N-(BENZHYDRYL)CYCLOALKYLCARBOXAMIDE DERIVATIVES AS INHIBITORS OF GLYCOGEN SYNTHASE 1 (GYS1) AND METHODS OF USE THEREOF

Abstract

Provided herein are compounds of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y.sup.1, Y.sup.2, X.sup.1, X.sup.2, L, and Q.sup.1 are as defined elsewhere herein. Also provided herein CN are methods of preparing compounds of formula (I). Also provided herein are methods of inhibiting GYSI and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

##STR00001##

Claims

1. A compound of formula (I): ##STR00272## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; either (1) L is absent; and Q.sup.1 is: (i) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; or (2) L is CH.sub.2; and Q.sup.1 is C.sub.3-10cycloalkyl; m is 0 or 1; n is 0 or 1; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compounds of formula (I) has a stereochemical configuration of ##STR00273##

3. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.1 is H.

4. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.1 is halo.

5. The compound of claim 1 or claim 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.1 is fluoro.

6. The compound of any one of claims 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.2 is H.

7. The compound of any one of claims 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.2 is halo.

8. The compound of any one of claims 1-5 and 7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.2 is fluoro.

9. The compound of any one of claims 1-8 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.3 and R.sup.4 are each independently CH.sub.3.

10. The compound of any one of claims 1-8 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

11. The compound of any one of claims 1-8 and 10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl.

12. The compound of any one of claims 1-8 and 10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclobutyl.

13. The compound of any one of claims 1-12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is absent.

14. The compound of any one of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), or NHC(NCN)NH.sub.2, NH(C.sub.1-6alkyl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

15. The compound of any one of claims 1-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), or NHC(NCN)NH.sub.2, NH(C.sub.1-6alkyl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

16. The compound of any one of claims 1-15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of ##STR00274## ##STR00275## ##STR00276##

17. The compound of any one of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo.

18. The compound of any one of claims 1-13 and 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 9-10 membered heterocyclyl, wherein the 9-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo.

19. The compound of any one of claims 1-13, 17, and 18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of ##STR00277##

20. The compound of any one of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

21. The compound of any one of claims 1-13 and 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 6-10 membered heteroaryl, wherein the 6-10 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

22. The compound of any one of claims 1-13, 20, and 21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of ##STR00278##

23. The compound of any one of claims 1-12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is CH.sub.2 and Q.sup.1 is C.sub.3-10cycloalkyl.

24. The compound of claim any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m and n are each independently 0.

25. The compound of any one of claims 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m and n are each independently 1.

26. The compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is selected from the group consisting of H, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, and NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2.

27. The compound of any one of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is H.

28. The compound of any one of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is selected from the group consisting of CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, and NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2.

29. The compound of any one of claims 1-26 and 28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is selected from the group consisting of CN, ##STR00279##

30. The compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is H or halo.

31. The compound of any one of claims 1-25 and 30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is H or fluoro.

32. The compound of any one of claims 1-25, 30, and 31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is fluoro.

33. The compound of any one of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is H.

34. The compound of any one of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is halo.

35. The compound of any one of claims 1-32, and 34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is fluoro.

36. The compound of any one of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is OH.

37. The compound of any one of claims 1-21, and 24-36, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A): ##STR00280## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein either: i. X.sup.4-8 are each independently H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-9 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-9 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl; or ii. X.sup.6 is taken together with either of X.sup.4 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, or oxo, or 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; or iii. X.sup.7 is taken together with either of X.sup.5 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, or oxo, or 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

38. The compound of any one of claims 1-10, 13, 15, or 20-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-C): ##STR00281## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

39. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

40. A process for preparing a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the process comprises: (a) reacting a compound of formula (I-1): ##STR00282## or a salt thereof, wherein Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; either (1) L is absent; and Q.sup.1 is: (i) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; or (2) L is CH.sub.2; and Q.sup.1 is C.sub.3-10cycloalkyl, with a compound of formula (I-2): ##STR00283## wherein, m is 0 or 1; n is 0 or 1; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH in the presence of a coupling reagent to provide a compound of formula (I).

41. A pharmaceutical composition comprising (i) a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

42. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41.

43. The method of claim 42, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

44. The method of claim 42 or claim 43, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

45. The method of any one of claims 42-44, wherein the disease, disorder, or condition is Pompe disease.

46. The method of claim 42, wherein the disease, disorder, or condition is cancer.

47. The method of claim 42 or claim 46, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

48. The method of claim 42, wherein the individual has a GAA mutation.

49. The method of claim 48, wherein the GAA mutation is a loss-of-function mutation.

50. A kit, comprising (i) a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

51. The kit of claim 50, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

52. The kit of claim 50 or claim 51, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

53. The kit of any one of claims 50-52, wherein the disease, disorder, or condition is Pompe disease.

54. The kit of claim 50, wherein the disease, disorder, or condition is cancer.

55. The kit of claim 50 or claim 54, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

56. The kit of claim 52, wherein the individual has a GAA mutation.

57. The kit of claim 56, wherein the GAA mutation is a loss-of-function mutation.

58. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41.

59. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41.

60. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41.

61. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy, wherein the glycogen substrate reduction therapy comprises administering to the individual an effective amount of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 39.

62. The method of claim 61, comprising subjecting the individual to glycogen substrate reduction therapy in combination with enzyme replacement therapy.

63. The method of claim 62, wherein the enzyme replacement therapy is selected from the group consisting of alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) Myozyme and Lumizyme.

64. The method of any one of claims 61-63, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

65. The method of any one of claims 61-64, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

66. The method of any one of claims 61-65, wherein the disease, disorder, or condition is Pompe disease.

67. The method of any one of claims 61-63, wherein the disease, disorder, or condition is cancer.

68. The method of any one of claims 61-63, or 67, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

69. The method of any one of claims 61-63, wherein the individual has a GAA mutation.

70. The method of claim 69, wherein the GAA mutation comprises a loss-of-function mutation.

71. The method of any one of claims 58-60 wherein the compound is selective for GYS1 over GYS2.

72. The method of claim 71, wherein the compound is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

73. The method of any one of claims 42-49 or 58-72, comprising reducing the level of glycogen in skeletal muscle.

74. A compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

75. A compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, for use in modulating GYS1 in a cell.

76. A compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, for use in inhibiting GYS1 in a cell.

77. A compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, for use in reducing tissue glycogen stores in an individual in need thereof.

78. A compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41, for use in a glycogen substrate reduction therapy for treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

79. Use of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, in the manufacture of a medicament for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

80. Use of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, in the manufacture of a medicament for use in modulating GYS1 in a cell.

81. Use of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, in the manufacture of a medicament for use in inhibiting GYS1 in a cell.

82. Use of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41, in the manufacture of a medicament for use in reducing tissue glycogen stores in an individual in need thereof.

83. Use of a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41, in the manufacture of a medicament for use in a glycogen substrate reduction therapy for treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 depicts the pathway in which PPP1R3A Loss of Function (LoF) leads to reduction in muscle glycogen.

[0051] FIGS. 2A and 2B depict the association between PPP1R3A protein truncating variant (PTV) and left ventricular ejection (LVEF) (%) and left ventricle wall thickness (mm) in UK Biobank.

[0052] FIGS. 2C and 2D depict the association between PPP1R3A protein truncating variant (PTV) and exercise output (watts) and max heart rate (HR) exercise (bpm) in UK Biobank.

[0053] FIGS. 2E and 2F depict the association between PPP1R3A protein truncating variant (PTV) and PQ interval (ms) and QRS duration (ms) in UK Biobank.

[0054] FIGS. 2G and 2H depict the association between PPP1R3A protein truncating variant (PTV) and QT interval (ms) and serum glucose (mmol/L) in UK Biobank.

DETAILED DESCRIPTION OF THE INVENTION

[0055] Individual refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human.

[0056] As used herein, about a parameter or value includes and describes that parameter or value per se. For example, about X includes and describes X per se.

[0057] As used herein, an at risk individual is an individual who is at risk of developing a disease or condition. An individual at risk may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

[0058] Treatment or treating is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).

[0059] As used herein, delaying development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

[0060] As used herein, the term therapeutically effective amount or effective amount intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., 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.

[0061] As used herein, unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

[0062] As used herein, by pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

[0063] The term alkyl, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C.sub.1-20alkyl), 1-16 carbons (i.e., C.sub.1-16alkyl), 1-12 carbons (i.e., C.sub.1-12alkyl), 1-10 carbons (i.e., C.sub.1-10alkyl), 1-8 carbons (i.e., C.sub.1-8alkyl), 1-6 carbons (i.e., C.sub.1-6alkyl), 1-4 carbons (i.e., C.sub.1-4alkyl), or 1-3 carbons (i.e., C.sub.1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassedfor example, butyl includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and propyl includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent alkyl group, may be referred to as an alkylene.

[0064] The term alkenyl, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C.sub.2-20alkenyl), 2-16 carbons (i.e., C.sub.2-16alkenyl), 2-12 carbons (i.e., C.sub.2-12alkenyl), 2-10 carbons (i.e., C.sub.2-10alkenyl), 2-8 carbons (i.e., C.sub.2-8alkenyl), 2-6 carbons (i.e., C.sub.2-6alkenyl), 2-4 carbons (i.e., C.sub.2-4alkenyl), or 2-3 carbons (i.e., C.sub.2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2-butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassedfor example, propenyl includes prop-1-enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent alkenyl group, may be referred to as an alkenylene.

[0065] The term alkynyl, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynyl has 2-20 carbons (i.e., C.sub.2-20alkynyl), 2-16 carbons (i.e., C.sub.2-16alkynyl), 2-12 carbons (i.e., C.sub.2-12alkynyl), 2-10 carbons (i.e., C.sub.2-10alkynyl), 2-8 carbons (i.e., C.sub.2-8alkynyl), 2-6 carbons (i.e., C.sub.2-6alkynyl), 2-4 carbons (i.e., C.sub.2-4alkynyl), or 2-3 carbons (i.e., C.sub.2-3alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed for example, propynyl includes prop-1-ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent alkynyl group, may be referred to as an alkynylene.

[0066] The term alkoxy, as used herein, refers to an O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0067] The term aryl, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term aryl encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C.sub.6-20aryl), 6 to 16 annular carbon atoms (i.e., C.sub.6-16aryl), 6 to 12 annular carbon atoms (i.e., C.sub.6-12aryl), or 6 to 10 annular carbon atoms (i.e., C.sub.6-10aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0068] The term cycloalkyl, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term cycloalkyl encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond.

[0069] Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C.sub.3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C.sub.3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C.sub.3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C.sub.3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C.sub.3-8cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C.sub.3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C.sub.3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

[0070] The term halo, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0071] The term heteroaryl, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term heteroaryl includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

[0072] The term heterocyclyl, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term heterocyclyl includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety).

[0073] Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0074] The term oxo, as used herein, refers to a O moiety.

[0075] The terms optional and optionally, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term optionally substituted infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase methyl optionally substituted with one or more chloro encompasses CH.sub.3, CH.sub.2Cl, CHCl.sub.2, and CCl.sub.3 moieties.

[0076] It is understood that aspects and embodiments described herein as comprising include consisting of and consisting essentially of embodiments.

[0077] The term pharmaceutically acceptable salt, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0078] Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32p, 353 .sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively. In some embodiments, a compound of formula (A) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0079] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

[0080] Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 (2008), which is incorporated herein by reference.

[0081] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

[0082] A stereoisomer refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes enantiomers, which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. Diastereomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0083] Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

##STR00011##

[0084] Where enantiomeric and/or diastereomeric forms exist of a given structure, wedged or hashed bonds indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with known stereochemistry, e.g.,

##STR00012##

[0085] Where relevant, combinations of the above notation may be used. Exemplified species may contain stereogenic centers with known stereochemistry and stereogenic centers with unknown stereochemistry, e.g.,

##STR00013##

Compounds

[0086] In one aspect, provided is a compound of formula (I):

##STR00014## [0087] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: [0088] Y.sup.1 and Y.sup.2 are each CH, or [0089] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; [0090] X.sup.1 and X.sup.2 are each independently H or halo; [0091] R.sup.3 and R.sup.4 are each CH.sub.3, or [0092] R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; [0093] either [0094] (1) L is absent; and [0095] Q.sup.1 is: [0096] (i) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0097] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0098] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0099] (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or [0100] (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; [0101] or [0102] (2) L is CH.sub.2; and [0103] Q.sup.1 is C.sub.3-10cycloalkyl; [0104] m is 0 or 1; [0105] n is 0 or 1; [0106] R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein [0107] the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and [0108] the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and [0109] R.sup.2 is H, halo, or OH.

[0110] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2. In some embodiments, m is 0, and n is 1, or 2. In some embodiments, m is 0, and n is 1. In some embodiments, m is 0, and n is 2. In some embodiments, m is 1, and n is 0, or 1. In some embodiments, m is 1, and n is 0. In some embodiments, m is 1, and n is 1. In some embodiments, m+n is 1. In some embodiments, m+n is 2.

[0111] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH. In some embodiments, Y.sup.1 and Y.sup.2 are each CH. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH.

[0112] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1 is H.

[0113] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1 is halo. In some embodiments, X.sup.1 is fluoro.

[0114] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.2 is H.

[0115] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.2 is halo. In some embodiments, X.sup.2 is fluoro.

[0116] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1 and X.sup.2 are each independently H or halo. In some embodiments, X.sup.1 and X.sup.2 are each independently H or F. In some embodiments, X.sup.1 and X.sup.2 are each independently H. In some embodiments, X.sup.1 and X.sup.2 are each independently halo. In some embodiments, X.sup.1 and X.sup.2 are each independently F. In some embodiments, one of X.sup.1 and X.sup.2 is H and the other of X.sup.1 and X.sup.2 is halo. In some embodiments, one of X.sup.1 and X.sup.2 is H and the other of X.sup.1 and X.sup.2 is F.

[0117] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.3 and R.sup.4 are each CH.sub.3. In some embodiments, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl. In some embodiments, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclobutyl.

[0118] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.3 and R.sup.4 are each CH.sub.3, and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, R.sup.3 and R.sup.4 are each CH.sub.3, and X.sup.1 or X.sup.2 is F. In some embodiments, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclobutyl and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl and X.sup.1 or X.sup.2 is F.

[0119] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y.sup.1 and Y.sup.2 are each CH, R.sup.3 and R.sup.4 are each CH.sub.3, and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, Y.sup.1 and Y.sup.2 are each CH, R.sup.3 and R.sup.4 are each CH.sub.3, and X.sup.1 or X.sup.2 is F. In some embodiments, Y.sup.1 and Y.sup.2 are each CH, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, Y.sup.1 and Y.sup.2 are each CH, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclobutyl and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, Y.sup.1 and Y.sup.2 are each CH, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl and X.sup.1 or X.sup.2 is F.

[0120] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH, R.sup.3 and R.sup.4 are each CH.sub.3, and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH, R.sup.3 and R.sup.4 are each CH.sub.3, and X.sup.1 or X.sup.2 is F. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclobutyl and X.sup.1 and X.sup.2 are each hydrogen. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH, R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl and X.sup.1 or X.sup.2 is F.

[0121] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y.sup.1 and Y.sup.2 are each CH.

