. Referring toFIGS.20-22, the general cross-sectional profile of the grooves520may remain generally similar from the top rail182to the sole190. However, the cross sectional profile including the lengths, widths and/or the depths of the regions571and572of each of the grooves520may progressively vary from the top rail182to the sole192. InFIGS.21and22, the horizontal cross sections of the grooves538and544, respectively, are shown. For example, the regions571and572of the groove538are smaller in length than the regions571and572of the groove532, respectively. Similarly, the regions571and572of the groove544are smaller in length than the regions571and572of the groove538, respectively. In another example, the regions571and572of the groove538may have smaller depths than the regions571and572of the groove532, respectively. Similarly, the regions571and572of the groove544may have smaller depths than the regions571and572of the groove538, respectively. The progressive increase in the length, depth and/or width of the regions571and572of the grooves522-532from the top rail182to the center of the ball striking face512and/or the decrease in the size of the regions571and572of the grooves532-544form the center of the ball striking face512to the sole192forms a central strike zone560(shown inFIG.18). The regions571and572may have the greatest length at the center of the ball striking face512and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions571and572vary depending on the location of the grooves520on the ball striking face512, the depth of similar regions for each groove520may be similar or different. For example, the greatest depth of the groove544may be similar to the greatest depth of the groove532. Alternatively, the depth of the grooves522-544may vary based on the location of grooves520on the ball striking face512. Alternatively yet, the depths of the grooves522-544may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include more or less horizontal regions. The grooves220,320,420and520described above illustrate four examples of horizontal cross-sectional profile of grooves for use with the putter100. Other examples of horizontal cross sectional profiles are shown inFIGS.29-37, where each groove may have a length590, a first depth591, a second depth592and/or a third depth593. A groove may be defined by any number of horizontal regions, where any one or more regions have similar properties or dissimilar properties. A groove that may be symmetric or asymmetric about the y axis, for example, may have a bottom surface with a complex combination of linear and nonlinear shapes defining similar or various depths from the toe end180to the heel end190. Such a groove may be described with a large number of horizontal regions, where each region defines one or more of the noted complex shapes. Accordingly, the number, arrangement, sizes and the other properties of the horizontal ranges described above are in no way limiting to the groove cross-sectional profiles according to the disclosure. In the above examples, the grooves on each corresponding ball striking face have similar shapes. However, the grooves on ball striking face may have dissimilar shapes. For example, a ball striking face may include a combination of grooves220and320. In another example, the ball striking face may include a combination of grooves420and520. Thus, any combination of groove cross-sectional profiles may be used on a ball striking face to impart a particular ball striking property to the putter. The horizontal cross-sectional profiles of the grooves may progressively and proportionally vary from the top rail182to the center of the ball striking face and may progressively vary from the center of the ball striking face to the sole192. The noted progressive variation may define a ball strike zone that is larger at the center of the ball striking face than near the top rail182and the sole192. Furthermore, the progressive noted variation of the grooves' horizontal cross-sectional profiles provides grooves at the center of the ball striking face and around the center of the ball striking face that have longer deep groove sections than grooves near the top rail182and the sole192. However, the above-described progressive variation of the grooves is exemplary and other progressive variation schemes may be used to impart particular ball striking properties to various portions of the ball striking face. Referring toFIG.23, a ball striking face612according to another example is shown having grooves620.FIGS.24-26show a vertical cross-sectional shape of the grooves620as viewed from section line24-24ofFIG.23. InFIG.24, the vertical cross-sectional shape of the groove620is box-shaped, rectangular or square. InFIG.25, the vertical cross-sectional shape of the groove620is V-shaped. InFIG.26, the vertical cross-sectional shape of the groove620is U-shaped. The vertical cross-sectional groove shapes ofFIGS.24-26are applicable to any groove according to the disclosure. For example, the vertical cross-sectional shape of the grooves220may be rectangular or square according to the grooves620ofFIG.24. In another example, the vertical cross-sectional shape of the grooves620may be V-shaped according to the groove620ofFIG.25. Furthermore, the vertical cross-sectional shape of a groove may vary from the toe end180to the heel end190. For example, with reference toFIGS.4and5, a groove220may be have a square or rectangular vertical cross-sectional shape in regions271and275, U-shaped vertical cross-sectional shape in regions271and274, and V-shaped vertical cross-sectional shape in region273. Additionally, the vertical cross-sectional shapes of the grooves may also vary from the top rail182to the sole190. For example, grooves near the top rail182and the sole192may have a square vertical cross-sectional shape, while the grooves at the center of the club face may have a U-shaped vertical cross-sectional shape. The ball striking face of the putter in the above examples is shown to have grooves from the top rail182to the sole192. However, a ball striking face may have more or less grooves, or have sections that are without grooves. For example, a ball striking face may have several grooves at the center section of the ball strike face and be without grooves at sections near the top rail182or the sole192. The grooves are not limited to extending horizontally across the ball striking face. The ball striking face may have vertical grooves that vary in depth as described above or a combination of vertical and horizontal grooves with varying horizontal and/or vertical cross-sectional profiles. The orientation of the grooves may be such that a matrix-like ball striking face is provided on the putter. Referring toFIG.27, a ball striking face712having grooves720may be horizontally separated into three portions, which are the toe portion780, a center portion785and a heel portion790. The ball striking face712may be similar to the ball striking face212and312described above. Accordingly the grooves720have regions271-275and371-375similar to grooves220and320, respectively, described above. The three portions described above horizontally separate the ball striking face712and span vertically from the top rail182to the sole192. The toe portion780is near the toe end180, the heel portion790is near the heel end190, and the center portion785is between the toe portion780and the heel portion790. According to various examples, the depth of the grooves720at the toe portion780and the heel portion790may not be greater than the depth of the grooves720at the center portion785. In one example, the shallowest depth of the grooves720, which may be nearest to the toe end180or nearest to the heel end190may be approximately 0.003 inch. At or near the center portion785, the depth of the grooves720may increase as described above to a depth of approximately 0.017 inch. The variable depth may include a portion with a depth of at least 0.020 inches but less than 0.022 inches. The variable width may include a portion with a width of at least 0.035 inches but less than 0.037 inches. Referring toFIG.28, the ball striking face712may be vertically separated into three portions, which are the top rail portion782, the mid portion786and the sole portion792. These portions vertically separate the ball striking face712and span horizontally from the toe end180to the heel end190. The top rail portion782is near the top rail182, the sole portion792is near the sole192, and the mid portion786is between the top rail portion782and the sole portion792. The length of the deepest portion of a groove720may vary from the top rail portion782to the mid portion786and from the mid portion786to the sole portion792. For example, with respect to the examples described above, the length of the deepest portion of a groove may refer to the groove720that is proximately centrally located between the top rail portion782and the sole portion792. As shown inFIGS.27and28, the length of the grooves710may be greatest at the mid portion786and gradually reduce toward the top rail portion782and toward the sole portion792. FIGS.29-37show examples of different groove horizontal cross-sectional profiles according to the disclosure. In the above examples, the width of the grooves220,320,420and520is shown to have a rectangular profile. However, a groove according to the disclosure may have different width profiles as shown by the examples ofFIGS.38-45. Accordingly, a groove according to the disclosure may have any horizontal cross-sectional profile, vertical cross-sectional profile, width profile and/or depth profile. A cross-sectional profile of a groove including variations in lengths, depth, width and/or cross-sectional shape of the groove may affect ball speed, control, and/or spin. The disclosed variable depth grooves may improve the consistency of the ball speed after being struck by the putter face by about 50% over a plastic putter face insert, and by about 40% over a non-grooved aluminum putter face insert. Striking a ball with a putter having grooves according to the disclosure: (1) may result in lower ball speeds, which may result in decreased ball roll out distance; (2) may result in heel and toe shots to have decreased ball speeds compared to center hits, and also may result in shorter ball roll out distance; (3) allow relatively lower and higher handicap players to strike the ball with different locations on the putter face (higher handicap players tend to hit lower on the ball striking face whereas lower handicap player tend to hit higher on the ball striking face. Also, relatively higher handicap players may have a wider range of hit locations whereas relatively lower handicap players may have a closer range of hit locations; and/or (4) a putter face with grooves in the center of the face may result in reduced ball speed/roll out distance for center shots, which may result in a more consistent ball speed/roll out distances for center/heel/toe shots. Referring toFIG.46, another example of a putter face810having grooves of variable cross-sectional profiles is shown. The putter face810is shown to have fourteen grooves, which are grouped into grooves822-828near the toe end180, grooves830-840at the center of the putter face810, and grooves842-848near the heel end190. In this example, the more prominent grooves are located at the center of the putter face810, and less prominent grooves are on the periphery of the center. A more prominent groove may refer to a groove that has a greater depth and/or width as compared to a less prominent groove. As shown inFIG.46, the grooves832-838may be more prominent that the remaining grooves on the putter face810. Furthermore, portions of the putter face810may be without grooves. These portions are referred to with reference number850. Referring toFIG.47, another example of a putter face910having grooves of variable cross-sectional profile is shown. The putter face910is shown to have ten grooves922-940. The length of each groove progressively increases from the top rail182to the sole190. Each of the grooves922-940or groups of the grooves922-940may have different vertical cross-sectional shapes. For example, grooves922-930are shown to have box-shaped vertical cross sections, while grooves932-940are shown to have V-shaped vertical cross sections. Referring toFIG.48, a horizontal cross section of a groove922according to another embodiment is shown. A bottom surface954of the groove922is shown to gradually recede from the edges950and952of the groove to a greatest depth951of the groove922. Any of the grooves according to the disclosure may have the same horizontal cross-sectional shape as the groove922. Any of the grooves according to the disclosure may have the same depth951. However, the depth951may be proportionally reduced as the length of the groove is reduced. In another example shown inFIG.49, a ball striking face1012may include grooves1220(shown specifically as grooves1222-1256). The ball striking face1012may be for use with the putter100. Accordingly, parts of the putter100and the putter head102are referred to with the same reference numbers presented above. The grooves may have any cross sectional shape, length and width according to the disclosure. Referring toFIG.49, a side cross-sectional view of a ball striking face1012having grooves1220according to another example is shown. The ball striking face1012may be separated into two portions with respect to the grooves1220. The ball striking face1012may include a top rail portion1282and the sole portion1286. The top rail portion1282and the sole portion1286may vertically separate the ball striking face1012and span horizontally from the toe end180to the heel end190. The top rail portion1282may extend generally from a center portion of the ball striking face1012, which is represented by the center line1284, to near the top rail182and include the grooves1222. The sole portion1286may extend generally from near the sole192to the center portion1284and include the grooves1224. The grooves1224of the sole portion1286may have a greater depth at one or more locations along each groove1224than the grooves1222of the top rail portion1282. By having shallower grooves1222at the top rail portion1282, the speed by which a golf ball rolls forward after being struck by the putter may increase so as to provide a more consistent and smooth ball roll out. Alternatively, the depth of the grooves1220may progressively reduce in one or more groove steps from the center portion1284to the top rail182(not shown). In another example, the depth of pairs of grooves may progressively reduce from the center portion1284to the top rail182(not shown). Accordingly, the reduction in groove depth from the sole192to the top rail182may be for each groove, for pairs of grooves or for various groupings of the grooves. Referring toFIG.50, the grooves1224of the sole portion1286may have a smaller depth at one or more locations along each groove1224than the grooves1222of the top rail portion1282. Alternatively, the depth of the grooves1220may progressively increase in one or more groove steps from the center portion1284and/or the sole192to the top rail182(not shown). In another example, the depth of pairs of grooves may progressively increase from the center portion1284and/or the sole192to the top rail182(not shown). Accordingly, the increase in groove depth from the center portion1284and/or the sole192to the top rail182may be for each groove, for pairs of grooves or for various groupings of the grooves. FIGS.51and52show other examples according to the disclosure. Referring toFIG.51, a putter head1300includes a ball striking face1312, which has a plurality of horizontal grooves1320and vertical grooves1322. Each of the grooves1320and1322may have a different configuration as compared to another groove, such as variable cross-sectional profiles, depth profiles, width profiles, length profiles and/or other groove characteristics from the toe end1380to near the heel end1390and/or from a top rail1382to a sole1392. For example, the depth of the horizontal grooves1320may progressively increase in one or more groove steps from the top rail1382to the sole1386. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. Referring toFIG.52, a putter head1400includes a ball striking face1412, which has a plurality of first diagonal grooves1420and second diagonal grooves1422. The first diagonal grooves1420may be generally parallel to each other. Similarly, the second diagonal grooves1422may be generally parallel to each other. The first diagonal grooves1420and the second diagonal grooves1422may be transverse to each other as shown inFIG.52. For example, the first diagonal grooves1420may intersect the second diagonal grooves1422at an angle of 30°, 45°, 60° or 90°. Each of the grooves1420and1422may have a different configuration as compared to another groove, such as variable cross-sectional profiles, depth profiles, width profiles, length profiles and/or other groove characteristics from the toe end1480to near the heel end1490and/or from a top rail1482to a sole1492. For example, the depth of the first diagonal grooves1420may progressively increase in one or more groove steps from the top rail1482to the sole1486. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. Referring toFIG.52, a process2000of manufacturing a golf club head according to one example is shown. The process2000includes forming a golf club face (block2002) defined by a toe end, a heel end, a top rail and a sole. A golf club face may be formed with a golf club head so that the golf club head and the golf club face are a one-piece continuous part. Alternatively, the golf club head and the golf club face may be formed separately. The golf club face may then be attached to the golf club face by using adhesive, tape, welding, soldering, fasteners and/or other suitable methods and devices. The golf club head and/or the golf club face may be manufactured from any material. For example, the golf club head and/or the golf club face may be made from titanium, titanium alloy, other titanium-based materials, steel, aluminum, aluminum alloy, other metals, metal alloys, plastic, wood, composite materials, or other suitable types of materials. The golf club head and/or the golf club face may be formed using various processes such as stamping (i.e., punching using a machine press or a stamping press, blanking, embossing, bending, flanging, or coining, casting), injection molding, forging, machining or a combination thereof, other processes used for manufacturing metal, plastic and/or composite parts, and/or other suitable processes. In one example, when manufacturing a putter head, the material of the putter face and/or the ball striking face may be determined so as to impart a certain ball strike and rolling characteristics to the putter face. In another example, when the ball striking face212is separate from the putter face110and is inserted and attached into a correspondingly shaped depression on the putter face110, the striking face212may be constructed from a lighter material than the putter face110to generally reduce the overall weight of the putter. According to the process2000, grooves are formed on the club face and/or club head between the top rail and the sole such that each groove extends between the toe end and the heel end and depths of the grooves vary in a direction extending between the top rail and the sole and in a direction extending between the heel end and the toe end (block2004). The grooves may be formed using various processes such as casting, forging, machining, spin milled, and/or other suitable processes. The vertical cross-sectional shape of a groove may depend on the method by which a groove is manufactured. For example, the type of cutting bit when machining a groove may determine the vertical cross-sectional shape of the groove. The vertical cross sectional shape of a groove may be symmetric, such as the examples described above, or may be asymmetric (not shown). In one example, the width of a groove can be 0.032 inch, which may be the width of the cutting bit. Accordingly, when machining a groove, the shape and dimensions of the cutting bit may determine the shape and dimension of the groove. The grooves may be manufactured by spin milling the ball strike face, or stamping or forging the grooves into the ball striking face. The grooves may also be manufactured direction on the putter head to create a ball striking face as described above directly on the putter head. A groove may be manufactured by press forming the groove on the putter head. For example, a press can deform and/or displace material on the putter head to create the groove. A groove may be manufacturing by a milling process where the rotating axis of the milling tool is normal to putter face. The rotating axis of the milling tool may be oriented at an angle other than normal to the putter face. A groove may be manufactured by overlaying one material that is cut clean through to form a through groove onto a base or solid material. A groove may be manufactured by laser and/or thermal etching or eroding of the putter face material. A groove may be manufactured by chemically eroding the putter face material using photo masks. A groove may be manufactured by electro/chemically eroding the putter face material using a chemical mask such as wax or a petrochemical substance. A groove may be manufactured by abrading the face material using air or water as the carry medium of the abrasion material such as sand. Any one or a combination of the methods discussed above can be used to manufacture one or more of the grooves on the putter head. Furthermore, other methods used to create depressions in any material may be used to manufacture the grooves. As the rules to golf may change from time to time (e.g., new regulations may be adopted or old rules may be eliminated or modified by golf standard organizations and/or governing bodies), golf equipment related to the methods, apparatus, and/or articles of manufacture described herein may be conforming or non-conforming to the rules of golf at any particular time. Accordingly, golf equipment related to the methods, apparatus, and/or articles of manufacture described herein may be advertised, offered for sale, and/or sold as conforming or non-conforming golf equipment. The methods, apparatus, and/or articles of manufacture described herein are not limited in this regard. Although a particular order of actions is described above, these actions may be performed in other temporal sequences. For example, two or more actions described above may be performed sequentially, concurrently, or simultaneously. Alternatively, two or more actions may be performed in reversed order. Further, one or more actions described above may not be performed at all. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. While the invention has been described in connection with various aspects, it will be understood that the invention is capable of further modifications. This application is intended to cover any variations, uses or adaptation of the invention following, in general, the principles of the invention, and including such departures from the present disclosure as come within the known and customary practice within the art to which the invention pertains. | 48,714 |
RE49857 | DESCRIPTION In general, grooves of golf club heads and methods to manufacture grooves of golf club heads are described herein. Golf equipment related to the methods, apparatus, and/or articles of manufacture described herein may be conforming or non-conforming to the rules of golf at any particular time. Further, the figures provided herein are for illustrative purposes, and one or more of the figures may not be depicted to scale. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. In the examples ofFIG.1, a putter100is shown. Although grooves for a putter100are described herein, the apparatus, methods, and articles of manufacture described herein may be applicable other types of club head (e.g., a driver-type club head, a fairway wood-type club head, a hybrid-type club head, an iron-type club head, etc.). For example, grooves for iron-type club heads are described in detail in U.S. Patent Application Publication U.S. 2010/0035702, filed Aug. 5, 2009, the entire disclosure of which is expressly incorporated by reference. Accordingly, any reference made herein to a putter may include any type of golf club. The putter100includes a putter head102having a putter face110. The putter face110may be generally planar. The putter face110includes a ball striking face112that may be generally on the same plane as the putter face110or slightly projected outward from the putter face110. The ball striking face112may be the same size or smaller (as shown inFIG.1) than the putter face110. The ball striking face112may be a region on the putter face110that is generally used to strike a golf ball (not shown). However, an individual may also strike a ball with a section of the putter face110that is outside the ball striking face112. The ball striking face112may be a continuous or integral part of the putter face110or formed as an insert that is attached to the putter face110. Such an insert may be constructed from the same material or different materials as the putter face110and then be attached to the putter face110. The ball striking face112may include one or more grooves, generally shown as grooves120, and one or more land portions170. For example, the ball striking face112is shown to have twelve grooves, generally shown as122,124,126,128,130,132,134,136,138,140,142, and144. The grooves120may be generally referred to with a single reference number such as120. However, when specifically describing one of the grooves on the ball striking face112, the reference number for that specific groove may be used. Two adjacent grooves may be separated by a land portion170. A land portion170between each groove120and an adjacent groove120may have the same or different width as a land portion170between another pair of adjacent grooves120. The land portions170may also define the top surface of the ball striking face112. In general, two or more of the grooves120may be parallel to each other. For example, the grooves122and124may be parallel to each other. However, the grooves120may be oriented relative to each other in any manner. For example, any of the grooves120may be diagonally, vertically and/or horizontally oriented. As shown in the example ofFIG.2, one or more of the grooves120may be substantially linear and generally parallel to an adjacent groove120and extend between a toe end180and a heel end190of the putter face110. As described in detail below, the depth, length, width, a horizontal cross-sectional shape, and/or a vertical cross-sectional shape of the grooves120may linearly, nonlinearly, in regular or irregular step-wise intervals, arcuately and/or according to one or more geometric shapes increase, decrease and/or vary from the toe end180to the heel end190and/or from a top rail182to a sole192of the putter head102. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. Referring toFIG.2, the ball striking face112is shown having grooves122-144. The ball striking face112may be an integral part of the putter face110such as to be co-manufactured with the putter face110. Alternatively, the ball striking face112may be an insert that is attached to the putter face110. Each of the grooves120may extend from the toe end180to the heel end190to define a corresponding length193(only the length193of groove144is shown inFIG.2). The lengths193of some or all of the grooves120may vary in a direction from the top rail182to the sole192so that each groove120may generally conform to the shape of the perimeter of the ball striking face112. For example, the length of the grooves may increase from near the top rail182to a center184of the ball striking face112and decrease from the center184to near the sole192. The center184may be a geometric center of the ball striking face112. Alternatively, the center184may represent an inertial or weight related center of the ball striking face112. However, the center184may be generally defined, by a region of the ball striking face112that typically strikes the ball. As shown inFIG.1, the length193of the grooves120may be similar. In other examples, such as the example shown inFIG.2, the length193of the grooves may decrease from near the top rail182to the center184and decrease from near the sole192to the center184. Thus, any groove length arranged on the ball striking face112is within the scope of the disclosure. In another example shown inFIG.3, a ball striking face212may include grooves220(shown specifically as grooves222-244). The ball striking face212may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face212, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.4shows a schematic view of the groove232andFIG.5shows a horizontal cross section of the groove232taken at section line5-5ofFIG.3. The groove232is shown to be divided into horizontally spanning regions, generally shown as regions271-275, which are visually defined inFIGS.3and4by vertical boundary lines. The horizontal regions271-275may define variations in the horizontal cross-sectional profile of the groove232from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove may refer to any property of the groove along the length293of the groove, such as length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.3-7, the grooves220include a first vertical wall250and a second vertical wall252that define the length293of the grooves220. Each of the grooves220has a bottom surface254which defines a depth of the groove220. The depth of each groove may vary from the first wall250to the second wall252according to the cross-sectional profile of the groove220in the regions271-275. Each groove220also includes a first horizontal wall256and a second horizontal wall258that define the vertical boundaries of the groove220. The distance between the first horizontal wall256and the second horizontal wall258defines a width280of the groove220. The width280may vary from the first vertical wall250to the second vertical wall252as shown in the examples ofFIGS.38-45, where a groove may have a length590, a first width594, a second width595and/or a third width596. In the example ofFIGS.3-7, however, the first horizontal wall256and the second horizontal wall258are generally parallel to define a generally constant width280. Referring toFIG.5, the bottom surface254at the region271is downwardly sloped or curved to define a first depth282at the boundary between regions271and272. The bottom surface254in the region272transitions with a steeper downward curve from the first depth282to a second depth284at the boundary between regions272and273. If the bottom surface254is flat in the region273, the second depth284may generally define the greatest depth of the groove232. However, if the bottom surface254is not flat, the greatest depth of the groove232may be defined in another part of the region273. Any of the grooves220may be symmetric about the vertical axis y. Accordingly, the shape of the groove220on each side of the y axis may mirror the shape of the groove232on the other side of the y axis. However, any of the grooves220may be asymmetric. The regions271and275define shallow portions of the groove232and the region273defines the deeper center portion of the groove232. The deepest part of any of the grooves220may be at the center of the groove220. The regions272and274facilitate transition of the bottom surface254from the depth282to the depth284. Referring toFIGS.3and5, the general cross-sectional profile of each of the grooves220may remain generally similar from the top rail182to the sole190. However, the cross-sectional profile including lengths, widths and/or depths of the regions271-275of each of the grooves220may progressively vary from the top rail182to the sole192. InFIGS.6and7, the horizontal cross sections of the grooves238and244, respectively, are shown. For example, the regions271-275of the groove238are smaller in length than the regions271-275of the groove232, respectively. Similarly, the regions271-275of the groove244are smaller in length than the regions271-275of the groove238, respectively. In another example, the regions271-275of the groove238may have smaller depths than the regions271-275of the groove232, respectively. Similarly, the regions271-275of the groove244may have smaller depths than the regions271-275of the groove238, respectively. The progressive increase in the length, depth and/or width of the regions271-275of the grooves222-232from the top rail182to generally the center of the ball striking face212and/or the decrease in the size of the regions271-275of the grooves232-244from generally the center of the ball striking face212to the sole192forms a central strike zone260(shown inFIG.3), which may resemble the shape of a golf ball when viewed by an individual in an address position. The approximate visual representation of a golf ball can assist an individual with lining up the ball striking face212with the ball. The regions273, which define the deepest parts of the grooves220may be larger in length at the center of the ball striking face212and progressively reduce in length toward the top rail182and the sole192. Similarly, the transition regions272and274may have the greatest length at the center of the ball striking face212and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions271-275may vary depending on the location of the grooves220on the ball striking face212, the depth of similar regions for each groove220may be similar or different. For example, the greatest depth of the groove232may be similar to the greatest depth of the groove244. Alternatively, the depth of the grooves222-244may vary based on the location of the groove220relative to ball striking face212. Alternatively yet, the depths of the grooves222-244may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include more or less horizontal regions. In another example shown inFIG.8, a ball striking face312includes grooves320(shown specifically as grooves322-344). The ball striking face312may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face312, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.9shows a schematic view of the groove332andFIG.10shows a horizontal cross section of the groove332taken at section line10-10ofFIG.8. The groove332is shown to be divided into horizontally spanning regions371-375, which are visually defined inFIGS.8and9by vertical boundary lines. The horizontal regions371-375may define variations in the horizontal cross-sectional profile of the groove332from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove may refer to any property of the groove along the length393of the groove, such as length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.8-12, the grooves320include a first vertical wall350and a second vertical wall352that define the length393of the grooves320. Each of the grooves320has a bottom surface354which defines a depth of the groove320. The depth of each groove may vary from the first wall350to the second wall352according to the cross-sectional, profile of the groove320in the regions371-375. Each groove320also includes a first horizontal wall356and a second horizontal wall358that define the vertical boundaries of the groove320. The distance between the first horizontal wall356and the second horizontal wall358defines a width380of the groove320. The width380may vary from the first vertical wall350to the second vertical wall352as shown in the examples ofFIGS.38-45. In the example ofFIGS.8-12, however, the first horizontal wall256and the second horizontal wall258are generally parallel to define a generally constant width380. Referring toFIG.10, the bottom surface354at the region371may be generally flat and/or slightly sloped to define a first depth382at the boundary between371and372. The bottom surface354in the region372transitions with a step downward from the first depth382to a second depth384at the boundary between the regions372and373. The bottom surface354in the region312may be generally flat and/or slightly sloped such that the groove320has a generally uniform depth384in the region372. The bottom surface354in the region372transitions with a step downward from the second depth384to a third depth386. The bottom surface354in the region373may be generally flat or slightly sloped such that the groove320has a generally uniform depth386in the region373. Any of the grooves320may be symmetric about the vertical axis y. Accordingly, the shape of the groove320on each side of the y axis mirrors the shape of the groove320on the other side of the y axis. However, any of the grooves320may be asymmetric. The depth386represents the greatest depth of the grooves320. Referring toFIGS.10-12, the general cross-sectional profile of the grooves320may remain generally similar from the top rail182to the sole190. However, the cross-sectional profile including the lengths, widths and/or the depths of the regions371-375of each of the grooves320may progressively vary from the top rail182to the sole192. InFIGS.11and12, the horizontal cross sections of the grooves338and344, respectively, are shown. For example, the regions371-375of the groove338are smaller in length than the regions371-375of the groove332, respectively. Similarly, the regions371-375of the groove344are smaller in length than the regions371-375of the groove338, respectively. In another example, the regions371-375of the groove338may have smaller depths than the regions371-375of the groove332, respectively. Similarly, the region371-275of the groove344may have smaller depths than the regions371-375of the groove338, respectively. The progressive increase in the length, depth and/or width of the regions371-375of the grooves322-332from the top rail182to the center of the ball striking face312and/or the decrease in the size of the regions371-375of the grooves332-344form the center of the ball striking face312to the sole192forms a central strike zone360(shown inFIG.8), which may discretely resemble the shape of a golf ball when viewed by an individual in an address position. The approximate visual representation of a golf ball can assist an individual with lining up the ball striking face312with the ball. The regions373, which define the deepest parts of the grooves360may be larger in length at the center of the ball striking face312and progressively reduce in length toward the top rail182and the sole192. Similarly, the transition regions372and374may have the greatest length at the center of the ball striking face312and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions371-375vary depending on the location of the grooves320on the ball striking face312, the depth of similar regions for each groove320may be similar or different. For example, the greatest depth of the groove344may be similar to the greatest depth of the groove332. Alternatively, the depth of the grooves322-344may vary based on the location of grooves320on the ball striking face312. Alternatively yet, the depths of the grooves322-344may vary in any manner from the top rail182to the sole. Although the above, examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described, herein may include more or less horizontal regions. In another example shown inFIG.13, a ball striking face412includes grooves420(shown specifically as grooves422-444). The ball striking face412may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face412, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.14shows a schematic view of the groove432andFIG.15shows a horizontal cross section of the groove432taken at section line15-15ofFIG.13. The groove432is shown to be divided into horizontally spanning regions471and472, which are visually defined inFIGS.13and14by the boundary lines of the groove432and a vertical line at the center of the groove432. The horizontal regions471and472may define variations in the horizontal cross-sectional profiles of the groove432from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove refers to any property of the groove along the length493of the groove, such as length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.13-17, the grooves420include a first vertical wall450and a second vertical wall452that define the length493of the grooves420. Each of the grooves420has a bottom surface454which defines a depth of the groove420. The depth of each groove may vary from the first wall450to the second wall452according to the cross-sectional profile of the groove420in the regions471and472. Each groove420also includes a first horizontal wall456and a second horizontal wall458that define the vertical boundaries of the groove420. The distance between the first horizontal wall456and the second horizontal wall458defines a width480of the groove420. The width480may vary from the first vertical wall450to the second vertical wall452as shown in the examples ofFIGS.38-45. In the example ofFIGS.13-17, however, the first horizontal wall456and the second horizontal wall458are generally parallel to define a generally constant width480. Referring toFIG.15, the bottom surface454at the region471has a linear profile and is downwardly sloped. The grooves450are symmetric about the center vertical axis y. Accordingly, the bottom surface454at the region472has a similar linear profile and is similarly downwardly sloped as the bottom surface454at the region471. Accordingly, the depth of the grooves420gradually increase from a depth482at the first wall452and second wall454to a depth484at the center of the grooves420. The depth484represents the deepest part of the grooves420, which may be at the center of the groove420. Referring toFIGS.15-17, the general cross-sectional profile of the grooves420may remain generally similar from the top rail182to the sole190. However, the cross-sectional profile including the lengths and/or the depths of the regions471and472of each of the grooves420may progressively vary from the top rail182to the sole192. For example, the regions471and472of the groove438are smaller in length than the regions471and472of the groove332, respectively. Similarly, the regions471and471of the groove444are smaller in length than the regions471and472of the groove438, respectively. In another example, the regions471and472of the groove438may have smaller depths than the regions471and472of the groove432, respectively. Similarly, the regions471and472of the groove444may have smaller depths than the regions471and472of the groove438, respectively. The progressive increase in the length, depth and/or width of the regions471and472of the grooves422-432from the top rail182to the center of the ball striking face412and/or the decrease in the size of the regions471and472of the grooves432-444form the center of the ball striking face412to the sole192forms a central strike zone460(shown inFIG.13). The regions471and472may have the greatest length at the center of the ball striking face412and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions471and472vary depending on the location of the grooves420on the ball striking face412, the depth of similar regions for each groove420may be similar or different. For example, the greatest depth of the groove444may be similar to the greatest depth of the groove432. Alternatively, the depth of the grooves422-444may vary based on the location of grooves420on the ball striking face412. Alternatively yet, the depths of the grooves422-444may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include, more or less horizontal regions. In another example shown inFIG.18, a ball striking face512includes grooves520(shown specifically as grooves522-544). The ball striking face512may be an integral part of the putter face110or a separate piece that is attached to the putter face110. Accordingly, when describing the ball striking face512, parts of the putter100and the putter head102are referred to with the same reference numbers described above. FIG.19shows a schematic view of the groove532andFIG.20shows a horizontal cross section of the groove532taken at section line20-20ofFIG.18. The groove532is shown to be divided into horizontally spanning regions571and572, which are visually defined inFIGS.18and19by the boundary lines of the groove532and a vertical line at the center of the groove532. The horizontal regions571and572may define variations in the horizontal cross-sectional profiles of the groove532from near the toe end180to near the heel end190and/or from near the top rail182to near the sole192. Horizontal cross-sectional profile of a groove refers to any property of the groove along the length593of the groove, such as a length of a certain section of the groove, depth, width, cross-sectional shape, and/or construction materials. In the example ofFIGS.18-22, the grooves520include a first vertical wall550and a second vertical wall552that define the length593of the grooves520. Each of the grooves520has a bottom surface554which defines a depth of the groove520. The depth of each groove may vary from the first wall550to the second wall552according to the cross-sectional profile of the groove520in the regions571and572. Each groove520also includes a first horizontal wall556and a second horizontal wall558that define the vertical boundaries of the groove520. The distance between the first horizontal wall556and the second horizontal wall558defines a width580of the groove520. The width580may vary from the first vertical wall550to the second vertical wall552as shown in the examples ofFIGS.38-45. In the example ofFIGS.18-22, however, the first horizontal wall556and the second horizontal wall558are generally parallel to define a generally constant width580. Referring toFIG.20, the bottom surface554at the region571has a linear profile and is downwardly sloped. The bottom surface554in the region572also has a linear profile and is downwardly sloped. However, because the second wall552is longer than the first wall550, the bottom surface554in the region572has a smaller slope than the bottom surface554in the region571. Accordingly, the grooves550of this example are asymmetric about the vertical center axis y. Thus, the grooves250have a first depth582defined by the first wall550, a second depth584defined by the second wall552and a center depth586, which is gradually reached from the depths582and584according to the downwardly sloped bottom surface554of the regions571and572, respectively. The center depth586may be the depth of the deepest part of the groove520. Referring toFIGS.20-22, the general cross-sectional profile of the grooves520may remain generally similar from the top rail182to the sole190. However, the cross sectional profile including the lengths, widths and/or the depths of the regions571and572of each of the grooves520may progressively vary from the top rail182to the sole192. InFIGS.21and22, the horizontal cross sections of the grooves538and544, respectively, are shown. For example, the regions571and572of the groove538are smaller in length than the regions571and572of the groove532, respectively. Similarly, the regions571and572of the groove544are smaller in length than the regions571and572of the groove538, respectively. In another example, the regions571and572of the groove538may have smaller depths than the regions571and572of the groove532, respectively. Similarly, the regions571and572of the groove544may have smaller depths than the regions571and572of the groove538, respectively. The progressive increase in the length, depth and/or width of the regions571and572of the grooves522-532from the top rail182to the center of the ball striking face512and/or the decrease in the size of the regions571and572of the grooves532-544form the center of the ball striking face512to the sole192forms a central strike zone560(shown inFIG.18). The regions571and572may have the greatest length at the center of the ball striking face512and progressively reduce in length toward the top rail182and the sole192. Although the lengths of the regions571and572vary depending on the location of the grooves520on the ball striking face512, the depth of similar regions for each groove520may be similar or different. For example, the greatest depth of the groove544may be similar to the greatest depth of the groove532. Alternatively, the depth of the grooves522-544may vary based on the location of grooves520on the ball striking face512. Alternatively yet, the depths of the grooves522-544may vary in any manner from the top rail182to the sole. Although the above examples may describe a particular number of horizontal regions, the apparatus, methods, and articles of manufacture described herein may include more or less horizontal regions. The grooves220,320,420and520described above illustrate four examples of horizontal cross-sectional profile of grooves for use with the putter100. Other examples of horizontal cross sectional profiles are shown inFIGS.29-37, where each groove may have a length590, a first depth591, a second depth592and/or a third depth593. A groove may be defined by any number of horizontal regions, where any one or more regions have similar properties or dissimilar properties. A groove that may be symmetric or asymmetric about the y axis, for example, may have a bottom surface with a complex combination of linear and nonlinear shapes defining similar or various depths from the toe end180to the heel end190. Such a groove may be described with a large number of horizontal regions, where each region defines one or more of the noted complex shapes. Accordingly, the number, arrangement, sizes and the other properties of the horizontal ranges described above are in no way limiting to the groove cross-sectional profiles according to the disclosure. In the above examples, the grooves on each corresponding ball striking face have similar shapes. However, the grooves on ball striking face may have dissimilar shapes. For example, a ball striking face may include a combination of grooves220and320. In another example, the ball striking face may include a combination of grooves420and520. Thus, any combination of groove cross-sectional profiles may be used on a ball striking face to impart a particular ball striking property to the putter. The horizontal cross-sectional profiles, of the grooves may progressively and proportionally vary from the top rail182to the center of the ball striking face and may progressively vary from the center of the ball striking face to the sole192. The noted progressive variation may define a ball strike zone that is larger at the center of the ball striking face than near the top rail182and the sole192. Furthermore, the progressive noted variation of the grooves' horizontal cross-sectional profiles provides grooves at the center of the ball striking face and around the center of the ball striking face that have longer deep groove sections than grooves near the top rail182and the sole192. However, the above-described progressive variation of the grooves is exemplary and other progressive variation schemes may be used to impart particular ball striking properties to various portions of the ball striking face. Referring toFIG.23, a ball striking face612according to another example is shown having grooves620.FIGS.24-26show a vertical cross-sectional shape of the grooves620as viewed from section line24-24ofFIG.23. InFIG.24, the vertical cross-sectional shape of the groove620is box-shaped, rectangular or square. InFIG.25, the vertical cross-sectional shape of the groove620is V-shaped. InFIG.26, the vertical cross-sectional shape of the groove620is U-shaped. The vertical cross-sectional groove shapes ofFIGS.24-26are applicable to any groove according to the disclosure. For example, the vertical cross-sectional shape of the grooves220may be rectangular or square according to the grooves620ofFIG.24. In another example, the vertical cross-sectional shape of the grooves620may be V-shaped according to the groove620ofFIG.25. Furthermore, the vertical cross-sectional shape of a groove may vary from the toe end180to the heel end190. For example, with reference toFIGS.4and5, a groove220may be have a square or rectangular vertical cross-sectional shape in regions271and275, U-shaped vertical cross-sectional shape in regions271and274, and V-shaped vertical cross-sectional, shape in region273. Additionally, the vertical cross-sectional shapes of the Moves may also vary from the top rail182to the sole190. For example, grooves near the top rail182and the sole192may have a square vertical cross-sectional shape, while the grooves at the center of the club face may have a U-shaped vertical cross-sectional shape. The ball striking face of the putter in the above examples is shown to have grooves from the top rail182to the sole192. However, a ball striking face may have more or less grooves, or have sections that are without grooves. For example, a ball striking face may have several grooves at the center section of the ball, strike face and be without grooves at sections near the top rail182or the sole192. The grooves are not limited to extending horizontally across the ball striking face. The ball striking face may have, vertical grooves that vary in depth as described above or a combination of vertical and, horizontal grooves with varying horizontal and/or vertical cross-sectional profiles. The orientation of the grooves may be such that a matrix-like ball striking face is provided on the putter. Referring toFIG.27, a ball striking face712having grooves720may be horizontally separated into three portions, which are the toe portion780, a center portion785and a heel portion790. The ball striking face712may be similar to the ball striking face212and312described above. Accordingly the grooves720have regions271-275and371-375similar to grooves220and320, respectively; described above. The three portions described above horizontally separate the ball striking face712and span vertically from the top rail182to the sole192. The toe portion780is near the toe end180, the heel portion790is near the heel end190, and the center portion785is between the toe portion780and the heel portion790. According to various examples, the depth of the grooves720at the toe portion780and the heel portion790may not be greater than the depth of the grooves720at the center portion785. In one example, the shallowest depth of the grooves720, which may be nearest to the toe end180or nearest to the heel end190may be approximately 0.003 inch. At or near the center portion785, the depth of the grooves720may increase as described above to a depth of approximately 0.017 inch. The variable depth may include a portion with a depth of at least 0.020 inches but less than 0.022 inches. The variable width may include a portion with a width of at least 0.035 inches but less than 0.037 inches. Referring toFIG.28, the ball striking face712may be vertically separated into three portions, which are the top rail portion782, the mid portion786and the sole portion792. These portions vertically separate the ball striking face712and span horizontally from the toe end180to the heel end190. The top rail portion782is near the top rail182, the sole portion792is near the sole192, and the mid portion786is between the top rail portion782and the sole portion792. The length of the deepest portion of a groove720may vary from the top rail portion782to the mid portion786and from the mid portion786to the sole portion792. For example, with respect to the examples described above, the length of the deepest portion of a groove may refer to the groove720that is proximately centrally located between the top rail portion782and the sole portion792. As shown inFIGS.27and28, the length of the grooves710may be greatest at the mid portion786and gradually reduce toward the top rail portion782and toward the sole portion792. FIGS.29-37show examples of different groove horizontal cross-sectional profiles according to the disclosure. In the above examples, the width of the grooves220,320,420and520is shown to have a rectangular profile. However, a groove according to the disclosure may have different width profiles as shown by the examples ofFIGS.38-45. Accordingly, a groove according to the disclosure may have any horizontal cross-sectional profile, vertical cross sectional profile, width profile and/or depth profile. A cross-sectional profile of a groove including variations in lengths, depth, width and/or cross-sectional shape of the groove may affect ball speed, control, and/or spin. The disclosed variable, depth grooves may improve the consistency of the ball speed after being struck by the putter face by about 50% over a plastic putter face insert, and by about 40% over a non-grooved aluminum putter face insert. Striking a ball with a putter having grooves according to the disclosure: (1) may result in lower ball speeds, which may result in decreased ball, roll out-distance; (2) may result in heel and toe shots to have decreased ball speeds compared to center hits, and also may result in shorter ball roll out distance; (3) allow relatively lower and higher handicap players to strike the ball with different locations on the putter face (higher handicap players tend to hit lower on the ball striking face whereas lower handicap player tend to hit higher on the ball striking face. Also, relatively higher handicap players may have a wider range of hit location's whereas relatively lower handicap players may have, a closer range of hit locations; and/or (4) a putter face with grooves in the center of the face may result in reduced ball speed/roll out distance for center shots, which may result in a more consistent ball speed/roll out distances for center/heel/toe shots. Referring toFIG.46, another example of a putter face810having grooves of variable cross-sectional profiles is shown. The putter face810is shown to have fourteen grooves, which are grouped into grooves822-828near the toe end180, grooves830-840at the center of the putter face810, and grooves842-848near the heel end190. In this example, the more prominent grooves are located at the center of the putter face810, and less prominent grooves are on the periphery of the center. A more prominent groove may refer to a groove that has a greater depth and/or width as compared to a less prominent groove. As shown inFIG.46, the grooves832-838may be more prominent that the remaining grooves on the putter face810. Furthermore, portions of the putter face810may be without grooves. These portions are referred to with reference number850. Referring toFIG.47, another example of a putter face910having grooves of variable cross-sectional profile is shown. The putter face910is shown to have ten grooves922-940. The length of each groove progressively increases from the top rail182to the sole190. Each of the grooves922-940or groups of the grooves922-940may have different vertical cross-sectional shapes. For example, grooves922-930are shown to have box-shaped vertical cross-sections, while grooves932-940are shown to have V-shaped vertical cross sections. Referring toFIG.48, a horizontal cross section of a groove922according to another embodiment is shown. A bottom surface954of the groove922is shown to gradually recede from the edges950and952of the groove to a greatest depth951of the groove922. Any of the grooves according to the disclosure may have the same horizontal cross-sectional shape as the groove922. Any of the grooves according to the disclosure may have, the same depth951. However, the depth951may be proportionally reduced as the length of the groove is reduced. In another example shown inFIG.49, a ball striking face1012may include grooves1220(shown specifically as grooves1222-1256). The ball striking face1012may be for use with the putter100. Accordingly, parts of the putter100and the putter head102are referred to with the same reference numbers presented above. The grooves may have any cross sectional shape, length and width according to the disclosure. Referring toFIG.49, a side cross-sectional view of a ball striking face1012having grooves1220according to another example is shown. The ball striking face1012may be separated into two portions with respect to the grooves1220. The ball striking face1012may include a top rail portion1282and the sole portion1286. The top rail portion1282and the sole portion1286may vertically separate the ball striking face1012and span horizontally from the to end180to the heel end190. The top rail portion1282may extend generally from a center portion of the ball striking face1012, which is represented by the center line1284, to near the top rail182and include the grooves1222. The sole portion1286may extend generally from near the sole192to the center portion1284and include the grooves1224. The grooves1224of the sole portion1286may have a greater depth at one or more locations along each groove1224than the grooves1222of the top rail portion1282. By having shallower grooves1222at the top rail portion1282, the speed by which a golf ball rolls forward after being struck by the putter may increase so as to provide a more consistent and smooth ball roll out. Alternatively, the depth of the grooves1220may progressively reduce in one or more groove steps from the center portion1284to the top rail182(not shown). In another example, the depth of pairs of grooves may progressively reduce from the center portion1284to the top rail182(not shown). Accordingly, the reduction in groove depth from the sole192to the top rail182may be for each groove, for pairs of grooves or for various groupings of the grooves. Referring toFIG.50, the grooves1224of the sole portion1286may have a smaller depth at one or more locations along each groove1224than the grooves1222of the top rail portion1282. Alternatively, the depth of the grooves1220may progressively increase in one or more groove steps from the center portion1284and/or the sole192to the top rail182(not shown). In another example, the depth of pairs of grooves may progressively increase from the center portion1284and/or the sole192to the top rail182(not shown). Accordingly, the increase in groove depth from the center portion1284and/or the sole192to the top rail182may be for each groove, for pairs of grooves or for various groupings of the grooves. FIGS.51and52show other examples according to the disclosure. Referring toFIG.51, a putter head1300includes a ball striking face1312, which has a plurality of horizontal grooves1320and vertical grooves1322. Each of the grooves1320and1322may have a different configuration as compared to another groove, such as variable cross-sectional profiles, depth profiles, width profiles, length profiles and/or other groove characteristics from the toe end1380to near the heel end1390and/or from a top rail1382to a sole1392. For example, the depth of the horizontal grooves1320may progressively increase in one or more groove steps from the top rail1382to the sole1386. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. Referring toFIG.52, a putter head1400includes a ball striking face1412, which has a plurality of first diagonal grooves1420and second diagonal grooves1422. The first diagonal grooves1420may be generally parallel to each other. Similarly, the second diagonal grooves1422may be generally parallel to each other. The first diagonal grooves1420and the second diagonal grooves1422may be transverse to each other as shown inFIG.52. For example, the first diagonal grooves1420may intersect the second diagonal grooves1422at an angle of 30°, 45°, 60° or 90°. Each of the grooves1420and1422may have a different configuration as compared to another groove, such as variable (cross-sectional profiles, depth profiles, width profiles, length profiles and/or other groove characteristics from the toe end1480to near the heel end1490and/or from a top rail1482to a sole1492. For example, the depth of the first diagonal grooves1420may progressively increase in one or more groove steps from the top rail1482to the sole1486. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. Referring toFIG.52, a process2000of manufacturing a golf club head according to one example is shown. The process2000includes forming a golf club face (block2002) defined by a toe end, a heel end, a top rail and a sole. A golf club face may be formed with a golf club head so that the golf club head and the golf club face are a one-piece continuous part. Alternatively, the golf club head and the golf club face may be formed separately. The golf club face may then be attached to the golf club face by using adhesive, tape, welding, soldering, fasteners and/or other suitable methods and devices. The golf club head and/or the golf club face may be manufactured from any material. For example, the golf club head and/or the golf club face may be made from titanium, titanium alloy, other titanium-based materials, steel, aluminum, aluminum alloy, other metals, metal alloys, plastic, wood, composite materials, or other suitable types of materials. The golf club head and/or the golf club face may be formed using various processes such as stamping (i.e., punching using a machine press or a stamping press, blanking, embossing, bending, flanging, or coining, casting), injection molding, forging, machining or a combination thereof, other processes used for manufacturing metal, plastic and/or composite parts, and/or other suitable processes. In one example, when manufacturing a putter head, the material of the putter face and/or the ball striking face may be determined so as to impart a certain ball strike and rolling characteristics to the putter face. In another example, when the ball striking face212is separate from the putter face110and is inserted and attached into a correspondingly shaped depression on the putter face110, the striking face212may be constructed from a lighter material than the putter face110to generally reduce the overall weight of the putter. According to the process2000, grooves are formed on the club face and/or club head between the top rail and the sole such that each groove extends between the toe end and the heel end and depths of the grooves vary in a direction extending between the top rail and the sole and in a direction extending between the heel end and the toe end (block2004). The grooves may be formed using various processes such as casting, forging, machining, spin milled, and/or other suitable processes. The vertical cross-sectional shape of a groove may depend on the method by which a groove is manufactured. For example, the type of cutting bit when machining a groove may determine the vertical cross-sectional shape of the groove. The vertical cross sectional shape of a groove may be symmetric, such as the examples described above, or may be asymmetric (not shown). In one example, the width of a groove can be 0.032 inch, which may be the width of the cutting bit. Accordingly, when machining a groove, the shape and dimensions of the cutting bit may determine the shape and dimension of the groove. The grooves may be manufactured by spin milling the ball strike face, or stamping or forging the grooves into the ball striking face. The grooves may also be manufactured direction on the putter head to create a ball striking face as described above directly on the putter head. A groove may be manufactured by press forming the groove on the putter head. For example, a press can deform and/or displace material on the putter head to create the groove. A groove may be manufacturing by a milling process where the rotating axis of the milling tool is normal to putter face. The rotating axis of the milling tool may be oriented at an angle other than normal to the putter face. A groove may be manufactured by overlaying one material that is cut clean through to form a through groove onto a base or solid material. A groove may be manufactured by laser and/or thermal etching or eroding of the putter face material. A groove may be manufactured by chemically eroding the putter face material using photo masks. A groove may be manufactured by electro/chemically eroding the putter face material using a chemical mask such as wax or a petro-chemical substance. A groove may be manufactured by abrading the face material using air or water as the carry medium of the abrasion material such as sand. Any one or a combination of the methods discussed above can be used to manufacture one or more of the grooves on the putter head. Furthermore, other methods used to create depressions in any material may be used to manufacture the grooves. As the rules to golf may change from time to time (e.g., new regulations may be adopted or old rules may be eliminated or modified by golf standard organizations and/or governing bodies), golf equipment related to the methods, apparatus, and/or articles of manufacture described herein may be conforming or non-conforming to the rules of golf at any particular time. Accordingly, golf equipment related to the methods, apparatus, and/or articles of manufacture described herein may be advertised, offered for sale, and/or sold as conforming or non-conforming golf equipment. The methods, apparatus, and/or articles of manufacture described herein are not limited in this regard. Although a particular order of actions is described above, these actions may be performed in other temporal sequences. For example, two or more actions described above may be performed sequentially, concurrently or simultaneously. Alternatively, two or more actions may be performed in reversed order. Further, one or more actions described above may not be performed at all. The apparatus, methods, and articles of manufacture described herein are not limited in this regard. While the invention has been described in connection with various aspects, it will be understood that the invention is capable of further modifications. This application is intended to cover any variations, uses or adaptation of the invention following, in general, the principles of the invention, and including such departures from the present disclosure as come within the known and customary practice within the art to which the invention pertains. | 48,728 |
RE49858 | DETAILED DESCRIPTION OF THE INVENTION First Embodiment Hereinafter, a description is given of a rear part structure of a vehicle according to a first embodiment of the present invention with reference toFIG.5throughFIG.12. Also, in the embodiment, “front” means the side in the forward direction of a vehicle, “rear” means the side in the rearward direction of a vehicle, “up or upper” means the upper side in the perpendicular direction, “down” means the lower side in the perpendicular direction, and “left and right” means the width direction of a vehicle. As shown inFIG.5, a vehicle1is, for example, a minivan, station wagon, or hatchback. A pop-up type tailgate3composed of a hinge structure is provided at the rear part2a of the vehicle body2. A gate opening portion2d opened and closed by the tailgate3is formed at the rear face side at the rear part2a of the vehicle body2, and the gate opening portion2d is provided with a hinge4and a hinge cover5at both left and right ends of the upper part thereof. A luggage compartment2h is formed in a vehicle interior at the rear part2a of the vehicle body2, wherein loads can be loaded and unloaded by opening the tailgate3. The roof portion2b is aceilingportion of the vehicle body2, and is composed of a roof panel R disposed at the middle portion and side frames S disposed at both left and right end sides in the vehicle width direction of the roof panel R. The left and right end sides of the roof panel R and the upper end side of the side frames are joined to each other by welding means.TheEach of theconnectedportionportionshas a groove (mohican groove)2c formed, which consists of a junction groove, extendingfrom bothinto eitherthe leftandend portion orright endportionsportionin the vehicle width direction of the roof portion2b of the vehicle body2in the longitudinal direction, the section of which is roughly channel-shaped opening upwards. Thegroovegrooves2cisare eachformed along the longitudinal direction of the vehicle1from the edge of the front glass (not illustrated) at the front end of the roof portion2b to the edge of the gate opening portion2d at the rear end thereof. The width ofeach ofthegroovegrooves2c in the vehicle width direction is widened at the rear part2a of the vehicle body2, anda hingehinges 4,4which rotatablysupportssupportthe tailgate3on the vehicle body2isareinstalled in the widened rear end bottomportionportions 2g,2g.TheEachhinge4is hidden bya corresponding one ofthe hingecovercovers 5,5.TheEachhinge cover5is fitted at the rear part2a side where the hinge4is installed, and acorresponding one ofroofmouldingmouldings 6,6is continuously fitted forward of the hinge cover5. Further, the rear end bottom part2g of the groove2c corresponds to an “attaching portion” described in the claims. As shown inFIG.12,a damper member which dampens an impact generated when closing the tailgate3, a waterproof member which prevents rainwater from invading, anda weatherstrip W operating as a sealing material, which prevents air and sound from invadingareisinstalled at the flange2f in the inner circumferential edge of the gate opening portion2d.AAs shown in FIG. 5, astriker21with which a lock portion33secured at the tailgate3is engaged is installed at the lower middle part of the gate opening portion2d. Also, the weatherstrip W is formed of a synthetic rubber or foamed resin material. In addition, a rear roof rail (upper)11and a rear roof rail (lower)12, which extend in the vehicle width direction, overlap each other and are installed inside the roof panel R at the rear part2a of the vehicle body2(Refer toFIG.12). The tailgate3is a backdoor for opening and closing the gate opening portion2d and is formedby a hemming processusing an outer panel31and an inner panel32, which are rolled steel plates. As shown inFIG.5, a gate hinge member42rotatably attached to the hinge base member41by means of a hinge pin43and anopenstay7which holds the tailgate in an open position, or open stay,installed at the right edge of the gate opening portion2d so as to turn arerespectivelyattached at theside plane portion3a at the left and right upper end partspart and the right side plane portion 3ain the vehicle width direction of the tailgate3.Another gate hinge member 42 (not shown in FIG. 5) is attached at the left upper end part in the vehicle width direction of the tailgate 3.Window glass34is secured in the tailgate3so that the rear view of the vehicle1can be visually confirmed during driving. As shown inFIG.12, a grommet G is provided at the upper part3c of the tailgate3, through which a cable to be connected to lamps (not illustrated) such as a stop lamp secured in the tailgate3and a pipe to be connected to a wiper washer nozzle WN are passed. Also, the upper part3c of the tailgate3is formed to be comparatively long in the longitudinal direction and to be thick so that a rear spoiler (not illustrated) can be installed. As shown inFIG.8,a hingehinges 4,4isareinstalled to open and close the tailgate3in the form of pop-up type centering around the upper end portion of the gate opening portion2d of the vehicle body2.TheEachhinge4is made of, for example, a steel plate pressed material.TheEachhinge4is composed of a hinge base member41fixed ata corresponding one ofthegroovegrooves2c of the vehicle body2, a gate hinge member42attached to the tailgate3, and a hinge pin43for connecting the hinge base member41and the gate hinge member42so as to be freely turned (pivoted). Also, the hinge4corresponds to the hinge in the claims. As shown inFIG.7andFIG.10, the hinge base member41on the left side of the vehicle bodyis composed of a thick metal plate material which is roughly L-shaped when being observed from the rear side. At the hinge base member41, the fixing part41a at the vehicle body2side (that is, the base end side) is firmly attached to theleft side of theupper part2i of the gate opening portion2d of the vehicle body2by means of fixing members8for a vehicle, and the connection portion41b (refer toFIG.10) at the tip end side is connected to the gate hinge member42by the hinge pin43so as to be turned. The fixing part41a is fixed at the rear end bottom portion2g of thecorrespondinggroove2c lowered by a height L4from theceilingsurface2k of the roof portion2b. The hinge base member41is covered up with thecorrespondinghinge cover5continued from the roof moulding6(refer toFIG.5) secured in the groove2c. The fixing members8for a vehicle are members for firmly fixing the hinge base member41in the vehicle body2, for example, and may be composed of weldingboltsattachment members. Also, the fixing members8for a vehicle may be rivets, etc. As shown inFIG.8,each ofthe gate hingemembermembers 42,42is composed of a thick metal flat plate which is roughly L-shaped in its side view. The gate hingemembermembers 42,42extendsextendalongrespective planes parallel tothe opening and closing directions (the directions of the arrows D and E) of the tailgate3and the side plane portion3a of the tailgate3. As shown inFIG.8,each ofthe gate hingemembermembers 42,42is provided with a through-hole42c having the hinge pin43inserted through the front end part thereof, through-holes42d and42e for attachingafixingboltbolts BO,BO, which are drilled at the rear end part and the middle part thereof, and through-holes42f and42g, drilled between the through-hole42d and the through-hole42e, in which a provisional setting bolt (not illustrated) may be inserted for provisionally fixing a fixture (not illustrated).TheEach of thegate hingemembermembers 42,42is composed so that the connection portion42b at the front end part side is installed so as to be turned at thecorrespondinghinge base member41by the hinge pin43, and at the same time, the fixing part42a at the rear end part side attaches the side plane portion3a of the tailgate3while adjusting the position thereof in the vertical and longitudinal directions (the arrows H, I, J and K) as shown insFIG.8. The tailgate3is provided so that the connection portion42b is adjusted in the longitudinal directions (the arrow directionsH and IJ and K) of the vehicle1and in the height directions (the arrow directionsJ and KH and I) thereof with respect to the vehicle body2by means of the gate hinge member42continued from the hinge pin43. The hinge pin43is composed of, for example, a rivet-shaped metal axial member for pivotally connecting the hinge base member41and the gate hinge member42. The hinge pin43is made maintenance-free by fitting a bushing44composed of oil-contained resin or oil-contained sintered metal in order not to require oil supply to the hinge4as shown inFIG.10. As shown inFIG.5,each ofthe hingecovercovers 5,5covers up the upper part of thecorrespondinghinge base member41and is formed of plate-shaped synthetic resin formed to the shape of the rear end portion of the groove2c. As shown inFIG.11with respect to the left hinge cover 5,theeachhinge cover5has an engagement portion5a formed at the front end portion, a bracket portion5b (Refer toFIG.8) for clip CL installation, which is formed on the underside, reinforcement ribs5d formed at a plurality of points on the underside, and the notched portion5c formed at the middle part of the rear end portion, all of which are formed to be integral with each other. Theleft sidehinge cover5is fixed, as shown inFIG.11, at the vehicle body2side by placing its engagement portion5a in the rear end portion of thecorrespondingroof moulding6and fitting the clip CL in the cover fixing member10fixed on the upper plane of the hinge base member41as shown inFIG.8. Theleft sidehinge cover5forms a notch5c at the middle of the rear end portion,byinwhich thecorrespondinggate hinge member42can beturnedmovedwhen the tailgate3is turned in the direction of the arrow D and is opened. Further, the cover fixing member10is a trapezoidal bracket which is formed of, for example, flat plates, and has a through-hole in which the clip CL is engaged. As shown inFIG.5, the open stay7is composed of a gas spring to be fixed in the vehicle body2so that the tailgate3can be opened and closed while balancing with the weight of the pop-up tailgate3when it is opened and closed. The open stay7includes a piston rod71pivotally attached to the right end part of the gate opening portion2d of the vehicle body2and a tube cylinder72pivotally attached to the tailgate3while advancing and retreating resiliently with respect to the piston rod71. The open stay7is provided in the vicinity of the attaching portion (the rear end bottom portion2g) of the hinge base member41fixed at the vehicle body2includes one end attached at a vertically intermediate portion of the side plane portion 3a of the tailgate 3 while the gate hinge member is provided at an upper portion of the side plane portion as shown. Next, a description is given of an assembling procedure of the rear part structure of a vehicle according to the first embodiment of the invention. As shown inFIG.5, where the tailgate3is attached to the rear part2a of the vehicle body2, first, thehingehinges 4,4,ineach ofwhich the hinge base member41and gate hinge member42are connected by means of the hinge pin43is, areattached to the rear end bottomportionportions 2g,2g of thegroovegrooves 2c,2c by the fixing members8for a vehicle. Next, the roofmouldingmouldings 6,6isarefixed in thegroovegrooves 2c,2c by using an adhesive agent. The engagement portion5a oftheeachhinge cover5is fitted to the rear end of thecorrespondingroof moulding6(Refer toFIG.11), the clip CL attached to the underside oftheeachhinge cover5is pressure-fitted into thecorrespondingcover fixing member10, andtheeachhinge cover5is fixed so as to cover up thecorrespondinghinge base member41fixed at the vehicle body2(Refer toFIG.8). Thegroovegrooves 2c,2c whichisareconventionally available to connect the roof panel R and the sideframeframes S,S to each other can be effectively used as an attaching point of thehingehinges 4,4and hingecovercovers 5,5. Therefore, the profile of the upper portion of the rear part2a of the vehicle body2can be established without any limitation. The hingecovercovers 5,5can be attached with only one-touch operation by engaging the engagement portion5a formed at the front end with the rear end of thecorrespondingroof moulding6as shown inFIG.11and pushing the clip CL attached to the underside into the cover fixing member10fixed at thecorrespondinghinge base member41as shown inFIG.8. TheEachhinge base member41is covered up by thecorrespondinghinge cover5and is prevented from being exposed as shown inFIG.5, and at the same time is disposed in the longitudinal direction to thecorrespondingroof moulding6. And by making the upper surface of the roofmouldingmouldings 6,6flush with the upper surface of the hingecovercovers 5,5, it is possible to secure a design shape matched to the appearance of the surrounding parts such as the roofmouldingmouldings 6,6, wherein the appearance can be improved. Next, as shown inFIG.5, the piston rod71of the open stay7is rotatably disposed at the right upper edge of the gate opening portion2d. And, the tube cylinder72of the open stay7is rotatably attached to the side plane portion3a of the tailgate3with a fixture (not illustrated) attached to the tailgate3. Next, as shown inFIG.8,aprovisional fixingboltbolts(not illustrated)isareinserted into the through-holes42f and42g ofeach ofthe gate hingemembermembers 42,42with the tailgate3opened in the direction of the arrow D and is screwed in the tailgate3, thereby causing the tailgate3to be provisionally fixed at thehingehinges 4,4. If a fixture (not illustrated) is moved in the vertical and longitudinal directions (the arrows H, I, J and K) in a state where thehingehinges 4,4isareprovisionally fixed at the tailgate3, the tailgate3is moved in the same direction. And, the fixing bolts BO of the tailgate3are inserted into through-holes42e and42d, respectively, and the attaching positions thereof are adjusted in the vertical and longitudinal directions of the arrows H, I, J and K in the respective adjustable ranges DA. Then, the tailgate3is matched to a prescribed position of thehingehinges 4,4, and the fixing bolts BO are firmly tightened for regular tightening of the tailgate3. And, the respective provisional fixing bolts (not illustrated) are removed from the through-holes42f and42g and the fixture is removed. As a result, the tailgate3is fixed in a state determined with respect to the gate opening portion2d and thehingehinges 4,4. As described above, since, only by adjusting the positions in the through-holes42e and42d, the tailgate3can be adjusted in terms of position with respect to the gate opening portion2d of the vehicle body2and thehingehinges 4,4thereof, the number of steps of adjusting the positions is reduced, and the work can be simplified. The work for attaching the tailgate3on thehingehinges 4,4by the fixingboltboltsBO is carried out from the direction of the side planeportionportions 3a,3a of the tailgate3with the tailgate3opened, wherein since the attaching point of the gate hingemembermembers 42,42by using the fixingboltboltsBO can be visually confirmed, the work can be easily earned out. Also, since work for attaching thehingehinges 4,4to the tailgate3or detaching the same therefrom is carried out from the direction of the side planeportionportions 3a,3a where any member hindering the work is not provided, the work can be smoothly carried out. Since the gate hingemembermembers 42,42isareinstalled at the left and right side plane portions3a and3a of the tailgate3, the supporting span between the hinge4on the left side plane portion3a and the hinge4on the right side plane portion3a is widened, wherein the retaining ability and rigidity of the tailgate3can be improved by means of the hinges4and4. Further regarding the hinges4and4, since the flat gate hinge members42and42are attached to the side plane portions3a and3a of the tailgate3, the occupancy of the hinges4and4in the vehicle width direction is slight, wherein there is no case where the length L6of the gate opening portion2d in the width direction (Refer toFIG.5) is limited. The length L6of the gate opening portion2d in the width direction (Refer toFIG.5) is lengthened so as to widen the area, and thereby the loading and unloading work of loads can be facilitated. Also, as shown inFIG.5, since, in the gate hingemembermembers 42,42, the hinge basemembermembers 41,41isareinstalled in thegroovegrooves 2c,2c on the roof portion2b, and the gate hingemembermembers 42,42isareinstalled at the side planeportionportions 3a,3a of the tailgate3, the hinge basemembermembers 41,41and the gate hingemembermembers 42,42are not exposed to the luggage compartment2h. Therefore, the appearance inside the luggage compartment2h can be improved, and at the same time, clearance of the gate opening portion2d and space in the luggage compartment2h can be widened. Accordingly, loading of loads into the luggage compartment2h and unloading thereof through the gate opening portion2d can be easily carried out. Next, a description is given of actions of the rear part structure of a vehicle according to the first embodiment of the present invention. If the tailgate3is opened, as shown inFIG.5, the tailgate3and gate hingemembermembers 42,42are integrally turned and opened in the direction of the arrow D centering around the hingepinpins 43,43disposed between the roof portion2b and the tailgate gate3. At this time, the tailgate3is slowly opened by means of the open stay7. And, as shown inFIG.8, the partingedge3b at the upper end of the tailgate3is turned in the direction of the arrow M centering around the hingepinpins 43,43. At this time, the partingedge3b is disposed at a position apart by a distance L5rearward from the hingepinpins43, wherein the rotating locus is made to be above theceilingsurface2k (Refer toFIG.10), wherein the partingedge3b can turn without any interference with the vehicle body2. Therefore, it becomes possible to make short the length L3of an arm oftheeachhinge base member41protruding upwards from the lower portion2g of the rear end of thecorrespondinggroove2c of the vehicle body2. Accordingly, it is possible to make short the height L4fromtheeachrear end lower portion2g to theceilingsurface2k (Refer toFIG.10), whereinaninstallationgroovegroovesfor installing thehingehinges 4,4at the rear part2a of the vehicle body2may become sufficient with a shallow groove such as thegroovegrooves 2c,2c. And, as regards the rear part2a of the vehicle body2, a degree of freedom in design and setting of the dimensions of the gate opening portion2d can be brought about, and the setting is enabled with a sufficient allowance. As shown inFIG.5, even if a moment anddistorsionaldistortionaldeformation are added to thehingehinges 4,4and the open stay7when opening and closing the tailgate3since theright sidehinge4is installed comparatively in the vicinity of the open stay7, the moment applied to the tailgate3is less, wherein the tailgate3is free from any distortion. As shown inFIG.7, the tailgate3is turned in the direction of the arrow E and the gate opening portion2d is closed. At this time,theeachgate hinge member42is turned in theextending directionsdirection(that is, the shearing direction)ofalong whichthe gate hinge member42on its surface and rear sidesextends, and its turning direction is roughly coincident with the turning direction of the tailgate3, wherein a. Aforce applied to opening and closing of the tailgate3is given tothegate hinge member 42 alongplane directionson its surface and rear sides of the gate hinge member42in which they extend. Therefore, thehingehinges 4,4hashavestrength with respect to the opening and closing directions of the tailgate3, wherein the rigidity is improved to a large extent, and the gate hingemembermembers 42,42can be downsized. Second Embodiment Hereinafter, with reference toFIG.13throughFIG.15, a description is given of a rear part structure of a vehicle according to a second embodiment of the present invention. Hereinafter, a description is based on a mode where the present invention is applied to a minivan type vehicle. As shown inFIG.13, a rear part structure of a vehicle according to the present invention mainly comprises a tailgate101attached to the opening portion104a formed on the rear face of a vehicle body104, a pair of left and right gate hinge members(hereinafter merely called a “hinge member”)102, 102which are attached upward in the rear part of a vehicle and support the tailgate101so as to turn to open and close in the vertical direction, and an open stay103forconnectingholdingthe tailgate101in an open position relativeto the vehicle body104, which is attached only to one side of the tailgate101. The open stay103is installed at one side portion of the tailgate101(in the present embodiment, at the right side portion). For example, a gas damper which has been publicly known is applied as the open stay103. The gas damper has a force of turning and pushing the tailgate101in its opening direction in order to help a user when he or she manually opens the tailgate101and has an adequate resisting force when the tailgate101is closed. Respective hinge members102, 102are attached to the vehicle body104via hinge attaching seats105, 105. The respective hinge attaching seats105, 105are installed and fixed at the bottomportionportions 109,109of a pair of left and right grooves108, 108formedat a junctionofa side endlateralsideends 106,106of the roof panel R of a vehicle andanupper endsidesides 107,107of the roof side frame S in the rear upper part of the vehicle. Roof reinforcing members extending in the vehicle width direction, center pillars (both of which are not illustrated), etc., are disposed inside the roof panel R, and these members are coupled to the roof panel R, roof side frame S, etc., and compose the basic frame of the vehiclebody104. As shown inFIG.14, the hinge attaching seat105is composed of a flat base plate portion105a fixed and installed in contact with the bottom portion109(Refer toFIG.13), a hinge axial-supporting plate portion105b erected on the side portion of the base plate portion105a, and a cover attaching portion105c for attaching the hinge cover110later described in detail. Attaching pins105d fitted into attaching holes109a and109b (FIG.13), which are drilled in the bottom portion109(FIG.13) are provided so as to protrude from the bottom surface of the base plate portion105a. For example, a rivet or the like is available as the attaching pin105d. The cover attaching portion105c is composed of a leg portion105e formed upwards of the head portion of one attaching pin105d and an engagement hole105f drilled in the upper surface of the leg portion105e. A rotating axis111whose axial direction is made into the vehicle width direction is formed on the hinge axial supporting plate portion105b, and the hinge member102is attached so that it rotates centering around the rotating axis111. A hinge coverHinge covers 110,110is a memberare membersfor covering up the hinge attachingseatseats 105,105by being attached to thegroovegrooves 108,108(FIG.13). And,theeachhinge cover110is composed of a roughly triangular plate-shaped cover base body110c having a narrow end portion110a and a wide end portion110b at both end portions in the lengthwise direction (that is, the longitudinal direction of a vehicle), a mouldingbraidconnection portion110d secured at the narrow end portion110a, an engagement portion110e engaged in the engagement hole105f, and a cover portion110f secured at the wide end portion110b. The mouldingbraidconnection portion110d is composed of a narrow end portion110a of the cover base body110c, and an engagement tongue portion110g branched from the underside of the narrow end portion110a and extending in the forward direction of a vehicle. On the underside of the narrow end portion110a, a linear projection110h for upper engagement is provided toward the engagement tongue portion110g along the vehicle width direction. On the upper surface of the engagement tongue portion110g, another linear projection110i for lower engagement is provided so as to correspond to the upper engagement linear projection110h. The engagement portion110e is composed of a hollow box-shaped base110j formed on the underside of the cover base body110c and an engagement pin112, which is attached to the underside of the base110j and is resiliently deformable. In addition, a relief groove110k for inserting thecorrespondingturning hinge member102is formed on the wide end portion110b oftheeachcover base body110c. InFIG.13, the roofmouldingmouldings 113,113isarefitted to theportionportionsforward of thegroovegrooves 108,108, and when attaching the hingecovercovers 110,110composed of the above components before or after fitting the roofmouldingmouldings 113,113, the rear end of the roofmouldingmouldings 113,113(FIG.13)isareplaced between the narrow endportionportions 110a,110a of the mouldingbraidconnectionportionportions 110d,110d and the engagement tongueportionportions 110g,110g inFIG.14, and at the same time, the engagementpinpins 112,112isareengaged in the engagementholeholes 105f,105f, whereby when the hingecovercovers 110,110isareattached to the rearpartpartsof thegroovegrooves 108,108inFIG.13, the uppersurfacesurfacesof the roofmouldingmouldings 113,113isaremade flush with the uppersurfacesurfacesof the hingecovercovers 110,110to secure a smooth configuration. Now, as shown inFIG.14,each ofthe hingemembermembers102is composed of a turning arm portion102a axially supported on the rotating axis111in the forward side of the vehicle and a gate supporting portion102b formed to be integral with the turning arm portion102a and becomes an attaching supporting portion of the tailgate101.TheEachhinge member102is formed of, for example, a steel plate pressed article, and in the present embodiment, it is formed to be a roughly flat plate-shaped member. The plate surface thereof extendsalmost on thealong a respectiveplaneincludingparallel tothe opening and closing directions of the tailgate101, that is, aperpendicularplanealongparallel tothe longitudinal direction of the vehicle. In the tailgate101, as shown inFIG.13, the side planeportionportions 101a,101aisareformed in the vicinity of the left and right edge portions at the plane side facing the inside of the vehicle compartment so thatit is erectedthey extendtoward the inside of the compartment and along the vertical direction of the tailgate101. (InFIG.13, only the right side plane portion101a is shown). The tailgate101is attached in the form thattheeachside plane portion101a is brought into facial contact with the gate supporting portion102b of thecorrespondinghinge member102. Concretely speaking, as shown inFIG.15,theeachhinge member102is slightly bent and formed so that it becomes roughly elbow-shaped in its side view, and the recess portion side thereof is disposed so as to face the inside of the compartment, whereintheeachgate supporting portion102b is connected to the upper part of thecorrespondingside plane portion101a of the tailgate101. As shown inFIG.15A,the gate supporting portion 102b of each hinge member 102 includesa gate attaching portion121which is positioned at the upper edge side of the tailgate101and a gate attaching portion122which is positioned downward of the gate attaching portion121are provided in the gate supporting portion102bwith the tailgate101fully closed. With the tailgate101fully closed, the gate attaching portions121and122are positioned downward of the rotating axis111, and in the present embodiment, these components are located at the rearward side of the vehicle more than the rotating axis111of the corresponding hinge member 102. Further, in the embodiment, the gate attaching portions121and122are formed as gate attaching holes that pass through in the width direction of the vehicle, whereby the tailgate101is connected to and fixed at the hingemembermembers 102,102by fixing bolts (not illustrated) in theportionportionsof the side planeportionportions 101a,101a thereof via the respective gate attaching portions121and122formed as holes. Further, insertion holes123and124of bolts for provisionally fixing a fixture (not illustrated) used to attach the tailgate101are drilled between both the gate attaching portions121and122. The present invention is mainly featured in that, in a state where the tailgate101shown inFIG.15Ais closed, the positions of the gate attaching portions121and122of the hinge member102at the side where the open stay103(FIG.13) is provided are set downward of the positions of the gate attaching portions121and122of the other hinge member102.FIGS.15(a),and15(b) are views, partly in cross section,showing a side section of the vehicle as described above. Therefore, inthethese sideviews,it seems thatthe pair of hinge members102appear tooverlap each other. Therefore, in the following description, a description is based on the hinge member102shown inFIG.15(a)(that is, this is a hinge member positioned at the left side of a vehicle, which is the hinge member at the side where the open stay103(FIG.13) is not provided) being given a reference number102A, the distance dimensions thereof are given reference numbers L7and L9while the hinge member102positioned at the deep side of the paper (that is, this is a hinge member positioned at the right side of the vehicle, which is the hinge member at the side where the open stay103is provided) is given a reference number102B and the distance dimensions thereof are given reference numbers L8and L10. The distance dimensions L8and L10with respect to the perpendicular direction between the center of the rotating axis in the hinge member102B and the respective gate attaching portions121and122(respectively indicating the center of the hole) are set to greater values than the same distance dimensions L7and L9in the hinge member102A. That is, since the positions of the rotating axes111in both the hinge members102A and102B are set to the same height, the positions of the gate attaching portions121and122of the hinge member102B are located downward of the positions of the gate attaching portions121and122of the hinge member102A. In the present embodiment, for example, the distance dimensions L8and L10at the hinge member102B side are, respectively, set to 23.1 mm and 79.4 mm while those L7and L9at the hinge member102A side are, respectively, set to 22.5 min and 78.7 mm. That is, the respective hinge members102A and102B are formed so that dimensional differences are produced by 0.6 mm at the gate attaching portion121and by 0.7 mm at the gate attaching portion122. Thus, if, with the tailgate101closed, the hole positions of the gate attaching portions121and122at the hinge member102B side are set to be lower than the hole positions of the other side, and are set to so-called left-right asymmetrical hole positions, it is possible, in an assembling process of the open stay103, to absorb a deviation error without requiring any adjustment work, for example, by using a shim, etc., with respect to correction of the deviation between the left and right sides of the tailgate101, which results from a reaction from the open stay103, in detail, a deflection at the side where the open stay103is not provided. Therefore, when assembling the tailgate101in the vehicle body104or attaching the open stay103, no adjustment work is required, wherein working efficiency can be improved. Also, if, for example, the through-holes of the gate attaching portions121and122are drilled as holes which are slightly greater than the fixing bolts (not illustrated), and the hinge member102is composed so that it is adjustable in the longitudinal and vertical directions of the vehicle with respect to the tailgate101, it is possible to improve the assembling accuracy of the hinge member102and tailgate101with simple work. Also, if the hingemembermembers 102,102isareshaped so as to extend alongthe plane includingrespective planes parallel tothe opening and closing directions of the tailgate101and the gate attaching portions121and122are formed as gate attaching holes passing through in the width direction of the vehicle, an opening and closing load operates on the hingemembermembers 102,102initstheirextending planedirectiondirectionswhen the tailgate101is opened and closed. Therefore, it is possible to secure strength against the opening and closing load. Accordingly, the outer shape and plate thickness of the hingemembermembers 102,102can be reduced, wherein weight and production costs can be reduced. Further, by attaching the hingemembermembers 102,102to the side planeportionportions 101a,101a of the tailgate101, assembling work of the hingemembermembers 102,102can be carried out at a lateral position of the tailgate101, which becomes an open space, wherein the assembling work can be easily carried out, and the detailed attaching point oftheeachhinge member102with respect to the tailgate101can be visually confirmed. In addition, such a structure can be obtained, in which, when the tailgate101is opened and closed, a force isaddedappliedto the fixingportionportionsof the hingemembermembers 102,102and the side planeportionportions 101a,101a not in the direction along which the hingemembermembers 102,102isarepeeled off from the tailgate101but in the shearing direction thereof. Therefore, it is possible to obtain large fixing strength by tightening means such as bolts. Also, if such a structure is employed, in which the hingemembermembers 102,102isareprovided in thegroovegrooves 108,108whichisarerecessed with respect to the roof panel R, it is possible to prevent the attachingportionportionsof the hingemembermembers 102,102from protruding from the roof panel R. In this case, for example, as in the present embodiment, by attaching the hingecovercovers 110,110to thegroovegrooves 108,108, it is possible to cover up the attaching portion oftheeachhinge member102, wherein appearance design thereof can be improved. Third Embodiment Hereinafter, with reference toFIG.16throughFIG.24, a description is given of a rear part structure of a vehicle according to a third embodiment of the invention. As shown inFIG.16, the rear part structure of a vehicle according to the present embodiment is provided withatailgate hingemembermembers 202,202at both left and right sides of the upper part in the rear opening portion of a vehicle andahingecovercovers 205,205.TheEachtailgate hinge member202is composed of a hinge base member203and a gate hinge portion204attached to the tailgate201, and thecorrespondinghinge cover205covers up the upper part of the hinge base member203. In the tailgate hingemembermembers202,theeachhinge base member203is caused to extend in the longitudinal direction of a vehicle at the junction portion between thesideend side206of the roof panel R of a vehicle and the upper end side207of thecorrespondingside frame S, and is installed and fixed at the rear end bottom portion209of acorrespondinggroove208opening upwards, the section of which is channel-shaped (Refer toFIG.16,FIG.18,FIG.22andFIG.24). A roof reinforcement, a center pillar, etc., (not illustrated) extending in the vehicle width direction are disposed inside the roof panel R, and are connected to the roof panel R and side panel S, etc., all of which constitutes the basic structure of a vehicle. TheEachhinge base member203is composed,asone of which isshown inFIG.17, of a flat plate base body210, a cover attaching portion211erected on the base body210, and a gate hinge axial supporting portion212erected at the sideofthe base body210. Also, attaching pins214a and214b to be fitted into attaching holes213a and213b (Refer toFIG.16,FIG.20andFIG.22) drilled in the rear end bottom portion209of thecorrespondinggroove208are provided on the base body210so as to protrude therefrom. In addition,theeachcover attaching portion211includes leg portions216and216striding the head portion of thecorrespondingattaching pin214a and an engagement hole217drilled in the top surface of theleg portion216corresponding head portion 211a (refer to FIG. 24). The gate hinge axial supporting portion212has a roughly semi-circular plate hinge supporting portion219on which arotating axispivot shaft218for axially supporting the gate hinge portion204so as to turn is provided so as to protrude therefrom. Also, as shown inFIG.17, the gate hinge portion204oftheeachtailgate hinge member202is composed of a turning arm portion221and a hinge body223connected to the turning arm portion221. A hole220for turning the turning arm portion221, into whicha rotating axispivot shaft218of the gate hinge axial supporting portion212is fitted so as to turn,is drilled in the turning arm portion221. Attaching holes224and224for inserting bolts (not illustrated) to screw the hinge body223in the tailgate201(refer toFIG.16andFIG.19) are drilled in the hinge body223. Further,theeachhinge cover205is provided, as shown inFIG.17, with a roughly triangular plate-shaped cover base body225having a narrow end portion225a and a wide end portion225b at the end part in the lengthwise direction, a mouldingbraidconnection portion226secured at the narrow end part225a of the cover base body225, an engagement portion227, and a cover portion228secured at the wide end portion225b. In addition, it is preferable that ribs (positioning ribs)205a and205b capable of adjusting the position of the upper part outer surface F of the corresponding hinge cover205to the outer plane D(Outer plane of the roof panel and outer plane of the side frame, refer toFIG.22andFIG.24.)of the rear part of a vehicle are provided alongthe lengthwise directionand protrude fromboth side ends in the width direction (the direction orthogonal to the lengthwise direction)respective lateral sidesof the underside of the cover base body225.The outer plane D corresponds to the outer plane of the roof panel and the outer plane of the side frame, refer to FIG. 22 and FIG. 24.The ribs205a and205b are brought into contact with the shoulder portion206a of the side endside206of the roof panel and the shoulder portion207a of the upper end side of the side frame as shown inFIG.22andFIG.24, wherein bothend portionssides251a and251b in the width direction oftheeachhinge cover205are securely supported by the ribs205a and205b, and it becomes possible to prevent the hinge cover205from swaying in the width direction. The mouldingbraidconnection portion226is composed, as shown inFIG.17, of the narrow end portion225a of the cover base body225and an engagement tongue portion229bifurcated from the narrow end portion225a and extending therefrom. A linear projection230for upper engagement is provided along the width direction of the narrow end portion225a toward the engagement tongue portion229on the underside of the narrow end portion225a. Also, a linear projection231for lower engagement is provided along the width direction of the engagement tongue portion229opposed to the upper engagement linear projection230on the upper side of the engagement tongue portion229. The engagement portion227is composed of a hollow box-shaped base232disposed on the underside of the cover base body225and a fitting member234fitted into a linear groove233drilled in the underside of the base232. The fitting member234includes, as shown inFIG.20andFIG.24, a neck portion234a fitted to the linear groove233, an engagement head portion234b fitted to and inserted into the base232, a flange portion234c brought into contact with the outer surface of the base232, and an anchor-shaped fitting portion234d fitted into the engagement hole217drilled in the hinge base body203. The linear groove233is drilled along the lengthwise direction of the hinge cover205on the underside of the base232. The engagement head portion234b of the fitting member234has a recess234e at its middle part. The recess234c234efunctions as a bending allowance for flexing or bending the edge part of the engagement head portion234b when fitting the neck portion234a (Refer toFIG.24) in the linear groove233and attaching the fitting member234to the base232. Also, as shown inFIG.20, the fitting portion234d of the fitting member234is roughly rectangular when being observed from the lengthwise direction of the hinge cover205andis in the form ofananchor having pressing branch portions235a and235b(Refer toFIG.20)bifurcated in the left and right sides when being observed from the width direction (that is, the direction orthogonal to the lengthwise direction). With such a structure, the pressing branch portions235a and235b arebent, as shown inFIG.24,pressed toward each otherwhen fitting the fitting portion234d in the engagement hole217of thecorrespondinghinge base member203, and pass through the engagementholeshole217. After that, the head portion21a211aof the cover attaching portion211is placed between the pressing branch portions235a,235b and the flangeportionsportion234c. Further, the cover portion228of each of the covers 205, 205is composed, as shown inFIG.17, of two cover ends228a and228b secured at the tip end of the wide end portion225b of the cover base body225such that the cover ends will be disposedon opposite sides of a hinge supporting portion219of thecorrespondinghinge base member203and acorrespondingturning arm portion221axially supported at the rotating axis218of the hinge supporting portion219, and a curved cover228d for accommodating thecorrespondingturning arm portion221so as to turn. A groove228c,into which the turning arm portion221of thecorresponding gatehingecover205portion 204is idly inserted,is provided between the cover ends228a and228b. In theWith eachhinge cover205having thefittingengagementportion227, by fitting the fitting portion234d (Refer toFIG.20) of the fitting member234into the engagement hole217of the cover attaching portion211secured at one point inofthe hinge base member203of thecorrespondingtailgate hinge portion202,andtherebyengaging the engagement portion227with the cover attaching portion211,thehinge cover205is easily assembled at thecorrespondinghinge base member203at one fixing point (the cover attaching portion211). Herein, sincetheeachhinge cover205is fitted intoincludesthe linear groove233,in whichdefined intheneck portion234a of the fitting member234is drilledbase 232along the lengthwise direction thereof,at the fitting member234, theeachhinge cover205is not displaced with respect to the width direction. However,ittheycan be displacedrelative to the corresponding fitting member 234along thecorrespondinglinear groove233in the lengthwise direction. Further, as shown inFIG.23A(a), wheretheeachhinge cover205is connected to the rear end of thecorrespondingroof moulding236fitted in thecorrespondinggroove208, the rear end oftheeachroof moulding236is held and secured between the upper engagement linear projection230of the mouldingbraidconnection portion226of thecorrespondinghinge cover205and the lower engagement linear projection231thereof. For this reason,theeachmouldingbraidconnection portion226is not displaced with respect to the width direction but can be displaced in the lengthwise direction with the rear end of thecorrespondingroof moulding236placed therebetween. With such a construction capable of displacing in the lengthwise direction in the engagement portion227and such a construction capable of displacing in the lengthwise direction in the mouldingbraidconnection portion226, sincetheeachhinge cover205can be displaced relative to the extending direction of thecorrespondingroof moulding (that is, the longitudinal direction of a vehicle) after being attached to the vehicle,theeachroof moulding236andthe correspondingtailgate hinge member202can be better matched to each other. In addition, the hingecovercovers 205,205isareconnected to the rear end of the roofmouldingmouldings 236,236fitted in thegroovegrooves 208,208along the longitudinal direction of a vehicle, and as shown inFIG.22andFIG.24, it is preferable thattheeachhinge cover205has an outer ornamentally-designed surface formed to be roughly flush with the outer surface D of the rear part of the vehicle, whereby the upper outer surface F oftheeachhinge cover205is integrated with the outer surface D of the rear part of the vehicle, and the appearance of the vehicle can be improved. Further, as shown inFIG.22andFIG.24FIGS. 22-24, it is preferable that the outer ornamentally-designed surface (upper outer surface F) oftheeachhinge cover205is formed to be an ornamentally-designed appearance which issubstantiallycontinued from the outer ornamentally-designed plane236a of thecorrespondingroof moulding236fitted in thecorrespondinggroove208, whereby the outer ornamentally-designed plane (upper outer surface F) oftheeachhinge cover205issubstantiallycontinued to the outer ornamentally-designed surface236a (Refer toFIG.23) of thecorrespondingroof moulding236fitted in thecorrespondinggroove208, thereby presenting an integrated ontamentally-designed appearance. Hereinafter, a description is given of the rear part structure of a vehicle. Further, in the following description, the left rear part side of a vehicle is shown inFIG.18throughFIG.23for description. However, the tailgate hingemembermembers 202,202and hingecovercovers 205205are assembledrespectivelyat the right rear partas inandthe left rear part. When forming the rear part structure, first, the hinge base members203of the respective tailgate hinge members202arefixed inthe rear end bottom portions of the grooves208disposed at both the upper left and right ends of the rear part opening portion of the vehicle. Thereby, as shown inFIG.20andFIG.21, the gate hingeportionportions 204,204isareaxially supported on the rotatingaxisaxesof the hinge basemembermembers 203,203so as to turn thereon, and the tailgate201attached to the hingebodybodies 223,223of the gate hingeportionportions 204,204isaresupported so as to turn. Next, as shown in FIG,18, in order to cover uptheeachhinge base member203, the rear part of thecorrespondingroof moulding236fitted into thecorrespondinggroove208along the longitudinal direction of a vehicle is placed between the narrow end portion225a of the mouldingbraidconnection portion226of thecorrespondinghinge cover205and the engagement tongue portion229, and at. Atthe same time, the fitting portion234d oftheeachfitting member234mounted at thecorrespondingengagement portion227is pushed into the engagement hole217of thecorrespondinghinge base member203, whereby the fitting portion234d oftheeachfitting member234passes through the engagement hole217of thecorrespondinghinge base member203with the pressing bifurcated portions235a and235bbentpressed toward each otheras shown inFIG.20andFIG.24, and the head portionof the211a of thecorrespondingcover attaching portion211is placed between the pressing bifurcated portions235a,235b and the flange portion234c. Thereby,theeachfitting portion234d is fitted in thecorrespondingengagement hole217. At this time, asAsshown inFIG.20,theeachhinge cover205can be easily assembled at one fixing point(the cover attaching portion211)of thecorrespondingcover attaching portion211and therebysecured at one point in the hinge base member203of thecorrespondingtailgate hinge member202. At this time,thehinge supporting portion219of thecorrespondinghinge base member203and the turning arm portion221of thecorrespondinggate hinge portion204pivotally supported on the hinge supporting portion219by therotating axispivot shaft218are accommodated in the curved cover228d of thecorrespondinghinge cover205as shown inFIG.22(that is, the sectional view taken along the arrow line C-C in.FIG.20), and the turning arm portion221idly moves vertically in the groove228c secured between the cover ends228a and228b of thecorrespondinghinge cover205. On the other hand, in the mouldingbraidconnection portion226oftheeachhinge cover205, as shown inFIG.23(a)andFIG.23(b)(that is, the sectional view taken along the arrow lineE-E23(b)-23(b)inFIG.23(a), the rear end237of thecorrespondingroof moulding236placed between the narrow end portion225a and the engagement tongue portion229is held and secured between the upper engagement linear projection230and the lower engagement linear projection231. At this time, it is preferable that,in thefor eachroof moulding236, the upper engagement linear projection230is engaged with the upper surface of the shoulder portion236b secured at the rear end upper portion of thecorrespondingroof moulding236, the side plane236c of the shoulder portion236b is brought into contact with the tip end of the narrow end portion225a of the mouldingbraidconnection portion226, and the rear end of thecorrespondingroof moulding236and the tip end of thecorrespondinghinge cover205continuouslyform asubstantially continuousflush surface. As described above, as shown inFIG.19, a rear part structure of a vehicle in which the tailgate201is attached so as to be freely opened and closed by the tailgate hinge members202disposed at both upper left and right ends of the rear part opening portion of the vehicle is thus constructed. At this time, the tailgate hinge member202is composed of a hinge base member203fixed on the rear end bottom portion of the groove208disposed between the roof panel R and the side frame S and the gate hinge portion204attached to the tailgate201and simultaneously axially supported on the hinge base member203so as to freely turn. The upper part of the hinge base member203is covered up by the hinge cover205fitted into the groove208, wherein the outer appearance of the vehicle can be ornamentally improved. In the above, some embodiments of the invention were described. However, it is a matter of course that the shapes, layouts and quantities of the respective components are subject to change within a scope not deviating from the spirit of the invention. | 50,035 |
RE49859 | DETAILED DESCRIPTION First Exemplary Embodiment Explanation follows regarding a first exemplary embodiment of a vehicle framework structure according to the present invention, with reference toFIG.1toFIG.6. Note that in the respective drawings, the arrow FR indicates the front in the vehicle front-rear direction, the arrow OUT indicates the vehicle width direction outer side, and the arrow UP indicates upward in the vehicle vertical direction. As illustrated inFIG.1, a vehicle12provided with a vehicle framework structure10includes a front framesection16, a rear framesection20, an intermediate framesection22, and coupling sections24,32, each located at a vehicle lower side of a floor panel, not illustrated in the drawings. The front framesection16configuresformspart of the framework of a front section of the vehicle12, and specifically, is configured including a pair of left and right front-side members26extending along the vehicle front-rear direction. A power unit and a front suspension member (neither of which are illustrated in the drawings) are attached to the front framesection16. Note that in the present exemplary embodiment, the floor panel of the vehicle12has a configuration that does not include a floor tunnel extending along the vehicle front-rear direction. The rear framesection20configuresformspart of the framework of a rear section of the vehicle12, and specifically, is configured including a pair of left and right rear-side members28extending along the vehicle front-rear direction. A trunk floor panel18(seeFIG.2) is attached to the rear framesection20from the vehicle upper side. The intermediate framesection22configuresformspart of the framework of an intermediate section of the vehicle12, and is disposed between the front framesection16and the rear framesection20. Specifically, the intermediate framesection22is configured including a pair of left and right rockers30serving as framework members extending along the vehicle front-rear direction, a front cross member34serving as a cross member extending in the vehicle width direction and coupling vehicle front end portions of the pair of left and right rockers30together in the vehicle width direction via the coupling sections32, and a rear cross member38serving as a cross member extending in the vehicle width direction and coupling vehicle rear end portions of the pair of left and right rockers30together in the vehicle width direction via the coupling sections24. Note that in plan view of the vehicle, the pair of left and right rockers30are disposed at the vehicle width direction outer sides of the front framesection16and the rear framesection20. Configuration may also be made in which the rockers30are joined directly to the front cross member34and the rear cross member38, with thejoinsjointsbeing covered by firstconfigurationcouplingmembers40. As illustrated inFIG.2, each coupling section24is configured including a firstconfigurationcouplingmember40and a secondconfigurationcouplingmember42. The firstconfigurationcouplingmember40is disposed on the intermediate framesection22side and is formed by casting so as to have a substantially L-shaped profile in plan view of the vehicle. A base end portion44configuringforminga vehicle front side of the firstconfigurationcouplingmember40is formed with a substantially L-shaped profile in vehicle front view by a horizontal wall portion46with a plate thickness direction in the vehicle vertical direction, and a vertical wall portion48with a plate thickness direction in the vehicle width direction. The base end portion44is connected to the rocker30in a state in which a ridge line, notillustratedlabeledin the drawings, formed between the horizontal wall portion46and the vertical wall portion48of the base end portion44issubstantially superimposed onlocated adjacent toa ridge line52on an upper face of the rocker30. Namely, the firstconfigurationcouplingmember40is attached to the rocker30so as to be continuous theretoalonga portion of the rocker 30 that extends inthe vehicle front-rear direction. Note that the coupling sections24according to the present exemplary embodiment are configured so as to basically have left-right symmetry to each other (left-right symmetry about a vehicle front-rear direction line passing through an intermediate location in the vehicle width direction).FIG.2accordingly illustrates one side in the vehicle width direction (on the right of the vehicle), and the following explanation primarily focuses on the one side in the vehicle width direction. Moreover, the coupling sections32(seeFIG.1) according to the present exemplary embodiment are configured so as to basically have front-rear symmetry to the coupling sections24(front-rear symmetry about a vehicle width direction line passing through an intermediate location in the vehicle front-rear direction), and so detailed explanation thereof will be omitted. As illustrated inFIG.4, aleadinglargerend portion54on the opposite side of the firstconfigurationcouplingmember40to the base end portion44isconfiguredformedincluding a joining wall portion56with a plate thickness direction in the vehicle front-rear direction. In vehicle front view, the joining wall portion56is set with larger dimensions in the vehicle vertical direction and the vehicle width direction than the base end portion44(seeFIG.2). The base end portion44and theleadinglargerend portion54(joining wall portion56) are integrally formed as a single member, with nojoinjointpresent therebetween. Moreover, plural fastening portions58are respectively formed at a vehicle upper end portion and a vehicle lower end portion of the joining wall portion56. Each fastening portion58has a greater plate thickness than the plate thickness of the joining wall portion56at locations ether than the fastening portions58. Accordingly, a vehicle rear face60of each fastening portion58projects out toward the vehicle rear with respect to the locations of the joining wall portion56other than the fastening portions58. Each fastening portion58of the joining wall portion56is formed with a fastening hole62with an axial direction along the plate thickness direction. The fastening holes62in the fastening portions58formed of the vehicle upper end portion of the joining wall portion56are, for example, through holes penetrating the fastening portions58in the plate thickness direction. The fastening holes62of the fastening portions58formed at the vehicle lower end portion of the joining wall portion56are, for example, non-penetrating holes that are open toward the vehicle rear. The joining wall portion56is formed with ribs64running toward the vehicle front. The ribs64are configured by plural first ribs66, each with a plate thickness direction in the vehicle vertical direction, and, as illustrated inFIG.2, plural second ribs68, each with a plate thickness direction in the vehicle width direction. Each of the plural first ribs66are disposed discretely to one another, and each of the plural second ribs68are disposed discretely to one another. Accordingly, in vehicle front view, the first ribs66and the second ribs68are disposed in a lattice pattern. Note that leading end portions of the plural first ribs66are respectively curved such that in plan view of the vehicle, the leading end portions of the first ribs66are positioned further toward the vehicle rear on progression toward the vehicle width direction inner side. Moreover, as illustrated inFIG.5, leading end portions of the plural second ribs68are also positioned further toward the vehicle rear on progression toward the vehicle width direction inner side so as to correspond to the leading end portions of the first ribs66. Moreover, a first cover member70that curves so as to span from the base end portion44to the cross member38is attached to the firstconfigurationcouplingmember40so as to partially follow the leading end portions of the plural first ribs66and partially follow of the leading end portions of the plural second ribs68. Due to the above configuration, the firstconfigurationcouplingmember40is formed so as to gradually increase in size in the vehicle width direction and the vehicle vertical direction on progression from the base end portion44toward theleadinglargerend portion54(joining wall portion56). Note that a vehicle lower side end portion of the first cover member70is integrally formed with a flange71extending along a substantially horizontal direction and toward the vehicle front. Moreover, as illustrated inFIG.2, a length direction end portion72of the rear cross member38is connected to a vehicle width direction inner side of the joining wall portion56. Specifically, a rear vertical wall portion74of the rear cross member38is connected to a vehicle front face of the joining wall portion56(see FIG.54). Note that the first cover member70is connected to the length direction end portion72of the rear cross member38from the vehicle front and the vehicle upper side. The secondconfigurationcouplingmember42is attached to the firstconfigurationcouplingmember40so as tobe continuous thereto alongextend therefrom inthe vehicle front-rear direction. Specifically, at each coupling section24, the secondconfigurationcouplingmember42is disposed at the vehicle rear of the firstconfigurationcouplingmember40. Moreover, at each coupling section32, the secondconfigurationcouplingmember42is disposed at the vehicle front of the firstconfigurationcouplingmember40(seeFIG.1). The secondconfigurationcouplingmember42is formed by casting so as to have a substantially L-shaped profile in plan view of the vehicle. As illustrated inFIG.3, a base end portion80configuringforminga vehicle rear side of the secondconfigurationcouplingmember42is formed with a substantially L-shaped profile in vehicle front view by a horizontal wall portion82with a plate thickness direction in the vehicle vertical direction, and a vertical wall portion83with a plate thickness direction in the vehicle width direction. The rear framesection20is connected to the base end portion80in a state in which a ridge line84between the horizontal wall portion82and the vertical wall portion83of the base end portion80issubstantially superimposed onlocated adjacent toa ridge line88at a lower face86of the rear framesection20. Namely, the ridge line84of the secondconfigurationcouplingmember42(the coupling section24) is configured so as to becontinuous withadjacent tothe ridge line88of the rear framesection20extendingin the vehicle front-rear direction. Note that in the coupling sections32, the ridge line84of the secondconfigurationcouplingmember42(the coupling section32) is configured so as tobe continuousextendin the vehicle front-rear directionadjacentto a non-illustrated ridge line of the front framesection16, so as to be symmetrical to the coupling sections24in the vehicle front-rear direction. Similarly to in the firstconfigurationcouplingmember40, aleadinglargerend portion92on the opposite side of the secondconfigurationcouplingmember42to the base end portion80isconfiguredformedincluding a joining wall portion90with a plate thickness direction in the vehicle front-rear direction. The joining wall portion90is formed in substantially the same shape as the joining wall portion56of the firstconfigurationcouplingmember40in vehicle front view (see alsoFIG.2). Moreover, in vehicle front view, the joining wall portion90of the secondconfigurationcouplingmember42is set with larger dimensions in the vehicle vertical direction and the vehicle width direction than the base end portion80. Moreover, as illustrated inFIG.4, plural fastening portions98corresponding to the respective fastening portions58of the firstconfigurationcouplingmember40are formed at a vehicle upper end portion and a vehicle lower end portion of the joining wall portion90. Each of the fastening portions98has a greater plate thickness than the plate thickness of the joining wall portion90at locations other than the fastening portions98. Accordingly, a vehicle front face100of each fastening portion98projects out toward the vehicle front with respect to the locations of the joining wall portion90other than the fastening portions98. The fastening portions98of the joining wall portion90are each formed with a fastening hole102having an axial direction along the plate thickness direction. The fastening holes102of the fastening portions98formed at the vehicle upper end portion of the joining wall portion90are, for example, non-penetrating holes open toward the vehicle front, and the fastening holes102of the fastening portions98formed at the vehicle lower end portion of the joining wall portion90are, for example, through holes penetrating the fastening portions98in the plate thickness direction. Fasteners104are inserted into the fastening portions98formed at the vehicle lower end portion of the joining wall portion90from the vehicle rear, and are screwed together with the fastening portions58formed at the vehicle lower end portion of the joining wall portion56of the firstconfigurationcouplingmember40. Similarly, fasteners104are inserted into the fastening portions58formed at the vehicle upper end portion of the joining wall portion56of the firstconfigurationcouplingmember40from the vehicle front, and are screwed together with the fastening portions98formed at the vehicle upper end portion of the joining wall portion90. The firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are thereby fastened together.Note that some ridge lines of plural ridge lines extending along the vehicle front-rear direction of the joining wall portion56of the first configuration member40are disposed so as to be continuous with some ridge lines of plural ridge lines extending along the vehicle front-rear direction of the joining wall portion90of the opposing second configuration member42. Moreover, in vehicle front view, some ridge lines of plural ridge lines within the face (vehicle rear face) of the joining wall portion56of the first configuration member40that is a face opposing the second configuration member42are disposed so as to be superimposed on some ridge lines of plural ridge lines within the face (vehicle front face) of the joining wall portion90of the second configuration member42that is a face opposing the first configuration member40. In other words, some of the ridge lines within the vehicle rear face of the joining wall portion56are disposed so as to oppose some of the ridge lines within the vehicle front face of the joining wall portion90in the vehicle front-rear direction. The joining wall portion90is formed with ribs108running toward the vehicle rear. The ribs108are configured by plural first ribs110with a plate thickness direction in the vehicle vertical direction and plural second ribs112(seeFIG.2andFIG.3) with a plate thickness direction in the vehicle width direction. Each of the plural first ribs110are disposed discretely to one another, and each of the plural second ribs112are disposed discretely to one another. Moreover, the plural first ribs110and the plural second ribs112are disposed so as to be substantially superimposed on the first ribs66and the second ribs68of the firstconfigurationcouplingmember40in vehicle front view (see alsoFIG.5). Accordingly, in vehicle front view, the first ribs110and the second ribs112are disposed in a lattice pattern. Note that as illustrated inFIG.3,leadingend portions of the plural first ribs110are respectively curved such that in plan view of the vehicle, theleadingend portions of the plural first ribs110are positioned further toward the vehicle front on progression toward the vehicle width direction outer side. Moreover, as illustrated inFIG.5,leadingend portions of the plural second ribs112are also positioned further toward the vehicle front on progression toward the vehicle width direction outer side so as to correspond to theleadingend portions of the first ribs110. Namely, the secondconfigurationcouplingmember42is formed so as to gradually increase in size in the vehicle width direction and the vehicle vertical direction on progression from the base end portion80toward theleadinglargerend portion92(joining wall portion90). A second cover member116is provided to the secondconfigurationcouplingmember42so as to cover the secondconfigurationcouplingmember42from the vehicle upper side. The second cover member116is configured from a plate member with a plate thickness direction in the vehicle vertical direction. As illustrated inFIG.2, a vehicle width direction inner side end portion of the second cover member116is disposed so as to substantially follow the vehicle front-rear direction from a vehicle width direction inner side end portion of the joining wall portion90. Moreover, vehicle width direction outer side end portions of the respective secondconfigurationcouplingmembers42follow vehicle width direction inner side faces of a pair of left and right wheel houses120provided at the vehicle width direction outer sides of the rear framesection20. Note that a vehicle width direction inner side end portion of the second cover member116is integrally formed with a flange122that follows the vehicle width direction inner side face of the wheel house120and stands up toward the vehicle upper side. Operation and Advantageous Effects of the First Exemplary Embodiment Explanation follows: regarding operation and advantageous effects of the present exemplary embodiment. As illustrated inFIG.1, in the present exemplary embodiment, the coupling sections32are capable of coupling the front framesection16configuringformingpart of thevehicleframeworkofatthe vehicle front section and the intermediate framesection22configuringformingpart of thevehicleframeworkofatthe vehicle intermediate section together in the vehicle front-rear direction. Similarly, the coupling sections24are capable of coupling the rear framesection20configuringformingpart of thevehicleframeworkofatthe vehicle rear section and the intermediate framesection22together in the vehicle front-rear direction. The coupling sections24,32each include the firstconfigurationcouplingmember40that is attachedso as to be continuous withtothe rocker30of the intermediate framesection22so as to extendin the vehicle front-rear direction, and the secondconfigurationcouplingmember42that is attachedso as to be continuous withtothe firstconfigurationcouplingmember40so as to extendin the vehicle front-rear direction. This thereby enables stress to be suppressed from concentrating between the intermediate framesection22and the firstconfigurationcouplingmember40and between the front framesection16or the rear framesection20and the secondconfigurationcouplingmember42. Moreover, theleadinglargerend portion54of the firstconfigurationcouplingmember40and theleadinglargerend portion92of the secondconfigurationcouplingmember42opposing theleadinglargerend portion54of the firstconfigurationcouplingmember40are joined together, thus respectively coupling the front framesection16or the rear framesection20to the intermediate framesection22in the vehicle front-rear direction. Note that the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are respectively formed so as to gradually increase in size along at least one of the vehicle width direction and the vehicle vertical direction on progression from the base end portions44,80toward theleadinglargerend portions54,92. Namely, the location where the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are joined together isconfiguredformedwith larger dimensions in the vehicle width direction and the vehicle vertical direction than other locations, thereby improving the ability to withstand input load. This thereby enables input load to be transmitted smoothly to elsewhere in the framework. Load transmission efficiency can accordingly be improved in a vehicle body structure not provided with a floor tunnel. Moreover, the intermediate framesection22includes the rockers30extending along the vehicle front-rear direction, and the front cross member34and the rear cross member38that respectively couple the rockers30together in the vehicle width direction via the firstconfigurationcouplingmembers40of the coupling sections24,32. Accordingly, load input to the intermediate framesection22from the coupling sections24,32can be transmitted smoothly to both the rockers30and the front cross member34or the rear cross member38by the firstconfigurationcouplingmember40. This thereby enables input load to be dispersed such that the load is borne by the overall framework. Moreover, in each of the coupling sections24,32, the location where the firstconfigurationcouplingmember40is joined to the rocker30and the location where the firstconfigurationcouplingmember40is joined to the front cross member34or to the rear cross member38areconfiguredformedas a single body, so as not to form ajoinjointwhere stress is liable to concentrate between the rocker30and the front cross member34or the rear cross member38. This thereby enables stress to be suppressed from concentrating in the firstconfigurationcouplingmembers40, and therefore in the coupling sections24,32. Furthermore, in each of the coupling sections24,32, at least one ridge line of the plural ridge lines extending in the vehicle front-rear direction in the vicinity of the leading end portion54of the first configuration member40is disposed so as to be continuous with at least one ridge line of the plural ridge lines extending in the vehicle front-rear direction in the vicinity of the leading end portion92of the second configuration member42. Accordingly, when load is input to the coupling sections24,32along the vehicle front-rear direction, the load can be transmitted smoothly from the first configuration member40to the second configuration member42or from the second configuration member42to the first configuration member40, along the ridge lines that have high bending rigidity. Moreover, in each of the coupling sections24,32, in vehicle front view, at least one ridge line of the plural ridge lines within the face of the leading end portion54of the first configuration member40that is a face opposing the second configuration member42is disposed so as to be substantially superimposed on at least one ridge line of the plural ridge lines within the face of the leading end portion92of the second configuration member42that is a face opposing the first configuration member40. Accordingly, when load is input to the coupling sections24,32along the vehicle front-rear direction, the load can be transmitted smoothly from the first configuration member40to the second configuration member42or from the second configuration member42to the first configuration member40, along the ridge lines that have high bending rigidity. This thereby enables a further improvement to load transmission efficiency in a vehicle body structure not provided with a floor tunnel. Moreover, in each of the coupling sections24,32, the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are respectively formed with the ribs64,108that extend along the vehicle front-rear direction. The respective ribs64,108are disposed so as to be substantially superimposed on one another in vehicle front view. Accordingly, when load is input to the coupling sections24,32along the vehicle front-rear direction, load input from one of the ribs64or the ribs108is borne by the other out of the ribs64or the ribs108, thereby enabling the load to be more reliably transmitted. Moreover, at least one ridge line of the plural ridge lines provided at the coupling sections24,32is configured so as to becontinuous withadjacent toat least one ridge line of the plural ridge lines provided at the front framesection16or the rear framesection20extendingin the vehicle front-rear direction, such that load can be transmitted from the front framesection16or the rear framesection20to the intermediate framesection22, or from the intermediate framesection22to the front framesection16or the rear framesection20, along the ridge lines that have high bending rigidity. This thereby enables a further improvement in load transmission efficiency in a vehicle body structure not provided with a floor tunnel. Moreover, in each of the coupling sections24,32, since the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are fastened together using the fasteners104, joining the firstconfigurationcouplingmember40and secondconfigurationcouplingmember42together is easier than in cases in which welding is employed. This thereby enables an improvement in productivity. Note that in the first exemplary embodiment described above, the ribs64and the ribs108are disposed so as to be substantially superimposed on each other in vehicle from view. However, there is no limitation thereto, and the ribs64and the ribs108may be disposed at positions that are not superimposed on each other. Moreover, the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are fastened together using the fasteners104. However, there is no limitation thereto, and configuration may be made in which the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42are joined together using another type of fastening, such as rivets, or are joined together by welding. Moreover, configuration is made in which the rocker30and either the front cross member34or the rear cross member38are attached to each firstconfigurationcouplingmember40. However, there is no limitation thereto, and configuration may be made in which only the rocker30is attached to the firstconfigurationcouplingmember40, or configuration may be made in which only either the front cross member34or the rear cross member38is attached to the firstconfigurationcouplingmember40. Further, each of the coupling sections24,32is configured such that the joining wall portion56of the firstconfigurationcouplingmember40is joined to the joining wall portion90of the secondconfigurationcouplingmember42. However there is no limitation thereto, and configuration may be made in which one length direction end portion of the rocker30is joined to one length direction end portion of either the front-side member26or the rear-side member28, with reinforcement members having an outer profile increasing in size on progression toward an end portion being provided at respective outer peripheral faces of the respective one length direction end portions, and these reinforcement members being joined together. MODIFIED EXAMPLE In the present exemplary embodiment, configuration is made in which the firstconfigurationcouplingmember40and the secondconfigurationcouplingmember42of the coupling section24are joined together at the joining wall portions56,90. However, there is no limitation thereto, and as illustrated inFIG.6, for example, configuration may be made in which a projection142is formed projecting out from a vehicle width direction outer side of the firstconfigurationcouplingmember40toward the vehicle rear, with the projection142being abutted against or joined to a vehicle width direction outer side of the secondconfigurationcouplingmember42. Namely, the projection142projects out toward the secondconfigurationcouplingmember42of the coupling section24, and since the projection142overlaps with the secondconfigurationcouplingmember42in the vehicle width direction, when load is input to one of the firstconfigurationcouplingmember40orandthe secondconfigurationcouplingmember42substantially along the vehicle width direction, the secondconfigurationcouplingmember42and the projection142abut one another, thereby enabling the load to be transmitted. This thereby enables shear deformation of the coupling sections24to be suppressed. Note that here, configuration is made in which the projection142is provided to the firstconfigurationcouplingmember40. However, there is no limitation thereto, and configuration may be made in which the projection142is provided to the secondconfigurationcouplingmember42so as to project out toward the firstconfigurationcouplingmember40. Moreover, the projection142is disposed at the vehicle width direction outer side of the firstconfigurationcouplingmember40. However, there is no limitation thereto, and the projection142may be disposed at the vehicle width direction inner side of the firstconfigurationcouplingmember40, or may be disposedat theupper side and/or lower side of the firstconfigurationcouplingmember40in the vehicle vertical direction. Second Exemplary Embodiment Next, explanation follows regarding a vehicle framework structure according to a second exemplary embodiment of the present invention, with reference toFIG.7toFIG.10. Note that configuration portions that are basically the same as those of the first exemplary embodiment described above are allocated the same reference numerals, and explanation thereof is omitted. The vehicle framework structure according to the second exemplary embodiment has the same basic configuration as the first exemplary embodiment, but is distinctive in the point that a hollow portion152is provided inside a coupling section150. Namely, as illustrated inFIG.7, a pair of left and right coupling sections150are eachconfiguredformedincluding a firstconfigurationcouplingmember154and a secondconfigurationcouplingmember156. The firstconfigurationcouplingmember154is disposed on the intermediate framesection22side (not illustrated inFIG.7), and is formed with a substantially L-shaped profile in vehicle front view. A base end portion158configuringformingthe vehicle front of the firstconfigurationcouplingmember154is formed with a substantially L-shaped profile in vehicle front view by a horizontal wall portion160with a plate thickness direction in the vehicle vertical direction, and a vertical wall portion162with a plate thickness direction in the vehicle width direction. The base end portion158is joined to the rocker30in a state in which a ridge line164between the horizontal wall portion160and the vertical wall portion162of the base end portion158issubstantially superimposed onadjacent tothe ridge line52(seeFIG.2) at the upper face of the rocker30. Note that the horizontal wall portion160and the vertical wall portion162extend toward the vehicle rear and are joined to a joining wall portion166, described later. As illustrated inFIG.8, aleadinglargerend portion168on the opposite side of the firstconfigurationcouplingmember154to the base end portion158isconfiguredformedincluding the joining wall portion166that has a plate thickness direction in the vehicle front-rear direction. In vehicle front view, the joining wall portion166is set with larger dimensions in the vehicle vertical direction and the vehicle width direction than the base end portion158, and vehicle rear end portions of the horizontal wall portion160and the vertical wall portion162are respectively joined to the vicinity of a vehicle upper end portion of the joining wall portion166. Accordingly, the horizontal wall portion160is curved toward the vehicle upper side on progression from the base end portion158toward theleadinglargerend portion168, and the vertical wall portion162is curved toward the vehicle width direction inner side on progression from the base end portion158toward theleadinglargerend portion168. The base end portion158and theleadinglargerend portion168(joining wall portion166) are thus formed as a single body. Moreover, the length direction end portion72of the rear cross member38is joined to the vehicle width direction inner side of the firstconfigurationcouplingmember154so as to be superimposed thereon from the vehicle upper side. The secondconfigurationcouplingmember156is disposed at the vehicle rear of the firstconfigurationcouplingmember154, and is formed with a substantially L-shaped profile in plan view of the vehicle. A base end portion159of the secondconfigurationcouplingmember156is, for example, integrally formed to the rear framesection20disposed at the vehicle rear of the secondconfigurationcouplingmember156. Note that the secondconfigurationcouplingmember156of a non-illustrated coupling section provided with front-rear symmetry is integrally formed to the front framesection16. As illustrated inFIG.8, similarly to the firstconfigurationcouplingmember154, aleadinglargerend portion172of the secondconfigurationcouplingmember156isconfiguredformedincluding a joining wall portion174with a plate thickness direction in the vehicle front-rear direction. The joining wall portion174is formed with substantially the same shape as the joining wall portion166of the firstconfigurationcouplingmember154in vehicle front view. The joining wall portion174is set with larger dimensions in the vehicle vertical direction and the vehicle width direction than the base end portion159of the secondconfigurationcouplingmember156. As illustrated inFIG.9, the joining wall portion174of the secondconfigurationcouplingmember156is formed with a through hole180that serves as an opening and as a fitted-to portion, and that penetrates the joining wall portion174in the plate thickness direction. Moreover, asconceptuallyillustrated inFIG.10, the firstconfigurationcouplingmember154is formed with the hollow portion152that is open toward the vehicle rear at a position corresponding to the through hole180. A portion of a suspension arm182is inserted toward the vehicle front into the through hole180and the hollow portion152. An outer peripheral edge of the hollow portion152projects out toward the vehicle rear and is inserted into the through hole180of the secondconfigurationcouplingmember156, and is provided with a fitting portion184that abuts against an inner peripheral wall face of the through hole180in the secondconfigurationcouplingmember156. Operation and Advantageous Effects of the Second Exemplary Embodiment Next, explanation follows regarding operation and advantageous effects of the present exemplary embodiment. With the exception of the point that the hollow portion152is provided inside the coupling section150, the configuration described above is similar to the vehicle framework structure of the first exemplary embodiment, and is thereby capable of obtaining the same advantageous effects as the first exemplary embodiment. Moreover, the wright of the coupling section can be reduced as a result of forming the hollow portion152and the through hole180in the coupling section150. This thereby enables a reduction in weight. Moreover, a portion of the suspension arm182is inserted into the hollow portion152and the through hole180of the coupling section150, thereby enabling space to be saved. This thereby enables more efficient utilization of space in the vehicle. Moreover, in the coupling section150, the fitting portion184is formed at one of the firstconfigurationcouplingmember154or the secondconfigurationcouplingmember156, and the through hole180, into which the fitting portion184is fitted by being inserted in the vehicle front-rear direction, is formed at the other of the firstconfigurationcouplingmember154or the secondconfigurationcouplingmember156. Accordingly, when connecting the firstconfigurationcouplingmember154and the secondconfigurationcouplingmember156together, positioning of the firstconfigurationcouplingmember154and the secondconfigurationcouplingmember156can be performed easily by inserting the fitting portion184into the through hole180. Moreover, since it is possible for load to be transmitted either from the fitting portion184to the through hole180or from the through hole180to the fitting portion184, when load is input to one of the firstconfigurationcouplingmember154orandthe secondconfigurationcouplingmember156substantially along the vehicle vertical direction or substantially along the vehicle width direction, the load can be better transmitted to the otheroutof the firstconfigurationcouplingmember154orandthe secondconfigurationcouplingmember156. This thereby enables the load transmission efficiency to be improved for load input in any direction. Moreover, the secondconfigurationcouplingmember156of the coupling section150is formed as a single body withat leastone of the front framesection16orandthe rear framesection20, rendering an operation to attach the secondconfigurationcouplingmember156toat leastone of the front framesection16orandthe rear framesection20unnecessary. A reduction in the number of assembly processes can accordingly be achieved. This thereby enables an improvement in productivity. Note that in the second exemplary embodiment described above, configuration is made in which the hollow portion152is formed in the firstconfigurationcouplingmember154. However, there is no limitation thereto, and the hollow portion152may be provided in the secondconfigurationcouplingmember156, or hollow portions152may be provided in both the firstconfigurationcouplingmember154and the secondconfigurationcouplingmember156. Moreover, a member other than the suspension arm182may be inserted into the hollow portion152, or configuration may be made in which nothing is inserted into the hollow portion152. Moreover, configuration is made in which the fitting portion184is provided to the firstconfigurationcouplingmember154, and is fitted into the through hole180in the secondconfigurationcouplingmember156. However, there is no limitation thereto, and configuration may be made in which a fitting hole, not illustrated in the drawings, is formed in the secondconfigurationcouplingmember156for the fitting portion184, and the fitting portion184is fitted into the fitting hole. Moreover, configuration may be made in which the fitting portion184is provided to the secondconfigurationcouplingmember156and is fitted together with the hollow portion152formed in the firstconfigurationcouplingmember154, or with another fitting hole, not illustrated in the drawings, formed in the firstconfigurationcouplingmember154. Moreover, in the first and second exemplary embodiments described above, configuration is made in which in each of the coupling sections24,32,150, the cross member is attached to the firstconfigurationcouplingmember40,154. However, there is no limitation thereto, and configuration may be made in which the cross member is attached to the secondconfigurationcouplingmember42,156. Moreover, configuration may be made in which the cross member is not attached to the coupling sections24,32,150. Moreover, configuration is made in which the firstconfigurationcouplingmember40,154and the secondconfigurationcouplingmember42,156gradually increase in size in the vehicle vertical direction and in the vehicle width direction on progression from the base end portion44,80,158,159toward theleadinglargerlarger end portion54,92,168,172. However, there is no limitation thereto, and configuration may be made in which the gradual increase in size is only in at least one of the vehicle vertical direction or the vehicle width direction. Moreover, in the firstconfigurationcouplingmember40,154, the base end portion44that is joined to the rocker30, and the portion of the firstconfigurationcouplingmember40,154that is joined to the cross member, are configured as a single body so as not to formjoinsjoints. However, there is no limitation thereto, and configuration may be made in which these portions are each configured by separate bodies with ajoinjointpresent therebetween. Moreover, some ridge lines of the plural ridge lines of the joining wall portion56,166of the first configuration member40,154are disposed so as to be continuous with the ridge lines of the joining wall portion90,174of the opposing second configuration member42,156. However, there is no limitation thereto, and these ridge lines may be non-continuous with each other. Moreover, configuration is made in which at least one ridge line of each of the coupling sections24,32,150is continuous with at least one ridge line of the front frame16, the rear frame20, or the intermediate frame22. However, there is no limitation thereto, and these ridge lines may be non-continuous with each other. Although explanation has been given regarding exemplary embodiment of the present invention, is the present invention is not limited to the above, and obviously various modification either than the above may be implemented in a range that does not depart from the spirit of the present invention. | 40,528 |
