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Title:
METHODS OF LOWERING MIRO2 TO TREAT NEURODEGENERATIVE DISEASES
Document Type and Number:
WIPO Patent Application WO/2024/081653
Kind Code:
A2
Abstract:
Disclosed herein are methods of reducing Miro2 level, for example, in a cell by contacting the cell with a Miro2 reducer and/or Miro2-reducing agent. For instance, the method can comprise contacting the cell with an effective amount of a T-type calcium channel antagonist.

Inventors:
PINTCHOVSKI SEAN (US)
SHRADER WILLIAM D (US)
Application Number:
PCT/US2023/076480
Publication Date:
April 18, 2024
Filing Date:
October 10, 2023
Export Citation:
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Assignee:
ACUREX BIOSCIENCES CORP (US)
International Classes:
G01N30/72; G16H20/10
Attorney, Agent or Firm:
HOM, Roy K. et al. (US)
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Claims:
WHAT IS CLAIMED IS: 1. A method to determine the Miro2 status of a subject comprising measuring the Miro2 response to mitochondrial depolarization using mass spectrometry, immunocytochemistry (ICC), immunohistochemistry (IHC), flow cytometry, biochemical assays, western blotting or ELISA, to determine if a subject is deficient in the removal of Miro2 following depolarization, wherein a subject deficient in the removal of Miro2 following depolarization is selected for treatment by administration of a Miro2 reducer. 2. The method of claim 1, comprising detecting Miro2 level in the subject, and comparing the Miro2 level to a control Miro2 level from a control subject. 3. The method of claim 2, wherein the detecting Miro2 level comprises ELISA. 4. The method of claim 2, wherein the detecting Miro2 level comprises detecting Miro2 in a sample in the subject. 5. The method of claim 4, wherein the sample comprises a skin cell. 6. The method of claim 2, wherein the Miro2 level in the subject is higher than the control Miro2 level from a control subject. 7. The method of claim 2, wherein the Miro2 level in the subject is about 20% or more than the control Miro2 level from a control subject. 8. The method of claim 5, comprising diagnosing the subject with a neurodegenerative disorder. 9. The method of claim 8, wherein the neurodegenerative disorder is Parkinson’s disease. 10. The method of claim 2, further comprising treating the subject with the Miro2 reducer. 11. The method of claim 10, further comprising monitoring Miro2 levels before and after treatment with the Miro2 reducer.

12. A method of treating a neurodegenerative disorder comprising administering to a subject in need thereof a Miro2-reducing agent. 13. The method of claim 12, wherein the Miro2-reducing agent reduces Miro2 in Parkinson’s disease cells with depolarized mitochondria as compared to reduction of Miro2 in control depolarized Parkinson’s disease cells with depolarized mitochondria not contacted with the Miro2-reducing agent. 14. The method of claim 13, wherein the Parkinson’s disease cells with depolarized mitochondria are Parkinson’s disease cells contacted with a mitochondrial depolarizing agent. 15. The method of claim 13, wherein the Parkinson’s disease cells are Parkinson’s disease cells. 16. The method of claim 13, wherein the Parkinson’s disease cells are fibroblasts. 17. The method of claim 12, wherein the Miro2-reducing agent reduces Miro2 in the following assay: (a) fibroblast cells from a Parkinson’s disease patient are plated into wells of an array; (b) 24 hours after step (a), a candidate agent is added to a test well and the candidate agent is not added to a control well; (c) 10 hours after step (b), FCCP is added to the test well and control well; 14 hours after step (c) cells of the test well and control well are fixed with ice- cold 90% methanol; and (d) the cells of the test well and control well are immunostained with anti- Miro2 and 4’,6-diamidino-2-phenylindole, dihydrochloride (DAPI) and imaged with a confocal microscope to measure Miro2 intensity/cell for those images of the test well and control well; wherein when the candidate agent reduces Miro2 in the test well relative to the control well, the candidate agent is a Miro2-reducing agent.

18. The method of claim 12, wherein the Miro2-reducing agent has a molecular weight of from 200 to 2000 Daltons. 19. The method of claim 12, wherein the Miro2-reducing agent is a T-type calcium channel antagonist. 20. The method of claim 12, wherein the subject has at least about 20% or more, or about 30% or more Miro2than a control subject. 21. The method of claim 12, wherein the neurodegenerative disorder is Parkinson’s disease. 22. A method for selecting a subject for treatment with a therapeutic agent for a neurodegenerative disorder, comprising: (a) collecting cells from the subject and evaluating a first control portion of the cells for the pre-depolarization Miro2 level in the cells; (b) contacting a second test portion of the cells with a depolarizing agent; and (c) evaluating the post-depolarization Miro2 level in the second test portion of cells contacted with the depolarizing agent and comparing the Miro2 level to the pre-depolarization Miro2 level in the first control portion of cells; wherein when the post-depolarization Miro2 level in the second test portion of cells is reduced by 40% or less relative to the pre-depolarization Miro2 level in the first control portion of cells, the subject is treated with a therapeutic agent for neurodegenerative disorder. 23. The method of claim 22, wherein when the post-depolarization Miro2 level in the second test portion of cells is reduced by 10% to 50% relative to the pre- depolarization Miro2 level in the first control portion of cells, the subject is treated with a therapeutic agent for neurodegenerative disorder. 24. The method of claim 23, wherein the neurodegenerative disorder is Parkinson’s disease. 25. The method of claim 22, wherein the therapeutic agent is a Miro2- reducing agent.

26. The method of any one of claims 1 to 25, wherein the Miro2reducer and/or Miro2-reducing agent is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are each independently C6-C10 aryl or 5- to 10-membered heteroaryl; R1, R2, and R3 are each independently H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R4a and R4b are each independently H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6a and R6b are each independently H or C1-C6 alkyl; R7 is H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2- C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R8 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R9 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; and each R11, R12a, and R12b is independently H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN. 27. The method of any one of claims 1 to 25, wherein the Miro2reducer and/or Miro2-reducing agent is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein ring B is C6-C10 aryl or 5- to 10-membered heteroaryl; R1, R2, and R3 are each independently H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, -(CH2)n-(C3-C7 cycloalkyl), 4- to 7-membered heterocyclyl, or -(CH2)n-(4- to 7-membered heterocyclyl), wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R4a and R4b are each independently H or C1-C6 alkyl, or R4a and R4b and the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6 is H, C1-C6 alkyl, or C1-C6 haloalkyl; X1 and X5 are each independently N or CR8, provided that at least one of X1 and X5 is CR8; X2, X3, and X4 are each independently N, NR9, O, S, or CR9, provided that at least one of X2, X3, and X4 is N, NR9, O, or S; R8 is H, halogen, CN, OR11, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C1-C6 haloalkyl; R9 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; each R11, R12a, and R12b is independently H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN; and n is 1, 2, or 3; provided that the compound does not have the structure: , or a pharmaceutically acceptable salt thereof. 28. The method of claim 27, wherein X1 is CR8. 29. The method of claim 27 or 28, wherein R8 is H. 30. The method of any one of claims 27 to 29, wherein X2, X3, and X4 are each independently N, NR9, or CR9, provided that at least one of X2, X3, and X4 is N or NR9. 31. The method of any one of claims 27 to 30 having the structure of Formula (III): or a pharmaceutically acceptable salt thereof. 32. The method of any one of claims 27 to 31, wherein R1, R2, and R3 are each independently H, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, or C3-C7 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1- C6 haloalkyl. 33. The method of any one of claims 27 to 32, wherein R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, or C3-C7 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl. 34. The method of any one of claims 27 to 33, wherein R1 and R2 are each independently H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkoxyalkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1, 2, or 3 halogen, CN, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, or C1-C3 haloalkyl. 35. The method of any one of claims 27 to 34, wherein R4a and R4b are each independently H or CH3. 36. The method of any one of claims 27 to 35, wherein R6 is H or C1-C3 alkyl. 37. The method of any one of claims 27 to 36, wherein R6 is CH3. 38. The method of any one of claims 27 to 37 having the structure of Formula (IV): or a pharmaceutically acceptable salt thereof. 39. The method of any one of claims 27 to 38, wherein R9 is C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl. 40. The method of any one of claims 27 to 39, wherein R9 is C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 4- to 7- membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl. 41. The method of any one of claims 27 to 40, wherein ring B is phenyl or 5- to 6-membered heteroaryl. 42. The method of any one of claims 27 to 41, wherein ring B is phenyl or pyridyl. 43. The method of any one of claims 27 to 42 wherein the compound has the structure of Formula (V): or a pharmaceutically acceptable salt thereof. 44. The method of any one of claims 27 to 43 wherein the compound has the structure of any one of the compounds in Table 1 or Table 2. 45. A method of reducing Miro2 level in a cell, the method comprising contacting the cell with an effective amount of a T-type calcium channel antagonist.

46. The method of claim 45, wherein the T-type calcium channel antagonist has selectivity for a T-type calcium channel of at least about 1.2-fold or more over one or more of L-type, N-type, P-type, and/or R-type calcium channels. 47. The method of claim 45, wherein the T-type calcium channel antagonist has the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein ring B is C6-C10 aryl or 5- to 10-membered heteroaryl; R1, R2, and R3 are each independently H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, -(CH2)n-(C3-C7 cycloalkyl), 4- to 7-membered heterocyclyl, or -(CH2)n-(4- to 7-membered heterocyclyl), wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R4a and R4b are each independently H or C1-C6 alkyl, or R4a and R4b and the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6 is H, C1-C6 alkyl, or C1-C6 haloalkyl; X1 and X5 are each independently N or CR8, provided that at least one of X1 and X5 is CR8; X2, X3, and X4 are each independently N, NR9, O, S, or CR9, provided that at least one of X2, X3, and X4 is N, NR9, O, or S; R8 is H, halogen, CN, OR11, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C1-C6 haloalkyl; R9 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; each R11, R12a, and R12b is independently H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7- membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN; and n is 1, 2, or 3. 48. The method of any one of claims 45 to 47, wherein the T-type calcium channel antagonist has the structure of Formula (III): or a pharmaceutically acceptable salt thereof. 49. The method of any one of claims 45 to 48, wherein the T-type calcium channel antagonist has the structure of Formula (IV): or a pharmaceutically acceptable salt thereof. 50. The method of any one of claims 45 to 49, wherein the T-type calcium channel antagonist has the structure of Formula (V): or a pharmaceutically acceptable salt thereof. 51. The method of any one of claims 45 to 50, wherein the cell is a muscle cell.

52. The method of any one of claims 45 to 51, wherein the cell is a neuronal cell. 53. The method of any one of claims 45 to 52, wherein the reducing Miro2 level is in vitro or ex vivo. 54. The method of any one of claims 45 to 52, wherein the reducing Miro2 level is in vivo. 55. A method for identifying a subject at risk of developing a Miro2- related disorder, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; and b) identifying the subject at risk of developing a Miro2-related disorder if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; wherein the biological sample and the control biological sample comprise iPSCs or cells differentiated from iPSCs. 56. The method of claim 55, wherein the ratio of the Miro2 level to the control Miro2 level is from about 0.5 to about 10. 57. The method of claim 55, wherein the ratio of the Miro2 level to the control Miro2 level is from about 0.7 to about 4. 58. The method of claim 55, wherein the mitochondrial stressor comprises antimycin A or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). 59. A method for identifying a subject at risk of developing a Miro2- related disorder, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; b) identifying the subject at risk of developing a Miro2-related disorder if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; and c) treating the subject at risk of developing a Miro2-related disorder by administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are each independently C6-C10 aryl or 5- to 10-membered heteroaryl; R1, R2, and R3 are each independently H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R4a and R4b are each independently H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6a and R6b are each independently H or C1-C6 alkyl; R7 is H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2- C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R8 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R9 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; and each R11, R12a, and R12b is independently H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN or pharmaceutically acceptable salt thereof. 60. The method of claim 59, wherein the ratio of the Miro2 level to the control Miro2 level is from about 0.5 to about 10. 61. The method of claim 59, wherein the ratio of the Miro2 level to the control Miro2 level is from about 0.7 to about 4. 62. The method of claim 59, wherein the mitochondrial stressor comprises antimycin A or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). 63. The method of claim 59, wherein the biological sample and the control biological sample comprise fibroblasts. 64. A method for treating a neurodegenerative disorder in a subject in need thereof, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; b) identifying the subject for treatment if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; and c) administering a therapeutically effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are each independently C6-C10 aryl or 5- to 10-membered heteroaryl; R1, R2, and R3 are each independently H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R4a and R4b are each independently H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6a and R6b are each independently H or C1-C6 alkyl; R7 is H, halogen, CN, OR11, NR12aR12b, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2- C6 alkenyl, C2-C6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR11, NR12aR12b, C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R8 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; R9 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, or C1-C6 haloalkyl; and each R11, R12a, and R12b is independently H, C1-C6 alkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 7- membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN or pharmaceutically acceptable salt thereof to the subject. 65. The method of claim 64, wherein the ratio of the Miro2 level to the control Miro2 level is from about 0.5 to about 10.

66. The method of claim 64, wherein the ratio of the Miro2 level to the control Miro2 level is from about 0.7 to about 4. 67. The method of claim 64, wherein the mitochondrial stressor comprises antimycin A or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). 68. The method of claim 64, wherein the biological sample and the control biological sample comprise fibroblasts. 69. The method of any one of claims 64 to 68, wherein the neurodegenerative disorder is Drug-induced Parkinsonism, Progressive supranuclear Palsy, Vascular Parkinsonism, Dementia with Lewy Bodies, diffuse Lewy body disease, Corticobasal degeneration, multisystem degeneration (Shy-drager syndrome), Parkinson’s disease, Alzheimer's disease, Pick's disease, frontotemporal dementia, multiple systems atrophy, vascular dementia, or progressive supranuclear palsy (Steel-Richardson syndrome). 70. The method of any one of claims 64 to 69, wherein the subject is asymptomatic for the neurodegenerative disorder.
Description:
METHODS OF LOWERING MIRO2 TO TREAT NEURODEGENERATIVE DISEASES CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to US provisional appl. no.63/379,228, filed October 12, 2022, which is incorporated by reference herein in its entirety for all purposes. BACKGROUND [0002] Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. Defects in the key features of mitochondrial dynamics, such as mitochondrial fusion, fission, transport and mitophagy are associated with neurodegenerative disorder. Several major neurodegenerative disorders—including Parkinson’s, Alzheimer’s and Huntington’s disease—involve disruption of mitochondrial dynamics. [0003] Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Mitochondrial motility ceases prior to the initiation of mitophagy, a crucial cellular mechanism by which depolarized mitochondria are degraded through autophagosomes and lysosomes. The arrest of motility may sequester damaged mitochondria, preventing them from moving and from reintroducing damage to other healthy mitochondria. [0004] Miro is an outer mitochondrial membrane (OMM) protein that anchors the microtubule motors kinesin and dynein to mitochondria (Glater et al., “Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent,” The Journal of cell biology, 2006,173:545–557; and Koutsopoulos et al., “Human Miltons associate with mitochondria and induce microtubule-dependent remodeling of mitochondrial networks,” Biochimica et biophysica acta, 2010,1803:564–574). This depolarization- triggered mitochondrial arrest is achieved by removal of Miro from the damaged mitochondrial surface (Wang et al., “PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility,” Cell, 2011,147:893–906). Miro is subsequently degraded by proteasomes (Wang et al., 2011). Evidence has shown that two PD-linked proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin, act in concert to target Miro for degradation (Ashrafi et al., “Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin,” The Journal of cell biology, 2014,206:655– 670; Liu et al., “Parkinson’s disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria,” PLoS genetics, 2012,8:e1002537; and Wang et al., 2011). Mutations in PINK1 or Parkin are tied to rare forms of recessive early-onset PD. [0005] Altered mitochondrial transport is one of the pathogenic changes in major adult- onset neurodegenerative diseases (Sheng ZH, Cai Q, “Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration,” Nat Rev Neurosci, 2012 Jan 5;13(2):77-93). In mutant LRRK2GS2019 cells, the mitochondrial outer membrane protein Miro is stabilized and remains on damaged mitochondria for longer than normal, prolonging active transport and inhibiting mitochondrial degradation (Hsieh et al., “Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease,” Cell Stem Cell, 2016 Dec 1;19(6):709-724). Miro degradation and mitochondrial motility are also impaired in sporadic PD patients (Hsieh et al., 2016). Prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis. [0006] Two Miro GTPases, named as Miro1 and Miro2, are encoded by the RHOT1 gene located on chromosome 17 and RHOT2 gene located on chromosome 16, respectively. Miro1 and Miro2 are both ubiquitously expressed, consisting of 662 amino acid residues, and display a 60% peptide sequence homology. Miro GTPases are conserved in almost all eukaryotes containing mitochondria. Genetic screening suggests that Miro1 and Miro2 may be candidates for treating Parkinson’s disease. See, Anvret, et al. Open Neurology Journal 2012, 6: 1-5. To date, it is unknown whether increased activity or levels of Miro1, Miro2, or a combination of Miro1 and Miro2, in a patient in comparison with a control individual gives rise to the altered mitochondrial transport leading to neurodegenerative disorders in humans. [0007] T-type voltage-dependent calcium channels or T-type calcium channels are low voltage activated calcium channels that become deinactivated during cell membrane hyperpolarization but then open to depolarization. There are three known T-type calcium channel subtypes: Cav3.1, Cav3.2, and Cav3.3. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. T-type calcium channels are present within cardiac and smooth muscle, as well as in many neuronal cells within the central nervous system. [0008] T-type calcium channel antagonists have been reported to be able to reduce Miro1 levels in a Parkinson’s disease fibroblast assay. See, WO 2022/216386, page 203, Table 6. [0009] There is a need for novel compounds and methods to reduce Miro2 level in a cell, for example, for treating neurodegenerative disease such as Parkinson’s disease. BRIEF SUMMARY [0010] In some embodiments, a method of the present disclosure is a method to determine the Miro2 status of a subject comprising measuring the Miro2 response to mitochondrial depolarization using mass spectrometry, immunocytochemistry (ICC), immunohistochemistry (IHC), flow cytometry, biochemical assays, western blotting or ELISA, to determine if a subject is deficient in the removal of Miro2 following depolarization, wherein a subject deficient in the removal of Miro2 following depolarization is selected for treatment by administration of a Miro2 reducer. [0011] In some embodiments, a method of the present disclosure is a method of treating a neurodegenerative disorder comprising administering to a subject in need thereof a Miro2- reducing agent. [0012] In some embodiments, a method of the present disclosure is a method for selecting a subject for treatment with a therapeutic agent for a neurodegenerative disorder, comprising: (a) collecting cells from the subject and evaluating a first control portion of the cells for the pre-depolarization Miro2 level in the cells; (b) contacting a second test portion of the cells with a depolarizing agent; and (c) evaluating the post-depolarization Miro2 level in the second test portion of cells contacted with the depolarizing agent and comparing the Miro2 level to the pre-depolarization Miro2 level in the first control portion of cells; wherein when the post-depolarization Miro2 level in the second test portion of cells is reduced by 40% or less relative to the pre-depolarization Miro2 level in the first control portion of cells, the subject is treated with a therapeutic agent for neurodegenerative disorder. [0013] In some embodiments, a method of the present disclosure is a method of reducing Miro2 level in a cell, the method comprising contacting the cell with an effective amount of a T-type calcium channel antagonist. [0014] In some embodiments, a method of the present disclosure is a method for identifying a subject at risk of developing a Miro2-related disorder, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; and b) identifying the subject at risk of developing a Miro2-related disorder if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; wherein the biological sample and the control biological sample comprise iPSCs or cells differentiated from iPSCs. [0015] In some embodiments, a method of the present disclosure is a method for identifying a subject at risk of developing a Miro2-related disorder, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; b) identifying the subject at risk of developing a Miro2-related disorder if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; and c) treating the subject at risk of developing a Miro2-related disorder by administering a therapeutically effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are each independently C 6 -C 10 aryl or 5- to 10-membered heteroaryl; R 1 , R 2 , and R 3 are each independently H, halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 4a and R 4b are each independently H or C 1 -C 6 alkyl; R 5 is H or C 1 -C 6 alkyl; R 6a and R 6b are each independently H or C 1 -C 6 alkyl; R 7 is H, halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR 11 , NR 12a R 12b , C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; and each R 11 , R 12a , and R 12b is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN, or pharmaceutically acceptable salt thereof. [0016] In some embodiments, a method of the present disclosure is a method for treating a neurodegenerative disorder in a subject in need thereof, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; b) identifying the subject for treatment if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; and c) administering a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof, to the subject. BRIEF DESCRIPTION OF THE DRAWINGS [0017] FIG.1 shows the effect of Compound 1 in Parkinson’s disease patient N370S GBA iPSC-derived dopaminergic neurons. N370S GBA iPSC DA neurons exhibited a Miro1 and Miro2 retention phenotype in response to mitochondrial stress. Compound 1 rescued Miro1 and Miro2 retention in the neurons. DETAILED DESCRIPTION [0018] The present disclosure provides for, inter alia, methods of reducing a Miro2 level in a cell comprising administering a Miro2 reducer and/or Miro2-reducing agent, such as a selective T-type voltage-dependent calcium channel antagonist of Formula (I) or pharmaceutically acceptable salt thereof. Accordingly, a selective T-type voltage-dependent calcium channel antagonist, or a mixed selectivity calcium channel antagonist that has T-type antagonist activity, may be useful in reducing a Miro2 level in diseases or conditions that would benefit from the reduction of a Miro2 level in a cell, for example, a neuronal cell. Such diseases or conditions include neurodegenerative diseases, such as Parkinson’s disease. See, Examples 1 and 60-62. In an illustrative embodiment, Compound 1 of Example 1 has been shown to reduce Miro1 and/or Miro2 in iPSC-derived dopaminergic neurons from Parkinson’s disease patients. See, Example 61. Therefore, a compound of Formula (I) is capable of reducing a Miro2 level in a cell, and may be useful in treating neurodegenerative diseases such as Parkinson’s disease. [0019] Further provided is a method of identifying a subject at risk of developing a Miro2- related disorder, by measuring a Miro2 level from the subject’s biological sample, that had been treated with a mitochondrial stressor, in comparison with a control Miro2 level measured from a corresponding untreated biological sample. Miro2-related disorders include any of the neurodegenerative disorders described herein, for example, Parkinson’s disease. I. DEFINITIONS [0020] 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. [0021] “Miro2 reducer” or “Miro2-reducing agent”, refers to any agent that decreases the level of a Miro2 nucleic acid, e.g., a Miro2 RNA or a Miro2 DNA, and/or a Miro2 protein in cells. In an exemplary embodiment, a Miro2-reducing agent may decrease at least one biological activity of a Miro2 protein in a cell with depolarized mitochondria. Exemplary biological activities of Miro2 include promoting mitochondrial transport, mitophagy, microtubule binding, mitochondrial fission and fusion among others. A Miro2-reducing agent can be, for example, a small molecule, a peptide, an aptamer, a protein or a functional fragment of a protein. A functional fragment of a protein, as used here, refers to all or part of the molecular elements of a protein which affect a specified function such as protein binding, signal transduction etc. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent is a compound of the present disclosure, e.g., a compound of Formula (II), or pharmaceutically acceptable salt thereof. [0022] “Alkyl” is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 18 carbon atoms (i.e., C 1-18 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t- Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1- butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (- CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), and 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 )3. Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadcyl, hexadecyl, heptadecyl and octadecyl. [0023] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted. [0024] “Alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 . Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted. [0025] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C 1-6 . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted. [0026] “Alkoxyalkyl” refers an alkoxy group linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. Alkoxyalkyl can have any suitable number of carbon, such as from 2 to 6 (C 2-6 alkoxyalkyl), 2 to 5 (C 2-5 alkoxyalkyl), 2 to 4 (C 2-4 alkoxyalkyl), or 2 to 3 (C 2-3 alkoxyalkyl). The number of carbons refers to the total number of carbons in the alkoxy and the alkyl group. For example, C 6 alkoxyalkyl refers to ethoxy (C 2 alkoxy) linked to a butyl (C 4 alkyl), and n-propoxy (C 3 alkoxy) linked to a isopropyl (C 3 alkyl). Alkoxy and alkyl are as defined above where the alkyl is divalent, and can include, but is not limited to, methoxymethyl (CH 3 OCH 2 -), methoxyethyl (CH 3 OCH 2 CH 2 -) and others. [0027] “Halo” or “halogen” as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I). [0028] “Haloalkyl” as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent, which may be the same or different. For example, C 1-4 haloalkyl is a C 1-4 alkyl wherein one or more of the hydrogen atoms of the C 1-4 alkyl have been replaced by a halo substituent. Examples of haloalkyl groups include but are not limited to fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl. [0029] “Cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms. The term “cycloalkyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1- cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl. [0030] “Heterocyclyl” or “heterocycle” or “heterocycloalkyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a multiple ring system having at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur) wherein the multiple ring system includes at least non-aromatic ring containing at least one heteroatom. The multiple ring system can also include other aromatic rings and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has from 3 to 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from 1 to 6 annular carbon atoms and from 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The heteroatoms can optionally be oxidized to form –N(-OH)- , =N(-O-)-, -S(=O)- or –S(=O) 2 -. The rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6- azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6- yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3- azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4- azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like. [0031] “Aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like. [0032] “Heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from 1 to 6 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8- naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has 1-20 carbon atoms and 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It also to be understood that when a reference is made to a certain atom-range membered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl. [0033] Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium. [0034] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (II), can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. [0035] A “compound of the disclosure” includes compounds described herein, for example a compound of the disclosure includes compounds of Formula (I), (II), (III), (IV), and (V), including the compounds of the Examples. [0036] “Composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and deleterious to the recipient thereof. [0037] “Pharmaceutically effective amount” refers to an amount of a compound of the present disclosure in a formulation or combination thereof, that provides the desired therapeutic or pharmaceutical result. [0038] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. [0039] “Treatment” or “treat” or “treating” as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In some embodiments, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. [0040] “Therapeutically effective amount" or “effective amount” as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount can vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co- administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds. [0041] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors. [0042] “Co-administration” as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient. [0043] “Subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human. In some embodiments, the subject is a patient. [0044] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. [0045] Mitochondrial stress can be caused by various insults from environment (e.g., radiation, toxic chemicals), genetic mutations (e.g., mutations in genes for metabolic processes or repair pathways), pathogen infection (e.g., virus, bacteria), or be spontaneous (e.g., as a result of a reactive oxygen species (ROS) generated as a byproduct of electron transport). A “mitochondrial stressor” is an agent, such as a chemical, e.g., antimycin A or CCCP (carbonyl cyanide chlorophenylhydrazone), that can be used to model the stress experienced by mitochondria in a Miro2-related disorder. II. COMPOUNDS [0046] Any Miro2 reducer and/or Miro2-reducing agent can be used in the methods described herein. In some embodiments, the Miro2-reducing agent is a small molecule. In some embodiments, the Miro2-reducing agent has a molecular weight of from 200 to 2000 Daltons. For instance, the Miro2-reducing agent may inhibit formation of hydroperoxides from polyunsaturated fatty acid substrates. In some embodiments, the Miro2-reducing agent is a T-type calcium channel antagonist. In some embodiments, the compounds described below can be used in any of the methods and/or uses described herein. [0047] In some embodiments, the compound has the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are each independently C6-C10 aryl or 5- to 10-membered heteroaryl; R 1 , R 2 , and R 3 are each independently H, halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 4a and R 4b are each independently H or C 1 -C 6 alkyl; R 5 is H or C 1 -C 6 alkyl; R 6a and R 6b are each independently H or C 1 -C 6 alkyl; R 7 is H, halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR 11 , NR 12a R 12b , C1- C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; and each R 11 , R 12a , and R 12b is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN. [0048] In some embodiments of the compound of Formula (I), or pharmaceutically acceptable salt thereof, ring A is a 9- to 10-membered heteroaryl. [0049] In some embodiments of the compound of Formula (I), or pharmaceutically acceptable salt thereof, ring B is phenyl or 5- to 6-membered heteroaryl. [0050] In some embodiments, the compound has the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein ring B is C6-C10 aryl or 5- to 10-membered heteroaryl; R 1 , R 2 , and R 3 are each independently H, halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 7 cycloalkyl, -(CH 2 )n-(C 3 -C 7 cycloalkyl), 4- to 7-membered heterocyclyl, or -(CH 2 )n-(4- to 7-membered heterocyclyl), wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 4a and R 4b are each independently H or C 1 -C 6 alkyl, or R 4a and R 4b and the carbon atom to which they are attached form a C3-C5 cycloalkyl; R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 and X 5 are each independently N or CR 8 , provided that at least one of X 1 and X 5 is CR 8 ; X 2 , X 3 , and X 4 are each independently N, NR 9 , O, S, or CR 9 , provided that at least one of X 2 , X 3 , and X 4 is N, NR 9 , O, or S; R 8 is H, halogen, CN, OR 11 , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, or C 1 -C 6 haloalkyl; R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; each R 11 , R 12a , and R 12b is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN; and n is 1, 2, or 3. [0051] In some embodiments, X 1 is CR 8 . [0052] In some embodiments, R 8 is H. [0053] In some embodiments, X 2 , X 3 , and X 4 are each independently N, NR 9 , or CR 9 , provided that at least one of X 2 , X 3 , and X 4 is N or NR 9 . [0054] In some embodiments, X 1 is N or CR 8 , X 2 and X 3 are each independently N or NR 9 , X 4 is N, NR 9 , or CR 9 , and X 5 is CR 8 . For instance, X 1 can be CR 8 , X 2 and X 3 can be each independently N or NR 9 , X 4 can be N, NR 9 , or CR 9 , and X 5 can be CR 8 . In some embodiments, X 1 is N or CR 8 ; X 2 is N or NR 9 ; X 3 is N, NR 9 , or CR 9 ; X 4 is N or CR 9 ; and X 5 is CR 9 . In some embodiments, X 1 is CR 8 ; X 2 is N or NR 9 ; X 3 is N, NR 9 , or CR 9 ; X 4 is N or CR 9 ; and X 5 is CR 9 . [0055] In some embodiments, the compound has the structure: or a pharmaceutically acceptable salt thereof, wherein ring B is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; R 1 , R 2 , and R 3 are each independently H, halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C 3 -C 7 cycloalkyl, -(CH 2 ) n -(C 3 -C 7 cycloalkyl), 4- to 7-membered heterocyclyl, or -(CH 2 )n-(4- to 7-membered heterocyclyl), wherein the phenyl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OR 11 , NR 12a R 12b , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; R 4a and R 4b are each independently H or C 1 -C 6 alkyl, or R 4a and R 4b and the carbon atom to which they are attached form a C 3 -C 5 cycloalkyl; R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 and X 5 are each independently N or CR 8 , provided that at least one of X 1 and X 5 is CR 8 ; X 2 , X 3 , and X 4 are each independently N, NR 9 , O, S, or CR 9 , provided that at least one of X 2 , X 3 , and X 4 is N, NR 9 , O, or S; R 8 is H, halogen, CN, OR 11 , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, or C 1 -C 6 haloalkyl; R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl; each R 11 , R 12a , and R 12b is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen or CN; and n is 1, 2, or 3; provided that the compound does not have the structure: , or a pharmaceutically acceptable salt thereof. [0056] In some embodiments, the compound has the structure of Formula (III): or a pharmaceutically acceptable salt thereof. [0057] In some embodiments of the compound of Formula (I), (II) and/or (III), R 1 , R 2 , and R 3 are each independently H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, or C 3 -C 7 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C1- C 6 alkylamino, or C 1 -C 6 haloalkyl. [0058] In some embodiments of the compound of Formula (I), (II) and/or (III), R 3 is H, halogen, or CN. In some embodiments, R 3 is H or halogen. In some embodiments, R 3 is H. [0059] In some embodiments of the compound of Formula (I), (II) and/or (III), R 4b is H or CH 3 . [0060] In some embodiments of the compound of Formula (I), (II) and/or (III), R 4a and R 4b are each independently H or CH 3 . [0061] In some embodiments of the compound of Formula (I), (II) and/or (III), ring B is phenyl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, benzo[d][1,3]dioxol-5-yl, 2H- indazol-6-yl, thiophen-2-yl, pyridin-2-yl, or pyridin-3-yl; R 1 is F, Me, iPr, CF 3 , CF 2 CH 3 , cyclopropyl, 1-fluorocyclopropyl, 1-cyanocyclopropyl, 2,2-difluorocyclopropyl, or 1- trifluoromethylcyclopropyl, 1,1-difluoromethylcyclopropyl; R 2 is H, F, Cl, CN, or CH 3 ; R 3 is H or CH 3. [0062] In some embodiments, the compound has the structure of Formula (IV): or a pharmaceutically acceptable salt thereof. [0063] In some embodiments of the compound of (I), (II), (III), and/or (IV), ring B is phenyl or 5- to 6-membered heteroaryl. In some embodiments, ring B is phenyl or pyridyl. [0064] In some embodiments of the compound of Formula (I), (II) and/or (III), R 4a is H or CH 3 . [0065] In some embodiments, the compound has the structure of Formula (V): (V), or a pharmaceutically acceptable salt thereof. [0066] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), R 1 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 2 -C 6 alkoxyalkyl. In some embodiments, R 1 is H, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, R 1 is H or halogen. In some embodiments, R 1 is C 1 -C 3 haloalkyl. In some embodiments, R 1 is CF 3 . [0067] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), R 2 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 2 -C 6 alkoxyalkyl. In some embodiments, R 2 is H, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, R 2 is H or halogen. In some embodiments, R 2 is H. [0068] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), R 1 and R 2 are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, or C 3 -C 7 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl. In some embodiments, R 1 and R 2 are each independently H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 2 -C 3 alkoxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1, 2, or 3 halogen, CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C1- C 3 alkylamino, or C 1 -C 3 haloalkyl. In some embodiments, R 1 and R 2 are each independently H, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, R 1 and R 2 are each independently H or halogen. In some embodiments, R 1 and R 2 are each independently H, C1- C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, R 1 and R 2 are each independently H or C 1 -C 3 haloalkyl. [0069] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), R 1 is H or C 1 -C 3 haloalkyl; and R 2 is H or halogen. In some embodiments, R 1 is C 1 -C 3 haloalkyl; and R 2 is H. In some embodiments, R 1 is CF 3 ; and R 2 is H. [0070] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), R 6 is H or C 1 -C 3 alkyl. In some embodiments, R 6 is CH 3 . [0071] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl. In some embodiments, R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is substituted by 0, 1, 2, or 3 halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, or C 1 -C 6 haloalkyl. In some embodiments, R 9 is C 1 -C 3 alkyl, C 2 -C 3 alkoxyalkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is substituted by 0, 1, 2, or 3 F, Cl, CN, OH, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, or C 1 -C 3 haloalkyl. In some embodiments, R 9 is C 1 -C 3 alkyl, C 2 -C 3 alkoxyalkyl, or C 1 -C 3 haloalkyl. In some embodiments, R 9 is C 1 -C 3 haloalkyl. In some embodiments, R 9 is CH 2 CF 3 . [0072] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), the compound does not have the structure: , or a pharmaceutically acceptable salt thereof. [0073] Depending on the specific substitution pattern, the compound of Formula (I), (II), (III), (IV), and/or (V), or pharmaceutically acceptable salt thereof, can have one or more stereocenters. To facilitate compound evaluation, in certain instances, it may be advantageous to separate and to evaluate individual enantiomers and/or diastereomers. Methods to generate individual diastereomers and/or enantiomers are known in the art, including, but not limited to, chromatography, such as chiral chromatography, e.g., supercritical fluid chromatography on a chiral amylose column, and diastereoselective and/or enantioselective synthesis using a chiral auxiliary, for example, organometallic addition to a chiral sulfinimine. See, for instance, procedures described in Example 8. Accordingly, in some embodiments, the compound is enantiomerically enriched, and is present in from about 90% to about 99.999% enantiomeric excess (ee), such as from about 90% to about 99.99%, from about 93% to about 99.99%, from about 95% to about 99.99%, from about 95% to about 99.9%, from about 97% to about 99.9%, from about 98% to about 99.9%, or from about 99% to about 99.99% ee. Absent any other indication, the predominant isomer is the stereochemistry shown in the compound structure herein. In some embodiments, the compound is predominantly the R isomer. In some embodiments, the compound is predominantly the S isomer. [0074] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), the compound has a structure of any one of the compounds in Table 1 and Table 2, or a pharmaceutically acceptable salt thereof. [0075] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), the compound has a structure of any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. Table 1 10 11 [0076] For example, in some embodiments, the compound of the disclosure has the structure: or a pharmaceutically acceptable salt thereof. [0077] In some embodiments of the compound of Formula (I), (II), (III), (IV), and/or (V), the compound has a structure of any one of the compounds in Table 2, or a pharmaceutically acceptable salt thereof. Table 2