[0122] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, of formula

##STR00015##

of formula (I) is selected from the group consisting of

##STR00016##

In some embodiments,

##STR00017##

of formula (I) is selected from the group consisting of

##STR00018##

In some embodiments,

##STR00019##

of formula (I) is selected from the group consisting of

##STR00020##

In some embodiments,

##STR00021##

of formula (I) is

##STR00022##

In some embodiments,

##STR00023##

of formula (I) is

##STR00024##

In some embodiments,

##STR00025##

of formula (I) is

##STR00026##

[0123] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH.

[0124] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

##STR00027##

of formula (I) is selected from the group consisting of

##STR00028##

In some embodiments

##STR00029##

of formula (I) is selected from the group consisting of

##STR00030##

and

##STR00031##

In some embodiments,

##STR00032##

of formula (I) is

##STR00033##

In some embodiments,

##STR00034##

of formula (I) is

##STR00035##

In some embodiments,

##STR00036##

of formula (I) is selected from the group consisting of

##STR00037##

[0125] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent.

[0126] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0127] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), or NHC(NCN)NH.sub.2, NH(C.sub.1-6alkyl), wherein [0128] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0129] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0130] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.3-6cycloalkyl, 5-10 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-3alkyl), NHC(O)C.sub.1-3alkyl, NHC(O)C.sub.3-6cycloalkyl, NHC(O)-(3-6 membered heterocyclyl), or NHC(NCN)NH.sub.2, NH(C.sub.1-3alkyl), wherein the 3-6 membered heterocyclyl of the NHC(O)-(3-6 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-3alkyl or C.sub.1-6alkyl, wherein the C.sub.1-3alkyl is optionally substituted with one or more halo, C.sub.1-3alkoxy, or C.sub.3-6cycloalkyl, and the 3-6 membered heterocyclyl of the NH-(3-6 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-3alkyl.

[0131] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is selected from the group consisting of

##STR00038## ##STR00039##

In some embodiments, Q.sup.1 is selected from the group consisting of

##STR00040##

In some embodiments, Q.sup.1 is selected from the group consisting of

##STR00041##

In some embodiments, Q.sup.1 is

##STR00042##

In some embodiments, Q.sup.1 is

##STR00043##

[0132] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo. In some embodiments, L is absent and Q.sup.1 is 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo. In some embodiments, Q.sup.1 is 6-10 membered heterocyclyl, wherein the 6-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl. In some embodiments, Q.sup.1 is 9-10 membered heterocyclyl, wherein the 9-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo. In some embodiments, Q.sup.1 is selected from the group consisting of

##STR00044##

In some embodiments Q.sup.1 is selected from the group consisting of

##STR00045##

[0133] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, Q.sup.1 is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein the 5-10 membered heteroaryl of Q.sup.1 contains at least 1 annular N. In some embodiments, Q.sup.1 is pyridinyl, wherein the pyridinyl of Q.sup.1 is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, Q.sup.1 is pyridinyl. In some embodiments, Q.sup.1 is pyrazolyl.

[0134] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, Q.sup.1 is 6-10 membered heteroaryl, wherein the 6-10 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, Q.sup.1 is selected from the group consisting of

##STR00046##

In some embodiments, Q.sup.1 is selected from the group consisting of

##STR00047##

In some embodiments, Q.sup.1 is selected from the group consisting of

##STR00048##

[0135] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is CH.sub.2.

[0136] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is CH.sub.2 and Q.sup.1 is C.sub.3-10cycloalkyl. In some embodiments, L is CH.sub.2 and Q.sup.1 is C.sub.3-6cycloalkyl.

[0137] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1, and n is 0, or 1. In some embodiments, m is 0, and n is 1. In some embodiments, m is 0, and n is 0. In some embodiments, m is 0, n is 1 or 0. In some embodiments, m is 1, and n is 0. In some embodiments, m is 1, and n is 1. In some embodiments, m is 1, and n is 0 or 1.

[0138] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2 and R.sup.2 is H, halo, or OH. In some embodiments, R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-3alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-3alkyl of the C(O)NH(C.sub.1-3alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-3alkoxy, and the C.sub.1-3alkyl of the NHC(O)C.sub.1-3alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-3alkyl or C(O)NH.sub.2. In some embodiments,

[0139] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is selected from the group consisting of H, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, and NHC(O)C.sub.1-6alkyl, wherein [0140] the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and [0141] the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2.

[0142] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2.

[0143] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is H.

[0144] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is selected from the group consisting of CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, and NHC(O)C.sub.1-6alkyl, wherein [0145] the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and [0146] the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2.

[0147] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is selected from the group consisting of CN,

##STR00049##

[0148] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is H or halo. In some embodiments, R.sup.1 is H or fluoro. In some embodiments, R.sup.1 is H. In some embodiments, R.sup.1 is fluoro.

[0149] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is H, halo, or OH. In some embodiments, R.sup.2 is H. In some embodiments, R.sup.2 is halo. In some embodiments, R.sup.2 is F. In some embodiments, R.sup.2 is OH.

[0150] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-F2), (I-G), (I-G1), (I-G2), (I-G3), (I-G4), (I-H), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, has a stereochemical configuration of the formula

##STR00050##

wherein m, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, L and Q.sup.1, are as defined elsewhere herein.

[0151] In some embodiments of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-F2), (I-G), (I-G1), (I-G2), (I-G3), (I-G4), (I-H), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, has a stereochemical configuration of the formula

##STR00051##

wherein m, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, and Q.sup.1 are as defined elsewhere herein.

[0152] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1; n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH. In some embodiments, m is 0, or 1, and n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.6-10cycloalkyl, 5-10 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-3alkyl), NHC(O)C.sub.1-3alkyl, NHC(O)C.sub.3-6cycloalkyl, NHC(O)-(3-6 membered heterocyclyl), NHC(NCN)NH.sub.2, NH(C.sub.1-3alkyl), NH-(3-10 membered heterocyclyl), or NH-(5-10 membered heteroaryl), wherein the 3-10 membered heterocyclyl of the NHC(O)-(3-10 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-3alkyl or C.sub.1-3alkyl, wherein the C.sub.1-3alkyl is optionally substituted with one or more halo, C.sub.1-3alkoxy, or C.sub.6-10cycloalkyl, and the 3-10 membered heterocyclyl of the NH-(3-10 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-3alkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-3alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-3alkyl, wherein the C.sub.1-3alkyl of the C(O)NH(C.sub.1-3alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-3alkoxy, and the C.sub.1-3alkyl of the NHC(O)C.sub.1-3alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-3alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH.

[0153] In some embodiments, m is 0, or 1, and n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, F, CH.sub.3, OCH.sub.3, C.sub.6-10cycloalkyl, 5-10 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(CH.sub.3), NHC(O) CH.sub.3, NHC(O)C.sub.3-6cycloalkyl, NHC(O)-(3-6 membered heterocyclyl), NHC(NCN)NH.sub.2, NH(C.sub.1-3alkyl), NH-(3-10 membered heterocyclyl), or NH-(5-10 membered heteroaryl), wherein the 3-10 membered heterocyclyl of the NHC(O)-(3-6 membered heterocyclyl) is optionally substituted with one or more C(O)CH.sub.3 or CH.sub.3, wherein the CH.sub.3 is optionally substituted with one or more halo, OCH.sub.3, or C.sub.6-10cycloalkyl, and the 3-6 membered heterocyclyl of the NH-(3-6 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-3alkyl; R.sup.1 is H, F, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(CH.sub.3), NHC(O)NH.sub.2, or NHC(O) CH.sub.3, wherein the CH.sub.3 of the C(O)NH(CH.sub.3) of R.sup.1 is optionally substituted with one or more C(O)OCH.sub.3, and the CH.sub.3 of the NHC(O)CH.sub.3 of R.sup.1 is optionally substituted with one or more NHC(O)CH.sub.3 or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH.

[0154] In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; R.sup.3 and R.sup.4 are each CH.sub.3; X.sup.1 is H; X.sup.2 is H; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, F, CH.sub.3, OCH.sub.3, C.sub.6-10cycloalkyl, 5-10 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(CH.sub.3), NHC(O)CH.sub.3, NHC(O)C.sub.3-6cycloalkyl, NHC(O)-(3-6 membered heterocyclyl), NHC(NCN)NH.sub.2, NH(C.sub.1-3alkyl), NH-(3-10 membered heterocyclyl), or NH-(5-10 membered heteroaryl), wherein the 3-10 membered heterocyclyl of the NHC(O)-(3-6 membered heterocyclyl) is optionally substituted with one or more C(O)CH.sub.3 or CH.sub.3, wherein the CH.sub.3 is optionally substituted with one or more halo, OCH.sub.3, or C.sub.6-10cycloalkyl, and the 3-6 membered heterocyclyl of the NH-(3-6 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-3alkyl; R.sup.1 is H; and R.sup.2 is H.

[0155] In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; R.sup.3 and R.sup.4 are each CH.sub.3; X.sup.1 is H; X.sup.2 is F; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more NHC(O)NH.sub.2; R.sup.1 is H or F; and R.sup.2 is H.

[0156] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; and n is 1; Y.sup.1 is CH; Y.sup.2 is N; R.sup.3 and R.sup.4 are each CH.sub.3; X.sup.1 and X.sup.2 are each independently H; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl or NHC(O)C.sub.1-3alkyl; R.sup.1 is H; and R.sup.2 is H. In some embodiments, m is 0; and n is 1; Y.sup.1 is CH; Y.sup.2 is N; R.sup.3 and R.sup.4 are each CH.sub.3; X.sup.1 and X.sup.2 are each independently H; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more CH.sub.3 or NHC(O)CH.sub.3; R.sup.1 is H; and R.sup.2 is H.

[0157] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; and n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more 5-10 membered heteroaryl; R.sup.1 is H; and R.sup.2 is halo. In some embodiments, m is 0; and n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more pyrazolyl; R.sup.1 is H; and R.sup.2 is F.

[0158] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1, and n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl; R.sup.1 is H, F, C(O)NH(CH.sub.3), NHC(O)NH.sub.2, or NHC(O)CH.sub.3, wherein the CH.sub.3 of the NHC(O)CH.sub.3 of R.sup.1 is optionally substituted with one or more NHC(O)CH.sub.3 or C(O)NH.sub.2; and R.sup.2 is H, or halo.

[0159] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1, and n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl; R.sup.1 is H, F, C(O)NH(CH.sub.3), NHC(O)NH.sub.2, or NHC(O)CH.sub.3, wherein the CH.sub.3 of the NHC(O)CH.sub.3 of R.sup.1 is optionally substituted with one or more NHC(O)CH.sub.3 or C(O)NH.sub.2; and R.sup.2 is H, OH, or halo.

[0160] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1, and n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl; R.sup.1 is H, F, C(O)NH(CH.sub.3), NHC(O)NH.sub.2, or NHC(O)CH.sub.3, wherein the CH.sub.3 of the NHC(O)CH.sub.3 of R.sup.1 is optionally substituted with one or more NHC(O)CH.sub.3 or C(O)NH.sub.2; and R.sup.2 is H, OH, or halo.

[0161] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1, and n is 0, or 1; one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is phenyl; R.sup.1 is H, or F; and R.sup.2 is H, or halo.

[0162] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, or 1; n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-3alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-3alkyl, wherein the C.sub.1-3alkyl of the C(O)NH(C.sub.1-3alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-3alkoxy, and the C.sub.1-3alkyl of the NHC(O)C.sub.1-3alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-3alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH. In some embodiments, m is 0, or 1; n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is (i) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or (ii) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-3alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-3alkyl, wherein the C.sub.1-3alkyl of the C(O)NH(C.sub.1-3alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-3alkoxy, and the C.sub.1-3alkyl of the NHC(O)C.sub.1-3alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-3alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH.

[0163] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH. In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH.

[0164] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.1 is H; X.sup.2 is halo; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH. In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH.

[0165] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH. In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH.

[0166] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more C.sub.1-6alkyl; R.sup.1 is H; and R.sup.2 is H. In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more C.sub.1-3alkyl; R.sup.1 is H; and R.sup.2 is H.

[0167] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is halo; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more C.sub.1-6alkyl; R.sup.1 is H, or halo; and R.sup.2 is H, or halo. In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more C.sub.1-3alkyl; R.sup.1 is H, halo; and R.sup.2 is H, halo, or OH.

[0168] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more C.sub.1-6alkyl; R.sup.1 is H, halo; and R.sup.2 is H, or halo. In some embodiments, m is 0; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; R.sup.3 and R.sup.4 are each CH.sub.3; Q.sup.1 is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more C.sub.1-3alkyl; R.sup.1 is H, or halo; and R.sup.2 is H, or halo.

[0169] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is (i)C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH.

[0170] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 1; n is 0, or 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is (i)C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH. In some embodiments, m is 1; n 1; Y.sup.1 and Y.sup.2 are each CH, or one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are each independently H or halo; R.sup.3 and R.sup.4 are each CH.sub.3, or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl; Q.sup.1 is (i)C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl; R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and R.sup.2 is H, halo, or OH.

[0171] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A):

##STR00052##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, either: [0172] i. X.sup.4-8 are each independently H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0173] the 3-9 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0174] the 3-9 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl; or [0175] ii. X.sup.6 is taken together with either of X.sup.4 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is [0176] 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.1 are each independently H, or oxo, or [0177] 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; or [0178] iii. X.sup.7 is taken together with either of X.sup.5 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is [0179] 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, or oxo, or [0180] 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

[0181] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.4-8 are each independently X.sup.4-8 are each independently H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0182] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.4-8 are each independently H.

[0183] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0184] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0185] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl. [0186] and the others of X.sup.4-8 are each independently H.

[0187] In some embodiments, one of X.sup.4-8 is selected from the group consisting of methyl, OH, Cl, OCH.sub.3, NH.sub.2, NH(CH.sub.3)

##STR00053## ##STR00054##

and the others of X.sup.4-8 are each independently H.

[0188] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.6 is taken together with either of X.sup.4 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is [0189] 3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, or oxo, or [0190] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

[0191] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.6 is taken together with either of X.sup.4 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is [0192] 3-6 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, or oxo, or [0193] 5-6 membered heteroaryl, wherein the 5-10 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

[0194] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.6 is taken together with either of X.sup.4 or X.sup.8, and the atoms to which they are attached, to form ring A, wherein ring A is 3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo. In some embodiments, ring A is 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-3alkyl. In some embodiments, ring A is selected from the group consisting of

##STR00055##

wherein # represents a point of attachment to the rest of the molecule.

[0195] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, ring A is 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl of ring A is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, ring A is

##STR00056##

wherein # represents a point of attachment to the rest of the molecule.

[0196] In some embodiments, provided herein is a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A1):

##STR00057##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.4 is H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0197] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0198] In some embodiments, provided herein is a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A2):

##STR00058##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.6 is H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0199] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0200] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-B):

##STR00059##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.3 is H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0201] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0202] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0203] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1 and X.sup.2 are independently H or halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, X.sup.1 and X.sup.2 are independently H or F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0204] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are independently H or halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are independently H or F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, Y.sup.1 and Y.sup.2 are each CH; one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, Y.sup.1 and Y.sup.2 are each CH; one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0205] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are independently H or halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; X.sup.1 and X.sup.2 are independently H or F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH, one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0206] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.3 is H, OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0207] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0208] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0209] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.3 is H.