RE49860 | EXAMPLES Example 1 Methyl 4-bromo-2-methoxybenzoate (XV) 3.06 kg (22.12 mol) of potassium carbonate are initially charged in 3.6 l of acetone and heated to reflux. To this suspension are added 1.2 kg of 4-bromo-2-hydroxybenzoic acid (5.53 mol), suspended in 7.8 l of acetone and is further rinsed with 0.6 l of acetone. The suspension is heated under reflux for 1 hour (vigorous evolution of gas!). 2.65 kg (21.01 mol) of dimethyl sulphate are then added over 4 hours while boiling. The mixture is subsequently stirred under reflux for 2.5 hours. The solvent is largely distilled off (to the point of stirrability) and 12 l of toluene are added and the residual acetone is then distilled off at 110° C. About 3 l of distillate are distilled off, this being supplemented by addition of a further 3 l of toluene to the mixture. The mixture is allowed to cool to 20° C. and 10.8 l of water are added and vigorously stirred in. The organic phase is separated off and the aqueous phase is extracted once more with 6.1 l of toluene. The combined organic phases are washed with 3 l of saturated sodium chloride solution and the toluene phase is concentrated to ca. 4 l. Determination of the content by evaporation of a portion results in a converted yield of 1.306 kg (96.4% of theory). The solution is used directly in the subsequent stage. HPLC method A: RT ca. 11.9 min. MS (EIpos): m/z=245 [M+H]+ 1H NMR (400 MHz, CD2Cl2): δ=3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, 1H). Example 2 4-Bromo-2-methoxybenzaldehyde (XVI) 1.936 kg (6.22 mol) of a 65% Red-Al solution in toluene is charged with 1.25 l of toluene at −5° C. To this solution is added 0.66 kg (6.59 mol) of 1-methylpiperazine, which is rinsed with 150 ml of toluene, keeping the temperature between −7 and −5° C. The mixture is then allowed to stir at 0° C. for 30 minutes. This solution is then added to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 4 l of toluene, keeping the temperature at ˜8 to 0° C. After further rinsing twice with 0.7 l of toluene, the mixture is then stirred at 0° C. for 1.5 hours. For the work-up, the solution is added to cold aqueous sulphuric acid at 0° C. (12.5 l of water+1.4 kg of conc. sulphuric acid). The temperature should increase at maximum to 10° C. (slow addition). The pH is adjusted to pH 1, if necessary, by addition of further sulphuric acid. The organic phase is separated off and the aqueous phase is extracted with 7.6 l of toluene. The combined organic phases are washed with 5.1 l of water and then substantially concentrated and the residue taken up in 10 l of DMF. The solution is again concentrated to a volume of ca. 5 l. Determination of the content by evaporation of a portion results in a converted yield of 1.041 kg (94.1% of theory). The solution is used directly in the subsequent stage. HPLC method A: RT ca. 12.1 min. MS (EIpos): m/z=162 [M+H]+ 1H-NMR (CDCl3, 400 MHz): δ=3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10.40 (1H, s) Example 3 4-Formyl-3-methoxybenzonitrile (VI) 719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 l of DMF are charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K4[Fe(CN)6]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate are added. The mixture is stirred at 120° C. for 3 hours. The mixture is allowed to cool to 20° C. and 5.7 l of water is added to the mixture. The mixture is extracted with 17 l of ethyl acetate and the aqueous phase washed once more with 17 l of ethyl acetate. The organic phases are combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to ca. 2 l. The mixture is heated to boiling and 2 l of water added dropwise. The mixture is allowed to cool to 50° C. and 2 l of water added anew. The mixture is cooled to 3° C. and stirred at this temperature for one hour. The product is filtered off and washed with water (2 times 1.2 l). The product is dried at 40° C. under vacuum. Yield: 469 g (87% of theory) of a beige solid. HPLC method A: RT ca. 8.3 min. MS (EIpos): m/z=162 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H). Example 4 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-3-carboxylate (X) Variant A 1.035 kg (6.422 mol) of 4-formyl-3-methoxybenzonitrile (VI), 1.246 kg (8.028 mol) of 2-cyanoethyl 3-oxobutanoate, 54.6 g (0.642 mol) of piperidine and 38.5 g (0.642 mol) of glacial acetic acid are heated under reflux in 10 l of dichloromethane for 6.5 hours on a water separator. The mixture is allowed to cool to room temperature and the organic phase is washed twice with 5 l of water each time. The dichloromethane phase is then concentrated at atmospheric pressure and the still stirrable residue is taken up in 15.47 kg of 2-butanol and 0.717 kg (5.78 mol) of 4-amino-5-methylpyridone is added. The residual dichloromethane is distilled off until an internal temperature of 98° C. is reached. The mixture is subsequently heated under reflux for 20 hours. The mixture is cooled to 0° C., allowed to stir at this temperature for 4 hours and the product is filtered off. The product is dried at 40° C. under vacuum under entraining gas. Yield: 2.049 kg (87.6% of theory based on 4-amino-5-methylpyridone, since this component is used substoichiometrically) of a pale yellow solid. HPLC method A: RT ca. 9.7 min. MS (EIpos): m/z=405 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H). Variant B 1.344 kg (8.34 mol) of 4-formyl-3-methoxybenzonitrile (VI), 71 g (0.834 mol) of piperidine and 50.1 g (0.834 mol) of glacial acetic acid are charged in 6 l of isopropanol and at 30° C. a solution of 1.747 kg (11.26 mol) of 2-cyanoethyl 3-oxobutanoate in 670 ml of isopropanol is added over 3 hours. The mixture is then stirred at 30° C. for one hour. The mixture is cooled to 0-3° C. and stirred for 0.5 hours. The product is filtered off and washed twice with 450 ml of cold isopropanol each time. To determine the yield, the product is dried at 50° C. under vacuum (2.413 kg, 97% of theory); however, due to the high yield, the isopropanol-moist product is generally further processed directly. For this purpose, the product is taken up in 29 l of isopropanol and 1.277 kg (7.92 mol) of 4-amino-5-methylpyridone are added and then the mixture is heated to an internal temperature of 100° C. under a positive pressure of ca. 1.4 bar for 24 h in a closed vessel. The mixture is then cooled to 0° C. by means of a gradient over a period of 5 h and then stirred at 0° C. for 3 hours. The product is then filtered off and washed with 2.1 l of cold isopropanol. The product is dried at 60° C. under vacuum. Yield: 2.819 kg (88% of theory based on 4-amino-5-methylpyridone, since this component is used substoichiometrically) of a pale yellow solid. HPLC method A: RT ca. 9.7 min. MS (EIpos): m/z=405 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H). Example 5 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI) 2.142 kg (5.3 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (X) and 4.70 kg (29 mol) of triethyl orthoacetate are dissolved in 12.15 l of dimethylacetamide and 157.5 g of concentrated sulphuric acid are added. The mixture is heated at 115° C. for 1.5 hours and then cooled to 50° C. At 50° C., 12.15 l of water are added dropwise over 30 minutes. After completion of the addition, the mixture is seeded with 10 g of the title compound (XI) and a further 12.15 l of water are added dropwise over 30 minutes at 50° C. The mixture is cooled to 0° C. (gradient, 2 hours) and stirred at 0° C. for two hours. The product is filtered off, washed twice with 7.7 l each time of water and dried at 50° C. under vacuum. Yield: 2114.2 g (92.2% of theory) of a pale yellow solid. HPLC method B: RT ca. 10.2 min. MS (EIpos): m/z=433 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H). Alternatively, the reaction may be carried out in NMP (1-methyl-2-pyrrolidone) 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI) 2.142 kg (5.3 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (X) and 2.35 kg (14.5 mol) of triethyl orthoacetate are dissolved in 3.21 kg of NMP (1-methyl-2-pyrrolidone) and 157.5 g of concentrated sulphuric acid are added. The mixture is heated at 115° C. for 1.5 hours and then cooled to 50° C. At 50° C., 2.2 l of water are added dropwise over 30 minutes. After completion of the addition, the mixture is seeded with 10 g of the title compound (XI) and a further 4.4 l of water are added dropwise over 30 minutes at 50° C. The mixture is cooled to 0° C. (gradient, 2 hours) and then stirred at 0° C. for two hours. The product is filtered off, washed twice with 4 l each time of water and dried at 50° C. under vacuum. Yield: 2180.7 g (95.1% of theory) of a pale yellow solid. HPLC method B: RT ca. 10.2 min. Example 6 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic Acid (XII) 2.00 kg (4.624 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI) are dissolved in a mixture of 12 l of THF and 6 l of water and cooled to 0° C. To this solution at 0° C. is added dropwise over 15 minutes an aqueous sodium hydroxide solution (prepared from 0.82 kg of 45% aq. NaOH (9.248 mol) and 4.23 l of water and the mixture is then stirred at 0° C. for 1.5 hours. The mixture is extracted twice with 4.8 l of methyl tert-butyl ether each time and once with 4.8 l of ethyl acetate. The aqueous solution at 0° C. is adjusted to pH 7 with dilute hydrochloric acid (prepared from 0.371 kg of 37% HCl and 1.51 l of water). The solution is allowed to warm to 20° C. and an aqueous solution of 2.05 kg of ammonium chloride in 5.54 l of water is added. The solution is stirred at 20° C. for 1 hour, the product filtered and washed twice with 1.5 l of water each time and once with 4 l of acetonitrile. The product is dried at 40° C. under entraining gas. Yield: 1736.9 g (99% of theory) of an almost colourless powder (very light yellow tint). HPLC method C: RT: ca. 6.8 min. MS (EIpos): m/z=380 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H). Alternative work-up using toluene for the extraction: 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic Acid (XII) 2.00 kg (4.624 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI) are dissolved in a mixture of 12 l of THF and 6 l of water and cooled to 0° C. To this solution at 0° C. is added dropwise over 15 minutes an aqueous sodium hydroxide solution (prepared from 0.82 kg of 45% aq. NaOH (9.248 mol) and 4.23 l of water and the mixture is then stirred at 0° C. for 1.5 hours. 5 L of toluene and 381.3 g of sodium acetate are added and stirred in vigorously. The phases are allowed to settle and the organic phase is separated. The aqueous phase is adjusted to pH 6.9 with 10% hydrochloric acid (at ca. pH 9.5 the solution is seeded with 10 g of the title compound). After precipitation of the product is complete, the mixture is stirred at 0° C. for one hour and is then filtered and washed twice with 4 l of water each time and twice with 153 ml of toluene each time. The product is dried at 40° C. under vacuum under entraining gas (nitrogen, 200 mbar. Yield: 1719.5 g (98% of theory) of an almost colourless powder (very slight yellow tint). HPLC method C: RT: ca. 6.8 min.) Example 7 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) 1.60 kg (4.22 mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (XII) and 958 g (5.91 mol) of 1,1-carbodiimidazole are charged in 8 l of THF and 51 g (0.417 mol) of DMAP is added at 20° C. The mixture is stirred at 20° C. (evolution of gas!) for one hour and then heated to 50° C. for 2.5 hours. 2.973 kg (18.42 mol) of hexamethyldisilazane is added to this solution and is boiled under reflux for 22 hours. A further 1.8 l of THF is added and the mixture cooled to 5° C. A mixture of 1.17 l of THF and 835 g of water is added over 3 hours such that the temperature remains between 5 and 20° C. The mixture is subsequently boiled under relux for one hour, then cooled via a gradient (3 hours) to 0° C. and stirred at this temperature for one hour. The product is filtered off and washed twice with 2.4 l of THF each time and twice with 3.2 l of water each time. The product is dried at 70° C. under vacuum under entraining gas. Yield: 1.501 kg (94% of theory) of an almost colourless powder (very slight yellow tint). HPLC method B: RT ca. 6.7 min. MS (EIpos): m/z=379 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H). Example 8 (4S)-4-(4-Cyano-2-methoxphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) as a Solution in Acetonitrile/Methanol 40:60 Enantiomer Separation on an SMB System The feed solution is a solution corresponding to a concentration consisting of 50 g of racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), dissolved in 1 liter of a mixture of methanol/acetonitrile 60:40. The solution is chromatographed by means of an SMB system on a stationary phase: Chiralpak AS-V, 20 μm. The pressure is 30 bar and a mixture of methanol/acetonitrile 60:40 is used as eluent. 9.00 kg of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XII) are dissolved in 180 l of a mixture consisting of methanol/acetonitrile 60:40 and chromatographed by means of SMB. After concentrating the product-containing fractions, 69.68 liters of a 6.2% solution (corresponding to 4.32 kg of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) is obtained as a solution in acetonitrile/methanol 40:60). Yield: 4.32 kg (48% of theory), as a colourless fraction dissolved in 69.68 liters of acetonitrile/methanol 40:60. Enantiomeric purity: >98.5% e.e. (HPLC, method D) A sample is concentrated under vacuum and gives: MS (EIpos): m/z=379 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H). Example 9 (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Crystallization and Polymorph Adjustment 64.52 liters of a 6.2% solution from Example 8 in a mixture of acetonitrile/methanol 40:60 (corresponding to 4.00 kg of compound 1) were filtered through a filter cartridge (1.2 um) and subsequently sufficiently concentrated at 250 mbar such that the solution is still stirrable. 48 l of ethanol, denatured with toluene, was added and distilled again at 250 mbar up to the limit of stirrability (redistillation in ethanol). A further 48 l of ethanol, denatured with toluene, was added and then distilled off at atmospheric pressure down to a total volume of ca. 14 l (jacket temperature 98° C.). The mixture was cooled via a gradient (4 hours) to 0° C., stirred at 0° C. for 2 hours and the product filtered off. The product was washed twice with 4 l of cold ethanol each time and then dried at 50° C. under vacuum. Yield: 3.64 kg (91% of theory) of a colourless crystalline powder. Enantiomeric purity: >>99% e.e. (HPLC method D); Retention times/RRT: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 11 min. RRT: 1.00; (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 9 min. RRT: 0.82 Purity: >99.8% (HPLC method B), RT: ca. 6.7 min. Content: 99.9% (relative to external standard) specific rotation (chloroform, 589 nm, 19.7° C., c=0.38600 g/100 ml): −148.8°. MS (EIpos): m/z=379 [M+H]+ 1H NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H). Melting point: 252° C. (compound of the formula (I) in crystalline form of polymorph I) Physicochemical Characterization of Compound of the Formula (I) in Crystalline Form of Polymorph I Compound of the formula (I) in crystalline form of polymorph I melts at 252° C., ΔH=95-113 Jg−1(heating rate 20 Kmin−1,FIG.1). A depression of the melting point was observed depending on the heating rate. The melting point decreases at a lower heating rate (e.g. 2 Kmin−1) since decomposition occurs. No other phase transitions were observed. A loss of mass of ca. 0.1% was observed up to a temperature of 175° C. Stability and Moisture Absorption Samples of compound of the formula (I) in crystalline form of polymorph I were stored at 85% and 97% rel. humidity (25° C.). The samples were evaluated after 12 months by DSC, TGA and XRPD. After 12 months, a mass change of <0.1% is observed in both cases. This means that compound of the formula (I) in crystalline form of polymorph I shows no significant absorption of water under these storage conditions. According to DSC, TGA and XRPD, no difference exists in compound of the formula (I) in crystalline form of polymorph I. Pharmaceutical Formulation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the Formula (I) A granular solution of the compound of the formula (I) in crystalline form of polymorph I in micronized form, hypromellose 5 cP and sodium lauryl sulphate was prepared in purified water. Microcrystalline cellulose, lactose monohydrate and croscarmellose sodium were mixed (premix) in a container or a fluidized bed granulator. The premix and the granular solution were granulated in the fluid-bed granulator. The lubricant magnesium stearate was added after which the granulate was dried and sieved. A ready to press mixture was thus prepared. The ready to press mixture was compressed to give tablets using a rotary tablet press. A homogeneous coating suspension was prepared from hypromellose, talc, titanium dioxide, yellow iron oxide, red iron oxide and purified water. The coating suspension was sprayed onto the tablets in a suitable coating device. Ph IIbPh IIbPh IIbPh IIbPh IIbPh IIbPh IIbComposition[mg][mg][mg][mg][mg][mg][mg]Compound1.252.505.007.5010.0015.0020.00of the formula (I) inpolymorph ImicronizedExcipientsMicrocrystalline73.8072.5069.9067.3064.7062.0059.30celluloseCroscarmellose4.504.504.504.504.504.504.50sodiumHypromellose 5 cP4.504.504.504.504.504.504.50Lactose monohydrate45.0045.0045.0045.0045.0042.5040.00Magnesium stearate0.900.900.900.900.900.900.90Sodium lauryl0.050.100.200.300.400.600.80sulphateWeight (uncoated130.00130.00130.00130.00130.00130.00130.00tablet)Film-coatingHypromellose 5 cP3.03363.03363.03363.03363.03363.03363.0336Titanium dioxide2.31962.31962.31962.31962.31962.31962.3196Talc0.60720.60720.60720.60720.60720.60720.6072Yellow iron oxide0.03240.03240.03240.03240.03240.03240.0324Red iron oxide0.00720.00720.00720.00720.00720.00720.0072Weight (film-6.00006.00006.00006.00006.00006.00006.0000coating)Weight (coated136.00136.00136.00136.00136.00136.00136.00tablet) HPLC Conditions/Methods Method A YMC Hydrosphere C18 150*4.6 mm, 3.0 μm 25° C., 1 ml/min, 270 nm, 4 nm 0′: 70% TFA 0.1%*; 30% acctonitrile 17′: 20% TFA 0.1%*; 80% acetonitrile 18′: 70% TFA 0.1%*; 30% acetonitrile *: TFA in water Method B YMC Hydrosphere C18 150*4.6 mm, 3.0 μm 25° C., 1 ml/min., 255 nm, 6 nm 0′: 90% TFA 0.1%; 10% acetonitrile 20′: 10% TFA 0.1%; 90% acetonitrile 18′: 10% TFA 0.1%; 90% acetonitrile Method C Nucleodur Gravity C-18 150*2 mm, 3.0 μm 35° C.; 0.22 ml/min., 255 nm, 6 nm Solution A: 0.58 g of ammonium hydrogen phosphate and 0.66 g of ammonium dihydrogen phosphate in 1 L of water (ammonium phosphate buffer pH 7.2) Solution B: acetonitrile 0′: 30% B; 70% A 15′: 80% B; 20% A 25′: 80% B; 20% A Method D Column length: 25 cm Internal Diameter: 4.6 mm Packing: Chiralpak IA, 5 μm Reagents: 1. Acetonitrile HPLC grade 2. Methyl tert-butyl ether (MTBE), p.a. Test solution The sample is dissolved at a concentration of 1.0 mg/mL in acetonitrile. (e.g. ca. 25 mg of sample, weighed exactly, dissolved in acetonitrile to 25.0 mL). Eluent A. acetonitrile B. Methyl tert-butyl ether (MTBE), p.a. Flow rate 0.8 ml/min Column oven temperature 25° C. Detection measuring wavelength: 255 nm Band width: 6 nm Injection volumes 5 μL Mix composition of eluents A and B in ratio by volume of 90:10 Chromatogram run time 30 min Retention times/RRT:(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 11 min. RRT: 1.00(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 9 min. RRT: 0.82 Lattice Constants of Compound of the Formula (I) in Crystalline Form of Polymorph I Polymorph I Crystal system orthorhombic Space group P2(1)2(1)2(1) Molecules per unit cell 4 Length of axis a [Å] 7.8610(3) Length of axis b [Å] 11.7797(6) Length of axis c [Å] 20.1792(8) α [°] 90 β [°] 90 γ [°] 90 Calculated density at 100 K [g cm-3] 1.345 Measuring parameters of the x-ray diffractometry for the measurementof compound of the formula (I) in crystalline form of polymorph IData set name2429-08a r2Scan axis2Theta-OmegaStart position [°2Th.]2.0000End position [°2Th.]37.9900Type of divergence screenFixedSize of divergence screen [°]1.0000Measurement temperature [° C.]25Anode materialCuK-Alpha1 [Å]1.54060Generator setting35 mA, 45 kVDiffractometer typeTransmission diffractometerGoniometer radius [mm]240.00Focus-div. screen gap [mm]91.00Primary beam monochromatorYesSample rotationYes Peak maximum[2 Theta]Polymorph I8.511.411.913.414.114.815.015.416.017.218.519.019.820.520.822.122.723.023.123.623.924.624.925.225.626.026.527.127.328.328.528.829.630.130.631.531.932.432.933.133.433.734.534.735.035.836.236.537.237.4 Measuring Conditions for the IR and Raman Spectroscopy for the Measurement of the Compound of the Formula (I) in Crystalline Form of Polymorph I: IR:InstrumentPerkin Elmer Spectrum OneNumber of scans32Resolution4 cm−1TechniqueDiamond ATR unitRaman:InstrumentBruker Raman RFS 100/SNumber of scans64Resolution2-4 cm−1Laser Power350 mWLaser wavelength1064 nm Band maximum [cm−1]1R-ATRRamanPolymorph IPolymorph I347530743416299733662970307429412992292029522836283522312230165916811641165816231606160115721577148514871464144314541383143113621420132714071303138112671355123013411191132511611303112312851093126710321255991122988312228271161810113675910977341031708991671976613967528924505909471875442847346827320810297776186758155746114733723706697670 DESCRIPTION OF THE FIGURES FIG.1: DSC (20 Kmin−1) and TGA of compound of the formula (I) in crystalline form of polymorph I FIG.2: X-ray of a single crystal of polymorph 1 of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) FIG.3: X-ray diffractogram of compound of the formula (I) in crystalline form of polymorph I FIG.4: Raman spectrum of compound of the formula (I) in crystalline form of polymorph I FIG.5: FT-Infrared (IR) spectrum (KBr) of compound of the formula (I) in crystalline form of polymorph I FIG.6: FT-Infrared (IR) spectrum (ATR) of compound of the formula (I) in crystalline form of polymorph I FIG.7: FT-Near-infrared (NIR) spectrum of compound of the formula (I) in crystalline form of polymorph I FIG.8: FT-Far-infrared (FIR) spectrum of compound of the formula (I) in crystalline form of polymorph I FIG.9: Solid state13C-NMR spectrum of compound of the formula (I) in crystalline form of polymorph I FIG.10: Stability of compound of the formula (I) in crystalline form of polymorph I in air humidity (x-axis % relative humidity/y-axis weight change in % | 25,117 |
RE49861 | DETAILED DESCRIPTION OF THE INVENTION Novel features which are characteristic of the invention, as to organization and method of operation, together with further objects and advantages thereof will be better understood from the following description considered in connection with the accompanying drawings, in which preferred embodiments of the invention are illustrated by way of example. It is to be expressly understood, however, that the drawings are for illustration description only and are not intended as definitions of the limits of the invention. The various features of novelty which characterize the invention are recited with particularity in the claims. There has been broadly outlined more important features of the invention in the summary above and in order that the detailed description which follows may be better understood, and in order that the present contribution to the art may be appreciated. There are, of course, additional features of the invention that will be described hereinafter and which will form additional subject matter of the claims appended hereto. Those skilled in the art will appreciate that the conception upon which this disclosure is based readily may be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important therefore, that claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention. Certain terminology and the derivations thereof may be used in the following description for convenience and reference only, and will not be limiting. For example, words such as “upward,” “downward,” “left,” and “right” refer to directions in the drawings to which reference is made unless otherwise stated. Similar words such as “inward” and “outward” refer to directions toward and away from, respectively, the geometric center of a device or area and designated parts thereof. Reference in the singular tense include the plural and vice versa, unless otherwise noted. As noted previously, prior attempts to produce bio coal through torrefaction have not been cost-effective both in terms of capital expenditures and maintenance costs. In addressing these issues, the present invention employs a device as depicted in the appended figures in carrying out the presently claimed method. In turning toFIG.1, the device of the present invention for carrying out the claimed method is, in effect, a double-pipe heat exchanger such that process fluid carrying the requisite cellulosic material flows through pipe30typically having a wall thickness of approximately ⅛ to 0.375 inches having linear sections60, a linear section diameter, longitudinal axes62and substantially circular circumference. Pipe30is provided with inlet11and outlet12, linear segments3060being joined by curved segments61creating a substantially serpentine structure. The segments are joined with others creating an array as depicted inFIG.2. Such arrays can be contained within housing40as standalone modular units which can be joined to similar modular units for increasing the overall length of the device as needed. Typically, torrefaction can be completed in practicing the present method by pipe lengths of approximately ⅓ to 2 miles with pipes having a thermal conductivity of 10-55 W/(m*C). In that the device depicted herein acts, in effect, as a countercurrent heat exchanger, linear segments60are surrounded by sleeves50creating annular spaces56(FIG.5). The ratio of pipe diameter to sleeve diameter is typically approximately 0.522 to 0.875. The cellulosic feedstock carried by process fluid is introduced to the device at inlet11and heating fluid introduced to sleeves50at inlet13and having outlet14thus filling annular spaces56. As shown, longitudinal axes of tubular sleeves50coincide with longitudinal axes62of pipe30. When stacked as shown inFIG.2, outlet12of pipe30is in fluid communication with inlet11of the next downstream pipe and outlet14of sleeve50is in fluid communication with inlet13of a downstream annular space56. To facilitate the uniform mixing of the cellulosic material, such as wood chips or nut shells within the process fluid, mixing elements33,34,35and36are provided. These mixing elements are capable of mixing the cellulosic material and process fluid while not creating nooks or dead spaces which would act to inhibit fluid flow within conduit30. In turning toFIGS.3-5, mixing elements33,34,35and36are characterized as having no edges or surfaces perpendicular to longitudinal axes62and are sized so that no such elements are in contact with one another resulting in an open region of travel96for fluids passing through conduit30along its longitudinal axis. Ideally, each mixing element is seated within conduit30at an angle between approximately 25° to 45° to said longitudinal axis. Most importantly, however, the mixing elements are positioned within conduit orpurepipe30as to not inhibit flow or clog as these are provided with no points of contact and no nooks or crotches which would otherwise result in fluid hangup. Ideally these mixing elements enable cellulosic material carried within heat transfer fluid having effective diameters of 40% or more of the conduit diameter to pass through the conduit without entrainment. Such a geometry is disclosed and claimed in U.S. Pat. No. 5,758,967, the disclosure of which is incorporated by reference. As a preferred embodiment, the mixing elements are provided as pairs such as33/34and35/36. Each complementary pair causes flowing material to rotate about axis62of conduit30in opposite directions. As is further noted, the four mixing elements are each shown primarily as a circular segments each of a height of approximately D/10 wherein D is the diameter of conduit30. Various mixing elements are set in a non-opposing fashion at the pipe wall so as to present to the fluid in any plane normal to axes62of conduit30a non-symmetrical cross-section. This serves to break up the normal circular symmetry of flow and to substantially reduce the length of conduit30necessary to achieve torrefaction. Ideally, the heating or high temperature fluid has a specific heat of approximately 0.26 to 0.40 BTU/(lb*° F.) and capable of exhibiting an inlet temperature of approximately 900 to 1500° F. An excellent example would be a molten salt. The process fluid is introduced at typical inlet temperatures between approximately 100 to 400° F. and can be any liquid having a high boiling point and which is devoid of oxygen. An example of a suitable process fluid with a relatively high boiling point as to not boil off while the cellulosic feedstock is being processed is an oil available by Permanente Corporation sold under the brand name GRC88. As noted, the heating fluid passes within annulus56which can also be configured with mixing elements53,54,55and5657which are used in pairs causing fluid to rotate in opposite directions. These mixing elements are employed in order to ensure even temperature of the heating fluid as uneven temperature gradients could lead to the heating fluid parially solidifying within the annular space. These elements are used as a low pressure drop solution in order to increase turbulence in the annulus, thus ensuring uniform temperature gradient across the cross-section. The above disclosure is sufficient to enable one of ordinary skill in the art to practice the invention, and provides the best mode of practicing the invention presently contemplated by the inventor. While there is provided herein a full and complete disclosure of the preferred embodiments of the invention, it is not desired to limit the invention to the exact construction, dimensions, relationships, or operations as described. Various modifications, alternative constructions, changes and equivalents will readily occur to those skilled in the art and may be employed as suitable without departing from the true spirit and scope of the invention. Such changes might involve alternative materials, components, structural arrangements, sizes, shapes, forms, functions, operational features or the like. Therefore, the above description and illustration should not be considered as limiting the scope of the invention, which is defined by the appended claims. | 8,354 |
RE49862 | SUMMARY OF THE INVENTION The primary object of the present invention is to provide a quiet, attractive, energy efficient air circulating device that is mounted coplanar to, and extends a minimal distance from a ceiling, said device combining the functions of a ceiling fan with the functions and aesthetic appeal of a ceiling medallion but which also provides a solution to some of the stated shortcomings of the prior art. It is a further object of the invention to provide such a device from which a lighting fixture, pendent or chandelier may be mounted as shown inFIG.1. It is a further object of some embodiments of the invention to optionally embody a means to filter dust, pollen and other particulate matter from the circulating airstream. It is a further object of some embodiments of the invention to optionally embody, any of the following; heating, cooling, positive ion generation means, and/or air sterilization means. DETAILED DESCRIPTION OF THE INVENTION According to a broad aspect of the present invention there is provided an air circulating device comprising a ceiling plate which is mounted coplanar to a ceiling and to which is mounted an air inlet; air impelling means which in preferred embodiments is driven by a motor; internal airflow channeling means; primary airflow discharge outlet and means to direct the discharge airflow in the direction intended. All of the forgoing is to be structured in such a manner that the outer surfaces provide an external appearance similar to a ceiling medallion. It is within the scope of the invention that said structure may be generally circular, rectangular or polygonal and may have decorative embellishment about the perimeter and on downward facing surfaces. In the simplest embodiment, the top surface of a ceiling plate is mounted coplanar to a ceiling, proximate to an electrical supply run within said ceiling and said ceiling plate is rigidly affixed to a supporting frame member of said ceiling. Additional fastening means may be required peripherally to hold the ceiling plate and corresponding assembly tightly to the ceiling sheeting material. In preferred embodiments, the static part of a motor is fixedly mounted, centrally within the enclosing structure and an air impelling means is driven by the driving part of the motor. The motor drives the air impelling means rotationally causing air to be drawn in through an intake opening, be pushed through internal airflow channeling means and expelled through one or more air discharge openings. Air deflecting means proximate to said air discharge openings distributes discharged air about the surrounding area to provide the desired level of comfort. Optionally said air deflecting means may be alternately repositioned to distribute discharged air in a direction more or less downward from the ceiling in cooling season or an outward, horizontal direction across the ceiling in heating season. According to a further aspect of the present invention, a wiring box on the downward facing side of the enclosing structure is provided to enclose motor controlling devices and for the optional mounting of a lighting fixture or chandelier. According to a further optional aspect of the invention filtration means are mounted at the primary airstream inlet such that air drawn into the inlet must pass though said filtration means before it enters the area of the impelling means. it is fully within the scope of this aspect of the invention that the filtration means be either or both mechanical or electrostatic. According to a further optional aspect of the invention, primary air discharged by said impelling means temporarily dwells within a plenum chamber where it is becomes pressurized before it is further discharged at high velocity through a narrow, slotted opening that is coincident with and tangent to a cambered surface such as to cause consistent fluid wall attachment of said discharged air. Said fluid wall attachment is well known to the art as the Coanda Effect and said cambered surface is known as a Coanda Surface and the attached fluid flow is also known as a Wall Jet A significant amount of adjacent ambient air will then become entrained in the flow of the wall jet to create a secondary airflow. In preferred embodiments, a second cambered surface, is positioned a distance peripheral and adjacent to the said Coanda surface to act as a guide for said secondary airflow. In said embodiments, adjacent cambered surfaces converge near the horizontal mid- plane which is normal to the chord of both cambered surfaces, and diverge at both the inlet and outlet of secondary flow, thereby funneling ambient air into the area of convergence and causing an area of tow pressure at the discharge, and thereby drawing additional ambient air into the secondary airflow. In the present invention a unique Coanda flow reversing mechanism is provided by a section of said Coanda surface that can be repositioned so as to close the slotted opening through which said wall jet is generated and to open a second slotted opening oriented in the opposite direction, causing a reversal of the wall jet and secondary airflow. This allows overall airflow to be directed from ceiling to floor in the cooling season and floor to ceiling in the heating season. According to a further optional aspect of the invention, discharged air may be further conditioned by positive ion generation means or ultra violet radiation. According to a further optional aspect of the invention, heating or cooling means may be mounted in the airstream. A preferred embodiment of the present invention, is shown inFIG.2,2A,2B,FIG.3,3A,3B,3C,3DandFIG.4. Referring toFIG.2BandFIG.3, a ceiling plate12, is fixedly mounted coplanar to a ceiling and motor1has a centrally located stator1A fixedly mounted to ceiling plate12and an external, peripheral rotor18on which an air impelling means2, that in this embodiment, is a centrifugal impeller of a design common to the trade, is affixed. Air is drawn in by air impelling means2, enters through Filter Cover3and passes through Filtration Means4. Air is pushed by air impelling means2, between impeller shroud5and ceiling plate12, where it is directed in a generally downward direction by diverter guides6and7. A hollow conduit though motor stator1A, provides a pathway for a wiring harness8from an electrical supply within the ceiling to an electrical wiring box9, which is provided for electrical motor controlling devices and the optional mounting of a light or chandelier. Filter support13, provides support for filtration means4and filter cover3. A cover10may be provided if no lighting fixture is to be mounted. Ceiling plate12provides a frame and support for the preceding assembly and also provides the means to affix the said assembly to the ceiling. In this embodiment of the present invention, peripherally mounted air deflection means may be adapted to direct effluent air downward for summer cooling or horizontally across the ceiling to improve heat distribution during the heating season. InFIG.3,3B,3D, a plurality of positioning devices11, which in this embodiment are of a snap-over-center spring type, allow diverter guide7to be positioned either to direct discharged air flow downward for coolingFIG.3B, or across the ceiling for improved distribution of warm air during heating seasonFIG.3D. In other embodiments of the present invention,FIG.5and6, the air acceleration means is a radial impeller. It is fully within the scope of this invention that a plurality of stationary blades, peripheral to the radial impeller, known to the trade as stators be arrayed at angles more or less tangential to impeller axis of rotation to improve efficiency but at such an to angle and quantity as to prevent resonance and consequential noise. In this embodiment of the present invention,FIG.5andFIG.6, optional heat exchanging means is mounted in the air flow path. Said heat exchanging means may be of a tubular radiator type common to the trade which is supplied with a flow of heated or chilled liquid or evaporating refrigerant to provide additional heating or cooling. InFIG.5,FIG.6and6Athe motor1is affixed to the Ceiling plate12, which is mounted coplanar to a ceiling, proximate to an electrical power source, and the radial impeller2is affixed to the rotatable body of the motor1. Referring toFIG.6A, the rotating impeller2causes air to be drawn in through filter cover3and through filtration means4, after which it is pushed by radial impeller2through a passage between impeller shroud5and ceiling plate12, to be discharged through cooling I heating means14. Air discharged through heating I cooling means14is then directed in a generally downward direction by diverters6and7. In this embodiment, the curved surfaces of diverters6and7serve as foils to disperse discharged air about the room. It is within the scope of the present invention that other diverting means, such as louvers, fixed or adjustable, may be used to disperse discharged air. Item19is a decorative cover. Electrical wiring box9is attached to the non-rotating body of motor1and wiring harness8passes, from said electrical power source within the ceiling, through said non-rotating body of motor1to electrical wiring box9which, in preferred embodiments encloses motor controlling devices and also provides means to mount and supply power to an optionally attached lighting fixture. It is it is within the scope of the present invention that said heating means be of another type such as electric resistive heating. It is also within the scope of the present invention that said heating or cooling means be either totally integrated within the present invention or be part of a heating and/or cooling system central to a building. In a further embodiment,FIG.7,7A,7B,FIG.8,8A,8B, andFIG.9, airflow amplification means, which in this embodiment comprises a unique, reversible, Coanda Effect, air amplifying assembly. Air enters a radial impeller in a fashion similar to the foregoing embodiments, but is compressed by said radial impeller and is then discharged into a plenum chamber at an elevated pressure where it dwells before being discharged through a slot, at an accelerated velocity, as a primary airflow in an essentially tangential relationship to a cambered surface, which in this embodiment is an exterior wall of said plenum chamber, and to which said primary air flow remains in fluid attachment as a wall jet. Said cambered surface is one of a pair of peripherally offset, concentric and adjacent, cambered surface features. In this embodiment, a peripheral Flow Guide is positioned external to the circumference and concentric to said plenum chamber and has a cambered inner surface which is in mirrored relation to the Coanda Surface of said plenum chamber. Ambient air is drawn in and entrained by the primary wall jet and by the low pressure zone, created, at the divergence of the two cambered surfaces. This significantly multiplies the total volume of air flow for a given motor size. The cambered Coanda surface of the plenum chamber is comprised of first and second fixed sections and a repositionable portion that defines the position and direction of the primary discharge slot and thus the direction of both primary and secondary airflow. InFIG.7A, Air flow is directed from ceiling to floor. Motor1drives impeller2rotationally which draws ambient air in as a primary intake through Filter Cover3and Filter4and then drives said intake air through a narrowing section formed by the impeller shroud5and the Ceiling Plate12until it enters the plenum chamber which comprises first and second plenum sections15,16and repositionable section17, where it dwells and becomes pressurized until discharged through a slot defined by First Plenum Section16and repositionable plenum section17. The cambered surfaces of17and15form the Coanda surface to which said primary wall jet becomes fluidly attached. The peripherally facing surfaces of Plenum sections15,16and17, and the adjacent inward facing surface of Flow Guide18, together form a pair of geometrically opposed cambered surfaces, converging at the entrance of airflow and diverging at the discharge. Ambient air becomes entrained with the primary wall jet, establishing a coincident secondary airflow. An area of low pressure is formed near the point of discharge as air exits the flow path between said diverging walls causing additional ambient air to be entrained. The flow of entrained ambient air shrouds the high velocity air flow from the plenum and acts as a barrier to attenuate sound created by said high velocity air flow. InFIG.8Arepositionable plenum section17has been repositioned for flow reversal. The slot through which the primary wall jet flow was generated between first plenum section16and repositionable section17inFIG.7A and7Bhas closed and a slot is now open between second plenum section15and repositionable plenum section17. This new geometry mirrors, to some extent, the geometry of this area revealed previously inFIG.7A and7B. The wall jet now flows in the opposite direction in fluid attachment to the Coanda surface formed by plenum section15and repositioned plenum section17, as does the secondary flow of entrained ambient air, causing total airflow to be directed from floor to ceiling as would be most advantageous during the heating season. FIG.9is provided to better understand the general arrangement of components of the embodiment revealed inFIG.7andFIG.8where the stator of motor1is fixedly mounted to the ceiling plate12and the impeller2is mounted to the driven rotatable body of motor1. The rotating impeller causes air to be drawn in through intake grating3and through filtration means4which is supported by filter support13, after which it is pushed through a passage between impeller shroud5, and ceiling plate12to where it is compressed within a plenum chamber, which comprises plenum sections,15and17and repositionable plenum section16. Said pressurized air is then discharged from said plenum chamber through a slot between either plenum sections15and17or16and17depending on the position of repositionable plenum section17, coincident with a Coanda surface formed by the outward facing surfaces of either Plenum sections15and17or16and17, The outwardly facing combined surfaces of said plenum chamber together with the inwardly facing cambered surface of flow guide18which essentially mirrors the cambered surfaces of said plenum chamber, form a pair of peripherally offset, adjacent and geometrically opposite cambered surfaces. Said surfaces converge to funnel ambient air into the area influenced by the wall jet and cause an area of low pressure where these surfaces diverge. In another embodiment of the device of the present invention revealed inFIG.10,FIG.11,11AandFIG.12, the outline of the device, as viewed from below, is non-circular and, as illustrated in this embodiment, is rectangular. It is, however, fully within the scope of this embodiment that said plan form could be polygonal. FIG.10is an illustration of this embodiment with a pendant fixture attached. (Shown in phantom) inFIG.11,FIG.11Athe motor,1, is mounted to the Ceiling plate, Item12, and the impeller,2, is mounted to the rotatable body of the motor1. The rotating impeller causes air to be drawn in through intake grating,3, and through filtration means, Item4, after which it is directed through a passage formed between impeller shrouds5,23and ceiling plate12into plenums20, from which it is discharged and distributed about the room by diverters, Items6. FIG.12is provided to better understand the general arrangement of components where the motor1, is mounted to the Ceiling plate12, and the impeller, Item2, is mounted to the rotatable body of the motor1. Item3is the intake grating, Item4is filtration means, Item5and Item23are the impeller shrouds, Items20are the plenums and Items6, are the diverters. Item13is a filter support Items22are decorative blocks, items24are plenum covers and Item9is a wiring box which encloses motor controlling devices and also provides means to mount and supply power to an optionally attached lighting fixture perFIG.12. | 16,243 |
RE49863 | DESCRIPTION OF THE PREFERRED EMBODIMENT A preferred embodiment of the present invention will be given herein below in conjunction with the illustrations shown in the attached figures. A variable refrigerant package21is shown inFIG.1installed in a closet23formed by frame25on floor27of a space to be cooled. Frame25extends to the outside29of the space being cooled. For illustration purposes, the sheetrock or other covering material for the frame25has been removed. Inside of the closet23is installed a base31on which the variable refrigerant package21sits. A duct adapter33is installed near the top of the closet23for connection to the top of the variable refrigerant package21to direct the conditioned air to a desired location. The variable refrigerant package21is inserted into the closet23through door opening35. Referring now toFIG.2, the variable refrigerant package21has been removed. During construction of the closet23by the contractor building the hotel/motel, a plenum37is installed that has an interior wall plenum39that telescopes inside of exterior wall plenum41. The lower portion of both the interior wall plenum39and exterior wall plenum41slopes downward toward the outside29. A plenum divider baffle43is located inside of the interior wall plenum39and exterior wall plenum41. The plenum37extends from the outside29to the inside of closet23. Because of the telescoping feature of the plenum37, varying widths of the outside wall45can be accommodated with typical widths being between four to eight incises. An outdoor louvre grill47covers the outside opening of plenum37. The outdoor louvre grill47has downwardly sloped louvres49to keep rain from entering through plenum37. In addition to installing the plenum37through outside wall45, a contractor building the hotel/motel will install base31inside of closet23. The outer portion of the base31will extend over the inside lower edge of interior wall plenum39in a manner as will be subsequently described. To provide good sealing contact with the variable refrigerant package21(shown inFIG.1), a plenum gasket51is located on the inside of interior wall plenum39. To seal with the bottom of the variable refrigerant package21, a base gasket53is provided on the top edge of base31. InFIG.3, the installation of the variable refrigerant package21inside of the closet23is illustrated. The variable refrigerant package21is inserted through the door opening35. Installation rails55are mounted on the bottom of the variable refrigerant package21to slide in grooves in the top of base31until the variable refrigerant package21slides through and presses against the plenum gasket51to provide a good seal between the plenum37and the variable refrigerant package21. The bottom of the variable refrigerant package21rests on the base gasket53. After the variable refrigerant package21is in place, duct adapter33moves downward to enclose supply duct flanges57. While not shown inFIGS.1through3, closet23will be wired by the contractor with electricity so the variable refrigerant package may be plugged in for power. Also, a connection (not shown) is provided in closet23to the room sensor. By installing the return air door59in the door opening35of the closet23and plugging into power and the room sensor, the variable refrigerant package21as shown inFIG.3is ready for operation. The installation of the variable refrigerant package21can be completed by non-certified personnel. FIG.4shows an exploded perspective view of the mechanical parts of the variable refrigerant package21. The condenser base assembly61has a drain tray63in the bottom thereof, which rests on base65. Below base65are located the installation rails55. Compressor67rests on the drain tray63, which is supported by the base65. Extending upward from the base65are corner posts69. On the top of corner posts69is located the condenser top cover71. Connected to the underside of the condenser top cover71are fresh air modules73, which will be discussed in more detail subsequently. Control box75is located between corner posts69. Adjacent the control box75is control box cover77. Located below the control box cover77is condenser access panel79. Lower side covers81enclose the sides of the condenser base assembly61. Upper side covers83enclose the upper sides of the variable refrigerant package21. Any return air coming back into the variable refrigerant package21has to enter through the return air filter85. Located within the condenser base assembly61are the condenser87and the condenser shroud89. The condenser fan assembly91is located within the condenser shroud89and blows air through the condenser87. Condenser drain pan93will collect any moisture that drips off of condenser87or the evaporator drain pan103. Located above the compressor67is the reversing valve assembly95. Located above the condenser top cover71is an insulation plate97, which is mounted between the condenser top cover71and the evaporator base99. Located above the evaporator base99is evaporator101with an evaporator drain pan103there below. Connecting from the evaporator drain pan103to the bottom of the variable refrigerant package21is evaporator drain tube105. To draw air through the evaporator101, a blower assembly107draws air through blower inlet panel109. Between the blower inlet panel109and the evaporator101is located electric heater111. Allowing access to the electric heater111is heater access panel113. Conditioned air after flowing through evaporator101, electric heater111, blower inlet panel109and blower assembly107leaves through supply duct flanges57as previously described in conjunction withFIG.3. A reheat coil115is located behind the evaporator101. Referring now toFIG.5, a pictorial cross-sectional view of the variable refrigerant package21is shown. The same numbers as applied to prior component parts described inFIGS.1through4will be used inFIG.5. The blower assembly107brings indoor entering air across the return air filter85, evaporator coil101, reheat coil115and out blower inlet panel109to give indoor leaving air. Any moisture that is collected drains out through evaporator drain tube105. Outdoor entering air is drawn in through outdoor air inlet117by the condenser fan assembly91with the majority of the air blowing out through the condenser shroud89and through condenser87to give outdoor leaving air. The flow of the outdoor air provides cooling for the control box75as well as removing heat from condenser87. A small amount of the outdoor entering air flows through the fresh air module73. Rectangular openings121and honeycomb openings119(seeFIG.4) in evaporator base99allows the fresh air to flow there through. From the honeycomb openings119, the fresh air flows to the inlet side of evaporator101. Therefore, excess moisture in the fresh air is removed as the fresh air flows through the evaporator101. To ensure that an appropriate amount of fresh air is being drawn into the space being cooled, each of the fresh air modules73have fans inside of them to control the fresh air flow, as will be described in more detail subsequently. The fresh air entering through the fresh air module73is cooled and dehumidified by the evaporator101. The fresh air is mixed with the indoor entering air, cooled and dehumidified with the evaporator101with any moisture being collected by evaporator drain panel103and discharged out the evaporator drain tube105. During the heating mode for the variable refrigerant package21, electric heaters111may be turned ON to heat the indoor entering air. If humidity needs to be removed from the fresh air, the evaporator101is operated just enough to remove the humidity. The reheat coil115will provide any reheating necessary due to the operation of the evaporator101in removing humidity. Referring toFIGS.5and6in combination,FIG.6shows an enlarged, cross-sectional view of one of the fresh air modules73. The fresh air module73has an outdoor air fan123for drawing air into fresh air chamber125. The outdoor air fan123has a housing, fan blade and motor very similar to a computer-style fan. From the fresh air chamber125fresh air flows through outdoor air filter127. Rectangular openings121and honeycomb openings119allows some of the outdoor entering air to be mixed with indoor entering air in front of the evaporator coil101. The mixed air streams of outdoor entering air and indoor entering air are then conditioned to whatever condition the variable refrigerant package21is set. The mixed air can be cooled, dehumidified or heated. If dehumidified, the evaporator drain pan103will collect the moisture which is subsequently discharged out evaporator drain tube105(seeFIGS.4and6). Any air entering the air conditioned space is filtered by the outdoor air filter127or, upon recirculation, by the return air filter85. Traditional air conditioners simply control the temperature of the space being cooled. They turn ON or OFF based upon the temperature set point inside the space being conditioned. The traditional air conditioner may not run long enough to remove moisture from the space. Most traditional air conditioners do not bring fresh air into the space being cooled. Fresh air is required for the occupants to breathe and to displace noxious fumes, plus bring oxygen into the space being conditioned. The present invention brings fresh air into the space being conditioned and by a sophisticated control system that coordinates the motors and compressor allows the variable refrigerant package21to run longer so that it will cause more dehumidification of the air. As the space being conditioned gets closer and closer to the desired temperature, the motors and compressor are slowed down so that the unit will run longer to dehumidify the space being conditioned. The variable refrigerant package21varies its ability to cool the enclosed space by two distinct methods. In the first method, the variable refrigerant package21reduces its capacity or ability to cool by varying the speeds of the motors or compressor as the conditioned space approaches the desired temperature. The second method is to add some reheat back to the space being cooled as is provided by the re-heater coil115. In the reheat method, the evaporator101is allowed to continue to run and remove moisture from the air, but heat is then added back through re-heater coil115. In this method the conditioned space is being actively dehumidified. The electrical controls for the variable refrigerant package21are illustrated inFIG.7. A wall controller129, commonly called a thermostat, sets the desired temperature inside of enclosed space. The wall controller129may be communicated with through an external communications module131. Also, setting up the operating parameters of the variable refrigerant package21may be done with SD card133. The wall controller129communicates with the main controller135. The main controller135has a wall controller communications137for communicating with the wall controller129. The main controller135has a processor136in which provisional data may be programmed by data switches138. The main controller135communicates with motor control system139via MCS communication141. Also, main controller135communicates with heater board143via heater communication145. The main controller135could be referred to as the master unit with the motor control system139and/or the heater board143being referred to as slave units. Both the motor control system139and the heater board143receive commands from the processor136in the main controller135. If a problem is detected in either the motor control system139or the heater board143, the message is communicated back through the main controller135and is displayed on the wall controller129. The wall controller129may receive commands or send commands back and forth with the main controller135, plus having an external communications module131. The main controller135has a USB interface147for communicating with a personal computer149. The personal computer149may be programmed to set data points in the main controller135, retrieve data, send commands, or remotely control the entire variable refrigerant package21. Also, the personal computer149may be used to do monitor control tests to make sure the variable refrigerant package21is operating properly. Any error history in the main controller135may be downloaded and observed in the personal computer149. The personal computer149may be used for troubleshooting or upgrading software in the main controller135. The parameters set in the main controller135can be changed through the personal computer149. Inside of the motor control system139, processor151controls fan driver153that operates the indoor fan155. By providing pulse width modulation to the indoor fan155, the speed of the indoor fan155and its power consumption is controlled. Also, processor151controls the fan driver157for the outdoor fan159. The indoor fan155is the same as blower assembly107shown inFIGS.4and5. Outdoor fan159is the same as condenser fan assembly91shown inFIGS.4and5. Processor161inside of motor control system139operates a compressor driver163that in turn operates the compressor67. By pulse width modulation from the processor161via the compressor driver163, the speed of the compressor67may be varied. Outside power feeds through power input lines165and fuses167to the power supply169. The power supply169has power factor correction therein as will be subsequently described in conjunction withFIGS.8and9. Service personnel that may work on the variable refrigerant package21will probably not have a personal computer149to connect through USB interface147. Therefore, an SD socket171is provided to receive SD card173. The SD card173may be used to upgrade the program or firmware inside of the main controller135. Also, the SD card173may be used for troubleshooting or downloading the history of the operation of the variable refrigerant package21. The SD card173can also provide extra memory for the main controller135. The motor control system139may have its own SD card175. By having the SD card173in the main controller135and SD card175in the motor control system139, extra memory is provided for a remote upgrade. If the motor control system139is being upgraded from the wall controller129, SD card175needs to be installed to provide as a temporary memory storage space while the motor control system139is being upgraded. Similarly, to upgrade the main controller135through the wall controller129, SD card173must be installed to provide temporary memory storage. The main controller135also controls a stepping driver177that operates electronic expansion valve179. The electronic expansion valve179controls the flow of the refrigerant inside the system. The operation of the electronic expansion valve179is controlled by the temperature entering the evaporator101and the temperature entering the compressor67(seeFIG.5). The electronic expansion valve179is opened or closed to maintain a certain temperature range between the evaporator inlet and the compressor inlet. The electronic expansion valve179acts like a modulating valve. As an alternative to the motor control system139operating the indoor fan155, an indoor fan181may be pulse width modulated by motor control183inside of main controller135. The heater board143energizes and de-energizes the reversing valve185. Assuming the variable refrigerant package21has been in the cooling mode and is switched to the heating mode, the main controller135will cause the heater board143to switch the reversing valve185. Communication between the main controller135and the heater board143is provided by heater communication145with the microcontroller187. From the microcontroller187, a signal is sent to the reversing valve triac189to switch the reversing valve relay191. A microcontroller187that could be used is a Freescale KL02. Since the microcontroller187provides pulse width modulation, the zero cross-detector193lets the microcontroller187know when the alternating current provided in power input lines165crosses the zero axis. If heat is being called for, the microcontroller187will operate heater relay drivers194to switch heater relays195and/or197, which controls heaters199and201, respectively. A heater silicon controlled rectifier203completes the circuit for heaters199and/or201and is operated by microcontroller187. A 3.3 volt regulator192is provided internally in a heater board143. Internally within the main controller135are a +3.3 volt regulator205and a +5 volt regulator207. Feeding into microcontroller135is a number of temperature sensors209of the variable refrigerant package21. FIG.8is a more in-depth review of the motor control system139. The power input lines165connect from an alternating current source211, which may vary from 180 to 293 volts AC, into the motor control system139. The alternating current source211feeds through an EMI filter213prior to connecting to 2-phase interleaved active power factor correction215. The 2-phased interleaved active power factor correction215has a current sensor217and a voltage sensor219. With the current sensor217and voltage sensor219, the power being consumed can continually be determined. From the 2-phase interleaved active power factor correction215, a 430 volt DC bus221is generated. From the 430 volt DC bus221, an isolated auxiliary power supply223generates +12 volts DC at 2.5 amps. Inside of motor control system139is processor161as previously explained in connection withFIG.7. Processor161controls the compressor motor67through compressor driver163. The 430 volt DC bus221supplies DC voltage to the compressor driver163. Processor151controls outdoor fan motor159through outdoor fan driver157and indoor fan motor155through indoor fan driver153. The processor151provides pulse width modulated power via outdoor fan driver157to outdoor fan motor159. Likewise, processor151provides pulse width modulated power to indoor fan155via indoor fan driver153. The motor control system139shown inFIG.8has an active power factor correction which is provided in part by the 2-phase interleaved active power factor correction215. The signal being delivered to the compressor motor67through the compressor driver163from the processor161senses the rotor position inside the compressor67. The signal being received from the 430 volt DC bus221is chopped and converted into a simulated three-phase AC signal to make the motor axis of the compressor67spin at the desired rate. The outdoor fan driver157for the outdoor fan motor159is doing essentially the same thing by taking the signal from the 430 volt DC bus221, chopping it and providing a simulated three-phase AC current to the outdoor fan motor159. Likewise, the indoor fan driver153does essentially the same thing for the indoor fan motor155. While the compressor driver163is being controlled by processor161, outdoor fan driver157and indoor fan driver153are being controlled by processor151. A bias power supply225receives voltage from 430 volts DC bus221and generates +15 volts DC and +3.3 volts DC, which is used to supply power to any part of the variable refrigerant package21that may need those voltage levels. The +3.3 volt DC is used to operate processors161and processor151. All of the conditioning of the power received and converted to DC signals is done inside of the motor control system139. While the bias power supply225generates +15 volts and +3.3 volts, multiplexer227has an isolated RS-485 duplexer229for connection to an external device. The external device may be similar to the personal computer149shown inFIG.7. The isolated RS-485 duplexer229allows for external connections and controls to the motor control system139. Also, the motor control system139has an isolated serial peripheral interface231that may connect to a micro SD card175. The SD card175may be used to update the motor control system139, check error messages and exchange information therewith. The motor control system139is where all of the power conversion is done. This is where the drivers163,157and153are all located. This is where regulated power is generated from a highly unregulated source. When the variable refrigerant package21is turned OFF so the alternating current source211no longer connects through the EMI filter213to the 2-phase interleaved active power factor correction215, inductive or capacitive charges may still remain in the circuit. A bleeder circuit220is provided through which the inductive and/or capacitive charges may drain down. The LED222will remain lit until the bleeder circuit220has fallen below a predetermined current. Turning now toFIG.9, a schematic view is shown of the 2-phase interleaved active power factor correction215. The alternating current source211feeds through the EMI filter213to the 2-phase interleaved active power factor correction215. Within the 2-phase interleaved active power factor correction215, the alternating current is changed by a full wave rectifier301to a rectified AC signal. The rectified AC signal from the full wave rectifier301feeds through inductors303and305. The inductors303and305are connected to current sensors307and309, respectively. Each current sensor307and309connects to MOSFETs311and313, respectively. Resistor network on the front of the N-phase interleaved active PFC215are resistors315and317. While resistors315and317provide sensing on the front end of the two-phase interleaved active PFC215, resistors319and321provide a feedback voltage323to a controller325. The controller325also receives a current sense327from current sensor307and current sense329from current sensor309, respectively. Further, the controller325receives the input voltage333as developed across input resistors315and317. Diodes335,337and339insure that current only flows in one direction to capacitor341. The controller325monitors the input voltage333, feedback voltage323, along with current sense327and329to decide if the power factor needs to be corrected. The controller325controls the point at which each of the MOSFETs311and/or313are fired to get the maximum power factor. The maximum power factor is when the current and the voltage are in phase with each other. An example of such a controller325that can control the firing of MOSFETs311and313is a Texas Instrument, Part No. UCC-2807. The controller325is taking the feedback voltage323and the input voltage333and comparing them with the current sense327and329and firing the MOSFETs311and313to get a power factor as close to 1 as possible. “Power factor” in an AC electrical power system is the ratio of real power flowing to the load versus apparent power in the circuit. A power factor of less than 1 means the voltage and current wave forms are not in phase. Real power is the capacity of the circuit for performing work in a particular time. Apparent power is the product of the current load of the circuit. In an electrical power system, a load with a low power factor draws more current than a load with a high power factor. Higher currents increase the energy loss in the system. The present system uses an active power factor which is built into the power consuming portion of the variable refrigerant package21. In the 2-phase interleaved active power factor correction215, there is continuous “ebb-and-flow” of the reactants (capacitive and inductive). The power factor will continue to change unless there are corrections in the power factor. The present invention uses a2-phase interleaved active factor correction215, but could use a single phase or other multi-phase configurations. InFIG.9, the unregulated AC voltage being received from alternating current source211is taken and converted into a regulated DC output voltage by using a switched mode power supply. The DC voltage is regulated even though the AC voltage may vary over a broad range. For example, the AC voltage can vary from 180 volts AC to 293 volts AC, yet the DC bus will be maintained at 430 volts DC. Referring toFIG.10, and exploded perspective view of the base31is shown. The base31has a hard plastic top257which is fairly thin. The hard plastic top257has ribs259formed on either side thereof. The ribs define a channel261on each side of the hard plastic top257of the base31. A drain basin263is provided in the internal trough265provided inside of raised rib seat267. One end of the internal trough265provides outdoor drain access269. Sealing the top of the raised rim seat267to the underside of the variable refrigerant package21is chassis seal271. On the underside of the base31is located bottom cover273. Between the bottom cover273and the hard plastic top257is located a three-way tee275that connects to drain hole277of drain basin263via drain connecting tube279which connects to retaining rings281. Connected to the lower side of the three-way tee275are building drain tubes283(a), (b) and (c). Building drain tubes283are held into slots285(a), (b) and (c), respectively, by retaining rings287(a), (b), and (c), respectively. The ends of the filling drain tubes283are temporarily sealed by end caps289(a), (b) and (c), respectively. When assembled, a two-part expanding foam is injected between hard plastic top257and bottom cover273through injection port291until a portion of the two-part expanding foam can be seen at each of the outlet ports293. The two-part expanding foam (not shown) gives rigidity to the base31so that it can support the variable refrigerant package21. When installed, the installation rails55(seeFIG.3) will rest inside of channels261. When installing the base31, the end cap289(a), (b), or (c) that is the most convenient to the building drain system is removed and the appropriate building drain tube283(a), (b) or (c) is connected to the building drain system (not shown). By having the drain basin263drain to any of three sides of the base31, it is more convenient for the construction crew to connect to the building drain system. If the building drain system becomes clogged, the outdoor drain access269extends over the inside edge of the plenum37so that any accumulated moisture will drain outside the building. Thereafter, if service personnel sees the drainage flowing through the plenum37to outside the building, the service personnel will know that the drain system for that particular room is clogged and needs to be cleaned. However, no damage will have been caused inside the room. When installing the variable refrigerant package21, a notch295is provided in the raised rib seat267. This notch295allows the lower end of the evaporator drain tube105to move there through when being installed until the lower end of the evaporator drain tube105is just above the drain basin263. After installation of the variable refrigerant package21a piece of foam may be placed inside of notch295. Because hotel/motel rooms may be different, the shape of the base31may need to be different to accommodate different plenum37and door openings35being located on different sides of the closet23. Referring toFIG.11, base31inFIG.11(a)is the straight install base.FIG.11(b)is the right install base297.FIG.11(c)is the left install base299. Each of the bases31,297and299allows for access water to drain outside of the building if the normal drain line is plugged. At the time of construction, the contractor will decide which style base31,297or299will be used. | 27,348 |
RE49864 | DETAILED DESCRIPTION Overview Referring generally to the FIGURES, systems and methods are shown for analyzing alarm panels, according to various exemplary embodiments. Many buildings may include an alarm panels, which operate or otherwise provide a security system for the building. The alarm panels may be communicably coupled to various security sensors. The sensors may trigger alarm events when, for instance, security issues occur. In a large or complex connected security system, where alarms (including false alarms) may be numerous and noisy, it can be difficult for security personnel to identify those alarm panels and their associated devices that may be underperforming or incorrectly configured, or to highlight other causes for concern, such as systemic issues with a panel, or a persistent security threat affecting an area supervised by that panel. In a connected security system, data about alarms is collected, for example, the type of alarm, time of occurrence, relevant alarm panel, and so on. Identifying alarm panels that have numerous alarm events associated with them is one way for system monitors to highlight possible underlying issues. In larger, more complex systems, however, some of the data may be anomalous, making it more difficult for system personnel to meaningfully assess individual alarm panel performance by reference to patterns in the system as a whole. For example, in considering a set of alarms, a given system may need to identify which alarms and panels need the most attention. Comparing alarm panels may be difficult due to the different types, and occurrence, of alarms. The present disclosure is generally directed to systems and methods for analysis and diagnosis of alarm panel conditions. The present disclosure uses Pareto optimality approaches in order to rank alarm panels by their performance against that of the alarm system as a whole, using multiple variables. Pareto optimality typically involves multi-objective optimization. In its application to this disclosure, alarm panels are ranked according to how relatively noisy they are. Connected security systems usually classify alarms by type. Two common examples of alarm types are: Burglary Alarms (BA) and Hold-up or panic alarms (HU)—though many other types of alarms may be used and included in various alarm and security systems. A single system may have many alarm type classifications. For all alarm panels to be classified, the disclosed systems and methods count the number of alarm types (for example, BU, HU, and so on) occurring on each alarm panel over a similar measurement period. For each alarm type, each alarm panel may be represented in a dimensional space or dataset. Using various Pareto optimality calculations, a number of levels or rankings may be assigned to the alarm panels in terms of noisiness, such as: ‘Very High’, ‘High’, ‘Medium’, ‘Low’, and ‘Very Low.’ Building Management System and HVAC System Referring now toFIG.1, an exemplary building management system (BMS) and HVAC system in which the systems and methods of the present invention can be implemented are shown, according to an exemplary embodiment. Referring particularly toFIG.1, a perspective view of a building10is shown. Building10is served by a BMS. A BMS is, in general, a system of devices configured to control, monitor, and manage equipment in or around a building or building area. A BMS can include, for example, a HVAC system, a security system, a lighting system, a fire alerting system, any other system that is capable of managing building functions or devices, or any combination thereof. The BMS that serves building10includes an HVAC system100. HVAC system100can include a plurality of HVAC devices (e.g., heaters, chillers, air handling units, pumps, fans, thermal energy storage, etc.) configured to provide heating, cooling, ventilation, or other services for building10. For example, HVAC system100is shown to include a waterside system120and an airside system130. Waterside system120can provide a heated or chilled fluid to an air handling unit of airside system130. Airside system130can use the heated or chilled fluid to heat or cool an airflow provided to building10. An exemplary waterside system and airside system which can be used in HVAC system100are described in greater detail with reference toFIGS.2-3. HVAC system100is shown to include a chiller102, a boiler104, and a rooftop air handling unit (AHU)106. Waterside system120can use boiler104and chiller102to heat or cool a working fluid (e.g., water, glycol, etc.) and can circulate the working fluid to AHU106. In various embodiments, the HVAC devices of waterside system120can be located in or around building10(as shown inFIG.1) or at an offsite location such as a central plant (e.g., a chiller plant, a steam plant, a heat plant, etc.). The working fluid can be heated in boiler104or cooled in chiller102, depending on whether heating or cooling is required in building10. Boiler104can add heat to the circulated fluid, for example, by burning a combustible material (e.g., natural gas) or using an electric heating element. Chiller102can place the circulated fluid in a heat exchange relationship with another fluid (e.g., a refrigerant) in a heat exchanger (e.g., an evaporator) to absorb heat from the circulated fluid. The working fluid from chiller102and/or boiler104can be transported to AHU106via piping108. AHU106can place the working fluid in a heat exchange relationship with an airflow passing through AHU106(e.g., via one or more stages of cooling coils and/or heating coils). The airflow can be, for example, outside air, return air from within building10, or a combination of both. AHU106can transfer heat between the airflow and the working fluid to provide heating or cooling for the airflow. For example, AHU106can include one or more fans or blowers configured to pass the airflow over or through a heat exchanger containing the working fluid. The working fluid can then return to chiller102or boiler104via piping110. Airside system130can deliver the airflow supplied by AHU106(i.e., the supply airflow) to building10via air supply ducts112and can provide return air from building10to AHU106via air return ducts114. In some embodiments, airside system130includes multiple variable air volume (VAV) units116. For example, airside system130is shown to include a separate VAV unit116on each floor or zone of building10. VAV units116can include dampers or other flow control elements that can be operated to control an amount of the supply airflow provided to individual zones of building10. In other embodiments, airside system130delivers the supply airflow into one or more zones of building10(e.g., via supply ducts112) without using intermediate VAV units116or other flow control elements. AHU106can include various sensors (e.g., temperature sensors, pressure sensors, etc.) configured to measure attributes of the supply airflow. AHU106can receive input from sensors located within AHU106and/or within the building zone and can adjust the flow rate, temperature, or other attributes of the supply airflow through AHU106to achieve setpoint conditions for the building zone. Referring now toFIG.2, a block diagram of a building automation system (BAS)200is shown, according to an exemplary embodiment. BAS200can be implemented in building10to automatically monitor and control various building functions. BAS200is shown to include BAS controller202and a plurality of building subsystems228. Building subsystems228are shown to include a building electrical subsystem234, an information communication technology (ICT) subsystem236, a security subsystem238, a HVAC subsystem240, a lighting subsystem242, a lift/escalators subsystem232, and a fire safety subsystem230. In various embodiments, building subsystems228can include fewer, additional, or alternative subsystems. For example, building subsystems228can also or alternatively include a refrigeration subsystem, an advertising or signage subsystem, a cooking subsystem, a vending subsystem, a printer or copy service subsystem, or any other type of building subsystem that uses controllable equipment and/or sensors to monitor or control building10. In some embodiments, building subsystems228include a waterside system and/or an airside system. A waterside system and an airside system are described with further reference to U.S. patent application Ser. No. 15/631,830 filed Jun. 23, 2017, the entirety of which is incorporated by reference herein. Each of building subsystems228can include any number of devices, controllers, and connections for completing its individual functions and control activities. HVAC subsystem240can include many of the same components as HVAC system100, as described with reference toFIG.1. For example, HVAC subsystem240can include a chiller, a boiler, any number of air handling units, economizers, field controllers, supervisory controllers, actuators, temperature sensors, and other devices for controlling the temperature, humidity, airflow, or other variable conditions within building10. Lighting subsystem242can include any number of light fixtures, ballasts, lighting sensors, dimmers, or other devices configured to controllably adjust the amount of light provided to a building space. Security subsystem238can include occupancy sensors, video surveillance cameras, digital video recorders, video processing servers, intrusion detection devices, access control devices and servers, or other security-related devices. Still referring toFIG.2, BAS controller266is shown to include a communications interface207and a BAS interface209. Interface207can facilitate communications between BAS controller202and external applications (e.g., monitoring and reporting applications222, enterprise control applications226, remote systems and applications244, applications residing on client devices248, etc.) for allowing user control, monitoring, and adjustment to BAS controller266and/or subsystems228. Interface207can also facilitate communications between BAS controller202and client devices248. BAS interface209can facilitate communications between BAS controller202and building sub-systems228(e.g., HVAC, lighting security, lifts, power distribution, business, etc.). Interfaces207,209can be or include wired or wireless communications interfaces (e.g., jacks, antennas, transmitters, receivers, transceivers, wire terminals, etc.) for conducting data communications with building subsystems228or other external systems or devices. In various embodiments, communications via interfaces207,209can be direct (e.g., local wired or wireless communications) or via a communications network246(e.g., a WAN, the Internet, a cellular network, etc.). For example, interfaces207,209can include an Ethernet card and port for sending and receiving data via an Ethernet-based communications link or network. In another example, interfaces207,209can include a Wi-Fi transceiver for communicating via a wireless communications network. In another example, one or both of interfaces207,209can include cellular or mobile phone communications transceivers. In one embodiment, communications interface207is a power line communications interface and BAS interface209is an Ethernet interface. In other embodiments, both communications interface207and BAS interface209are Ethernet interfaces or are the same Ethernet interface. Still referring toFIG.2, BAS controller202is shown to include a processing circuit204including a processor206and memory208. Processing circuit204can be communicably connected to BAS interface209and/or communications interface207such that processing circuit204and the various components thereof can send and receive data via interfaces207,209. Processor206can be implemented as a general purpose processor, an application specific integrated circuit (ASIC), one or more field programmable gate arrays (FPGAs), a group of processing components, or other suitable electronic processing components. Memory208(e.g., memory, memory unit, storage device, etc.) can include one or more devices (e.g., RAM, ROM, Flash memory, hard disk storage, etc.) for storing data and/or computer code for completing or facilitating the various processes, layers and modules described in the present application. Memory208can be or include volatile memory or non-volatile memory. Memory208can include database components, object code components, script components, or any other type of information structure for supporting the various activities and information structures described in the present application. According to an exemplary embodiment, memory208is communicably connected to processor206via processing circuit402and includes computer code for executing (e.g., by processing circuit204and/or processor206) one or more processes described herein. In some embodiments, BAS controller202is implemented within a single computer (e.g., one server, one housing, etc.). In various other embodiments BAS controller202can be distributed across multiple servers or computers (e.g., that can exist in distributed locations). Further, whileFIG.4shows applications222and226as existing outside of BAS controller202, in some embodiments, applications222and226can be hosted within BAS controller202(e.g., within memory208). Still referring toFIG.2, memory208is shown to include an enterprise integration layer210, an automated measurement and validation (AM&V) layer212, a demand response (DR) layer214, a fault detection and diagnostics (FDD) layer216, an integrated control layer218, and a building subsystem integration later220. Layers210-220can be configured to receive inputs from building subsystems228and other data sources, determine optimal control actions for building subsystems228based on the inputs, generate control signals based on the optimal control actions, and provide the generated control signals to building subsystems228. The following paragraphs describe some of the general functions performed by each of layers210-220in BAS200. Enterprise integration layer210can be configured to serve clients or local applications with information and services to support a variety of enterprise-level applications. For example, enterprise control applications226can be configured to provide subsystem-spanning control to a graphical user interface (GUI) or to any number of enterprise-level business applications (e.g., accounting systems, user identification systems, etc.). Enterprise control applications226can also or alternatively be configured to provide configuration GUIs for configuring BAS controller202. In yet other embodiments, enterprise control applications226can work with layers210-220to optimize building performance (e.g., efficiency, energy use, comfort, or safety) based on inputs received at interface207and/or BAS interface209. Building subsystem integration layer220can be configured to manage communications between BAS controller202and building subsystems228. For example, building subsystem integration layer220can receive sensor data and input signals from building subsystems228and provide output data and control signals to building subsystems228. Building subsystem integration layer220can also be configured to manage communications between building subsystems228. Building subsystem integration layer220translates communications (e.g., sensor data, input signals, output signals, etc.) across a plurality of multi-vendor/multi-protocol systems. Demand response layer214can be configured to optimize resource usage (e.g., electricity use, natural gas use, water use, etc.) and/or the monetary cost of such resource usage in response to satisfy the demand of building10. The optimization can be based on time-of-use prices, curtailment signals, energy availability, or other data received from utility providers, distributed energy generation systems224, from energy storage227, or from other sources. Demand response layer214can receive inputs from other layers of BAS controller202(e.g., building subsystem integration layer220, integrated control layer218, etc.). The inputs received from other layers can include environmental or sensor inputs such as temperature, carbon dioxide levels, relative humidity levels, air quality sensor outputs, occupancy sensor outputs, room schedules, and the like. The inputs can also include inputs such as electrical use (e.g., expressed in kWh), thermal load measurements, pricing information, projected pricing, smoothed pricing, curtailment signals from utilities, and the like. According to an exemplary embodiment, demand response layer214includes control logic for responding to the data and signals it receives. These responses can include communicating with the control algorithms in integrated control layer218, changing control strategies, changing setpoints, or activating/deactivating building equipment or subsystems in a controlled manner. Demand response layer214can also include control logic configured to determine when to utilize stored energy. For example, demand response layer214can determine to begin using energy from energy storage227just prior to the beginning of a peak use hour. In some embodiments, demand response layer214includes a control module configured to actively initiate control actions (e.g., automatically changing setpoints) which minimize energy costs based on one or more inputs representative of or based on demand (e.g., price, a curtailment signal, a demand level, etc.). In some embodiments, demand response layer214uses equipment models to determine an optimal set of control actions. The equipment models can include, for example, thermodynamic models describing the inputs, outputs, and/or functions performed by various sets of building equipment. Equipment models can represent collections of building equipment (e.g., sub-plants, chiller arrays, etc.) or individual devices (e.g., individual chillers, heaters, pumps, etc.). Demand response layer214can further include or draw upon one or more demand response policy definitions (e.g., databases, XML files, etc.). The policy definitions can be edited or adjusted by a user (e.g., via a graphical user interface) so that the control actions initiated in response to demand inputs can be tailored for the user's application, desired comfort level, particular building equipment, or based on other concerns. For example, the demand response policy definitions can specify which equipment can be turned on or off in response to particular demand inputs, how long a system or piece of equipment should be turned off, what setpoints can be changed, what the allowable set point adjustment range is, how long to hold a high demand setpoint before returning to a normally scheduled setpoint, how close to approach capacity limits, which equipment modes to utilize, the energy transfer rates (e.g., the maximum rate, an alarm rate, other rate boundary information, etc.) into and out of energy storage devices (e.g., thermal storage tanks, battery banks, etc.), and when to dispatch on-site generation of energy (e.g., via fuel cells, a motor generator set, etc.). Integrated control layer218can be configured to use the data input or output of building subsystem integration layer220and/or demand response later214to make control decisions. Due to the subsystem integration provided by building subsystem integration layer220, integrated control layer218can integrate control activities of the subsystems228such that the subsystems228behave as a single integrated supersystem. In an exemplary embodiment, integrated control layer218includes control logic that uses inputs and outputs from a plurality of building subsystems to provide greater comfort and energy savings relative to the comfort and energy savings that separate subsystems could provide alone. For example, integrated control layer218can be configured to use an input from a first subsystem to make an energy-saving control decision for a second subsystem. Results of these decisions can be communicated back to building subsystem integration layer220. Integrated control layer218is shown to be logically below demand response layer214. Integrated control layer218can be configured to enhance the effectiveness of demand response layer214by enabling building subsystems228and their respective control loops to be controlled in coordination with demand response layer214. This configuration can reduce disruptive demand response behavior relative to conventional systems. For example, integrated control layer218can be configured to assure that a demand response-driven upward adjustment to the setpoint for chilled water temperature (or another component that directly or indirectly affects temperature) does not result in an increase in fan energy (or other energy used to cool a space) that would result in greater total building energy use than was saved at the chiller. Integrated control layer218can be configured to provide feedback to demand response layer214so that demand response layer214checks that constraints (e.g., temperature, lighting levels, etc.) are properly maintained even while demanded load shedding is in progress. The constraints can also include setpoint or sensed boundaries relating to safety, equipment operating limits and performance, comfort, fire codes, electrical codes, energy codes, and the like. Integrated control layer218is also logically below fault detection and diagnostics layer216and automated measurement and validation layer212. Integrated control layer218can be configured to provide calculated inputs (e.g., aggregations) to these higher levels based on outputs from more than one building subsystem. Automated measurement and validation (AM&V) layer212can be configured to verify that control strategies commanded by integrated control layer218or demand response layer214are working properly (e.g., using data aggregated by AM&V layer212, integrated control layer218, building subsystem integration layer220, FDD layer216, or otherwise). The calculations made by AM&V layer212can be based on building system energy models and/or equipment models for individual BAS devices or subsystems. For example, AM&V layer212can compare a model-predicted output with an actual output from building subsystems228to determine an accuracy of the model. Fault detection and diagnostics (FDD) layer216can be configured to provide on-going fault detection for building subsystems228, building subsystem devices (i.e., building equipment), and control algorithms used by demand response layer214and integrated control layer218. FDD layer216can receive data inputs from integrated control layer218, directly from one or more building subsystems or devices, or from another data source. FDD layer216can automatically diagnose and respond to detected faults. The responses to detected or diagnosed faults can include providing an alarm message to a user, a maintenance scheduling system, or a control algorithm configured to attempt to repair the fault or to work-around the fault. FDD layer216can be configured to output a specific identification of the faulty component or cause of the fault (e.g., loose damper linkage) using detailed subsystem inputs available at building subsystem integration layer220. In other exemplary embodiments, FDD layer216is configured to provide “fault” events to integrated control layer218which executes control strategies and policies in response to the received fault events. According to an exemplary embodiment, FDD layer216(or a policy executed by an integrated control engine or business rules engine) can shut-down systems or direct control activities around faulty devices or systems to reduce energy waste, extend equipment life, or assure proper control response. FDD layer216can be configured to store or access a variety of different system data stores (or data points for live data). FDD layer216can use some content of the data stores to identify faults at the equipment level (e.g., specific chiller, specific AHU, specific terminal unit, etc.) and other content to identify faults at component or subsystem levels. For example, building subsystems228can generate temporal (i.e., time-series) data indicating the performance of BAS200and the various components thereof. The data generated by building subsystems228can include measured or calculated values that exhibit statistical characteristics and provide information about how the corresponding system or process (e.g., a temperature control process, a flow control process, etc.) is performing in terms of error from its setpoint. These processes can be examined by FDD layer216to expose when the system begins to degrade in performance and alarm a user to repair the fault before it becomes more severe. Systems and Methods for Analyzing Alarm Panels Referring now toFIG.3, a security system300is shown for multiple buildings, according to an exemplary embodiment. The security system300is shown to include buildings10a-10d. Each of buildings10a-10d is shown to be associated with a corresponding alarm panel302a-302d. The buildings10a-10d may be the same as and/or similar to building10as described with reference toFIG.1. The alarm panels302a-302d may be one or more controllers, servers, and/or computers located in a security panel or part of a central computing system for a building. The alarm panels302a-302d may communicate with various security sensors that are part of the building subsystems228. For example, fire safety subsystems230may include various smoke sensors and alarm devices, carbon monoxide sensors and alarm devices, etc. The security subsystems238are shown to include a surveillance system315, an entry system316, and an intrusion system318. The surveillance system315may include various video cameras, still image cameras, and image and video processing systems for monitoring various rooms, hallways, parking lots, the exterior of a building, the roof of the building, etc. The entry system316can include one or more systems configured to allow users to enter and exit the building (e.g., door sensors, turnstiles, gated entries, badge systems, etc.) The intrusion system318may include one or more sensors configured to identify whether a window or door has been forced open. The intrusion system318can include a keypad module for arming and/or disarming a security system and various motion sensors (e.g., IR, PIR, etc.) configured to detect motion in various zones of the building10a. Each of buildings10a-10d may be located in various cities, states, and/or countries across the world. There may be any number of buildings10a-10b. The buildings10a-10b may be owned and operated by one or more entities. For example, a grocery store entity may own and operate buildings10a-10d in a particular geographic state. The alarm panels302a-302d may record data from the building subsystems228and communicate collected security system data to the cloud server304. The cloud server304is shown to include a security system306that receives the security system data from the alarm panels302a-302d of the buildings10a-10d. The cloud server304may include one or more processing circuits (e.g., memory devices, processors, databases) configured to perform the various functionalities described herein. The processing circuits may be the same and/or similar to the processing circuit204, the processor206, and/or the memory208as described with reference toFIG.2. The cloud server304may be a private server. In some embodiments, the cloud server304is implemented by a cloud system, examples of which include AMAZON WEB SERVICES® (AWS) and MICROSOFT AZURE®. In some embodiments, the cloud server304can be located on premises within one of the buildings10a-10d. For example, a user may wish that their security, fire, or HVAC data remain confidential and have a lower risk of being compromised. In such an instance, the cloud server304may be located on-premises instead of within an off-premises cloud platform. The security system306may implement an interface system308, an alarm analysis system310, and a database storing historical security data312, security system data collected from the alarm panels302a-302d. The interface system308may provide various interfaces of user devices314for monitoring and/or controlling the alarm panels302a-302d of the buildings10a-10d. Security systems e.g., the alarm panel302a, can protect residential or commercial premises by implementing functionality e.g., intrusion detection, access control, video surveillance, and fire detection. In each case, sensors deployed at various locations in and around the building transmit data back to a central system for analysis, e.g., the alarm panels302a-302d. In some instances, such data is further transmitted to an offsite location that serves as a monitoring center, e.g., the alarm analysis system310. In either case, the sensor data can be analyzed to determine if a condition exists at the premises that requires attention by a security professional. For example, if a motion sensor detects that someone has entered a building at a time that the intrusion system is armed or if an access control system detects that a door is being forced open, that information is transmitted to the local or remote monitoring center which can deploy security guards or call the police. Unfortunately, such security systems for detecting alarms (e.g., a fire, an intrusion, etc.) may not be foolproof. If a sensor is going bad or requires maintenance, it may produce spurious data falsely indicating that there has been a security breach. For example, a smoke detector may indicate the presence of smoke in the building when it is simply an accumulation of dust on the device. Likewise, a contact switch on a warehouse door may indicate that the door has been opened when, in fact, the magnetic switch has simply stopped working correctly. Such false alarm situations can be numerous and can cost building owners a substantial amount of money each year in business down-time, security agency response fees, and maintenance personnel truck rolls. In many instances, the purported cause of a false alarm is repaired but other related problems exist with the systems that are not detected until further false alarms events occur. In some instances, some buildings10a-10d may be located in geographical locations which are more prone to crime. As such, these buildings10a-10d may experience more alarm events (e.g., rather than false alarms). In these instance, it may be advantageous for owners or operators of the buildings10a-10d to be made aware of the number of alarm events so that such owners/operators may reinforce their security measures at the corresponding buildings10a-10d. Referring now toFIG.4, a block diagram of the alarm analysis system310as described with reference toFIG.3is shown, according to an exemplary embodiment. The alarm analysis system310can be configured to identify patterns of alarm events based on event data reported by the alarm panels302a-302d. Such patterns may be used for diagnosing errors in the alarm panels302a-302d, security equipment or sensors, and for upgrading security systems as needed. The alarm analysis system310is shown to include a processing circuit402that includes a processor404and a memory406. The memory406can include instructions which, when executed by the processor404, cause the processor404to perform the one or more functions described herein. The processor404may be the same and/or similar to the processor206as described with reference toFIG.2and the memory406may be the same as and/or similar to the memory208as described with reference toFIG.2. In addition to a traditional processor and memory, the processing circuit402may include integrated circuitry for processing and/or control, e.g., one or more processors and/or processor cores (e.g., microprocessor and/or microcontroller) and/or FPGAs (Field Programmable Gate Array) and/or ASICs (Application Specific Integrated Circuitry). The processing circuit402can include and/or be connected to and/or be configured for accessing (e.g., writing to and/or reading from) the memory406, which may include any kind of volatile and/or non-volatile memory, e.g., cache and/or buffer memory and/or RAM (Random Access Memory) and/or ROM (Read-Only Memory) and/or optical memory and/or EPROM (Erasable Programmable Read-Only Memory). The memory406can be configured to store code executable by control circuitry and/or other data, e.g., data pertaining to communication, e.g., configuration and/or address data of nodes, etc. The processing circuit402can be configured to implement any of the methods described herein and/or to cause such methods to be performed, e.g., by the processor404. Corresponding instructions may be stored in the memory406, which may be readable and/or readably connected to the processing circuit402. It may be considered that the processing circuit402includes or may be connected or connectable to the memory406, which may be configured to be accessible for reading and/or writing by the controller and/or the processing circuit402. The security system302a includes a communication interface408. The communication interface408is configured to facilitate communicate with a domain expert device410and/or the alarm panels302in some embodiments. Furthermore, the communication interface408can be configured to communicate with all of the devices and systems described with reference toFIG.3. Via the communication interface408, the historical security database412can be configured to receive (collect) and store security system data from the security system302a. The security system data may be events (e.g., alarm events) such as an occurrence detected by a sensor of the security system302a. For example, an intrusion sensor or other burglary alarm may identify that an individual is trying to force a window or door open. Another event may be a door being opened or closed. The detection of an occupant walking through the door may also be an event. As another example, a hold-up alarm may be triggered when a person (e.g., a robber) attempts a hold-up of a business. The alarm events414may be binary (e.g., indicating a high, or “1”, when the alarm event is detected). In some embodiments, the alarm events414can further include signals containing various information, such as which sensor triggered the alarm event414, a location (e.g., within a building10a-10d, which particular building10a-10d) corresponding to the sensor, etc. In each of these embodiments, the historical security database412may be configured to store an event type for the alarm event414, and data corresponding to the building10a-10d associated with the alarm event414. The historical security database412may receive and store the alarm event414, and may store the alarm event type (e.g., burglary alarm, hold-up alarm, fire alarm, etc.) based on data contained in the alarm event414, since the particular sensor sent a binary high, and so forth. The historical security database412may store the data corresponding to the building10a-10d associated with the alarm event414based on data contained in the alarm event414, since the particular sensor which sent the binary high is located at a particular building10a-10d, etc. The memory406is shown to include an event classifier416. The event classifier416can be configured to classify the alarm panels302a-302d. The event classifier416may classify the alarm panels302a-302d according to the alarm events received via the communications interface408from the respective alarm panels302a-302d. As described above, the alarm panels302a-302d can be configured to communicate events414responsive to triggers or signals from respective sensors in or corresponding to the building10a-10d. The alarm panels302a-302d can be configured to communicate the alarm events414in real-time, at various intervals (e.g., the end of business, end of the day, end of the week, etc.). The alarm events414may be stored in the historical security database412(with data associated therewith). The event classifier416may be communicably coupled to the historical security database412and, therefore, may access the alarm events414stored therein for each alarm panel302a and data associated therewith. The event classifier416can be configured to identify an alarm type for each alarm event414. The event classifier416can be configured to access the historical security database412. As described above, the historical security database412may store the alarm type for each alarm event414. The event classifier416can be configured to retrieve, from the historical security database412, the alarm events414and data associated therewith (e.g., the alarm type, the sensor location within the building10a-10d which triggered the alarm event414, the particular building in which the alarm event414occurred, etc.). In receiving such data, the event classifier416can quantify particular occurrences of each alarm event type, which may be used for diagnosing faults within the security system, bolstering the security system as needed, etc. In some embodiments, the event classifier416can be configured to receive data corresponding to whether various alarm events414are false alarms. For instance, the alarm panels302a-302d can be configured to communicate alarm events414to the historical security database412upon a triggering event from an alarm sensor in a particular security system for a building10a-10d. An authorized user device314may subsequently communicate a false alarm signal associated with the alarm event414(e.g., following a user inspecting the building10a-10d determining that the alarm event414was a false alarm). The historical security database412may be configured to receive and store the false alarm signal associated with the particular alarm event414. Such data may be used for identifying faults in security systems, required updates, etc., particularly where reoccurring false alarm signals are received for the same sensor(s) in a given building10a-10d. The event classifier416can be configured to determine, quantify, or evaluate a number of occurrences of each alarm type for each alarm panel302a-302d. The event classifier416can be configured to identify the alarm type for the data corresponding to particular alarm events414(e.g., described above). The event classifier416may be configured to build a matrix or dataset corresponding to each alarm panel302a-302d. Each cell (also referred to herein as “data point”) in the matrix or dataset may define the number of occurrences of each alarm type. For purposes of a simple example, a building10a-10d may have two types of alarms—burglary alarms and hold-up alarms. Hence, the alarm panels302a-302d may report, provide, communicate, etc. alarm events414for burglary events and hold-up events. A given building10a may have, for a duration (e.g., a month, a week, a year, etc.) ten burglary events and two hold-up events. For the building10a, the event classifier416can generate a cell for the building which indicates the number of alarm events414(e.g., a cell [10,2]). As the event classifier416identifies new alarm events414(e.g., within the historical security database412), the event classifier416can be configured to update, revise, edit, etc. the matrix or dataset and corresponding cells or data points. Hence, each data point may represent a number of occurrences of each alarm type for a respective alarm panel302a-302d. In some embodiments, the event classifier416can be configured assign a weight to particular alarm events414. The event classifier416may assign weights to particular alarm events414based on alarm type. For instance, the event classifier416may apply a greater weight to some alarm types (such as hold-up alarm events414), a lesser weight to some alarm types (such as fire or smoke alarm events414). The weights may be generated, created or determined by a security administrator on a corresponding user device, such as the domain expert device410, and communicated to the event classifier416. The weights may be defaulted to “1”, and increased or decreased by the security administrator on the user device314. The event classifier416can be configured to multiply the number of occurrences of particular alarm events414by their corresponding weight. The weights may be used for modifying the dataset to emphasize or prioritize particular alarm events414, as described in greater detail below. The event classifier416can be configured to identify statistical dividers in the dataset. The statistical dividers may be used for assigning a ranking of each of the data points and, correspondingly, alarm panels302a-302d. The event classifier416can be configured to analyze the dataset to compute the statistical dividers, as described in greater detail below. The event classifier416can be configured to generate a graphical representation of the dataset. The graphical representation can include each of the data points or cells within the dataset. Hence, the graphical representation can represent each alarm type and corresponding number of occurrences for each alarm panel302a-302d. Referring now toFIG.5, a graphical representation500of an example dataset is shown, according to an exemplary embodiment. While the graphical representation500shown inFIG.5is two dimensional (for purposes of illustrating a simple example), the graphical representation500may include any number of dimensions. For instance, the graphical representation500may include a third dimension which quantifies the number of fire alarm events, false alarm events or bypasses, etc. In the graphical representation500depicted inFIG.5, each data point502corresponds to a particular alarm panel302a-302d. Additionally, each data point502may have an x component and a y component. The x component may be the number of burglary alarm events (BA) for the alarm panel302a-302d, and the y component may be the number of hold-up alarm events (HU) for the alarm panel302a-302d. The event classifier416can be configured to apply one or more filters to the dataset. For instance, the event classifier416can filter data points502for alarm panels302a-302d which have zero occurrences of each of the alarm types (e.g., zero burglary alarm events and zero hold-up alarm events). The event classifier416can be configured to filter outlier data points502. As one example, the event classifier416can be configured to calculate a standard deviation for the dataset and filter alarm panels which fall outside of a number of standard deviations from a mean or median number of alarm events. As shown in the graphical representation500, the dataset may be filtered to remove two alarm panels302(e.g., one outlier and one alarm panel302having zero occurrences of alarm events). Referring now toFIG.6, a graphical representation600of the example dataset ofFIG.5following application of the one or more filters, according to an exemplary embodiment. The event classifier416can be configured to compute an upper Pareto frontier602and/or a lower Pareto frontier604within the graphical representation600. The event classifier416can be configured to compute the upper Pareto frontier602by determining maximum dominate data points within the filtered dataset. Similarly, the event classifier416can be configured to compute the lower Pareto frontier604by determining minimum dominate data points within the filtered dataset. The event classifier416can be configured to analyze each of the data points502in the filtered dataset. Generally speaking, Pareto analysis solves an optimization problem. The event classifier416analyzes the dataset to determine optimal solutions. The event classifier416defines an order or relation on the data points within the dataset. In a bidirectional case where maximization of objectives is of importance, for two data points [(3,4) and (2,4)], (3,4) dominates (2,4) because 3>=2 and 4>=4. In a bidirectional case where minimization of objectives is of importance, for two data points [(1,2) and (3,4)], (1,2) dominates (3,4) because 1<=3 and 2<=4. In a Pareto frontier, each of the dominant data points are a set of multi-objective solutions which are not dominated by any other existing solution, or a set of optimal or undominated solutions. The event classifier416can determine the maximum and minimum dominant data points. The event classifier416can connect the maximum dominant points to form the upper Pareto frontier602, and connect the minimum dominant points to form the lower Pareto frontier604. Referring now toFIG.7, a graphical representation700including upper and lower Pareto centroids702,704and a midpoint706for the filtered dataset is shown, according to an exemplary embodiment. The event classifier416can be configured to compute the upper Pareto centroid, CUPF,702for the upper Pareto frontier602and the lower Pareto centroid, CLPF,704for the lower Pareto centroid604. The event classifier416may compute the upper Pareto centroid702by averaging the data points located along the upper Pareto frontier602. Continuing the example shown inFIG.6, the upper Pareto frontier602includes data points at (3,16), (6,15), (8,10), (9,7), and (10,2). The event classifier416can be configured to compute the average for the x values—e.g., (3+6+8+9+10)/5, or 7.7—and the average for the y values—e.g., (16+15+10+7+2)/5, or 10. The event classifier416can define the upper Pareto centroid702as the average x and y values, or (7.7, 10). Similarly, the event classifier416may compute the lower Pareto centroid704by averaging the data points located along the lower Pareto frontier604. Continuing the example inFIG.6, the lower Pareto frontier604includes data points at (0,4), (1,1), and (2,0). The event classifier415can be configured to compute the average for the x values—e.g., (0+1+2)/3, or 1—and the average for they values—e.g., (4+1+0)/3, or 1.33. The event classifier416can define the lower Pareto centroid704as the average x and y values, or (1, 1.33). The event classifier416can be configured to calculate the midpoint, CMPF,706between the upper Pareto centroid702and lower Pareto centroid704. The event classifier416can be configured to calculate the midpoint706by averaging the x values for the upper Pareto centroid702and lower Pareto centroid704—e.g., (7.7+1)/2, or 4.35—and averaging the y values for the upper Pareto centroid702and lower Pareto centroid704—e.g., (10+1.33)/2, or 5.66. The event classifier416can define the midpoint706as the average x and y values, or (4.35, 5.66). The event classifier416can be configured to define a number of statistical dividers in the dataset. The event classifier416can be configured to define the statistical dividers in several different ways, some of which will be described herein. The event classifier416can assign rankings to each of the data points in the dataset according to their location in relation to the statistical dividers, as described in greater detail below. Referring now toFIG.8, a graphical representation800of the dataset including a plurality of statistical dividers802-810is shown, according to an exemplary embodiment. In the embodiment shown inFIG.8, the statistical dividers802-810are hyperplanes—though, as described in greater detail below, the statistical dividers may take different shapes. In some embodiments, the event classifier416can be configured to define an upper statistical divider802, a lower statistical divider804, and a middle statistical divider806. The event classifier416may construct the statistical dividers802-806to extend parallel to one another (e.g., be equidistant from one another) and in relation to at least one of the upper Pareto centroid CUPF702, the lower Pareto centroid CUPF704, and/or the midpoint CMPF706. The event classifier416can be configured to select a value, α, which defines a spacing between the statistical dividers. In some embodiments, the event classifier416receives the value a via the communications interface408from the domain expert device510. In some embodiments, the value a is a preset value used by the event classifier416. The value a may have a fixed, or limited, range of possible values. In some embodiments, the value a may be between zero and one (e.g., 0<α<1). In some embodiments, the value a may be between zero and 0.5 (e.g., 0<α<0.5). In some embodiments, the value a may be between zero and 0.25 (e.g., 0<α<0.25). The event classifier416can be configured to define the statistical dividers using the value a. In some embodiments, the event classifier416defines the statistical dividers by constructing one of the statistical dividers to extend through one of the upper Pareto centroid CUPF702, lower Pareto centroid CLPF704, and midpoint CMPF706. The event classifier416may define the remaining statistical dividers by performing shifts from the constructed statistical divider. In some embodiments, the event classifier416can be configured to first define middle statistical divider806. The event classifier416may define the middle statistical divider806as extending through the midpoint CMPF706. The middle statistical divider806may have a slope of (−1). The event classifier416may define the upper statistical divider802and lower statistical divider804in relation to the middle statistical divider806. The event classifier416can be configured to calculate a centroid CVHfor the upper statistical divider802as CVH=(1+2α)CMPF. The event classifier416can be configured to calculate a centroid CVLfor the lower statistical divider804as CVL=(1−2α)CMPF. In some embodiments, the event classifier416can be configured to calculate a centroid CHfor the middle upper statistical divider808as CH=(1+α)CMPF, and a centroid CLfor the middle lower statistical divider810as CL=(1−α)CMPF. The event classifier416can be configured to define each of the statistical dividers (e.g., the upper statistical divider802, the middle upper statistical divider808, the middle lower statistical divider810, and the lower statistical divider804) in relation to the middle statistical divider806. Each of the statistical dividers802-804and808-810as extending parallel to the middle statistical divider806and through their corresponding centroids (e.g., VVH, CVL, CH, and CLrespectively). Such embodiments and examples are shown inFIG.8. Referring now toFIG.9, another example graphical representation900of the dataset including a plurality of statistical dividers902-910is shown, according to an exemplary embodiment. In the embodiment shown inFIG.9, the statistical dividers902-910take the shape of one of the Pareto curves. Hence, the statistical dividers902-910are themselves Pareto curves. In some embodiments, the event classifier416can be configured to first define the upper statistical divider902. The event classifier416may define the upper statistical divider UPFD902along the upper Pareto frontier602. In this embodiment, the upper statistical divider902follows along the upper Pareto frontier602. The event classifier416may define the middle upper statistical divider908, middle statistical divider906, the middle lower statistical divider910, and lower statistical divider904in relation to the upper statistical divider802. The event classifier416can be configured to calculate data points for the middle upper statistical divider908according to UPFH=(1−α) UPFD. The event classifier416can be configured to calculate data points for the middle statistical divider906according to UPFM=(1−2α) UPFD. The event classifier416can be configured to calculate data points for the middle lower statistical divider910according to UPFL=(1−3α) UPFD. The event classifier416can be configured to calculate data points for the lower statistical divider904according to UPFVL=(1−4α) UPFD. In some embodiments, the event classifier416can be configured to first define the lower statistical divider904. The event classifier416may define the lower statistical divider UPFA904along the lower Pareto frontier604. In this embodiment, the lower statistical divider904follows along the lower Pareto frontier604. The event classifier416may define the upper statistical divider902, middle upper statistical divider908, middle statistical divider906, and the middle lower statistical divider910in relation to the lower statistical divider904. The event classifier416can be configured to calculate data points for the upper statistical divider902according to UPFVH=(1+4α) UPFA. The event classifier416can be configured to calculate data points for the middle upper statistical divider902according to UPFVH=(1+3α). The event classifier416can be configured to calculate data points for the middle statistical divider906according to UPFM=(1+2α) UPFD. The event classifier416can be configured to calculate data points for the middle lower statistical divider910according to UPFL=(1+α) UPFD. Referring back toFIG.4, the event classifier416can be configured to assign a ranking to each of the data points in the dataset (e.g., the full dataset prior to any filtering described above). The event calculator416can be configured to assign the ranking to each of the data points based on their location in relation to the statistical dividers defined by the event calculator416and described above. The possible rankings may be defined by the number of statistical dividers. For instance, continuing the example above, the event calculator416can select a ranking of very high, high, middle, low, and very low since there are five statistical dividers. However, the number of rankings may increase or decrease in accordance with the number of statistical dividers. The event classifier416can be configured to analyze the location of each data point in relation to the statistical dividers. In some embodiments, the event classifier416is configured to determine a proximity of a given data point in relation to the statistical dividers. The event classifier416can be configured to assign a ranking to the data point corresponding to the statistical divider nearest to the data point. For instance, where a given data point is located nearest to the upper statistical divider, the data point may be assigned a very high ranking, where a given data point is located nearest to the middle upper statistical divider, the data point may be assigned a high ranking, where a given data point is located nearest to the middle statistical divider, the data point may be assigned a middle ranking, where a given data point is located nearest to the middle lower statistical divider, the data point may be assigned a low ranking, and where a given data point is located nearest to the lower statistical divider, the data point may be assigned a very low ranking. In some embodiments, the event classifier416assigns a ranking to a data point based on which statistical dividers the data point is located between. For instance, where a given data point is located between the upper and middle upper statistical dividers, the data point may be assigned a very high ranking, where a given data point is located between the middle upper and middle statistical dividers, the data point may be assigned a high ranking, where a given data point is located between the middle and middle lower statistical dividers, the data point may be assigned a middle ranking, where a given data point is located between the middle lower and lower statistical dividers, the data point may be assigned a low ranking, and where a given data point is located beneath lower statistical divider, the data point may be assigned a very low ranking. As another example, where a given data point is located above the upper statistical divider, the data point may be assigned a very high ranking, where a given data point is located between the upper and middle upper statistical dividers, the data point may be assigned a high ranking, where a given data point is located between the middle upper and middle statistical dividers, the data point may be assigned a middle ranking, where a given data point is located between the middle and middle lower statistical dividers, the data point may be assigned a low ranking, where a given data point is located between the middle lower and lower statistical dividers, the data point may be assigned a very low ranking. The interface system308can be configured provide, provision, or otherwise render a monitoring dashboard to the user device314(e.g., on a display for the user device314). The interface system308is shown to include a dashboard generator424. The dashboard generator424can be configured to receive the rankings from the event classifier416. The dashboard generator424can be configured to generate the monitoring dashboard. The monitoring dashboard may be, for instance, a listing of rankings for each of the alarm panels302. The monitoring dashboard may be a listing of rankings for a subset of the alarm panels302. For instance, the monitoring dashboard may be configured to identify those alarm panels302having a ranking which is higher than a middle ranking, higher than a high ranking, etc. The dashboard generator424can be configured to communicate the monitoring dashboard (or various information or data for rendering the monitoring dashboard) to the user device314for rendering. An end user may view the monitoring dashboard and may replace or modify various security sensors, increase security measures by adding additional security sensors, etc. Referring now toFIG.10, a flow diagram of a process1000that can be performed by the alarm analysis system310for analyzing the alarm panels302is shown, according to an exemplary embodiment. The alarm analysis system310can be configured to perform the process1000. Furthermore, any one or combination of the computing devices described herein can be configured to perform the process1000. In step1005, the alarm analysis system310can receive a plurality of alarm events414from respective alarm panels302. In some embodiments, the alarm analysis system310can receive the plurality of alarm events414from the respective alarm panels302via the communications interface408. The communications interface408may be communicably coupled to the plurality of alarm panels302at respective buildings10. Hence, the communications interface408may be configured to receive alarm events414from the alarm panels302. In some embodiments, the alarm events414may indicate an alarm type. In step1010, the alarm analysis system310can classify the alarm panels302according to the plurality of alarm events414. The process for classifying the alarm panels302is described with reference to steps1015-1035. It is noted that, while showing as being sub-processes of step1010, in some embodiments, some of the steps1015-1035may be performed separately from or outside of step1010. In step1015, the alarm analysis system310can identify an alarm type. The alarm analysis system310may identify an alarm type for each of the alarm events414. The alarm analysis system310may identify an alarm type for a subset of the alarm events414. The alarm events414may indicate (or include data which indicates) the alarm type. The alarm analysis system310may identify the alarm type based on the alarm events414(or data from the alarm events414). In step1020, the alarm analysis system310can determine a number of occurrences of each alarm type for the alarm panels302. The alarm analysis system310may determine the number of occurrences of each alarm type for each of the alarm panels302. The alarm analysis system310may determine the number of occurrences of each alarm type for a subset of the alarm panels302. The alarm analysis310may compute the number of occurrences of each alarm type by maintaining a ledger of the alarm types identified at step1015. The alarm analysis system310may determine the number of occurrences based on the data contained in the ledger. In step1025, the alarm analysis system310can generate a data point for a data set corresponding to the alarm panels302. The data point may represent the number of occurrences of the alarm types for a respective alarm panel302. The alarm analysis system310may generate the data point using the determined number of occurrences of each alarm type (e.g., at step1020). The alarm analysis system310may generate the data point with a structure such that each representation of the alarm panels302in a data point have a similar structure. For instance, where an alarm panel302has three occurrences of burglary alarms and two occurrences of hold-up alarms, the alarm analysis system310may generate a data point of (3, 2) which represents the alarm panel302. In step1030, the alarm analysis system310can identify statistical dividers in the data points for the dataset. The statistical dividers may define a separation of rankings for the data points within the dataset. The alarm analysis system310can perform Pareto analysis to determine, for instance, a Pareto frontier. The alarm analysis system310can determine a centroid for the Pareto frontier. The alarm analysis system310may identify the statistical dividers based on the location of the centroid and/or the determined Pareto frontier. In some embodiments, the alarm analysis system310can determine two Pareto frontiers (e.g., a minimum [or lower] Pareto frontier and maximum [or upper] Pareto frontier). The alarm analysis system310can determine a centroid for the two Pareto frontiers and a midpoint between the two centroids. The alarm analysis system310may identify the statistical dividers in relation to the two centroids and/or the midpoint. In step1035, the alarm analysis system310can assign a ranking for the alarm panels302based on their respective location in relation to the statistical dividers. In some embodiments, the alarm analysis system310may assign a ranking of very high, high, medium, low, or very low based on the corresponding data point's location with respect to the statistical dividers. The alarm analysis system310may assign a ranking to the alarm panels302based on which statistical divider the corresponding data point is located nearest to. The alarm analysis system310may assign a ranking to the alarm panels302based on which statistical dividers the data point located between. In step1040, the alarm analysis system310can construct a monitoring dashboard which includes the ranking of the alarm panels302according to the classification of the alarm panels. In some embodiments, the alarm analysis system310can construct the monitoring dashboard to include the ranking of each of the alarm panels302. In some embodiments, the alarm analysis system310can construct the monitoring dashboard to include the ranking of a subset of (including but not limited to one of) the alarm panels302. The alarm analysis system310can construct the monitoring dashboard to list alarm panels302having a ranking which exceeds a threshold ranking (e.g., medium ranking, high ranking, etc.). In step1045, the alarm analysis system310can cause the monitoring dashboard to be rendered on a display to an end user. The alarm analysis system310can communicate data corresponding to the monitoring dashboard (e.g., constructed at step1040) to a user device314. The user device314may then render the monitoring dashboard on the display for the user device314. The user device314may display the monitoring dashboard to indicate the ranking of each (or a subset) of the alarm panels. The user viewing the monitoring dashboard may then service the alarm panels. Configuration of Exemplary Embodiments The construction and arrangement of the systems and methods as shown in the various exemplary embodiments are illustrative only. Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.). For example, the position of elements may be reversed or otherwise varied and the nature or number of discrete elements or positions may be altered or varied. Accordingly, all such modifications are intended to be included within the scope of the present disclosure. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions and arrangement of the exemplary embodiments without departing from the scope of the present disclosure. The present disclosure contemplates methods, systems and program products on any machine-readable media for accomplishing various operations. The embodiments of the present disclosure may be implemented using existing computer processors, or by a special purpose computer processor for an appropriate system, incorporated for this or another purpose, or by a hardwired system. Embodiments within the scope of the present disclosure include program products comprising machine-readable media for carrying or having machine-executable instructions or data structures stored thereon. Such machine-readable media can be any available media that can be accessed by a general purpose or special purpose computer or other machine with a processor. By way of example, such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to carry or store desired program code in the form of machine-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer or other machine with a processor. When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a machine, the machine properly views the connection as a machine-readable medium. Thus, any such connection is properly termed a machine-readable medium. Combinations of the above are also included within the scope of machine-readable media. Machine-executable instructions include, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing machines to perform a certain function or group of functions. Although the figures show a specific order of method steps, the order of the steps may differ from what is depicted. Also two or more steps may be performed concurrently or with partial concurrence. Such variation will depend on the software and hardware systems chosen and on designer choice. All such variations are within the scope of the disclosure. Likewise, software implementations could be accomplished with standard programming techniques with rule based logic and other logic to accomplish the various connection steps, processing steps, comparison steps and decision steps. | 67,019 |