III. COMPOSITIONS [0078] The disclosure provides for, inter alia, compositions of one or more compounds that are Miro2 reducers and/or Miro2-reducing agents as disclosed herein. The compositions of the one or more compounds can decrease the level of Miro2 in a cell. [0079] In some embodiments, the composition comprises a compound of the present disclosure, or a salt thereof. In some embodiments, the composition further comprises a carrier or excipient. [0080] The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day. A. Formulation [0081] In some embodiments, the present disclosure provides a pharmaceutical composition, or pharmaceutical formulation, comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is capable of delivering an amount of a compound of the disclosure sufficient to produce a therapeutically effective treatment as described further below. Also provided herein is a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of Formula (I), (II), (III), (IV), and/or (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. [0082] For preparing pharmaceutical compositions from the compound or pharmaceutically acceptable salt of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, cachets, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, binders, preservatives, disintegrating agents, or an encapsulating material. [0083] The compounds herein are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. [0084] While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. [0085] The formulations include those suitable for the administration routes described below. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. [0086] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets 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 or non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste. [0087] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% or 10% to 70% of the compound of the present invention. [0088] A tablet is 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 active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. [0089] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. [0090] Pharmaceutical formulations herein comprise a combination together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. [0091] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient can be present in such formulations in a concentration of about 0.5 to about 20%, such as about 0.5 to about 10%, for example about 1.5% w/w. [0092] Aqueous solutions suitable for oral use can be prepared by dissolving the compound or pharmaceutically acceptable salt of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolality. [0093] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0094] Oil suspensions can be formulated by suspending the compound or pharmaceutically acceptable salt of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent. [0095] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol.49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months. [0096] In another embodiment, the compositions of the present invention can be formulated for parenteral administration into a body cavity. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV, intratumoral, or intravitreal administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol. [0097] In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46: 1576-1587, 1989). [0098] Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present invention include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®, Capryol®, Capmul®, Captex®, and Peceol®. B. Administration [0099] The compound or pharmaceutically acceptable salt and compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods. [0100] A compound or composition of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life. [0101] The dosage or dosing frequency of a compound or composition of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician. [0102] The compound or composition may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily. [0103] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. [0104] The compounds and compositions of the present invention can be co-administered with other agents. Co-administration includes administering the compound or composition of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the other agent. Co-administration also includes administering simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Moreover, the compounds and compositions of the present invention can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day. [0105] In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including the compounds and compositions of the present invention and any other agent. Alternatively, the various components can be formulated separately. [0106] The compounds and compositions of the present invention, and any other agents, can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable dosage ranges include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. The composition can also contain other compatible therapeutic agents. The compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating ferroptosis, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. IV. METHODS A. Assays [0107] A compound of the present disclosure, e.g., a compound of Formula (I), or pharmaceutically acceptable salt thereof, capable of reducing Miro2 level and/or activity may be validated as such by any convenient method in the art for detecting the level and/or activity of Miro2 in the presence versus absence of the compound of the present disclosure. For example, the level and/or the phosphorylation state of a Miro protein (Ser156, Thr298 or Thr299 of Miro1 and Miro2, see, e.g., Wang et al. Cell 2011, 147(4): 893-906) may be detected, for example by immunoprecipitation with a mitochondrial transport protein-specific antibody followed by Western blotting with a phospho-specific or a general antibody, where an increase in phosphorylation of Miro proteins and/or a decrease of total Miro protein levels, or a decrease in phosphorylation of Khc following contact with the agent may indicate that the agent will treat Parkinson’s Disease. As another example, the level and/or the ubiquitination of a Miro2 protein may be detected, for example by immunoprecipitation with a mitochondrial transport protein-specific antibody followed by Western blotting with a ubiquitin-specific antibody, where an increase in ubiquitination following contact with the candidate agent indicates that the agent will treat Parkinson’s Disease. As another example, the ability of the target mitochondrial protein to transport mitochondria within a cell may be assessed by, for example, treating cultured cells (e.g., neurons) with the compound of the present disclosure and observing the transport of mitochondria in the cells as compared to cells not treating with the compound of the present disclosure, e.g., using live cell imaging techniques (see, e.g., Brickley and Stephenson J. Biol Chem 286(20): 18079-92 (2011); Misko et al. J Neurosci 30(19): 4232-40 (2010); Russo GJ et al. J. Neurosci 29(17):5443-55 (2009)). As another example, because the formation of a complex between Miro (e.g., Miro 1 and 2), TRAK (e.g., TRAK1 and 2), and Khc is essential for mitochondrial transport in neurons (see e.g., Brickley and Stephenson J. Biol Chem 286(20): 18079-92 (2011)), the effect of the compound of the present disclosure on Miro2 function may be assessed by assessing the ability of Miro2, TRAK and Khc to form a complex in the presence of the compound of the present disclosure. Such an assessment can be performed using any technique to determine protein-protein interaction including, but not limited to, co- immunoprecipitation and affinity purification techniques. In specific embodiments, the ability is assessed in a cell having a familial PD mutation, e.g. a PINK1 or LRRK2 mutation. [0108] Affinity assays, which are often immunoassays, are an assay or analytic procedure that relies on the binding of the target molecule, i.e. Miro2, to receptors, antibodies or other macromolecules. A detection method is used to determine the presence and extent of the binding complexes that are formed. Many formats for such assays are known and used in the art, and are suitable for detection of Miro2 degradation following mitochondrial uncoupling or depolarization. In some embodiments, the assay format is suitable for high-throughput analysis. [0109] Included in suitable assay formats are immunoassays that utilize antibodies specific for Miro2. Suitable antibodies for this purpose are known and commercially available as polyclonal or monoclonal compositions, e.g. from Miro2 polyclonal from proteintech (cat #11237-1-AP), LSBio, Abcam (ab154946); and the like. [0110] Assays of interest include, for example, Western blots; immunocytochemistry; immunohistochemistry; flow cytometry; immunoprecipitation; etc., and particularly include immunoassays such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA); enzyme immunoassay (EIA). [0111] Enzyme-linked immunosorbent assays (ELISAs) are used to qualitatively and quantitatively analyze the presence or concentration of a particular soluble antigen such as Miro2, in liquid samples, such as cell lysates. These assays generally make use of the ability of multiwell plates or others to bind antibodies which trap the cognate antigen. Usually a colorimetric endpoint that can be detected via absorbance wavelength and quantitated from a known standard curve of antigen or antibody dilutions is used. The detection antibody is often labelled with an enzyme such as horseradish peroxidase or alkaline phosphatase, or a fluorescent tag, or an electrochemiluminescent label or through an intermediary label such as biotin. [0112] Common ELISA formats include the sandwich ELISA, so named because the analyte is “sandwiched” between two different antibodies. The capture substrate in this format is a capture antibody, often a monoclonal antibody, to increase the specificity of the assay and reduce background noise. The analyte is bound to the capture antibody, then detected by binding to a detection antibody. A variation of sandwich ELISA assay, called Single-Molecule Assay (Simoa), uses beads are coated with a capture antibody; each bead is bound to either one or zero target molecule, and individual beads are detected with another antibody (detection antibody) and a labeling enzyme. [0113] Other ELISA formats include indirect ELISA, where the capture substrate is the specific antigen that is being tested and the detection step is mediated by a primary antibody and an enzyme-conjugated secondary antibody which is reactive against the primary antibody. Thus, the primary antibody that recognizes the antigen is not labeled. In a direct ELISA the capture substrate is the specific antigen that is being tested, and the enzyme that catalyzes the color-change reaction is conjugated to the antigen detector antibody. [0114] Immuno-PCR (I-PCR) is a technique that combines the sensitivity of the nucleic acid amplification by PCR with the specificity of the antibody-based assays resulting in an increase of the detection sensitivity. [0115] Immunocytochemistry (ICC) is a technique that is used to visualize the localization of a specific protein or antigen in cells by use of a specific primary antibody that binds to the protein or antigen. The primary antibody allows visualization of the protein under a fluorescence microscope when it is bound by a secondary antibody that has a conjugated fluorophore. ICC permits evaluation of whether or not cells in a particular sample express the protein in question. In cases where an immunopositive signal is found, ICC also allows researchers to determine which sub-cellular compartments are expressing the antigen. [0116] Immunohistochemistry (IHC) is an application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. Visualising an antibody-antigen interaction can be accomplished in a number of ways, for example, chromogenic immunohistochemistry (CIH), wherein an antibody is conjugated to an enzyme, such as peroxidase (the combination being termed immunoperoxidase), that can catalyse a color-producing reaction, or immunofluorescence, where the antibody is tagged to a fluorophore, such as fluorescein or rhodamine. [0117] Flow cytometry is a technology that rapidly analyzes single cells or particles as they flow past single or multiple lasers while suspended in a buffered salt-based solution. Each particle is analyzed for visible light scatter and one or multiple fluorescence parameters. Visible light scatter is measured in two different directions, the forward direction (Forward Scatter or FSC) which can indicate the relative size of the cell and at 90° (Side Scatter or SSC) which indicates the internal complexity or granularity of the cell. Light scatter is independent of fluorescence. Samples are prepared for fluorescence measurement through transfection and expression of fluorescent proteins (ex. Green Fluorescent Protein, GFP), staining with fluorescent dyes (e.g., Propidium Iodide, DNA) or staining with fluorescently conjugated antibodies (e.g., CD3 FITC). [0118] Mass spectrometry (MS) analysis of proteins measures the mass-to-charge ratio of ions to identify and quantify molecules in simple and complex mixtures. Mass spectrometry assays can qualitatively or quantitatively measure specific analytes in complex biological matrices (such as urine, blood or tissues). Certain macromolecule ionization methods, for example, electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI), permits the study of protein structure by MS. [0119] Calcium channel antagonist activity, including T-type calcium channel antagonist activity, can be assessed using patch clamp assays or fluorescence imaging plate reader (FLIPR) assays known in the art. See, for example, Leech, C.A. and Holz, G.G., IV. Methods Cell Biol.1994; 40: 135-151; Bell, D.C. and Dallas, M.L. Br. J. Pharmacology 2018, 175, 2312-2321; Bezençon et al., J. Med. Chem.2017, 60, 9769; Uebele et al., Cell Biochem Biophys 2009.55, 81; Xiang et al, ACS Chemical Neuroscience 2011, 2, 730; and US 10,562,857. B. Methods of Reducing Miro2 [0120] Provided herein is a method of reducing Miro2 level in a cell, the method comprising contacting the cell with an effective amount of a Miro2 reducer and/or Miro2- reducing agent. In some embodiments, the Miro2 reducer and/or Miro2-reducing agent is a T- type calcium channel antagonist. Any T-type calcium channel antagonist can be used in the methods described herein, such as those described in Wang D, Ragnarsson L, Lewis RJ. T- type Calcium Channels in Health and Disease. Curr Med Chem.2020;27: 3098–3122; and Nam G. T-type calcium channel blockers: a patent review (2012-2018). Expert Opin Ther Pat.2018;28: 883–901. Exemplary T-type calcium channel antagonists include mibefradil, NNC 55-0396, MK-8998 (JZP385, Suvecaltamide), ACT-709478 (NBI-827104), Z-944 (PRAX-944), ST101 (ZSET1446) CAS# 887603-94-3, TTA-A2, ABT-639, zonisamide, ethosuximide, pimozide, fluspirilene, penfluridol, ML218, KYS05090, and NMP-7. In some embodiments, the T-type calcium channel antagonist has the structure of one or more of the compounds of Formula (I), (II), (III), (IV), and/or (V) described herein. For instance, the method of reducing Miro2 level in a cell can be performed with any one of the compounds of Table 1 and Table 2, or a pharmaceutically acceptable salt thereof. [0121] T-type calcium channel antagonists have been described in US Patent Nos. 8,377,968; 9,403,798; 10,562,857; US application publication nos.20120264804; 20150329533; 20160340322; EP 3572403; and PCT publication nos. WO2011022315; WO2012094615; WO2013148640; WO2018200850; WO2019175395; WO2020072773; and WO2021007487; each of which are incorporated in its entirety by reference thereto. Any one of the T-type calcium channel antagonists in the aforementioned publications can be used in a method as described herein. [0122] In some embodiments, a reduction of a Miro2 level in a method as described herein is a reduction in the amount of a Miro2 nucleic acid, e.g., a Miro2 RNA or a Miro2 DNA, and/or a reduction in the activity of a Miro2 protein. The Miro2 nucleic acid can be any type of nucleic acid known in the art. For example, a Miro2 RNA can be a messenger RNA (mRNA), a transfer RNA (tRNA), or a ribosomal RNA (rRNA). In some embodiments, the Miro2 RNA is a messenger RNA (mRNA). In some embodiments, the reduction of a Miro2 level is a reduction in the amount of a Miro2 nucleic acid as determined by any assay method, including assays known in the art and the assays described in the present disclosure, that results in a reduction in the Miro2 activity. [0123] In some embodiments, a reduction of a Miro2 level in a method as described herein is a reduction in the amount of a Miro2 protein and/or a reduction in the activity of a Miro2 protein. In some embodiments, the reduction of a Miro2 level is a reduction in the amount of a Miro2 protein as determined by any assay method, including assays known in the art and the assays described in the present disclosure, that results in a reduction in the Miro2 activity. [0124] Any suitable cell can be used in a method of reducing, or downregulating, Miro2 level described herein. Cultured cells may be derived from a subject (e.g., a patient), or control samples; and may be modified to generate genetically-modified cells, in vitro differentiated cells, cells exposed to a candidate therapeutic agent; and the like. In some embodiments, the cell is a skin cell. In some embodiments, the cell is a muscle cell. For example, the muscle cell can be a cardiac cell, that is, a cardiomyocyte. In some embodiments, the cell is a renal cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a neuronal cell. The method can be performed in a cell in vitro, ex vivo, or in vivo. In some embodiments, the reducing Miro2 level is in vitro or ex vivo. In some embodiments, the reducing Miro2 level is in vivo. [0125] Any suitable biological sample comprising cells can be used in the methods described herein. The methods can be performed with a biological sample obtained from a subject, including without limitation biological samples such as fibroblasts, such as skin fibroblasts, peripheral blood lymphocytes, peripheral blood mononuclear cells (PBMCs), induced pluripotent stem cells (iPSCs), iPSC neuronal types, iPSC-derived cells (such as iPSCs converted to neurons), and the like. [0126] In some embodiments, control values are measured from corresponding control samples from control, i.e., non-diseased, subjects. For example, in some embodiments, a Miro2 level of a skin fibroblast from a subject is compared to a control Miro2 level of a control skin fibroblast from a control subject. [0127] A Miro2 level measured in a method described herein can be compared to a control Miro2 level by any method known in the art. See, for example, the assays described in Cao, Y. et al. Circulation Research 2019; 125(8):728-743; Oeding, S. J. et al Journal of Cell Science 2018; 131(17): jcs219469; and Furnish, M. et al. Molecular Cancer Research 2022; 20(4): 607-621. [0128] In some embodiments, a Miro2 reducer and/or Miro2-reducing agent, e.g., a T-type calcium channel antagonist, reduces the level of Miro2 to a normal range. For example, in some embodiments, a Miro2 normal range can be the range observed between untreated or naïve healthy fibroblast or iPSC DA neuron cells (top of the range) and mitochondrial stressor-challenged healthy fibroblast or iPSC DA neuron cells (bottom of the range). [0129] In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces, or downregulates, the level of Miro2 to within about 50%, about 40%, about 30%, or about 20% relative to a control level of Miro2. In some embodiments, the control level of Miro2 is measured in a control cell from a control subject that does not have or is not suspected of having a disease or disorder mediated by an aberrant Miro2 level. For example, a Miro2 reducer and/or Miro2-reducing agent can downregulate the Miro2 level in a neuronal cell from a Parkinson’s disease patient to within about 50% relative to a control level of Miro2 in a control neuronal cell from an age-matched patient that does not have or is not suspected of having Parkinson’s disease. [0130] The level of Miro2 in a cell after contacting with the Miro2 reducer and/or Miro2- reducing agent can be higher or lower than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Miro2 reducer and/or Miro2-reducing agent is about 20%, about 30%, about 40%, or about 50% higher than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Miro2 reducer and/or Miro2-reducing agent is from about 20% to about 50% higher than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Miro2 reducer and/or Miro2-reducing agent is about 20%, about 30%, about 40%, or about 50% lower than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Miro2 reducer and/or Miro2-reducing agent is from about 20% to about 50% lower than the control level of Miro2 in the control cell. [0131] Any suitable concentration of a Miro2 reducer and/or Miro2-reducing agent in a cell can be used to effect reducing the Miro2 level in the cell to a desired level. In some embodiments, the concentration of Miro2 reducer and/or Miro2-reducing agent in the cell can be from about 1 nM to about 100 µM, such as from about 1 nM to about 10 µM, from about 1 nM to about 1 µM, from about 10 nM to about 100 µM, from about 10 nM to about 10 µM, from about 10 nM to about 1 µM, from about 100 nM to about 100 µM, from about 100 nM to about 10 µM, from about 100 nM to about 1 µM, from about 1 µM to about 100 µM, or from about 1 µM to about 10 µM. [0132] In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% or more, for example, about 30% or more, about 40% or more, or about 50% or more, about 60% or more, about 70% or more, or about 80% or more, e.g. about 90%, about 95%, or about 100%, relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 25% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 30% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 35% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 40% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 45% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 50% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 55% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 60% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 65% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 70% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 75% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 80% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 85% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 90% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 95% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. [0133] In some embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% to about 100% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% to about 90% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2- reducing agent reduces the level or biological activity of Miro2 by about 20% to about 80% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% to about 70% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% to about 60% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% to about 50% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 20% to about 40% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 30% to about 50% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. In embodiments, a Miro2 reducer and/or Miro2-reducing agent reduces the level or biological activity of Miro2 by about 40% to about 60% relative to an untreated control not contacted with the Miro2 reducer and/or Miro2-reducing agent. C. Methods of Identifying a Subject at Risk of Developing a Miro2-Related Disorder [0134] A deficiency in the ability to degrade or clear Miro2 from cells is believed to correlate with the development of a Miro2-related disorder, for example, a neurodegenerative disorder, such as Parkinson’s disease, before a subject displays an overt symptom of the neurodegenerative disorder, such as one or more of the symptoms described herein. Accordingly, in some embodiments, the subject is asymptomatic for a neurodegenerative disorder. Miro2 may be used as a predictive biomarker for a neurodegenerative disorder in a subject at risk of developing such disorder, for example, as an initial step in treating the neurodegenerative disorder before symptoms appear. The subject at risk can have familial history of developing a neurodegenerative disorder, can present a genetic marker associated with increased risk of developing a neurodegenerative disorder, for example, LRRK2 G2019S mutation for Parkinson’s disease, or can have no known risk of developing a neurodegenerative disorder. [0135] A Miro2 level in cells treated with a mitochondrial stressor is expected to be lower than a control Miro2 level in untreated control cells due to mitophagy processes induced by the mitochondrial stressor. With biological sample cells derived from a subject, a Miro2 level that is similar or higher in cells treated with a mitochondrial stressor compared to a control Miro2 level in untreated control cells may indicate a neurodegenerative disorder that correlates with defective mitophagy processes. [0136] Accordingly, in some embodiments, the method of the present disclosure is a method to determine the Miro2 status of a subject comprising measuring the Miro2 response to mitochondrial depolarization using mass spectrometry, immunocytochemistry (ICC), immunohistochemistry (IHC), flow cytometry, biochemical assays, western blotting or ELISA, to determine if a subject is deficient in the removal of Miro2 following depolarization, wherein a subject deficient in the removal of Miro2 following depolarization is selected for treatment by administration of a Miro2 reducer. In some embodiments, the method comprises detecting Miro2 level in the subject, and comparing the Miro2 level to a control Miro2 level from a control subject. In some embodiments, the detecting Miro2 level comprises detecting Miro2 in a sample in the subject. In some embodiments, the sample comprises a skin cell. In some embodiments, the Miro2 level in the subject is higher than the control Miro2 level from a control subject. In some embodiments, the Miro2 level in the subject is about 20% or more than the control Miro2 level from a control subject. In some embodiments, the method comprises diagnosing the subject with a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder is Parkinson’s disease. In some embodiments, the method further comprises treating the subject with the Miro2 reducer. In some embodiments, method further comprises monitoring Miro2 levels before and after treatment with the Miro2 reducer. [0137] In some embodiments, the method of the present disclosure is a method for identifying a subject at risk of developing a Miro2-related disorder, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; and b) identifying the subject at risk of developing a Miro2-related disorder if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample, wherein the biological sample and the control biological sample comprise iPSCs or cells differentiated from iPSCs. In some embodiments, the method further comprises treating the subject at risk of developing a Miro2-related disorder by administering a therapeutically effective amount of a compound of the present disclosure described herein, or pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound as described in Table 1, or a pharmaceutically acceptable salt thereof. [0138] In some embodiments, provided is a method for identifying a subject at risk of developing a Miro2-related disorder, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; b) identifying the subject at risk of developing a Miro2-related disorder if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample. In some embodiments, the ratio of the Miro2 level to the control Miro2 level is from about 0.5 to about 10, such as from about 0.7 to about 4. In some embodiments, the method comprises treating the subject at risk of developing a Miro2-related disorder by administering a therapeutically effective amount of a compound described herein, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (I), (II), (III), (IV), and/or (V), or pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound as described in Table 1, or a pharmaceutically acceptable salt thereof. [0139] A Miro2-related disorder is any disease or disorder that correlates with abnormal degradation and/or clearance of a Miro2 protein, and includes any one of the neurodegenerative disorders described herein. In some embodiments, the Miro2-related disorder is Drug-induced Parkinsonism, Progressive supranuclear Palsy, Vascular Parkinsonism, Dementia with Lewy Bodies, diffuse Lewy body disease, Corticobasal degeneration, multisystem degeneration (Shy-drager syndrome), Parkinson’s disease, Alzheimer's disease, Pick's disease, frontotemporal dementia, multiple systems atrophy, vascular dementia, or progressive supranuclear palsy (Steel-Richardson syndrome). In some embodiments, the Miro2-related disorder is Parkinson’s disease. In some embodiments, the Miro2-related disorder is Alzheimer's disease. In some embodiments, the Miro2-related disorder is Pick's disease. In some embodiments, the Miro2-related disorder is frontotemporal dementia. In some embodiments, the Miro2-related disorder is multiple systems atrophy. [0140] Further provided herein is a method for treating a neurodegenerative disorder in a subject in need thereof, the method comprising: a) detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated; b) identifying the subject for treatment if the Miro2 level is similar or higher in the biological sample compared to the control Miro2 level in the control biological sample; and c) administering a therapeutically effective amount of a compound as described herein, or pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the neurodegenerative disorder is Drug-induced Parkinsonism, Progressive supranuclear Palsy, Vascular Parkinsonism, Dementia with Lewy Bodies, diffuse Lewy body disease, Corticobasal degeneration, multisystem degeneration (Shy-drager syndrome), Parkinson’s disease, Alzheimer's disease, Pick's disease, frontotemporal dementia, multiple systems atrophy, vascular dementia, or progressive supranuclear palsy (Steel-Richardson syndrome). In some embodiments, the compound is a compound of Formula (I), (II), (III), (IV), and/or (V), or pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound as described in Table 1, or a pharmaceutically acceptable salt thereof. [0141] Any suitable biological sample described herein, including urine, tissue, or blood, can be used in the methods. In some embodiments, the biological sample and the control biological sample comprise fibroblasts. For example, skin fibroblasts can be directly obtained from the subject. In some embodiments, the biological sample and the control biological sample comprise iPSCs or cells differentiated from iPSCs. [0142] iPSCs can be directly obtained from a subject or be cultured from other cell types obtained from a subject according to any method known in the art. See, Shi, Y. et al. Nature Reviews Drug Discovery vol.16, pages 115-130 (2017), and references cited therein. For example, iPSCs can be dedifferentiated from fibroblast cells that were directly obtained from a subject. Additionally, iPSCs can be redifferentiated into a variety of different cell types, including neuronal cells, skin cells, blood cells, and liver cells. [0143] Such cells differentiated from iPSCs of a subject can be used to determine a personalized therapy in a convenient manner without directly obtaining a target cell type directly from a subject. In an illustrative example, a skin fibroblast can be obtained from a subject at risk for developing Parkinson’s disease. The skin fibroblast can be dedifferentiated into iPSCs, which can then be redifferentiated into motor neurons. The motor neurons differentiated from iPSCs can be tested in an assay described herein for Miro2 deficit with and without treatment of a mitochondrial stressor in order to identify whether the subject may be responsive to a Miro2 reducing therapy, such as one containing a compound of the disclosure. [0144] Methods for comparing a Miro2 level to a control Miro2 level are known in the art. When detecting whether a Miro2 level is similar or higher in a biological sample obtained from the subject and treated with a mitochondrial stressor, as compared to a control Miro2 level in a control biological sample obtained from the subject and is untreated, the ratio of the Miro2 level to the control Miro2 level can be compared. In some embodiments, the ratio of the Miro2 level to the control Miro2 level is from about 0.5 to about 10, such as from about 0.5 to about 5, from about 0.6 to about 6, from about 0.7 to about 4, from about 0.7 to about 3, from about 0.8 to about 3, or from about 0.9 to about 2. For example, the ratio of the Miro2 level to the control Miro2 level can be from about 0.5 to about 10. In another example, the ratio of the Miro2 level to the control Miro2 level can be from about 0.7 to about 4. [0145] Any mitochondrial stressor known in the art may be used in the methods described herein. Suitable mitochondrial stressors include mitochondrial depolarizing agents, such as carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and carbonyl cyanide 3- chlorophenylhydrazone (CCCP); mitochondrial electron transport chain inhibitors, including Complex I inhibitors, such as rotenone, piericidin A, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), and paraquat, Complex III inhibitors, such as antimycin A, Complex V inhibitors, such as oligomycin A, and mitochondrial membrane potassium ionophores, such as valinomycin; metabolic modulators, including modulators of insulin signaling, such as metformin, and inhibitors of mTOR master signaling pathway required for cell growth and metabolism, such as rapamycin. In some embodiments, the mitochondrial stressor comprises antimycin A or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In some embodiments, the mitochondrial stressor comprises carbonyl cyanide 4- (trifluoromethoxy)phenylhydrazone (FCCP). D. Methods of Treatment [0146] Provided herein is a method of treating a neurodegenerative disorder, the method comprising administering to the subject a therapeutically effective amount of a Miro2 reducer and/or Miro2-reducing agent, or a pharmaceutical composition thereof. In some embodiments, the Miro2 reducer and/or Miro2-reducing agent is a T-type calcium channel antagonist, such as a compound of Formula (I), (II), (III), (IV), and/or (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the method delivers a therapeutically effective amount of a compound of the disclosure, or a pharmaceutical composition thereof, sufficient to treat one or more symptoms of a condition described further below. [0147] Neurodegenerative disorders included within the methods of the present disclosure include, but are not limited to neurological disorders that share symptoms similar to those seen in Parkinson’s disease and related disorders. In some cases, the neurological disorders may show symptoms similar to Parkinson’s disease, atypical Parkinson’s disease or Parkinson’s plus disease. Examples include but are not limited to Drug-induced Parkinsonism, Progressive supranuclear Palsy, Vascular Parkinsonism, Dementia with Lewy Bodies, diffuse Lewy body disease, Corticobasal degeneration, multisystem degeneration (Shy-drager syndrome), Alzheimer's disease, Pick's disease, frontotemporal dementia, multiple systems atrophy, vascular dementia, and progressive supranuclear palsy (Steel- Richardson syndrome). In some embodiments, the neurodegenerative disorder is Parkinson’s disease. Parkinson’s disease may be sporadic or familial. Familial forms of Parkinson’s disease can be caused by mutations in the LRRK2, such as G2019S, GBA, PARK7, PINK1, PRKN, or SNCA gene. [0148] Other conditions also included within the methods of the present invention include age-related dementia and other dementias and conditions with memory loss including vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica and frontal lobe dementia. In some cases, the neurological disorder may not respond well to dopaminergic treatments and may be caused as a result of various vascular, drug-related, infectious, toxic, structural and other known secondary causes. Drug-induced Parkinsonism may be caused by agents that block post-synaptic dopamine D2 receptors with high affinity, such as anti-psychotic and anti-emetic medications and sodium valproate, anti- depressants, reserpine, tetrabenazine etc. [0149] A variety of subjects are suitable for treatment with a T-type calcium channel antagonist of the present disclosure. Suitable subjects include any subject who displays symptoms of Parkinson’s disease such as bradykinesia, repetitive movements, tremors, limb rigidity, gait and balance problems, inability to aim the eyes due to weakness of eye muscles, weakness, sensory loss, non-motor manifestations such as REM sleep behavior disorder, neuropsychiatric symptoms including mood disturbances and cognitive changes, anxiety, apathy, changes in thinking ability, level of attention or alertness and visual hallucinations, intellectual and functional deterioration, forgetfulness, personality changes, autonomic dysfunction affecting cardiovascular, respiratory, urogenital, gastrointestinal and sudomotor function, difficulties in breathing and swallowing, inability to sweat, orthostatic hypotension, pain, constipation, and loss of olfaction, e.g., hyposmia. In some embodiments, the subjects may experience predominant speech or language disorder, predominant frontal presentation and gait freezing. [0150] In some embodiments, the subject may not display any overt symptoms of Parkinson’s disease. In some cases, the subject in need may show increased susceptibility to infections, hypothermia, weaker bones, joint stiffness, arthritis, stooped posture, slowed movements, decrease in overall energy, constipation, urinary incontinence, memory loss, slower thinking, slower reflexes, difficulty with balance, decrease in visual acuity, diminished peripheral vision, hearing loss, wrinkling skin, greying hair, weight loss, loss of muscle tissue. [0151] In some embodiments, the subject is selected from those that have been diagnosed as having Alzheimer's disease; subjects who have suffered one or more strokes; subjects who have suffered traumatic head injury; individuals who have high serum cholesterol levels; subjects who have proteinopathies including deposits in brain tissue; subjects who have had one or more cardiac events; subjects undergoing cardiac surgery; and subjects with multiple sclerosis. [0152] In some embodiments, the subject displays symptoms associated with neurological diseases that include motor neuron diseases such as amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Sträussler- Scheinker disease, Kuru and fatal familial insomnia). Also other neurodegenerative disorders resulting from cerebral ischemia or infaction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type (including, but not limited to, epidural, subdural, subarachnoid and intracerebral), and intracranial and intravertebral lesions (including, but not limited to, contusion, penetration, shear, compression and laceration). [0153] In some embodiments, the method of the present disclosure is a method for selecting a subject for treatment with a therapeutic agent for a neurodegenerative disorder, comprising: (a) collecting cells from the subject and evaluating a first control portion of the cells for the pre-depolarization Miro2 level in the cells; (b) contacting a second test portion of the cells with a depolarizing agent; and (c) evaluating the post-depolarization Miro2 level in the second test portion of cells contacted with the depolarizing agent and comparing the Miro2 level to the pre-depolarization Miro2 level in the first control portion of cells; wherein when the post-depolarization Miro2 level in the second test portion of cells is reduced by 40% or less relative to the pre-depolarization Miro2 level in the first control portion of cells, the subject is treated with a therapeutic agent for neurodegenerative disorder. [0154] Compounds of the disclosure or pharmaceutically acceptable salts thereof are also useful for methods of aiding the treatment of a disease, a disorder, and/or a health condition associated with a Miro2-related disease or disorder, such as Parkinson’s disease. As used herein, a “method of aiding” generally refers to methods of assisting in performing or practicing a method disclosed herein, for example, methods of assisting in (i) performing, (ii) practicing, and/or (iii) making a determination concerning the detection, classification, treatment regiment, or nature, of a Miro2-related disorder (e.g., a neurodegenerative disease such as Parkinson’s disease), disease, and/or a health condition. [0155] Accordingly, in some embodiments, a method of aiding in the treatment of a Miro2- related disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0156] In some embodiments, a use of the present disclosure comprises a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for the manufacture of a medicament for aiding in the treatment of a Miro2-related disorder in a subject in need thereof. [0157] In some embodiments, a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure is for use in aiding in the treatment of a Miro2-related disorder in a subject in need thereof. [0158] Kits that comprise a compound of the present disclosure, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above, are also included in the present disclosure. In some embodiments, a kit further includes instructions for use. In some embodiments, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, such as the diseases or conditions, described herein. In some embodiments,kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided. [0159] Provided herein are also articles of manufacture that include a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag. V. EXAMPLES [0160] The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular materials and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof. [0161] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013.) [0162] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. For example, disclosed compounds can be purified via silica gel chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969. [0163] Compounds were characterized using standard instrumentation methods. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR) and mass spectrum (MS). 1 H-NMR was measured at 400 MHz, unless otherwise specified. In some cases, exchangeable hydrogen could not be clearly observed depending on the compound and measurement conditions. The designation br. or broad, used herein, refers to a broad signal. HPLC preparative chromatography was carried out by a commercially available ODS column in a gradient mode using water/methanol (containing formic acid) as eluents, unless otherwise specified. [0164] Abbreviations. Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, listed below are many of these abbreviations and acronyms. Example 1. Synthesis of (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5- yl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (Compound 1) [0165] Step 1. Synthesis of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5- carbaldehyde [0166] A solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (760 mg), 1,1,1-trifluoro- 2-iodoethane (0.51 mL) and Cs 2 CO 3 (2.5 g) in DMF (10 mL) was stirred at 100°C for 12 hr. The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH=1:0 to 20:1) to give 1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridine-5-carbaldehyde (500 mg) as a yellow solid. LC/MS ESI (m/z): 230 [M+H] + . [0167] Step 2. Synthesis of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)methylene)propane-2-sulfinamide [0168] A solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbal dehyde (500 mg), (R)-2-methylpropane-2-sulfinamide (396.7 mg) and copper sulfate pentahydrate (1.0 g) in DCM (15 mL) was stirred at 25 °C for 12 hr. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH =1:0 to 20:1) to give (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene)propane-2-sulfinamide (450 mg) as a yellow solid. LC/MS ESI (m/z): 333 [M+H] + . [0169] Step 3. Synthesis of (R)-2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)propane-2-sulfinamide [0170] To a solution of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)methylene)propane-2-sulfinamide (450 mg) in THF (5 mL) was added CH 3 MgBr (3.0M in ether, 1.35 mL) at -78 °C. The mixture was stirred at -78 °C for 2 hr. The mixture was quenched with NH4Cl solution and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH =1:0 to 20:1) to give (R)-2-methyl- N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)propane-2- sulfinamide (350 mg) as a yellow solid. LC/MS ESI (m/z): 349 [M+H] + . [0171] Step 4. Synthesis of (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride [0172] To a solution of (R)-2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[ 3,4- c]pyridin-5-yl)ethyl)propane-2-sulfinamide (300 mg) in dioxane (2.0 mL) was added HCl/dioxane (4N in dioxane, 2.0 mL). The mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethan-1-amine hydrochloride (300 mg, crude) as a white solid. LC/MS ESI (m/z): 245 [M+H] + . [0173] Synthesis of (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5- yl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (Compound 1) [0174] A solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (96.4 mg) and HATU (269.5 mg) in 3 mL DMF was stirred at room temperature for 15 min (Solution A). DIEA (0.48 mL) was added to (R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl]ethan- 1-amine hydrochloride from Step 4 (150 mg) in 2 mL DMF until the pH of the solution higher than 7 by wet pH paper (Solution B). Solution B was added to Solution A, and the reaction was stirred for 1 hour, at which time LCMS showed the reaction was complete. The reaction was diluted with EA and water. The two phases were separated, the aqueous phase was extracted with DCM (10 mLx2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with methanol in DCM (0-7%) to afford a crude product, which was purified by prep-HPLC (Column: YMC-Actus Triart C18250*20mm; Mobile phase: from 28% to 95% MeCN with H2O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) and SFC (Column:ChiralPak IA, 250x21.2mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH3H2O;Gradient: B 40%;Flow rate: 50mL /min; Wavelength: 210 nm) to give N-[(1R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridi n-5-yl]ethyl]-2-[4- (trifluoromethyl)phenyl]acetamide (92.1 mg) as white solid. LC/MS ESI (m/z): 431 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ): δ 8.87 (s, 1H), 8.10 (s, 1H), 7.63 - 7.51 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 6.9 Hz, 1H), 5.26-5.24 (m, 1H), 5.04 (q, J = 8.3 Hz, 2H), 3.63 (s, 2H), 1.48 (d, J = 6.8 Hz,3H). 19 F-NMR (377 MHz, CDCl 3 ): δ -62.54, -70.81. Example 2. (R)-2-(4-isopropylphenyl)-N-(1-(2-methyl-2H-pyrazolo[3,4-c]p yridin-5- yl)ethyl)acetamide [0175] Step 1. Synthesis of (R,E)-2-methyl-N-((2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide [0176] To a solution of 2-methyl-2H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (210 mg) in anhydrous dichloromethane (10 mL) were added (R)-2-methylpropane-2-sulfinamide ( 190 mg) and CuSO 4 ( 520 mg), and the reaction was stirred at rt for overnight. Then, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column to give (R,E)-2-methyl-N-((2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (421 mg, crude) as a white solid. LC/MS ESI : 265( M+H ) + . 1 H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 4.31 (s, 3H), 1.21 (s, 9H). [0177] Step 2. Synthesis of (R)-2-methyl-N-((R)-1-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide [0178] To a solution of (R,E)-2-methyl-N-((2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (274 mg) in THF (8.0 mL) was added methylmagnesium bromide (1.38 mL, 3M in ether) at -78 °C, and the mixture was stirred at -78 °C for 4 hr. The mixture was then quenched with NH 4 Cl solution and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give (R)-2- methyl-N-((R)-1-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)eth yl)propane-2-sulfinamide (285 mg). LC/MS ESI : 281( M+H ) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.20 (s, 1H), 7.90 (s, 1H), 7.49 (d, J = 0.8 Hz, 1H), 4.65 – 4.62 (m, 1H), 4.43 (d, J = 6.0 Hz, 1H), 4.28 (d, J = 3.0 Hz, 3H), 1.57 (d, J = 6.7 Hz, 3H), 1.25 (s, 9H). [0179] Step 3. Synthesis of (R)-1-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1- amine hydrochloride [0180] To a solution of (R)-2-methyl-N-((R)-1-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide ( 215 mg) in dioxane (6 mL) were added 4N HCl-dioxane (2 mL), and the reaction was stirred at rt for 1 hr. The reaction was then concentrated and used directly in the next step. LC/MS ESI : 177( M+H ) + . [0181] Step 4. Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide [0182] (R)-1-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (135 mg), EDCI ( 177 mg), HOBt (125 mg) and 2-(4-isopropylphenyl)acetic acid (151 mg) were dissolved in anhydrous N,N-dimethylformamide (5.0 mL), and DIEA ( 0.51 mL, 3.064) was then added to the solution. The reaction was stirred at rt for 1h and extracted from water with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaCl, and concentrated in vacuo. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C180250*21mm; Mobile phase: from 20% to 95% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; Flow rate: 50mL /min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength:220 nm), to give (R)-2-(4-isopropylphenyl)-N-(1-(2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide (46.5 mg). LC/MS ESI : 337( M+H ) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.11 (s, 1H), 7.89 (s, 1H), 7.38 (s, 1H), 7.18 (s, 4H), 6.64 (d, J = 6.8 Hz, 1H), 5.24 – 5.16 (m, 1H), 4.27 (s, 3H), 3.54-3.52 (m, 2H), 2.93-2.86 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H). Example 3. (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[4,3-c]p yridin-6- yl)ethyl)acetamide [0183] Step 1. Synthesis of methyl 1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate and methyl 2-methyl-2H-pyrazolo[4,3-c]pyridine-6-carboxylate [0184] To a solution of methyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate (2.0 g) in anhydrous DMF (20 mL) were added Cs 2 CO 3 (5.5 g) and iodomethane(1.8 g), and the reaction was stirred at RT for 18 hr. Water and EtOAc were then added to the reaction mixture. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by silica gel column chromatography to give methyl 1- methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (1.2 g) and methyl 2-methyl-2H- pyrazolo[4,3-c]pyridine-6-carboxylate (0.54 g). [0185] Methyl 1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate: LC/MS ESI (m/z):192 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 1.2 Hz, 1H), 8.44 (t, J = 1.0 Hz, 1H), 8.41 (d, J = 0.9 Hz, 1H), 4.17 (s, 3H), 3.92 (s, 3H). [0186] Methyl 2-methyl-2H-pyrazolo[4,3-c]pyridine-6-carboxylate: LC/MS ESI (m/z):192 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 1.2 Hz, 1H), 8.78 (s, 1H), 8.28 (t, J = 1.0 Hz, 1H), 4.28 (s, 3H), 3.89 (s, 3H). [0187] Step 2. Synthesis of (1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)methanol [0188] To a solution of methyl 1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (350 mg) in THF (5 mL) was added lithium aluminum hydride (208.42 mg) at 0 °C, and the mixture was stirred at 25 °C for 2 hr. The mixture was then quenched with an aqueous NaOH solution (2M) and extracted with DCM. The combined extracts were dried, filtered and concentrated to give (1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)methanol (160 mg) as a yellow oil, which was directly used for next step. LC/MS ESI (m/z): 164 [M+H]+ [0189] Step 3. Synthesis of 1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carbaldehyde [0190] To a solution of (1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)methanol (160 mg) in DCM (5 mL) was added manganese dioxide (426.3 mg). The mixture was stirred at 25 °C for 3 hr. The mixture was then filtered, and the filtrate was concentrated in vacuo to provide a residue, which was directly used for next reaction. LC/MS ESI (m/z): 265 [M+H] + [0191] Step 4. Synthesis of methyl (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[4,3- c]pyridin-6-yl)methylene)propane-2-sulfinamide [0192] To the solution of (1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)methanol (140 mg) in CH 2 Cl2 (10 mL) was added (R)-2-methylpropane-2-sulfinamide (105.3 mg) and copper(II) sulfate (693.3 mg ) at rt, and the mixture was stirred at rt overnight. LC/MS showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted twice with EtOAc. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 2: 1) to give (R,E)-2-methyl-N-((1-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)methylene)propane-2-sulfinami de (110 mg) as a yellow solid. LC/MS ESI (m/z): 265 [M+H] + . [0193] Step 5. Synthesis of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6- yl)ethyl)propane-2-sulfinamide [0194] To a solution of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[4,3-c]pyridin-6- yl)methylene)propane-2-sulfinamide (110 mg) in THF (5 mL) was added CH 3 MgBr (0.41 mL, 3M in ether) under N2 at -78 °C, and the mixture was stirred at -78 °C for 1h. LC/MS showed the reaction was complete. The reaction mixture was then quenched with ice-water and extracted with twice EtOAc. The combined extracts were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH = 10:1) to give (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6- yl)ethyl)propane-2-sulfinamide (80 mg) as a light yellow oil. LC/MS ESI (m/z): 281 [M+H] + . [0195] Step 6. Synthesis of (R)-1-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)ethan-1-amine hydrochloride [0196] To a solution of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6- yl)ethyl)propane-2-sulfinamide (85 mg) in dioxane (3.0 mL) was added 4N HCl in dioxane (253.9 mg) at room temperature, and the mixture was stirred at room temperature for 2 hrs. LC/MS showed the reaction was completed. The solvent was removed to give (R)-1-(1- methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)ethan-1-amine hydrochloride (85 mg). LC/MS ESI (m/z): 177 [M+H] + . [0197] Step 7. Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[4,3- c]pyridin-6-yl)ethyl)acetamide [0198] To a solution of (R)-1-(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)ethan-1-amine hydrochloride (91 mg) in CH 2 Cl 2 (5 mL) was added 2-(4-isopropylphenyl)acetic acid (92 mg), HATU (392 mg) and triethylamine (156 mg), and the mixture was stirred at room temperature for 2 hrs. LC/MS showed the reaction was complete. The reaction mixture was then quenched by ice-water and extracted with twice EtOAc. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 3: 1) and then prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H2O; Gradient: B 40%) to give (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[4,3-c]p yridin-6- yl)ethyl)acetamide (28 mg) as a white solid. LC/MS ESI (m/z): 337 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 1H), 8.14 (s, 1H), 7.36 (s, 1H), 7.20 – 7.11 (m, 4H), 6.87 (d, J = 7.5 Hz, 1H), 5.28-5.24 (m, 1H), 4.06 (s, 3H), 3.57 (s, 2H), 2.89 -2.85 (m, 1H), 1.50 (t, J = 8.0 Hz, 3H), 1.23 (t, J = 8.0 Hz, 6H). Example 4. (R)-2-(4-isopropylphenyl)-N-(1-(2-methyl-2H-pyrazolo[4,3-c]p yridin-6- yl)ethyl)acetamide [0199] Step 1. (2-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)methanol [0200] To a solution of methyl 2-methyl-2H-pyrazolo[4,3-c]pyridine-6-carboxylate (530 mg) in THF(10 mL) was added lithium aluminum hydride (315.6 mg ) at 0 °C, and the mixture was stirred at 25 °C for 3 hr. The mixture was then quenched with aqueous NaOH (2M) and extracted with DCM. The combined extracts were dried, filtered and concentrated to give (2-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)methanol (280 mg, colorless oil), which was used for next step directly. LC/MS ESI (m/z): 164 [M+H] + . [0201] Step 2.2-methyl-2H-pyrazolo[4,3-c]pyridine-6-carbaldehyde [0202] To a solution of (2-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)methanol (280 mg) in DCM (5 mL) was added manganese dioxide (0.12 mL), and the mixture was stirred at 25 °C for 3 hr. The mixture was then filtered, and the filtrate was concentrated in vacuo to provide crude 2-methyl-2H-pyrazolo[4,3-c]pyridine-6-carbaldehyde, which was directly used for next step. LC/MS ESI (m/z): 162 [M+H] + . [0203] Step 3. (R,E)-2-methyl-N-((2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl)methylene)propane-2-sulfinamide [0204] A solution of 2-methyl-2H-pyrazolo[4,3-c]pyridine-6-carbaldehyde (280 mg), (R)- 2-methylpropane-2-sulfinamide (316 mg) and copper sulfate pentahydrate (465 mg) in DCM (5.0 mL) was stirred at 25 °C for 3 hr. The mixture was then filtered and concentrated to give a yellow oil, which was purified by column chromatography on silica gel (DCM: MeOH = 50:1 to 20:1) to give (R,E)-2-methyl-N-((2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl)methylene)propane-2-sulfinamide (400 mg) as a yellow solid. LC/MS ESI (m/z): 265 [M+H] + [0205] Step 4. (R)-2-methyl-N-((R)-1-(2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl)ethyl)propane-2-sulfinamide [0206] To a solution of (R,E)-2-methyl-N-((2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl)methylene)propane-2-sulfinamide (180 mg ) in THF (5 mL) was added CH 3 MgBr (3M in ether, 2.0 mL) at -70 °C, and the mixture was stirred at -70 °C for 2 hr. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with EtOAc (10 mL). The organic layer was dried, filtered and concentrated to give a yellow oil, which was purified by column chromatography on silica gel (DCM: MeOH =50:1 to 20:1) to give (R)-2-methyl-N-((R)-1-(2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl)ethyl)propane-2- sulfinamide (40 mg) as a white solid. LC/MS ESI (m/z): 281 [M+H] + [0207] Step 5. (R)-1-(2-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)ethan-1-amine hydrochloride [0208] To a solution of 2-methyl-N-[(1R)-1-{2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl}ethyl]propane-2-sulfinamide (40 mg ) in dioxane (2 mL) was added HCl/dioxane (4 N in dioxane, 1 mL), and the mixture was stirred at 25 °C for 30 min. The mixture was then concentrated to get (R)-1-(2-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)ethan-1-amine hydrochloride (30 mg, crude) as a white solid. LC/MS ESI (m/z): 177 [M+H] + [0209] Step 6. (R)-2-(4-isopropylphenyl)-N-(1-(2-methyl-2H-pyrazolo[4,3-c]p yridin-6- yl)ethyl)acetamide [0210] A solution of (R)-1-(2-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)ethan-1-amine hydrochloride (30 mg), 2-[4-(propan-2-yl)phenyl]acetic acid (33.4 mg), HATU (97 mg) and TEA (0.07 mL) in DCM (2.0 mL) was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue product, which was purified by prep-HPLC [Column: Shim- pack GIST C18250*21mm; Mobile phase: from 10% to 85% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to give (R)-2-(4- isopropylphenyl)-N-(1-(2-methyl-2H-pyrazolo[4,3-c]pyridin-6- yl)ethyl)acetamide (14 mg) as a colorless oil. LC/MS ESI (m/z): 337 (M+H) + ; [0211] 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.06 (s, 1H), 7.40 (s, 1H), 7.20 (s, 4H), 6.67 (d, J = 7.6 Hz, 1H), 5.26-6.19 (m, 1H), 4.25 (s, 3H), 3.57-3.56 (m, 2H), 2.94-2.87 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 8.0 Hz, 6H). Example 5. (R)-2-(4-isopropylphenyl)-N-(1-(3-methylisoxazolo[4,5-c]pyri din-6- yl)ethyl)acetamide [0212] Synthesis of 4,6-dichloro-N-methoxy-N-methylnicotinamide. [0213] To a solution of 4,6-dichloronicotinic acid (5.0 g) in DCM (70 mL) was added HATU (10.9 g, 28.6) at rt, and the reaction was stirred for 10 min. Then N- methoxymethanamine, HCl (3.0 g) and TEA (10.8 mL) were added at rt, and the mixture was stirred at rt for 2 h. The mixture was then quenched with water and extracted with EA. The combined extracts were washed with brine, dried over with Na 2 SO 4 and concentrated in vacuo to give 4,6-dichloro-N-methoxy-N-methylnicotinamide (6.0 g) as a yellow oil. LC/MS ESI: 234( M+H ) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.96 (s, 1H), 3.49 (s, 3H), 3.32 (s, 3H). [0214] Synthesis of 1-(4,6-dichloropyridin-3-yl)ethan-1-one [0215] 4,6-Dichloro-N-methoxy-N-methylnicotinamide (6.0 g) was dissolved in anhydrous THF (86 mL) and stirred at 0-5°C for 10 min. MeMgBr (14 mL, 3 M in ether) was then added slowly to the solution. After 2h at 0-5°C, the starting material was consumed, and the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined exrracts were washed with brine, dried over with Na 2 SO 4 , and evaporated to give an oil. The oil was purified by silica gel column chromatography affording 1-(4,6- dichloropyridin-3-yl)ethan-1-one (4.3 g). LC/MS ESI: 190 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 7.46 (s, 1H), 2.68 (s, 3H). [0216] Step 3. Synthesis of (E)-1-(4-chloro-6-styrylpyridin-3-yl)ethan-1-one and (E)-1-(6- chloro-4-styrylpyridin-3-yl)ethan-1-one [0217] To a mixture of 1-(4,6-dichloropyridin-3-yl)ethan-1-one (228 mg) and (E)- styrylboronic acid (266 mg) in DMF ( 6.0 mL) was added Pd(PPh3)4 (100 mg) and 2 N Cs 2 CO 3 (1.8 mL). The reaction was charged with N 2 for three time and stirred at 80 °C for 6 h, 50 mL of EA was added to the reaction. The organic phase was washed with brine, dried over Na 2 SO 4 , filtered. The filtrate was concentrated under vacuo, and the residue was purified by silica gel column chromatography (10% EA in PE) to give (E)-1-(4-chloro-6- styrylpyridin-3-yl)ethan-1-one and (E)-1-(6-chloro-4-styrylpyridin-3-yl)ethan-1-one as a mixture of isomers. LC/MS ESI (m/z): 258(M+H) + . [0218] Synthesis of 1-(4-chloro-6-((E)-styryl)pyridin-3-yl)ethan-1-one oxime To a solution of (E)-1-(4-chloro-6-styrylpyridin-3-yl)ethan-1-one and (E)-1-(6-chloro-4- styrylpyridin-3-yl)ethan-1-one (1.5 g, mixture of isomers) in EtOH (25 mL) and H 2 O (5 mL) were added hydroxylamine hydrochloride (0.80 g) and Na 2 CO 3 (1.2 g). The reaction was stirred at 65 °C overnight. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography to give 1-(4-chloro-6-((E)-styryl)pyridin-3-yl)ethan-1-one oxime (307 mg). LC/MS ESI: 273 ( M+H ) + . [0219] Synthesis of (E)-3-methyl-6-styrylisoxazolo[4,5-c]pyridine [0220] To a solution of 1-(4-chloro-6-((E)-styryl)pyridin-3-yl)ethan-1-one oxime (307 mg) in DMSO (15 mL ) were added K2CO3 (466.741 mg), and the reaction was stirred at 100 °C for 2 hr. After cooling to rt, water and EtOAc were added. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography to give (E)-3-methyl-6-styrylisoxazolo[4,5-c]pyridine (235 mg). LC/MS ESI: 237 M+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.7 Hz, 1H), 7.87 – 7.83 (m, 2H), 7.70 (d, J = 7.3 Hz, 2H), 7.46 – 7.42 (m, 3H), 7.36 (d, J = 7.3 Hz, 1H), 2.64 (s, 3H). [0221] Synthesis of 3-methylisoxazolo[4,5-c]pyridine-6-carbaldehyde [0222] Ozone was bubbled through a solution of (E)-3-methyl-6-styrylisoxazolo[4,5- c]pyridine (486 mg) in anhydrous DCM (20 mL) at -78°C for 10 mins. The ozone gas was then purged with nitrogen for ten minutes, and PPh3 (644 mg) was added at room temperature. The reaction was stirred for another 40 minutes. The solvent was filtered, and the filtrate was concentrated in vacuum to get a residue, which was purified by silica gel column chromatography to give 3-methylisoxazolo[4,5-c]pyridine-6-carbaldehyde (150 mg). LC/MS ESI : 163( M+H ) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 10.27 (s, 1H), 9.15 (d, J = 0.4 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 2.74 (s, 3H). [0223] Synthesis of (R,E)-2-methyl-N-((3-methylisoxazolo[4,5-c]pyridin-6- yl)methylene)propane-2-sulfinamide [0224] To a solution of 3-methylisoxazolo[4,5-c]pyridine-6-carbaldehyde (150 mg) in anhydrous DCM (15 mL ) was added (R)-2-methylpropane-2-sulfinamide (145.8 mg) and CuSO 4 ( 738 mg), and the reaction mixture was stirred at rt overnight. The reaction was then filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography, to give (R,E)-2-methyl-N-((3-methylisoxazolo[4,5-c]pyridin-6- yl)methylene)propane-2-sulfinamide (197 mg) as a white solid. LC/MS ESI : 266( M+H ) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (d, J = 0.9 Hz, 1H), 8.86 (s, 1H), 8.19 (d, J = 0.9 Hz, 1H), 2.72 (s, 3H), 1.32 (s, 9H) ppm. [0225] Synthesis of (R)-2-methyl-N-((R)-1-(3-methylisoxazolo[4,5-c]pyridin-6- yl)ethyl)propane-2-sulfinamide [0226] To a solution of (R,E)-2-methyl-N-((3-methylisoxazolo[4,5-c]pyridin-6- yl)methylene)propane-2-sulfinamide (197 mg) in anhydrous THF (10 mL) was added CH 3 MgBr (1.2 mL, 3.0M in ether) dropwise at -78°C under N 2 . The Grignard regent was added at such a rate that the internal reaction temperature was never warmer than -60°C. After addition, the reaction mixture was stirred for 2h at -78 °C then warmed to room temperature and quenched with saturated aqueous ammonium chloride. The organic layer was separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over with Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (R)-2-methyl-N-((R)-1-(3- methylisoxazolo[4,5-c]pyridin-6-yl)ethyl)propane-2-sulfinami de (187 mg). LC/MS ESI : 282 ( M+H ) + ; 1H NMR (400 MHz, CDCl 3 ) δ 8.93 (d, J = 1.0 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 4.72 – 4.63 (m, 2H), 2.64 (s, 3H), 1.57 (d, J = 6.5 Hz, 3H), 1.26 (s, 9H). [0227] Synthesis of (R)-1-(3-methylisoxazolo[4,5-c]pyridin-6-yl)ethan-1-amine, hydrochloride [0228] To a solution of (R)-2-methyl-N-((R)-1-(3-methylisoxazolo[4,5-c]pyridin-6- yl)ethyl)propane-2-sulfinamide (172 mg) in dioxane (6.0 mL) were added 4N HCl-Dioxane (2.0 mL). The reaction was stirred at rt for 20 min, and the mixture was concentrated to provide (R)-1-(3-methylisoxazolo[4,5-c]pyridin-6-yl)ethan-1-amine, hydrochloride, as a residue, which was directly used in the next step. LC/MS ESI : 178( M+H ) + . [0229] Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(3-methylisoxazolo[4,5-c]pyri din-6- yl)ethyl)acetamide [0230] (R)-1-(3-methylisoxazolo[4,5-c]pyridin-6-yl)ethan-1-amine hydrochloride (108 mg) was dissolved in anhydrous DCM (10 mL) and then 2-(4-isopropylphenyl)acetic acid (119.5 mg) , HATU ( 347.6 mg) and DIPEA (0.2 mL) were added. The reaction was stirred at rt for 1h, and the mixture was diluted with water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by prep-HPLC [Column: Shim-pack GIST C18250*21mm; Mobile phase: from 10% to 95% MeCN with H 2 O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to give (R)-2-(4- isopropylphenyl)-N-(1-(3-methylisoxazolo[4,5-c]pyridin-6-yl) ethyl)acetamide (93.7 mg) as a white solid. LC/MS ESI : 338( M+H ) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 7.34 (s, 1H), 7.23 – 7.18 (m, 4H), 6.60 (d, J = 7.3 Hz, 1H), 5.29-5.22 (m, 1H), 3.57 (s, 2H), 2.95-2.90 (m, 1H), 2.63 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 6.9 Hz, 6H). Example 6. (R)-2-(4-isopropylphenyl)-N-(1-(3-methylisoxazolo[5,4-c]pyri din-5- yl)ethyl)acetamide [0231] Synthesis of 2,5-dichloro-N-methoxy-N-methylisonicotinamide. [0232] To a solution of 2,5-dichloroisonicotinic acid (5.0 g) in DCM (70 mL) were added HATU (10.9 g) at rt, and the reaction was stirred at rt for 10 min. Hydrochloride N- methoxymethanamine (3.0 g) and TEA (10.8 mL) was then added to the reaction mixture, and the mixture solution was stirred at rt for 2 h. The reaction was quenched with water and extracted with EA. The organic layer was separated, washed with brine, dried over with Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 2,5-dichloro-N-methoxy-N-methylisonicotinamide (6.0 g) as a white solid. [0233] Synthesis of 1-(2,5-dichloropyridin-4-yl)ethan-1-one. [0234] 2,5-dichloro-N-methoxy-N-methylisonicotinamide (5.0 g) was dissolved in anhydrous tetrahydrofuran (71 mL) and stirred at 0-5 °C under N2 for 10 mins. Then, CH 3 MgBr (11 mL, 3.0M in ether) was slowly added to the solution, and the reaction was stirred at 0-5°C for 2h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give an oil which was purified by silica gel column chromatography to give 1-(2,5-dichloropyridin-4-yl)ethan-1-one ( 3.4 g ). LC/MS ESI (m/z): 189.9 [M+H] + [0235] Synthesis of (E)-1-(5-chloro-2-styrylpyridin-4-yl)ethan-1-one [0236] To a solution of 1-(2,5-dichloropyridin-4-yl)ethan-1-one (1.1 g), (E)-styrylboronic acid (1.3 g) in DMF was added 2.0 N Cs 2 CO 3 (6.0 mL) and Pd(PPh 3 ) 4 (420 mg). The reaction mixture was stirred at 80 °C for 5 hours. EA (50 mL) and H 2 O (40 mL) were added. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography (eluting with 10% EA in PE) to give (E)-1-(5-chloro-2-styrylpyridin-4-yl)ethan-1-one as yellow solid (900 mg). [0237] Synthesis of 1-(5-chloro-2-((E)-styryl)pyridin-4-yl)ethan-1-one oxime [0238] To a solution of 1-(5-chloro-2-styrylpyridin-4-yl)ethan-1-one ( 1.48 g) in EtOH (25 mL ) and H 2 O (5 mL ) were added NH 2 OH·HCl (0.8 g) and Na 2 CO 3 (1.21 g). The reaction was stirred at 65°C overnight. Then the reaction was then diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography to give 1-(5-chloro-2-((E)- styryl)pyridin-4-yl)ethan-1-one oxime ( 294 mg ). LC/MS ESI (m/z): 273 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.71 (s, 1H), 7.76 - 7.70 (m, 3H), 7.57 (s, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 11.7 Hz, 2H), 2.18 (s, 3H) ppm. [0239] Synthesis of (E)-3-methyl-5-styrylisoxazolo[5,4-c]pyridine [0240] To a solution of 1-(5-chloro-2-((E)-styryl)pyridin-4-yl)ethan-1-one oxime (294 mg) in DMSO (10 mL) were added K 2 CO 3 (448.2 mg). The reaction was stirred at 100°C for 2 hr. After cooling to RT, water and EtOAc were added to the reaction mixture. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography to give (E)-3-methyl-5-styrylisoxazolo[5,4- c]pyridine (231 mg) as a yellow solid. LC/MS ESI (m/z): 237 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.06 (s, 1H), 7.69 (t, J = 11.2 Hz, 3H), 7.50 – 7.39 (m, 3H), 7.33 (t, J = 7.3 Hz, 1H), 2.63 (s, 3H). [0241] Synthesis of 3-methylisoxazolo[5,4-c]pyridine-5-carbaldehyde [0242] Ozone was bubbled through a solution of (E)-3-methyl-5-styrylisoxazolo[5,4- c]pyridine (483 mg) in anhydrous DCM (10 mL) at -78°C for 10 min. Excess ozone gas was then purged with nitrogen, followed by the addition of triphenylphosphine (644 mg). The mixture was stirred for another 40 min and then concentrated in vacuum to get a residue, which was purified by silica gel column chromatography to give 3-methylisoxazolo[5,4- c]pyridine-5-carbaldehyde (200 mg) . LC/MS ESI (m/z):163 [M+H] + . [0243] 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 9.16 (s, 1H), 8.35 (d, J = 0.9 Hz, 1H), 2.70 (s, 3H). [0244] Synthesis of (R,E)-2-methyl-N-((3-methylisoxazolo[5,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide [0245] To a solution of 3-methylisoxazolo[5,4-c]pyridine-5-carbaldehyde (0.23 g) in anhydrous dichloromethane (10 mL) were added (R)-2-methylpropane-2-sulfinamide (0.26 g) and CuSO 4 ( 1.15 g), and the reaction was stirred at rt overnight. The reaction solution was then filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give (R,E)-2-methyl-N-((3-methylisoxazolo[5,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (309 mg ) as a white solid. LC/MS ESI (m/z):266 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 1.1 Hz, 1H), 8.69 – 8.62 (m, 2H), 2.69 (s, 3H), 1.24 (s, 9H) ppm. [0246] Synthesis of (R)-2-methyl-N-((R)-1-(3-methylisoxazolo[5,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide [0247] To a solution of (R,E)-2-methyl-N-((3-methylisoxazolo[5,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (337 mg) in Anhydrous tetrahydrofuran (5.0 mL ) was added CH 3 MgBr (1.7 mL, 3.0M in Et2O) dropwise at -78 °C. The Grignard regent was added at a rate such that the internal reaction temperature was never higher than -60 °C. After addition, the mixture was stirred for 3h at -78 °C, then warmed to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography to give (R)-2-methyl-N-((R)-1-(3- methylisoxazolo[5,4-c]pyridin-5-yl)ethyl)propane-2-sulfinami de (226 mg). LC/MS ESI (m/z):282 [M+H] + . [0248] Synthesis of (R)-1-(3-methylisoxazolo[5,4-c]pyridin-5-yl)ethan-1-amine, hydrochloride [0249] To a solution of (R)-2-methyl-N-((R)-1-(3-methylisoxazolo[5,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide (219 mg) in dioxane (3 mL) were added 4N HCl-Dioxane (1 mL), and the reaction was stirred at rt for 30 min. Then the mixture was concentrated in vacuo to get a crude product of (R)-1-(3-methylisoxazolo[5,4-c]pyridin-5-yl)ethan-1-amine, hydrochloride, which was used as is in next step. LC/MS ESI (m/z):178 [M+H] + . [0250] Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(3-methylisoxazolo[5,4-c]pyri din-5- yl)ethyl)acetamide [0251] (R)-1-(3-methylisoxazolo[5,4-c]pyridin-5-yl)ethan-1-amine, hydrochloride (137 mg) was dissolved in anhydrous DCM (15 mL) and then 2-[4-(propan-2-yl)phenyl]acetic acid (151.6 mg), HATU (587.9 mg) and TEA ( 0.32 mL) were added to the solution. The reaction was stirred at rt for 1h and then diluted with water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by Prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to give (R)-2-(4- isopropylphenyl)-N-(1-(3-methylisoxazolo[5,4-c]pyridin-5-yl) ethyl)acetamide (146.8 mg) as a colorless oil. LC/MS ESI (m/z):338 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 7.48 (s, 1H), 7.20 – 7.16 (m, 4H), 6.55 (d, J = 7.6 Hz, 1H), 5.32-5.25 (m, 1H), 3.55 (s, 2H), 2.92-2.89 (m, 1H), 2.60 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H). Example 7. (R)-2-(4-isopropylphenyl)-N-(1-(1-propyl-1H-pyrazolo[3,4-c]p yridin-5- yl)ethyl)acetamide [0252] Synthesis of methyl 1-propyl-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde [0253] A solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (480 mg), 1-iodopropane (0.35 mL) and Cs 2 CO 3 (1.6 g) in DMF (1.0 mL) was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue which was purified by column chromatography on silica gel (DCM: MeOH = 1:0 to 20:1) to give 1-propyl-1H-pyrazolo[3,4-c]pyridine-5- carbaldehyde (185 mg) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 10.22 (s, 1H), 9.06 (s, 1H), 8.39 (d, J = 1.2Hz, 1H), 8.24 (s, 1H), 4.51 (t, J = 7.2 Hz, 2H), 2.06-2.04 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). and 2-propyl-2H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (125 mg) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 10.18 (s, 1H), 9.32 (s, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.20 (s, 1H), 4.49 (t, J = 7.2 Hz, 2H), 2.12-2.08 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). [0254] Synthesis of (R,E)-2-methyl-N-((1-propyl-1H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide [0255] To a solution of 1-propyl-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (185 mg) in anhydrous DCM (11 mL) were added (R)-2-methylpropane-2-sulfinamide (154.0 mg) and CuSO4 (234.1 mg). The reaction was stirred at RT for overnight. The solid was filtered with Celite. Then, the filtrate was concentrated to provide a residue, which was purified by silica gel column chromatography to give (R,E)-2-methyl-N-((1-propyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)methylene)propane-2-sulfinamide (233 mg). LC/MS ESI (m/z): 293 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 4.57 (t, J = 6.9 Hz, 2H), 1.94 – 1.89 (m, 2H), 1.22 (s, 9H), 0.84 (t, J = 7.4 Hz, 3H). [0256] Synthesis of (R)-2-methyl-N-((R)-1-(1-propyl-1H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide [0257] To a solution of (R,E)-2-methyl-N-((1-propyl-1H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (233 mg) in anhydrous THF (10 mL) was added 3M CH 3 MgBr (1.328 mL, 3M in ether) dropwise under N 2 , and the reaction was stirred at -60°C for 2 hr. The reaction was quenched with aq. NH4Cl and extracted with EA. The combined extracts were washed with saturated NaCl, dried over with Na 2 SO 4 , filtered and concentrated in vacuo. The residue was then purified by silica gel column chromatography to give (R)-2- methyl-N-((R)-1-(1-propyl-1H-pyrazolo[3,4-c]pyridin-5-yl)eth yl)propane-2-sulfinamide (146 mg). LC/MS ESI (m/z): 309 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.19 (d, J = 0.6 Hz, 1H), 7.80 (d, J = 0.6 Hz, 1H), 5.63 (d, J = 7.5 Hz, 1H), 4.62 – 4.44 (m, 2H), 1.93 – 1.84 (m, 2H), 1.48 (d, J = 6.8 Hz, 3H), 1.14 (s, 9H), 0.83 (t, J = 7.4 Hz, 3H) ppm. [0258] Synthesis of (R)-1-(1-propyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethanamine, hydrochloride [0259] To a solution of (R)-2-methyl-N-((R)-1-(1-propyl-1H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide (95 mg) in dioxane (3 mL) was added 4N HCl-dioxane (1.0 mL). The reaction was stirred at rt for 30 min. Then the mixture was concentrated to provide (R)-1-(1-propyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethanamine hydrochloride, which was used directly in the next step. LC/MS ESI (m/z): 205 [M+H] + . [0260] Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(1-propyl-1H-pyrazolo[3,4-c]p yridin- 5-yl)ethyl)acetamide [0261] To a solution of (R)-1-(1-propyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethanamine hydrochloride (82 mg) in anhydrous DMF were added DIEA (0.12 mL, Solution A). To a solution of 2-(4-isopropylphenyl)acetic acid (78.7 mg) in anhydrous DMF were added HATU ( 167.9 mg) and stirred 3 min at RT (Solution B). Solution A was added to the solution B and stirred at RT for 1h. The mixture was diluted with water, and the aqueous phase was extracted with DCM (10 mL x3). The combined extracts were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by Prep-HPLC [Column: YMC Triart C18 250*20mm I.D,5um; Mobile phase: from 10% to 95% MeCN with H 2 O (0.1%FA); flow rate: 14 mL/min; wavelength: 220 nm/254 nm] to give (R)-2-(4-isopropylphenyl)-N-(1-(1-propyl- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. LC/MS ESI (m/z): 365 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 1H), 7.98 (s, 1H), 7.49 (s, 1H), 7.19 (s, 4H), 6.62 (d, J = 7.8 Hz, 1H), 5.28-5.21 (m, 1H), 4.42 (t, J = 7.0 Hz, 2H), 3.56 -3.55(m, 2H), 2.92-2.88 (m, 1H), 2.00 - 1.96 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H), 0.93 (t, J = 7.4 Hz, 3H). Example 8. (R)-N-(1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-(4 - isopropylphenyl)acetamide [0262] Synthesis of 5-bromo-1H-pyrazolo[3,4-c]pyridine [0263] To a solution of 6-bromo-4-methylpyridin-3-amine (1.0 g) in acetic acid (60 mL) were added sodium nitrite (0.37 mL) in an ice bath. The reaction was stirred at RT overnight. Then the reaction was concentrated and then treated with saturated aqueous NaHCO 3 . The aqueous mixture was extracted with EA. The combined extracts were washed with brine, dried over with Na 2 SO 4 , filtered and concentrated in vacuo. Then the residue was purified by silica gel column chromatography, to give 5-bromo-1H-pyrazolo[3,4-c]pyridine (442 mg). LC/MS ESI (m/z): 198 [M+H] + . [0264] Synthesis of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde [0265] To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (3.3 g) in anhydrous THF (100 mL) was added n-BuLi (20.0 mL, 2 N in THF) at -78 °C. The mixture was stirred at - 78 °C for 1 hr. DMF (3.87 mL) was then added to the mixture at -78 °C, and the mixture was stirred at -78 °C for 1 hr. The reaction was warmed to rt and quenched with an NH4Cl solution. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (DCM:MeOH =1:0 to 20:1) to give 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (1.0 g) as a white solid. LC/MS ESI (m/z): 148 [M+H] + [0266] Synthesis of 1-ethyl-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde [0267] A solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (480 mg), ethyl iodide (0.35 mL) and Cs 2 CO 3 (1.6 g) in DMF (1.0 mL) was stirred at 25 °C for 12 hr. The mixture was then diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (DCM:MeOH = 1:0 to 20:1) to give 1-ethyl-1H-pyrazolo[3,4-c]pyridine-5- carbaldehyde (185 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ10.11 (s, 1H), 9.39 (s, 1H), 8.53 – 8.39 (m, 2H), 4.65 (q, J =7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H). and 2-propyl- 2H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (125 mg) as a white solid. 1 H NMR (400 MHz, DMSO): 10.05 (s, 1H), 9.36 – 9.23 (m, 1H), 8.85 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H). [0268] Synthesis of (R,E)-N-((1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)methylene)- 2- methylpropane-2-sulfinamide [0269] To a solution of 1-ethyl-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (186 mg) in anhydrous DCM (10 mL) were added 2-methylpropane-2-sulfinamide (157.6 mg) and CuSO4 (239.4 mg). The reaction was stirred at rt overnight. The mixture was then filtered, and the filtrate was concentrated in vacuum to get a residue, which was purified by silica to give (R,E)-N-((1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)methylene)- 2-methylpropane-2- sulfinamide (207 mg) as a white solid. LC/MS ESI (m/z): 279 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.64 (s, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 0.6 Hz, 1H), 4.66 – 4.61 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.22 (s, 9H) ppm. [0270] Synthesis of (R)-N-((R)-1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)- 2- methylpropane-2-sulfinamide [0271] To a solution of (R,E)-N-((1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)methylene)- 2- methylpropane-2-sulfinamide (207 mg ) in anhydrous THF (15 mL) were added CH 3 MgBr (1.24 mL, 3.0M in ether) dropwise. The reaction was stirred at -60°C for 2 hr. The reaction was then quenched with saturated NH4Cl solution. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography, to give (R)-N-((R)-1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)-2-methylpropane-2-sulfinamide (103 mg) as a yellow oil: LC/MS ESI (m/z): 295 [M+H] + . [0272] Synthesis of (R)-1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine, hydrochloride [0273] To a solution of (R)-N-((R)-1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)- 2- methylpropane-2-sulfinamide (142 mg) in dioxane (3 mL) was added 4N HCl-dioxane (1 mL), and the reaction was stirred at rt for 30 min. The mixture was then concentrated to provide the (R)-1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine, hydrochloride, which was used directly for next step. LC/MS ESI (m/z): 191 [M+H] + . [0274] Synthesis of (R)-N-(1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-(4 - isopropylphenyl)acetamide [0275] To a solution of (R)-1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethanamine hydrochloride (134 mg) in anhydrous DMF were added DIEA (0.5 mL) to provide Solution A. To a solution of 2-(4-isopropylphenyl)acetic acid (95.9 mg) in anhydrous DMF was added HATU (225 mg) and stirred at RT for 3 min to provide Solution B. Solution A was added to the Solution B and stirred at RT for 1h. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by prep-HPLC [Column: Xbudge prep C18250*19mm 5um OBD; Mobile phase: from 10% to 95% MeCN with H 2 O (0.1 FA); flow rate: 20 mL/min; wavelength: 205 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; wavelength: 220 nm) to give (R)-N-(1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-(4 - isopropylphenyl)acetamide (44.8 mg) as a white solid. LC/MS ESI (m/z): 351 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 7.97 (s, 1H), 7.49 (s, 1H), 7.19 (s, 4H), 6.62 (d, J = 7.2 Hz, 1H), 5.28-5.21 (m, 1H), 4.52 (q, J = 7.3 Hz, 2H), 3.55 (s, 2H), 2.92-2.87 (m, 1H), 1.56 (t, J = 7.3 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H). Example 9. (R)-N-(1-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-(4 - isopropylphenyl)acetamide [0276] Step 1. Synthesis of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5- carbaldehyde [0277] A solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (760 mg), 1,1,1-trifluoro- 2-iodoethane (0.51 mL) and Cs 2 CO 3 (2.5 g) in DMF (10 mL) was stirred at 100°C for 12 hr. The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH=1:0 to 20:1) to give 1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridine-5-carbaldehyde (500 mg) as a yellow solid. LC/MS ESI (m/z): 230 [M+H] + . [0278] Step 2. Synthesis of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)methylene)propane-2-sulfinamide [0279] A solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbal dehyde (500 mg), (R)-2-methylpropane-2-sulfinamide (396.7 mg) and copper sulfate pentahydrate (1.0 g) in DCM (15 mL) was stirred at 25 °C for 12 hr. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH =1:0 to 20:1) to give (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene)propane-2-sulfinamide (450 mg) as a yellow solid. LC/MS ESI (m/z): 333 [M+H] + . [0280] Step 3. Synthesis of (R)-2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)propane-2-sulfinamide [0281] To a solution of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)methylene)propane-2-sulfinamide (450 mg) in THF (5 mL) was added CH 3 MgBr (3.0M in ether, 1.35 mL) at -78 °C. The mixture was stirred at -78 °C for 2 hr. The mixture was quenched with NH 4 Cl solution and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH =1:0 to 20:1) to give (R)-2-methyl- N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)propane-2- sulfinamide (350 mg) as a yellow solid. LC/MS ESI (m/z): 349 [M+H] + . [0282] Step 4. Synthesis of (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride [0283] To a solution of (R)-2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[ 3,4- c]pyridin-5-yl)ethyl)propane-2-sulfinamide (300 mg) in dioxane (2.0 mL) was added HCl/dioxane (4N in dioxane, 2.0 mL). The mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethan-1-amine hydrochloride (300 mg, crude) as a white solid. LC/MS ESI (m/z): 245 [M+H] + . [0284] Step 5. Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0285] A solution of (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan- 1-amine hydrochloride (300 mg), 2-[4-(propan-2-yl)phenyl]acetic acid (240.8 mg), HATU (560.49 mg) and DIEA (0.41 mL) in DCM (10 mL) was stirred at 25 °C for 12 hr. The mixture was washed with water. The organic layer was dried, filtered and concentrated to give a residue. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C18 250*21mm; Mobile phase: from 50% to 95% MeCN with H2O (0.1% FA); flow rate: 20 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; wavelength: 220 nm) to give (R)-2-(4-isopropylphenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide (128.6 mg) as a white solid. LC/MS ESI (m/z): 405 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.85 (s, 1H), 8.08 (s, 1H), 7.54 (s, 1H), 7.24 - 7.12 (m, 4H), 6.58 (d, J = 7.6 Hz, 1H), 5.27-5.24 (m, 1H), 5.03 (q, J = 8.4 Hz, 2H), 3.59 - 3.51 (m, 2H), 2.95-2.85 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.8 ppm. Example 10. (R)-N-(1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)ethyl)-2-( 4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide [0286] Synthesis of 1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde [0287] To a solution of 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (594 mg) in anhydrous DMF (10 mL) were added Cs 2 CO 3 (1.97 g) and iodomethane ( 630.3 mg), and the reaction was stirred at rt overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 1-methyl-1H-pyrazolo[3,4- b]pyridine-5-carbaldehyde (285 mg).1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde: LC/MS ESI (m/z): 162 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J = 1.3 Hz, 1H), 9.06 (s, 1H), 8.81 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 4.12 (d, J = 1.2 Hz, 3H). [0288] 2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carbaldehyde : LC/MS ESI (m/z): 162 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 9.01 (d, J = 2.1 Hz, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.75 (s, 1H), 4.25 (s, 3H). [0289] Synthesis of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl) methylene)propane-2-sulfinamide [0290] To a solution of 1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (285 mg) in anhydrous DCM (15 mL) were added (R)-2-methylpropane-2-sulfinamide (278.6 mg) and CuSO 4 (423.4 mg), and the reaction was stirred at RT overnight. The solution was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5- yl)methylene)propane-2-sulfinamide (158 mg). LC/MS ESI (m/z): 265 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (d, J = 1.9 Hz, 1H), 8.74 (s, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.13 (s, 1H), 4.20 (s, 3H), 1.29 (s, 9H) ppm. [0291] Step 3. Synthesis of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5- yl)ethyl)propane-2-sulfinamide [0292] To a solution of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5- yl)methylene)propane-2-sulfinamide (407 mg) in anhydrous THF (30 mL) was dropwise added CH 3 MgBr (9.0 mL, 3.0M in ether) and the reaction was stirred at -78°C for 6 hr. The reaction was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The combined extracts were separated, washed with saturated NaCl solution, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5- yl)ethyl)propane-2-sulfinamide (236 mg). LC/MS ESI (m/z): 281 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, J = 2.0 Hz, 1H), 8.04 – 7.95 (m, 2H), 4.79 – 4.73 (m, 1H), 4.16 (s, 3H), 3.43 (d, J = 2.7 Hz, 1H), 1.63 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H). [0293] Step 4. Synthesis of (R)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)ethan-1-amine hydrochloride [0294] To a solution of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5- yl)ethyl)propane-2-sulfinamide (77 mg) in dioxane (3 mL) was added 4N HCl-Dioxane (1.0 mL), and the reaction was stirred at rt for 30 min. Then the mixture was concentrated to provide (R)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)ethan-1-amine hydrochloride and used directly for next step. LC/MS ESI (m/z): 177 [M+H] + . [0295] Step 5. Synthesis of (R)-N-(1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)ethyl)-2- (4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide [0296] To a solution of (R)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)ethan-1-amine hydrochloride (107 mg) in anhydrous DMF (4.0 mL) were added DIEA (0.5 mL) to provide Solution A. To a solution of 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid (134.8 mg) in anhydrous DMF (4.0 mL) was added HATU ( 230.9 mg) and stirred at RT for 10 min to provide Solution B. Then Solution B was added to solution A and stirred at rt for 1h. The reaction was then diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, dried over with Na 2 SO 4 and concentrated in vacuo. The residue was then purified by prep-HPLC (Column: YMC Triart C18250*20mm I.D,5um; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) to give (R)-N-(1-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)ethyl)-2-( 4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide (67.3 mg). LC/MS ESI (m/z): 403 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 5.71 (d, J = 7.4 Hz, 1H), 5.30-5.23 (m, 1H), 4.14 (s, 3H), 3.56 (s, 2H), 1.52 (d, J = 7.0 Hz, 3H), 1.37-1.34 (m, 2H), 1.02-1.01 (m, 2H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.08 (s). Example 11. (R)-2-(4-isopropylphenyl)-N-(1-(2-propyl-2H-pyrazolo[3,4-c]p yridin-5- yl)ethyl)acetamide [0297] Synthesis of (R,E)-2-methyl-N-((2-propyl-2H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide [0298] To a solution of 2-propyl-2H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (34 mg) in CH 2 Cl 2 (2 mL) was added (R)-2-methylpropane-2-sulfinamide (28.3 mg) and copper sulfate pentahydrate (129.5 mg) at rt. The reaction was stirred at room temperature overnight, and LC/MS showed the reaction was complete. The reaction mixture was quenched with ice- water and then extracted with EtOAc. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 3: 1) to give (R,E)-2- methyl-N-((2-propyl-2H-pyrazolo[3,4-c]pyridin-5-yl)methylene )propane-2-sulfinamide (25 mg, yellow solid). LC/MS ESI (m/z): 293 [M+H] + . [0299] Synthesis of (R)-2-methyl-N-((R)-1-(2-propyl-2H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide [0300] To a solution of (R,E)-2-methyl-N-((2-propyl-2H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (100 mg) in THF (3.0 mL) was added CH 3 MgBr (0.45 mL; 3M in ether) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 2 hrs, and LC/MS showed the reaction was complete. The reaction mixture was quenched with ice- water and then extracted with EtOAc twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 3: 1) to give (R)- 2-methyl-N-((R)-1-(2-propyl-2H-pyrazolo[3,4-c]pyridin-5-yl)e thyl)propane-2-sulfinamide (80 mg) as yellow solid. LC/MS ESI (m/z): 309 [M+H] + . [0301] Synthesis of (R)-1-(2-propyl-2H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochlorid [0302] To a solution of (R)-2-methyl-N-((R)-1-(2-propyl-2H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide (80 mg) in dioxane (3 mL) was added HCl-dioxane (0.18 mL, 4N in dioxane) at room temperature. The mixture was stirred at room temperature for 2 hrs, and LC/MS showed the reaction was complete. The solvent was concentrated to give the (R)- 1-(2-propyl-2H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (120 mg, yellow solid), which was used directly for next step. LC/MS ESI (m/z): 204 [M+H] + . [0303] Step 4. Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(2-propyl-2H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide [0304] To a solution of 2-(4-isopropylphenyl)acetic acid (50 mg) in DMF (3.0 mL) were added (R)-1-(2-propyl-2H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (57.0 mg), HATU (160 mg) and DIEA (108.6 mg). The mixture was stirred at room temperature for 2 hrs, and LC/MS showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted with EtOAc twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 1: 1) and further purified by prep-HPLC [Column: YMC-Triart C18250*20.0mm; Mobile phase: from 80% to 5% H 2 O(0.1%FA), from 20% to 95% MeCN; flow rate: 20 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; wavelength: 220 nm) to give (R)-2- (4-isopropylphenyl)-N-(1-(2-propyl-2H-pyrazolo[3,4-c]pyridin -5-yl)ethyl) acetamide (6.7 mg) as a colorless oil. LC/MS ESI (m/z): 365 [M+H] + . [0305] 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 7.17 (s, 4H), 6.66 (d, J = 7.7 Hz, 1H), 5.23-5.15 (m, 1H), 4.42 (t, J = 7.1 Hz, 2H), 3.53 – 3.52 (m, 2H), 2.90-2.85 (m, 1H), 2.08– 2.02 (m, 2H), 1.44 (t, J = 6.9 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). Example 12. (R)-N-(1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-( 4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide [0306] Synthesis of (R)-N-(1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-( 4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide [0307] To a solution of (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (41.2 mg) in anhydrous DMF (5.0 mL) was added DIEA (0.21 mL) to provide Solution A. To a solution of 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid (51.9 mg) in anhydrous DMF (5.0 mL) was added HATU (88.9 mg) and stirred at rt for 5 min to provide Solution B. Solution A was added to the solution B and stirred at RT for 1h. The reaction was then diluted with EA and water. The organic layer was separated, washed with saturated NaCl, dried over Na 2 SO 4 and concentrated in vacuo to get a residue, which was purified by (Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 14 mL/min; wavelength: 220 nm/254 nm) and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; Wavelength: 220 nm) to give (R)-N-(1-(1-methyl- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-(4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide (28.5 mg). LC/MS ESI (m/z): 403 [M+H] + ; 1H NMR (400 MHz, CDCl 3 ) δ 8.80 (s, 1H), 7.97 (s, 1H), 7.49 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.74 (d, J = 7.6 Hz, 1H), 5.27-5.20 (m, 1H), 4.17 (s, 3H), 3.57 (s, 2H), 1.47 (d, J = 6.8 Hz, 3H), 1.36-1.34 (m, 2H), 1.04-1.00 (m, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.07 (s). Example 13. (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[3,4-c]p yridazin-5- yl)ethyl)acetamide [0308] Synthesis of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-ol [0309] A solution of methyl 3,6-dichloropyridazine-4-carboxylate (500 mg), methylhydrazine sulfate (417 g) and DIEA (1.1 g) in MeOH (20 mL) was stirred at 70 °C for 12 hr. The mixture was concentrated to give a residue, which was purified by column chromatography on silica gel (DCM:MeOH = 50:1 to 10:1) to provide 5-chloro-1- methyl-1H-pyrazolo[3,4-c]pyridazin-3-ol (400 mg) as an orange solid. LC/MS ESI (m/z): 185 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 11.90 (s, 1H), 8.23 (s, 1H), 3.96 (s, 3H). [0310] Synthesis of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl trifluoromethanesulfonate [0311] To a solution of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-ol (2.0 g) in DCM (30 mL) were added N-bis(trifluoromethanesulfonyl)aniline (7.7 g), TEA (4.5 mL) and DMAP (264.7 mg). The mixture was stirred at 25 °C for 12 hr and was then washed with water. The organic layer was dried, filtered and concentrated to give a residue, which was purified by chromatography on silica gel (PE:DCM =50:1 to 0:1) to give 5-chloro-1- methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl trifluoromethanesulfonate (600 mg) as a white solid. LC/MS ESI (m/z): 317 [M+H] + . [0312] Synthesis of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazine [0313] A solution of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl trifluoromethanesulfonate (1.1 g), Pd(PPh3)4 (0.20 g) and triethylsilane (1.12 mL) in DMF (2 mL) was stirred at 60 °C for 12 hr. The mixture was diluted with water and DCM, the two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel chromatography (PE:DCM =50:1 to 0:1) to give 5-chloro-1- methyl-1H-pyrazolo[3,4-c]pyridazine (400 mg) as a white solid. LC/MS ESI (m/z): 169 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (s, 1H), 7.79 (s, 1H), 4.28 (s, 3H). [0314] Synthesis of 1-methyl-5-vinyl-1H-pyrazolo[3,4-c]pyridazine [0315] A solution of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridazine (400 mg), pinacol vinylboronate (0.80 mL), K 3 PO 4 (1.2 g) and dichloro[1,1'-bis(dicyclohexylphosphino) ferrocene]palladium(II) (179.3 mg) in dioxane (20 mL) and H 2 O (4 mL) was charged with N 2 and stirred at 100 °C for 12 hr under N 2 . The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue, which was purified by chromatography(PE:DCM= 50:1 to 0:1) to give 1-methyl-5-vinyl-1H- pyrazolo[3,4-c]pyridazine (400 mg, crude) as a yellow solid, which was used for next step. LC/MS ESI (m/z): 161 [M+H] + . [0316] Synthesis of 1-methyl-1H-pyrazolo[3,4-c]pyridazine-5-carbaldehyde [0317] Ozone was bubbled through a solution of 1-methyl-5-vinyl-1H-pyrazolo[3,4- c]pyridazine (382 mg) in anhydrous DCM (10 mL) at -78°C for 10 mins. Excess ozone was purged with nitrogen for 10 mins, and then PPh3 (751 mg) was added and stirred at rt for 40 min. The reaction mixture was concentrated in vacuo to afford the crude product, which was used for next step. LC/MS ESI (m/z): 163 [M+H] + . [0318] Synthesis of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-c]pyridazin-5- yl)methylene)propane-2-sulfinamide [0319] To a solution of 1-methyl-1H-pyrazolo[3,4-c]pyridazine-5-carbaldehyde (400 mg) in anhydrous DCM (10 mL) were added CuSO4 (1.18 g) and (R)-2-methylpropane-2- sulfinamide (358.8 mg), and the reaction was stirred at rt overnight. The solution was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-c]pyridazin-5- yl)methylene)propane-2-sulfinamide (255 mg). LC/MS ESI (m/z): 266 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.26 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 4.42 (s, 3H), 1.32 (s, 9H). [0320] Synthesis of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridazin- 5- yl)ethyl)propane-2-sulfinamide [0321] To a solution of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-c]pyridazin-5- yl)methylene)propane-2-sulfinamide (205 mg) in anhydrous THF (15 mL ) was added 3M CH 3 MgBr (1.29 mL, 3.0M in ether) dropwise at -78°C under nitrogen. The reaction was stirred at -78°C for 2 hr. Then the reaction was quenched with saturated NH4Cl solution and extracted with EA. The combined extracts were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridazin- 5-yl)ethyl)propane-2- sulfinamide (50 mg). LC/MS ESI (m/z): 282 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.87 (s, 1H), 4.95 (t, J = 6.8 Hz, 1H), 4.35 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H), 1.26 (s, 9H) ppm. [0322] Synthesis of (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)ethan-1-ami ne hydrochloride [0323] To a solution of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridazin- 5- yl)ethyl)propane-2-sulfinamide (55 mg) in dioxane (1.5 mL) were added 4M HCl-dioxane (1 mL), and the reaction was stirred at rt for 30 min. The mixture was then concentrated to provide (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)ethan-1-ami ne hydrochloride as a residue, which was then used for next step. LC/MS ESI (m/z): 178 [M+H] + . [0324] Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[3,4- c]pyridazin-5-yl)ethyl)acetamide [0325] To a solution of (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)ethan-1-ami ne hydrochloride (61 mg) in DMF (1 mL) was added DIEA (242.6 mg, 0.31mL ) to provide Solution A. To a solution of 2-(4-isopropylphenyl)acetic acid (55.8 mg) in DMF (1 mL) were added HATU (131 mg) and stirred for 5 min at rt to provide Solution B. Solution B was added to Solution A and stirred at rt for 1h.. The reaction was then diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by prep-HPLC (Column: YMC-Actus Triart C18 250*21mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% TFA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) to give (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl- 1H-pyrazolo[3,4-c]pyridazin-5-yl)ethyl)acetamide (14.6 mg). LC/MS ESI (m/z): 338 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.75 (s, 1H), 7.19 (s, 4H), 6.68 (d, J = 7.6 Hz, 1H), 5.48 – 5.41 (m, 1H), 4.34 (s, 3H), 3.55-3.54 (m, 2H), 2.93-2.86 (m, 1H), 1.60 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H) ppm. Example 14. (R)-N-(1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl)ethyl)-2- (4-isopropylphenyl)acetamide [0326] Synthesis of 2,2-difluoropropyl 4-methylbenzenesulfonate [0327] To a solution of 2,2-difluoropropan-1-ol (2.0 g) in anhydrous DCM (40 mL) was added TEA (8.7 mL). TsCl (11.9 g) was added to the reaction solution at 0 °C, and the reaction was stirred at RT overnight. The reaction was then diluted with water, the two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to give 2,2-difluoropropyl 4- methylbenzenesulfonate (5 g). LC/MS ESI (m/z): 251 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.09 (t, J = 11.1 Hz, 2H), 2.47 (s, 3H), 1.64 (t, J = 18.7 Hz, 3H) ppm; 19 F NMR (377 MHz, CDCl 3 ) δ -98.43 (s). [0328] Synthesis of 1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine-5-carbalde hyde [0329] To a solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (498 mg) in anhydrous DMF (30 mL) were added Cs 2 CO 3 (1.3g) and 2,2-difluoropropyl 4-methylbenzenesulfonate (1.0 g). The reaction was stirred at 100 °C overnight, and the reaction was then diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to give 1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine-5-carbalde hyde (181 mg). LC/MS ESI (m/z): 226 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 9.13 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.29 (s, 1H), 4.88 (t, J = 12.1 Hz, 2H), 1.67 (t, J = 18.7 Hz, 3H) ppm. 19 F NMR (377 MHz, CDCl 3 ) δ -93.83 (s). [0330] Synthesis of (R,E)-N-((1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 - yl)methylene)-2-methylpropane-2-sulfinamide [0331] To a solution of 1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine-5-carbalde hyde (209 mg) in anhydrous DCM (14 mL) were added CuSO 4 (444.4 mg) and (R)-2- methylpropane-2-sulfinamide (146.2 mg). The reaction was stirred at rt overnight, the solution was then filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)-N-((1-(2,2-difluoropropyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene)-2-methylpropane-2-sul finamide (229 mg). LC/MS ESI (m/z): 329 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.84 (s, 1H), 8.36 (d, J = 1.1 Hz, 1H), 8.23 (d, J = 0.6 Hz, 1H), 4.86 (t, J = 12.1 Hz, 2H), 1.66 (t, J = 18.4 Hz 3H), 1.31 (s, 9H). ppm. 19 F NMR (377 MHz, CDCl 3 ) δ -93.83 (s). [0332] Synthesis of (R)-N-((R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyrid in-5- yl)ethyl)-2-methylpropane-2-sulfinamide [0333] To a solution of (R,E)-N-((1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 - yl)methylene)-2-methylpropane-2-sulfinamide (229 mg) in anhydrous THF (9.0 mL) was added CH 3 MgBr (1.2 mL, 3.0 M in ether) dropwise at -78°C under nitrogen. The reaction was stirred at -78°C for 2 hr. The reaction solution was then quenched with aqueous NH 4 Cl and extracted with EA. The organic layer was separated, washed with brine, dried, and concentrated in vacuo. The residue was then purified by silica gel column chromatography, to give (R)-N-((R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyrid in-5-yl)ethyl)-2- methylpropane-2-sulfinamide (193 mg) as a yellow oil. LC/MS ESI (m/z): 345 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.06 (d, J = 0.5 Hz, 1H), 7.62 (d, J = 0.9 Hz, 1H), 4.79 (t, J = 12.0 Hz, 2H), 4.73 – 4.66 (m, 1H), 4.49 (d, J = 6.2 Hz, 1H), 1.68 – 1.56 (m, 6H), 1.25 (s, 9H).ppm. 19 F NMR (377 MHz, CDCl 3 ) δ -93.56 (d, J = 5.5 Hz). [0334] Synthesis of (R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5-yl )ethan-1- amine hydrochloride [0335] To a solution of (R)-N-((R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyrid in-5- yl)ethyl)-2-methylpropane-2-sulfinamide (153 mg) in dioxane (3.0 mL ) were added 4N HCl- dioxane (1.5 mL). The reaction was stirred at rt for 30 min, and the mixture was then concentrated to provide crude (R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride, which was directly used for next step. LC/MS ESI (m/z): 241 [M+H] + [0336] Synthesis of (R)-N-(1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 - yl)ethyl)-2-(4-isopropylphenyl)acetamide [0337] To a solution of (R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride(123 mg) in anhydrous DMF (3 mL) was added DIEA to provide Solution A. To a solution of 2-(4-isopropylphenyl)acetic acid (80.75 mg) in anhydrous DMF were added HATU (156 mg) and stirred 15 min at rt to provide Solution B. Solution B was added to the solution A and stirred at rt for 1h. The reaction was then diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by [Column: YMC-Actus Triart C18 250*21mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; Wavelength:220 nm) to give (R)-N-(1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 - yl)ethyl)-2-(4-isopropylphenyl)acetamide (98.6 mg). LC/MS ESI (m/z): 401 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 7.19 (s, 4H), 6.61 (d, J = 7.4 Hz, 1H), 5.29-5.22 (m, 1H), 4.78 (t, J = 12.0 Hz, 2H), 3.55-3.54 (m, 2H), 2.94-2.87 (m, 1H), 1.66-1.56 (m, 3H), 1.46 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H); 19 F NMR (377 MHz, CDCl 3 ) δ -93.56 (s). Example 15. (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[3,4-c]p yridin-5- yl)ethyl)acetamide [0338] Step 1. Synthesis of 5-bromo-1H-pyrazolo[3,4-c]pyridine [0339] To a solution of 6-bromo-4-methylpyridin-3-amine (1.0 g) in acetic acid (60 mL) were added sodium nitrite (0.37 mL) while cooling in an ice bath. The reaction was stirred at RT overnight. Then the reaction was concentrated and then treated with saturated aqueous NaHCO 3 . The aqueous mixture was extracted with EA. The organic layer was separated, washed with brine, dried over with Na 2 SO 4 , filtered and concentrated in vacuo. Then the residue was purified by silica gel column chromatography, to give 5-bromo-1H-pyrazolo[3,4- c]pyridine (442 mg). LC/MS ESI (m/z): 198 [M+H] + . [0340] Step 2. Synthesis of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde [0341] To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (3.3 g) in anhydrous THF (100 mL) was added n-BuLi (20.0 mL,2 N in THF) at -78 °C. The mixture was stirred at - 78 °C for 1 hr. DMF (3.87 mL) was then added to the mixture at -78 °C, and the mixture was stirred at -78 °C for 1 hr. The reaction was warmed to rt and quenched with an NH 4 Cl solution. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (DCM:MeOH =1:0 to 20:1) to give 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (1.0 g) as a white solid. LC/MS ESI (m/z): 148 [M+H] + . [0342] Step 3. Synthesis of 1-methyl-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde [0343] To a solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (1 g) in DMF (15 mL) was added Cs 2 CO 3 (4.4 g) and iodomethane (1.1 g). The mixture was stirred at 25 °C for 12 hr. The mixture was then diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give 1-methyl-1H-pyrazolo[3,4-c]pyridine-5- carbaldehyde (400 mg) [ 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.35 (s, 1H), 8.43 (s, 2H), 4.25 (s, 3H).] and 2-methyl-2H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (200 mg) [ 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.27 (s, 1H), 8.80 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 4.31 (s, 3H).] as a yellow solid. LC/MS ESI (m/z): 162 [M+H] + . [0344] Step 4. Synthesis of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide [0345] To a solution of 1-methyl-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (235 mg) in DCM (15 mL) were added (R)-2-methylpropane-2-sulfinamide (230 mg) and CuSO 4 (349 mg). The reaction was stirred at rt overnight. The solution was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)- 2-methyl-N-((1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)methyle ne)propane-2-sulfinamide (340 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 4.25 (s, 3H), 1.31 (s, 9H) ppm. LC/MS ESI (m/z): 265 [M+H] + . [0346] Step 5. Synthesis of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide To a solution of (R,E)-2-methyl-N-((1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)methylene)propane-2-sulfinamide (347 mg) in anhydrous THF (20 mL) were added CH 3 MgBr (3.0M in ether, 2.2 mL) dropwise. The reaction was stirred at -60°C for 2 hr. Then the reaction was quenched with saturated NH 4 Cl and extracted with EtOAc. The organic layer was separated, washed with additional saturated NaCl, dried over with Na 2 SO 4 , filtered and concentrated in vacuo. Then the residue was purified by silica gel column chromatography to give (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)propane-2-sulfinamide (314 mg) as pale yellow oil. LC/MS ESI (m/z): 281 [M+H] + . [0347] Step 6. Synthesis of (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride To a solution of (R)-2-methyl-N-((R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)propane-2-sulfinamide (57 mg ) in dioxane (2.0 mL ) were added HCl-Dioxane (4M in dioxane, 1.0 mL), and the reaction was stirred at rt for 30 min. Then the mixture was concentrated to provide crude (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride, which was used for next step. LC/MS ESI (m/z): 177 [M+H] + . [0348] Step 7. Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide [0349] A solution of crude (R)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (70 mg), 2-[4-(propan-2-yl)phenyl]acetic acid (77.88 mg), EDCI (91.38 mg), HOBt (64.41 mg) and DIEA (0.08 mL) in DMF (5 mL) was stirred at 25 °C for 3 hr. The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to provide a residue. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column: ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 35%; wavelength: 220 nm) to give (R)-2-(4- isopropylphenyl)-N-(1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)ethyl)acetamide (17.1 mg) as a white solid. LC/MS ESI (m/z): 337 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 7.20 (s, 4H), 6.62 (d, J = 7.6 Hz, 1H), 5.30-5.23 (m, 1H), 4.18 (s, 3H), 3.60 – 3.52 (m, 2H), 2.95-2.88 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 8.0 Hz, 6H) ppm. Example 16. (R)-2-(6-(1,1-difluoroethyl)pyridin-3-yl)-N-(1-(1-(2,2,2-tri fluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0350] Synthesis of 2-(1,1-difluoroethyl)-5-methylpyridine [0351] To a solution of 1-(5-methylpyridin-2-yl)ethan-1-one (2.0 g) in DCM (30 mL) was added DAST (19.6 mL) at 0 °C. The mixture was stirred at 25 °C for 48 hr. The mixture was quenched with NaHCO 3 solution. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by chromatography on silica gel (PE:EA=1:0 to 20:1) to give 2-(1,1-difluoroethyl)-5-methylpyridine (1.1 g) as colorless oil. LC/MS ESI (m/z): 158 [M+H] + . [0352] Synthesis of 5-(bromomethyl)-2-(1,1-difluoroethyl)pyridine [0353] To a solution of 2-(1,1-difluoroethyl)-5-methylpyridine (1.02 g) in CCl4 (30 mL) were added NBS (1.28 g) and AIBN (0.048 mL). The reaction was stirred at 80 °C overnight. The reaction was filtered, and the filtrate was concentrated in vacuo to provide a residue, which was purified by silica gel column chromatography (PE:EA=1:0 to 10:1) to afford 5- (bromomethyl)-2-(1,1-difluoroethyl)pyridine (780 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, J = 1.6 Hz, 1H), 7.85-7.83 (m, 1H), 7.66-7.64 (m, 1H), 4.49 (s, 2H), 2.07-1.97 (m, 3H); LC/MS ESI (m/z): 237 [M+H] + . [0354] Synthesis of 2-(6-(1,1-difluoroethyl)pyridin-3-yl)acetonitrile [0355] To a solution of 5-(bromomethyl)-2-(1,1-difluoroethyl)pyridine (780 mg) in DMF (15 mL) were added TMSCN (1.6 mL) and K 2 CO 3 (685 mg). The reaction was stirred at 50 °C overnight. The reaction was diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA = 10:1) to give 2-[6-(1,1- difluoroethyl)pyridin-3-yl]acetonitrile (194 mg). LC/MS ESI (m/z): 183 [M+H] + . [0356] Synthesis of 2-(6-(1,1-difluoroethyl)pyridin-3-yl)acetic acid [0357] A solution of 2-[6-(1,1-difluoroethyl)pyridin-3-yl]acetonitrile (194 mg) in concentrated aqueous HCl (3.0 mL) was stirred at 100 °C for 2 hr. The mixture was added to water and extracted with EA. The combined extracts were dried, filtered and concentrated to provide 2-(6-(1,1-difluoroethyl)pyridin-3-yl)acetic acid (110 mg, crude) as a white solid. LC/MS ESI (m/z): 200 [M-H]-. [0358] Synthesis of (R)-2-(6-(1,1-difluoroethyl)pyridin-3-yl)-N-(1-(1-(2,2,2-tri fluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0359] A solution of 2-[6-(1,1-difluoroethyl)pyridin-3-yl]acetic acid (110 mg) and HATU (312 mg) in DMF (2.0 mL) was stirred at room temperature for 15 min. Then (R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (173.6 mg) and DIEA (0.542 mL, 3.281) were added. The mixture was stirred at rt for 1 hour, and LC/MS showed the reaction was complete. The reaction was diluted with EA and water, the two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by prep-HPLC [Column：YMC-Actus Triart C18250*20mm Mobile phase: from 15% to 95% MeCN with H 2 O (1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO2 and B for IPA+0.1%NH3H2O; Gradient: B 40%; flow rate: 50 mL/min; wavelength: 210 nm) to afford (R)-2-(6-(1,1-difluoroethyl)pyridin-3-yl)-N-(1-(1- (2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl) acetamide (121 mg) as a white solid. LC/MS ESI (m/z): 428 [M+H] + ; 1 H-NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 8.54 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J= 8.1, 2.1 Hz, 1H), 7.60 (dd, J = 4.2, 3.2 Hz, 2H), 6.96 (t, J = 14.2 Hz, 1H), 5.28-5.24 (m, 1H), 5.07(q, J = 8.3 Hz, 2H), 3.62 (s, 2H), 2.05-1.95 (m, 3H), 1.52 (t, J = 6.3 Hz, 3H). 19 F-NMR (377 MHz, CDCl 3 ) δ -70.76, -90.68. Example 17. (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)-2- (5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl)acetamide [0360] Step 1. Synthesis of (1-(5-bromothiophen-2-yl)-2,2,2- trifluoroethoxy)trimethylsilane [0361] To a solution of 5-bromothiophene-2-carbaldehyde (8.4 mL, 70.7 mmol) in 1,2- dimethoxyethane (30 mL) were added (trifluoromethyl)trimethylsilane (13.7 mL, 91.9 mmol) and cesium fluoride (0.26 mL, 7.01 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hrs, and TLC showed the reaction was complete. The reaction mixture was quenched with ice-water and then extracted twice with EtOAc. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 3: 1) to give (1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethoxy)trimethylsil ane (19.6 g) as colorless oil. [0362] Step 2.Synthesis of 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethan-1-ol [0363] To a solution of (1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethoxy)trimethylsil ane (19.4 g, 58.2 mmol) in MeOH (20 mL) was added HCl (9.7 mL, 116.4 mmol, 12 mol/L) at 0 °C. The mixture was stirred at room temperature for 3 hrs, and TLC showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted twice with EtOAc. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 5: 1) to give 1-(5-bromothiophen-2-yl)-2,2,2- trifluoroethan-1-ol (14.8 g) as colorless oil. [0364] Step 3. Synthesis of 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethan-1-one [0365] To the solution of 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethan-1-ol (17.3 g, 66.3 mmol) in CH 2 Cl 2 (30 mL) was added Dess-Martin periodinane (30.9 mL, 99.4 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 3 hrs. TLC showed the reaction was complete. The reaction mixture was quenched with ice-water and then extracted twice with EtOAc. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (100% PE) to give 1-(5-bromothiophen-2-yl)-2,2,2- trifluoroethan-1-one (10.4 g) as a light yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.64 (dd, J = 2.5, 1.3 Hz, 1H), 7.17 – 7.12 (m, 1H); 19 F NMR (377 MHz, CDCl 3 ): δ -72.2. [0366] Step 4. Synthesis of 2-bromo-5-(3,3,3-trifluoroprop-1-en-2-yl)thiophene [0367] Methyl triphenylphosphonium iodine (1.8 g, 4.6 mmol) was dissolved in THF (25 mL) under argon atmosphere. The suspension was cooled 0 °C, followed by dropwise addition of n-BuLi (2.5 mL, 2.5 N). The mixture was stirred at 0 °C for 10 minutes, and the reaction was then cooled to -78 °C.1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanone (1.0 g, 3.9 mmol) in THF (1.0 mL) was added. The mixture was stirred at -78 °C for 30 min and then stirred at rt overnight. The reaction was quenched with sat. NH 4 Cl and extracted with petroleum ether (10 mL). The organic layer was washed with saturated NaCl, dried with anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 10: 1) to give 2-bromo-5-(3,3,3- trifluoroprop-1-en-2-yl)thiophene as a colorless oil (435 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 7.00-6.98 (m, 1H), 6.96-6.93 (m, 1H), 5.82 (s, 1H), 5.75 (s, 1H). 19 F NMR (377 MHz, CDCl 3 ): δ -65.9. [0368] Step 5. Synthesis of 2-bromo-5-(1-(trifluoromethyl)cyclopropyl)thiophene [0369] To an oven dried 20 mL vial containing 2-bromo-5-(3,3,3-trifluoroprop-1-en-2- yl)thiophene (200 mg, 0.78 mmol) and methyldiphenylsulfonium tetrafluoroborate (291 mg, 1.0 mmol) in anhydrous tetrahydrofuran (5 mL) was added sodium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 1 h. The reaction was quenched with 250 µL of methanol and the crude mixture was concentrated in vacuo to get a residue, which was purified by automated flash column chromatography (eluant:100 PE% to 50% PE in EA) to provide 2-bromo-5-(1-(trifluoromethyl)cyclopropyl)thiophene as colorless oil (70 mg). 1HNMR (400 MHz, CDCl 3 ): δ 6.90 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 4.0 Hz,1H), 1.42-1.39 (m, 2H), 1.15-1.11 (m, 2H); 19 FNMR (377 MHz, CDCl 3 ): δ -70.4. [0370] Step 6. Synthesis of ethyl 2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2- yl)acetate [0371] A Schlenk tube equipped with a stir bar was evacuated and backfilled with nitrogen. Pd 2 (allyl) 2 Cl 2 (3.65 mg, 0.01 mmol), BINAP (18.7 mg, 0.03 mmol), DMAP (6.1 mg, 0.05 mmol) and ethyl potassium malonate (128 mg, 0.75 mmol) were added. Then 2-bromo-5-(1- (trifluoromethyl)cyclopropyl)thiophene (136 mg, 0.5 mmol) and mesitylene (2 mL) were added. The reaction mixture was stirred under N 2 in the sealed the tube for 10 min at rt, then heated at 120 °C overnight. Upon completion, the reaction was cooled to rt and diluted with EA (30 mL). The resulting mixture was washed with saturated NaCl and concentrated. The residue was purified by flash column chromatography (eluting with 5%-10% PE in EA) to give ethyl 2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl)acetate as yellow liquid (50 mg). 1 HNMR (400 MHz, CDCl 3 ): δ 6.95 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 4.0 Hz, 1H), 4.21- 4.16 (m, 2H), 3.76 (s, 2H), 1.40-1.37 (m, 2H), 1.28 (t, J = 6.8 Hz, 3H), 1.16-1.12 (m, 2H) ppm; 19 FNMR(377 MHz, CDCl 3 ): δ -70.34 ppm. [0372] Step 7. Synthesis of 2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl)acetic acid [0373] To a mixture of ethyl 2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl)acetate (50 mg, 0.18 mmol) in ethanol (10 mL) was added NaOH (7.2 mg, 0.18 mmol), and the mixture was stirred under reflux for 16 h. After cooling to rt, the pH of the reaction was adjusted to 2 by adding 1 N hydrogen chloride. The reaction mixture was then extracted with ethyl acetate (2 x20 mL), and the combined extracts were washed with sat. NaCl. The organic phase was concentrated to give 2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl)acetic acid as a brown solid (40 mg). 1 HNMR (400 MHz, CDCl 3 ): 6.96 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 3.82 (s, 2H), 1.41-1.38 (m, 2H), 1.16-1.14 (m, 2H); 19 FNMR (377 MHz, CDCl 3 ): δ -70.4. [0374] Step 8. Synthesis of (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5- yl)ethyl)-2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl )acetamide [0375] A solution 2-(5-(1-(trifluoromethyl)cyclopropyl)thiophen-2-yl)acetic acid (158 mg) and HATU (360 mg) in DMF (2.5 mL) was stirred at rt for 15 min. Then (R)-1-[1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]ethan-1-amine hydrochloride (200 mg) and DIEA (0.63 mL) were added, and the mixture was stirred for 1 hour. LC/MS showed the reaction was complete. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; flow rate: 50 mL/min; wavelength: 210 nm) to afford (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)-2-(5-(1-(trifluoromethyl)cyclopropyl)t hiophen-2-yl)acetamide (80.9 mg) as a white solid. LC/MS ESI (m/z): 477 [M+H] + ; 1 H-NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.12 (s, 1H), 7.60 (s, 1H), 6.97 (d, J = 3.5 Hz, 2H), 6.79 (d, J = 3.5 Hz, 1H), 5.28-5.24 (m, 1H), 5.05 (q, J = 8.3 Hz, 2H), 3.78 - 3.68 (m, 2H), 1.51 (d, J = 6.8 Hz,3H), 1.39-1.35 (m, 2H), 1.13-1.11 (m, 2H); 19 F-NMR (377 MHz, CDCl 3 ) δ -70.32, -70.81. Example 18. (R)-N-(1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c] pyridin-5- yl)ethyl)-2-(4-isopropylphenyl)acetamide [0376] Synthesis of 1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]pyridine-5 - carbaldehyde [0377] To a solution of 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (546 mg ) in anhydrous DMF (1.5 mL) were added Cs 2 CO 3 (1.45 g) and (1-fluorocyclopropyl)methyl 4- methylbenzenesulfonate (1.09 g) and the reaction was stirred at rt for 4 hr. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to provide a residue, which was purified by silica gel column to give 1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]pyridine-5 -carbaldehyde (192 mg). LC/MS ESI (m/z): 230 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 9.18 (d, J = 0.7 Hz, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.27 (s, 1H), 4.88 (d, J = 21.2 Hz, 2H), 1.29 – 1.10 (m, 2H), 1.05 – 0.91 (m, 2H). [0378] Synthesis of (R,E)-N-((1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)methylene)-2-methylpropane-2-sulfinamide [0379] To a solution of 1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]pyridine-5 - carbaldehyde (192 mg) in anhydrous DCM (8.0 mL) were added CuSO4 (419.4 mg) and (R)- 2-methylpropane-2-sulfinamide (138.0 mg). The reaction was stirred at rt overnight. The solution was then filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)-N-((1-((1-fluorocyclopropyl)methyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)methylene)-2-methylpropane-2- sulfinamide (294 mg). LC/MS ESI (m/z): 323 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.17 (d, J = 0.8 Hz, 1H), 8.83 (s, 1H), 8.35 (d, J = 1.1 Hz, 1H), 8.20 (d, J = 0.5 Hz, 1H), 4.86 (d, J = 21.0 Hz, 2H), 1.31 (s, 9H), 1.22 – 1.13 (m, 2H), 1.01 – 0.93 (m, 2H) ppm. [0380] Synthesis of (R)-N-((R)-1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3, 4- c]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide [0381] To a solution of (R,E)-N-((1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)methylene)-2-methylpropane-2-sulfinamide (290 mg) in anhydrous THF (12 mL) was added CH 3 MgBr (1.499 mL, 3.0M in ether) dropwise at -78°Cunder nitrogen, and the reaction was stirred at -78°C for 2 hr. The reaction solution was then quenched with aqueous NH 4 Cl. The two phases separated, and the aqueous phase was extracted with EA. The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide a residue, which was purified by silica gel column chromatography to give (R)-N- ((R)-1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]py ridin-5-yl)ethyl)-2- methylpropane-2-sulfinamide ( 228 mg ). LC/MS ESI (m/z): 339 [M+H] + . [0382] Synthesis of (R)-1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]pyr idin-5- yl)ethan-1-amine hydrochloride [0383] To a solution of (R)-N-((R)-1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3, 4- c]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (212 mg) in dioxane (5 mL) was added 4N HCl-dioxane (2.5 mL). The reaction was stirred at rt for 30 min. The mixture was concentrated and used for next step directly. LC/MS ESI (m/z): 235 [M+H] + [0384] Synthesis of (R)-N-(1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c] pyridin- 5-yl)ethyl)-2-(4-isopropylphenyl)acetamide [0385] To a solution of (R)-1-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]pyr idin- 5-yl)ethan-1-amine hydrochloride (170 mg) in anhydrous DMF was added DIEA (487 mg) to provide Solution A. To a solution of 2-(4-isopropylphenyl)acetic acid (107.8 mg) in anhydrous DMF was added HATU (252.9 mg) and stirred 15 min at RT to provide Solution B. Solution B was added to the solution A, and the resulting mixture was stirred at rt for 1h. The reaction was then diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by prep-HPLC (Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H2O (1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) to give (R)-N-(1-(1- ((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl )ethyl)-2-(4- isopropylphenyl)acetamide (162.2 mg). LC/MS ESI (m/z): 395 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.19 (s, 4H), 6.74 (d, J = 6.9 Hz, 1H), 5.30- 5.23 (m, 1H), 4.80 (d, J = 21.1 Hz, 2H), 3.55 (s, 2H), 2.93-2.86 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H), 1.18-1.13 (m, 2H), 0.95 -0.93 (m, 2H) ppm; 19 F NMR (377 MHz, CDCl 3 ) δ -183.10 (s). Example 19. (R)-2-(4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2,2-trifluoro ethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0386] Step 1. ethyl 2-(4-(1,1-difluoroethyl)phenyl)acetate [0387] A solution of 1-bromo-4-(1,1-difluoroethyl)benzene (0.54 mL), ethyl potassium malonate (924.0 mg), allylpalladium chloride dimer (26.5 mg), BINAP (135.2 mg) and DMAP (442.2 mg) in 1,3,5-trimethylbenzene (10 mL) was charged with N2 and stirred at 140 °C for 1 hr. The mixture was then stirred at 120 °C for an additional 12 hr. The reaction was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (PE:EA = 20:1) to give ethyl 2-[4-(1,1-difluoroethyl)phenyl]acetate (180 mg) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.20-4.12 (m, 2H), 3.64 (s, 2H), 1.91 (t, J = 18.