[0210] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.3 is OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O)2-C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0211] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0212] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[0213] In some embodiments, one of X.sup.3 is selected from the group consisting of methyl, OH, Cl, OCH.sub.3, NH.sub.2, NH(CH.sub.3),

##STR00060## ##STR00061##

[0214] In some embodiments, provided herein is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-B1):

##STR00062##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0215] In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1 and X.sup.2 are independently halo; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0216] In some embodiments, X.sup.1 and X.sup.2 are independently F; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0217] In some embodiments, provided is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B2):

##STR00063##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0218] In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.2 is halo; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl. In some embodiments, X.sup.2 is F; and R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0219] In some embodiments, provided is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B3):

##STR00064##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0220] In some embodiments of a compound of formula (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0221] In some embodiments, provided herein is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-B4):

##STR00065##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0222] In some embodiments, provided is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B5):

##STR00066##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0223] In some embodiments of a compound of formula (I-B5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.2 is halo; and X.sup.3 is C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl of X.sup.3 is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, X.sup.2 is F; and X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl, wherein the C.sub.3-6cycloalkyl of X.sup.3 is optionally substituted with one or more C.sub.1-3alkyl.

[0224] In some embodiments, provided is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B6):

##STR00067##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0225] In some embodiments of a compound of formula (I-B6), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.3 and R.sup.4 are each CH.sub.3 or R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.

[0226] In some embodiments, provided here is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-C):

##STR00068##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is [0227] 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, [0228] 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

[0229] In some embodiments, provided here is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-D):

##STR00069## [0230] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is [0231] 3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, [0232] 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

[0233] In some embodiments of a compound of formula (I-C), (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl of ring A is optionally substituted with one or more oxo. In some embodiments, ring A is selected from the group consisting of

##STR00070##

wherein # represents a point of attachment to the rest of the molecule.

[0234] In some embodiments of a compound of formula (I-C), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, ring A is

##STR00071##

wherein # represents a point of attachment to the rest of the molecule.

[0235] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-E):

##STR00072##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0236] In some embodiments, provided herein is a compound of formula (I), or (I-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-E1):

##STR00073##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0237] In some embodiments, provided herein is a compound of formula (I), or (I-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-E2):

##STR00074##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0238] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F):

##STR00075##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0239] In some embodiments, provided herein is a compound of formula (I), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F1):

##STR00076##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0240] In some embodiments, provided herein is a compound of formula (I), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F2):

##STR00077##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0241] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G):

##STR00078##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0242] In some embodiments, provided is a compound of formula (I), or (I-G) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G1):

##STR00079##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0243] In some embodiments, provided is a compound of formula (I), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G2):

##STR00080##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0244] In some embodiments, provided is a compound of formula (I), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G3):

##STR00081##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0245] In some embodiments, provided is a compound of formula (I), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G4):

##STR00082##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0246] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H):

##STR00083##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0247] In some embodiments, provided is a compound of formula (I), or (I-H) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H1):

##STR00084##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0248] In some embodiments, provided is a compound of formula (I), (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H2):

##STR00085##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0249] In some embodiments, provided is a compound of formula (I), (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H3):

##STR00086##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0250] In some embodiments, provided is a compound of formula (I), (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H4):

##STR00087##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0251] In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

[0252] Compound Names included in Table 1 and for all intermediates and compounds were generated using ChemDraw Professional software version 17.1.1.0 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.

[0253] A Knime workflow was created to retrieve structures from an internal ChemAxon Compound Registry, generate the canonical smiles using RDKit Canon SMILES node, remove the stereochemistry using ChemAxon/Infocom MolConverter node, and name the structure using ChemAxon/Infocom Naming node. The following denotes the version of the Knime Analytics Platform and extensions utilized in the workflow: [0254] Knime Analytics Platform 4.2.2 [0255] RDKit Knime Integration 4.0.1.v202006261025 (this extension includes the RDKit Canon SMILES node) [0256] ChemAxon/Infocom Marvin Extensions Feature 4.3.0v202100 (this extension includes the MolConverter node) [0257] ChemAxon/Infocom JChem Extensions Feature 4.3.0v202100 (this extension includes the Naming node)

TABLE-US-00001 TABLE 1 Cmpd No. Structure Cmpd Name 1 [00088] (R)-N-((2-acetamidophenyl)(4- isopropylphenyl)methyl)cyclopropane- carboxamide 2 [00089] (1R,2S)-N-((S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl)- 2-fluorocyclopropane-1- carboxamide 3 [00090] (1R,2S)-2-fluoro-N-((S)-(6-fluoro-5- isopropylpyridin-2-yl)(1H-indazol- 6-yl)methyl)cyclopropane-1- carboxamide 4 [00091] (1R,2S)-N-((S)-(3-(1H-pyrazol-5- yl)phenyl)(6-fluoro-5- isopropylpyridin-2-yl)methyl)-2- fluorocyclopropane-1- carboxamide 5 [00092] (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4- isopropylphenyl)(2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4- yl)methyl)cyclopropane-1- carboxamide 6 [00093] (R)-N-((3-acetamidophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 7 [00094] (1R,2S)-2-cyano-N-((R)-(4- isopropylphenyl)(o- tolyl)methyl)cyclopentane-1- carboxamide 8 [00095] N-((1R)-(4-isopropylphenyl)(2-((1- methyl-2,5-dioxoimidazolidin-4- yl)amino)phenyl)methyl) cyclopropanecarboxamide 9 [00096] N-(2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl)phenyl)-1- (2,2,2-trifluoroethyl)piperidine-4- carboxamide 10 [00097] (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4- isopropylphenyl)(2- ureidophenyl)methyl)cyclopropane-1- carboxamide 11 [00098] (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4- isopropylphenyl)(1H-pyrazol-5- yl)methyl)cyclopropane-1- carboxamide 12 [00099] N-(2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl)phenyl)-1- methylpiperidine-4-carboxamide 13 [00100] N-(2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl)phenyl)-1- (2-methoxyethyl)piperidine-4- carboxamide 14 [00101] 1-(cyclopropylmethyl)-N-(2-((R)- ((1R,2S)-2-fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl)phenyl) piperidine-4-carboxamide 15 [00102] (R)-N-((4-isopropylphenyl)(2-oxo- 2,3-dihydrobenzo[d]oxazol-7- yl)methyl)cyclopropanecarboxamide 16 [00103] (1R,2S)-N.sup.1-((R)-(4- isopropylphenyl)(o-tolyl)methyl)- N.sup.2-methylcyclopentane-1,2- dicarboxamide 17 [00104] (R)-N-((4-cyclopropylphenyl)(2- ureidophenyl)methyl)cyclopropane- carboxamide 18 [00105] (R)-N-((4-cyclobutylphenyl)(2- ureidophenyl)methyl)cyclopropane- carboxamide 19 [00106] (R,E)-N-((2-(2- cyanoguanidino)phenyl)(4- isopropylphenyl)methyl)cyclo- propanecarboxamide 20 [00107] methyl 3-((1S,2R)-2-(((R)-(4- isopropylphenyl)(o- tolyl)methyl)carbamoyl)cyclo- pentane-1-carboxamido)propanoate 21 [00108] (1R,2S)-2-(2-acetamidoacetamido)- N-((S)-(4- isopropylphenyl)(phenyl)methyl) cyclopentane-1-carboxamide 22 [00109] (1S,2R)-N.sup.1-cyano-N.sup.2-((R)-(4- isopropylphenyl)(o- tolyl)methyl)cyclopentane-1,2- dicarboxamide 23 [00110] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl)-1- (2,2,2-trifluoroethyl)azetidine-3- carboxamide 24 [00111] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl)-1- (2-methoxyethyl)azetidine-3- carboxamide 25 [00112] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl)-1- (cyclopropylmethyl)azetidine-3- carboxamide 26 [00113] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl)-1- methylazetidine-3-carboxamide 27 [00114] (1S,2R)-2-fluoro-N-((S)-(4- isopropylphenyl)(phenyl)methyl) cyclopropane-1-carboxamide 28 [00115] (S)-2-acetamido-N.sup.1-((1S,2R)-2-(((S)- (4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentyl)succinamide 29 [00116] (R)-N-((4-isopropylphenyl)(2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-4- yl)methyl)cyclopropanecarboxamide 30 [00117] (1R,2S)-N.sup.1-((R)-(4- isopropylphenyl)(o- tolyl)methyl)cyclopentane-1,2- dicarboxamide 31 [00118] (R)-N-((4-isopropylphenyl)(2- (oxazol-2- ylamino)phenyl)methyl)cyclopropane- carboxamide 32 [00119] (R)-N-((4-isopropylphenyl)(2- oxoindolin-7- yl)methyl)cyclopropanecarboxamide 33 [00120] (S)-N-((5-isopropylpyridin-2-yl)(2- methoxyphenyl)methyl)cyclopropane- carboxamide 34 [00121] (1S)-3-fluoro-N-((S)-(4- isopropylphenyl)(phenyl)methyl) cyclopentane-1-carboxamide 35 [00122] (1S)-3-hydroxy-N-((S)-(4- isopropylphenyl)(phenyl)methyl) cyclopentane-1-carboxamide 36 [00123] (1R,2S)-2-fluoro-N-((S)-(4- isopropylphenyl)(phenyl)methyl) cyclopropane-1-carboxamide 37 [00124] (R)-1-acetyl-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) azetidine-3-carboxamide 38 [00125] (1R,2S)-N-((S)-(4- isopropylphenyl)(phenyl)methyl)-2- ureidocyclopentane-1-carboxamide 39 [00126] (R)-N-((4-isopropylphenyl)(2- (methylamino)phenyl)methyl) cyclopropanecarboxamide 40 [00127] (S)-N-((4- cyclobutylphenyl)(phenyl)methyl) cyclopropanecarboxamide 41 [00128] (S)-N-((4- cyclopropylphenyl)(phenyl)methyl) cyclopropanecarboxamide 42 [00129] (S)-1-acetyl-N-(2-((R)- cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) azetidine-2-carboxamide 43 [00130] (R)-N-((4-isopropylphenyl)(3- methyl-1H-pyrazol-4- yl)methyl)cyclopropanecarboxamide 44 [00131] (R)-N-((2-acetamido-5- fluorophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 45 [00132] (S)-N-((5-isopropylpyridin-2- yl)(phenyl)methyl) cyclopropanecarboxamide 46 [00133] (S)-N-((2-acetamidophenyl)(5- isopropylpyridin-2- yl)methyl)cyclopropanecarboxamide 47 [00134] (S)-N-((5-isopropylpyridin-2-yl)(o- tolyl)methyl)cyclopropanecarboxamide 48 [00135] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) azetidine-3-carboxamide 49 [00136] (S)-N-(2-((R)- cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) azetidine-2-carboxamide 50 [00137] (R)-N-(2-((R)- cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) azetidine-2-carboxamide 51 [00138] (R)-N-((2-aminopyridin-3-yl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 52 [00139] (S)-N-((3-fluoro-4- isopropylphenyl)(phenyl)methyl) cyclopropanecarboxamide 53 [00140] (R)-N-((4-isopropylphenyl)(2-(3- methylureido)phenyl)methyl) cyclopropanecarboxamide 54 [00141] (R)-N-((4-isopropylphenyl)(2- ureidophenyl)methyl) cyclopropanecarboxamide 55 [00142] (1R,2S)-2-acetamido-N-((S)-(4- isopropylphenyl)(phenyl)methyl) cyclopentane-1-carboxamide 56 [00143] (R)-N-((4-isopropylphenyl)(1H- pyrazol-5- yl)methyl)cyclopropanecarboxamide 57 [00144] (R)-N-((4-isopropylphenyl)(2- (methylsulfonamido)phenyl)methyl) cyclopropanecarboxamide 58 [00145] (R)-N-((2-chlorophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 59 [00146] (R)-N-((4-isopropylphenyl)(2- propionamidophenyl)methyl) cyclopropanecarboxamide 60 [00147] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) oxetane-3-carboxamide 61 [00148] (R)-N-(2- (cyclopropanecarboxamido(4- isopropylphenyl)methyl)phenyl) cyclopropanecarboxamide 62 [00149] (R)-N-((3-hydroxyphenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 63 [00150] (R)-N-((4-isopropylphenyl)(3- methoxy-2- methylphenyl)methyl) cyclopropanecarboxamide 64 [00151] (R)-N-((2-aminophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 65 [00152] (R)-N-((4-isopropylphenyl)(o- tolyl)methyl) cyclopropanecarboxamide 66 [00153] (R)-N-((4-isopropylphenyl)(m- tolyl)methyl)cyclopropanecarboxamide 67 [00154] (R)-N-((2-hydroxyphenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 68 [00155] (R)-N-((4-hydroxyphenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 69 [00156] (R)-N-((4-isopropylphenyl)(1- methyl-1H-pyrazol-5- yl)methyl)cyclopropanecarboxamide 70 [00157] (R)-N-((4-isopropylphenyl)(3- methoxyphenyl)methyl) cyclopropanecarboxamide 71 [00158] (R)-N-((4-isopropylphenyl)(2- methoxyphenyl)methyl) cyclopropanecarboxamide 72 [00159] (R)-N-((4-isopropylphenyl)(4- methoxyphenyl)methyl) cyclopropanecarboxamide 73 [00160] (S)-N-((4- isopropylphenyl)(phenyl)methyl) cyclopropanecarboxamide