RE49865 | Like reference numbers and designations in the various drawings indicate like elements. DETAILED DESCRIPTION Implementations of the present disclosure relates generally to reconciling data from multiple electronic data sources across disparate datasets having distinct feature sets. More specifically, implementations of the present disclosure are related to reconciling health care data from multiple different data sources such as, for example, product sales data, insurance data, prescription data, and government agency data to determine the eligibility status of pharmaceutical products for government mandated discounts. Implementations of the present disclosure include reconciling and linking the specific data features from across multiple data sets into a uniquely linked database that permits a user to accurately track complex transactions. For example, computing systems using the reconciled electronic data sets can provide pharmaceutical manufacturers with actionable information indicating whether particular product sales are eligible for government mandated discounts. Moreover, while advances in computer technology have greatly increased the amount of available information, the sheer volume of information can be overwhelming and cumbersome to the extent that processors may struggle to operate on datasets in time such that a user receives actionable information. Therefore, by reconciling the disparate datasets into a uniquely linked database, the user is provided with an investigative tool that allows the retrieval of actionable information that would not otherwise be available. Implementations of the present disclosure will be discussed in further detail with reference to an example context. The example context includes a health care data services environment. It is appreciated, however, that implementations of the present disclosure can be realized in other appropriate contexts, for example, consumer data services, financial data services, government or political data services, marketing data services, public opinion data services, etc. FIG.1depicts an example system100that can execute implementations of the present disclosure. The example system100is illustrated in a health care data services environment, including a client organization104, an information services organization (ISO)106, and one or more external systems108. The ISO106may be a business, non-profit organization, or government entity that provides information services to other organizations or individuals. Client organization104may be, for example a pharmaceutical manufacturer, a hospital, a pharmacy, a health insurance entity, or a pharmaceutical benefit manager (PBM). The external systems108may be, for example, third-party data providers such as government agency data systems. Each of the client organization104, the ISO106, and the external systems108include one or more computing systems130. The computing systems130can each include a computing device130a and computer-readable memory provided as a persistent storage device130b, and can represent various forms of server systems including, but not limited to a web server, an application server, a proxy server, a network server, or a server farm. In addition, each of the client organization104, the ISO106, and the external systems108can include one or more user computing devices114. However, for simplicity, a user computing device114is only depicted at the client organization104. Computing devices114may include, but are not limited to, one or more desktop computers, laptop computers, notebook computers, tablet computers, and other appropriate devices. In addition, the ISO106can include, for example, one or more data reconciliation systems (DRS)116. A DRS116can be one or more computing systems130configured to perform data reconciliation between distinct electronic data sets distributed across multiple separate computing systems in accordance with implementations of the present disclosure. The ISO106also includes one or more data repository systems120,122. In some examples, the data repository systems120,122include one or more databases storing data compiled by the ISO116. In some implementations, one or more of the data repository systems120,122can be a secure data repository storing sensitive data in one or more secure data sets. For example, a secure data repository can be a data repository with restricted access and may require special credentials to obtain access. For example, a secure data repository may contain confidential information, personally identifiable information or other protected information. Furthermore, the data in the secure data repository can be encrypted. The DRS116at the ISO106communicates with computing systems130at the client organization104and the external systems108over network110. The network110can include a large network or combination of networks, such as a PSTN, a local area network (LAN), wide area network (WAN), the Internet, a cellular network, a satellite network, one or more wireless access points, or a combination thereof connecting any number of mobile clients, fixed clients, and servers. In some examples, the network110can be referred to as an upper-level network. In some examples, ISO106may include, for example, an internal network (e.g., an ISO network118). The DRS116can communicate with the computing systems130of the one or more of the data repository systems120,122over the ISO network118. FIG.2depicts an example data reconciliation process flow200within the example system100. The process flow200involves reconciliation of data between distinct electronic data sets distributed across multiple separate computing systems, and can be performed by the DRS116. In the example healthcare data services context, the DRS116can reconcile the data contained in the data sets to automatically determine whether a pharmaceutical product sold by a merchant was eligible for a manufacturer discount by verifying whether a prescribing physician has an association with an approved entity. An approved entity can be an entity that was certified to receive a discount on pharmaceutical products at the time the physician issued the prescription. Furthermore, in response to making such a determination, the DRS116can send an electronic notification (e.g., alert112) including supporting data from the appropriate data sets to the client organization104. For example, the DRS116accesses at least a portion of data from each of several electronic data sets (e.g., electronic data sets202,204,206,208,210). For example, a client organization104can transmit all or part (e.g., less than all of the data records220) of a data set (e.g., data set1or data set5) to the DRS116. In some examples, the DRS116can obtain remote access to a data set (e.g., data set3) from an external system108to search the data records of the data set. Each of the electronic data sets can include a plurality of data records220. Data can be organized into a plurality of data fields222and sub-fields224within each record220. In some examples, each data set has distinct features, data fields, data formats and other distinct properties. In some examples, each electronic data set can include between millions, tens of millions, or hundreds of millions of data records220. In some examples, the data records and/or the data contained in the data fields can be encrypted. The DRS116reconciles data across the data sets by analyzing data in each data set, identifying corresponding data fields in other data sets, and searching the records of the other data sets to find matching data in the corresponding data fields to identify one or more corresponding data records. The DRS116can extract data from distinct data fields of the other data sets (e.g., data fields including data not present one or more of the analyzed data sets). The DRS116can use the extracted data to further reconcile the data sets. In some examples, the DRS116can analyze the extracted data to automatically generate a reconciliation report in the form of an electronic notification212. In some examples, the data reconciliation process flow can be an interactive process. The data reconciliation process flow200is described in more detail in reference toFIGS.2and3.FIG.3depicts example data sets in accordance with implementations of the present disclosure and provides a graphical representation of the example data reconciliation process flow ofFIG.2. For example, in the example health care data services context, data set1(202) includes prescription fulfillment data, data set2(204) includes third-party prescription information compiled by, for example, the ISO106, data set3(206) includes discount eligibility information, data set4(208) includes a directory of physicians, and data set5(210) includes product sales data. Edges302represent relationships established by the DRS116between data contained in the various data sets. Electronic data set1(202) includes data contained in data fields such as, for example, Unique Script ID, Seller ID, Product ID, Dispense Date, in addition to other data fields. Electronic data set1(202) includes data contained in data fields such as, for example, Unique Script ID, Seller ID, Product ID, and Dispense Date, in addition to other data fields. Electronic data set2(204) includes data contained in data fields such as, for example, Unique Script ID, Seller ID, Product ID, Dispense Dates (e.g., Dates 1-N), and Physician ID, in addition to other data fields. Electronic data set3(206) includes data contained in data fields such as, for example, Certified Entity in addition to other data fields, and sub-fields including Merchant ID sub-fields 1-N and Relationship and Date sub-fields indicating a relationship and dates of the relationship between the Certified Entity and each Merchant identified by the Merchant ID sub-fields. Electronic data set4(208) includes data contained in data fields such as, for example, Physician ID and Entities 1-N in addition to other data fields, and sub-fields including Relationship and Date sub-fields indicating a relationship and dates of the relationship between a physician and each entity identified by the Entity fields. Electronic data set5(210) includes data contained in data fields such as, for example, Product ID, Purchaser, Shipping Data, Sales Price, and Discount, in addition to other data fields. Continuing the description of the example data reconciliation process flow200in reference toFIGS.2and3, the DRS116receives electronic data set1(202) from the client organization104. In addition, the DRS116accesses electronic data set2(204), for example, from data repository system122. The DRS116can analyze and extract appropriate data from one or more of data set1's data fields, and use the extracted data to search for corresponding records in data set2(204) to automatically identify additional information related to the data in data set1. For example, data set1(202) may include information related to a prescription and pharmaceuticals sold under the prescription, but not include a prescribing physician. The DRS116can automatically identify and use the information from data set1to locate corresponding records in data set2. The DRS116can then identify information from the records of data set2that identifies the prescribing physician who wrote the prescription identified by the information in data set1. For example, the DRS116can search corresponding data fields of data set2for matching data from the data set1. In some examples, the DRS116can link data set1and data set2(or records from data set1and data set2) based on matching data contained in the two data sets. As illustrated inFIG.3data from the Unique Script ID, Seller ID, and Product ID fields form data set1(202) are matched with data in corresponding data fields of data set2(204). For example, data set1(202) may identify a prescription using a unique prescription identification code (e.g., Script ID or RxID), and can include an identity (e.g., name or identification code) for the product sold under the prescription (e.g., a pharmaceutical product such as a prescription drug identified in the Product ID field), an identity (e.g., name and address or identification code of a specific pharmacy or chain of pharmacies in the Seller ID field) of a merchant that sold the product, and the date that the product was sold (e.g., Dispense Date). Similarly data set2(202) may identify the same prescription and include additional information such as, for example, an identity (e.g., a name and address or identification code in the Physician ID field) of a physician that wrote the prescription a list of multiple dates on which the prescription was fulfilled (e.g., for a prescription that requires regular refills). The DRS116can automatically identify the prescribing physician's identifier from data set2(204) based on the data sets1and2. In addition, the DRS116accesses electronic data set3(206) from an external system108. Using the data from the Seller ID field of data set1, the DRS116can automatically identify one or more records from data set3(206) associated with a merchant identified in the Seller ID field of data set1, for example, a pharmacy that sold a pharmaceutical product identified in data set1(202). In addition, data set3(206) contains data related to certified entities (e.g., an entity approved to receive a discount on a pharmaceutical product) such as, for example, merchants having approved associations with the certified entity (e.g., Merchant ID fields), a status of the association (e.g., Relationship fields), and effective dates of the relationships (e.g., Date fields). For example, from data set3(206), the DRS116can verify whether the merchant had an approved relationship with one or more certified entities on the date that the pharmaceutical product from data set1(202) was dispensed. The DRS116can use the identities of the one or more certified entities from data set3(206) and the physician ID form data set2(204) to determine whether the physician was associated with any of the same certified entities with which the merchant also has an approved relationship from data set4(208). In addition, the DRS116can determine an association type for associations that the physician may have with any of the same certified entities. For example, the DRS116can access electronic data set4(208) from data repository system120, and data set4(208) may include physician directory information including which entities (e.g., hospitals and clinics) the physicians have associations with (e.g., Entity fields), the types of relationships (e.g., Relationship fields), and the effective dates of the relationships (e.g., Date fields). The DRS116can identify a data record in data set4(208) related to the physician from data set2(204), and compare the certified entities identified from data set3(206) with the entities with which that the physician is associated in the identified data set4(208) record. In other words, the DRS116can use data from data sets2,3and4to determine whether the physician has (or had) an association with any of the same certified entities as the merchant that sold a pharmaceutical product identified by data set1(202), the type of association the physician has with the certified entity, and the effective dates of the association. In some examples, the DRS116will verify whether the physician had an association with the certified entity on or near the date that the pharmaceutical product from data set1was sold (e.g., date dispensed from data set1), and the type of the association. For example, association types may include attending, IDN affiliated, admitting, or staff. In addition, the DRS116can use data in data set4to identify other entities with which the physician has associations, the number of other associations, the type of those associations, and their effective dates (e.g., when the associations began and if or when the associations changed or ended). In response to determining that the physician has an association with any of the same certified entities as the merchant that sold a pharmaceutical product identified by data set1(202), the DRS116automatically generates and sends an electronic notification to the client organization (e.g., user computing device114) indicating that a product sold by the merchant may be eligible for a discount. The electronic notification (e.g., alert212) can be an e-mail, text message, etc. In some examples, the notification includes applicable data from one or more of the data sets to document the determination made by the DRS116. Thus, by reconciling the data contained in data sets1,2,3, and4, the DRS116can automatically determine whether a pharmaceutical product sold by a merchant was eligible for a manufacturer discount. More specifically, the data contained in data sets1,2,3, and4, the DRS116can verify whether a prescribing physician had an association with an entity certified to receive a discount on pharmaceutical products at the time the physician issued the prescription. Furthermore, in response to making such a determination, the DRS116can sent an electronic notification including supporting data from the appropriate data sets to the client organization104. In some examples, the DRS116can use the physician data obtained from data set4(208) to determine a confidence level associated with data contained in the electronic notification, as illustrated inFIG.4. The confidence level can indicate a likelihood that the pharmaceutical product sold by the merchant under the prescription identified from data set1(202) was eligible for a manufacturer discount.FIG.4depicts an example process400for determining reconciliation confidence that can be executed in accordance with implementations of the present disclosure. In some examples, the example process400can be provided as one or more computer-executable programs executed using one or more computing devices such as, for example, DRS116. Referring toFIGS.2-4, upon determining that the physician has an association with any of the same certified entities as the merchant that sold a pharmaceutical product identified by data set1(202), the DRS116identifies the type relationship(s) that the prescribing physician has or had with the certified entities at the date that the pharmaceutical product was prescribed (402). Types of association relationship(s) may include, for example, attending, IDN affiliated, admitting, or staff. If the identified physician has either an attending or IDN affiliated relationship with one of the certified entities (404) the confidence level is set to a high confidence level (406). For example, attending and IDN affiliated relationships may indicate a high likelihood that the physician was working under his/her association with the certified entity when the identified prescription for the pharmaceutical product was issued. Otherwise, if the physician does not have an attending or IDN affiliated relationship with one of the certified entities (404), the DRS116determines the number of associations that the physician has or had with certified entities at the date that the pharmaceutical product was prescribed (408). If the number of certified entities with which the physician has an association is at or below a threshold number then the confidence level is set to a medium confidence level (410). Conversely, if the number of certified entities with which the position has an association is above a threshold number then the confidence level is set to a low confidence level (412). For example, if the prescribing physician has admitting or staff relationships with multiple different entities, some of which are certified entities and some of which are not certified entities, there is a moderate likelihood that the pharmaceutical product was prescribed in connection with the physician's association with one of the certified entities. Even more, if some of the certified entities with which the physician is associated are not also associated with the merchant that sold a pharmaceutical product identified by data set1(202), there is a lesser likelihood the pharmaceutical product was sold in relation to one of the certified entities. In some implementations, the number of associations that the physician has may be represented by a ratio. For example, the number of associations may be represented by a ratio as the number of associations that the physician has with certified entities to the total number of associations that the physician has with both certified and noncertified entities. In some examples, the ratio may be one of the number of associations that the physician has with certified entities in common with the merchant that sold the pharmaceutical product to the total number of associations that the physician has with both certified and noncertified entities. Referring again toFIGS.2and3, in some examples, the DRS116also reconciles data from data set5(210) with related data from data sets1,3, and4to establish information related to a sale of the pharmaceutical product. Electronic data set5(210) includes information related to the sale of pharmaceutical products such as, for example, product identification data (e.g., product codes), purchaser data (e.g., an identity of and payment information form a purchaser), shipping data (e.g., recipient identity and address), regular sales price, and any discounts applied to the sale. The DRS116can determine whether any sales data from data set5identifies a pharmaceutical product purchased by the certified entity and sent to the merchant that filled the physician's prescription, and thereby, further verify both whether and which discounts have already been applied to the pharmaceutical product. In addition, the notification can include appropriate sales data identified from data set5(210). In some examples, data set1can include prescription fulfillment data from a Pharmacy Benefits Manager (PBM). In some examples, data set3can include discount eligibility information related to entities entitled to receive a government mandated discount under a government program such as, for example, the 340B drug discount program. In some implementations, the second and first data sets (e.g.,202and204) may be combined into a single data set. For example, Medicaid prescriptions data may be included in one data set that contains the feature sets similar to those of both example data set1(202) and data set2(204). In such implementations, steps related to linking data from example data set1(202) and data set2(204) would not be necessary. FIG.5depicts an example data reconciliation process500that can be executed in accordance with implementations of the present disclosure. In some examples, the example process500can be provided as one or more computer-executable programs executed using one or more computing devices such as, for example, DRS116. A first electronic data set including a first set of data fields is received from a first party (510). The first electronic data set can include prescription fulfillment data. For example, the first data set may be data received from an insurance PBM. The first electronic data set is linked to a second set of data fields from a second electronic data set (520). The second electronic data set can include third-party prescription information, and the data sets can be linked based on matching data from at least one of the first set of data fields of the first electronic data set to data from at least one of a second set of data fields of the second electronic data set. For example, data such as prescription identification numbers, seller identification, product identification numbers, and dispense dates can be matched between the two data sets. An identifier for a prescribing physician is automatically identified based on the linked first and second electronic data sets (530). For example, linking the data from the first and second data sets can reveal an identifier of the prescribing physician from the second data set. A third electronic data set is accessed (540). The third electronic data set can include discount eligibility information and identify entities approved to receive a discount. One or more approved entities having an approved relationship with a merchant are automatically identified from the third data set (550). For example, the third data set may be a government database of entities approved to receive a government mandated discount (e.g., a 340B discount). The merchant may be associated with the merchant identifier from the first data set and, the one or more certified entities may be identified using the merchant identifier. A relationship between the physician associated with the prescribing physician identifier and at least one of the approved certified entities is determined (560). The relationship may be determined based on comparing the prescribing physician identifier and identifiers of the one or more approved entities to a fourth set of data fields from a fourth electronic data set. In some examples, the number and type of relationships that the physician has with both certified and other entities may be determined. The physician's relationships may be used to determine a confidence level associated with the likelihood that particular products were prescribed in connection with the physician's relationship with a certified entity. In response to determining the relationship between the physician and the at least one of the approved entities, an electronic notification indicating that a product sold by the merchant is eligible for the discount is automatically generated (570). The electronic notification can be an e-mail, text message, etc. In some examples, the notification includes applicable data from one or more of the data sets to document the determination. For example, the electronic notification can include a report of discount eligibility data related to multiple products sold by the manufacturer. Implementations of the subject matter and the operations described in this specification can be realized in digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. Implementations of the subject matter described in this specification can be realized using one or more computer programs, i.e., one or more modules of computer program instructions, encoded on computer storage medium for execution by, or to control the operation of, data processing apparatus. Alternatively or in addition, the program instructions can be encoded on an artificially generated propagated signal, for example, a machine-generated electrical, optical, or electromagnetic signal that is generated to encode information for transmission to suitable receiver apparatus for execution by a data processing apparatus. A computer storage medium can be, or be included in, a computer-readable storage device, a computer-readable storage substrate, a random or serial access memory array or device, or a combination of one or more of them. Moreover, while a computer, storage medium is not a propagated signal; a computer storage medium can be a source or destination of computer program instructions encoded in an artificially generated propagated signal. The computer storage medium can also be, or be included in, one or more separate physical components or media (e.g., multiple CDs, disks, or other storage devices). The operations described in this specification can be implemented as operations performed by a data processing apparatus on data stored on one or more computer-readable storage devices or received from other sources. The term “data processing apparatus” encompasses all kinds of apparatus, devices, and machines for processing data, including by way of example a programmable processor, a computer, a system on a chip, or multiple ones, or combinations, of the foregoing. The apparatus can include special purpose logic circuitry, for example, an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit). The apparatus can also include, in addition to hardware, code that creates an execution environment for the computer program in question, for example, code that constitutes processor firmware, a protocol stack, a database management system, an operating system, a cross-platform runtime environment, a virtual machine, or a combination of one or more of them. The apparatus and execution environment can realize various different computing model infrastructures, such as web services, distributed computing and grid computing infrastructures. A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, declarative or procedural languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, object, or other unit suitable for use in a computing environment. A computer program may, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub-programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network. The processes and logic flows described in this specification can be performed by one or more programmable processors executing one or more computer programs to perform actions by operating on input data and generating output. The processes and logic flows can also be performed by, and apparatus can also be implemented as, special purpose logic circuitry, for example, an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit). Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only memory or a random access memory or both. Elements of a computer can include a processor for performing actions in accordance with instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, for example, magnetic, magneto-optical disks, or optical disks. However, a computer need not have such devices. Moreover, a computer can be embedded in another device, for example, a mobile telephone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a Global Positioning System (GPS) receiver, or a portable storage device (e.g., a universal serial bus (USB) flash drive), to name just a few. Devices suitable for storing computer program instructions and data include all forms of non-volatile memory, media and memory devices, including by way of example semiconductor memory devices, for example, EPROM, EEPROM, and flash memory devices; magnetic disks, for example, internal hard disks or removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry. To provide for interaction with a user, implementations of the subject matter described in this specification can be implemented on a computer having a display device, for example, a CRT (cathode ray tube) or LCD (liquid crystal display) monitor, for displaying information to the user and a keyboard and a pointing device (e.g., a mouse or a trackball) by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be any form of sensory feedback, for example, visual feedback, auditory feedback, or tactile feedback; and input from the user can be received in any form, including acoustic, speech, or tactile input. In addition, a computer can interact with a user by sending documents to and receiving documents from a device that is used by the user; for example, by sending web pages to a web browser on a user's client device in response to requests received from the web browser. Implementations of the subject matter described in this specification can be implemented in a computing system that includes a back-end component (e.g., such as a data server), or that includes a middleware component (e.g., an application server), or that includes a front-end component (e.g., a client computer having a graphical user interface or a Web browser through which a user can interact with an implementation of the subject matter described in this specification), or any combination of one or more such back-end, middleware, or front-end components. The components of the system can be interconnected by any form or medium of digital data communication (e.g., a communication network). Examples of communication networks include a local area network (“LAN”) and a wide area network (“WAN”), an inter-network (e.g., the Internet), and peer-to-peer networks (e.g., ad hoc peer-to-peer networks). The computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. In some implementations, a server transmits data (e.g., an HTML page) to a client device (e.g., for purposes of displaying data to and receiving user input from a user interacting with the client device). Data generated at the client device (e.g., a result of the user interaction) can be received from the client device at the server. While this specification contains many specific implementation details, these should not be construed as limitations on the scope of any implementation of the present disclosure or of what may be claimed, but rather as descriptions of features specific to example implementations. Certain features that are described in this specification in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be advantageous. Moreover, the separation of various system components in the implementations described above should not be understood as requiring such separation in all implementations, and it should be understood that the described program components and systems can generally be integrated together in a single software product or packaged into multiple software products. Thus, particular implementations of the subject matter have been described. Other implementations are within the scope of the following claims. In some cases, the actions recited in the claims can be performed in a different order and still achieve desirable results. In addition, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In certain implementations, multitasking and parallel processing may be advantageous. | 36,615 |
RE49866 | DETAILED DESCRIPTION The disclosed embodiments include methods, systems and devices for logging transaction processing in heterogeneous networks that include a combination of instrumented and non-instrumented components. The disclosed embodiments also include methods and systems for instrumenting components to perform logging of transaction processing and to, in some instances, generate impersonated log records for non-instrumented components involved in the transaction processing. The term transaction and transaction processing broadly refer herein to one or more computer-executable processes that are performed with one or more related data objects. In many instances, the terms transaction and transaction processing corresponds to a group of operations that are performed by one or more computing components, in series and/or in parallel. During a handoff of the transaction/transaction processing, one component completes its processing of the data object(s) and triggers another downstream component to begin performing processing of the data object(s) associated with the transaction. In some embodiments, instrumented components are configured to generate impersonated log records for one or more upstream and/or downstream non-instrumented components that are involved in handoff transaction processing with the instrumented components. The impersonated log records are consolidated with other log records that are generated by one or more instrumented components performing some of the transaction processing. A central logging system stores the various log records in a composite log which reflects a complete flow of the transaction processing performed on the object, including the flow through the non-instrumented component(s). A logging control computing system is configured for managing and logging records received from the instrumented components and to determine which components are non-instrumented. The control computing system is also configured to notify the instrumented components of the non-instrumented components and to instruct/instrument the logging components to generate log records for the non-instrumented components when receiving or handing of transaction processing to the non-instrumented components. The ability to generate a composite log that reflects a complete flow of the transaction processing performed on the corresponding data objects of the transaction in a distributed network that includes one or more non-instrumented components is a technical improvement in the area of log generation and was not previously possible. Many benefits can be achieved, in some instances, by utilizing the disclosed embodiments to generate logs with impersonated log records that are created by instrumented components in behalf of non-instrumented components that are involved in transaction processing handoffs with the instrumented components. These benefits include the ability to generate a log that reflects a full flow of processing that is performed by a distributed network of components, including the non-instrumented components. The benefits also include the ability to instrument a logging component with the functionality to generate impersonated log records in behalf of non-instrumented components. Attention will now be directed toFIG.1, which illustrates a computing system100that includes a logging control system110connected to one or more networked devices, including logging component140, and other connected devices142,144and146. While shown as standalone systems, it will be appreciated that each of the disclosed logging control system110and the disclosed devices/components140,142,144,146can, alternatively, be configured as distributed systems that are connected through one or more of the network connections130. The logging component140and the other connected devices142,144and146are examples of the recited ‘components,’ described herein. The term component should be broadly interpreted to be any computing device or system that includes a processor configured to process computer-executable instructions and a communication interface configured to enable the component to engage in a wireless or wired communication with another computing device or system. In some instances, the components are IoT devices (Internet of Things devices). In other instances, the components are more complex computing systems or devices, such as mobile phones, tablets or standalone computing devices. The components can also be, in some instances, different parts that are all integrated into a single computing device. The network connections130include any combination of wired or wireless connections, such as, but not limited to Ethernet, cellular connections, or even computer to computer connections through serial, parallel, USB, or other connections. These connections allow the various computing systems/devices to access services at other computing systems and to quickly and efficiently receive application data from other computing systems/devices. The network connections130, together with the disclosed systems, may be referred to, herein, as “cloud” computing systems. In this description, “cloud computing” may be any combination of systems or resources for enabling ubiquitous, convenient, on-demand network access to a shared pool of configurable computing resources (e.g., networks, servers, storage, applications, services, etc.) that can be provisioned and released with reduced management effort or service provider interaction, such as under the control of the logging control system. A cloud model can be composed of various characteristics (e.g., on-demand self-service, broad network access, resource pooling, rapid elasticity, measured service, etc), service models (e.g., Software as a Service (“SaaS”), Platform as a Service (“PaaS”), Infrastructure as a Service (“IaaS”), and deployment models (e.g., private cloud, community cloud, public cloud, hybrid cloud, etc.). The logging control system110is configured to manage logging of the log records124in storage122. The storage122may include any number of separate logs124corresponding to different transactions and objects. In this regard, the granularity of each log may be the same or vary. The storage122also stores, in some instances, a log that includes a correlation vector for a particular transaction or object being processed. The log may also include multiple log records that each have their own correlation vector. The correlation vector, which reflects the processing path of transaction activities will be described in more detail below in reference toFIGS.10and11. The storage122may include any combination of persistent and/or volatile storage, which may be local, remote and/or distributed. The logging control system110includes one or more processors112, which include hardware processors configured to execute computer-executable instructions stored in the storage122. The one or more processors comprise, in some instances, means for processing stored computer-executable instructions that are executable for causing the logging control computing system110to perform the disclosed methods for logging activities performed by multiple components involved in a transaction. The logging control system110also includes I/O hardware interfaces110and communication interfaces120. These interfaces include input and output hardware and software user interfaces to facilitate user interaction and communication with the device(s)/system(s) connected to the logging control system110. The hardware and communication interfaces may include, for example, a keyboard, mouse, touchpad, camera, etc. for allowing a user to input data into the computer. In addition, various software user interfaces may also be available. Examples of software user interfaces include graphical user interfaces, text command line based user interface, function key or hot key user interfaces, gesture detection software, and the like. Examples of hardware output devices include display devices, speakers and haptic feedback devices. As illustrated, the logging control system110also includes a log record processing engine118which is configured to receive, analyze and process log records and to store the log records in appropriate logs124in the storage122. The log record processing engine, alone and/or with the processor(s)112, comprises means for receiving the log records. The log record processing engine with the processor(s)112and/or the storage122also comprise the means for causing the logging control computing system to perform the disclosed methods for logging activities performed by multiple components involved in a transaction and for storing the log records in persistent memory. The log record processing engine also includes, with or without the processor(s)112, means for determining when a log record generated by a logging component is generated for a non-logging component. The logging control system110also includes an instrumenting engine116that is configured to instrument components for generating log records for their own processing and, in some instances, for non-instrumented components. The instrumenting engine, alone and/or with the processor(s)112, comprises means for causing the logging component to generate the disclosed handoff log record for the non-logging component in response to the non-logging component handing off transaction processing to the logging component and to generate the disclosed processing log record for the non-logging component in response to handing off the transaction processing to the non-logging component. The instrumenting engine116obtains logging instructions for instrumenting the logging component(s) from storage122and/or from a remote third party. Then, when the instrumenting engine116is in communication with the logging component(s), the instrumenting engine116transmits the logging instructions and other related information to the logging component(s). The logging control system110is configured to communicate with one or more component(s) involved in the transaction processing, including a combination of instrumented and, in some instances, non-instrumented components, through one or more network communication links130. As will be appreciated from the foregoing, the logging control system110includes means for processing stored computer-executable instructions that are executable by the one or more processor(s)112for causing the logging control computing system110to perform a method for logging activities performed by multiple components involved in a transaction. These means for processing, as described above, include the one or more processor(s)112, the log record processing engine118and the storage122. For instance, the logging control system includes means for instrumenting the components to generate log records (such as instrumenting engine116). In some instances, the means for instrumenting is described as means for causing a logging component to generate a handoff log record for a non-logging component in response to the non-logging component handing off transaction processing to the logging component and to generate a processing log record for the non-logging component in response to handing off the transaction processing to the non-logging component. The logging control system also includes means for receiving log records (such as the communication interface (s)120and the log record processing engine118) and means for storing the log records in persistent memory (including the processor(s) and the storage122). The logging control system also includes means for determining when a log record generated by a logging component is generated for a non-logging component (such as log record processing engine118). As shown inFIG.1, the logging control system110is in communication with at least one component that is instrumented for logging. In some instances, the logging control system110instrumented the logging component to generate one or more log records, as described herein, for itself and for one or more non-instrumented components. Logging component device140is an example of a component that has been instrumented for logging. As shown, the logging component device140includes one or more processor(s)150and storage180. The storage180, which includes persistent and/or volatile storage, stores the logging instructions that instruct the logging component device140when and how to generate and register log records with the logging control system110. The logging instructions182may also include protocol instructions that specify the different value and naming conventions for data fields to include in a log record, such as the values identified in the table ofFIG.10, which will be discussed later. The logging instructions may also include notifications and/or indices that identify which other components (142,144,146) are non-instrumented components. The logging component device140also includes a log record engine170which is configured to generate the log records and to register the log records with the logging control system110, as instructed from the logging instructions maintained in the storage180. The logging component140may also store the log records in the storage180prior to sending the log records to the logging control system, such that the log records can be sent at any desired/appropriate time and in response to different triggering events (e.g., periodic intervals, in response to a request, in response to enqueuing a predetermined number of log records, etc.). In some instances, the logging component140batches a plurality of log records prior to transmitting the batch of log records to the logging control system110. The logging component device110also includes one or more communication interface(s) for communicating with the logging control system and the one or more other components in communication with the logging component device140, such as devices142,144and/or146. Each of the illustrated devices142,144and146are configured, in some instances, to include at least some of the elements described in reference to logging component device140, such as processors, communication interfaces and storage. In some instances, one or more of the illustrated devices142,144and146omit, however, the logging instructions and/or the log record engine. In such instances, the corresponding device(s) will be configured as non-instrumented components that are not configured for generating and/or registering log records with the logging control system110. It will be appreciated that although the devices140,142,144and146are illustrated as comprising IoT devices, it is not necessary that these devices be characterized this way. In some instances, for example, one or more of the devices are not IoT devices. Any combination of these devices140,142,144and146(as well as one or more other similar devices) are utilized to perform a transaction on one or more data objects. Some of the devices are configured as instrumented components (such as instrumented component device140) to generate log records associated with their transaction processing to reflect the flow and/or processing performed on the data objects. According to some of the disclosed embodiments, the log records that are generated also include at least one or more impersonated log records that are created by instrumented component(s) for non-instrumented component(s) to reflect the handling and/or processing of the data object(s) by the non-instrumented component(s), as described herein. The following discussion will now refer to a number of methods and method acts that may be performed during implementation of some of the disclosed embodiments. Although the method acts may be discussed in a certain order or illustrated in a flow chart as occurring in a particular order, no particular ordering is required unless specifically stated, or required because an act is dependent on another act being completed prior to the act being performed. FIG.2illustrates a flow diagram200of acts associated with methods for an instrumented component, such as logging component140, to create and/or register a log record for a downstream non-instrumented component. In such embodiments, the instrumented component includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As shown, the acts include the logging component receiving a transaction to process (act210). This transaction can include any transaction processing associated with a particular transaction that is being performed by a plurality of different components, including at least one non-instrumented component. The transaction processing can include any data operation that is performed on an object associated with the transaction, including any data structures, files, threads, etc. In some embodiments, the data operation is merely handling of the transaction process, such as accepting and/or handing the transaction process off to another component. In some embodiments, the data operation includes modifying a data object, creating a new data object and/or deleting a data object associated with the transaction. Each of the different components are configured with special functionality to perform different processing on data objects as part of the transaction processing that is passed through a processing pipeline that includes the various components. However, in some embodiments, the different components can also perform similar or the same processes on the data objects as part of the transaction processing. In response to performing the transaction processing, the logging component is configured to create an initial first component log record that reflects the transaction processing (act220). Next, the logging component passes the transaction processing off to a next component (act230). In some instance, the transaction processing is passed off to another component that is specified in a pre-established processing pipeline and/or in response to dynamic instructions included with the object. The transaction processing can also be handed off in response to dynamic instructions received from the logging control system or another component, based on attributes of the object or other triggering events. When the logging component passes off the transaction processing, it creates a handoff log record for the next component that the transaction processing is passed off to (act240). If the transaction processing is handed off to multiple different components, a separate log record with unique identification is created for each of the different components receiving the transaction processing. In some instances, the transaction processing is handed off to another component that is not instrumented for logging. In these instances, the logging component determines that the receiving component is not instrumented for logging (act250). This determination can be made by referencing a stored table or index at the logging component that identifies the components that are not instrumented for logging. Alternatively, the logging component can query the receiving component and/or the logging control system for logging capabilities of the receiving component. Upon failing to receive a positive reply to the query about logging capabilities, the logging component can determine that the receiving component is not instrumented for logging. The logging component can also receive a notification from a remote system (e.g., the logging control system, or another device or system than the particular receiving component) that the particular receiving component is a non-logging component. Then, upon determining the receiving component is not instrumented for logging, the logging component creates a new component log record associated with the transaction processing being performed by the receiving component (act260). The log records created by the logging component are sent to the logging control system for persistent storage. All of the log records are sent on demand, according to a predetermined schedule, when batched into a plurality of log records (to improve efficiencies) and/or automatically in response to being created. Instructions for the manner in which the log records are created and the conditions/timing for sending the log records are specified in the logging instructions that are stored by and/or that are accessible to the logging component. In some instances, the disclosed flow ofFIG.2also includes the logging component creating a secondary first component log record associated with passing the transaction processing off to the next component, to reflect a reception of the transaction processing by the next component, wherein the secondary first component log record is a unique log record having a unique incremented component value that distinguishes the secondary log record from at least one other secondary log record associated with passing the transaction processing off to a different next component. In some instances, the new component log record that was created also includes the transaction ID and the incremented component value, as well as a new extension component value that corresponds to the transaction processing by the new component, since the new component is a non-logging/non-instrumented component that is incapable of generating/registering a similar log record to show the processing being performed by the new downstream component. FIG.3illustrates a flow diagram300of acts associated with related methods for an instrumented component, such as logging component140, to create or refrain from creating log records for downstream components depending on whether or not the downstream components are instrumented components. In such embodiments, the instrumented component includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As illustrated, the instrumented component first receives a transaction to process, which may include any portion of transaction processing associated with the transaction (act310). Next, a first log record is created by the instrumented component to reflect the transaction processing (act320). This first log record includes, according to some embodiments, a transaction ID (identifier) and an initial component value corresponding to the instrumented component. Next, the instrumented component identifies a next component to pass of the transaction processing to (act330). This may be specified by the previous component, by an established processing pipeline, by the object(s) being processed, by a remote system and/or in response to stored instructions. Once the transaction processing is passed off or handed off to the next component (act340), the instrumented component creates a second log record to reflect the handing off of the transaction processing. When the transaction processing is handed off to multiple different downstream components, the instrumented component creates a separate ‘second log’ record for each hand-off. The second log record includes the transaction ID and an incremented component value associated with the handing off or passing off of the transaction processing. When the transaction processing is handed off to multiple downstream components, a separate ‘second’ log record for each downstream component will be created as a unique log record having a unique incremented component value. This protocol structure for the log records will be described in more detail with reference toFIGS.10and11. Next, a determination is made whether the next ‘downstream’ component is a logging/instrumented component or not, such as, for example, by receiving a notification from a remote system other than the new component that the new component is a non-logging component. If a determination is made that the downstream component is not instrumented for logging, the instrumented component will create a third log record, which is an impersonated log record, to reflect the transaction processing by the new downstream component that is not instrumented for logging. Otherwise, if it is determined that the new component is capable of logging, then the instrumented component refrains from creating the third log record. The third log record will include the transaction ID, the incremented component value and (for each new component receiving the handoff) a new extension component value that corresponds to processing of the transaction with the new component (such that each third log record will be unique). This protocol structure for the log records will be described in more detail with reference toFIGS.10and11. FIG.4illustrates a flow diagram400of acts associated with methods for an instrumented component to create or refrain from creating log records for a non-logging upstream component. In such embodiments, the instrumented component includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As illustrated an instrumented component first receives a transaction to process from a particular upstream component (act410). Then, upon determining that the particular upstream component is a non-logging component which has not been instrumented for logging the transaction processes (act420), the instrumented component creates an initial passing off log record associated with handing off or passing off of the transaction processing from the upstream non-logging component to the receiving component (act430). The determining act can be performed using any of the techniques described above in reference toFIGS.2and3, including receiving a notification from a logging control system, from a third party, examining stored index values, etc. Each log record that is created by the instrumented component is sent to the logging control system for persistent storage with other transaction log records associated with the transaction being processed. The instrumented component may also optionally store the log record(s) until a predetermined time or condition, such as to batch log records and/or to only provide the log records when requested by the logging control system. Alternatively, the log records may be transmitted automatically as they are created. Subsequently, once the instrumented component processes and hands-off the transaction processing to one or more downstream components, the instrumented component will create a log record for the processing and one or more log records for handing off the transaction processing, as described previously, and which may include generating impersonated reception and processing log records for downstream non-instrumented components. FIG.5illustrates a flow diagram500of acts associated with related methods for an instrumented component to create or refrain from creating log records for upstream components depending on whether or not the upstream components are instrumented components. In such embodiments, the instrumented component includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As shown, the instrumented component (referred to in this embodiment as a receiver component) receives a handoff of a transaction (i.e., transaction processing) from a particular upstream component (referred to in this embodiment as a caller component) (act510). Then, a determination is made as to whether the upstream caller component has been instrumented as a logging component or not (act520). This determination can be made, as described previously, based on information that is stored at the instrumented component or that is received from a remote system, such as the logging control system. Upon determining the caller component is not instrumented for logging, the instrumented receiver component creates a new log record associated with a handoff of the transaction processing from the non-logging caller component to the instrumented receiver component (act530). Alternatively, upon determining that the upstream caller component is instrumented for logging, the instrumented receiver component will refrain from creating the impersonated new log record to reflect the handoff from the caller component (act540). The instrumented receiver component will also create a processing log record to reflect processing of the transaction by the receiver component (act550). Likewise, when the transaction processing is subsequently handed off to another downstream component, the receiver component will create one or more passing off log records to reflect this subsequent handoff and one or more processing log records, if appropriate, for receiving non-instrumented components, as previously described. FIG.6illustrates a flow diagram600of acts associated with methods for a logging control system to receive and process log records. In such embodiments, the logging control system includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As reflected, the logging control system receives a first component log record that is generated by a ‘first’ instrumented component (act610). This first component log record was generated by the first component, as described above, in response to handling or otherwise performing some of the transaction processing of a particular transaction. In some instances, the logging control system will receive multiple log records from the first component, one for accepting the handoff of transaction processing, one for performing the transaction processing and one for handing off the transaction processing. In some instances, as reflected in act620, the logging control system will also receive an impersonated information log record associated with handling of the transaction processing by a second component which is not instrumented for logging and which received the transaction processing from the instrumented component (act620). This impersonated information log record was generated by the first component rather than from the second component in response to a determination being made that the second component is a non-instrumented component. In some instances, the logging control system also notifies/instructs the first component to generate the impersonated information log record for the second component and any other non-logging components that the first component hands off the transaction processing to. The logging control system also, in some instances, notifies the first component that the second component is a non-logging component. This set of instructions may occur during a single instrumenting of the first component. Alternatively, the instructions/notifications may be received over time through a series of different communications. For instance, the logging control system may perform an initial instrumenting of the first component with instructions for generating log records and to provide protocol information necessary for generating the log records. The logging control system may then later update the protocol information, the instructions and/or an index of non-instrumented components. In some instances, the logging control system also receives a handoff log record from the first component, subsequent to receiving the first component log record and prior to receiving the impersonated information log record. Such a handoff log record would be generated, for example, by the first component to reflect handing off of the transaction processing to the second component. The logging control computing system may also receive a subsequent handoff log record that is generated by a third component that receives a handoff of the transaction processing from the second component, the subsequent handoff log record will correspond to the second component's handing off the transaction processing to the third component. In such an embodiment, the logging control computing system may also receive a new log record generated by the third component that corresponds with the third component performing the transaction processing at the third component. This third log record will include an appropriate transaction ID, an incremented component value and a unique extension component value that corresponds to processing of the transaction with the third component, as described in more detail below in reference toFIGS.10and11. The logging control system may also receive an additional log record for each different component that the first component passes the transaction processing off to, wherein each additional log record is a unique log record having a unique incremented component value. Once the logging control system receives any/all of the log records, the logging control system stores the log records in persistent storage to reflect the flow and processing/handling of the transaction processing by the first and second components (act630), and any other components involved in the processing of the transaction, even without receiving an action log record from the second ‘non-instrumented’ component or any other non-instrumented component. This is an improvement over existing systems that are not configured to receive/record log records for non-instrumented components and which would otherwise create incomplete transaction logs for distributed networks that include one or more non-instrumented components. FIG.7illustrates a flow diagram700of acts associated with related methods for a logging control system to receive and process log records. In such embodiments, the logging control system includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As reflected, the logging control system receives a handoff log record that was generated by a receiving component that is instrumented for logging transaction processes (act710). Notably, this handoff log record was generated by the receiving component in response to receiving the handoff of the transaction processing from an upstream caller component that was not instrumented for generating log records. The handoff log record would normally be generated by the caller component, but wasn't. In this regard, the handoff log record is an impersonated log record. In some instances, the handoff log record is based on a stored log record that includes a transaction ID and an initial component value associated with a previous component that passed the transaction processing off to the caller non-logging component. In such instances, the handoff log record includes the transaction ID and an incremented component value that corresponds to the transaction processing being passed off by the caller non-logging component. The logging control system determines that the caller component is a non-logging component (act720). This determination may be made in response to receiving the handoff log record from the receiving component, rather than from the caller component. For instance, this determination can be made by examining the log record for data that reflects that the log record is for a handoff from the caller component (e.g., the incremented component value), even though the caller component is not submitting the log record. Alternatively, or additionally, the logging control system can verify that the caller component is a non-instrumented component by referencing stored indexes that reflect which components are instrumented. The foregoing determination can be useful, particularly for scenarios in which the caller component was previously instrumented for logging, but is failing to generate appropriate log records for some reason, the logging control system can update the indexes to reflect that the caller component is a non-instrumented component. In such instances, the logging control system can notify other instrumented components that the caller component is a non-logging component. Once the logging control system receives the log records, the logging control system stores the log records in persistent storage to reflect the flow and processing/handling of the transaction processing by the various components (act730). As described, above, in reference toFIG.7, the logging control system may also receive other types of log records as well, which are also stored in the persistent storage to reflect a complete flow/handling of a transaction by the various components of a distributed heterogeneous network that includes at least some non-instrumented components. The logging control system may also append or modify the log to reflect which of the components are not instrumented for logging. Some of the additional log records that may be received and stored by the logging control system include: a subsequent handoff log record associated with handing off of the transaction processing from the receiving component to a new logging component; a new log record associated with the transaction processing at the receiving component prior to the subsequent handoff log record; a transaction processing log record associated with processing of the transaction by the receiving component, the transaction processing log record being generated by the receiving component and including the transaction ID, the incremented component value and a new extension component value that is associated with the receiving component; and a new handoff log record associated with handing off of the transaction processing from the receiving component to a new logging component and which includes the transaction ID, the incremented component value and new value that increments and is based on the new extension component value. These log records are described in more detail in reference toFIGS.10and11. Attention is now directed toFIG.8, which illustrates a flow diagram800of acts associated with methods for a logging control system to instrument components for generating log records in a heterogeneous network that includes at least one component that is not configured to generate log records. In such embodiments, the logging control system includes one or more processors and stored computer-executable instructions which are executed by or executable by the one or more processors to implement the disclosed methods. As reflected, the logging control system instruments one or more components to generate log records. This includes instrumenting a particular component to generate a first processing log record for transaction processing handled by the particular component (act810). This is accomplished by providing the particular component with code for generating the log record in a single transmission and/or through multiple transmissions, when the particular component is connected to the logging control system with one or more network connections. The code provides the particular component with the necessary instructions for generating the log record, as well as information for the protocol to use to generate the log records and the instructions for timing and conditions to use for sending the log records to the logging control system. Sometimes, the information provided to the component(s) during instrumentation also includes an index or listing of components that are non-instrumented in the network. In some instances, the logging control system instruments the particular component to generate the first processing log record with a transaction ID, an incremented component value and a unique extension component value that corresponds to processing of the transaction with the particular component. The transaction ID can be obtained from the logging control system or an object being operated on during processing of the transaction. The incremented component value can be an integer and the unique extension component value can also be an integer. The protocol for generating this and other log records is described in more detail, below, with reference toFIGS.10and11. The code and information provided to the component during instrumenting can also include additional instructions and information that are necessary for the component(s) to generate the other log records described herein, including the log records referenced in acts820,830and840. In some embodiments, the logging control system instruments the particular component to generate a handoff log record to reflect a handoff of the transaction processing from the particular component to any subsequent component receiving the transaction processing from the particular component (act820). The particular component is also instrumented to generate a handoff log record for each subsequent component that the particular component passes the transaction processing off to, with each handoff record comprising a unique log record having a unique incremented component value. The logging control system also instruments, in some embodiments, the particular component to generate a second processing log record when it is determined that said any subsequent component is a non-logging component that is not instrumented for generating the second processing log record and to refrain from generating the second processing log record when it is determined that said any subsequent component is a logging component that is instrumented for generating the second processing log record (act830). In some embodiments, the logging control system also instruments the particular component to generate an additional handoff log record associated with the particular component receiving a handoff of the transaction processing from a preceding component in response to determining that the preceding component is a non-logging component that is not instrumented for generating the additional handoff log record and to refrain from generating the additional handoff log record in response to determining that the preceding component is a logging component that is instrumented for generating the additional handoff log record (act840). This additional handoff log record is based on a stored log record that includes a transaction ID and an initial component value associated with a preceding component that passed the transaction processing off to the preceding component, the additional handoff log record including the transaction ID and an incremented component value that corresponds to the transaction processing being passed off by the preceding non-logging component. Attention is now directed toFIG.9, which illustrates a flow of event data/objects as they flow through the overall system during implementation of some of the disclosed methods. As shown, event data objects will pass through a logger (e.g., the component processing the object) which generates a log record for the object that is buffered until it is transmitted to a repository system, such as the logging control system, for storage. Each event object, for which a log record is created during handling, can be referred to as an EventData object and is configured with various properties, including an event name. The EventData object can also include other properties such as a time stamp to reflect process/handling timing or sequences. The EventData object will also include information identifying the logging component (e.g., component handling the object), as well as information identifying components passing the object to the logging component or receiving the object from the logging component. The EventData object can also be configured to store error information and a correlation vector appended to the object. The correlation vector and/or the other EventData properties can be used to illustrate an objects path through a processing pipeline that includes multiple components, including at least some components that are not instrumented for logging and/or for updating the correlation vector. In some instances, the correlation vector comprises an activity ID substring (e.g., ‘name’ and ‘number sequence’), followed by a vector clock substring indicating the previous path of activity for the object. Examples of vector clock substrings are provided in the value column of the table inFIG.10. The correlation vector can be appended to the object being processed, added to a log record and/or be a stored data structure that is updated at the logging control system to reflect the object processing path. The table ofFIG.10illustrates several correlation vectors that will be generated to reflect the processing and handling of objects during the processing of a transaction across the components illustrated inFIG.11. For instance, the transaction processing illustrated inFIG.11, and referenced inFIG.10, includes component A performing transaction processing for a particular transaction, referred to as activity N. Then, component A passes off the transaction processing (activity N) to components B and D. Likewise component B passes of the transaction processing to component C. As shown inFIG.10, the vector correlations include the name of the transaction processing or transaction ID (e.g., activity ‘N’) followed by a vector clock substring that reflects the processing/handling path of the activity/object. For instance, when component A processes activity N, it will generate a log record that includes vector correlation N:0, reflecting a first processing of the activity/object, with a transaction ID of N and an initial component value of 0. Then, when the transaction processing is passed to component B, a new log record is generated with vector correlation N:1, which includes the transaction ID of N and a unique incremented component value associated with the handoff. Next, when the transaction processing is passed to component D, the vector correlation for that log record will include the transaction ID (i.e., N) followed by a new unique incremented component value of 2. For each additional component that component A hands activity/object N off to will cause the generation of a new correlation vector and, sometimes a corresponding log record that is unique, with a unique incremented component value, such as can be created by continually incrementing the incremented component value for each new receiving component. When a receiving component accepts the transaction processing, such as when component D accepts the transaction processing from A, the correlation vector will be updated and/or a log record will be created with the updated correlation vector to reflect this. In the current embodiment, this is reflected by updating the vector correlation to N:2:0, which indicates the path of activity N from component A, which handed activity N off to component D (shown in third row as N:2), and which has been accepted by component D, reflected by component D adding an extension (‘0’) to the vector correlation (‘0’). When component D subsequently performs a process or completes the process on activity/object N, it will update the correlation vector and create a log with the updated correlation vector that has an incremented extension component value. If D thereafter passes the activity off to another component, it will also increment the extension component value to reflect this, such as by logging/updating a log record with correlation vector N:2:2 (not shown). When the new component accepts the activity N from component D, it will also create a new log record with an updated correlation vector that has a new extension (N:2:2:0—not shown inFIG.10). A related example of this in the table ofFIG.10is illustrated by the correlation vector N:1:1:0, which reflects that component C has accepted activity N from component B. Accordingly, each time a component performs a transaction process on an activity or object associated with a transaction it will increment the incremented component value associated with the component in the correlation vector. This includes processes performed by the component, such as performing an operation on the object/activity and passing the activity/object on to another component. Then, each time a component accepts an activity/object associated with the transaction, the correlation vector is extended with a new extension component value. However, that new extension component value becomes an incremented component value for that component and is incremented for each activity performed. In this manner, a new value field is added to the correlation vector each time the activity/transaction processing is accepted by a new component and the value in that new value field is incremented each time a process is performed on the activity/transaction processing by the component associated with that value field. Although not required, the different incremented component values/extension component values of the vector correlation can be separated by a period or other separator. This can be helpful when the values are integers and there are more than nine processes performed, such that the value will be at least a double digit value. The foregoing process for creating/modifying the correlation vector will be iterated until the transaction is complete. Each time the correlation vector is changed, a new log record with the correlation vector is created and sent to the logging control system for persistent storage. Alternatively, the correlation vector is simply updated in a data structure appended to the object/event/activity that is flowing through the transaction processing pipeline and/or a data structure maintained by the logging control system is updated to reflect the latest changes to the correlation vector, based on the log records or other data received from the logging components. Either way, it is possible to identify the entire flow of the transaction processing by reviewing the correlation vector that is associated with the last log and/or that is appended to the transaction element(s) and/or that is maintained by the logging control system. Unfortunately, as described earlier, some components are not instrumented for logging and/or are unable to perform the modifications to the correlation vector. In these instances, the current embodiments include having the adjacent component (which is configured for logging) generate a log record (or modify the correlation vector) for the non-logging component. For instance, a logging component will be made aware when it receives transaction processing from a non-logging component or passes off the transaction processing to a non-logging component. Then, when this occurs, the logging component will generate the corresponding log record that the non-logging component would have created if it were a logging component. By way of example, when a logging component passes off transaction processing to a non-logging component, the logging component will generate a log record of the non-logging component accepting the transaction processing, in addition to its own log record for handing off the processing. Sometimes, the logging component can also generate a separate log to reflect the non-logging component processing the transaction processing. For instance, in regard toFIGS.10and11, if component B were a non-logging component and component A were a logging component, then component A would generate the log entry having correlation vector N:1:0. If component D were a non-logging entity too, then component A could also generate the log entries having correlation vectors N:2:0 and N:2:1. By way of another example, when a logging component receives a handoff of transaction processing from a non-logging component, the logging component will generate an impersonated log record reflecting the handoff by the non-logging component, separate from its own log record for accepting the handoff. The logging component could also generate a log record reflecting the processing performed by the non-logging component. For instance, in regard toFIGS.10and11, if component B were a non-logging component and component C were a logging component, then component C would generate the log entry having correlation vector N:1:1. As described herein, the embodiments of the present invention may comprise or utilize a special purpose or general-purpose computer including computer hardware, including physical computer-readable storage devices and other computer-readable media for carrying or storing computer-executable instructions and/or data structures. Such computer-readable media can be any available media that can be accessed by a general purpose or special purpose computer system. Computer-readable media that store computer-executable instructions are physical/tangible storage devices/media. Computer-readable media that carry computer-executable instructions are transmission media. Thus, by way of example, and not limitation, embodiments of the invention can comprise at least two distinctly different kinds of computer-readable media: physical computer-readable hardware storage media and transmission computer-readable media. Physical computer-readable hardware storage media are devices such as RAM, ROM, EEPROM, CD-ROM or other optical disk storage (such as CDs, DVDs, etc.), magnetic disk storage or other magnetic storage devices, or any other hardware devices which can be used to store desired program code means in the form of computer-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer. Computer-executable instructions comprise, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing device to perform a certain function or group of functions, such as the methods described herein. The computer-executable instructions may be, for example, binaries, intermediate format instructions such as assembly language, or even source code. Although the subject matter has been described in language specific to structural features and/or methodological acts, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the described features or acts described above. Rather, the described features and acts are disclosed as example forms of implementing the claims. Those skilled in the art will appreciate that the invention may be practiced in network computing environments with many types of computer system configurations, including, personal computers, desktop computers, laptop computers, message processors, hand-held devices, multi-processor systems, microprocessor-based or programmable consumer electronics, network PCs, minicomputers, mainframe computers, mobile telephones, PDAs, pagers, routers, switches, and the like. The invention may also be practiced in distributed system environments where local and remote computer systems, which are linked (either by hardwired data links, wireless data links, or by a combination of hardwired and wireless data links) through a network, both perform tasks. In a distributed system environment, program modules may be located in both local and remote memory storage devices. Alternatively, or in addition, the functionality described herein can be performed, at least in part, by one or more hardware logic components. For example, and without limitation, illustrative types of hardware logic components that can be used include Field-programmable Gate Arrays (FPGAs), Program-specific Integrated Circuits (ASICs), Program-specific Standard Products (ASSPs), System-on-a-chip systems (SOCs), Complex Programmable Logic Devices (CPLDs), etc. The present invention may be embodied in other specific forms without departing from its spirit or characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope. | 56,428 |
RE49867 | DETAILED DESCRIPTION The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. Referring toFIG.1there is shown a highly simplified schematic diagram10illustrating a portion of an induction system for a motor vehicle. In this example the vehicle engine has two cylinder banks12a and12b. An intake manifold14is used to provide intake air to the combustion chambers of the two cylinder banks12a/12b, as well as to provide a vacuum source14, via a vacuum actuator solenoid valve16, which assists in controlling independent actuators18a and18b. Actuators18a and18b are used for the control of the movement and modulating position of the CMCV for each bank of engine cylinders. Typically, the actuators may be vacuum or pressure actuated diaphragm and/or piston actuators. The vacuum source may advantageously be from the intake manifold of the engine. The flow restrictor of the present disclosure can be implemented in a plurality of different embodiments.FIGS.2and3show one such embodiment in which an actuator101of the present disclosure includes an actuator cover100having an internal flow restrictor102(visible only inFIG.3) in communication with an inlet port104. The flow restrictor102includes an internal wall106having a reduced diameter aperture106a that forms a restriction of a predetermined cross-sectional area. While the flow restrictor102is integrally formed within the actuator cover100, it is possible that the flow restrictor could form a separate component that is inserted into the inlet port104and mechanically secured (e.g., by adhesives or fasteners) therein. The cover100in one embodiment is manufactured form plastic as a single piece component with the restrictor100located within the air flow inlet port104. The airflow through the restrictor102thus affects how rapidly it's associated actuator18a or18b responds, and advantageously can have apertures configured to coordinate and synchronize movement and modulation of the CMCV for each bank of engine cylinders such the valves move and are positioned in unison. In this manner, the response of each actuator18a and18b can be controlled so that the two actuators are synchronized in operation to achieve coordinated movement of the CMCV. FIG.4shows a hose component200in accordance with another embodiment of the present disclosure. The hose component200in this embodiment includes a hose201and an air flow restrictor202inserted into an interior flow channel204of the hose201. In this embodiment an outer diameter of the flow restrictor202should be sized just slightly larger than the diameter of the flow channel204so that insertion of the flow restrictor202can be accomplished within the flow channel204, but that the flow restrictor, once inserted, will remain stationary within the flow channel204. The hose component200may be any type of flexible hose typically used in vehicle induction systems, for example a rubber hose, an elastomeric hose, or a hose made from any other form of resilient material suitable for automotive engine applications. The flow restrictor202inFIG.4includes a main body portion206having an end wall206a at one end with a reduced diameter air flow aperture208. The main body portion206may be made from a suitable plastic, from steel, aluminum or any other suitably rigid material. It is anticipated, however, that a particularly desirable implementation of flow restrictor202will have the main body portion206, the end wall206a and the reduced diameter aperture208molded as a single piece plastic component. The precise diameter of the reduced diameter aperture208is selected so that the flow restrictor202will reduce air flow through the hose201sufficiently to equalize the response of the two actuators18a and18b. As such, the flow restrictor202will be located in separate hoses leading to the two actuators18a and18b. As shown in simplified diagrammatic form inFIG.1, two flow restrictors202a and202b are illustrated located within a pair of the hose components200a and200b, respectively, to control the vacuum air flow being used to actuate the actuators18a and18b. Referring toFIG.5, a T-fitting component300in accordance with a third embodiment of the present disclosure is shown. The T-fitting component300may be made from a suitably strong plastic, from metal, from aluminum or any other material suitable for use in an automotive vehicle engine environment. However, it is anticipated that the T-fitting component300will in most instances be molded as a single piece component part from high strength plastic. The T-fitting component300includes a first port302, a second port304and a third port306, all in flow communication with one another. A first flow restrictor308a is formed in the second port304and a second flow restrictor308b is formed in the third port306. In this example the flow restrictors308a and308b are shown formed close to an internal intersection of the three flow paths associated with the ports302/304/306, although they need not be formed close to the internal intersection. Instead, the flow restrictors308a and308b could be formed closer to distal ends304a and306a of the ports304and306, respectively. The flow restrictors308a and308b are shown molded as integral internal portions of the T-fitting component300. In this form the flow restrictors308a and308b include walls309a and309b each having reduced diameter apertures310a and310b, respectively. The reduced diameter apertures310a and310b form flow restrictions that each have a precise cross-sectional flow area needed to balance the operation of the actuators18a and18b. It is also possible that the flow restrictors308a and308b could be formed as a single, separate component, and then inserted into either of ports304or306to the point of intersection of the three ports302-306. It would be important that the flow restrictor in such an embodiment, which would be similar to the flow restrictor202shown inFIG.4, is securable at the intersection of the three ports302-306, and this could be accomplished by a pin or other suitable means that extends through a portion of the T-fitting component300and engages the flow restrictor to hold it precisely in place. The various embodiments of the present disclosure all provide a means for balancing the response of a pair of actuators associated with a pair of CMCV for the cylinders of a motor vehicle engine, and which are both dependent on a single source for a vacuum airflow. The various embodiments described herein all enable a single solenoid valve to be used with the vehicle's intake manifold. This reduces cost, assembly complexity, weight, and further is expected to enhance overall reliably of a vehicle induction system. The various embodiments of the present disclosure free up space within the engine compartment and help to de-clutter the engine compartment. While various embodiments have been described, those skilled in the art will recognize modifications or variations which might be made without departing from the present disclosure. The examples illustrate the various embodiments and are not intended to limit the present disclosure. Therefore, the description and claims should be interpreted liberally with only such limitation as is necessary in view of the pertinent prior art. | 7,471 |
RE49868 | SUMMARY OF THE INVENTION The primary object of the present invention is to provide a quiet, attractive, energy efficient air circulating device that is mounted coplanar to, and extends a minimal distance from a ceiling, said device combining the functions of a ceiling fan with the functions and aesthetic appeal of a ceiling medallion but which also provides a solution to some of the stated shortcomings of the prior art. It is a further object of the invention to provide such a device from which a lighting fixture, pendent or chandelier may be mounted as shown inFIG.1. It is a further object of some embodiments of the invention to optionally embody a means to filter dust, pollen and other particulate matter from the circulating airstream. It is a further object of some embodiments of the invention to optionally embody, any of the following; heating, cooling, positive ion generation means, and/or air sterilization means. DETAILED DESCRIPTION OF THE INVENTION According to a broad aspect of the present invention there is provided an air circulating device comprising a ceiling plate which is mounted coplanar to a ceiling and to which is mounted an air inlet; air impelling means which in preferred embodiments is driven by a motor; internal airflow channeling means; primary airflow discharge outlet and means to direct the discharge airflow in the direction intended. All of the forgoing is to be structured in such a manner that the outer surfaces provide an external appearance similar to a ceiling medallion. It is within the scope of the invention that said structure may be generally circular, rectangular or polygonal and may have decorative embellishment about the perimeter and on downward facing surfaces. In the simplest embodiment, the top surface of a ceiling plate is mounted coplanar to a ceiling, proximate to an electrical supply run within said ceiling and said ceiling plate is rigidly affixed to a supporting frame member of said ceiling. Additional fastening means may be required peripherally to hold the ceiling plate and corresponding assembly tightly to the ceiling sheeting material. In preferred embodiments, the static part of a motor is fixedly mounted, centrally within the enclosing structure and an air impelling means is driven by the driving part of the motor. The motor drives the air impelling means rotationally causing air to be drawn in through an intake opening, be pushed through internal airflow channeling means and expelled through one or more air discharge openings. Air deflecting means proximate to said air discharge openings distributes discharged air about the surrounding area to provide the desired level of comfort. Optionally said air deflecting means may be alternately repositioned to distribute discharged air in a direction more or less downward from the ceiling in cooling season or an outward, horizontal direction across the ceiling in heating season. According to a further aspect of the present invention, a wiring box on the downward facing side of the enclosing structure is provided to enclose motor controlling devices and for the optional mounting of a lighting fixture or chandelier. According to a further optional aspect of the invention filtration means are mounted at the primary airstream inlet such that air drawn into the inlet must pass though said filtration means before it enters the area of the impelling means. it is fully within the scope of this aspect of the invention that the filtration means be either or both mechanical or electrostatic. According to a further optional aspect of the invention, primary air discharged by said impelling means temporarily dwells within a plenum chamber where it is becomes pressurized before it is further discharged at high velocity through a narrow, slotted opening that is coincident with and tangent to a cambered surface such as to cause consistent fluid wall attachment of said discharged air. Said fluid wall attachment is well known to the art as the Coanda Effect and said cambered surface is known as a Coanda Surface and the attached fluid flow is also known as a Wall Jet A significant amount of adjacent ambient air will then become entrained in the flow of the wall jet to create a secondary airflow. In preferred embodiments, a second cambered surface, is positioned a distance peripheral and adjacent to the said Coanda surface to act as a guide for said secondary airflow. In said embodiments, adjacent cambered surfaces converge near the horizontal mid- plane which is normal to the chord of both cambered surfaces, and diverge at both the inlet and outlet of secondary flow, thereby funneling ambient air into the area of convergence and causing an area of tow pressure at the discharge, and thereby drawing additional ambient air into the secondary airflow. In the present invention a unique Coanda flow reversing mechanism is provided by a section of said Coanda surface that can be repositioned so as to close the slotted opening through which said wall jet is generated and to open a second slotted opening oriented in the opposite direction, causing a reversal of the wall jet and secondary airflow. This allows overall airflow to be directed from ceiling to floor in the cooling season and floor to ceiling in the heating season. According to a further optional aspect of the invention, discharged air may be further conditioned by positive ion generation means or ultra violet radiation. According to a further optional aspect of the invention, heating or cooling means may be mounted in the airstream. A preferred embodiment of the present invention, is shown inFIG.2,2A,2B,FIG.3,3A,3B,3C,3DandFIG.4. Referring toFIG.2BandFIG.3, a ceiling plate12, is fixedly mounted coplanar to a ceiling and motor1has a centrally located stator1A fixedly mounted to ceiling plate12and an external, peripheral rotor18on which an air impelling means2, that in this embodiment, is a centrifugal impeller of a design common to the trade, is affixed. Air is drawn in by air impelling means2, enters through Filter Cover3and passes through Filtration Means4. Air is pushed by air impelling means2, between impeller shroud5and ceiling plate12, where it is directed in a generally downward direction by diverter guides6and7. A hollow conduit though motor stator1A, provides a pathway for a wiring harness8from an electrical supply within the ceiling to an electrical wiring box9, which is provided for electrical motor controlling devices and the optional mounting of a light or chandelier. Filter support13, provides support for filtration means4and filter cover3. A cover10may be provided if no lighting fixture is to be mounted. Ceiling plate12provides a frame and support for the preceding assembly and also provides the means to affix the said assembly to the ceiling. In this embodiment of the present invention, peripherally mounted air deflection means may be adapted to direct effluent air downward for summer cooling or horizontally across the ceiling to improve heat distribution during the heating season. InFIG.3,3B,3D, a plurality of positioning devices11, which in this embodiment are of a snap-over-center spring type, allow diverter guide7to be positioned either to direct discharged air flow downward for coolingFIG.3B, or across the ceiling for improved distribution of warm air during heating seasonFIG.3D. In other embodiments of the present invention,FIG.5and6, the air acceleration means is a radial impeller. It is fully within the scope of this invention that a plurality of stationary blades, peripheral to the radial impeller, known to the trade as stators be arrayed at angles more or less tangential to impeller axis of rotation to improve efficiency but at such an to angle and quantity as to prevent resonance and consequential noise. In this embodiment of the present invention,FIG.5andFIG.6, optional heat exchanging means is mounted in the air flow path. Said heat exchanging means may be of a tubular radiator type common to the trade which is supplied with a flow of heated or chilled liquid or evaporating refrigerant to provide additional heating or cooling. InFIG.5,FIG.6and6Athe motor1is affixed to the Ceiling plate12, which is mounted coplanar to a ceiling, proximate to an electrical power source, and the radial impeller2is affixed to the rotatable body of the motor1. Referring toFIG.6A, the rotating impeller2causes air to be drawn in through filter cover3and through filtration means4, after which it is pushed by radial impeller2through a passage between impeller shroud5and ceiling plate12, to be discharged through cooling I heating means14. Air discharged through heating I cooling means14is then directed in a generally downward direction by diverters6and7. In this embodiment, the curved surfaces of diverters6and7serve as foils to disperse discharged air about the room. It is within the scope of the present invention that other diverting means, such as louvers, fixed or adjustable, may be used to disperse discharged air. Item19is a decorative cover. Electrical wiring box9is attached to the non-rotating body of motor1and wiring harness8passes, from said electrical power source within the ceiling, through said non-rotating body of motor1to electrical wiring box9which, in preferred embodiments encloses motor controlling devices and also provides means to mount and supply power to an optionally attached lighting fixture. It is it is within the scope of the present invention that said heating means be of another type such as electric resistive heating. It is also within the scope of the present invention that said heating or cooling means be either totally integrated within the present invention or be part of a heating and/or cooling system central to a building. In a further embodiment,FIG.7,7A,7B,FIG.8,8A,8B, andFIG.9, airflow amplification means, which in this embodiment comprises a unique, reversible, Coanda Effect, air amplifying assembly. Air enters a radial impeller in a fashion similar to the foregoing embodiments, but is compressed by said radial impeller and is then discharged into a plenum chamber at an elevated pressure where it dwells before being discharged through a slot, at an accelerated velocity, as a primary airflow in an essentially tangential relationship to a cambered surface, which in this embodiment is an exterior wall of said plenum chamber, and to which said primary air flow remains in fluid attachment as a wall jet. Said cambered surface is one of a pair of peripherally offset, concentric and adjacent, cambered surface features. In this embodiment, a peripheral Flow Guide is positioned external to the circumference and concentric to said plenum chamber and has a cambered inner surface which is in mirrored relation to the Coanda Surface of said plenum chamber. Ambient air is drawn in and entrained by the primary wall jet and by the low pressure zone, created, at the divergence of the two cambered surfaces. This significantly multiplies the total volume of air flow for a given motor size. The cambered Coanda surface of the plenum chamber is comprised of first and second fixed sections and a repositionable portion that defines the position and direction of the primary discharge slot and thus the direction of both primary and secondary airflow. InFIG.7A, Air flow is directed from ceiling to floor. Motor1drives impeller2rotationally which draws ambient air in as a primary intake through Filter Cover3and Filter4and then drives said intake air through a narrowing section formed by the impeller shroud5and the Ceiling Plate12until it enters the plenum chamber which comprises first and second plenum sections15,16and repositionable section17, where it dwells and becomes pressurized until discharged through a slot defined by First Plenum Section16and repositionable plenum section17. The cambered surfaces of17and15form the Coanda surface to which said primary wall jet becomes fluidly attached. The peripherally facing surfaces of Plenum sections15,16and17, and the adjacent inward facing surface of Flow Guide18, together form a pair of geometrically opposed cambered surfaces, converging at the entrance of airflow and diverging at the discharge. Ambient air becomes entrained with the primary wall jet, establishing a coincident secondary airflow. An area of low pressure is formed near the point of discharge as air exits the flow path between said diverging walls causing additional ambient air to be entrained. The flow of entrained ambient air shrouds the high velocity air flow from the plenum and acts as a barrier to attenuate sound created by said high velocity air flow. InFIG.8Arepositionable plenum section17has been repositioned for flow reversal. The slot through which the primary wall jet flow was generated between first plenum section16and repositionable section17inFIG.7A and7Bhas closed and a slot is now open between second plenum section15and repositionable plenum section17. This new geometry mirrors, to some extent, the geometry of this area revealed previously inFIG.7A and7B. The wall jet now flows in the opposite direction in fluid attachment to the Coanda surface formed by plenum section15and repositioned plenum section17, as does the secondary flow of entrained ambient air, causing total airflow to be directed from floor to ceiling as would be most advantageous during the heating season. FIG.9is provided to better understand the general arrangement of components of the embodiment revealed inFIG.7andFIG.8where the stator of motor1is fixedly mounted to the ceiling plate12and the impeller2is mounted to the driven rotatable body of motor1. The rotating impeller causes air to be drawn in through intake grating3and through filtration means4which is supported by filter support13, after which it is pushed through a passage between impeller shroud5, and ceiling plate12to where it is compressed within a plenum chamber, which comprises plenum sections,15and17and repositionable plenum section16. Said pressurized air is then discharged from said plenum chamber through a slot between either plenum sections15and17or16and17depending on the position of repositionable plenum section17, coincident with a Coanda surface formed by the outward facing surfaces of either Plenum sections15and17or16and17, The outwardly facing combined surfaces of said plenum chamber together with the inwardly facing cambered surface of flow guide18which essentially mirrors the cambered surfaces of said plenum chamber, form a pair of peripherally offset, adjacent and geometrically opposite cambered surfaces. Said surfaces converge to funnel ambient air into the area influenced by the wall jet and cause an area of low pressure where these surfaces diverge. In another embodiment of the device of the present invention revealed inFIG.10,FIG.11,11AandFIG.12, the outline of the device, as viewed from below, is non-circular and, as illustrated in this embodiment, is rectangular. It is, however, fully within the scope of this embodiment that said plan form could be polygonal. FIG.10is an illustration of this embodiment with a pendant fixture attached. (Shown in phantom) inFIG.11,FIG.11Athe motor,1, is mounted to the Ceiling plate, Item12, and the impeller,2, is mounted to the rotatable body of the motor1. The rotating impeller causes air to be drawn in through intake grating,3, and through filtration means, Item4, after which it is directed through a passage formed between impeller shrouds5,23and ceiling plate12into plenums20, from which it is discharged and distributed about the room by diverters, Items6. FIG.12is provided to better understand the general arrangement of components where the motor1, is mounted to the Ceiling plate12, and the impeller, Item2, is mounted to the rotatable body of the motor1. Item3is the intake grating, Item4is filtration means, Item5and Item23are the impeller shrouds, Items20are the plenums and Items6, are the diverters. Item13is a filter support Items22are decorative blocks, items24are plenum covers and Item9is a wiring box which encloses motor controlling devices and also provides means to mount and supply power to an optionally attached lighting fixture perFIG.12. | 16,243 |
RE49869 | DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION The present invention is related to an approach to scale up GaN production using ion-beam crystal alignment for epitaxial films. The process is sometimes called ion-beam assisted deposition (IBAD), but it really refers to texturing of films with IBAD. IBAD texturing can occur at different time scales or thicknesses of films, but preferably occurs right at initial film nucleation and coalescence, which is known as ion-texturing at nucleation (ITaN). It typically occurs in the first 5-10 nm of deposit and has been demonstrated to be extremely fast, can occur in less than 1 second of deposition time. IBAD texturing can be performed on a large-area substrate that is typically a flexible metal foil. IBAD texture formation can alternatively be performed on flexible glass, ceramic, plastic or polymer. The process is easily scalable to long lengths with flexible substrates that can be put onto a spool suitable for roll-to-roll processing. The substrate itself can be polycrystalline but is preferably chosen for its mechanical as well thermal properties. Thus the material and the thickness of the foil are preferably optimized for the final application. Thin foils are preferably flexible and ductile. Additionally, since MOCVD growth (when utilized) is performed at high temperature, the material preferably has a good match to the coefficient of thermal expansion (CTE) of the thick GaN layers that will subsequently be deposited. For GaN molybdenum or tungsten or alloys thereof are preferably used. By eliminating the need for lattice matching in the substrate a greater variety of substrates may be chosen. Embodiments of the present invention are based on a novel GaN growth process which, compared to existing methods reported for GaN growth, comprises the use of non-single crystal substrates such as polycrystalline commercial metal foils or amorphous glass, upon which epitaxial GaN films are deposited directly and can be used for various applications including electronics, optics and optoelectronics, etc. In some embodiments, several different uniform films of thicknesses in the range of tens of nm are preferably evaporated or sputtered onto biaxially textured layers that are generated by an IBAD process. Amorphous wafers (amorphous materials such as glass, or a singlecrystal wafer coated by a vacuum deposited amorphous thin film) or polycrystalline metal substrates, for example, can be used as flat substrates. For metal substrates it is preferable to utilize materials having a coefficient of thermal expansion closely matching that of GaN, for example elements such as molybdenum, tungsten, tantalum and alloys thereof.FIG.1is a schematic of an embodiment of the present invention. The process of putting GaN on metal typically comprises three steps: 1) SDP, 2) IBAD+buffer layers, and 3) MOCVD GaN. The first step is solution deposition planarization (SDP). It is essentially chemical solution deposition (CSD) that has been optimized to smooth, or level, the surface by multiple coatings. In practice an initial root mean square (RMS) roughness of 20-100 nm on 5×5 μm scale can be reduced to about 0.5 nm after 10-30 coatings. A schematic and results of the SDP process are shown inFIGS.22and23. SDP prepares the substrate for the IBAD texturing process, especially for ITaN, for which only a thin deposit is needed. ITaN typically requires a very smooth surface, i.e. less than 2 nm RMS roughness, and the smoother texture the better. In addition to smoothing the substrate, SDP can be adjusted to additionally provide an appropriate base layer material on which the IBAD layer is deposited. ITaN, in particular, requires appropriate chemistry in the base layer for the ion texturing to work. SDP is typically not required if the substrate is sufficiently smooth. In past decades a number of ITaN materials have been explored, but most work was focused on MgO. IBAD-MgO produces <100> out of plane orientation and that is suitable for depositing cubic materials on top with the same orientation. However, for deposition of hexagonally symmetric materials, such as wurtzite GaN, it can produce two epitaxial domains that are 30° rotated with respect to one another. In order to go from a cubic material to a hexagonal structure one would need a <111> orientation, as shown inFIG.24. This is commonly done today in growing GaN on Si, where one uses a <111> oriented Si substrate. The quality of <111> IBAD in terms of the full width half maximum (FWHM) of the in-plane orientation has not been good enough to grow GaN, and not nearly as good as IBAD-MgO. IBAD-MgO has been reported down to 1.5° FWHM, with homoepi layers. The best <111> with CaF2obtained has been about 15°. One embodiment of the present invention uses CeO2with a FWHM in-plane orientation of about 8°. However, by growing GaN using MOCVD, that improved to less than 1° in the GaN layer. The way that GaN grows by MOCVD, starting with small seeds that coalesce and grow into large grains, accommodates an IBAD structure with poorer texture and still achieves high quality materials. Thus other IBAD materials, such as bixbyite structures, may be used. The IBAD layer can in principle be chosen to lattice match the functional epitaxial layer, e.g. GaN. In order to come closer to the GaN lattice an epitaxial buffer layer can be deposited that transitions from the 3.826 Å lattice parameter of CeO2to 3.189 Å of GaN. Many materials with intermediate lattice parameters can be used. In one embodiment, Sc2O3and Zr are used as two intermediate layers that will transition to AlN. A sputtered AlN surface is then used as a seed layer for GaN growth. That complete structure, called the IBAD template, can then be used as a template for epitaxial GaN growth. MOCVD GaN is grown directly on AlN or on GaN deposited by physical vapor deposition (PVD) on the IBAD template. In one embodiment a substrate comprises a metal foil, preferably having a CTE matched to the desired functional semiconductor material. Deposited on the substrate is a base layer to enable IBAD. This layer can also be used to planarize the substrate and act as a diffusion barrier. Next is deposited an IBAD textured layer, then one or more intermediate buffer layer(s). The final layer is a hexagonal material, preferably a semiconductor material such as III-N or ZnO. The substrate is preferably chosen to match the functional layer or semiconductor layer coefficient of thermal expansion as closely as possible. The IBAD layer is preferably chosen to match the lattice constant of the semiconductor layer as closely as possible. This enables the decoupling of matching the two properties in selecting the substrate. In a conventional single-crystal substrate one has to use the materials that have a good enough lattice match and cannot independently adjust other properties. For substrates used for IBAD texturing, a substrate with desired mechanical properties, such as flexibility and thermal properties such as CTE (coefficient of thermal expansion) can be selected, and then the IBAD layer with the desired lattice constant can be chosen independently. Furthermore, a large area substrate, not one that is limited to single-crystal boule sizes, can be used, enabling production to be scaled to extremely large areas, and enabling production of integrated devices over those large areas via printing, for example. Roll-to-roll (R2R) is a method to scale production to very large areas (in small volumes), but it can also be scaled up sheet-to-sheet (S2S). Also, the substrate and IBAD layer can have different orientations, lattice mismatches, etc., greatly increasing the versatility of the present invention. One embodiment of the present invention comprises a single-crystal-like hexagonal-structure material, epitaxially deposited on an ion-beam-assist deposit (IBAD) textured layer. Epitaxial intermediate buffer layers between the IBAD layer and the hexagonal-structure material may optionally be deposited. The hexagonal-structure material optionally comprises graphene, MoS2, WS2, or another two dimensional material, or GaN, AlN, InGaN, or another III-N material. The IBAD layer material preferably comprises a cubic structure in the (111) orientation giving a 3-fold symmetry for alignment of the hexagonal materials on top, such as fluorite or bixbyite structure materials. Another embodiment of the present invention is ion-beam alignment of a film of a bixbyite-structure material, i.e. structure of (Mn—Fe)2O3, such as Sc2O3or Y2O3, on top with a (111) orientation out of plane and in-plane orientation, preferably with in-plane orientation better than 15°, and more preferably with in-plane orientation better than 10°. Embodiments of the present invention comprise a CTE-matched metal substrate for IBAD obtained by alloying the metal to get perfect matching to the semiconductor, such as in the Mo—Cu alloy system. Embodiments of the present invention comprise base (or planarization) layers for IBAD flourites or bixbyites that include amorphous-Al2O3, Y2O3, SiOx; these layers can be deposited by chemical solution deposition in manner that produces planarization (e.g. SDP). Embodiments of the present invention comprise integration of active devices fabricated using epitaxial III-N materials on IBAD substrates, such as metal foils with a textured layer. Devices are printed using several different possible printing technologies, e.g. screen printing or inkjet printing, patterned and contacts and passive devices are preferably printed on top afterwards. A display can be manufactured using this printing of LED devices on IBAD substrates. Power devices integrated with LEDs can provide constant power, switching, or dimming control of LED devices, or different colors and different color temperatures. Embodiments of the present invention are novel methods for GaN growth on non-single-crystal substrates with the use of an IBAD template (4-fold symmetric and 3-fold symmetric IBAD) that can be applied to almost any substrate that can sustain the GaN growth temperature, in the case of MOCVD above 1000° C., such as metals, ceramics or glass (quartz). Other methods for deposition of GaN-based devices are reactive evaporation (esp. MBE) and reactive sputtering. The latter methods utilize a lower temperature during deposition and growth and hence are more amenable to non-standard substrates that are not single-crystal wafers, such as plastics and glass. Matching the coefficient of thermal expansion (CTE) enables metals to be used ideally as substrates for GaN growth. These metals include, for example, molybdenum, tantalum, tungsten and alloys of these elements with other elements, such as TZM, an alloy of molybdenum and small amounts of titanium and zirconium, or molybdenum-copper alloys. These alloys exhibit a high thermal conductivity which is useful for devices requiring conductive cooling such as GaN power electronics. Embodiment substrates for growth of epitaxial films of group-Ill nitride formed by ion-beam textured layers with epitaxial overlayers comprise IBAD biaxially textured layers comprising IBAD-MgO, TiN, or other rock-salt structured materials, previously known to be amenable to ion-beam biaxial texturing, but also IBAD-CeO2(cerium dioxide) or other fluorite structure materials such as CaF2, cubic ZrO2, or HfO2, which form a (111) orientation during IBAD. Other materials include IBAD-ScOx(with the Sc2O3structure) and other oxides or nitrides in the bixbyite structure, such as Y2O3or Mn2O3, bixbyite being a vacancy ordered derivative of the fluorite structure; epitaxial overlayers (buffer layers) lattice matched for growth of GaN or other group III nitride compounds, such as AlN or other nitrides, or elemental metal layers such as Zr or Hf, or oxides such as cubic Al2O3. A single-crystal-like cubic film with a (111) orientation on an arbitrary surface can be manufactured for growth of epitaxial III-N, or other hexagonal structure semiconductor or semi-metal such as InP (111), transition metal dichalogenides, and Indium Gallium Zinc Oxide (IGZO), layers using ion beam textured layers. These same textured layers can be obtained by other means besides IBAD such as inclined substrate evaporation or inclined sputtering. III-N layers can be grown by MOCVD, MBE, reactive evaporation, reactive sputtering, or other methods. A metal substrate may be used to produce III-N layers on a flexible metal foil or other metal substrate by use of an ion beam textured layer; metal substrates include materials such as molybdenum, tantalum, tungsten and alloy of these elements with other elements. III-N layers may be grown on a glass substrate with an intermediate ion beam assisted deposition (IBAD) textured layer. An electronic or optoelectronic device can be manufactured that comprises the epitaxial III-N material on an IBAD template substrate; such a device includes MOSFET's, MESFETs, HEMTs, Heterojunction FETs, heterojunction bipolar transistors (HBTs), thin-film transistors, sensors, memristors, light emitting diodes (LEDs), laser diodes (LD), SAW devices, spintronic devices, photodetectors, photovoltaic (PV) diodes. Furthermore these devices can be used in products such as LED-based displays, LED-based lighting products, PV cells and modules. Some embodiments of the present invention are a process for making an aligned layer on top of a metal to manufacture an LED; an LED structure made on top of an ion-aligned layer; a metal/amorphous planarizing layer/(111) textured layer/hexagonal semiconductor layer structure; IBAD texturing of Bixbyite materials; base layers deposited on a flexible substrate for IBAD layers, such as amorphous Al2O3, Y2O3, or SiO2; a GaN PVD layer used as a nucleation layer for MOCVD GaN; and a metal alloy substrate to match the CTE of GaN very closely, such as Mo—Cu alloy. The IBAD texture has been improved in embodiments of the present invention to below 10°, and the use of additional buffer layers and a high temperature MOCVD process for GaN growth produces GaN of much higher quality, <1° in-plane FWHM (as opposed to >10°) and less than 0.5° out-of-plane (as opposed to <1.5°) that enables the manufacture of high quality devices. The way that epitaxial GaN grows in embodiments of the present process is fundamentally different from epitaxial growth of Si and other semiconductors. This means that active devices such as a light-emitting diode (LED) consisting of III-N materials (such as InGaN) fabricated on a (111) ion-beam-assist deposit (IBAD) textured layer can be fabricated. Example 1 To demonstrate the applicability of IBAD templates for epitaxial growth of GaN and related group III nitride materials, MOCVD growth of GaN, also known as MOVPE (metal-organic vapor phase epitaxy), was performed. Samples were briefly heated to 800-1000° C. in flowing H2prior to growth. The GaN nucleation layer was grown using trimethylgallium (TMGa) and ammonia (NH3) using H2and N2push flows at a substrate temperature of 530° C. After the growth of the GaN NL, the TMGa was turned off and the wafers were ramped in temperature to 1050° C. over 8 minutes. At 1050° C. the TMGa was turned on for 1 hour resulting in ≤2 μm of GaN film. After growth the wafers were cooled in the NH3, H2, and N2flows and removed from the growth reactor. For the templates for GaN growth, substrates were prepared separately prior to GaN growth. In one embodiment we utilized IBAD-textured MgO films. These films are oriented with the (100) axis out of the plane and form a square, 4-fold symmetric lattice on the surface. IBAD-MgO films were first deposited on amorphous Y2O3surfaces, the base layer for IBAD texturing. For good texturing of MgO during the ion beam assisted deposition (IBAD) it is important to have a smooth surface, which was obtained by sequential chemical solution deposition of Y2O3or Al2O3using acetate precursors dissolved in methanol. This process is called solution deposition planarization or SDP, and can produce surfaces as smooth as 0.5 nm RMS roughness when starting with a 50 nm RMS roughness metal foil substrate. The substrate was then placed in the vacuum deposition system where MgO is deposited at a rate of about 3-5 Å/s and an Ar ion beam incident at 45° and with an ion energy of 700-1000 eV. Deposition typically takes about 10-30 seconds. Following IBAD a 50 nm thick film of homoepitaxial MgO was deposited in the vacuum chamber by evaporation at a substrate temperature of 400-700° C. During the IBAD process as well as homoepitaxial deposition, film growth was monitored by Reflection High Energy Electron Diffraction (RHEED) to verify the crystalline alignment of the film.FIG.2shows RHEED images of the MgO film after IBAD and after homoepitaxial MgO.FIG.3shows an x-ray pole figure of the (202) peak demonstrating high degree of in-plane alignment.FIG.31shows an XRD (101) pole figure of MOCVD-grown GaN. In a second embodiment of the IBAD template, we utilized IBAD-textured CeO2textured films. These IBAD films are oriented with the (111) axis out of the plane and form a 3-fold symmetric lattice on the surface, suitable for growth of hexagonal structure materials such as wurtzite GaN, hexagonally close packed (hcp) metals, or other 3-fold ymmetric (111) buffer layers. IBAD-CeOxfilms were grown on amorphous Al2O3sufaces, the base layer for IBAD CeOx. Other amorphous layers such as SiOxand Y2O3are also suitable for IBAD-CeOx. Just as for MgO, to obtain the best texturing it is important to have a smooth surface, which was produced by sequential chemical solution deposition planarization (SDP) of Y2O3or Al2O3. With multiple coatings surfaces as smooth as 0.5 nm RMS roughness when starting with a 50 nm RMS roughness metal foil substrate can be achieved. The substrate was then placed in the vacuum deposition system where CeO2was deposited at a rate of about 3-5 Å/s by electron-beam evaporation and with an Ar ion beam incident at 45° and with an ion energy of 700-1000 eV. Deposition typically took about 10-30 seconds. Following IBAD a 50 nm thick film of homoepitaxial CeO2was deposited in the vacuum chamber by evaporation. During the IBAD process as well as homoepitaxial deposition, film growth was monitored by Reflection High Energy Electron Diffraction (RHEED) to verify the crystalline alignment of the film.FIG.4shows RHEED images of the CeOxfilm after IBAD and after homoepitaxial CeOx. Several different epitaxial buffer layers were deposited on IBAD-textured substrates by evaporation in vacuum. Although growth of epitaxial GaN on CeO2is challenging due to the large lattice mismatch of the two crystalline lattices (GaN has a 16.7% smaller lattice constant than CeO2(111)), by providing suitable intermediate buffer layers one can transition or step-grade to a lattice match close to GaN. These intermediate buffer layers consisted of (111) metal oxides (such as ZrO2, Sc2O3, Y2O3), hexagonally close packed metals (such as Zr, Hf, Ti, Sc, etc.), and wurtzite or (111) metal nitrides (such as AlN, ZrN, TiN, etc.) During deposition of epitaxial buffer layers, film growth was also monitored by RHEED to verify the crystalline alignment.FIG.4Bshows a RHEED image of epitaxial GaN grown on top of buffered IBAD. For MOCVD GaN growth, several intermediate epitaxial buffer layers comprising metal oxides, metal nitrides and elemental metals were used. For the IBAD-MgO template we successfully grew epitaxial GaN on γ-Al2O3(cubic aluminum oxide) and SrN. For the IBAD-CeOxtemplate GaN was grown succesfully on epitaxial Hf and AlN. FIG.5shows an x-ray diffraction GADDS 2D detector image that demonstrates a sharp GaN peak due to the single-crystal-like nature of the GaN film on top of the polycrystalline metal substrate.FIG.6shows the (101) pole figure for the GaN grown on the 4-fold symmetric IBAD. The resulting GaN has a 12-fold symmetric (101) pole figure. This is because there are 2 different symmetric orientations of the hexagon on a square lattice, resulting in two domains that are rotated with respect to each other by 30°. In contrast, GaN grows in a single domain on top of 3-fold symmetric IBAD such as (111) cube orientation.FIG.7shows a 3-fold symmetric IBAD pole figure andFIG.8shows 6-fold symmetric GaN on the 3-fold IBAD-CeO. The in-plane full width half maximum of this GaN layer is 1-2°. Out of plane rocking curve is 0.6-0.7° for GaN on IBAD/metal and 0.3° for IBAD/sapphire. FIG.9shows several electron micrographs of epitaxial GaN layers on top of our 3-fold IBAD (111) template. This template includes a thin buffer layer (less than 50 nm) of either Hf or AlN. Although in this case the coverage of the GaN film is not complete due to incomplete coalescence of grains, we can see very smooth (atomically smooth) surfaces on the GaN mesa structures.FIG.10shows optical images of epitaxial GaN grown on a double buffer layer structure that includes an epitaxial metal, such as Zr or Hf, together with an AlN layer grown by pulsed dc sputtering. GaN has also been grown on the AlN by reactive evaporation in this manner. This has so far yielded the best coverage of the GaN layer by MOCVD.FIG.11shows a cross section of the film analyzed by transmission electron microscopy where one can see the robustness of the IBAD and intermediate layers, as well as the smoothing of the SDP layers. The epitaxial arrangement is preserved from the IBAD layer into the GaN layer. FIGS.12and13show RHEED in situ images of IBAD-CeO2samples, immediately after IBAD deposition and following homoepitaxial CeO2on IBAD-CeO2, respectively. The images indicate single crystalline orientation as well as in-plane alignment.FIG.17shows the in-plane alignment of the CeO2crystalline layer. FIG.15shows a cross-sectional TEM micrograph of the complete structure including the thick GaN layer. One can see, from bottom, the rough metal foil, the smoothing layers of the SDP planarization, followed by IBAD and subsequent epitaxial buffer layers. The very top surface is extremely smooth enabling planar and other device fabrication. FIG.16shows electroluminescence (EL) from an LED structure comprising an InGaN multi-quantum well structure and a p-doped GaN layer on top that was deposited epitaxially on top of the GaN film on the IBAD template on a metal foil. FIGS.18A-Bshow SEM micrographs of thick (about 5 micron) GaN films. Typically there are some defects, but also areas that are smooth over 100 μm areas. FIGS.19A-B, show RHEED images of IBAD-Sc2O3and homoepitaxial Sc2O3on top of IBAD-Sc2O3, respectively, with (111) orientation. Similar to CeO2IBAD layers with (111) orientation can be obtained under the right conditions, in this case the same conditions as for CeO2IBAD. IBAD-Sc2O3texturing is formed on the amorphous SDP deposited Al2O3layers. FIG.20shows the theta-2*theta scan of the IBAD-Sc2O3film with a homoepitaxial layer on top of the IBAD layer. The bright spot on the right is the (222) reflection of Sc2O3and the ring on the left represents the polycrystalline metal substrate. The main peak visible is due to the (111)-oriented Sc2O3material.FIG.21shows the pole figure for the (440) pole of the Sc2O3with 3-fold symmetry. These two x-ray scans demonstrate biaxial orientation for the Sc2O3layer. Example 2 A thick layer of GaN was deposited on an IBAD template. Typically GaN is 4 to 6 micrometers in thickness, the top part of which is n-doped with Si, as can be seen inFIGS.25A and25B.FIG.30shows dislocations in the structure. As shown inFIG.26, on top of the GaN layer an LED structure pn junction is grown, together with a multi-quantum well (MQW) structure, which is a multilayer of 5 alternating InGaN and GaN layers. On top of the MQW is p-doped electron blocking layer followed by the p-GaN doped with Mg. Such a heterostructure is standard for making LEDs in industry. Performance of such an LED device was measured as compared to LEDs prepared on single-crystal sapphire, which is a standard substrate in industry. Results are shown inFIGS.27-29. Comparisons were done with photoluminescence (PL) (shining a light on the device), and electroluminescence (EL) (passing a current through the device), light measurements. For the first devices fabricated PL shows between 10 and 40% of light in IBAD LEDs compared to standard sapphire LEDs. EL of IBAD LEDs shows up to 12% (and increasing) of the sapphire LEDs. The EL device characteristics are dominated by leakage due to shorts in the current devices, although the performance should improve significantly as the material quality of the GaN layers improves. Devices Embodiments of the present invention are structures to improve certain aspects of, enable new functionalities in, and scale-up manufacturing of Group-III devices. In some embodiments, packaged InGaN LED devices are simplified, thereby reducing their cost significantly. An embodiment of the present invention is a light-emitting LED device consisting of an InGaN p-n diode with a multiple-quantum-well (MQW) active region, fabricated directly on a metal foil substrate by use of an IBAD textured template prepared on the metal prior to GaN deposition. Such a device is shown inFIGS.32A,32B,32C, and34.FIGS.33A and33Bshow test results for two such devices. The present invention enables large-area deposition of Group-III materials on flexible metal sheets. IBAD texturing enables high-quality epitaxial materials can be deposited on appropriate metal substrates while approaching the performance of epitaxial materials on single-crystal substrates such as sapphire.FIG.35shows a schematic of an LED fabricated on a metal foil substrate. The LED is preferably re-packaged on the metal substrate and does not necessarily require a transfer to another substrate before application. For example, micro-LED's don't have to be transferred to a different substrate and/or backplane. Conducting layers and phosphors can be printed on top of the LED metal foil sheets. FIG.36shows an artist's rendition of a light emitting strip that can be fabricated using the GaN-on-metal technology of the present invention. Instead of point sources of light that LEDs are typically today, Light Emitting Strips (LESs) and Sheets become possible and economically feasible using the present invention. In this approach light emitting areas are patterned over significantly larger areas, reducing the required current density. The edge of an LES preferably comprises bus bars to carry higher currents along the length of the strip. LESs have the advantage of being a continuous light source, compared to conventional LEDs which have a pixelated nature in the source emitter. By spreading the light over a larger area, one also obtains a lower operating temperature, in addition to the benefits provided by the lower thermal resistance of the devices. A metal strip light source has the additional benefit of being flexible and conformable. The GaN-on-metal approach for LEDs has many advantages when compared to GaN-on-sapphire, including:A flexible substrate enables roll-to-roll processing (R2R). R2R in turn enables scaled up manufacturing and implementation of printed electronics technologies. It is easy to scale manufacturing from 6-inch substrates to km-long webs of metal foil. This scale up alone will yield significant reduction in cost.Better thermal conduction of the substrate and uniformity in production should ultimately result in higher manufacturing yields.The coefficient of thermal expansion (CTE) of the metal substrate is better matched to that of GaN. CTE of molybdenum metal is 5.5×10−6/K, compared to GaN of 5.6, a 2% mismatch which can be further reduced by use of a molybdenum-copper alloy. Sapphire CTE is about 7.5, causing a significant bowing of substrate upon cool down after high temperature growth.There is potentially a better lattice match of the substrate with GaN, once better lattice match materials are implemented in IBAD. Sapphire has a 16% lattice mismatch. The IBAD material, CeO2is also 16%, but other materials that are known to be amendable to IBAD texturing are only a few % mismatched to GaN.Simpler packaging of LEDs is due to the use of metal substrate as both a reflector and a heat sink for the LED. With typical LEDs, a reflector metal is deposited on a roughened surface of the LED in backend processing. A rough surface is preferred since the light needs to bounce a few times before exiting the LED. Also, in the course of packaging the LED is bonded to a separate heat sink. In contrast, in embodiments of the present invention the starting metal substrate preferably has a rough surface and is used as a built-in reflector for the light emitted by the LED. The metal substrate such as molybdenum can additionally be coated with a higher reflectivity material for better reflectance at shorter wavelengths, where InGaN LED emitters are most efficient. The metal substrate furthermore preferably has a high enough thermal conductivity (142 W/m·K for molybdenum, compared to sapphire at 25 W/m·K) and thickness to be an effective heat sink for heat generated by the LED, without the need for substrate removal even at high power requirements. Thus, with some embodiments of LEDs of the present invention, no external heat sink or reflector is required.The simplified packaging coupled with roll-to-roll processing of devices, among other aspects of applying phosphors and other down converters and printing of contacts, such as screen printing and laser etching, yield significantly lower costs for LEDs. Cost per unit area is expected to be >10× lower once roll-to-roll processes are implemented.The ability to reduce droop due to larger area LED devices is possible. Since the cost of epi area is reduced, larger areas can be utilized, thus reducing current densities in operating LEDs. This in turn will increase efficiency of devices by reducing the droop.A reduction in thermal droop can be achieved due to the reduction in thermal resistance by utilizing a thin metal substrate for the LED device. It is estimated that the operating temperature of LEDs on metal will be about ½ that of LEDs on sapphire. Thus, even without a heat sink, high brightness LED's will be cool to the touch, unlike current ones.More robust operation and longer lifetimes can be achieved due to lower temperature of operation because of better thermal resistance. This is especially applicable to light downconverters, such as phosphors, that are placed on LEDs.Large-area GaN sheets also enable monolithic integration of various GaN-based devices, such as LEDs and power transistors, to control the current in the LEDs.GaN power devices, such as HEMT, will also benefit from some of the features described above, in particular better thermal management and scaled up manufacturing. Although the invention has been described in detail with particular reference to the disclosed embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover all such modifications and equivalents. The entire disclosures of all patents and publications cited above are hereby incorporated by reference. | 31,319 |