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). [0388] Step 2.2-(4-(1,1-difluoroethyl)phenyl)acetic acid To a solution of ethyl 2-[4-(1,1-difluoroethyl)phenyl]acetate (150 mg) in MeOH (0.5 mL) was added NaOH (2M in H 2 O, 2.0 mL), and the mixture was stirred at 25 °C for 12 hr. The mixture was adjusted pH = 3 and extracted with EtOAc. The combined extracts were dried, filtered, and concentrated to give 2-[4-(1,1-difluoroethyl)phenyl]acetic acid (110 mg) as a white solid. LC/MS ESI (m/z): 199 [M-H]-. [0389] Step 3. (R)-2-(4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2,2-trifluoro ethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0390] A solution of (1R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl]ethan- 1-amine hydrochloride (140 mg), 2-[4-(1,1-difluoroethyl)phenyl]acetic acid (114.8 mg), HATU (239.8 mg) and DIEA (0.28 mL) in DMF (5.0 mL) was stirred at 25 °C for 1 hr. The mixture was diluted with water and extracted with DCM. The combined extracts were dried, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C18250*20mm; Mobile phase: from 25% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to give (R)-2-(4-(1,1- difluoroethyl)phenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyra zolo[3,4-c]pyridin-5- yl)ethyl)acetamide (109.9 mg) as a white solid. LC/MS ESI (m/z): 427 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 5.28-5.24 (m, 1H), 5.05 (q, J = 8.4 Hz, 2H), 3.61 (s, 2H), 1.91 (t, J = 18.0 Hz, 3H), 1.50 (d, J = 6.8 Hz, 3H) ppm; 19 F NMR (377 MHz, CDCl 3 ) δ -70.78, - 87.35 ppm. Example 20. (R)-2-(6-isopropylpyridin-3-yl)-N-(1-(1-(2,2,2-trifluoroethy l)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0391] Synthesis of methyl 6-(prop-1-en-2-yl)nicotinate [0392] To a solution of methyl 6-bromonicotinate (7.0 g) in dioxane/water (20 mL, 9:1) were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.1 mL), Pd(PPh3)4 (0.75 g), PPh 3 (1.70 g) and K 2 CO 3 (13.44 g). The mixture was charged with N 2 and stirred at 80 °C overnight under nitrogen, at which point LC/MS showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted with EtOAc twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE : EA = 10 : 1) to give methyl 6-(prop-1-en-2-yl)nicotinate (4.9 g) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 9.36 - 8.82 (m, 1H), 8.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.00 (d, J = 0.5 Hz, 1H), 5.53 - 5.02 (m, 1H), 3.94 (s, 3H), 2.23 (d, J = 0.5 Hz, 3H) ppm. [0393] Synthesis of methyl 6-isopropylnicotinate [0394] To a solution of methyl 6-(prop-1-en-2-yl)nicotinate (2.5 g ) in MeOH (20 mL) was added 10% Pd/C (1.46 mL). The mixture was stirred at room temperature under hydrogen for 2 hrs, and LC/MS showed the reaction was complete. The reaction was filtered, and the solvent was concentrated to provide a residue, which was purified by column chromatography on silica gel (PE : EA = 5 : 1) to give methyl 6-isopropylnicotinate (2.0 g) as a colorless oil. 1 H NMR (400 MHz, CD3OD) δ 9.01 (d, J = 2.1 Hz, 1H), 8.29 (dd, J = 8.2, 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 3.13 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H) ppm. [0395] Synthesis of (6-isopropylpyridin-3-yl)methanol [0396] To a solution of methyl 6-isopropylnicotinate (1.5 g) in THF (10 mL) was added LiAlH4 (0.95 g) and the mixture was stirred at room temperature for 4 hrs. LC/MS showed the reaction was complete. The reaction mixture was then quenched by ice-water and extracted with EtOAc twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE : EA = 1 : 1) to give (6- isopropylpyridin-3-yl)methanol (1.0 g) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.0, 2.3 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.24 (t, J = 5.7 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.05-2.95 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H); LC/MS ESI (m/z): 152 [M+H] + . [0397] Step 4. Synthesis of 5-(bromomethyl)-2-isopropylpyridine [0398] To a solution of (6-isopropylpyridin-3-yl)methanol (1.0 g) in CH 2 Cl 2 (10 mL) was added phosphorus tribromide (1.24 mL). The mixture was stirred at room temperature overnight, at which point LC/MS showed the reaction was complete. The reaction mixture was quenched with ice-water and then extracted with EtOAc twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE : EA = 5 : 1) to give 5-(bromomethyl)-2-isopropylpyridine (1.1 g) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.47 (m, 1H), 7.86 - 7.69 (m, 1H), 7.30 (t, J = 11.2 Hz, 1H), 4.72 (s, 2H), 3.12 - 2.90 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H); LC/MS ESI (m/z): 214 [M+H] + . [0399] Step 5. Synthesis of 2-(6-isopropylpyridin-3-yl)acetonitrile [0400] To a solution of 5-(bromomethyl)-2-isopropylpyridine (1.1 g) in DMF (15 mL) was added KCN (1.67 g). The mixture was stirred 50 °C for 3 hrs. LC/MS and TLC showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted with EtOAc twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (PE : EA = 5 : 1) to give 2-(6-isopropylpyridin-3- yl)acetonitrile (120 mg) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 3.74 (s, 2H), 3.21 - 2.91 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H) ppm; LC/MS ESI (m/z): 161 [M+H] + . [0401] Step 6. Synthesis of 2-(6-isopropylpyridin-3-yl)acetic acid hydrochloride [0402] To a solution of 2-(6-isopropylpyridin-3-yl)acetonitrile (120 mg) in water (3.0 mL) was added 12N HCl (1.4 g). The mixture was stirred at 100 °C for 2 hrs, and LC/MS showed that the reaction was complete. The reaction mixture was quenched by ice-water and then extracted with EtOAc twice. The water phase was evaporated to dryness to give 2-(6- isopropylpyridin-3-yl)acetic acid hydrochloride (130 mg) as a brown solid, which was used next step; LC/MS ESI (m/z): 180 [M+H] + . [0403] Step 7. Synthesis of (R)-2-(6-isopropylpyridin-3-yl)-N-(1-(1-(2,2,2-trifluoroethy l)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0404] A solution of (1R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl]ethan- 1-amine hydrochloride (140 mg), 2-(6-isopropylpyridin-3-yl)acetic acid hydrochloride (102.0 mg), HATU (239.8 mg) and DIEA (0.28 mL) in DMF (4.0 mL) was stirred at 25 °Cfor 1 hr. The mixture was diluted with water and DCM. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 10% to 85% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column:ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; Wavelength: 220 nm) to give (R)-2-(6- isopropylpyridin-3-yl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyr azolo[3,4-c]pyridin-5- yl)ethyl)acetamide (67.9 mg) as a white solid. LC/MS ESI (m/z): 406 (M+H) + ; 1 H-NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.50 (s, 1H), 8.09 (s, 1H), 7.81-7.74 (m, 1H), 7.56 (s, 1H), 7.27 (s, 1H), 6.98-6.90 (m, 1H), 5.29-5.22 (m, 1H), 5.11-5.02 (m, 2H), 3.60 (s, 2H), 3.27-3.17 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.34-1.32 (m, 6H); 19 F-NMR (377 MHz, CDCl 3 ) δ -70.79. Example 21. (R)-2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)-N-(1-( 1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0405] Step 1.1-(5-bromopyridin-2-yl)cyclopropane-1-carbonitrile [0406] To a solution of NaOH (10.1 g) in H2O (20 mL) was added 2-(5-bromopyridin-2- yl)acetonitrile (5.0 g), 1,2-dibromoethane (2.2 mL), tetrabutylammonium bromide (7.9 mL) and CH 3 CN (80 mL). The mixture was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give a residue, which was purified by chromatography on silica gel (PE:EA=1:0 to 50:1) to give 1-(5-bromopyridin-2-yl)cyclopropane-1-carbonitrile (4.5 g) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.62 (m, 1H), 8.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.51 (dd, J = 8.4, 0.6 Hz, 1H), 1.91 - 1.78 (m, 2H), 1.73 - 1.61 (m, 2H). [0407] Step 2.1-(5-bromopyridin-2-yl)cyclopropane-1-carbaldehyde [0408] To a solution of 1-(5-bromopyridin-2-yl)cyclopropane-1-carbonitrile (4.5 g) in THF (80 mL) was added diisobutylaluminium hydride (1.0M in THF, 40.3 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 2 hr. The reaction was quenched with MeOH (20 mL) and 1 N HCl (30 mL) and extracted with EtOAc. The combined extracts were dried, filtered and concentrated to give 1-(5-bromopyridin-2-yl)cyclopropane-1-carbaldehyde (1.8 g) as yellow oil. LC/MS ESI (m/z): 246 [M+H] + . [0409] Step 3.5-bromo-2-(1-(difluoromethyl)cyclopropyl)pyridine [0410] To a solution of 1-(5-bromopyridin-2-yl)cyclopropane-1-carbaldehyde (1.8 g) in DCM (30 mL) was added DAST (3.2 mL). The mixture was stirred at 25 °C for 12 hr. Then the reaction was quenched with NaHCO3 solution at 0 °C and washed with water. The organic layer was dried, filtered and concentrated to give a residue, which was purified by chromatography on silica gel (PE:EtOAc =1:0 to 50:1) to give 5-bromo-2-[1- (difluoromethyl)cyclopropyl]pyridine (700 mg) as colorless oil. LC/MS ESI (m/z): 248 [M+H] + . [0411] Step 4. ethyl 2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)acetate [0412] A solution of 5-bromo-2-[1-(difluoromethyl)cyclopropyl]pyridine (700 mg), 1-ethyl 3-potassium propanedioate (720 mg), allylpalladium chloride dimer (103.2 mg), BINAP (527.1 mg) and DMAP (344.7 mg) in mesitylene (10 mL) was charged with N 2 three times and stirred at 140 °C for 1 hr. The mixture was then stirred at 120°C for an additional 12 hr. The mixture was concentrated to give a residue, which was purified by chromatography silica gel (PE: EtOAc =1:0 to 20:1) to give ethyl 2-{6-[1-(difluoromethyl)cyclopropyl]pyridin-3- yl}acetate (430 mg) as yellow oil. LC/MS ESI (m/z): 256 [M+H] + . [0413] Step 5.2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid [0414] To a solution of ethyl 2-{6-[1-(difluoromethyl)cyclopropyl]pyridin-3-yl}acetate (430 mg) in MeOH (1.0 mL) was added NaOH (1 M in H 2 O, 4.0 mL), and the mixture was stirred at 25 °C for 30 min. The mixture was then concentrated, diluted with water and extracted with EtOAc. The aqueous phase was adjusted to pH = 4 with 1 N aqueous HCl and then lyophilized to give 2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid (230 mg) as white solid. LC/MS ESI (m/z): 226 [M-H]-. [0415] Step 6. (R)-2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)-N-(1-( 1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0416] A solution of 2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid (130 mg), (R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl]ethan-1-amine hydrochloride (153.7 mg), HATU (239.3 mg) and DIEA (0.284 mL) in DMF (5 mL) was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with DCM. The combined extracts were dried, filtered and concentrated to give a residue, which was purified by prep-HPLC [Column: Shim-pack GIST C18250*20mm; Mobile phase: from 10% to 95% MeCN with H 2 O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to give (R)-2-(6-(1-(difluoromethyl)cyclopropyl)pyridin-3-yl)-N-(1-( 1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide (89.4 mg) as a white solid. LC/MS ESI (m/z): 454 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.62 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.18 (t, J = 57.1 Hz, 1H), 5.27-5.24 (m, 1H), 5.06 (q, J = 8.3 Hz, 2H), 3.55 (s, 2H), 1.51 (d, J = 6.8 Hz, 3H), 1.40 - 1.11 (m, 4H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.80, -119.76. Example 22. (R)-2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)-N-(1-(1-(2,2 ,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0417] Synthesis of 1-(4-bromophenyl)cyclopropane-1-carbonitrile [0418] To a 250 mL round bottom flask containing a solution of 1,2-dibromoethane (6.17 mL) and 2-(4-bromophenyl)acetonitrile (10 g) in toluene（40 mL) were added 50% aqueous NaOH (40mL) and tetrabutylammonium bromide (3.17 mL) at rt. The reaction mixture was stirred vigorously at rt for 24 h. Then the reaction was poured into 450 mL ice-water solution, and this solution was extracted with EA (130 mL×3). The combined extracts were washed with water (150 mL×2), washed with brine (150 mL), and finally dried over anhydrous Na 2 SO 4 , filtered. The solvent was removed under vacuo to provide a crude product, which was purified by silica gel flash chromatography to afford 1-(4-bromophenyl)cyclopropane-1- carbonitrile as a yellow oil(7.75 g). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.51- 7.44 (m, 2H), 7.21- 7.11 (m, 2H), 1.81 - 1.67 (m, 2H), 1.45 - 1.31 (m, 2H) ppm. [0419] Synthesis of 1-(4-bromophenyl)cyclopropane-1-carbaldehyde [0420] A mixture of 1-(4-bromophenyl)cyclopropane-1-carbonitrile (4.0 g) and diisobutylaluminum hydride (36.02 mL) in THF (30 mL) were stirred at 0°C for 1 hour, and the reaction mixture was allowed to warm to room temperature. Upon completion of the reaction, the reaction mixture was cooled to 0°C and quenched with MeOH. The reaction was slowly warmed to room temperature over 15 min and then 1 M HCl was added. The reaction was extracted with EA and washed with NaCl solution. The organic phase was concentrated to provide the 1-(4-bromophenyl)cyclopropane-1-carbaldehyde as a yellow oil (3.79 g, crude). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.16 (s, 1H), 7.51- 7.46 (m, 2H), 7.20- 7.15 (m, 2H), 1.60- 1.56 (m, 2H), 1.41 - 1.37 (m, 2H) ppm. [0421] Synthesis of 1-bromo-4-(1-(difluoromethyl)cyclopropyl)benzene [0422] To a solution of 1-(4-bromophenyl)cyclopropane-1-carbaldehyde (3.79 g) in DCM (40 mL) was added DAST (22 g), and the reaction was stirred at room temperature overnight. The reaction was diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (PE: EA = 10:1) to give 1-bromo-4-[1- (difluoromethyl)cyclopropyl]benzene as a yellow oil (2.2 g). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.56-7.35 (m, 2H), 7.29-7.26 (m, 2H), 5.58 (t, J = 56.0 Hz, 1H), 1.21-1.07 (m, 2H), 0.99-0.86 (m, 2H) ppm. 19 F-NMR (377 MHz, CDCl 3 ) δ -117.06 ppm. [0423] Synthesis of ethyl 2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)acetate [0424] To a solution of 1-bromo-4-[1-(difluoromethyl)cyclopropyl]benzene (636 mg) in Mesitylene (10 mL) were added diallylpalladium dichloride (18.8 mg,), BINAP (96.2 mg), DMAP (31.4 mg) and ethyl potassium malonate (657.2 mg). The reaction was charged with N 2 for three times and stirred at 120 °C overnight. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (PE: EA = 10: 1) to give ethyl 2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)acetate (267 mg) as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 8.0 Hz, 2H), 7.26-7.20 (m, 2H), 5.64 (t, J = 56.0 Hz, 1H), 4.20-4.10 (m, 2H), 3.60 (s, 2H), 1.26 (t, J = 4.0 Hz, 3H), 1.16-1.12 (m, 2H), 0.98-0.92 (m, 2H) ppm. 19 F-NMR (377 MHz, CDCl 3 ) δ -117.51 ppm. [0425] Synthesis of 2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)acetic acid [0426] In a 25 mL round-bottomed flask were combined ethyl 2-(4-(1- (difluoromethyl)cyclopropyl)phenyl)acetate (66 mg) and 1M aqueous NaOH (2.0 mL) and MeOH (2.0 mL) to provide a colorless solution. The reaction mixture was stirred at rt for 1 hour. Water (20 mL) was then added and the aqueous layer was washed with EA. The aqueous layer was acidified to pH < 3 with 1M aqueous HCl, and the mixture was extracted with EA. The combined EtOAc extracts from the acidic water layer were washed with saturated NaCl, dried with Na 2 SO 4 , filtered, and concentrated to provide 2-(4- (1-(difluoromethyl)cyclopropyl)phenyl)acetic acid as a white solid (244 mg, crude). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.63 (t, J = 56.0 Hz, 1H), 3.64 (s, 2H), 1.16-1.11 (m, 2H), 0.97 - 0.92 (m, 2H) ppm; 19 F-NMR (377 MHz, CDCl 3 ) δ -117.43 ppm. [0427] Synthesis of (R)-2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)-N-(1-(1-(2,2 ,2- trifluoroethyl)-1H-indazol-5-yl)ethyl)acetamide [0428] A solution of 2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)acetic acid (164 mg) and HATU (413.5 mg) in DMF (5.0 mL) was stirred at room temperature for 15 min. Then (R)-1-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)ethan-1-amin e hydrochloride (230.2 mg) and DIEA (0.72 mL) were added. The reaction was stirred for 1 hour, and LC/MS indicated that the reaction was complete. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic phase was dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by prep-HPLC [Column: YMC-Actus Triart C18250*20mm; Mobile phase: from 25% to 95% MeCN with H2O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to afford (R)-2-(4-(1-(difluoromethyl)cyclopropyl)phenyl)-N-(1-(1-(2,2 ,2- trifluoroethyl)-1H-indazol-5-yl)ethyl)acetamide (160 mg) as a brown-yellow solid. LC/MS ESI (m/z): 453 (M+H) + ; 1 H-NMR (400 MHz, CDCl 3 ): δ 8.88 (s, 1H), 8.11 (s, 1H), 7.57 (s, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.23 (d, J= 8.2 Hz, 2H), 6.75 (s, 1H), 5.63 (t, J = 57.3 Hz, 1H), 5.26-5.23 (m, 1H), 5.04 (q, J = 8.3 Hz, 2H), 3.57 (s, 2H), 1.49 (d, J = 6.8 Hz, 3H), 1.14 (dd, J = 6.3, 4.7 Hz, 2H), 0.95 (d, J = 2.1 Hz, 2H); 19 F-NMR (377 MHz, CDCl 3 ) δ -70.81, -117.15. Example 23. (R)-2-(6-cyclopropylpyridin-3-yl)-N-(1-(1-(4-fluorophenyl)-1 H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0429] Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine [0430] A suspension of 5-bromo-1H-pyrazolo[3,4-c]pyridine (4.0 g), 4-fluoro-l- iodobenzene (6.95 g), 2-Isobutyrylcyclohexanone (1.69 mL), CuI (0.77 g) and Cs 2 CO 3 (12.5 g) in 30 mL of DMA was degassed with nitrogen for 15 min. The reaction mixture was then warmed to 100°C and stirred overnight. The reaction mixture was then cooled and diluted with DCM. The organic phase was washed with 1 N aqueous NaOH and water, dried with Na 2 SO 4 and concentrated to dryness. The solid residue was suspended in ether, stirred for 30 min, and filtered to collect the desired product 5-bromo-1-(4-fluorophenyl)-1H- pyrazolo[3,4-c]pyridine (1.66 g) as a white solid. LC/MS ESI (m/z): 292 (M+H) + ; 1 H-NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 8.24-8.14 (m, 1H), 7.91 (d, J = 4.0 Hz, 1H), 7.76 -7.63 (m, 2H), 7.33 -7.27 (m, 2H) ppm; 19 F-NMR (377 MHz, CDCl 3 ) δ -113.02. [0431] Synthesis of 1-(4-fluorophenyl)-5-vinyl-1H-pyrazolo[3,4-c]pyridine [0432] To a solution of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine (2.24 g) in dioxane/water 5:1 (100 mL) were added 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.95 mL), K 3 PO 4 (4.07 g), and Pd(dppf)Cl 2 (0.56 g). The reaction was charged with N 2 (3x) and stirred at 100 °C overnight. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined extracts were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified using silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to afford 1-(4-fluorophenyl)-5-vinyl-1H-pyrazolo[3,4-c]pyridine (1.21 g). LC/MS ESI (m/z): 240 (M+H) + ; 1 H-NMR: (400 MHz, CDCl 3 ) δ 9.17 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.76-7.65 (m, 3H), 7.32-7.27 (m, 2H), 7.03-6.88 (m, 1H), 6.31 (d, J = 16.0 Hz, 1H), 5.50 (d, J = 12.0 Hz, 1H) ppm. [0433] Synthesis of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde [0434] To a solution of 1-(4-fluorophenyl)-5-vinyl-1H-pyrazolo[3,4-c]pyridine (1.2 g) in THF (80 mL) and H 2 O (10 mL) were added sodium periodate (6.4 g) and potassium osmate dihydrate (0.18 g). The reaction was stirred at room temperature for 0.5 h and then diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue which was purified using silica gel column chromatography eluting with 14% ethyl acetate in petroleum ether to afford 1-(4-fluorophenyl)-1H- pyrazolo[3,4-c]pyridine-5-carbaldehyde (701 mg). LC/MS ESI (m/z): 242(M+H) + . [0435] Synthesis of (R,E)-N-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)methylene)-2-methylpropane-2-sulfinamide [0436] A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (700 mg), (R)-(+)-2-methyl-2-propanesulfinamide (457 mg) and CuSO4 (1.4 g) in DCM (20 mL) were stirred at room temperature overnight. LC/MS showed that the reaction was complete. The reaction mixture was diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by chromatography on silica gel (PE: EA =5:1) to provide (R,E)-N-((1-(4- fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)methylene)-2-me thylpropane-2-sulfinamide (811 mg); LC/MS ESI (m/z): 345 (M+H) + . [0437] Step 5. Synthesis of (R)-N-((R)-1-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)ethyl)-2-methylpropane-2-sulfinamide [0438] To a solution of (R,E)-N-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)methylene)-2-methylpropane-2-sulfinamide (300 mg) in THF (10 mL) was added CH 3 MgBr (4.1 mL, 3.0 M in Et 2 O). The reaction was stirred at -78°C for 2 hr. The reaction was diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by chromatography on silica gel (DCM: MeOH = 15:1) afford (R)-N-((R)-1-(1-(4-fluorophenyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide as a yellow solid (602 mg); LC/MS ESI (m/z): 361 (M+H) + . [0439] Step 6. Synthesis of (R)-1-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride [0440] To a solution of (R)-N-((R)-1-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5 - yl)ethyl)-2-methylpropane-2-sulfinamide (602 mg,) in dioxane (10 mL) was added 4N HCl- Dioxane (5.0 mL), and the reaction was stirred at rt for 30 min. The reaction was evaporated in vacuo. The resulting solid was filtered, washed with EtOAc and then dried under vacuum to provide (R)-1-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)eth an-1-amine hydrochloride as a white solid (545 mg, crude). LC/MS ESI (m/z): 257 (M+H) + . [0441] Step 7. Synthesis of (R)-2-(6-cyclopropylpyridin-3-yl)-N-(1-(1-(4-fluorophenyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0442] A mixture of 2-(6-cyclopropylpyridin-3-yl)acetic acid (250 mg, crude) and HATU (321.9 mg) in DMF (5.0 mL) was stirred at room temperature for 15 min. Then, (R)-1-(1-(4- fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (205.4 mg, crude ) and DIEA (0.56 mL) were added until the pH of the solution was higher than 7 by using pH paper. After stirring for 1 hour, LC/MS showed the reaction was complete. The reaction was diluted with EA and water, and the two phases were separated. The aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue. The residue was precipitated in CH 3 CN and washed by CH 3 CN to provide 149.8 mg of the product as white solid. LC/MS ESI (m/z): 416(M+H) + . 1 H-NMR (400 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.74 - 7.67(m, 2H), 7.58-7.50 (m, 2H), 7.33 – 7.26 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 7.0 Hz,1H), 5.35 – 5.17 (m, 1H), 3.53 (s, 2H), 2.11 – 2.02 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.04 – 0.97 (m, 4H). 19 F-NMR (377 MHz, CDCl 3 ) δ -113.66. Example 24. (R)-2-(4-cyclopropylphenyl)-N-(1-(3-(2,2,2-trifluoroethyl)-3 H- [1,2,3]triazolo[4,5-c]pyridin-6-yl)ethyl)acetamide [0443] Synthesis of 2-chloro-5-fluoropyridine 1-oxide [0444] To a solution of 2-chloro-5-fluoropyridine (19.28 mL) in 30% H2O2 (96 mL) was added TFA (175 mL), and the reaction was stirred at 70°C overnight. The reaction was concentrated in vacuo and diluted with toluene. Then the reaction solution was concentrated in vacuo again and diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated to give 2-chloro-5-fluoropyridine 1-oxide (26.2 g) as a crude product. LC/MS ESI (m/z): 148 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 – 8.28 (m, 1H), 7.52 – 7.43 (m, 1H), 7.11 – 7.01 (m, 1H) ppm. [0445] Synthesis of 2-chloro-5-fluoro-4-nitropyridine 1-oxide [0446] To a solution of 2-chloro-5-fluoropyridine 1-oxide (10 g) in H 2 SO 4 (102 mL) were slowly added KNO 3 (27.4 g) at rt. The reaction was stirred at 110 °C under nitrogen for 16 hr. The reaction was poured into ice at 0°C and neutralized by addition of 30% ammonium hydroxide dropwise while maintaining the temperature below 15°C with an ice bath. The pale yellow crystals precipitated was collected by filtration. The precipitate was then purified by flash chromatography on silica gel to give 2-chloro-5-fluoro-4-nitropyridine 1-oxide (1.6 g). LC/MS ESI (m/z): 193 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (d, J = 5.7 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H). [0447] Synthesis of 2-chloro-4-nitro-5-((2,2,2-trifluoroethyl)amino)pyridine 1-oxide [0448] To a solution of 2-chloro-5-fluoro-4-nitropyridine 1-oxide (1.89 g) in THF (24 mL) was added 2,2,2-trifluoroethan-1-amine (1.568 mL), and the reaction was stirred at rt overnight. The reaction was then diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was further concentrated under high vacuum to give 2-chloro-4-nitro-5-((2,2,2- trifluoroethyl)amino)pyridine 1-oxide (2.1 g ). LC/MS ESI (m/z): 272 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 8.33 (s, 1H), 8.16 (s, 1H), 7.98 (brs, 1H), 3.98 - 3.87 (m, 2H). [0449] Synthesis of 6-chloro-N 3 -(2,2,2-trifluoroethyl)pyridine-3,4-diamine [0450] To a solution of 2-chloro-4-nitro-5-((2,2,2-trifluoroethyl)amino)pyridine 1-oxide (2.0 g) in glacial acetic acid (21 mL) was slowly added Fe (0.209 mL) at 0 °C. The reaction was stirred at rt for 1 hr and the reaction diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was concentrated in vacuo to give 6-chloro-N 3 -(2,2,2-trifluoroethyl)pyridine-3,4-diamine (2.28 g, crude). LC/MS ESI (m/z): 226 [M+H] + . [0451] Synthesis of 6-chloro-3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]p yridine [0452] To a solution of 6-chloro-N 3 -(2,2,2-trifluoroethyl)pyridine-3,4-diamine (2.67 g) and H 2 SO 4 (1.8 mL) in 30 mL of water was slowly added NaNO 2 (1.63 g) in water (17 mL) under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 4 h, and then the reaction was neutralized to pH 8 with saturated NaHCO 3 . The resulting solid was collected and purified by silica gel column to afford 6-chloro-3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5- c]pyridine (872 mg). LC/MS ESI (m/z): 237 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (s, 1H), 8.06 (s, 1H), 5.38 – 5.32 (m, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.30 (s). [0453] Synthesis of 3-(2,2,2-trifluoroethyl)-6-vinyl-3H-[1,2,3]triazolo[4,5-c]py ridine [0454] To a solution of 6-chloro-3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]p yridine (872 mg) in dioxane-water (25 mL ) were added vinylboronic acid pinacol ester (149.55 mg) , K 3 PO 4 (1.9 g) and Pd(dcpf)Cl 2 (276.38 mg). The reaction was charged with N2 and stirred at 100 °C under nitrogen overnight. The reaction was diluted with EA and water and filtered through Celite. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to give 3-(2,2,2-trifluoroethyl)-6-vinyl-3H-[1,2,3]triazolo[4,5-c]py ridine (807 mg). LC/MS ESI (m/z): 229 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 7.93 (d, J = 0.9 Hz, 1H), 7.01 – 6.94 (m, 1H), 6.38 – 6.33 (m, 1H), 5.57 – 5.54 (m, 1H), 5.38 – 5.32 (m, 2H). [0455] Synthesis of 3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]pyridine-6 - carbaldehyde [0456] To a solution of 3-(2,2,2-trifluoroethyl)-6-vinyl-3H-[1,2,3]triazolo[4,5-c]py ridine (802 mg) in THF-Water (8:1, 30 mL) were added NaIO4 ( 4.5 g) and potassium osmate (1.3 g), and the reaction was stirred at rt for 1 hr. The reaction was filtered through Celite and diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to give 3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]pyridine-6 - carbaldehyde (584 mg). LC/MS ESI (m/z): 231 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 10.29 (s, 1H), 9.29 (s, 1H), 8.72 (s, 1H), 5.46 – 5.40 (m, 2H). [0457] Synthesis of (R,E)-2-methyl-N-((3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazo lo[4,5- c]pyridin-6-yl)methylene)propane-2-sulfinamide [0458] To a solution of 3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]pyridine-6 - carbaldehyde (584 mg) in anhydrous DCM (15 mL) were added CuSO 4 (1.2 g) and (R)-2- methylpropane-2-sulfinamide (399.8 mg). The reaction was stirred at rt overnight. The solution was filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)-2-methyl-N-((3-(2,2,2-trifluoroethyl)-3H- [1,2,3]triazolo[4,5-c]pyridin-6-yl)methylene)propane-2-sulfi namide (840 mg). LC/MS ESI (m/z): 334 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.26 (s, 1H), 8.90 (s, 1H), 8.74 (d, J = 0.8 Hz, 1H), 5.45 – 5.36 (m, 2H), 1.32 (s, 9H). [0459] Synthesis of (R)-2-methyl-N-((R)-1-(3-(2,2,2-trifluoroethyl)-3H-[1,2,3]tr iazolo[4,5- c]pyridin-6-yl)ethyl)propane-2-sulfinamide [0460] To a solution of (R,E)-2-methyl-N-((3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazo lo[4,5- c]pyridin-6-yl)methylene)propane-2-sulfinamide in anhydrous THF (26 mL ) was added MeMgBr (4.20 mL, 3.0M in ether) dropwise at -78°C under nitrogen. The reaction was stirred at -78°C for 2 hr. The reaction solution was then quenched with aqueous NH 4 Cl and extracted with EA. The combined extracts were separated, washed with brine, and concentrated in vacuo. Then the residue was purified by silica gel column chromatography to give (R)-2-methyl-N-((R)-1-(3-(2,2,2-trifluoroethyl)-3H-[1,2,3]tr iazolo[4,5-c]pyridin-6- yl)ethyl)propane-2-sulfinamide (690 mg). LC/MS ESI (m/z): 350 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 5.43 – 5.31 (m, 2H), 4.80 – 4.72 (m, 1H), 4.51 (d, J = 6.7 Hz, 1H), 1.61 (d, J = 6.7 Hz, 3H), 1.25 (s, 9H). [0461] Synthesis of (R)-1-(3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]pyr idin-6- yl)ethan-1-amine hydrochloride [0462] To a solution of (R)-2-methyl-N-((R)-1-(3-(2,2,2-trifluoroethyl)-3H- [1,2,3]triazolo[4,5-c]pyridin-6-yl)ethyl)propane-2-sulfinami de (680 mg) in dioxane (6.0 mL) was added 4N HCl-dioxane (2.0 mL), and the reaction was stirred at rt for 1 hr. Then the mixture was concentrated in vacuo and directly used in the next step. LC/MS ESI (m/z): 246 [M+H] + . [0463] Synthesis of (R)-2-(4-cyclopropylphenyl)-N-(1-(3-(2,2,2-trifluoroethyl)-3 H- [1,2,3]triazolo[4,5-c]pyridin-6-yl)ethyl)acetamide [0464] To a solution of (R)-1-[3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]pyr idin-6- yl]ethan-1-amine hydrochloride (150 mg) in anhydrous DMF was added DIEA (0.607 mL) to provide Solution A. To a solution of 2-(4-cyclopropylphenyl)acetic acid (129.3 mg) in DMF (1 mL) was added HATU ( 255.85 mg) and stirred 15 min at RT to provide Solution B. Solution B was added to the solution A, and the mixture was stirred at rt for 1h. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H2O (1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column: ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 35%; Wavelength: 220 nm) to give (R)-2-(4-cyclopropylphenyl)-N-(1-(3-(2,2,2- trifluoroethyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)ethyl) acetamide (89.3 mg). LC/MS ESI (m/z): 404 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 9.06 (s, 1H), 7.90 (s, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.48 (d, J = 7.6 Hz, 1H), 5.37 – 5.31 (m, 3H), 3.56 (s, 2H), 1.92-1.86 (m, 1H), 1.48 (d, J = 6.9 Hz, 3H), 0.98-0.96 (m, 2H), 0.70-0.68 (m, 2H) ppm; 19 F NMR (377 MHz, CDCl 3 ) δ -70.30 (s). Example 25. (R)-2-(6-cyclopropylpyridin-3-yl)-N-(1-(1-(2,2,2-trifluoroet hyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0465] Synthesis of ethyl 2-(6-cyclopropylpyridin-3-yl)acetate [0466] To a solution of ethyl 2-(6-chloropyridin-3-yl)acetate (1.5 g), cyclopropylboronic acid (1.94 g) and potassium carbonate (1.04 g) in dioxane (40 mL) was added Pd(PPh 3 ) 4 (0.87 g) and the mixture was charged with N2 for three times and stirred at 110 °C overnight. After cooling to room temperature, the reaction was diluted with EA (30 mL) and water (40 mL), and the two layers were separated. The aqueous layer was then extracted with EA (30 mL). The combined organic layers were washed with water and brine (40 mL each), dried over Na 2 SO 4 , filtered, and concentrated. The crude product was purified by silica gel chromatography (5-18% EA/PE) to give ethyl 2-(6-cyclopropylpyridin-3-yl)acetate (1.21 g) as a colorless oil. LC/MS ESI (m/z): 192 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J = 4.0 Hz, 1H), 7.51-7.48 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 3.57 (s, 2H), 2.06-2.01 (m, 1H), 1.05 – 0.92 (m, 4H). [0467] Synthesis of 2-(6-cyclopropylpyridin-3-yl)acetic acid [0468] To a 250 mL round-bottomed flask was added methyl 2-(6-cyclopropylpyridin-3- yl)acetate (1.2 g) and 50 mL of MeOH. Aqueous NaOH (1N, 50 mL) was added to the mixture resulting in a colorless solution. The reaction mixture was stirred at room temperature for 1 hour, and the aqueous layer was extracted with EA. The aqueous layer was acidified to pH < 3 with 1N aqueous HCl. The aqueous phase was then extracted with EA. The EtOAc extraxt from the acidified aqueous phase was washed with saturated NaCl solution, filtered, and concentrated to provide 2-(6-cyclopropylpyridin-3-yl)acetic acid as a white solid (2.31 g, crude). [0469] Synthesis of (R)-2-(6-cyclopropylpyridin-3-yl)-N-(1-(1-(2,2,2-trifluoroet hyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0470] A solution of 2-(6-cyclopropylpyridin-3-yl)acetic acid (250 mg, crude) and HATU (321.9 mg) in DMF (5.0 mL) was stirred at room temperature for 15 min. Then (R)-1-(1- (2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan- 1-amine hydrochloride (179.2 mg) and DIEA (0.56 mL) were added. The mixture was stirred for 1 hour, and LC/MS showed the reaction was complete. The reaction was diluted with EA and water. The two phases were separated, the aqueous phase was extracted with DCM (10 mL x2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo to provide a residue, which was purified by prep-HPLC [Column: YMC-Actus Triart C18 250*20mm; Mobile phase: from 10% to 95% MeCN with H2O (1% NH 3 .H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to afford (R)-2-(6-cyclopropylpyridin-3-yl)-N-(1-(1- (2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl) acetamide (141.8 mg) as a white solid. LC/MS ESI (m/z): 404 (M+H) + ; 1 H-NMR (400 MHz, CDCl 3 ): δ 8.86 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.64 (s, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 5.32-5.20 (m, 1H), 5.14-4.95 (m, 2H), 3.65-3.47(m, 2H), 2.17 (s, 1H), 1.49 (d, J = 8.0 Hz, 3H), 1.11-1.01 (m, 4H); 19 F- NMR (377 MHz, CDCl 3 ) δ -70.78. Example 26. (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)-2- (6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetamide [0471] Synthesis of methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate [0472] A mixture of methyl 6-bromonicotinate (5.47 g), 4,4,6-trimethyl-2-(3,3,3- trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (7.87 g), PdCl2(dppf) (1.85 g), K2CO3 (26.8 mL of 2 M in water) in acetonitrile (104 mL) was charged three times with N 2 and heated at 80 °C for 90 minutes. LC/MS showed formation of the desired product. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by Silica gel column chromatography (0-20% ethyl acetate/PE) to provide methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate as a colorless oil (3.6 g). LC/MS ESI (m/z): 232 [M+H] + ; 1 HNMR (400 MHz, CDCl 3 ): δ 9.22 (d, J = 2.4 Hz, 1H), 8.75-8.74 (m, 1H), 8.34-8.31 (m, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 11.6 Hz, 1H), 3.97 (s, 3H); 19 FNMR (376.48 MHz, CDCl 3 ): -63.98 ppm. [0473] Synthesis of methyl 6-(1-(trifluoromethyl)cyclopropyl)nicotinate [0474] To a suspension of methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate (2.47 g) and methyldiphenylsulfonium tetrafluoroborate (4.0 g) in anhydrous tetrahydrofuran (30 mL) was added sodium bis(trimethylsilyl)amide (2 M in THF) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 1 h. Methanol (250 µL) of was added to quench the reaction. The crude mixture was concentrated in vacuo to get a residue, which was purified by silica gel column chromatography (10% EA in PE) to provide methyl 6-(1-(trifluoromethyl)cyclopropyl)nicotinate as a white solid (1.3 mg). LC/MS ESI (m/z): 246[M+H] + ; 1 HNMR (400 MHz, CDCl 3 ): δ 9.09 (d, J = 2.4 Hz, 1H), 8.26- 8.23 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 1.54-1.53 (m, 2H), 1.50-1.49 (m, 2H) ppm; 19 FNMR (376.48 MHz, CDCl 3 ): δ -67 ppm. [0475] Synthesis of 6-(1-(trifluoromethyl)cyclopropyl)nicotinic acid [0476] To a solution of methyl 6-(1-(trifluoromethyl)cyclopropyl)nicotinate (345 mg) in MeOH (20 mL) was added 4.0 mL of NaOH ( 2.0 M). The mixture was stirred at 65 °C for 2 hours, and TLC indicated the reaction was complete. The solvent was concentrated in vacuo and the reaction mixture was adjusted pH to 2 -3 with 1 N HCl. The reaction was extracted with EA (50 mL), washed with brine, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to give 6-(1-(trifluoromethyl)cyclopropyl)nicotinic acid as a white solid (300 mg). LC/MS ESI (m/z): 232 [M+H] + . [0477] Synthesis of 2-diazo-1-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)et hanone [0478] 6-(1-(trifluoromethyl)cyclopropyl)nicotinic acid (300 mg) in DCM (10 mL) was cooled to 0 °C. Oxaly chloride (1.1 mL) and DMF (2 drops) were added and the resulting solution was stirred at rt for 2 hours. The volatiles were then removed under vacuum. The residue was redissolved in DCM (10 mL) and cooled to 0 °C. TMSCHN 2 (1.28 mL, 2 M solution in hexane) and TEA (0.33 mL) were added slowly, and the resulting solution was maintained at 5 °C for 12 hours. The reaction was then filtered, and the filtrate was concentrated under reduced pressure to give 2-diazo-1-(6-(1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)ethenone as brown residue, which was directly used in the next step. LC/MS ESI (m/z): 256 [M+H] + . [0479] Step 5. Synthesis of methyl 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3- yl)acetate [0480] To a mixture of 2-diazo-1-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)et hanone (600 mg, crude) in methanol (20 mL) was added Ag 2 O (175 mg). The reaction was stirred at 65 °C for 2 hours. TLC showed trace product had formed, and an additional 142 mg of Ag 2 O was added. The mixture was stirred at 65 °C for another 2 hours. The reaction was concentrated under vacuo and the residue was purified by silica gel column chromatography (10%EA -20% EA in PE) to give methyl 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3- yl)acetate as yellow oil (100 mg). LC/MS ESI (m/z): 260 [M+H] + . [0481] Step 6. Synthesis of 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid [0482] To a solution of methyl 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetate (100 mg) in MeOH (10 mL) was added 2.0 mL of NaOH ( 2.0 M). The mixture was stirred at 65 °C for 2 hours. After completion, the reaction was removed under reduced pressure and the reaction was adjusted pH to 2 -3 by 1 N HCl. The reaction mixture was extracted with EA (50 mL x3). The combined extracts were washed with brine, dried with anhydrous Na 2 SO 4 , filtered and concentrated to give 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid as white solid (70 mg). LC/MS ESI (m/z): 246 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ 8.43 (d, J = 1.6 Hz, 1H), 7.78-7.75 (m, 1H), 7.59-7.56 (m, 1H), 3.69 (s, 2H), 1.43-1.40 (m, 2H), 1.32-1.29 (m, 2H) ppm. 19 FNMR (CDCl 3 , -376.48): δ -69.78 ppm. [0483] Step 7. Synthesis of (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5- yl)ethyl)-2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl) acetamide [0484] To a mixture of 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid (125.0 mg) in DMF (1.0 mL) was added HATU (213 mg), and the mixture was stirred at rt for 5 min to provide Solution A. To another round flask containing (R)-1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethanamine hydrochloride (186 mg) was added DMF (1.0 mL) and DIEA (197 mg), and the mixture was stirred for 1 min (Solution B). Solution B was added to Solution A, and the reaction mixture was stirred at rt for 2 hours. EA (50 mL) and water (40 mL) were added, and the organic layer was washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 10% to 85% MeCN with H2O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to give a white solid (106.9 mg). LC/MS ESI (m/z): 472 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ): δ 8.90 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.64-7.62 (m, 1H), 7.58 (s, 1H), 7.52-7.49 (m, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.30-5.23 (m, 1H), 5.08-5.02 (m, 2H), 3.56 (s, 2H), 1.51 (d, J = 6.4 Hz, 3H), 1.41-1.37 (m, 4H); 19 FNMR (377 MHz, CDCl 3 ): δ -67.70, -70.79. Example 27. (R)-2-(4-cyclopropylphenyl)-N-(1-(1-(4-fluorophenyl)-1H-pyra zolo[3,4- c]pyridin-5-yl)ethyl)acetamide [0485] Synthesis of ethyl 2-(4-cyclopropylphenyl)acetate [0486] To a solution of ethyl 4-bromophenylacetate (2.0 g), cyclopropylboronic acid (0.92 g), tricyclohexylphosphine (0.23 g) and K3PO4 (6.11 g) in toluene/water (40 mL, 20:1) was added palladium (II) acetate (0.09 g). The reaction mixture was charged with N 2 and stirred at 100 °C overnight. After cooling to room temperature, the reaction was diluted with EA and water and the two layers were separated. The aqueous layer was extracted with EA (20 mL). The combined organic layers were washed with water and brine (40 mL each), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (5- 18% EA/PE) to give ethyl 2-(4-cyclopropylphenyl)acetate (1.368 g) as a pale-yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.15 (q, J = 8.0 Hz, 2H), 3.56 (s, 2H), 1.90-1.84 (m, 1H), 1.24 (t, J = 8.0 Hz, 3H), 0.95-0.92 (m, 2H), 0.7- 0.63 (m, 2H). [0487] Step 2. Synthesis of 2-(4-cyclopropylphenyl)acetic acid [0488] To a solution of ethyl 2-(4-cyclopropylphenyl)acetate (1.24 g) in THF (20.0 mL) and MeOH (8.0 mL) was added 2.5 M aqueous LiOH (12 mL), and the resulting solution was stirred at room temperature for 2 hours. After completion, the mixture was acidified with aqueous 1N HCl, and the aqueous phase was extracted with DCM. The combined organic layers were dried over NaSO 4 , filtered, and concentrated to provide 2-(4- cyclopropylphenyl)acetic acid (1.04 g) as a yellow solid, which used for next step. [0489] Step 3. Synthesis of (R)-2-(4-cyclopropylphenyl)-N-(1-(1-(4-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0490] A solution of 2-(4-cyclopropylphenyl)acetic acid (100 mg) and HATU (323.7 mg) in DMF (5.0 mL) was stirred at room temperature for 15 min. Then (R)-1-(1-(4- fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (206.6 mg) and DIEA (0.56 mL) was added. The reaction was stirred at rt for 1 hour, and LC/MS showed the reaction was complete. The reaction was diluted with EA and water. The two phases were then separated. The aqueous phase was extracted with EA (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by prep-HPLC [Column: YMC-Actus Triart C18250*20mm; Mobile phase: from 20% to 80% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] to afford the compound (R)-2-(4-cyclopropylphenyl)-N-(1-(1-(4- fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide (140 mg) as a white solid. LC/MS ESI (m/z): 415 (M+H) + ; 1 H-NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.20 (s, 1H), 7.76 - 7.65 (m, 2H), 7.60 (s, 1H), 7.32 - 7.26 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.07 - 7.01 (m, 2H), 6.61 (s, 1H), 5.29-5.24 (m, 1H), 3.64 - 3.44 (m, 2H), 1.93 - 1.82 (m, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.02 - 0.88 (m, 2H), 0.75- 0.61 (m, 2H). 