[0258] In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: [0259] N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; [0260] N-[(4-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0261] N-[(2-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0262] N-[(3-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0263] N-[(1-methyl-1H-pyrazol-5-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0264] N-[(4-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0265] N-[(2-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0266] N-[(3-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0267] N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0268] N-[(2-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0269] N-[(2-aminophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0270] N-[(3-methoxy-2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0271] N-[(3-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0272] N-[(2-cyclopropaneamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0273] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}oxetane-3-carboxamide; [0274] N-{[4-(propan-2-yl)phenyl](2-propanamidophenyl)methyl}cyclopropanecarboxamide; [0275] N-[(2-chlorophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0276] N-[(2-methanesulfonamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0277] N-{[4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}cyclopropanecarboxamide; [0278] 2-acetamido-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; [0279] N-{[2-(carbamoylamino)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; [0280] N-({2-[(methylcarbamoyl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide; [0281] N-[(2-aminopyridin-3-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0282] N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}cyclopropanecarboxamide; [0283] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-2-carboxamide; [0284] N-[(2-methylphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]cyclopropanecarboxamide; [0285] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-3-carboxamide; [0286] N-[(4-cyclopropylphenyl)(phenyl)methyl]cyclopropanecarboxamide; [0287] N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}cyclopropanecarboxamide; [0288] N-[(4-cyclobutylphenyl)(phenyl)methyl]cyclopropanecarboxamide; [0289] N-[(2-acetamido-5-fluorophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0290] N-[(3-methyl-1H-pyrazol-4-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0291] N-{[2-(methylamino)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; [0292] 1-acetyl-N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-2-carboxamide; [0293] 2-(carbamoylamino)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; [0294] N-[(2-methoxyphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]cyclopropanecarboxamide; [0295] 1-acetyl-N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-3-carboxamide; [0296] 2-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropane-1-carboxamide; [0297] 3-hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; [0298] 3-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; [0299] N-[(2-oxo-2,3-dihydro-1H-indol-7-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0300] N-({2-[(1,3-oxazol-2-yl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide; [0301] N1-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide; [0302] N-[(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0303] 2-acetamido-N-[2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentyl]butanediamide; [0304] 2-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropane-1-carboxamide; [0305] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-methylazetidine-3-carboxamide; [0306] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(cyclopropylmethyl)azetidine-3-carboxamide; [0307] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(2-methoxyethyl)azetidine-3-carboxamide; [0308] N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamide; [0309] N1-cyano-N2-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide; [0310] 2-(2-acetamidoacetamido)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; [0311] methyl 3-[(2-{[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentyl)formamido]propanoate; [0312] N-{[2-(N-cyanocarbamimidamido)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; [0313] N-{[2-(carbamoylamino)phenyl](4-cyclobutylphenyl)methyl}cyclopropanecarboxamide; [0314] N1-methyl-N2-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide; [0315] N-{[2-(carbamoylamino)phenyl](4-cyclopropylphenyl)methyl}cyclopropanecarboxamide; [0316] N-[(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0317] 1-(cyclopropylmethyl)-N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)piperidine-4-carboxamide; [0318] N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)-1-(2-methoxyethyl)piperidine-4-carboxamide; [0319] N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)-1-methylpiperidine-4-carboxamide; [0320] 2-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}cyclopropane-1-carboxamide; [0321] N-{[2-(carbamoylamino)phenyl][3-fluoro-4-(propan-2-yl)phenyl]methyl}-2-fluorocyclopropane-1-carboxamide; [0322] N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide; [0323] N-({2-[(1-methyl-2,5-dioxoimidazolidin-4-yl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide; [0324] 2-cyano-N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1-carboxamide; [0325] N-[(3-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; [0326] 2-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl}cyclopropane-1-carboxamide; [0327] 2-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}cyclopropane-1-carboxamide; [0328] 2-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}cyclopropane-1-carboxamide; and [0329] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-2-fluorocyclopropane-1-carboxamide;
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0330] In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: [0331] (R)N-((2-acetamidophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0332] (1R,2S)N((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-fluorocyclopropane-1-carboxamide; [0333] (1R,2S)-2-fluoro-N((S)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide; [0334] (1R,2S)N((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-fluorocyclopropane-1-carboxamide; [0335] (1R,2S)-2-fluoro-N((R)-(3-fluoro-4-isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)cyclopropane-1-carboxamide; [0336] (R)N-((3-acetamidophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0337] (1R,2S)-2-cyano-N((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide; [0338] N-((1R)-(4-isopropylphenyl)(2-((1-methyl-2,5-dioxoimidazolidin-4-yl)amino)phenyl)methyl)cyclopropanecarboxamide; [0339] N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide; [0340] (1R,2S)-2-fluoro-N((R)-(3-fluoro-4-isopropylphenyl)(2-ureidophenyl)methyl)cyclopropane-1-carboxamide; [0341] (1R,2S)-2-fluoro-N((R)-(3-fluoro-4-isopropylphenyl)(1H-pyrazol-5-yl)methyl)cyclopropane-1-carboxamide; [0342] N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide; [0343] N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)-1-(2-methoxyethyl)piperidine-4-carboxamide; [0344] 1-(cyclopropylmethyl)-N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)piperidine-4-carboxamide; [0345] (R)N-((4-isopropylphenyl)(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)methyl)cyclopropanecarboxamide; [0346] (1R,2S)N1-((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N2-methylcyclopentane-1,2-dicarboxamide; [0347] (R)N-((4-cyclopropylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide; [0348] (R)N-((4-cyclobutylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide; [0349] (R,E)-N-((2-(2-cyanoguanidino)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0350] methyl 3-((1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxamido)propanoate; [0351] (1R,2S)-2-(2-acetamidoacetamido)-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; [0352] (1S,2R)N1-cyano-N2-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide; [0353] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamide; [0354] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(2-methoxyethyl)azetidine-3-carboxamide; [0355] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(cyclopropylmethyl)azetidine-3-carboxamide; [0356] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide; [0357] (1S,2R)-2-fluoro-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopropane-1-carboxamide; [0358] (S)-2-acetamido-N1-((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)succinamide; [0359] (R)N-((4-isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)cyclopropanecarboxamide; [0360] (1R,2S)N1-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide; [0361] (R)N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide; [0362] (R)N-((4-isopropylphenyl)(2-oxoindolin-7-yl)methyl)cyclopropanecarboxamide; [0363] (S)N-((5-isopropylpyridin-2-yl)(2-methoxyphenyl)methyl)cyclopropanecarboxamide; [0364] (1S)-3-fluoro-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; [0365] (1S)-3-hydroxy-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; [0366] (1R,2S)-2-fluoro-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopropane-1-carboxamide; [0367] (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide; [0368] (1R,2S)N((S)-(4-isopropylphenyl)(phenyl)methyl)-2-ureidocyclopentane-1-carboxamide; [0369] (R)N-((4-isopropylphenyl)(2-(methylamino)phenyl)methyl)cyclopropanecarboxamide; [0370] (S)N-((4-cyclobutylphenyl)(phenyl)methyl)cyclopropanecarboxamide; [0371] (S)N-((4-cyclopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; [0372] (S)-1-acetyl-N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide; [0373] (R)N-((4-isopropylphenyl)(3-methyl-1H-pyrazol-4-yl)methyl)cyclopropanecarboxamide; [0374] (R)N-((2-acetamido-5-fluorophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0375] (S)N-((5-isopropylpyridin-2-yl)(phenyl)methyl)cyclopropanecarboxamide; [0376] (S)N-((2-acetamidophenyl)(5-isopropylpyridin-2-yl)methyl)cyclopropanecarboxamide; [0377] (S)N-((5-isopropylpyridin-2-yl)(o-tolyl)methyl)cyclopropanecarboxamide; [0378] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide; [0379] (S)N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide; [0380] (R)N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide; [0381] (R)N-((2-aminopyridin-3-yl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0382] (S)N-((3-fluoro-4-isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; [0383] (R)N-((4-isopropylphenyl)(2-(3-methylureido)phenyl)methyl)cyclopropanecarboxamide; [0384] (R)N-((4-isopropylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide; [0385] (1R,2S)-2-acetamido-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; [0386] (R)N-((4-isopropylphenyl)(1H-pyrazol-5-yl)methyl)cyclopropanecarboxamide; [0387] (R)N-((4-isopropylphenyl)(2-(methylsulfonamido)phenyl)methyl)cyclopropanecarboxamide; [0388] (R)N-((2-chlorophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0389] (R)N-((4-isopropylphenyl)(2-propionamidophenyl)methyl)cyclopropanecarboxamide; [0390] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)oxetane-3-carboxamide; [0391] (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)cyclopropanecarboxamide; [0392] (R)N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0393] (R)N-((4-isopropylphenyl)(3-methoxy-2-methylphenyl)methyl)cyclopropanecarboxamide; [0394] (R)N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0395] (R)N-((4-isopropylphenyl)(o-tolyl)methyl)cyclopropanecarboxamide; [0396] (R)N-((4-isopropylphenyl)(m-tolyl)methyl)cyclopropanecarboxamide; [0397] (R)N-((2-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0398] (R)N-((4-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; [0399] (R)N-((4-isopropylphenyl)(1-methyl-1H-pyrazol-5-yl)methyl)cyclopropanecarboxamide; [0400] (R)N-((4-isopropylphenyl)(3-methoxyphenyl)methyl)cyclopropanecarboxamide; [0401] (R)N-((4-isopropylphenyl)(2-methoxyphenyl)methyl)cyclopropanecarboxamide; [0402] (R)N-((4-isopropylphenyl)(4-methoxyphenyl)methyl)cyclopropanecarboxamide; [0403] (S)N-((4-isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; and
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Methods of Treatment

[0404] Provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, is selective for GYS1 over GYS2. In some embodiments, the compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

[0405] Provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising an effective amount of a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

[0406] Provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0407] In some embodiments, the compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selective for GYS1 over GYS2. In some embodiments, the compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the individual has a GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML). In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is late-onset Pompe disease (LOPD).

[0408] Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0409] Provided herein is a method of inhibiting glycogen synthesis in an individual in need thereof, comprising administering to the individual an effective amount of (i) compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0410] Provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

[0411] Provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the level of glycogen in the individual is reduced upon treatment. In some embodiments, the level of glycogen in muscle is reduced. In some embodiments, the level of glycogen is skeletal muscle is reduced. In some embodiments, the level of glycogen is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective for treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[0412] Provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the level of glycogen in the individual is reduced upon treatment. In some embodiments, the level of glycogen in muscle is reduced. In some embodiments, the level of glycogen is skeletal muscle is reduced. In some embodiments, the level of glycogen is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective for treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[0413] Provided herein is a method of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has infant onset Pompe disease. In some embodiments, the individual has non-classic infant-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual has a deficiency in acid alfa glucosidase (GAA). In some embodiments, the individual has reduced expression of GAA.

[0414] Provided herein is a method of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) a composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has infant onset Pompe disease. In some embodiments, the individual has non-classic infant-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual has a deficiency in acid alfa glucosidase (GAA). In some embodiments, the individual has reduced expression of GAA.

[0415] In some embodiments, the compounds provided herein reduce and/or eliminate one or more symptoms associated with Pompe disease. In some embodiments, the compounds reduce and/or eliminate weak muscles, poor muscle tone, enlarged liver, failure to grow and gain weight, trouble breathing, feeding problems, infections in the respiratory system, problems with hearing, motor skill delay, heart enlargement, tiredness, lung infection, frequent falling, or irregular heartbeat. In some embodiments, the compounds herein delay progression of Pompe disease.

[0416] In some embodiments, the compounds provided herein increase the lifespan of the individual. In some embodiments, the lifespan is increased at least 5, at least 10, or at least 20 years upon treatment.

[0417] In some embodiments, the compounds provided herein prevent, reduce, or delay muscle weakness. In some embodiments, muscle weakness is determined by manual muscle testing, sit to stand test, heel-raise test, hand-held dynamometry, or hand grip dynamometry. In some embodiments, strength is graded according to the following scale: 0: No visible muscle contraction; 1: Visible muscle contraction with no or trace movement; 2: Limb movement, but not against gravity; 3: Movement against gravity but not resistance; 4: Movement against at least some resistance supplied by the examiner; 5: Full strength.

[0418] Also provided herein is a method of inhibiting a GYS1 enzyme in an individual comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual. In some embodiments the GYS1 enzyme is human GYS1 (hGYS1). In some embodiments, the compounds provided herein are inhibit GYS1 at a concentration of less than 10 M, less than 1 M, less than 0.5 M, or less than 0.1 M. In some embodiments, the compounds provided herein inhibit GYS1 at a concentration of 1-10 M, 0.01 to 1 M, or 0.01 to 10 M.

[0419] In some embodiments, the compounds have an IC.sub.50 of less than 10 nM, less than 10 M, less than 1 M, less than 0.5 M, or less than 0.1 M. In some embodiments, the compounds provided herein have an IC.sub.50 of 1 to 10 nM, 1 to 10 M, 0.01 to 1 M, 0.01 to 10 M, or 0.001 to 0.01 M.

[0420] In some embodiments, glycogen synthesis is inhibited upon administration of a compound provided herein. In some embodiments, glycogen synthesis is reduced at least 10%, at least 20%, at least 40% or at least 50% upon administration.

[0421] In some embodiments, the individual receiving treatment is a juvenile human or an infant. In some embodiments, the individual is less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, or less than one year old.

[0422] In some embodiments, the methods further comprise enzyme replacement therapy (ERT). Exemplary ERTs include alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) and those described in Byrne B J et al (2011). Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab 103: 1-11 (herein incorporated by reference in its entirety). In some embodiments, the ERT is selected from the group consisting of Myozyme and Lumizyme. In some embodiments, the ERT is Myozyme. In some embodiments, the ERT is Lumizyme. In some embodiments, the individual has an advanced glycogen storage disease. In some embodiments, the individual has late onset Pompe Disease. Thus, provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to (a) glycogen substrate reduction therapy, such as administering to the individual an effective amount of (i) compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, and (b) enzyme replacement therapy. In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease, such as late-onset Pompe disease. In some embodiments, the compound of formula (I) is selective for GYS1 over GYS2. In some embodiments, the compound of formula (I) is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

[0423] In some embodiments, the individual has a mutation in the GAA gene. In some embodiments, the mutation reduces the level of GAA protein. In some embodiments, the mutation is a loss-of-function mutation. In some embodiments, the mutation is a missense mutation. In some embodiments, the mutation is a deletion. In some embodiments, the mutation is a recessive mutation. In some embodiments, the mutation is a splicing variant.

[0424] In some embodiments of the foregoing, the administration is oral administration.

Kits

[0425] The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and/or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

[0426] Provided herein are kits, comprising (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof

[0427] Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

Methods of Preparing

[0428] The present disclosure further provides processes for preparing the compounds of present invention. In some aspects, provided herein are processes of preparing a compound of (I), (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-G), (1-G1), (I-G2), (I-G3), (I-G4), (I-H), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0429] In some embodiments, a process for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises [0430] (a) reacting a compound of formula (I-1):

##STR00161##

or a salt thereof, wherein
Y.sup.1 and Y.sup.2 are each CH, or
one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH;
X.sup.1 and X.sup.2 are each independently H or halo;
R.sup.3 and R.sup.4 are each CH.sub.3, or
R.sup.3 and R.sup.4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl;
either
(1) L is absent; and

Q.SUP.1 .is:

(i) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more OH, NH.sub.2, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-10cycloalkyl, 5-20 membered heteroaryl, NHC(O)NH.sub.2, NHC(O)NH(C.sub.1-6alkyl), NHC(O)C.sub.1-6alkyl, NHC(O)C.sub.3-10cycloalkyl, NHC(O)-(3-15 membered heterocyclyl), NHC(NCN)NH.sub.2, NHS(O).sub.2C.sub.1-6alkyl, NH(C.sub.1-6alkyl), NH-(3-15 membered heterocyclyl), or NH-(5-20 membered heteroaryl), wherein [0431] the 3-15 membered heterocyclyl of the NHC(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more C(O)C.sub.1-6alkyl or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0432] the 3-15 membered heterocyclyl of the NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C.sub.1-6alkyl, or
(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or
(iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises at least one annular N atom and is optionally substituted with one or more NH.sub.2, halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl;
or

(2) L is CH.SUB.2.; and

Q.sup.1 is C.sub.3-10cycloalkyl,
with a compound of formula (I-2):

##STR00162##

wherein,
m is 0 or 1;
n is 0 or 1;
R.sup.1 is H, halo, CN, C(O)NH.sub.2, C(O)NH(CN), C(O)NH(C.sub.1-6alkyl), NHC(O)NH.sub.2, or NHC(O)C.sub.1-6alkyl, wherein [0433] the C.sub.1-6alkyl of the C(O)NH(C.sub.1-6alkyl) of R.sup.1 is optionally substituted with one or more C(O)C.sub.1-6alkoxy, and [0434] the C.sub.1-6alkyl of the NHC(O)C.sub.1-6alkyl of R.sup.1 is optionally substituted with one or more NHC(O)C.sub.1-6alkyl or C(O)NH.sub.2; and
R.sup.2 is H, halo, or OH
in the presence of a coupling reagent to provide a compound of formula (I).