RE49870 | DETAILED DESCRIPTION The following describes apparatus, systems and methods for controlling the electricity supply to a load from an electricity transmission network. In particular some embodiments relate to a system for storing electrical energy and later releasing it to a load in a building, under external control, to deliver financial and operational benefits to electricity utilities and consumers. In this regard reference is made toFIG.1which illustrates a schematic diagram according to some embodiments. An electricity transmission and distribution network or utility102supplies electricity to a premises or building104via a meter106. The electricity transmission and distribution network102provides an electricity supply via one or more transformers (not shown) to step down the voltage of the electricity for the purposes of domestic or office use. Typically the electricity comprises an alternating current (AC). In this way the electricity transmission and distribution network102provides an electricity supply also known as “mains” electricity to the building104via a mains electricity circuit130. In some embodiments the electricity supply is not limited to domestic use but can be used in other sectors such as transport or industry. Typically the electricity transmission and distribution network102can be controlled and managed by an electricity system operator110. The meter106comprises measuring apparatus for measuring the amount of electricity consumed by the building104. The meter can, in some embodiments be a “smart meter” which can detect multidirectional flow of electricity; electricity being consumed or electricity being supplied by the building104to the electricity transmission and distribution network102. In other embodiments, the meter is a traditional meter which only detects electricity consumed from the electricity transmission and distribution network102. The building104consumes the electricity supplied by the electricity transmission and distribution network102. The consumption of electricity by the building104is represented by a load108. The load108can comprise the electrical demand of one or more electrical appliances which use electricity during their operation. For example, the load108of a domestic building can comprise electricity being consumed by heating, air conditioning, swimming pool pumps, washing machines, televisions, cookers, lighting, and any other suitable electrical means for using electricity. The system100for controlling the electricity supply in the building104will now be described in further detail. The system100comprises a battery124, a charger126for charging the battery and an inverter128for providing a suitable electricity supply to the load108from the battery124. The battery124can be any type of suitable means for storing electrical energy. In some embodiments the battery124comprises one or more lead-acid batteries, similar to batteries used in vehicles. A lead acid battery is a flooded liquid electrolyte type. Advantageously a lead acid battery is a simple and cheap option to use in the system100. Alternatively the battery124can comprise one or more sealed valve regulated lead acid battery (VRLA). A VRLA comprises an absorbent glass mat or gel electrolyte which does not require battery maintenance. In some other embodiments the battery124can comprise one or more lithium ion or any other suitable battery technology. The charger126can be any suitable means for charging the battery124from the mains electricity circuit130. In some embodiments the battery can be charged from the mains electricity circuit in the building and the charger can be connected between meter and load. In some embodiments the charger126charges the battery124at a constant, low rate. Optionally the charger126can have a variable charge rate. The inverter128can be any suitable means for converting the electrical energy stored in the battery124into an electrical supply suitable for the load108. Typically the battery124outputs a direct current (DC) voltage. The inverter128can take the DC voltage and convert the DC voltage into an AC voltage suitable for the appliances comprised in the load108. Preferably the inverter128can synthesise a full wave AC voltage which is compliant with the electricity supply of the electricity transmission network. Preferably the inverter converts a 12V DC output from the battery124into 115V 60 Hz or 230V 50 Hz output. In some embodiments the inverter128and the charger126are connected to the mains electricity circuit130by the same connection. In some embodiments the same connection is a bi-directional connection. In other embodiments the inverter128and the charger126are connected to the mains electricity circuit130with different connections. The battery124, the charger126and the inverter128are controlled by the controlling apparatus112in some embodiments. The controlling apparatus112comprises one or more processors114coupled to internal memory116and other components118for controlling the supping of electricity to the load108. The processor114can be linked to a user interface for receiving instructions from a user. In some embodiments the user interface comprises a 2 line LCD display and one or more input keys or may be any other suitable user interface. The controlling apparatus112can also comprise a power supply unit (PSU)402as shown inFIG.4which can power the controlling apparatus. The PSU402can be powered by the either the load108or the battery124. The processor114in some embodiments can be configured to execute various program codes. For example, the implemented program code may comprise a code for controlling the electricity supply to the load108. The implemented program codes can in some embodiments be stored, for example, in the memory116and specifically in a program code section of the memory116for retrieval by the processor114whenever needed. The memory116in some embodiments can further provide a section for storing data, for example, data that has been processed in accordance with the application. The controlling apparatus112can further comprise an interface406as shown inFIG.4for receiving and/or sending information from the electricity system operator110and/or a service provider120. The service provider120in various embodiments is a demand response aggregator, an electricity retailer or a distribution network operator. The service provider120can provide instructions and/or information to one or more controlling apparatuses112in separate buildings. The interface406of the controlling apparatus112can be an over-the-air type interface for communicating with the system operator110or service provider120. In some embodiments the interface comprises a GPRS, 3G or other mobile telecommunication based interface for providing a data link over-the-air with the system operator110or the service provider120. In other embodiments the interface406for communicating with the system operator110or the service provider120comprises a wireless network interface such as a 802.11x or WiFi™ interface. In this way the controlling apparatus112can communicate via the building's104wireless router (not shown) which provides a connection to the system operator110and the service provider120via an Internet connection. The user interface can be used to select an appropriate wireless network and input the relevant security key by the user during set up of the system100. Alternatively, the wireless interface406can be a home area network (HAN) which is connected to a suitable gateway means. In some embodiments the HAN can be a short range radio link conforming to the Zigbee™ standard. Indeed the controlling apparatus112may include any suitable radio interface for communicating with the system operator110and/or the service provider120. In some other embodiments the interface406of the controlling apparatus112can be a wired type connection such as an Ethernet connection with the building's104router (not shown) which provides a connection to the system operator110and the service provider120via an Internet connection. Alternatively the interface406can be a powerline communications (PLC) type interface. In this way a PLC interface can use the building's104power lines to communicate with the system operator110and/or the service provider120. In some other embodiments, a standard public operating telephone system (POTS) line can be used to communicate between the controlling apparatus112and the system operator110and/or the service provider120. Indeed the controlling apparatus may comprise any suitable interface for wired communications. Furthermore the controlling apparatus can comprise a plurality of the aforementioned interfaces to provide redundancy in communications with the system operator110and/or the service provider120. The processor114of the controlling apparatus112can be configured to communicate with the system operator110and/or the service provider120using a standardised communication protocol. In particular, the processor114can be configured to send messages comprising a DLMS/COSEM (device language message specification/companion specification for energy metering) format. In some embodiments the communication interface406can be optional. For example, the information from the electricity transmission network, such as the times of offpeak and peak electricity tariffs can be pre-programmed into the memory116of the controlling apparatus112. A sensor122is located near the meter106for detecting and measuring the electricity supplied to the building104. In some embodiments the sensor122is a current sensor for detecting the magnitude and direction of the electricity supply current. The sensor122can be attached to the live input electricity cable either the electricity transmission and distribution network side102of the meter106or the building104side of the meter. In other embodiments the sensor can be configured to measure one or more other parameters of the electricity supply such as voltage and power factor. The sensor122according to some embodiments is shown inFIG.2, which shows a schematic representation of the wireless sensor122. The sensor122comprises a processor202and a wireless interface comprises a transmitter/receiver204for communicating with the controlling apparatus112and a power source206such as a battery. The controlling apparatus112comprises a reciprocal wireless transmitter/receiver404as shown inFIG.4. The wireless interface between the sensor122and the controlling apparatus112can comprise any suitable wireless communication format such as Zigbee™ or Bluetooth™ or another suitable two way wireless communication format. Alternatively the wireless interface can be a one way wireless interface whereby the sensor122only sends measurements to the controlling apparatus112. The sensor122can also comprise circuitry for performing digital signal processing such as signal conditioning on the current measurements. In some embodiments the processor of the wireless sensor can detect whether the battery206of the wireless sensor has a low voltage. The processor of the sensor122can then send an indication to the controlling apparatus112that the wireless sensor122needs a replacement battery. The sensor according to some other embodiments is shown inFIG.3, which shows a schematic representation of the wired sensor122. The sensor122comprises a processor202and a wired interface with the controlling apparatus112. In this way the sensor122sends the measurements via a fixed wire to the controlling apparatus112. A wire connection between the controlling apparatus112and the sensor122means that the sensor can be powered by the controlling apparatus112and can operate continuously. In some embodiments the sensor122according the embodiments described inFIG.2or3makes measurements of the electricity supply continuously. Alternatively the sensor122periodically makes measurements of the electricity supply. Indeed the sensor122can change the frequency with which measurements of the electricity supply are made. In some embodiments the controlling apparatus112can configure the sensor122and in particular configure how the sensor122operates. For example, the sensor122ofFIG.2can perform measurements more frequently during peak demand periods of the electricity transmission and distribution network102than measurements made during the off-peak demand periods of the electricity transmission and distribution network102. This can reduce the amount of energy drawn from the battery206. In some embodiments the sensor122can be used to detect the condition where a net flow of electricity out of the building104is possible, so that the controlling apparatus112can prevent the net flow of electricity out of the building104. Optionally the sensor122may not been needed. For example, in some embodiments the meter106is a “smart meter”. This means that the meter106is designed to allow electricity to flow either in or out of the building104. FIG.4shows are more detailed embodiment of the system100for controlling the electricity supply in the building104. For the purposes of clarity the same numbering has been used as in the embodiments shown inFIG.1. The embodiments shown inFIG.4are the same as the embodiments shown inFIG.1except that the system100for controlling the electricity supply further comprises a safety isolator408. The safety isolator408is configured to prevent electric shock when the system100or the electricity transmission and distribution network102requires maintenance, or when the system100is disconnected from the load108. For example, if an out of range voltage, such as an undervoltage, is detected when there is a load present or if over-current flowing out is detected, then the electricity supply from outside the building104may be lost. In order to protect utility personnel potentially working outside the building104on fault rectification, the safety isolator may automatically open the connection from the inverter128to the electricity supply. The processor114of the controlling apparatus112may be configured to also shut down the inverter128and charger126when the safety isolator408trips. Furthermore, the safety isolator408can also automatically open the connection from the inverter128to the electricity supply when no current, or lower than expected current, is flowing out when the inverter128is on, or if over-voltage is detected at the output of the inverter. In order to protect a user from a potential electric shock on the plug, the safety isolator408will automatically open the connection from the inverter output to the mains electricity supply. Again, the processor114of the controlling apparatus112may be configured to also shut down the inverter128and charger126when the safety isolator408trips. In some embodiments the safety isolator408is actuated by the processor114of the controlling apparatus112once the processor114determines an under voltage or no current flowing when the inverter128is on based on received sensor122measurements. In some embodiments there may be a separate sensor (not shown) for detecting the current and/or voltage for actuating the safety isolator408. FIG.5shows a schematic representation of some alternative embodiments.FIG.5is the same as the embodiments described in reference toFIG.4except that the inverter128and charger126are replaced with a bi-directional synchronous buck boost converter502.FIG.6shows a more detailed circuit diagram of the converter502used in the embodiments as shown inFIG.5. The converter502comprises 2 high frequency switching MOSFETs602for both charging and discharging. The converter502further comprises four lower frequency switching MOSFETs604in the H-Bridge606. The lower frequency switching MOSFETs604can have a frequency of 100 Hz. The converter502comprises a filter capacitor608which is small to improve reliability and reduce manufacturing costs over large capacitors. In some embodiments the battery124can be subjected to a minimally filtered 100 Hz current waveform. The capacitor608can be used to filter out the high switching frequency of the buck boost converter. In some circumstances the battery life124can be reduced if the battery is subjected to large current fluctuations. In some cases the filter capacitor608is set to a high enough value to avoid subjecting the battery124to large current fluctuations. The converter502further comprises a tapped inductor610which is used to manage the duty cycle of the MOSFET602switching. As the duty cycle varies greatly in order to synthesise 100 Hz semi-sinewaves, some embodiments comprise means for limiting the maximum duty cycle. The tapped inductor610can help reduce voltage stress and the maximum duty cycle of the converter502. For battery124discharge the converter502operates in a boost mode, synthesising from the battery energy, under processor and gate drive circuit control, full wave rectified sinewaves at the filter capacitor608for conversion to 50 Hz sinewaves by the H bridge under processor and gate driver control. In the discharge mode the battery energy augments the normal supply to the load. For battery charging the H bridge, operating under processor and gate driver control, rectifies mains to a 100 Hz full-wave rectified signal at the filter capacitor608and the converter502operating in buck mode under processor and gate driver control delivers the energy to charge the battery124. The charging rate is controllable and charging can be done at unity power factor. In some embodiments the converter502can operate in a current control mode when charging and/or discharging the battery124. In some embodiments the inverter128or converter502can be used to generate out-of-phase and/or non-sinusoidal current output when discharging the battery. The inverter128or converter502synthesises the current waveform to be delivered to the load108from the DC battery output, and is capable of providing a current waveform that has a predetermined phase angle and/or shape with respect to the mains supply voltage seen at the load108. The system operator110or service provider120may request or instruct the controlling apparatus112to deliver a discharge current with a certain phase angle and/or waveform shape relative to the voltage and the processor114instructs the inverter128or converter502to generate such a current waveform. Alternatively the controlling apparatus112and/or sensor122may determine the phase relationship between voltage and current seen at the load108based upon measurements of voltage and current waveform cycle timing, and then in response instruct the inverter128or converter502to deliver a pre-determined phase relationship in the discharge output, in order to provide compensation for a non-ideal measured supply phase relationship at the load108. Operation of the system100for controlling the electricity supply will now be described in further detail with reference toFIG.9.FIG.9discloses a flow diagram of the method according to some embodiments. The system100can operate in an idle mode whereby the load108of the building104is being supplied with electricity from the mains electricity circuit130. The mains electricity circuit130is in turn being supplied from the electricity transmission and distribution network102via the meter106. That is, the load108is running off mains electricity circuit130. In the idle mode the battery124does not draw or feed any electrical energy to or from the battery from or to the mains electricity circuit130. In reference toFIG.7, the system being in the idle mode is represented by t0.FIG.7illustrates a graph of time versus energy for some embodiments. The processor114may receive information associated with the mains electricity circuit130and/or the associated electricity supply. In some embodiments the information associated with the electricity supply comprises information associated with the electricity transmission and distribution network102providing the electricity supply to the mains electricity circuit130as shown in block902. In some embodiments, the processor114can receive information comprising an indication of either the condition of the electricity supply, for example frequency or demand level or an indication of the condition of the network. In some countries the frequency of the electricity supply may be 50 or 60 Hz. In the UK, the electricity system operators are required to keep the electricity supply at 50 Hz±0.5 Hz. If the frequency changes from 50 Hz, this may indicate a mismatch between supply and demand. The frequency may need to change from 50 Hz by a predetermined amount in order to trigger a change in mode. That amount may be 0.2 Hz or more. However this is by way of example and in some implementations the predetermined amount may be more or less than 0.2 Hz. It should be appreciated that different countries may have different electricity supply frequencies and/or different tolerated deviations. As such this may change the predetermined amount. In some embodiments, a change in frequency may be determined in order to determine if a mode should be changed. It should be appreciated that alternatively or additionally another characteristic or parameter of the frequency of the supply (other than frequency value or change in frequency) may be used to trigger a change in mode. In some embodiments the processor114may receive via the communication interface406information associated with the capacity of the network. The information associated with the capacity of the network can comprise information regarding the timing of peak and off peak demand on the network and the associated price of electricity. The information can comprise information about the availability of excess electricity from wind, solar or another renewable source at off-peak time. Furthermore the information can comprise the timing and optionally pricing of providing balancing services such as providing fast response frequency balancing services. The information associated with the capacity of the network may be received infrequently such as monthly. Alternatively the information can be received frequently such as every half hour, or as a time-critical immediate request to take action within a pre-determined time period, e.g. a few seconds. The latter request would permit a “real-time” response. The processor114can also receive direct demand response requests from the system operator110or the service provider120as shown at t1inFIG.7. The demand response request may also be received by the communication interface406. The demand response request may be time critical. In response to receiving the demand response request, the processor114may be required to start discharging the battery124within a pre-determined time period, e.g. a few seconds. The request may indicate the length of time for which the battery is to be charged/discharged, the rate at which the battery is to be charged/discharged and/or the level to which the battery is to be charged/discharged and/or any other information. In order to respond quickly to a time-critical demand response or balancing services request, the processor114may receive the request via a broadband connection using TCP/IP. TCP/IP or another secure connection protocol is preferred in order to avoid hacking or other security threats. The processor114is configured to open connections with the system operator110or the service provider120and send a message to a server (not shown). The message can interrogate the server as to whether there is an impending time-critical demand response or balancing services event. In some embodiments the processor114can receive information indicating that a time-critical demand response or balancing services event is likely. The processor114can keep a connection open with the server for a period of time and wait to receive a time-critical demand response or balancing services request. The connection can be configured to time out after a period of time and the processor114can re-open a connection with the server. In some embodiments the connection will remain open for 5 minutes. In some embodiments the processor114may immediately open a new connection when a previous connection has been closed. When a time-critical demand response or balancing services event is likely, such as during a time of peak capacity, the processor114may more frequently open connections with the server than at times during of off-peak capacity. In some embodiments the processor114may optionally receive some messages warning about an impending time-critical demand response or balancing services event. The processor114can acknowledge the warning message. Alternatively, the processor114can respond to the warning message and indicate that the system100is not ready or cannot discharge the battery124. The processor114may preferably initiate the opening of a connection to the server (not shown) using the hypertext transfer protocol secure (HTTPS). Alternatively the hypertext transfer protocol (HTTP) can be used together with security features to assist with authentication of the controlling apparatus112. The controlling apparatus112may be provided with a unique identification code at the time of manufacture, which can be used for secure log-in to the server. The processor114and server may exchange information in order to test the effectiveness of the connection between them and ensure the connection is capable of meeting the response time requirements. The processor114can open a connection to the server and the server can subsequently send a dummy instruction that is not to be acted upon by the processor114other than for the processor114to establish the speed and quality of the connection and report the result to the server. The processor114on receiving the information from the server of the system operator110or service provider120will then determine if the information satisfies one or more criteria as shown in block904. For example, the processor114will determine if the demand response request requires immediate action or a later timed response. Alternatively for example, the processor114may determine that the price of the electricity is above a threshold. That is the processor114would determine that discharging is preferable when the price of electricity is high. It should be appreciated that discharging the battery is used to augment the supply of electricity in some embodiments and in others may even replace the electricity supply. Furthermore the processor114can be configured to determine if other information satisfies one or more predetermined criteria. In some embodiments the processor114can determine whether the mains electricity is present, and thus whether it is safe to operate the system100, from information received from the sensor122or from other measurement circuits, the discharge being disabled if there is no mains electricity present. The processor114may also determine whether other suitable parameters of the electricity transmission and distribution network satisfy predetermined criteria. The processor114may receive information about parameters of the electricity transmission and distribution network102or about the mains electricity circuit130from the sensor122. Once the processor114has determined that the information of the electricity transmission and distribution network102satisfies the correct criteria, the processor determines whether information associated with the system100satisfy one or more criteria as shown in block908and described below. The processor114can determine information associated with the system100from received measurements from the sensor122as shown in block906. The measurements are received from the sensor122periodically whilst the sensor is active. That is the measurements can be received before the processor114receives the demand response request. Operation of the current sensor will now be discussed. The sensor122in some embodiments continually measures the current of the electricity supply into the building104. In some buildings104the meter106is not a smart meter and therefore the meter106cannot accommodate a net current flow from the building104to the electricity transmission and distribution network102. Therefore the sensor122detects fluctuations of the current of the electricity supply relative to certain thresholds. The sensor122is configured in some embodiments to send a message to the controlling apparatus112when the current of the electricity supply into the building104makes a transition in either direction through a first current threshold corresponding to the maximum output current of the inverter128. When the processor114determines that the total current of the electricity supply is below that of the maximum output of the inverter128, the processor114does not initiate turning the inverter128on if a demand response is requested. Alternatively the processor114reduces the maximum current output of the inverter128such that output of inverter128does not cause a net current out of the building104. In this way the total net current into the building is kept above 0 amps. The sensor122is also configured to send a message to the controlling apparatus112when the current of the electricity supply into the building104makes a transition in either direction through a threshold corresponding to a near zero net total current of the electricity supply into the building104. The processor114determines that if the total current into the building104is near zero, then the processor114initiates the inverter to reduce its output or turn off in order to keep the current of the electricity supply a net inflow. During a period of time where the current value remains above or below either threshold, the wireless current sensor only transmits a periodic signal to indicate to the processor114that the sensor122is still working and the communication link is good. In some embodiments the sensor122is configured to send a message to the controlling apparatus112when the current flowing into the load108changes by a value more than a pre-determined amount. In some embodiments the wireless sensor122is configured to operate in a low power mode during certain time periods. During the low power modes, the sensor122transmits less or no messages to the controlling apparatus112. In some embodiments the sensor122is configured to operate in a low power mode during the times when a demand response event is not likely to occur, for example in off-peak periods. The processor114can send the timings of the periods of time to the sensor122when the sensor122can operate in a low power mode. In this way the sensor122can conserve battery life. In some embodiments a wired sensor122is used with the controlling apparatus112. In this case the sensor122can continuously transmit current measurements to the controlling apparatus112and the processor114of the controlling apparatus112can determine whether the current measurements go above or below pre-determined current thresholds. The processor114determines that the sensor122is operational having received at least one or more messages from the wireless sensor within a pre-determined maximum time period. If the processor determines that the sensor122is not operational, the processor114may avoid discharging the battery124because the processor114cannot be sure that the net inflow current of the electricity supply will remain above zero. If the processor114determines that the sensor122has a low battery, the processor114can display a notification for a user. The processor114determines whether the inflow current of the electricity supply into the building104is above the threshold of the maximum output of the inverter128. As mentioned above, in embodiments in which there is no smart meter present in the building, the processor114may prevent discharging the battery if the discharge of the battery124would cause a current outflow of the building104. The processor114may determine the state of charge of the battery124. In some embodiments the processor determines whether the charge of the battery is above an upper threshold indicating that the battery has a substantially full charge. For example the processor may initiate the discharge of the battery124if the charge of the battery124is above 80%. If the processor determines that the criteria have not been met, the processor114determines that the system should stay in the same mode, as shown in block912. For example, if the system is in the idle mode, the processor114determines that the system will remain in the idle mode. Similarly if the system100is in the discharging mode or the charging mode, the system will remain in the same mode. If the processor determines that the criteria have been met, the processor114determines that the system should switch from one mode to another mode to modify the electricity supply as shown in block910. Switching between modes will be discussed by referring toFIG.10which shows a schematic flow diagram of switching between different modes to modify the electricity supply. The processor determines that the system should switch from the idle mode to the discharging mode and initiates the switch as shown in block1002. In the idle mode, the system100is connected to the mains electricity circuit130but the system does not feed or draw current to or from the mains electricity circuit.FIG.7illustrates the system switching from the idle mode to the discharging mode at time t1. In the discharging mode, the processor114initiates discharge of the battery124and subsequently electricity is supplied to the load108from the battery124via the mains electricity circuit130as shown in block1004. In some embodiments the electricity is supplied to the load108from the battery124and from the mains electricity supply in the discharging mode. FIG.7indicates discharge of the battery124showing the battery124energy flow out and the corresponding load of the building104being reduced by an equivalent amount. In some embodiments, preferably when meter106is a smart meter, the system100may discharge the battery124into the load108and through the meter106into the transmission and distribution network102. The processor114initiates stopping the discharge of the battery124if the system or the electricity transmission network meet certain conditions. In particular the processor is configured to stop the discharge of the battery if one or more of the follow conditions are met; a loss of mains electricity supply, a battery charge of less than a predetermined charge level, e.g. 40%, the inflow current of the mains electricity supply being below the threshold for the near zero net current flow, a wireless current sensor fault, a low price, a request to stop the discharge, a request to start charging, or the expiry of a pre-determined discharge period. If the criteria are met, the processor114then initiates switching from the discharge mode back to the idle mode as shown in block1010ofFIG.10.FIG.7shows the switch of the system from the discharging mode to the idle mode at time t2. The battery124stops discharging and supplying the load via the mains electricity circuit130and the load108of the building104returns to a pre-discharge level as shown in block1012. At time t3the processor114determines thart the electricity transmission and distribution network102is an off-peak period. In some embodiments the processor114will initiate charging the battery124if the following conditions are met; the mains electricity supply is present, the battery has a charge of less than a pre-determined charge level, e.g. 90%, and the price of the electricity is low. Alternatively the processor114initiates a charging of the battery124if a direct charge request is received. The processor114determines that the system100needs to switch from the idle mode to the charging mode, which is shown in block1006. The battery124is then charged from the mains electricity circuit130as shown in block1008. FIG.7shows that whilst the battery124is charging, energy is flowing into the battery124and the total load of the building104is increased. During the charging mode the mains electricity circuit can supply electricity to the load108and the battery124via the charger126. This means that the charging of the battery124can be considered to comprise part of the load of the building104since the total load of the building104increases. The processor114determines that the charging stops on determining one or more of the following conditions; loss of the mains electricity supply, a state of charge of the battery124of more than a pre-determined charge level, e.g. 95%, a high price, a direct request to stop charging, a direct request to discharge, or the expiry of a pre-determined charging period. Time t4shows the point whereby the battery has stopped being charged and the load108returns to a pre-charge load. That is the processor114causes the system to switch from the charging mode to the idle mode as shown in block1014. In this way, the battery124stops being charged from the mains electricity circuit130as shown in block1016. In some embodiments the processor114can also cause the system to switch from the discharging mode to the charging mode or vice versa in dependence of information associated with the mains electricity supply. In some embodiments the processor114may initiate a battery maintenance cycle, in response to measurements of battery condition and taking account of information from the system operator110or service provider120concerning the condition of the electricity transmission and distribution network102. In some embodiments the processor114may initiate a discharge and charge cycle of the battery according to manufacturer's specifications. The processor114preferably discharges during peak periods and charges during off peak periods. The processor114may ensure that the maintenance is initiated during a period whereby a demand response event is not expected to occur. In some embodiments the processor114may initiate periods of charging the battery124in order to ensure the battery is in a state of full charge. The battery124may require a top-up charge because the battery124may lose a small amount of charge over time. In additional embodiments other maintenance to the battery may be carried out such as maintaining the battery cell balance by charging the battery124at an over-voltage and requiring the user to top up the battery with distilled water. FIG.8illustrates a graph of energy versus time according to some embodiments. Operation of the system is similar to the embodiments described with reference toFIG.7. In addition the processor114can be configured to reduce the load108of the building104. The processor114detects that a large load such as a washing machine has been switched on during peak usage. The processor receives a message from the wireless sensor122that the load has increased and information about the amount of the load current increase, and initiates discharging the battery124so as to match the discharge current to the load increase. In this way a peak reduction that emulates the time shift of the appliance is achieved without actually performing time-shifting use of the appliance. In this way the embodiments do not require the consumer to change their behaviour to implement peak load reduction. Indeed the consumer is not even aware that the system is operating. Furthermore advantageously the system allows time shifting of consumption of electricity and therefore the peaks in electricity usage can be mitigated without the consumer changing behaviour. This means that less electricity generation capacity needs to be built because the electricity usage peaks can be smoothed out and existing capacity is sufficient. In certain embodiments the processor114can record in memory116a history of events or log including one or more of the following demand response events, charging events (e.g. timing, duration and amount of energy), discharging events (e.g. timing, duration and amount of energy), and maintenance cycles over a period of time such as a week, month or year. The processor114via the interface406can initiate a periodic upload of this history to the system operator110or service provider120. Alternatively the system operator110or service provider120can via the interface406interrogate the processor114to request an upload of the history. In some embodiments the processor114may periodically send a message to notify the status of the system100and the availability of the system100to the system operator110or the service provider120. In some embodiments the controlling apparatus112can take measurements of the condition of the electricity supply from the transmission and distribution network102such as voltage and power factor (phase angle between voltage and current at the load108) and send the measurements via the interface406to the system operator110or service provider120. In some embodiments the information which is used to switch a mode may need to be present for at least a predetermined length of time. By way of example only, the deviation from a frequency threshold may need to be present for at least a predetermined length of time in order to cause a mode to be switched. In some embodiments, the system may be associated with a load108that is made up of two or more buildings or premises. There may be a meter positioned in the electricity transmission and distribution network. Alternatively there may be no meter and no sensor. The load made up of the two or more buildings or premises may operate in a similar way to the previously described embodiments. Various different parameters and/or information has been described as being used to control the switching from one mode to another. It should be appreciated, that in some embodiments, only one parameter/information is taken into account. In some embodiments more than one parameter/information may be used. In some embodiments, the information/parameter(s) used to control the switching from one mode to a second may be different from that used when switching from the second or another mode. In general, the various embodiments of the invention may be implemented in hardware or special purpose circuits, software, logic or any combination thereof. For example, some aspects may be implemented in hardware, while other aspects may be implemented in firmware or software which may be executed by a controller, microprocessor or other computing device, although the invention is not limited thereto. While various aspects may be illustrated and described as block diagrams, flow charts, or using some other pictorial representation, it is well understood that these blocks, apparatus, systems, techniques or methods described herein may be implemented in, as non-limiting examples, hardware, software, firmware, special purpose circuits or logic, general purpose hardware or controller or other computing devices, or some combination thereof. The embodiments of this invention may be implemented by computer software executable by a data processor, such as in the processor entity, or by hardware, or by a combination of software and hardware. Further in this regard it should be noted that any blocks of the logic flow as in the Figures may represent program steps, or interconnected logic circuits, blocks and functions, or a combination of program steps and logic circuits, blocks and functions. The memory may be of any type suitable to the local technical environment and may be implemented using any suitable data storage technology, such as semiconductor-based memory devices, magnetic memory devices and systems, optical memory devices and systems, fixed memory and removable memory. The data processors may be of any type suitable to the local technical environment, and may include one or more of general purpose computers, special purpose computers, microprocessors, digital signal processors (DSPs) and processors based on multi-core processor architecture, as non-limiting examples. Embodiments of the inventions may be practiced in various components such as integrated circuit modules. The design of integrated circuits is by and large a highly automated process. Complex and powerful software tools are available for converting a logic level design into a semiconductor circuit design ready to be etched and formed on a semiconductor substrate. The foregoing description has provided by way of exemplary and non-limiting examples a full and informative description of the exemplary embodiment of this invention. However, various modifications and adaptations may become apparent to those skilled in the relevant arts in view of the foregoing description, when read in conjunction with the accompanying drawings and the appended claims. However, all such and similar modifications of the teachings of this invention will still fall within the scope of this invention as defined in the appended claims. Indeed there is a further embodiment which comprises the combination of two or more embodiments herein described. | 45,083 |
RE49871 | DETAILED DESCRIPTION Throughout the following discussion, numerous references will be made regarding servers, services, interfaces, portals, platforms, or other systems formed from computing devices. It should be appreciated that the use of such terms is deemed to represent one or more computing devices having at least one processor configured to execute software instructions stored on a computer readable tangible, non-transitory medium. For example, a server can include one or more computers operating as a web server, database server, or other type of computer server in a manner to fulfill described roles, responsibilities, or functions. The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. The inventive subject matter describes systems and methods for providing both wired and wireless audio output for each device of an in-flight entertainment system. Thus, for example, it is contemplated that in some vehicles, each seat may have a device that displays video and outputs audio for a passenger. In many cases, the device may be mounted to the seat back of the immediate row in front of the seat. In such embodiment, each seat's device can have an audio output device for outputting audio via both wired and wireless connections. Although the below discussion focuses on an aircraft, it is contemplated that the systems and methods discussed herein could likewise be used on ships, trains, busses, and other vehicles. Using the systems and methods contemplated herein, passengers in an aircraft or other vehicle are able to choose whether to connect headphones wirelessly, via Bluetooth or other commercially suitable protocol for example, and/or via a wired audio jack. Thus, both the wireless and wired audio outputs can function at the same time if desired because the system creates parallel wireless and analog wired audio outputs. Contemplated audio output devices comprises a traditional 3.5 mm stereo audio jack for analog audio output and a 2.5 mm ARINC C1 jack for 12 VDC for Noise Cancelling Headphones, for example. Of course, it is contemplated that other wired outputs could be used as technology involves, without departing from the scope of the invention. The audio output device preferably also includes a push button or other actuator, which could be digital, that permits pairing and unpairing of a wireless device such as wireless headphones for example. Importantly, pairing or unpairing of the wireless device does not affect (e.g., turn on or off) audio output via the wired audio output(s). A light source, such as a light-emitting diode (LED), can be included to indicate the Bluetooth pairing state of the audio output device (e.g., Unpaired, Pairing, Paired, Faulty, etc.). In one contemplated embodiment, the LED can be installed to create a ring of light around the push button, for example, and through a Bluetooth logo, and could be done with different colors or by blinking. An exemplary audio output device100is shown below inFIG.1. The Bluetooth logo is disposed on the push button or other actuator102disposed on a surface of a housing104. It is further contemplated that the audio output device100can either be disposed at an individual seat within the vehicle (where analog audio and +12 VDC are received, for example) or be daisy chained (where analog audio and +12 VDC are passed-through to the next audio output device) depending on the vehicle's configuration. As an example shown inFIG.3, the audio output device300may be disposed at a seat directly in front of where a passenger will be sitting, and where a wireless device310(Bluetooth slave) may be located). Thus, for example, in an aircraft with N rows, each having at least two seats, an audio output device could be disposed at each row, and even at each seat. The device100can further include a wireless transmitter112as well as one or more wired audio outputs (jacks)110. The audio output device can include a processor for managing the wireless transmitter, for example, or could utilize a processor of the associated entertainment system. FIG.2illustrates a typical channel listing for the Bluetooth protocol having 79 channels in the 2.4 GHz ISM band. Bluetooth devices can form a small network, called a Piconet, which can accommodate up to eight devices. In a Piconet, a Bluetooth device can either be a Master or a Slave device. Each Piconet uses the 79 channels in a frequency hopping manner, using the Frequency Hopped Spread Spectrum (FHSS) mechanism. The 79 channels are visited synchronously, following a pseudo-random hopping sequence, by the Master and all Slaves in the Piconet, with a dwell time of 625 microseconds in a channel (i.e. a hopping rate of 1,600 times per second). The amount of interference observed by a Piconet is affected by the number of other Piconets in its proximity, since all of the Piconets are using the same set of 79 Bluetooth channels. If there is only a small number of co-located Piconets, the probability that some of them are hopping to the same channel at one particular time might be low. However, this collision probability increases as the number of co-located Piconets is increased. In order to maintain some level of Quality of Service (QoS) in an environment where many Bluetooth Piconets are deployed in a close proximity, e.g. in an aircraft cabin or vehicle's interior, where a Piconet may correspond to the Bluetooth devices installed in a seat, a strategy of minimizing the transmit power of the Bluetooth Master should be employed. An exemplary method of minimizing transmission power is presented inFIG.4. It is preferred that such methods ensure that a Piconet observes interference only from three seat rows: the one in front, its own row, and the one row at its rear. To determine the required transmission power, the method requires the following steps that utilizes a dynamic algorithm and processor to adjust transmission power of a master device. In step405, a default initial transmit power for a wireless transmitter of a master device is set via a processor. To ensure that the transmission power is unlikely to interfere with wireless transmitters located more than a seat row in front of or behind where the master device is located, the processor can be configured to determine whether the transmission power should be increased or decreased. On a periodic basis, the Received Signal Strength Indicator (RSSI) level of a wireless device (i.e., connected Slave to the master device) can be measured in step410. In step415, a transmission power of the slave device can be requested by the processor of the master device. In step420, using the processor, a distance between the master device and the slave device can be estimated based on the transmission power of the slave device. The RSSI of the master device at the slave device can be estimated in step425using the processor and based on the estimated distance between the master device and the slave device. Based on estimated RSSI of the master device at the slave device, a transmission power of the master device can be increased or decreased, such that the estimated RSSI of the master device at the slave device is a set threshold above the slave device's receiver sensitivity. Thus, by scaling down both transmission power of devices in Bluetooth Piconets, interferences are less likely, allowing more Bluetooth devices to work simultaneously in a dense environment such as an aircraft. As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As used herein, and unless the context dictates otherwise, the term “coupled to” is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms “coupled to” and “coupled with” are used synonymously. Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints and open-ended ranges should be interpreted to include only commercially practical values. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value with a range is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims. It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B, C . . . and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc. | 11,761 |
RE49872 | DETAILED DESCRIPTION OF PREFERRED EMBODIMENT In general, the present disclosure is directed at a method and apparatus for providing a configurable LED Driver/dimmer. In the current description, the Driver/dimmer will be referred to as a dimmer, however, it will be understood that the configurable apparatus can function as either a driver, a dimmer or both. In the preferred embodiment, the dimmer is used for Solid State Lighting (SSL) applications. Turning toFIG.1, a perspective view of an LED dimmer is shown. The LED dimmer10includes a body portion12, or housing, which includes a monolithic aluminum heatsink14and a U-shaped chassis16. Cross-sectional views of the dimmer10are provided inFIGS.2a and2b. The dimmer10further includes a front plate18which includes a plurality of ports20along with a set of conductor cables22. The front plate18is fastened to the body portion12via a set of fasteners24, such as screws. In this embodiment, as conductor cables are used to provide output power to LED/OLED loads, the space requirement for the front plate18is reduced with respect to other known connection means such as terminal blocks. Turning toFIGS.2a and2b, a pair of cross-sectional views of the LED dimmer are provided.FIG.2cis a schematic view of one embodiment of an internal layout of the dimmer10. The cross-sectional views forFIGS.2a and2bare taken along lines A-A and B-B ofFIG.2crespectively. As shown, the heatsink14includes a receptacle portion26for receiving the ends of the chassis16. In order to increase, or optimize, the heat dissipation capability of the configurable dimmer10at full output power, the extruded aluminum heatsink14includes fins28to increase the surface area for heat dissipation. The heatsink14also has a mounting platform30for receiving power components, or semiconductors32, such as a bridge rectifier, MOSFETs, and/or diodes to efficiently transfer heat to the outside surface of the heatsink14. These components will be discussed in more detail below with respect toFIG.3. A power factor inductor and main isolation transformer pair34are thermally coupled to the chassis16by a thermally conductive, electrically isolated material36to further improve heat dissipation of these components. A circuit board38is also mounted to the heatsink14. Turning toFIG.3, a block diagram of another embodiment of the LED dimmer is shown. The LED dimmer10includes an inrush current limit40, or inrush current limit circuit, which receives power from an AC power source or supply42, located external to the dimmer10. The inrush circuit40is connected to a Power Factor Correction (PFC) Boost44which, in turn, is connected to a DC/DC Converter46, or power conversion stage. The converter46is connected to an Output Voltage bus48which is connected to a power limiter50. The inrush circuit40, the PFC boost44, the DC/DC converter46, the Output Voltage bus48and the power limit50can be seen as a power circuit47. Although only one power limit50is shown, it will be understood that there could be multiple power limits. The power limiter50is connected to a set of output current drivers52, whereby each of the output current drivers52has an associated in-circuit serial programming (ICSP) port54. The output of the output current drivers52is connected to individual Organic Light-Emitting Diodes (OLED)/Light-Emitting Diodes (LED) loads56, further referred to as LED loads. Along with the above-identified components and circuitry, the dimmer10further includes a primary digital controller58which is connected to an auxiliary power source60and an ICSP Port62. The primary digital controller58is further connected, via an isolated communication bus61to a secondary digital controller64, which receives power from the auxiliary power source60. An ICSP port68is also connected to the secondary digital controller64. The auxiliary power source60is also used to power an interface component70which includes an optional address selector72and a communication interface74. The communication interface74receives inputs from an external transmitter76and communicates via an isolated serial communication bus78with the secondary digital controller64. A set of isolation barriers80and81are located within the dimmer10, each barrier separating various components of the dimmer10from each other. As will be understood, not all of the components or connections of the LED dimmer10required for operation are shown as they will be understood by one skilled in the art. For instance, the dimmer10can also include an EMI filter and a bridge rectifier. With respect to connections, it will be understood that the primary digital controller58can also be connected to the PFC boost44, the inrush current limit40and the DC/DC converter46while the secondary digital controller64can be connected to the output voltage bus48, the power limit50and the output current drivers52. In operation, the PFC Boost44and DC/DC Converter46are controlled by the primary side digital controller58while the secondary digital controller64monitors the output voltage bus48and provides digital feedback control information via isolated communication bus61to regulate the output voltage bus48. Secondary digital controller64also translates dimming and/or color mixing information from the external transmitter76into LED control information for the output current drivers52. The primary58and secondary64digital controllers and output current drivers52have an associated programming port for further configuring the LED dimmer10. Turning toFIG.4, a prior art inrush current limit is shown. In order to limit inrush current limit during initial start up of the power source, one approach is to utilize a negative temperature coefficient thermistor (NTC) in parallel with a relay contact. During initial turn on of the power source, the NTC thermistor limits the inrush current. When the PFC boost stage bulk capacitor is charged, and before the PFC stage is enabled by the primary controller, the primary controller closes the relay contact to bypass the NTC thermistor. This is accomplished by applying a DC voltage via a switch across the coil in the relay. A limitation of this approach is the power consumption of the relay coil when a continuous DC voltage is applied. This power consumption becomes significant in terms of Energy Star requirements during no load or standby operation such as when a “black out” or minimum light intensity state is received by the communication interface. Turning toFIG.5, an embodiment of an improved inrush current limit40is shown. An EMI filter82is connected between the power supply and the current limit40and is connected directly to the PFC boost44and via the current limit40. The current limit40includes a thermistor84, a relay or relay contact86and a switch59. The relay contact86is connected in parallel with the thermistor84. A typical relay coil requires greater energy to close the contacts than is required with the currently described limiter40to maintain the contacts in a closed position since less holding force is required. After the relay contacts have been closed by applying a voltage of 12 Vdc, modulation of the relay coil voltage can be initiated by the primary controller58to effectively reduce the average voltage across the coil to approximately 5 volts versus a DC voltage of 12V, reducing power consumption. It should be noted that the pulse duty cycle and frequency can also be changed to improve or optimize performance. In one embodiment, the primary controller58pulses the DC voltage across the relay coil via the switch59to reduce power consumption. In one embodiment, for the PFC boost44, as shown inFIG.3, the PFC Boost44utilizes a boost topology with an input AC voltage mains range of 103 Vac to 300 Vac from the AC supply42. Energy stored in an inductor within the PFC boost44is transferred and stored in the bulk capacitor on a cycle by cycle switching basis at a loosely regulated 430V DC over the input range. The energy is controlled in a manner that forces AC input current to be sinusoidal and in phase with the AC line voltage. By drawing current in phase with the input mains voltage42, the amount of harmonic currents of the fundamental AC mains frequency being introduced into the power line is reduced. For the DC/DC convertor46and the output voltage bus48, the preferred embodiment for the DC/DC converter46is derived from the isolated buck converter topology and comprises a galvanically isolated full bridge converter employing a primary side phase modulation technique with a secondary side current doubler rectifier circuit. The full bridge converter parasitic circuit elements in conjunction with primary magnetization current and reflected inductor ripple current cause resonant edge switching transitions on the MOSFET switch thus forcing zero voltage across the MOSFET switching device before turn on. The result is higher efficiency due to the elimination of Coss (drain to source MOSFET Capacitance) switching losses, reduction of gate charge across the Miller capacitance and minimized power loss during switching transitions when voltage and current are changing simultaneously. Since the output of the DC/DC converter is a tightly regulated DC bus48, the set of power limit circuits50are coupled to either one or more current drivers52to limit the power output of each of the output current drivers.52The power limit circuits50each include a current sensor that is monitored by the secondary controller64. In the event of a single component failure within the output current driver module, the power limit circuits50limit the energy to the loads in accordance with the UL standard1310Class2. Supplementary protection to the power limit circuits can also include one or more fuses. For the primary digital controller44, the controller44provides digital feedback control for the PFC Boost44and DC/DC Converter46. The digital feedback method for the PFC Boost44utilizes average current mode control with duty cycle feed forward for the inner current loop and voltage mode control for the outer control loop. The DC/DC Converter46utilizes voltage mode control for the digital control loop. The primary digital controller44also controls the inrush current limit circuit40, provides primary current limit protection, and over voltage protection for the output of the PFC Boost44. The primary digital controller44also disables the PFC Boost44and the DC/DC Converter46during black out or no load conditions to reduce power dissipation. With respect to the output current drivers52, configuring the required number of outputs and required output current is accomplished by populating the appropriate sections of a single printed circuit board with the appropriate electrical components and programming the output current driver via the in-circuit serial programming (ICSP) ports54. Turning toFIG.6, which is an embodiment of an output current driver, the output current driver52comprises a load controller90, a current source92, and current sense94. Although only one current driver52is shown, it will be understood that multiple are present as reflected inFIG.3. The output current driver may utilize either the dimming/color mixing techniques for LEDs described in detail in US Patent Publication No. 2007/0103086, or the techniques described in detail in International Publication WO2011/140660 which is hereby incorporated by reference. The secondary controller64receives dimming or color mixing information in the form of a serial data stream from the external transmitter76via the communication interface74and then translates the data stream into LED control information. The LED control information is transmitted to the load controller90in the form of instructions to generate a digital signal98and an analog signal100. The load controller90further comprises a signal generator102which transmits the digital signal98and the analog signal100to the current source92. The digital control signal98and the analog signal100are preferably generated via a digital control algorithm and 1 Bit algorithm, respectively. The current source92preferably includes ancillary circuitry for operation and comprises a buck topology power stage with hysteretic control. The current sense94provides a digital feedback loop for each current source92. In the preferred embodiment, the current source92is a buck circuit topology however other embodiments can include topologies such as boost, buck-boost, or single ended primary inductor converter (SEPIC). Output104of the current driver52provides a current pulse via current source92to the LED Load56whereby on times, off times, and period are not held constant. Each output current driver52, has an associated in-circuit serial programming (ICSP) port54. The ICSP port54provides access to the load controller90such that firmware updates are possible to permit the configuration of the output current drivers52. The ICSP port(s)54for the output current driver(s)52can be located on the printed circuit board assembly of the apparatus or they can be located on the outside of the enclosure. The configuration options include, but are not limited to, such parameters as the adjustment of the frequency range of the dimming current pulse for the range of light intensity output or the set point adjustment of the peak on time output current. For example, it might be necessary to increase the frequency range of the dimming current pulse in video recording applications where the dimming current pulse frequency can be programmed for a 2000 Hz to 2500 Hz range. This would negate a visible beat frequency effect that would other wise be noticeable on recorded video. There can be other applications where the adjustment of the dimming current frequency range is required to reduce EMI effects. The default peak output current set point is programmed via the ICSP port54which provides flexibility in the number of possible LEDs types that can be driven and is typically dependent on the recommended operating current specified by the manufacturer such as 350 mA, 700 mA, etc. The set point current is preferably programmed to within 4% of the manufacturer's specification. The peak output current set point can then be precisely calibrated to within typically 1% via the secondary controller64during factory calibration. An alternate embodiment of an output current driver52is shown inFIG.7. In this embodiment, the output current driver52comprises a load controller110including a signal generator112. A current source114and a current sense116are located within an apparatus118, such as a light fixture. The light fixture118also includes the LED load56. After receiving the LED control information from the secondary controller64, the signal generator112provides a data signal to the light fixture118to operate the LED load56via the current source114and the current sense116. This is also schematically shown inFIG.8. FIG.8is a schematic diagram of an alternate embodiment of a configurable LED dimmer10. As shown, individual current sources114and current senses116are mounted in the light fixture containing the LED load56, and power and data signals are provided to each output current source114by the multi conductor cable22. In this embodiment, the current sources114are configured to regulate to a predetermined peak current. The load controller110transmits the data signal containing the output current information encoded within the three variables of on time, off time, and period whereby no three variables are held constant. Turning toFIG.9, a known application of internal auxiliary power requirements in a multistage power source is shown and illustrates how auxiliary power is provided to the various blocks of a multistage power source P1, P2. . . P10represents the various power and voltage transfer requirements for each functional block. For simplicity, the various voltage regulator and filter circuits required for each of the power outputs have been omitted. In operation, the bridge rectifier converts the AC mains voltage P1to a rectified voltage P2. A portion of power P6from the output of the bridge rectifier P2is supplied to the start up circuit. The start up circuit is comprised of a power transistor or MOSFET and is intended to provide power P8to the PFC analog controller for only a short duration of a few seconds. Power P8to the PFC analog controller will allow the PFC Boost stage to begin switching, providing power P10to the DC/DC controller, and power P3to the DC/DC converter power stage. Since the start up circuit dissipates an excessive amount of power, it is turned off by the voltage component of P7supplied by the PFC boost stage. The P7power is permitted to ‘flow through’ the start up circuit to continue to supply power P8to the PFC analog controller. The output of the DC/DC Analog Converter provides power P4to the multi output voltage bus, power P9to the Communication Interface, and the Output Current Drivers by means of P5. In this implementation, the PFC and DC/DC Controllers are typically analog controllers. It should be noted that in this implementation, in order for the communication interface to continually receive dimming information from an external transmitter, the DC/DC Converter stage must remain turned on. Similarly, in order for the DC/DC converter stage to provide power P4, the PFC Boost stage must remain on. In a ‘black out’ state, the communication interface may receive a “0” intensity value out of 255 intensity levels for all of its output current drivers via the external transmitter such as a DMX512A or RDM controller interface, or it may receive an analog voltage of between 0 to 1V via a controller compliant to ESTA E1.3-2001 or IEC60929 as one of many communication interface options. In this ‘black out’ state, the DC/DC Converter and PFC Boost Stage continue to dissipate an excessive amount of power. FIG.10is directed at an embodiment of an improved internal auxiliary power distribution in a multistage power source for providing auxiliary power to the various blocks of a multistage power source. For simplicity, the various voltage regulator and filter circuits required for each of the power outputs have been omitted. The transfer of power from AC mains to the Output Current Drivers (52) is unchanged. This embodiment shows an improved implementation of an independent auxiliary power source providing power to the primary digital controller58, the secondary digital controller64, and the communication interface74. The auxiliary power source60comprises an efficient isolated flyback topology with a wide input voltage range and pulse skipping capability to minimize its power dissipation at light loads or no load conditions. In other words power can be provided to the primary digital controller58, the secondary digital controller64, and the communication interface74via an auxiliary flyback converter. A ‘black out’ state received from the external transmitter76to the communication interface74is communicated to the secondary digital controller64and then the primary digital controller58via the isolated communication bus66. The primary digital controller58then disables the PFC Boost Stage44and DC/DC Converter Stage46reducing overall power dissipation of the configurable power source. It should be noted that even when the PFC Boost44is disabled, power can continue to be supplied to the auxiliary power source60since rectified voltage from a bridge rectifier120can continue to peak charge the PFC boost44through an internal capacitor via the boost diode. The auxiliary power source60continues to provide power to the primary digital controller58, secondary digital controller64, and communication interface74in order to be able to ‘listen’ for or sense a change in light intensity state that may be communicated by the external transmitter76. Alternate embodiments can include additional ancillary circuits that can be powered by the independent auxiliary power source that can be disabled by a controller to reduce over all power dissipation in black out or no load conditions. With respect to the communication interface74, the communication interface74comprises a removable and interchangeable module with each module adapted for different control options such as DMX512A, RDM, 0-10 Vdc and Zigbee. Operation of the communication interface with such control options will be understood by one skilled in the art. The communication interface module receives lighting control information via the external transmitter76and converts the various protocols into a serial data stream. It then transmits this data by means of a Universal Asynchronous Receiver Transmitter (UART) to the secondary digital controller64via the isolated serial communication bus78. The isolated serial communication bus78is comprised of a isolation barrier82to “float” the communication interface and prevent ground loops. Turning toFIG.11, an embodiment of the communication interface is shown. In this embodiment, an analog interface module adapted for 0-10 Vdc IEC60929 or ESTA E1.3-2001 dimming methods as the communication interface74is shown. The analog interface module can be adapted to receive one or more analog control voltages from one or more associated external transmitters76. The external transmitter76is preferably an electronic resistor or potentiometer that sinks current from the current source located on the analog interface module and outputs a variable 0-10 Vdc control voltage proportional to the required light intensity. Individual external transmitters76supply signals to various controls122within the communication interface74. Each control122is representative of an area or group of LED loads56. Within each control122is a current source124, a voltage sensor126and a differential amplifier128. The differential amplifier128senses a voltage across the voltage sensor126and converts this into a correlated voltage (Vm,V1,V2. . . Vn) supplied to a controller130. The controller130converts this analog voltage into a serial data stream for transmission to the secondary digital controller64via the isolated serial communication bus78. The communication interface74can be configured to have one 0-10 Vdc control voltage simultaneously control via the secondary digital controller64, all output current drivers52and LED loads56. This application is beneficial in monochromatic color or white lighting applications since only one control signal and associated wiring is required to control multiple light loads. Furthermore, the communication interface74can be adapted to have one or more 0-10 Vdc signal voltages control an associated group of one or more output current drivers in zonal dimming applications. An optional master 0-10 Vdc signal voltage could be able to simultaneously control all of the individual groups of output current drivers. In applications not requiring the complexity of DMX512A, these analog control options are beneficial in red/green/blue or red/green/blue/amber color changing or monochromatic color or white light applications whereby the addressability and corresponding control of individual LED light loads is not required. With respect to the secondary digital controller64, the controller64monitors and transmits digital output voltage bus information (feedback loop) via the two way isolated serial communication bus78, decodes the serial data from the communication interface74, and transmits control information to the output current drivers52. As a protection feature, the secondary controller64also monitors output currents from the power limit stages50supplied to the output current drivers52 The secondary digital controller64includes the ICSP port68to program and calibrate the output voltage bus48to the required voltage. In DMX512A applications, the ICSP port68also allows for the mapping of each of the output channels to a wide variety of addresses. Similarly, in 0-10 Vdc analog control applications, the secondary digital controller ICSP port allows for the mapping of output channels into groups for each associated 0-10 Vdc control signal. This mapping capability is particularly useful in addressable-networked lighting systems using a DMX512A control protocol where different lighting zones are required to respond to different illumination information. For example, in a 12 channel output configuration, the first 6 channels could be mapped to the DMX base address of the power source (i.e. DMX01) and the last 6 channels could be mapped to DMX address +1 (i.e. DMX02). This mapping capability is also useful in zone dimming applications using 0-10 Vdc analog controls as the communication interface. For example, a 12 channel output LED dimmer configuration can have 7 output channels grouped for a first associated 0-10 Vdc signal, the next 3 channels can be grouped to a second associated 0-10 Vdc control signal, and the last 2 channels can be grouped to a third associated control signal. Turning toFIG.12, a block diagram of an embodiment of a configurable LED dimmer implemented in a low voltage DC distribution LED lighting system is shown. For reference, a low voltage DC distribution system is defined as a system where all power from the Configurable LED dimmer provided to the LED loads meets Class 2 requirements as defined in UL1310 Class 2 Power Units and NEC (National Electrical Code) Article 725 for Class 2 Power Limited Circuits. The low voltage DC distribution LED lighting system200includes a LED dimmer10, which receives power from an AC supply42, and is connected to at least one breakout module51which in turn is connected to a set of series connect modules53by means of communications cabling204. Similarly, the series connect modules are connected to individual Organic Light Emitting Diodes (OLED)/Light Emitting Diodes (LED) loads56, or LED loads, via communications cabling206. Referring to the LED dimmer10, an example of which was previously described with respect toFIG.3, the power circuit47comprises a DC to DC converter46and a power limit or power limit function50. The DC to DC power converter may be an isolated full bridge converter or an isolated half bridge LLC resonant converter. Although only one power limit is shown, there may be multiple power limits whereby each power limit is connected to a set of output current drivers52to limit the power output supplied to the set of output current drivers. The power limit50may be a fuse, a resettable fuse or an electronic circuit that includes a current sense. The power limit may also include any ancillary circuits or components that limit power to the output current drivers or shut off the LED dimmer10or both. The power limit circuit50limits the amount of power supplied to a set of output current drivers under normal operation of each. Similarly, in the event of a single component failure within any output current driver52within the set, the power limit50may also limit the power to the set of current drivers52. In one embodiment, the power is limited to less than 100 watts in accordance with UL standard1310, Class 2 Power Units. The set of output current drivers52includes a quantity of output drivers such that the total output power of the set of output drivers does not exceed 100 watts under normal operating conditions. Each set of output current drivers52is connected to the breakout module51by means of communications cabling202. With respect to the communication interface74, the communication interface74comprises a removable and interchangeable module with each module adapted for different control options such as DMX512A, RDM (Remote Device Management), 0-10 Vdc analog control, Zigbee, and DALI (Digital Addressable Lighting Interface). DALI requirements are defined in standards IEC 62386-101; System General Requirements, IEC 62386-102; General Requirements-Control Gear, and IEC 62386-207; Particular Requirements for Control Gear-LED Modules. The communication interface module receives lighting control information via the external transmitter76and converts the information regardless of the various protocols into a serial data stream for use by the dimmer10. As shown inFIG.12, the output current drivers or the set of output current drivers52are connected via the cabling202,204,206, directly or indirectly, to breakout modules51, and series connect modules53to the LED loads56, and such connectivity may be referred to as individual channels or a set of channels respectively. In one embodiment, the cabling, communications cabling has an overall insulation sheath and may be shielded or unshielded. It is available in either insulated multi-conductor or insulated twisted pair stranded wiring and the wire gauge is typically 18 AWG. Alternate cabling options may also include 20 AWG or 22 AWG and type PLTC (power limited tray cable), CL2 (Class 2) or CL3 (Class 3) as permitted in Article 725 of the NEC. The LED dimmer10, via the output current drivers52, connects into at least one breakout module51via the cabling202as a set of output channels. The breakout module51then splits the set of channels into individual channels or into a predetermined number of channels depending on the required configuration of the lighting system. For example, a connection from the LED dimmer10may have four (4) individual cables202connected to the breakout module51, each cable further comprising six (6) conductors or three (3) twisted pairs for connection (positive and negative) of 3 channels per cable. This represents a feed in of 12 channels in 4 groups of 3 into the breakout module51. The breakout module51regroups the channels into groups of 2 for connection to the series connect module53using communications cabling204with 4 conductors or 2 twisted pairs of conductors. This may be seen as the output of the breakout module51and represents a feed out of 12 channels with 6 groups of 2 channels. In other embodiments, there are a number of other feed in cable and feed out cable combinations possible for the break out module51. The series connect modules53connect multiple LED loads56, in series for every channel. In one embodiment, the series connect module53receives a four (4) conductor cable204feed in (representing 2 channels) and then electrically connects, via cabling206, at least 2 LED loads56in series for each channel. The cabling204is typically a 4 conductor or 2 twisted pair configuration. A number of different LED load56configurations are possible. Typically, the LED loads56are part of a light fixture and comprise one or more LED arrays or a group of individual LEDs. The LEDs are typically mounted on a suitable heat sink and installed in various types of housings. Such housings or configurations may include recessed cans with an associated electrical junction box, pendants, rail systems or track systems. A rail fixture includes fixed location LED sources mounted on a linear rail and a track system includes moveable LED light sources mounted on a track system. In one embodiment, the LED loads56may have a lumen output of up to 1200 lumens. It is of course possible to have loads with a higher or lower lumen output. The LED dimmer10may be remotely mounted from the LED loads and in some cases may be up to 200 feet from the LED loads. Alternate distances between the LED dimmer and the LED load are also possible and dependent on the forward voltage drops in the LED loads and the voltage drops dependent on the wire gauge of the communications cabling. FIG.13ais a diagram of one implementation of the break out module51. The break out module51comprises two printed circuit board (PCB) assemblies420with modular power connectors422arranged as terminal blocks to provide an electrical connection between the feed in channels and the feed out channels which are seen as cabling204. The break out module51regroups or separates the feed in channels with a different grouping of feed out channels. It may also provide visual means for an installer to easily organize and keep track of the grouping and arrangement of channels during installation. In this embodiment, the feed in includes 6 channels of 3 cables202with each cable providing 2 channels. The feed out comprises 6 channels of 6 cables204with each cable providing one channel. The cabling includes an optional shield wire424for connection to the system ground. Other implementations are contemplated. The power connectors422preferably include apparatuses to enable a method of quickly inserting or releasing the cabling by means of a tool or push button on the connector(s). The connectors422may be either cage clamp or push wire type connectors. FIG.13bshows a schematic representation of the break out module51ofFIG.13a. With reference toFIG.14a, a diagram of an embodiment of a series connect module53is shown. The series connect module53contains at least one PCB assembly502with feed in modular power connectors512for electrical connection of the feed in cable seen as cabling204. The feed in cable204comprises 4 conductors or 2 pairs representing 2 channels (CH1and CH2) with an optional shield connection504. The feed out modular connectors508are connected in series on the PCB assembly502in order to connect the LED loads56in series via feed out cables206as shown schematically inFIG.14b. The feed out cables206may be comprised of one pair of two conductors and an optional shield connection510to the system ground. The power connectors508,512, preferably include apparatuses to enable a method of quickly inserting or releasing the cabling by means of a tool or push button on the connector. The connectors may be either cage clamp or push wire type connectors. It is understood that many other embodiments are possible for the series connect module53whereby there may be multiple feed in cables where each feed in cable may comprise any number of channels. The series connection of LED loads56may also include any number greater than two. Turning toFIG.15, a block diagram of another embodiment of a configurable dimmer implemented in a low voltage DC distribution LED lighting system is shown. In this embodiment, the series connect module is excluded from the low voltage DC distribution LED lighting system600. The series connect means is completed within an electrical junction box602associated with each LED load56. As before, the system600includes a dimmer10connected to a break out module51via cabling202and204. The typical number of LED loads connected in series is two, and twist-on wire connectors are used to make the electrical series connections between the LED loads56and the cable206. With reference toFIG.16, a block diagram of an alternate embodiment of a configurable dimmer implemented in a low voltage DC distribution LED lighting system is shown. This embodiment shows the break out module51as an integral part of the LED dimmer10within the system650. Turning toFIG.17, a block diagram of a further embodiment of a configurable dimmer implemented in a low voltage DC distribution LED lighting system is shown. In this embodiment of the system680, the break out module51and the series connect modules53are integrated into a single enclosure or module682. The electrical connection684between the break out module51and the series connect modules53may be accomplished by means such as cabling, hook up wire, or PCB (printed circuit board) copper tracks. Turning toFIGS.18a,18b, and18c, alternate embodiments of the break out module are shown. All configurations include modular power connectors422arranged as terminal blocks and mounted on a PCB420to provide an electrical connection between the feed in channels and the feed out channels. The connectors include apparatus to allow for a quick means to insert or release the wiring by means of a tool or push button on the connector. InFIG.18aone feed in cable202, comprises conductors for 2 channels and an optional shield wire connection424. The feed out includes 2 cables204each with 2 conductors for one channel and an optional shield wire connection424. InFIG.18b, one feed in cable202, comprises conductors for 4 channels and an optional shield wire connection. The feed out includes 4 cables204, each with 2 conductors representing one channel and an optional shield wire connection424. InFIG.18c, one feed in cable202, comprises conductors for 4 channels and an optional shield wire connection. The feed out includes 2 cables204, each with 4 conductors representing two channels and an optional shield wire connection424. Turning toFIG.19, a method of providing low voltage power to a set of LED loads is shown. In operation, an AC voltage700is applied to the power circuit of the LED dimmer and converted to low voltage DC702. The low voltage DC bus is then power limited704by at least one power limit circuit or like components to less than 100 watts in accordance with UL1310 Class 2 characteristics. The low voltage DC power is the converted to multiple constant current outputs706via the power limit such as by means of the output current drivers which generate a constant peak current for each output channel. The power is then transmitted in the form of low voltage and pulsed current on each channel708to the breakout module via the cabling connecting the dimmer and the breakout module. The breakout module splits or regroups, or both, the power channels710and transmits the power to the series connect modules. The series connect module provides power for each channel to multiple LED loads connected in series712by means of cabling. FIG.19also shows a method for control of the LED dimmer. Lighting control information such as dimming intensity levels in the form of various protocols is transmitted by an external transmitter into the communication interface714of the LED dimmer. The various protocols are converted to a data stream, preferably serial, and transmitted to the secondary digital controller which in turn translates the data stream into LED control information716. The LED control information, which in one embodiment is in the form of a digital and analog signal, is transmitted to the controllers of the associated output current drivers718. The output current drivers generate power as pulsed current at low voltages based on the dimming intensity levels received as lighting control information for each channel of the low voltage lighting system. Embodiments of the disclosure can be represented as a software product stored in a machine-readable medium (also referred to as a computer-readable medium, a processor-readable medium, or a computer usable medium having a computer-readable program code embodied therein). The machine-readable medium can be any suitable tangible medium, including magnetic, optical, or electrical storage medium including a diskette, compact disk read only memory (CD-ROM), memory device (volatile or non-volatile), or similar storage mechanism. The machine-readable medium can contain various sets of instructions, code sequences, configuration information, or other data, which, when executed, cause a processor to perform steps in a method according to an embodiment of the disclosure. Those of ordinary skill in the art will appreciate that other instructions and operations necessary to implement the described disclosure can also be stored on the machine-readable medium. Software running from the machine-readable medium can interface with circuitry to perform the described tasks. The above-described embodiments of the disclosure are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art without departing from the scope of the disclosure, which is defined solely by the claims appended hereto. | 39,793 |
RE49873 | DETAILED DESCRIPTION In certain embodiments bioflavonoid analogues are identified that that inhibit β-secretase mediated APP processing by a novel mechanism. In particular, it is believed these molecules inhibit the BACE cleavage of the MBP-C125 APP substrate, resulting in the inhibition of the production of C99 but not the β-site peptide substrate (P5-P5′). In addition, various bioflavonoids and analogues thereof identified herein inhibit sAPPβ in neuroblastoma SHSY5Y cells. Further it was demonstrated that the inhibitory activity is associated with binding to the MBP-C125 substrate. Accordingly, these molecules appear to be APP specific BACE inhibitors (ASBIs) and provide a new mechanism to modulate APP processing. These ASBIs can be used in the treatment and/or prophylaxis of pathogolies characterized by pathological APP processing (e.g., Alzheimer's disease, pre-Alzheimer's conditions such as MCI or pre-symptomatic MCI, and the like). The ASBIs are at least selective and appear to be specific for the APP substrate and are believed to show fewer undesired side-effects because the ASBIs are typically not active on other substrates for the enzyme. With respect to inhibitors of γ-secretase, substrates other than APP, such as Notch, raise concerns for potential side effects of γ-secretase inhibition, and the recent failure of the γ-secretase inhibitor, semagacestat, serves to reinforce such concerns. Similarly in the case of BACE, for example, inhibition of non-APP substrates such as PSGL1 or LRP can produce adverse side-effects. Therefore, the optimal BACE inhibitor would be one that would bind not to BACE but rather to APP, leading to APP-specific BACE inhibition (ASBI). Without being bound to a particular theory it is believed that such ASBIs would interact with APP or the APP-BACE complex (“inactive” complex) at the membrane and prevent its transition to the “active” complex in early endosomes, where at pH<5 BACE is fully active (see, e.g.,FIG.10). Some β-site binding antibodies have been shown to block the cleavage of APP by BACE and also work in animal models of AD, however for effective pharmaceutical development small organic molecules are typically preferred to relatively large biomolecules such as antibodies. The data described herein on the identification of the first ASBIs, demonstrates that such an approach is feasible. APP-Specific-BACE-Inhibitors (ASBIs) inhibit the BACE cleavage of the Amyloid Precursor Protein (APP) but not the proteolytic cleavage of other substrates. Such therapeutics are believed to represent a new class of Alzheimer's disease (or other amyloidogenic disease) therapeutics. Initially a clinical library of 448 compounds was screened and this assay led to the identification of a single bioflavonoid that specifically inhibited the MBP-C125 substrate of BACE while not preventing the cleavage of the P5-P5′ substrate. This bioflavonoid Rutin (see, e.g.,FIG.1) is a nutritional supplement was also found to inhibit sAPPβ in cells. A panel of bioflavonoids was then tested in the ASBI and sAPPβ assay in cell culture. This testing identified a second bioflavonoid Galangin (see, e.g.,FIG.1) another nutritional supplement with known human use that was effective in the ASBI assay and in cells in preventing the BACE cleavage of APP. Galangin also has been reported to be an inhibitor of acetylcholine esterase (AChE). Using a simple nitrocellulose filter ligand-binding assay initial binding of various bioflavonoids to the MBP-C125 substrate was demonstrated. A panel of bioflavonoids were screened in the ASBI assay. Rutin and Galangin were identified as effective in modulating sAPPβ levels in cells and shows binding to the APP substrate (see Example 1). It was demonstrated that the bioflavonoids could inhibit BACE cleavage of APP and APLP2. A HEK-293 assay transfected with APP or APLP2-Gal4 to obtain this data. This assay system is described by Orcholski et al. (2011) J. Alzheimers Dis., 23(4):689-699. Transactivation is achieved upon transfection with Mint3 and Taz. The ASBI was expected to inhibit only the transactivation of APP-Gal4, not that of APLP2-Gal4. For these experiments cells were co-transfected with a Gal4-luciferase reporter plasmid (to measure transactivation), a beta-galactosidase plasmid (to normalize for transfection efficiency), and the test plasmids identified. The normalized luciferase activity was expressed as fold induction over transcription by APP-Gal4 alone (FIG.7A), or as fold induction over APLP2-Gal4 alone (FIG.7B). Preliminary testing of galangin at 10 μM in this assay showed that it inhibits APP-Gal4 and APLP2-Gal4. Initial pharmacokinetic evaluation of these two bioflavonoids in brain uptake assay using NTg mice showed that Rutin does not have any brain levels at 10 mpk after a sc dose, while Galangin did show significant brain levels (40 ng/g at 1 h) thus enabling its evaluation for proof-of-concept studies in the transgenic (Tg) mouse model. Treatment of the Tg mice were done by sc route at 100 mpk over 5 days. Galangin was then evaluated for its effect on sAPPα, and Aβ40 and Aβ42 (see Example 1). The reduction of Aβ levels was very encouraging in this study. Further increase in brain levels of galangin was possible using a prodrug of galangin (see, e.g.,FIG.1). The examples provided herein indicate that certain bioflavanoids have the ability to bind APP and inhibit the BACE cleavage of APP and APLP2 thus suggest that they are APP specific BACE inhibitors. These molecules represent a new class of therapeutics for Alzheimer's disease that would be devoid of the potential toxicity from direct inhibition of BACE. Galangin was also shown to be effective in reducing Aβ40 and Aβ42 in the AD mouse model. While Rutin was not effective in the mouse model it is believed this is due to difficulty passing the blood brain barrier. However, this does not mean that rutin and derivatives or analogues thereof are unsuitable for use in the methods described herein. Numerous methods for transporting a molecule through the blood brain barrier and/or for circumventing the blood brain barrier are known to those of skill in the art. Typically mechanisms for drug targeting in the brain involve going either “through” or “behind” the BBB. In various embodiments modalities for drug delivery through the BBB entail its disruption by osmotic means; biochemically by the use of vasoactive substances such as bradykinin; or even by localized exposure to high-intensity focused ultrasound (HIFU) (see, e.g., McDannold et al. (2008) Ultrasound in Medicine and Biology, 34(5): 834-840). Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters such as glucose and amino acid carriers; receptor-mediated transcytosis; and the blocking of active efflux transporters such as p-glycoprotein. Methods for drug delivery behind the BBB also include intracerebral implantation (such as with needles) and convection-enhanced distribution. In certain embodiments mMannitol can be used in bypassing the BBB. Nanoparticles can also help in the transfer of drugs across the BBB (see, e.g., Silva, (2008). BMC Neuroscience, 9:S4, and the like). In view of the discovery of ASBI activity in Galangin and Rutin, similar activity is believed to exist in a number of additional bioflavonoid analogues described herein. Particular ASBI activity of any of these analogues can readily be further confirmed using, for example, the assays described above and illustrated in the Examples provided herein. The sequential cleavage of APP by membrane-bound proteases β-secretase and γ-secretase results in the formation of Aβ. The β-Site APP cleavage enzyme-1 (BACE1) was identified as the major β-secretase activity that mediates the first cleavage of APP in the β-amyloidogenic pathway. In view of the ability of the ASBI compounds described herein to specifically block BACE1 activity at APP, it is believed (and the data presented herein show) that these ASBI compounds can lower Aβ levels or prevent the formation of the neurotoxic Aβ species. Accordingly, these compounds are believed to prevent or slow the progression of the disease and/or to prevent or slow the progression of pre-clinical manifestations of the amyloidogenic disease pathway. Accordingly it is believed that these agents can be used to prevent or delay the onset of a pre-Alzheimer's cognitive dysfunction, and/or to ameliorate one or more symptoms of a pre-Alzheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, and/or to promote the processing of amyloid precursor protein (APP) by the non-amyloidogenic pathway. In certain embodiments these agents can be used in the treatment of Alzheimer's disease (e.g., to lessen the severity of the disease, and/or to ameliorate one or more symptoms of the disease, and/or to slow the progression of the disease). Therapeutic and Prophylactic Methods. In various embodiments therapeutic and/or prophylactic methods are provided that utilize the active agent(s) (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) are provided. Typically the methods involve administering one or more active agent(s) to a subject (e.g., to a human in need thereof) in an amount sufficient to realize the desired therapeutic or prophylactic result. Prophylaxis In certain embodiments active agent(s) (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) are utilized in various prophylactic contexts. Thus, for example, ion certain embodiments, the active agent(s) can be used to prevent or delay the onset of a pre-Alzheimer's cognitive dysfunction, and/or to ameliorate one more symptoms of a pre-Alzheimer's condition and/or cognitive dysfunction, and/or to prevent or delaying the progression of a pre-Alzheimer's condition and/or cognitive dysfunction to Alzheimer's disease. Accordingly in certain embodiments, the prophylactic methods described herein are contemplated for subjects identified as “at risk” and/or as having evidence of early Alzheimer's Disease (AD) pathological changes, but who do not meet clinical criteria for MCI or dementia. Without being bound to a particular theory, it is believed that even this “preclinical” stage of the disease represents a continuum from completely asymptomatic individuals with biomarker evidence suggestive of AD-pathophysiological process(es) (abbreviated as AD-P, see, e.g., Sperling et. al. (2011) Alzheimer's & Dementia, 1-13) at risk for progression to AD dementia to biomarker-positive individuals who are already demonstrating very subtle decline but not yet meeting standardized criteria for MCI (see, e.g., Albert et al. (2011) Alzheimer's and Dementia, 1-10 (doi:10.1016/j.j-alz.2011.03.008). This latter group of individuals might be classified as “Not normal, not MCI” but would be can be designated “pre-symptomatic” or “pre-clinical or “asymptomatic” or “premanifest”). In various embodiments this continuum of pre-symptomatic AD can also encompass (1) individuals who carry one or more apolipoprotein E (APOE) ε4 alleles who are known or believed to have an increased risk of developing AD dementia, at the point they are AD-P biomarker-positive, and (2) carriers of autosomal dominant mutations, who are in the presymptomatic biomarker-positive stage of their illness, and who will almost certainly manifest clinical symptoms and progress to dementia. A biomarker model has been proposed in which the most widely validated biomarkers of AD-P become abnormal and likewise reach a ceiling in an ordered manner (see, e.g., Jack et al. (2010) Lancet Neurol., 9: 119-128). This biomarker model parallels proposed pathophysiological sequence of (pre-AD/AD), and is relevant to tracking the preclinical (asymptomatic) stages of AD (see, e.g.,FIG.3in Sperling et al. (2011) Alzheimer's & Dementia, 1-13). Biomarkers of brain amyloidosis include, but are not limited to reductions in CSF Aβ42and increased amyloid tracer retention on positron emission tomography (PET) imaging. Elevated CSF tau is not specific to AD and is thought to be a biomarker of neuronal injury. Decreased fluorodeoxyglucose 18F (FDG) uptake on PET with a temporoparietal pattern of hypometabolism is a biomarker of AD-related synaptic dysfunction. Brain atrophy on structural magnetic resonance imaging (MRI) in a characteristic pattern involving the medial temporal lobes, paralimbic and temporoparietal cortices is a biomarker of AD-related neurodegeneration. Other markers include, but are not limited to volumetric MRI, FDG-PET, or plasma biomarkers (see, e.g., Vemuri et al. (2009) Neurology, 73: 294-301; Yaffe et al. (2011) JAMA 305: 261-266). In certain embodiments the subjects suitable for the prophylactic methods contemplated herein include, but are not limited to subject characterized as having asymptomatic asymptomatic cerebral amyloidosis. In various embodiments these individuals have biomarker evidence of Aβ accumulation with elevated tracer retention on PET amyloid imaging and/or low Aβ42 in CSF assay, but typically no detectable evidence of additional brain alterations suggestive of neurodegeneration or subtle cognitive and/or behavioral symptomatology. It is noted that currently available CSF and PET imaging biomarkers of Aβ primarily provide evidence of amyloid accumulation and deposition of fibrillar forms of amyloid. Data suggest that soluble or oligomeric forms of Aβ are likely in equilibrium with plaques, which may serve as reservoirs. In certain embodiments it is contemplated that there is an identifiable preplaque stage in which only soluble forms of Aβ are present. In certain embodiments it is contemplated that oligomeric forms of amyloid may be critical in the pathological cascade, and provide useful markers. In addition, early synaptic changes may be present before evidence of amyloid accumulation. In certain embodiments the subjects suitable for the prophylactic methods contemplated herein include, but are not limited to, subjects characterized as amyloid positive with evidence of synaptic dysfunction and/or early neuro-degeneration. In various embodiments these subjects have evidence of amyloid positivity and presence of one or more markers of “downstream” AD-P-related neuronal injury. Illustrative, but non-limiting markers of neuronal injury include, but are not limited to (1) elevated CSF tau or phospho-tau, (2) hypometabolism in an AD-like pattern (i.e., posterior cingulate, precuneus, and/or temporoparietal cortices) on FDG-PET, and (3) cortical thinning/gray matter loss in a specific anatomic distribution (i.e., lateral and medial parietal, posterior cingulate, and lateral temporal cortices) and/or hippocampal atrophy on volumetric MRI. Other markers include, but are not limited to fMRI measures of default network connectivity. In certain embodiments early synaptic dysfunction, as assessed by functional imaging techniques such as FDG-PET and fMRI, can be detectable before volumetric loss. Without being bound to a particular theory, it is believed that amyloid-positive individuals with evidence of early neurodegeneration may be farther down the trajectory (i.e., in later stages of preclinical (asymptomatic) AD). In certain embodiments the subjects suitable for the prophylactic methods contemplated herein include, but are not limited to, subjects characterized as amyloid positive with evidence of neurodegeneration and subtle cognitive decline. Without being bound to a particular theory, it is believed that those individuals with biomarker evidence of amyloid accumulation, early neurodegeneration, and evidence of subtle cognitive decline are in the last stage of preclinical (asymptomatic) AD, and are approaching the border zone with clinical criteria for mild cognitive impairment (MCI). These individuals may demonstrate evidence of decline from their own baseline (particularly if proxies of cognitive reserve are taken into consideration), even if they still perform within the “normal” range on standard cognitive measures. Without being bound to a particular theory, it is believed that more sensitive cognitive measures, particularly with challenging episodic memory measures, may detect very subtle cognitive impairment in amyloid-positive individuals. In certain embodiments criteria include, but are not limited to, self-complaint of memory decline or other subtle neurobehavioral changes. As indicated above, subjects/patients amenable to prophylactic methods described herein include individuals at risk of disease (e.g., a pathology characterized by amyloid plaque formation such as MCI) but not showing symptoms, as well as subjects presently showing certain symptoms or markers. It is known that the risk of MCI and later Alzheimer's disease generally increases with age. Accordingly, in asymptomatic subjects with no other known risk factors, in certain embodiments, prophylactic application is contemplated for subjects over 50 years of age, or subjects over 55 years of age, or subjects over 60 years of age, or subjects over 65 years of age, or subjects over 70 years of age, or subjects over 75 years of age, or subjects over 80 years of age, in particular to prevent or slow the onset or ultimate severity of mild cognitive impairment (MCI), and/or to slow or prevent the progression from MCI to early stage Alzheimer's disease (AD). In certain embodiments, the methods described herein present methods are especially useful for individuals who do have a known genetic risk of Alzheimer's disease (or other amyloidogenic pathologies), whether they are asymptomatic or showing symptoms of disease. Such individuals include those having relatives who have experienced MCI or AD (e.g., a parent, a grandparent, a sibling), and those whose risk is determined by analysis of genetic or biochemical markers. Genetic markers of risk toward Alzheimer's disease include, for example, mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations respectively (see Hardy (1997) Trends. Neurosci., 20: 154-159). Other markers of risk include mutations in the presenilin genes (PS1 and PS2), family history of AD, having the familial Alzheimer's disease (FAD) mutation, the APOE ε4 allele, hypercholesterolemia or atherosclerosis. Further susceptibility genes for the development of Alzheimer's disease are reviewed, e.g., in Sleegers, et al. (2010) Trends Genet. 26(2): 84-93. In some embodiments, the subject is asymptomatic but has familial and/or genetic risk factors for developing MCI or Alzheimer's disease. In asymptomatic patients, treatment can begin at any age (e.g., 20, 30, 40, 50 years of age). Usually, however, it is not necessary to begin treatment until a patient reaches at least about 40, 50, 60 or 70 years of age. In some embodiments, the subject is exhibiting symptoms, for example, of mild cognitive impairment (MCI) or Alzheimer's disease (AD). Individuals presently suffering from Alzheimer's disease can be recognized from characteristic dementia, as well as the presence of risk factors described above. In addition, a number of diagnostic tests are available for identifying individuals who have AD. These include measurement of CSF Tau, phospho-tau (pTau), Aβ42 levels and C-terminally cleaved APP fragment (APPneo). Elevated total-Tau (tTau), phospho-Tau (pTau), APPneo, soluble Aβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and decreased Aβ42 levels, Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα levels, sAPP≢/sAPPβ ratio, sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio signify the presence of AD. In some embodiments, the subject or patient is diagnosed as having MCI. Increased levels of neural thread protein (NTP) in urine and/or increased levels of α2-macroglobulin (α2M) and/or complement factor H (CFH) in plasma are also biomarkers of MCI and/or AD (see, e.g., Anoop et al. (2010) Int. J. Alzheimer's Dis. 2010:606802). In certain embodiments, subjects amenable to treatment may have age-associated memory impairment (AAMI), or mild cognitive impairment (MCI). The methods described herein are particularly well-suited to the prophylaxis and/or treatment of MCI. In such instances, the methods can delay or prevent the onset of MCI, and or reduce one or more symptoms characteristic of MCI and/or delay or prevent the progression from MCI to early-, mid- or late-stage Alzheimer's disease or reduce the ultimate severity of the disease. Mild Cognitive Impairment (MCI) Mild cognitive impairment (MCI, also known as incipient dementia, or isolated memory impairment) is a diagnosis given to individuals who have cognitive impairments beyond that expected for their age and education, but that typically do not interfere significantly with their daily activities (see, e.g., Petersen et al. (1999) Arch. Neurol. 56(3): 303-308). It is considered in many instances to be a boundary or transitional stage between normal aging and dementia. Although MCI can present with a variety of symptoms, when memory loss is the predominant symptom it is termed “amnestic MCI” and is frequently seen as a risk factor for Alzheimer's disease (see, e.g., Grundman et al. (2004) Arch. Neurol. 61(1): 59-66; and on the internet at en.wikipedia.org/wiki/Mild_cognitive_impairment-cite_note-Grundman-1). When individuals have impairments in domains other than memory it is often classified as non-amnestic single- or multiple-domain MCI and these individuals are believed to be more likely to convert to other dementias (e.g. dementia with Lewy bodies). There is evidence suggesting that while amnestic MCI patients may not meet neuropathologic criteria for Alzheimer's disease, patients may be in a transitional stage of evolving Alzheimer's disease; patients in this hypothesized transitional stage demonstrated diffuse amyloid in the neocortex and frequent neurofibrillary tangles in the medial temporal lobe (see, e.g., Petersen et al. (2006) Arch. Neurol. 63(5): 665-72). The diagnosis of MCI typically involves a comprehensive clinical assessment including clinical observation, neuroimaging, blood tests and neuropsychological testing. In certain embodiments diagnostic criteria for MIC include, but are not limited to those described by Albert et al. (2011) Alzheimer's & Dementia. 