19 F-NMR (377 MHz, CDCl 3 ) δ - 113.57. Example 28. (R)-2-(4-cyclopropylphenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1 H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide [0491] Synthesis of (R)-2-(4-cyclopropylphenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1 H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0492] To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride (151 mg) in anhydrous DMF (1 mL) was added DIEA (0.61 mL, 3.71 mmol) to get Solution A. To a solution of 2-(4-cyclopropylphenyl)acetic acid (130.8 mg) in DMF were added HATU (258.6 mg) and stirred 5 min at RT to get Solution B. Solution B was added to the solution A and stirred at RT for 1h. The reaction was diluted with EA and water, the two phases were separated, and the aqueous phase was extracted with DCM (10 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by prep-HPLC [Column: YMC-Actus Triart C18250*20mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm] and SFC (Column: ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; Wavelength:220nm) to give (R)-2-(4-cyclopropylphenyl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de as a white solid (97 mg). LC/MS ESI (m/z): 403 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 1H), 8.08 (s, 1H), 7.53 (s, 1H), 7.16-7.03 (m, 4H), 6.53 (d, J = 7.6 Hz, 1H), 5.30 - 5.23 (m, 1H), 5.06-5.00 (m, 2H), 3.54-3.53 (m, 2H), 1.93- 1.86 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.03 - 0.90 (m, 2H), 0.69-0.68 (m, 2H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.81 (s). Example 29. (R)-2-(4-(1-fluorocyclopropyl)phenyl)-N-(1-(1-(2,2,2-trifluo roethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0493] Synthesis of 1-(2-bromo-1-fluoroethyl)-4-methylbenzene [0494] To an ice cooled solution of 1-ethenyl-4-methylbenzene (9.45 g,) in DCM (80.0 mL) were added triethylamine trihydrofluoride (40 mL) and N-bromosuccinimide (17.0 g). After stirring 30 min at 0°C, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into ice water (500 mL) and neutralized with aqueous NH4OH. The two phases were separated, and the aqueous phase was extracted with DCM (600 mL). The combined organic layers were washed with 0.1 M HCl (600 mL), 5% NaHCO 3 and water (200 mL), and dried over Na 2 SO 4 . The organic layer was then filtered and concentrated in vacuo. The residue was purified by silica gel column (5% EA in PE) to give 1-(2-bromo-1-fluoroethyl)-4-methylbenzene (13.69 g) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (d, J = 8.0, 2H), 7.16 (d, J =8.0 Hz, 2H), 5.66-5.63 (m, 1H), 5.54-5.51 (m, 1H), 3.70-3.61 (m, 3H), 2.35-2.32 (m, 1H); 19 F NMR (377 MHz, CDCl 3 ) δ -172.35 (s). [0495] Synthesis of 1-(1-fluorovinyl)-4-methylbenzene [0496] 1-(2-bromo-1-fluoroethyl)-4-methylbenzene (2.0 g) was dissolved in pentane (60 ml), and tBuOK (2.09 g) was added slowly at 0 °C. The reaction mixture was stirred under reflux for 1 h. After cooling to room temperature, the mixture was poured into ice water (50 ml). After separation of the phases, the aqueous phase was extracted with pentane (300 ml). The combined organic layers were washed with 5% NaHCO 3 (50 ml), 0.05 M HCl (25 ml), and water (50ml). The organic phase was dried (NaSO 4 ) and filtered. The filtrate was concentrated in vacuo to get a residue, which was purified by silica gel column (5% EA in PE) to give 1-(1-fluorovinyl)-4-methylbenzene (711 mg) as a colorless liquid. 1 H-NMR: (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.36-5.22 (m, 1H), 4.90-4.85 (m, 1H), 2.33 (s, 3H); 19 F-NMR (377 MHz, DMSO) δ -107.97. [0497] Synthesis of 1-(2,2-dichloro-1-fluorocyclopropyl)-4-methylbenzene [0498] A mixture of 1-(1-fluorovinyl)-4-methylbenzene (500 mg), CHCl 3 (10 mL), NaOH (40%, 10 mL) and benzyltriethylammonium chloride (30 mg) was stirred at rt overnight. The mixture was poured into H2O (50 mL) and then extracted with CHCl3 (3 × 20 mL). The CHCl3 layer was washed with H2O (3 × 20 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide crude 1-(2,2-dichloro-1-fluorocyclopropyl)- 4-methylbenzene (500 mg) as colorless liquid, which was used directly in the next reaction. 1H-NMR: (400 MHz, DMSO-d6) δ 7.40 (t, J = 12.7 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.86- 2.63 (m, 1H), 2.39-2.35 (m, 1H), 2.33 (s, 3H). [0499] Synthesis of 1-(1-fluorocyclopropyl)-4-methylbenzene [0500] To a mixture of 1-(2,2-dichloro-1-fluorocyclopropyl)-4-methylbenzene (500 mg) in THF (10 mL) was added lithium aluminium tetrahydride (436 mg) at 0 °C , and the resulting mixture was stirred at rt overnight. The mixture was poured into H2O (50 mL) and then extracted with EA (3 × 20 mL). The combined EA layers were washed with H 2 O (3 × 20 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide crude 1-(1-fluorocyclopropyl)-4-methylbenzene (250 mg) as colorless liquid, which was used directly in the next step. 1 H-NMR: (400 MHz, DMSO-d6) δ 7.25 - 7.04 (m, 4H), 2.38 -2.25 (m, 3H), 1.51- 1.33 (m, 2H), 1.10- 1.01 (m, 2H). [0501] Step 5. Synthesis of 1-(bromomethyl)-4-(1-fluorocyclopropyl)benzene [0502] To a solution of 1-(1-fluorocyclopropyl)-4-methylbenzene (200 mg) in CCl4 (4 mL) were added AIBN (0.02 mL) and NBS (355.5 mg). The reaction was stirred at 80 °C for 16 hr. The reaction was the diluted with DCM and water. The organic layer was separated and concentrated in vacuo to give an oil, which was purified by column chromatography to give 1-(bromomethyl)-4-(1-fluorocyclopropyl)benzene (170 mg) as colorless oil. 1 H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 4.55 (s, 2H), 1.52 - 1.37 (m, 2H), 1.14 - 1.04 (m, 2H). [0503] Step 6. Synthesis of 2-(4-(1-fluorocyclopropyl)phenyl)acetonitrile [0504] To a solution of 1-(bromomethyl)-4-(1-fluorocyclopropyl)benzene (100.0 mg, crude) in DMSO (5.0 mL) was added NaCN (107.0 mg), and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was then poured into water (10 mL) and extracted with EA (20 mL). The organic layer was separated, dried (NaSO 4 ), filtered and concentrated in vacuo to get a residue, which was purified by silica gel column (5% EA in PE) to afford 2- (4-(1-fluorocyclopropyl)phenyl)acetonitrile (30 mg) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (dd, J = 22.6, 8.2 Hz, 4H), 3.75 (s, 2H), 1.55 – 1.43 (m, 2H), 1.11 – 1.00 (m, 2H). [0505] Step 7. Synthesis of 2-(4-(1-fluorocyclopropyl)phenyl)acetic acid [0506] To a solution of 2-[4-(1-fluorocyclopropyl)phenyl]acetonitrile (30 mg) in H 2 O (3 mL) was added sodium peroxide (40 mg). The mixture was stirred at 50 °C for 24 hr. Then the mixture was stirred at 60 °C for 24 hr. The pH of the mixture was adjusted to 4 with 1N HCl solution and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to give 2-[4-(1-fluorocyclopropyl)phenyl]acetic acid (30 mg) as a white solid. LC/MS ESI (m/z): 193 [M-H]-; 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 3.66 (s, 1H), 1.53 – 1.48 (m, 1H), 1.48 – 1.42 (m, 2H), 1.10 – 1.01 (m, 2H). [0507] Step 8. Synthesis of (R)-2-(4-(1-fluorocyclopropyl)phenyl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0508] A solution of 2-[4-(1-fluorocyclopropyl)phenyl]acetic acid (30 mg), (R)-1-[1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]ethan-1-amine hydrochloride (49.0 mg), HATU (64.6 mg) and DIEA (0.077 mL) in DMF (5 mL) was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with DCM. The combined organic extracts were dried, filtered, and concentrated to give a residue. The residue was purified by prep- HPLC (Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 25% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) to give (R)- 2-(4-(1-fluorocyclopropyl)phenyl)-N-(1-(1-(2,2,2-trifluoroet hyl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)ethyl)acetamide (26.9 mg) as a white solid. LCMS ESI (m/z): 421 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.31 - 7.27 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.71 (s, 1H), 5.35 – 5.20 (m, 1H), 5.18 – 4.93 (m, 2H), 3.59 (s, 2H), 1.52 – 1.46 (m, 5H), 1.10 – 1.02 (m, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.78, -179.26. Example 30.2-(4-(2,2-difluorocyclopropyl)phenyl)-N-((R)-1-(1-(2,2,2- trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide diastereomer A [0509] Step 1.1-bromo-4-(2,2-difluorocyclopropyl)benzene A solution of 1-bromo-4-ethenylbenzene (2.50 mL), trimethyl(bromodifluoromethyl)silane (4.46 mL) and tetrabutylammonium bromide (0.178 mL) in toluene (50 mL) was stirred at 110 °C for 12 hr. The mixture was concentrated to a residue, and the residue was purified by chromatography on silica gel (PE: EA=1:0 to 50:1) to give racemic 1-bromo-4-(2,2- difluorocyclopropyl)benzene (4.2 g ) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 – 7.43 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 2.78 – 2.61 (m, 1H), 1.92 – 1.74 (m, 1H), 1.66 – 1.56 (m, 1H). [0510] Step 2. ethyl 2-(4-(2,2-difluorocyclopropyl)phenyl)acetate A solution of 1-bromo-4-(2,2-difluorocyclopropyl)benzene (4 g), 1-ethyl 3-potassium propanedioate (4.38 g), allylpalladium chloride dimer (0.13 g), BINAP (0.64 g) and DMAP (2.10 g) in mesitylene (10 mL) was charged with N2. The mixture was stirred at 140 °C for 1 hr and then at 120 °C for 12 hr. The mixture was concentrated to give a residue, and the residue was purified by chromatography on silica gel (PE: EtOAc = 1:0 to 50:1) to give ethyl 2-[4- (2,2-difluorocyclopropyl)phenyl]acetate as a white solid (1.54 g) as a white solid. LCMS ESI (m/z): 241 (M+H) + . [0511] Step 3.2-(4-(2,2-difluorocyclopropyl)phenyl)acetic acid [0512] To a solution of racemic ethyl 2-[4-(2,2-difluorocyclopropyl)phenyl]acetate (1.3 g) in MeOH (4.0 mL) was added NaOH (1 M in H 2 O, 30 mL), and the mixture was stirred at 25 °C for 12 hr. The reaction mixture was then concentrated, diluted with H 2 O and washed with EtOAc. The aqueous phase was adjusted pH = 3 with 1N HCl and extracted with EtOAc. The combined organic extracts were dried, filtered and concentrated to give racemic 2-(4-(2,2-difluorocyclopropyl)phenyl)acetic acid as a white solid. [LC/MS ESI (m/z): 211 [M-H]-; 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 – 7.23 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 3.64 (s, 2H), 2.81 – 2.64 (m, 1H), 1.90 – 1.71 (m, 1H), 1.65- 1.60 (m, 1H). Racemic 2- (4-(2,2-difluorocyclopropyl)phenyl)acetic was resolved by chiral prep-SFC (Column: ChiralPak AD, 250×21.2mm I.D., 5µm; Mobile phase: A for CO 2 and B for MeOH; Gradient: B 15%; wavelength: 220 nm) to give 2-[4-(2,2-difluorocyclopropyl)phenyl]acetic acid enantiomer P1 (200 mg) and 2-[4-(2,2-difluorocyclopropyl)phenyl]acetic acid enantiomer P2 (240 mg) as white solids. [0513] Step 4A.2-(4-((R or S)-2,2-difluorocyclopropyl)phenyl)-N-((R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0514] A solution of 2-[4-(2,2-difluorocyclopropyl)phenyl]acetic acid enantiomer P2 (120 mg), (R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl]ethan-1-amine hydrochloride (165.7 mg), HATU (236.5 mg) and DIEA (0.28 mL) in DMF (5 mL) was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with DCM. The combined organic extracts were dried, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (Column: GEMINI C18250*21.2mm 5um; Mobile phase: from 25% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) to give 2-(4-((R or S)-2,2-difluorocyclopropyl)phenyl)-N-((R)-1-(1-(2,2,2-triflu oroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide (79.6 mg) as a white solid. LCMS ESI (m/z): 439 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 7.2 Hz, 1H), 5.33 – 5.16 (m, 1H), 5.15 – 4.93 (m, 2H), 3.58 (s, 2H), 2.88 – 2.60 (m, 1H), 1.92 – 1.75 (m, 1H), 1.70 – 1.58 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.79, -125.90, -142.41. Example 31.2-(4-(2,2-difluorocyclopropyl)phenyl)-N-((R)-1-(1-(2,2,2- trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide diastereomer B [0515] Step 4B.2-(4-((R or S)-2,2-difluorocyclopropyl)phenyl)-N-((R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0516] A solution of 2-[4-(2,2-difluorocyclopropyl)phenyl]acetic acid enantiomer P1 (100 mg), (R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl]ethan-1-amine hydrochloride (138.1 mg), HATU (197.1 mg) and DIEA (0.23 mL) in DMF (5 mL) was stirred at 25 °C for 12 hr. The mixture was diluted with water and extracted with DCM. The combined organic extracts were dried, filtered and concentrated to give a residue, which was purified by prep-HPLC (Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 55% to 95% MeCN with H 2 O (0.1% FA); flow rate: 20 mL/min; wavelength: 220 nm/254 nm) to give 2-(4-((R or S)-2,2-difluorocyclopropyl)phenyl)-N-((R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de (50.7 mg, white solid). LCMS ESI (m/z): 439 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.72 (s, 1H), 5.38 – 5.20 (m, 1H), 5.14 – 4.95 (m, 2H), 3.58 (s, 2H), 2.86 – 2.62 (m, 1H), 1.95 – 1.76 (m, 1H), 1.70 – 1.58 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.80, -125.92, -142.30. Example 32. (R)-2-(4-isopropylphenyl)-N-(1-(3-methyl-1-(2,2,2-trifluoroe thyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0517] Synthesis of 2-bromo-5-fluoro-N-methoxy-N-methylisonicotinamide [0518] To a solution of 2-bromo-5-fluoroisonicotinic acid (10 g) in DCM (400 mL) were added HATU (22.47 g), TEA (18.9 mL) and N,O-dimethylhydroxylamine hydrochloride (4.88 g). The reaction was stirred at 20 °C for 16 h under nitrogen atmosphere. The solvent was evaporated under reduced pressure to provide a residue. The residue was dissolved in EA (500 mL), washed twice with water (500 mL) and then brine (500 mL). The organic layer was separated, dried with Na 2 SO 4 , filtered, and concentrated to get a residue, which was purified via Biotage (from 0% to 15% EA with PE) to give 2-bromo-5-fluoro-N-methoxy-N- methylisonicotinamide (10.3 g) as yellow oil: LCMS ESI (m/z): 262.9 (M+H) + . [0519] Synthesis of 1-(2-bromo-5-fluoropyridin-4-yl)ethan-1-one [0520] 2-bromo-5-fluoro-N-methoxy-N-methylisonicotinamide (10.3 g) was suspended in THF (200 mL) and stirred at 0 °C for 5 min. Methylmagnesium bromide (19.58 mL, 3.0 M in ether) was slowly added to the reaction mixture under a nitrogen atmosphere, and the reaction was stirred at 20 °C for 16 h. The reaction was quenched with saturated ammonium chloride. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to provide a residue, which was purified via Biotage (from 0% to 10% EA with PE) to give 1-(2-bromo-5- fluoropyridin-4-yl)ethan-1-one (8.3 g) as colorless oil. LCMS ESI (m/z): 218.0 (M+H) + . [0521] Synthesis of 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine [0522] To a solution of 1-(2-bromo-5-fluoropyridin-4-yl)ethan-1-one (8.3 g) in ethylene glycol (50 mL) were added hydrazine hydrate (4.793 mL) and the reaction was stirred at 120 °C for 72 hr under a nitrogen atmosphere. Upon completion, the reaction was diluted with EA (200 mL), and the resulting mixture was washed twice with water (2 L) and brine (500 mL). The organic layer was separated, dried with Na 2 SO 4 , filtered, and evaporated to provide a residue, which was purified via Biotage (from 0% to 20% EA with PE) to give 5-bromo-3- methyl-1H-pyrazolo[3,4-c]pyridine (2.7 g) as a white solid. LCMS ESI (m/z): 212 (M+H) + ; 1H NMR (400 MHz, CDCl 3 ): δ 8.80 (d, J = 0.9 Hz, 1H), 7.80 (d, J = 0.9 Hz, 1H), 2.60 (s, 3H). [0523] Synthesis of 5-bromo-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c] pyridine [0524] To a solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine (5.30 g) in anhydrous DMF (26 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.3 mL) and Cs 2 CO 3 (9.82 g). The reaction was stirred at 25 °C for 16 hr under a nitrogen atmosphere. Upon completion, the reaction mixture was poured into H2O and extracted with EA three times. The combined organic layers were washed with brine, dried with Na 2 SO 4 , filtered and evaporated in vacuo. The residue was purified via Biotage (from 0% to 10% EA with PE; 80 g Cartridge column) to give 5-bromo-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridine (5.72 g) as a white solid. LCMS ESI (m/z): 294 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 7.79 (d, J = 0.9 Hz, 1H), 5.02 – 4.87 (m, 2H), 2.57 (s, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.91 (s). [0525] Synthesis of 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine -5- carbaldehyde [0526] To a solution of 5-bromo-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridine (2 g) in anhydrous DMF (60 mL) were added Na2CO3 (1.082 g), Pd(dppf)2Cl2 (498 mg) and Et3SiH (2.2 mL). The reaction was charged with N2 and stirred at 100°C under CO (7 bar) atmosphere for 16 hr . After completion, water was added into the reaction. The reaction mixture was extracted with Ethyl Acetate. The combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give as a black oil, which was purified via Biotage (from 0% to 20% EA with PE; 40 g Cartridge column). Collected fractions and evaporated to get 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine - 5-carbaldehyde (1.2 g) as a yellow solid. LCMS ESI (m/z): 244 (M+H) + 1 H NMR (400 MHz, CDCl 3 ) : δ 10.24 (s, 1H), 9.04 (s, 1H), 8.37 (d, J = 0.6 Hz, 1H), 5.10 – 4.98 (m, 2H), 2.66 (s, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.80 (s). [0527] Synthesis of (R,E)-2-methyl-N-((3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyra zolo[3,4- c]pyridin-5-yl)methylene)propane-2-sulfinamide [0528] To a solution of 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine -5- carbaldehyde (1.2 g) in anhydrous DCM (15 mL) were added CuSO4 (2.36 g) and (R)-2- methylpropane-2-sulfinamide (0.78 g). The reaction mixture was stirred at rt overnight. The solution was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by silica gel column to give (R,E)-2-methyl-N-((3-methyl-1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)methylene)pro pane-2-sulfinamide (1.5 g). LCMS ESI (m/z): 347 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.85 (s, 1H), 8.31 (d, J = 1.1 Hz, 1H), 5.07 – 4.95 (m, 2H), 2.66 (s, 3H), 1.31 (s, 9H). [0529] Synthesis of (R)-2-methyl-N-((R)-1-(3-methyl-1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)propane-2-sulfinamide [0530] To a solution of (R,E)-2-methyl-N-((3-methyl-1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene)propane-2-sulfinamide (1.6 g, 4.62 mmol) in anhydrous THF (17 mL) was added methylmagnesium bromide (7.699 mL, 3.0 M in ether) dropwise at -78°C under nitrogen. The reaction was stirred at -78 °C for 2 hr. Then the reaction solution was quenched with aqueous NH 4 Cl. The two phases were separated, and the aqueous phase was extracted with EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. Then the residue was purified by silica gel column chromatography, to give (R)-2-methyl-N-((R)-1-(3-methyl-1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)propane -2-sulfinamide (1.5 g, 4.139 mmol) as a white solid . LCMS ESI (m/z): 363 (M+H) + [0531] Synthesis of (R)-1-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]p yridin-5- yl)ethan-1-amine hydrochloride [0532] To a solution of (R)-2-methyl-N-[(R)-1-[3-methyl-1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl]ethyl]propane-2-sulfinamide (1.0 g, 2.76 mmol) in dioxane (4.0 mL) was added 4 N HCl-Dioxane (2.0 mL), and the reaction was stirred at rt for 1 hr. Then the mixture was then concentrated to provide a residue, which was directly used in the next step. LCMS ESI (m/z): 259 (M+H) + . [0533] Synthesis of (R)-2-(4-isopropylphenyl)-N-(1-(3-methyl-1-(2,2,2-trifluoroe thyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0534] To a solution of (R)-1-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]p yridin- 5-yl)ethan-1-amine hydrochloride (238 mg) in anhydrous DMF (1.5 mL) were added DIEA (0.6 mL) to provide solution A. To a solution of 2-(4-isopropylphenyl)acetic acid (126.4 mg) in DMF(1 mL) were added HATU (296.5 mg) and stirred 15 min at rt to provide solution B. Solution A was added to the solution B and stirred at rt for 1h. The reaction was diluted with EA and water. The two phases were separated, and the organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by Prep- HPLC ((Column: AZZOTA C1830*250mm*10um; Mobile phase: from 25% to 95% MeCN with H 2 O (1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm)) and SFC (Column: ChiralPak IG, 250×21.2mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 40%; wavelength: 220nm) to give (R)-2-(4- isopropylphenyl)-N-(1-(3-methyl-1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5- yl)ethyl)acetamide as a white solid (100.2 mg). LCMS ESI (m/z): 419.5 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 7.47 (s, 1H), 7.19 (s, 4H), 6.58 (s, 1H), 5.34 - 5.20 (m, 1H), 5.01 - 4.87 (m, 2H), 3.55 (d, J = 1.8 Hz, 2H), 2.95 - 2.85 (m, 1H), 2.56 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.92. Example 33. (R)-2-(4-cyclopropylphenyl)-N-(1-(3-methyl-1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0535] Synthesis of (R)-2-(4-cyclopropylphenyl)-N-(1-(3-methyl-1-(2,2,2-trifluor oethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0536] To a solution of (R)-1-[3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]p yridin- 5-yl]ethan-1-amine hydrochloride (242 mg) in anhydrous DMF (1.5 mL) was added DIEA (0.6 mL) to provide Solution A. To a solution of 2-(4-cyclopropylphenyl)acetic acid (111.58 mg) in DMF (1.0 mL) was added HATU (264.83 mg) and stirred 15 min at rt to provide Solution B . Solution A was added to the Solution B and stirred at rt for 1h. The reaction was diluted with EA and water. The organic layer was washed with aqueous NaCl, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC ((Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 40% to 90% MeCN with H 2 O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wavelength: 220 nm/254 nm)) and SFC (Column: ChiralPak IG, 250×21.2mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1%NH 3 H 2 O; Gradient: B 45%; Flow rate: 50mL/min; wavelength: 220nm) to give (R)-2-(4-cyclopropylphenyl)-N-(1-(3-methyl-1-(2,2,2-trifluor oethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide as a white solid (86.7 mg). LCMS ESI (m/z): 417.5 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 7.44 (d, J = 0.9 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.52 (d, J = 7.4 Hz, 1H), 5.31 – 5.22 (m, 1H), 5.00 – 4.87 (m, 2H), 3.54 (d, J = 2.4 Hz, 2H), 2.55 (s, 3H), 1.93 – 1.84 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.00 – 0.92 (m, 2H), 0.72 – 0.64 (m, 2H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.92 (s). Example 34. (R)-2-(5-cyclopropylpyridin-2-yl)-N-(1-(1-(2,2,2-trifluoroet hyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0537] Synthesis of methyl 2-(5-cyclopropylpyridin-2-yl)acetate [0538] To a solution of methyl 2-(5-bromopyridin-2-yl)acetate (1 g ) in toluene-water (10:1, 16.5 mL) were added potassium cyclopropyltrifluoroborate (1.29 g), Cs 2 CO 3 (4.25 g), Pd(OAc)2 (0.20 g) and di(adamantan-1-yl)(butyl)phosphine (0.31 g). The reaction was charged with N2 and stirred at 110 °C overnight. The reaction was diluted with EA and water. The two phases were separated, and the organic layer was washed with saturated NaCl, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to provide methyl 2-(5-cyclopropylpyridin-2-yl)acetate (582 mg) as an oil. LCMS ESI (m/z): 192 (M+H) + . [0539] Synthesis of 2-(5-cyclopropylpyridin-2-yl)acetic acid [0540] To a solution of methyl 2-(5-cyclopropylpyridin-2-yl)acetate (582 mg) in MeOH- H 2 O (2:1, 9.5 mL) was added NaOH (183 mg). The reaction was stirred at rt for 3 hr. Then the MeOH was removed under reduced pressure and the pH of the water layer adjusted to 5 with 2M HCl while cooling in an ice bath. Ethyl acetate was added to acidic water later, and the resulting precipitate was collected by filtration. The water layer was then extracted with DCM-MeOH (10:1), and the combined organic layers were concentrated in vacuum. Both the residue and the precipitate were combined to give 2-(5-cyclopropylpyridin-2-yl)acetic acid (354 mg) as a white solid. LCMS ESI (m/z): 178 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 2.0 Hz, 1H), 8.05 – 8.00 (m, 1H), 7.73 (d, J = 8.3 Hz, 1H), 4.06 (s, 2H), 2.18 – 2.08 (m, 1H), 1.15 – 1.08 (m, 2H), 0.93 – 0.85 (m, 2H). [0541] Synthesis of (R)-2-(5-cyclopropylpyridin-2-yl)-N-(1-(1-(2,2,2-trifluoroet hyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0542] To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride (308 mg) in anhydrous DMF (1.5 mL) was added DIEA (1 mL) to provide Solution A. To a solution of 2-(5-cyclopropylpyridin-2-yl)acetic acid (150 mg) in DMF (1 mL) was added HATU (405.76 mg) and stirred 5 min at rt to provide Solution B. Solution A was added to the Solution B, and the reaction mixture was stirred at rt for 1h. The reaction was then diluted with EA and water. The organic layer was washed with aqueous NaCl, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC ((Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 10% to 90% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm)) to give (R)-2-(5-cyclopropylpyridin-2-yl)-N-(1-(1-(2,2,2-trifluoroet hyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide as a white solid (135.4 mg). LCMS ESI (m/z): 404.4 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.94 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.09 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 5.32 – 5.18 (m, 1H), 5.11 – 4.98 (m, 2H), 3.87 (d, J = 2.3 Hz, 2H), 2.00 – 1.90 (m, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.17 – 1.06 (m, 2H), 0.81 – 0.72 (m, 2H); 19 F NMR (377 MHz, CDCl 3 ) δ -70.81 (s). Example 35. (R)-2-(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)-N-(1-(1-( 2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0543] Synthesis of 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide [0544] To a solution of 5-bromo-3-chloropyridine-2-carboxylic acid (4.76 g) in DCM (10 mL) were added HATU (9.94 g), methoxy(methyl)amine (3.396 mL) and TEA (8.4 mL). The reaction was stirred at room temperature for 2 hr. The reaction was then diluted with DCM and water, the two phases were separated. The organic phase was washed with saturated NaCl, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by using silica gel column chromatography eluting with ethyl acetate in petroleum ether (15%) to afford the 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide (5.11 g) as a white solid. LCMS ESI (m/z): 281 (M+H) + . [0545] Synthesis of 1-(5-bromo-3-chloropyridin-2-yl)ethan-1-one [0546] To a solution of 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide (5.48 g) in THF (65 mL) was added methylmagnesium bromide (32.6 mL, 3.0 M in Et 2 O) at -78°C under N 2 . The reaction was stirred at -78°C for 2 hr. Upon completion, the reaction was diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (30 mL x3). The combined organic phase was dried over Na 2 SO 4 , filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (6%) to afford 1-(5-bromo-3- chloropyridin-2-yl)ethan-1-one as a white solid (602 mg). LCMS ESI (m/z): 234 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 2.67 (s, 3H). [0547] Synthesis of 5-bromo-3-chloro-2-(1,1-difluoroethyl)pyridine [0548] To a solution of 1-(5-bromo-3-chloropyridin-2-yl)ethan-1-one (2 g) in 1,2- dichloroethane (40 mL) was added DAST (11.27 mL). The mixture was stirred at 80 °C in a sealed tube for 12 hr. The mixture was quenched with saturated sodium bicarbonate and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give a residue, which was purified by chromatography on silica gel (PE: EA=20:1) to give 5- bromo-3-chloro-2-(1,1-difluoroethyl)pyridine (1.0 g) as a yellow oil. [0549] 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 2.06 (t, J = 18.8 Hz, 3H). [0550] Synthesis of ethyl 2-(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)acetate [0551] A solution of 5-bromo-3-chloro-2-(1,1-difluoroethyl)pyridine (200 mg), potassium ethyl malonate (199.1 mg), allylpalladium chloride dimer (34.24 mg), BINAP (97.11 mg) and DMAP (95.27 mg) in mesitylene (10 mL) was charged with N2 and stirred at 140 °C for 1 hr. The mixture was then stirred at 120 °C for 12 hr. The mixture was concentrated to give a residue, which was purified by chromatography on silica gel (PE: EA=10:1) to provide ethyl 2-[5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl]acetate (50 mg) as a yellow oil. LCMS ESI (m/z): 264 (M+H) + . [0552] Step 5. Synthesis of 2-(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)acetic acid [0553] To a solution of ethyl 2-[5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl]acetate (50 mg) in MeOH (1.0 mL) was added NaOH (1M in H 2 O, 1.0 mL). The mixture was stirred at 25 °C for 12 hr. The mixture was then concentrated, diluted with water, and extracted with EtOAc. The aqueous layer was adjusted pH to 3 with 1 N HCl and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give 2-[5-chloro-6-(1,1- difluoroethyl)pyridin-3-yl]acetic acid (25 mg) as a white solid. LCMS ESI (m/z): 234 (M-H)-. [0554] Step 6. Synthesis of (R)-2-(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)-N-(1-(1- (2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl) acetamide [0555] A solution of 2-[5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl]acetic acid (80 mg), (1R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl]ethan-1-amine hydrochloride (107.80 mg), HATU (142.0 mg) and DIEA (0.168 mL) in DMF (1.0 mL) was stirred at 25 °C for 2 hr. The reaction was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18250*20mm; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wavelength: 220 nm/254 nm) to give (R)- 2-(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)-N-(1-(1-(2,2, 2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide (82.3 mg) as a white solid. LCMS ESI (m/z): 462 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.67 (s, 1H), 7.02 (d, J = 14.4 Hz, 1H), 5.38 – 5.24 (m, 1H), 5.19 – 5.00 (m, 2H), 3.61 (s, 2H), 2.07 (t, J = 18.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.73, -89.61. Example 36. (R)-2-(5-chloro-6-cyclopropylpyridin-3-yl)-N-(1-(1-(2,2,2-tr ifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0556] Step 1: 3-chloro-2-cyclopropyl-5-methylpyridine. A solution of 2-bromo-3-chloro- 5-methylpyridine (4.2 g), cyclopropylboronic acid (1.92 g), Pd(PPh3)4 (2.35 g) and K3PO4 (12.95 g) in toluene (80 mL)/H 2 O (8 mL) was stirred at 110 °C for 12 hours under N 2 . The reaction was complete monitored by LCMS. The mixture was concentrated under vacuo to give a residue, and the residue was purified by column chromatography on silica gel (PE: EA=10:1) to give 3-chloro-2-cyclopropyl-5-methylpyridine (1.4 g) as colorless oil. LCMS ESI (m/z): 168 (M+H) + . [0557] Step 2: 5-(bromomethyl)-3-chloro-2-cyclopropylpyridine. A solution of 3-chloro-2- cyclopropyl-5-methylpyridine (960 mg), NBS (1.12 g) and AIBN (0.042 mL,) in carbon tetrachloride (15 mL) was stirred at 80 °C for 12 hours under N 2 . The reaction was filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE: EA=30:1) to give 5-(bromomethyl)-3-chloro-2-cyclopropylpyridine (700 mg) as colorless oil. LCMS ESI (m/z): 246 (M+H) + . [0558] Step 3: 2-(5-chloro-6-cyclopropylpyridin-3-yl)acetonitrile. A solution of 5- (bromomethyl)-3-chloro-2-cyclopropylpyridine (600 mg, 2.43 mmol) and NaCN (239 mg) in DMF (5 mL) was stirred at 25 °C for 12 hours. The reaction was complete monitored by LCMS. The mixture was diluted with water and extracted with DCM. The mixture was dried, filtered and concentrated to give 2-(5-chloro-6-cyclopropylpyridin-3-yl)acetonitrile (380 mg) as a yellow oil. LCMS ESI (m/z): 193 (M+H) + . [0559] Step 4: 2-(5-chloro-6-cyclopropylpyridin-3-yl)acetic acid. To a solution of 2-(5-chloro- 6-cyclopropylpyridin-3-yl)acetonitrile (380 mg) in MeOH (2 mL) was added NaOH (10 mL, 20.0 mmol, 2N). The mixture was stirred at 25 °C for 12 hours, and the reaction was complete by LCMS. The reaction was then extracted with EtOAc. The aqueous layer was adjusted pH=3 with 1 N HCl solution and lyophilized to give a white solid. The white solid was dissolved in MeOH/DCM (10:1), filtered and concentrated to give 2-(5-chloro-6-cyclopropylpyridin-3- yl)acetic acid (150 mg) as a white solid. LCMS ESI (m/z): 210 (M-H)-. [0560] Step 5: (R)-2-(5-chloro-6-cyclopropylpyridin-3-yl)-N-(1-(1-(2,2,2-tr ifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. A solution of 2-(5-chloro-6- cyclopropylpyridin-3-yl)acetic acid (150 mg), (R)-1-[1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl]ethan-1-amine hydrochloride (258.89 mg), HATU (296 mg) and DIEA (0.35 mL) in DMF (5 mL) was stirred at 25 °C for 12 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18 250*21mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(5-chloro-6-cyclopropylpyridin-3-yl)- N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-y l)ethyl)acetamide (203 mg) as a white solid: LCMS ESI (m/z): 438 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.03 - 6.89 (m, 1H), 5.36 - 5.21 (m, 1H), 5.16 - 5.01 (m, 2H), 3.51 (s, 2H), 2.56 - 2.42 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.12 - 1.07 (m, 2H), 1.06 - 1.01 (m, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.73. Example 37. (R)-2-(3-chloro-4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2,2- trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0561] Step 1: 4-bromo-2-chloro-N-methoxy-N-methylbenzamide. To a solution of 4- bromo-2-chlorobenzoic acid (2.0 g) in DCM (25 mL) were added HATU (4.20 g), methoxy(methyl)amine hydrochloride (4.54 g), and TEA (3.5 mL). The reaction was then stirred at room temperature overnight, and the reaction was complete as monitored by LCMS. The reaction was diluted with DCM and water, and the organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 25% ethyl acetate in petroleum ether to afford 4- bromo-2-chloro-N-methoxy-N-methylbenzamide (2.209 g) as a pale-yellow oil. LCMS ESI (m/z): 279[M+H] + . [0562] Step 2: 1-(4-bromo-2-chlorophenyl)ethan-1-one. To a solution of 4-bromo-2-chloro- N-methoxy-N-methylbenzamide (1.07 g) in THF (10 mL) was added MeMgBr (6.4 mL, 3.0 M in Et 2 O). The reaction was stirred at -78°C for 2 h and then stirred at room temperature overnight. The reaction was diluted with DCM and water, and the two phases were separated. The aqueous phase was further extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel (PE: EA = 10:1) to afford 1-(4-bromo- 2-chlorophenyl)ethan-1-one as a pale-yellow solid (820 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.50 -7.44 (m, 2H), 2.64 (s, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.65. [0563] Step 3: 4-bromo-2-chloro-1-(1,1-difluoroethyl)benzene. To a solution of 1-(4- bromo-2-chlorophenyl)ethan-1-one (2.2 g) in BAST (2.6 mL) was added two drops of methanol. Upon completion of the addition, the reaction mixture was placed under a nitrogen atmosphere and heated to 70°C overnight. The reaction mixture was cooled to room temperature and quenched with 50 ml of water. The resulting mixture was extracted twice with 50 ml of ether. The combined ether phases were washed twice with water, twice with aqueous sodium bicarbonate, once with 10% aqueous citric acid, once with brine, and then dried over magnesium sulfate. The solvent was removed under reduced pressure and was purified by column chromatography on silica gel (2% EA in PE) to afford 4-bromo-2-chloro- 1-(1,1-difluoroethyl)benzene (1.71 g) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J = 4.0Hz, 1H), 7.50 - 7.43 (m, 2H), 2.02 (t, J = 18.4 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.65. [0564] Step 4: ethyl 2-(3-chloro-4-(1,1-difluoroethyl)phenyl)acetate. To a solution of 4- bromo-2-chloro-1-(1,1-difluoroethyl)benzene (1.5 g) in mesitylene (2 mL) were added diallylpalladium dichloride (1.56 mg), BINAP (0.22 g), DMAP (0.72 g) and ethyl potassium malonate (1.50 g). The reaction was charged with N2 and stirred at 120 °C overnight. The reaction was diluted with EA and water, the two phases were separated, and the aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases wwere dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (PE: EA = 20: 1) to give ethyl 2-(3-chloro-4-(1,1- difluoroethyl)phenyl)acetate (590 mg, 2.246 mmol) as a pale-yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.17 (q, J = 20.0 Hz, 2H), 3.61 (s, 2H), 2.03 (t, J = 36.0 Hz, 3H), 1.27 (t, J = 16.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.45. [0565] Step 5. 2-(3-chloro-4-(1,1-difluoroethyl)phenyl)acetic acid. In a 25 mL round- bottomed flask were added ethyl 2-(3-chloro-4-(1,1-difluoroethyl)phenyl) acetate (590 mg) , 1M aqueous NaOH (10 mL) and MeOH (10 mL). The reaction mixture was stirred at rt for 1 hour. The reaction was complete monitored by LCMS. Water (50 mL) was then added, and the aqueous layer was washed with EA. The aqueous layer was acidified to pH < 3 with 1M aqueous HCl, and the mixture was extracted with EA. The combined organic phases were washed with saturated NaCl, dried with Na 2 SO 4 , filtered, and concentrated to provide 2-(3- chloro-4-(1,1-difluoroethyl)phenyl)acetic acid (465 mg) as a green-yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 3.67 (s, 2H), 2.03 (t, J = 36.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.53. LCMS ESI (m/z): 233(M-H) + . [0566] Step 6. (R)-2-(3-chloro-4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2,2- trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. A solution of 2-(3-chloro-4-(1,1- difluoroethyl) phenyl) acetic acid (120 mg) and HATU (292 mg) in 2 mL DMF was stirred at room temperature for 15 min (Solution A). To another vessel was added (R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (186 mg) and DMF (2.0 mL). DIEA（0.566 mL）was added until the pH of the solution higher than 7 by wet pH paper (Solution B). Solution B was added to Solution A, and the reaction was stirred for 1 hour, at which time LCMS showed the reaction was complete. The reaction was diluted with EA and water, the two phases were separated, and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuo. The residue was purified by prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 35% to 95% MeCN with H 2 O (0.1% FA); flow rate: 20 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(3-chloro-4-(1,1- difluoroethyl)phenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyra zolo[3,4-c]pyridin-5- yl)ethyl)acetamide (130 mg) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 8.14 (s, 1H), 7.62 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.32-5.25 (m, 1H), 5.10-5.03 (m, 2H), 3.57 (s, 2H), 2.02 (t, J = 16.0 Hz, 3H), 1.53 (d, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.76, -87.39. LC/MS ESI (m/z): 461[M+H] + . Example 38. (R)-2-(4-(1,1-difluoroethyl)-3-fluorophenyl)-N-(1-(1-(2,2,2- trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0567] 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide. To a solution of 4-bromo-2- fluorobenzoic acid (1.0 g) in DCM (15 mL) were added HATU (2.26 g), methoxy(methyl)amine hydrochloride (4.54 g), and TEA (1.9 mL). The reaction mixture was stirred at room temperature overnight and then diluted with DCM and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 17% ethyl acetate in petroleum ether to afford the title compound 4-bromo-2-fluoro-N-methoxy-N- methylbenzamide (1.166 g) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.29 (m, 3H), 3.55 (s, 3H), 3.34 (s, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -110.95. LCMS ESI (m/z): 262 (M+H) + . [0568] 1-(4-bromo-2-fluorophenyl)ethan-1-one. To a solution of 4-bromo-2-fluoro-N- methoxy-N-methylbenzamide (1.116 g) in THF (10 mL) was added MeMgBr (7.1 mL, 3.0 M in Et2O). The reaction was stirred at -78°C for 2 hours and then stirred at room temperature overnight. The reaction was complete as monitored by LCMS. The reaction was diluted with DCM and water, the two phases were separated, and the aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel (PE: EA = 10:1) to afford 1-(4-bromo-2-fluorophenyl)ethan-1-one (667 mg) as a pale-yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (t, J = 8.0 Hz, 1H), 7.40-7.34 (m, 2H), 2.63 (d, J = 4.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -107.01 (s). [0569] Synthesis of 4-bromo-1-(1,1-difluoroethyl)-2-fluorobenzene. To a solution of 1-(4- bromo-2-fluorophenyl)ethan-1-one (667 mg) in BAST (0.8 mL) was added two drops of methanol. Upon completion of the addition, the reaction mixture was placed under a nitrogen atmosphere and heated to 70 °C overnight. The reaction mixture was cooled to room temperature and quenched with 10 ml of water. The resulting mixture was extracted twice with 20 ml of ether. The combined ether phases were washed twice with water, twice with aqueous sodium bicarbonate, once with 10% aqueous citric acid, once with brine, and then dried over magnesium sulfate. The solvent was removed under reduced pressure and was purified by a gel silica column (3% EA in PE) to afford 4-bromo-1-(1,1-difluoroethyl)-2- fluorobenzene (294 mg) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.44-7.40 (m, 1H), 7.36-7.31 (m, 2H), 2.02-1.93 (m, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.13, -112.27. [0570] Ethyl 2-(4-(1,1-difluoroethyl)-3-fluorophenyl)acetate. To a solution of 4-bromo-1- (1,1-difluoroethyl)-2-fluorobenzene (290 mg) in mesitylene (5 mL) were added BINAP (45 mg), 1-ethyl 3-potassium propanedioate (310 mg), DMAP (148 mg, 1.21 mmol) and diallylpalladium dichloride (1.6 mg). The reaction was charged with N 2 and stirred at 120 °C overnight. The reaction was complete as monitored by LCMS. The reaction was diluted with EA and water, the two phases were separated, and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (4% ethyl acetate in petroleum ether) to give ethyl 2-(4-(1,1-difluoroethyl)- 3-fluorophenyl)acetate (121mg) as a pale-yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.451- 7.47 (m, 1H), 7.11-1.07 (m, 2H), 4.17 (q, J = 8.0 Hz, 2H), 3.63 (s, 2H), 2.03-1.94 (m, 3H), 1.27 (t, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -86.88, -114.99. [0571] 2-(4-(1,1-difluoroethyl)-3-fluorophenyl)acetic acid. To a 25 mL round-bottomed flask were added ethyl 2-(4-(1,1-difluoroethyl)-3-fluorophenyl)acetate (121 mg), 1M aqueous NaOH (3 mL) and MeOH (3 mL). The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was then added, and the aqueous layer was washed with EA. The aqueous layer was acidified to pH < 3 with 1M aqueous HCl, and the mixture was extracted with EA. The combined organic phases were washed with saturated NaCl, dried with Na 2 SO 4 , filtered, and concentrated to product 2-(4-(1,1-difluoroethyl)-3- fluorophenyl)acetic acid (100 mg) as a yellow solid. LCMS ESI (m/z): 217(M-H) + . [0572] (R)-2-(4-(1,1-difluoroethyl)-3-fluorophenyl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. A solution of 2-(4-(1,1-difluoroethyl)-3- fluorophenyl)acetic acid (100 mg) and HATU (261 mg) in 2 mL DMF was stirred at room temperature for 15 min (Solution A). DIEA (0.46 mL) was added to (R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (167 mg) in 2 mL DMF, and the pH of the solution higher than 7 by wet pH paper (Solution B). Solution B was added to Solution A, and the reaction was stirred at room temperature for 1 hour, at which time LCMS showed the reaction was complete. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated under vacuo. The residue was purified by prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 30% to 95% MeOH with H 2 O (0.1% FA); flow rate: 20 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(4-(1,1-difluoroethyl)-3-fluorophenyl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de (59 mg) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (s, 1H), 8.12 (s, 1H), 7.60 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 2H), 6.83 (d, J = 4.0 Hz, 1H), 5.31-5.24 (m, 1H), 5.09-5.03 (m, 2H), 3.59 (s, 2H), 1.98 (t, J = 16.0 Hz, 3H), 1.51 (d, J = 4.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ - 70.78, -86.83, -114.72. LC/MS ESI (m/z): 445 [M+H] + . Example 39. (R)-2-(6-cyclopropyl-5-fluoropyridin-3-yl)-N-(1-(1-(2,2,2-tr ifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0573] 2-cyclopropyl-3-fluoro-5-methylpyridine. To a solution of 2-bromo-3-fluoro-5- methylpyridine (3.75 g) in toluene:H2O (50 mL, 10:1) were added K3PO4 (12.57 g), cyclopropylboronic acid (2.54 g) and Pd(PPh 3 ) 4 (2.28 g). The reaction was stirred at 110°C under N 2 overnight, and the reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was then purified by silica gel column chromatography to give 2-cyclopropyl-3-fluoro-5- methylpyridine (2.2 g) as a colorless oil: LCMS ESI (m/z): 152 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.13 -7.06 (m, 1H), 2.30 - 2.24 (m, 4H), 1.12 -0.92 (m, 4H). 19 F NMR (377 MHz, CDCl 3 ) δ -131.54 (s). [0574] 5-(bromomethyl)-2-cyclopropyl-3-fluoropyridine. To a solution of 2-cyclopropyl- 3-fluoro-5-methylpyridine (2.2 g) in CCl 4 (55 mL) were added NBS (3.63 g) and AIBN (0.22 mL), and the reaction was stirred at 80°C under nitrogen overnight. The reaction was diluted with DCM and water, and the organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo at 30°C. The reaction was complete monitored by LCMS. The residue was purified by silica gel column chromatography to give 5-(bromomethyl)-2- cyclopropyl-3-fluoropyridine (897 mg) as a purple oil. LCMS ESI (m/z): 230.0 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1H), 7.36 -7.29 (m, 1H), 4.43 (s, 2H), 2.36 - 2.29 (m, 1H), 1.16 - 1.00 (m, 4H). 19 F NMR (377 MHz, CDCl 3 ) δ -129.72 (s). [0575] 2-(6-cyclopropyl-5-fluoropyridin-3-yl)acetonitrile. To a solution of 5- (bromomethyl)-2-cyclopropyl-3-fluoropyridine (897 mg) in DMF (5 mL) were added NaCN (385 mg), and the reaction was stirred at RT for 30 min. The reaction was complete as monitored by LCMS. The reaction was then diluted with DCM and water, and the organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 2-(6-cyclopropyl-5- fluoropyridin-3-yl)acetonitrile (513 mg) as a yellow oil: LCMS ESI (m/z): 177 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 - 8.14 (m, 1H), 7.36 - 7.28 (m, 1H), 3.73 (s, 2H), 2.40 - 2.25 (m, 1H), 1.15 - 1.09 (m, 2H), 1.09 - 1.01 (m, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -128.87 (s). [0576] 2-(6-cyclopropyl-5-fluoropyridin-3-yl)acetic acid. 2-(6-cyclopropyl-5- fluoropyridin-3-yl)acetonitrile (589 mg) was dissolved in 2M NaOH (5 mL) and stirred at 100°C for 1 hr. The reaction solution was acidified to pH = 1 with 2 M HCl and extracted with EA (50 mL x 3). The organic layer was concentrated to give the 2-(6-cyclopropyl-5- fluoropyridin-3-yl)acetic acid as yellow solid (553 mg) and used in the next step without further purification. LCMS ESI (m/z): 196 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.15 (s, 1H), 7.56 - 7.48 (m, 1H), 3.63 (s, 2H), 2.32 - 2.21 (m, 1H), 1.04 - 0.93 (m, 4H). 19 F NMR (377 MHz, DMSO) δ -131.95 (s). [0577] (R)-2-(6-cyclopropyl-5-fluoropyridin-3-yl)-N-(1-(1-(2,2,2-tr ifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (206 mg) in anhydrous DMF (1.5 mL) was added DIEA (1 mL) to provide Solution A . To a solution of 2-(6-cyclopropyl- 5-fluoropyridin-3-yl)acetic acid (110 mg) in anhydrous DMF (1.5 mL) was added HATU (236 mg), and the mixture was stirred for 15 min at RT to provide Solution B. Solution A was added to the Solution B, and the reaction was stirred at RT for 1 hr. The mixture was then diluted with EA and water, and the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under vacuo. The residue was purified by prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 20 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(6-cyclopropyl-5-fluoropyridin- 3-yl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyrid in-5-yl)ethyl)acetamide (145 mg) as a white solid. LCMS ESI (m/z): 422 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.11 (d, J = 6.0 Hz, 2H), 7.56 (s, 1H), 7.30 - 7.27 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 5.30 - 5.23 (m, 1H), 5.08 – 5.02 (m, 2H), 3.52 (s, 2H), 2.31 - 2.27 (m, 1H), 1.49 (d, J = 6.4Hz, 3H), 1.12 - 0.97 (m, 4H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.79 (s), -130.20 (s). Example 40. (R)-N-(1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl)ethyl)-2- (4-(trifluoromethyl)phenyl)acetamide [0578] 5-bromo-1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine. To a solution of 2,2- difluoropropyl 4-methylbenzenesulfonate (3.0 g,) in DMF (30 mL) were added 5-bromo-1H- pyrazolo[3,4-c]pyridine (2.19 g) and Cs 2 CO 3 (3.61 g). The reaction was stirred at 90 °C under nitrogen overnight. The reaction was then diluted with EA and water, and the organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. Then the residue was purified by silica gel column chromatography to give 5-bromo-1-(2,2- difluoropropyl)-1H-pyrazolo[3,4-c]pyridine (1.2 g) as a white solid. LCMS ESI (m/z): 276 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 1.0 Hz, 1H), 4.79 (t, J = 12.2 Hz, 2H), 1.63 (t, J = 18.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -93.76 (s). [0579] 1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine-5-carbalde hyde. To a solution of 5-bromo-1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine (1.3 g) in anhydrous DMF (50 mL) were added Na 2 CO 3 (0.75 g), Pd(dppf)Cl 2 (0.34 g) and Et 3 SiH (1.10 g). Then the reaction was stirred at 100°C under CO (5 bar) overnight. The reaction was diluted with EA and water, and the organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was then purified by silica gel column chromatography to give 1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridine-5-carbalde hyde (828 mg) as yellow solid. LCMS ESI (m/z): 226 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 9.13 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.29 (s, 1H), 4.88 (t, J = 12.2 Hz, 2H), 1.67 (t, J = 18.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -93.83 (s). [0580] (R,E)-N-((1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl)methylene)-2- methylpropane-2-sulfinamide. To a solution of 1-(2,2-difluoropropyl)-1H-pyrazolo[3,4- c]pyridine-5-carbaldehyde (1.04 g) in anhydrous DCM (15 mL) were added CuSO 4 (2.21 g) and (R)-2-methylpropane-2-sulfinamide (0.73 g). Then the reaction mixture was stirred at RT overnight, and the solution was filtered through a pad of Celite and the filtrate concentrated. The residue was purified by silica gel column to give (R,E)-N-((1-(2,2-difluoropropyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene)-2-methylpropane-2-sul finamide (1.4 g) as a white solid. LCMS ESI (m/z): 329 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.84 (s, 1H), 8.36 (d, J = 1.0 Hz, 1H), 8.23 (s, 1H), 4.86 (t, J = 12.2 Hz, 2H), 1.65 (t, J = 18.8 Hz, 3H), 1.31 (s, 9H). 19 F NMR (377 MHz, CDCl 3 ) δ -93.82 (s). [0581] (R)-N-((R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyrid in-5-yl)ethyl)-2- methylpropane-2-sulfinamide. To a solution of (R,E)-N-((1-(2,2-difluoropropyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene)-2-methylpropane-2-sul finamide (1.4 g) in anhydrous THF (20 mL) was added MeMgBr (3.0 M in ether, 7.11 mL) dropwise at -78°C under nitrogen. Then the reaction was stirred at -78°C for 2 hr, and the reaction solution was then quenched with saturated ammonium chloride and extracted with EA. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography to give (R)-N-((R)-1-(1-(2,2-difluoropropyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-methylpropane-2-sulf inamide (1.1 g) as a yellow oil. LCMS ESI (m/z): 264 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.06 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 1.0 Hz, 1H), 4.79 (t, J = 12.0 Hz, 2H), 4.72 - 4.66 (m, 1H), 1.65 - 1.58 (m, 6H), 1.25 (s, 9H). 19 F NMR (377 MHz, CDCl 3 ) δ -93.55 (d, J = 5.6 Hz). [0582] (R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5-yl )ethan-1-amine hydrochloride. To a solution of (R)-N-((R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (1.1 g) in dioxane (6 mL) was added HCl-dioxane (3 mL, 4N), and the reaction was stirred at rt for 1 hr. Then the mixture was concentrated, and the residue used directly in next step. LCMS ESI (m/z): 241 (M+H) + . [0583] (R)-N-(1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5 -yl)ethyl)-2-(4- (trifluoromethyl)phenyl)acetamide. To a solution of (R)-1-(1-(2,2-difluoropropyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (264 mg) in anhydrous DMF was added DIEA (655 mg) to provide Solution A. To a solution of 2-(4- (trifluoromethyl)phenyl)acetic acid (173 mg) in anhydrous DMF was added HATU (354 mg) and the mixture was stirred 15 min at RT to provide Solution B. Solution A was then added to the Solution B, and the mixture was stirred at RT for 1 hr. The reaction was diluted with EA and water, and the organic layer was washed brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18 150*20mm*5um; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1%NH 3 H 2 O); flow rate: 25 mL/min; wave length: 220 nm/254 nm) to give (R)-N-(1-(1-(2,2-difluoropropyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)-2-(4-(trifluoromethyl)phe nyl)acetamide (188 mg) as a white solid. LCMS ESI (m/z): 427 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.68 – 7.60 (m, 3H), 7.49 (d, J = 8.0 Hz, 2H), 5.19 - 5.00 (m, 3H), 3.62 (s, 2H), 1.68 (t, J = 19.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -62.53 (s), -93.63 (s). Example 41. (R)-2-(4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2-difluoropro pyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0584] To a solution of (R)-1-(1-(2,2-difluoropropyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride (359 mg) in anhydrous DMF was added DIEA (0.63 mL) to provide Solution A. To a solution of 2-(4-(1,1-difluoroethyl)phenyl)acetic acid (230 mg) in anhydrous DMF (3 mL) was added HATU (481 mg), and the mixture was stirred 15 min at RT to provide Solution B. Then Solution A was added to the Solution B, and the reaction was stirred at RT for 1 hr. The reaction was diluted with EA and water, and the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by prep-HPLC (Column: AZZOTA C18 GEMINI 250*20mm 10um; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2-difluoropro pyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide (207 mg) as a white solid. LCMS ESI (m/z): 423 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.04 (s, 1H), 7.51-7.46 (m, 3H), 7.33 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 5.29 - 5.22 (m, 1H), 4.79 (t, J = 12.0 Hz, 2H), 3.60 (s, 2H), 1.91 (t, J = 18.4 Hz, 3H), 1.62-1.57 (m, 3H), 1.47 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.38 (s), -93.61 (s). Example 42. (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(1-(1-(2,2,2-tr ifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0585] 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene. To a solution of (3-fluoro-4- (trifluoromethyl)phenyl)methanol (1 g) in DCM (10 mL) was added PBr3 (1 mL) at 0°C, and the reaction was stirred at RT for 30 min. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated under vacuo. The residue was then purified by silica gel column chromatography to give 4-(bromomethyl)-2-fluoro-1- (trifluoromethyl)benzene (542 mg) as a colorless oil. LCMS ESI (m/z): no MS signal. 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 7.4 Hz, 2H), 4.45 (s, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -61.43, -113.43. [0586] Synthesis of 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetonitrile. To a solution of 4- (bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (542 mg) and TMSCN (0.32 mL) in anhydrous MeCN (5 mL) was added TBAF (2.5 mL, 1M in THF). The reaction mixture was stirred at RT for 18 hr and then diluted with DCM and water. The organic layer was separated, washed with brine, and concentrated in vacuo. Then the residue was purified by silica gel column chromatography, to give 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetonitrile (262 mg) as a colorless oil. LCMS ESI (m/z): no MS signal. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 11.8 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 4.22 (s, 2H). 19 F NMR (377 MHz, DMSO) δ -59.99, -115.24. [0587] 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid.2-(3-fluoro-4- (trifluoromethyl)phenyl)acetonitrile (262 mg) was dissolved in conc. Hydrogen chloride (4.0 mL) and stirred at 100 °C for 1h. The reaction solution was diluted with water and extracted with EA. The organic layer was separated and concentrated in vacuo to give 2-(3-fluoro-4- (trifluoromethyl)phenyl)acetic acid as a colorless oil (149 mg), which was used in the next step without further purification. LCMS ESI (m/z): 443 (2M-H)-. 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 12.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 3.81 (s, 2H). [0588] (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(1-(1-(2,2,2-tr ifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (196 mg) in anhydrous DMF was added DIPEA (0.53 mL) to provide Solution A. To a solution of 2-(3-fluoro-4- (trifluoromethyl)phenyl)acetic acid (119 mg) in anhydrous DMF was added HATU (224 mg), and the mixture was stirred for 15 min at RT to provide Solution B. Solution A was then added to the Solution B, and the reaction was stirred at RT for 1 hr. The reaction was diluted with EA and water, and the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Then the residue was purified by silica gel column chromatography and prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 25% to 95% MeCN with H 2 O (1%FA); flow rate: 28 mL/min; wave length: 220 nm/254 nm), to give (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(1-(1-(2,2,2-tr ifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide (119 mg) as white solid. LCMS ESI (m/z): 449 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.31 (s, 1H), 7.72 - 7.68 (m, 2H), 7.40 – 7.29 (m, 2H), 5.66 – 5.59 (m, 2H), 5.10 - 5.07 (m, 1H), 3.64 (s, 2H), 1.45 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -59.72, -69.80, -116.73. Example 43. (R)-2-(3-chloro-4-(trifluoromethyl)phenyl)-N-(1-(1-(2,2,2-tr ifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0589] 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene. To a solution of [3-fluoro-4- (trifluoromethyl)phenyl]methanol (1 g) in DCM (4 mL) was added PBr 3 (0.9 mL) at 0°C, and the reaction was stirred at RT for 30 min. The reaction was diluted with EA and water, and the organic layer was separated, washed with sat. brine, and concentrated in vacuo. The residue was then purified by silica gel column chromatography to give 4-(bromomethyl)-2- chloro-1-(trifluoromethyl)benzene as a colorless oil (690 mg). LCMS ESI (m/z): no MS signal. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.82 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 4.77 (s, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -61.16 (s). [0590] Synthesis of 2-(3-chloro-4-(trifluoromethyl)phenyl)acetonitrile.4-(bromom ethyl)-2- chloro-1-(trifluoromethyl)benzene (700 mg) and TMSCN (0.384 mL) were dissolved in anhydrous MeCN (5 mL) and stirred at RT for 30min. TBAF (3 mL, 1M in THF) was then added, and the reaction was stirred at RT for 3h. The reaction was diluted with DCM and water and the organic layer was separated, washed with brine, and concentrated under vacuo. The residue was purified by silica gel column chromatography to give 2-(3-chloro-4- (trifluoromethyl)phenyl)acetonitrile (292 mg) as a colorless oil. LCMS ESI (m/z): 218 (M- H)-. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 4.21 (s, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -61.17 (s).

[0591] 2-(3-chloro-4-(trifluoromethyl)phenyl)acetic acid.2-(3-chloro-4- (trifluoromethyl)phenyl)acetonitrile (290 mg) was dissolved in conc. hydrochloric acid (2.5 mL) and stirred at 100°C for 1 hr. The reaction solution was diluted with water and extracted with EA, and the organic layer was separated, and concentrated under vacuo to give 2-(3- chloro-4-(trifluoromethyl)phenyl)acetic acid as a colorless oil (250 mg) without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 3.75 (s, 2H). [0592] (R)-2-(3-chloro-4-(trifluoromethyl)phenyl)-N-(1-(1-(2,2,2-tr ifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (353 mg) in anhydrous DMF was added DIEA (0.96 mL) to provide Solution A. To a solution of 2-(3-chloro-4- (trifluoromethyl)phenyl)acetic acid (230 mg) in anhydrous DMF was added HATU (403 mg), and the mixture was stirred 15 min at RT to provide Solution B. Solution A was then added to the Solution B, and the reaction was stirred at RT for 2h. The reaction was diluted with EA and water, and the organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (Column: AZZOTA C18 GEMINI 250*20mm 10um; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1%FA); flow rate: 15 mL/min; wave length: 220 nm/254 nm), to give (R)-2-(3-chloro-4-(trifluoromethyl)phenyl)-N-(1-(1-(2,2,2-tr ifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide (347 mg) as a white solid. LCMS ESI (m/z): 465 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 5.31 – 5.23 (m, 1H), 5.08 – 5.02 (m, 2H), 3.59 (s, 2H), 1.51 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -62.46 (s), -70.79 (s). Example 44. (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)-2- (4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide [0593] Synthesis of 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene. To a flame dried flask with methyl triphenylphosphonium iodine Ph 3 PCH 3 I (15.2 g, 0.04 mol) was added THF (60 mL) under an argon atmosphere. Cool the resulting suspension to 0 °C and add n -BuLi (15.6 mL, 2.5 N) dropwise. The mixture was stirred at 0 °C for 10 minutes, then cooled to - 78 °C.1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one (8.2 g, 0.03 mol) in THF (10 mL) was added and the mixture was stirred at -78 °C for 30 min and then stirred at rt overnight. It was quenched with sat. NH4Cl and extracted with PE (300 mL). The organic layer was washed with sat. NaCl, dried with anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 10 : 1) to give 1- bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene as a colorless oil (6.1 g, 74%). 1 HNMR （400 MHz, CDCl 3 ): 7.53-7.50 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.97 (d, J = 1.2 Hz, 1H), 5.77-5.76 (m, 1H) ppm. 19 FNMR (376.48 MHz, CDCl 3 ): -64.9 ppm. [0594] 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene. To an oven dried 100 mL vessel containing 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (2.2 g) and methyldiphenylsulfonium tetrafluoroborate (3.3 g) in anhydrous tetrahydrofuran (40 mL) was added sodium bis(trimethylsilyl)amide 2 M in THF (7.0 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 1 h. To the solution was added 2.5 mL of methanol, and the crude mixture was concentrated in vacuo. The residue was dissolved in PE (100 mL) and washed with water (30 mL x 2) and brine. The combined organic layers were collected and concentrated under vacuo. The crude residue was purified by automated flash chromatography on silica gel (PE100%) to give 1-bromo-4-(1- (trifluoromethyl)cyclopropyl)benzene a colorless oil (1.4g). 1 HNMR (400 MHz, CDCl 3 ):7.49-7.44 (m, 2H), 7.34-7.32 (m, 2H), 1.42-1.33 (m, 2H), 1.02-0.95 (m, 2H). 19 FNMR (376.48 MHz, CDCl 3 ): -70.2 ppm. [0595] Dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate. To a 100 mL round bottom flask containing diethylmalonate (0.77 g) and 1-bromo-4-(1- (trifluoromethyl)cyclopropyl)benzene (1.4 g) in PhMe (50 mL) were added K 3 PO 4 (3.4 g), Pd(OAc) 2 (40 mg) and JohnPhos (CAS# 224311-51-7, 90 mg). The reaction mixture was stirred at 125 °C for 4.0 h under N 2 and monitored by LCMS. After completion of the reaction, the crude mixture was filtered and concentrated in vacuo. The residue was purified by automated flash chromatography on silica gel eluting with 100% PE to 50% PE in EA to give the dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate as a white solid (693 mg). LCMS ESI (m/z): 317 (M+H) + . 1 HNMR (400 MHz, CDCl 3 ): 7.45 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.65 (s, 1H), 3.75 (s, 6H), 1.36-1.33 (m, 2H), 1.02 (m, 2H). 19 FNMR (376.48 MHz, CDCl 3 ): -70.0 ppm. [0596] 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonic acid. To a solution of dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate (540 mg) in toluene (10 mL) was added 8 mL of 32% NaOH. The mixture was stirred at 100 °C for 24 h. After cooling to rt, the aqueous layer was washed with toluene and adjusted pH = 1 with 2 N HCl. The aqueous layer was extracted with EA and washed with brine. The combined organic layers were concentrated to give a yellow solid which was used in the next step without further purification (450 mg). LCMS ESI (m/z): 287 (M-H) + ; [0597] 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid. A mixture of 2-(4-(1- (trifluoromethyl)cyclopropyl)phenyl)malonic acid (400 mg) in toluene (6 mL) and 6 N HCl (6 mL) was stirred at 100 °C for 16 h. The organic layer was collected and washed with saturated brine and concentrated under vacuo to give 2-(4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetic acid as a yellow solid (250 mg), which was used in the next step without further purification. 1 HNMR (400 MHz, CD3OD): 7.41 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 3.60 (s, 2H), 1.34-1.31 (m, 2H), 1.06-1.03 (m, 2H) ppm. 19 FNMR (376.48 MHz, CD3OD): -71.5 ppm. [0598] (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)-2-(4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide. To a solution of (R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (272 mg) in anhydrous DMF (2.0 mL) was added DIEA (0.85 mL) to provide Solution A. To a mixture of 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid (209 mg) in DMF (1.5 mL) was added HATU (358 mg), and the reaction was stirred for 15 min at RT to provide Solution B. Solution A was added to Solution B, and the reaction was stirred at RT for 1 hr. The reaction was then diluted with EA and water, and the organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column (Column: AZZOTA C18 GEMINI 250*20mm 10um; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wave length: 220 nm/254 nm) to give (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl)-2-(4-(1- (trifluoromethyl)cyclopropyl)phenyl)acetamide (126 mg) as a white solid: LCMS ESI (m/z): 471 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.84 (s, 1H), 8.11 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 7.6 Hz, 1H), 5.27- 5.24 (m, 1H), 5.07- 5.01 (m, 2H), 3.58 (s, 2H), 1.49 (d, J = 6.8 Hz, 3H), 1.38 -1.31 (m, 2H), 1.01 (s, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.11 (s), -70.82 (s). Example 45. (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)propyl)-2- (4-(trifluoromethyl)phenyl)acetamide [0599] 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine. To a solution of 5- bromo-1H-pyrazolo[3,4-c]pyridine (10 g) in DMF (50 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.7 mL) and Cs2CO3 (19.7 g). The reaction was stirred at rt overnight, and the reaction was then diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 40% ethyl acetate in petroleum ether to afford the title compound 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridine (7.5 g) as a white solid. LC/MS ESI (m/z): 280 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 5.05 (q, J = 8.2 Hz, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.79 (s). [0600] 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbal dehyde. To a solution of 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine (5 g) in DMF (28 mL) were added Na 2 CO 3 (2.84 g), Pd(dppf)Cl2 (0.52 g) and Et3SiH (5.8 mL). The reaction was then stirred at 80 °C under carbon monoxide for 3 hr. The reaction was diluted with EA and water, and the organic layer was separated, washed with brine, and concentrated in vacuo. Then the residue was purified by silica gel column chromatography to give 1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridine-5-carbaldehyde (2.34 g) as white solid. LC/MS ESI (m/z): 230 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 10.24 (s, 1H), 9.13 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 5.15 (q, J = 8.2 Hz, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.72 (s). [0601] (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5- yl)methylene)propane-2-sulfinamide. To a solution of 1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridine-5-carbaldehyde (2.39 g) in DCM (15 mL) were added (R)-2- methylpropane-2-sulfinamide (1.64 g) and CuSO 4 (4.16 g). Then the reaction was stirred at 30°C for 18 hr, and the mixture was filtered through Celite. The organic layer was concentrated in vacuo and purified by silica gel column chromatography to give (R,E)-2- methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridi n-5-yl)methylene)propane-2- sulfinamide (3.23 g) as white solid. LC/MS ESI (m/z): 333 [M+H] + . [0602] (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)propan-1-amine. To a solution of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5- yl)methylene)propane-2-sulfinamide (600 mg) in DCM (10.0 mL) at -45°C was added EtMgBr (0.72 mL, 3 mol/L in ether) dropwise. The reaction mixture was stirred at -45°C for 30 minutes and then quenched with water. The layers were separated, and the organic layer was concentrated under vacuo. The residue was purified by column chromatography on silica gel (0-10% MeOH in CH 2 Cl 2 ) to give 2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)propyl)propane-2-sulfinamide (350 mg) as an oil. LCMS ESI (m/z): 363 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (s, 1H), 8.10 (d, J = 4.0 Hz, 1H), 7.57 (t, J = 16.0 Hz, 1H), 5.08 - 4.94 (m, 2H), 4.51 (d, J = 8.0 Hz, 1H), 4.38 (d, J =8.0 Hz, 1H), 1.96 - 1.87 (m, 2H), 1.26 (s, 9H), 0.91 (t, J = 8.0 Hz, 3H). [0603] (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)propan-1-amine. To a solution of 2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5- yl)propyl)propane-2-sulfinamide (300 mg) in dioxane (5 mL) was added HCl (1mL, 4N in dioxane). The mixture was stirred at room temperature for 2 hrs. LCMS showed the reaction was complete. The reaction mixture was quenched with ice-water and extracted with EA twice. The combined extracts were concentrated to give (R)-1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)propan-1-amine (200 mg) as a oil. LCMS ESI (m/z): 259 [M+H] + . [0604] (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)propyl)-2-(4- (trifluoromethyl)phenyl)acetamide. To a solution of 2-[4-(trifluoromethyl)phenyl]acetic acid (186 mg) in DMF (3.0 mL) were added HATU (347 mg) and N,N-diisopropylethylamine (0.41 mL). The solution was allowed to stir at room temperature for 10 min before the addition of (R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl]propan-1-amine (214 mg). The mixture was stirred at RT overnight, and the reaction was diluted with water (5 mL) and extracted with EA (10 mL x 2). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to provide crude product, which was purified by prep- HPLC (Column: AZZOTA C18 GEMINI 250*20mm 10um; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1% FA); flow rate: 15 mL/min; wave length: 205 nm/254 nm) to give (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)propyl)-2-(4- (trifluoromethyl)phenyl)acetamide (114 mg) as a white solid. LC/MS ESI (m/z): 445 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.11 (s, 1H), 7.59 - 7.55 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, 1H), 5.05-5.03 (m, 3H), 3.63 (s, 2H), 2.42 - 1.65 (m, 2H), 0.81 (d, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -62.54, -70.80. Example 46. (R)-2-(2,3-dimethyl-2H-indazol-6-yl)-N-(1-(1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0605] Ethyl 2-(2,3-dimethyl-2H-indazol-6-yl)acetate. To a solution of 6-bromo-2,3- dimethyl-2H-indazole (500 mg) in mesitylene (6 mL) were added BINAP (84 mg), potassium 3-ethoxy-3-oxopropanoate (570 mg), DMAP (273 mg) and allylpalladium(II) chloride (17 mg). The reaction was stirred at 140 °C during the day and 120 °C overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to afford ethyl 2-(2,3-dimethyl-2H-indazol-6-yl)acetate (240 mg) as a yellow solid. LCMS ESI (m/z): 233.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 11.2 Hz, 2H), 6.97 (d, J = 8.6 Hz, 1H), 4.19 - 4.11 (m, 2H), 4.08 (s, 3H), 3.69 (s, 2H), 2.59 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). [0606] 2-(2,3-dimethyl-2H-indazol-6-yl)acetic acid. To a solution of ethyl 2-(2,3-dimethyl- 2H-indazol-6-yl)acetate (120 mg) in EtOH (2 mL) was added 2M NaOH (1 mL), and the reaction was stirred at RT for 1 hr. The reaction was diluted with water (0.5 mL) and EA. The aqueous phase was adjusted to pH = 1 with 2M HCl, and extracted with EA. The product was found to be dissolved in the aqueous phase. The aqueous phase was separated and concentrated in vacuo to give 2-(2,3-dimethyl-2H-indazol-6-yl)acetic acid and NaCl as a crude white solid (174 mg) that was used in the next step without purification. LCMS ESI (m/z): 205.2 (M+H) + . [0607] (R)-2-(2,3-dimethyl-2H-indazol-6-yl)-N-(1-(1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (310 mg) in anhydrous DMF was added DIEA (0.845 mL) to provide Solution A. To a solution of crude 2-(2,3-dimethyl- 2H-indazol-6-yl)acetic acid (174 mg) in anhydrous DMF was added HATU (356 mg ), and the reaction was stirred 15 min at RT to provide Solution B. Solution A was added to solution B, and the mixture stirred at RT for 1 hr. The reaction was diluted with EA and water, and the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18250*21mm; Mobile phase: from 20% to 95% MeCN with H2O (0.1% FA); flow rate: 15 mL/min; wave length: 220 nm/254 nm), to give (R)-2-(2,3-dimethyl-2H-indazol-6-yl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de (117 mg) as a white solid. LCMS ESI (m/z): 431.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 7.63 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.64 - 5.57 (m, 2H), 5.10 - 5.06 (m, 1H), 4.01 (s, 3H), 3.53 (s, 2H), 2.57 (s, 3H), 1.43 (d, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -69.77 (s). Example 47. (R)-2-(4-(1-cyanocyclopropyl)phenyl)-N-(1-(1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0608] 1-(4-bromophenyl)cyclopropane-1-carbonitrile. To a 250 mL round bottom flask containing a solution of 1,2-dibromoethane (1.24 mL) and 2-(4-bromophenyl)acetonitrile (2 g) in toluene (20 mL) were added 50% aqueous NaOH (20 mL) and tetrabutylammonium bromide (0.63 mL) at room temperature. The reaction mixture was stirred vigorously at room temperature overnight, and the reaction was then poured into 450 mL of ice-water. The resulting mixture was extracted with EA (130 mL × 3). The combined organic layers were washed with water (150 mL × 2) and brine (150 mL), and finally dried over anhydrous Na 2 SO 4 . The solvent was removed under vacuo, and the residue was purified by silica gel flash chromatography (PE: EA = 5: 1) to afford 1-(4-bromophenyl)cyclopropane-1- carbonitrile as a yellow oil (1.5 g). 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 1.74 (q, J = 5.2 Hz, 2H), 1.38 (q, J = 5.2 Hz, 2H). [0609] Ethyl 2-(4-(1-cyanocyclopropyl)phenyl)acetate. To a solution of 1-(4- bromophenyl)cyclopropane-1-carbonitrile (500 mg) in mesitylene (10 mL) were added diallylpalladium dichloride (1.56 mg), BINAP (95 mg), DMAP (311.58 mg) and ethyl potassium malonate (651 mg). The reaction was charged with N2 and stirred at 120 °C overnight. The reaction was diluted with EA and water, and the two phases were separated. The aqueous phase was extracted with DCM (10 mL x 3), and the combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE: EA = 5: 1) to give ethyl 2-(4-(1- cyanocyclopropyl)phenyl)acetate (200 mg) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32-7.23 (m, 4H), 4.15 (q, J = 7.2 Hz, 2H), 3.60 (s, 2H), 1.71 (q, J = 5.2 Hz, 2H), 1.39 (q, J = 5.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). [0610] 2-(4-(1-cyanocyclopropyl)phenyl)acetic acid. In a 25 mL round-bottomed flask were added ethyl 2-(4-(1-cyanocyclopropyl)phenyl)acetate (330 mg), 2M aqueous NaOH (2.0 mL) and MeOH (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was then added, and the aqueous layer was washed with EA. The aqueous layer was acidified to pH < 3 with 1M aqueous HCl, and the mixture was extracted with EA. The combined organic phases were washed with saturated NaCl, dried with Na 2 SO 4 , filtered, and concentrated to provide 2-(4-(1- cyanocyclopropyl)phenyl)acetic acid as a crude white solid (280 mg) which can be used in the next step without purification. [0611] (R)-2-(4-(1-cyanocyclopropyl)phenyl)-N-(1-(1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. A solution of 2-(4-(1- cyanocyclopropyl)phenyl)acetic acid (200 mg) and HATU (567 mg) in 4 mL DMF was stirred at room temperature for 15 min to provide Solution A. DIEA (1.0 mL) was added to (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride (362 mg) in 2 mL DMF until the pH of the solution higher than 7 by wet pH paper (Solution B). Solution B was added to Solution A, and the reaction was stirred at room temperature for 1 hour, at which time LCMS indicated complete reaction. The reaction mixture was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 25% to 95% MeCN with H2O (0.1% FA); flow rate: 30 mL/min; wave length: 220 nm/254 nm) to afford (R)-2-(4-(1- cyanocyclopropyl)phenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-p yrazolo[3,4-c]pyridin-5- yl)ethyl)acetamide (256 mg) as a white solid. LCMS ESI (m/z): 428 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 8.14 (s, 1H), 7.62 (s, 1H), 7.30-7.22 (m, 4H), 6.80 (d, J = 6.8 Hz, 1H), 5.29-5.25 (m, 1H), 5.07 (q, J = 8.0 Hz, 2H), 3.57 (s, 2H), 1.73-1.70 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H), 1.43-1.34 (m, 2H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.76 ppm. Example 48. (R)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(1-(2,2,2- trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0612] 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetic acid. To a 25 mL round bottom flask were added 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (200 mg), 6 M aqueous NaOH (2.0 mL) and EtOH (2.0 mL), and the mixture was stirred at 80°C overnight. The reaction was cooled to room temperature, and the ethanol was evaporated under vacuum. Water (20 mL) was added, and the aqueous layer was washed with EA. The aqueous layer was acidified to pH < 3 with 1M aqueous HCl, and the mixture was extracted with EA. The combined organic phases were washed with saturated NaCl, dried with Na 2 SO 4 , filtered, and concentrated to provide 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetic acid (200 mg, crude) which was used directly in the next step. [0613] (R)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. A solution of 2-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)acetic acid (200 mg) and HATU (528 mg) in DMF (5.0 mL) was stirred at room temperature for 15 min. (R)-1-(1-(2,2,2-Trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (337 mg) and DIEA (0.92 mL) were added. The reaction was stirred for 1 hour, and LC/MS indicated that the reaction was complete. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with EA (10 mL x 3). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1% FA); flow rate: 30 mL/min; wave length: 220 nm/254 nm) to afford (R)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide (263 mg) as a white solid. LCMS ESI (m/z): 443 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, 1H), 8.13 (s, 1H), 7.61 (s, 1H), 7.02-6.96 (m, 3H), 6.82 (d, J = 8.0 Hz, 1H), 5.31-5.24 (m, 1H), 5.06 (q, J = 8.0 Hz, 2H), 3.56 (s, 2H), 1.51 (d, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -49.97 ppm, -70.78 ppm. Example 49. (R)-2-(1,3-dimethyl-1H-indazol-5-yl)-N-(1-(1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0614] Ethyl 2-(1,3-dimethyl-1H-indazol-5-yl)acetate. To a solution of 5-bromo-1,3- dimethyl-1H-indazole (500 mg) in mesitylene (5 mL) were added BINAP (84 mg), potassium 3-ethoxy-3-oxopropanoate (572 mg), DMAP (274 mg) and allylpalladium(II) chloride (16 mg). The reaction was stirred at 140 °C during the day and 120 °C overnight under nitrogen. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography to afford the title compound ethyl 2-(1,3-dimethyl-1H-indazol-5-yl)acetate (342 mg) as a colorless oil: LCMS ESI (m/z): 233.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 1H), 7.33 - 7.26 (m, 2H), 4.21 - 4.08 (m, 2H), 3.98 (s, 3H), 3.72 (s, 2H), 2.55 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). [0615] 2-(1,3-dimethyl-1H-indazol-5-yl)acetic acid. To a solution of ethyl 2-(1,3-dimethyl- 1H-indazol-5-yl)acetate (385 mg) in EtOH (4.0 mL) was added 2M NaOH (2 mL), and the reaction was stirred at 100°C for 1 hr. The reaction was diluted with water (0.5 mL) and washed with EA. The water phase was adjusted to pH = 1 with 2M HCl, extracted with EA, and the resulting organic phase was concentrated in vacuo to give 2-(1,3-dimethyl-1H- indazol-5-yl)acetic acid as a white solid (320 mg). LCMS ESI (m/z): 205.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 3.58 (s, 2H), 2.38 (s, 3H). [0616] (R)-2-(1,3-dimethyl-1H-indazol-5-yl)-N-(1-(1-(2,2,2-trifluor oethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (232 mg) in anhydrous DMF was added DIEA (0.63 mL) to provide Solution A. To a solution of 2-(1,3-dimethyl-1H- indazol-5-yl)acetic acid (130 mg) in anhydrous DMF was added HATU (266 mg), and the reaction was stirred for 15 min at RT to provide solution B. Solution A was added to the Solution B and stirred at RT for 1h. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Then the residue was purified by prep-HPLC (Column: AZZOTA C18 GEMINI 250*20mm 10um; Mobile phase: from 15% to 80% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wave length: 220 nm/254 nm), to give (R)-2-(1,3-dimethyl-1H-indazol-5-yl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de (109 mg) as a white solid. LCMS ESI (m/z): 431.5 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 1H), 8.08 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 2.4 Hz, 2H), 6.59 (d, J = 7.6 Hz, 1H), 5.30 - 5.27 (m, 1H), 5.05 - 4.99 (m, 2H), 4.00 (s, 3H), 3.69 (s, 2H), 2.54 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.81 (s). Example 50. (R)-2-(3-cyano-1-methyl-1H-indol-5-yl)-N-(1-(1-(2,2,2-triflu oroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0617] 5-bromo-1-methyl-1H-indole-3-carbonitrile. To a solution of 5-bromo-1H-indole-3- carbonitrile (500 mg) in DMF (8 mL) was added NaH (273 mg, 60% in mineral oil) at 0°C, and the reaction was stirred at the same temperature for 30 min. Then iodomethane (0.2 mL) was added to the reaction, and the reaction was stirred at room temperature for 1h. The reaction was quenched with water and extracted with EA. The organic layer was separated, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 5-bromo-1-methyl-1H-indole-3-carbonitrile (507 mg) as a white solid. LCMS ESI (m/z): 235.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.48 - 7.35 (m, 1H), 3.80 (s, 3H). [0618] Ethyl 2-(3-cyano-1-methyl-1H-indol-5-yl)acetate. To a solution of 5-bromo-1- methyl-1H-indole-3-carbonitrile (507 mg) in mesitylene (10 mL) were added BINAP (81 mg), potassium 3-ethoxy-3-oxopropanoate (554 mg), DMAP (265 mg) and allylpalladium(II) chloride (15.6 mg), and the reaction was stirred under nitrogen at 140°C during the day and 120°C overnight. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography to afford ethyl 2-(3-cyano-1-methyl-1H-indol-5-yl)acetate (270 mg) as a colorless oil. LCMS ESI (m/z): 243.4 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.54 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.32 - 7.27 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H). [0619] 2-(3-cyano-1-methyl-1H-indol-5-yl)acetic acid. To a solution of ethyl 2-(3-cyano-1- methyl-1H-indol-5-yl)acetate (270 mg) in MeOH:THF:H 2 O (1:1:1, 9 mL) was added aqueous LiOH (234 mg), and the reaction was stirred at room temperature for 2 hr. The reaction was diluted with water (0.5 mL) and washed with EA. The water phase was separated, the pH adjusted 1 with 2M HCl, and extracted with EA. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo, to give 2-(3-cyano-1-methyl-1H-indol-5-yl)acetic acid (246 mg) as a grey solid. LCMS ESI (m/z): 215.4 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.53 - 7.43 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 2H). [0620] (R)-2-(3-cyano-1-methyl-1H-indol-5-yl)-N-(1-(1-(2,2,2-triflu oroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of (R)-1-(1-(2,2,2-trifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (204 mg) in anhydrous DMF was added DIEA (0.56 mL) to provide Solution A. To a solution of 2-(3-cyano-1-methyl-1H- indol-5-yl)acetic acid (120 mg) in DMF was added HATU (234 mg) and stirred 15 min at room temperature to provide Solution B. Solution A was added to Solution B and stirred at room temperature for 1h. The reaction was diluted with EA and water. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by prep-HPLC (AZZOTA C18 GEMINI 250*20mm 10um; Mobile phase: from 15% to 75% MeCN with H2O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wave length: 220 nm/254 nm) and SFC (Column: ChiralPak IA, 250x21.3mm I.D., 5µm; Mobile phase: A for CO 2 and B for MEOH+0.1% NH 3 H 2 O; Gradient: B 35%; flow rate: 45 mL/min; wave length: 220 nm) to give (R)-2-(3-cyano-1-methyl-1H-indol-5-yl)-N-(1-(1-(2,2,2-triflu oroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl)acetamide (142 mg) as white solid. LCMS ESI (m/z): 441.5 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 7.57-7.55 (m, 2H), 7.35 - 7.30 (m, 1H), 7.30 (d, J = 8.4 Hz 1H), 6.65 (d, J = 7.2 Hz, 1H), 5.34 - 5.22 (m, 1H), 5.14 - 4.97 (m, 2H), 3.85 (s, 3H), 3.71 (s, 2H), 1.46 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.81 (s). Example 51. (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)ethyl)-2-(4- (trifluoromethyl)phenyl)acetamide [0621] 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridine. To a solution of 5- bromo-1H-pyrrolo[2,3-c]pyridine (1.50 g) in DCM (10.0 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.21 mL) and Cs 2 CO 3 (2.98 g), and the reaction was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 40% ethyl acetate in petroleum ether to give 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridine (2.00 g) as a white solid. LCMS ESI (m/z): 279 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.76 (s, 1H), 7.65 (d, J = 4.0 Hz, 1H), 6.57 (d, J = 4.0 Hz, 1H), 5.29 (q, J = 8.0 Hz, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -70.45 (s). [0622] 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridine-5-carbald ehyde. To a solution of 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridine (800 mg) in DMF (15 mL) were added triethylsilane (0.69 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloride (210 mg), and DIEA (0.95 mL) under CO atmosphere, and the reaction was stirred at 100 °C overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate in petroleum ether to afford 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridine-5-carbald ehyde (400 mg) as white solid. [0623] (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c ]pyridin-5- yl)methylene)propane-2-sulfinamide. To a solution of 1-(2,2,2-trifluoroethyl)-1H- pyrrolo[2,3-c]pyridine-5-carbaldehyde (400 mg) in DCM (5.0 mL) were added CuSO4 (839 mg) and 2-methylpropane-2-sulfinamide (276 mg), and the reaction was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated brine solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 40% ethyl acetate in petroleum ether. The organic layer was collected, concentrated in vacuo, and dried to afford (R,E)-2- methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin -5-yl)methylene)propane-2- sulfinamide (440 mg) as white solid. LCMS ESI (m/z): 332[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 7.70 (d, J = 4.0 Hz, 1H), 6.77 (d, J = 4.0 Hz, 1H), 5.39-5.37 (m, 2H), 1.14 (s, 9H). 19 F NMR (377 MHz, DMSO-d6) δ - 70.39 ppm. [0624] 2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c ]pyridin-5- yl)ethyl)propane-2-sulfinamide. To a solution of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)methylene)propane-2-sulfinamid e (400 mg) in THF (10.0 mL) at -45°C was added MeMgBr (0.400 mL, 3 M in ether) dropwise. The reaction mixture was stirred at -78°C for 30 minutes and then diluted with water. The layers were separated, and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give 2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H- pyrrolo[2,3-c]pyridin-5-yl)ethyl)propane-2-sulfinamide (320 mg) as a colorless oil. LCMS ESI (m/z): 348[M+H] + . [0625] (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin-5-y l)ethan-1-amine hydrochloride. To a solution of 2-methyl-N-((R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)ethyl)propane-2-sulfinamide (320 mg) in dioxane (2.00 mL) was added 4 N HCl in dioxane (1.00 mL). The mixture was stirred at room temperature for 2 hours, and LCMS showed the reaction was complete. The reaction mixture was quenched by ice-water and extracted with EA twice. The combined extracts were concentrated to give (R)-1-(1- (2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)ethan-1 -amine hydrochloride (220 mg) as a white solid. LCMS ESI (m/z): 244[M+H] + . [0626] (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)ethyl)-2-(4- (trifluoromethyl)phenyl)acetamide. To a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (227 mg) in DMF (5 mL) were added HATU (422 mg) and DIEA (358 mg). The solution was allowed to stir at room temperature for 10 min before the addition of (R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)ethan-1-amine hydrochloride (225 mg). The mixture was stirred at room temperature overnight, and LCMS showed the desired MS was detected. The reaction was diluted with water (5 mL) and extracted with EA (10 mL x 2). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC (Column: YMC TA C18250*21.2mm 5um; Mobile phase: from 5% to 95% MeCN with H 2 O (0.1% FA); flow rate: 20 mL/min; wave length: 205 nm/254 nm) to give (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)ethyl)-2-(4- (trifluoromethyl)phenyl)acetamide (200 mg) as a white solid. LC/MS ESI (m/z): 430 [M+H] + .1H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.39-7.29 (m, 2H), 6.67-6.58 (m, 1H), 5.25-5.21 (m, 1H), 4.74 (q, J = 8.0 Hz, 2H), 3.63 (s, 2H), 1.51 (d, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -62.52, - 71.50. Example 52. (R)-2-(3-cyano-4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2,2-t rifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0627] Synthesis of 4-bromo-2-chloro-1-(1,1-difluoroethyl)benzene. To a solution of 1-(4- bromo-2-chlorophenyl)ethan-1-one (4 g) in BAST (15 mL) was added MeOH (0.3 mL). The mixture was stirred at 70 °C for 12 hours in a microwave tube. The mixture was quenched with NaHCO3 solution and extracted with DCM. The organic layer was dried, filtered and concentrated to give a residue. The residue was purified by chromatography on silica gel (100%PE) to give 4-bromo-2-chloro-1-(1,1-difluoroethyl)benzene (3.5 g) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.53 - 7.41 (m, 2H), 2.01 (t, J = 18.4 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -87.64 ppm. [0628] Synthesis of ethyl 2-(3-chloro-4-(1,1-difluoroethyl)phenyl)acetate. A solution of 4- bromo-2-chloro-1-(1,1-difluoroethyl)benzene (3.5 g), potassium 3-ethoxy-3-oxopropanoate (3.50 g), Pd 2 (allyl) 2 Cl 2 (0.10 g), BINAP (0.51 g) and DMAP (1.67 g) in mesitylene (40 mL) was stirred at 140 °C for 1 hr. The mixture was then stirred at 120 °C for 12 hours, and the mixture was concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE:EA=10:1) to give ethyl 2-(3-chloro-4-(1,1- difluoroethyl)phenyl)acetate (1.8 g) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.61 (s, 2H), 2.03 (t, J = 18.4 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). [0629] Synthesis of ethyl 2-(3-cyano-4-(1,1-difluoroethyl)phenyl)acetate. A solution of ethyl 2-(3-chloro-4-(1,1-difluoroethyl)phenyl)acetate (1.0 g), Zn(CN) 2 (1.02 g), S-Phos (0.32 g) and Pd 2 (dba) 3 (0.36 g) in DMF (2.0 mL) was stirred at 150 °C for 30 min in a microwave. The mixture was concentrated and purified by column chromatography on silica gel (PE:EA=10:1) to give ethyl 2-(3-cyano-4-(1,1-difluoroethyl)phenyl)acetate (400 mg, 1.579) as a yellow oil. [0630] Synthesis of 2-(3-cyano-4-(1,1-difluoroethyl)phenyl)acetic acid. To a solution of ethyl 2-(3-cyano-4-(1,1-difluoroethyl)phenyl)acetate (400 mg) in MeOH (2.0 mL) was added 1 M NaOH (3 mL), and the mixture was stirred at 25 °C for 12 hr. MeOH was removed under vacuum, and the aqueous residue was washed with EA. The aqueous phase was adjusted pH = 4 with 1 N HCl solution and extracted with EA. The organic layer was dried, filtered and concentrated to give 2-(3-cyano-4-(1,1-difluoroethyl)phenyl)acetic acid (50 mg) as colorless oil which was used in the next step without further purification. LCMS ESI (m/z): 449 (2M-H)-. [0631] Synthesis of (R)-2-(3-cyano-4-(1,1-difluoroethyl)phenyl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de. A solution of 2-(3-cyano-4- (1,1-difluoroethyl)phenyl)acetic acid (50 mg) and HATU (110 mg) in DMF (2.0 mL) was stirred at 25 °C for 10 min. (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride (70.5 mg) and DIEA (0.110 mL) were added to the mixture. The mixture was stirred at 25 °C for 2 hours, and the mixture was diluted with water and extracted with EA. The organic layer was dried, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (YMC-Actus Triart C18150*20mm*5um; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1% FA) to give (R)-2-(3-cyano-4-(1,1- difluoroethyl)phenyl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyra zolo[3,4-c]pyridin-5- yl)ethyl)acetamide (57.4 mg) as a white solid. LCMS ESI (m/z): 452 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.94 (s, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.64 - 7.57 (m, 3H), 6.86 (d, J = 7.6 Hz, 1H), 5.31 - 5.22 (m, 1H), 5.07 (q, J = 8.4 Hz, 2H), 3.62 (s, 2H), 2.04 (t, J = 18.4 Hz, 3H), 1.53 (d, J = 6.8 Hz, 3H). 19 F NMR (400 MHz, CDCl 3 ) δ -70.78, -87.16 ppm. Example 53. (R)-2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-N-(1-(1-(2,2,2 - trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de [0632] (1,2-dimethyl-1H-benzo[d]imidazol-5-yl)methanol. To a solution of methyl 1,2- dimethyl-1H-1,3-benzodiazole-5-carboxylate (1.0 g) in THF (40 mL) was added 4.90 mL 1M lithium aluminum hydride at 0° C. After 2 hours sodium sulfate decahydrate and citric acid were added to the reaction to destroy the excess of lithium aluminum hydride. After 1 hour, methanol (25 ml) was added and the fine suspension was filtered off. The filtrate was evaporated under reduced pressure to afford a brown solid. EA (50 ml) was added and the suspension was treated in an ultra sonic bath. The solid was filtered off and this procedure was repeated twice. The yellow filtrate was evaporated under reduced pressure to afford crude (1,2-dimethyl-1H-1,3-benzodiazol-5-yl)methanol (700 mg) as white solid. LC/MS ESI (m/z):177 [M+H] + . [0633] 5-(chloromethyl)-1,2-dimethyl-1H-benzo[d]imidazole. A solution of (1,2-dimethyl- 1H-1,3-benzodiazol-5-yl)methanol (700 mg) in SOCl2 (5.0 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the crude product as a yellow oil which was used for the next step without further purification. LC/MS ESI (m/z):195 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (s, 1H), 7.55 (s, 2H), 4.67 (s, 2H), 3.84 (s, 3H), 3.07 (s, 3H). [0634] 2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)acetonitrile. To a solution of 5- (chloromethyl)-1,2-dimethyl-1H-1,3-benzodiazole (230 mg) in CH 3 CN (2.0 mL) was added 1.4 mL 1 M TBAF in THF and TMSCN (0.18 mL). The resulting solution was stirred 2 h at room temperature. TLC, and LCMS showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted with EA twice. The combined extracts were concentrated, and the residue was purified by column chromatography on silica gel (DCM/MeOH=10/1) to give 2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)acetonitrile (170 mg) as a colorless oil. LC/MS ESI (m/z):186 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.86 (s, 2H), 3.74 (s, 3H), 2.62 (s, 3H). [0635] 2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)acetic acid. A solution of 2-(1,2- dimethyl-1H-1,3-benzodiazol-5-yl) acetonitrile (100 mg) in conc. HCl (0.5 mL) was stirred at 90°C for 2 hours until the reaction was complete by LC/MS. The mixture was then concentrated to dryness to give crude 2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)acetic acid as an oil, which was used for the next step without further purification. LC/MS ESI (m/z):205 [M+H] + . [0636] (R)-2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-N-(1-(1-(2,2,2 -trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. To a solution of 2-(1,2-dimethyl-1H-1,3- benzodiazol-5-yl) acetic acid (80 mg,) and HATU (193 mg) in DMF (2.0 mL) was added DIEA (152 mg). The solution was allowed to stir at room temperature for 10 min before the addition of (R)-1-[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl]ethan-1-amine hydrochloride (124 mg). The mixture was stirred at room temperature for 16 h, and LCMS detected the desired mass. The reaction was diluted with water (5 mL) and extracted with EA (10 mL x 2). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by prep-HPLC (Column: YMC-Actus Triart C18 250*21mm; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1% NH 3 H 2 O); flow rate: 15 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(1,2-dimethyl-1H-benzo[d]imidazol- 5-yl)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyrid in-5-yl)ethyl)acetamide as a white solid (77.5 mg). LC/MS ESI (m/z):431 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.07 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 7.30-7.21 (m, 2H), 6.55 (d, J = 8.0 Hz, 1H), 5.30-5.23 (m, 1H), 5.06 – 5.03 (m, 2H), 3.76 (s, 3H), 3.71 (d, J = 4.0 Hz, 2H), 2.67 (s, 3H), 1.42 (d, J = 8.0 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.80 (s). Example 54. (R)-2-(3-cyano-1,2-dimethyl-1H-indol-5-yl)-N-(1-(1-(2,2,2-tr ifluoroethyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide [0637] 5-bromo-1,2-dimethyl-1H-indole. To a solution of 5-bromo-2-methyl-1H-indole (3.0 g) in DMF (15 mL) was added NaH (60% suspension in mineral oil, 1.71 g) at 0 °C. The mixture was stirred at 0 °C for 30 min before addition of iodomethane (3.04 g). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then quenched with H2O and extracted by Et 2 O (3 x 40 mL). The combined organic layers were washed with H2O (50 mL) then dried over Na 2 SO 4 . The crude material was purified by column on silica gel (PE: EA= 5:1) to afford 5-bromo-1,2-dimethyl-1H-indole (3.142 g) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 1.6 Hz, 1H), 7.23-7.17 (m, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.17 (s, 1H), 3.62 (s, 3H), 2.40 (s, 3H). LC/MS ESI (m/z): 224[M+H] + . [0638] 5-bromo-1,2-dimethyl-1H-indole-3-carbaldehyde. POCl 3 (1.66 mL) was added to the DMF (5 mL) at 0°C and stirred for 30 min. Then 5-bromo-1,2-dimethyl-1H-indole (2 g) in DMF (5 mL) was added to the above mixture while cooling in an ice water bath. The reaction was then and stirred at 50 °C overnight. The reaction was cooled to the room temperature and poured into ice water. Aqueous NaOH (2 M) was added to the mixture to adjust the pH to 9, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over Na 2 SO 4. Concentration under reduced pressure gave crude 5- bromo-1,2-dimethyl-1H-indole-3-carbaldehyde (2.17 g, crude) as a yellow solid which was used in the next step without further purification. LC/MS ESI (m/z): 252[M+H] + . [0639] 5-bromo-1,2-dimethyl-1H-indole-3-carbonitrile. To a solution of 5-bromo-1,2- dimethyl-1H-indole-3-carbaldehyde (2.17 g, crude) in DMF (10 mL) were added pyridine (0.84 mL) and NH 2 OH·HCl (712 mg) and the reaction was stirred at 60 °C for 30 min. LCMS and TLC indicated that the reaction was complete, and the mixture was then cooled to 0°C. CDI (4.2 g) and TEA (1.44 mL) were sequentially added. The reaction was stirred at 60 °C overnight and then diluted with EA and water. The organic layer was separated, washed with saturated aqueous NaCl, and concentrated in vacuo. The residue was purified by silica gel column chromatography (23% EA in PE) to give 5-bromo-1,2-dimethyl-1H-indole-3- carbonitrile (1.57 g) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J = 1.2 Hz, 1H), 7.29 (dd, J = 8.8, 1.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H), 2.51 (s, 3H). LC/MS ESI (m/z): 249[M+H] + . [0640] Ethyl 2-(3-cyano-1,2-dimethyl-1H-indol-5-yl)acetate. To a solution of 5-bromo-1,2- dimethyl-1H-indole-3-carbonitrile (1.57 g) in mesitylene (15 mL) were added diallylpalladium dichloride (0.10 g), BINAP (0.24 g), DMAP (0.72 g) and ethyl potassium malonate (1.61 g). The reaction was charged with N2 and stirred at 120 °C overnight. The reaction was concentrated to give a residue, which was purified by silica gel column chromatography (PE: EA = 5: 1) to give ethyl 2-(3-cyano-1,2-dimethyl-1H-indol-5- yl)acetate (884 mg) as a white solid. LC/MS ESI (m/z): 257[M+H] + . [0641] 2-(3-cyano-1,2-dimethyl-1H-indol-5-yl)acetic acid. To a solution of ethyl 2-(3- cyano-1,2-dimethyl-1H-indol-5-yl)acetate (884 mg) in MeOH (3 mL) and THF (3 mL) was added LiOH (724 mg) in H 2 O (3 mL). The reaction mixture was stirred at room temperature for 1 hour, water (15 mL) was then added, and the aqueous layer was washed with EA. The aqueous layer was acidified to pH < 3 with 1 M aqueous HCl, the mixture was extracted with EA, and the combined organic phases from were washed with saturated NaCl, dried with Na 2 SO 4 , filtered, and concentrated to give crude 2-(3-cyano-1,2-dimethyl-1H-indol-5- yl)acetic acid (530 mg) as a white solid. LC/MS ESI (m/z): 229[M+H] + . [0642] (R)-2-(3-cyano-1,2-dimethyl-1H-indol-5-yl)-N-(1-(1-(2,2,2-tr ifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetamide. A solution of crude 2-(3-cyano-1,2-dimethyl- 1H-indol-5-yl)acetic acid (200 mg) and HATU (500 mg) in 2 mL DMF was stirred at room temperature for 15 min (Solution A). DIEA (0.87 mL) was added to (R)-1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethan-1-amine hydrochloride (319 mg) in 2 mL DMF until the pH of the solution higher than 7 by wet pH paper (Solution B). Solution B was added to Solution A, and the reaction was stirred at room temperature for 1 hour, at which time LCMS showed the reaction was complete. The reaction was diluted with EA and water. The two phases were separated, and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Column: AZZOTA C1830*250mm*10um; Mobile phase: from 20% to 95% MeCN with H 2 O (0.1%FA); flow rate: 30 mL/min; wave length: 220 nm/254 nm) to give (R)-2-(3-cyano-1,2-dimethyl-1H-indol-5-yl)-N-(1-(1-(2,2,2- trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)ethyl)acetami de (63.3 mg) as a white solid. LC/MS ESI (m/z): 455[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.30-7.27 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.35-5.25 (m, 1H), 5.16-4.99 (m, 2H), 3.71 (s, 3H), 3.69 (d, J = 3.2 Hz, 2H), 2.59 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -70.78 (s). Example 55. (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl-1- d)-2-(4-(trifluoromethyl)phenyl)acetamide [0643] 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbox ylic acid. To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbal dehyde (1.8 g) in DMSO (20 mL) were added a solution of KH 2 PO 4 (1.4 mL) in H2O (10 mL) and a solution of sodium chlorite (2.13 g) in H 2 O (10 mL). The mixture was stirred at 25 °C for 12 hr. The mixture was diluted with 1N NaOH solution and extracted with EA. Then the aqueous phase was adjusted pH = 4 with 1 N HCl and extracted with EA. The organic layer was dried, filtered and concentrated to give 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5- carboxylic acid (2.2 g，crude) as a yellow solid. LCMS ESI (m/z): 246 (M+H) + . [0644] N-methoxy-N-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridine-5- carboxamide. A solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbox ylic acid (2.2 g), N,O-dimethylhydroxylamine hydrochloride (0.96 g), HATU (4.43 g) and TEA (3.8 mL) in DMF (20 mL) was stirred at 25 °C for 12 hr. The reaction was diluted with water and extracted with EA. The organic layer was dried, filtered and concentrated and the residue was purified by column chromatography on silica gel (DCM: MeOH = 20:1) to give N- methoxy-N-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c] pyridine-5-carboxamide (2 g) as a yellow solid. LCMS ESI (m/z): 289 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 5.12 (q, J = 8.4 Hz, 2H), 3.78 (s, 3H), 3.46 (s, 3H). [0645] 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbal dehyde-d. To a solution of N-methoxy-N-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridine-5-carboxamide (2000 mg) in THF (30 mL) was added LiAlD 4 (437 mg). The mixture was stirred at 25 °C for 12 hr. The mixture was quenched with water and 2 N aqueous NaOH solution, and extracted with EA. The organic layer was dried, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20:1) to give 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridine-5-carbal dehyde-d (820 mg) as a white solid. LCMS ESI (m/z): 231 (M+H) + [0646] (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5- yl)methylene-d)propane-2-sulfinamide. To a solution of 1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridine-5-carbaldehyde-d (820 mg) in DCM (10 mL) was added (R)-2- methylpropane-2-sulfinamide (561 mg) and copper(II) sulfate pentahydrate (209 mg). The mixture was stirred at 25 °C for 12 hr. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20:1) to give (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5- yl)methylene-d)propane-2-sulfinamide (740 mg) as a yellow solid. LCMS ESI (m/z): 234 (M+H) + [0647] 2-methyl-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]py ridin-5-yl)ethyl-1- d)propane-2-sulfinamide. To a solution of (R,E)-2-methyl-N-((1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)methylene-d)propane-2-sulfinamid e (640 mg) in THF (15 mL) was added Methylmagnesium bromide (3.200 mL, 3.0 M in Et2O) at -78 °C. The mixture was stirred at -78 °C for 2 hr. The mixture was quenched with aqueous NH 4 Cl solution and extracted with EA. The organic layer was dried, filtered and concentrated to give a yellow solid. The yellow solid was purified by column chromatography on silica gel (DCM:MeOH = 20:1) to give 2-methyl-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]py ridin-5-yl)ethyl-1- d)propane-2-sulfinamide (380 mg) as a white solid. LCMS ESI (m/z): 350 (M+H) + . [0648] (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)ethan-1-amine hydrochloride. To a solution of 2-methyl-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)ethyl-1-d)propane-2-sulfinamide (280 mg) in dioxane (2 mL) was added HCl/dioxane (2 mL, 4M in dioxane). The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated to give (R)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)ethan-1-amine hydrochloride (300 mg, crude) as a white solid. LCMS ESI (m/z): 246 (M+H) + [0649] (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin -5-yl)ethyl-1-d)-2-(4- (trifluoromethyl)phenyl)acetamide. To a solution of 1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethan-1-d-1-amine hydrochloride (300 mg) and 2-[4- (trifluoromethyl)phenyl]acetic acid (300 mg) in DMF (5 mL) was added HATU (558 mg) and DIEA (0.6 mL). The mixture was stirred at 25 °C for 3 hr. The reaction was diluted with water and extracted with EA. The organic layer was dried, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (YMC-Actus Triart C18 150*20mm*5um; Mobile phase: from 30% to 95% MeCN with H2O (0.1% FA); flow rate: 25 mL/min; wave length: 205 nm/254 nm) to give (R)-N-(1-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)ethyl-1-d)-2-(4-(trifluoromethyl )phenyl)acetamide (241.8 mg) as a white solid. LCMS ESI (m/z): 432 (M+H) + . 1 HNMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.11 (s, 1H), 7.61 - 7.56 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 5.05 (q, J = 8.4 Hz, 2H), 3.64 (s, 2H), 1.48 (s, 3H). 19 F NMR (377 MHz, CDCl 3 ) δ -62.54, -70.81 ppm. Example 56.2-(4-isopropylphenyl)-N-[(1R)-1-(5-(2,2,2-trifluoroethoxy )pyridin-2- yl)ethyl]acetamide [0650] The title compound was synthesized according to Example 16 of US Patent No. 7,875,636. Example 57. (R)-N-(1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethyl )-2-(4- isopropylphenyl)acetamide [0651] Synthesis of methyl 2-thioxo-[1,3]dioxolo[4,5-c]pyridine-6-carboxylate. To a solution of methyl 4,5-dihydroxypyridine-2-carboxylate (1.0 g) and DIEA (1.95 mL) in DCM (15 mL) was added thiophosgene (0.90 mL) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give a brown oil, which was purified by column chromatography on silica gel (PE: EA=5:1) to give methyl 2-thioxo-[1,3]dioxolo[4,5- c]pyridine-6-carboxylate (1.0 g) as a white solid. [0652] Synthesis of methyl 2,2-difluoro-[1,3]dioxolo[4,5-c]pyridine-6-carboxylate. To a solution of 2-thioxo-[1,3]dioxolo[4,5-c]pyridine-6-carboxylate (1.0 g) in DCM (30 mL) was added Hydrogen fluoride-pyridine (70% HF) (3.0 mL)，followed by 1,3-dibromo-5,5- dimethylhydantoin (4.1 g) at -78 °C. The mixture was stirred at -78 °C for 20 min, and the cooling bath was then replaced with ice-NaCl and the mixture stirred at -10 °C for 1 hour. The mixture was quenched with 50% NaOH solution (10 mL) until the pH was neutral. Then Na 2 S 2 O 3 (10% solution, 20 mL) was added, and the mixture was extracted with DCM (20 mL×3). The combined organic layers were dried, filtered and concentrated to give a yellow oil. The yellow oil was purified by column chromatography on silica gel (PE: EA=5:1) to give methyl 2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridine-6-carboxylate (850 mg) as a white solid. [0653] Synthesis of (2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)methanol. To a solution of methyl 2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridine-6-carboxylate (480 mg) in THF (10 mL) was added diisobutylaluminium hydride (6.6 mL, 1 M) at 0°C. The mixture was stirred at 0 °C for 2 hours, and the mixture was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were dried, filtered and concentrated to give crude {2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridin-6- yl}methanol (230 mg) as colorless oil, which was used in the next step without further purification. [0654] Synthesis of 2,2-difluoro-[1,3]dioxolo[4,5-c]pyridine-6-carbaldehyde. To a solution of {2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridin-6-yl}methanol (230 mg) in DCM (5.0 mL) was added manganese oxide (106 mg) , and the mixture was stirred at 25 °C for 12 hours. The mixture was then filtered, and the filtrate was concentrated to give crude 2,2- difluoro-[1,3]dioxolo[4,5-c]pyridine-6-carbaldehyde, which was used for the next step without further purification. [0655] Synthesis of (R,E)-N-((2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)methy lene)-2- methylpropane-2-sulfinamide. To a solution of 2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridine- 6-carbaldehyde (250 mg) in DCM (10 mL) was added CuSO 4 (640 mg) and (R)-2- methylpropane-2-sulfinamide (210 mg). The reaction was stirred at 25 °C for 36 hours, and the mixture was filtered and the filtrate concentrated to give a brown oil. The brown oil was purified by column chromatography on silica gel (PE: EA=5:1) to give (R,E)-N-((2,2- difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)methylene)-2-methyl propane-2-sulfinamide (240 mg) as a white solid.

[0656] Synthesis of (R)-N-((R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)e thyl)-2- methylpropane-2-sulfinamide. To a solution of (R,E)-N-((2,2-difluoro-[1,3]dioxolo[4,5- c]pyridin-6-yl)methylene)-2-methylpropane-2-sulfinamide (240 mg) in THF (5 mL) was added methylmagnesium bromide (1.1 mL, 3 M in THF) at -78°C. The mixture was stirred at -78 °C for 1 hour, and the mixture was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with EtOAc (10 mL × 2). The organic layer was dried, filtered and concentrated to give a yellow oil. The yellow oil was purified by column chromatography on silica gel (PE: EA = 5:1 to 1:1) to give (R)-N-((R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin- 6-yl)ethyl)-2-methylpropane-2-sulfinamide (190 mg) as a white solid. [0657] Synthesis of (R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethan-1- amine hydrochloride. To a solution of (R)-N-((R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6- yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg) in dioxane (1.0 mL) was added HCl/dioxane (4 N, 1 mL). The mixture was stirred at 25 °C for 1 hour, and the mixture was concentrated to give (R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethan-1- amine hydrochloride (70 mg , crude) as a white solid. [0658] (R)-N-(1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethyl )-2-(4- isopropylphenyl)acetamide. To a solution of (R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin- 6-yl)ethan-1-amine hydrochloride (70 mg) in DMF (5.0 mL) was added 2-[4-(propan-2- yl)phenyl]acetic acid (67.9 mg), EDCI HCl (79.6 mg), HOBT (56.1 mg) and DIEA (0.23 mL). The reaction was stirred at 25 °C for 3 hours, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried, filtered and concentrated to give a yellow oil. The yellow oil was purified by prep-HPLC [YMC-Actus Triart C180250*21mm; Mobile phase: from 30% to 95% MeCN with H 2 O (0.1%FA)] to give (R)-N-(1-(2,2-difluoro- [1,3]dioxolo[4,5-c]pyridin-6-yl)ethyl)-2-(4-isopropylphenyl) acetamide (51.6 mg) as a white solid. LCMS ESI (m/z): 363 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 7.24 - 7.15 (m, 4H), 6.98 (s, 1H), 6.53 (d, J = 6.8 Hz, 1H), 5.18 - 4.97 (m, 1H), 3.56 (s, 2H), 2.98 - 2.80 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.26 (s, 3H), 1.24 (s, 3H). Example 58. (R)-N-(1-(5-chlorothiazol-2-yl)ethyl)-2-(6-(1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)acetamide [0659] Synthesis of (R,E)-N-((5-chlorothiazol-2-yl)methylene)-2-methylpropane-2- sulfinamide. To the solution of 5-chloro-1,3-thiazole-2-carbaldehyde (160 mg) in CH 2 Cl 2 (3.0 mL) were added (R)-2-methylpropane-2-sulfinamide (131 mg) and CuSO 4 (865 mg) at room temperature. The mixture was stirred at room temperature for 2 hours, and LCMS showed the reaction was complete. The reaction mixture was quenched by ice-water and then extracted twice with EtOAc. The combined extracts were concentrated and the residue was purified by column chromatography on silica gel (PE: EA = 3: 1) to give (R,E)-N-((5- chlorothiazol-2-yl)methylene)-2-methylpropane-2-sulfinamide (246 mg) as a yellow solid. [0660] Synthesis of (R)-N-((R)-1-(5-chlorothiazol-2-yl)ethyl)-2-methylpropane-2- sulfinamide. To the solution of (R,E)-N-((5-chlorothiazol-2-yl)methylene)-2-methylpropane- 2-sulfinamide (246 mg) in THF (5.0 mL) was added methylmagnesium bromide (0.98 mL, 2.5 mol/L in THF) dropwise at -78 °C under N 2 . The mixture was stirred at - 78 °C for 1 hour, and LCMS indicated the reaction was complete. The reaction mixture was quenched by ice-water and then extracted twice with EtOAc. The combined extracts were concentrated and the residue was purified by column chromatography on silica gel (PE: EA = 1: 1) to give (R)-N-((R)-1-(5-chlorothiazol-2-yl)ethyl)-2-methylpropane-2- sulfinamide (220 mg) as a yellow oil. LC/MS ESI (m/z): 267 [M+H] + . [0661] Synthesis of (R)-1-(5-chlorothiazol-2-yl)ethanamine hydrochloride. To the solution of (R)-N-((R)-1-(5-chlorothiazol-2-yl)ethyl)-2-methylpropane-2- sulfinamide (220 mg) in dioxane (5.0 mL) was added HCl in dioxane (0.82 mL, 4 M) at room temperature. The mixture was stirred at room temperature for 2 hours, and LCMS indicated the reaction was complete. The solvent was removed to give crude (R)-1-(5-chlorothiazol-2-yl)ethanamine hydrochloride (117 mg) as a yellow oil. LC/MS ESI (m/z): 163 [M+H] + . [0662] Synthesis of methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate. A mixture of methyl 6-bromonicotinate (5.47 g), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2- dioxaborinane (7.87 g), Pd(dppf)Cl 2 (1.85 g), K 2 CO 3 (26.8 mL of 2 M in water) in acetonitrile (104 mL) was charged with N 2 and heated at 80 °C for 90 minutes. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by silica gel column chromatography (0-20% ethyl acetate/PE) to provide methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate as a colorless oil (3.0 g): LC/MS ESI (m/z): 232 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (d, J = 2.4 Hz, 1H), 8.75-8.74 (m, 1H), 8.34-8.31 (m, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 11.6 Hz, 1H), 3.97 (s, 3H); 19 F NMR (376.48 MHz, CDCl 3 ): -63.98 ppm. [0663] Synthesis of methyl 6-(1-(trifluoromethyl)cyclopropyl)nicotinate. To a suspension of methyl 6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate (2.47 g) and methyldiphenylsulfonium tetrafluoroborate (4.0 g) in anhydrous tetrahydrofuran (30 mL) was added 4.27 mL NaHMDS (2 M in THF) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 1 h. Methanol (0.25 mL) was then added to quench the reaction. The crude mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (10% EA in PE) to give methyl 6-(1- (trifluoromethyl)cyclopropyl)nicotinate as a white solid (345 mg). LC/MS ESI (m/z): 246[M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ 9.09 (d, J = 2.4 Hz, 1H), 8.26-8.23 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 1.54-1.53 (m, 2H), 1.50-1.49 (m, 2H) ppm. 19 FNMR (376.48 MHz, CDCl 3 ): δ -67 ppm. [0664] Synthesis of 6-(1-(trifluoromethyl)cyclopropyl)nicotinic acid. To a solution of methyl 6-(1-(trifluoromethyl)cyclopropyl)nicotinate (345 mg) in MeOH (20 mL) was added 4.0 mL of 2.0 M NaOH. The mixture was stirred at 65 °C for 2 hours, and TLC showed total consumption of starting material. The MeOH was removed under vacuo and the reaction was adjusted pH to 2 -3 with 1 N HCl. The reaction was extracted with EA (50 mL). The EA extract was washed with brine, dried with anhydrous Na 2 SO 4 , filtered and concentrated to give crude 6-(1-(trifluoromethyl)cyclopropyl)nicotinic acid (300 mg) as a white solid. LC/MS ESI (m/z): 232 [M+H] + . [0665] Synthesis of 2-diazo-1-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)et hanone.6- (1-(trifluoromethyl)cyclopropyl)nicotinic acid (300 mg) in DCM (10 mL) was cooled to 0 ° C. Oxaly chloride (1.1 mL) and DMF (2 drops) were added, and the resulting solution was stirred at rt for 2 hours. The mixture was concentrated under vacuo, and the residue was redissolved in DCM (10 mL) and cooled to 0 °C. (Diazomethyl)trimethylsilane (1.28 mL, 2 M solution in hexane) and TEA (0.33 mL) were added slowly, and the resulting solution was maintained at 5 °C for 12 hours. The reaction was then filtered, and the filtrate was concentrated under reduced pressure to give ~600 mg 2-diazo-1-(6-(1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)ethanone as a brown residue, which was directly used in the next step directly. LC/MS ESI (m/z): 256 [M+H] + . [0666] Synthesis of methyl 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetate. To a mixture of 2-diazo-1-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)et hanone (600 mg, crude) in methanol (20 mL) was added Ag 2 O (175 mg). The reaction was stirred at 65 °C for 2 hours, and TLC showed formation of trace product. Additional Ag 2 O (142 mg) was added, and the mixture was stirred at 65 °C for another 2 hours. The reaction was concentrated under vacuo and the residue purified by silica gel column chromatography (10%EA -20% EA in PE) to give 100 mg methyl 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetate as a yellow oil. LC/MS ESI (m/z): 260 [M+H] +.

[0667] Synthesis of 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid. To a solution of methyl 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetate (100 mg) in MeOH (10 mL) was added 2.0 mL of 2.0 M NaOH . After stirring the mixture at 65 o C for 2 hours, some of the volatiles were removed under reduced pressure, and the reaction was adjusted pH to 2 -3 by 1 N HCl. The mixture was then extracted with EA (50 mL x3), and the combined organic phases were washed with brine, dried with anhydrous Na 2 SO 4 , filtered and concentrated to give crude 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid (50 mg) as a white solid, which was used in the next step without further purification. LC/MS ESI (m/z): 246 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ 8.43 (d, J = 1.6 Hz, 1H), 7.78-7.75 (m, 1H), 7.59-7.56 (m, 1H), 3.69 (s, 2H), 1.43-1.40 (m, 2H), 1.32-1.29 (m, 2H) ppm. 19 FNMR (CDCl 3 , -376.48): δ -69.78 ppm. [0668] Synthesis of (R)-N-(1-(5-chlorothiazol-2-yl)ethyl)-2-(6-(1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)acetamide. To a mixture of 2-(6-(1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid (50 mg) in DMF (1.0 mL) was added HATU (85 mg), and the mixture was stirred at room temperature for 5 min (Solution A). To another flask was added (R)-1-(5-chlorothiazol-2-yl)ethanamine hydrochloride (40 mg) and DMF (0.5 mL). DIEA was then added until the (R)-1-(5-chlorothiazol-2-yl)ethanamine was dissolved in DMF and the pH was about 8 (Solution B). Solution B was added to Solution A, and the mixture was stirred at room temperature for 2 hours. EA (50 mL) and H 2 O (30 mL) were then added, and the two phases were separated. The aqueous phase was further extracted with DCM (10 mL x 3), and the combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by prep-HPLC (Column: Xbudge prep C18250*19mm 5um OBD; Mobile phase: from 10% to 55% MeCN with H 2 O (0.1%NH4OH); flow rate: 20 mL/min; wave length: 205 nm/254 nm) and SFC (Column: Mobile phase: A for CO 2 and B for MEOH+0.1% NH 3 H 2 O; Gradient: B 40%; flow rate: 50 mL/min; wave length: 220 nm) to provide 25 mg (R)-N-(1-(5-chlorothiazol-2-yl)ethyl)-2-(6- (1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetamide was obtained as a white solid. 1 HNMR (400 MHz, CDCl 3 ): δ 8.43 (d, J = 2.0 Hz, 1H), 7.65-7.63 (m, 1H), 7.55-7.53 (m, 1H), 7.46 (s, 1H), 6.24-6.23 (m, 1H), 5.32-5.25 (m, 1H), 3.57 (s, 2H), 1.56 (d, J = 6.8 Hz, 3H), 1.43-1.41 (m, 2H), 1.40-1.39 (m, 2H) ppm. 19 FNMR (376.48, CDCl 3 ): δ -67.8 ppm. Example 59. (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(6- (1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)acetamide [0669] To a mixture of 2-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)acetic acid (40 mg) in DMF (1.5 mL) was added HATU (68 mg), and the mixture was stirred at room temperature for 5 min (Solution A). To (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethanamine hydrochloride (49 mg) in DMF (0.5 mL) was added DIEA until (R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine was dissolved in DMF and the pH was about 8 (Solution B). Solution B was added to Solution A, and the mixture was stirred at room temperature for 2 hours. EA (50 mL) and H 2 O (40 mL) were added, and the organic layer was washed by sat. NaCl, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC (Column: Xbudge prep C18250*19mm 5um OBD; Mobile phase: from 10% to 55% MeCN with H 2 O (0.1%FA); flow rate: 20 mL/min; wave length: 205 nm/254 nm) to give (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(6- (1- (trifluoromethyl)cyclopropyl)pyridin-3-yl)acetamide as a yellow solid (23.3 mg). LC/MS ESI (m/z): 448 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ): δ 8.43 (d, J =2.0 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 7.65-7.62 (m, 1H), 7.52-7.50 (m, 1H),7.25-7.18 (m, 2H), 6.87 (d, J = 7.2 Hz, 1H), 5.13-5.06 (m, 1H), 4.38 (q, J = 8.0 Hz, 2H), 3.55 (s, 2H), 1.43-1.38 (m, 5H), 1.36-1.35 (m, 2H) ppm. 19 FNMR (376.48, CDCl 3 ): δ -67.7ppm, -73.9 ppm. Example 60. In Vitro Patch Clamp Data for T-type Calcium Channel Antagonists [0670] Patch clamp assays were performed at Charles River. HEK293 cells were cultured in Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 (D-MEM/F-12) supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 ^g/mL streptomycin sulfate and 500 ^g/mL G418. Before testing, cells in culture dishes were washed twice with Hank’s Balanced Salt Solution, treated with accutase TM and re-suspended in the culture media (~20 x10 6 cells in 20 mL). Cells in suspension were allowed to recover for 10 minutes in tissue culture incubator set at 37°C in a humidified 95% air: 5% CO2 atmosphere. Immediately before use in the SyncroPatch 384PE system (SP384PE), the cells were washed twice in extracellular buffer (HB-PS) to remove the culture medium and re-suspended in 20 mL of HB-PS. Extracellular buffer was loaded into the wells of Nanion 384-well Patch Clamp (NPC-384, 4xM) chip (60 μL per well). Then, cell suspension was pipetted into the wells (20 ^L per well) of the chip. After establishment of the whole-cell configuration, membrane currents were recorded using patch clamp amplifier in the SP384PE system. [0671] The illustrative compounds of the present disclosure showed inhibition of a T-type calcium channel in a patch clamp assay. Table 4. Cav3.2 Activity

Example 61. Miro2 Cellular Data (Neurons) [0672] The Miro2 protein is retained at the mitochondria in cells from PD subjects. Specifically, the Miro2 retention phenotype has been shown in PD subject iPSC-derived dopaminergic neurons with the N370S glucocerebrosidase (GBA) mutation. [0673] N370S GBA iPSC-derived dopaminergic neuronal cultures were treated with a mitochondrial stressor Antimycin A with a series of concentrations for 6 hrs to induce oxidative stress. Neurons were challenged with Antimycin A in combination with 0-10μM Compound 1 in a dose response. Data were represented as Mean ± SEM, N=2 wells/condition, n=306-919 cells / condition. [0674] N370S GBA iPSC-derived neuronal cultures showed an Antimycin A dose- dependent loss of neurons, depicting a vulnerability to mitochondrial stress. N370S GBA neurons treated with Miro2-reducing agent Compound 1 rescued the loss of N370S GBA neurons caused by 1 or 10 μM Antimycin A, indicating a protection against neuronal loss caused by mitochondrial stress (FIG. 1). Compound 1 exhibited a Miro1 EC50 = 1.2 µM with Emax = 21%, and Miro2 EC 50 = 1.5 µM with Emax = 14%. Example 62. Miro2 Cellular Data (Fibroblasts) [0675] Primary human fibroblasts are used to assess whether the Miro2 protein is retained at the mitochondria of Parkinson's disease (PD) subject-derived cells and, if so, whether Compound 1 rescues that retention phenotype. Fibroblast cell lines derived from healthy subjects and PD subjects are maintained using standard cell culture procedures. For experiments, fibroblast lines are seeded at 250K per well in 6-well plates and maintained (with medium refreshed every 3-4 days, as needed) until they reach ~100% confluency prior to treatment. Each assay condition consists of three wells of a 6-well plate, in which three wells are treated either with Vehicle, 40μM CCCP (C2759, Sigma-Aldrich), 10μM Compound 1, or 40μM CCCP plus 10μM Compound 1. To achieve this, fibroblasts are pre-treated with either Vehicle or 10μM Compound 1 for 1-3 hours, then treated with either Vehicle or CCCP for 6 hours.6-well plates are then placed on crushed ice, culture media aspirated, and cells washed twice with ice-cold PBS (being careful not to dispense PBS directly onto the cells). In the second PBS wash, cells from within each well are lifted with cell scrapers, collected into individual 1.5mL Eppendorf tubes, and pelleted by spinning at 10,000 x g for 10 minutes at 4C. PBS is then completely aspirated and cell pellets flash- frozen on dry ice and stored in liquid nitrogen. Samples are then lysed and homogenized, reduced by TCEP, denatured, and alkylated by iodoacetamide for 30 minutes using standard sample preparation procedures for ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The denatured/alkylated samples are digested with trypsin and then Miro1, Miro 2, PMPCA, Cytochrome C, TOMM20, Actin, and Beta-Tubulin protein levels are quantified by UPLC-MS/MS. [0676] Miro2 protein levels are lowered by CCCP challenge in healthy subject fibroblast lines as a key initial step in the mitophagy process. Miro2 protein levels are not lowered by CCCP challenge in PD subject fibroblast lines, consistent with the previously established mitophagy defect in PD patient cells. Pre-treatment with Compound 1 rescues the Miro2 retention phenotypes, indicating that this compound restores the proper lowering of Miro2 protein levels in PD subject fibroblast lines to normalize mitophagy. [0677] Although the foregoing invention has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.




 
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