[0435] In some embodiments, the coupling reagent comprises propanephosphonic acid anhydride (T3P), or N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (TFCH).

[0436] In some embodiments, the process further comprises the presence of a base. In some embodiments, the base comprises an amine. In some embodiments, the base comprises a tertiary amine. In some embodiments, the amine is N-methylmorpholine or N-methylimidazole.

EXAMPLES

[0437] The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

[0438] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0439] Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art.

Synthetic Examples

[0440] As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein.

Schemes

##STR00163##

[0441] Compounds of formula S1-3 can be prepared according to general Scheme 1. Reaction of carboxylic acid S1-1 with amine S1-2 using a coupling reagent such as propanephosphonic acid anhydride (T3P) and a tertiary amine base such as N-methylmorpholine in an aprotic solvent such as DMF provides compounds of formula S1-3.

##STR00164##

[0442] Compounds of formula S2-3 can be prepared according to the alternative reaction conditions shown in general Scheme 2. Reaction of carboxylic acid S2-1 with amine S2-2 using a coupling reagent such as N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (TFCH) and a tertiary amine base such as N-methylimidazole in an aprotic solvent such as acetonitrile provides compounds of formula S2-3.

[0443] Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed. The following examples are intended to be illustrative only and not limiting in any way.

TABLE-US-00002 C. degrees Celsius K.sub.2CO.sub.3 potassium carbonate L microliter LDA lithium diisopropylamide [M + XX].sup.+ observed mass LiHMDS lithium AC.sub.50 half-maximal activity bis(trimethylsilyl)amide concentration MeOH Methanol ACN acetonitrile MeCN acetonitrile app apparent (NMR) m multiplet (NMR) BH.sub.3THF borane-tetrahydrofuran mg milligrams complex min minutes BBr.sub.3 boron tribromide mL milliliter Calc'd calculated mmol millimole Cbz-Cl benzyl chloroformate mM millimolar CO.sub.2 carbon dioxide M molarity or molar Cs.sub.2CO.sub.3 cesium carbonate MS mass spectrometry d deuterated (NMR MsCl methanesulfonyl chloride solvents) MTBE methyl tert-butyl ether d doublet (NMR) n/a not applicable dd doublet of doublets NBS N-bromosuccinimide (NMR) NH.sub.4 ammonium DCM dichloromethane NH.sub.4OH ammonium hydroxide DIAD diisopropyl NH.sub.4HCO.sub.3 ammonium bicarbonate azodicarboxylate Na.sub.2SO.sub.4 sodium sulfate DMF N,N-dimethylformamide NaBH.sub.3CN sodium EC.sub.50 half-maximal effective cyanoborohydride concentration NMI N-methylimidazole EDCI 1-Ethyl-3-(3- NMM N-methylmorpholine dimethylaminopropyl)carbodiimide NMR nuclear magnetic resonance ESI electrospray ionization NaOH sodium hydroxide EtOAc ethyl acetate PCy.sub.3 Tricyclohexylphosphine EtOH ethanol PdCl.sub.2(dppf) [1,1- eq equivalents Bis(diphenylphosphino)fer- g grams rocene]dichloropalladium(II) h hours H hydrogen pH potential of hydrogen HCl hydrochloric acid PPh.sub.3 triphenyl phosphine HPLC high-performance liquid s singlet (NMR) chromatography SFC super fluid IC.sub.50 half-maximal inhibitory chromatography concentration t triplet (NMR) In vacuo in a vacuum T3P Propanephosphonic acid IUPAC International Union of anhydride Pure and Applied TBAB tetrabutylammonium Chemistry bromide MHz megahertz TEA triethylamine J J-coupling value (NMR) TFA trifluoroacetic acid TFCH N,N,N,N- THF tetrahydrofuran tetramethylchloroformamidinium TMSCl trimethylsilyl chloride hexafluorophosphate wt. % weight percent

Example S-1

TABLE-US-00003 TABLE 2 Exact Observed Cmpd Mass Mass No. Cmpd Name (g/mol) (M + H) 1 (R)-N-((2-acetamidophenyl)(4- 350.2 351.2 isopropylphenyl)methyl)cyclopropanecarboxamide 2 (1R,2S)-N-((S)-(5-cyclopropyl-6-fluoropyridin-2- 328.1 329.2 yl)(phenyl)methyl)-2-fluorocyclopropane-1-carboxamide 3 (1R,2S)-2-fluoro-N-((S)-(6-fluoro-5-isopropylpyridin-2- 370.2 371.1 yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide 4 (1R,2S)-N-((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5- 396.2 397.1 isopropylpyridin-2-yl)methyl)-2-fluorocyclopropane-1- carboxamide 5 (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(2-oxo- 385.2 386.0 2,3-dihydro-1H-benzo[d]imidazol-4- yl)methyl)cyclopropane-1-carboxamide 6 (R)-N-((3-acetamidophenyl)(4- 350.2 351.2 isopropylphenyl)methyl)cyclopropanecarboxamide 7 (1R,2S)-2-cyano-N-((R)-(4-isopropylphenyl)(o- 360.2 361.3 tolyl)methyl)cyclopentane-1-carboxamide 8 N-((1R)-(4-isopropylphenyl)(2-((1-methyl-2,5- 420.2 419.1 (M H) dioxoimidazolidin-4- yl)amino)phenyl)methyl)cyclopropanecarboxamide 9 N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4- 519.3 520.3 isopropylphenyl)methyl)phenyl)-1-(2,2,2- trifluoroethyl)piperidine-4-carboxamide 10 (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(2- 387.2 388.1 ureidophenyl)methyl)cyclopropane-1-carboxamide 11 (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(1H- 319.1 320.1 pyrazol-5-yl)methyl)cyclopropane-1-carboxamide 12 N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4- 451.3 452.2 isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4- carboxamide 13 N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4- 495.3 496.3 isopropylphenyl)methyl)phenyl)-1-(2- methoxyethyl)piperidine-4-carboxamide 14 1-(cyclopropylmethyl)-N-(2-((R)-((1R,2S)-2- 491.3 492.3 fluorocyclopropane-1-carboxamido)(4- isopropylphenyl)methyl)phenyl)piperidine-4-carboxamide 15 (R)-N-((4-isopropylphenyl)(2-oxo-2,3- 350.2 351.1 dihydrobenzo[d]oxazol-7- yl)methyl)cyclopropanecarboxamide 16 (1R,2S)-N.sup.1-((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N.sup.2- 392.2 393.2 methylcyclopentane-1,2-dicarboxamide 17 (R)-N-((4-cyclopropylphenyl)(2- 349.2 350.2 ureidophenyl)methyl)cyclopropanecarboxamide 18 (R)-N-((4-cyclobutylphenyl)(2- 363.2 364.1 ureidophenyl)methyl)cyclopropanecarboxamide 19 (R,E)-N-((2-(2-cyanoguanidino)phenyl)(4- 375.2 376.2 isopropylphenyl)methyl)cyclopropanecarboxamide 20 methyl 3-((1S,2R)-2-(((R)-(4-isopropylphenyl)(o- 464.3 465.2 tolyl)methyl)carbamoyl)cyclopentane-1- carboxamido)propanoate 21 (1R,2S)-2-(2-acetamidoacetamido)-N-((S)-(4- 435.3 436.3 isopropylphenyl)(phenyl)methyl)cyclopentane-1- carboxamide 22 (1S,2R)-N.sup.1-cyano-N.sup.2-((R)-(4-isopropylphenyl)(o- 403.2 404.3 tolyl)methyl)cyclopentane-1,2-dicarboxamide 23 (R)-N-(2-(cyclopropanecarboxamido(4- 473.2 474.1 isopropylphenyl)methyl)phenyl)-1-(2,2,2- trifluoroethyl)azetidine-3-carboxamide 24 (R)-N-(2-(cyclopropanecarboxamido(4- 449.3 450.1 isopropylphenyl)methyl)phenyl)-1-(2- methoxyethyl)azetidine-3-carboxamide 25 (R)-N-(2-(cyclopropanecarboxamido(4- 445.3 446.3 isopropylphenyl)methyl)phenyl)-1- (cyclopropylmethyl)azetidine-3-carboxamide 26 (R)-N-(2-(cyclopropanecarboxamido(4- 405.2 406.1 isopropylphenyl)methyl)phenyl)-1-methylazetidine-3- carboxamide 27 (1S,2R)-2-fluoro-N-((S)-(4- 311.2 312.1 isopropylphenyl)(phenyl)methyl)cyclopropane-1- carboxamide 28 (S)-2-acetamido-N.sup.1-((1S,2R)-2-(((S)-(4- 492.3 493.2 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)succinamide 29 (R)-N-((4-isopropylphenyl)(2-oxo-2,3-dihydro-1H- 349.2 350.1 benzo[d]imidazol-4-yl)methyl)cyclopropanecarboxamide 30 (1R,2S)-N.sup.1-((R)-(4-isopropylphenyl)(o- 378.2 379.2 tolyl)methyl)cyclopentane-1,2-dicarboxamide 31 (R)-N-((4-isopropylphenyl)(2-(oxazol-2- 375.2 376.2 ylamino)phenyl)methyl)cyclopropanecarboxamide 32 (R)-N-((4-isopropylphenyl)(2-oxoindolin-7- 348.2 349.2 yl)methyl)cyclopropanecarboxamide 33 (S)-N-((5-isopropylpyridin-2-yl)(2- 324.2 325.2 methoxyphenyl)methyl)cyclopropanecarboxamide 34 (1S)-3-fluoro-N-((S)-(4- 339.2 340.1 isopropylphenyl)(phenyl)methyl)cyclopentane-1- carboxamide 35 (1S)-3-hydroxy-N-((S)-(4- 337.2 338.1 isopropylphenyl)(phenyl)methyl)cyclopentane-1- carboxamide 36 (1R,2S)-2-fluoro-N-((S)-(4- 311.2 312.1 isopropylphenyl)(phenyl)methyl)cyclopropane-1- carboxamide 37 (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4- 433.2 434.2 isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide 38 (1R,2S)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)-2- 379.2 380.3 ureidocyclopentane-1-carboxamide 39 (R)-N-((4-isopropylphenyl)(2- 322.2 323.2 (methylamino)phenyl)methyl)cyclopropanecarboxamide 40 (S)-N-((4- 305.2 306.1 cyclobutylphenyl)(phenyl)methyl)cyclopropanecarboxamide 41 (S)-N-((4- 291.2 292.1 cyclopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide 42 (S)-1-acetyl-N-(2-((R)-cyclopropanecarboxamido(4- 433.2 434.3 isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide 43 (R)-N-((4-isopropylphenyl)(3-methyl-1H-pyrazol-4- 297.2 298.2 yl)methyl)cyclopropanecarboxamide 44 (R)-N-((2-acetamido-5-fluorophenyl)(4- 368.2 369.1 isopropylphenyl)methyl)cyclopropanecarboxamide 45 (S)-N-((5-isopropylpyridin-2- 294.2 294.9 yl)(phenyl)methyl)cyclopropanecarboxamide 46 (S)-N-((2-acetamidophenyl)(5-isopropylpyridin-2- 351.2 352.1 yl)methyl)cyclopropanecarboxamide 47 (S)-N-((5-isopropylpyridin-2-yl)(o- 308.2 309.2 tolyl)methyl)cyclopropanecarboxamide 48 (R)-N-(2-(cyclopropanecarboxamido(4- 391.2 392.4 isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide 49 (S)-N-(2-((R)-cyclopropanecarboxamido(4- 391.2 392.4 isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide 50 (R)-N-(2-((R)-cyclopropanecarboxamido(4- 391.2 392.4 isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide 51 (R)-N-((2-aminopyridin-3-yl)(4- 309.2 310.2 isopropylphenyl)methyl)cyclopropanecarboxamide 52 (S)-N-((3-fluoro-4- 311.2 312.2 isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide 53 (R)-N-((4-isopropylphenyl)(2-(3- 365.2 366.2 methylureido)phenyl)methyl)cyclopropanecarboxamide 54 (R)-N-((4-isopropylphenyl)(2- 351.2 352.2 ureidophenyl)methyl)cyclopropanecarboxamide 55 (1R,2S)-2-acetamido-N-((S)-(4- 378.2 379.2 isopropylphenyl)(phenyl)methyl)cyclopentane-1- carboxamide 56 (R)-N-((4-isopropylphenyl)(1H-pyrazol-5- 283.2 284.2 yl)methyl)cyclopropanecarboxamide 57 (R)-N-((4-isopropylphenyl)(2- 386.2 387.2 (methylsulfonamido)phenyl)methyl)cyclopropanecarboxamide 58 (R)-N-((2-chlorophenyl)(4- 327.1 328.1 isopropylphenyl)methyl)cyclopropanecarboxamide 59 (R)-N-((4-isopropylphenyl)(2- 364.2 365.4 propionamidophenyl)methyl)cyclopropanecarboxamide 60 (R)-N-(2-(cyclopropanecarboxamido(4- 392.2 393.3 isopropylphenyl)methyl)phenyl)oxetane-3-carboxamide 61 (R)-N-(2-(cyclopropanecarboxamido(4- 376.2 377.2 isopropylphenyl)methyl)phenyl)cyclopropanecarboxamide 62 (R)-N-((3-hydroxyphenyl)(4- 309.2 310.1 isopropylphenyl)methyl)cyclopropanecarboxamide 63 (R)-N-((4-isopropylphenyl)(3-methoxy-2- 337.2 338.2 methylphenyl)methyl)cyclopropanecarboxamide 64 (R)-N-((2-aminophenyl)(4- 308.2 309.3 isopropylphenyl)methyl)cyclopropanecarboxamide 65 (R)-N-((4-isopropylphenyl)(o- 307.2 308.3 tolyl)methyl)cyclopropanecarboxamide 66 (R)-N-((4-isopropylphenyl)(m- 307.2 308.2 tolyl)methyl)cyclopropanecarboxamide 67 (R)-N-((2-hydroxyphenyl)(4- 309.2 310.1 isopropylphenyl)methyl)cyclopropanecarboxamide 68 (R)-N-((4-hydroxyphenyl)(4- 309.2 310.1 isopropylphenyl)methyl)cyclopropanecarboxamide 69 (R)-N-((4-isopropylphenyl)(1-methyl-1H-pyrazol-5- 297.2 298.2 yl)methyl)cyclopropanecarboxamide 70 (R)-N-((4-isopropylphenyl)(3- 323.2 324.1 methoxyphenyl)methyl)cyclopropanecarboxamide 71 (R)-N-((4-isopropylphenyl)(2- 323.2 324.2 methoxyphenyl)methyl)cyclopropanecarboxamide 72 (R)-N-((4-isopropylphenyl)(4- 323.2 324.2 methoxyphenyl)methyl)cyclopropanecarboxamide 73 (S)-N-((4- 293.2 294.1 isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide

Intermediate A-1: Synthesis of (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride

##STR00165##

[0444] Step a: To a solution of 6-bromo-1H-indazole (8 g, 40.6 mmol, 1 eq) in DMF (50 mL) was added trityl chloride (TrtCl, 12.4 g, 44.6 mmol, 1.1 eq) and TEA (7.06 mL, 50.7 mmol, 1.25 eq). The resulting mixture was stirred at 25 C. for 16 h. The reaction mixture was then diluted with water, and the resulting biphasic mixture was extracted with ethyl acetate (350 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (30 mL) and filtered to give 6-bromo-1-trityl-1H-indazole, which was carried forward to the next step without further purification or characterization.