1-10. As described therein, diagnostic criteria include (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebro-spinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. In certain embodiments clinical evaluation/diagnosis of MCI involves: (1) Concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time); (2) Objective evidence of Impairment in one or more cognitive domains, typically including memory (i.e., formal or bedside testing to establish level of cognitive function in multiple domains); (3) Preservation of independence in functional abilities; (4) Not demented; and in certain embodiments, (5) An etiology of MCI consistent with AD pathophysiological processes. Typically vascular, traumatic, medical causes of cognitive decline, are ruled out where possible. In certain embodiments, evidence of longitudinal decline in cognition is identified, when feasible. Diagnosis is reinforced by a history consistent with AD genetic factors, where relevant. With respect to impairment in cognitive domain(s), there should be evidence of concern about a change in cognition, in comparison with the person's previous level. There should be evidence of lower performance in one or more cognitive domains that is greater than would be expected for the patient's age and educational background. If repeated assessments are available, then a decline in performance should be evident over time. This change can occur in a variety of cognitive domains, including memory, executive function, attention, language, and visuospatial skills. An impairment in episodic memory (i.e., the ability to learn and retain new information) is seen most commonly in MCI patients who subsequently progress to a diagnosis of AD dementia. With respect to preservation of independence in functional abilities, it is noted that persons with MCI commonly have mild problems performing complex functional tasks which they used to perform shopping. They may take more time, be less efficient, and make more errors at performing such activities than in the past. Nevertheless, they generally maintain their independence of function in daily life, with minimal aids or assistance. With respect to dementia, the cognitive changes should be sufficiently mild that there is no evidence of a significant impairment in social or occupational functioning. If an individual has only been evaluated once, change will be inferred from the history and/or evidence that cognitive performance is impaired beyond what would have been expected for that individual. Cognitive testing is optimal for objectively assessing the degree of cognitive impairment for an individual. Scores on cognitive tests for individuals with MCI are typically 1 to 1.5 standard deviations below the mean for their age and education matched peers on culturally appropriate normative data (i.e., for the impaired domain(s), when available). Episodic memory (i.e., the ability to learn and retain new information) is most commonly seen in MCI patients who subsequently progress to a diagnosis of AD dementia. There are a variety of episodic memory tests that are useful for identifying those MCI patients who have a high likelihood of progressing to AD dementia within a few years. These tests typically assess both immediate and delayed recall, so that it is possible to determine retention over a delay. Many, although not all, of the tests that have proven useful in this regard are wordlist learning tests with multiple trials. Such tests reveal the rate of learning over time, as well as the maximum amount acquired over the course of the learning trials. They are also useful for demonstrating that the individual is, in fact, paying attention to the task on immediate recall, which then can be used as a baseline to assess the relative amount of material retained on delayed recall. Examples of such tests include (but are not limited to: the Free and Cued Selective Reminding Test, the Rey Auditory Verbal Learning Test, and the California Verbal Learning Test. Other episodic memory measures include, but are not limited to: immediate and delayed recall of a paragraph such as the Logical Memory I and II of the Wechsler Memory Scale Revised (or other versions) and immediate and delayed recall of nonverbal materials, such as the Visual Reproduction subtests of the Wechsler Memory Scale-Revised I and II. Because other cognitive domains can be impaired among individuals with MCI, it is desirable to examine domains in addition to memory. These include, but are not limited to executive functions (e.g., set-shifting, reasoning, problem-solving, planning), language (e.g., naming, fluency, expressive speech, and comprehension), visuospatial skills, and attentional control (e.g., simple and divided attention). Many clinical neuropsychological measures are available to assess these cognitive domains, including (but not limited to the Trail Making Test (executive function), the Boston Naming Test, letter and category fluency (language), figure copying (spatial skills), and digit span forward (attention). As indicated above, genetic factors can be incorporated into the diagnosis of MCI. If an autosomal dominant form of AD is known to be present (i.e., mutation in APP, PS1, PS2), then the development of MCI is most likely the predursor to AD dementia. The large majority of these cases develop early onset AD (i.e., onset below 65 years of age). In addition, there are genetic influences on the development of late onset AD dementia. For example, the presence of one or two 84 alleles in the apolipoprotein E (APOE) gene is a genetic variant broadly accepted as increasing risk for late-onset AD dementia. Evidence suggests that an individual who meets the clinical, cognitive, and etiologic criteria for MCI, and is also APOE ε4 positive, is more likely to progress to AD dementia within a few years than an individual without this genetic characteristic. It is believed that additional genes play an important, but smaller role than APOE and also confer changes in risk for progression to AD dementia (see, e.g., Bertram et al. (2010) Neuron, 21: 270-281). In certain embodiments subjects suitable for the prophylactic methods described herein include, but need not be limited to subjects identified having one or more of the core clinical criteria described above and/or subjects identified with one or more “research criteria” for MCI, e.g., as described below. “Research criteria” for the identification/prognosis of MCI include, but are not limited to biomarkers that increase the likelihood that MCI syndrome is due to the pathophysiological processes of AD. Without being bound to a particular theory, it is believed that the conjoint application of clinical criteria and biomarkers can result in various levels of certainty that the MCI syndrome is due to AD pathophysiological processes. In certain embodiments, two categories of biomarkers have been the most studied and applied to clinical outcomes are contemplated. These include “Aβ” (which includes CSF Aβ42and/or PET amyloid imaging) and “biomarkers of neuronal injury” (which include, but are not limited to CSF tau/p-tau, hippocampal, or medial temporal lobe atrophy on MRI, and temporoparietal/precuneus hypometabolism or hypoperfusion on PET or SPECT). Without being bound to a particular theory, it is believed that evidence of both Aβ, and neuronal injury (either an increase in tau/p-tau or imaging biomarkers in a topographical pattern characteristic of AD), together confers the highest probability that the AD pathophysiological process is present. Conversely, if these biomarkers are negative, this may provide information concerning the likelihood of an alternate diagnosis. It is recognized that biomarker findings may be contradictory and accordingly any biomarker combination is indicative (an indicator) used on the context of a differential diagnosis and not itself dispositive. It is recognized that varying severities of an abnormality may confer different likelihoods or prognoses, that are difficult to quantify accurately for broad application. For those potential MCI subjects whose clinical and cognitive MCI syndrome is consistent with AD as the etiology, the addition of biomarker analysis effects levels of certainty in the diagnosis. In the most typical example in which the clinical and cognitive syndrome of MCI has been established, including evidence of an episodic memory disorder and a presumed degenerative etiology, the most likely cause is the neurodegenerative process of AD. However, the eventual outcome still has variable degrees of certainty. The likelihood of progression to AD dementia will vary with the severity of the cognitive decline and the nature of the evidence suggesting that AD pathophysiology is the underlying cause. Without being bound to a particular theory it is believed that positive biomarkers reflecting neuronal injury increase the likelihood that progression to dementia will occur within a few years and that positive findings reflecting both Ab accumulation and neuronal injury together confer the highest likelihood that the diagnosis is MCI due to AD. A positive Aβ biomarker and a positive biomarker of neuronal injury provide an indication that the MCI syndrome is due to AD processes and the subject is well suited for the methods described herein. A positive Aβ biomarker in a situation in which neuronal injury biomarkers have not been or cannot be tested or a positive biomarker of neuronal injury in a situation in which Aβ biomarkers have not been or cannot be tested indicate an intermediate likelihood that the MCI syndrome is due to AD. Such subjects are believed to be is well suited for the methods described herein Negative biomarkers for both Aβ and neuronal injury suggest that the MCI syndrome is not due to AD. In such instances the subjects may not be well suited for the methods described herein. There is evidence that magnetic resonance imaging can observe deterioration, including progressive loss of gray matter in the brain, from mild cognitive impairment to full-blown Alzheimer disease (see, e.g., Whitwell et al. (2008) Neurology 70(7): 512-520). A technique known as PiB PET imaging is used to clearly show the sites and shapes of beta amyloid deposits in living subjects using a C11 tracer that binds selectively to such deposits (see, e.g., Jack et al. (2008) Brain 131 (Pt 3): 665-680). In certain embodiments, MCI is typically diagnosed when there is 1) Evidence of memory impairment; 2) Preservation of general cognitive and functional abilities; and 3) Absence of diagnosed dementia. In certain embodiments MCI and stages of Alzheimer's disease can be identified/categorized, in part by Clinical Dementia Rating (CDR) scores. The CDR is a five point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. The necessary information to make each rating is obtained through a semi-structured interview of the patient and a reliable informant or collateral source (e.g., family member). The CDR table provides descriptive anchors that guide the clinician in making appropriate ratings based on interview data and clinical judgment. In addition to ratings for each domain, an overall CDR score may be calculated through the use of an algorithm. This score is useful for characterizing and tracking a patient's level of impairment/dementia: 0=Normal; 0.5=Very Mild Dementia; 1=Mild Dementia; 2=Moderate Dementia; and 3=Severe Dementia. An illustrative CDR table is shown in Table 1. TABLE 1Illustrative clinical dementia rating (CDR) table.Impairment:NoneQuestionableMildModerateSevereCDR:00.5123MemoryNo memoryConsistentModerateSevereSevereloss or slightslightmemory loss;memorymemoryinconsistentforgetfulness;more markedloss; onlyloss; onlyforgetfulnesspartialfor recenthighlyfragmentsrecollectionevents; defectlearnedremainof events'interferesmaterial“benign”withretained;forgetfulnesseverydaynew materialactivitiesrapidly lostOrientationFullyFullyModerateSevereOriented toorientedorienteddifficultydifficultyperson onlyexcept forwith timewith timeslightrelationships;relationships;difficultyoriented forusuallywith timeplace atdisorientedrelationshipsexamination;to time, oftenmay haveto place.geographicdisorientationelsewhereJudgment &SolvesSlightModerateSeverelyUnable toProblemeverydayimpairmentdifficulty inimpaired inmakeSolvingproblems &in solvinghandlinghandlingjudgmentshandlesproblems,problems,problems,or solvebusiness &similarities,similaritiessimilaritiesproblemsfinancialandandandaffairs well;differencesdifferences;differences;judgmentsocialsocialgood injudgmentjudgmentrelation tousuallyusuallypastmaintainedimpairedperformanceCommunityIndependentSlightUnable toNo pretense of independentAffairsfunction atimpairmentfunctionfunction outside of homeusual levelin theseindependentlyAppears wellAppears tooin job,activitiesat theseenough to beill to beshopping,activitiestaken totaken tovolunteer,although mayfunctionsfunctionsand socialstill beoutside aoutside agroupsengaged infamily homefamilysome;home.appearsnormal tocasualinspectionHome andLife atLife at home,Mild bitOnly simpleNoHobbieshome,hobbies, anddefinitechoressignificanthobbies, andintellectualimpairmentpreserved;function inintellectualinterestsof function atveryhomeinterestsslightlyhome; morerestrictedwellimpaireddifficultinterests,maintainedchorespoorlyabandoned;maintainedmorecomplicatedhobbies andinterestsabandonedPersonalFully capable of self-careNeedsRequiresRequiresCarepromptingassistance inmuch helpdressing,withhygiene,personalkeeping ofcare;personalfrequenteffectsincontinence A CDR rating of ˜0.5 or ˜0.5 to 1.0 is often considered clinically relevant MCI. Higher CDR ratings can be indicative of progression into Alzheimer's disease. In certain embodiments administration of one or more agents described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) is deemed effective when there is a reduction in the CSF of levels of one or more components selected from the group consisting of Tau, phospho-Tau (pTau), APPneo, soluble Aβ40, soluble Aβ42, and/or Aβ42/Aβ40 ratio, and/or when there is a reduction of the plaque load in the brain of the subject, and/or when there is a reduction in the rate of plaque formation in the brain of the subject, and/or when there is an improvement in the cognitive abilities of the subject, and/or when there is a perceived improvement in quality of life by the subject, and/or when there is a significant reduction in clinical dementia rating (CDR), and/or when the rate of increase in clinical dementia rating is slowed or stopped and/or when the progression from MCI to early stage AD is slowed or stopped. In some embodiments, a diagnosis of MCI can be determined by considering the results of several clinical tests. For example, Grundman, et al., Arch Neurol (2004) 61:59-66, report that a diagnosis of MCI can be established with clinical efficiency using a simple memory test (paragraph recall) to establish an objective memory deficit, a measure of general cognition (Mini-Mental State Exam (MMSE), discussed in greater detail below) to exclude a broader cognitive decline beyond memory, and a structured clinical interview (CDR) with patients and caregivers to verify the patient's memory complaint and memory loss and to ensure that the patient was not demented. Patients with MCI perform, on average, less than 1 standard deviation (SD) below normal on nonmemorycognitive measures included in the battery. Tests of learning, attention, perceptual speed, category fluency, and executive function may be impaired in patients with MCI, but these are far less prominent than the memory deficit. Alzheimer's Disease (AD). In certain embodiments the active agent(s) (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) and/or formulations thereof are contemplated for the treatment of Alzheimer's disease. In such instances the methods described herein are useful in preventing or slowing the onset of Alzheimer's disease (AD), in reducing the severity of AD when the subject has transitioned to clinical AD diagnosis, and/or in mitigating one or more symptoms of Alzheimer's disease. In particular, where the Alzheimer's disease is early stage, the methods can reduce or eliminate one or more symptoms characteristic of AD and/or delay or prevent the progression from MCI to early or later stage Alzheimer's disease. Individuals presently suffering from Alzheimer's disease can be recognized from characteristic dementia, as well as the presence of risk factors described above. In addition, a number of diagnostic tests are available for identifying individuals who have AD. Individuals presently suffering from Alzheimer's disease can be recognized from characteristic dementia, as well as the presence of risk factors described above. In addition, a number of diagnostic tests are available for identifying individuals who have AD. These include measurement of CSF Tau, phospho-tau (pTau), sAPPα, sAPPβ, Aβ40, Aβ42 levels and/or C terminally cleaved APP fragment (APPneo). Elevated Tau, pTau, sAPPβ and/or APPneo, and/or decreased sAPPα, soluble Aβ40 and/or soluble Aβ42 levels, particularly in the context of a differential diagnosis, can signify the presence of AD. In certain embodiments subjects amenable to treatment may have Alzheimer's disease. Individuals suffering from Alzheimer's disease can also be diagnosed by Alzheimer's disease and Related Disorders Association (ADRDA) criteria. The NINCDS-ADRDA Alzheimer's Criteria were proposed in 1984 by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) and are among the most used in the diagnosis of Alzheimer's disease (AD). McKhann, et al. (1984) Neurology 34(7): 939-44. According to these criteria, the presence of cognitive impairment and a suspected dementia syndrome should be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. However, histopathologic confirmation (microscopic examination of brain tissue) is generally used for a dispositive diagnosis. The NINCDS-ADRDA Alzheimer's Criteria specify eight cognitive domains that may be impaired in AD: memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). These criteria have shown good reliability and validity. Baseline evaluations of patient function can made using classic psychometric measures, such as the Mini-Mental State Exam (MMSE) (Folstein et al. (1975) J. Psychiatric Research 12 (3): 189-198), and the Alzheimer's Disease Assessment Scale (ADAS), which is a comprehensive scale for evaluating patients with Alzheimer's Disease status and function (see, e.g., Rosen, et al. (1984) Am. J. Psychiatr., 141: 1356-1364). These psychometric scales provide a measure of progression of the Alzheimer's condition. Suitable qualitative life scales can also be used to monitor treatment. The extent of disease progression can be determined using a Mini-Mental State Exam (MMSE) (see, e.g., Folstein, et al. supra). Any score greater than or equal to 25 points (out of 30) is effectively normal (intact). Below this, scores can indicate severe (≤9 points), moderate (10-20 points) or mild (21-24 points) Alzheimer's disease. Alzheimer's disease can be broken down into various stages including: 1) Moderate cognitive decline (Mild or early-stage Alzheimer's disease), 2) Moderately severe cognitive decline (Moderate or mid-stage Alzheimer's disease), 3) Severe cognitive decline (Moderately severe or mid-stage Alzheimer's disease), and 4) Very severe cognitive decline (Severe or late-stage Alzheimer's disease) as shown in Table 2. TABLE 2Illustrative stages of Alzheimer's disease.Moderate Cognitive Decline (Mild or early stage AD)At this stage, a careful medical interview detects clear-cut deficienciesin the following areas:Decreased knowledge of recent events.Impaired ability to perform challenging mental arithmetic. For example,to count backward from 100 by 7 s.Decreased capacity to perform complex tasks, such as marketing,planning dinner for guests, or paying bills and managing finances.Reduced memory of personal history.The affected individual may seem subdued and withdrawn, especially insocially or mentally challenging situations.Moderately severe cognitive decline (Moderate or mid-stageAlzheimer's disease)Major gaps in memory and deficits in cognitive function emerge. Someassistance with day-to-day activities becomes essential. At this stage,individuals may:Be unable during a medical interview to recall such important details astheir current address, their telephone number, or the name of the collegeor high school from which they graduated.Become confused about where they are or about the date, day of theweek or season.Have trouble with less challenging mental arithmetic; for example,counting backward from 40 by 4 s or from 20 by 2 s.Need help choosing proper clothing for the season or the occasion.Usually retain substantial knowledge about themselves and know theirown name and the names of their spouse or children.Usually require no assistance with eating or using the toilet.Severe cognitive decline (Moderately severe or mid-stage Alzheimer'sdisease)Memory difficulties continue to worsen, significant personality changesmay emerge, and affected individuals need extensive help with dailyactivities. At this stage, individuals may:Lose most awareness of recent experiences and events as well as of theirsurroundings.Recollect their personal history imperfectly, although they generallyrecall their own name.Occasionally forget the name of their spouse or primary caregiver butgenerally can distinguish familiar from unfamiliar faces.Need help getting dressed properly; without supervision, may makesuch errors as putting pajamas over daytime clothes or shoes onwrong feet.Experience disruption of their normal sleep/waking cycle.Need help with handling details of toileting (flushing toilet, wiping anddisposing of tissue properly).Have increasing episodes of urinary or fecal incontinence.Experience significant personality changes and behavioral symptoms,including suspiciousness and delusions (for example, believing that theircaregiver is an impostor); hallucinations (seeing or hearing things thatare not really there); or compulsive, repetitive behaviors such ashand-wringing or tissue shredding.Tend to wander and become lost.Very severe cognitive decline (Severe or late-stage Alzheimer's disease)This is the final stage of the disease when individuals lose the ability torespond to their environment, the ability to speak, and, ultimately, theability to control movement.Frequently individuals lose their capacity for recognizable speech,although words or phrases may occasionally be uttered.Individuals need help with eating and toileting and there is generalincontinence.Individuals lose the ability to walk without assistance, then the ability tosit without support, the ability to smile, and the ability to hold theirhead up.Reflexes become abnormal and muscles grow rigid. Swallowing isimpaired. In various embodiments administration of one or more agents described herein to subjects diagnosed with Alzheimer's disease is deemed effective when the there is a reduction in the CSF of levels of one or more components selected from the group consisting of Tau, phospho-Tau (pTau), APPneo, soluble Aβ40, soluble Aβ42, and/or and Aβ42/Aβ40 ratio, and/or when there is a reduction of the plaque load in the brain of the subject, and/or when there is a reduction in the rate of plaque formation in the brain of the subject, and/or when there is an improvement in the cognitive abilities of the subject, and/or when there is a perceived improvement in quality of life by the subject, and/or when there is a significant reduction in clinical dementia rating (CDR) of the subject, and/or when the rate of increase in clinical dementia rating is slowed or stopped and/or when the progression of AD is slowed or stopped (e.g., when the transition from one stage to another as listed in Table 3 is slowed or stopped). In certain embodiments Subjects amenable to the present methods generally are free of a neurological disease or disorder other than Alzheimer's disease. For example, in certain embodiments, the subject does not have and is not at risk of developing a neurological disease or disorder such as Parkinson's disease, and/or schizophrenia, and/or psychosis. Active Agent(s). The methods described herein are based, in part, on the discovery that administration of one or more active agents e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof find use in the treatment and/or prophylaxis of diseases characterized by amyloid deposits in the brain, for example, mild cognitive impairment, Alzheimer's disease, macular degeneration, and the like. Bioflavanoids. In certain embodiments the active agent(s) used in the methods described herein comprise a flavanoid such as galangin or rutin or a derivative and/or analogue thereof. In certain embodiments the flavonoid is characterized by Formula I: where R1is selected from the group consisting of OH, O-saccaharide, O-alkyl, O-trifluoromethyl, O-aryl, O-heteroaryl; R4and R5are independently selected from the group consisting of H, OH, NH2, O-alkyl, O-trifluoromethyl, S-alkyl, S-aryl, carboxylate, halogen, NH-alkyl, N,N-dialkyl, NHCO-alkyl, and heteroaryl, alkyl urea, and carbamate; and R2and R3are independently selected from the group consisting of H, OH, NH2, O-alkyl, O-trifluoromethyl, S-alkyl, S-aryl, carboxylate, halogen, NH-alkyl, N,N-dialkyl, NHCO-alkyl, heteroaryl, alkyl urea, and carbamate. In certain embodiments R2and/or R3is OH. In certain embodiments R2is OH and R3is OH. In certain embodiments R2and/or R3are independently selected from the group consisting of O-alkyl, S-alkyl, NH-alkyl and NHCO-alkyl. In certain embodiments the alkyl component of the O-alkyl, S-alkyl, NH-alkyl and NHCO-alkyl is a C1-2alkyl, or a C1-9alkyl, or a C1-6alkyl, or a C1-3alkyl. In certain embodiments R2and/or R3is halogen. In certain embodiments R2is halogen and R3is halogen. In certain embodiments R2and/or R3are independently selected from the group consisting of Cl, Br, Fl, and I. In certain embodiments R2and/or R3is selected from the group consisting of S-aryl and heteroaryl. In certain embodiments R2and R3are independently selected S-aryl. In certain embodiments R2and R3are independently selected heteroaryl. In certain embodiments R4and/or R5is OH. In certain embodiments R4is H and R5is OH or R4is OH and R5is H. In certain embodiments R4is OH and R5is OH. In certain embodiments R4and/or R5is H. In certain embodiments R4is H and R5is H. In certain embodiments when R4and/or R5is OH, R1is O-Saccharide. In certain embodiments R4and/or R5are independently selected from the group consisting of O-alkyl, S-alkyl, NH-alkyl and NHCO-alkyl. In certain embodiments R4and R5are independently selected from the group consisting of O-alkyl, S-alkyl, NH-alkyl and NHCO-alkyl. In certain embodiments the alkyl component of said O-alkyl, S-alkyl, NH-alkyl and NHCO-alkyl is a C1-12alkyl, or a C1-9alkyl, or a C1-6alkyl, or a C1-3alkyl. In certain embodiments R4and/or R5is halogen. In certain embodiments R4is halogen and R5is halogen. In certain embodiments R4and/or R5are independently selected from the group consisting of Cl, Br, Fl, and I. In certain embodiments R4and/or R5is selected from the group consisting of S-aryl and heter In certain embodiments R4and R5are independently selected heteroaryl. In certain embodiments R1is O-Saccharide (e.g., O-monosaccharide, O-disaccharide, O-trisaccharide, etc.). In certain embodiments R1is O-alkyl, O-trifluoromethyl, O-aryl, or O-heteroaryl. In certain embodiments the APP specific BACE inhibitor is galangin or a derivative thereof. In certain embodiments APP specific BACE inhibitor is rutin or a derivative thereof. Methods of making galangin and/or rutin and/or the various derivatives thereof contemplated herein are known to those of skill in the art. Both galangin and rutin are commercially available as are certain derivatives. These compounds can be further functionalized to prepare the various derivatives and analogues described herein using methods well known to those of skill in the art. For example the procedure described in example 2 would be used in the synthesis of analogs using various commercially available Dihydroxy-2-phenyl-4H-chromen-4-ones. The cobversion to the acetoxy groups would be done as described in example 2. Treatment with dimethyldioxirane would used to convert to the 3-hydroxyflavone. Further hydrolysis with mild base can be done to remove the acetoxy protecting groups, the crude mixture of the flavone derivatives can be purified by flash chromatography and recrystallisation to obtain the desired flavone analogs. Flavanoid Prodrugs. In certain embodiments it is contemplated that the various flavonoids described herein can be provided as flavonoid prodrugs. Illustrative galangin prodrugs are shown inFIG.2. In certain embodiments the prodrug is a galangin prodrug is characterized by Formula II: where R1, R2, and R3are H, or a protecting group that is removed in vivo in a mammal, wherein at least one of R1, R2, and R3is not H; and wherein said prodrug partially or completely inhibits BACE processing of APP when administered to a mammal. In certain embodiments at least one of R1, R2, and R3are independently selected from the group consisting of least one of R1, R2, and R3are independently selected from the group consisting of In certain embodiments R1is H. In certain embodiments R2is Group a, above and R3is Group a, b, c, d, or e, above. In certain embodiments R3is Group a, above and R2is Group a, b, c, d, or e, above. In certain embodiments, R2and R3are both group a above. In certain embodiments R1is H. In certain embodiments R2is Group b, above and R3i Group a, b, c, d, or e, above. In certain embodiments R3is Group b, above and R2is Group a, b, c, d, or e, above. In certain embodiments, R2and R3are both group b above. In certain embodiments R1is H. In certain embodiments R2is Group c, above and R3is Group a, b, c, d, or e, above. In certain embodiments R3is Group c, above and R2is Group a, b, c, d, or e, above. In certain embodiments, R2and R3are both group c above. In certain embodiments R1is H. In certain embodiments R2is Group d, above and R3is Group a, b, c, d, or e, above. In certain embodiments R3is Group d, above and R2is Group a, b, c, d, or e, above. In certain embodiments, R2and R3are both group d above. In certain embodiments R1is H. In certain embodiments R2is Group e, above and R3is Group a, b, c, d, or e, above. In certain embodiments R3is Group e, above and R2is Group a, b, c, d, or e, above. In certain embodiments, R2and R3are both group e above. Methods of preparing galangin prodrugs such as are described herein are known to those of skill in the art. One such protocol is illustrated in Example 2 (see synthesis scheme inFIG.11for the synthesis of compound 2. The various active agents and synthesis schemes are intended to be illustrative and not limiting. Using the teachings provided herein, numerous other flavonoid, flavonoid derivative, and flavonoid prodrug ASBI compounds can be synthesized and identified by one of skill in the art. Pharmaceutical Formulations. In certain embodiments one or more active agents described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) are administered to a mammal in need thereof, e.g., to a mammal at risk for or suffering from a pathology characterized by abnormal processing of amyloid precursor proteins, a mammal at risk for progression of MCI to Alzheimer's disease, and so forth. In certain embodiments the active agent(s) are administered to prevent or delay the onset of a pre-Alzheimer's condition and/or cognitive dysfunction, and/or to ameliorate one or more symptoms of a pre-Alzheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, and/or to promote the processing of amyloid precursor protein (APP) by a non-amyloidogenic pathway. The active agent(s) can be administered in the “native” form or, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method(s). Salts, esters, amides, prodrugs and other derivatives of the active agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. N.Y. Wiley-Interscience, and as described above. For example, a pharmaceutically acceptable salt can be prepared for any of the agent(s) described herein having a functionality capable of forming a salt. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered. In various embodiments pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, lithium, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Methods of formulating pharmaceutically active agents as salts, esters, amide, prodrugs, and the like are well known to those of skill in the art. For example, salts can be prepared from the free base using conventional methodology that typically involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or can be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include, but are not limited to both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt can be reconverted to the free base by treatment with a suitable base. Certain particularly preferred acid addition salts of the active agents herein include halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, preparation of basic salts of the active agents of this invention are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. Particularly preferred basic salts include alkali metal salts, e.g., the sodium salt, and copper salts. For the preparation of salt forms of basic drugs, the pKa of the counterion is preferably at least about 2 pH units lower than the pKa of the drug. Similarly, for the preparation of salt forms of acidic drugs, the pKa of the counterion is preferably at least about 2 pH units higher than the pKa of the drug. This permits the counterion to bring the solution's pH to a level lower than the pHmaxto reach the salt plateau, at which the solubility of salt prevails over the solubility of free acid or base. The generalized rule of difference in pKa units of the ionizable group in the active pharmaceutical ingredient (API) and in the acid or base is meant to make the proton transfer energetically favorable. When the pKa of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate (i.e., break down into the individual entities of drug and counterion) in an aqueous environment. Preferably, the counterion is a pharmaceutically acceptable counterion. Suitable anionic salt forms include, but are not limited to acetate, benzoate, benzylate, bitartrate, bromide, carbonate, chloride, citrate, edetate, edisylate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), phosphate and diphosphate, salicylate and disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide, valerate, and the like, while suitable cationic salt forms include, but are not limited to aluminum, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, zinc, and the like. Preparation of esters typically involves functionalization of hydroxyl and/or carboxyl groups that are present within the molecular structure of the active agent. In certain embodiments, the esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties that are derived from carboxylic acids of the formula RCOOH where R is alky, and preferably is lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. Amides can also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. In various embodiments, the active agents identified herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) are useful for parenteral administration, topical administration, oral administration, nasal administration (or otherwise inhaled), rectal administration, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment of one or more of the pathologies/indications described herein (e.g., pathologies characterized by excess amyloid plaque formation and/or deposition or undesired amyloid or pre-amyloid processing). The active agents described herein can also be combined with a pharmaceutically acceptable carrier (excipient) to form a pharmacological composition. Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s). Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, protection and uptake enhancers such as lipids, compositions that reduce the clearance or hydrolysis of the active agents, or excipients or other stabilizers and/or buffers. Other physiologically acceptable compounds, particularly of use in the preparation of tablets, capsules, gel caps, and the like include, but are not limited to binders, diluent/fillers, disentegrants, lubricants, suspending agents, and the like. In certain embodiments, to manufacture an oral dosage form (e.g., a tablet), an excipient (e.g., lactose, sucrose, starch, mannitol, etc.), an optional disintegrator (e.g. calcium carbonate, carboxymethylcellulose calcium, sodium starch glycollate, crospovidone etc.), a binder (e.g. alpha-starch, gum arabic, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, cyclodextrin, etc.), and an optional lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000, etc.), for instance, are added to the active component or components (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) and the resulting composition is compressed. Where necessary the compressed product is coated, e.g., using known methods for masking the taste or for enteric dissolution or sustained release. Suitable coating materials include, but are not limited to ethyl-cellulose, hydroxymethylcellulose, POLYOX®yethylene glycol, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and Eudragit (Rohm & Haas, Germany; methacrylic-acrylic copolymer). Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. One skilled in the art would appreciate that the choice of pharmaceutically acceptable carrier(s), including a physiologically acceptable compound depends, for example, on the route of administration of the active agent(s) and on the particular physio-chemical characteristics of the active agent(s). In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, mucoadherent films, topical varnishes, lipid complexes, etc. Pharmaceutical compositions comprising the active agents described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries that facilitate processing of the active agent(s) into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. In certain embodiments, the active agents described herein are formulated for oral administration. For oral administration, suitable formulations can be readily formulated by combining the active agent(s) with pharmaceutically acceptable carriers suitable for oral delivery well known in the art. Such carriers enable the active agent(s) described herein to be formulated as tablets, pills, dragees, caplets, lizenges, gelcaps, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. For oral solid formulations such as, for example, powders, capsules and tablets, suitable excipients can include fillers such as sugars (e.g., lactose, sucrose, mannitol and sorbitol), cellulose preparations (e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose), synthetic poymers (e.g., polyvinylpyrrolidone (PVP)), granulating agents; and binding agents. If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques. The preparation of enteric-coated particles is disclosed for example in U.S. Pat. Nos. 4,786,505 and 4,853,230. For administration by inhalation, the active agent(s) are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. In various embodiments the active agent(s) can be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Methods of formulating active agents for rectal or vaginal delivery are well known to those of skill in the art (see, e.g., Allen (2007) Suppositories, Pharmaceutical Press) and typically involve combining the active agents with a suitable base (e.g., hydrophilic (PEG), lipophilic materials suc as cocoa butter or Witepsol W45), amphiphilic materials such as Suppocire AP and polyglycolized glyceride, and the like). The base is selected and compounded for a desired melting/delivery profile. For topical administration the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) can be formulated as solutions, gels, ointments, creams, suspensions, and the like as are well-known in the art. In certain embodiments the active agents described herein are formulated for systemic administration (e.g., as an injectable) in accordance with standard methods well known to those of skill in the art. Systemic formulations include, but are not limited to, those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. For injection, the active agents described herein can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer and/or in certain emulsion formulations. The solution(s) can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In certain embodiments the active agent(s) can be provided in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. For transmucosal administration, and/or for blood/brain barrier passage, penetrants appropriate to the barrier to be permeated can be used in the formulation. Such penetrants are generally known in the art. Injectable formulations and inhalable formulations are generally provided as a sterile or substantially sterile formulation. In addition to the formulations described previously, the active agent(s) may also be formulated as a depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the active agent(s) may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. In certain embodiments the active agent(s) described herein can also be delivered through the skin using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the active agent(s) are typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. It will be appreciated that the term “reservoir” in this context refers to a quantity of “active ingredient(s)” that is ultimately available for delivery to the surface of the skin. Thus, for example, the “reservoir” may include the active ingredient(s) in an adhesive on a backing layer of the patch, or in any of a variety of different matrix formulations known to those of skill in the art. The patch may contain a single reservoir, or it may contain multiple reservoirs. In one illustrative embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. The backing layer in these laminates, which serves as the upper surface of the device, preferably functions as a primary structural element of the “patch” and provides the device with much of its flexibility. The material selected for the backing layer is preferably substantially impermeable to the active agent(s) and any other materials that are present. Alternatively, other pharmaceutical delivery systems can be employed. For example, liposomes, emulsions, and microemulsions/nanoemulsions are well known examples of delivery vehicles that may be used to protect and deliver pharmaceutically active compounds. Certain organic solvents such as dimethylsulfoxide also can be employed, although usually at the cost of greater toxicity. In certain embodiments the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) are formulated in a nanoemulsion. Nanoemulsions include, but are not limited to oil in water (O/W) nanoemulsions, and water in oil (W/O) nanoemulsions. Nanoemulsions can be defined as emulsions with mean droplet diameters ranging from about 20 to about 1000 nm. Usually, the average droplet size is between about 20 nm or 50 nm and about 500 nm. The terms sub-micron emulsion (SME) and miniemulsion are used as synonyms. Illustrative oil in water (O/W) nanoemulsions include, but are not limited to: Surfactant micelles—micelles composed of small molecules surfactants or detergents (e.g., SDS/PBS/2-propanol); Polymer micelles—micelles composed of polymer, copolymer, or block copolymer surfactants (e.g., Pluronic L64/PBS/2-propanol); Blended micelles—micelles in which there is more than one surfactant component or in which one of the liquid phases (generally an alcohol or fatty acid compound) participates in the formation of the micelle (e.g., octanoic acid/PBS/EtOH); Integral micelles—blended micelles in which the active agent(s) serve as an auxiliary surfactant, forming an integral part of the micelle; and Pickering (solid phase) emulsions—emulsions in which the active agent(s) are associated with the exterior of a solid nanoparticle (e.g., polystyrene nanoparticles/PBS/no oil phase). Illustrative water in oil (W/O) nanoemulsions include, but are not limited to: Surfactant micelles—micelles composed of small molecules surfactants or detergents (e.g., dioctyl sulfosuccinate/PBS/2-propanol, isopropylmyristate/PBS/2-propanol, etc.); Polymer micelles—micelles composed of polymer, copolymer, or block copolymer surfactants (e.g., PLURONIC® L121/PBS/2-propanol); Blended micelles—micelles in which there is more than one surfactant component or in which one of the liquid phases (generally an alcohol or fatty acid compound) participates in the formation of the micelle (e.g., capric/caprylic diglyceride/PBS/EtOH); Integral micelles—blended micelles in which the active agent(s) serve as an auxiliary surfactant, forming an integral part of the micelle (e.g., active agent/PBS/polypropylene glycol); and Pickering (solid phase) emulsions—emulsions in which the active agent(s) are associated with the exterior of a solid nanoparticle (e.g., chitosan nanoparticles/no aqueous phase/mineral oil). As indicated above, in certain embodiments the nanoemulsions comprise one or more surfactants or detergents. In some embodiments the surfactant is a non-anionic detergent (e.g., a polysorbate surfactant, a polyoxyethylene ether, etc.). Surfactants that find use in the present invention include, but are not limited to surfactants such as the TWEEN®, TRITON®, and TYLOXAPOL® families of compounds. In certain embodiments the emulsions further comprise one or more cationic halogen containing compounds, including but not limited to, cetylpyridinium chloride. In still further embodiments, the compositions further comprise one or more compounds that increase the interaction (“interaction enhancers”) of the composition with microorganisms (e.g., chelating agents like ethylenediaminetetraacetic acid, or ethylenebis(oxyethylenenitrilo)tetraacetic acid in a buffer). In some embodiments, the nanoemulsion further comprises an emulsifying agent to aid in the formation of the emulsion. Emulsifying agents include compounds that aggregate at the oil/water interface to form a kind of continuous membrane that prevents direct contact between two adjacent droplets. Certain embodiments of the present invention feature oil-in-water emulsion compositions that may readily be diluted with water to a desired concentration without impairing their anti-pathogenic properties. In addition to discrete oil droplets dispersed in an aqueous phase, certain oil-in-water emulsions can also contain other lipid structures, such as small lipid vesicles (e.g., lipid spheres that often consist of several substantially concentric lipid bilayers separated from each other by layers of aqueous phase), micelles (e.g., amphiphilic molecules in small clusters of 50-200 molecules arranged so that the polar head groups face outward toward the aqueous phase and the apolar tails are sequestered inward away from the aqueous phase), or lamellar phases (lipid dispersions in which each particle consists of parallel amphiphilic bilayers separated by thin films of water). These lipid structures are formed as a result of hydrophobic forces that drive apolar residues (e.g., long hydrocarbon chains) away from water. The above lipid preparations can generally be described as surfactant lipid preparations (SLPs). SLPs are minimally toxic to mucous membranes and are believed to be metabolized within the small intestine (see e.g., Hamouda et al., (1998) J. Infect. Disease 180: 1939). In certain embodiments the emulsion comprises a discontinuous oil phase distributed in an aqueous phase, a first component comprising an alcohol and/or glycerol, and a second component comprising a surfactant or a halogen-containing compound. The aqueous phase can comprise any type of aqueous phase including, but not limited to, water (e.g., dionized water, distilled water, tap water) and solutions (e.g., phosphate buffered saline solution or other buffer systems). The oil phase can comprise any type of oil including, but not limited to, plant oils (e.g., soybean oil, avocado oil, flaxseed oil, coconut oil, cottonseed oil, squalene oil, olive oil, canola oil, corn oil, rapeseed oil, safflower oil, and sunflower oil), animal oils (e.g., fish oil), flavor oil, water insoluble vitamins, mineral oil, and motor oil. In certain embodiments, the oil phase comprises 30-90 vol % of the oil-in-water emulsion (i.e., constitutes 30-90% of the total volume of the final emulsion), more preferably 50-80%. The formulations need no be limited to particular surfactants, however in certain embodiments, the surfactant is a polysorbate surfactant (e.g., TWEEN 20®, TWEEN 40®, TWEEN 60®, and TWEEN 80®), a pheoxypolyethoxyethanol (e.g., TRITON® X-100, X-301, X-165, X-102, and X-200, and TYLOXAPOL®), or sodium dodecyl sulfate, and the like. In certain embodiments a halogen-containing component is present. the nature of the halogen-containing compound, in some preferred embodiments the halogen-containing compound comprises a chloride salt (e.g., NaCl, KCl, etc.), a cetylpyridinium halide, a cetyltrimethylammonium halide, a cetyldimethylethylammonium halide, a cetyldimethylbenzylammonium halide, a cetyltributylphosphonium halide, dodecyltrimethylammonium halides, tetradecyltrimethylammonium halides, cetylpyridinium chloride, cetyltrimethylammonium chloride, cetylbenzyldimethylammonium chloride, cetylpyridinium bromide, cetyltrimethylammonium bromide, cetyldimethylethylammonium bromide, cetyltributylphosphonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, and the like In certain embodiments the emulsion comprises a quaternary ammonium compound. Quaternary ammonium compounds include, but are not limited to, N-alkyldimethyl benzyl ammonium saccharinate, 1,3,5-Triazine-1,3,5(2H,4H,6H)-triethanol; 1-Decanaminium, N-decyl-N,N-dimethyl-, chloride (or) Didecyl dimethyl ammonium chloride; 2-(2-(p-(Diisobuyl)cresosxy)ethoxy)ethyl dimethyl benzyl ammonium chloride; 2-(2-(p-(Diisobutyl)phenoxy)ethoxy) ethyl dimethyl benzyl ammonium chloride; alkyl 1 or 3 benzyl-1-(2-hydroxethyl)-2-imidazolinium chloride; alkyl bis(2-hydroxyethyl)benzyl ammonium chloride; alkyl demethyl benzyl ammonium chloride; alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride (100% C12); alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride (50% C14, 40% C12, 10% C16); alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride (55% C14, 23% C12, 20% C16); alkyl dimethyl benzyl ammonium chloride; alkyl dimethyl benzyl ammonium chloride (100% C14); alkyl dimethyl benzyl ammonium chloride (100% C16); alkyl dimethyl benzyl ammonium chloride (41% C14, 28% C12); alkyl dimethyl benzyl ammonium chloride (47% C12, 18% C14); alkyl dimethyl benzyl ammonium chloride (55% C16, 20% C14); alkyl dimethyl benzyl ammonium chloride (58% C14, 28% C16); alkyl dimethyl benzyl ammonium chloride (60% C14, 25% C12); alkyl dimethyl benzyl ammonium chloride (61% C11, 23% C14); alkyl dimethyl benzyl ammonium chloride (61% C12, 23% C14); alkyl dimethyl benzyl ammonium chloride (65% C12, 25% C14); alkyl dimethyl benzyl ammonium chloride (67% C12, 24% C14); alkyl dimethyl benzyl ammonium chloride (67% C12, 25% C14); alkyl dimethyl benzyl ammonium chloride (90% C14, 5% C12); alkyl dimethyl benzyl ammonium chloride (93% C14, 4% C12); alkyl dimethyl benzyl ammonium chloride (95% C16, 5% C18); alkyl dimethyl benzyl ammonium chloride (and) didecyl dimethyl ammonium chloride; alkyl dimethyl benzyl ammonium chloride (as in fatty acids); alkyl dimethyl benzyl ammonium chloride (C12-C16); alkyl dimethyl benzyl ammonium chloride (C12-C18); alkyl dimethyl benzyl and dialkyl dimethyl ammonium chloride; alkyl dimethyl dimethybenzyl ammonium chloride; alkyl dimethyl ethyl ammonium bromide (90% C14, 5% C16, 5% C12); alkyl dimethyl ethyl ammonium bromide (mixed alkyl and alkenyl groups as in the fatty acids of soybean oil); alkyl dimethyl ethylbenzyl ammonium chloride; alkyl dimethyl ethylbenzyl ammonium chloride (60% C14); alkyl dimethyl isoproylbenzyl ammonium chloride (50% C12, 30% C14, 17% C16, 3% C18); alkyl trimethyl ammonium chloride (58% C18, 40% C16, 1% C14, 1% C12); alkyl trimethyl ammonium chloride (90% C18, 10% C16); alkyldimethyl (ethylbenzyl) ammonium chloride (C12-18); Di-(C8-10)alkyl dimethyl ammonium chlorides; dialkyl dimethyl ammonium chloride; dialkyl dimethyl ammonium chloride; dialkyl dimethyl ammonium chloride; dialkyl methyl benzyl ammonium chloride; didecyl dimethyl ammonium chloride; diisodecyl dimethyl ammonium chloride; dioctyl dimethyl ammonium chloride; dodecyl bis(2-hydroxyethyl) octyl hydrogen ammonium chloride; dodecyl dimethyl benzyl ammonium chloride; dodecylcarbamoyl methyl dimethyl benzyl ammonium chloride; heptadecyl hydroxyethylimidazolinium chloride; hexahydro-1,3,5-thris(2-hydroxyethyl)s-triazine; myristalkonium chloride (and) Quat RNIUM 14; N,N-Dimethyl-2-hydroxypropylammonium chloride polymer; n-alkyl dimethyl benzyl ammonium chloride; n-alkyl dimethyl ethylbenzyl ammonium chloride; n-tetradecyl dimethyl benzyl ammonium chloride monohydrate; octyl decyl dimethyl ammonium chloride; octyl dodecyl dimethyl ammonium chloride; octyphenoxyethoxyethyl dimethyl benzyl ammonium chloride; oxydiethylenebis (alkyl dimethyl ammonium chloride); quaternary ammonium compounds, dicoco alkyldimethyl, chloride; trimethoxysily propyl dimethyl octadecyl ammonium chloride; trimethoxysilyl quats, trimethyl dodecylbenzyl ammonium chloride; n-dodecyl dimethyl ethylbenzyl ammonium chloride; n-hexadecyl dimethyl benzyl ammonium chloride; n-tetradecyl dimethyl benzyl ammonium chloride; n-tetradecyl dimethyl ethylbenzyl ammonium chloride; and n-octadecyl dimethyl benzyl ammonium chloride. Nanoemulsion formulations and methods of making such are well known to those of skill in the art and described for example in U.S. Pat. Nos. 7,476,393, 7,468,402, 7,314,624, 6,998,426, 6,902,737, 6,689,371, 6,541,018, 6,464,990, 6,461,625, 6,419,946, 6,413,527, 6,375,960, 6,335,022, 6,274,150, 6,120,778, 6,039,936, 5,925,341, 5,753,241, 5,698,219, and 5,152,923 and in Fanun et al. (2009) Microemulsions: Properties and Applications (Surfactant Science), CRC Press, Boca Ratan Fl. In certain embodiments, one or more active agents described herein can be provided as a “concentrate”, e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water, alcohol, hydrogen peroxide, or other diluent. Extended Release (Sustained Release) Formulations. In certain embodiments “extended release” formulations of the active agent(s) described herein are contemplated. In various embodiments such extended release formulations are designed to avoid the high peak plasma levels of intravenous and conventional immediate release oral dosage forms. Illustrative sustained-release formulations include, for example, semipermeable matrices of solid polymers containing the therapeutic agent. Various uses of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization can be employed. In certain embodiments such “extended release” formulations utilize the mucosa and can independently control tablet disintegration (or erosion) and/or drug dissolution and release from the tablet over time to provide a safer delivery profile. In certain embodiments the oral formulations of active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) provide individual, repetitive doses that include a defined amount of the active agent that is delivered over a defined amount of time. One illustrative sustained release formulation is a substantially homogeneous composition that comprises about 0.01% to about 99% w/w, or about 0.1% to about 95%, or about 0.1%, or about 1%, or about 2%, or about 5%, or about 10%, or about 15%, or about 20% to about 80%, or to about 90%, or to about 95%, or to about 97%, or to about 98%, or to about 99%1 of the active ingredient(s) (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof, or tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said ASBI(s), said stereoisomer(s), or said tautomer(s), or analogues, derivatives, or prodrugs thereof) and one or more mucoadhesives (also referred to herein as “bioadhesives”) that provide for adherence to the targeted mucosa of the subject (patient) and that may further comprise one or more of the following: one or more binders that provide binding of the excipients in a single tablet; one or more hydrogel forming excipients; one or more bulking agents; one or more lubricants; one or more glidants; one or more solubilizers; one or more surfactants; one or more flavors; one or more disintegrants; one or more buffering excipients; one or more coatings; one or more controlled release modifiers; and one or more other excipients and factors that modify and control the drug's dissolution or disintegration time and kinetics or protect the active drug from degradation. In various embodiments a sustained release pharmaceutical dosage form for oral transmucosal delivery can be solid or non-solid. In one preferred embodiment, the dosage from is a solid that turns into a hydrogel following contact with saliva. Suitable excipients include, but are not limited to substances added to the formulations that are required to produce a commercial product and can include, but are not limited to: bulking agents, binders, surfactants, bioadhesives, lubricants, disintegrants, stabilizers, solubilizers, glidants, and additives or factors that affect dissolution or disintegration time. Suitable excipients are not limited to those above, and other suitable nontoxic pharmaceutically acceptable carriers for use in oral formulations can be found in Remington's Pharmaceutical Sciences, 17th Edition, 1985. In certain embodiments extended release formulations of the active agent(s) described herein for oral transmucosal drug delivery include at least one bioadhesive (mucoadhesive) agent or a mixture of several bioadhesives to promote adhesion to the oral mucosa during drug delivery. In addition the bioadhesive agents may also be effective in controlling the dosage form erosion time and/or, the drug dissolution kinetics over time when the dosage form is wetted. Such mucoadhesive drug delivery systems are very beneficial, since they can prolong the residence time of the drug at the site of absorption and increase drug bioavailability. The mucoadhesive polymers forming hydrogels are typically hydrophilic and swellable, containing numerous hydrogen bond-forming groups, like hydroxyl, carboxyl or amine, which favor adhesion. When used in a dry form, they attract water from the mucosal surface and swell, leading to polymer/mucus interaction through hydrogen bonding, electrostatic, hydrophobic or van der Waals interaction. Illustrative suitable mucoadhesive or bioadhesive materials, include, but are not limited to natural, synthetic or biological polymers, lipids, phospholipids, and the like. Examples of natural and/or synthetic polymers include cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, etc), natural gums (such as guar gum, xanthan gum, locust bean gum, karaya gum, veegum etc.), polyacrylates (such as CARBOPOL®, polycarbophil, etc), alginates, thiol-containing polymers, POLYOX®yethylenes, polyethylene glycols (PEG) of all molecular weights (preferably between 1000 and 40,000 Da, of any chemistry, linear or branched), dextrans of all molecular weights (preferably between 1000 and 40,000 Da of any source), block copolymers, such as those prepared by combinations of lactic and glycolic acid (PLA, PGA, PLGA of various viscosities, molecular weights and lactic-to-glycolic acid ratios) polyethylene glycol-polypropylene glycol block copolymers of any number and combination of repeating units (such as PLURONICS®, TEKTRONIX® or GENAPOL® block copolymers), combination of the above copolymers either physically or chemically linked units (for example PEG-PLA or PEG-PLGA copolymers) mixtures. Preferably the bioadhesive excipient is selected from the group of polyethylene glycols, POLYOX®yethylenes, polyacrylic acid polymers, such as CARBOPOL® (such as CARBOPOL® 71G, 934P, 971P, 974P, and the like) and polycarbophils (such as NOVEON® AA-1, NOVEON® CA-1, NOVEON® CA-2, and the like), cellulose and its derivatives and most preferably it is polyethylene glycol, carbopol, and/or a cellulosic derivative or a combination thereof. In certain embodiments the mucoadhesive/bioadhesive excipient is typically present at 1-50% w/w, preferably 1-40% w/w or most preferably between 5-30% w/w. A particular formulation may contain one or more different bioadhesives in any combination. In certain embodiments the formulations for oral transmucosal drug delivery also include a binder or mixture of two or more binders which facilitate binding of the excipients into a single dosage form. Exemplary binders are selected from the group consisting of cellulosic derivatives (such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, etc.), polyacrylates (such as CARBOPOL®, polycarbophil, etc.), POVIDONE® (all grades), POLYOX®® of any molecular weight or grade, irradiated or not, starch, polyvinylpyrrolidone (PVP), AVICEL®, and the like. In certain embodiments the binder is typically present at 0.5-60% w/w, preferably 1-30% w/w and most preferably 1.5-15% w/w. In certain embodiments the formulations also include at least one hydrogel-forming excipient. Exemplary hydrogel forming excipients are selected from the group consisting of polyethylene glycols and other polymers having an ethylene glycol backbone, whether homopolymers or cross linked heteropolymers, block copolymers using ethylene glycol units, such as POLYOX®yethylene homopolymers (such as POLYOX®® N10/MW=100,000 POLYOX®-80/MW=200,000; POLYOX® 1105/MW=900,000; POLYOX®-301/MW=4,000,000; POLYOX®-303/MW=7,000,000, POLYOX® WSR-N-60K, all of which are tradenames of Union Carbide), hydroxypropylmethylcellylose (HPMC) of all molecular weights and grades (such as METOLOSE® 90SH50000, METOLOSE® 90SH30000, all of which are tradenames of Shin-Etsu Chemical company), Poloxamers (such as LUTROL® F-68, LUTROL® F-127, F-105 etc., all tradenames of BASF Chemicals), GENAPOL®, polyethylene glycols (PEG, such as PEG-1500, PEG-3500, PEG-4000, PEG-6000, PEG-8000, PEG-12000, PEG-20,000, etc.), natural gums (xanthan gum, locust bean gum, etc.) and cellulose derivatives (HC, HMC, HMPC, HPC, CP, CMC), polyacrylic acid-based polymers either as free or crosslinked and combinations thereof, biodegradable polymers such as poly lactic acids, polyglycolic acids and any combination thereof, whether a physical blend or cross-linked. In certain embodiments, the hydrogel components may be cross-linked. The hydrogel forming excipient(s) are typically present at 0.1-70% w/w, preferably 1-50% w/w or most preferably 1-30% w/w. In certain embodiments the formulations may also include at least one controlled release modifier which is a substance that upon hydration of the dosage form will preferentially adhere to the drug molecules and thus reduce the rate of its diffusion from the oral dosage form. Such excipients may also reduce the rate of water uptake by the formulation and thus enable a more prolonged drug dissolution and release from the tablet. In general the selected excipient(s) are lipophilic and capable of naturally complexing to the hydrophobic or lipophilic drugs. The degree of association of the release modifier and the drug can be varied by altering the modifier-to-drug ratio in the formulation. In addition, such interaction may be appropriately enhanced by the appropriate combination of the release modifier with the active drug in the manufacturing process. Alternatively, the controlled release modifier may be a charged polymer either synthetic or biopolymer bearing a net charge, either positive or negative, and which is capable of binding to the active via electrostatic interactions thus modifying both its diffusion through the tablet and/or the kinetics of its permeation through the mucosal surface. Similarly to the other compounds mentioned above, such interaction is reversible and does not involve permanent chemical bonds with the active. In certain embodiments the controlled release modifier may typically be present at 0-80% w/w, preferably 1-20% w/w, most preferably 1-10% w/w. In various embodiments the extended release formulations may also include other conventional components required for the development of oral dosage forms, which are known to those skilled in the art. These components may include one or more bulking agents (such as lactose USP, Starch 1500, mannitol, sorbitol, malitol or other non-reducing sugars; microcrystalline cellulose (e.g., AVICEL®), dibasic calcium phosphate dehydrate, sucrose, and mixtures thereof), at least one solubilizing agent(s) (such as cyclodextrins, pH adjusters, salts and buffers, surfactants, fatty acids, phospholipids, metals of fatty acids etc.), metal salts and buffers organic (such as acetate, citrate, tartrate, etc.) or inorganic (phosphate, carbonate, bicarbonate, borate, sulfate, sulfite, bisulfite, metabisulfite, chloride, etc.), salts of metals such as sodium, potassium, calcium, magnesium, etc.), at least one lubricant (such as stearic acid and divalent cations of, such as magnesium stearate, calcium stearate, etc., talc, glycerol monostearate and the like), one or more glidants (such as colloidal silicon dioxide, precipitated silicon dioxide, fumed silica (CAB-O-SIL® M-5P, trademark of Cabot Corporation), stearowet and sterotex, silicas (such as SILOID® and SILOX® silicas trademarks of Grace Davison Products, Aerosil—trademark of Degussa Pharma), higher fatty acids, the metal salts thereof, hydrogenated vegetable oils and the like), flavors or sweeteners and colorants (such as aspartame, mannitol, lactose, sucrose, other artificial sweeteners; ferric oxides and FD&C lakes), additives to help stabilize the drug substance from chemical of physical degradation (such as anti-oxidants, anti-hydrolytic agents, aggregation-blockers etc. Anti-oxidants may include BHT, BHA, vitamins, citric acid, EDTA, sodium bisulfate, sodium metabisulfate, thiourea, methionine, surfactants, amino-acids, such as arginine, glycine, histidine, methionine salts, pH adjusters, chelating agents and buffers in the dry or solution form), one or more excipients that may affect tablet disintegration kinetics and drug release from the tablet, and thus pharmacokinetics (disintegrants such as those known to those skilled in the art and may be selected from a group consisting of starch, carboxy-methylcellulose type or crosslinked polyvinyl pyrrolidone (such as cross-povidone, PVP-XL), alginates, cellulose-based disintegrants (such as purified cellulose, methylcellulose, crosslinked sodium carboxy methylcellulose (Ac-Di-Sol) and carboxy methyl cellulose), low substituted hydroxypropyl ethers of cellulose, microcrystalline cellulose (such as AVICEL®), ion exchange resins (such as AMBRELITE® IPR 88), gums (such as agar, locust bean, karaya, pectin and tragacanth), guar gums, gum karaya, chitin and chitosan, smecta, gellan gum, isapghula husk, polacrillin potassium (Tulsion339) gas-evolving disintegrants (such as citric acid and tartaric acid along with the sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate), sodium starch glycolate (such as EXPLOTAB® and PRIMOGEL®), starch DC and the likes, at least one biodegradable polymer of any type useful for extended drug release. Exemplary polymer compositions include, but are not limited to, polyanhydrides and co-polymers of lactic acid and glycolic acid, poly(dl-lactide-co-glycolide) (PLGA), polylactic acid) (PLA), poly(glycolic acid) (PGA), polyorthoesters, proteins, and polysaccharides. In certain embodiments, the active agent(s) can be chemically modified to significantly modify the pharmacokinetics in plasma. This may be accomplished for example by conjugation with poly(ethylene glycol) (PEG), including site-specific PEGylation. PEGylation, which may improve drug performance by optimizing pharmacokinetics, decreasing immunogenicity and dosing frequency. Methods of making a formulation of the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) for GI or oral transmucosal delivery are also provided. One method includes the steps of powder grinding, dry powder mixing and tableting via direct compression. Alternatively, a wet granulation process may be used. Such a method (such as high shear granulation process) involves mixing the active ingredient and possibly some excipients in a mixer. The binder may be one of the excipients added in the dry mix state or dissolved in the fluid used for granulating. The granulating solution or suspension is added to the dry powders in the mixer and mixed until the desired characteristics are achieved. This usually produces a granule that will be of suitable characteristics for producing dosage forms with adequate dissolution time, content uniformity, and other physical characteristics. After the wet granulation step, the product is most often dried and/or then milled after drying to get a major percentage of the product within a desired size range. Sometimes, the product is dried after being wet sized using a device such as an oscillating granulator, or a mill. The dry granulation may then processed to get an acceptable size range by first screening with a sieving device, and then milling the oversized particles. Additionally, the formulation may be manufactured by alternative granulation processes, all known to those skilled in the art, such as spray fluid bed granulation, extrusion and spheronization or fluid bed rotor granulation. Additionally, the tablet dosage form of the invention may be prepared by coating the primary tablet manufactured as described above with suitable coatings known in the art. Such coatings are meant to protect the active cores against damage (abrasion, breakage, dust formation) against influences to which the cores are exposed during transport and storage (atmospheric humidity, temperature fluctuations), and naturally these film coatings can also be colored. The sealing effect of film coats against water vapor is expressed by the water vapor permeability. Coating may be performed by one of the available processes such as Wurster coating, dry coating, film coating, fluid bed coating, pan coating, etc. Typical coating materials include polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone vinyl acetate copolymer (PVPVA), polyvinyl alcohol (PVA), polyvinyl alcohol/polyethylene glycol copolymer (PVA/PEG), cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, methacrylates, methyl cellulose, hydroxyl propyl methyl cellulose (HPMC of all grades and molecular weights), carrageenan, shellac and the like. In certain embodiments the tablet core comprising the active agent(s) described herein can be coated with a bioadhesive and/or pH resistant material to enable material, such as those defined above, to improve bioadhesion of the tablet in the sublingual cavity. In certain embodiments, the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) are formulated as inclusion complexes. While not limited to cyclodextrin inclusion complexes, it is noted that cyclodextrin is the agent most frequently used to form pharmaceutical inclusion complexes. Cyclodextrins (CD) are cyclic oligomers of glucose, that typically contain 6, 7, or 8 glucose monomers joined by α-1,4 linkages. These oligomers are commonly called α-CD, β-CD, and γ-CD, respectively. Higher oligomers containing up to 12 glucose monomers are known, and contemplated to in the formulations described herein. Functionalized cyclodextrin inclusion complexes are also contemplated. Illustrative, but non-limiting functionalized cyclodextrins include, but are not limited to sulfonates, sulfonates and sulfinates, or disulfonates of hydroxybutenyl cyclodextrin; sulfonates, sulfonates and sulfinates, or disulfonates of mixed ethers of cyclodextrins where at least one of the ether substituents is hydroxybutenyl cyclodextrin. Illustrative cyclodextrins include a polysaccharide ether which comprises at least one 2-hydroxybutenyl substituent, wherein the at least one hydroxybutenyl substituent is sulfonated and sulfinated, or disulfonated, and an alkylpolyglycoside ether which comprises at least one 2-hydroxybutenyl substituent, wherein the at least one hydroxybutenyl substituent is sulfonated and sulfinated, or disulfonated. In various embodiments inclusion complexes formed between sulfonated hydroxybutenyl cyclodextrins and one or more of the active agent(s) described herein are contemplated. Methods of preparing cyclodextrins, and cyclodextrin inclusion complexes are found for example in U.S. Patent Publication No: 2004/0054164 and the references cited therein and in U.S. Patent Publication No: 2011/0218173 and the references cited therein. Pharmacokinetics (PK) and Formulation Attributes One advantage of the extended (controlled) release oral (GI or transmucosal) formulations described herein is that they can maintain the plasma drug concentration within a targeted therapeutic window for a longer duration than with immediate-release formulations, whether solid dosage forms or liquid-based dosage forms. The high peak plasma levels typically observed for such conventional immediate release formulations will be blunted by the prolonged release of the drug over 1 to 12 hours or longer. In addition, a rapid decline in plasma levels will be avoided since the drug will continually be crossing from the oral cavity into the bloodstream during the length of time of dissolution of the tablet, thus providing plasma pharmacokinetics with a more stable plateau. In addition, the dosage forms described herein may improve treatment safety by minimizing the potentially deleterious side effects due to the reduction of the peaks and troughs in the plasma drug pharmacokinetics, which compromise treatment safety. In various embodiments the oral transmucosal formulations of the active agent(s) described herein designed to avoid the high peak plasma levels of intravenous and conventional immediate release oral dosage forms by utilizing the mucosa and by independently controlling both tablet disintegration (or erosion) and drug dissolution and release from the tablet over time to provide a safer delivery profile. The oral formulations described herein provide individual, repetitive doses that include a defined amount of the active agent. An advantage of the bioadhesive oral transmucosal formulations described herein is that they exhibit highly consistent bioavailability and can maintain the plasma drug concentration within a targeted therapeutic window with significantly lower variability for a longer duration than currently available dosage forms, whether solid dosage forms or IV dosage forms. In addition, a rapid decline in plasma levels is avoided since the drug is continually crossing from the oral cavity or GI tract into the bloodstream during the length of time of dissolution of the tablet or longer, thus providing plasma pharmacokinetics with an extended plateau phase as compared to the conventional immediate release oral dosage forms. Further, the dosage forms described herein can improve treatment safety by minimizing the potentially deleterious side effects due to the relative reduction of the peaks and troughs in the plasma drug pharmacokinetics, which compromise treatment safety and is typical of currently available dosage forms. In various embodiments bioadhesive formulations described herein can be designed to manipulate and control the pharmacokinetic profile of the active agent(s) described herein. As such, the formulations can be adjusted to achieve ‘slow’ disintegration times (and erosion kinetic profiles) and slow drug release and thus enable very prolonged pharmacokinetic profiles that provide sustained drug action. Although such formulations may be designed to still provide a fast onset, they are mostly intended to enable the sustained drug PK and effect while maintaining the other performance attributes of the tablet such as bioadhesion, reproducibility of action, blunted Cmax, etc. The performance and attributes of the bioadhesive transmucosal formulations of this invention are independent of the manufacturing process. A number of conventional, well-established and known in the art processes can be used to manufacture the formulations of the present invention (such as wet and dry granulation, direct compression, etc.) without impacting the dosage form physicochemical properties or in vivo performance. An illustrative mathematical ratio that demonstrates the prolonged plateau phase of the measured blood plasma levels of the active agent(s) described herein, following administration of the dosage forms of the invention is the term “Optimal Therapeutic Targeting Ratio” or “OTTR”, which represents the average time that the drug is present at therapeutic levels, defined as time within which the drug plasma concentration is maintained above 50% of Cmaxnormalized by the drug's elimination half-life multiplied by the ratio of the Cmaxobtained in the dosage form of interest over the normalized C. following IV administration of equivalent doses. In certain embodiments the OTTR can be calculated by the formula: OTTR=(CIVmax/Cmax)×(Dose/DoseIV)(Time above 50% of Cmax)/(TerminalIVelimination half-life of the drug). In certain embodiments the OTTR is greater than about 15, or greater than about 20, or greater than about 25, or greater than about 30, or greater than about 40, or greater than about 50. Administration In certain embodiments one or more active agents described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) are administered to a mammal in need thereof, e.g., to a mammal at risk for or suffering from a pathology characterized by abnormal processing of amyloid precursor proteins, a mammal at risk for progression of MCI to Alzheimer's disease, and so forth. In certain embodiments the active agent(s) are administered to prevent or delay the onset of a pre-Alzheimer's cognitive dysfunction, and/or to ameliorate one or more symptoms of a pre-Alzheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, and/or to promote the processing of amyloid precursor protein (APP) by a non-amyloidogenic pathway. In certain embodiments one or more active agent(s) are administered for the treatment of early stage, mid stage, or late-stage Alzheimer's disease, e.g., to reduce the severity of the disease, and/or to ameliorate one or more symptoms of the disease, and/or to slow the progression of the disease. In various embodiments the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) can be administered by any of a number of routes. Thus, for example they can be administered orally, parenterally, (intravenously (IV), intramuscularly (IM), depo-IM, subcutaneously (SQ), and depo-SQ), sublingually, intranasally (inhalation), intrathecally, transdermally (e.g., via transdermal patch), topically, ionophoretically or rectally. Typically the dosage form is selected to facilitate delivery to the brain (e.g., passage through the blood brain barrier). In this context it is noted that the compounds described herein are readily delivered to the brain. Dosage forms known to those of skill in the art are suitable for delivery of the compound. The active agent(s) are administered in an amount/dosage regimen sufficient to exert a prophylactically and/or therapeutically useful effect in the absence of undesirable side effects on the subject treated. The specific amount/dosage regimen will vary depending on the weight, gender, age and health of the individual; the formulation, the biochemical nature, bioactivity, bioavailability and the side effects of the particular compound. In certain embodiments the therapeutically or prophylactically effective amount may be determined empirically by testing the agent(s) in known in vitro and in vivo model systems for the treated disorder. A therapeutically or prophylactically effective dose can be determined by first administering a low dose, and then incrementally increasing until a dose is reached that achieves the desired effect with minimal or no undesired side effects. In certain embodiments, when administered orally, an administered amount of the agent(s) described herein effective to prevent or delay the onset of a pre-Alzheimer's cognitive dysfunction, and/or to ameliorate one or more symptoms of a pre-Alzheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, and/or to promote the processing of amyloid precursor protein (APP) by a non-amyloidogenic pathway, and/or to treat or prevent AD ranges from about 0.1 mg/day to about 500 mg/day or about 1,000 mg/day, or from about 0.1 mg/day to about 200 mg/day, for example, from about 1 mg/day to about 100 mg/day, for example, from about 5 mg/day to about 50 mg/day. In some embodiments, the subject is administered the compound at a dose of about 0.05 to about 0.50 mg/kg, for example, about 0.05 mg/kg, 0.10 mg/kg, 0.20 mg/kg, 0.33 mg/kg, 0.50 mg/kg. It is understood that while a patient may be started at one dose, that dose may be varied (increased or decreased, as appropriate) over time as the patient's condition changes. Depending on outcome evaluations, higher doses may be used. For example, in certain embodiments, up to as much as 1000 mg/day can be administered, e.g., 5 mg/day, 10 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day or 1000 mg/day. In various embodiments, active agent(s) described herein can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.5 to about 100 mg/day, preferably from about 5 to about 50 mg daily should be delivered. When a depot formulation is used for injection once a month or once every two weeks, the dose should be about 0.5 mg/day to about 50 mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In part because of the forgetfulness of the patients with Alzheimer's disease, it is preferred that the parenteral dosage form be a depo formulation. In various embodiments, the active agent(s) described herein can be administered sublingually. When given sublingually, the compounds and/or analogs thereof can be given one to four times daily in the amounts described above for IM administration. In various embodiments, the active agent(s) described herein can be administered intranasally. When given by this route, the appropriate dosage forms are a nasal spray or dry powder, as is known to those skilled in the art. The dosage of compound and/or analog thereof for intranasal administration is the amount described above for IM administration. In various embodiments, the active agent(s) described herein can be administered intrathecally. When given by this route the appropriate dosage form can be a parenteral dosage form as is known to those skilled in the art. The dosage of compound and/or analog thereof for intrathecal administration is the amount described above for IM administration. In certain embodiments, the active agent(s) described herein can be administered topically. When given by this route, the appropriate dosage form is a cream, ointment, or patch. When administered topically, the dosage is from about 1.0 mg/day to about 200 mg/day. Because the amount that can be delivered by a patch is limited, two or more patches may be used. The number and size of the patch is not important, what is important is that a therapeutically effective amount of compound be delivered as is known to those skilled in the art. The compound can be administered rectally by suppository as is known to those skilled in the art. When administered by suppository, the therapeutically effective amount is from about 1.0 mg to about 500 mg. In various embodiments, the active agent(s) described herein can be administered by implants as is known to those skilled in the art. When administering the compound by implant, the therapeutically effective amount is the amount described above for depot administration. In various embodiments the dosage forms can be administered to the subject 1, 2, 3, or 4 times daily. It is preferred that the compound be administered either three or fewer times, more preferably once or twice daily. It is preferred that the agent(s) be administered in oral dosage form. It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, and other medication the individual may be taking as is well known to administering physicians who are skilled in this art. While the compositions and methods are described herein with respect to use in humans, they are also suitable for animal, e.g., veterinary use. Thus certain preferred organisms include, but are not limited to humans, non-human primates, canines, equines, felines, porcines, ungulates, largomorphs, and the like. The foregoing formulations and administration methods are intended to be illustrative and not limiting. It will be appreciated that, using the teaching provided herein, other suitable formulations and modes of administration can be readily devised. Combination Therapies In certain embodiments, the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) can be used in combination with other therapeutic agents or approaches used to treat or prevent diseases characterized by amyloid deposits in the brain, including MCI and/or AD. Such agents or approaches include: acetylcholinesterase inhibitors (including without limitation, e.g., (—)-phenserine enantiomer, tacrine, ipidacrine, galantamine, donepezil, icopezil, zanapezil, rivastigmine, huperzine A, phenserine, physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, edrophonium, ladostigil and ungeremine); NMDA receptor antagonist (including without limitations e.g., Memantine); muscarinic receptor agonists (including without limitation, e.g., Talsaclidine, AF-102B, AF-267B (NGX-267)); nicotinic receptor agonists (including without limitation, e.g., Ispronicline (AZD-3480)); beta-secretase inhibitors (including without limitations e.g., thiazolidinediones, including rosiglitazone and pioglitazone); gamma-secretase inhibitors (including without limitation, e.g., semagacestat (LY-450139), MK-0752, E-2012, BMS-708163, PF-3084014, begacestat (GSI-953), and NICS-15); inhibitors of Aβ aggregation (including without limitation, e.g., Clioquinol (PBT1), PBT2, tramiprosate (homotaurine), Scyllo-inositol (a.k.a., scyllo-cyclohexanehexol, AZD-103 and ELND-005), passive immunotherapy with Aβ fragments (including without limitations e.g., Bapineuzemab) and Epigallocatechin-3-gallate (EGCg)); anti-inflammatory agents such as cyclooxygenase II inhibitors; anti-oxidants such as Vitamin E and ginkolides; immunological approaches, such as, for example, immunization with Aβ peptide or administration of anti-Aβ peptide antibodies; statins; and direct or indirect neurotrophic agents such as Cerebrolysin™, AIT-082 (Emilieu (2000) Arch. Neurol. 57:454), Netrin (Luorenco (2009) Cell Death Differ 16: 655-663), Netrin mimetics, NGF, NGF mimetics, BDNF and other neurotrophic agents of the future, agents that promote neurogenesis e.g. stem cell therapy. Further pharmacologic agents useful in combination with tropisetron, disulfiram, honokiol and/or nimetazepam to treat or prevent diseases characterized by amyloid deposits in the brain, including MCI and/or AD, are described, e.g., in Mangialasche, et al., Lancet Neurol (2010) 9:702-716. In various embodiments, combination therapy with one or more of the active agents described herein expressly excludes administration of these agents in conjunction with an acetylcholinesterase inhibitor. Use of ASBIs in Age Related Macular Degeneration and Glaucoma. While in various embodiments, the use of ASBIs are contemplated for the preventing or delaying the onset of a pre-Alzheimer's condition and/or cognitive dysfunction, and/or ameliorating one or more symptoms of a pre-Alzheimer's condition and/or cognitive dysfunction, or preventing or delaying the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, and/or for the treatment of Alzheimer's disease, other uses of ASBIs are also contemplated. In particular, in certain embodiments, the use of ASBIs is contemplated for the treatment and/or prophylaxis of age-related macular degeneration and/or glaucoma. Without being bound to a particular theory, it is believed that abnormal extracellular deposition of proteins may contribute to age-related macular degeneration (AMD) pathogenesis and progression, which is also the case in Alzheimer's disease and atherosclerosis. In both conditions, the protein deposits contain many shared constituents such as apoE, complement, and Aβ peptides. For instance, in human AMD, Aβ peptide deposition is associated with drusen, where it accumulates and colocalizes with activated complement components (Anderson et al. (2004) Exp. Eye. Res., 78:243-256; Dentchev et al. (2003) Mol. Vis., 9: 184-190; Johnson et al. (2002) Proc Natl Acad Sci USA 99: 11830-11835). Luibl et al. (2006) J. Clin. Invest., 116: 378-385, showed the presence of potentially toxic amyloid oligomers in drusen, sub-RPE basal deposits, and RPE of human donor eyes using an antibody that specifically recognizes the oligomeric form of Aβ. These Aβ oligomers were not detected in control age-matched donor eyes without drusen. Isas et al. (2010) Invest. Ophthalmol Vis. Sci., 51: 1304-1310, also detected soluble as well as mature Aβ fibrils in drusen. Collectively, these findings implicate Aβ in the pathogenesis of AMD. In addition, Aβ peptide has been detected in sub-RPE basal deposits and neovascular lesions in a murine model of AMD (Ding et al. (2008) Vision Res., 48: 339-345; Malek et al. (2005) Proc Natl Acad Sci USA, 102: 11900-11905). In this model, aged human APOE4-targeted replacement mice (APOE4 mice) fed a high-fat, cholesterol-enriched (HFC) diet (APOE4-HFC mice) exhibit morphologic hallmarks observed in both dry and wet AMD. These hallmarks include thick diffuse sub-RPE deposits, lipid- and protein-containing focal drusen-like deposits, thickening of Bruch's membrane, patchy regions of RPE atrophy opposed to areas of photoreceptor degeneration, and CNV (Malek et al. (2005) Proc Natl Acad Sci USA, 102: 11900-11905). It is believed that, in the APOE4-HFC mouse model of AMD, Aβ accumulation provokes damage at the level of the RPE/choroid and has previously been shown that systemic administration of anti-Aβ40-specific antibodies can partially attenuate the decline in visual function exhibited in this model (Ding et al. (2008) Vision Res., 48: 339-345). It has also been demonstrated that anti-Aβ immunotherapy simultaneously targeting both Aβ40 and Aβ42 blocks histopathologic changes and completely protects visual function in APOE4-HFC mice (Ding et al. (2011) Proc. Nat'l. Acad. Sci. U.S.A., 108 (28): E279-E287). Without being bound by a particular theory, it is believed that APP processing to Aβ in the eye occurs by the activities of BACE and γ-secretase in the retina and retinal pigmented epithelial (RPE) cell layers and that sAPPα and Aβ are secreted into the vitreous humor (see, e.g., (Prakasam et al. (2008) J. Alzh. Dis., 20: 1243-1253). Aβ is further transported into the aqueous humor where it is readily measured. In view of these findings, it is believe that ASBIs, e.g., as described herein, can find use in the treatment or prophylaxis of age-related macular degeneration (AMD) and/or glaucoma. Accordingly, it is believed that ASBIs can be administered to a subject to slow or prevent the appearance of AMD (and/or glaucoma), and/or to reduce one or more symptoms of AMD, and/or to slow, stop, or reverse progression of the disease. In various embodiments one or more ASBIs (e.g., any one or more of the active agent(s) described herein) are administered to a subject (e.g., a human, a non-human mammal) for these purposes. As described above, in various embodiments, the ASBI is administered via a route selected from the group consisting of oral delivery, isophoretic delivery, transdermal delivery, parenteral delivery, aerosol administration, administration via inhalation, intravenous administration, and rectal administration. In certain embodiments, the administration is directly to the eye. Thus for example, in certain embodiments, the agent(s) can be administered to the eye in the form of eye drops, via intraocular injection, and the like. Typically the ASBIs are administered in an effective amount for the treatment and/or prophylaxis of AMD or glaucoma, where the effective amount will vary by the modality of administration. In certain embodiments effective amount is an amount sufficient to mitigating in a mammal one or more symptoms associated with age-related macular degeneration (AMD). In certain embodiments the effective amount is an amount, an amount sufficient to reduce the risk or delaying the onset, and/or reduce the ultimate severity of a AMD disease (or glaucoma) characterized by reduction of Aβ in the vitreous and/or aqueous humor and/or the amyloid deposits on the retina and/or the RPE cell layer. Assay Systems to Evaluate APP Processing Without being bound to a particular theory, it is believed that the active agent(s) described herein (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) promote processing of APP by the nonamyloidogenic pathway and/or reduce or inhibits processing of APP by the amyloidogenic pathway. In the nonamyloidogeic pathway, APP is first cleaved by α-secretase within the Aβ sequence, releasing the APPsα ectodomain (“sAPPα”). In contrast, the amyloidogenic pathway is initiated when β-secretase cleaves APP at the amino terminus of the Aβ, thereby releasing the APPsβ ectodomain (“sAPPβ”). APP processing by the nonamyloidogenic and amyloidogenic pathways is known in the art and reviewed, e.g., by Xu (2009) J Alzheimers Dis., 16(2): 211-224, and De Strooper, et al. (2010 Nat Rev Neurol 6(2): 99-107. One method to evaluate the efficacy of the active agent(s) is to determine a reduction or elimination in the level of APP processing by the amyloidogenic pathway, e.g., a reduction or elimination in the level of APP processing by β-secretase cleavage in response to the administration of the agent(s) of interest. Assays for determining the extent of APP cleavage at the β-secretase cleavage site are well known in the art. Illustrative assays are described, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400. Kits for determining the presence and levels in a biological sample of sAPPα and sAPPβ, as well as APPneo and Aβ commercially available, e.g., from PerkinElmer. ASBI Assay. ASBI activity of any of the compounds described herein can readily be verified using, for example, assays illustrated in the examples provided herein. Basically, in certain embodiments a pair of assays are utilized to identify compounds that inhibit BACE cleavage of the MBP-C125 APP substrate, resulting in the inhibition of the production of C99 but not the β-site peptide substrate (P5-P5′). As illustrated in the Examples, in one embodiment, an MBP-C125 APP695 wt fusion protein can be used as one of the substrates. The second substrate can be the commercially available P5-P5′ fluorescence substrate. Each of these substrates is incubated with recombinant BACE (R&D (cat#931-AS-050) in, for example, a 96 well plate format. For the MBP-C125 substrate the C-99 product from the BACE cleavage can be measured using an AlphaLisa assay as a readout. For the P5-5′ substrate the loss of fluorescence upon BACE cleavage can be used as the readout. An ASBI would inhibit the BACE cleavage of the MBP-C125 substrate while not being inhibitory of the fluorescence substrate. Other Cell Free Assays Illustrative assays that can be used to demonstrate the inhibitory activity of the active agent(s) are described, for example, in WO 00/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346. Such assays can be performed in cell-free incubations or in cellular incubations using cells expressing an alpha-secretase and/or beta-secretase and an APP substrate having a alpha-secretase and beta-secretase cleavage sites. In one illustrative embodiment, the agent(s) of interest are contacted with an APP substrate containing alpha-secretase and beta-secretase cleavage sites of APP, for example, a complete APP or variant, an APP fragment, or a recombinant or synthetic APP substrate containing the amino acid sequence: KM-DA or NL-DA (APP-SW), is incubated in the presence of an alpha-secretase and/or beta-secretase enzyme, a fragment thereof, or a synthetic or recombinant polypeptide variant having alpha-secretase or beta-secretase activity and effective to cleave the alpha-secretase or beta-secretase cleavage sites of APP, under incubation conditions suitable for the cleavage activity of the enzyme. agent(s) having the desired activity reduce or prevent cleavage of the APP substrate. Suitable substrates optionally include derivatives that may be fusion proteins or peptides that contain the substrate peptide and a modification useful to facilitate the purification or detection of the peptide or its alpha-secretase and/or beta-secretase cleavage products. Useful modifications include the insertion of a known antigenic epitope for antibody binding; the linking of a label or detectable moiety, the linking of a binding substrate, and the like. Suitable incubation conditions for a cell-free in vitro assay include, for example: approximately 200 nanomolar to 10 micromolar substrate, approximately 10 to 200 picomolar enzyme, and approximately 0.1 nanomolar to 10 micromolar of the agent(s), in aqueous solution, at an approximate pH of 4-7, at approximately 37° C., for a time period of approximately 10 minutes to 3 hours. These incubation conditions are exemplary only, and can be varied as required for the particular assay components and/or desired measurement system. Optimization of the incubation conditions for the particular assay components should account for the specific alpha-secretase and/or beta-secretase enzyme used and its pH optimum, any additional enzymes and/or markers that might be used in the assay, and the like. Such optimization is routine and will not require undue experimentation. Another illustrative assay utilizes a fusion peptide having maltose binding protein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBP portion is captured on an assay substrate by anti-MBP capture antibody. Incubation of the captured fusion protein in the presence of alpha-secretase and/or beta-secretase results in cleavage of the substrate at the alpha-secretase and/or beta-secretase cleavage sites, respectively. This system can be used to screen for the inhibitory activity of the agent(s) of interest. Analysis of the cleavage activity can be, for example, by immunoassay of cleavage products. One such immunoassay detects a unique epitope exposed at the carboxy terminus of the cleaved fusion protein, for example, using the antibody SW192. This assay is described, for example, in U.S. Pat. No. 5,942,400. Cellular Assays Numerous cell-based assays can be used to evaluate the activity of agent(s) of interest on relative alpha-secretase activity to beta-secretase activity and/or processing of APP to release amyloidogenic versus non-amyloidogenic AP oligomers. Contact of an APP substrate with an alpha-secretase and/or beta-secretase enzyme within the cell and in the presence or absence of the agent(s) can be used to demonstrate alpha-secretase promoting and/or beta-secretase inhibitory activity of the agent( ) Preferably, the assay in the presence of the agent(s) provides at least about 30%, most preferably at least about 50% inhibition of the enzyuratic activity, as compared with a non-inhibited control. In one embodiment, cells that naturally express alpha-secretase and/or beta-secretase are used. Alternatively, cells are modified to express a recombinant alpha-secretase and/or beta-secretase or synthetic variant enzymes, as discussed above. The APP substrate may be added to the culture medium and is preferably expressed in the cells. Cells that naturally express APP, variant or mutant forms of APP, or cells transformed to express an isoform of APP, mutant or variant APP, recombinant or synthetic APP, APP fragment, or synthetic APP peptide or fusion protein containing the alpha-secretase and/or beta-secretase APP cleavage sites can be used, provided that the expressed APP is permitted to contact the enzyme and enzymatic cleavage activity can be analyzed. Human cell lines that normally process Aβ from APP provide a useful means to assay inhibitory activities of the agent(s). Production and release of Aβ and/or other cleavage products into the culture medium can be measured, for example by immunoassay, such as Western blot or enzyme-linked immunoassay (EIA) such as by ELISA. Cells expressing an APP substrate and an active alpha-secretase and/or beta-secretase can be incubated in the presence of the agents to demonstrate relative enzymatic activity of the alpha-secretase and/or beta-secretase as compared with a control. Relative activity of the alpha-secretase to the beta-secretase can be measured by analysis of one or more cleavage products of the APP substrate. For example, inhibition of beta-secretase activity against the substrate APP would be expected to decrease release of specific beta-secretase induced APP cleavage products such as Aβ, sAPPβ and APPneo. Promotion or enhancement of alpha-secretase activity against the substrate APP would be expected to increase release of specific alpha-secretase induced APP cleavage products such as sAPPα and p3 peptide. Although both neural and non-neural cells process and release Aβ, levels of endogenous beta-secretase activity are low and often difficult to detect by EIA. The use of cell types known to have enhanced beta-secretase activity, enhanced processing of APP to Aβ, and/or enhanced production of Aβ are therefore preferred. For example, transfection of cells with the Swedish Mutant form of APP (APP-SW); with the Indiana Mutant form (APP-IN); or with APP-SW-IN provides cells having enhanced beta-secretase activity and producing amounts of Aβ that can be readily measured. In such assays, for example, the cells expressing APP, alpha-secretase and/or beta-secretase are incubated in a culture medium under conditions suitable for alpha-secretase and/or beta-secretase enzymatic activity at its cleavage site on the APP substrate. On exposure of the cells to the agent(s), the amount of Aβ released into the medium and/or the amount of CTF99 fragments of APP in the cell lysates is reduced as compared with the control. The cleavage products of APP can be analyzed, for example, by immune reactions with specific antibodies, as discussed above. Preferred cells for analysis of alpha-secretase and/or beta-secretase activity include primary human neuronal cells, primary transgenic animal neuronal cells where the transgene is APP, and other cells such as those of a stable 293 cell line expressing APP, for example, APP-SW. In Vivo Assays: Animal Models Various animal models can be used to analyze the activity of agent(s) of interest on relative alpha-secretase and/or beta-secretase activity and/or processing of APP to release AP. For example, transgenic animals expressing APP substrate, alpha-secretase and/or beta-secretase enzyme can be used to demonstrate inhibitory activity of the agent(s). Certain transgenic animal models have been described, for example, in U.S. Pat. Nos. 5,877,399; 5,612,486; 5,387,742; 5,720,936; 5,850,003; 5,877,015, and 5,811,633, and in Ganes et al., 1995, Nature 373:523. Preferred are animals that exhibit characteristics associated with the pathophysiology of AD. Administration of the agent(s) to the transgenic mice described herein provides an alternative method for demonstrating the inhibitory activity of the agent(s). Administration of the agent(s) in a pharmaceutically effective carrier and via an administrative route that reaches the target tissue in an appropriate therapeutic amount is also preferred. Inhibition of beta-secretase mediated cleavage of APP at the beta-secretase cleavage site and of Aβ release can be analyzed in these animals by measure of cleavage fragments in the animal's body fluids such as cerebral fluid or tissues. Likewise, promotion or enhancement of alpha-secretase mediated cleavage of APP at the alpha-secretase cleavage site and of release of sAPPα can be analyzed in these animals by measure of cleavage fragments in the animal's body fluids such as cerebral fluid or tissues. In certain embodiments, analysis of brain tissues for Aβ deposits or plaques is preferred. On contacting an APP substrate with an alpha-secretase and/or beta-secretase enzyme in the presence of the agent(s) under conditions sufficient to permit enzymatic mediated cleavage of APP and/or release of Aβ from the substrate, desirable agent(s) are effective to reduce beta-secretase-mediated cleavage of APP at the beta-secretase cleavage site and/or effective to reduce released amounts of Aβ. The agent(s) are also preferably effective to enhance alpha-secretase-mediated cleavage of APP at the alpha-secretase cleavage site and to increase released amounts of sAPPα. Where such contacting is the administration of the agent(s) to an animal model, for example, as described above, the agent(s) is effective to reduce Aβ deposition in brain tissues of the animal, and to reduce the number and/or size of beta amyloid plaques. Where such administration is to a human subject, the agent(s) is effective to inhibit or slow the progression of disease characterized by enhanced amounts of Aβ, to slow the progression of AD in the, and/or to prevent onset or development of AD in a patient at risk for the disease. Methods of Monitoring Clinical Efficacy In various embodiments, the effectiveness of treatment can be determined by comparing a baseline measure of a parameter of disease before administration of the agent(s) (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) is commenced to the same parameter one or more time points after the agent(s) or analog has been administered. One illustrative parameter that can be measured is a biomarker (e.g., a peptide ofigomer) of APP processing. Such biomarkers include, but are not limited to increased levels of sAPPα, p3 (Aβ17-42 or Aβ17-40), sAPPβ, soluble Aβ40, and/or soluble Aβ42 in the blood, plasma, serum, urine, mucous or cerebrospinal fluid (CSF). Detection of increased levels of sAPPα and/or p3, and decreased levels of sAPPβ and/or APPneo is an indicator that the treatment is effective. Conversely, detection of decreased levels of sAPPα and/or p3, and/or increased levels of sAPPβ, APPneo, Tau or phospho-Tau (pTau) is an indicator that the treatment is not effective. Another parameter to determine effectiveness of treatment is the level of amyloid plaque deposits in the brain. Amyloid plaques can be determined using any method known in the art, e.g., as determined by CT, PET, PIB-PET and/or MRI. Administration of the agent(s) (e.g., ASBIs such as galangin, rutin, and analogues, derivatives, or prodrugs thereof) can result in a reduction in the rate of plaque formation, and even a retraction or reduction of plaque deposits in the brain. Effectiveness of treatment can also be determined by observing a stabilization and/or improvement of cognitive abilities of the subject. Cognitive abilities can be evaluated using any art-accepted method, including for example, Clinical Dementia Rating (CDR), the mini-mental state examination (MMSE) or Folstein test, evaluative criteria listed in the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) or DSM-V, and the like. Clinical efficacy can be monitored using any method known in the art. Measurable biomarkers to monitor efficacy include, but are not limited to, monitoring blood, plasma, serum, urine, mucous or cerebrospinal fluid (CSF) levels of sAPPα, sAPPβ, Aβ42, Aβ40, APPneo and p3 (e.g., Aβ17-42 or Aβ17-40). Detection of increased levels of sAPPα and/or p3, and decreased levels of sAPPβ and/or APPneo are indicators that the treatment or prevention regime is efficacious. Conversely, detection of decreased levels of sAPPα and/or p3, and increased levels of sAPPβ and/or APPneo are indicators that the treatment or prevention regime is not efficacious. Other biomarkers include Tau and phospho-Tau (pTau). Detection of decreased levels of Tau and pTau are indicators that the treatment or prevention regime is efficacious. Efficacy can also be determined by measuring amyloid plaque load in the brain. The treatment or prevention regime is considered efficacious when the amyloid plaque load in the brain does not increase or is reduced. Conversely, the treatment or prevention regime is considered inefficacious when the amyloid plaque load in the brain increases. Amyloid plaque load can be determined using any method known in the art, e.g., including CT, PET, PIB-PET and/or MRI. Efficacy can also be determined by measuring the cognitive abilities of the subject. Cognitive abilities can be measured using any method known in the art. Illustrative tests include assigning a Clinical Dementia Rating (CDR) score or applying the mini mental state examination (MMSE) (Folstein, et al., Journal of Psychiatric Research 12 (3): 189-98). Subjects who maintain the same score or who achieve an improved score, e.g., when applying the CDR or MMSE, indicate that the treatment or prevention regime is efficacious. Conversely, subjects who receive a score indicating diminished cognitive abilities, e.g., when applying the CDR or MMSE, indicate that the treatment or prevention regime has not been efficacious. In certain embodiments, the monitoring methods can entail determining a baseline value of a measurable biomarker or parameter (e.g., amyloid plaque load or cognitive abilities) in a subject before administering a dosage of the agent(s), and comparing this with a value for the same measurable biomarker or parameter after treatment. In other methods, a control value (e.g., a mean and standard deviation) of the measurable biomarker or parameter is determined for a control population. In certain embodiments, the individuals in the control population have not received prior treatment and do not have AD, MCI, nor are at risk of developing AD or MCI. In such cases, if the value of the measurable biomarker or clinical parameter approaches the control value, then treatment is considered efficacious. In other embodiments, the individuals in the control population have not received prior treatment and have been diagnosed with AD or MCI. In such cases, if the value of the measurable biomarker or clinical parameter approaches the control value, then treatment is considered inefficacious. In other methods, a subject who is not presently receiving treatment but has undergone a previous course of treatment is monitored for one or more of the biomarkers or clinical parameters to determine whether a resumption of treatment is required. The measured value of one or more of the biomarkers or clinical parameters in the subject can be compared with a value previously achieved in the subject after a previous course of treatment. Alternatively, the value measured in the subject can be compared with a control value (mean plus standard deviation/ANOVA) determined in population of subjects after undergoing a course of treatment. Alternatively, the measured value in the subject can be compared with a control value in populations of prophylactically treated subjects who remain free of symptoms of disease, or populations of therapeutically treated subjects who show amelioration of disease characteristics. In such cases, if the value of the measurable biomarker or clinical parameter approaches the control value, then treatment is considered efficacious and need not be resumed. In all of these cases, a significant difference relative to the control level (e.g., more than a standard deviation) is an indicator that treatment should be resumed in the subject. In certain embodiments the tissue sample for analysis is typically blood, plasma, serum, urine, mucous or cerebro-spinal fluid from the subject. Kits. In various embodiments, the active agent(s) (e.g., APP specific BACE inhibitor (ASBI) such as galangin, rutin, and analogues, derivatives, a tautomer or stereoisomer thereof, or prodrug thereof as described herein) can be enclosed in multiple or single dose containers. The enclosed agent(s) can be provided in kits, for example, including component parts that can be assembled for use. For example, an active agent in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include an active agent and a second therapeutic agent for co-administration. The active agent and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the compounds. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration, e.g., as described herein. In certain embodiments, a kit is provided where the kit comprises: one or more ASBI compounds described herein, or prodrug, a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer or prodrug preferably provided as a pharmaceutical composition and in a suitable container or containers and/or with suitable packaging; optionally one or more additional active agents, which if present are preferably provided as a pharmaceutical composition and in a suitable container or containers and/or with suitable packaging; and optionally instructions for use, for example written instructions on how to administer the compound or compositions. In another embodiment, a kit is provided that comprises a single container or multiple containers: (a) a pharmaceutically acceptable composition comprising one or more ASBI compounds described and/or claimed herein, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, optionally a pharmaceutically acceptable composition comprising one or more additional therapeutic agents; and optionally instructions for use their use. The kit may optionally comprise labeling (e.g., instructional materials) appropriate to the intended use or uses. As with any pharmaceutical product, the packaging material(s) and/or container(s) are designed to protect the stability of the product during storage and shipment. In addition, the kits can include instructions for use or other informational material that can advise the user such as, for example, a physician, technician or patient, regarding how to properly administer the composition(s) as prophylactic, therapeutic, or ameliorative treatment of the disease of concern. In some embodiments, instructions can indicate or suggest a dosing regimen that includes, but is not limited to, actual doses and monitoring procedures. In some embodiments, the instructions can include informational material indicating that the administering of the compositions can result in adverse reactions including but not limited to allergic reactions such as, for example, anaphylaxis. The informational material can indicate that allergic reactions may exhibit only as mild pruritic rashes or may be severe and include erythroderma, vasculitis, anaphylaxis, Steven-Johnson syndrome, and the like. In certain embodiments the informational material(s) may indicate that anaphylaxis can be fatal and may occur when any foreign protein is introduced into the body. In certain embodiments the informational material may indicate that these allergic reactions can manifest themselves as urticaria or a rash and develop into lethal systemic reactions and can occur soon after exposure such as, for example, within 10 minutes. The informational material can further indicate that an allergic reaction may cause a subject to experience paresthesia, hypotension, laryngeal edema, mental status changes, facial or pharyngeal angioedema, airway obstruction, bronchospasm, urticaria and pruritus, serum sickness, arthritis, allergic nephritis, glomerulonephritis, temporal arthritis, eosinophilia, or a combination thereof. While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. In some embodiments, the kits can comprise one or more packaging materials such as, for example, a box, bottle, tube, vial, container, sprayer, insufflator, intravenous (I.V.) bag, envelope, and the like; and at least one unit dosage form of an agent comprising active agent(s) described herein and a packaging material. In some embodiments, the kits also include instructions for using the composition as prophylactic, therapeutic, or ameliorative treatment for the disease of concern. In some embodiments, the kits can comprise one or more packaging materials such as, for example, a box, bottle, tube, vial, container, sprayer, insufflator, intravenous (I.V.) bag, envelope, and the like; and a first composition comprising at least one unit dosage form of an agent comprising one or more active agent(s) (e.g., APP specific BACE inhibitor (ASBI) such as galangin, rutin, and analogues, derivatives, a tautomer or stereoisomer thereof, or prodrug thereof as described herein) within the packaging material, along with a second composition comprising a second agent such as, for example, an agent used in the treatment and/or prophylaxis of Alzheimer's disease (e.g., as described herein), or any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof. In some embodiments, the kits may also include instructions for using the composition as a prophylactic, therapeutic, or ameliorative treatment for the disease of concern. In certain embodiments the instructions/instructional materials when present teach dosages and/or treatment regimen(s) and/or counter-indictions for the active agents contained in the kit. While the instructional materials, when present, typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. EXAMPLES The following examples are offered to illustrate, but not to limit the claimed invention. Example 1 APP-Specific BACE Inhibitors (ASBI) A Novel Class of Therapeutic Agents for Alzheimer's Disease A critical limitation of protease inhibitory strategies (e.g., BACE inhibitors) in the treatment of various pathologies is the promiscuity of substrate target effects, i.e., the inhibition of cleavage of all substrates of a given targeted protease, such as BACE or the γ-secretase complex. In the case of γ-secretase, substrates other than APP, such as Notch, raise concerns for potential side effects of γ-secretase inhibition, and the recent failure of the γ-secretase inhibitor, Semagacestat, serves to reinforce such concerns. In the case of BACE, inhibition of non-APP substrates such as PSGL1 or LRP raises similar concerns. Therefore, the optimal BACE inhibitor would be one that would bind not to BACE but rather to APP, leading to APP-specific BACE inhibition (ASBI). Such a therapeutic would represent a new class of Alzheimer's disease therapeutics: ASBIs. The data reported in this example on the identification of the first ASBIs demonstrate that such an approach is feasible. APP-specific BACE inhibitors (ASBIs) inhibit the BACE cleavage of the amyloid precursor protein (APP) but not the proteolytic cleavage of other substrates. Through screening of a small library of 448 clinical compounds (NCC 3364) in the ASBI assays a bioflavonoid was identified—rutin, a citrus flavonoid glycoside—that was effective as an ASBI at a dose of 1 μM. Further analysis of a group of bioflavonoids revealed a second molecule, galangin, a bioflavonoid from the galangal rhizome, that similarly acts as an ASBI at a dose of 50 μM. These bioflavonoids represent the first members of what believed to be new class of disease-modifying therapeutic agents for AD. It is believed, the systematic application of the approach outlined herein to identify APP-specific BACE inhibitors, and evaluate their in vivo ability to modulate APP processing specifically, has not been previously reported. A bioflavonoid nutritional supplement is identified that provides molecular lead compound that acts as an ASBI in cell models. It has been shown that increasing brain levels of this bioflavonoid through a prodrug approach leads to reduction of Aβ42 upon in the AD mouse model. Thus ASBIs represent a novel class of therapeutic agents for AD. Materials and Methods Compounds. Rutin (ASBI-1) was obtained from Sigma (cat # R5143, St. Louis, Mo.), Galangin (ASBI-2) was obtained from Sigma (cat#282200, St. Louis, Mo.) and progalangin (PG-1) was synthesized. ASBI Assay. Consist of two parts a) evaluation of a compound for inhibition of the BACE cleavage of the MBP-C125 substrate and b) evaluation of the candidate for BACE inhibition of the P5-P5′ substrate. a) MBP-C125 Cleavage Assay. A protein construct of Maltose-Binding-Protein carrying the 125 C-terminal residues of APP (1 uL of 1 mM in water) was incubated with a flavonoid (100 uM) for 15 minutes. The mix was then submitted to cleavage by BACE (Sigma #B9059, 5 μl of 3 unit/ml in BACE buffer) for 30 minutes. After 0, 10, 20 and 30 minutes, 2 uL the reaction mixture were frozen and the different time points were quantified simultaneously for the amount of APP-C99 created. The quantification was done by using a Perkin Elmer ALPHALisa Amyloid Amyloid Beta kit (AL275C) modified by replacing the anti-Abeta acceptor beads (AL275AC) with anti-APP acceptor beads (AL275AC) and making the antibody mix with 2×ALPHALisa buffer. b) P5-P5′ Cleavage Assay. The inhibition of BACE cleavage of the fluorescence substrate P5-P5′ by the flavonoids at 100 uM was measured using the β-Secretase (BACE1) Activity Detection Kit from Sigma-Aldrich (CS0010) and the standard protocol. Plasmids. The pAPtag5-NRG1-β1 construct was kindly provided by Dr. Carl Blobel (Horiuchi et al. (2005) Dev. Biol. 283: 459-471). The BACE1 construct was a gift from Dr. Michael Willem and Dr. Christian Haass (Willem et al. (2006) Science 314: 664-666). Constructs pCMV5-Mint3, pMst-AβPP, pG5E1B-luc, and pCMV-LacZ were generously provided by Dr. Thomas Sildhof, Dr. Patrick Mehlen, and Dr. Veronique Corset (Cao (2001) Science 293: 115-120. Construct pEF-N-FLAG-TAZ was kindly provided by Dr. Michael Yaffe and Dr. lain Farrance. Construct pcDNA3.1-APLP2-Gal4 was described previously (Orcholski et al. (2011) J. Alzheimers Dis. 23: 689-699). Cell Culture and Western Blot. The Chinese Hamster Ovary (CHO) cell line over-expressing human AβPP (7 W) was kindly provided by Dr. Edward Koo. Plasmid constructs were transiently transfected into HEK293T or 7 W cells with Lipofectamine 2000 (Invitrogen). Western Blot analysis was performed as previously described (Swistowski et al. (2009) J. Neurosci., 29: 15703-15712). Briefly, 48 hr after transfection, cells were harvested and lysed in NP-40 Cell Lysis Buffer (50 mM TrisHCl, pH 8.0, 150 mM NaCl and 1% NP-40). Cell lysates were mixed with 1×LDS loading buffer (Invitrogen) and 50 mM DTT, and boiled at 100° C. for 10 min. After SDS-PAGE and electrotransfer, Western blotting was performed using anti-APP antibodies (CT15, a kind gift from Dr. Edward Koo, for β-CTF; 6E10 (Covance) for full length APP and sAPPα). Thirty minutes of TBS-Tween wash were followed by incubation with secondary antibodies. Neuregulinl Shedding Assay. A cDNA construct encoding a human placental secreted alkaline phosphatase (SEAP)-NRG1 (pAPtag5-NRG1-β1) fusion protein was transfected in HEK293 cells in a 6-well format with or without full-length wild-type BACE1 using Lipofectamine 2000 (Invitrogen) as described previously (Vassar et al. (1999) Science, 286: 735-741). After transfection the medium was replaced with DMEM containing 10% heat-inactivated Fetal Bovine Serum and incubated for 24 hr. SEAP activity was measured in the conditioned medium. For alkaline phosphatase activity measurements, 200 μl of reaction solution (0.1 M glycine, pH 10.4, 1 mM MgCl2, 1 mM ZnCl2containing 1 mg/ml 4-nitrophenyl phosphate disodium salt hexahydrate, Sigma) were added to 20 μ1 of the conditioned medium. The absorbance was read at 405 nm. Statistical analyses were performed using a two tailed Student's t-test. Transactivation Assay. HEK293T cells were co-transfected with five plasmids: (1) pG5E1B-luc, 0.3 μg; (2) pCMV-LacZ, 0.1 μg; (3) pMst-APP (APP-Gal4) or pcDNA3.1-APLP2-Gal4, 0.3 μg; (4) pCMV5-Mint3, 1.0 μg; (5) pEF-N-FLAG-TAZ, 1.0 μg. Cells were harvested 48 hr after transfection in 0.2 ml per well Cell Culture Lysis Buffer (Promega), and their luciferase and β-galactosidase activities were determined with the Promega luciferase assay kit and the Promega β-galactosidase assay kit, respectively. The luciferase activity was standardized by the β-galactosidase activity to control for transfection efficiency and general effects on transcription. Transfections were performed at 80-90% cofluency in six-well plates using Lipofectamine 2000 (Invitrogen). Surface Plamon Resonance (SPR) Testing. The surfaces of four flow cells (FC1, FC2, FC3, FC4) of a carboxymethylated-dextran (CM-5) chip were washed sequentially with 50 mM NaOH, 1 mM HCl, 0.05% H3PO4and 20 mM sodium phosphate pH 7.4, 125 mM sodium chloride in parallel using a flow rate of 30 μl/min for 1 min using a Biacore T-100 (GE Healthcare). Three fusion proteins were immobilized via amine coupling using 20 mM phosphate, 125 mM sodium chloride pH 7.4. The three proteins were MBP-eAPP230-624—a fusion protein containing maltose binding protein (MBP) and residues 230624 of the ectodomain of APP (90-kDa) (FC4), eAPP230-624—a protein that contains only residues 230-624 (45-kDa)(FC2), and TRX-eAPP575-624—a fusion protein containing thioredoxin (TRX) and residues 575-624 of the ectodomain (20 -kDa) (FC3). The proteins were produced as described in Libeu, et al. (2011) J. Alzheimers Dis., 25(3): 547-566 Libeu et al (2011). The flow cell FC1 was used as a control. Galangin was diluted from 10 mM solutions in DMSO to 50 μM in 1% DMSO, 20 mM sodium phosphate pH 7.4, 125 mM sodium chloride, 0.05% Tween and then serially diluted by 1.5 for 10 steps. Binding traces were recorded for each dilution with a binding phase of 60 seconds and a dissociation phase of 240 seconds. Each cycle was performed at 20° C. with a constant flow rate of 20 μl/min. An additional 240 seconds of buffer flow at 60 μl per min across the cells was applied as a regeneration phase to facilitate complete dissociation of the compound from the protein. The sensograms were obtained by subtraction of the reference and buffer signals using the Biacore T100 Evaluation software. The binding curves were modeled with the PRISM (Graphpad Inc). Pharmacokinetic (PK) Analysis. The brain penetrance of galangin and progalangin were assessed in a standard PK comprising subcutaneous (Sub-Q) injection of 5 adult non-transgenic mice with 50 ul of a 5 mg/ml stock of compound in dimethylsulfoxide (DMSO) or a dose of 10 mg/kg for a 25 g mouse. Injected mice were anesthetized with ketamine/xylazine at 1, 2, 4, 6, and 8 hours and blood collected by cardiac puncture. The mice were then perfused with saline and brain tissue dissected and snap frozen on dry ice. Blood was centrifuged at 3000 rpm for 10 minutes and the plasma supernatant collected. Both plasma and the right hemibrain were sent to Integrated Analytical Solutions (IAS, Berkeley, Calif.) with a reference sample of compound for compound level analysis in tissue and plasma. The compound levels were determined using a LC-MS/MS approach. Pilot Efficacy Testing. Galangin and progalangin (PG-1) were dissolved in 10% solutol/15% DMSO/75% polyethylene glycol (PEG). Stock solutions were prepared at 10 mg/ml for each compound and 100 ul was injected subcutaneously daily for 14 days at a dose of 40 mkd. There were 5 PDAPP AD model J20 mice in both the galangin and progalangin groups, and 9 vehicle-only treated J20 controls. Mice were anesthetized, blood collected for plasma, and brain tissue collected as described above 2 hours after injection on the last day of treatment. The right hemibrain was further microdissected to isolate hippocampus and entorhinal cortex and this combined tissue was used for biochemical analysis. The remaining tissue and plasma was sent to IAS for compound level analysis. Biochemistry. Aβ1-42 and Aβ1-40 levels were determined using the hippocampal/entorhinal cortical tissue. Briefly, frozen tissue samples were weighed, and a 20% w/v sonicate prepared in 5M guandine-HCl/50 mM Tris, pH8. Sonication was performed with sample tubes in ice water, 4×5 seconds at 60 Hz, then 3×5 seconds at 80 Hz. Samples were then rotated at room temperature for 3 hours and frozen at −20° C. until assay. Invitrogen ELISA kits were used for Aβ1-40 and Aβ1-42 according to the manufacturer's instructions. Results Identification of APP-Specific BACE Inhibitors (ASBIs) A primary high-throughput screening (HTS) assay was set up for identification of ASBIs using a dual-substrate testing paradigm (FIGS.3A &3B). The previously reported (Sinha et al. (1999) Nature, 402: 537-540) BACE substrate the MBP-C125 APP695wt fusion protein consisting of maltose binding protein fused to the carboxyterminal 125 amino acids of wild type APP, was used as the primary substrate; and the commercially available P5-P5′ fluorescence substrate, derived from the P5-P5′ residues of the BACE cleavage site of APP, was used as the secondary substrate. Each of these substrates was incubated with recombinant BACE (R&D (cat#931-AS-050) in a 96-well plate format. For the MBP-C125 substrate, the C-99 product from the BACE cleavage was measured using an AlphaLISA assay as a readout (FIG.3B). For the P5-5′ substrate, the loss of fluorescence following BACE cleavage was used as the readout. An ASBI would be predicted to inhibit the BACE cleavage of the MBP-C125 substrate, while not necessarily inhibiting cleavage of the fluorescence substrate, depending on where the ASBI bound the APP substrate. Based on the preliminary screening of a clinical compound library of 448 compounds, the hit-rate was anticipated to be very low, since only one compound was identified in the initial screen. Dose response curves of potential ‘hits’ were next be done to identify validated ‘hits’ for further development. The HTS screening was performed at an initial concentration of 10 uM for each candidate. An initial screen of a small clinical compound library of 448 commercially available clinical compounds was completed. The screen yielded a single hit (FIG.3A), identified as the bioflavonoid rutin (ASBI-1, also referred to as rutoside), which is derived from the citrus flavonoid glycoside found in buckwheat. This bioflavonoid decreased sAPPβ in SH-SY5Y cells, and was shown to be specific for APP, supporting the notion that rutin acts specifically on the BACE cleavage of APP. Next a panel of bioflavonoids (FIG.4) was tested, first for their abilities to inhibit sAPPβ in the cells. Another bioflavonoid, galangin, was identified that also behaved as an ASBI, inhibiting the cleavage of the MBP substrate by BACE (FIG.4, diamonds) while showing no inhibition of the P5-P5′ substrate (FIG.4, circles). Galangin (ASBI-2) is a flavanol found in galangal rhizome, and is commonly used as a nutritional supplement. Effect of Bioflavonoid ASBIs on sAPPβ and APP Processing in Cells. APP is processed through two major pathways: the non-amyloidogenic pathway involves α-secretase cleavage, proteolyzing APP into sAPPα and α-CTF (C83), while the amyloidogenic pathway starts with β-secretase cleavage, cleaving APP into sAPPβ and β-CTF (C99). The β-CTF is then cleaved by the γ-secretase, which produces Aβ and AICD. The ability of the ASBIs to inhibit the β-secretase processing of APP was tested in SH-SY5Y neuroblastoma cells that express APP. The sAPPβ fragment formed from the BACE cleavage product was measured using an AlphaLisa assay from Perkin-Elmer (Cat# A2132). Following the discovery of rutin in the initial screen, it was demonstrated that at 1 μM it slightly inhibited the production of sAPPβ by SH-SY5Y cells (FIG.5A). Testing of a panel of bioflavonoids led to the identification of galangin as an ASBI. Treatment of SH-SY5Y cells with galangin similarly decreased sAPPβ levels at 50 μM. No effect on APP levels was detected. Bioflavonoid ASBIs Inhibit APP-Gal4 and APLP2-Gal4 Transactivation While the APP-C31 cleavage is associated with cell death, the APP intracellular domain (AICD) created following the γ-secretase cleavage has been implicated in various signaling pathways, and has been shown to modulate the expression of many genes including KAI1, neprilysin, and APP itself (Hong et al. (2000) Science, 290: 150-153). An APP-Gal4/Mint3/TAZ transactivation assay (Maillard et al. (2007) J. Med. Chem., 50: 776-781; Hardy et al. (1991) Trends Pharmacol. Sci., 12: 383-388) was established, and using this assay, it was found that ASBIs inhibited APP-Gal4 transactivation (FIG.7). To confirm this effect, the APP-Gal4/Fe65 transactivation assay was employed. The effect of the ASBIs in the APLP2-Gal4 transactivation was examined (FIG.7). These results indicate that rutin (ASBI-1) and galangin (ASBI-2) inhibit both APP and related family member APLP2-Gal4 transactivation. Interaction of ASBIs with APP To explore the interaction of ASBIs with APP a ligand blot technique was used, where MBP-C125 APP was dot blotted on a nitrocellulose blot and binding to the protein was detected upon treatment with the bioflavonoids. A nitrocellulose filter-binding assay with bovine serum albumin (BSA) was used as a control. The binding of bioflavonoids was determined using both UV and MALDI mass spectrometric analysis. This is a qualitative measure of protein small molecule interaction but does show that the ASBI bound to APP. Surface plasmon resonance (SPR) was then used to demonstrate binding to APP and to determine the affinity of galangin for APP. Surface Plasmon Resonance (SPR) Screening: The binding affinity of the compounds for the ectodomain of APP was determined using SPR. A technique for measuring the affinity of compounds to fragments of the ectodomain of APP was developed. For the galangin binding experiments TRX-eAPP575-624 was used. The eAPP was crosslinked linked to the CMS Biacore chips (GE Health-care). Galangin at various concentrations were used in the flow through over the chip and the plasmon resonance signal was determined using a Biacore T100 (FIG.5B). Bioflavonoid ASBI Treatment Reduces Aβ in an AD Transgenic Mouse Model The brain permeability of the bioflavonoids rutin and galangin in mice was evaluated and it was found that after a 10 mpk sc administration no rutin was detectable in the brain, while low levels of galangin (Cmax˜50 ng/g at 1 h) could be detected in the brain (FIG.8). The brain to plasma ratio was 1:10. In order to see if the brain levels of galangin could be enhanced, the prodrug (PG-1) was tested and it resulted in increased delivery of galangin to the brain (Cmax˜100 ng/g at 1 h). Based on these pharmacokinetic analysis it was decided to test galangin and progalangin (PG-1) in an AD mouse model, the PDAPP (J20) mice. Treatment of J20 mice at 40 mpk with galangin shows some reduction of Aβ40 while Aβ42 was unchanged in the hippocampus and the cortex. However, treatment with progalangin shows both reduction of Aβ40 and Aβ42 consistent with the increased brain levels of galangin seen upon treatment with the prodrug. These results, taken together, indicate that the bioflavonoid galangin interacts directly with APP, inhibits BACE cleavage of APP but not neuregulin or a BACE-target peptide, inhibits BACE-dependent APP nuclear signaling, and reduces Aβ1-42 in a transgenic mouse model of AD. Discussion Two bioflavonoid analogs that are used as nutritional supplements and that inhibit the β-secretase mediated APP processing by a novel mechanism were identified. These molecules inhibit the BACE cleavage of the MBP-C125 APP substrate, resulting in the inhibition of the production of C99, but do not inhibit cleavage of the β-site peptide substrate (P5-P5′). In addition, these bioflavonoids reduce sAPPβ in neuroblastoma SH-SY5Y cells, whereas galangin fails to reduce neuregulin BACE-dependent shedding. Further, it was demonstrated that the activity is associated with binding to the MBP-C125 substrate. These findings define a new mechanism to modulate APP processing. The approach described herein addresses a critical limitation of the protease inhibitory strategies for Alzheimer's disease (AD), providing a mechanism by which the inhibition of cleavage of all substrates of a given targeted protease, such as BACE or the γ-secretase complex, is avoided. The γ-secretase substrates other than APP, such as Notch, raise concerns for potential side effects of γ-secretase inhibition, and the recent failure of the γ-secretase inhibitor, Semagacestat, serves to reinforce such concerns. In the case of BACE, non-APP substrates such as PSGL1 and LRP raise similar concerns. Therefore, the optimal BACE inhibitor would be one that would bind to APP rather than to BACE, leading to APP-specific BACE inhibition (ASBI). Such a therapeutic, as described herein, represents a new class of Alzheimer's disease therapeutics. Two known BACE substrates are likely to be important in immunological function: the P-selectin glycoprotein ligand-1 (Lichtenthaler et al. (2003) J. Biol. Chem. 278: 48713-48719), which mediates leukocyte adhesion, and the sialyl-transferase ST6Gal I (Kitazume et al. (2003) J. Biol. Chem., 278: 14865-14871), an enzyme that is secreted after cleavage and is involved in regulating immune responses. The interaction of a sialyl-alpha-2,6 galactose residue, which is synthesized solely by ST6Gal I, with a B-cell-specific lectin, CD22/Siglec-2, is important for B-cell function (Id.). It is notable that mice deficient in some glycosylation enzymes appear to grow normally but show subtle neurological abnormalities with increasing age; glycosphingolipid-deficient mice show lethal audiogenic seizures induced by a sound stimulus. In this regard, it is important to note that no reports have yet appeared on the response of BACE1 null mice to immune challenge. BACE1 has also been shown to process the APP homologue, APLP2; this homologue has a different sequence specificity than that of APP around the putative BACE1 cleavage site, yet galangin also inhibited cleavage of APLP2 by BACE. The levels of APLP2 proteolytic products were decreased in BACE1 deficient mice and increased in BACE1 overexpressing mice (Pastorino et al. (2004) Mol. Cell Neurosci., 25: 642-649). Given the great need for disease modifying therapies in AD, this approach of developing a APP substrate-specific BACE inhibitor is novel and could lead to clinical candidates that are effective against the disease. An HTS assay to identify ASBIs was set up. Initial screening of a clinical library of 448 compounds in this assay led to the identification of a bioflavonoid that specifically inhibited the MBP-C125 substrate of BACE while not preventing the cleavage of the P5-P5′ substrate. This bioflavonoid, rutin, is a nutritional supplement that was also found to inhibit sAPPβ production in cells. A panel of bioflavonoids was then tested in the ASBI and sAPPβ assays in cell culture. From this testing another bioflavonoid, galangin, was identified. Galangin is another nutritional supplement that was effective in the ASBI assay, as well as in cells, in preventing the BACE cleavage of APP. Using a simple nitrocellulose filter ligand-binding assay initial binding of various bioflavonoids to the MBP-C125 substrate was demonstrated. A panel of bioflavonoids was screened in the ASBI assay. However, only rutin and galangin were effective as ASBIs (FIG.4). Galangin modulates sAPPβ levels in cells and demonstrated binding to the APP substrate (FIG.5). Interestingly, galangin also has been reported to be an inhibitor of acetylcholine esterase (AChE) (Guo et al. (2010) Chemico-Biol. Interaction, 187: 246-248) and to induce autophagy (Wen et al. (2012) Pharmacology, 89: 247-255). It was demonstrated that the bioflavonoids inhibit BACE cleavage of APP and APLP2, using a HEK-293 assay transfected with APP or APLP2-Gal4 (see, e.g., Orcholski et al. (2011) J. Alzheimers Dis., 23(4):689-99 for a description of the assay). Transactivation is achieved upon transfection with Mint3 and Taz. The ASBI as expected to inhibit only the transactivation of APP-Gal4, not that of APLP2-Gal4. However, galangin inhibited both APP-Gal4 and APLP2Gal4. Thus galangin exhibits APP-family specificity rather than APP specificity; however, given the demonstration of Aβ-like fragments derived from APLP2, the ability to inhibit BACE cleavage of both APP and APLP2 may be more desirable than inhibiting the cleavage of APP alone (Eggert et al. (2004) J. Biol. Chem. 279(18): 18146-18156). Initial pharmacokinetic evaluation of these two bioflavonoids in brain uptake assays using NTg mice showed that rutin does not cross the blood-brain barrier, whereas galangin did show some brain penetration, thus enabling its evaluation for proof-of-concept studies in the transgenic (Tg) mouse model. Galangin was then evaluated for its in vivo effect on Aβ40 and Aβ42 (FIG.7). The reduction of Aβ levels is very encouraging in this study. Further increase in brain levels of galangin is possible using a prodrug of galangin (PG-1), and it was demonstrated that PG-1 is more effective in vivo than galangin to reduce Aβ40 and Aβ42. In conclusion, this current study indicates that certain bioflavonoids have the ability to bind APP and inhibit the BACE cleavage of APP and APLP2 thus suggesting that they function as APP specific BACE inhibitors. These represent a new class of therapeutics for Alzheimer's disease that would be devoid of the potential toxicity from direct inhibition of BACE. Galangin as its prodrug analog, progalangin-1 was also shown to be effective in reducing Aβ40 and Aβ42 in the AD mouse model. Example 2 Progalangin as an ASBI CNS exposure studies were performed and consisted of a time-course design to collect heparinized plasma and brains. Following sc administration of the galangin or progalangin (compound-2) at 10 mg/kg, plasma and brain levels of the compounds were determined by quantitative LC/MS/MS methodology. Plasma samples were precipitated with acetonitrile:methanol (1:1) cocktail containing an internal standard. The brain samples were homogenized directly in ethylacetate or extracted from 5M guanidine homogenates with the liquid-liquid method. The resulting supernatant was evaporated to dryness and subjected to the LC/MS/MS analysis. For each compound 5 mice were used for the analysis. The brain-to-plasma ratios and plasma/brain Cmax levels were then determined (see, e.g.,FIG.8). Experimental Procedures—Compound Synthesis. 5,7-Diacetoxyflavone 5,7-Dihydroxy-2-phenyl-4H-chromen-4-one (5.00 g, 19.67 mmol) was added to a solution of acetic anhydride in pyridine (1:5, 42 mL) and the reaction mixture was stirred for 60 hours at ambient temperature. The reaction mixture was diluted with diethyl ether (100 mL) and filtered. The solids were washed with additional diethyl ether (3×50 mL) and dried under high vacuum to afford 4-oxo-2-phenyl-4H-chromene-5,7-diyl diacetate (6.40 g, 18.92 mmol, 96%) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H, CH3COO), 2.45 (s, 3H, CH3COO), 6.67 (s, 1H, H-3), 6.85 (d, J=2 Hz, 1H, H-6), 7.36 (d, J=2 Hz, 1H, H-8), 7.50 (m, 3H, H-3′, 5′, H-4′), 7.84 (dd, J=8 Hz, 2H, H-2′, 6′); 13C NMR (100 MHz, CDCl3) δ 21.2 (q, CH3COO), 21.3 (q, CH3—C═O), 108.7 (d, C-3), 109.1 (d, C-8), 113.7 (d, C-6), 115.1 (s, C-4a), 126.3 (2×d, C-2′, 6′), 129.2 (2×d, C-3′, 5′), 131.2 (d, C-4′), 131.9 (s, C-1′), 150.3 (s, C-5), 154.0 (s, C-7), 157.8 (s, C-8a), 162.6 (s, C-2), 168.1 (s, CH3—C═O), 169.5 (s, CH3COO), 176.5 (s, C-4). Preparation of DMDO: A 3 L, three-necked, round-bottomed reaction flask was equipped with an efficient mechanical stirrer, an addition funnel for solids, and a condenser (30 cm), set for downward displacement, attached to a two necked receiving flask, the latter cooled at −78° C. by means of a dry ice/acetone bath. The reaction flask was charged with a mixture of water (254 mL), acetone (192 mL), and NaHCO3 (58 g) and cooled at 5-10° C. with the help of an ice/water bath. While vigorously stirring and cooling, solid OXONE® (120 g, 0.195 mol) was added in five portions at 3 minute intervals. After 3 min of the last addition, the addition funnel was replaced with a stopper, and a moderate vacuum (80-100 mmHg) was applied to the flask. The cooling bath (5-10° C.) was removed from the reaction flask, and while vigorously stirring the DMDO/acetone solution was distilled and collected in the cooled (−78° C.) receiving flask over a period of 90 minutes. The receiving flask was warmed to −20° C. and dried for 3 hours over K2CO3. The DMDO solution was filtered into a dry flask and kept at −20° C. until used. Approximately 130 ml of DMDO solution was collected. The concentration of DMDO was determined by NMR by dissolving a 0.2 mL aliquot of the dried DMDO solution in CDCl3and comparing the height of the methyl proton signal of the dimethyldioxirane (at δ 1.65) with that of the13C satellite peak to the right of acetone (0.5%), resulting in a 0.05 M DMDO solution. This analysis must be done without delay! 5,7-Diacetoxy-3-hydroxyflavone 4-Oxo-2-phenyl-4H-chromene-5,7-diyl diacetate (1.80 g, 5.32 mmol) was added to a suspension of dried powdered 4 Å molecular sieves (1.80 g) in DCM (32 ml) and cooled to 0° C. DMDO solution (120 ml, 7.02 mmol, 1.32 equiv.) was added dropwise. The resulting solution was stirred at 0° C. for 3 hours and allowed to warm to ambient temperature and stirred at that temperature for 48 hours. The reaction mixture was filtered through a layer of anhydrous sodium sulfate on a bed of CELITE® and the volatiles were removed in vacuo at ambient temperature to afford crude 7-oxo-1α-phenyl-7,7α-dihydro-1αaH-oxireno[2,3-b]chromene-4,6-diyl diacetate (ca. 1.90 g) as an oil. This oil was carried through to the next stage. Crude reaction mixture (ca. 1.90 g) was stirred in DCM (32 ml) containing 15 mg of p-TSA. The reaction mixture solidified almost immediately. The reaction mixture was diluted with DCM (20 ml) and stirred for 2 days where TLC analysis indicated consumption of 7-oxo-1α-phenyl-7,7α-adihydro-1αH-oxireno[2,3-b]chromene-4,6-diyl diacetate. The reaction mixture was adsorbed onto silica gel and repeated flash column chromatography (Chloroform as eluent) afford impure 3-hydroxy-4-oxo-2-phenyl-4H-chromene-5,7-diyl diacetate (800 mg). Further purification was achieved by recrystallization from acetone/diethyl ether mixtures to afford 3-hydroxy-4-oxo-2-phenyl-4H-chromene-5,7-diyl diacetate (660 mg, 1.86 mmol, 35% over 2 steps) as a cream solid. The material was isolated as a hydrate. In addition, trace diethyl ether could not be removed under vacuum even after extended drying under vacuum. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. | 183,905 |