[0445] Step b: To a mixture of 6-bromo-1-trityl-1H-indazole (16.7 g, 38.0 mmol, 1 eq), potassium vinyltrifluoroborate (10.1 g, 76.0 mmol, 2 eq) and TEA (15.8 mL, 14.0 mmol, 3 eq) in i-PrOH (160 mL), was added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (1.55 g, 1.90 mmol, 0.05 eq) under N2. The resulting mixture was then degassed and placed under an N2 atmosphere. The reaction mixture was then warmed to 100 C. and stirred for 2 h under N2. After cooling, the mixture was filtered, and the filter cake was washed with ethyl acetate (3100 mL). The combined filtrates were concentrated, and the crude residue obtained was purified by column chromatography to give 1-trityl-6-vinyl-1H-indazole. LC-MS (ESI): m/z: [2M+Na].sup.+ calculated for C.sub.28H.sub.22N.sub.2: 795.4; found 795.3.

[0446] Step c: To a solution of 1-trityl-6-vinyl-1H-indazole (14.2 g, 36.7 mmol, 1 eq) in THF:H.sub.2O (5:1) (300 mL) at 0 C. was added NaIO.sub.4 (31.4 g, 146 mmol, 4 eq) and K.sub.2OsO.sub.4.Math.2H.sub.2O (676 mg, 1.84 mmol, 0.05 eq). The resulting mixture was warmed to 50 C. and stirred for 1 h. The reaction mixture was then cooled to 25 C. and quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 (100 mL). The resulting mixture was extracted with ethyl acetate (3100 mL), and the combined extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1-trityl-1H-indazole-6-carbaldehyde.

[0447] Step d: To a solution 1-trityl-1H-indazole-6-carbaldehyde (7.3 g, 18.8 mmol, 1 eq) in DCM (75 mL) was added Cs.sub.2CO.sub.3 (6.74 g, 20.7 mmol, 1.1 eq) and 2-methylpropane-2-sulfinamide (2.51 g, 20.6 mmol, 1.1 eq). The mixture was then warmed to 40 C. and stirred for 16 h. The reaction mixture was then filtered, and the filter cake was washed with ethyl acetate (3100 mL). The filtrate was then filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (E)-2-methyl-N-((1-trityl-1H-indazol-6-yl)methylene)propane-2-sulfinamide.

[0448] Step e: To a solution of 6-bromo-2-fluoro-3-isopropylpyridine (665 mg, 3.05 mmol, 1.5 eq) in THE (5 mL) at 78 C. under N2 was added n-BuLi (1.22 mL, 2.5 M, 1.5 eq). The resulting mixture was stirred at 78 C. for 0.5 h. After this time, (E)-2-methyl-N-((1-trityl-1H-indazol-6-yl)methylene)propane-2-sulfinamide (1 g, 2.03 mmol, 1 eq) in THE (5 mL) cooled to 78 C. under N2 was added, and the resulting mixture was stirred at 78 C. for 4 h. The reaction was then quenched with saturated aqueous NH.sub.4Cl (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (320 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-((6-fluoro-5-isopropylpyridin-2-yl)(1-trityl-1H-indazol-6-yl)methyl)-2-methylpropane-2-sulfinamide.

[0449] Step f: To a solution of N-((6-fluoro-5-isopropylpyridin-2-yl)(1-trityl-1H-indazol-6-yl)methyl)-2-methylpropane-2-sulfinamide (600 mg, 951 mol, 1 eq) in EtOAc (3 mL) at 0 C. was added HCl/EtOAc (4 M, 3 mL, 12.6 eq). The resulting mixture was then warmed to 40 C. and stirred for 16 h. The reaction mixture was then filtered and concentrated to give (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride. LC-MS (ESI): m/z: [M-NH.sub.3].sup.+ calculated for C.sub.16H.sub.17FN.sub.4: 268.1; found 268.2.

Intermediate A-2: Synthesis of (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride

##STR00166##

[0450] Step a: To a solution of 5-(3-bromophenyl)-1H-pyrazole (408 mg, 1.83 mmol, 1.5 eq) in THF (3 mL) at 60 C. under N2 was added n-BuLi (2.5 M, 1.22 mL, 2.5 eq) in a dropwise manner. Once this addition was complete, (E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (330 mg, 1.22 mmol, 1 eq) in THF (2 mL) was added in a dropwise manner. The resulting mixture was stirred at 60 C. for 2 h. The reaction mixture was then poured into ice-water (30 mL) and stirred for 2 min. The resulting biphasic mixture was then extracted with ethyl acetate (320 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-((3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.22H.sub.26FN.sub.4OS: 415.2; found 415.2.

[0451] Step b: To a solution of N-((3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (410 mg, 989 umol, 1 eq) in dioxane (2 mL) at 15 C. was added HCl/dioxane (4 mL) in a dropwise manner. The resulting mixture was stirred at 15 C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.18H.sub.19FN.sub.4: 311.2; found 311.2.

Intermediate A-3: Synthesis of tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate

##STR00167##

[0452] Step a: To a mixture of 4-isopropylbenzaldehyde (10.0 g, 67.4 mmol, 10.2 mL, 1 eq) and 2-methylpropane-2-sulfinamide (9.00 g, 74.2 mmol, 1.1 eq) in dry THF (75 mL) at 0 C. under N2 was added Ti(OEt).sub.4 (30.7 g, 134 mmol, 2 eq) in one portion. The reaction mixture was then degassed and charged with N.sub.2 three times. The reaction mixture was then warmed to 25 C. and stirred for 4 h under N.sub.2. The reaction was then cooled to 0 C. and quenched by adding H.sub.2O (150 mL) and stirring for 20 min. The reaction mixture was then filtered, and the filter cake was washed with ethyl acetate (2100 mL). The filtrate was then extracted with ethyl acetate (2100 mL). The combined organic extracts were then washed with saturated aqueous NH.sub.4Cl (100 mL), brine (70 mL), dried over anhydrous Na.sub.2SO.sub.4, and filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.21NOS: 252.1; found 252.1.

[0453] Step b: To a solution of tert-butyl (2-iodophenyl)carbamate (25.4 g, 79.6 mmol, 2 eq) in THF (200 mL) at 0 C. was added i-PrMgCl.Math.LiCl (107 mL, 1.3 M, 3.5 eq) in a dropwise manner over 30 min. After the addition was complete, the resulting mixture was stirred at 0 C. for 2 h. The reaction mixture was then cooled to 20 C. before (E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (10 g, 39.8 mmol, 1 eq) in THF (200 mL) was added in a dropwise manner. The resulting mixture was then stirred at 20 C. for 3 h. The reaction mixture was then warmed to 0 C. and quenched by addition water (100 mL). The resulting biphasic mixture was extracted with ethyl acetate (2250 mL). The combined organic extracts were washed with brine (225 mL), dried over anhydrous Na.sub.2SO.sub.4, and filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2-(((tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.36N.sub.2O.sub.3S: 445.2; found 445.4.

[0454] Step c: A mixture of tert-butyl (2-(((tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)carbamate (15 g, 33.7 mmol, 1 eq) and 12 (6.85 g, 26.9 mmol, 0.8 eq) in THE (150 mL) and H.sub.2O (30 mL) was degassed and purged with N.sub.2, and then the mixture was warmed to 50 C. and stirred for 2 h under N.sub.2 atmosphere. The reaction mixture was then cooled to 0 C. and quenched by addition of water (100 mL). The resulting biphasic mixture was extracted with ethyl acetate (2250 mL). The combined organic extracts were washed with brine (225 mL), dried over anhydrous Na.sub.2SO.sub.4, and filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.28N.sub.2O.sub.2: 341.2; found 341.4.

Intermediate A-4: Synthesis of(S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride

##STR00168##

[0455] Step a: To a mixture of 4-bromo-3-fluoro-benzaldehyde (200 g, 985 mmol, 1.00 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (215 g, 1.28 mol, 1.30 eq) in toluene (3.70 L) and H.sub.2O (410 mL) at 25 C. under N.sub.2 was added Pd(dppf)Cl.sub.2 (36.0 g, 49.3 mmol, 0.05 eq) and K.sub.3PO.sub.4 (418 g, 1.97 mol, 2.00 eq). The mixture was warmed to 90 C. and stirred for 12 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 3-fluoro-4-isopropenyl-benzaldehyde. The compound was carried forward to the next step without further characterization.

[0456] Step b: To a solution of 3-fluoro-4-isopropenyl-benzaldehyde (124 g, 755 mmol, 1.00 eq) in EtOAc (1.20 L) under N.sub.2 was added Pd/C (85.0 g, 10 wt. %). The suspension was degassed and purged with H.sub.2 several times. The mixture was stirred at 25 C. under H.sub.2 (15 psi) for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 3-fluoro-4-isopropyl-benzaldehyde. The compound was carried forward to the next step without further characterization.

[0457] Step c: To a mixture of 3-fluoro-4-isopropyl-benzaldehyde (80.0 g, 481 mmol, 1.00 eq) and (R)-2-methylpropane-2-sulfinamide (64.2 g, 523 mmol, 1.10 eq) in DCM (450 mL) at 25 C. was added Cs.sub.2CO.sub.3 (173 g, 530 mmol, 1.10 eq). The mixture was warmed to 40 C. and stirred for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.

[0458] The residue was purified by column chromatography to obtain (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.20FNOS: 270.1; found 270.0.

[0459] Step d: To a solution of (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (30.0 g, 111 mmol, 1.00 eq) in THE (400 mL) 65 C. under N.sub.2 was added, dropwise, a solution of phenylmagnesium bromide (3 M in Et.sub.2O, 55.7 mL, 1.50 eq) over a period of 30 min. The reaction mixture was stirred at 65 C. for 6 h, then warmed to 25 C. and stirred for an additional 6 h. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (330 mL). The combined organic extracts were washed with water (330 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to obtain (R)N((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. The compound was carried forward to the next step without further characterization.

[0460] Step e: To a mixture of (R)N((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (35.0 g, 101 mmol, 1.00 eq) in EtOAc (300 mL) at 25 C. was added HCl/EtOAc (4 M, 50.4 mL, 2.00 eq), and the mixture was stirred for 2 h. The reaction mixture was filtered and the solid so obtained was set aside. The filtrate was concentrated under reduced pressure and the resulting residue was combined with the previously obtained solid. The mixture was dissolved in MTBE (200 mL) and filtered, and the filtrate was concentrated under reduced pressure to give (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride.

Intermediate A-5: Synthesis of (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride

##STR00169##

[0461] Step a: In four parallel reactions, 6-fluoropyridin-2-amine (125 g, 1.11 mol, 1 eq) in MeCN (1.2 L) at 0 C. under N.sub.2 was treated with NBS (209 g, 1.17 mmol, 1.05 eq) in MeCN (1.2 L). The reaction mixtures were stirred at 20 C. for 2 h. The four parallel reactions were combined, and the resulting mixture was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 5-bromo-6-fluoropyridin-2-amine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.4BrFN.sub.2: 190.9; found 191.0.

[0462] Step b: To a mixture of 5-bromo-6-fluoropyridin-2-amine (200 g, 1.04 mol, 1 eq) and cyclopropylboronic acid (226 g, 2.63 mol, 2.5 eq) in 1,4-dioxane (2 L) and H.sub.2O (200 mL) under N.sub.2 were added K.sub.3PO.sub.4 (666 g, 3.14 mol, 3 eq), PCy.sub.3 (58.6 g, 209 mmol, 0.2 eq), and Pd(OAc)2 (11.7 g, 52.3 mmol, 0.05 eq). The system was then degassed and charged with nitrogen three times. The reaction mixture was warmed to 100 C. and stirred for 12 h. The reaction mixture was then cooled to room temperature and filtered through Celite. The resulting filtrate was diluted with H.sub.2O (2 L) and then extracted with EtOAc (3500 mL). The combined organic extracts were washed with brine (2300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-cyclopropyl-6-fluoropyridin-2-amine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9FN.sub.2: 153.1; found 153.0.

[0463] Step c: To a mixture of 5-cyclopropyl-6-fluoropyridin-2-amine (120 g, 788 mmol, 1 eq) in dibromomethane (564 mL) under N.sub.2 was added isopentyl nitrite (110 g, 946 mmol, 127 mL, 1.2 eq). To the resulting mixture was added CuBr.sub.2 (211 g, 946 mmol, 44.3 mL, 1.2 eq) over 0.5 h. The final mixture was then degassed and charged with nitrogen three times before stirring at 20 C. for 16 h. The reaction mixture was then filtered, and the filtrate was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-bromo-3-cyclopropyl-2-fluoropyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.7BrFN: 216.0; found 216.1.

[0464] Step d: To a mixture of 6-bromo-3-cyclopropyl-2-fluoropyridine (90 g, 416 mmol, 1 eq) and trifluoro(vinyl)-4-borane, potassium salt (83.7 g, 624 mmol, 1.5 eq) in i-PrOH (900 mL) at 20 C. under N.sub.2 was added TEA (126 g, 1.25 mol, 3 eq) and Pd(dppf)Cl.sub.2.Math.DCM (17 g, 20.8 mmol, 0.05 eq). The resulting mixture was degassed and charged with nitrogen three times. The reaction mixture was then warmed to 100 C. and stirred for 2 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography to give 3-cyclopropyl-2-fluoro-6-vinylpyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.10FN: 164.1; found 164.1.

[0465] Step e: To a mixture of 3-cyclopropyl-2-fluoro-6-vinylpyridine (47 g, 288 mmol, 1 eq) in THE (800 mL) and H.sub.2O (160 mL) at 20 C. under N.sub.2 was added NaIO.sub.4 (246 g, 1.15 mol, 4 eq) and K.sub.2OsO.sub.4.Math.2H.sub.2O (2.12 g, 5.76 mmol, 0.02 eq). The resulting mixture was degassed and charged with nitrogen three times before stirring for 2 h. The reaction mixture was then filtered, and the filtrate was diluted with H.sub.2O (500 mL), and extracted with EtOAc (3300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 5-cyclopropyl-6-fluoropicolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.8FNO: 166.1; found 166.2.

[0466] Step f: To a mixture of 5-cyclopropyl-6-fluoropicolinaldehyde (38 g, 230 mmol, 1 eq) and (S)-2-methylpropane-2-sulfinamide (30.6 g, 253 mmol, 1.1 eq) in DCM (200 mL) at 20 C. under N.sub.2 was added Cs.sub.2CO.sub.3 (82.4 g, 253 mmol, 1.1 eq). The system was then degassed and charged with nitrogen three times. The resulting mixture was then warmed to 40 C. and stirred for 12 h. The reaction solution was then diluted with H.sub.2O (300 mL) and extracted with DCM (3200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was then purified by column chromatography to give (S,E)-N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.17FN.sub.2OS: 269.1; found 269.2.