RE49874 | DETAILED DESCRIPTION OF THE INVENTION Embodiments of the present invention will hereinafter be described. FIG.1is a full sectional view of a gas sensor (NOx sensor)1according to an embodiment of the present invention in the direction of an axial line O.FIG.2andFIG.3are perspective views of metal terminals20and30.FIG.4is a perspective view of a front-end-side separator90.FIGS.5A and5Bare process drawings in which one of the metal terminals20is being inserted into a corresponding one of insertion holes90h of the front-end-side separator90.FIG.6is a sectional diagram in the radial direction illustrating a state where the metal terminals20are inserted and held in the insertion hole90h of the front-end-side separator90.FIG.7is a sectional diagram in the direction of the axial line O illustrating a state where the metal terminals20are inserted and held in the insertion holes90h of the front-end-side separator90.FIG.6illustrates a section that is along line A-A inFIG.5Band that is perpendicular to the direction of the axial line O.FIG.7illustrates a section that is along line B-B inFIG.5Band that is along the direction of the axial line O. The gas sensor1is a NOx sensor that detects oxygen concentration in an exhaust gas of an automobile or various internal combustion engines. InFIG.1, the gas sensor1includes a tubular metal shell138including a screw portion139used to be secured to an exhaust pipe and formed on an outer surface, a plate-shaped sensing element10extending in the direction of the axial line O (the longitudinal direction of the gas sensor1or the vertical direction in the figure), a tubular ceramic sleeve106disposed such that the ceramic sleeve106surrounds the sensing element10in the radial direction, the front-end-side separator90that is formed of a ceramic tube and that is disposed in an interior space on the front-end side thereof such that the front-end-side separator90surrounds a rear-end portion of the sensing element10, and six metal terminals20and30(only four metal terminals are illustrated inFIG.1) that are inserted and held in the insertion holes90h extending through the front-end-side separator90in the direction of the axial line O. A rear-end-side separator95that is formed of a ceramic tube is disposed on and in contact with the front-end-side separator90on the rear-end side, as described later. The front-end-side separator90corresponds to a “separator” in CLAIMS. The six insertion holes90h of the front-end-side separator90are in communication with the interior space on the front-end side of the front-end-side separator90. The metal terminals20and30face the outer surface of the sensing element10on the rear-end side and are electrically connected to electrode pads11a to12c (seeFIG.9) formed on the outer surface. Three of the electrode pads11a to12c are arranged in the width direction on both surfaces of the sensing element10on the rear-end side. The electrode pads11a to12c can be formed, for example, as sintered bodies mainly formed of Pt. A gas-detecting portion11at an end of the sensing element10is coated with a porous protective coat14such as alumina. As illustrated inFIG.9, the sensing element10is formed in a plate shape extending in the direction of the axial line O and formed of a gas-detecting portion11whose end portion10s detects oxygen concentration and NOx concentration. The gas-detecting portion11is coated with the porous protective coat14. The sensing element10itself has a known structure and includes the gas-detecting portion including a NOx detecting cell, a reference cell, and an oxygen concentration cell having a solid electrolyte body permeable to oxygen ions and a pair of electrodes, and a heater that heats the gas-detecting portion and that maintains a constant temperature thereof, although this is not illustrated. The two electrode pads11a and11b are arranged in the direction of the width W on the rear-end side of a main surface (front surface)10A of the sensing element10. A sensor output signal from the oxygen concentration cell is outputted from the electrode pads11a and11b via a lead portion (not illustrated). The electrode pad11c is formed between the electrode pads11a and11b in the width direction at a position nearer than the electrode pads11a and11b to the front-end side in the direction of the axial line O. The two electrode pads12a and12b are arranged in the width direction on the rear-end side of the other main surface (back surface)10B that faces the main surface10A. Power is supplied to the heater via the lead portion (not illustrated). The electrode pad12c is formed between the electrode pads12a and12b in the width direction at a position nearer than the electrode pads12a and12b to the front-end side in the direction of the axial line O. The electrode pad11c applies a reference voltage to the reference cell via the lead portion. A sensor output signal from the NOx cell is outputted from the electrode pad12c via the lead portion. The electrode pads11a to12c are rectangular and elongated in the direction of the axial line O and can be formed as, for example, sintered bodies mainly formed of Pt. According to the present embodiment, the electrode pads11a,11b, and11c and the electrode pads12a,12b, and12c, which are disposed on the surfaces of the sensing element10, respectively face and are paired with each other with the sensing element10interposed therebetween. Specifically, a pair of the electrode pad11a and the electrode pad12a face each other, another pair of the electrode pad11b and the electrode pad12b face each other, and the other pair of the electrode pad11c and the electrode pad12c face each other. In other words, according to the present embodiment, there are three pairs of the electrode pads11a to12c. The six metal terminals20and30are held in the insertion holes90h (90h1and90h2) of the separator90(FIG.4). The two metal terminals20that face the electrode pads11c and12c with the sensing element10interposed therebetween and the four metal terminals30that face the electrode pads11a,12a,11b, and12b with the sensing element10interposed therebetween correspond to “pairs of the metal terminals” (seeFIG.4). In other words, according to the present embodiment, there are three pairs of the metal terminals20and30. The metal shell138is composed of stainless steel, has a through-hole154extending in the direction of the axial line, and is formed in a substantially tubular shape having a ledge152protruding toward the inside of the through-hole154in the radial direction. The sensing element10is disposed in the through-hole154such that an end portion of the sensing element10protrudes from an end thereof. The ledge152is formed so as to have a tapered surface inclined inward with respect to a plane perpendicular to the direction of the axial line. Inside the through-hole154of the metal shell138, an alumina ceramic holder151having a substantially annular shape, a powder-filled layer153(also referred to below as a talc ring153), and the ceramic sleeve106are stacked in this order from the front-end side to the rear-end side in a state where the sensing element10is surrounded in the radial direction. A sheet packing157is disposed between the ceramic sleeve106and a rear-end portion140of the metal shell138. The rear-end portion140of the metal shell138is crimped so as to press the ceramic sleeve106toward the front-end side with the sheet packing157interposed therebetween. As illustrated inFIG.1, an outer protector142and an inner protector143, as a metallic (for example, stainless steel) double protector, which cover the protruding portion of the sensing element10and have holes, are installed on the outer circumference of the metal shell138on the front-end side (lower side inFIG.1) by, for example, welding. A metal pipe144is secured to the outer circumference of the metal shell138on the rear-end side. A rubber grommet170, which has a lead-wire insertion hole170h in which four lead wires146(only two lead wires are illustrated inFIG.1) electrically connected to the six metal terminals20and30(only four metal terminals are illustrated inFIG.1) of the sensing element10are inserted, is disposed in an opening of the metal pipe144on the rear-end side (upper side inFIG.1). The lead wires146are pulled from the rear-end side of the metal terminals20and30toward the rear-end side of the front-end-side separator90, extend through an insertion hole (not illustrated) of the rear-end-side separator95and the grommet170, and are pulled to the outside of the gas sensor1. The front-end-side separator90is disposed on the rear-end side (upper side inFIG.1) of the sensing element10protruding from the rear-end portion140of the metal shell138, and a flange portion90p protruding from an outer surface outward in the radial direction is provided. The front-end-side separator90is held inside the metal pipe144in a manner in which the flange portion90p is in contact with the metal pipe144with a holding member169interposed therebetween. The rear-end-side separator95is disposed between the grommet170and the front-end-side separator90. The rear-end-side separator95presses the front-end-side separator90toward the front-end side by using an elastic force of the grommet170. Thus, the flange portion90p is pressed against the holding member169, and the front-end-side separator90and the rear-end-side separator95are held inside the metal pipe144. FIG.2andFIG.3are perspective views of the metal terminals20and30, respectively. According to the present embodiment, two kinds of the metal terminals20and30are used. As illustrated inFIG.6, regarding the four front-end-side metal terminals30, the front-end-side metal terminals30adjacent to each other in the front-end-side separator90are symmetric with each other with respect to a line, and accordingly, one of the front-end-side metal terminals30(at a position I on the upper left side inFIG.6) is described. The front-end-side metal terminal30on the lower left side at a position II inFIG.6is symmetric with the front-end-side metal terminal30at the position I with respect to a line extending in the direction along a surface of the sensing element10. The front-end-side metal terminal30on the lower right side at a position III inFIG.6is symmetric with the front-end-side metal terminal30at the position II with respect to a line perpendicular to the direction along a surface of the sensing element10. The front-end-side metal terminal30on the upper right side at a position IV inFIG.6is symmetric with the front-end-side metal terminal30at the position I with respect to the line perpendicular to the direction along a surface of the sensing element10. Regarding the two front-end-side metal terminals20, the front-end-side metal terminals20adjacent to each other in the front-end-side separator90are symmetric with each other with respect to a line, and accordingly, one of the front-end-side metal terminals20(at an upper position inFIG.6) is described. The front-end-side metal terminal20on the lower side inFIG.6is symmetric with the front-end-side metal terminal20on the upper side with respect to a line extending the direction along a surface of the sensing element10. Each front-end side metal terminal20is located between the front-end-side metal terminals30in the width direction of the sensing element10. As illustrated inFIG.2, each of the metal terminals20extends in the direction of the axial line O as a whole and includes a lead-wire-connecting portion23that is connected to the corresponding lead wire146(seeFIG.1), a substantially plate-shaped main body21connected to the lead-wire-connecting portion23on the front-end side, and an elastic portion22that is folded toward the sensing element10on the front-end side of the main body21, which are integrally formed. A flat surface of the main body21forms a flat board portion20f. The metal terminals20can be manufactured, for example, in a manner in which a metallic plate (Inconel (registered trademark), for example) is punched and subsequently folded into a predetermined shape, but are not limited thereto. The lead-wire-connecting portion23is a known tubular press-fit terminal. A part of the lead wire146at which a covering is removed and a conducting wire is exposed is inserted into the tube and press-fitted, so that the lead wire146is electrically connected thereto. Outer portions of the main body21on both sides in the width direction are folded at 90 degrees toward the sensing element10at the center in the direction of the axial line O and form holding portions27having a U-shaped section. The main body21serves as a base portion of each metal terminal20and maintains the strength of the metal terminal20. The distance between the pair of the holding portions27gradually increases in the direction to the rear-end side. A pair of rectangular rear-end-side restricting portions25that are flush with the main body21extend from both sides of the main body21in the width direction toward the outside on the rear-end side in the direction of the axial line O. Similarly, a pair of rectangular front-end-side restricting portions29that are flush with the main body21extend from both sides of the main body21in the width direction toward the outside on the front-end side in the direction of the axial line O. The elastic portion22is folded from an end of the main body21toward the sensing element10and the rear-end side and is elastically connected to the electrode pad11c or12c (seeFIG.1andFIG.9) at a contact point P1. The elastic portion22elastically bends in the radial direction with respect to the main body21. The back surfaces (surfaces opposite the elastic portion22)29a and25a of the front-end-side restricting portions29and the rear-end-side restricting portions25correspond to “opposed surfaces” that face the wall surface of the separator forming the insertion holes in CLAIMS. As illustrated inFIG.3, each of the metal terminals30extends in the direction of the axial line O as a whole and includes a lead-wire-connecting portion33that is connected to the corresponding lead wire146(seeFIG.1), a main body31connected to the lead-wire-connecting portion23on the front-end side, and an elastic portion32that is folded toward the sensing element10on the front-end side of the main body31, which are integrally formed. The metal terminals30can be manufactured, for example, in a manner in which a metallic plate (Inconel (registered trademark), for example) is punched and subsequently folded into a predetermined shape, but are not limited thereto. Each lead-wire-connecting portion33is a press-fit terminal as in the case of the lead-wire-connecting portion23. Each lead wire146is electrically connected thereto. The main body31has an L-shaped section, and an outer portion thereof in the width direction is folded at 90 degrees toward the sensing element10and forms a position-restricting portion35. A flat surface of the position-restricting portion35forms a flat board portion30f. The main body31serves as a base portion of each metal terminal30and maintains the strength of the metal terminals30. The elastic portion32is folded from an end of the main body31toward the sensing element10and the rear-end side and is elastically connected to the electrode pad11a,12a,11b, or12b (seeFIG.9) at a contact point P2. The elastic portion32elastically bends in the radial direction with respect to the main body31. An end portion35f of the position-restricting portion35is folded in the width direction of the main body31inward (toward the elastic portion32). A part of the position-restricting portion35nearer than the contact point P2to the front-end side forms a front-end-side restricting portion352and a part thereof nearer than the contact point P2to the rear-end side forms a rear-end-side restricting portion351, which is described in detail later. An edge surface (surface on the same side of the elastic portion32)35a of the position-restricting portion35corresponds to one of the “opposed surfaces” that face the wall surface of the separator forming the insertion holes in CLAIMS. As illustrated inFIG.4, the front-end-side separator90has the insertion holes90h (90h1and90h2). The insertion holes90h1and90h2are in communication with an interior space90v on the side of an end F of the front-end-side separator90. The insertion holes90h2are located at four corners of the front-end-side separator90. The insertion holes90h1are located between the insertion holes90h2in the width direction of the sensing element10. A rear-end facing surface90s1is formed on the front-end side of each insertion hole90h1. A rear-end facing surface90s2is formed on the front-end side of each insertion hole90h2. As illustrated inFIGS.5A and5B, when each metal terminal20is inserted into the corresponding insertion hole90h1of the front-end-side separator90, the front-end-side restricting portions29and the rear-end-side restricting portions25are inserted toward the front-end side along a groove of the insertion hole90h1, and an end of one of the front-end-side restricting portions29comes into contact with the rear-end facing surface90s1of the insertion hole90h1on the front-end side, and the position thereof in the direction of the axial line O is set. The pair of the holding portions27that have a gradually increased distance from each other in the direction to the rear-end side are in contact with the wall surface of the insertion hole90h1, and the metal terminal20is held in the insertion hole90h1. Similarly, when each metal terminal30is inserted into the corresponding insertion hole90h2of the front-end-side separator90, the position-restricting portion35is inserted toward the front-end side along a substantially L-shaped groove of the insertion hole90h2, and an end35f of the position-restricting portion35comes into contact with the rear-end facing surface90s2of the insertion hole90h2, and the position thereof in the direction of the axial line O is set. As illustrated inFIGS.5A and5B, the insertion holes90h2are located at four corners of the front-end-side separator90. The insertion holes90h1are located between the insertion holes90h2in the width direction of the sensing element10. As illustrated inFIG.7, the front-end-side restricting portions29and the rear-end-side restricting portions25of each metal terminal20face a wall surface90w1(seeFIG.4) of the corresponding insertion hole90h1along the direction of the axial line O on the side opposite the sensing element10with a clearance G interposed therebetween. Specifically, the back surfaces29a and25a (seeFIG.2) of the front-end-side restricting portions29and the rear-end-side restricting portions25opposite the sensing element10face the wall surface90w1. Similarly, the position-restricting portion35of each metal terminal30faces a wall surface90w2(seeFIG.4) of the corresponding insertion hole90h2along the direction of the axial line O on the side of the sensing element10with the clearance G interposed therebetween. Specifically, the edge surface35a (seeFIG.2) of the position-restricting portion35on the side of the sensing element10faces the wall surface90w2. In a view from the direction of the axial line O, the back surfaces29a and25a of the front-end-side restricting portions29and the rear-end-side restricting portions25overlap (are flush with each other). Similarly, in a view from the direction of the axial line O, the edge surface35a of the position-restricting portion35is a straight line (parallel to the direction of the axial line O). InFIG.7, one of the metal terminals20and30that face each other is omitted for easy understanding. When each elastic portion22comes into contact with the electrode pad11c or12c of the sensing element10at the contact point P1, a reaction force F is applied from the electrode pad11c or12c toward the outside (right-hand side inFIG.7or the side opposite the sensing element10) in the radial direction. At this time, the metal terminals20slightly shift from the axial line O and are pressed toward the back-surface side (right-hand side inFIG.7), the back surfaces29a and25a of the front-end-side restricting portions29and the rear-end-side restricting portions25come into contact with the wall surface90w1, and the metal terminals20are supported. That is, further movement (shift) of the metal terminals20in the direction (radial direction of the front-end-side separator90) intersecting the direction of the axial line O inside the insertion holes90h1is restricted at the same locations (back surfaces29a and25a) interposing the contact point P1in the direction of the axial line O. Thus, the metal terminals20are inhibited from further shifting from the axial line O about the contact point P1, and moment acting about the contact point P1of the metal terminals20is smaller than that in the case where movement of the metal terminals20is restricted at one location on the front-end side or the rear-end side of the contact point P1. Consequently, the electrical connection between the electrode pads11c and12c and the metal terminals20can be inhibited from being unstable due to the shift of the metal terminals20from the axial line O. Similarly, when a vehicle equipped with the gas sensor1vibrates during driving, the occurrence of moment about the contact point P1of the metal terminals20is reduced, and the metal terminals20can be inhibited from shifting from the axial line O. Since the front-end-side restricting portions29and the rear-end-side restricting portions25are connected to each other with the flat board portion20f interposed therebetween, the front-end-side restricting portions29and the rear-end-side restricting portions25can be accurately formed at expected positions without strain due to residual stress as in the case where the restricting portions29and25are formed by a bending process, and the metal terminals20can be inhibited from shifting from the axial line O with more certainty. Also in the case of the metal terminals30, when each elastic portion32comes into contact with the electrode pad11a,12a,11b, or12b of the sensing element10at the contact point P2, a reaction force F is applied from the electrode pad11a,12a,11b, or12b toward the outside (left-hand side inFIG.7or the side opposite the sensing element10) in the radial direction. At this time, the metal terminals30slightly shift from the axial line O and are pressed toward the back-surface side (left-hand side inFIG.7), the edge surface35a of the position-restricting portion35comes into contact with the wall surface90w2, and the metal terminals30are supported. That is, further movement (shift) of the metal terminals30in the direction (radial direction of the front-end-side separator90) intersecting the direction of the axial line O inside the insertion holes90h2is restricted at the same locations (edge surface35a) interposing the contact point P2in the direction of the axial line O. Thus, the metal terminals30are also inhibited from further shifting from the axial line O about the contact point P2. The position-restricting portion35(edge surface35a) extends in the direction of the axial line O beyond the contact point P2. A part of the position-restricting portion35(edge surface35a) nearer than the contact point P2to the front-end side forms the front-end-side restricting portion352, and a part thereof nearer than the contact point P2to the rear-end side forms the rear-end-side restricting portion351. Since the front-end-side restricting portion352and the rear-end-side restricting portion351are connected to each other with the flat board portion30f interposed therebetween, the front-end-side restricting portion352and the rear-end-side restricting portion351can be accurately formed at expected positions without strain due to residual stress as in the case where the restricting portions352and351are formed by a bending process, and the metal terminals30can be inhibited from shifting from the axial line O with more certainty. According to the present embodiment, as illustrated inFIG.7, a distance L2between the front end of the front-end-side restricting portions29and the rear end of the rear-end-side restricting portions25in the direction of the axial line O exceeds L1/2where L1is the length of the metal terminals20in the direction of the axial line O inside the insertion holes90h1. When the distance L2exceeds ½ of the length L1, a span (distance L2) in the direction of the axial line O when the back surfaces29a and25a restrict movement of the metal terminals20in front and behind of the contact point P1increases against the length L1, and the occurrence of moment about the contact point P1can be further reduced. The same is true for the metal terminals30. According to the present embodiment, as illustrated inFIG.8, burrs25P,29P are formed on edge surfaces of the main body21, the front-end-side restricting portions29, and the rear-end-side restricting portions25so as to protrude toward the side of the elastic portion22(sensing element10). This inhibits the burrs from protruding from the back surfaces29a and25a toward the wall surfaces90w1and90w3and thereby interfering with the wall surfaces90w1and90w3(seeFIG.4andFIG.6). As a result, the back surfaces29a and25a can be in close contact with the wall surfaces90w1and90w3, so that movement of the metal terminals20in the direction intersecting the direction of the axial line O can be restricted with certainty. In particular, when the burr protrudes toward the side of the back surfaces29a and25a facing the wall surface90w3, there is a risk that the main body21is separated from the wall surface90w3in the opposite direction, the spring stroke of the elastic portion22increases, an excess load is applied to the sensing element10, and the element is broken. Accordingly, it is more effective that the burr does not protrude thereto. In addition, it is not necessary to remove the burr. As a result, productivity is improved. The burr is a “residue outside a geometric shape at an edge of a corner, and a residue on a component during machining or molding”, which is defined in JIS-B0051 (2004). According to the present embodiment, burrs29p and25p are created, for example, when a metallic plate is punched with a press and sheared to manufacture the metal terminals20. A method according to a first aspect of an embodiment of the present invention for manufacturing the gas sensor will now be described with reference toFIG.10toFIGS.13A-13D. FIG.10is a plan view of a first jig300used according to the first aspect of the embodiment.FIG.11is a sectional view ofFIG.10taken along line A-A.FIG.12illustrates a state where the metal terminals20and30are inserted in the separator (first separator)90accommodated in the first jig300.FIGS.13A-13Dare process drawings of the method according to the first aspect of the embodiment for manufacturing the gas sensor. As illustrated inFIG.10andFIG.11, the first jig300is formed in a cylindrical shape with a bottom and has, at the center, a cylindrical accommodating space300h that opens to the upper surface. A protruding portion310in the form of a substantially H-shape in a top view protrudes upward from the center of the bottom surface300b of the accommodating space300h. The protruding portion310is formed at a position corresponding to the insertion hole90h at the center of the separator90. The protruding portion310includes two prism portions314at the center, three planar portions312in a plate shape that connect the two prism portions314to each other, that extend from end portions of the two prism portions314, and that are flush with each other, and two side wall portions316that vertically extend from both sides of the planar portions312and that each have ends flush with other opposed surfaces of the prism portions314. The prism portions314and the side wall portions316protrude from flat surfaces of the planar portions312. The three planar portions312are formed at positions corresponding to the opposed surfaces of a pair of metal terminals20a and20b at the contact points P1and the opposed surfaces (seeFIG.12) of two pairs of metal terminals30a to30d at the contact points P2. The protruding portion310protrudes up to a position higher than the upper surface302of the first jig300. A portion around the accommodating space300h forms a straight-line portion300s and prevents rotation of the separator90in the circumferential direction, which is described later. The first jig300and the protruding portion310can be made of, for example, metal such as stainless steel. In a metal-terminal holding step of the method according to the first aspect of the embodiment for manufacturing the gas sensor, as illustrated inFIG.12, the six metal terminals20a,20b, and30a to30d are inserted in six insertion holes90h1and90h2of the separator90accommodated in the first jig300, which is described in detail later. At this time, the prism portions314and the side wall portions316come into contact with the side surfaces (surfaces intersecting surfaces of the elastic portions22and32) of the metal terminals20a,20b, and30a to30d and restrict movement of the metal terminals in the width direction, and the metal terminals can be prevented from shifting inside the separator90(inside the first jig300). The detail of the method according to the first aspect of the embodiment for manufacturing the gas sensor will now be described with reference toFIGS.13A-13D.FIGS.13A-13Dillustrate a pair of the metal terminals30b and30d only. However, the same is true for the other two pairs of the metal terminals, which are into the page and concealed inFIGS.13A-13D. The separator90is first moved from the rear-end side (upper side) of the first jig300in the direction of the axial line and accommodated, and the planar portions312are inserted to positions corresponding to the above opposed surfaces in the insertion holes90h of the separator90(inFIGS.13A and13B, a separator accommodating step). Subsequently, the metal terminals30b and30d are inserted into the insertion holes90h from the rear-end side of the separator90such that the planar portions312are interposed between the contact points P2(the opposed surfaces) and held (inFIGS.13B and13C, the metal-terminal holding step). The lead wires146are press-fitted to the lead-wire-connecting portions33of the metal terminals30b and30d in advance. Subsequently, the first jig300is relatively removed from the separator90to the front-end side (lower side) (inFIG.13D, a jig removing step). According to the first aspect of the embodiment, when one or more pairs of the metal terminals20and30are thus installed in the separator90such that the contact points P2(P1) face each other, the planar portions312of the first jig300are interposed between the contact points P2(P1). Accordingly, the metal terminals30b and30d (or20a and20b, or30a and30c) that face each other are inhibited from coming into contact and being entangled with each other, the metal terminals are inhibited from being damaged and deformed, and workability can be improved. According to the present embodiment, when the separator90is accommodated in the first jig300in the separator accommodating step inFIG.13B, the planar portions312protrude up to positions nearer than the rear end of the separator90to the rear-end side. Thus, at the beginning of the subsequent metal-terminal holding step in which the metal terminals30b and30d (or20a and20b, or30a and30c) are inserted into the insertion holes90h, the metal terminals (contact points P2and P1) that face each other are isolated from each other by the planar portions312, and accordingly, the metal terminals can be inhibited from coming into contact and being entangled with each other with certainty. According to the present embodiment, as illustrated inFIG.10andFIG.12, the first jig300includes the straight-line portion300s, and the separator90includes a second straight-line portion (second restricting member)90t that engages the straight-line portion300s. This prevents the separator90from rotating in the circumferential direction in the first jig300and inhibits the metal terminals from coming into contact and being entangled with each other due to rotation of the separator90. According to the present embodiment, the thickness of each planar portion312is less than the thickness of the sensing element10between the pair of the electrode pads11a and12a (or11b and12b, or11c and12c) on the front and back surfaces. This inhibits the planar portions312from causing the metal terminals to plastically deform by increasing the distance between the metal terminals (contact points P2and P1) that face each other, and inhibits reliability of the electrical connection from decreasing due to a decrease in the pressure of contact with the electrode pads11a to12c of the sensing element10, which subsequently occurs. A method according to a second aspect of the embodiment of the present invention for manufacturing the gas sensor will now be described with reference toFIG.14toFIG.18. FIG.14is a plan view of a second jig400used according to the second aspect of the embodiment.FIG.15is a sectional view ofFIG.14taken along line B-B.FIG.16illustrates a state where the metal terminals20and30are accommodated in the second jig400.FIGS.17A-17Eare process drawings of the method according to the second aspect of the embodiment for manufacturing the gas sensor.FIG.18illustrates a state where the metal terminals20and30shift in arrangement directions with respect to planar portions412. As illustrated inFIG.14andFIG.15, the second jig400is formed in a cylindrical shape with a bottom and has, at the center, a cylindrical accommodating space400h that opens to the upper surface. The two planar portions412in a plate shape protrude upward from the center of the bottom surface400b of the accommodating space400h. The planar portions412are formed at positions corresponding to the insertion hole90h at the center of the separator90. The planar portions412are formed at positions corresponding to at least the opposed surfaces of a pair of the metal terminals20a and20b at the contact points P1and the opposed surfaces of the other two pairs of the metal terminals30a to30d at the contact points P2(seeFIG.16). The planar portions412protrude up to positions higher than the upper surface402of the second jig400. A portion around the accommodating space400h forms a straight-line portion400s as in the straight-line portion300s and forms the “first restricting member” that prevents rotation of the separator90in the circumferential direction. The separator90includes the second straight-line portion (second restricting member)90t described above. The second jig400and the planar portions412can be made of, for example, metal such as stainless steel. In a metal-terminal holding step of the method according to the second aspect of the embodiment for manufacturing the gas sensor, as illustrated inFIG.16, the six metal terminals20a,20b, and30a to30d are inserted in the accommodating space400h of the second jig400. At this time, the planar portions412are inserted between the opposed surfaces of the metal terminals at the contact points P1and P2. As illustrated inFIG.16, the metal terminals30a,20a, and30b are arranged in a direction L along the main surfaces of the planar portions412, and the metal terminals30c,20b, and30d are arranged in the same manner on the opposite side with respect to the planar portions412. The width of each metal terminal at the contact points P1and P2is denoted by W1, and the width of the main surfaces of the planar portions412is denoted by W2. As illustrated inFIG.18, in the case where the total width (3×W1) in the direction (arrangement direction) L in which the metal terminals30a,20a, and30b (or30c,20b, and30d) are arranged is less than W2, even when the metal terminals30a,20a, and30b shift in the arrangement direction L, the metal terminals30a,20a, and30b can be inhabited from passing over the planar portions412and coming into contact and being entangled with the metal terminals30c,20b, and30d located on the opposed side with certainty. As illustrated in a lower part ofFIG.16, in the case where expression 1: GL+GR=W3−W2, GL<W1, and GR<W1holds where W3is the maximum width of the insertion holes90h of the separator90in the arrangement direction L, even when the metal terminals30a and30b shift in the arrangement direction L, the metal terminals30a and30b can be inhabited from passing over the planar portions412and coming into contact and being entangled with the metal terminals30c and30d located on the opposed side with certainty. The reason is that GL and GR in the expression 1 represent left and right spaces between the planar portions412and the insertion holes90h, and, when the spaces GL and GR are less than the terminal width W1, the metal terminals30a and30b cannot reach the opposite side with respect to the planar portions412. The width of the metal terminals30a and30b described herein is donated by W1. However, in the case where the widths of the metal terminals are different, it is preferable that the widths of the terminals closest to the spaces GL and GR be less than the spaces GL and GR. The detail of the method according to the second aspect of the embodiment for manufacturing the gas sensor will now be described with reference toFIGS.17A-17E.FIGS.17A-17Eillustrate a pair of the metal terminals30b and30d only. However, the same is true for the other two pairs of the metal terminals20b and20d, which are into the page and concealed inFIGS.17A-17E. The lead wires146to be connected to the metal terminals30b and30d are inserted into the insertion holes90h of the separator90so as to protrude from the front-end side of the insertion holes90h (a lead-wire inserting step). Subsequently, the lead-wire-connecting portions33of the metal terminals30b and30d are press-fitted (electrically connected) to ends of the lead wires146(inFIG.17A, a metal-terminal connecting step). Subsequently, the metal terminals30b and30d are moved from the rear-end side of the second jig400and accommodated in the accommodating space400h at the same positions as the metal terminals30b and30d are held in the separator90, and the planar portions are inserted (interposed) between the contact points P2(inFIG.17B, a metal-terminal accommodating step). Subsequently, an end of the separator90is brought into contact with the rear end (upper surface)402of the second jig400while the lead wires146are pulled toward the rear-end side (inFIG.17C, a separator contacting step). As illustrated inFIG.17C, the inner diameter D1of the accommodating space400h is smaller than the maximum outer diameter D2of an end portion of the separator90. Subsequently, the metal terminals30b and30d are inserted from the front-end side of the insertion holes90h of the separator90in contact with the rear end of the second jig400and held in the insertion holes90h (inFIG.17D, the metal-terminal holding step). Subsequently, the second jig400is relatively removed from the separator90to the front-end side (lower side) (inFIG.17E, a jig removing step). According to the second aspect of the embodiment, when one or more pairs of the metal terminals20and30are thus installed in the separator90such that the contact points P2(P1) face each other, the planar portions412of the second jig400are interposed between the contact points P2(P1). Accordingly, the metal terminals30b and30d (or20a and20b, or30a and30c) that face each other are inhibited from coming into contact and being entangled with each other, the metal terminals are inhibited from being damaged and deformed, and workability can be improved. According to the present embodiment, in the separator contacting step inFIG.17D, the planar portions412protrude up to positions nearer than the contact points P2(P1) to the rear-end side. Thus, when the metal terminals are held in the insertion holes90h of the separator90, the metal terminals (contact points P2(P1)) that face each other are isolated from each other by the planar portions412, and the metal terminals can be inhibited from coming into contact and being entangled with each other with certainty. According to the present embodiment, the separator90is prevented from rotating in the circumferential direction in the second jig400as described above, and the metal terminals can be inhibited from coming into contact and being entangled with each other due to rotation of the separator90. It goes without saying that the present invention is not limited to the above embodiments and contains various modifications and equivalents within the spirit and scope of the present invention. For example, the shape of the metal terminals and the insertion holes of the front-end-side separator is not limited to the above embodiments. Examples of the gas sensor include an oxygen sensor and a universal gas sensor in addition to a NOx sensor. The shape of the first jig, the second jig, the separator, and the metal terminals is not limited. The metal terminals may be paired as one pair or two or more pairs. A pin for positioning may be disposed, as the first restricting member that prevents rotation of the separator in the circumferential direction, on a part of an edge surface of the separator or in the terminal accommodating space of the separator. A plurality of the first restricting members may be provided. REFERENCE SIGNS LIST 1gas sensor 10sensing element 11a to12c electrode pad 20,30metal terminal 20f,30f flat board portion 21,31main body 22,32elastic portion 25,351rear-end-side restricting portion 29,352front-end-side restricting portion 25a,29a,35a facing surface 20p burr 90separator (front-end-side separator) 90h,90h1,90h2insertion hole 90w1,90w2wall surface of the insertion hole 90t second restricting member 300first jig 300h,400h accommodating space 300b,400b bottom surface of the accommodating space 300s,400s first restricting member 312,412planar portion 314,316metal-terminal restricting member 400second jig O axial line P1, P2contact point D1inner diameter of the accommodating space D2maximum outer diameter of an end portion of the separator L arrangement direction | 42,323 |
RE49875 | DETAILED DESCRIPTION A system memory installed in a host device is managed by paging. Therefore, data in the system memory is fragmentarily managed page-by-page. To efficiently perform data read/write to a memory card, a host controller supports DMA algorithm capable of data transfer managed page-by-page. That is, data fragmented in the system memory can be transferred by DMA by using a descriptor as a data transfer list. Unfortunately, conventional DMA algorithm generates an interrupt in order to generate a new system address in the boundary between pages. This disturbs the operation of a CPU. ADMA has been developed in order to eliminate this problem. ADMA has a function of transferring data to fragmented data areas in the system memory by paging, in accordance with one read/write command of an SD card. Accordingly, ADMA controls data transfer between the host controller and system memory without any interrupt to the CPU by loading the descriptor in the system memory. A host driver controls the issue of a command to the memory card by setting a register set in the host controller, thereby controlling data transfer between the host controller and memory card, and interruption to the CPU has been used. This method poses no problem when the bus performance is low as in a conventional memory. As the bus performance improves and high-speed data transfer becomes possible in recent years, however, the processing of the host driver generates an overhead. Since it is not always possible to continuously use the area of the memory card, a memory command must be divided into a plurality of memory commands. To control command issue to the memory card by the host driver, the host driver must be executed by causing the host CPU to generate an interrupt midway along data transfer. Therefore, it takes a certain time to respond to the interrupt. This deteriorates the performance because of the influence of the waiting time of the driver processing even when using a high-speed bus. Accordingly, demands have arisen for a method of efficiently performing data transfer by making it possible to execute, by DMA, the processing requiring the host driver during data transfer. Embodiment In general, according to one embodiment, a memory system includes a host controller and DMA unit. The host controller includes a register set configured to control command issue to a device, and a direct memory access (DMA) unit configured to access a system memory, and controls transfer between the system memory and the device. First, second, third and fourth descriptors are stored in the system memory. The first descriptor includes a set of a plurality of pointers indicating a plurality of second descriptors. Each of the second descriptors comprises the third descriptor and fourth descriptor. The third descriptor includes a command number, a command operation mode, and an argument as information necessary to issue a command to the device, and a block length and the number of blocks as information necessary for data transfer. The fourth descriptor includes information indicating addresses and sizes of a plurality of data arranged in the system memory. The ADMA unit sets, in the register set, the contents of the third descriptor forming the second descriptor, from the head of the first descriptor as a start point, and loads and transfers data from the system memory in accordance with the contents of the fourth descriptor. The embodiment will be explained below with reference to the accompanying drawing. The ADMA described below is an ADMA improved by the embodiment. FIG.1schematically shows the memory system according to this embodiment. This embodiment makes it possible to issue SD commands by a host controller during DMA transfer by extending a descriptor capable of data transfer of a system memory, thereby reducing the overhead caused by host driver processing. A system controller11shown inFIG.1controls interfaces with a CPU12, system memory13, and SD controller14. The system memory13stores a host driver21, descriptor table22, and data23. An operating system (OS) secures areas required to store the host driver21, descriptor table22, and data23in the system memory13. The host driver21is a driver provided for, e.g., the SD host controller14and unique to the OS, and is executed by the CPU12. The host driver21generates the descriptor table22before executing ADMA (to be described later). The descriptor table22is a list of information necessary for data transfer between the system memory13and an SD card, and is described by format which can be interpreted by the SD host controller. The structure of the descriptor table22will be described later. The SD host controller14has a function of bidirectionally transferring data between the system memory13and an SD card by using SD commands. The SD host controller14mainly includes a system bus interface circuit31, a memory card interface circuit32, a register set33including a plurality of registers, an ADMA34, and a timer35. The system bus interface circuit31is connected to the system controller11via a system bus. The memory card interface circuit32is connectable to SD cards, e.g., an SD memory card15and SDIO card16, via an SD bus interface (not shown). The SD bus interface is not limited to 4-bits type, but can be applied to e.g. UHS (Ultra High Speed)-II using LVDS (Low Voltage Differential Signaling) system. In UHS-II, commands are transferred in packet form. The register set33of the SD host controller14is classified into a plurality of units (not shown) such as an SD command generation unit, response unit, buffer data port unit, host control unit, interrupt control unit, and ADMA unit. Information such as a command number, command mode, and argument necessary to issue an SD command and information such as a block length and the number of blocks necessary to transfer data are set in the SD command generation unit of the register set33. When these pieces of information are set, the SD command generation unit issues a command to an SD card. The response unit in the register set33receives a response supplied from the SD card in response to the command. The ADMA34is a circuit for transferring data between an SD card and the system memory13without any intervention of the CPU12. The ADMA34executes data transfer in accordance with contents described in the descriptor table22in the system memory13. The timer35detects a timeout error. For example, the timer35detects a timeout error if the operation of a read command is not complete within a time set from the issue to the end of the read command. The CPU12is notified of this timeout error by an interrupt, and the timeout error is processed by the host driver. FIG.2shows an example of the relationship between paging management of the system memory13and SD physical addresses. The system memory13is managed by paging for each small area, e.g., a 4-Kbyte area. An application executed by the host CPU12accesses the system memory13by a logical address by using a paging function managed by the host CPU12. As indicated by a logical address system memory map, therefore, data are apparently arranged in a continuous address area. However, positions in the system memory13in which data are actually recorded are arbitrary, and fragmented as indicated by a physical address system memory map. These data are managed by the addresses and data lengths. The data length is variable. Also, the relationship between the physical address and logical address of data stored in the system memory13is managed by a page table (not shown). On the other hand, data stored in the SD memory card13are managed for each page (each block) having, e.g., 512 bytes to a few Mbytes, and completely independent of the system memory13. When data in the system memory13is to be stored in the SD memory card15, therefore, as indicated by an SD physical address memory map, the data in the system memory13is stored by a size different from that in the system memory13. Data in the SD memory card15is held in continuous memory area designated for each command and has an address designated by the command. The data length is variable and is designated by the other command. DMA transfer directly accesses the system memory13by the physical address. Accordingly, DMA can be executed by forming a descriptor as a transfer list in the system memory13. FIG.3shows a descriptor according to this embodiment. This descriptor is formed in the descriptor table22of the system memory13. The descriptor of this embodiment extends a conventional descriptor and has a hierarchical structure. When using the descriptor of this embodiment, data transfer performed between the system memory13and SD memory card15by ADMA is completely executable by hardware. This obviates the need to interrupt the host CPU12during data transfer. Although an error processing request is notified by an interrupt, no problem arises because the probability of its occurrence is very low. As shown inFIG.3, a first descriptor (integrated descriptor) is a set of pointers to a plurality of second descriptors (partial descriptors). Each second descriptor (partial descriptor) is a pair of a third descriptor (SD command descriptor) and a fourth descriptor (system memory descriptor). The contents of the third descriptor are formed by information for issuing an SD command. That is, the contents of the third descriptor are formed by, e.g., a command number, a command mode, an argument, and a block length and the number of blocks as information necessary for data transfer. The command mode indicates, e.g., read/write. One SD command is issued by writing the third descriptor in the SD command generation unit of the register set33of the SD host controller14. The contents of the fourth descriptor (system memory descriptor) are formed by an address indicating the position of each data in the system memory13, and a length indicating the data length, and indicate a set of a plurality of fragmented data. Since the third descriptor corresponds to one of read/writ commands, one continuous region of the SD memory card can be designated. As shown inFIG.2, when the memory region is divided into two or more regions, each of the regions needs the third descriptor. Therefore, the fourth descriptor corresponding to the third descriptor is programmed to the same data length as that of each third descriptor. The first to fourth descriptors each have attribute information Att. Each attribute information Att contains, e.g., information for identifying the type of descriptor, and an end bit indicating the end position of the descriptor. Note that the third descriptor has a format different from that of the other descriptors, so the attribute information Att may be provided in accordance with at least the first command number. Moreover, the attribute information Att may be provided with each line the same as another descriptor. FIG.4shows an outline of the arrangement of the ADMA34. The ADMA34includes a system address controller34a, data buffer34b, SD command controller34c, and buffer memory34d. The system address controller34a manages addresses in the system memory13. More specifically, the system address controller34a manages the load of the first to fourth descriptors stored in the system memory13. That is, the start address of the first descriptor (integrated descriptor) is set in the system address controller34a as initial value. Thereby, the system address controller34a is able to read information of the first descriptor from the memory13. Since pointers of each of the second descriptors are described in the first descriptor, the system address controller34a reads an address of the second descriptor designated by each of the pointers and reads the second descriptor in accordance with the address. Then, the system address controller34a transfers an SD command descriptor as the third descriptor forming the second descriptor to the SD command controller34c. In addition, the system address controller34a sequentially loads the address and data length of data described in the fourth descriptor forming the second descriptor. In accordance with the loaded address and data length, the system address controller34a reads data from the system memory13and transfers the data to the data buffer34b when performing memory write. When performing memory read, the system address controller13a transfers data from the data buffer34b to the system memory13. To execute these operations, the system address controller34a includes a plurality of registers34a_1to34a_4, and a multiplexer (MPX)34a_5for selecting output signals from these registers, in order to hold the start address of the first descriptor (integrated descriptor), the pointer of the second descriptor (partial descriptor), and the address and data length of data. The SD command controller34c sequentially generates register addresses for setting values in the SD command generation unit, and sequentially sets, in the SD command generation unit of the register set33of the host controller14, register setting information contained in an SD command descriptor as the third descriptor. When the setting of the registers is complete, the SD command generation unit of the register set33issues an SD command. In memory write, the buffer memory34d loads data in the system memory13, which is designated by the system address controller34a, and temporarily holds the supplied data. The data held in the data buffer34b is transferred to the SD memory card15in synchronism with an issued SD command. In memory read, the buffer memory34d temporarily holds data loaded from the SD memory card15as a memory device in synchronism with an issued SD command, and transfers the data to a position in the system memory13, which is designated by the system address controller34a. The operation of the ADMA34using the extended descriptor in the above-mentioned configuration will be explained below with reference toFIG.5. To perform data transfer between the system memory13and SD memory card15, the host driver21forms the extended descriptor as shown inFIG.3in the system memory13. The host driver21sets the start address of the first descriptor in register34a_1of the system address controller34a. When the host driver21activates the ADMA34after that, the system address controller34a loads a second descriptor pointer (partial descriptor pointer) described at the head of the first descriptor (integrated descriptor), based on the start address of the first descriptor held in register34a_1, and holds the second descriptor pointer in register34a_2(ST11). Then, the system address controller34a loads a second descriptor in the location indicated by the second descriptor pointer (ST12). The third descriptor (SD command descriptor) described at the head of the second descriptor is supplied to the SD command controller34c. The SD command controller34c writes data described in the third descriptor, in the SD command generation unit forming the register set33of the SD host controller14. Consequently, the SD command generation unit issues a command to the SD memory card15(ST13). Subsequently, the system address controller34a loads the fourth descriptor (system memory descriptor). The system address controller34a holds the address and data length described in the fourth descriptor, in register34a_3(address) and register34a_4(length), respectively. In memory write, the system address controller34a reads data from the system memory13by using the address in register34a_3(address) as the start address, and transfers the read data to the data buffer34b. In memory read, the system address controller34a writes data of the data buffer34b in the system memory13by using the address in register34a_3(address) as the start address (ST14). In memory write, fragmented data supplied from the system memory13are combined into continuous data in the data buffer34b. The fourth descriptor (system memory descriptor) is made up of a plurality of data each formed by a pair of the address and data length, and the ADMA performs data transfer between the system memory and data buffer34b by repeating this. After that, the ADMA transfers the data held in the data buffer34b to the SD memory card15(ST15). The ADMA accesses data in the system memory13in synchronism with an issued command (read/write command), and data transfer between the memory and card is executed via the data buffer34b by synchronizing them. The total data transfer amounts on the memory device side and system memory side must be set at the same value. When data transfer based on one second descriptor is complete, whether the execution of the whole first descriptor is complete is determined (ST16). If the execution of the whole first descriptor is not complete, the control returns to step ST12, the next second descriptor is loaded in accordance with the partial descriptor pointer described in the first descriptor, and the above operation is executed (ST16-ST12). Each descriptor has the end bit in the above-mentioned attribute information Att, and the end position of the descriptor program can be designated by this end bit. When the third descriptor is set in the register of the SD host controller14in accordance with the next second descriptor, an SD command is issued, and data is transferred in accordance with the fourth descriptor. In memory read, for example, after final data is transferred to the data buffer34b, it is also possible to issue the SD command of the next transmission during DMA transfer to the system memory by reading the following third descriptor. In this case, the operation speed can further be increased because the command issuing time is hidden. On the other hand, if all the contents described in the first descriptor have been executed, the SD host controller14generates an ADMA completion interrupt (ST17). This allows the CPU12(host driver21) to know the normal termination of the ADMA processing. If no error occurs, the host CPU12need not participate in transfer from the activation to the termination of the ADMA, so the host driver does not deteriorate the performance. In addition, the descriptor formation time has no influence on the transfer performance because the next descriptor can be prepared during data transfer. A file system is instructed by the host driver to update information, when the transmission is completed. Thereby, the data transferred to the SD memory card is decided. In the above embodiment, the host driver21generates the extended descriptor in the system memory13in order to perform data transfer between the system memory13and SD memory card15. This extended descriptor includes the first descriptor as a set of pointers indicating the positions of the second descriptors. When the host driver21activates the ADMA34, the ADMA34sequentially loads the contents of the second descriptors based on the contents of the start address of the first descriptor, and executes data transfer between the system memory13and SD memory card15in accordance with the contents of the third and fourth descriptors described in the second descriptors. Therefore, the host driver21does not participate in data transfer executed by the ADMA34. This enables the ADMA34to perform high-speed data transfer. Also, after being activated, the ADMA34generates a command by setting the third descriptor in the SD command generation unit of the register set33, and can execute data transfer between the system memory13and SD memory card15by using hardware alone. This makes the operation speed much higher than that when the host driver21intervenes in the operation. Furthermore, to operate the host driver during data transfer, the host driver is normally activated by an interrupt. Accordingly, the data transfer performance deteriorates if the interrupt response time is not negligible. However, the method of this embodiment can avoid the performance deterioration like this. While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Indeed, the novel embodiments described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions and changes in the form of the embodiments described herein may be made without departing from the spirit of the inventions. The accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the inventions. | 20,611 |
RE49876 | DETAILED DESCRIPTION Embodiments of the disclosure relate to a system, a digital device and method for secure configuration of a headless networking device. The objective of secure configuration is to frustrate the interception of the network configuration by an adversary. Another objective is to limit the network to devices that are intended to have access. Embodiments are described that provide strong authentication of the HD (Headless Device) to the CD (Configuring Device). The authentication ensures that the devices that the CD configures and allows on the network are authentic. As a result, the HD does not need strong authentication of the CD. The HD can accept configuration by any device that proves it has possession of the HD unique credentials. As described herein the CD ensures that only valid devices are configured, and configurable. Herein, certain terminology is used to describe features for embodiments of the disclosure. For example, the term “digital device” generally refers to any hardware device that includes processing circuitry running at least one process adapted to manage the flow of control traffic into the device. Examples of digital devices include a computer, a tablet, a laptop, a desktop, a netbook, a server, a web server, authentication server, an authentication-authorization-accounting (AAA) server, a Domain Name System (DNS) server, a Dynamic Host Configuration Protocol (DHCP) server, an Internet Protocol (IP) server, a Virtual Private Network (VPN) server, a network policy server, a mainframe, a television, a content receiver, a set-top box, a video gaming console, a television peripheral such as Apple® TV, a printer, a mobile handset, a smartphone, a personal digital assistant “PDA”, a wireless receiver and/or transmitter, an access point, a base station, a communication management device, a router, a switch, and/or a controller. Examples of digital devices also include a sensor, an appliance, a security device, such as a gate, door or window lock, or a physical plant controller such as for a water heater, steam generator, pumping system, or climate control system. One type of digital device, referred to as a “controller,” is a combination of hardware, software, and/or firmware that is configured to process and/or forward information between digital devices within a network. It is contemplated that a digital device may include hardware logic such as one or more of the following: (i) processing circuitry; (ii) one or more communication interfaces such as a radio (e.g., component that handles the wireless data transmission/reception) and or a physical connector to support wired connectivity; and/or (iii) a non-transitory computer-readable storage medium (e.g., a programmable circuit; a semiconductor memory such as a volatile memory such as random access memory “RAM,” or non-volatile memory such as read-only memory, power-backed RAM, flash memory, phase-change memory or the like; a hard disk drive; an optical disc drive; etc.) or any connector for receiving a portable memory device such as a Universal Serial Bus “USB” flash drive, portable hard disk drive, or the like. Herein, the terms “logic” (or “logic unit”) and process” are generally defined as hardware and/or software. For example, as hardware, logic may include a processor (e.g., a microcontroller, a microprocessor, a CPU core, a programmable gate array, an application specific integrated circuit, etc.), semiconductor memory, combinatorial logic, or the like. As software, logic may be one or more software modules, such as executable code in the form of an executable application, an application programming interface (API), a subroutine, a function, a procedure, an object method/implementation, an applet, a servlet, a routine, source code, object code, a shared library/dynamic load library, or one or more instructions. These software modules may be stored in any type of a suitable non-transitory storage medium, or transitory computer-readable transmission medium (e.g., electrical, optical, acoustical or other form of propagated signals such as carrier waves, infrared signals, or digital signals). The term “interconnect” is a communication path between two or more digital devices. The communication path may include wired and/or wireless segments. Examples of wired and/or wireless segments include electrical wiring, optical fiber, cable, bus trace, or a wireless channel using infrared, radio frequency (RF), or any other wired/wireless signaling mechanism. The term “message” is a grouping of data such as a packet, a frame, a stream (e.g., a sequence of packets or frames), an Asynchronous Transfer Mode (ATM) cell, or any other series of bits having a prescribed format. Herein, a message comprises a control payload and a data payload. The control payload is adapted to include control information such as source and destination MAC (Media Access Control) addresses, Internet Protocol (IP) addresses (e.g., IPv4 or IPv6 addressing), protocol, source and destination port information, and/or packet type. Lastly, the terms “or” and “and/or” as used herein are to be interpreted as inclusive or meaning any one or any combination. Therefore, “A, B or C” or “A, B and/or C” mean “any of the following: A; B; C; A and B; A and C; B and C; A, B and C.” An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive. Certain details are set forth below in order to provide a thorough understanding of various embodiments of the disclosure, albeit the invention may be practiced through many embodiments other that those illustrated. For instance, illustrative embodiments describe configuring a headless device. Such discussions are for illustrative purposes and do not preclude this invention from being conducted on other types of devices and using different encryption and key exchange systems. Also, well-known logic and operations may not be set forth in detail in order to avoid unnecessarily obscuring this description. I. General Architecture Referring toFIG.1, an exemplary embodiment of a headless device (HD)100is shown in block diagram form. In accordance with one embodiment of the disclosure, the headless device100comprises a hardware external interface110, processing logic120, storage logic130, and optionally a sensor suite150and actuation logic160. One or more of these logic units are coupled together via an interconnect140. The interface110enables the headless device100to communicate with other devices supporting wired and/or wireless connectivity. For instance, the interface110may be implemented as a wireless adapter (e.g., one or more radios, antenna(s) or the like) adapted to receive ingress messages and/or a wired adapter (e.g. connector) through which ingress messages are received over a wired interconnect. In embodiments, the network interface is a Wi-Fi interface, but the invention is not so limited and other wireless and wired interfaces may be used. Processing logic120is adapted with logic to receive and process ingress packets, and provide any packet processing. The processing logic analyzes ingress packets, interprets any commands or other information, performs any calculations and sends commands to any of the other logic. The processing logic also generates egress packets and provides, for example, (1) destination MAC address, (2) source MAC address, (3) IP (DEST IP) address, (4) source IP (SRC IP) address, (5) protocol, (6) destination port number (DEST PORT), and/or (7) source port number (SRC PORT) for any egress packets as appropriate. The processing logic operates using the received network configuration to receive and send packets to designated nodes on the network through the interface110. As further shown inFIG.1, storage logic130is volatile and/or non-volatile memory implemented within the headless device100and used by the processing logic120. The storage logic may contain programming instructions and temporary variables for the operation of the processing logic. According to one embodiment of the disclosure, the storage logic contains the network configuration received on setup from a configuring device. According to one embodiment of the disclosure, the storage logic130contains keys135. This may include a public and a private key or a symmetric key. There may be multiple keys for different purposes. There may also be temporary and ephemeral keys. Alternatively, the keys may be stored in the processing logic. The keys may be stored in a special trusted or secure module within the storage logic or provided separately. As further shown inFIG.1, the headless device may optionally include a sensor suite150and actuation logic160both coupled to the interconnect140to provide additional functions to the headless device. The particular sensor and actuators may depend on the nature of the device. The sensor suite and actuation logic may be coupled to external devices for information and control either through the interconnection or directly as indicated by the arrows. For a water heater, the sensors may be temperature sensors and the actuator logic may control a heat source. For a thermostat, the sensors may include temperature sensors in different locations as well as humidity, barometric pressure and air particulates or contaminants. The actuator logic may drive heating, cooling, humidifiers, filters, and other device. For a robot, the sensors and actuator logic may correspond to the entire robot. For a wireless access point, there may be no sensors or actuation logic because the device provides only network interfaces and packet processing. Finally, the headless device has a label170with the device's public key on it. The key may be simply printed as numerical, hexadecimal, or alphanumeric text. Alternatively, or in addition, the key may be printed in machine readable form, such a bar code, a QR code, a holographic code, a magnetic code, or a radio code, such as a passive RFID (Radio Frequency Identification) code. The label may be attached to a housing of the device or it may be in separate documentation provided with the device. In embodiments, a user reads the key from the label and provides it to a configuring device in order to start the authentication of the headless device. Alternatively, the configuring device or a reader attached directly or remotely to the configuring device may read the label. The label may be human or machine-readable or both. The public key on the label170may also be stored in the key storage135. In the described example, the headless device has no user interface. There is no display and no user input device, no keyboard, mouse, touch screen, touchpad, or other device. However, the invention is not so limited. The headless device as described herein is not required to have no user interface. Some devices, such as a wireless access point or a wired network switch have no user interface and must be configured remotely. In other devices, such as for example a thermostat or a water heater, there may be a display and some type of user interface such as buttons, or a touch screen for controlling the device, however the device must still be configured remotely. Simpler appliances, such as those on a smart grid, a refrigerator, a television set-top box, or a thermostat, may have a user interface, such as a touchscreen, remote control or other interface that allows for network configuration but may still be configured remotely without using the user interface. Still other devices, such as remote computers, handheld smart devices, such as telephones, media players, and tablets may be configured using the user interface. As described herein, each of these devices may be configured without using the user interface. They are headless for purposes of the remote configuration described herein. Referring toFIG.2, an exemplary embodiment of a configuring device (CD)200is shown in block diagram form. In accordance with one embodiment of the disclosure, the configuring device200comprises a hardware external interface210, processing logic220, storage logic230, and a user interface250. One or more of these logic units are coupled together via an interconnect240. The interface210enables the configuring device200to communicate with other devices supporting wired and/or wireless connectivity. For instance, the interface210may be implemented as a wireless adapter (e.g., one or more radios, antenna(s) or the like) adapted to receive ingress messages and/or a wired adapter (e.g. connector) through which ingress messages are received over a wired interconnect. In embodiments, the network interface is a Wi-Fi interface, but the invention is not so limited and other wireless and wired interfaces may be used. Processing logic220is adapted with logic to receive and process ingress packets, and provide any packet processing. If the configuring device is a switch, router, or access point, the processing logic may analyzes ingress packets and perform packet processing and routing operations. The processing logic also performs any calculations and drives any operations appropriate for configuring new devices on the network through the interface210. As further shown inFIG.2, storage logic230is volatile and/or non-volatile memory implemented within the configuring device200and used by the processing logic220. The storage logic may contain programming instructions and temporary variables for the operation of the processing logic. According to one embodiment of the disclosure, the storage logic contains the network configuration235that is provided to any new network devices, such as the domain parameter set235. According to one embodiment of the disclosure, the storage logic230contains keys236. This may include a public and a private key or a symmetric key. There may be multiple keys for different purposes. There may also be temporary and ephemeral keys. Alternatively, the keys may be stored in the processing logic. The keys may be stored in a special trusted or secure module within the storage logic or provided separately. As further shown inFIG.2, the configuring device also includes a user interface250. The user interface may include any of a variety of different devices for reading machine readable codes, such as a camera or scanner for optically readable codes, such as bar codes and QR codes. The configuring device may also include RF and magnetic readers. The user interface also includes a display and an input device. This may be a display and a keyboard or a touchscreen or another type of user input device. FIG.3is a diagram of a general packet processing and routing system architecture with headless devices, switching devices, and one or more configuring devices. A router or data center110is coupled to or includes a distribution switch120that is coupled to one or more other data centers and domains for packet communication. The distribution switch has uplink and downlink trunks to connect with a variety of different nodes. Among the nodes, there may be one or more access switches140to serve one or more external clients or client ports. Each access switch may include Ethernet ports or a WiFi interface or both. The distribution switch may also be coupled to any of a variety of different client end connections and types, such as trusted or entrusted user data, workstation, and computing terminals150, wireless access points151, voice terminals152, and other devices153, such as smart displays, appliances, set-top boxes, sensors, and smart grid enabled devices. The end terminals may be connected directly through a single one of the access switches or indirectly through an intermediate switch or access point. II. Device Configuration The following description refers to configuring a headless device (HD) using a configuring device (CD). While the described approaches are well-suited to devices that do not have any direct user interface, the HD is only necessarily headless in that no user interface is required for its authentication and configuration. In embodiments, the HD possesses a public/private key pair, based for example on discrete logarithm cryptography. The key pair may be generated at manufacture time for convenience or, if desired, it may be installed later by an administrator or a user. An identifying label170may be attached to or shipped with the HD to allow a user to access the public key. The label may show the public key in plain text or in an encoded or fingerprint form. A bar code, QR code, or other optical or magnetic code may provide the public key on packaging or elsewhere. The public key and its domain parameter set may be affixed to the HD or be part of the documentation or paperwork that accompanies the HD. FIG.4is a process flow diagram for a more detailed example of authenticating a device for configuration. The device that is to be configured is referred to as the HD and the device that will configure the HD is referred to as the CD. At410, the CD obtains the public key, for example by scanning the QR code, and implicitly trusts it as being the public key of the HD that the CD wishes to configure. The label could be attached to the physical case of the HD or the HD could use another device to display its label, for example, an HD could be a TV set top box that uses a TV to display its label. Alternatively, if the label contains a fingerprint of the HD's public key then the CD obtains the HD's public key in another manner and verifies the fingerprint before trusting it. In either case, the CD obtains the public key and uses the label to provide the trust necessary for subsequent authentication. At412, the CD then generates a secret. In one embodiment, the CD derives an ephemeral public/private key pair, such as a Diffie-Hellman public/private key pair, although other anonymous authentication techniques may be used instead. At414, the CD uses its ephemeral private key and the HD's static public key to generate a shared secret using an ephemeral-static key exchange. An example of such an exchange is described in “Recommendations for Pair-Wise Key Establishment Schemes Using Discrete Logarithm Cryptography”, by E. Barker, D. Johnson, and M. Smid, National Institute for Standards and Technology, NIST Special Publication 800-56A, March 2007, see especially Section 6.2.2 (hereinafter referred to as “SP 800-56A § 6.2.2”). However, the invention is not so limited. At416, a message is sent to the HD. In one embodiment, the CD's ephemeral public key is sent to the HD. As an optimization, in addition to the public key, the CD may also formulate a test word for the HD. As an example, the resulting shared secret derived by the CD may be used to wrap a test word for use in testing the HD. In this example, the test word is wrapped using, for example, an authenticated encryption scheme. The test word may be any of a variety of different test words. In one embodiment the CD generates a random nonce, NCD, of the CD's choosing. At418, the CD sends its ephemeral public key and the wrapped NCDto the HD. At420, the HD receives the message and derives a shared secret with the CD. In one embodiment, the HD uses discrete logarithm cryptography, for example, SP 800-56A § 6.2.2, with the ephemeral public key received from the CD and its own static private key to derive the secret. The HD's static private key may be stored in a secure register as described above with respect toFIG.1. If the CD has sent the wrapped nonce, then, using the derived secret, the HD uses the shared secret at422to unwrap the random nonce, NCD, that it received from the CD. If the CD sent a wrapped nonce, the HD may then apply a variety of different tests to determine whether the CD knows the HD's public key and whether the exchange should continue. At424, if the HD cannot unwrap the random nonce, then the HD knows that the CD does not possess the HD's public key and is not a valid device. In this case, the authenticated key exchange fails. The first test for which this test word has been established is failed and the process ends. The HD may apply additional tests, depending on the particular implementation. If the HD is able to unwrap the nonce, or if no nonce was sent, the exchange continues. If the exchange continues, then at426, the HD produces its own test word, such as another random nonce, NHD. At428, the HD combines the two nonces into a single word and then wraps them in the shared secret. In a simple example, the HD concatenates the two nonces as NCD, NHD. While concatenation and wrapping are described herein, any of a variety of different approaches may be used to encrypt integrity protect the two test words with the shared secret, depending on the particular implementation. The HD then sends the two test words in the encrypted and integrity protected form to the CD at430. At this stage in the process, the HD still has no assurance that the CD is real or that the message that it received was not a replay of a previous message from a different node or device. For more security, the HD will not yet accept configuration from the sender of the message. If the CD did not send a random nonce, then the HD produces its own test word wraps it in the derived secret and sends it to the CD without any concatenation. At432, the CD receives the wrapped concatenation of the two nonces. At434, the CD uses the shared secret to unwrap the two notices. At436, the CD determines whether the two nonces are recoverable by verifying the integrity of the message using the authenticated encryption scheme. If both nonces NCD, NHD, are not recoverable, then at436the key exchange fails. The CD knows that there is a security risk. It can assume that the HD does not possess the private analog to the public key that the CD obtained from the label. The HD is therefore an imposter so the authenticated key exchange fails. If the CD has sent only its own nonce, then the same operations are performed with only the one nonce. At438, if the one or both nonces are recoverable, depending on how many were received, then the CD checks that its nonce, NCD, was returned accurately. If not, then the CD aborts the exchange and the authenticated key exchange fails. If NCDwas unwrapped, however, then at440, the CD builds a new test word combining the nonces in a way that differs from how the HD combined them, and encrypting and integrity protecting them in some way. In one example, the CD concatenates the two nonces in the reverse order NHD, NCD, wraps the concatenated nonces with the shared secret key and at442, sends the wrapped concatenation to the HD. In another example, the CD generates a message which proves that it knows NHDthe nonce generated by the HD. This could be by adding the value 1 to the nonce or any other technique that results in a different message from the received message but still proves that the CD knows NHD. At this point, the CD has authenticated the HD. It knows that the HD knows the private analog to the public key whose trust was obtained from access to the HD's label. It has proof that the HD is an active participant in the exchange because the HD proved possession of a shared secret that could only have been generated by the HD, and, in some cases, has returned the CD's random nonce. The CD knows that only one device can complete the protocol, the CD can therefore safely proceed to the configuration step with the assurance that the CD has authenticated the headless device that is being configured (the HD). The HD, however, does not yet have assurance that the CD can be trusted because the CD has not proven knowledge of the shared secret nor that it is an active participant in the exchange. At444, the HD obtains the message from the CD and at446, uses the shared secret to unwrap the two nonces. At448, if they are not recoverable, then the HD knows the CD was unable to unwrap its nonce, that the CD does not possess the HD's public key, and that the CD is not authorized to configure the HD. The authenticated key exchange fails. Alternatively, if the CD did not send its nonce at416, then the HD similarly attempts to recover the message which proves the CD was able to determine NHD. If the HD is able to unwrap the two nonces, or recover the proof of knowledge of the shared secret, then the process continues. At450, it checks that its nonce, NHD, was returned by the CD, or if the CD demonstrated a proof that it knows NHD. If proof of knowledge of NHDwas not returned, then the HD aborts the exchange and again the authenticated key exchange fails. If NHDwas successfully returned or knowledge was successfully demonstrated, then the HD has an assurance that the CD is an active participant in the exchange, knows the secret, and is in valid possession of the HD's public key. In the example described herein, access to the HD's public key is used to determine whether a user of the CD has physical possession of the HD or some other valid authorization to configure the HD. The exchange has also confirmed that this CD is the active participant in the exchange and not an interloper, snooper, or other imposter. Returning the HD's random nonce shows the CD's possession of the shared secret. Optionally, for additional security, the CD can check to determine whether the CD's nonce, NCD, was also successfully returned. At this stage, if all of the tests are passed, then the CD has authenticated the HD and the HD has an assurance that the device that wants to configure it is in physical possession of its label (or is in possession of the HD's public key by some other means) and is therefore allowed to configure it. At452, the HD allows the CD to configure it and the CD can now begin a separate protocol to configure the HD. The CD can configure the HD in any of a variety of different ways. In embodiments, a domain parameter235will be sent to the HD together with the addresses for domain name servers. The CD may also configure the HD's IP address, DHCP settings, passwords, and provide any host names for use by the HD, Protocols and packet formats for use on the network may also be defined. There are other variants involving the protected content that is exchanged, or how the exchange is initiated. In the example described above, a label is used for bootstrapping trust of a public key and a static ephemeral Diffie-Hellman key exchange is used to address an asymmetric security problem involving a headless networking device. The asymmetric security problem relates to a requirement on the CD for strong security. The CD must know that the CD is configuring the right HD and needs proof that the responding HD is the right HD. So in the above example, the CD proves that it is in possession of the public key which the CD has previously trusted through the bootstrapping process. The HD, on the other hand, has low security. It merely needs to know that it is being configured by an entity that controls it, or demonstrates knowledge of its physical characteristics, namely, the label which contains its public key FIG.5is a process flow diagram of an alternative message exchange for authenticating the CD and the HD. In the example ofFIG.5, the message exchange is simplified and generalized. The process begins at510, when the CD scans the HD's label170. As mentioned above, the label may be attached to or printed on the HD or in documentation or other supporting material of the HD whether machine or human-readable. In one embodiment, a human readable label is read by a human and the code or key is then manually entered into the user interface of the CD. The person reading the label and the person entering the information do not need to be the same or in the same location. At512, the CD obtains the HD's public key based on the scanning of the label. At514, the CD performs an ephemeral key exchange with the HD. This may be a Diffie-Hellman key exchange or any other type key pair exchange. This generates a shared secret between the HD and the CD. At516, the CD encrypts a first information, for example a nonce with the shared secret. The information may be any test word that is difficult for imposters to guess. A random or pseudorandom number may be used, but the invention is not so limited. At518, the CD sends the encrypted and integrity protected information and, the ephemeral public key, to the HD. The HD uses its static private key and the ephemeral public key of the CD to compute the shared secret. At520, the HD derives the information, e.g. the nonce, using the shared secret. To prove itself to the CD, at522, the HD generates a second information to indicate that it possesses the shared secret from the key exchange. In embodiments, the HD encrypts and integrity protects the received nonce using the same shared secret and at524, the HD sends the encrypted nonce to the CD. For additional security, as mentioned above, the CD may include its own nonce or any other information or test word. At526, the CD receives the second information from the HD and then recovers the received nonce using the shared secret. The CD checks whether the received decrypted nonce matches the one that it originally sent. If there is a match, then the CD has determined that the HD possesses the shared secret and has shown that it is an active participant in the exchange by returning the CD's nonce wrapped in the shared secret. The HD has therefore been authenticated to the CD. At528, the CD configures the HD. The CD may also produce a third information (not shown) that is composed of the two nonces transposed in a different manner than the second information. In one embodiment, the order of the nonces is swapped. If the CD did not send a nonce at516the CD may compute a third information in a way that proves knowledge of the recovered NHD. In one embodiment, the value one is added to NHDto produce the third information. The CD encrypts and integrity protects the third information using the shared secret and sends the encrypted and integrity protected third message to the HD. If a third information has been produced and sent then the HD receives and unwraps the encrypted and integrity protected third information using the shared secret. If the nonces are unable to be recovered, then the HD knows that the CD was unable to successfully unwrap the second information, does not know NHD, does not know the shared secret and therefore is not authorized to configure it. If the third information was successfully unwrapped and NHD, or knowledge of NHD, was demonstrated, then the exchange completes successfully. The HD has received assurance from the CD that it is in physical possession of the HD or has knowledge of its physical characteristics. Additional advantages and modifications will readily occur to those skilled in the art. Therefore, the invention in its broader aspects is not limited to the specific details and representative embodiments shown and described herein. Accordingly, various modifications may be made without departing from the spirit or scope of the general inventive concept as determined by the appended claims and their equivalents. For instance, different or additional tests may be performed between the two devices, different forms of key generation and exchange may be used, and different test words may be used, depending on the particular implementation. The description is thus to be regarded as illustrative instead of limiting. | 31,557 |
RE49877 | DESCRIPTION OF PREFERRED EMBODIMENTS The present invention will now be described in terms of specific example embodiments. It is to be understood that the invention is not limited to the example embodiments disclosed. It should also be understood that not every feature of the methods and system handling the method is necessary to implement the invention as claimed in any particular one of the appended claims. Various elements and features of the method are described to fully enable the invention. It should also be understood that throughout this disclosure, where a method is shown or described, the steps of the method may be performed in any order or simultaneously, unless it is clear from the context that one step depends on another being performed first. Before explaining several embodiments of the invention in detail, it is to be understood that the invention is not limited in its application to the details as set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The systems, methods, and examples provided herein are illustrative only and not intended to be limiting. In the description and claims of the present application, each of the verbs “comprise”, “include” and “have”, and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of members, components, elements or parts of the subject or subjects of the verb. It is an object of the present invention to allow effective matching between people by using Collaborative Filtering. The System FIG.1is a diagram of the environment in which the system operates. The System101is preferably software running on a Server102, connected to the Internet103. Users104connect to the Internet using Devices105running Internet Browsers such as Microsoft Internet Explorer or Mozilla FireFox. The Users104direct their Browsers to connect to the Server, where they are presented with a User Interface to the System101. The Process FIG.2is a diagram of the process performed by the System once Users are connected to it: In step201some or all of the Users are each connected to another User. This connection may be done using text chat, voice, video, email or any other suitable medium. The System may additionally present to each User information about the other User, such as age, gender, location, a picture etc. In one preferred embodiment, the connection is limited in time. In step202each of the connected Users is asked for his opinion about the User he was just connected to. The opinion may be a score or a decision on whether he would like to further communicate with the other User. The opinions are stored. The System then attempts to match between Users. The System's goal is to find matches that have a relatively high likelihood of being successful (i.e. a match in which each User has a positive opinion on the other). The System matches Users by estimating the opinion each User would have on all or some of the other Users, and choosing the matches in which both Users are estimated to have a positive opinion on the other User. In step203, the System uses Collaborative Filtering to estimate opinions. In other words, the opinions the User gave on other Users is compared to the opinions other Users gave, in order to predict the opinion of the User on Users for which he did not yet give an opinion. Any effective Collaborative Filtering algorithm may be used for this purpose. Once the System has estimated opinions of all Users on all (or some of the) other Users, it attempts to make one-to-one matches that create the overall highest number of successful matches. In order to simplify the matching process, in step204the System first normalizes all estimated opinions to represent the likelihood (between 0 and 1) that a User will have a positive opinion on another User. The system then multiplies each likelihood by the opposite likelihood (that the other User will have a positive opinion on the first User), thereby reaching the likelihood that both Users will have a positive opinion on each other. In step205, the system then calculates for each User the difference between his highest likelihood match and his second highest likelihood match (“likelihood difference”). The likelihood difference represents the ‘importance’ of matching that User to his most likely match. In step206, the system finds the User who had the highest likelihood difference, and matches him to his most likely match. The two matched Users are removed from the list, and the process is repeated from step205until no more Users remain or no more effective matches (i.e. matches with high likelihood of mutual positive opinion) can be found. Once the matching process is complete, each User is connected to their match, as in step201, and the process is repeated. In each iteration of the process, more information about Users' opinions is accumulated, which should result in higher accuracy of the Collaborative Filtering algorithm and overall matching. In a preferred embodiment of the present invention, additional filtering is applied to the matches. For example, a female user may require to be matched only to male users aged 25-30. This may be enforced in step204by placing a likelihood of 0 for the match between that female user and all users not matching the criteria. This process can also be applied to all user-pairs who were already connected, thereby preventing repeated matches. In one embodiment of the present invention, if both Users provided in step202a positive opinion on the other, then they are provided mutual communication details such as email address, phone number, instant messaging address, or physical address. Since the process described above involves checking the match between all possible user-pairs, processing time may become unacceptable when servicing a large number of Users. In such a case, the System may divide the Users to smaller groups, and run the process on each group separately. This may of course cause the System to miss possible matches. To reduce this effect, the System may place each User in several groups, as well as choose groups that are a-priori more likely to create good matches (e.g. group together Users of similar age and location). Referring now toFIG.3, which describes another embodiment of the current invention, it is provided a method300of matching several pairs out of a plurality of persons. The method includes step301of connecting persons to each other, step305of receiving from the persons personal opinions on other persons, step310of calculating from the personal opinions a first estimated opinion of a first person on a second person and a second estimated opinion of the second person on the first person, based on at least a collaborative filtering algorithm, step315of multiplying mutual estimated opinions for user-pairs, and step320of matching the first person and the second person in accordance with the first and second estimated opinions. In some embodiments, the method may include the step325of connecting the first person and the second person for a predetermined time duration. The connecting is done using a communications channel like text chat over internet protocol, voice over internet protocol, video over internet protocol, and electronic mail. The method may further include the step330of receiving a first personal opinion of the first person on the second person and a second personal opinion of the second person on the first person. Also, the method may include the step335of providing mutual communication details to the first person and to the second person in accordance with the first personal opinion and the second personal opinion. Exemplary communication details are electronic mail address, phone number, instant messaging address and physical address. In some embodiments, the first estimated opinion is the estimated probability that the first person wants to be matched to the second person, and the second estimated opinion is the estimated probability that the second person wants to be matched to the first person. The matching320of the first person and the second person is done in accordance with the result of the multiplication of the probabilities. While the present invention mainly discusses aspects related to online dating, it will be appreciated by persons skilled in the art that it may be easily extended to other situations applicable to matching people, such as non-romantic social relationships and business relationships. While particular embodiments of the invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the invention in its broader aspects, and therefore, the aim in the appended claims is to cover all such changes and modifications as fall within the true spirit and scope of the invention. | 9,353 |
RE49878 | DETAILED DESCRIPTION As discussed in more detail below, in some embodiments, the present disclosure is directed to a transparent “one-sided” display/screen system where the on-screen or broadcast talent or presenter can see interactive content, tool palettes, prompts (and the like) as well as their own sketches and annotations, but the camera/audience will see the broadcast talent, but will not view certain other elements viewable to the broadcast talent. With touch, gesture or tracking information of the broadcast talent's performance, relevant high resolution, high-quality computer generated (CG) graphics, 3D renderings, and HD video and images can be synchronized and composited (or superimposed) over the camera feed of just the talent's performance, resulting in production-quality video commentary of the broadcast talent with overlays. Some embodiments of the present disclosure provide a transparent “two-sided” display/screen system, which allows at least one person on each side of the display/screen to see each other, as well as independent 2D or 3D content from each person's side of the screen. Such screens could also be used in advertising billboards, windows, and information signage, as well as interactive games, and the like. If solely a standard transparent screen (e.g., a transparent OLED TV) between the broadcast talent (or presenter) and the camera were used, it would allow content to be presented to the viewing audience without occlusion and allow some eye-contact between the talent and the viewing audience; however, the content viewed by the talent would also be visible to the camera (and, thus, the viewing TV audience). Such an arrangement also presents visual imaging or interpretation problems with content being backwards for either the talent or the viewing TV audience. If the screen were flipped horizontally to obviate such visual imaging problems, it would also flip the appearance of the talent, which, in many cases, may make the talent look unfamiliar (e.g., hair parts on the wrong side) or change their trademark or distinctive look. Some embodiments of the present disclosure may use a transparent scattering screen with specially designed optical filtering or gating of an optical property (e.g., polarization-based (linear or circular) or wavelength/color-based) of a source light (or image) and a reflected light (or image), which leverages the benefits of a standard transparent display while avoiding its drawbacks or problems. In particular, for polarization and wavelength gating, a principle of some embodiments of the present disclosure is to project a first optical property (or state) of the light (e.g., using a projector filter located at the projector or near the screen) onto a transparent scattering screen, so the talent (located on one side of the screen) can see the projected image, then use a camera-side filter (located over the camera lens or near the screen) to block the reflected light, e.g., having the first optical property (or state) of the light so it is not seen by the camera. Simultaneously, the broadcast talent (or presenter) is illuminated by studio/stage light (or ambient light) having optical properties other than the first optical property (or having multiple optical properties or states); thus, much of the light (i.e., the talent image) will pass through the camera filter allowing the talent to be seen by camera. In some embodiments, the camera/projector filters may be consolidated at the screen (or screen assembly). Accordingly, the present disclosure uses certain beneficial features of standard transparent displays while avoiding non-beneficial ones, and also enables other more advanced interactive arrangements, such as multi-person 2-way screen interaction, 3D imaging, and others. Referring toFIG.1A, an overall view of an embodiment of a gated, one-sided transparent display system8of the present disclosure is shown. In particular, in some embodiments, the display system8includes a transparent display screen10(discussed hereinafter), a viewer12, e.g., a talent, located on one side (e.g., Side B or back side (inFIG.1A) or talent side or right side (in the side-views shown herein)) of the transparent screen10, and a camera system40(or camera or viewer or viewing system) and a projector system32(or projection system or projector) both located on an opposite side (e.g., Side A or front side (inFIG.1A) or camera side or left side (in the side-views shown herein)) of the transparent screen10(also seeFIG.2A). Other labels may be used for each side of the screen10if desired. The display system8is configured to allow the talent12or, generally, a “viewer” (e.g., an individual performing for a viewing TV audience, such as an analyst, broadcaster, presenter, or the like) to view and interact (if desired) with a talent graphics image (or signal)30, also referred to herein as the optical projection image (or signal) or graphics image or GUI image30, which may include various graphical user interface (GUI) elements, such as interactive graphics or content14(e.g., players on a court/field), tool palettes, such as user choices16and tool bar options18, user/talent prompts19(e.g., prompts for the talent from a producer, director, other talent in the studio), and the like, as well as the talent's12sketches and annotations20(discussed more hereinafter withFIG.1C). Other interactive/GUI features of the image30may be displayed or provided if desired. While annotation-type interaction with the talent graphics by the talent12may be used if desired, such annotation-type interaction by the talent12is optional. For example, in some embodiments, the talent12may provide only commentary (verbal or hand/body gestures) on or near the talent graphics being viewed by the talent12and not actually annotate on the talent graphics image14. Also, in addition to the talent12seeing the projection image30on the transparent screen10, the talent12also sees through the transparent screen10to things or images located on the other side of the screen (e.g., on Side A), as shown in the talent's view of the screen10(discussed more hereinafter). In particular, inFIG.1A, the talent12sees the camera system40through the screen10. The graphics image30may be received from the projector system32, which projects the image30onto the screen10, and which may include a projector (discussed herein) and optical components to provide the graphics image30having the desired optical signal characteristics or gating (discussed hereinafter). The camera system40may contain a video camera (discussed herein) and optical components to perform the desired optical signal filtering or gating (discussed hereinafter) to view the talent12through the screen10, but omit the talent graphics image30(or the graphic elements14,16,18,19) that are seen by the talent12from the image input to the camera. The camera system40provides a digital camera optical signal (or image) on a line42, indicative of the image(s) seen by the camera system40, which includes the talent12located behind the transparent screen10and any graphics images displayed on (or displayed by) the screen10that are seen by the camera40(none in this case), collectively shown (for illustrative purposes) as a digital camera image44, shown by a dashed line43. The digital camera optical signal42is provided to a rendering engine50, which processes the image for use in the system (discussed hereinafter). The transparent screen10may also have touch or gesture (movement or voice or sound based) tracking sensors built into the screen10or external thereto (not shown), which may provide an annotation tracking signal on a line52to the rendering engine50, indicative of the talent's12annotations (or telestrations)20made on the interactive graphics element14seen on the screen10by the talent12(or presenter). In particular, the touch or gesture may be measured by the tracking sensors and the tracking signal is recognized and translated by the rendering engine50to be interpreted as a command. These commands (described more hereinafter) may be used to interact with the graphics on the screen10to create the visual effects desired by the talent12. The tracking sensors may also map the location (or coordinates) of the gesture or touches to know where in the projection image30(and the viewing audience image) to show the annotations (or telestrations)20. The rendering engine50(or RE) receives input signals (described above) on the lines42,52, and an input base image or video on a line49, and provides a digital content optical signal (or digital content signal) on a line53to the projector system32, indicative of the talent graphics output image (or projection image)30projected on the screen10by the projector system32to be viewed by a talent12. The rendering engine50also provides a composited broadcast signal70, which is provided to the viewing TV audience (described hereinafter). The rendering engine50contains the necessary hardware, software, firmware, and the like, needed to perform the functions described herein. The rendering engine50receives the touch or gesture data on the line52from the screen10(or corresponding sensors, hardware, firmware, or software) and creates a digitized input graphic image54shown by a dashed line51having digital pixels or location coordinates which map to the transparent screen10. The digital image54is indicative of the options (e.g., tool bar18) selected by the talent12and the detected talent movements, which are mapped onto the image54, such as the talent annotation graphic arrow20. The rendering engine50then combines (or mergers or adds) the talent annotation graphic20(or the entire image54) to the digital image signal on the line53provided to the projector system32using the mapping information to create an updated digital content signal53. The resultant combined image (indicative of the updated digital content signal) is then displayed on the screen10for the talent12to view, as shown by the arrow20in the graphic element14. In addition, the rendering engine50creates a Computer-Generated Graphic Imagery (or CGI) digital overlay56, shown by a dashed line55. The digital overlay56is indicative of the imagery desired to be shown to the viewing audience, which may include an upper portion60corresponding to the transparent screen10, having certain portions or graphic elements that are also displayed to the talent12, e.g., the players/court graphic element (or talent graphics image)14, and also includes the talent's annotation graphic20(arrow) derived from the digitized input graphic image54(discussed above). The overlay56may also include other graphics or images not displayed to the talent12, such as a game or tournament logo61, game clock and score banner62, stats and graphic for a given player64, or other graphics or information. In some embodiments, the talent annotation graphic arrow20may be fed to both the projector image30and the digital overlay image50. The digital overlay56(without the talent annotation20), may be referred to as the “base” image on the line49, which is provided to the rendering engine50in real-time, from an external digital source, such as a computer or server controlled by a show producer, or other source that determines the base image to be shown to the viewing audience. Any other type of overlay or combination or integration or compilation of images, graphics or video may be used if desired. The rendering engine50combines the digital overlay image56with the digital camera image44(talent only view from the camera system40) to create the composited broadcast signal70, shown by a line57, which is a digital output signal (or image or video) provided to a viewing audience. Accordingly, with the transparent one-sided display screen10, the broadcast talent12can see interactive content14, tool palettes16,18, prompts19, and the like, as well as the talent's12own sketches and annotations20, but the camera system40(and viewing audience) sees only the talent image44. In particular, with talent touch, gesture or tracking input information on the line52added to the “Base” image, the rendering engine50creates the resulting digital CGI overlay image56, which may include relevant high resolution high-quality computer-generated imagery (CGI) graphics, such as HD video and images, including 3D renderings. The resultant CGI overlay may then be synchronized, mapped and composited (or superimposed) over the camera feed image44(of just the talent's audio/visual “performance”), resulting in production quality video commentary with digital overlays, shown as the image70. Referring toFIG.1B, a flow diagram100illustrates one embodiment of a process or logic for implementing the Rendering Engine Logic50, which may be implemented in hardware, software, or firmware, or the like. The process/logic100begins at block102by receiving a “base” or underlying broadcast image, graphics or video desired to be broadcast to the viewing audience. For example, using the images ofFIG.1A, the base image may be the graphic elements14,61,62,64, of the image56, without the annotation arrow20. Next, at block104, the logic100extracts interactive graphic elements (e.g., interactive graphic element14) from the Base image and adds graphics for visual tools for talent to use (e.g., talent graphic tools16,18,19) and sends the collection of talent graphics14,16,18,19from the base image to the projector system32for display on the screen10to be viewed by the talent12. The graphics items to be displayed to the talent12on the screen10may be predetermined and flagged digitally with a code or label such that the rendering logic50may identify the items from the rest of the image data and extract the desired talent graphics to be displayed to the talent12. Next, block106determines if data has been received that is indicative of talent annotation activity, e.g., screen touch or hand gesture, detected directly by the screen10(e.g., touch screen), or by sensors (in the screen or separate therefrom) which identify hand motion (or other gesture) of the talent12, which indicate a particular annotation action is desired to be illustrated on the projected image30. If touch/gesture data has been received, a block108determines the type of annotation action and creates or updates the talent annotation image14to include the talent annotation, e.g., the arrow20(FIG.1A). If the result of block106is NO, or after performing block108, the logic proceeds to block110which combines the “base” image with the latest version of the talent annotation image to make the CGI Overlay Image. Next, a block112retrieves the Camera Talent View image, i.e., the camera's view of the screen, e.g., the image44(FIG.1A), which would include the image of the talent12as viewed by the camera seeing the talent12through the transparent screen10and no images projected on the screen for the talent12to view (as discussed hereinafter). Next, a block114combines the CGI Overlay Image and Camera Talent View image to create the digital Composite Broadcast Image70(FIG.1A). Next, block116sends (or provides) the digital Composite Broadcast Image70to the appropriate broadcast server or distribution network to be broadcast, streamed, or otherwise distributed or provided, to the viewing audience. Then, the logic exits. Referring toFIG.1C, a screen illustration of an embodiment of the talent graphics image30, or projection image or a talent graphical user interface (GUI) or talent GUI30, which are projected on the transparent screen10(FIG.1) and viewed by the talent12. The talent GUI may include various graphic elements or talent GUI elements150, such as the interactive graphics or content14(e.g., players on a court/field), and various interactive GUI visual tools, such as a “Video/Image” choice section16, showing current video or image selection of the user/talent12, “Tool Bar”18, “Colors”152, video player buttons164(pause, stop, play, forward, and reverse, listed as shown from left), and user/talent “Prompts”19(e.g., prompts for the talent from a producer, director, other talent in the studio), and the like, as well as the talent's12sketches and annotations20, as discussed herein above. Other display or annotation features may be provided in the talent GUI30if desired. In particular, for the talent12(FIG.1A) to insert the arrow20on the GUI30, the talent12would first touch the GUI screen10on the Play1button162, which illuminates the Play1button162and selects the play to display on the interactive portion14of the screen10. Then, the talent12selects a Pause button which causes a thick circle166to appear around the Pause button and pauses the play where the talent12wants to annotate. Next, the talent12touches a draw icon (pen) which causes a circle154to appear around the Pen icon in the Tool Bar18and the word “Pen” to be displayed in the Status section16. Next, the talent12may touch the GUI screen on a White color icon which will cause a circle156to appear in the color selection area152around the word White (or the color white if so provided) and the word “White” to appear in the Status section16. Next, the talent12may touch the GUI screen on an Arrow icon which will cause a circle160to appear around the Arrow icon in the Tool Bar18and the word “Arrow” to appear in the Status section16. Finally, the talent12would touch the screen10at the location desired to place the arrow20, as shown on the GUI30. Instead of touching the screen10to perform selections on the screen10, the talent may gesture or point toward the screen while a tracking system tracks and interprets the talent's movement, or use voice commands any other approach to cause the screen10to select the desired actions of the talent12. In addition, one reason for the talent12drawing the arrow20may come from a “Prompt” comment162, e.g., “Provide commentary on position of Player #2 (Forward)”, provided by another commentator/talent or the show producer or director or other input source, indicating they would like the talent12to discuss (and possibly annotate) the talent's thoughts about the position of Player #2 in the basketball play image14shown to the talent12. In that case, the Prompt data162(e.g., sentence or phrase) may be entered into a computer from the input source person and the prompt data162provided in the prompt field19or specially flagged text in the “Base” image provided to the Rendering Engine50, which will identify and extract the Prompt data162(e.g., at block104of the Rendering Engine Logic100,FIG.1B) and include the Prompt data162in the prompt field19of the talent graphics image53(FIG.1) sent to the projector system32to be included in the image30for the talent12to see. Referring toFIGS.2A and2B, in some embodiments, the system of the present disclosure may use polarization-gating to achieve the optical effects described above (using the optical property of polarization of the light). In particular, the projector system32may include a projector202, e.g., a “long-throw” projector, Type/Model No. D963HD, made by Vivtek, and a vertical polarizer204, e.g., Type/Model No. AP42-008T-PSA, made by American Polarizer, in the path of the optical projection signal30(or image or projection), which causes the optical projection image30to be vertically polarized, as indicated by a vertical polarization symbol210. Other projectors and vertical polarizers may be used if desired. The long-throw projector202may be located about 15 feet from the screen10. Other distances may be used provided the projector can focus the desired projection image30on the screen10with sufficient clarity for the talent12to read and interact with the image30. Also, the camera system40may include a video camera206, e.g., Type/Model No. EOS Rebel T7 made by Canon, and a horizontal polarizer208, which only passes incident light that is horizontally polarized (or the horizontal polarization component of unpolarized light), as indicated by a horizontal polarization symbol212, to the video camera206. The projection image30is incident on the screen10, and can be seen by the talent12, and not by the camera40, as described below. In addition, the transparent screen10has a first surface9(or left surface for screen side-views shown herein) and an opposite second surface11(or right surface for screen side-views shown herein). The first surface9faces “Side A” (or first side or left side for screen side-views shown herein) of the screen10, and the second surface11faces “Side B” (or second side or right side for screen side-views shown herein) of the screen10, as used herein. More specifically, as used herein, the phrase “Side A” (or first side or left side for screen side-views shown herein) of the screen10refers to positions in space located anywhere to the left of the left surface9of the screen10(or left-most surface of a screen assembly) for screen side-views shown herein. Thus, when a viewer is viewing from Side A (or the left side), it means a viewer located at and viewing from a position in space located anywhere to the left of the left surface9of the screen10. A similar convention is used regarding the phrase “Side B” (or second side or right side for screen side-views shown herein) of the screen10, which refers to positions in space located anywhere to the right of the right surface11of screen10(or right-most surface of a screen assembly) for screen side-views shown herein. Thus, when a viewer is viewing from Side B (or the right side), it means a viewer located at and viewing from a position in space located anywhere to the right of the right surface11of the screen10. In some embodiments, the optical projection image30provides vertically polarized210light that is projected onto the left surface9of the transparent screen10. The transparent screen10may be a polarization-preserving, transparent, scattering projection screen, such that a portion216of the projected optical image30is reflected off of the screen10as reflected light216at various angles (back towards the camera40) on the camera-side (or left side or first side or Side A) of the screen10and a portion220of the optical projection image30passes through the transparent screen as pass-through light220, some of the pass-through light220passing straight through222the screen10, and other portions222of the pass-through light220being scattered at various angles on the talent-side (or right side or second side, or Side B) of the screen10. The reflected and pass-through light signals216,220retain their polarization states, and are thus both vertically polarized210, the same as the incident optical projection light signal30. A similar result would be obtained if the vertical polarizer204and horizontal polarizer208are swapped. In that case, the projected (or projection) image30would be horizontally polarized which would be blocked by the horizontal polarizer208at the camera. The polarization-preserving transparent projection screen10may be a transparent particle-embedded plastic screen, such as Type/Model No. Cineclear II, made by ACP Noxtat or a transparent holographic screen, such as Type/Model No. HSI100 Holofoil, made by MediaScreen. Also, polarization-preserving transparent projection screen10may be tuned for use with the type of projector system40used, e.g., long-throw or short-throw projectors or other projectors. Any other type of polarization-preserving transparent projection screen may be used if desired, provided it provides the function and performance discussed herein. For example, in some embodiments, a pixelated transparent display or a micro-LED display, or an OLED (organic-LED) display (where the space between the pixels may be randomly polarized), may be used if desired. In that case, the display may emit one state of polarization or one set of blue, green, red (or BGR) wavelengths for the content, while passing the orthogonal polarization or a different set of BGR wavelengths, respectively. Any other display screen that is emissive or projective may be used if desired, provided it performs the functions described herein. A portion218of the vertically polarized reflected light216is incident on the camera system40, the reflected light portion218also being vertically polarized210. However, the horizontal polarizer208of the camera system40blocks the vertically polarized reflected light portion218from reaching the video camera206. As a result, the camera206(or anyone or any device viewing from the camera side of the polarizer208and capable of viewing horizontally polarized light212) does not view (or “see”) the optical projection image30that is projected onto the screen10. In addition, because the vertically polarized pass-through light220scatters at various angles off the screen10, the projection image30is visible to the talent12on the talent-side of the screen10(or anyone or any device viewing from that side of the screen10and capable of viewing vertically polarized light210). Thus, the various graphical elements14,16,18,19(FIG.1A) of the projection image30are visible to the talent12(viewing from one side, e.g., Side B, of the screen10), but are not visible to (or not “seen” by) the camera system40(viewing from the opposite side, e.g., Side A, of the screen10), due to polarization gating (or blocking) by the camera system40. In addition, studio or stage lights240, which provide stage lighting242is randomly polarized232(or un-polarized or non-polarized) and illuminates (or reflects off) the talent12, as an illuminated talent image230. The talent image230passes through the transparent projection screen10toward the camera40, where the horizontal component of the randomly polarized image230passes through the horizontal polarizer208to the camera206and the non-horizontal components of the image230, e.g., vertical component, are extinguished or blocked, as indicated by the “X”. As a result, the camera206(or anyone or any device viewing from the camera side of the polarizer208and capable of viewing horizontally polarized light212) views (or “sees”) the talent image230of the talent12standing on the other side of the screen10. The brightness of talent image230may be attenuated due to the blocking of the non-horizontal polarization components by the horizontal polarizer208. To compensate for such attenuation, the brightness of the image230viewed by the camera208may be increased by increasing the intensity of stage lighting242to the desired brightness or the camera gain (or sensitivity or amplification) may be increased to boost the intensity of the viewed image signal. In some embodiments, to reduce such attenuation, the stage lighting may be polarized (linearly or circularly) in way that causes the talent image to polarized (or at least partially polarized) such that it is passed by the polarizer (or filter) on the camera side of the screen. Thus, the camera image provided on the line42by the camera system40to the rendering engine50will include the talent image230of the talent12and will not include the projection image30, as shown by the image44inFIG.1A(discussed herein above). FIGS.3A and3Bare similar to that shown inFIGS.2A and2Busing polarization gating described hereinbefore, except the system8is configured with a projection system32where the projector202A may be a “short-throw” projector, e.g., Type/Model No. GT5500, made by Optoma. In that case, the projector system32may be placed close to the screen10, e.g., less than 1 foot (or between 1 and 2 feet) from the screen10and may be disposed on the floor (or other location that is conveniently close to the screen10). This is different from the “long-throw” projector202ofFIGS.2A and2B(mounted to the ceiling or a point above the screen10), may be placed a predetermined long distance from the screen10, e.g., more than 10 feet (or between 6 and 12 feet) from the screen10. In some embodiments, the projector system32and screen10may be disposed on a portable cart302having a platform304, a stand306holding the screen10, and wheels308, which may be lockable to hold the cart302in the desired position between the talent and the camera system40. The projector system32is disposed a predetermined distance, e.g., 1 foot, from the screen10. Other distances may be used provided the projector system focuses the projection image30on the screen10with sufficient clarity for the talent12to read and interact with the image30. The cart302, the platform304, and stand306are made of a material strong enough to provide sufficient support and stability for the projector system32and the screen10, to allow the system8to perform the functions described herein. The cart302may be used with any of the embodiments described herein. Also, for any of the embodiments disclosed herein, the angle of the projector system32(or the projector) or the projection image30or other components are not critical to the performance of the system of the present disclosure. In particular, the system8is projection-angle and viewing-angle independent or agnostic, and does not have any requirements or rely on the angle of the camera40, the angle of the projector system32(or projector), the viewing angle of the talent12, or the angle of the screen10to provide the functions and performance described herein. This is different from certain prior art transparent display systems that are reflection-angle based, such as certain teleprompters, heads-up displays, and the like. Referring toFIGS.4A and4B, to avoid cross-talk from depolarization due to scattering or for other reasons, some embodiments of the present disclosure may use wavelength (or color) filtering or gating (using the optical property of wavelength of light). In particular, the projector202A of the projector system32provides a projection image402having a broad wavelength range, shown by the wavelength graph404, that includes wavelengths associated with Red, Green, and Blue colors. The light402from the projector202A passes through a color filter406, e.g., Type/Model No. Primor, made by Infitec, which allows a small range of wavelengths associated with each of Blue (wavelength B1), Green (wavelength G1), Red (wavelength R1) colors, or b1g1r1, that make-up the projection image30. Also, the camera system40may include the video camera206(discussed herein above) and an inverse (or orthogonal) color filter407, e.g., Type/Model No. Primor, made by Infitec, which blocks (or absorbs) wavelengths corresponding to each of Blue (wavelength B1), Green (wavelength G1), Red (wavelength R1) colors, or b1g1r1, as indicated by a graph410. The two filters406,407may come as a set in a Primor Development Kit. The projection image30(having only wavelengths B1,G1,R1, or b1g1r1) is incident on the transparent projection screen10and can be seen by the talent12; however, the image30is not seen by the camera40, as described below. In particular, the projection image30is incident on the screen10such that a portion416of the projection image30is reflected off of the screen10as reflected light416at various angles on the camera-side of the screen10and a portion420of the optical projection image30passes through the transparent screen10as pass-through light420, a portion422of the pass-through light420passing straight through the screen10, and other portions of the pass-through light420being scattered at various angles on the talent-side of the screen10. The reflected and pass-through light signals416,420retain their wavelength components, and, thus, both optical light signals416,420have the wavelengths B1,G1,R1(as indicated by the wavelength graph408), which is the same as the optical projection light signal (or image)30incident on the screen10. A portion418of the B1,G1,R1wavelength reflected light416is incident on the camera system40. However, the inverse color filter404of the camera system40blocks (or absorbs, or filters-out, or attenuates, or extinguishes) the B1,G1,R1wavelengths of the reflected light418from reaching the video camera206. As a result, the camera206does not view (or “see”) the B1,G1,R1optical projection image30that is projected onto (and reflected off) the left surface9of the screen10. In addition, because the pass-through light420scatters at various angles off the screen10on the talent-side of the screen10, the B1,G1,R1optical projection image30is visible to the talent12(or anyone or any device viewing from that side of the screen10and capable of viewing B1,G1,R1wavelength light408). Thus, the various graphical elements14,16,18,19(FIG.1A) of the projection image30are visible to the talent12, but are not visible to (or not “seen” by) the camera system40, due to wavelength gating (or blocking) by the camera system40. In addition, studio or stage lighting242covers the visible spectrum and thus has the broad wavelength spectrum (shown as the graph404) and illuminates (or reflects off) the talent12, as a broad-wavelength illuminated talent image430. The broad-wavelength talent image430passes through the transparent projection screen10towards the camera40, where only the 3 narrow color bands are absorbed by the inverse color filter407(shown by the wavelength graph410), and the rest of the incident light signal passes through to the video camera206. As a result, the camera206views (or “sees”) the talent image430of the talent12standing on the other side of the screen10. For this embodiment, the transparent projection screen10may be the same as the screen10shown inFIGS.2A and2B; however, the screen10should be wavelength-preserving (i.e., not shift or alter the wavelength upon reflection or transmission), and it is not necessary for the screen10to be polarization-preserving (as polarization is not relevant for this embodiment). Referring toFIGS.5A and5B, in some embodiments, the system of the present disclosure may use circular polarization (with reflection cancellation) to achieve the optical effects described herein. In particular, the short-throw projector202A of the projector system32provides a projection image502having a randomly polarized light. The light502from the projector202A passes through an anti-reflection coating505and a right circular polarizer506, e.g., Type/Model No. APNCP42-010T-RH, made by American Polarizer, which passes only right circularly polarized light, as indicated by a right circularly polarized symbol510(as viewed from the light source), which is the projection image30. Also, the camera system40may include the video camera206(discussed herein above) and a right circular polarizer507, similar to the polarizer506, which passes only right circularly polarized light, as indicated by a right circularly polarized symbol510(as viewed from the propagation direction of the light beam). Unless otherwise indicated herein, the convention used for circularly-polarized light herein is as viewed from the propagation direction of the light beam. The projection image30(having only right-circularly polarized light) is incident on the transparent projection screen10, e.g., a polarization preserving transparent screen, and the image30can be seen by the talent12; however, the image30is not seen by the camera40, as described below. In particular, the projection image30is incident on the screen10such that a portion516of the projection image30is reflected off of the screen10as reflected light516at various angles on the camera-side of the screen10and a portion520of the optical projection image30passes through the transparent screen10as pass-through light520, a portion522of the pass-through light520passing straight through the screen10, and other portions of the pass-through light520being scattered at various angles on the talent-side of the screen10. The reflected light516from the screen10of the image30becomes left-circularly polarized of opposite handedness (because of the reflection), as shown by the symbol508, which is the opposite polarization to the right-circularly polarized510of the optical projection light signal30incident on the screen10. However, the pass-through light signals520,522retain their right-circularly polarized state (as indicated by the symbol510), which is the same as the polarization of optical projection light signal30incident on the screen10. A portion518of the left-circularly polarized reflected light516is incident on the camera system40. However, the right circular polarizer507of the camera system40only passes (allows through) right-circularly polarized light and blocks (or absorbs, or filters-out, or attenuates, or extinguishes, as indicated by an “X”) the left-circularly polarized reflected light518from reaching the video camera206. As a result, the camera206does not view (or “see”) the optical projection image30that is projected onto and reflected off the left surface9screen10as the reflected light518. In addition, because the pass-through light520scatters at various angles off the screen10on the talent-side of the screen10, the optical projection image30is visible to the talent12(or anyone or any device viewing from that side of the screen10). Thus, the various graphical elements14,16,18,19(FIG.1A) of the projection image30are visible to the talent12(viewing from one side, e.g., Side B, of the screen10), but are not visible to (or not “seen” by) the camera system40(viewing from one side, e.g., Side A, of the screen10), due to polarization gating (or blocking) by the camera system40described above. In addition, studio or stage lighting242is randomly polarized532(or un-polarized or non-polarized) and illuminates (or reflects off) the talent12, as an illuminated talent image530. The talent image530passes through the transparent projection screen10toward the camera40, where the right-circularly polarized component of the randomly polarized image530passes through the right-circular polarizer507to the camera206(and the non-right circular components of the talent image530, e.g., left-circular component, are extinguished or blocked). As a result, the camera206views (or “sees”) the talent image530of the talent12standing on the other side of the screen10. The brightness of talent image530may be attenuated due to the blocking of the non-right circular components by the polarizer507; however, the brightness of the image530viewed by the camera208may be increased by increasing the intensity of stage lighting242to the desired brightness, similar to that discussed herein above with linear polarization gating. A similar result would be obtained if the right-circular polarizers506,507in the projector system32and the camera system40, respectively, are replaced with left-circular polarizers. In that case, the projection image30would be left-circularly polarized, and the reflected image518would be right-circularly polarized, which would be blocked by the left circular polarizer507at the video camera206. Similarly, the unpolarized talent image530would pass through the screen10toward the camera40and the left-polarization component would pass through the left circular polarizer507and be viewed by the camera206. Also, a similar result would be obtained if the right-circular polarizer507is reversed (or flipped) such that the incident light508,530passes backwards through the right circular polarizer507. In the case, the light534exiting the flipped polarizer507would be −45 degree linearly polarized (and still be seen by the camera206), and the circularly polarized light518would still be blocked, similar to that described withFIG.5Chereinafter. Referring toFIGS.5C and5D, instead of using separate (left and right) circular polarizers506,507, respectively, shown inFIGS.5A,5Bas separate optical components associated with the camera206(or the camera system40) and the projector202A (or the projector system32), in some embodiments, the circular polarizers506,507may be a single optical component or element540disposed on or near or integrated into the surface of the screen10. In particular, inFIGS.5C and5D, a left circular polarizer540, having an anti-reflection coating542, may be disposed on or near or integrated into the camera-side (or left side or Side A) of the screen10, to provide the optical effects described herein, which may be referred to herein as an “on screen” polarization-gating arrangement. Also, the combination of the left circular polarizer540with anti-reflection coating542and the screen10, may collectively be referred to as a screen assembly514. In that case, the projection light502from the projector202A, which is randomly polarized532, passes through the anti-reflection coating542and the left-circular polarizer540, as the projection image30having left-circular polarization508(propagation direction of the light beam), which is incident on the screen10. The pass-through portion520of the projection image30passes through the screen10having the same polarization508as the incident light30, and the projection image30is visible to the talent12as described herein above. The reflected portion516(toward the camera206) of the projection image30will change polarization upon reflection off the screen10(as described herein above) and become right-circularly polarized510, which will be extinguished by the left-circular polarizer540(as indicated by the “X”). The randomly polarized (or unpolarized) talent image530would pass through the screen10toward the camera40and would pass backwards through the left circular polarizer540and through the anti-reflection coating542, and become −45 degree linearly polarized533light534(as viewed from the talent light source along the propagation path of the light) and would be viewed by the camera206(as described herein above). In particular, a circular polarizer is created using a 45 degree linear polarizer followed by a quarter-wave plate (or retarder) in that order, for light propagating “forward” through the polarizer (as is known) and converts unpolarized light to circularly polarized light. Conversely, when light is passed “backwards” thru the polarizer, unpolarized light will be converted to 45 degree linearly polarized light (as is known). One can use either 45 degree linearly polarized light and −45 degree linearly polarized light or horizontal and vertical polarized light, depending on the orientation of the linear polarizers. Also, the symbol for unpolarized light may be shown herein as dual clockwise and counterclockwise circular arrows532, or dual perpendicular crossing line arrows532A, depending on the desired convention, e.g. polar or rectangular, respectively. Using “on-screen” polarization-gating described herein avoids the need to have separate polarization-gating polarizers or filters, respectively, placed over the video camera206and the projector202,202A, as part of the camera system40and the projector system32, respectively. Thus, the camera image44(FIG.1A) provided by the camera system40to the rendering engine50on the line42will include the talent image530of the talent12and will not include the projected (or projection) image30from the projector202A. Also, as discussed herein above withFIG.1A, in addition to the talent12seeing the projection image30on the transparent screen10, the talent12also sees through the transparent screen10(or screen assembly) and views things or images on the camera side (because the screen10is transparent and the images are illuminated with studio or stage lighting). In particular, the camera system40(and anything on the camera side of the screen10) is visible to the talent12through the transparent screen10. In some embodiments, the camera206(except for the camera lens) may be covered by a cover screen or other cover material570to improve or enhance the contrast for the talent12viewing the projection image30on the transparent screen10, or for other reasons to avoid having the talent12see the camera40, provided the camera206viewing lens572can view or see the screen10. In that case, there may be a background or foreground image or video (or a single color or color scheme) displayed or projected on the cover screen570to enhance the view seen by the talent12. In some embodiments, there may be one or more people (not shown) located on the camera-side (Side A) of the screen10, e.g., one or more commentators, that are visible to the talent12through the screen10and may be interacting with the talent12, or providing the talent12with visual instructions or cues. Referring toFIGS.6A and6B, in some embodiments, circular polarization gating (with reflection-cancellation), such as that shown inFIGS.5C &5D, may be used to provide a “two-sided” (or multi-person) display screen system600, as described below. In particular, a first viewer612A (or Viewer A, similar to the video camera206or the camera system40in other embodiments herein), may be located on one side (e.g., the left side or Side A) of the polarization-preserving transparent screen10, and a second viewer612B (or Viewer B), may be located on an opposite side (e.g., the right side) of the screen10. Also, a first short-throw projector602A, similar to the short throw projector202A (FIG.5A), is located on the same side as the Viewer A, and a second short-throw projector602B, similar to the short throw projector202A, is located on the same side of the screen10as the Viewer B. As described in more detail below, the Viewers A and B,612A,612B, respectively, can see each other through the transparent display10together with images projected on the screen10by only the opposite-side's projector602B,602A, respectively. Thus, the Viewer A612A (viewing from Side A of the screen10) can see Viewer B612B (located on Side B of the screen10) and images and graphics634B projected on the screen10by only the second projector602B (located on Side B, i.e., the opposite side of the screen10from Viewer A). Similarly, the Viewer B612B (viewing from Side A of the screen10) can see Viewer A612A (located on Side A of the screen10) and images and graphics634A projected on the screen10by the first projector602A (located on Side A, i.e., the opposite side of the screen10from Viewer B). Such visual effects are achieved using similar components and circular polarization-gating to that described above withFIGS.5C and5Don both sides of the screen10, and replacing the camera system40with the Viewer A612A, and the talent12with the Viewer B612B. Also, in that case, a nonreflecting circular polarizer610,612would be disposed on each side of the screen10, respectively, between the screen10and the respective projectors602A,602B, each of the polarizers610,612being similar to the on-screen circular polarizer540and AR coating542, described withFIG.5C. In particular, the polarizer610has an outer surface609that faces the Viewer A612A (or Side A) and an inner surface613that faces (and may touch or be disposed on or contiguous with) the left surface9of the screen10. Also, the polarizer612has an outer surface611that faces the Viewer B612B (or Side B) and an inner surface615that faces (and may touch or be disposed on or contiguous with) the right surface11of the screen10. As described herein, the screen assembly614includes the polarizers610,612with the transparent screen10disposed therebetween, and the outer surface609faces Side A (where the Viewer A is located and views from) and the outer surface611faces Side B (where the Viewer B is located and views from). The circular polarizer610on the Viewer A side (left side or Side A) of the screen10may comprise an anti-reflection (AR) coating620A, a 45 degree linear polarizer622A, and a quarter-wave retarder (or quarter-wave plate)624A, which may be configured as a contiguous single optical assembly610. Similarly, the circular polarizer612on the Viewer B side (right side or Side B) of the screen10may comprise an anti-reflection (AR) coating620B, a 45 degree linear polarizer622B, and a quarter-wave retarder (or quarter-wave plate)624B, which may be configured as a contiguous single optical assembly612. For each of the circular polarizers610,612, the combination of a 45 degree linear polarizer with a quarter-wave retarder (quarter-wave plate) create a left-circular polarizer (when viewed from the light receiving end) or a right-circular polarizer (when viewed from the light source end along the propagation direction of the light), as is known. The circular polarizers610,612may each be disposed on or near their respective opposite sides of the screen10, to provide the optical effects described herein. Also, the combination of the circular polarizers610,612and the screen10, may collectively be referred to as a screen assembly614. From the Viewer A side, the short throw projector602A projects the imagery634A (to be viewed by Viewer B only), towards a screen assembly614. The projection light634A passes through the AR (Anti-Reflection) coated right circular polarizer610, which causes the projection image30A to become right circularly polarized (when viewed from the source along the propagation direction of the light). The right circularly polarized projection light30A is incident on the polarization-preserving transparent projection screen10, similar to that described herein above. The pass-through light660remains right-circularly polarized662, and passes “backwards” through the right circular polarizer612, to become 45 degree linearly polarized664which can be seen by the Viewer B (612B). The projection light30A is also reflected665by the screen10back towards the Viewer A and becomes left-circularly polarized668of the opposite handedness, but is extinguished (or blocked) by the combination of the quarter-wave retarder (or quarter-wave plate)624A and the 45 degree polarizer622A (equivalently, a (right) circular polarizer), as indicated by an “X” inFIGS.6A and6B. More specifically, referring toFIG.6B, the incident light30A reflects off the screen10and becomes left circularly polarized668, and then becomes −45 degree linearly polarized667light665by the quarter-wave plate624A and then is blocked (or extinguished) by the +45 degree linear polarizer622A (as it is opposite polarization from the −45 degree polarized light665). Thus, the Viewer A612A (viewing from Side A of the screen10) does not see the reflected image665of the projection image30A from the short throw projector602A on Viewer A's side (Side A) of the screen10, similar to that discussed withFIGS.5C and5D. Similarly, from the Viewer B side (Side B of the screen10), the short throw projector602B projects the imagery634B, towards a screen assembly614. The projection light634B passes through the anti-reflection coating620B and the right circular polarizer612, which causes the projection image30B to become right circularly polarized (when viewed from the source along the propagation direction of the light). The right circularly polarized projection light30A is incident on the polarization-preserving transparent projection screen10, similar to that described herein above. The pass-through light670remains right-circularly polarized662, and passes “backwards” through the right circular polarizer610, to become 45 degree linearly polarized664which can be seen by the Viewer A (612A). The projection image light30B is also reflected672by the screen10back towards the Viewer B and becomes left-circularly polarized668of the opposite handedness, but is extinguished by the combination of the quarter-wave retarder (or quarter-wave plate)624B and the 45 degree linear polarizer622B (equivalently a right circular polarizer), as indicated by an “X” inFIGS.6A and6B. More specifically, referring toFIG.6B, the incident light30B reflects off the screen10and becomes left circularly polarized668, and then becomes −45 degree linearly polarized667light672by the quarter-wave plate624B and then is blocked (or extinguished) by the +45 degree linear polarizer622B. Thus, the Viewer B612B (viewing from Side B of the screen10) does not see the reflected image672of projection image30B from the short throw projector602B on Viewer B's side (Side B) of the screen10, similar to that discussed withFIGS.5C and5D. Referring toFIG.6B, the polarization states are shown for the incident light634A from the projector202A (from the left side (Side A) of the screen10) as it passes through the components622A,624A of the circular polarizer610to the screen10, and the polarization states for the incident light634B from the projector202B (from the right side (Side B) of the screen10) as it passes through the components622B,624B of the circular polarizer612to the screen10. Ambient or studio light630A reflected from the Viewer A is randomly polarized632and travels towards the Viewer B through the right circular polarizer610, where it becomes right circularly polarized662, then passes through the transparent projection screen10, and then passes “backwards” through the right circular polarizer612, to become 45 degree linearly polarized664which is visible by the Viewer B as the image630B. A similar effect occurs for ambient (or studio) light631B reflected from the Viewer B is randomly polarized632, and travels towards the Viewer A through the right circular polarizer612, where it becomes right-circularly polarized662, then passes through the transparent projection screen10, and then passes “backwards” through the right circular polarizer610, to become 45 degree linearly polarized664which is visible by the Viewer A as the image631A. Thus, the Viewer A (FIG.6A), viewing from Side A of the screen10, can see the Viewer B through the projection screen10and the Viewer A can also see the projection image30B projected by the projector602B. Similarly, the Viewer B (viewing from Side B of the screen10) can see the Viewer A through the projection screen10and Viewer B can also see the projection image30A projected by the projector602A. In some embodiments, the projectors602A,602B and the screen assembly614, may be disposed on a portable cart692, similar to the cart302described herein above withFIG.3A, having a platform691, and wheels694, which may be lockable to hold the cart692in the desired position between the Viewers A,B. The screen assembly614may be rigidly disposed directly to the platform (as shown) or may be elevated and held by a stand, like the stand306shown inFIG.3A. The short-throw projectors602A,602B are disposed a predetermined distance from the screen10, as discussed herein above, that allows the projectors602A,602B to focus the projection images634A,634B on the screen assembly614with sufficient clarity for the Viewers A,B to read and interact with the projection images634A,634B or30A,30B. Any other cart or platform or structure may be used if desired to support the projectors602A,602B and screen assembly614. A rendering engine50A (FIG.6A) for the two-sided display screen10is similar to the Rendering Engine50for the one-sided screen shown inFIGS.1A,2A, and the like, except that there are two digital image signals (digital Viewer A Image signal and digital Viewer B image signal) on lines653A,653B, providing signals to two projectors602A,602B, creating two projection images30A,30B, for separate viewing by the two Viewers B,A respectively, and there is no Camera40(FIG.1A). There are also two image inputs, Base Image A provided on a line649A, to be projected by the projector602A (together with the Viewer A's actions, or the results thereof) and viewed only by Viewer B, and Base Image B provided on a line649B, to be projected by the projector602B (together with the Viewer B's actions, or the results thereof) and viewed only by Viewer A, as described above. Also, the two-sided rendering engine50A receives two action/motion inputs on lines652A,652B, one from the left side of screen10(capturing actions by Viewer A) and the other right side of the screen10(capturing actions by Viewer B), respectively. The screen10or a separate device (not shown) may have the necessary sensors, hardware, firmware, or software capable of sensing such actions of the Viewers A,B and providing data associated therewith to the rendering engine50A, similar to that done for the one-sided display discussed herein. Referring toFIG.8, a flow diagram800illustrates one embodiment of a process or logic for implementing the two-sided Rendering Engine Logic50A, which may be implemented in hardware, software, or firmware, or the like. The process/logic800begins at block802by receiving a “Base” Image A to be viewed by Viewer B and a Base Image B to be viewed by Viewer A. The Base Images A,B may be an underlying background image (or graphics or video) desired to be used as a background image for Viewers A,B, respectively. Next, block804determines if data has been received that is indicative of action or motion by Viewer A, e.g., swinging a ping-pong paddle, detected directly by the screen10(e.g., touch screen), or by sensors such as cameras or other detectors (in the screen or separate therefrom) which identify hand motion (or other action) of the Viewer A. If action/motion data has been received for Viewer A, a block806determines the type of motion and creates or updates a Viewer A Image (from Viewer A's perspective) and a corresponding Viewer B Image (from Viewer B's perspective) in response to Viewer A's motion. If the result of block804is NO, or after performing block806, the logic proceeds to block808, which determines if data has been received that is indicative of motion by Viewer B. If action/motion data has been received for Viewer B, a block810determines the type of action and creates or updates a Viewer A Image (from Viewer A's perspective) and a corresponding Viewer B Image (from Viewer B's perspective) in response to Viewer B's motion. Then, the logic exits. Accordingly, the “two-sided” Rendering Engine50A (FIG.6A) creates side-specific digitized input graphic images (similar to the single-sided image54,FIG.1A), one for each side, having side-specific digital pixels or location coordinates which map to the corresponding side of transparent screen10, indicative of the movements (or the reaction of the movements) of the respective Viewers A,B, which are detected and mapped onto the side-specific digitized graphic images, such each of the Viewers' A,B motions. The rendering engine50B then combines (or mergers or adds) the Viewers' A,B motions (or the reaction of the motions) with the corresponding Base Image A and Base Image B, using the side-specific mapping information and software that interprets the movement and a reaction thereto, to create the digital Viewer A Image signal and the digital Viewer B image signal which are provided to the projectors602A,602B on the lines653A,653B. Then, the resultant Viewer A Image is displayed on the screen10for the Viewer B to view (and react to if desired), and the resultant Viewer B Image is displayed on the screen10for the Viewer B to view (and react to if desired). Referring toFIG.9, a screen illustration is shown of an image900of an interactive game, e.g., an electronic ping-pong game having the Viewers A,B as players, as viewed by Viewer B from Viewer B's side of the screen10. In particular, the image900seen by the Viewer B, includes the Base Image B, i.e., the virtual items in the image, e.g., the ping-pong table902, the net904, the ping-pong ball908, and the surrounding areas, together with the real-world visible items, including the Viewer A holding an actual ping-pong paddle906, which would be real and visible by Viewer B through the transparent screen10. When the game is being played, if Viewer B (near side of image) hits the virtual ping-pong ball908with his real-world ping-pong paddle (not shown, near side), Viewer B's image would show the virtual ball908traveling on a path910, over the net904and bouncing on the virtual table902and traveling away from Viewer B and toward Viewer A. Simultaneously, the Viewer A's projection image on the screen10(not shown) would be the reverse of the image900, i.e., it would show Viewer B hitting the virtual ball908from across the virtual table902, and the virtual ball908traveling over the net904and bouncing on the table902toward Viewer A and away from Viewer B. Thus, for every action of each Viewer A,B, both projectors and both Talent Graphic Images would need to updated at substantially the same time. Other examples of multi-person activities that may be used with the present disclosure include, but are not limited to, two viewers viewing opposite sides of a machine or item, such as the front and back of a robot, or doing an interview, where the interviewer and interviewee are on opposite sides of screen; acting where there are separate scripts for each person; games having different (exclusive or non-exclusive) views (such as guessing games, connection to other abstract strategy games, board games, or the like); video conferencing; teleprompting; or any other multi-person applications or uses where it is useful for each person to see different information (or a different view or perspective) associated with a common activity they are participating in or a common object or thing they are interacting with. Referring toFIG.7, in some embodiments, “two-sided” (or multi-person) display screen using circular polarization (with reflection-cancellation), such as that shown inFIGS.6A &6B and5C &5D, may be used to provide three-dimensional (or 3D) imaging (using multiple color projection), as described below, also referred to as spectral comb filtering, or wavelength multiplex visualization, or super-anaglyph imaging technique. In particular, the left and right projection images for Viewers A,B, respectively, may each be encoded with separate primary color wavelength sets (r1g1b1, r2g2b2) associate with a Viewer's left eye and right eye, respectively, and are projected onto the screen assembly614by the projectors702A,704A (for Viewer B image) and the projectors702B,704B (for Viewer A image), and the viewers612A,612B wear optical 3D-glasses750,752(e.g., super-anaglyph 3D glasses). The projector702A (similar to projector system32ofFIGS.4A and4Bhaving the projector202A and the color filter406having r1g1b1) provides a color-encoded image710A, encoded with r1g1b1shown by graph710, and the projector704A (similar to projector system32ofFIGS.4A and4Bhaving the projector202A and the color filter406having r2g2b2) provides a color-encoded image712A, encoded with r2g2b2shown by graph712. The color-encoded images710A,712A collectively provide the projection image634A (FIG.6A) incident on the screen assembly614. Similarly, the projector702B provides a color-encoded image710B, encoded with r1g1b1shown by graph710, and the projector704B provides a color-encoded image712B, encoded with r2g2b2shown by graph712. The color-encoded images710B,712B collectively provide the projection image634B (FIG.6A) incident on the screen assembly614. The projection images634A,634B exhibit the same circular polarization gating effects (with reflection cancellation) described inFIGS.6A and6B, and provide a color-encoded projection image760(similar to the image660ofFIG.6A), viewed by Viewer B, and a color-encoded projection image770(similar to the image660ofFIG.6A), viewed by Viewer A. The color encoded optical signals are then color-decoded by each Viewer A,B using appropriate optical 3D-glasses750,752(e.g., super-anaglyph glasses) worn by the Viewers A,B, respectively, so as to allow only the corresponding color coded image (or wavelengths) r1b1g1, r2b2g2, to pass to the corresponding left or right eye of the Viewer A,B, such that the Viewers A,B see the 3D the projected images or video in 3-Dimensions. Other types of stereoscopic 3D techniques, such as traditional “anaglyph” technique, where there is one color for each eye, such as left=red, right=cyan (blue-green)) or “active shutter” 3D, where lenses for each eye of the wearer are actively switched on and off, or other 3D techniques, may be used if desired, provided they provide the function and performance described herein. Ambient or studio light640A reflected from the Viewer A is randomly polarized (as described withFIG.6A) and has a broad wavelength spectrum714(as described withFIG.4A), and travels towards the Viewer B through the screen assembly614to become 45 degree linearly polarized with the broad wavelength spectrum714, which is visible by the Viewer B as the image730B. A similar effect occurs for ambient or studio light640B reflected from the Viewer B which is randomly polarized (as described withFIG.6A) and has a broad wavelength spectrum714(as described withFIG.4A), and travels towards the Viewer A through the screen assembly614to become 45 degree linearly polarized with the broad wavelength spectrum714, which is visible by the Viewer A as the image731A. The 3D-glasses750,752will not affect the ability of the Viewers A,B to see the broad wavelength spectrum images731A,730B, respectively. Thus, the Viewer A can see the Viewer B through the projection screen assembly416and the Viewer A can also see the projected multi-color 3D image734B projected by the projector702B. Similarly, the Viewer B can see the Viewer A through the projection screen assembly614and Viewer B can also see the projected multi-color 3D image734A projected by the projector702A. The two-sided rendering engine50A for the two-sided 3D display system ofFIG.7is similar to the two-sided rendering engine50A for the two-sided two-dimensional (2D) display system shown inFIGS.6A and6B, except there are two projection signals (for two-color 3D effect) for each side of the screen10. In particular, separate color-banded projection signals on lines751A,752A, collectively referred to as lines753A, are provided to left side projectors702A,704A, to produce the color-banded optical projection images710A,712A, having the color bands (b1g1r1, b2g2r2), to be viewed by Viewer B, as discussed herein above. Similarly, separate color-banded projection signals on lines751B,752B, collectively referred to as lines753B, are provided to the right side projectors702B,704B, to produce the color-banded optical projection images710B,712B, having the color bands (b1g1r1, b2g2r2), to be viewed by Viewer A, as discussed herein above. Accordingly, in that case, the two-sided rendering engine50A processing logic800(FIG.8), at block806, would send the Viewer A Image as the color-banded projection signals to the right side projectors702B,704B on lines751B,752B, and, at block810, would send the Viewer B Image as the color-banded projection signals to the left side projectors702A,704A on the lines751A,752A. In some embodiments, the three-dimensional (or 3D) imaging (using multiple color projection), as described above withFIG.7, may also be used for the one-sided display screen10such as that shown inFIGS.1A-1C,2A,2B,3A,3B,4A,4B, and5A-5Dherein. In that case, the projector202A would be replaced by two color-banded projectors (like the projectors702A,704A inFIG.7). This would allow the talent12(while wearing the appropriate 3D glasses) to view the talent graphics GUI30in 3D, if desired. This may be useful in the case where the broadcast signal70(FIG.1), is provided to the viewing audience in 3D (e.g., 3D graphic elements or images or videos). In that case, the rendering engine50for a one-sided 3D display system would have two projection signals (for two-color 3D effect) for each side of the screen10, similar to the separate color-banded projection signals on lines751A,752A (FIG.7), provided to left side projectors702A,704A, to produce the color-banded optical projection images710A,712A, having the color bands (b1g1r1, b2g2r2), to be viewed by the talent12, who would be wearing the 3D glasses, similar to Viewer B ofFIG.7, as discussed herein above. As used herein, the polarizations and wavelengths of light of the images or optical signals described herein may each be referred to herein as an “optical property” of the light or associated image. For any of the embodiments herein, either or both of the Viewers A,B may be replaced by respective video cameras or viewing devices and the content being viewed may be viewed by remote viewers, receiving a video feed or signals from the respective cameras, either in realtime, e.g., realtime online streaming over the internet or other network, or digitally stored for viewing at a later time (where appropriate or practical). Also, the term “viewer” as used herein may be used to collectively include people or individuals or video cameras or viewing devices, or the like that are viewing or watching something as described herein. The system, computers, servers, devices and the like described herein have the necessary electronics, computer processing power, interfaces, memory, hardware, software, firmware, logic/state machines, databases, microprocessors, communication links (wired or wireless), displays or other visual or audio user interfaces, printing devices, and any other input/output interfaces, to provide the functions or achieve the results described herein. Except as otherwise explicitly or implicitly indicated herein, process or method steps described herein may be implemented within software modules (or computer programs) executed on one or more general-purpose computers. Specially designed hardware may alternatively be used to perform certain operations. Accordingly, any of the methods described herein may be performed by hardware, software, or any combination of these approaches. In addition, a computer-readable storage medium may store thereon instructions that when executed by a machine (such as a computer) result in performance according to any of the embodiments described herein. In addition, computers or computer-based devices described herein may include any number of computing devices capable of performing the functions described herein, including but not limited to: tablets, laptop computers, desktop computers, smartphones, mobile communication devices, smart TVs, set-top boxes, e-readers/players, and the like. Although the disclosure has been described herein using exemplary techniques, algorithms, or processes for implementing the present disclosure, it should be understood by those skilled in the art that other techniques, algorithms and processes or other combinations and sequences of the techniques, algorithms and processes described herein may be used or performed that achieve the same function(s) and result(s) described herein and which are included within the scope of the present disclosure. Any process descriptions, steps, or blocks in process or logic flow diagrams provided herein indicate one potential implementation, do not imply a fixed order, and alternate implementations are included within the scope of the preferred embodiments of the systems and methods described herein in which functions or steps may be deleted or performed out of order from that shown or discussed, including substantially concurrently or in reverse order, depending on the functionality involved, as would be understood by those reasonably skilled in the art. It should be understood that, unless otherwise explicitly or implicitly indicated herein, any of the features, functions, characteristics, alternatives or modifications described regarding a particular embodiment herein may also be applied, used, or incorporated with any other embodiment described herein. Also, the drawings herein are not drawn to scale, unless indicated otherwise. Conditional language, such as, among others, “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments could include, but do not require, certain features, elements, or steps. Thus, such conditional language is not generally intended to imply that features, elements, or steps are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without user input or prompting, whether these features, elements, or steps are included or are to be performed in any particular embodiment. Although the invention has been described and illustrated with respect to exemplary embodiments thereof, the foregoing and various other additions and omissions may be made therein and thereto without departing from the spirit and scope of the present disclosure. | 72,319 |