[0467] Step g: To a solution of (S,E)-N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (58 g, 216 mmol, 1 eq) in dry DCM (600 mL) at 70 C. under nitrogen was added PhMgBr (3 M in Et.sub.2O, 93.6 mL, 281 mmol, 1.3 eq) in a dropwise manner. The resulting reaction mixture was stirred at 70 C. for 1 h. The reaction mixture was then quenched with saturated aqueous NH.sub.4Cl solution (500 mL), warmed to room temperature, and extracted with EtOAc (3200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (S)N((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.23FN.sub.2OS: 347.2; found 347.3.

[0468] Step h: To a solution of (S)N((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (74 g, 213 mmol, 1 eq) in EtOAc (100 mL) at 0 C. under N.sub.2 was added HCl/EtOAc (4 M, 740 mL, 2940 mmol, 13.8 eq). The resulting mixture was then warmed 20 C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was triturated with MTBE (500 mL). The resulting solid was collected by filtration and dried under reduced pressure to give (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.15FN.sub.2: 243.1; found 243.2.

Intermediate A-6: Synthesis of (R)-(4-isopropylphenyl)(2-(1-methylpiperidine-4-carboxamido)phenyl)methanaminium chloride

##STR00170##

[0469] Step a: To a solution of tert-butyl (2-iodophenyl)carbamate (15 g, 47.0 mmol, 1 eq) and (4-isopropylphenyl)boronic acid (9.25 g, 56.4 mmol, 1.2 eq) in toluene (100 mL) was added K.sub.2CO.sub.3 (19.5 g, 141 mmol, 3 eq) and Pd(PPh.sub.3).sub.2Cl.sub.2 (1.65 g, 2.35 mmol, 0.05 eq) under N.sub.2. The resulting mixture was then degassed and purged with CO. The resulting mixture was warmed to 120 C. and stirred for 10 h under CO (15 psi). The reaction mixture was then cooled to room temperature and poured into ice water (100 mL). The resulting biphasic mixture was extracted with EtOAc (3100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2-(4-isopropylbenzoyl)phenyl)carbamate.

[0470] Step b: To a solution of tert-butyl (2-(4-isopropylbenzoyl)phenyl)carbamate (10 g, 29.4 mmol, 1 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 100 mL), and the resulting mixture was stirred at 20 C. for 16 h. The reaction mixture was then diluted with water (50 mL), and the pH was adjusted to 8 with saturated aq. NaHCO.sub.3. The resulting biphasic mixture was extracted with ethyl acetate (350 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (2-aminophenyl)(4-isopropylphenyl)methanone. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.17N.sub.2O: 240.1; found 240.1.

[0471] Step c: To a solution of (2-aminophenyl)-(4-isopropylphenyl)methanone (7.3 g, 30.5 mmol, 1 eq) in THE (120 mL) was added (R)-2-methylpropane-2-sulfinamide (4.07 g, 33.5 mmol, 1.1 eq) and Ti(OEt)4 (13.9 g, 61.0 mmol, 2 eq), sequentially. The reaction was warmed to 80 C. and stirred for 16 h. The reaction mixture was then cooled to room temperature and quenched with water (50 mL). The resulting biphasic mixture was exacted with ethyl acetate (250 mL), and the combined organic extracts were washed with brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain (R,E)-N-((2-aminophenyl)(4-isopropylphenyl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.26N.sub.2OS: 343.2; found 343.1.

[0472] Step d: To a solution of (R,E)-N-((2-aminophenyl)(4-isopropylphenyl)methylene)-2-methylpropane-2-sulfinamide (2.5 g, 7.30 mmol, 1 eq) in THE (25 mL) at 78 C. was added DIBAL-H (20.4 mL, 1 M, 2.8 eq). The resulting mixture was stirred at 78 C. for 2 h. The reaction mixture was then diluted with brine (50 mL), and the resulting biphasic mixture was extracted with EtOAC (340 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R)N((R)-(2-aminophenyl)(4-isopropylphenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+Na].sup.+ calculated for C.sub.20H.sub.28N.sub.2OS: 367.2; found 367.1.

[0473] Step e: To a solution of (R)N((R)-(2-aminophenyl)(4-isopropylphenyl)methyl)-2-methylpropane-2-sulfinamide (250 mg, 725 mol, 1 eq) in CH.sub.3CN (2 mL) at 20 C. was added N-methylimidazole (148 mg, 1.81 mmol, 2.5 eq), 1-methylpiperidine-4-carboxylic acid (114 mg, 798 mol, 1.1 eq), and chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (244 mg, 870 mol, 1.2 eq). The resulting mixture was warmed to 0 C. and stirred for 3 h. The reaction mixture was then diluted with water, extracted with EtOAc 30 mL (310 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-(2-((R)-(((R)-tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.39N.sub.3O.sub.2S: 470.3; found 470.3.

[0474] Step f: To a solution of N-(2-((R)-(((R)-tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide in EtOAc (2 mL) at 0 C. was added HCl/EtOAc (2 mL). The mixture was then warmed to 15 C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was triturated with MTBE at 15 C. for 30 min to obtain (R)-(4-isopropylphenyl)(2-(1-methylpiperidine-4-carboxamido)phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.23H.sub.31N.sub.3: 366.3; found 366.3.

[0475] The following compounds in Table B-1 were synthesized using procedures similar to Intermediates A-1 through A-6 using the appropriate starting materials and reagents.

TABLE-US-00004 TABLE B-1 Inter- Exact LCMS, mediate mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ B-1-1 [00171] (3-fluoro-4- isopropylphenyl)(2- oxo-2,3-dihydro-1H- benzo[d]imidazol-4- yl)methanaminium chloride 299.1 282.9 [M NH.sub.3].sup.+ B-1-2 [00172] (4-isopropylphenyl)(2- oxo-1,2,3,4- tetrahydroquinolin-8- yl)methanaminium chloride 294.2 278.3 [M NH.sub.3].sup.+ B-1-3 [00173] (3-fluoro-4- isopropylphenyl)(2- ureidophenyl) methanaminium chloride 301.2 B-1-4 [00174] (4-isopropylphenyl)(2- oxo-2,3- dihydrobenzo[d]oxazol- 7-yl)methanaminium chloride 282.1 266.2 [M NH.sub.3].sup.+ B-1-5 [00175] (4-isopropylphenyl)(2- oxo-2,3- dihydrobenzo[d]oxazol- 4-yl)methanaminium chloride 282.1 266.1 [M NH.sub.3].sup.+ B-1-6 [00176] (4-isopropylphenyl)(2- oxo-2,3-dihydro-1H- benzo[d]imidazol-4- yl)methanaminium chloride 281.1 265.1 [M NH.sub.3].sup.+ B-1-7 [00177] (4-isopropylphenyl)(2- oxoindolin-7- yl)methanaminium chloride 280.2 264.3 [M NH.sub.3].sup.+ B-1-8 [00178] (2-acetamido-5- fluorophenyl)(4- isopropylphenyl) methanaminium chloride 300.2 301.2 B-1-9 [00179] (4-isopropylphenyl)(3- methyl-1H-pyrazol-4- yl)methanaminium chloride 229.2 213.1 [M NH.sub.3].sup.+ B-1-10 [00180] tert-butyl (3-(amino(4- isopropylphenyl) methyl)pyridin-2- yl)carbamate 341.2 342.2 B-1-11 [00181] (R)-(2- chlorophenyl)(4- isopropylphenyl) methanaminium chloride 259.1 243.2 [M NH.sub.3].sup.+ B-1-12 [00182] (R)-(4- isopropylphenyl)(3- methoxyphenyl) methanaminium chloride 255.2 239.1 [M NH.sub.3].sup.+ B-1-13 [00183] (R)-(4- isopropylphenyl)(3- methoxy-2- methylphenyl) methanaminium chloride 269.2 253.3 [M NH.sub.3].sup.+ B-1-14 [00184] (R)-(4- isopropylphenyl)(o- tolyl)methanaminium chloride 239.2 223.2 [M NH.sub.3].sup.+ B-1-15 [00185] (R)-(4- isopropylphenyl)(m- tolyl)methanaminium chloride 239.2 223.2 [M NH.sub.3].sup.+ B-1-16 [00186] (4- isopropylphenyl)(1H- pyrazol-5- yl)methanaminium chloride 215.1 199.1 [M NH.sub.3].sup.+ B-1-17 [00187] (R)-(4- isopropylphenyl)(1- methyl-1H-pyrazol-5- yl)methanaminium chloride 229.1 230.1 B-1-18 [00188] (R)-(4- isopropylphenyl)(2- methoxyphenyl) methanaminium chloride 255.2 239.1 [M NH.sub.3].sup.+ B-1-19 [00189] (S)-(4- isopropylphenyl) (phenyl) methanaminium chloride 225.1 209.1 [M NH.sub.3].sup.+ B-1-20 [00190] (3- acetamidophenyl)(4- isopropylphenyl) methanaminium chloride 282.2 266.1 [M NH.sub.3].sup.+ B-1-21 [00191] (2- acetamidophenyl)(4- isopropylphenyl) methanaminium chloride 282.2 266.2 [M NH.sub.3].sup.+ B-1-22 [00192] (R)-(4- isopropylphenyl)(4- methoxyphenyl) methanaminium chloride 255.2 239.1 [M NH.sub.3].sup.+ B-1-23 [00193] (2-fluorophenyl)(4- isopropylphenyl) methanaminium chloride 243.1 227.1 [M NH.sub.3].sup.+ B-1-24 [00194] (3-fluoro-4- isopropylphenyl)(1H- pyrazol-5- yl)methanaminium chloride 233.1 217.1 [M NH.sub.3].sup.+ B-1-25 [00195] (4- cyclopropylphenyl)(2- ureidophenyl) methanaminium chloride 281.1 282.1 B-1-26 [00196] (4- cyclobutylphenyl)(2- ureidophenyl) methanaminium chloride 295.2 296.2 B-1-27 [00197] (5-isopropylpyridin-2- yl)(2- methoxyphenyl) methanaminium chloride 256.1 257.1 B-1-28 [00198] (5-isopropylpyridin-2- yl)(o- tolyl)methanaminium chloride 240.2 241.1 B-1-29 [00199] (R)-(4- isopropylphenyl)(2-(1- (2- methoxyethyl) piperidine-4- carboxamido)phenyl) methanaminium chloride 409.3 410.3 B-1-30 [00200] (R)-(2-(1- (cyclopropylmethyl) piperidine-4- carboxamido)phenyl) (4-isopropylphenyl) methanaminium chloride 405.3 406.2 B-1-31 [00201] (R)-(4- isopropylphenyl)(2-(1- (2,2,2- trifluoroethyl) piperidine-4- carboxamido)phenyl) methanaminium chloride 433.2 434.2

Example S-1: Synthesis of (1R,2S)-2-fluoro-N((S or R)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide (Compound 3)

##STR00202##

[0476] Step a: To a solution of (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride (150 mg, 468 mol, 1 eq) in DMF (2 mL) at 0 C. was added (1R,2S)-2-fluorocyclopropane-1-carboxylic acid (58 mg, 561 mol, 1.2 eq), NMM (1.87 mmol, 206 L, 4 eq), and T3P (595 mg, 935 mol, 50% purity, 2 eq). The resulting mixture was warmed to 25 C. and stirred for 1 h. The reaction mixture was then diluted with water, and the resulting biphasic mixture was extracted with ethyl acetate (320 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (1R,2S)-2-fluoro-N-((6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide. This mixture of diastereomers was separated by chiral SFC (column: DAICEL CHIRALPAK AD) to give (1R,2S)-2-fluoro-N((S or R)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide as the second eluting isomer. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.20F.sub.2N.sub.4O: 371.2; found 371.1.

Example S-2: Synthesis of (R)N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (Compound 64) and (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide (Compound 26)

##STR00203##

[0477] Step a: To a solution of tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate (4 g, 7.05 mmol, 60% purity, 1 eq) in DCM (100 mL) at 15 C. was added NMM (14.1 mmol, 1.55 mL, 2 eq) and cyclopropanecarbonyl chloride (884 mg, 8.46 mmol, 1.2 eq). The resulting mixture was stirred at 15 C. for 1 h. The reaction mixture was then poured into ice-water (50 mL) and stirred for 3 min. The resulting biphasic mixture was extracted with ethyl acetate (350 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.32N.sub.2O.sub.3: 409.2; found 409.3.

[0478] Step b: To a solution of tert-butyl (2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamate (3.5 g, 8.57 mmol, 1 eq) in EtOAc (30 mL) at 15 C. was added HCl/EtOAc (35 mL). The resulting mixture was stirred at 15 C. for 16 h. The reaction mixture was then concentrated under reduced pressure to give N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. This mixture of enantiomers was separated by chiral SFC ((s, s) WHELK-01, First Eluting Isomer) to give (R)N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide as the first eluting isomer. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.24N.sub.2O: 309.2; found 309.4.

[0479] Step c: To a solution of (R)N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (60 mg, 0.194 mmol, 1 eq) in MeCN (2 mL) was added 1-methylazetidine-3-carboxylic acid (44 mg, 0.389 mmol, 2 eq). The resulting mixture was cooled to 0 C. before N-methylimidazole (39.9 mg, 0.486 mmol, 2.5 eq) and TCFH (17.5 mg, 0.486 mmol, 2.5 eq) were added sequentially. The resulting mixture was warmed to 20 C. and stirred for 2 h. The reaction mixture was then quenched by addition of ice-water (10 mL), and the resulting biphasic mixture was extracted with EtOAc (310 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.31N.sub.3O.sub.2: 406.2; found 406.2.

Example S-3: Synthesis of (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide (Compound 48) and (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide (Compound 37)

##STR00204##

[0480] Step a: To a mixture of (RN-((2-aminophenyl)4-isopropylphenyl)methyl)cyclopropanecarboxamide (150 mg, 486 mol, 1 eq), N-methylimidazole (120 mg, 1.46 mmol, 3 eq) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (108 mg, 535 mol, 1.1 eq) in MeCN (5 mL) at 20 C. under N.sub.2 was added TCFH (136 mg, 486 umol, 1 eq). The resulting mixture was then stirred at 20 C. for 1 h. The reaction mixture was then poured into ice-water (10 mL), and the resulting biphasic mixture was extracted with EtOAc (220 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (R)-3-((2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamoyl)azetidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.29H.sub.37N.sub.3O.sub.4: 492.3; found 492.3.

[0481] Step b: A mixture of tert-butyl (R)-3-((2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamoyl)azetidine-1-carboxylate (160 mg, 325 mol, 1 eq) in DCM (3 mL) at 25 C. was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 41.5 eq), and the resulting mixture was stirred at 25 C. for 30 min. The reaction mixture was then diluted with H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (220 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.29N.sub.3O.sub.2: 392.2; found 392.4.

[0482] Step c: To a mixture of (R)N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide (10 mg, 25.5 mol, 1 eq) and methylmorpholine (5.17 mg, 51.1 mol, 2 eq) in DCM (1 mL) at 20 C. under N.sub.2 was added acetyl chloride (2.01 mg, 25.5 mol, 1 eq) in a dropwise manner. The resulting mixture was allowed to warm to 15 C. and stir for 1 h. The reaction mixture was then cooled to 0 C. and quenched by addition of H.sub.2O (5 mL). The resulting biphasic mixture was stirred for 5 min before it was extracted with ethyl acetate (210 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.31N.sub.3O.sub.3: 434.2; found 434.2.