RE49879 | Throughout the drawings, it should be noted that like reference numbers are used to depict the same or similar elements, features, and structures. DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention as defined by the claims and their equivalents. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the invention. In addition, descriptions of well-known functions and constructions may be omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention is provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their equivalents. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component surface” includes reference to one or more of such surfaces. Exemplary embodiments of the present invention provide a method and an apparatus for performing a Discontinuous Reception (DRX) operation based on a DRX cycle. First Exemplary Embodiment The first exemplary embodiment of the present invention provides a method for implementing a long System Frame Number (SFN) in order to extend a DRX cycle of a machine-type communication device, and a method for supporting a DRX operation compatible with existing DRX in a mobile communication system. Hereinafter, according to the first exemplary embodiment of the present invention, a method for extending the length of an SFN of a machine-type communication device, and a DRX operation method for a machine-type communication device using a long DRX cycle will be described one after another. In order to extend the length of an SFN to extend a DRX cycle of a machine-type communication device, an evolved Node B (eNB) must additionally transmit SFN bits to the machine-type communication device, and the transmission methods are as follows. 1) Transmitting additional SFN bits in a Master Information Block (MIB); 2) Transmitting additional SFN bits in an existing System Information Block (SIB); 3) Defining a new SIB for a machine-type communication device, and transmitting additional SFN bits in the new SIB. In the first method of transmitting additional SFN bits in an MIB, the MIB includes necessary information, such as a downlink frequency band, a Physical Hybrid ARQ Indicator CHannel (PHICH) configuration information, and an SFN. In addition, the MIB contains 10 unused spare bits, which may be used to extend the length of an SFN. While general UEs use the existing SFN of 8 bits, machine-type communication devices can use not only the existing SFN of 8 bits but also extended SFN bits. Accordingly, while exerting no influence on the DRX operations of general UEs, machine-type communication devices can perform a DRX operation in a longer cycle. In the second method of transmitting additional SFN bits in an existing SIB, the SIB has no resource limit in transmitting SFN bits, as compared with the MIB. By taking SFN bits of an MIB and SFN bits added to the SIB together into consideration, it is possible to express an SFN with a longer length. General UEs take only SFN bits of an MIB into consideration, and machine-type communication devices take the SFN bits of the MIB and the SFN bits added to the SIB together into consideration. The added SFN bits represent a value which is obtained by increasing by one every existing one SFN cycle (or every multiple of an SFN cycle, e.g., ½ SFN cycle, 3 SFN cycle, etc.). Through the value represented as above, it is possible to express an SFN length longer than the existing SFN length. Also, according to the third method, SFN bits to be added may be included in a new SIB for a machine-type communication device. As described above, because the same additional SFN bit value is used within one SFN cycle, it is unnecessary to transmit an additional SFN bit value in all radio frames within one SFN cycle. Therefore, when additional SFN bits are transmitted in a SIB that is not frequently transmitted (e.g., preference of SIB2 to SIB 1), or when additional SFN bits are transmitted only in an SIB transmitted in a specific radio frame, it is possible to reduce an overhead due to the additional SFN bits. For example, when an SFN length is 1024, additional SFN bits may be transmitted only in an SIB transmitted in every radio frame corresponding to “SFN=0.” Also, in consideration of the probability of reception failure, additional SFN bits may be transmitted in more radio frames. Also, in order to deliver information for a machine-type communication device, a new SIB may be made. In this case, additional SFN bits may be carried by the new SIB. Generally, because the new SIB is not frequently transmitted, the resulting overhead increase is small. According to the number of added SFN bits, the DRX cycle is extended as Table 1 below. As shown in Table 1 below, when 10 bits are added, the DRX cycle can be extended up to a maximum of about three hours. TABLE 1Extended Bits2nCycle (Min)120.3240.7381.44162.75325.566410.9712821.8825643.7951287.4101024174.8 Hereinafter, the aforementioned DRX operation for a machine-type communication device using a long SFN will be described. The first exemplary embodiment of the present invention proposes a method for extending a DRX cycle, and for simultaneously receiving a paging signal several times during a predetermined DRX cycle in order to increase the probability of reception success of the paging signal. To this end, a paging occasion is determined through a procedure including two steps. 1) First step: determining additional SFN bits to transmit a paging signal for a machine-type communication device; 2) Second step: determining an SFN at which a paging signal is to be transmitted in the additional SFN bits determined in the first step. In the first step, additional SFN bits to transmit a paging signal are determined. The additional SFN bits have a value increased by one every SFN cycle. A value expressed by the additional SFN bits is defined as a Super SFN (SSFN). Equation 2 below is used to find an SSFN at which a paging signal is to be transmitted. SSFN mod TM=(TMdiv NM)*(UE_ID mod NM) (2) In Equation 2, NMis min (TM, nBM), and TMand nBMare values provided from an eNB and may be included in an SIB2. UE_ID is an IMSI mod 1024 (or MTC device group ID mode 1024), and can be derived from the same IMSI module operation as the general UE. In addition, in the case of a machine-type communication device, because the communication device can be expressed in the form of a group ID, the UE_ID may be expressed by a group ID. After an SSFN at which a paging signal is to be transmitted is determined, as described above, it is determined which radio frames in the determined SSFN are used to transmit the paging signal. This can be implemented in such a way as described with reference to Equation 1. As described above, when an occurrence occasion of a paging signal is defined by the two steps, and machine-type communication devices have a DRX cycle according to the defined occurrence occasion, it is possible to greatly reduce power consumption. Also, because a paging signal can be repeatedly transmitted according to “T” and “nB” set in an SSFN, which has been determined in the first step, it is possible to increase the reception probability of the paging signal. FIG.3is a view showing a conception of a paging occasion according to the first exemplary embodiment of the present invention. Referring toFIG.3, an SSFN305increases by one every SFN cycle of 1024. Based on Equation 2, an SSFN315at which a paging signal is to be transmitted is determined. An SFN310increases by one every radio frame. In the SSFN315determined based on Equation 2, an eNB transmits a paging signal320based on Equation 1. FIG.4is a flowchart illustrating the operation of a UE according to the first exemplary embodiment of the present invention. Here, the UE according to the first embodiment of the present invention is a machine-type communication device. Referring toFIG.4, in step410, a UE monitors an SSFN and an SFN. For example, the UE monitors the SSFN and the SFN at the same time by additional SFN bits in an MIB, by additional SFN bits in an existing SIB, or by additional SFN bits in a new SIB, as described above. In this case, because the UE is aware of a time interval of one SFN and SSFN in step410, it is unnecessary to perform a real-time monitoring, and it is enough to occasionally perform a monitoring so as to reduce the power consumption. In step415, the UE determines whether the monitored current SSFN satisfies Equation 2. When the current SSFN satisfies Equation 2, a paging signal can be transmitted in the current SSFN. Accordingly, the UE proceeds to step420in order to prepare the performance of a DRX. In contrast, when the current SSFN does not satisfy Equation 2 in step415, the UE returns to step410. In step420, the UE determines whether the monitored current SFN satisfies Equation 1. When the current SFN satisfies Equation 1, it means that a paging signal can be transmitted in the current SFN, so that the UE proceeds to step425in order to perform a DRX. In contrast, when the current SFN does not satisfy Equation 1 in step420, the UE returns to step410. Then, in step425, the UE decodes a PDCCH, and performs a DRX when a decoding-resultant PDCCH includes a paging signal. FIG.5is a block diagram illustrating the configuration of a UE according to the first exemplary embodiment of the present invention. Referring toFIG.5, a UE500includes a transceiver505, a controller510, and a buffer515. The transceiver505receives an MIB, an SIB, or a new SIB from an eNB, and monitors an SSFN and an SFN. As an example, the monitoring is controlled by the controller510. The SFN increases by one every radio frame of 10 ms, and the SSFN increases by one every SFN cycle having a length of 1024, which the UE500is aware of in advance. Therefore, the transceiver505in the UE500needs not decode a PBCH and a PDCCH every time in order to receive an MIB or SIB, and has only to occasionally monitor the PBCH and PDCCH. The controller510determines whether the monitored current SFN and SSFN satisfy Equation 1 and Equation 2, respectively, and calculates a time point when a paging signal is transmitted. Then, when the time point when a paging signal is transmitted is reached, the controller510shifts the transceiver505into a reception mode, and attempts to decode a PDCCH. Then, when receiving a paging signal, the controller510stores the received paging signal in the buffer515, and transfers information on the received paging signal to an upper layer. FIG.6is a flowchart illustrating the operation of an eNB according to the first exemplary embodiment of the present invention. Referring toFIG.6, the eNB determines whether a paging signal is required for the UE500in step610. That is, when receiving data, which is to be transmitted to the UE500, from an upper layer in step610, the eNB determines that a paging signal is required, and proceeds to step615. In contrast, when the eNB does not receive data to be transmitted to the UE500in step610, the eNB is maintained in a waiting state until the eNB receives data to be transmitted to the UE500. In step615, the eNB determines a timing (i.e., an SSFN and SFN), at which a paging signal is to be transmitted by taking an UE_ID (or MTC group ID) of the UE500. Then, in step620, the eNB checks the current SSFN and SFN. In step625, the eNB determines whether the checked current SSFN satisfies Equation 2, and proceeds to step630when the current SSFN satisfies Equation 2. In contrast, when current SSFN does not satisfy Equation 2 in step625, the eNB returns to step620. In step630, the eNB determines whether the checked current SFN satisfies Equation 1, and proceeds to step635in order to transmit a paging signal when the current SFN satisfies equation 1. In contrast, when current SFN does not satisfy Equation 1 in step630, the eNB returns to step620. Then, in step635, when a transmission timing according to the checked SSFN and SFN is reached, the eNB transmits a paging signal to the UE500by a PDCCH. FIG.7is a block diagram illustrating the configuration of an eNB according to an exemplary embodiment of the present invention. Referring toFIG.7, the eNB700includes a buffer705, a controller710, and a transceiver715. The controller710determines whether data to be transmitted to the UE500has been received through the buffer705from an upper layer. Then, the controller710calculates a timing (i.e., an SSFN and SFN), at which a paging signal is to be transmitted by taking an UE_ID (or MTC group ID) of the UE500. When the calculated SSFN and SFN (i.e., a timing at which the paging signal is to be transmitted), is reached based on Equations 1 and 2, the controller710transmits a Physical Downlink Control CHannel (PDCCH) including the paging signal through the transceiver715to the UE500. Second Exemplary Embodiment Hereinafter, a DRX operation method using a long DRX cycle according to the second exemplary embodiment of the present invention. In the related art, a Mobility Management Entity (MME) compares a UE-specific DRX cycle and a cell-specific DRX cycle, and determines and uses a smaller value of the two DRX cycles as a paging cycle of a corresponding UE. Thus, in the related art, although a UE wants to receive a paging in a cycle longer than a cell-specific DRX cycle and transmits a UE-specific DRX cycle of a long cycle to the MME, the UE cannot be provided with the long UE-specific DRX cycle as a paging cycle of the UE. For example, an MTC requiring reduction of power consumption, as described in the first exemplary embodiment of the present invention, needs a DRX cycle longer than a cell-specific DRX cycle, which has been set for supporting general UEs. As another example, there is a UE which supports dual radio. For a UE which supports both 3GPP LTE and 3GPP 1X system, it is necessary to set a DRX cycle in accordance with a system having a long DRX cycle in order to reduce power consumption. Therefore, the second exemplary embodiment of the present invention provides a method for making it possible to apply a UE to apply a UE-specific DRX cycle, which is a relatively longer cycle, in a UE. FIG.8is a flow diagram illustrating a procedure for applying a UE-specific DRX cycle according to the second exemplary embodiment of the present invention. Referring toFIG.8, in step820, a UE805receives an SIB2 message from an eNB810, and is provided with a cell-specific DRX cycle included in the SIB2. In this case, the UE805may receive a paging through the use of the cell-specific DRX cycle received from the eNB810, or may receive a paging after providing a UE-specific DRX cycle to a Mobility Management Entity (MME)815. In step825, the UE805transfers an indication, representing that the UE805does not follow the existing DRX cycle determination scheme, and a UE-specific DRX cycle which is a long cycle desired by the UE805to the MME815, through an attach request message. Then, in step830, the MME815notifies the UE805that the attach request message has been successfully received, through an attach accept message. Thereafter, in step835, the UE805compares the cell-specific DRX cycle with the UE-specific DRX cycle, and determines a longer cycle value of the two DRX cycles to be applied. As an example, the UE805may determine the UE-specific DRX cycle to be applied, without performing the comparing process of step835. In step840, the MME815provides the eNB810with the indication and UE-specific DRX cycle, which have been received from the UE805, so that the eNB810can calculate a DRX cycle of the UE805. In step845, the eNB810determines a paging cycle of the UE805in a manner different from the existing determination scheme, due to the indication provided from the MME815. That is, in step845, the eNB810compares the cell-specific DRX cycle with the UE-specific DRX cycle, and determines a longer cycle value of the two cycles to be applied. As an example, without performing the comparing process of step845, the MME815may apply the UE-specific DRX cycle. Then, in step850, the eNB810transmits a paging to the UE805in the determined DRX cycle. While the second exemplary embodiment of the present invention shows an example in which the UE805directly provides the MME815with a desired DRX cycle, exemplary embodiments of the present invention may be implemented in such a manner that the UE805notifies the MME815that the UE805uses a DRX cycle having a specific cycle pattern. Also, the UE805may inform that the UE805does not follow the existing DRX cycle determination scheme, through an indication. In this case, the UE805may define cycles having various patterns in advance, and use indication values indicating the cycles having various patterns. Third Exemplary Embodiment Hereinafter, according to the third exemplary embodiment of the present invention, a method for supporting a long DRX cycle provided in a wireless network environment where homogeneous or heterogeneous eNBs, of which the supportable DRX cycles are different, exist together, will be described. In a wireless network environment for the next-generation mobile communication, heterogeneous wireless networks can be constructed in the same area. Such heterogeneous wireless networks existing in the same area have a function of performing an intersystem overhead in order to maximize the performances thereof, and can provide a UE with a high-quality service in cooperation with each other. Also, even in wireless networks of the same system, eNBs of various versions may be installed for performance improvement, wherein as the version is upgraded, new functions may be added. A UE may receive a service in a wireless network environment where homogeneous or heterogeneous eNBs, the maximums of offerable DRX cycles of which are different, exist together. Therefore, although a UE requests a network to apply a long DRX cycle, a paging message may not be provided in the long DRX cycle requested by the UE depending on whether or not homogeneous or heterogeneous eNBs can support the corresponding DRX cycle. Therefore, an UE needs to be aware of whether an eNB of a cell, on which the UE is currently camping, can support a DRX cycle requested by the UE, and accordingly, the operation of the UE varies. According to the third exemplary embodiment of the present invention, a UE's operation for supporting a long DRX cycle in the aforementioned wireless network environment is defined. Here, a state in which the UE is camping on a cell represents a state in which the UE can receive control information from the cell. A method for supporting a long DRX cycle according to the third exemplary embodiment of the present invention is as follows. A UE requests an eNB to apply a UE-specific DRX cycle through a registration process (which is called an attach process in 3GPP). When the requested UE-specific DRX cycle is equal to or longer than a predetermined reference cycle, the UE determines whether a long DRX cycle is supported in a corresponding cell whenever moving from a cell to another cell in an idle state. In a cell where a long DRX cycle is supported, a UE calculates a paging occasion through the use of a larger value of two DRX cycles (i.e., a long DRX cycle requested by the UE, and a cell-specific DRX cycle broadcasted in the cell). In contrast, in a cell where a long DRX cycle is not supported, a UE calculates a paging occasion through the use of a smaller value of two DRX cycles, (i.e., a UE-specific DRX cycle, which is a long DRX cycle requested by the UE, and a cell-specific DRX cycle broadcasted in the cell). Consequently, in a cell where a long DRX cycle is not supported, a cell-specific DRX cycle is used at all times. Also, according to the third exemplary embodiment of the present invention, in the case in which a UE requests a long DRX cycle equal to or greater than a predetermined reference value in a registration process and so on, when transmitting a paging message for the UE, an MME inserts and transmits a value requested by the UE as the UE-specific DRX cycle of the paging message with respect to cells supporting a long DRX cycle among cells to which the paging message must be transmitted. In contrast, with respect to cells in which a long DRX cycle is not supported, the MME inserts and transmits a predetermined value as the UE-specific DRX cycle of the paging message. The predetermined value is used to allow a resultant value to be a cell-specific DRX cycle at all times when in a cell where a long DRX cycle is not supported uses a smaller value of two DRX cycles (i.e., a UE-specific DRX cycle provided by a MME, and a cell-specific DRX cycle managed by the cell according to the related technology). Therefore, the predetermined value may be the largest value (i.e., 2.56 seconds), of DRX cycles, other than the long DRX cycle. When an eNB supporting a long DRX cycle receives a paging message from an MME, the eNB determines whether the UE-specific DRX cycle of the paging message is a long DRX cycle, and calculates a paging occasion, during which the paging message is to be transmitted to the UE, by applying the UE-specific DRX cycle when the UE-specific DRX cycle of the paging message is a long DRX cycle. In contrast, when the UE-specific DRX cycle of the paging message is not a long DRX cycle, the eNB calculates a paging occasion, during which the paging message is to be transmitted to the UE, through the use of a smaller value of two DRX cycles (i.e., a cell-specific DRX cycle, and the UE-specific DRX cycle). Hereinafter, the third exemplary embodiment of the present invention will be described in detail with reference toFIG.9. FIG.9is a flow diagram illustrating the operations of a UE and an MME according to the third exemplary embodiment of the present invention. Referring toFIG.9, when powered on, an UE905performs an attach process to an MME910in step915. In step915, the UE905provides a desired DRX cycle to the MME910. When an eNB920of cell #1 on which the UE905is camping in step925is an eNB which cannot provide a long DRX cycle, the eNB920, broadcasts system information that the eNB920cannot support the long DRX cycle to the UE905in step930. When the UE905recognizes that the eNB920of cell #1, on which the UE905is currently camping, cannot provide the long DRX cycle requested by the UE905, the UE905determines a DRX cycle by Equation 3 below in step935. DRX cycle=min(cell specific DRX, UE specific DRX) (3) When the UE905is camping on the eNB920, which cannot support the long DRX cycle requested by the UE905, the MME910sets a paging DRX cycle to 2.56 seconds, which is the maximum cycle, in step940, and transmits a paging to the eNB920in step945when the paging occurs. In contrast, when an eNB950of cell #2 on which the UE905is camping in step955is an eNB which can provide a long DRX cycle, the eNB950broadcasts system information that the eNB950can support the long DRX cycle to the UE905in step960. When the UE905recognizes that the eNB950of cell #2, on which the UE905is currently camping, can provide the long DRX cycle requested by the UE905, the UE905determines a DRX cycle by Equation 4 below in step965. DRX cycle=max(cell specific DRX, UE specific DRX) (4) When the UE905is camping on the eNB950, which can support the long DRX cycle requested by the UE905, the MME910sets a paging DRX cycle to the long DRX cycle requested by the UE905in step970, and transmits a paging to the eNB950in step975when the paging occurs. FIG.10is a flowchart illustrating the operation of a UE according to the third exemplary embodiment of the present invention. Before performing the operation described inFIG.10, the UE905performs a registration process with the MME910, wherein an eNB is notified of a UE-specific DRX cycle in the registration process. The operation of the UE905, presented inFIG.10, corresponds to the operation of the UE905which makes a request for the UE-specific DRX cycle (i.e., a long DRX cycle), having a value larger than the maximum value defined in LTE Rel-8/-9. After performing the registration process, the UE905transitions to an idle state and performs an idle mode operation in general. FIG.10illustrates an operation of the UE905for receiving a paging message in an idle state. Referring toFIG.10, when the UE905is camping on a cell in step1010, the UE905proceeds to step1015at which the UE905determines whether or not the eNB of the cell supports a long DRX cycle. Determination as to whether the eNB of the cell supports a long DRX cycle can be made in a manner as described in the second exemplary embodiment of the present invention. That is, it may be determined that the cell supports a long DRX cycle when system information broadcasted in the cell includes a “long DRX Support indication,” and it may be determined that the cell does not support a long DRX cycle when system information broadcasted in the cell does not include a “long DRX Support indication.” Otherwise, whether or not a long DRX cycle is supported may be set depending on each Tracking Area (TA). Here, the TA represents a unit area for identifying the mobility of a UE being in an idle state, and is constituted by a plurality of cells. When a UE being in an idle state is camping on a cell included in a TA different from a previous TA, the UE performs a location update procedure. For example, when the UE905performs a location update procedure, the MME910indicates whether or not a long DRX cycle is supported in a corresponding TA, and the UE905determines that a cell supports a long DRX cycle when the cell belongs to a TA supporting a long DRX cycle, and determines that a cell does not support a long DRX cycle when the cell belongs to a TA not supporting a long DRX cycle. The UE905proceeds to step1020when a corresponding cell corresponds to a cell not supporting a long DRX cycle, and proceeds to step1025when the corresponding cell corresponds to a cell supporting a long DRX cycle. In step1020, the UE905selects a smaller value of a cell-specific DRX cycle and a UE-specific DRX cycle as a DRX cycle, and calculates a paging occasion by applying the selected DRX cycle. When the UE905uses a long DRX cycle, the UE-specific DRX cycle always is longer than the cell-specific DRX cycle, so that the DRX cycle selected by the UE905in step1020is the cell-specific DRX cycle at all times. Therefore, step1020may be changed to a step in which the UE905selects the cell-specific DRX cycle without taking the UE-specific DRX cycle into consideration. In step1025, the UE905selects a larger value of a cell-specific DRX cycle and a UE-specific DRX cycle as a DRX cycle, and calculates a paging occasion by applying the selected DRX cycle. When the UE905uses a long DRX cycle, the UE-specific DRX cycle always is longer than the cell-specific DRX cycle, so that the DRX cycle selected by the UE905in step1025is the UE-specific DRX cycle. Therefore, step1025may be changed to a step in which the UE905selects the UE-specific DRX cycle without taking the cell-specific DRX cycle into consideration. In step1030, the UE905performs a DRX operation of determining whether a paging message is received every paging occasion, which has been calculated in step1020or1025. FIG.11is a flowchart illustrating the operation of the MME according to the third exemplary embodiment of the present invention. Referring toFIG.11, while the MME910performs an attach process with the UE905in step1110, the MME910receives a request for a long DRX cycle from the UE905in step1115. Then, the MME910stores the DRX cycle and so on requested by the UE905, and when a paging message for the UE905is generated, the MME910proceeds to step1120for determining a UE-specific DRX cycle which is inserted into a paging message to be transmitted to eNBs belonging to a TA, where the UE905is located. For example, in step1120, it may be determined whether the cell supports a long DRX cycle. Next, the MME910proceeds to step1125when an eNB of a cell belonging to a TA in which the UE905is located does not support a long DRX cycle, and proceeds to step1130when the corresponding eNB supports a long DRX cycle. In step1125, the MME910inserts a predetermined value (e.g., 2.56 seconds), other than the UE-specific DRX cycle of the UE905, into a UE-specific DRX cycle section of the paging message to be transmitted to the eNB, and then transmits the paging message. In step1130, the MME910inserts the UE-specific DRX cycle requested by the UE905into the UE-specific DRX cycle section of the paging message to be transmitted to the eNB, and then transmits the paging message. While the invention has been shown and described with reference to certain exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents. | 29,902 |
RE49880 | EXAMPLES Preparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (I), can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein. are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature. Abbreviations Ac acetylAcOH acetic acidACN acetonitrileAIBN 2,2-azobisiosbutyronitrileanhyd. anhydrousaq. aqueousBH3DMS boron dimethylsulfideBn benzylBu butylBoc tert-butoxycarbonylCV Column VolumesDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCE dichloroethaneDCM dichloromethaneDEA diethylamineDIPEA diisopropylethylamineDMF dimethylformamideDMAP dimethylaminopyridineDMF-DMA N,N-dimethylformamide dimethyl acetalDMSO dimethylsulfoxideEt3N triethylamineEtOAc ethyl acetateEt ethylEtOH ethanolEt2O diethyl etherH or H2hydrogen h, hr or hrs hour(s)HATU O-(7-azabenzotriazol-1-yl)-N, N, N′,N′-tetramethyluronium hexafluorophosphatehex hexanei isoIPA isopropyl alcoholHOAc acetic acidHCl hydrochloric acidHPLC high pressure liquid chromatographyLAH lithium aluminum hydrideLC liquid chromatographyLCMS Liquid Chromatograph-Mass SpectroscopyM molarmM millimolarMe methylMeOH methanolMHz megahertzmin. minute(s)mins minute(s)M+1(M+H)+MOM-Cl chloromethyl methyl etherMS mass spectrometryn or N normalNBS n-bromosuccinimideNIS N-iodosuccinimidenm nanometernM nanomolarNMP N-methylpyrrolidinePd/C palladium on carbonPdCl2(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd2(dba)3tris-(dibenzylideneacetone)dipalladium Pd(OAc)2palladium acetatePet ether petroleum etherPh phenylRet Time retention timesat. saturatedTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTsCl 4-toluenesulfonyl chloride2nd Generation Xphos Precatalyst: (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) Analytical and Preparative HPLC Conditions: Method QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. QC Method: Method QC-ACN-TFA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Method A1: L3 Acquity: Column: (LCMS) BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98% B (to 1.5 min) 98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1: UV at 254 nm; Detector 2: MS (ESI+). Method B1: L2 Aquity(4); Column: (LCMS) BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98% B (to 1.5 min) 98%-2% B (to 1.5 min); Gradient Time: 1.8 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1: UV at 254 nm; Detector 2: MS (ESI+). Method C1 SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate. Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm. Method D1 SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm. Method E1 iPAC: Column: Waters Xbridge C18 4.6×50 mm 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate. Temperature: 50° C.; Gradient: 0-100% B over 1 minute; Flow: 4 mL/min; Detection: UV at 220 nm. Method F1 iPAC: Column: Waters Acquity BEH C18 2.1×50 mm 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 2.20 minutes; Flow: 0.800 mL/min; Detection: UV at 220 nm. (A): Column-Ascentis Express C18 (50×2.1 mm 2.7 μm) Mphase A: 10 mM NH4COOH in water: ACN (98:02); Mphase B: 10 mM NH4COOH in water: ACN (02:98), Gradient: 0-100% B over 3 minutes, Flow=1 mL/min. (B): Waters Acquity BEH C18 (2.1×50 mm) 1.7 μm; Buffer: 5 mM ammonium acetate pH 5 adjusted with HCOOH, Solvent A:Buffer:ACN (95:5), Solvent B:Buffer:ACN (5:95), Method: % B: 0 min-5%:1.1 min-95%: 1.7 min-95%, Flow: 0.8 mL/min. (C): Column-Ascentis Express C18 (50×2.1 mm 2.7 μm) Mobile phase A: 0.1% HCOOH in water; Mobile phase B: ACN. Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow rate: 1.0 mL/min.(D): Kinetex XB—C18 (75×3 mm) 2.6 μm; Solvent A: 10 mM ammonium formate in water: acetonitrile (98:02); Mobile Phase B: 10 mM ammonium formate in water: acetonitrile (02:98); Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow rate: 1.1 mL/min; Detection: UV at 220 nm. (E): Column: Ascentis Express C18 (50×2.1)mm, 2.7 μm; Mobile Phase A: 5:95 acetonitrile: water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile: water with 10 mM NH4OAc; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min. (F): Column: Ascentis Express C18(50×2.1)mm, 2.7 μm; Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min. (G): Column: Waters Acquity UPLC BEH C18 (2.1×50 mm), 1.7 μm; Solvent A=100% water with 0.05% TFA; Solvent B=100% acetonitrile with 0.05% TFA; gradient=2-98% B over 1 minute, then a 0.5-minute hold at 98% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm. (H): Column: Acentis Express C18 (50×2.1 mm) 1.7 μm, Acentis C8 NH4COOH 5 min. M, Mobile Phase A: −10 mM ammonium formate: ACN (98:2), Mobile Phase B: −10 mM ammonium formate: ACN (2:98), Flow: 1 mL/min. (I) Column: Sunfire C18 (4.6×150) mm, 3.5 μm; Mobile Phase A: 5:95 acetonitrile: water with 0.05% TFA: Mobile Phase B: 95:5 acetonitrile: water with 0.05% TFA; Temperature: 50° C.; Gradient: 10-100% B over 12 minutes; Flow: 1 mL/min. (J) Column: Sunfire C18 (4.6×150)mm, 3.5 μm; Mobile Phase A: 5:95 acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.05% TFA; Temperature: 50° C.; Gradient: 10-100% B over 25 minutes; Flow: 1 mL/min. (K): Column: Acquity UPLC BEH C18, 3.0×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Method: % B: O min-20%:1.1 mM −90%:1.7 min-90%; Flow: 0.7 mL/min. (L): Column: Kinetex XB-C18 (75×3 mm-2.6 μm), Mobile Phase A: 10 mM ammonium formate: ACN (98:2), Mobile Phase B: 10 mM ammonium formate: ACN (2:98), Flow: 1 mL/min. (M): Column: Acquity BEH C18 (3.0×50 mm) 1.7 μm, Mobile phase A: 0.1% TFA in water: Mobile phase B: 0.1% TFA in ACN, % B: 0 min-20%: 1.0 min-90%: 1.6 min 90%, Flow: 0.7 mL/min. (N) Column: XBridge BEH XP C18 (50×2.1)mm, 2.5 μm; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, Flow: 1.1 mL/min; Detection: UV at 220 nm. INTERMEDIATES Intermediate T-1: tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate Intermediate T-1A: 5-bromo-3-isopropyl-1H-indole A 250 mL round bottom flask was charged with triethylsilane (8.90 g, 77 mmol), trichloroacetic acid (6.25 g, 38.3 mmol) and toluene (50 mL). The solution was heated to 70° C., then a solution of 5-bromo-1H-indole (5.0 g, 25.5 mmol) and acetone (2.247 mL, 30.6 mmol) in toluene (30 mL) was added drop wise via an addition funnel. The resulting brown solution was heated at 70° C. for 1.5 h. The solution was cooled to 10° C., quenched with 10% sodium bicarbonate and diluted with diethyl ether. The organic layer was separated, dried and concentrated under vacuum to afford crude compound. The crude compound was purified using silica gel chromatography eluting with 5% ethyl acetate in hexanes to afford 5-bromo-3-isopropyl-1H-indole (5.5 g, 23.10 mmol 95% yield) as an oil. LC retention time 1.42 min [D]. MS (E-) m/z: 238.2 (M+H). Intermediate T-1B: tert-butyl 4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate To a mixture of 5-bromo-3-isopropyl-1H-indole (5.5 g, 23.10 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (7.50 g, 24.25 mmol) in a 250 mL round bottom flask were added THF (50 mL) followed by an aqueous solution of potassium phosphate, dibasic (12.07 g, 69.3 mmol, 20 mL). The resulting reaction mixture was degassed for 10 minutes with nitrogen gas, then PdCl2(dppf)—CH2Cl2adduct, (0.472 g, 0.577 mmol) was added. The mixture was degassed again for 5 min. The resulting reaction mixture was heated at 75° C. for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL), poured into a separate funnel and was washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate, and concentrated to give crude product. The crude material was purified using silica gel chromatography, eluting with 15% ethyl acetate in hexane. The fractions were collected and concentrated to afford tert-butyl 4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-(2H)-carboxylate (6.5 g, 83% yield) as an oil. LCMS retention time 1.21 min [B]. MS (E-) m/z: 339 (M−H). Intermediate T-1C: tert-butyl 4-(3-isopropyl-1H-indol--yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-(2H)-carboxylate (7.9 g, 23.20 mmol) in ethyl acetate (150 mL) under a nitrogen atmosphere, was added palladium on carbon (0.617 g, 0.580 mmol). The vessel was pumped/purged three times with nitrogen gas and then evacuated. Hydrogen gas was introduced via a balloon and the mixture was stirred at room temperature for 5 hours. The suspension was filtered through celite and the filtrate was concentrated to give crude compound. The crude residue was purified by silica gel chromatography, eluting with 15% ethyl acetate in hexane. The combined fractions were collected and concentrated to afford tert-butyl 4-(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (6.5 g, 82% yield) as a white solid. LCMS retention time 2.48 min [C]. MS (E-) m/z: 341 (M−H). Intermediate T-1 To a solution of tert-butyl 4-(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (6.3 g, 18.40 mmol) in DCE (60 mL) was added NBS (3.27 g, 18.40 mmol) dissolved in DCE (50 mL) drop wise via an addition funnel over 10 min at 0° C. The resulting brown solution was stirred at room temperature for 20 min. The reaction was quenched with sodium sulfite solution (15 mL). The volatiles were removed. The residue was taken up in DCM (50 mL) and the aqueous layer was separated. The organic layer was dried over Na2SO4and concentrated to afford crude compound. The crude compound was purified by silica gel chromatography, the compound was eluted in 15% ethyl acetate in Pet ether, the fractions was collected, and concentrated to afford tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (6.4 g, 83% yield) as a white solid. LCMS retention time 2.58 min [H]. MS (E−) m/z: 367.2 (M−H).1H NMR (500 MHz, CHLOROFORM-d) δ 7.84 (br. s., 1H), 7.49 (d, J=0.9 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.5 Hz, 1H), 4.27 (br. s., 2H), 3.23 (quin, J=7.1Hz, 1H), 2.84 (br. s., 3H), 1.88 (d, J=13.1Hz, 2H), 1.50 (s, 9H), 1.43 (d, J=7.2 Hz, 6H), 1.24 (s, 2H). Alternative Preparation of Intermediate T-1 Intermediate T-1A A 5-liter 4-neck round bottom flask was charged with triethylsilane (489 mL, 3061 mmol), trichloroacetic acid (250 g, 1530 mmol) and toluene (500 mL). The solution was heated to 70° C. Next, 5-bromo-1H-indole (200 g, 1020 mmol) dissolved in acetone (150 mL, 2040 mmol) and toluene (700 mL) was added dropwise over 30 minutes. After the addition was complete, the resulting solution was heated at 90° C. for 3 h. The reaction was then quenched by adding 10% NaHCO3solution (˜2.5 liter) dropwise at 0-10° C. until the pH was basic. The organic layer and the aqueous layer were separated and the aqueous layer was extracted with MTBE (2×1000 mL). The combined organic layers were washed with water and brine solution, dried over Na2SO4and concentrated under vacuum to get a brown color oil. The crude residue was purified by 750 g silica gel chromatography eluting with PE:EtOAc (9:1). The product was eluted at 8% EtOAc in petroleum ether, collected, and concentrated under vacuum at 50° C. A light brown gummy liquid was obtained and hexane (100 mL) was added. The mixture was stirred and cooled to −40° C. to −50° C. After 10 min, a solid was formed which was filtered and washed with a minimal amount cold hexane. The compound was dried under vacuum to afford 5-bromo-3-isopropyl-1H-indole (215 g, 890 mmol, 87% yield) as an off-white solid. LCMS MH+: 237.5; HPLC Ret. Time 3.75 min. Method D. Intermediate T-1B 5-bromo-3-isopropyl-1H-indole (90 g, 378 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (140 g, 454 mmol) was dissolved in THF (1200 mL) in a 2 L round-bottomed flask. Tripotassium phosphate (241 g, 1134 mmol) was dissolved in water (300 mL). The aqueous solution was added to the reaction mixture. The reaction mixture was purged with N2. Then PdCl2(dppf)-CH2Cl2adduct (7.72 g, 9.45 mmol) was added to the reaction mixture. The reaction mixture was again purged with N2. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was filtered through celite and extracted with EtOAc. The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated to remove the solvent. The crude material was purified by silica gel chromatography. The product was collected by eluting with 30% EtOAc:PE to afford tert-butyl 4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (125 g, 367 mmol). LCMS MH+: 341.2; HPLC Ret. Time 2.90 min.; Method: Column: Zorbax SB-18 (50×4.6 mm-5.0 μm); M. phase A: 10 mM NH4COOH in H2O:ACN (98:2); M. phase B: 10 mM NH4COOH in H2O:ACN (2:98); Flow rate: 1.5/min; Gradient: 30% B-100% B over 4 min. UV 220 nm. Intermediate T-1C In a 2 L round-bottomed flask, tert-butyl 4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (125 g, 367 mmol) was dissolved in ethyl acetate (1200 mL). Pd/C (15.63 g, 14.69 mmol) was added and the reaction mixture was degassed under N2. The reaction mixture was stirred at room temperature for 18 h under H2. Approximately 80% starting material was converted to product. The reaction mass was filtered through celite and concentrated. The crude material was purified with silica gel chromatography. The product was collected by eluting with 20% EtOAc:PE to afford tert-butyl 4-(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (105 g, 307 mmol, 84% yield). LCMS MH+: 343.4; HPLC Ret. Time 2.61 min.; Method: Column: Zorbax SB-18 (50×4.6 mm-5.0 μm); M. phase A: 10 mM NH4COOH in H2O:ACN (98:2); M. phase B: 10 mM NH4COOH in H2O:ACN (2:98); Flow rate: 1.5/min; Gradient: 30% B-100% B over 4 min.; UV 220 nm. Intermediate T-1 In a 2 L round-bottomed flask tert-butyl 4-(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (100 g, 292 mmol) was dissolved in 1,2-dichloroethane (1200 mL). NBS (52.0 g, 292 mmol) solution in 1,2-dichloroethane (400 mL) and THF (800 mL) was added dropwise at 0° C. After the addition of NBS solution, the reaction mixture was stirred for 30 min. The reaction mass was quenched with 10% sodium thiosulfate solution at 0° C. and diluted with DCM. The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated. The crude material was purified with silica gel chromatography. The product was collected by eluting with 10% EtOAc:PE. The dibromo product was observed (approximately 5-10%). The material was washed with cooled hexane to remove the dibromo product and afford tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (87 g, 206 mmol, 70.7% yield). LCMS MH+-56: 365.0; HPLC Ret. Time 4.21 min.; Method: Column: Kinetex XB-C18 (75×3 mm-2.6 μm); M. phase A: 10 mM NH4COOH in H2O:ACN (98:02); M. phase B: 10 mM NH4COOH in H2O:ACN (02:98); Flow rate: 1.0/min; Gradient: 20% B-100% B over 4 min. UV 220 nm. Intermediate T-2: tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate To a mixture of tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (1.0 g, 2.373 mmol), 2-dicyclohexyphosphino-2′,6′-dimethoxybiphenyl (0.117 g, 0.285 mmol), and bis(benzonitrile)palladium(II)chloride (0.027 g, 0.071 mmol) in a 50 mL reaction tube was added dioxane (10 mL). The resulting reaction mixture was degassed for 10 mM and then pinacolborane (0.456 g, 3.56 mmol) was added followed by the dropwise addition of TEA (0.992 mL, 7.12 mmol). The solution was again degassed for 5 mM. The resulting reaction mixture was heated at 85° C. for 3 h. The reaction mixture was concentrated and the crude residue was dissolved in ethyl acetate (100 mL), poured into a separatory funnel and washed thoroughly with water (2×250 mL). The organic layer was dried over Na2SO4and filtered. The filtrate was concentrated under vacuum to afford the crude product. The residue was taken up in DCM (3 mL). The crude material was purified by combiflash system by eluting with 12% EtOAc/Pet ether. Following concentration of the fractions, the product was isolated as a white gummy product (0.75 g, 67.5% yield). LCMS retention time 4.27 min [H]. MS (E−) m/z: 467.3 (M−H).1H NMR (400 MHz, CHLOROFORM-d) δ 8.35-8.12 (m, 1H), 7.66-7.59 (m, 1H), 7.11-7.04 (m, 1H), 4.40-4.23 (m, 2H), 3.80-3.63 (m, 1H), 2.99-2.67 (m, 3H), 1.98-1.84 (m, 2H), 1.79-1.64 (m, 2H), 1.54-1.51 (m, 9H), 1.49-1.45 (m, 6H), 1.39-1.35 (m, 12H). Alternative Preparation of Intermediate T-2 In a 1 L round-bottomed flask, tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (85 g, 202 mmol) was dissolved in dioxane (850 mL). Next, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (9.11 g, 22.19 mmol) and bis(benzonitrile) palladium chloride (3.87 g, 10.09 mmol) were added. Pinacolborane (387 g, 3026 mmol) was added followed by the addition of TEA (84 mL, 605 mmol). The reaction mixture was purged with nitrogen for 15-20 min. The reaction mixture was stirred at 90° C. for 20 h. The reaction mixture was filtered through celite and the reaction was quenched with brine solution. Effervescence was observed. The reaction mixture was extracted with EtOAc, dried (sodium sulfate), and concentrated. The crude material was purified with silica gel chromatography. The product was collected by eluting with 10% EtOAc:PE to afford tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (62.5 g, 133 mmol, 66.1% yield). LCMS MH+: 469.4. HPLC Ret. Time 3.04 min.; Method: Column: Zorbax SB-18 (50×4.6 mm-5.0 μm); M. phase A: 10 mM NH4COOH in H2O:ACN (98:2); M. phase B: 10 mM NH4COOH in H2O:ACN (2:98); Flow rate: 1.5/min; Gradient: 30% B-100% B over 4 min.; UV 220 nm. Intermediate T-3: Tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate To a mixture of tert-butyl 4-(2-bromo-3-isopropyl-1H- indol-5-yl)piperidine-1-carboxylate (60 g. 142 mmol), bis(benzonitrile)palladium(ii) chloride (1.639 g, 4.27 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (3.51 g, 8.54 mmol) and anhydrous dioxane (407 ml) under N2at room temperature were added pinacolborane (62.0 mL, 427 mmol) and triethylamine (59.5 mL, 427 mmol). The mixture was heated at 85° C. for 5 min. The starting material was consumed. After the reaction mixture was cooled to room temperature (a water ice bath was used to fasten the cooling), 2 mL of 2 M K3PO4solution was added. After the generation of bubbles diminished, the remainder of the 2 M potassium phosphate tribasic solution (214 mL, 427 mmol) was added, followed by 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (29.9 g, 132 mmol) and PdCl2(dppf)-CH2Cl2adduct (4.07 g, 4.98 mmol). The reaction mixture was heated at 85° C. for 2 h. The reaction went to completion. After the mixture was cooled to room temperature, the organic layer (a suspension) and the aqueous layer was separated. The top organic layer was a suspension. It was concentrated and dissolved in DCM (1.5 L) to give a dark DCM solution and aqueous layer on the top. The water was removed and the DCM extraction was dried over Na2SO4, filtered through a Celite pad, washed with DCM and concentrated to give 150 g crude wet mud. The material was purified with silica gel chromatography using a Silica 40 g Gold column. The column was eluted with DCM and ethyl acetate. The product was collected when eluting with 50% ethyl acetate:DCM to afford tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (56.9 g, 117.0 mmol, 82% yield) as an off-white solid. LCMS MH+: 488.5. HPLC Ret. Time 1.13 min. Method G.1H NMR (499 MHz, CHLOROFORM-d) δ 8.45-8.41 (m, 1H), 8.36-8.33 (m, 1H), 7.90-7.84 (m, 1H), 7.66-7.63 (m, 1H), 7.39-7.34 (m, 1H), 7.17-7.12 (m, 1H), 4.39-4.26 (m, 2H), 3.04-2.94 (m, 1H), 2.92-2.75 (m, 3H), 2.72-2.65 (m, 3H), 2.27-2.21 (m, 3H), 2.00-1.90 (m, 2H), 1.83-1.71 (m, 2H), 1.54-1.51 (m, 9H), 1.42-1.38 (m, 6H). Intermediate T-4: Tert-butyl 4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate To a mixture of tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (40 g, 95 mmol), bis(benzonitrile)palladium(ii) chloride (1.092 g, 2.85 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.338 g, 5.70 mmol) and anhydrous dioxane (271 mL) under N2at room temperature, were added pinacolborane (41.3 mL, 285 mmol) and triethylamine (39.7 mL, 285 mmol). The mixture was heated at 85° C. for 10 min. The starting material was consumed. After the reaction mixture was cooled to room temperature, 2-5 mL of 2 M K3PO4aqueous solution was added. After bubbling slowed down, the remainder of the 2 M potassium phosphate tribasic solution (142 mL, 285 mmol) was added, followed by 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (20 g, 88 mmol) and PdCl2(dppf)-CH2Cl2adduct (3.10 g, 3.80 mmol). The mixture was heated at 70° C. for 1.5 h. After completion of the reaction, 81 g of crude product after concentration was purified by silica gel chromatography (3 kg Gold column) eluting with DCM and ethyl acetate. The product was collected at 35% ethyl acetate:DCM to afford tert-butyl 4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (52.6 g, 107 mmol, 113% yield). LCMS MH+: 490.1. HPLC Ret. Time 1.08 min. Method G. Intermediate F-1: 6-bromo-[1,2,4]triazolo[1,5-a]pyridine Commercially available reagent: CAS No 356560-80-0 Intermediate F-2: 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of 5-bromo-3-methylpyridin-2-amine (1.75 g, 9.36 mmol) in N,N-dimethylformamide (13.04 mL, 168 mmol) was added DMF-DMA (12.53 mL, 94 mmol). The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to afford a brown oil. To an ice-cooled, stirred solution of the crude product in methanol (100 mL) and pyridine (15 mL) was added hydroxylamine-O-sulfonic acid (1.587 g, 14.03 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed sequentially with water (10 mL) and saturated aqueous brine solution (10 mL), dried over magnesium sulfate, and concentrated in vacuo to afford 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (1.98 g). LC-MS: M+1=212/214. Rt=0.80 min, [Al];1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.48 (s, 1H), 7.67 (s, 1H), 2.55 (s, 3H). Intermediate F-3: 6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine To a 40 mL vial with a pressure relief septum were added 5-bromo-4-methylpyridin-2-amine (5.00 g, 26.7 mmol), DMF (10 mL) and N,N-dimethylformamide dimethyl acetal (11.99 mL, 90 mmol). The vial was heated to 130° C. for 6 hours. The vial was cooled to room temperature, the volatiles were removed under vacuum. The resulting oil was dissolved in MeOH (5 mL) and pyridine (3.24 mL, 40.1 mmol) and cooled to 0° C. Hydroxylamine-O-sulfonic acid (4.53 g, 40.1 mmol) was added over 15 minutes and the mixture was allowed to warm to room temperature overnight. The solution was concentrated under vacuum. The resulting white solid was partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated and the bicarbonate layer was extracted with EtOAc (2×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated to afford 6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine as a white solid. (4.5 g, 21.22 mmol, 79% yield). LC-MS: M+1=212/214, rt=0.70 min., [A1]. Intermediate F-4: 6-bromo-7,8-dimethyl-[1,2,41]triazolo[1,5-a]pyridine To a 40 mL vial with a pressure relief septum were added 5-bromo-3,4-dimethylpyridin-2-amine (5.00 g, 24.87 mmol), DMF (10 mL) and N,N-dimethylformamide dimethyl acetal (11.15 mL, 83 mmol). The vial was heated to 80° C. for 6 hours. The vial was cooled to room temperature. The volatiles were removed under vacuum and the resulting oil was dissolved in MeOH (5 mL) and pyridine (3.02 mL, 37.3 mmol) and cooled to 0° C. Hydroxylamine-O-sulfonic acid (4.22 g, 37.3 mmol) was added over 15 minutes and the mixture allowed to warm to room temperature overnight. The solution was concentrated under vacuum. The resulting white solid was partitioned between EtOAc and 1.5 M potassium phosphate solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give a white solid. The solid was dissolved in DCM and MeOH and charged to an 80G silica gel column which was eluted with 0-100% ethyl acetate/hexane. Following concentration of the fractions, 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (5.2 g, 23.00 mmol, 92% yield) was collected as a whitish solid. LC-MS: M+1=226/228, rt=0.75 min, [A1];1H NMR:1H NMR (400 MHz, CHLOROFORM-d) δ 8.68 (s, 1H), 8.26 (s, 1H), 2.68 (s, 3H), 2.50 (s, 3H). Alternative Preparation of Intermediate F-4 To the suspension of 5-bromo-3,4-dimethylpyridin-2-amine (10 g, 49.7 mmol) in DMF (50 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (15.32 mL, 114 mmol). The mixture was stirred at 110° C. for 12 h under N2. All the starting material amine was converted to intermediate imine (M+1, 256) after 12 h. The reaction mixture was concentrated to remove volatiles under high vacuum rotavap. Solvent DMF still remained in the black reaction mixture. The resulting residue was diluted with MeOH (50 mL) and pyridine (6.03 mL, 74.6 mmol). The mixture was cooled to 0° C. and hydroxylamine-O-sulfonic acid (8.88 g, 74.6 mmol) was added over 15 min. The mixture was stirred at room temperature over 24 h. The reaction was completed and the desired product was found after 19 h. The crude reaction mixture was concentrated to remove volatiles. The resulting yellow solid was dissolved in 200 mL EtOAc and quenched with saturated NaHCO3solution slowly (200 mL) with gas generated during the addition of sodium bicarbonate. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic layer was washed with H2O (30 mL), brine (2×30 mL) and dried over Na2SO4. The crude product was purified with silica gel chromatography eluting with EtOAc and hexane to afford 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (8 g, 35.4 mmol, 71.1% yield). LCMS MH+: 226.08. HPLC Ret. Time 0.71 min. Method G.1H NMR (400 MHz, CHLOROFORM-d) δ 8.79-8.63 (m, 1H), 8.39-8.10 (m, 1H), 2.81-2.61 (m, 3H), 2.57-2.48 (m, 3H). Intermediate F-5: 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of 5-bromo-3-methoxypyridin-2-amine (7.5 g, 36.9 mmol) in DMF (15 mL) was added DMF-DMA (15 mL, 112 mmol). The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to provide a brown oil. To an ice-cooled, stirred solution of the brown oil in methanol (150 mL) and pyridine (20 mL) was added hydroxylamine-O-sulfonic acid (6.27 g, 55.4 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed sequentially with water (10 mL) and saturated aqueous brine solution (10 mL), dried over sodium sulfate, and concentrated in vacuo to afford crude product. The residue was taken up in DCM (3 mL). The crude was purified by combiflash 3% MeOH: 97% CHCl3. Following concentration of fractions, 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (5.0 g, 21.93 mmol, 59.4% yield) was collected as a yellow solid. LCMS:M+1=228.5, Rt=1.06 min., Column: ZORBAX SB C18 (50×4.6 mm, 5.0 μM) Method: 10 mM NH4COOH in water +ACN;1H NMR (400 MHz, DMSO-d6) δ=4.01 (s, 3H), 7.26 (s, 1H), 8.45 (s, 1H), 8.95 (s, 1H). Intermediate F-6: 6-bromo-8-(methoxymethyl)-[1,2,4]triazolo[1,5-a]pyridine To a 40 mL reaction vial, were added 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.000 g, 9.43 mmol), AIBN (0.155 g, 0.943 mmol), NBS (1.679 g, 9.43 mmol), and CCl4(15 mL). The vial was sealed and heated to 75° C. overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was used without purification in the subsequent step. To a 40 mL vial, were added the above residue, THF (15 mL), MeOH (10 mL), and aqueous NaOH (28.3 mL, 28.3 mmol). The reaction vial was capped and heated to 75° C. for 1 hour. LC-MS showed clean conversion to the product. Water and ethyl acetate was added and the layers were separated. The organics were washed with water, then brine, dried over Na2SO4, filtered, and concentrated to give an off-white solid. LC-MS: M+1=242, rt=1.31 min, [A1].1H NMR (400 MHz, DMSO-d6) δ 9.41-9.28 (m, 1H), 8.52 (s, 1H), 7.78-7.65 (m, 1H), 4.84-4.70 (m, 2H), 3.42 (s, 3H). Intermediate F-7: 6-2-(2-amino-5-bromo-1,2-dihydropyridin-3-yl)ethanol In a 100 mL 2-neck round bottom flask, and under a nitrogen atmosphere, was added 2-(2-aminopyridin-3-yl)acetic acid (0.250 g, 1.622 mmol) and THF (8 mL). At 5° C., LAH was added portion-wise to the solution. The ice bath was removed and the reaction mixture was heated at reflux overnight. After 16 hours, the solvent had evaporated. Diethyl ether was added. Following cooling, the reaction mixture was placed in an ice bath. The LAH was quenched with MeOH, then water. Sodium sulfate was added and the mixture was filtered, and washed with diethyl ether. The filtrate was concentrated and then dissolved in DCM (5 mL) and cooled to 5° C. Next, NBS (0.289 g, 1.622 mmol) in DCM (2 mL) was added. The reaction mixture was warmed to room temperature. The reaction was quenched with 2 mL of a 10% sodium sulfite solution. DCM (20 mL) and water (20 mL) were added and the contents was added to a separatory funnel. The layers were separated. The organics were washed with brine dried over Na2SO4, filtered and concentrated to give crude product. LC-MS: M+1=219, Rt=0.49 min, [A1]. This material was carried on similarly as in general procedure for F-2 to afford (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethanol (0.065 g, 73%). LC-MS: M+1=242/244, Rt=0.65 min, [A1]. Intermediate F-8: (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol Intermediate F-8 was prepared according to general procedure for F-6 starting from 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine and without methanol in the second step. LC-MS: M+1=228/230, Rt=0.60 min, [A1]. Intermediate F-9: rac-1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethan-1-ol In a 40 mL reaction vial were added 2-amino-5-bromonicotinaldehyde (0.750 g, 3.73 mmol) and under nitrogen gas, THF (10 mL). The mixture was cooled to −20° C. and 3 M methylmagnesium chloride in Et2O (4.97 mL, 14.92 mmol) was added via syringe over 20 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to −20° C. and quenched slowly with saturated ammonium chloride. Water and ethyl acetate were added and the layers were separated. The collected organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to dryness to afford rac-1-(2-amino-5-bromopyridin-3-yl)ethanol. This material was carried on similarly as in general procedure for F-1 to afford rac-1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethan-1-ol (0.53 g, 58%). LC-MS: M+1=242/244, Rt=0.58 min, [A1]. Intermediate F-10: 2-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)propan-2-ol In a 40 mL reaction vial was added methyl 2-amino-5-bromonicotinate (1.240 g, 5.37 mmol) and under a nitrogen atmosphere, THF (10.73 mL). The mixture was cooled to −20° C. and 3 M methylmagnesium chloride in Et2O (7.16 mL, 21.47 mmol) was added via syringe over 20 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to −20° C. and the reaction was quenched slowly with the addition of saturated ammonium chloride. Water and ethyl acetate were added and the layers were separated. The collected organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to dryness to afford 2-(2-amino-5-bromopyridin-3-yl)propan-2-ol LC-MS: M+1=231.3/233.0, Rt=0.49 min, [A1]. This material was carried on similarly as in general procedure for F-1 to afford 2-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)propan-2-ol (0.65 g, 59%). LC-MS: M−1=255.6/257.8, Rt=0.85 min, [D1]. Intermediate F-1: (6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol Intermediate F-11A: (2-amino-4-methylpyridin-3-yl)methanol In a 100 mL Schlenk flask (heat gun dried) was added N-(4-methylpyridin-2-yl)pivalamide (0.300 g, 1.560 mmol). Diethyl ether (5.20 mL) was added and the reaction mixture was cooled to −78° C. Next, 1.7 M tert-butyllithium in pentane (2.019 mL, 3.43 mmol) was added via syringe, drop-wise. The reaction mixture was stirred at −78° C. for 3 hours and then chloromethyl methyl ether (0.142 mL, 1.872 mmol) was introduced. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water. Ethyl acetate was added to the mixture. The mixture was poured into a separatory funnel and the layers were separated. The organics were washed with water, then brine, dried over Na2SO4, filtered and concentrated. The crude oil was purified on a silica gel using 0-50% ethyl acetate/hexane. Following concentration of the fractions, N-(3-(methoxymethyl)-4-methylpyridin-2-yl)pivalamide was collected as a tan oil. This material was suspended in 4 M aqueous HCl and heated to 110° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and the contents poured into a separatory funnel. The layers were separated and the organic layer was discarded. The aqueous layer was basified with 1.5 M potassium phosphate dibasic solution and the suspension was extracted with ethyl acetate (three times extracted). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford (2-amino-4-methylpyridin-3-yl)methanol (0.1 g, 46%). LCMS: (M+1) not observed on instrument, Rt=0.39 min by UV only, [A1]. Intermediate F-11B: (2-amino-5-bromo-4-methylpyridin-3-yl)methanol In a 40 mL reaction vial was added (2-amino-4-methylpyridin-3-yl)methanol (0.200 g, 1.448 mmol), DCM, and NBS (0.258 g, 1.448 mmol) as a suspension in 5 mL of DCM. The reaction mixture was stirred for 15 minutes. The reaction was quenched with a 10% sodium sulfite solution (1 mL). The reaction mixture was diluted with water and DCM, and transferred to a separatory funnel. The layers were separated and the organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford (2-amino-5-bromo-4-methylpyridin-3-yl)methanol (0.08 g, 26%). LCMS: M+1=217/219, Rt=0.45 min, [A1]. Intermediate F-11 Intermediate F-11 was prepared from Intermediate F-11B according to the general procedure for F-2 to afford (6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl) methanol LC-MS: M+1=242/244, Rt=0.60 min, [A1]. Intermediate F-12: 6-bromo-8-(methoxymethyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine Intermediate F-12A: 6-bromo-8-(methoxymethyl)-7methyl-[1,2,4]triazolo[1,5-a]pyridine In a 40 mL reaction vial were added N-(3-(methoxymethyl)-4-methylpyridin-2-yl)pivalamide (0.100 g, 0.423 mmol) and 6 N aqueous HCl (2.116 mL, 2.116 mmol). The vial was capped and heated to 80° C. overnight. The mixture was basified with a 1.5 M dibasic potassium phosphate solution. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were washed with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated to afford 3-(methoxymethyl)-4-methylpyridin-2-amine (Rt=0.44 min.) [A1]. This material was suspended in DCM (4 mL). NBS (0.075 g, 0.423 mmol) was dissolved in 1 mL of DCM and added to the reaction mixture dropwise via a pipette over 5 minutes. The reaction was quenched with the addition of 1 mL of a 10% sodium sulfite solution. The organic layer was pipetted off and concentrated. The residue was purified on silica gel using 0-10% MeOH/DCM. Following concentration of the fractions, 5-bromo-3-(methoxymethyl)-4-methylpyridin-2-amine was collected as a tan oil. LC-MS: M+1=231/233, Rt=0.53 min. 0.60 min, [D1]. Intermediate F-12 Intermediate F-12 was prepared from Intermediate F-12A according to the general procedure for F-1 to afford 6-bromo-8-(methoxymethyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.03 g, 30%). LC-MS: M+1=256/258, Rt=1.07 min. 0.60 min, [A]. Intermediate F-13: 2-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetonitrile To a 40 mL reaction vial was added (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl) methanol (0.500 g 2.193 mmol) followed by the slow addition of SOCl2(1.600 mL, 21.93 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated and placed under vacuum to remove the excess thionyl chloride. Next, acetonitrile, water and KCN (0.714 g, 10.96 mmol) in water (1 mL) were added. The reaction vessel was sealed and heated to 50° C. overnight. The reaction mixture was diluted with 1.5 M dibasic potassium phosphate solution and ethyl acetate was added. The reaction mixture was poured into a separatory funnel and the layers were separated. The organics were washed with brine, then dried over Na2SO4, filtered and concentrated to afford 2-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetonitrile as a tan solid (0.21 g, 40%). LC-MS: M+1=236/238, Rt=0.60 min, [A1]. Intermediate F-14: 6-bromo-8-fluoro-7-methyl-[1,2,4]triazolo[1,5-a]pyridine In a 40 mL reaction vial was added 3-fluoro-4-methylpyridin-2-amine (0.250 g, 1.982 mmol) in DCM (5 mL). To this was added a suspension of NBS (0.353 g 1.982 mmol) in DCM (2 mL). The reaction mixture was stirred for 30 minutes. The reaction was quenched with the addition of 5 mL of a 10% sodium sulfite solution. DCM and water were added and the reaction mixture was poured into a separatory funnel. The layers were separated. The collected organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford 5-bromo-3-fluoro-4-methylpyridin-2amine. This material was carried on similarly as in general procedure for F-2 to afford 6-bromo-8-fluoro-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.45 g, 49%). LC-MS: M+1=230/232, Rt=0.71 min. 0.60 min, [A1]. Intermediate F-15: (6-bromo -[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol Intermediate F-15A: 6-bromo-7-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine In a 40 mL reaction vial were added 6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.670 g, 3.16 mmol), carbon tetrachloride (6.32 mL), NBS (0.562 g, 3.16 mmol) and AIBN (0.052 g, 0.316 mmol). The reaction vial was capped and heated at 75° C. for 5 hours. The reaction mixture was cooled to room temperature, filtered and the precipitate was washed with CCl4. The filtrate was concentrated to afford 6-bromo-7-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine as a light yellow residue (0.72 g, 78%). LC-MS: M+1=290/292/294, Rt=0.75 min., [A1]. Intermediate F-15 To a 40 mL vial were added 6-bromo-7-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.000 g, 3.44 mmol), acetone (11 mL), sodium iodide (0.515 g, 3.44 mmol) and potassium acetate (0.675 g, 6.87 mmol). The reaction mixture was capped and heated to 55° C. for 17 hours. The volatiles were removed under a stream of nitrogen gas and to the residue were added THF (10 mL), 1 mL of water, and sodium hydroxide (2.58 mL, 10.31 mmol). The vial was capped and heated at 65° C. for 8 hours. The mixture was treated with 1 N HCl to approximately pH 7. Ethyl acetate was added and the layers were separated. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol as a whitish solid (0.35 g, 44%). LC-MS: M+1=228/230, Rt=0.54 min., [A1]. Intermediate F-16: 2-((6-bromo-[1,2,4]triazolo[1,5a]pyridin-8-yl)oxy)ethyl acetate Intermediate F-16A: 2-((2-amino-5-bromopyridin-3-yl)oxy)ethyl acetate In a 40 mL reaction vial under nitrogen gas, was added 2-amino-5-bromopyridin-3-ol (0.320 g, 1.693 mmol) and DMF (5 mL). The mixture was cooled to 5° C. and NaH (0.102 g, 2.54 mmol) was added. The reaction mixture was stirred at 5° C. for 1 hour. Next, 2-bromoethyl acetate (0.283 mL, 2.54 mmol) was introduced neat via a syringe. The reaction mixture was stirred at 5° C. and slowly warmed to room temperature overnight. The mixture was cooled to 5° C. and carefully diluted with water. Ethyl acetate was added and the mixture was transferred to a separatory funnel. The layers were separated and the organics were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2-((2-amino-5-bromopyridin-3-yl)oxy)ethyl acetate as a tan oil (0.45 g, 97%). LC-MS: M+1=275/277, rt=0.52 min, [A1]. Intermediate F-16 Intermediate F-16A carried on similarly to general procedure for F-1 to afford 2-((6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)ethyl acetate as a tan solid. LC-MS: M+1=300/302, Rt=0.69 min, [A1]. Intermediate F-17: 6-bromo-8-(ethoxymethyl)-[1,2,4]triazolo[1,5-a]pyridine Intermediate F-17A: 6-bromo-8-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine To a 40 mL reaction vial were added 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.000 g, 9.43 mmol), AIBN (0.155 g, 0.943 mmol), NBS (1.679 g, 9.43 mmol), and CCl4(15 mL). The vial was sealed and heated to 75° C. overnight. The reaction mixture was cooled to room temperature, filtered and the precipitate was washed with CCl4. The filtrate was concentrated to dryness to afford 6-bromo-8-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine, as a light yellow residue (1.9 g, 69%). LC-MS: M+1=290/292/294, Rt=0.73 min., [A1]. Intermediate F-17 To a 40 mL reaction vial were added 6-bromo-8-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine (0.300 g, 1.031 mmol), ethanol (3.44 mL), sodium iodide (0.015 g, 0.103 mmol) and potassium acetate (0.051 g, 0.516 mmol). The reaction vial was capped and heated to 55° C. overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. Water and ethyl acetate were added and the mixture was transferred to a separatory funnel. The layers were separated and the organics were washed with water, then brine, dried over Na2SO4, filtered, and concentrated to afford 6-bromo-8-(ethoxymethyl)-[1,2,4]triazolo[1,5-a]pyridine (0.2 g, 72%). LC-MS: M+1=256/258, Rt=0.79 min, [A1]. The following Fragments were prepared in a fashion similar to the synthetic methods described above. TABLE 1Interm.LCMSRetHPLCNo.Starting MaterialStructureMH+TimeMethodF-185-bromo-3,6- dimethylpyridin-2- amine226/2280.77[TS1]F-192-amino-5- bromonicotinonitrile222.90.60[TS1]F-205-bromo-3- fluoropyridin- 2-amine216/2180.62[A1]F-215-bromo-4- methylpyridin- 2-amine212/2141.40DF-225-bromo-6- methylpyridin- 2-amine212/2141.47DF-235-bromo-3- methylpyridin- 2-amine226/2281.46DF-245-bromo-4- methylpyridin- 2-amine226/2281.45DF-255-bromo-3- fluoropyridin- 2-amine230/2321.22DF-265-bromo-4- fluoropyridin- 2-amine230/2321.12DF-275-bromo-3- (trifluoromethyl) pyridin-2-amine266/2681.73DF-285-bromo-4- methoxypyridin- 2-amine228/2301.39DF-295-bromo-3- ethoxypyridin- 2-amine242/2440.99DF-305-bromo-3- ethoxypyridin- 2-amine256/2581.93DF-315-bromo-3- methoxypyridin- 2-amine242/2441.55DF-325-bromo-3- (difluoromethoxy) pyridin-2-amine278/2802.06DF-335-bromo-4- isobutoxypyridin- 2-amine270/2722.06DF-345-bromo-3-chloro- 4-methylpyridin-2- amine260/2621.41BF-353,5-dibromo-4- methylpyridin- 2-amine242/2441.1BF-365-bromo-3-chloro- 4-methylpyridin-2- amine246/2489.9AF-375-bromo-6- methylpyridin- 2-amine226/2280.55AF-385-bromo-3- chloropyridin- 2-amine246/2480.55AF-395-bromo-3- chloropyridin- 2-amine232/2340.48AF-405-bromo-4- (trifluoromethyl) pyridin-2- amine280/2820.67K Intermediate F-41: 4-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)morpholine Intermediate F-41A: 5-bromo-3-iodopyridin-2-amine To a stirred solution of 5-bromopyridin-2-amine (4.0 g, 23.12 mmol), TFA (2.316 mL, 30.1 mmol) in DMF (100 mL) at 0° C. were added portion wise NIS (6.76 g, 30.1 mmol). The reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was quenched with ice cold water and sodium thiosulphate solution (3:1), the product was precipitated by adding the saturated NaHCO3solution (adjust pH-8), stirred for 10 min at 0° C. The resulting solid compound was collected by filtration to afford 5-bromo-3-iodopyridin-2-amine (5.1 g, 17.06 mmol, 73.8% yield) as a brown solid. MS (E+) m/z: 298.9 (M). Retention time: 1.16 min. [K]. Intermediate F-42B: (E)-N′-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylformimidamide A solution of DMF-DMA (11.42 mL, 85 mmol) and 5-bromo-3-iodopyridin-2-amine (5.1 g, 17.06 mmol) in DMF (20.0 mL) was stirred at 130° C. for 16 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The mixture was dried in high vacuum to afford (E)-N′-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylformimidamide (6.2 g, 17.51 mmol, 103% yield) as a brown semi-solid. MS (E+) m/z: 355.8 (M+2H). Retention time: 1.51 min. [K]. Intermediate F-43C: 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of (E)-N′-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylformimidamide (6.1 g, 17.23 mmol) and pyridine (6.97 mL, 86 mmol) in MeOH (80.0 mL) at 0° C. was added hydroxylamine-O-sulfonic acid (3.89 g, 34.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice cold water and volatiles were evaporated. The mixture was dried in high vacuum. The residue was dissolved in saturated NaHCO3solution and extracted with chloroform (2×200 mL) and washed with brine. The organic layer was dried over sodium sulphate and concentrated. The resulting material was purified by silica gel chromatography. The compound was eluted with 65% ethyl acetate and petroleum ether to afford 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (1.8 g, 5.56 mmol, 32.2% yield) as a light yellow solid. MS (E+) m/z: 325.8, Retention time: 1.577 min. [L]. Intermediate F-43 A stirred mixture of 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (0.300 g, 0.926 mmol), morpholine (0.403 g, 4.63 mmol), and Cs2CO3(0.905 g, 2.78 mmol) in DMF (10.0 mL) was degassed for 5 min. Next, Pd2(dba)3(0.085 g, 0.093 mmol) and Xantphos (0.054 g, 0.093 mmol) were added. The reaction mixture was stirred at 120° C. for 2.5 h in a microwave system. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate and evaporated to afford crude material. The crude material was purified using a 24 g silica gel column, compound was eluted with 35% ethyl acetate and petroleum ether to afford 4-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)morpholine (0.180 g, 0.636 mmol, 68.6% yield) as a light yellow solid. MS (E+) m/z: 285.0, Rt: 1.60 min. [L]. The following examples were prepared according to the general procedure described above for Intermediate F-43. TABLE 2IntermediateLCMSRtHPLCNo.Structure[M + 2H](min)MethodF-44298.00.78KF-45243.01.05KF-46297.01.06KF-47287.00.90KF-48319.00.76KF-49333.00.75KF-50271.00.79KF-51305.81.350K Intermediate F-52: 6-bromo-8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine A solution of 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (0.400 g, 1.235 mmol) and cyclopropylboronic acid (0.318 g, 3.70 mmol) in a mixture of toluene (10.0 mL) and water (2.0 mL) was degassed for 5 min. Next, tricyclohexylphosphine (0.069 g, 0.247 mmol), Pd(OAc), (0.028 g, 0.123 mmol) and Na2CO3(1.852 mL, 3.70 mmol) were added. The resultant reaction mixture was stirred at 100° C. for 14 h in a sealed tube. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate, and evaporated to afford the crude compound. The crude compound was purified using a 40 g silica column. The compound was eluted with 35% ethyl acetate and pet ether to afford 6-bromo-8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (0.240 g, 1.008 mmol, 82% yield) as a light yellow solid. MS (E+) m/z: 240.0, Rt: 1.05 min. [M]. Intermediate F-53: 4-(6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)morpholine Intermediate F-53A: (E)-N′-(5-bromo-3-iodopyridin-2-yl)-N, N-dimethylacetimidamide A solution of 1,1-dimethoxy-N,N-dimethylpropan-2-amine (24.63 g, 167 mmol) and 5-bromo-3-iodopyridin-2-amine (5.0 g, 16.73 mmol) in DMF (20.0 mL) was stirred at 130° C. for 16 h. The reaction mixture was cooled to room temperature. The volatiles were evaporated and the material was dried in high vacuum to afford (E)-N′-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylacetimidamide (5.8 g, 15.76 mmol, 94% yield) as a brown semi-solid. MS (E+) m/z: 370.0, Rt: 0.68 min. [M]. Intermediate F-53B: 6-bromo-8-iodo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of (E)-N′-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylacetimidamide (4.5 g, 12.23 mmol) and pyridine (4.94 mL, 61.1 mmol) in methanol (80.0 mL) at 0° C. was added hydroxylamine-O-sulfonic acid (2.76 g, 24.46 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with ice cold water. The volatiles were evaporated and the resulting material was dried in high vacuum. The residue was dissolved in saturated NaHCO3solution, extracted with chloroform (2×200 mL) and washed with brine. The organic layer was dried over sodium sulphate and concentrated to afford crude material. The crude material was purified using a 40 g silica column. The compound was eluted with 50% ethyl acetate and pet ether to afford 6-bromo-8-iodo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.2 g, 6.51 mmol, 53.2% yield) as a light yellow solid. MS (E+) m/z: 337.9 (M), Rt: 1.04 min. [L]. Intermediate F-53 A stirred mixture of 6-bromo-8-iodo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.300 g, 0.888 mmol), morpholine (0.232 g, 2.66 mmol), and Cs2COO3(0.723 g, 2.219 mmol) in DMF (10.0 mL) was degassed for 5 min. Next, Xantphos (0.051 g, 0.089 mmol) and Pd2(dba)3(0.081 g, 0.089 mmol) were added. The reaction mixture was stirred at 120° C. for 2.5 h in a microwave system. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate, and evaporated to obtain crude material. The crude material was purified using a 24 g silica column. The compound was eluted with 80% ethyl acetate and pet ether to afford 4-(6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)morpholine (0.180 g, 0.606 mmol, 68.2% yield) as a light yellow solid. MS (E+) m/z: 298.8, Rt: 1.08 min. [K]. Intermediate F-54: 6-bromo-8-cyclopropyl-2-methyl-[1,2,4]triazolo[1,5-a]pyridine A solution of 6-bromo-8-iodo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.400 g, 1.184 mmol) and cyclopropylboronic acid (0.305 g 3.55 mmol) in a mixture of toluene (10.0 mL) and water (2.0 mL) was degassed for 5 min. Next, tricyclohexylphosphine (0.066 g, 0.237 mmol), Pd(OAc)2(0.027 g, 0.118 mmol) and Na2CO3(1.775 mL, 3.55 mmol) were added. The reaction mixture was stirred at 100° C. for 14 h in a sealed tube. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate, filtered, and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate, and evaporated to afford the crude compound. The crude compound was purified using a 24 g silica column. The compound was eluted with 35% ethyl acetate and pet ether to afford 6-bromo-8-cyclopropyl-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.220 g, 0.873 mmol, 73.7% yield) as a light yellow solid. MS (E+) m/z: 254.0, Rt: 1.12 min. [K]. Intermediate F-55: 6-bromo-8-cyclopropyl-7methyl-[1,2,4]triazolo[1,5-a]pyridine Intermediate F-55A: 5-bromo-3-iodo-4-methylpyridin-2-amine To a stirred solution of 5-bromo-4-methylpyridin-2-amine (5.0 g, 26.7 mmol), TFA (2.471 mL, 32.1 mmol) in DMF (100 mL) at 0° C. was added portion-wise NIS (9.02 g, 40.1 mmol). The reaction mixture was stirred at 55° C. for 2 h. The reaction was quenched with ice cold water and sodium thiosulphate solution (3:1). The product was precipitated by adding saturated NaHCO3solution (adjust pH-8) and stirring for 10 min at 0° C. The solid compound was collected by filtration to afford 5-bromo-3-iodo-4-methylpyridin-2-amine (8 g, 25.6 mmol, 96% yield) as a brown solid. MS (E+) m/z: 314.9, Rt: 0.92 min. [M]. Intermediate F-55B: (E)-N-(5-bromo-3-iodo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide A solution of DMF-DMA (10.70 mL, 80 mmol) and 5-bromo-3-iodo-4-methylpyridin-2-amine (2.5 g, 7.99 mmol) in DMF (15.0 mL) was stirred at 130° C. for 16 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The material was dried in high vacuum to afford cnide (E)-N′-(5-bromo-3-iodo-4-methylpyridin-2-yl)-N,N-dimethylformimidamide (2.8 g. 7.61 mmol, 95% yield) as a brown semi-solid. MS (E+) m/z: 370.1, Rt: 1.59 min. [K]. Intermediate F-55C: 6-bromo-8-iodo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of (E)-N′-(5-bromo-3-iodo-4-methylpyridin-2-yl)-N,N-dimethyl formimidamide (2.8 g, 7.61 mmol) and pyridine (3.08 mL, 38.0 mmol) in methanol (60.0 mL) at 0° C. was added hydroxylamine-O-sulfonic acid (1.290 g, 11.41 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with ice cold water. The volatiles were evaporated and the mixture was dried in high vacuum. The residue was dissolved in saturated NaHCO3solution, extracted with chloroform (2×150 mL), and washed with brine. The organic layer was dried over sodium sulphate and concentrated to afford crude product. The crude product was purified by silica gel chromatography. The compound eluted with 65% ethyl acetate and pet ether to afford 6-bromo-8-iodo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 4.44 mmol, 58.3% yield) as a light yellow solid. MS (E+) m/z: 338.2 (M), Retention time: 1.11 min. [K]. Intermediate F-55 A solution of 6-bromo-8-iodo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.400 g, 1.184 mmol) and cyclopropylboronic acid (0.305 g, 3.55 mmol) in mixture of toluene (15.0 mL) and water (3.0 mL) was degassed for 5 min. Next, tricyclohexylphosphine (0.066 g, 0.237 mmol), Pd(OAc)2(0.027 g, 0.118 mmol) and Na2CO3(1.775 mL, 3.55 mmol) were added. The reaction mixture was stirred at 100° C. for 14 h in a sealed tube. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate, and evaporated to afford crude compound. The crude compound was purified by silica gel chromatography. The compound eluted with 35% ethyl acetate and pet ether to afford 6-bromo -8-cyclopropyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.280 g, 1.111 mmol, 94% yield) as a light yellow solid. MS (E+) m/z: 254.0, Rt: 2.11 min. [L] Intermediate F-56: 6-bromo-8-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine Intermediate F-56A: 5-bromo-3-methyl-1λ4-pyridine-1,2-diamine 2,4,6-trimethylbenzenesulfonate To a stirred solution of ethyl o-mesitylsulfonylacetohydroxamate (3.05 g, 10.69 mmol) in dioxane (20 mL) cooled to 0° C. was added perchloric acid (1.074 g, 10.69 mmol). The mixture was stirred at ambient temperature for 30 min. The reaction mass was quenched with ice cold water, extracted with dichloromethane (100 mL), dried over sodium sulphate, and concentrated to afford crude 1-amino-5-bromo-3-methyl-1λ4-pyridin-2-aminium 2,4,6-trimethylbenzenesulfonate. To a stirred solution of 5-bromo-3-methylpyridin-2-amine (2 g, 10.69 mmol) in DCM (10 mL) was added 1-amino-5-bromo-3-methyl-1λ4-pyridin-2-aminium 2,4,6-trimethylbenzenesulfonate at 0° C. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (25 mL), extracted with DCM (2×100 mL), dried over sodium sulphate, and concentrated to afford 1,2-diamino-5-bromo-3-methylpyridin-1-ium,2,4,6-trimethylbenzenesulfonate as a white solid (2.1 g, 93%).1NMR (300 MHz, CHLOROFORM-d) δ=7.91 (br. s., 1H), 7.63 (d, J=15.9 Hz, 1H), 7.28 (s, 2H), 6.89 (s, 1H), 3.72 (s, 1H), 2.81-2.47 (m, 6H), 2.36-2.02 (m, 6H), 1.23 (t, J=7.0 Hz, 2H). Intermediate F-56 To a stirred solution of 1,2-diamino-5-bromo-3-methylpyridin-1-ium,2,4,6-trimethylbenzenesulfonate (1 g, 2.141 mmol) in MeOH (25 mL) at 0° C. was added trifluoroacetic anhydride (0.351 mL, 2.486 mmol). The reaction mixture was stirred for 10 min at the same temperature. Next, Et3N (0.346 mL, 2.486 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated. The reaction was quenched with water (25 mL). The reaction mixture was extracted with EtOAc (2×100 mL), dried over sodium sulphate, and concentrated to afford 6-bromo-8-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine. The crude mass was purified by silica gel chromatography and eluted in 40% EtOAc in hexane to afford 6-bromo-8-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (500 mg, 71.8%) as off white solid. LC retention time-1.28 min [K]. MS (E−) m/z: 280.0 (M+H). Intermediate F-57: 6-bromo-8-methoxy-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine Intermediate F-57A: 3,5-dibromo-1λ4-pyridine-1,2-diamine 2,4,6-trimethylbenzenesulfonate To a stirred solution of ethyl o-mesitylsulfonylacetohydroxamate (2.266 g, 7.94 mmol) in dioxane (20 mL) cooled to 0° C. was added perchloric acid (1.074 g, 10.69 mmol). The reaction mixture was stirred at ambient temperature for 30 min. The reaction was quenched with ice cold water. The reaction mixture was extracted with dichloromethane (100 mL), dried over sodium sulphate, and concentrated to afford crude 1-amino-3,5-dibromo-1λ4-pyridin-2-aminium 2,4,6-trimethylbenzenesulfonate. To a stirred solution of 3,5-dibromopyridin-2-amine (2 g, 7.94 mmol) in DCM (10 mL) was added 1-amino-3,5-dibromo-1λ4-pyridin-2-aminium 2,4,6-trimethylbenzenesulfonate at 0° C. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (25 mL), extracted with DCM (2×100 mL), dried over sodium sulphate, and concentrated to afford 1,2-diamino-3,5-dibromopyridin-1-ium, 2,4,6-trimethylbenzenesulfonate as a white solid (2.1 g, 93.5%).1NMR (400 MHz, DMSO-d6) δ=7.88 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.12 (s, 1H), 6.70 (s, 4H), 3.56 (s, 1H), 2.10 (s, 6H). Intermediate F-57B: 6,8-dibromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of 1,2-diamino-3,5-dibromopyridin-1-ium, 2,4,6-trimethylbenzenesulfonate (1 g, 2.141 mmol) in MeOH (25 mL) cooled to 0° C. was added trifluoroacetic anhydride (0.351 mL, 2.486 mmol). The reaction mixture was stirred for 10 mins. After Et3N (0.346 mL, 2.486 mmol) was added, the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated, quenched with water (25 mL), extracted with EtOAc (2×100 mL), dried over sodium sulphate, and concentrated to afford 6,8-dibromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine. The crude mass was purified by silica gel chromatography, and eluted with 40% EtOAc in hexane to afford 6,8-dibromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (650 mg, 73.8%) as off white solid. LC retention time=1.37 min [K]. MS (E−) m/z: 344.0 (M+H). Intermediate F-57 To a solution of 6,8-dibromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (350 mg, 1.015 mmol) in acetonitrile (15 mL) was added sodium methoxide (54.8 mg, 1.015 mmol). The resulting mixture was stirred at 85° C. for 1 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×50 mL), dried over sodium sulphate, and concentrated to afford 6-bromo-8-methoxy-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine. The crude mass was purified by silica gel chromatography, and was eluted with 50% EtOAc in hexane to afford 6-bromo-8-methoxy-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (160 mg, 53.5%) as white solid. LC retention time-1.26 min [K]. MS (E−) m/z: 294.0 (M−H). Intermediate F-58: 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine Commercially available reagent: CAS No 356560-80-0. Intermediate F-59: 6-chloro-8-trideuteromethyl-[1,2,4]triazolo[1,5-a]pyridine 8-bromo-6-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared following the general procedure for F-2 starting from 3-bromo-5-chloropyridin-2-amine. LC retention time 0.67 min [TS1]. MS (ES+) m/z: 233.9 (M+H). A solution of 8-bromo-6-chloro-[1,2,4]triazolo[1,5-a]pyridine (150 mg, 0.645 mmol) in THF (5.0 mL) was degassed with nitrogen gas for 5 minutes. Iron(III) acetylacetonate (22.79 mg, 0.065 mmol) was added. The light yellow solution became red and was degassed again, and then evacuated and backfilled with nitrogen gas three times. Trideuteromethylmagnesium iodide (0.97 mL, 0.97 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature. Upon completion, the reaction mixture was diluted with dichloromethane (20 mL), ammonium chloride (10 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford a crude residue, which was purified using silica gel chromatography eluting with hexanes/ethyl acetate 0-70% to afford 6-chloro-8-trideuteromethyl-[1,2,4]triazolo[1,5-a]pyridine (41 mg, 0.240 mmol, 37.2% yield). LC retention time 0.64 min [TS1]. MS (ES+) m/z: 171.08 (M+H).1H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 7.29 (d, J=2.0 Hz, 1H). Example 1 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine Intermediate 1A: tert-butyl 4-(2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxy To a stirred solution of tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (50 mg, 0.107 mmol), 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (31.7 mg, 0.160 mmol) in tetrahydrofuran (5 mL), and water (0.5 mL) was added potassium phosphate tribasic (68.0 mg, 0.320 mmol). The solution was degassed with nitrogen for 10 mins. Next, PdCl2(dppf) (7.81 mg, 10.67 μmol) was added and the solution was degassed again for 10 mins. The reaction mixture was heated to 75° C. for 16 h. The reaction progress was monitored by LCMS. The reaction mass was filtered through a celite bed, washed with EtOAc, and concentrated to afford tert-butyl 4-(2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (50 mg, 0.109 mmol). The material was carried on directly into the subsequent step without further purification. Example 1 To a stirred solution of tert-butyl 4-(2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (50 mg, 0.109 mmol) in DCM (2 mL) was added 1,4-dioxane (4N HCl) (0.2 mL). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated and the crude material was purified by preparative LC/MS with the following conditions: Waters Xbridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A:5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TEA; Gradient: 2-20% B over 25 minutes, followed by a 10 minute hold at 20% B and 5 minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried using a Gene-vac centrifugal evaporator. The yield of the product was 5.4 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Ascentis Express C18(50×2.1)mm, 2.7 μm; Mobile Phase A: 5:95 Acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 Acetonitrile:water with 10 mM NH4OAc; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min. Injection 2 conditions: Column: Ascentis Express C18(50×2.1)mm, 2.7 μm; Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 Acetonitrile: water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min. LCMS MH+=360 Ret. Time=0.66 min [A1]; Proton NMR was acquired in deuterated DMSO.1H NMR (400 MHz, DMSO-d6) δ=11.24 (s, 1H), 9.01 (d, J=1.0 Hz, 1H), 8.66-8.55 (m, 1H), 8.03-7.96 (m, 1H), 7.79 (dd, J=9.0, 1.5 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.02 (dd, J=8.3, 1.3 Hz, 1H), 3.41 (d, J=12.0 Hz, 2H), 3.30-3.23 (m, 1H), 3.10-3.00 (m, 2H), 2.96-2.90 (m, 1H), 2.03-1.94 (m, 2H), 1.91-1.84 (m, 2H), 1.45 (d, J=7.0 Hz, 6H). Example 2 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine hydrochloride Intermediate 2A: tert-butyl 4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate The preparation was performed in two batches and combined for workup. Batch #1: To a mixture of tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (10 g, 23.73 mmol), bis(benzonitrile)palladium(II) chloride (0.182 g, 0.475 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.390 g, 0.949 mmol) in dioxane (80 mL) under nitrogen were added pinacolborane (8.61 mL, 59.3 mmol) and triethylamine (6.62 mL, 47.5 mmol). The mixture was heated at 85° C. for 5 min. After cooling down to room temperature, 2 M potassium phosphate tribasic solution (35.6 mL, 71.2 mmol) was added slowly. Next, 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (4.53 g, 21.36 mmol) was added, followed by PdCl2(dppf)-CH2Cl2adduct (0.775 g, 0.949 mmol). The reaction mixture was stirred for 30 min at 65° C. Batch #2: In a 1 L round bottom flask, pinacolborane (25.8 mL, 178 mmol) and triethylamine (19.85 mL, 142 mmol) were added to a mixture of tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (30 g, 71.2 mmol), bis(benzonitrile) palladium(II) chloride (0.546 g, 1.424 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.169 g, 2.85 mmol) in dioxane (240 mL) under nitrogen. The mixture was heated at 85° C. for 5 min. After cooling down to room temperature, 2 M potassium phosphate tribasic solution (107 mL, 214 mmol) was added very slowly first for the first 10 mL. When there were no more bubbles, the remainder of the K3PO4solution was rapidly added, followed by the additions of 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (13.59 g, 64.1 mmol) and PdCl2(dppf)-CH2Cl2adduct (2.326 g, 2.85 mmol). The reaction mixture was stirred for 1 h at 65° C. The two batches were combined for workup. The aqueous layer was removed and the organic layer was washed with brine, dried over Na2SO4, filtered through a Celite pad, and concentrated to give a dark oil (87 g). The material was purified by silica gel chromatography (hexanes/ethyl acetate as eluent) affording 29 grams of the product. LCMS MH+=430.1 Ret. Time=0.63 min [C1];1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.80 (d, J=0.7 Hz, 1H), 8.53 (s, 1H), 7.65-7.52 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.5 Hz, 1H), 4.19-4.04 (m, 2H), 3.28-3.19 (m, 1H), 2.96-2.70 (m, 3H), 2.63 (s, 6H), 2.38-2.26 (m, 1H), 1.80 (d, J=12.6 Hz, 2H), 1.56 (qd, J=12.4, 4.0 Hz, 2H), 1.47-1.38 (m, 12H). Alternative Preparation of Intermediate 2A To a 500 mL round bottle flask were added tert-butyl 4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (11 g, 26.1 mmol), bis(benzonitrile)palladium(II) chloride (0.200 g, 0.522 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.429 g, 1.044 mmol) and dioxane (87 mL). Nitrogen was bubbled through the reaction mixture for 5 min. Next, pinacolborane (9.47 ml, 65.3 mmol) and triethylamine (9.10 ml, 65.3 mmol) were added to the reaction mixture. The triethylamine was added in small portions slowly for the first ⅓ and then the rest ⅔ was added quickly. The reaction mixture was heated at 85° C. for 10 min under N2. The reaction temperature reached 100° C. The reaction mixture was cooled to room temperature with an ice-water bath. Next, 2 M potassium phosphate tribasic solution (39.2 mL, 78 mmol) was added. The first 1/20 was added slowly. When there was no more bubbles, the remainder of the K3PO4solution was added, followed by 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (4.98 g, 23.49 mmol), PdCl2(dppf)-CH2Cl2adduct (0.853 g, 1.044 mmol) washed in with dioxane (10 mL). The mixture was heated at 65° C. for 1 h under N2. After the mixture was cooled to room temperature, the organic layer and the aqueous layer was separated. EtOAc was used to wash the flask during the transfer. The organic layer was washed with brine, dried over Na2SO4, filtered through a Celite pad and concentrated to give 44.4 g crude oil. It was purified with silica gel chromatography using a 1.5 kg silica column. The column was eluted with hexane and ethyl acetate. The product was eluted at 60% ethyl acetate:hexane to afford tert-butyl 4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (9.27 g, 19.58 mmol, 75% yield) as a lighted tinted foam. LCMS MH+: 474.3; HPLC Ret. Time 1.15 min. Method G.1H NMR (400 MHz, CHLOROFORM-d) δ 8.61-8.54 (m, 1H), 8.43-8.38 (m, 1H), 7.96-7.88 (m, 1H), 7.70-7.64 (m, 1H), 7.48-7.44 (m, 1H), 7.40-7.35 (m, 1H), 7.17-7.09 (m, 1H), 4.40-4.23 (m, 2H), 3.40-3.26 (m, 1H), 2.75 (s, 6H), 1.98-1.89 (m, 2H), 1.85-1.67 (m, 2H), 1.53 (m, 12H), 1.52-1.49 (s, 3H). Example 2 To a stirred solution of tert-butyl 4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (29 g, 61.2 mmol) in DCM (102 mL), was added 4 M HCl in dioxane (77 mL, 306 mmol) through a syringe. The temperature was observed to increased several degrees. The solution turned into a suspension during the addition, then a clear solution, then a heavy suspension again. MeOH (306 mL) was added to give a clear solution. LCMS showed the reaction was close to completion after 2.5 hr at room temperature. The reaction mixture was concentrated under reduced pressure with a water bath (T=45° C.) and then diluted with diethyl ether (200 mL). The product was collected by filtration to afford 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride. LC-MS: M+1=374, rt=0.80 min., [A1];1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.80 (d, J=0.7 Hz, 1H), 8.54 (s, 1H), 7.66-7.50 (m, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.02 (dd, J=8.4, 1.5 Hz, 1H), 4.09 (q, J=5.3 Hz, 1H), 3.38-3.23 (m, 6H), 3.18 (d, J=5.3 Hz, 2H), 3.06 (d, J=11.5 Hz, 1H), 2.74-2.59 (m, 4H), 1.75 (d, J=10.0 Hz, 2H), 1.68-1.52 (m, 2H), 1.51-1.37 (m, 6H). Alternative Preparation of Example 2 To a stirred solution of tert-butyl 4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (7.45 g, 15.73 mmol) in DCM (40 mL) was added 4 M HCl in dioxane (35.4 mL, 142 mmol) through a syringe at room temperature. The solution turned to a suspension during the addition, then a clear solution, then a heavy suspension again. MeOH (100 mL) was added to give a clear solution. The reaction was complete in 2 h. The reaction mixture was concentrated under reduced pressure and then diluted with diethyl ether (200 mL). The desired product HCl salt was collected by filtration to afford 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine hydrochloride (6.4 g, 15.64 mmol, 99.4% yield) as a yellow. LCMS MH+: 374.1; HPLC Ret. Time 0.64 min. Method G. The following examples were prepared according to the general procedures disclosed in Examples 1 and 2. TABLE 3Ex.LCMSRtNo.StructureInterm.[M + H](min)Method3F-3374.31.07QC-ACN-TFA-XB4F-4388.31.26QC-ACN-AA-XB5F-5390.31.02Method E6F-6404.31.21QC-ACN-AA-XB Example 4 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8dimethyl-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride To a stirred suspension of tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (37.8 g, 78 mmol) in DCM (97 ml) and MeOH (291 ml) was added 4 M HCl in dioxane (97 mL, 388 mmol) at room temperature to give a clear solution. After a few hours, the reaction mixture became a white suspension. The reaction was complete after 4 h. The reaction mixture was concentrated under reduced pressure and then diluted with diethyl ether (250 mL). The product bis-HCl salt was collected by filtration to afford 6-(3isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, 2 HCl (34.66 g, 75 mmol, 97% yield) as an off-white solid. LCMS MH+: 388.3; HPLC Ret. Time 1.26 min. Method QC-ACN-AA-XB.1H NMR (500 MHz, DMSO-d6) δ1.08-10.95 (m, 1H), 8.77-8.67 (m, 1H), 8.55-8.41 (m, 1H), 7.64-7.48 (m, 1H), 7.39-7.27 (m, 1H), 7.05-6.94 (m, 1H), 3.47-3.34 (m, 1H), 3.11-2.99 (m, 2H), 2.98-2.82 (m, 2H), 2.61-2.57 (m, 3H), 2.56-2.54 (m, 1H), 2.18-2.13 (m, 3H), 2.03-1.83 (m, 4H), 1.39-1.26 (m, 6H). Example 5 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride To a stirred suspension of tert-butyl 4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (46.5 g, 95 mmol) in DCM (47.5 mL) and MeOH (190 mL), was added 4M HCl in dioxane (119 mL, 475 mmol) at room temperature. After 1 h, the clear solution became a white suspension. MeOH (50 mL) was added and the suspension was stirred for another hour. The reaction mixture was concentrated under reduced pressure and then diluted with diethyl ether (300 mL). The desired product HCl salt was collected by filtration and dried for two days to afford 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride (33.6 g, 72.7 mmol, 76% yield) as an off-white solid. LCMS MH+: 390.1. HPLC Ret. Time 0.64 min. Method G. Example 7 2-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide Triethylamine (9.70 mL, 69.6 mmol) and 2-chloro-N-methylacetamide (2.246 g, 20.88 mmol) were added to a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.6 g, 6.96 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction mass was concentrated under vacuum and the residue obtained was quenched with 150 mL ice cold water resulting in the formation of a precipitate. The solids were collected by vacuum filtration and air dried. The collected solids were further dried under vacuum for 15 h to afford 2-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) piperidin-1-yl)-N-methylacetamide (1.5 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ1.42 (d, J=7.20 Hz, 6H), 1.69-1.72 (m, 4H), 1.75-1.81 (m, 1H), 2.78-2.82 (m, 6H), 2.85-2.88 (m, 4H), 3.25-3.31 (m, 2H), 7.05 (dd, J=1.60, 8.40 Hz, 1H), 7.31 (d, J=8.40 Hz, 1H), 7.59 (d, J=10.00 Hz, 2H), 7.72-7.73 (m, 1H), 8.54 (s, 1H), 8.81 (s, 1H), 11.12 (s, 1H). LCMS for molecular formula C26H32N6O was 444.264; found 445 (M+). Waters Xbridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A:5:95 Acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 Acetonitrile:water with 10 mM NH4OAc; Gradient: 10-50% B over 25 minutes, followed by a 10 minute hold at 50% B and 5 minute hold at 100% B; Flow: 15 mL/min. RT Min: 1.91, Wave length: 220 nm. HPLC: XBridge Phenyl (4.6×150)mm, 3.5 μm SC/749 Buffer: 0.05% TFA in water pH 2.5 Mobile Phase A:Buffer: ACN (95:5) Mobile Phase B:ACN:Buffer (95:5) FLOW: 1 mL \min TIME B % 0 10, 12 100, 15 100. Retention Time: 6.19 minutes. The following examples were prepared according to the general procedures disclosed in Example 7. TABLE 4Ex.LCMSRtNo.StructureMH+(min)Method8413.31.28QC-ACN-TFA-XB9427.21.82QC-ACN-AA-XB104301.57QC-ACN-AA-XB11431.41.24QC-ACN-AA-XB12446.31.707Method E13427.31.46QC-ACN-TFA-XB14441.31.27QC-ACN-TFA-XB154451.19QC-ACN-TFA-XB16459.51.71QC-ACN-AA-XB174601.7QC-ACN-AA-XB18494.31.71QC-ACN-AA-XB19495.21.62QC-ACN-AA-XB20520.51.31QC-ACN-TFA-XB21429.21.94Method E22447.21.64Method E23461.21.73Method E24462.41.40Method E25475.41.37Method E Example 13 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-bromo-acetonitrile To a 1 dram vial were added 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine hydrochloride (0.050 g, 0.118 mmol), NMP, and DBU (0.025 nil, 0.164 mmol). The material went into solution and 2-bromoacetonitrile (0.014 g, 0.118 mmol) was added. The reaction vial was capped. The reaction mixture was stirred overnight at room temperature. The sample was diluted with solvent (90:10:0.1 CH3CN:water:TFA), filtered, and purified with preparative HLPC. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetonitrile (16.8 mg, 0.039 mmol, 32.7% yield). LCMS MH±+: 427.1. HPLC Ret. Time 1.30 min. Method QC-ACN-TFA-XB.1H NMR (500 MHz, DMSO-d6) δ 8.77-8.69 (m, 1H), 8.50-8.35 (m, 1H), 7.61-7.51 (m, 1H), 7.33-7.23 (m, 1H), 7.08-6.93 (m, 1H), 3.44-3.34 (m, 1H), 2.98-2.83 (m, 3H), 2.63-2.56 (m, 4H), 2.56-2.53 (m, 2H), 2.39-2.28 (m, 2H), 2.21-2.12 (m, 3H), 1.90-1.69 (m, 4H), 1.37-1.26 (m, 6H). Example 15 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl) piperidin-1-yl)acetamide To a reaction flask were added 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, 2 HCl (47.66 g, 104 mmol), DCE (220 mL), DBU (62.4 mL, 414 mmol), and 2-bromoacetamide (17.14 g, 124 mmol). The reaction flask was capped. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with water, and stirred for 30 minutes then filtered. The solid was recrystallized using ethanol to afford 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (42.3 g, 93 mmol, 90% yield) as a white solid. LCMS MH+: 445. HPLC Ret. Time 1.20 min. Method QC-ACN-TFA-XB.1H NMR (400 MHz, DMSO-d6) δ 10.97-10.86 (m, 1H), 8.78-8.69 (m, 1H), 8.54-8.40 (m, 1H), 7.64-7.49 (m, 1H), 7.30-7.21 (m, 2H), 7.17-7.09 (m, 1H), 7.06-6.93 (m, 1H), 2.99-2.82 (m, 5H), 2.62-2.54 (m, 4H), 2.24-2.12 (m, 5H), 1.92-1.72 (m, 4H), 1.37-1.29 (m, 6H). Example 18 6-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine Preparation 1: To a 40 ml vial was added 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.800 g, 2.064 mmol), DCM (5 mL) and DBU (0.622 mL, 4.13 mmol). The material went into solution and 2-bromoacetamide (0.299 g, 2.168 mmol) was added. The reaction vial was capped. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with DCM. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in minimal DCM and purified by silica gel chromatography, eluting with 0-10%/o MeOH/DCM. Following concentration of the fractions, the product was collected as a white solid (0.6 g). To this was added 40 mL of a 10% MeOH/ethyl acetate solution and the suspension was taken to a boil. The solids were filtered off and rinsed with hot MeOH/ethyl acetate (1:10). The filtrate was reheated and capped to recrystallize. After 3 days, the white solid was filtered off and washed with ethyl acetate, then ether, and dried on the vacuum pump overnight to afford 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (480 mg, 1.07 mmol, 51.8% yield). MS (M+1) m/z: 445.3 (MH+). LC retention time 0.69 min [G].1H NMR (400 MHz, DMSO-d6) δ 11.00-10.85 (m, 1H), 8.79-8.69 (m, 1H), 8.53-8.43 (m, 1H), 7.60-7.49 (m, 1H), 7.32-7.21 (m, 2H), 7.18-7.11 (m, 1H), 7.06-6.99 (m, 1H), 3.00-2.83 (m, 5H), 2.63-2.55 (m, 4H), 2.24-2.12 (m, 5H), 1.92-1.72 (m, 4H), 1.40-1.24 (m, 6H). Preparation 2: To a reaction vial were added 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1.5-a]pyridine, 2 HCl (40 g, 87 mmol), DCE (280 mL), and DBU (45.8 mL, 304 mmol). The material went into solution and 1-bromo-2-(methylsulfonyl) ethane (18.46 g, 99 mmol) was added. The reaction mixture was stirred overnight at room temperature under N2. The sample was concentrated, diluted with water, stirred for 30 minutes, and then filtered. The solid was recrystallized using EtOH to afford 6-(3-isopropyl-5-(1-(2-(methylsulfonyeethyl)piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (40 g, 81 mmol, 93% yield) as a white solid. LCMS MH+: 494.3; HPLC Ret. Time 1.70 min. Method QC-ACN-AA-XB.1H NMR (400 MHz, CHLOROFORM-d) δ 8.45-8.38 (m, 1H), 8.37-8.30 (m, 1H), 8.18-8.12 (m, 1H), 7.69-7.62 (m, 1H), 7.43-7.35 (m, 1H), 7.19-7.12 (m, 1H), 3.29-3.20 (m, 2H), 3.16-3.07 (m, 5H), 3.02-2.92 (m, 3H), 2.74-2.67 (m, 1H), 2.66-2.60 (m, 3H), 2.31-2.22 (m, 2H), 2.21-2.17 (m, 3H), 2.07-1.79 (m, 4H), 1.42-1.35 (m, 6H). Example 25 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide Preparation 1: To a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2.4]triazolo[1,5-a]pyridine (0.05 g, 0.128 mmol) in THF (2 mL) and DMF (1 mL) solvent mixture were added 2-chloro-N,N-dimethylacetamide (0.023 g, 0.193 mmol) and TEA (0.179 mL, 1.284 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under vacuum. To the solid material was added water (5 mL) and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5 μm particles; Mobile Phase A: 10 mM ammonium acetate; Mobile Phase B: methanol; Gradient: 10-50% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (14.2 mg, 0.03 mmol, 23.31% yield). MS (MH+1) m/z: 475.4 (MH+). LC retention time 1.38 min [A].1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.83-8.75 (m, 2H), 7.83 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.41 (d, J=1.2 Hz, 1H), 7.30 (dd, J=8.4, 1.6 Hz, 1H), 4.34 (s, 3H), 3.43 (d, J=5.9 Hz, 3H), 3.34 (s, 4H), 3.22 (d, J=11.0 Hz, 4H), 3.09 (s, 3H), 2.79 (d, J=1.7 Hz, 3H), 2.48-2.38 (m, 2H), 2.15 (s, 5H), 2.08-1.95 (m, 4H), 1.72 (d, J=7.1 Hz, 6H). Preparation 2: To a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine, HCl (30.6 g, 71.8 mmol) in a DMF (700 mL) solvent mixture were added 2-chloro-N,N-dimethylacetamide (9.62 mL, 93 mmol) and TEA (50.1 mL, 359 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The starting material was converted to product. Next, water (2 L) was added to the above solution, the upper layer and the lower layer were extracted with ethyl acetate. The combination of the organic layers was washed with brine, dried and concentrated to give a solid, which was purified by recrystallization from ethanol to afford 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (28.3 g, 59.3 mmol, 83% yield). LCMS MH+: 475.2. HPLC Ret. Time 0.66 min. Method G. C: 68.28%, H: 7.19%, N: 17.63%. Example 26 6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine To a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine hydrochloride (24.5 g, 59.8 mmol) in DCM (610 mL) were added triethylamine (24.19 g, 239 mmol), oxetan-3-one (17.23 g, 239 mmol), acetic acid (7.18 g, 120 mmol), and sodium triacetoxyborohydride (50.7 g, 239 mmol). The solution was stirred at room temperature. After 5 min, LCMS showed 20% conversion; and after overnight, HPLC showed no starting material. The solvent was removed under vacuum. The residue was dissolved in 500 mL ethyl acetate and washed with saturated NaHCO3solution (4×300 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by recrystallization from a mixture of EtOH/water (20/80), dried to afford 6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (24.6 g, 57.0 mmol, 95% yield) as a white solid. LCMS MH+=430.1 Ret. Time=0.63 min; Column: BEH C18 2.1×50 mm 1.7 pm Vial:3:1; HPLC Ret. Time 7.86 min. Waters XSelect CSH C18 2.5 μM 4.6 μM×7.5 mm. Solvent A: H2O w/0.1% TFA. Solvent B ACN w/0.1% TFA. Gradient Complex Start % B 10% 16 min 45% B 20 min 90% 24 min 90% 25 min 10% Stop time 25 min Flow Rate 1.5 mL/min. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.56 (d, J=16.5 Hz, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 4.64-4.33 (m, 4H), 4.72-4.27 (m, 4H), 3.65 (br. s., 2H), 3.47-3.12 (m, 2H), 2.79 (d, J=10.4 Hz, 2H), 2.61 (s, 3H), 1.99-1.59 (m, 7H), 1.41 (d, J=6.8 Hz, 6H). Alternative Preparation of Example 26 To a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine hydrochloride (24.5 g, 59.8 mmol) in DCM (610 ml) were added triethylamine (24.19 g, 239 mmol), oxetan-3-one (17.23 g, 239 mmol), acetic acid (7.18 g, 120 mmol) and sodium triacetoxyborohydride (50.7 g, 239 mmol). The solution was stirred at room temperature, after 5 min the reaction progressed 20%. The reaction went to completion overnight. The solvent was removed under reduced pressure. The residue was dissolved in 500 mL ethyl acetate and washed with saturated NaHCO3solution (300 mL×4), dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The crude material was purified to remove Pd in the treatment described below and recrystallized from a mixture of EtOH/water (20/80) and dried to afford 6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (24.6 g, 57.0 mmol, 95% yield) as a solid. LCMS MH+: 430.1; HPLC Ret. Time 0.63 min. Method G;1H NMR (400 MHz, DMSO-d6) δ 11.18-11.05 (m, 1H), 8.88-8.76 (m, 1H), 8.58-8.47 (m, 1H), 7.64-7.54 (m, 2H), 7.34-7.26 (m, 1H), 7.09-6.96 (m, 1H), 4.61-4.53 (m, 2H), 4.51-4.42 (m, 2H), 3.48-3.37 (m, 1H), 3.31-3.20 (m, 1H), 2.86-2.78 (m, 2H), 2.68-2.63 (m, 3H), 2.63-2.55 (m, 1H), 1.96-1.68 (m, 6H), 1.49-1.38 (m, 6H). Pd Removal Procedure: The sample was treated to remove Pd using the following steps: 1. The crude sample was dissolved in 500 mL THF and treated with SiliaMetS@DMT (40 g, from SiliCycle). The solution was stirred overnight at room temperature under N2. 2. After filtration, the solvent was removed and the residue was dissolved in AcOEt and washed with brine and dried. 3. After concentration, the residue was recrystallized from EtOH-water (20/80) to afford the product. The following examples were prepared according to the general procedure of Examples 26. TABLE 5Ex.LCMSRtNo.StructureMH+(min)Method27416.42.39Method F284161.43QC-ACN-AA-XB29430.11.7QC-ACN-AA-XB30454.21.29QC-ACN-TFA-XB31455.31.54QC-ACN-AA-XB32455.21.22QC-ACN-TFA-XB33455.41.11QC-ACN-TFA-XB34455.91.13QC-ACN-AA-XB35458.41.33QC-ACN-AA-XB36459.31.37Method A37506.31.43QC-ACN-AA-XB38444.31.24QC-ACN-TFA-XB39469.21.46QC-ACN-AA-XB40471.91.47QC-ACN-AA-XB41473.41.41QC-ACN-AA-XB424831.52QC-ACN-AA-XB434831.68QC-ACN-AA-XB44446.21.91Method E45474.41.31Method E Example 44 6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine To a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride (39.7 g, 86 mmol) in DCM (859 ml) was added triethylamine (34.8 g, 343 mmol), oxetan-3-one (24.75 g, 343 mmol), acetic acid (10.31 g, 172 mmol) and sodium triacetoxyborohydride (72.8 g, 343 mmol). The solution was stirred at room temperature. After 9 h, the starting material was no longer detected. The solvent was removed by rotavapor. The residue was dissolved in 1500 mL ethyl acetate and washed with saturated NaHCO3solution (500 mL×4), dried over Na2SO4, and concentrated under reduced pressure to give residue. The residue was purified by recrystallization from a mixture of EtOH/water (60/40) two times, dried to give 6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (32.3 g, 72.2 mmol, 84% yield) as a white solid. LCMS MH: 446.1. HPLC Ret, Time 0.63 min. Method G.1H NMR (400 MHz, CHLOROFORM-d) δ 8.42-8.31 (m, 2H), 8.20-8.10 (m, 1H), 7.77-7.67 (m, 1H), 7.44-7.36 (m, 1H), 7.31-7.26 (m, 1H), 7.21-7.12 (m, 1H), 6.95-6.85 (m, 1H), 4.80-4.63 (m, 4H), 4.12-4.03 (m, 3H), 3.62-3.51 (m, 1H), 3.42-3.25 (m, 1H), 3.02-2.87 (m, 2H), 2.73-2.58 (m, 1H), 2.10-1.85 (m, 6H), 1.55-1.44 (m, 6H). Example 46 2-(dimethylamino)-1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-one To a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (75 mg, 0.201 mmol) in DMF (1 mL) were added TEA (0.140 mL, 1.004 mmol), 2-(dimethylamino)acetic acid (20.71 mg, 0.201 mmol), and HATU (76 mg, 0.201 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mass was diluted with methanol (2 mL) and passed through a syringe pad to filter away inorganics, and then purified by reverse phase preparative chromatography. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Mobile Phase A: 10-mM ammonium acetate; Mobile Phase B: acetonitrile; Gradient: 20-60% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 11.7 mg, and its estimated purity by LCMS analysis was 96%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Ascentis Express C18(50×2.1)mm, 2.7 nm; Mobile Phase A: 5:95 Acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 Acetonitrile:water with 10 mM NH4OAc; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min. Injection 2 conditions: Column: Ascentis Express C18 (50×2.1) mm, 2.7 μm; Mobile Phase A: 5:95 Acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.00 Hz, 3H), 1.44 (d, J=6.80 Hz, 6H), 1.69-1.72 (m, 2H), 1.75-1.81 (m, 2H), 2.32-2.34 (m, 1H), 2.50 (s, 3H), 2.62-2.71 (m, 4H), 2.80-2.94 (m, 1H), 3.25-3.32 (m, 2H), 3.54-3.58 (m, 2H), 4.00-4.07 (m, 1H), 4.60 (d, J=11.20 Hz, 1H), 7.04 (dd, J=1.20, 8.40 Hz, 1H), 7.30 (d, J=8.40 Hz, 1H), 7.58 (d, J=8.80 Hz, 1H), 8.53 (s, 1H), 8.80 (s, 1H), 11.11 (s, 1H). LCMS for molecular formula C26H32N6was 444.264, found 445 (M+). Waters Xbridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A:5:95 Acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Gradient: 10-50% B over 25 minutes, followed by a 10 minute hold at 50% B and 5 minute hold at 100% B; Flow: 15 mL/min. R Min: 1.91, Wave length: 220 nm. Example 47 1-(4-(2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-(methylamino)ethan-1-one To a 1 dram vial were added 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (0.035 g, 0.091 mmol), CH3CN, TEA (0.038 mL, 0.273 mmol), and HATU (0.036 g, 0.091 mmol). The material went into solution and 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (0.034 g, 0.182 mmol) was added. The reaction vial was capped and allowed to stir overnight at room temperature. After 18 hrs LC-MS showed product had formed. The samples were diluted with ethyl acetate and washed with water. The combined organics were washed with brine, dried over Na2SO4filtered, and concentrated. To this was added 1 mL of DCM and 1 mL of 4 M HCl in dioxane. The reaction mixture was stirred for 30 minutes at room temperature, concentrated, diluted with Solvent B (90:10:0.1 CH3CN:Water:TFA, filtered and purified by preparative reverse phase chromatography. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-nm particles: Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 7.4 mg, and its estimated purity by LCMS analysis was 96%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100%0/B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Injection 2 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Proton NMR was acquired in deuterated DMSO. LC-MS: M+1=431, rt=1.127 min., [D1]. Proton NMR was acquired in deuterated DMSO.1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.97 (s, 1H), 8.58 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.79 (d, J=10.4 Hz, 1H), 7.56 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.55 (d, J=13.0 Hz, 1H), 3.88 (d, J=13.2 Hz, 1H), 3.58 (s, 1H), 3.33-3.21 (m, 1H), 3.16-3.06 (m, 1H), 2.88 (d, J=7.5 Hz, 2H), 2.77-2.63 (m, 2H), 2.38 (s, 5H), 1.73-1.59 (m, 2H), 1.43 (d, J=7.0 Hz, 6H). The following examples were prepared according to the general methods disclosed in Examples 46 or 47. TABLE 6Ex.LCMSRtNo.StructureMH+(min)Method48415.91.62QC-ACN-AA-XB49441.31.46QC-ACN-TFA-XB50445.31.47Method A51445.11.21QC-ACN-AA-XB52446.41.57Method E53446.21.70Method E54455.31.74QC-ACN-AA-XB55456.41.85Method E56457.41.27Method F57459.51.16QC-ACN-TFA-XB58459.41.29Method F59459.41.29Method F60460.31.79A61460.41.66Method F62461.31.43Method E63462.31.52Method E64472.41.56Method E65472.42.12Method E664731.65QC-ACN-AA-XB67475.31.50Method E Example 68 1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) piperidin-1-yl)-2-morpholinoethan-1-one 6-(3-Isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine hydrochloride (0.250 g, 0.610 mmol) was dissolved in NMP (5 mL). Et3N (0.255 mL, 1.829 mmol) and 2-chloroacetyl chloride (0.073 mL, 0.915 mmol) were added sequentially. The reaction was monitored by LCMS. After stirring for 1.5 hours, the reaction mixture was diluted with NMP and used as a solution in the next step. 2—Chloro-1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethanone (0.035 g, 0.078 mmol) was dissolved in NMP (1 mL). DBU (0.059 mL, 0.389 mmol) and morpholine (0.020 mL, 0.233 mmol) were added sequentially. The reaction was monitored by LCMS. The reaction mixture was stirred overnight. The reaction mixture was diluted with solvent (90:10 ACN: water, 0.1% TFA) and the crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 37.9 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Injection 2 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. LC-MS: M+1=501, rt=1.157 min., [D1]. Proton NMR was acquired in deuterated DMSO.1H NMR (400 MHz, DMSO-d6) δ=11.12 (s, 1H), 8.79 (d, J=0.8 Hz, 1H), 8.53 (s, 1H), 7.59 (d, J=6.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.2 Hz, 1H), 4.88-4.82 (m, 2H), 4.52-4.48 (m, 1H), 4.28-4.22 (m, 2H), 4.09-4.04 (m, 1H), 3.28-3.21 (m, 1H), 3.19-3.02 (m, 6H), 2.85-2.76 (m, 1H), 2.68-2.59 (m, 2H), 2.58 (s, 3H), 1.88-1.80 (m, 2H), 1.69-1.50 (m, 2H), 1.43 (d, J=7.2 Hz, 6H). The following examples were prepared according to the general process disclosed in Example 68. TABLE 7Ex.LCMSRtNo.StructureMH+(min)Method69487.41.28Method F70473.41.35Method E71489.41.40Method E72473.41.39Method E73487.41.25Method F Example 74 1-(1,1-dioxido-1,2,4-thiadiazinan-4-yl)-2-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-one Intermediate 74A: 2-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)acetic acid In a glass vial, 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.580 g, 1.233 mmol) was dissolved in CH2Cl2(8.22 mL) and N,N-diisopropylethylamine (1.074 mL, 6.16 mmol). Methyl 2-bromoacetate (0.141 mL, 1.479 mmol) was added to the vial, resulting in a clear, bright yellow solution. The reaction mixture was stirred for 1.5 h at room temperature. Excess solvent was evaporated from the reaction mixture under a nitrogen stream. The material was purified by silica gel chromatography using hexane and ethyl acetate as eluents (0%-100% Ethyl acetate gradient). The product fractions were combined and evaporated to dryness. The material was dissolved in 2 mL THF and 2 mL MeOH and treated with 2 mL of 4 M NaOH. Next, 1 mL of water was added and the mixture was stirred at 45° C. overnight. The mixture was diluted with water and acidified to pH=5 with 1 N HCl. Ethyl acetate was added and the layers were separated. The combined organics were washed with dried over Na2SO4, filtered and concentrated to afford 2-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)acetic acid. Example 74 In a 2 dram vial were added 2-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)acetic acid (0.025 g, 0.058 mmol), CH3CN and TEA (0.024 mL, 0.174 mmol). The sample went into solution and HATU (0.033 g, 0.087 mmol) was added. The reaction vial was capped and allowed to stir overnight at room temperature. The sample was diluted with solvent (90:10:0.1 CH3CN:water: TFA), filtered and then purified by preparative reverse phase HPLC. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge Phenyl, 19×200 mm, 5-μm particles: Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 0.8 mg and its estimated purity by LCMS analysis was 99%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Injection 2 conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm. Proton NMR was acquired in deuterated DMSO. The following examples were prepared according to the general process described in Example 74. TABLE 8Ex.LCMSRtNo.StructureMH+(min)Method75471.41.72Method E76473.41.56Method E77515.41.40Method E78485.41.25Method F79513.41.08Method F80487.41.29Method F81473.41.83Method E82515.41.10Method F83501.41.06Method F84501.41.05Method F85558.50.96Method F86471.41.13Method F87473.41.23Method F88501.41.11Method F89499.41.3Method F90485.41.59Method E91549.41.52Method E92501.41.66Method E93485.41.58Method E Example 94 8-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine Intermediate 94A: 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.309 mmol) in EtOH (20 mL) was added vinylboronic acid pinacol ester (62.0 mg, 0.463 mmol). The mixture was degassed for 10 min using N2. Next, PdCl2(dppf)-CH2Cl2(12.61 mg, 0.015 mmol) and Et3N (0.129 mL, 0.926 mmol) were added and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through pad of celite, washed with EtOAc, and concentrated organic layer to afford 6-bromo-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine (70 mg, 95%). LC retention time 1.0.4 min [K]. MS (E−) m/z: 226 (M+H). Intermediate 94B: tert-butyl 4-(3-isopropyl-2-(8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (300 mg, 0.640 mmol), and 6-bromo-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine (215 mg, 0.961 mmol) in dioxane (15 mL) and water (2 mL) was added potassium phosphate tribasic (408 mg, 1.921 mmol). The mixture was degassed with N2for 10 min. Next, PdCl2(dppf) (46.9 mg, 0.064 mmol) was added the mixture was degassed for 10 min. The reaction mixture was heated 80° C. for 16 h. The reaction mass was filtered through pad of celite, washed with EtOAc, and concentrated to afford tert-butyl 4-(3-isopropyl-2-(8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate. The crude mass was purified by silica gel chromatography to afford tert-butyl 4-(3-isopropyl-2-(8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (230 mg, 74%) as white solid. LC retention time 1.74 mM [K]. MS (E−) m/z: 486 (M+H). Intermediate 94C: tert-butyl 4-(2-(8-ethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate A solution of tert-butyl 4-(3-isopropyl-2-(8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (180 mg, 0.371 mmol) in ethyl acetate (15 mL) was purged with nitrogen (N2). Palladium on carbon (39.4 mg, 0.371 mmol)) was added and the mixture was purged with N2three times. Hydrogen gas (H2) was introduced via a balloon to the mixture. The reaction mixture was stirred at room temperature for 5 h. The suspension was filtered through celite, the filtrate was collected and concentrated to afford crude compound. The crude was purified by silica gel chromatography. The compound was eluted in 15% ethyl acetate in hexane, the fractions were collected and concentrated to afford to afford tert-butyl 4-(2-(8-ethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (150 mg, 83% yield) as a white solid. LCMS retention time 1.70 min [K]. MS (E−) m/z: 488 (M+H). Example 94 To a solution of tert-butyl 4-(2-(8-ethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (140 mg, 0.287 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (3.05 μl, 0.100 mmol at ambient temperature. The mixture was stirred at the same temperature for 1 h. The solution was concentrated to afford crude product. The crude material was purified by prep LCMS with the following conditions: Waters Xbridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A:5:95 methanol:water with 10 mM NH4OAc; Mobile Phase B: 95:5 methanol:water with 10 mM NH4OAc; Gradient: 15-65% B over 25 minutes, followed by a 10 minute hold at 65% B and 5 minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to provide 8-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (5.4 mg, 8.5%) as a white solid. LC retention time=1.38 min [E]. MS (E−) m/z: 388 (M+H). Example 95 8-isopropyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine Intermediate 95A: 6-bromo-8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 0.926 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (202 mg, 1.204 mmol) in dioxane (10 mL) and water (0.5 mL) was added potassium phosphate tribasic (590 mg, 2.78 mmol). The reaction mixture was degassed with N2for 10 min. Next, PdCl2(dppf) (67.8 mg, 0.093 mmol) was added and the reaction mixture was degassed for 10 min. The reaction mixture was heated to 80° C. for 16 h. The reaction mass was filtered through a pad of celite, washed with EtOAc, and concentrated. The crude mass was purified by silica gel chromatography using 60% EtOAc-hexanes to afford (6-bromo-8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.840 mmol, 91% yield) as an off-white solid. LC retention time 1.19 mM [K]. MS (E−) m/z: 240 (M+H). Intermediate 95B: tert-butyl 4-(3-isopropyl-2-(8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (300 mg, 0.640 mmol), 6-bromo-8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (229 mg, 0.961 mmol) in dioxane (15 mL), and water (2 mL) was added potassium phosphate tribasic (408 mg, 1.921 mmol) degassed with N2for 10 mins, then PdCl2(dppf) (46.9 mg, 0.064 mmol) was added. The reaction mixture was heated 100° C. for 16 h. Reaction mass filtered through celite bed washed with EtOAc and concentrated to afford crude material. This material was purified by silica gel chromatography to afford tert-butyl 4-(3-isopropyl-2-(8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate. The crude mass was purified by ISCO silica column to afford tert-butyl 4-(3-isopropyl-2-(8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (260 mg, 81% yield) as a brown liquid. LC retention time 1.87 min [K]. MS (E−) m/z: 500 (M+H). Intermediate 95C: tert-butyl 4-(3-isopropyl-2-(8-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate A solution of tert-butyl 4-(3-isopropyl-2-(8-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (180 mg, 0.360 mmol) in ethyl acetate (15 mL), was purged with nitrogen (N2). Next, palladium on carbon (38.3 mg, 0.360 mmol) was added and the mixture was purged with N2three times. Hydrogen gas (H2) was introduced via a balloon to the mixture. The reaction mixture was stirred at room temperature for 5 h. The suspension was filtered through celite and the filtrate was collected and concentrated to afford the crude compound. The crude material was purified by silica gel chromatography and the compound eluted in 15% ethyl acetate in hexane. The fractions were collected and concentrated to afford tert-butyl 4-(3-isopropyl-2-(8-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (160 mg, 89% yield). LCMS retention time 1.81 min [K]. MS (E−) m/z: 502 (M+H). Example 95 To a solution of tert-butyl 4-(3-isopropyl-2-(8-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (140 mg, 0.279 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (5 mL) at ambient temperature. The mixture was stirred at the same temperature for 1 h. The solution was concentrated to afford crude product. The crude sample was purified by preparative LCMS with the following conditions: Waters Xbridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A:5:95 Methanol:water with 10 mM NH4OAc; Mobile Phase B: 95:5 Methanol:water with 10 mM NH4OAc; Gradient: 15-65% B over 25 minutes, followed by a 10 minute hold at 65% B and 5 minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to provide 8-isopropyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 mg, 1.3%) as a white solid. LC retention time=1.49 min [E]. MS (E−) m/z: 402 (M+H). Example 96 8-chloro-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridine Intermediate 96A: tert-butyl 4-(2-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate A solution of tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (2.0 g, 4.27 mmol), 6-bromo-8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (1.158 g, 4.70 mmol) and potassium phosphate, tribasic (2.231 g, 12.81 mmol) in dioxane (60 mL) and water (4 mL) was degassed with N2for 10 min. Next, PdCl2(dppl)-CH2Cl2adduct (0.174 g, 0.213 mmol) was added and the mixture was degassed for 5 min. The resulting reaction mixture was heated at 90° C. for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was collected, dried over Na2SO4and concentrated to afford crude compound. The residue was taken up in DCM (1 mL) and recrystallized with pet ether (3×10 mL). The brown solid formed was filtered and dried to afford tert-butyl 4-(2-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (1.4 g, 2.76 mmol, 64.5%) as a pale yellow solid. LCMS retention time 3.74 min [D]. MS (E−) m/z: 508.3 (M+H). Example 96 To a stirred solution of tert-butyl 4-(2-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (250 mg, 0.492 mmol) in CH2Cl2(2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at the same temperature 2 h. The reaction mass was concentrated to afford crude compound. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Mobile Phase A: 0.1% trifluoroacetic acid: Mobile Phase B: acetonitrile; Gradient: 10-35% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 8-chloro-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.200 g, 99% yield) as a pale solid. LC retention time=2.31 min [E]. MS (E) m/z: 409.4 (M+H).1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.52 (m, 7H) 1.80-1.96 (m, 3H) 2.07 (s, 1H) 2.28-2.40 (m, 1H) 2.61-2.72 (m, 1H) 2.88-3.04 (m, 2H) 3.17 (d, J=5.02 Hz, 2H) 3.21-3.28 (m, 2H) 4.10 (q, J=5.02 Hz, 1H) 7.02 (dd, J=8.53, 1.51 Hz, 1H) 7.35 (d, J=8.03 Hz, 1H) 7.57 (s, 1H), 8.02 (d, J=1.51 Hz, 1H) 8.77-8.94 (m, 1H) 11.24 (s, 1H). Example 97 8-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridine Intermediate 97A: tert-butyl 4-(2-(8-ethyl-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate A solution of tert-butyl 4-(2-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (0.1 mg, 0.197 μmol), ethylboronic acid (0.015 mg, 0.197 μmol), and potassium phosphate, dibasic (0.086 mg, 0.492 μmol) in toluene (2 mL) and water (0.5 mL) was degassed with N2for 10 min. Next, Pd(OAc)2(4.42 g, 0.020 μmol) and tricyclohexylphosphine (2.76 g, 0.0098 μmol) were added and the reaction mixture was degassed for 5 min. The reaction mixture was heated at 100° C. for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was collected, dried over Na2SO4, and concentrated to afford tert-butyl 4-(2-(8-ethyl-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (80 mg, 1.59 mmol, 81%) as a pale yellow solid. LCMS retention time 3.93 min [D]. MS (E−) m/z: 502.3 (M+H). Example 97 To a solution of tert-butyl 4-(2-(8-ethyl-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (0.08 g, 0.159 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.399 mL, 1.595 mmol) drop wise. The reaction mixture was stirred at 25° C. for 1 h. The reaction mass was concentrated to afford crude compound. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Mobile Phase A: 10-mM ammonium acetate; Mobile Phase B: acetonitrile; Gradient: 8-38% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 8-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.0013 g, 2% yield) as a pale solid. LC retention time=1.369 min [D1]. MS (E) m/z: 402 (M+H).1H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (s, 1H), 8.69 (s, 1H), 7.54 (d, J=18.6 Hz, 2H), 7.41-7.30 (m, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.19-3.16 (m, 5H), (3.08-2.95 (m, 8H), 2.08 (s, 1H), 1.99 (d, J=13.2 Hz, 6H), 1.87 (d, J=12.2 Hz, 7H), 1.45 (d, J=7.1 Hz, 9H), 1.40-1.34 (m, 3H). Example 98 tert-butyl 4-(2-(8-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate Intermediate 98A: 6-bromo-7-methyl-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine A solution of 6-bromo-8-iodo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.25 g, 0.740 mmol) and potassium vinyltrifluoroborate (0.099 g, 0.740 mmol) in ethanol (5 mL) was degassed with N2for 10 min. Next, PdCl2(dppf)-CH2Cl2adduct (0.030 g, 0.037 mmol) was added and the reaction mixture was degassed for 5 min followed by the addition of TEA (0.412 mL, 2.96 mmol). The resulting reaction mixture was heated at 85° C. for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was collected, dried over Na2SO4, and concentrated to afford 6-bromo-7-methyl-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine (0.25 g, 0.473 mmol, 63.9% yield) as a yellow solid. LCMS retention time 1.42 min [H]. MS (E−) m/z: 240.3 (M+2H). Intermediate 98B: tert-butyl 4-(3-isopropyl-2-(7-methyl-8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate A solution of tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.4 g, 0.854 mmol), 6-bromo-7-methyl-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine (0.224 g, 0.939 mmol), and potassium phosphate tribasic (0.446 g, 2.56 mmol) in dioxane (5 mL) and water (1 mL) was degassed with N2for 10 min. Next, PdCl2(dppf)-CH2Cl2adduct (0.035 g, 0.043 mmol) was added and the mixture was again degassed for 5 min. The resulting reaction mixture was heated at 90° C. for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was collected, dried over Na2SO4, and concentrated to afford crude compound. The residue was taken up in DCM (1 mL) and recrystallized with pet ether (3×10 mL). The crude material was purified by combiflash 5% MeOH/CHCl3. Concentration of fractions provided tert-butyl 4-(3-isopropyl-2-(7-methyl-8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.35 g, 0.700 mmol, 82%) as a yellow solid. LCMS retention time 3.11 min [D]. MS (E−) m/z: 500.3 (M+H). Intermediate 98C: tert-butyl 4-(2-(8-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate A solution of tert-butyl 4-(3-isopropyl-2-(7-methyl-8-vinyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.35 g, 0.700 mmol) in methanol (10 mL) was purged with nitrogen (N2). Next, Pd/C (0.019 g, 0.018 mmol) was added and the mixture was purged with N2three times. Hydrogen gas (H2) was introduced via a balloon to the mixture. The reaction mixture was stirred at room temperature for 5 h. The suspension was filtered through celite bed, the filtrate was collected, and concentrated to afford tert-butyl 4-(2-(8-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1- carboxylate (250 mg, 0.498 mmol, 72%) as a white solid. LCMS retention time 4.45 min [H]. MS (E−) m/z: 502.3 (M+H). Example 98 To a solution of tert-butyl 4-(2-(8-ethyl-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (0.25 g, 0.498 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.249 mL, 0.997 mmol) drop wise. The reaction mixture was stirred at 25° C. for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Mobile Phase A: 10-mM ammonium acetate; Mobile Phase B: methanol; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 8-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (180 mg, 90%) as a pale solid. LCMS retention time 1.368 min [E]. MS (E) m/z: 402.2 (M+H). The following examples were prepared according to the general procedures disclosed in Examples 1 and 2. TABLE 9FragmentEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method99F-17418.21.33QC-ACN-AA-XB100F-10417.91.18QC-ACN-AA-XB101F-12418.00.65A1102F-14392.01.2QC-ACN-AA-XB103F-9403.91.14QC-ACN-TFA-XB104F-11404.20.99QC-ACN-AA-XB105F-13399.11.21QC-ACN-AA-XB106F-14392.01.2QC-ACN-TFA-XB107F-14392.01.42QC-ACN-AA-XB108F-8389.90.88QC-ACN-AA-XB109F-58361.30.71QC-ACN-AA-XB110F-18388.21.25QC-ACN-TFA-XB111F-19385.21.19QC-ACN-TFA-XB112F-20378.01.148QC-ACN-AA XB113F-8390.20.61A1114F16420.20.61A1115F-7—0.63A1116F-16462.20.67A1117F-59377.20.66TS1 TABLE 10FragmentEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method118F-39395.32.01E119F-36409.11.37E120F-40443.21.78E121F-1346.60.81E122F-21375.31.06E123F-22375.21.28E124F-23389.31.22F125F-24389.21.30F126F-25392.31.39F127F-26391.31.13E128F-27428.21.46F131F-28391.30.95E132F-29405.31.16E133F-31405.21.37E134F-32441.21.43E135F-30419.31.39E136F-33433.41.41E138F-34423.21.42E140F-35405.21.36E141F-54415.11.40F142F-21396.30.88E143F-41446.31.37E144F-45404.21.43F145F-46458.21.49F146F-47448.31.32F147F-48480.21.28F148F-49493.21.28F149F-44459.31.07F150F-41460.31.42F151F-52401.31.21F152F-55414.21.36F153F-40443.21.33E154F-57459.21.68E155F-37389.21.15F156F-5412.20.92E157F-5376.41.34D158F-2360.21.40D159F-51465.31.54N160426.21.35N Example 161 6-(3-(2,2-difluoroethyl)-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine Intermediate 161A: 5-bromo-1-tosyl-1H-indole To a stirred solution of 5-bromo-1H-indole (5.0 g, 25.5 mmol), TsCl (6.03 g, 1.855 mmol) in toluene (100 mL) was added NaOH (50% solution in water, 10.20 g, 255 mmol) dropwise. The reaction mixture was stirred for 16 h at room temperature. The reaction was quenched with water (20 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2×50 mL), the combined organic extracts were dried (Na2SO4) and concentrated to yield crude material. The crude material was purified by silica gel chromatography. The compound was eluted in 4% EA in hexanes, the fractions was collected and concentrated to afford 5-bromo-1-tosyl-1H-indole (7.1 g, 20.27 mmol) as a white solid. LC retention time=2.230 min [A]. MS (E−) m/z: 393.3 (M−H). Intermediate 161B: 1-(5-bromo-1-tosyl-1H-indol-3-yl) 2,2-difluoroethan-1-one To a suspension of AlCl3(6.85 g, 51.4 mmol) in DCM (50 mL) was added difluoroacetic anhydride (4.47 g, 25.7 mmol). The reaction mixture was stirred for 15 min, then a solution of 5-bromo-1H-indole (3 g, 8.57 mmol)) in DCM (30 mL) was added. The reaction mixture was stirred for 1 h at ambient temperature. The reaction was quenched with ice-water. The mixture was extracted with DCM (2×50 mL), combined extracts was washed with aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated to yield crude material. The crude material was purified by silica gel chromatography, the compound was eluted in 10% EtOAc in hexane, the fraction was collected and concentrated to afford 1-(5-bromo-1-tosyl-1H-indol-3-yl)-2,2-difluoroethanone (2.21 g, 4.1 mmol) as a crystalline solid. LC retention time=2.732 min [A]. MS (E−) m/z: 428.0 (M+H). Intermediate 161C: 1-(5-bromo-1H-indol-3-yl)-2,2-difluoroethan-1-one To a solution of 1-(5-bromo-1-tosyl-1H-indol-3-yl)-2,2-difluoroethanone (0.2 g, 0.467 mmol) in THF (4 mL) and MeOH (4.00 mL) solvent mixture was added Cs2CO3(0.45 g, 1.381 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated, the residue was diluted with minimum amount of water and undissolved solids were filtered and dried under vacuum to afford 1-(5-bromo-1H-indol-3-yl)-2,2-difluoroethanone (105 mg, 0.244 mmol) as a white solid. LC retention time=2.233 min [A]. MS (E−) m/z: 276 (M+2H). Intermediate 161D: 5-bromo-3-(2,2-difluoroethyl)-1H-indole To the stirred solution of 1-(5-bromo-1H-indol-3-yl)-2,2-difluoroethanone (0.25 g, 0.912 mmol) in THF (10 mL) was added BH3DMS (1.368 mL, 2.74 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 80° C. for 20 h. The reaction was quenched with water (2 mL) at 0° C. The reaction mixture was diluted with ethyl acetate (100 mL), washed with sodium bicarbonate (2×25 mL) and water (2×25 mL), combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated to yield crude compound. The crude material was purified on silica gel chromatography, the compound was eluted at 8% ethyl acetate/hexane, the fractions was collected and concentrated to afford 5-bromo-3-(2,2-difluoroethyl)-1H-indole (120 mg, 0.438 mmol) as an oil. LC retention time=2.802 min [D]. MS (E−) m/z: 260 (M+H). Intermediate 161E: tert-butyl 4-(3-(2,2-difluoroethyl)-1H-indol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate Tert-butyl 4-(3-(2,2-difluoroethyl)-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate was prepared according to the general procedure described in Intermediate T-1B using 5-bromo-3-(2,2-difluoroethyl)-1H-indole as the starting intermediate (0.14 g, 80% yield). LC retention time 3.075 min [D]. MS (E−) m/z: 361.2 (M−H). Intermediate 161F: tert-butyl 4-(3-(2,2-difluoroethyl)-1-indol-5-yl)piperidine-1-carboxylate Tert-butyl 4-(3-(2,2-difluoroethyl)-1H-indol-5-yl)piperidine-1-carboxylate was prepared according to the general procedure described in Intermediate T-1C using tert-butyl 4-(3-(2,2-difluoroethyl)-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as the starting intermediate (0.9 g, 88% yield). LC retention time 3.282 min [D]. MS (E) m/z: 265.0 (M+H-Boc). Intermediate 161G: tert-butyl 4-(2-bromo-3-(2,2-difluoroethyl)-1H-indol-5-yl)piperidine-1-carboxylate Tert-butyl 4-(2-bromo-3-(2,2-difluoroethyl)-1H-indol-5-yl)piperidine-1-carboxylate was prepared according to the general procedure described in Intermediate 194D using tert-butyl 4-(3-(2,2-difluoroethyl)-1H-indol-5-yl)piperidine-1-carboxylate as the starting intermediate (0.3 g, 52% yield). LC retention time 1.10 min [G]. MS (E−) m/z: 389.0 (M+2H-tBu). Intermediate 161H: tert-butyl 4-(3-(2,2-difluoroethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate A mixture of pinacolborane (1.444 g, 11.28 mmol), tertbutyl 4-(2-bromo-3-(2,2-difluoroethyl)-1H-indol-5-yl)piperidine-1-carboxylate (1.0 g, 2.256 mmol). bis(benzonitrile) palladium(II) chloride (0.086 g, 0.226 mmol), TEA (0.683 g, 6.77 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (0.092 g, 0.226 mmol) in dioxane (20 mL) was degassed with nitrogen for 10 min. The reaction mixture was stirred at 80° C. for 1 h in a sealed tube. The reaction was quenched with ice cold water. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate, combined organic layers was washed with water, brine, dried over sodium sulphate and evaporated to afford crude compound. The crude material was purified by silica gel chromatography, the compound was eluted with 25% ethyl acetate in hexane, the fractions were collected and concentrated to afford tert-butyl 4-(3-(2,2-difluoroethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.650 g, 1.325 mmol, 58.8% yield) as an off-white solid. LC retention time 3.282 min [D]. MS (E−) m/z: 435.4 (M+H-tBu). Intermediate 161I: tert-butyl 4-(3-(2,2-difluoroethyl)-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(3-(2,2-difluoroethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.300, 0.612 mmol), 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.156 g, 0.734 mmol), PdCl2(dppf)-CH2Cl2adduct (0.050 g, 0.061 mmol), and tripotassium phosphate (0.390 g, 1.835 mmol) in a solvent mixture of dioxane (20 mL) and water (2.5 mL) was degassed with nitrogen for 10 min. Next, the resulting slurry was stirred at 95° C. for 3 h in a sealed tube. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate, combined organic layers were washed with water, brine, dried over sodium sulphate and evaporated to afford crude compound. The crude material was purified by silica gel chromatography, the compound was eluted with 85% ethyl acetate and pet ether to afford tert-butyl 4-(3-(2,2-difluoroethyl)-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.210 g, 0.424 mmol, 69.3% yield) as a light yellow solid. LC retention time 1.42 min [G]. MS (E−) m/z: 496.4 (M+H). Example 161 To a solution of tert-butyl 4-(3-(2,2-difluoroethyl)-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.210 g, 0.424 mmol) in dioxane (5.0 mL) was added 4 M HCl in dioxane (1.059 mL, 4.24 mmol) at room temperature. The mixture was stirred at the same temperature for 2 h. The volatiles were evaporated and dried under vacuum to afford crude compound. The crude material was triturated with diethyl ether, dried under vacuum to afford 6-(3-(2,2-difluoroethyl)-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.165 g, 0.417 mmol, 98% yield) as a light yellow solid. LCMS retention time 1.021 min [E]. MS (E) m/z: 396.2 (M+H). Example 162 6-(3-(2,2-difluoroethyl)-5-(piperidin-4-yl)-1H-indol-2-yl)-2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine Intermediate 162A: tert-butyl 4-(3-(2,2-difluoroethyl)-2-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate Tert-butyl 4-(3-(2,2-difluoroethyl)-2-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate was prepared according to the general procedure described for Intermediate 161I using tert-butyl 4-(3-(2,2-difluoroethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.250 g, 0.510 mmol). LC retention time 3.102 min [D]. MS (E) m/z: 510.2 (M+H). Example 162 6-(3-(2,2-difluoroethyl)-5-(piperidin-4-yl)-1H-indol-2-yl)-2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine was prepared according to the general procedure described in Example 161 using tert-butyl 4-(3-(2,2-difluoroethyl)-2-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (0.200 g, 0.392 mmol). LC retention time 1.831 min [D]. MS (E−) m/z: 410.2 (M+H). The following examples were prepared according to the general procedures disclosed in Example 7. TABLE 11TemplateEx.StartingLCMSRtNo.MaterialStructureMH+(min)HPLC Method163EX-99503.21.31QC-ACN-TFA-XB164EX-1445.41.31QC-ACN-AA-XB165EX-2444.41.7QC-ACN-AA-XB166EX-2431.91.33QC-ACN-TFA-XB167EX-2550.91.75QC-ACN-AA-XB168EX-2481.21.48QC-ACN-AA-XB169EX-2484.01.85QC-ACN-AA-XB170EX-2427.11.17QC-ACN-TFA-XB171EX-2453.01.97QC-ACN-AA-XB172EX-2453.02.09QC-ACN-AA-XB173EX-2542.02.16QC-ACN-AA-XB174EX-2495.11.58QC-ACN-AA-XB175EX-2509.01.76QC-ACN-AA-XB176EX-2495.01.34QC-ACN-TFA-XB177EX-2480.11.08QC-ACN-TFA-XB178EX-2495.11.25QC-ACN-AA-XB179EX-2499.41.23QC-ACN-AA-XB180EX-3480.11.56QC-ACN-AA-XB181EX-3412.91.84QC-ACN-AA-XB182EX-3446.01.41QC-ACN-AA-XB183EX-3481.00.98QC-ACN-TFA-XB184EX-3495.01.47QC-ACN-AA-XB185EX-3509.11.71QC-ACN-AA-XB186EX-3453.02.19QC-ACN-AA-XB187EX-3453.31.32QC-ACN-TFA-XB188EX-3427.01.73QC-ACN-AA-XB189EX-3494.91.42QC-ACN-AA-XB190EX-3445.41.05QC-ACN-TFA-XB191EX-3459.41.33QC-ACN-AA-XB192EX-3431.11.35QC-ACN-AA-XB193EX-112463.31.27QC-ACN-TFA-XB194EX-112484.01.71QC-ACN-AA-XB195EX-112417.21.88QC-ACN-AA-XB196EX-112435.11.42QC-ACN-AA-XB197EX-112449.21.40QC-ACN-AA-XB198EX-6489.41.44QC-ACN-AA-XB199EX-6461.11.38QC-ACN-AA-XB200EX-6510.21.25QC-ACN-TFA-XB201EX-6443.01.84QC-ACN-AA-XB202EX-6475.01.25QC-ACN-TFA-XB203EX-6511.31.54QC-ACN-AA-XB204EX-4509.21.47QC-ACN-AA-XB205EX-4523.01.73QC-ACN-AA-XB206EX-4523.01.37QC-ACN-TFA-XB207EX-110473.01.35QC-ACN-TFA-XB208EX-110483.41.46QC-ACN-AA-XB209EX-110494.31.65QC-ACN-AA-XB210EX-110427.35, 427.35QC-ACN-TFA-XB211EX-100470.91.32QC-ACN-TFA-XB212EX-100457.31.33QC-ACN-TFA-XB213EX-100475.11.47QC-ACN-AA-XB214EX-100524.31.63QC-ACN-AA-XB215EX-100539.01.63QC-ACN-AA-XB216EX-100489.41.52QC-ACN-AA-XB217EX-100503.11.3QC-ACN-TFA-XB218EX-100525.11.15QC-ACN-TFA-XB219EX-101503.21.22QC-ACN-TFA-XB220EX-111506.21.24QC-ACN-AA-XB221EX-111457.01.31QC-ACN-TFA-XB222EX-111491.21.66QC-ACN-AA-XB223EX-111424.31.93QC-ACN-AA-XB224EX-111470.01.27QC-ACN-TFA-XB225EX-102489.41.1QC-ACN-TFA-XB226EX-104489.01.18QC-ACN-AA-XB227EX-104442.91.21QC-ACN-TFA-XB228EX-105484.31.43QC-ACN-AA-XB229EX-103443.01.27QC-ACN-TFA-XB230EX-108429.11.16QC-ACN-TFA-XB231EX-113475.11.0QC-ACN-TFA-XB232EX-113429.21.53QC-ACN-AA-XB233EX-113496.01.12QC-ACN-TFA-XB234EX-113461.30.97QC-ACN-TFA-XB235EX-113471.11.63QC-ACN-TFA-XB236EX-114505.21.19QC-ACN-AA-XB TABLE 12TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method237EX-122445.31.76E238EX-122459.31.62E239EX-122446.31.59E240EX-1431.21.71E241EX-1432.31.51E242EX-1431.21.75E243EX-2499.32.1D244EX-124459.31.74E245EX-124473.32.09D246EX-1244601.74E247EX-125473.31.56E248EX-125459.21.72E249EX-1254601.66E250EX-128499.32.08E251EX-1285131.65E252EX-1285001.74E253EX-128467.22.26E254EX-128534.12.07E255EX-142467.21.41E256EX-142481.21.26E257EX-1554731.65E258EX-1554591.83E259EX-153527.31.91E260EX-964931.73E261EX-964791.94E262EX-96480.31.61E263EX-5496.21.81E264EX-5510.25.65I265EX-5510.15.63I266EX-5448.21.87E267EX-131475.31.58E268EX-1324891.55E269EX-132475.31.95E270EX-132476.21.76E271EX-133489.31.71E272EX-133475.31.84E273EX-133476.31.7E274EX-134525.31.93E275EX-134511.31.98E276EX-135503.31.84E277EX-135489.32.09E278EX-136517.22.02E279EX-136503.41.93E280EX-1184791.68E281EX-1184651.85E282EX-1184661.74E283EX-137487.21.81E284EX-137474.11.95E285EX-137473.21.98E286EX-119493.11.75E287EX-119480.11.47E288EX-119479.11.91E289EX-119479.21.91E290EX-119514.21.97E291EX-143516.31.88E292EX-143530.31.69E293EX-94473.31.75E294EX-94459.21.95E295EX-95487.31.91E296EX-95473.32.1E297EX-144474.31.97E298EX-145542.31.83E299EX-145528.32.01E300EX-146532.31.62E301EX-146518.31.79E302EX-98487.31.76E303EX-140475.31.9E304EX-140489.31.69E305EX-140476.31.72E306EX-140510.31.72E307EX-147550.31.32F308EX-148564.31.73E309EX-148578.31.56E310EX-149564.31.71E311EX-149529.31.64E312EX-120527.32.17E313EX-120513.22.38E314EX-120514.22.26E315EX-150544.31.72E316EX-150530.31.91E317EX-154529.22.25E318EX-154543.22.08E319EX-151471.31.75E320EX-151485.31.27F321EX-151506.12.03E322EX-151472.21.86E323EX-141485.22.02E324EX-141486.21.89E325EX-141499.21.81E326EX-152485.12.05E327EX-152499.21.86E328EX-152486.21.92E329EX-156497.31.4E330EX-156483.21.55E331EX-157447.31.38E332EX-157482.31.44E333EX-157433.31.28E334EX-157448.31.26E335EX-157461.31.24E336EX-157434.31.22E337EX-158445.31.04F338EX-158431.31.44E339EX-158466.31.5E340EX-158417.31.33E341EX-158418.31.26E342EX-158432.31.31E343EX-161481.31.45E344EX-161467.21.58E345EX-162495.21.53E346EX-162481.21.68E347EX-160511.31.17E348EX-159550.31.97E349EX-156484.21.42E The following examples were prepared according to the general procedure of Example 26. TABLE 13TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method350EX-1374.01.05QC-AC N-TFA- XB351EX-1444.41.53QC-AC N-AA- XB352EX-1416.41.02QC-AC N-TFA- XB353EX-1455.21.06QC-AC N-TFA- XB354EX-1444.41.17QC-AC N-TFA- XB355EX-1430.41.24QC-AC N-AA- XB356EX-1404.41.09QC-AC N-AA- XB357EX-117433.20.66TS1358EX-1430.41.13QC-AC N-TFA- XB359EX-1481.91.79QC-AC N-AA- XB360EX-1417.04, 416.850.92QC-AC N-TFA- XB361EX-1455.21.89QC-AC N-AA- XB362EX-1499.21.96QC-AC N-AA- XB363EX-1482.41.44QC-AC N-AA- XB364EX-1468.41.15QC-AC N-TFA- XB365EX-1441.31.09QC-AC N-TFA- XB366EX-1494.21.45QC-AC N-TFA- XB367EX-1455.01.31QC-AC N-AA- XB368EX-1498.41.41QC-AC N-AA- XB369EX-1485.21.96QC-AC N-AA- XB370EX-1469.31.85QC-AC N-AA- XB371EX-1468.41.21QC-AC N-TFA- XB372EX-1469.01.54QC-AC N-AA- XB373EX-1468.01.87QC-AC N-AA- XB374EX-1456.91.96QC-AC N-AA- XB375EX-1482.41.42QC-AC N-AA- XB376EX-1454.01.25QC-AC N-AA- XB377EX-1457.21.16QC-AC N-TFA- XB378EX-1455.41.25QC-AC N-TFA- XB379EX-1440.21.14QC-AC N-TFA- XB380EX-1454.31.19QC-AC N-AA- XB381EX-1454.41.32QC-AC N-AA- XB382EX-1468.41.33QC-AC N-AA- XB383EX-1471.32.04QC-AC N-AA- XB384EX-1221.21.45QC-AC N-AA- XB385EX-2438.21.21QC-AC N-TFA- XB386EX-2469.41.2QC-AC N-TFA- XB387EX-2496.11.79QC-AC N-AA- XB388EX-2418.01.16QC-AC N-AA- XB389EX-2468.21.9QC-AC N-AA- XB390EX-2456.41.86QC-AC N-AA- XB391EX-2432.41.19QC-AC N-AA- XB392EX-2469.21.52QC-AC N-AA- XB393EX-2444.01.58QC-AC N-AA- XB394EX-2458.01.58QC-AC N-AA- XB395EX-2492.11.63QC-AC N-AA- XB396EX-2466.01.5QC-AC N-AA- XB397EX-2446.01.1QC-AC N-TFA- XB398EX-2500.02.37QC-AC N-AA- XB399EX-2482.01.31QC-AC N-AA- XB400EX-2530.01.92QC-AC N-AA- XB401EX-2525.12.35QC-AC N-AA- XB402EX-2466.41.72QC-AC N-AA- XB403EX-2472.41.24QC-AC N-AA- XB404EX-2469.01.77QC-AC N-AA- XB405EX-2482.01.96QC-AC N-AA- XB406EX-2471.01.6QC-AC N-AA- XB407EX-2485.31.99QC-AC N-AA- XB408EX-2471.02.18QC-AC N-AA- XB409EX-2468.01.4QC-AC N-AA- XB410EX-2482.21.52QC-AC N-AA- XB411EX-2472.11.36QC-AC N-TFA- XB412EX-2466.41.28QC-AC N-TFA- XB413EX-2496.41.38QC-AC N-AA- XB414EX-2480.01.76QC-AC N-AA- XB415EX-2480.21.77QC-AC N-AA- XB416EX-2481.01.32QC-AC N-TFA- XB417EX-2481.01.32QC-AC N-TFA- XB418EX-2493.91.69QC-AC N-AA- XB419EX-2482.41.26QC-AC N-AA- XB420EX-2468.21.22QC-AC N-TFA- XB421EX-2480.51.47QC-AC N-AA- XB422EX-2494.11.87QC-AC N-AA- XB423EX-2441.01.36QC-AC N-TFA- XB424EX-2480.01.83QC-AC N-AA- XB425EX-2474.11.67QC-AC N-AA- XB426EX-2484.11.15QC-AC N-AA- XB427EX-2551.12.25QC-AC N-AA- XB428EX-2536.51.53QC-AC N-TFA- XB429EX-2466.31.25QC-AC N-TFA- XB430EX-2565.41.89QC-AC N-AA- XB431EX-2563.42.17QC-AC N-AA- XB432EX-2476.31.25QC-AC N-AA- XB433EX-2470.31.92QC-AC N-AA- XB434EX-2469.21.27QC-AC N-TFA- XB435EX-2469.21.9QC-AC N-AA- XB436EX-2471.11.93QC-AC N-AA- XB437EX-2468.21.49QC-AC N-AA- XB438EX-2526.21.54QC-AC N-TFA- XB439EX-2496.21.34QC-AC N-TFA- XB440EX-2455.21.28QC-AC N-TFA- XB441EX-3430.41.66QC-AC N-AA- XB442EX-3496.21.08QC-AC N-TFA- XB443EX-3458.21.05QC-AC N-TFA- XB444EX-3468.41.81QC-AC N-AA- XB445EX-3468.31.1QC-AC N-TFA- XB446EX-3455.41.78QC-AC N-AA- XB447EX-3469.30.98QC-AC N-TFA- XB448EX-3454.01.3QC-AC N-AA- XB449EX-3469.41.33QC-AC N-AA- XB450EX-3471.01.79QC-AC N-AA- XB451EX-3455.01.5QC-AC N-AA- XB452EX-3465.91.69QC-AC N-AA- XB453EX-3469.01.95QC-AC N-AA- XB454EX-3466.21.46QC-AC N-AA- XB455EX-3506.01.69QC-AC N-AA- XB456EX-3526.02.05QC-AC N-AA- XB457EX-3469.11.42QC-AC N-AA- XB458EX-3456.21.77QC-AC N-AA- XB459EX-3455.41.05QC-AC N-TFA- XB460EX-3492.41.21QC-AC N-TFA- XB461EX-3466.11QC-AC N-TFA- XB462EX-3441.01.84QC-AC N-AA- XB463EX-3480.11.05QC-AC N-TFA- XB464EX-3494.11.73QC-AC N-AA- XB465EX-3480.41.71QC-AC N-AA- XB466EX-3480.01.33QC-AC N-TFA- XB467EX-3466.01.85QC-AC N-AA- XB468EX-112473.01.31QC-AC N-TFA- XB469EX-112434.11.18QC-AC N-TFA- XB470EX-6499.11.37QC-AC N-AA- XB471EX-6510.11.75QC-AC N-AA- XB472EX-6488.11.74QC-AC N-AA- XB473EX-6460.11.65QC-AC N-AA- XB474EX-6551.01.69QC-AC N-AA- XB475EX-4535.41.43QC-AC N-AA- XB476EX-4497.41.94QC-AC N-TFA- XB477EX-4515.01.29QC-AC N-TFA- XB478EX-4444.11.74QC-AC N-AA- XB479EX-4458.41.58QC-AC N-TFA- XB480EX-4416.11.32QC-AC N-AA- XB481EX-4430.01.62QC-AC N-AA- XB482EX-4416.11.54QC-AC N-TFA- XB483EX-4485.21.44QC-AC N-AA- XB484EX-4484.32.29QC-AC N-AA- XB485EX-4402.21.29QC-AC N-AA- XB486EX-4446.21.38QC-AC N-AA- XB487EX-110444.31.77QC-AC N-AA- XB488EX-110471.91.28QC-AC N-AA- XB489EX-110520.41.23QC-AC N-TFA- XB490EX-100524.21.8QC-AC N-AA- XB491EX-100512.21.53QC-AC N-AA- XB492EX-100474.41.15QC-AC N-TFA- XB493EX-100502.11.35QC-AC N-AA- XB494EX-100510.41.22QC-AC N-TFA- XB495EX-100513.41.15QC-AC N-TFA- XB496EX-100550.11.46QC-AC N-AA- XB497EX-100499.11.38QC-AC N-AA- XB498EX-100565.31.38QC-AC N-AA- XB499EX-101474.11.09QC-AC N-TFA- XB500EX-111469.21.42QC-AC N-AA- XB501EX-111441.21.18QC-AC N-TFA- XB502EX-102499.31.08QC-AC N-TFA- XB503EX-102460.31.06QC-AC N-TFA- XB504EX-104460.21.49QC-AC N-AA- XB505EX-104485.30.97QC-AC N-TFA- XB506EX-105483.21.26QC-AC N-TFA- XB507EX-107447.91.35QC-AC N-AA- XB508EX-108446.31.53QC-AC N-AA- XB509EX-108485.10.92QC-AC N-TFA- XB510EX-113446.01.39QC-AC N-AA- XB511EX-113485.31.16QC-AC N-AA- XB512EX-113496.41.04QC-AC N-TFA- XB513EX-113471.11QC-AC N-TFA- XB514EX-113522.41.34QC-AC N-AA- XB515EX-113512.41.56QC-AC N-AA- XB516EX-113484.11.27QC-AC N-AA- XB517EX-113482.11.45QC-AC N-AA- XB518EX-113488.01.26QC-AC N-TFA- XB519EX-113496.41.55QC-AC N-AA- XB520EX-113482.11.31QC-AC N-AA- XB521EX-113474.31.03QC-AC N-TFA- XB522EX-113486.11.46QC-AC N-AA- XB523EX-113485.21.01QC-AC N-TFA- XB524EX-113496.01.39QC-AC N-AA- XB525EX-114460.31.44QC-AC N-AA- XB526EX-114510.01.48QC-AC N-AA- XB527EX-114499.31.02QC-AC N-TFA- XB528EX-116518.01.71QC-AC N-AA- XB529EX-116475.91.11QC-AC N-TFA- XB530EX-116476.01.3QC-AC N-AA- XB TABLE 14TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method531EX-122431.30.93E532EX-122467.31.56E533EX-122416.31.48E534EX-122430.31.8E535EX-122458.31.45E536EX-1402.31.47E537EX-2470.22.5E538EX-25432.12E539EX-25002.11E540EX-2444.21.71E541EX-2444.21.72E542EX-124444.31.74E543EX-124473.31.71E544EX-1244441.82E545EX-124520.31.93E546EX-125472.31.56E547EX-125444.41.69E548EX-1255201.58E549EX-1284842.03E550EX-1285601.88E551EX-1284701.56E552EX-1285122.5D553EX-128484.22.24E554EX-128512.12.13E555EX-128512.32.15E556EX-128498.21.51F557EX-128498.22.03E558EX-155444.31.65E559EX-155430.31.53E560EX-155482.31.5E561EX-5522.41.51E562EX-5502.31.71E563EX-5502.26.03I564EX-5502.46.06I565EX-5489.31.55E566EX-5474.31.86E567EX-5469.21.89E568EX-5460.21.87D569EX-5460.11.73E570EX-5447.11.44E571EX-1324881.66E572EX-132460.11.34F573EX-1325361.9E574EX-133460.21.94E575EX-133474.21.92D576EX-133474.21.94D577EX-137486.21.8E578EX-137458.31.96E579EX-119492.21.7E580EX-119464.22.1E581EX-143501.32.01E582EX-94444.32.07E583EX-94444.32.08E584EX-95458.32.25E585EX-95458.22.24E586EX-145513.22.15E587EX-98458.32.11E588EX-140460.22.04E589EX-140488.32.05E590EX-147535.21.32F591EX-148549.21.87E592EX-149514.31.76E593EX-151456.31.88E594EX-141470.31.92E595EX-152470.12.21E596EX-158416.31.54E597EX-161452.21.67E598EX-156468.21.67E599EX-124430.31.49E600EX-157432.31.49E The following examples were prepared according to the general methods disclosed in Examples 46 and 47. TABLE 15TemplateEx.StartingLCMSRtNo.MaterialStructureMH+(min)HPLC Method601EX-1484.91.43QC-ACN-AA- XB602EX-2535.21.95QC-ACN-AA- XB603EX-2494.21.65QC-ACN-AA- XB604EX-2520.31.78QC-ACN- TFA-XB605EX-2498.01.63QC-ACN- TFA-XB606EX-2494.21.68QC-ACN-AA- XB607EX-2509.41.66QC-ACN-AA- XB608EX-2508.21.64QC-ACN-AA- XB609EX-4488.02.39QC-ACN-AA- XB610EX-4529.41.63QC-ACN-AA- XB611EX-110473.41.37QC-ACN-AA- XB TABLE 16TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method612EX-122459.32.76D613EX-122460.31.64E614EX-122474.31.83E615EX-122487.31.36E616EX-122487.31.3E617EX-122460.31.67E618EX-122445.21.38E619EX-1480.21.67E620EX-2468.31.23F621EX-2498.52.29E622EX-2487.31.42F623EX-2487.31.4E624EX-2487.31.3F625EX-24871.4E626EX-2501.21.46F627EX-2489.11.74E628EX-2529.31.5E629EX-124459.31.95D630EX-124473.32.35D631EX-124474.31.85E632EX-124488.31.96E633EX-124474.31.82E634EX-1246011.92E635EX-124501.31.36E636EX-124501.31.88D637EX-125474.31.71E638EX-1254731.54E639EX-1254591.21E640EX-112463.41.06F641EX-128499.31.59E642EX-128513.31.75E643EX-128500.31.83E644EX-128567.41.7E645EX-128526.41.9E646EX-128514.41.88E647EX-128500.31.64E648EX-128538.32.07E649EX-128527.41.48E650EX-128567.31.95E651EX-128528.21.92E652EX-128500.21.77E653EX-128564.32.22E654EX-128512.31.68E655EX-128555.41.82E656EX-142481.31.49E657EX-142482.21.7E658EX-142496.21.72E659EX-142467.31.4E660EX-1554731.6E661EX-1554591.49E662EX-96493.31.46E663EX-5488.41.62E664EX-5476.41.59E665EX-5539.41.38E666EX-5516.41.69E667EX-5489.41.32E668EX-5510.31.43E669EX-5490.41.64E670EX-5529.41.46E671EX-5529.31.46E672EX-5501.11.16E673EX-5517.41.55E674EX-5503.11.37E675EX-5517.31.56E676EX-5501.31.43E677EX-5515.27.94I678EX-5515.27.95I679EX-5501.31.43E680EX-132489.11.62E681EX-132475.11.48E682EX-133489.31.6E683EX-133475.31.42E684EX-136517.41.65E685EX-118480.21.02E686EX-118479.21.6E687EX-137487.41.64E688EX-137473.31.59E689EX-119493.11.68E690EX-143530.41.4E691EX-148578.31.52E692EX-120527.32.08E693EX-120513.31.93E694EX-120567.31.97E695EX-154543.21.98E696EX-151485.31.5E697EX-151471.21.56E698EX-141499.21.75E699EX-152499.21.77E700EX-152485.21.62E701EX-157461.31.19E702EX-157447.31.08E703EX-158445.31.24E704EX-158431.31.12E705EX-161482.21.57E706EX-161467.21.27E707EX-161482.21.58E708EX-161495.21.48E709EX-161496.21.68E710EX-161510.31.82E711EX-161481.31.37E712EX-161481.21.41E The following examples were prepared according to the general process disclosed in Example 68. TABLE 17TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method713EX-1487.21.17QC-AC N-TFA- XB714EX-2489.11.26QC-AC N-TFA- XB715EX-2515.22.36QC-AC N-AA- XB716EX-2520.92.55QC-AC N-AA- XB717EX-2549.12.08QC-AC N-AA- XB718EX-4561.41.46QC-AC N-TFA- XB719EX-4258.11.22QC-AC N-TFA- XB720EX-4543.11.97QC-AC N-AA- XB721EX-4612.21.83QC-AC N-AA- XB722EX-4543.31.78QC-AC N-AA- XB723EX-4258.41.44QC-AC N-TFA- XB724EX-4556.31.2QC-AC N-TFA- XB725EX-4528.21.68QC-AC N-AA- XB726EX-4512.11.87QC-AC N-AA- XB727EX-4513.21.53QC-AC N-TFA- XB728EX-4527.21.77QC-AC N-AA- XB729EX-4543.31.39QC-AC N-AA- XB730EX-4271.41.59QC-AC N-TFA- XB731EX-4529.31.6QC-AC N-AA- XB732EX-4501.21.49QC-AC N-AA- XB733EX-4515.31.84QC-AC N-AA- XB734EX-4244.21.33QC-AC N-TFA- XB735EX-4515.11.41QC-AC N-TFA- XB736EX-4515.11.54QC-AC N-AA- XB737EX-4487.11.54QC-AC N-AA- XB738EX-4259.41.29QC-AC N-TFA- XB739EX-4246.41.24QC-AC N-TFA- XB740EX-4473.21.37QC-AC N-AA- XB741EX-4549.02.01QC-AC N-AA- XB742EX-4485.11.76QC-AC N-AA- XB743EX-4503.01.57QC-AC N-AA- XB744EX-4513.41.73QC-AC N-AA- XB745EX-4250.31.3QC-AC N-TFA- XB746EX-4501.41.41QC-AC N-TFA- XB747EX-4541.12.28QC-AC N-AA- XB748EX-4502.41.37QC-AC N-TFA- XB749EX-4529.01.34QC-AC N-TFA- XB750EX-4543.11.76QC-AC N-AA- XB751EX-4541.14 541.14QC-AC N-TFA- XB752EX-4484.41.47QC-AC N-TFA- XB753EX-4459.01.4QC-AC N-AA- XB754EX-4264.41.41QC-AC N-TFA- XB755EX-4529.31.46QC-AC N-AA- XB756EX-4252.31.22QC-AC N-TFA- XB757EX-4489.21.28QC-AC N-AA- XB758EX-4250.31.35QC-AC N-TFA- XB759EX-4544.11.64QC-AC N-AA- XB760EX-4517.51.32QC-AC N-TFA- XB761EX-4527.21.86QC-AC N-AA- XB762EX-4501.11.74QC-AC N-AA- XB763EX-4501.21.58QC-AC N-AA- XB764EX-4499.51.37QC-AC N-TFA- XB765EX-4485.41.35QC-AC N-AA- XB766EX-4487.51.32QC-AC N-TFA- XB767EX-4501.41.37QC-AC N-TFA- XB TABLE 18TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method768EX-2485.41.72E769EX-2499.41.62E770EX-2485.41.35E771EX-2513.41.37E772EX-2558.51.53E773EX-2529.41.65E774EX-2501.41.29E775EX-2515.41.47E776EX-2501.41.29E777EX-128541.41.51F778EX-128527.41.44F779EX-128539.42.14E780EX-5505.31.55E781EX-5517.31.69E The following examples were prepared according to the general process described in Example 74. TABLE 19TemplateEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method782EX-2549.21.29QC-AC N-TFA- XB783EX-2535.41.31QC-AC N-TFA- XB784EX-2535.321.64QC-AC N-AA- XB785EX-2505.11.77QC-AC N-AA- XB786EX-2545.21.55QC-AC N-AA- XB787EX-2511.11.21QC-AC N-TFA- XB788EX-2503.21.26QC-AC N-TFA- XB789EX-2517.41.35QC-AC N-TFA- XB790EX-2515.21.54QC-AC N-AA- XB791EX-2529.41.58QC-AC N-AA- XB792EX-2503.21.49QC-AC N-AA- XB793EX-2515.21.33QC-AC N-TFA- XB794EX-2579.21.44QC-AC N-TFA- XB795EX-2531.21.22QC-AC N-TFA- XB796EX-2517.21.6QC-AC N-AA- XB797EX-2531.21.25QC-AC N-TFA- XB798EX-2515.21.63QC-AC N-AA- XB799EX-2529.31.7QC-AC N-AA- XB800EX-2545.21.56QC-AC N-TFA- XB801EX-2515.41.24QC-AC N-TFA- XB802EX-3485.01.33QC-AC N-TFA- XB803EX-3473.11.76QC-AC N-AA- XB804EX-3473.01.63QC-AC N-AA- XB805EX-3499.21.42QC-AC N-TFA- XB806EX-3471.41.59QC-AC N-AA- XB807EX-3459.11.25QC-AC N-TFA- XB808EX-3487.41.35QC-AC N-TFA- XB809EX-3501.31.5QC-AC N-AA- XB810EX-3489.31.23QC-AC N-TFA- XB811EX-6528.01.46QC-AC N-AA- XB812EX-6545.01.31QC-AC N-TFA- XB813EX-6580.11.58QC-AC N-AA- XB814EX-6533.21.48QC-AC N-AA- XB815EX-6558.91.53QC-AC N-AA- XB816EX-6489.01.63QC-AC N-AA- XB817EX-6517.01.58QC-AC N-AA- XB818EX-6519.01.28QC-AC N-AA- XB819EX-6503.01.44QC-AC N-TFA- XB820EX-6532.91.37QC-AC N-TFA- XB821EX-6503.01.3QC-AC N-TFA- XB822EX-6575.01.39QC-AC N-AA- XB823EX-6545.01.43QC-AC N-AA- XB824EX-6613.31.62QC-AC N-AA- XB825EX-6533.01.4QC-AC N-AA- XB826EX-6578.91.46QC-AC N-AA- XB827EX-6579.01.45QC-AC N-AA- XB828EX-6547.01.34QC-AC N-TFA- XB829EX-6561.01.27QC-AC N-TFA- XB830EX-6565.11.66QC-AC N-AA- XB831EX-6529.31.69QC-AC N-AA- XB832EX-6557.01.85QC-AC N-AA- XB833EX-6551.01.63QC-AC N-AA- XB834EX-6559.11.63QC-AC N-AA- XB835EX-6545.01.31QC-AC N-TFA- XB836EX-6569.11.3QC-AC N-AA- XB837EX-6559.11.31QC-AC N-TFA- XB838EX-6526.01.8QC-AC N-AA- XB839EX-6545.01.59QC-AC N-AA- XB840EX-6537.11.74QC-AC N-AA- XB841EX-6613.01.79QC-AC N-AA- XB842EX-6514.21.57QC-AC N-AA- XB843EX-4515.21.32QC-AC N-TFA- XB844EX-4485.41.74QC-AC N-AA- XB845EX-4563.31.56QC-AC N-AA- XB846EX-4515.11.32QC-AC N-TFA- XB847EX-4563.11.45QC-AC N-AA- XB848EX-4503.21.29QC-AC N-TFA- XB849EX-4527.21.67QC-AC N-AA- XB850EX-100545.01.3QC-AC N-TFA- XB TABLE 20FragmentEx.StartingLCMSRtHPLCNo.MaterialStructureMH+(min)Method851EX-1244991.83E852EX-1245151.75E853EX-124563.31.76E854EX-5517.21.86E855EX-5602.41.89E856EX-5545.41.72E857EX-5519.31.49E858EX-5565.31.44E859EX-5489.31.46E860EX-5515.31.92E861EX-5545.31.9E862EX-5531.31.79E863EX-5517.31.21E864EX-5505.31.56E865EX-5523.31.18F866EX-5530.31.23E867EX-5503.31.26E868EX-5519.31.15F869EX-5545.41.69E870EX-5487.31.5E871EX-5531.31.16F872EX-5537.31.71E873EX-5529.41.77E874EX-5517.31.02F875EX-5519.31.51E876EX-140545.31.73E877EX-140531.31.73E878EX-140501.41.21F879EX-140503.41.29F880EX-140579.31.6E881EX-140531.31.56E Example 882 1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-3-morpholinopropan-1-one To a two dram vial were added the TFA salt of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.025 g, 0.053 mmol), CH3CN, HATU (1.0 equiv.), TEA (3.0 equiv.), and 3-morpholinopropanoic acid (0.250 g, 1.570 mmol). The reaction vial was capped and stirred overnight at room temperature. The mixture was diluted with solvent (90:10:0.1 CH3CN: Water: TFA) and filtered. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-70% B over 19 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-3-morpholinopropan-1-one (21.2 mg, 0.041 mmol, 78% yield). LCMS MH+: 515.2 HPLC Ret. Time 1.52 min. Method QC-ACN-AA-XB.1H NMR (500 MHz, DMSO-d6) δ 8.85-8.72 (m, 1H), 8.55-8.48 (m, 1H), 7.63-7.50 (m, 2H), 7.36-7.22 (m, 1H), 7.06-6.94 (m, 1H), 4.63-4.51 (m, 1H), 4.06-3.98 (m, 1H), 3.63-3.56 (m, 5H), 3.30-3.20 (m, 1H), 2.70-2.53 (m, 11H), 2.46-2.39 (m, 3H), 1.89-1.79 (m, 2H), 1.70-1.59 (m, 1H), 1.53-1.46 (m, 1H), 1.45-1.39 (m, 6H). The following examples were prepared according to the general process described in Example 882. TABLE 21TemplateEx.StartingLCMSRtNo.MaterialStructureMH+(min)HPLC Method883EX-2529.01.63QC-ACN-AA-XB884EX-2563.21.29QC-ACN-TFA-XB885EX-3515.51.56QC-ACN-AA-XB886EX-4557.21.28QC-ACN-TFA-XB887EX-4543.21.44QC-ACN-AA-XB888EX-4531.21.32QC-ACN-TFA-XB889EX-4503.11.3QC-ACN-AA-XB890EX-4501.21.42QC-ACN-AA-XB891EX-4516.11.33QC-ACN-AA-XB892EX-4513.11.44QC-ACN-AA-XB893EX-4499.21.28QC-ACN-TFA-XB894EX-4501.21.31QC-ACN-TFA-XB895EX-4515.21.45QC-ACN-AA-XB896EX-4515.21.35QC-ACN-TFA-XB897EX-4558.21.42QC-ACN-AA-XB898EX-4531.21.35QC-ACN-TFA-XB899EX-4529.21.32QC-ACN-AA-XB900EX-4563.21.37QC-ACN-TFA-XB901EX-4517.21.32QC-ACN-TFA-XB902EX-4501.21.33QC-ACN-TFA-XB903EX-4487.11.29QC-ACN-TFA-XB904EX-4527.01.35QC-ACN-TFA-XB905EX-4473.11.31QC-ACN-AA-XB906EX-4557.21.65QC-ACN-AA-XB907EX-4626.21.56QC-ACN-AA-XB908EX-4555.21.62QC-ACN-AA-XB909EX-4543.21.32QC-ACN-AA-XB910EX-4541.21.5QC-ACN-AA-XB911EX-4557.21.48QC-ACN-AA-XB912EX-4570.21.31QC-ACN-AA-XB913EX-4542.21.44QC-ACN-AA-XB914EX-4517.21.32QC-ACN-AA-XB915EX-4557.21.43QC-ACN-AA-XB916EX-4513.11.38QC-ACN-AA-XB917EX-4543.21.35QC-ACN-AA-XB918EX-4513.21.39QC-ACN-TFA-XB919EX-4527.21.42QC-ACN-TFA-XB920EX-4541.21.49QC-ACN-TFA-XB921EX-4531.21.49QC-ACN-AA-XB922EX-4529.21.32QC-ACN-AA-XB923EX-4529.21.32QC-ACN-AA-XB924EX-4555.21.52QC-ACN-TFA-XB925EX-4505.21.31QC-ACN-TFA-XB926EX-4529.31.54QC-ACN-TFA-XB Example 927 Azetidin-3-yl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate 1-(tertbutoxycarbonyl)azetidin-3-yl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (15 mg, 0.026 mmol) and 2:1 trifluoroacetic acid:dichloromethane (1.2 mL, 0.026 mmol) were combined in a 1-dram vial containing a stir bar. The resulting clear, yellow solution was stirred at room temperature for 30 min. After completion of the reaction, toluene (150 μL) was added to the reaction mixture. The reaction mixture was stirred briefly and excess solvent was evaporated. The residue was taken up in DMF (1.5 mL) and purified by semi-preparative HPLC on a C-18 column on the Shimadzu instrument eluting with water/acetonitrile/TFA. Excess solvent was evaporated from product-containing fractions to afford azetidin-3-yl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate, TFA (14.9 mg, 0.025 mmol, 96% yield) as a white solid. LCMS MH+: 487.3. HPLC Ret. Time 1.40 min. Method QC-ACN-TFA-XB.1H NMR (400 MHz, METHANOL-d4) δ 8.68 (s, 1H), 8.58 (s, 1H), 7.60 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.08 (dd, J=8.4, 1.5 Hz, 1H), 5.33-5.24 (m, 1H), 4.45 (dd, J=12.7, 7.0 Hz, 2H), 4.38-4.25 (m, 2H), 4.21 (br. s., 2H), 3.17-3.06 (m, 1H), 2.98 (dq, J=13.6, 6.8 Hz, 4H), 2.88 (tt, J=12.0, 3.3 Hz, 1H), 2.67 (s, 3H), 2.30 (s, 3H), 1.96 (d, J=12.0 Hz, 2H), 1.75 (br. s., 2H), 1.40 (d, J=7.1 Hz, 6H). The following examples were prepared according to the general process described in Example 929. TABLE 22Ex.LCMSRtHPLCNo.StructureMH+(min)Method928475.11.45QC-ACN-TFA-XB929501.41.48QC-ACN-TFA-XB930515.41.42QC-ACN-TFA-XB931501.41.37QC-ACN-TFA-XB932529.31.54QC-ACN-AA-XB933515.41.4QC-ACN-TFA-XB934489.41.36QC-ACN-TFA-XB935515.41.4QC-ACN-TFA-XB936529.41.52QC-ACN-AA-XB937515.01.52QC-ACN-TFA-XB938515.01.58QC-ACN-AA-XB939515.11.52QC-ACN-TFA-XB940501.11.55QC-ACN-AA-XB941501.41.37QC-ACN-TFA-XB942528.91.64QC-ACN-AA-XB943503.41.35QC-ACN-TFA-XB944526.31.37QC-ACN-TFA-XB945543.51.45QC-ACN-TFA-XB946593.41.45QC-ACN-TFA-XB947543.51.45QC-ACN-TFA-XB948529.51.41QC-ACN-TFA-XB949531.31.47QC-ACN-TFA-XB950573.11.55QC-ACN-AA-XB951558.11.48QC-ACN-AA-XB952545.01.8QC-ACN-AA-XB953265.21.52QC-ACN-TFA-XB954515.11.67QC-ACN-AA-XB955545.11.76QC-ACN-AA-XB956529.11.59QC-ACN-TFA-XB Example 957 (4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)(4-methylpiperazin-1-yl)methanone 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (10 mg, 0.026 mmol) was dissolved in THF (0.25 mL). Phenyl carbonochloridate (6.06 mg, 0.039 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was blown down on a ZYmark Turbovap at 45° C. for 1 h. The residue was dissolved in NMP (0.25 mL). Next, 1-methylpiperazine (7.75 mg, 0.077 mmol) and DIPEA (6.76 μl, 0.039 mmol) were added to the NMP solution of the intermediate. The reaction mixture was stirred at 100° C. overnight. Crude samples with final volume of 1.8 mL in DMF/NMP in a stubby tube were purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford (4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)(4-methylpiperazin-1-yl)methanone (4 mg, 7.63 mol. 29.6% yield). LCMS MH+: 514.4. HPLC Ret. Time 1.29 min. Method QC-ACN-TFA-XB. The following examples were prepared according to the general process described in Example 957. TABLE 23Ex.StartingLCMSRtNo.MaterialStructureMH+(min)HPLC Method958EX-4565.91.57QC-ACN-AA-XB959EX-4488.31.27QC-ACN-TFA-XB960EX-4540.51.46QC-ACN-TFA-XB961EX-4500.01.31QC-ACN-AA-XB962EX-4474.41.27QC-ACN-AA-XB963EX-4528.51.56QC-ACN-AA-XB964EX-4514.21.36QC-ACN-AA-XB965EX-4542.61.83QC-ACN-AA-XB966EX-4528.51.39QC-ACN-TFA-XB967EX-4486.01.55QC-ACN-AA-XB968EX-4500.51.31QC-ACN-AA-XB969EX-4577.61.45QC-ACN-TFA-XB970EX-4528.51.33QC-ACN-TFA-XB971EX-4500.31.3QC-ACN-TFA-XB972EX-4488.01.43QC-ACN-TFA-XB973EX-4542.01.68QC-ACN-AA-XB974EX-4528.41.32QC-ACN-TFA-XB975EX-4572.51.45QC-ACN-TFA-XB976EX-4557.31.3QC-ACN-AA-XB977EX-4528.41.36QC-ACN-TFA-XB978EX-4502.41.33QC-ACN-AA-XB979EX-4544.51.3QC-ACN-TFA-XB980EX-4542.61.41QC-ACN-TFA-XB Example 981 2-(3-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetontrile Intermediate 981A: 3-isopropyl-1H-indole To a 500 mL round bottom flask were added 2,2,2-trichloroacetic acid (23.60 g, 144 mmol), toluene (150 mL), and triethylsilane (46.1 mL, 289 mmol). With stirring, the solution was heated to 70° C. and a solution of 1H-indole (11.28 g, 96 mmol) and acetone (8.48 mL, 116 mmol) in 75 mL of toluene was added drop-wise via an addition funnel. The reaction mixture was heated to 90° C. for 2.5 hours. The reaction mixture was cooled to room temperature, then to 5° C. To this were added 1.5 M dibasic potassium phosphate solution and diethyl ether. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel using ethyl acetate/hexane as the eluent to afford 3-isopropyl-1H-indole (12 g, 78%) as a white solid. LC retention time=1.04 min [A1]. MS (E+) m/z: 160.2 (M+H).1H NMR (400 MHz, CHLOROFORM-d) δ 7.72-7.65 (m, 1H), 7.41-7.36 (m, 1H), 7.21 (d, J=0.9 Hz, 1H), 7.14 (s, 1H), 6.99 (dd, J=2.2, 0.7 Hz, 1H), 3.31-3.17 (m, 1H), 1.40 (d, J=6.8 Hz, 6H). Intermediate 981B: 6-(3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine To a 100 mL round bottom flask were added 3-isopropyl-1H-indole (1.000 g, 6.28 mmol) and DCE (10 mL). NBS (1.062 g, 5.97 mmol) was dissolved in 10 mL of DCE and added to the reaction mixture drop-wise via an addition funnel over 15 minutes. The reaction was quenched with 5 mL of a 10% sodium sulfite solution. The volatiles were removed. Next, THF (10 mL), 7,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.54 g, 5.56 mmol), PdCl2(dppf)-CH2Cl2adduct (0.25 g, 0.314 μmol), and 3 M tribasic potassium phosphate solution (6.3 mL, 18.8 mmol) were added. The reaction vessel was capped and pump/purged with nitrogen gas three times. The reaction mixture was set to heat at 70° C. for 1 hour. The mixture was cooled to room temperature and concentrated. The crude residue was taken up in DCM (3 mL), filtered and purified on silica gel using ethyl acetate/hexane to afford 6-(3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.8 g, 41.8%) as a white foam. LC retention time=2.04 min [D1]. MS (E+) m/z: 305.0 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ 8.54-8.44 (m, 1H), 8.38-8.28 (m, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.13-7.01 (m, 2H), 3.28-3.16 (m, 1H), 2.66 (s, 3H), 2.32 (s, 3H), 1.38 (d, J=6.8 Hz, 6H). Intermediate 981C: tert-butyl 5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate To a 40 mL reaction vial were added 64-(3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.450 g, 1.478 mmol), AcOH (4 mL), water (0.5 mL), and NBS (0.263 g, 1.478 mmol). The vial was sealed and stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and 1 mL of a 10% sodium sulfite was added. This mixture was concentrated, dissolved in DCM/MeOH, filtered, and purified on silica gel using ethyl acetate/hexane to afford 5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole as a tan solid. LC retention time=1.01 min [A1]. MS (E+) m/z: 83/385 (M+H).1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.82 (s, 1H), 8.48 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.16 (dd, J=8.6, 1.8 Hz, 1H), 2.88 (br d, J=14.1 Hz, 1H), 2.60 (s, 3H), 2.15 (s, 3H), 1.43-1.15 (m, 5H), 1.18-1.09 (m, 1H). To this material were added DMAP (0.010 g, 0.0148 mmol), THF (10 mL), and BOC-anhydride (0.59 g, 2.95 mmol). The reaction mixture was stirred for 2 hours at room temperature, concentrated to a viscous oil, diluted with DCM, and washed with dilute IN HCl. The organic was washed with water and then brine. The solution was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel using ethyl acetate/hexane to afford tert-butyl 5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (0.45 g, 63%) as a yellowish solid. LC retention time=1.15 min [A1]. MS (P) m/z: 483/485 (M+H). Intermediate 981D: tert-butyl 5-(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate To a mixture of tert-butyl 5-bromo-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (0.130 g, 0.269 mmol), PdCl2(dppf)-CH2Cl2adduct (10.98 mg, 0.013 mmol), and (8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-en-3-yl) boronic acid (0.071 g, 0.282 mmol) in a screw cap vial was added THF (2 mL) followed by 3 M aqueous solution of tripotassium phosphate (0.269 mL, 0.807 mmol). The vial was fitted with a Teflon lined septum cap. The system was evacuated under vacuum and backfilled with nitrogen gas. The procedure was repeated three times. The vial was sealed and heated at 75° C. for 18 hours, The reaction mixture was diluted with EtOAc (100 mL) and poured into a separatory funnel. The organic layer was washed with water (2×50 mL), saturated aqueous NaCl solution (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford crude product. The crude product was purified on silica gel using 0-100% ethyl acetate/hexane. Following concentration of the fractions, the product was collected as a tan oil (0.11 g, 65%). LC retention time=1.19 min [A1]. MS (E+) m/z: 612.2 (M+H). Intermediate 981E: tert-butyl 5-(8-(tert-butoxycarbonyl)-8-azabicyclo [3.2.1]octan-3-yl)-2-(7,8-dimethyl-[1,2,4]triazol o[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate In a Parr bottle, tert-butyl 5-(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (0.11 g, 0.18 mmol) was suspended in ethyl acetate (3 mL) and treated with 10 mol % of 5% Pd/C (0.057 g, 0.027 mmol). Following degassing, the reaction mixture was placed under a hydrogen gas atmosphere (50 psi) and shaken for 16 hours at room temperature. Following the removal of the hydrogen atmosphere and back-filling with nitrogen gas, the reaction mixture was diluted with MeOH, filtered through celite, and concentrated to afford tert-butyl 5-(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3isopropyl-1H-indole-1-carboxylate (0.11 g, 100%) as a mixture of isomers. LC retention time=1.20 min [A1]. MS (E+) m/z: 614.4 (M+H). Intermediate 981F: 6-(5-(8-azabicyclo[3.2.1]octan-3-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine TFA salt To a solution of tert-butyl 5-(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (0.025 g, 0.041 mmol) was added DCM (0.5 mL) in a 2 dram reaction vial. To this was added TFA (1 mL) and the reaction vial was capped. The reaction mixture was stirred for 2 hours at room temperature. The volatiles were removed under a stream of nitrogen gas. The yield was considered quantitative. This material was used as is for final derivatization to prepare the compounds shown in Table 24. One example is described below for Example 981. Example 981 In a 2 dram reaction vial were added 6-(5-(8-azabicyclo[3.2.1]octan-3-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, TFA salt (0.021 g, 0.041 mmol), NMP, DBU (0.025 mL, 0.164 mmol), and drop-wise, bromoacetonitrile (0.017 g, 0.15 mmol). The reaction mixture was stirred for 1 hour at room temperature, then diluted with water, and filtered through a 0.45 micron syringe filter. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-80% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-75% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. 2-(3-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetonitrile (0.0021 g, 6.4% yield) was collected as a mixture of isomers. Two analytical LC/MS injections were used to determine the final purity. LC retention time 2.18 min [C1]. MS (E+) m/z: 453.0 (M+H).1H NMR (500 MHz, DMSO-d6) δ 10.95 (br d, J=18.2 Hz, 1H), 8.73-8.64 (m, 1H), 8.69 (br s, 1H), 8.52-8.39 (m, 1H), 8.46 (s, 1H), 7.62 (s, 1H), 7.62 (br d, J=18.2 Hz, 1H), 7.19 (s, 1H), 7.23 (br s, 1H), 7.01-6.88 (m, 1H), 7.05-6.84 (m, 1H), 3.34 (br s, 1H), 3.17 (s, 1H), 3.13-3.01 (m, 1H), 2.99-2.93 (m, 1H), 2.88-2.76 (m, 1H), 2.57 (s, 2H), 2.15 (s, 2H), 2.02-1.94 (m, 1H), 1.90 (br d, J=8.2 Hz, 1H), 1.75 (br s, 4H), 1.68-1.57 (m, 1H), 1.29 (br s, 5H). The following examples were prepared according to the general procedures disclosed in Example 981. TABLE 24Ex.LCMSRtHPLCNo.StructureMH+(min)Method982499.11.57C1983499.11.50C1984520.01.58C1985520.11.53C1 Example 986 6-(3-isopropyl-5-(1-(pyridin-2-yl)piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (19.4 mg, 0.050 mmol), 2-chloropyridine (6.2 mg, 0.055 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.8 mg, 10.00 nmol), Pd2(dba)3(4.6 mg, 5.00 nmol) and Cs2CO3(48.9 mg, 0.150 mmol) were suspended in dioxane (0.5 mL). The mixture was degassed with nitrogen gas for 5 minutes. The reaction vessel was sealed and heated to 90° C. for 2 hours. Upon completion, the reaction mixture was filtered, concentrated, dissolved in DMF, and purified via preparative LCMS using the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 6-(3-isopropyl-5-(1-(pyridin-2-yl)piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, TFA (10.1 mg, 0.017 mmol, 35% yield). LCMS retention time 1.25 [QC-ACN-TFA-XB]. MS (ES+) m/z: 465.4 (M+H).1NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.63 (br d, J=7.9 Hz, 1H), 8.44-8.38 (m, 2H), 8.36 (br d, J=9.5 Hz, 1H), 7.82-7.73 (m, 1H), 7.67 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.28-7.24 (m, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.12 (br d, J=8.5 Hz, 1H), 3.41 (br d, J=11.3 Hz, 2H), 3.11-2.93 (m, 3H), 2.85 (dt, J=14.0, 7.0 Hz, 1H), 2.42 (s, 3H), 2.06-1.96 (m, 2H), 1.96-1.82 (m, 5H), 1.35 (dd, J=16.5, 7.0 Hz, 6H). The following examples were prepared in a manner similar to Example 986. TABLE 25Ex.LCMSRtHPLCNo.StructureMH+(min)Method987522.50.96QC-ACN-TFA-XB988522.50.95QC-ACN-TFA-XB Example 989 6-(3-isopropyl-5-(1-(pyrimidin-2-yl)piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (19.4 mg, 0.050 mmol) and Et3N (0.021 mL, 0.150 mmol) were mixed in DMSO (1 mL). Next, 2-chloropyrimidine (6.9 mg, 0.060 mmol) was added. The reaction vial was sealed and heated to 90° C. for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (0.05 mL) and 1 mL of DMSO, and purified on preparative LCMS via the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 45-100% B over 20 minutes, then a 10-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to provide 6-(3-isopropyl-5-(1-(pyrimidin-2-yl)piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (5.0 mg, 10.2 μmol, 20.4% yield). LCMS retention time 1.71 [QC-ACN-TFA-XB]. MS (ES+) m/z: 466.3 (M+H). Example 990 2-(4-(2-(8-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide To a solution of 2-(4-(2-(8-(benzylamino)-[1,2,4]triazolo [1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl) piperidin-1-yl)-N,N-dimethylacetamide (0.040 g, 0.073 mmol) in methanol (10.0 mL) was added Pd/C (0.023 g, 0.218 mmol). The reaction mixture was stirred at room temperature for 6 h under hydrogen. The reaction mixture was diluted with ethyl acetate:methanol (1:1) filtered and washed with excess ethyl acetate. The combined organic layers were evaporated to afford crude compound. The crude material was purified ia preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Mobile Phase A: 0.05% TFA; Mobile Phase B: acetonitrile; Gradient: 15-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 2-(4-(2-(8-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (7.3 mg). LCMS retention time 1.44 min [E]. MS (E−) m/z: 460.3 (M−H).1H NMR (400 MHz, METHANOL-d4) δ ppm 8.31-8.39 (m, 1H) 8.16 (d, J=1.47 Hz, 1H) 7.66 (s, 1H) 7.36 (d, J=8.31 Hz, 1H) 7.08 (d, J=8.80 Hz, 1H) 6.84-6.97 (m, 1H) 4.26 (s, 2H) 3.76 (d, J=13.21 Hz, 2H) 3.33-3.43 (m, 2H) 3.25 (br. s., 2H) 2.94-3.12 (m, 8H) 2.19 (br. s., 4H) 1.50 (d, J=7.09 Hz, 7H) 1.28 (br. s., 1H). Example 991 2-(4-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide Intermediate 991A: 4-fluoro-3-isopropyl-1H-indole To a 40 mL vial with a red pressure-release cap were added 2,2,2-trichloroacetic acid (0.907 g, 5.55 mmol), toluene (7.40 mL) and triethylsilane (1.773 mL, 11.10 mmol). With stirring, the solution was heated to 70° C. and a solution of 4-fluoro-1H-indole (0.500 g, 3.70 mmol) and acetone (0.326 mL, 4.44 mmol) in 1 mL of toluene was added drop-wise via a syringe. The reaction mixture was stirred and heated to 90° C. for 3 h, venting with a nitrogen line. The reaction mixture was allowed to cool to 5° C., and to the reaction mixture were added 1 M aqueous K3PO4solution (˜4 mL) and ethyl acetate (4 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×5 mL). The combined organic extracts were dried over sodium sulfate and filtered, and excess solvent was evaporated off. The resulting red oil was taken up in DCM (˜2 mL) and purified by flash chromatography to afford 4-fluoro-3-isopropyl-1H-indole as a yellow liquid (483.2 mg, 2.67 mmol, 72.2% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (br s, 1H), 7.16-7.07 (m, 2H), 6.95 (d, J=2.2 Hz, 1H), 6.77 (ddd, J=11.3, 7.4, 1.1 Hz, 1H), 3.38 (dt, J=13.7, 6.8 Hz, 1H), 1.38 (dd, J=6.8, 0.6 Hz, 6H). HPLC Ret. Time 0.99 min. Method G. Intermediate 991B: 4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole 4-fluoro-3-isopropyl-1H-indole (0.475 g, 2.68 mmol) was dissolved in THF (10.72 mL) in a 40 mL vial. The solution was cooled to 0° C. under a nitrogen atmosphere with an ice bath, and sodium hydride (0.214 g, 5.36 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature, then triisopropylsilyl chloride (0.860 mL, 4.02 mmol) was added dropwise via syringe. The reaction mixture was then stirred at 50° C. for 1 h. The reaction completed. The reaction mixture was cooled to 0° C. and quenched by addition of 1 M KHSO4(˜4 mL) and water (4 mL). Ethyl acetate (4 mL) was added, and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×3 mL). The combined organic phases were extracted with brine (1×4 mL), and excess solvent was evaporated off. The resulting yellow oil was taken up in DCM (˜3.5 mL total volume) and purified by flash chromatography on a 24 g silica column, eluting with ethyl acetate and hexanes. The product 4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole was obtained as a clear, colorless liquid (0.92 g, 2.48 mmol, 92% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.24 (d, J=8.3 Hz, 1H), 7.03 (td, J=8.1, 5.4 Hz, 1H), 6.94 (s, 1H), 6.76 (dd, J=11.0, 7.8 Hz, 1H), 3.36 (spt, J=6.8 Hz, 1H), 1.36 (d, J=6.8 Hz, 6H), 1.16 (d, J=7.6 Hz, 18H). LCMS MH+: 334.3. HPLC Ret. Time 1.43 min. Method G. Intermediate 991C: 5-bromo-4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole Sec-butyllithium (2.144 mL, 3.00 mmol, 90% purity) was added to a −75° C. (dry ice/methanol bath) solution of 4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole (0.910 g, 2.73 mmol) and 1,1,4,7,7-pentamethyldiethylenetriamine (0.572 mL, 2.73 mmol) in THF (13.64 mL) in an oven-dried 50 mL recovery flask under a nitrogen atmosphere. The solution was stirred for 6.5 h at −75° C. for 6 h. Next, 1,2-dibromotetrafluoroethane (0.325 mL, 2.73 mmol) was added to the reaction mixture. The solution was stirred for 10 min at −75° C., then allowed to warm to room temperature. The reaction progressed 50%. Excess solvent was evaporated from the reaction mixture. The resulting orange oil was taken up in DCM (total volume ˜4 mL) and purified by flash chromatography on a 24 g silica column, eluting with hexanes. The product and remaining starting indole co-eluted. Fractions were pooled and excess solvent was evaporated off to yield 5-bromo-4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole (1.07 g, 1.68 mmol, 65% yield) and 4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole as a mixture in a clear, colorless liquid. The mixed products were taken forward directly. LCMS MH+: 412.08. HPLC Ret. Time 1.50 min. Method G. Intermediate 991D: tert-butyl 4-(4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate 5-bromo-4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indole (650 mg, 1.576 mmol) was dissolved in THF (7880 μl) in a 40 mL scintillation vial with a red pressure-release cap and containing a Teflon-covered stir bar. Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (585 mg, 1.891 mmol) was added to the vial, followed by tripotassium phosphate (2364 μl, 4.73 mmol). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min, then 2nd generation XPhos precatalyst (31.0 mg, 0.039 mmol) was added to the reaction mixture. The clear, yellow reaction mixture was placed under a nitrogen atmosphere and heated to 60° C. with stirring for 6 h. The reaction mixture was allowed to cool to room temperature. The aqueous phase was removed, and excess THF was evaporated from the reaction. The resulting oil residue was taken up in DCM (˜4 mL total volume) and purified by flash chromatography eluting with ethyl acetate and hexanes. The product fractions was concentrated and vacuumed to afford tert-butyl 4-(4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a pale yellow sticky solid (0.65 g, 1.14 mmol, 72.6% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.18 (d, J=8.6 Hz, 1H), 6.99-6.94 (m, 1H), 6.92 (s, 1H), 5.90 (br s, 1H), 4.10 (br s, 2H), 3.66 (br t, J=5.2 Hz, 2H), 3.36 (spt, J=6.8 Hz, 1H), 2.61 (br s, 2H), 1.53 (s, 9H), 1.35 (d, J=6.7 Hz, 6H), 1.16 (d, J=7.6 Hz, 18H). LCMS MH+: 515.5. HPLC Ret. Time 1.53 min. Method G. Intermediate 991E: tert-butyl 4-(4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indol-5-yl)piperidine-1-carboxylate 5% Pd on Carbon (100 mg, 1.271 mmol) was weighed into a 20 mL scintillation vial containing a Teflon-coated stir bar with a red pressure-release cap. Tert-butyl 4-(4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (654.4 mg, 1.271 mmol) was dissolved in MeOH (12.71 mL) and transferred into the vial containing the Pd on C while under a nitrogen atmosphere. Ammonium formate (401 mg, 6.36 mmol) was added to the reaction mixture, and the vial was capped. The reaction mixture was stirred at 50° C. for 4 h. Additional ammonium formate (401 mg, 6.36 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 60° C. for 3 h but did not reach completion. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was filtered through celite to remove Pd/C. Excess methanol was evaporated from the reaction mixture to afford tert-butyl 4-(4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indol-5-yl)piperidine-1-carboxylate (654 mg, 1.271 mmol, 100% yield, 30% purity) a clear, pale yellow oil. Product was checked by1H NMR and was approximately 30% reduced and 70% starting material alkene. LCMS MH+: 517.5. HPLC Ret. Time 1.53 min. Method G. Intermediate 991F: tert-butyl 4-(4-fluoro-3-isopropyl-1H-indol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate Tert-butyl 4-(4-fluoro-3-isopropyl-1-(triisopropylsilyl)-1H-indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.650 g, 1.263 mmol) (7:3 mix of piperidine alkene and piperidine alkane) and tetra-n-butylammonium fluoride (0.660 g, 2,53 mmol) were dissolved in THF (6.31 mL) in a 20 mL scintillation vial. The reaction mixture was stirred for 10 min at room temperature. The reaction was complete with 2 peaks corresponding to the product alkene (1.15 min, M+H+=359.3) and alkane (1.16 min, M+H+=359.3, 361.3). The reaction mixture was partitioned between brine and ethyl acetate (1:1, total volume ˜16 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2×4 mL). The combined organic phases were washed with brine (2×5 mL), dried over sodium sulfate, and filtered. Excess solvent was evaporated from the organic phase to afford tert-butyl 4-(4-fluoro-3-isopropyl-1H-indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.476 g, 1.263 mmol) as a pale yellow oil. LCMS MH+: 359.3. HPLC Ret. Time 1.15 min. Method G. Intermediate 991G: tert-butyl 4-(4-fluoro-3-isopropyl-1H-indol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 5% Pd on C on (150 mg, 1.264 mmol) was weighed into a 20 mL scintillation vial containing a Teflon-coated stir bar with a red pressure-release cap. Tert-butyl 4-(4-fluoro-3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (453 mg, 1.264 mmol) was dissolved in MeOH (6.32 mL) and transferred into the vial containing the Pd on C while under a nitrogen atmosphere. Ammonium formate (797 mg, 12.64 mmol) was added to the reaction mixture, and the vial was capped. The reaction mixture was stirred at 60° C. for 30 min. The reaction completed. The reaction mixture was filtered through celite to remove Pd/C. Excess methanol was evaporated from the reaction mixture. The resulting yellow oil was taken up in DCM (3 mL) and purified by flash chromatography on a 24 g silica column, eluting with ethyl acetate and hexanes to afford tert-butyl 4-(4-fluoro-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate as a white crystalline solid (370.3 mg, 1.017 mmol, 80% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.96 (br s, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.02-6.97 (m, 1H), 6.93 (d, J=2.1 Hz, 1H), 4.28 (br s, 2H), 3.37 (spt, J=6.8 Hz, 1H), 3.17 (tt, J=12.0, 3.6 Hz, 1H), 2.88 (br t, J=11.3 Hz, 2H), 1.89-1.81 (m, 2H), 1.81-1.68 (m, 2H), 1.52 (s, 9H), 1.36 (d, J=6.8 Hz, 6H). LCMS MH: 361.3. HPLC Ret. Time 1.16 min. Method G. Intermediate 991H: tert-butyl 5-(1-(tert-butoxycarbonyl-piperidin-4-yl)-4-fluoro-3-isopropyl-1H-indole-1-carboxylate Tert-butyl 4-(4-fluoro-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (370 mg, 1.026 mmol) and di-tert-butyl dicarbonate (540 μl, 2.258 mmol) were dissolved in THF (5132 μl) in a 20 mL vial containing a Teflon-covered stir bar. Next, 4-dimethylaminopyridine (12.54 mg, 0.103 mmol) was added. The vial was capped and the clear, pale yellow solution was stirred at room temperature for 2 h. The reaction finished. Excess solvent was evaporated from the reaction mixture. The residue was taken up in DCM (˜2 mL) and purified by flash chromatography on a 24 g silica column, eluting with ethyl acetate and hexanes to afford tert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-1H-indole-1-carboxylate as a white foam (4.57 g, 0.98 mmol, 99% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.85 (br s, 1H), 7.28 (br s, 1H), 7.12 (dd, J=8.4, 7.2 Hz, 1H), 3.29 (spt, J=6.8 Hz, 1H), 3.14 (tt, J=12.0, 3.5 Hz, 1H), 2.87 (br t, J=11.4 Hz, 2H), 1.88-1.79 (m, 2H), 1.51 (s, 9H), 1.34 (d, J=6.8 Hz, 6H). LCMS MH+: 461.4. HPLC Ret. Time 1.36 min. Method G. Intermediate 991I: tert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate Tert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-1H-indole-1-carboxylate (456.7 mg, 0.992 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (324 μl, 1.587 mmol) were dissolved in THF (7933 μl) in a 20 mL vial containing a Teflon-covered stir bar. The vial was cooled to −20° C. (dry ice/NMP bath) under a nitrogen atmosphere. Lithium diisopropylamide (992 μl, 1.983 mmol) was added dropwise to the vial (via a syringe through the septum cap) over ˜5 min. The reaction mixture was stirred at −20° C. for 1 h. then allowed to slowly warm to 0° C. Most starting material (˜75%) converted to product. The reaction mixture was allowed to warm to 10° C., then quenched by addition of 1 M KHSO4(5 mL). The resulting mixture was extracted with EtOAc (2×3 mL). The combined organic extracts were washed with brine (2×3 mL), and excess solvent was evaporated off. The residue was taken up in DCM (2 mL) and purified by flash chromatography on a 24 g silica column, eluting with ethyl acetate and hexane to afford tert-butyl-5-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate as a white solid (468.9 mg, 0.72 mmol, 72.6% yield, 90% purity).1H NMR (400 MHz, CHLOROFORM-d) δ 7.61 (d, J=8.6 Hz, 1H), 7.06 (dd, J=8.4, 7.1 Hz, 1H), 4.28 (br s, 2H), 3.35-3.26 (m, 1H), 3.14 (br s, 1H), 2.87 (br t, J=11.9 Hz, 2H), 1.88-1.81 (m, 2H), 1.71 (br s, 2H), 1.67 (s, 9H), 1.44 (s, 12H). LCMS MH+−56: 531.4. HPLC Ret. Time 1.39 min. Method G. Intermediate 991J: tert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(8-ethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-indole-1-carboxylate Tert-butyl 5-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (100 mg, 0.170 mmol) and 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (42.8 mg, 0.188 mmol) were weighed into a 1-dram vial with a red pressure-release cap and containing a Teflon-coated stir bar. THF (852 μl) and tripotassium phosphate (170 μl, 0.511 mmol) were added to the vial, and the reaction mixture was degassed by bubbling nitrogen through the reaction mixture for 3 min. 2ND generation XPhos precatalyst (4.02 mg, 5.11 μmol) was added to the vial, and the reaction mixture was placed under a nitrogen atmosphere and stirred at 60° C. overnight. The reaction was completed. The aqueous phase was removed, and excess solvent was evaporated from the organic phase. The resulting orange residue was taken up in DCM (˜3 mL) and purified by flash chromatography on a 12 g silica column, eluting with ethyl acetate and hexanes to afford tert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indole-1-carboxylate as a cloudy colorless glass (100.7 mg, 0.124 mmol, 72.9% yield, 75% purity).1H NMR (400 MHz, CHLOROFORM-d) δ 8.36 (s, 1H), 8.22 (d, J=1.1 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.28 (s, 1H), 7.23 (dd, J=8.6, 7.2 Hz, 1H), 6.72 (d, J=1.0 Hz, 1H), 4.39-4.22 (m, 2H), 4.04 (s, 3H), 3.19 (tt, J=12.0, 3.3 Hz, 1H), 2.99 (dtd, J=14.1, 7.0, 3.0 Hz, 1H), 2.88 (br t, J=11.2 Hz, 2H), 1.91-1.82 (m, 2H), 1.74 (br dd, J=12.5, 3.8 Hz, 2H), 1.50 (s, 9H), 1.24 (d, J=2.0 Hz, 15H). LCMS MH+: 608.6. HPLC Ret. Time 1.22 min. Method G. Example 991 Tert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indole-1-carboxylate (25 mg, 0.041 mmol) was Boc-deprotected by reacting with 2:1 trifluoroacetic acid/dichloromethane (1.2 mL, 0.041 mmol) in a 1-dram vial for 30 min. Toluene (˜0.15 mL) was added, and excess solvent was then evaporated from the reaction mixture. The resulting residue was stirred with 2-chloro-N,N-dimethylacetamide (10.00 mg, 0.082 mmol) and potassium carbonate (28.4 mg, 0.206 mmol) in NMP (0.411 mL) at 22° C. for 1.5 h. The reaction did not finish. The reaction mixture was stirred at 22° C. over the weekend. The reaction was completed. The reaction mixture was partitioned between water and ethyl acetate (3 mL total volume), and the aqueous phase was extracted with ethyl acetate (2×1 mL). Excess solvent was evaporated from the combined organic extracts. DMF (˜1.5 mL) was added to the resulting residue. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 2-(4-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (8.5 mg, 0.017 mmol, 42.1% yield).1H NMR (500 MHz, DMSO-d6) δ 11.44 (br s, 1H), 8.58 (s, 1H), 8.54-8.47 (m, 1H), 7.18 (br d, J=8.5 Hz, 1H), 7.13 (s, 1H), 7.09 (t, J=7.0 Hz, 1H), 4.06 (s, 3H), 3.30 (br s, 1H), 3.17 (s, 2H), 3.07 (s, 3H), 3.01-2.88 (m, 3H), 2.88-2.78 (m, 3H), 2.20 (br t, J=10.5 Hz, 3H), 1.83-1.75 (m, 3H), 1.73 (br s, 4H), 1.36 (br d, J=6.4 Hz, 6H). LCMS MH+: 493. HPLC Ret. Time 1.30 min. Method QC-ACN-AA-XB. The following examples were prepared in a manner similar to that described in Example 991. TABLE 26Ex.LCMSRtNo.StructureMH+(min)HPLC Method992464.51.5QC-ACN-AA-XB9935221.7QC-ACN-AA-XB Example 994 4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboximidamide 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (15.77 mg, 0.042 mmol) was stirred with 1H-pyrazole-1-carboximidamide (5.81 mg, 0.053 mmol) and DIPEA (0.037 mL, 0.211 mmol) in DMF (0.422 mL) at 75° C. for 8 h. DMF (1 mL) was added to the reaction mixture and the reaction mixture was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-55% B over 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation to afford 4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboximidamide (8.4 mg, 0.019 mmol, 45.0% yield). LCMS MH+: 416.2 HPLC Ret. Time 1.23 min. Method QC-ACN-AA-XB.1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.33-7.33 (m, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 7.11 (br d, J=8.1 Hz, 1H), 2.99-2.88 (m, 3H), 2.79 (s, 2H), 2.77-2.70 (m, 1H), 2.16-2.06 (m, 1H), 1.74-1.64 (m, 2H), 1.51 (s, 4H), 1.50-1.40 (m, 2H), 1.08-0.98 (m, 6H). BIOLOGICAL ASSAYS The pharmacological properties of the compounds of this invention may be confirmed by a number of biological assays. The exemplified biological assays, which follow, have been carried out with compounds of the invention. TLR7/8/9 Inhibition Reporter Assays HEK-Blue™-cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9 receptors were used for screening inhibitors of these receptors using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1-binding sites. Briefly, cells are seeded into Greiner 384 well plates (15000 cells per well for TLR7, 20,000 for TLR8 and 25,000 for TLR9) and then treated with test compounds in DMSO to yield a final dose response concentration range of 0.05 nM-50 μM. After a 30 minute compound pre-treatment at room temperature, the cells are then stimulated with a TLR7 ligand (gardiquimod at a final concentration of 7.5 μM), TLR8 ligand (R848 at a final concentration of 15.9 μM) or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB and AP-1 which induce the production of SEAP. After a 22 hour incubation at 37° C., 5% CO2, SEAP levels are determined with the addition of HEK-Blue™ Detection reagent (Invivogen), a cell culture medium that allows for detection of SEAP, according to manufacturer's specifications. The percent inhibition is determined as the % reduction in the HEK-Blue signal present in wells treated with agonist plus DMSO alone compared to wells treated with a known inhibitor. TABLE 27TLR7/8/9 Reporter Assay DataTLR7TLR8TLR9Ex.IC50IC50IC50No.(nM)(nM)(nM)134.569317723.75.1901533.92.2191240.30.7158950.52.781861.19.8119370.74.7663680.32.211729—0.521167100.51.7479110.32.45385120.81.930631312.54778142.41.523273151.41.451131611.66321171.90.52501181.51.5150081910.94802202.10.82694210.77.6—22—21845230.43.34811240.40.82865250.332425260.96.811110270.83.41767280.93.73052290.31.81159300.81.21534310.71.51998320.51.82399338.522.9131183418.6136.150000350.52.21426360.63.93545370.61.21907381.83.329477391.10.84245400.70.52462410.51.24334421.60.73114432.31.17816440.8711301450.31.11757460.55.53032474.845.510643482.183.795854914.256.850000500.86.234095112.261.44680521.850.4442935332.2210.650000540.634.630085553.186.36521561.523.91602574.77.43749582.741.62939594.365.93116601.242.540436611.678.842221620.74.5644631.846.537047641.461.6—6510.1175.611138660.73.72659671.19.25849681.42942823692.113.138337082.4558.750000711.110.72476720.47.51383730.961270742.93.366317513.97158760.83.72587770.62.51579780.75.87303791.43.562558016.12209810.8729110820.54.71654830.941958840.63.8974850.62.94818612.523268715.736053881.23.72005890.96.11594900.23.413889111.32784921.23.366139315.62645940.35.73200950.418.91964960.619.71281973.55.21549980.82.017569929.333.546521008.6169.4172110110.916.811330102116.83125.0138291035.3174.121921047.010.017221050.827.1813106126.23125.0124851072.15.3233010879.729.04236109153.0699.94271101.54.515161111.011291121.116.619741180.83.323821190.20.624871203.447.5201512120.115.55191229.689.566312328.932.020911244.633.750361255.067.2169512618.7312.960512781.521.613391280.412.12648131109.216.616051322.68.28441331.19.514361341.010.310761353.230.029113642.1189.327081380.319.67601400.77.225121410.913.2133114258.41543.03431435.7—4241442.07.87791459.992.0212714627.1178.6148714792.1730.81990114812.84.260214947.3709.4214150142.1338.26921510.35.015671520.83.711481536.4144.5342915410.435.41064155599.7191.08621562.817.222671570.83.011491580.72.919271597.063.287941600.75.449911611.813.414021623.245.3171116386.473.649471649.015.036641652.17.418161662.717.832201670.84.324711680.41.934141691.212.577521701.24.480871711.33.7115281720.44.152431732.314.628601740.52.136811750.85.8233141760.51.917081771.02.3106741780.83.518021791.33.9203818033.65.9128251811.92.6177018212.60.849391838.42.052081843.32.054701857.73.362661865.28.31424818712.03.0145591886.51.9179711896.51.727601902.311.01231019114.86.863591928.73.395931935.744.049751945.022.3156921951.635.939571961.325.180481972.979.6156941982.79.841071991.812.883212008.017.1340362011.89.619522021.416.7153392032.36.960282040.70.720202050.60.927642060.91.5573720710.88.8461820814.24.050412093.95.982192103.46.2428321114.8211.61436521210.6347.628552135.0103.372412145.2111.21650621515.5142.875792163.2243.5192472178.2238.781482185.2103.91125721934.018.3109592200.73.26722210.41.353152221.06.2181692230.812.010742241.59.569732259.9249.7122062268.98.91800222711.620.8507422878.3962.0382202292.043.5104723068.151.472852312.46.066412322.37.010992331.01.5156052340.66.272192351.710.4308723619.69.1118023710.8588.359352388.9347.5262523922.596.7—2406.622.9600324118.94.929882422.95.636002432.833.5440622441.010.062702451.210.526482460.22.322592477.448.543942484.265.7458224911.520.118232500.78.634222510.57.863162520.52.025512530.213.610012540.66.11600825595.01125.63771256178.61881.821212571703.8435.79952581235.5404.7588525912.2137.113552600.413.926032612.128.381142620.65.318952631.12.853012640.52.339492650.79.37028266560.4448.97984267102.930.873002682.815.718942694.237.1123142705.24.615732710.612.813462720.611.724162732.14.79732741.119.037312753.125.5101882765.452.0182427710.461.22442278100.670.6213427961.758.731642800.612.443002810.715.061532821.75.9100822834.96.324302843.38.019002851.515.160122860.50.831472871.00.530562880.61.4141052891.025.961262901.835.662542918.22.1156829218.31.413032930.515.857092940.821.1195392951.945.624492963.147.4104422975.026.3215329810.845.762529926.3139.7343230029.0113.1265830154.5252.564423024.36.129713031.67.0171143040.93.345413052.71.870343061.22.71696630748.2103.0532030840.02.1153330943.12.0709310181.4307.211231190.5352.31553125.755.643053135.480.6313231411.918.31640315268.6557.91931316318.9491.7369231719.871.885753186.825.522273190.27.9105203200.314.230243210.74.661783222.07.720863232.635.351893241.62.910013251.412.411143261.26.721873270.94.114533284.34.319013293.218.510513301.014.411213312.56.452943323.64.131653333.35.331833342.91.920923351.16.315013364.94.728353372.05.221063381.65.888743394.15.6148773401.56.558663411.94.228603423.73.017853433.619.03303441.513.454743455.137.614123464.266.646143471511.52255.286183485.5—11453491.53.917873505.612.5480935139.918.4532235229.556.51140935338.544.22469035418.212.522583558.3107.0623135813.629.760353596.88.918193603.522.3361936114.49.99225362325.0149.21579936319.410.18223649.27.015233655.610.6358736629.08.7191736716.33.8440436857.019.1206736919.24.7183937023.415.8226037117.06.1192737237.121.1347237321.46.5232937432.217.21007837511.610.321043769.55.219963779.03.0—37811.18.657323792.71.29903806.712.111953817.82.476438219.93.8189438379.859.6181773845.97.022663857.862.9315983860.99.351573871.46.133623881.67.161453892.82.1712839033.2151.4500003910.20.919043921.76.0500003932.71.514843941.22.713793952.310.4446603962.68.951133970.62.921833986.341.9125583991.13.88574002.513.520034015.998.5214454022.58.662714035.512.916624041.37.2500004052.11.923794060.61.87474071.51.922904082.04.998284090.51.16584101.51.011504111.77.8454914120.51.828654131.233.56324141.44.936274152.74.925034165.416.42230541710.146.9260224185.411.875904191.12.62794201.01.57254212.25.234054220.63.378554230.93.383874241.04.331524253.75.111494269.8877.3500004271.65.936504281.39.190344291.65.320744300.73.135724312.69.054624320.11.815524336.36.6325634341.43.752734357.711.8243164363.03.362544370.80.711864382.75.722054397.717.3232904403.45.7244664418.510.0413054429.13.9282344319.73.4514344442.15.41693444513.61.6332444641.56.34385244755.810.8500004487.80.5233844913.64.4712545015.82.01150845114.52.5514845211.02.899645320.93.41888645438.93.1100424557.31.4219845698.627.61510145716.41.666314587.88.13028345914.46.4134064607.36.0500004614.31.1—4623.02.2—46341.43.662214643.13.81347346518.51.8403846621.73.1871346714.12.245894683.711.427764694.537.1102754708.210.038814718.514.753114725.32.626594736.016.925227474—13.620954750.51.841724760.40.813554776.149.1500004781.70.724354792.93.739064800.61.042134810.70.822034822.111.841924835.21.6281634846.56.3500004850.81.434154861.31.031584877.111.2173984883.62.14172489—2.7457049010.3156.9923449111.549.929834925.6173.4162174937.176.439734945.582.8610649514.4186.5101064966.4104.380034972.297.243704986.5154.2951649955.031.2500005000.76.813485011.511.4806350211.947.93449503—143.55000050412.47.1474575054.42.530985064.028.46661507645.63125.02526550851.014.04863350959.85.928015101.44.6153005115.26.256245122.81.225685132.62.641385143.11.937495151.51.216755163.31.435105175.71.564135181.92.5115915193.02.437235202.83.268855212.63.948285224.56.2256145232.53.636605241.44.362345258.34.3134275264.41.824745274.41.556952830.816.5959152933.717.01020153010.57.065353233.3435.3555338.0281.1122753427.4677.0755753529.9209.014435368.415.935385372.23.365035380.512.514595391.215.132345400.41.518365410.31.816375422.356.7500005431.711.016325441.86.550085451.54.9130154671.685.3769954742.4135.060425485.530.043035491.520.7—5501.37.764135510.86.123175520.63.59955535.329.034865541.810.960935550.32.121605560.45.539245570.46.527305583125.03125.016753559634.2288.64835601308.6149.418975611.55.813275622.26.263485630.82.611335640.41.812345650.41.25495660.31.214695670.43.022355680.71.814515690.41.315655700.40.75355715.11.9123857220.330.5245385732.63.61571574—20.565705751.18.018595760.96.519145772.09.722375785.423.278595792.118.717995804.184.8508758131.51.924725820.63.625565831.012.2136155842.112.132965856.495.32559058634.684.521115874.47.973805882.410.6500005892.60.74122590172.6132.06275591180.42.05677592384.6353.6815930.716.1178559410.885.139285954.115.9143615964.312.2162775978.844.3109285985.249.663025992.910.917386006.514.1265260128.7147.9500006022.841.8—6032.150.0424046044.5132.1372706050.825.8407116060.736.1435966070.942.6443566081.855.65000060969.6243.3500006101.713.757116113.26.133826125.6174.9235361348.83125.05000061456.33125.04711061512.8470.8159561612.5607.490161732.73125.0500006189.1634.9254761919.3310.2500006200.71.35862116.3258.068096221.321.615906232.79.111066241.612.114906250.911.25546260.56.731816270.411.35872628—231.9500006290.77.431716301.18.719886313.566.9454736322.456.537917633568.13125.0500006348.731.5354836353.117.015156362.416.3244863734.01077.5429076385.8152.632216395.0140.130286401838.53125.037236410.314.910676420.214.025176430.6197.5221626444.834.757846452.8240.1500006465.7538.0500006471.3202.15000064814.71700.8500006491.610.1735565016.3931.3500006513.2260.9127376521.5157.23640065324.03125.0500006547.9603.3500006551.4115.59585656131.72533.8707657416.43125.050000658385.23125.050000659809.73125.037506601717.8268.11001661868.385.95446621.014.013496631.643.5500006642.256.959986654.177.9118476665.855.4121086673.08.645016681.236.934156669311.03125.0500006708.359.6500006712.130.3183656721.08.425196731.929.2424116741.214.46636750.814.535866767.864.616936771.943.8339786783.039.3422606790.45.211816802.725.99566815.547.711956821261.18.2778683—1.712468457.2338.4146868512.4590.1500006860.613.921726871.015.11738688—18.641366890.53.327796909.44.990169150.66.240869210.881.224156936.646.78936945.870.312886956.223.510826960.213.415476970.29.310936982.641.414346991.118.112157001.825.618447012.48.020487022.99.96587032.910.746017041.15.620137056.6217.7325017062.330.34737075.2156.8273667086.055.221107096.3357.5884671016.2290.8168937113.635.19897121.649.1305871324.4177.566267140.83.725377150.23.632577160.6117.2438167175.546.3466277183.436.7444717190.53.16167205.235.450377213.99.91907223.317.529737232.921.077137241.44.478272511.655.45000072610.735.8500007271.79.844977283.015.439037292.25.446273027.4152.8137407311.78.630257322.37.6312773310.178.2237927341.46.628627351.27.719637361.25.98127371.15.943427380.45.543127392.011.2151957401.04.7204474112.293.6500007421.09.258787430.95.124187443.713.413877450.75.114407464.512.946787473.520.062117481.814.336237490.83.513547501.35.416327512.711.6256075233.7144.7500007530.94.319237541.49.537897552.17.810197560.92.712757571.85.97827581.08.128937590.712.539977601.28.029507618.971.5500007620.98.151027632.58.147567641.410.940427650.93.411827661.311.448427670.22.724967682.312.567517691.07.317697700.77.417947711.512.322817721.730.248557731.011.933047740.55.910097750.75.617357760.45.813987770.422.649747780.317.029347791.164.871007800.48.06227781—4.33687821.66.253087830.54.130267842.36.366027851.05.8—7862.08.953427870.84.132467882.67.545757894.215.541537901.86.757427911.79.750287921.36.433777931.55.949637942.913.955887952.28.635487961.77.251417971.45.440757982.17.931467998.318.167918008.537.4166458011.810.528748023.35.856868037.610.0415318045.15.252838052.46.328308061.64.32228880711.57.1162168088.55.8598780917.310.360478106.64.336098111.113.840688121.314.437698137.814.550068141.719.851688159.246.078868164.838.1203618175.355.554168184.718.037348196.339.780318203.823.561118218.261.0227608229.844.240118236.726.9304082416.376.41693682511.534.3546882613.430.3631282715.523.7706482816.373.1127478294.832.119998306.737.895238319.568.32361583211.361.75000083313.043.91094083420.091.8175298359.933.3396883610.633.4322883710.435.75202838622.32352.4285018396.021.0557784017.082.85000084116.9112.13103784258.2342.0500008431.31.736548446.09.0236088451.41.198688461.11.3140788471.61.144308480.72.144928490.91.450178505.8206.056248511.014.3—8523.534.6108078530.53.220648540.44.9136028552.47.670428562.016.583378571.313.3169438580.82.433308590.76.833678601.724.5352908610.86.0130988620.32.913248630.42.01828640.43.530088650.23.441088661.12.83128671.14.613718680.55.620888692.011.820428700.54.731068710.76.924728720.57.228388730.88.639138741.710.97668750.46.522408764.53.9109928775.31.9162258781.82.056978792.24.951468802.01.361878812.95.060058824.731.3370528832.721.31207688412.171.75000088520.718.5150418863.411.64678872.511.618368881.04.817768892.07.64218904.924.043158910.25.25348921.67.513798931.35.011008942.31.833038951.13.310008962.49.427328971.22.223578982.212.036088993.821.222989004.119.7166429012.58.712869021.47.07079031.66.47249041.14.912399051.14.45679066.222.888549071.13.910539083.817.821929091.44.04609101.67.27899111.05.613869123.27.44399139.240.7500009140.94.214109151.14.513619161.65.519589171.14.315399181.911.235089193.821.031979203.915.215249211.410.029439223.012.432349231.66.66529243.011.919869251.07.923579265.335.228599270.96.036769281.310.6121189290.83.112899301.13.722779311.03.913179321.710.726869331.53.918149340.51.317159350.43.98759366.213.816019371.43.115329381.25.616989392.17.019629400.72.619129410.41.515209422.514.771729431.06.296109442.017.277359451.36.919549469.538.9302289472.612.4244894824.3125.91822394918.6128.9187019502.340.756889510.910.137679523.435.9279129532.313.458089541.24.021489551.810.0131729561.38.516299571.121.0500009581.39.4455795969.8186.9243509602.512.3503496116.337.750219626.012.725239634.230.9500009643.77.715229651.611.5562296614.831.830809670.85.8378096812.124.435889690.72.454297011.428.9338797120.922.326359723.915.5231197332.8134.2500009742.64.922419752.95.222239761.56.861559771.01.66049782.03.430409798.112.4115099801.93.686898116.9249.775309821.4—310698369.2258.961089840.98.447509852.459.6483298650.5335.81256987196.7384.61609881835.03125.041398974.2302.1500009901.912.125929910.51.855919922.21.714619932.05.465219949.185.413067 Inhibition Data In Vivo Mouse TLR7 PD Model: Adult male C57BL/6 mice were used for the experiments. Mice (7 to 10 per group) were randomized into different treatment groups based on body weight. Mice from the respective treatment groups were administered orally with vehicle or test compound. Thirty min after the oral administration of vehicle or test compound, mice were challenged with intraperitoneal injection of gardiquimod for TLR7 PD model. Ninety minutes after gardiquimod injection, mice were bled under isoflurane anaesthesia and plasma IL-6 and IFN-alpha levels were estimated by using commercially available ELISA kit (BD Biosciences, PBL Life Sciences). At the end of experiment, mean cytokine data was plotted and one way ANOVA with Dunnett's test was performed to calculate the significance of test compound treated group vs. vehicle control group. Percent inhibition of cytokine induction was calculated for test compound treated group vs vehicle control group. Data from multiple studies with different test compounds is shown in Table 28. TABLE 28Percent inhibition of IL-6 and IFN-alpha in mouseTLR7 PD modelEx.DoseNo.(mg/kg)% inhibition of IL6% inhibition of IFN-alpha60.00003751090.000187530310.0007556550.00364660.0158696150.00062518110.002549270.0165620.0484880.169199180.00055970.002222100.008850440.035260660.14088099250.000962220.0038539440.0154062620.0616089980.2464095100260.0006552010.00327640330.0163856680.081991990.409598100 NZB/W Model of Systemic Lupus Erythematosus (SLE): Female NZB/W mice of were screened and randomized based on the titers of anti-dsDNA antibodies and urinary NGAL (Neutrophil Gelatinase Associated Lipocalin). Mice were treated orally, once daily for 24 weeks with vehicle or test compound. The effect of test compound on disease severity was assessed by measuring end points including proteinuria, urinary-NGAL, urinary TIMP1, blood urea nitrogen (BUN), anti-dsDNA Ab titer, anti-smRNP Ab titer, and plasma levels of IL10 and IL12p40. In case of BUN the absolute increase was measured by subtracting the BUN values estimated before the initiation of treatment, from BUN values estimated after the completion of treatment. At the end of experiment, all mice were euthanized by CO2asphyxiation and kidney samples were subjected for histology. To calculate the significance of test compound treated group vs. vehicle control group, one way ANOVA with Dunnett's test was performed. Percent reduction in disease severity was calculated for each parameter, for test compound treated group vs vehicle control group. A cumulative disease score and the percent reduction in cumulative disease score was calculated by considering the average inhibition in proteinuria, urinary-NGAL, anti-dsDNA Ab titer and anti-sm Ab titer to reflect the impact on the overall severity of disease progression. Data from multiple studies with different test compounds is shown in Table 30. TABLE 30Inhibition of Disease Development by TLR7/8 Inhibitors in NZB/W Model of Lupus% inhibitionAnti-SmRAnti-dsExDoseUrinaryUrinaryNP AbDNAIL-12pCumulativeNo(mg/kg)ProteinuriaNGALTIMP1BUNtiterAb titer40IL-10score150.0696796610028206898560.2596847310048347893660.7598867210051458193702.59793801005555839775180.1987894100402375100600.598939410052338898691.599939510061438710074598939210066578910079250.5997771974149197653998073100515193987099983819865549210075309884821006862939778 | 211,525 |
RE49881 | Referring toFIGS.1and1a, a dialysis system, generally referred to as10, is shown. A dialyser12receives blood via an arterial line14connected to a patient by a vascular access device (not shown for clarity), for example a hollow needle as typically used for drawing blood from a patient. The blood is pumped from the patient to the dialyser by a peristaltic pump16. The blood passes through the dialyser in a known manner and is returned to the patient via a venous line18. The dialyser12comprises a cylindrical tube closed by opposing ends. A semi-permeable membrane (not shown) is provided within the dialyser tube and separates the patients blood from a dialysate solution. The membrane extends substantially between the opposing ends of the cylinder. The dialysate solution removes impurities from the patients blood in a known manner. The dialyser has an inlet20for receiving clean dialysate solution and an outlet22for removing spent dialysate solution from the dialyser12. The dialyser also has an inlet24for receiving untreated blood from the peristaltic pump16and an outlet26for returning processed blood to the patient. The dialyser12is typically provided in a substantially upright orientation, in use, with the patients blood flowing longitudinally through the dialyser12from the blood inlet24to the blood outlet26. The dialysate solution inlet20and dialysate solution outlet22are configured to be orientated substantially orthogonal to the blood inlet24and blood outlet26, and to provide a counter-flow. Dialysate solution is circulated through the hemodialysis machine at a fluid flow rate in the region of 400 ml/min for approximately four hours. The dialysis system defines a fluid circuit including a cartridge30as will now be described. The cartridge30is a consumable component in the hemodialysis machine described. The cartridge30is formed from an acrylic plastic such as SG-10 and has a machine side and a patient side. The cartridge30defines pump chambers which are closed by respective diaphragms, formed from, for example, DEHP-free PVC, to define respective pumps. In this embodiment, each diaphragm is part of a single, common sheet of material applied to the machine side of the cartridge30. The individual diaphragms are operable by pneumatic pressure applied thereto. A series of flow paths are formed in the cartridge30for carrying dialysate solution constituted from water, bicarbonate solution and acid solution. The flow paths are located between the sheet of material closing the machine side of the cartridge30and a further sheet of the same material closing the patient side of the cartridge30. In use, the variation of pressure applied to the flexible diaphragm of each pump chamber is controlled by conventional valving. A pressure source applies either a positive or negative pressure to one side of the diaphragm of each pump chamber, as required, to pump fluid through the fluid paths in the cartridge30, in a circuit defined by a plurality of valves. The valves of the cartridge30are conventional diaphragm valves defined by respective openings in the cartridge30and closed by respective flexible diaphragms. Each valve is operable by applying a negative pressure to the diaphragm to open the valve and applying a positive pressure to the diaphragm to close the valve. The diaphragm of each valve is part of the single, common sheet of material applied to the machine side of the cartridge30. The valves are opened and closed according to a flow control strategy, as will become apparent. The machine side of the cartridge30abuts a pump driver (not shown) comprising a platen having a plurality of recessed surfaces, each recessed surface substantially corresponding in geometry and volume to a pump chamber defined in the cartridge30. Each recessed surface has a fluid port connectable with a source of positive fluid pressure and, with a source of negative fluid pressure via a valve. The positive and negative fluid pressure sources include a pressure pump and a vacuum pump respectively. When the valve is operated to allow fluid to flow into a recessed surface from the source of positive fluid pressure, the diaphragm moves into a corresponding pump chamber and any fluid, i.e. dialysate solution, therein is expelled from that pump chamber via the series of flow paths. When the valve is operated to allow fluid to flow out of a recessed surface to the source of negative fluid pressure, the diaphragm is moved away from a pump chamber and into the corresponding recessed surface to permit fluid to be drawn into that pump chamber via the series of flow paths. The surface of the pump chambers and of the platen provide a positive stop for each diaphragm, to prevent overstretching thereof. The positive stop ensures that the volume of fluid drawn into and pumped from the pump chambers is accurately controlled. The cartridge30has two main functions, preparation of dialysate solution and flow balance. Each function is performed by a separate part of the cartridge as illustrated inFIGS.1and2by the schematic separation of the cartridge into two parts by the line A-A in the figures. The dialysate preparation function is performed by one part of the cartridge, generally referred to at34and the flow balance function is performed by the other part of the cartridge, generally referred to at36. The cartridge30prepares an accurately mixed homogenous dialysate solution and ensures that the flow of clean dialysate supplied to the dialyser12matches (to within clinical tolerances) the volume of spent dialysate drawn from the dialyser12. The cartridge30is provided with a plurality of connections to and from the cartridge30as described below. A first inlet port38, from hereon referred to as the water inlet port, defined in the machine side of the cartridge30receives purified water from a purified water supply31such as a reverse osmosis water supply. A first outlet port42, from hereon referred to as the water outlet port, defined in an edge of the cartridge30directs the purified water to a first dialysate solution constituent which, in the illustrated embodiment shown inFIGS.1and1a, is bicarbonate46. A second inlet port50, from hereon referred to as the bicarbonate inlet port, defined in the same edge of the cartridge30as the water outlet port42receives purified water mixed with the bicarbonate46. A third inlet port82, from hereon referred to as the acid inlet port, defined in the opposite edge of the cartridge30to the water outlet port42and bicarbonate inlet port50receives a second dialysate solution constituent which, in the illustrated embodiment shown inFIGS.1and1a, is acid80. A second outlet port104, from hereon referred to as the clean dialysate solution outlet port, is defined in the same edge of the cartridge as the water outlet port42and the bicarbonate inlet port50. The clean dialysate outlet port104directs clean dialysate solution to the dialyser12. A fourth inlet port106, from hereon referred to as the spent dialysate solution inlet port, is defined in the same edge of the cartridge30as the water outlet port42, bicarbonate inlet port50and clean dialysate outlet port104. The spent dialysate solution inlet port106receives spent dialysate solution from the dialyser12. A third outlet port122, from hereon referred to as the drain port, is defined in the same edge of the cartridge as the acid inlet port82. The drain port122directs spent dialysate solution out of the cartridge30. Dialysate Preparation Dialysate solution is prepared in the cartridge30by combining purified water with two dialysate constituents, namely a bicarbonate solution and an acid solution. Purified water is admitted into the cartridge30from a purified water supply31via the water inlet port38. The purified water passes through a channel40via a water inlet valve41, when open, and exits the cartridge30at the water outlet port42. From here, the purified water is carried by a tube44through a bicarbonate cartridge46in a known manner to generate a purified water and bicarbonate solution. The purified water and bicarbonate solution is carried by a tube48and re-admitted into the cartridge30via the bicarbonate inlet port50. The temperature of the bicarbonate solution is measured at sensing port52and the bicarbonate solution pressure is measured at sensing port54. The bicarbonate solution passes a bicarbonate control valve56, when open, before entering a bicarbonate solution reservoir58having an inlet and an outlet. The bicarbonate control valve56is closed when flow therethrough is not required. A bicarbonate dosing pump chamber60having an inlet and an outlet receives the bicarbonate solution from the bicarbonate solution reservoir58through a bicarbonate dosing pump inlet valve62. The bicarbonate dosing pump chamber60is closed by a diaphragm to define a bicarbonate dosing pump which, upon actuation of the diaphragm, pumps the bicarbonate solution from the bicarbonate dosing pump60to a first mixing pump chamber66(bicarbonate pump chamber). The bicarbonate dosing pump60has a bicarbonate dosing pump outlet valve64which is closed when the bicarbonate dosing pump inlet valve62is open. The bicarbonate dosing pump outlet valve64is opened to permit bicarbonate solution to be pumped to the bicarbonate pump chamber66. When the bicarbonate dosing pump outlet valve64is open, the bicarbonate dosing pump inlet valve62is closed to prevent bicarbonate solution from being pumped back into the bicarbonate solution reservoir58. The bicarbonate pump chamber66having an inlet and an outlet receives the purified water and bicarbonate solution from the bicarbonate dosing pump60via a bicarbonate pump inlet valve68. The bicarbonate pump inlet valve68, when open, can also admit purified water into the bicarbonate pump chamber66from the water inlet port38. The bicarbonate pump chamber66is closed by a diaphragm to define a pump which, upon actuation of the diaphragm, pumps the bicarbonate solution and purified water therein through a bicarbonate pump outlet valve70to a second mixing pump chamber76(acid pump). When the bicarbonate pump inlet valve68is open, the bicarbonate pump outlet valve70and water outlet valve41are closed. When the bicarbonate pump outlet valve70is open, the bicarbonate pump inlet valve68is closed to prevent the bicarbonate and purified water solution from being pumped back into channel40. From the bicarbonate pump outlet valve70, the bicarbonate and purified water solution enters a sensor channel72in which the hemodialysis machine measures the conductivity of the bicarbonate and purified water solution in a known manner. The bicarbonate and purified water solution then enters a temperature sensor74before, if the conductivity and temperature of the bicarbonate and purified water solution are within tolerance, entering the acid pump chamber76. The acid pump chamber76having an inlet and an outlet receives the bicarbonate and purified water solution from the bicarbonate pump66via an acid pump inlet valve78. The acid pump inlet valve78, when open, can also admit an acid solution into the pump chamber76. The acid pump chamber76is closed by a diaphragm to define a pump which, upon actuation of the diaphragm, pumps the acid solution, bicarbonate solution and purified water therein through an acid pump outlet valve88to the first flow balance pump chamber100. When the acid pump inlet valve78is open, the acid pump outlet valve88is closed. When the acid pump outlet valve88is open, the acid pump inlet valve78is closed. The acid solution is admitted into the cartridge30from a pre-determined supply of acid80via the acid solution inlet port82. From the acid solution inlet port the acid solution passes through an acid dosing pump chamber86via an acid dosing pump inlet valve84and an acid dosing pump outlet valve87. The acid dosing pump outlet valve87is closed when the acid dosing pump inlet valve84is open. The acid dosing pump inlet valve84is closed when the acid dosing pump outlet valve87is open. The dialysate solution exits the acid pump chamber via the acid pump outlet valve88and passes through a first dialysate solution temperature sensor90and a first dialysate solution conductivity sensor92. A second dialysate solution temperature sensor94and a second dialysate solution conductivity sensor96are provided to corroborate the data provided by the first dialysate solution temperature sensor90and the first dialysate solution conductivity sensor92. Providing the data measured by sensors90,92,94and96is within tolerance, the dialysate solution is admitted into a first flow balance pump chamber100 Flow Balance The flow balance function of the cartridge30provides first and second flow balance pump chambers100,108, each having two inlets and two outlets to define two independent flow paths therethrough. The first and second flow balance pump chambers100,108are of approximately equal volume. Either the first or second flow balance pump chamber100,108pumps dialysate solution to a dialyser12and the other of the first or second flow balance pump chambers100,108pumps dialysate solution from the dialyser12to the drain port122. After every approximately 20 strokes of the first and second flow balance pumps100,108, their function is reversed. From this point onwards, dialysate solution will be referred to as either clean dialysate solution or spent dialysate solution. Clean dialysate solution is intended to mean dialysate solution that is either new dialysate solution or clean dialysate solution that has been treated to remove waste product therefrom. Spent dialysate solution is intended to mean dialysate solution that has passed through the dialyser12to remove waste fluids from a patients blood into the dialysate solution. Each of the first and second flow balance pump chambers100,108are closed by a diaphragm to define respective pumps. The diaphragm is actuated away from a pump chamber by a negative pressure source to draw a volumetrically measured quantity of dialysate solution into the pump chamber. The diaphragm is actuated toward the pump chamber to pump the fluid therein out of an outlet. The first flow balance pump chamber100has a clean dialysate solution inlet valve98for receiving clean dialysate solution from the acid pump76and a clean dialysate solution outlet valve102for pumping clean dialysate solution to the dialyser12. The first flow balance pump chamber100also has a spent dialysate solution inlet valve118for receiving spent dialysate from the dialyser12and a spent dialysate solution outlet valve120for pumping the spent dialysate to drain via drain outlet port122. At any one time, only one of valves98,102,118or120will be open and the other three valves will be closed. The flow balance function, as described above, requires alternating the function of each flow balance pump approximately every 20 cycles. Therefore, when the first flow balance pump100is pumping clean dialysate solution to the dialyser12, only valves98and102are in use and when the first flow balance pump100is pumping spent dialysate solution from the dialyser12to drain, only valves118and120will be in use. The clean dialysate solution is pumped out of the first flow balance pump chamber100through the first flow balance pump clean dialysate solution outlet valve102, upon closure of the first flow balance pump clean dialysate inlet valve98, to the dialyser12via the dialyser outlet port104. Spent dialysate solution returns to the cartridge30from the dialyser12via the dialyser inlet port106. The second flow balance pump chamber108has a spent dialysate solution inlet valve110for receiving spent dialysate solution from the dialyser12and a spent dialysate solution outlet valve112for pumping the spent dialysate solution to drain via drain outlet port122. The second flow balance pump108also has a clean dialysate solution inlet valve114for receiving clean dialysate solution from the acid pump chamber76and a clean dialysate solution outlet valve116for pumping clean dialysate solution to the dialyser12. At any one time, only one of valves110,112,114,116will be open and the other three valves will be closed. When the second flow balance pump108is pumping clean dialysate solution to the dialyser12, only valves114and116will be in use and when the second flow balance pump108is pumping spent dialysate solution from the dialyser12to drain, only valves114and116will be in use. In the illustrated example, the operation of the first and second flow balance pumps100,108can be switched so that the first flow balance pump100is used to draw spent dialysate solution from the dialyser12and the second flow balance pump108is used to pump clean dialysate solution into the dialyser12as described below. The clean dialysate solution is drawn into the second flow balance pump chamber108from the acid pump76via the second flow balance pump clean dialysate solution inlet valve114upon actuation of the diaphragm. The clean dialysate solution is then pumped from the second flow balance pump chamber108via the second flow balance pump clean dialysate solution outlet valve116, upon closure of the clean dialysate solution inlet valve114, to the dialyser12. Spent dialysate solution from the dialyser12is drawn into the first flow balance pump100via the second flow balance pump spent dialysate solution inlet valve118. The spent dialysate solution is then pumped out of the first flow balance pump chamber100via the second flow balance pump spent dialysate solution outlet valve120, upon closure of the spent dialysate solution inlet valve118, to drain via drain outlet port122. The volume of fluid that is returned from the dialyser12is greater than the volume of fluid that is pumped to the dialyser via the first or second flow balance pump100,108. The first and second flow balance pumps have fixed volumes meaning that the excess fluid volume cannot be accommodated in the first or second flow balance pump. An ultrafiltration pump200is provided between the first and second flow balance pumps100,108and has an inlet valve210and an outlet valve212. The ultrafiltration pump200comprises a concave recess in the cartridge closed by a flexible diaphragm, the concave recess and the flexible diaphragm defining an ultrafiltration pump chamber. In use, the inlet valve210of the ultrafiltration pump200is opened to allow the ultrafiltration pump to draw in a pre-determined volume of spent dialysate solution. When the inlet valve210of the ultrafiltration pump is open, the outlet valve212of the ultrafiltration pump200is closed. When the ultrafiltration pump200has received a volume of spent dialysate solution, the outlet valve212is opened and the spent dialysate solution in the ultrafiltration pump chamber is pumped through the outlet valve212to drain via the drain outlet port122. When the outlet valve212of the ultrafiltration pump200is open, the inlet valve210of the ultrafiltration pump200is closed. FIG.2shows a representative view of a flow balance pump100according to the present invention. The flow balance pump chamber194is provided on the cartridge and is closed by a diaphragm196which, at rest, sits across the pump chamber194. The pump chamber receives either clean or spent dialysate solution via a dialysate solution inlet port210and pumps dialysate solution from the pump chamber via a dialysate solution outlet port212. The cartridge30is removably mounted into a hemodialysis machine which has a flow balance pump cavity198substantially corresponding in dimension and shape to the pump chamber194. Upon supply of positive or negative pressure via a pump cavity pressure inlet port214, the diaphragm is actuated into either the pump chamber194or pump cavity198to either draw fluid into the pump chamber194or pump fluid from the pump chamber194. Cartridge Cleaning After each use, the hemodialysis machine requires sanitising to prevent contamination of a patients bloodstream during subsequent dialysis sittings. The removable cartridge30, as described above, is usually disposed of after each sitting. In one embodiment of the invention, the cartridge30is sanitised to allow re-use in subsequent dialysis sittings. A sanitisation device188, such as a chemical cleaning receptacle, is connected to the cartridge30using the following method (seeFIGS.3a to3d):a) Connecting the spent dialysate solution inlet104to the clean dialysate solution outlet106;b) Connecting the water outlet42to the bicarbonate inlet50;c) Disconnecting the drain port122;d) Connecting the water inlet38to a purified water supply31;e) Flushing purified water through the cartridge30and out of the drain port122and out of the acid inlet82;f) Connecting the drain port122to the acid inlet82;g) Connecting a sanitisation device188between the spent dialysate solution inlet104and the clean dialysate solution outlet106;h) Flowing a liquid through the cartridge and the sanitisation device in a first direction;i) Flowing the liquid through the cartridge30in a second direction;j) Disconnecting the sanitisation device188and re-connecting the spent dialysate solution inlet104to the clean dialysate solution outlet106;k) Flushing purified water through the cartridge30and out of the drain port122and the acid inlet82;l) Disconnecting all cartridge ports104,106,42,38,122; and,m) Re-connecting the cartridge30to the hemodialysis machine10. An alternative method of cleaning the cartridge provides (SeeFIG.4):a) Connecting the spent dialysate solution inlet104, clean dialysate solution outlet106, bicarbonate inlet50, acid inlet82and water outlet42to a chemical bath190;b) Connecting the water inlet38to a purified water supply31;c) Connecting the drain port122to a drain;d) Flushing purified water through the cartridge30and out of the drain port122;e) Flowing a cleaning chemical from the chemical bath190through the cartridge130in a first direction;f) Measuring the conductivity level of the chemical to ensure that it indicates acid;g) Flowing the chemical from the chemical bath190through the cartridge30in a second direction;h) Flushing purified water through the cartridge30and out of the drain port122;i) Measuring the conductivity of the purified water to ensure that it indicates purified water;j) Disconnecting all cartridge ports104,106,50,82,42,38; and,k) Re-connecting the cartridge30to the hemodialysis machine10. The chemical bath190may be provided with a heater to heat the cleaning chemical contained therein before the cleaning chemical is flowed through the cartridge30. In another alternative method, with reference toFIG.5, the chemical bath190could be replaced by a manifold192with a chemical receptacle provided between the manifold and any one or more of the clean dialysate outlet, spent dialysate inlet, bicarbonate port, acid port and water outlet. In any of the methods of cleaning the cartridge described, the cleaning chemical is drawn through the cartridge by one or more of the acid pump, bicarbonate pump, first flow balance pump or second flow balance pump. The dialyser12, if connected to the cartridge30, can also be cleaned by the cleaning liquid to allow re-use for subsequent dialysis sessions. Cleaning fluid, when passing through the dialyser12, permeates through the semi-permeable membrane of the dialyser12and enters a blood pump (not shown) connected to the dialyser12. In this way, the membrane of the dialyser12and the blood pump are cleaned in the same manner as the cartridge30. The embodiments of the present invention, described with reference to the figures, are examples only and not exclude variations therefrom from the scope of the claims. | 23,667 |
RE49882 | In the drawings, like characters of reference indicate corresponding parts in the different figures. DETAILED DESCRIPTION InFIG.1is shown a covering material10within which is embedded steel material11and an anode body12. The covering material10is a suitable material which allows communication of ions through the covering material between the anode body12and the steel11. The covering material is generally concrete but can also include mortar or masonry materials, or soil, water or other ionically conductive material, where there is a steel structure which requires corrosion protection to prevent or inhibit corrosion. The steel material11is illustrated as being a reinforcing bar arrangement but other steel elements can be protected in the manner of the arrangement shown herein including steel structural members such as lintels, steel beams and columns, pipes, tanks or other elements in contact with the concrete or other covering material. The anode member may include or be constructed in part as the arrangement shown in U.S. Pat. No. 6,165,346 issued Dec. 26, 2000; U.S. Pat. No. 6,572,760 issued Jun. 3, 2003 U.S. Pat. No. 6,793,800 issued Sep. 21, 2004, U.S. Pat. No. 7,226,532 issued Jun. 5, 2007, U.S. Pat. No. 7,914,661 issued Mar. 29, 2011, and U.S. Pat. No. 7,959,786 issued Jun. 14, 2011 of the present inventor, and in U.S. Pat. No. 6,022,469 (Page) issued Feb. 8, 2000 and U.S. Pat. No. 6,303,017 (Page and Sergi) issued Oct. 16, 2001 assigned to Vector Corrosion Technologies and in U.S. Pat. No. 6,193,857 (Davison) issued Feb. 27, 2001 assigned to Vector Corrosion Tech., Bennett U.S. Pat. No. 6,217,742 issued Apr. 17, 2001, U.S. Pat. No. 7,160,433 issued Jan. 9, 2007, U.S. Pat. No. 8,157,983 issued Apr. 17, 2012 and U.S. Pat. No. 6,471,851 issued Oct. 29, 2002 assigned to Vector Corrosion Technologies, Giorgini U.S. Pat. No. 7,998,321 issued Aug. 16, 2011, Schwarz U.S. Pat. No. 7,851,022 issued Dec. 14, 2010, Glass et al. U.S. Pat. No. 8,211,289 issued Jul. 3, 2012, U.S. Pat. No. 8,002,964 issued Aug. 23, 2011, U.S. Pat. No. 7,749,362 issued Jul. 6, 2010, U.S. Pat. No. 7,909,982 issued Mar. 22, 2011, and U.S. Pat. No. 7,704,372 issued Apr. 27, 2010 assigned to Vector Corrosion Technologies, which are incorporated by reference and to which reference should be made for further details as required. A DC power supply14is provided which generates a voltage at terminals15and16of the power supply. In the embodiment shown the power supply is formed by a battery which may be a lead acid battery with an output of 6 or 12 volts and a lifetime of 1 to 20 weeks, or may be a zinc air battery well known and commercially available which provides an output voltage of the order of 1.5 volts and has a lifetime of the order of 3 to 5 years. The voltage may drop during current draw in operation from the nominal value of 1.5 volts to as low as 1.0 volts. Such batteries of this type are commercially available from ENSER Corporation or others. A suitable battery may have a capacity up to 1200 ampere hours. Alternative power supplies may be used including solar panels and conventional rectifiers which require an exterior AC supply voltage and which convert the AC supply into a DC voltage at the terminals15and16. The anode apparatus12includes a sacrificial anode20of zinc or other material which is less noble than the metal section together with an impressed current anode21. The sacrificial anode20is in the form of a rod and the impressed current anode21is in the form of a sleeve surrounding the rod with an ionically conductive filler material22which is generally not the ionically conductive material10located as a cylinder between the impressed current anode21and the sacrificial anode20. In this coaxial and combined structure, the impressed current anode is arranged in a radial plane of a central axis of the rod to fully surround the circumference of the sacrificial anode so that ionic current passing to or from the sacrificial anode around 360 degrees in the plane generally passes through the impressed current anode on its path to the steel11. Thus the sacrificial anode20and the impressed current anode21form common components of the anode apparatus12so that each of the sacrificial anode20and the impressed current anode21is in ionically conductive communication with the other and with the metal section. The filler material is not electrically conductive so that the impressed current anode and the sacrificial anode are electrically separated to prevent electrical communication therebetween. A switchable junction box23is provided having connectors231and232for connection to the positive and negative terminals of the power supply. The box further includes a connector233to a lead236to the impressed current anode21, a connector234to a lead237to the sacrificial anode20and a connector235to a lead238to the metal section11. Leads236,237and238are preferably wires and are preferably corrosion resistant. Lead236has the greatest need for corrosion resistance as it is connected to an impressed current anode during operation. Examples of corrosion resistant materials for the impressed current connection include titanium, niobium, nickel, platinized wires and insulated wires. The impressed current anode is perforated either with macroscopic holes211or a microscopic structure so to allow passage of ionic current from the anode20to pass through the impressed current anode. Macroscopic holes can be provided by forming the impressed current anode in separate pieces. In the arrangement where the anode21is perforated microscopically, the impressed current anode has sufficient porosity and ionically conductive material within the spaces between the impressed current anode material to allow the ionic current to pass through the impressed current anode. The ionically conductive filler material22preferably contains at least one activator to ensure continued corrosion of the sacrificial anode. The ionically conductive filler material preferably has a pH sufficiently high for corrosion of the sacrificial anode to occur and for passive film formation on the sacrificial anode to be avoided or minimized. For zinc, this pH is typically greater than 12 and may be greater than 13, 13.3 or 13.4. It is preferable that the zinc corrosion products remain partially or substantially soluble. This can be achieved by suitable pH or by incorporating ions or other chemicals which are corrosive to the sacrificial anode material and/or prevent the surface of the sacrificial anode material from passivating. Examples of materials which help to produce soluble corrosion products and/or prevent passivation are disclosed in the patent documents referenced above. The ionically conductive filler material22is also preferably highly ionically conductive, hygroscopic, and will accommodate volume changes as the sacrificial anode is charged and discharged. The ionically conductive filler material may also be porous or deformable to accommodate these changes. InFIG.6is shown a schematic illustration of the method using a second arrangement of anode apparatus in which the sacrificial anode20A and the impressed current anode21A are formed as two parallel plates, mesh, ribbon or wires with the filler material22A therebetween. In this case the recharging of the sacrificial anode may occur primarily on one side. In an alternative construction, the two parallel layers of plates or mesh may be applied to the surface of the covering material. InFIG.7is shown a schematic illustration of the method using a further arrangement of where an existing sacrificial anode40is re-charged by a temporary surface applied electrode (impressed current anode)41on an exterior surface of the concrete10forming the ionically conductive material. In this case a conductor42connects the impressed current anode41to one terminal of the power supply14and a conductor43connects the buried sacrificial anode40to the other terminal of the DC power supply. At the same time the second terminal can be connected to the steel if the protection of the steel is intended to continue during the recharging process. Although the surface applied electrode is a preferred embodiment for recharging an existing sacrificial anode, other impressed current anodes such as embedded impressed current anodes may be used. The four separate functions provided by the junction box can be performed simply as follows. These functions may also be performed manually by direct connection of the appropriate connectors without the need for a junction box. a) Normal galvanic anode as shown inFIG.2: the zinc core is connected to the steel via the junction box. The impressed current anode is set at the off position. This allows the anode to perform as a simple galvanic anode. b) Impressed current anode as shown inFIG.3: the zinc anode is set to the off position and the impressed current anode is connected to the steel via the DC power source. The current output can be regulated by controlling the applied voltage. c) Recharging of galvanic anode as shown inFIG.4: the impressed current anode is connected via the DC power source to the zinc anode. The steel is set to the off position. This allows the zinc ions or zinc corrosion products present in the electrolyte to be deposited onto the zinc core as zinc metal building up the thickness of the zinc anode. Zinc oxide, zincates and zinc hydroxide are three common corrosion products produced while the zinc anode is in operation. d) Recharging of galvanic anode and impressed current as shown inFIG.5: the impressed current anode is connected via the DC power source to both the zinc anode and the steel. This allows the re-charging process described at c) and the impressed current described at b) to proceed concurrently. The first two functions are well understood and need no further description. However the arrangement, where both options are available (and operable) concurrently is novel. The third function is novel with respect to the use of galvanic anodes for steel reinforcement protection and involves making the zinc anode cathodic allowing deposition of zinc. Zinc may be deposited from a number of zinc compounds and through various reactions and is likely to include Reactions 1, 2 and 3 if zinc is in an alkaline environment. ZnO+2OH−+H2O→Zn(OH)42−(1) Zn(OH)42−→Zn2++4OH−(2) Zn2++2e−→Zn (3) Theoretically, all the zinc oxide and other zinc ions and zinc corrosion products can be re-deposited on the core as usable zinc for subsequent consumption. In reality, as with rechargeable alkaline batteries, the level of each subsequent recharge is likely to be reduced. A typical reaction at the impressed current electrode is likely to be: 2OH−→½O2+H2O+2e−(4) or H2O→½O2+2H++2e−(5) There is therefore a net balance of the hydroxyl ions which means there is no overall loss in alkalinity within the assembly. There is a net increase in hydroxyl ions at the surface of the zinc anode which is beneficial in accommodating large amounts of the soluble zincate ions once the anode is used again, in galvanic mode, to protect the steel reinforcement. The reaction at the impressed current anode (Eq 4 or 5) involves the production of oxygen gas which needs to escape from the assembly and into the concrete pore structure. The impressed current anode, therefore, should be porous, be in the form of a net or be vented. A preferred way to employ the anode arrangement herein is to initially set it up as a normal galvanic anode, allowing it to run for a period of say 10-20 years according to exposure conditions. Occasional monitoring will determine when recharging of the anode is required. An external power supply is then used to recharge the anode over a relatively short period, preferably no more than 14-60 days. The anode is then able to produce adequate current for a further period of time, say 5-20 years. The process can be repeated several times until recharging becomes essentially ineffective. If required, the impressed current part of the anode can then be simply used as part of an impressed current corrosion protection system. Protection of the steel reinforcement could therefore be achieved for the whole life of the structure. The assembly has great flexibility which allows variable application types. For example, a preliminary use of the impressed current part of the anode can deliver an initial high level of charge over a limited period in order to passivate the steel to virtually stop any ongoing corrosion. Alternatively, the impressed current part of the anode can be operated to deliver a cumulative charge to increase the alkalinity of the concrete surrounding the steel and reduce future corrosion and current demand from the galvanic anode. Applied charge of 20,000 to 150,000 and more typically, 70,000 to 120,000 Coulombs per square meter of steel has been shown to be sufficient to passivate the steel. Applied charges of around 700,000 Coulombs/m2 have been effective at re-alkalizing (increasing the pH) of carbonated concrete. The charge required to increase the pH of concrete which is not carbonated will be less than 700,000 Coulombs/m2. This can then be followed by a lower level of galvanic current to maintain passivity of the steel. Using the impressed current anode to deliver the high initial charge is beneficial as this prevents unnecessary consumption and degradation of the sacrificial anode, allows a smaller sacrificial anode to be used and allows the sacrificial anode to provide higher current to the steel after the high initial charge has been passed to the steel by the impressed current anode. Recharging of the anodes can still be carried out if required. Furthermore, additional externally applied current can be delivered via the impressed current anode of the assembly if steel passivity is lost, if the current from the sacrificial anode is not sufficient to polarize the steel or if either the corrosion potential or the corrosion rate of the steel increases above desired levels. The sacrificial anode may be connected to the steel while the impressed current anode is polarising the steel for the purpose of reactivating or increasing the activation of the sacrificial anode. This can be achieved by increasing the alkalinity at the anode surface which can dissolve zinc oxide corrosion products into soluble zincate ions, according to equation (1), and allow them to dissipate away from the anode surface and allowing better subsequent current flow and improved performance of the anode. The current flowing to the sacrificial anode may be limited or controlled such that the sacrificial anode is reactivated without necessarily recharging the sacrificial anode. The assembly also has the capability to operate principally as an impressed current anode with a rechargeable galvanic anode backup for periods when the impressed current anode is off line or is otherwise non-functional. Similarly, the impressed current anode can be available to operate as a backup to the sacrificial anode should the sacrificial anode become non-functional. In a preferred arrangement, the inert anode may be capable of delivering a high level of current, possibly as high as 1 mA/cm2. The resistance of the electrolyte is preferably therefore as low as possible, so that a gel may be more suitable than a solid. Considerable levels of oxygen gas can be produced during charging which needs to disperse adequately through the anode walls and surrounding concrete. In order for the anode to be rechargeable, the electrolyte is preferably highly alkaline. This allows high concentrations of Zn(OH)42−in solution after the dissolution of zinc which, with supersaturation, is believed to precipitate out as ZnO. These reactions are believed to be as set out in Equations 6 and 7 below, which are essentially the reverse of Reactions 1 and 2. Zn+4OH−→Zn(OH)42−+2e−(6) Zn(OH)42−→ZnO+2OH−+H2O (7) Other electrolytes which are not highly alkaline are also suitable as long as soluble or electrochemically mobile zinc ions are present. Preferably the assembly includes sufficient moisture to be highly ionically conductive and to allow sacrificial anode ions to be mobile during charging or recharging. Humectants, gels and other hydroscopic materials can be beneficial in this regard. In an alternative arrangement, charging or recharging of sacrificial anodes can be improved by applying water or another wetting solution to at least a portion of the structure and or specifically the sacrificial anode to keep it sufficiently conductive during the charging or recharging process. Testing has shown that zinc can be deposited onto many substrates including; zinc, titanium, copper, brass, 70/30 brass, steel, stainless steel and alloys. As such, partially discharged and fully consumed sacrificial anodes can be regenerated. Example 1 In one example, a cast zinc anode, 8 cm long with a minimum diameter of 0.7 cm, was located in ZnO/thixotropic paste packed inside a conductive ceramic impressed current anode tube. The zinc paste was made from a solution saturated with LiOH with 2M KOH and 20% ZnO along with carboxymethyl cellulose sodium gelling agent. The paste was packed in the space between the zinc anode and the inner side of the 28 mm tube. Testing has shown that ions can pass through the porous tube walls such that the zinc anode can pass current onto the external steel reinforcing bar even though it is located inside the impressed current anode. Subsequently, charging of the zinc can be accomplished by reversing the flow of ions through the impressed current porous tubular anode by applying an external voltage between the impressed current anode and the sacrificial anode. An applied voltage of around 6-8 Volts resulted in a current of up to 1.6 A to be delivered to the inner zinc anode achieving a total charge/recharge of just under 40,000 Coulombs. Surprisingly, the zinc anode performed better after recharging than it did originally. After charging of the zinc anode, when the zinc anode was reconnected to the steel, the current output and cumulative charge output of the recharged zinc anode through the porous tubular impressed current anode to the steel is increased compared to the original zinc anode. The reasons for this improvement in performance are not fully understood but may relate to an increased surface area of the zinc metal after deposition or to the relative increase of hydroxyl ions at the immediate vicinity of the zinc surface which encourages dissolution of zinc and zinc corrosion products such as zinc oxide and deposition of zinc from zinc corrosion products such as zincate ions (equations 1-3). It is evident, nonetheless, that the current output of the anode after charging is increased. InFIG.8shows an example of an anode apparatus30as previously described where the apparatus includes a Cast Zinc Core31inside a 28 mm diameter porous conductive impressed current anode32. An upper end is closed by an attached disk33forming a porous form and a lower end is closed by a Porous Fabric Cap36. Between the core31and the cylindrical anode32is provided a filler material of LiOH+2M KOH+20% ZnO+carboxymethyl cellulose sodium35. The core is attached to a steel wire34for connection as described above. FIG.9is a graph of current output of the anode ofFIG.8to steel, a) with the anode as originally made, b) with the anode after a period of charging via the porous conductive impressed current anode. FIG.10is a graph of cumulative charge output of the anode to steel, a) with anode as originally made, b) after a period of charging via the porous conductive tube. Example 2 An assembly49to demonstrate the ability to charge/recharge an anode in situ was constructed as shown inFIG.11. It consisted of a zinc wire50partly immersed in a highly alkaline (7 molar OH—) gel51. A copper wire connector53for the sacrificial anode to be formed in situ was also immersed in the same gel. The gel was contained within a perforated plastic tube54lined both internally and externally by a layer of fibre fabric55and ionically conductive membrane acting as a separator of the anode and cathode56. Between the external fabric and the tube a mixed metal oxide (MMO) coated titanium mesh57was fixed circumferentially and had a titanium connection wire58attached to one side. The whole assembly was encased in a mortar59enriched with LiOH. The anode assembly49was cast centrally in a cement mortar prism approximately 80 mm×50 mm×40 mm high ensuring that the whole assembly was encased within the cement mortar59. As shown inFIG.12, the prism was then placed in a larger container61filled almost to the height of the prism with an alkaline solution60. An external mesh62of MMO coated titanium was placed along the periphery of the container to act as the metal section. The zinc wire50was connected electrically to the external titanium mesh62. The assembly49was then seen to act as a galvanic anode passing current to the external titanium mesh (metal section) and producing zinc corrosion products until all available zinc was consumed. An external power supply (not shown) was then connected to the internal MMO coated titanium mesh anode57within the anode assembly49and the copper wire53ensuring that the copper was cathodic. Zinc corrosion products from the consumed (corroded) zinc wire50were deposited on the copper wire53to form a sacrificial anode during this charging process. Subsequent connection of the copper wire53, now carrying the deposited zinc and the external MMO coated titanium mesh (metal section) allowed current to pass between the charged anode53and the metal section62. The current produced by the charged anode (copper wire with deposited zinc) was comparable to the current produced by the original zinc wire. Comparison of current produced by the original ‘discharge’ of the zinc wire and the zinc which was deposited on the copper wire is shown in Table 1. TABLE 1Current output of original zinc wireand deposited zinc on copper wireCurrent output (mA)MaximumMinimumMeanOriginal zinc wire5.470.050.70Deposited zinc on5.200.050.51Copper Wire Turning now toFIGS.13and14, a sacrificial anode100and an impressed current anode101are provided in the ionically conductive covering material102where a DC power supply107is connected across the sacrificial anode and impressed current anode. This provides a recharging phase which can be carried out during cathodic protection where the sacrificial anode is connected to the steel108or as a separate step. Movement of moisture towards the sacrificial anode100from the impressed current anode101is obtained during the recharge phase. This is believed to be by the process of electro-osmosis. A simple experiment, as depicted inFIG.13, demonstrated measurable water movement from the negatively charged electrode101to the positively charged electrode100embedded in the high alkalinity mortar102, the latter100representing the sacrificial anode material during recharge. Item103represents a perforated plastic tube at the anode101. Added water104was detected at the second plastic tube105. Table 2 below andFIG.14summarise the increase in volume of water observed with time of the recharged anode at a current of 1.5 mA. This application of current thus results in water movement which can replenish the electrolyte around the anode and facilitate better deposition of zinc metal during recharge. TABLE 2Moisture movement with time at an applied current of 1.5 mAbetween two electrodes embedded in a highly alkaline mortar.Current output (1.5 mA)Difference inVolume of waterRequired Driveheight of waterwhich migratesVoltage tolevel in twoduring applicationTimemaintain currentcompartmentsof recharge current(days)(V)(mm)(ml)01.940012.230.50.0362.1930.19222.0470.44281.987.50.47 Also shown inFIG.13is a separator106in the form of a microporous ionically conductive membrane, which is used primarily to limit or avoid dendritic growth of the sacrificial material (zinc metal) during recharge, to restrict zinc deposition to within the contained volume encased by the separator while allowing moisture movement and ionic conductivity through its pores. It is desirable that the pore size and pore distribution of the separator are such that it optimises movement of moisture. It is preferable that it restricts movement of moisture out of the anode-encasing electrolyte into the bulk surrounding electrolyte but allows the beneficial electro-osmotic movement of moisture back into the anode-encasing electrolyte during charging. As explained previously, the potential difference across the anodes100,101causes ions of the sacrificial anode material to move to the sacrificial anode100. Additives109are provided in the structure at or adjacent the anode100which acts to limit gassing from the sacrificial anode. The additives can be a surfactant, a form of cellulose or can comprise alloying zinc metal with suitable elements such as nickel or indium which is arranged to reduce the hydrogen over-potential significantly and hence limit hydrogen gassing. The membrane106acts for restricting dendritic growth of sacrificial anode material on the sacrificial anode. The membrane separator106is located around or adjacent to the sacrificial anode and acts to contain sacrificial material at the sacrificial anode, to avoid dendritic growth of sacrificial anode material on the sacrificial anode beyond the membrane and to allow moisture movement to the sacrificial anode. In order to provide ions for communication to the anode100, particles or powder110of sacrificial anode material or sacrificial anode corrosion products are provided alone or intermixed with an ionically conductive filler material111at or adjacent the sacrificial anode. As explained previously the potential difference caused by the DC power supply107causes an increase in the galvanic current generated by the sacrificial anode subsequent to application of the potential difference relative to that before the application. Also this action acts to increase alkalinity at the surface of the sacrificial anode where the increased alkalinity acts to dissolve zinc oxide corrosion products into soluble zincate ions and allow them to dissipate away from the surface. The DC power supply is in some cases arranged so as to limit current flowing to the sacrificial anode by the potential difference such that the sacrificial anode is reactivated without recharging the sacrificial anode with additional ions of the sacrificial material. The application of the DC power supply causes water movement from the negatively charged impressed current anode to the positively charged sacrificial anode. This also can cause an increase in a total surface area of the sacrificial anode material at the sacrificial anode. This can also result in increased quantity of hydroxyl ions at the immediate vicinity of the sacrificial anode. | 26,974 |
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