Example S-4: Synthesis of (R or S)N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide (Compound 31)

##STR00205##

[0483] Step a: To a solution of N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (500 mg, 1.62 mmol, 1.00 eq) in DCM (30.0 mL) at 0 C. was added phenyl carbonochloridate (305 mg, 1.95 mmol, 1.20 eq) and triethylamine (820 mg, 8.11 mmol, 5.00 eq). The resulting mixture was warmed to 25 C. and stirred for 1 h. 2,2-dimethoxyethan-1-amine (341 mg, 3.24 mmol, 2.00 eq) was then added to the reaction mixture, and the resulting mixture was at 25 C. for 11 h. The reaction mixture was then diluted with H.sub.2O (30 mL), and the resulting biphasic mixture was exacted with DCM (20 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-((2-(3-(2,2-dimethoxyethyl)ureido)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.33N.sub.3O.sub.4: 440.2; found 440.3.

[0484] Step b: To a solution of N-((2-(3-(2,2-dimethoxyethyl)ureido)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (250 mg, 569 mol, 1.00 eq) in MeOH (0.5 mL) at 0 C. was added HCl/MeOH (0.5 mL). The resulting mixture was warmed to 40 C. and stirred for 12 h. The reaction mixture was then concentrated under reduced pressure. The crude residue was then partitioned between water and DCM (30 mL). The organic layer was collected and washed with saturated aqueous NaHCO.sub.3 (10 mL) and saturated aqueous NaCl (10 mL). The washed organic layer was then dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide. This mixture of enantiomers was then separated using chiral SFC (column: DAICEL CHIRALPAK AD) to give (R or S)N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide as the first eluting isomer. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.23H.sub.25N.sub.3O.sub.2: 376.2; found 376.2.

Example S-5: Synthesis of (R)N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (Compound 62)

##STR00206##

[0485] Step a: To a solution of (R)N-((4-isopropylphenyl)(3-methoxyphenyl)methyl)cyclopropanecarboxamide (0.35 g, 1.08 mmol, 1 eq) in DCM (2 mL) at 78 C. was added BBr.sub.3 (1.36 g, 5.41 mmol, 521 L, 5 eq). The resulting mixture was warmed to 20 C. and stirred for 12 h. The reaction mixture was then diluted with saturated aqueous NaHCO.sub.3 to adjust the solution pH to 7. The resulting biphasic mixture was then extracted with dichloromethane (250 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (R)N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.23NO.sub.2: 310.2; found 310.1.

Example S-6: Synthesis of (1R,2S)-2-(2-acetamidoacetamido)-N((S)-(4-isopropylphenyl(phenyl methyl cyclopentane-1-carboxamide (Compound 21)

##STR00207##

[0486] Step a: To a solution of (S)-(4-isopropylphenyl)(phenyl)methanaminium chloride (0.25 g, 0.95 mmol, 1 eq) and (1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (0.44 g, 1.91 mmol, 1 eq) in DMF (4.8 mL) was added EDCI.Math.HCl (0.28 g, 1.4 mmol, 1.5 eq), 1-hydroxybenzotriazole hydrate (0.22 g, 1.43 mmol, 1.5 eq), and N,N-diisopropylethylamine (0.5 mL, 2.86 mmol, 3 eq). The resulting mixture was stirred at 25 C. for 4 h. The reaction mixture was then poured into water (150 mL), and the resulting solution was extracted with EtOAc (3150 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl ((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)carbamate.

[0487] Step b: To a solution of tert-butyl ((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)carbamate (0.4 g, 0.92 mmol, 1 eq) in methanol (4.6 mL) was added hydrochloric acid (1.14 mL, 4 M in dioxane, 4.6 mmol). The resulting reaction mixture was stirred at 25 C. for 2 h before the reaction mixture was concentrated under reduced pressure to give (1R,2S)-2-amino-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide hydrochloride salt.

[0488] Step c: To a solution of (1R,2S)-2-amino-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide hydrochloride salt (0.065 g, 0.17 mmol, 1 eq) and (tert-butoxycarbonyl)glycine (0.037 g, 0.209 mmol, 1.2 eq) in DMF (1 mL) was added EDCI.Math.HCl (0.05 g, 0.261 mmol, 1.5 eq), 1-hydroxybenzotriazole hydrate (0.04 g, 0.261 mmol, 1.5 eq), and N,N-diisopropylethylamine (0.091 mL, 0.523 mmol, 3 eq). The resulting mixture was stirred at 25 C. for 16 h before the reaction mixture was diluted with EtOAc (15 mL) and H.sub.2O (15 mL). The organic layer was collected and washed with H.sub.2O (15 mL) and brine (15 mL), sequentially. The washed organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give tert-butyl (2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)carbamate.

[0489] Step d: To a solution of tert-butyl (2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)carbamate (0.009 g, 0.018 mmol, 1 eq) in methanol (1 mL) was added hydrochloric acid (0.5 mL, 4 M in dioxane, 2 mmol, 18 eq). The resulting mixture was stirred at 25 C. for 4 h before the reaction mixture was concentrated under reduced pressure to give 2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethan-1-aminium chloride.

[0490] Step e: To a solution of 2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethan-1-aminium chloride (0.008 g, 0.019 mmol, 1 eq) in DCM (0.5 mL) was added N,N-diisopropylethylamine (0.007 mL, 0.038 mmol, 2 eq) and acetic anhydride (0.004 mL, 0.038 mmol, 2 eq), sequentially. The resulting mixture was stirred at 25 C. for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was purified by prep-HPLC to give (1R,2S)-2-(2-acetamidoacetamido)-N((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.33N.sub.3O.sub.3: 436.3; found 436.3.

Example S-7: Synthesis of (1R,2S)N((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (Compound 30) and (1R,2S)-2-cyano-N((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide (Compound 7)

##STR00208##

[0491] Step a: In two parallel reactions, (R)-(4-isopropylphenyl)(o-tolyl)methanaminium chloride (100 mg, 362 mol, 1 eq) was dissolved in dry THE (3 mL). The resulting solution was cooled to 0 C. before N,N-diisopropylethylamine (93.7 mg, 725 mol, 2 eq). The resulting mixture was stirred at 0 C. for 5 min before rel-(3aR,6aS)-tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (76.2 mg, 543 umol, 1.5 eq) was added in one portion. The resulting reaction mixture was warmed to 25 C. and stirred for 5 h. The two reactions were then combined for work up. The combined reactions were cooled to 0 C. and quenched by addition of H.sub.2O (10 mL). The pH of the resulting biphasic mixture was adjusted to pH=5 using 2 N aqueous HCl, and the resulting biphasic mixture was then extracted with EtOAc (320 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by chiral SFC (column: DAICEL CHIRALPAK AD) to give (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid as the second eluting isomer. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.29NO.sub.3: 380.2; found 380.3.

[0492] Step b: To a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (81.5 mg, 0.21 mmol, 1 eq) in DMF (1 mL, 0.2 M) was added N,N-diisopropylethylamine (113 L, 0.644 mmol, 3 eq), HOBt-NH.sub.3 (390 mg, 0.26 mmol, 1.2 eq) and TBTU (70 mg, 0.21 mmol, 1 eq), and the resulting reaction mixture was stirred at 25 C. for 16 h. The reaction mixture was then diluted with EtOAc (30 mL) and H.sub.2O (30 mL). The organic layer was collected and then washed with H.sub.2O (30 mL) and brine (30 mL), sequentially. The resulting organic solution was dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC to give (1R,2S)N.sup.1((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.30N.sub.2O.sub.2: 379.2; found 379.2.

[0493] Step c: (1R,2S)N.sup.1((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (48 mg, 0.127 mmol, 1 eq) in dichloromethane (1 mL) was added TFAA (0.027 mL, 0.19 mmol, 1.5 eq), and N,N-diisopropylethylamine (0.044 mL, 0.254 mmol, 2 eq). The reaction mixture was stirred at 25 C. for 4 h before it was concentrated under reduced pressure and purified by column chromatography to give (1R,2S)-2-cyano-N((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.28N.sub.2O; 361.2; found 361.3.

Example S-8: Synthesis of (1S,2R)N.SUP.1.-cyano-N.SUP.2.((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (Compound 22)

##STR00209##

[0494] Step a: To a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (25 mg, 0.066 mmol, 1 eq) in DCE (1 mL) was added oxalyl chloride (0.05 mL, 2 M, 0.099 mmol, 1.5 eq) followed by one drop of DMF. The resulting mixture was stirred at 25 C. for 16 h before the reaction mixture was concentrated under reduced pressure to give crude (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carbonyl chloride, which was directly used in the next step without further purification or characterization.

[0495] Step b: To a solution of cyanamide (5 mg, 0.131 mmol, 2 eq) and triethylamine (28*L, 0.196 mmol, 3 eq) in DCM (1 mL) under N.sub.2 atmosphere at 25 C. was added a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carbonyl chloride (26 mg, 0.065 mmol, 1 eq) in DCM (1 mL) in a dropwise manner. The resulting mixture was stirred for 16 h at 25 C. under N.sub.2 atmosphere. The reaction mixture was then concentrated under reduced pressure and purified by prep-HPLC to give (1S,2R)N.sup.1-cyano-N.sup.2((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.29N.sub.3O.sub.2: 404.2; found 404.3.

Example S-9: Synthesis of (1R,2S)N.SUP.1.((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N.SUP.2.-methylcyclopentane-1,2-dicarboxamide (Compound 16)

##STR00210##

[0496] Step a: To a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (50 mg, 0.132 mmol, 1 eq) in DMF (0.5 mL) was added EDCI.Math.HCl (38 mg, 0.198 mmol, 1.5 eq), 1-hydroxybenzotriazole hydrate (0.03 g, 0.198 mmol, 1.5 eq), and N,N-diisopropylethylamine (0.069 mL, 0.395 mmol, 3 eq). The resulting mixture was stirred at 25 C. for 16 h before the reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was collected and then washed with water (20 mL) and brine (20 mL), sequentially. The organic solution was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give (1R,2S)N.sup.1((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N.sup.2-methylcyclopentane-1,2-dicarboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.32N.sub.2O.sub.2; 393.2 found 393.2.

[0497] The following compounds in Table T-1 were synthesized using procedures similar to Examples S-1 through S-9 using the appropriate starting materials and reagents.

TABLE-US-00005 TABLE T-1 Exact LCMS, Cmpd. mass Found No. Structure IUPAC (g/mol) |[M + H].sup.+ 1 [00211] (R)-N-((2- acetamidophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 350.2 351.2 2 [00212] (1R,2S)-N-((S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl)-2- fluorocyclopropane-1- carboxamide 328.1 329.2 4 [00213] (1R,2S)-N-((S)-(3-(1H- pyrazol-5-yl)phenyl)(6- fluoro-5-isopropylpyridin- 2-yl)methyl)-2- fluorocyclopropane-1- carboxamide (SFC column: REGIS (s,s) WHELK-O1, first eluting isomer) 396.2 397.1 5 [00214] (1R,2S)-2-fluoro-N- ((R)-(3-fluoro-4- isopropylphenyl)(2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-4- yl)methyl)cyclopropane-1- carboxamide (SFC column: DAICEL CHIRALPAK IC, first eluting isomer) 385.2 386.0 6 [00215] (R)-N-((3- acetamidophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 350.2 351.2 8 [00216] N-((1R)-(4- isopropylphenyl)(2-((1- methyl-2,5- dioxoimidazolidin-4- yl)amino)phenyl)methyl) cyclopropanecarboxamide 420.2 419.1 (M H) 9 [00217] N-(2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl) phenyl)-1-(2,2,2- trifluoroethyl)piperidine-4- carboxamide 519.3 520.3 10 [00218] (1R,2S)-2-fluoro-N- ((R)-(3-fluoro-4- isopropylphenyl)(2- ureidophenyl)methyl) cyclopropane- 1-carboxamide (SFC column: DAICEL CHIRALPAK IC, second eluting isomer) 387.2 388.1 11 [00219] (1R,2S)-2-fluoro-N- ((R)-(3-fluoro-4- isopropylphenyl)(1H- pyrazol-5- yl)methyl)cyclopropane-1- carboxamide (SFC column: DAICEL CHIRALPAK IC, first eluting isomer) 319.1 320.1 12 [00220] N-(2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl) phenyl)-1- methylpiperidine- 4-carboxamide 451.3 452.2 13 [00221] N-(2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl) phenyl)-1-(2- methoxyethyl)piperidine-4- carboxamide 495.3 496.3 14 [00222] 1-(cyclopropylmethyl)-N- (2-((R)-((1R,2S)-2- fluorocyclopropane-1- carboxamido)(4- isopropylphenyl)methyl) phenyl)piperidine-4- carboxamide 491.3 492.3 15 [00223] (R)-N-((4- isopropylphenyl)(2-oxo- 2,3- dihydrobenzo[d]oxazol-7- yl)methyl)cyclo- propanecarboxamide (SFC column: DAICEL CHIRALPAK AD, second eluting isomer) 350.2 351.1 17 [00224] (R)-N-((4- cyclopropylphenyl)(2- ureidophenyl)methyl) cyclopropane- carboxamide (SFC column: DAICEL CHIRALPAK AD, first eluting isomer) 349.2 350.2 18 [00225] (R)-N-((4- cyclobutylphenyl)(2- ureidophenyl)methyl) cyclopropane- carboxamide (SFC column: DAICEL CHIRALPAK IC, first eluting isomer) 363.2 364.1 19 [00226] (R,E)-N-((2-(2- cyanoguanidino)phenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 375.2 376.2 20 [00227] methyl 3-((1S,2R)-2-(((R)- (4-isopropylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1- carboxamido)propanoate 464.3 465.2 23 [00228] (R)-N-(2- (cyclopropane- carboxamido(4- isopropylphenyl)methyl) phenyl)-1-(2,2,2- trifluoroethyl)azetidine-3- carboxamide 473.2 474.1 24 [00229] (R)-N-(2- (cyclopropane- carboxamido(4- isopropylphenyl)methyl) phenyl)-1-(2- methoxyethyl)azetidine-3- carboxamide 449.3 450.1 25 [00230] (R)-N-(2- (cyclopropane- carboxamido(4- isopropylphenyl)methyl) phenyl)-1- (cyclopropylmethyl) azetidine-3-carboxamide 445.3 446.3 27 [00231] (1S,2R)-2-fluoro-N-((S)-(4- isopropylphenyl)(phenyl) methyl)cyclopropane-1- carboxamide 311.2 312.1 28 [00232] (S)-2-acetamido-N.sup.1- ((1S,2R)-2-(((S)-(4- isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentyl)succinamide 492.3 493.2 29 [00233] (R)-N-((4- isopropylphenyl)(2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-4- yl)methyl)cyclo- propanecarboxamide (SFC column: REGIS (s,s) WHELK-O1, first eluting isomer) 349.2 350.1 32 [00234] (R or S)-N-((4- isopropylphenyl)(2- oxoindolin-7- yl)methyl)cyclo- propanecarboxamide (SFC column: REGIS (s,s) WHELK-O1, first eluting isomer) 348.2 349.2 33 [00235] (S)-N-((5-isopropylpyridin- 2-yl)(2- methoxyphenyl)methyl) cyclopropanecarboxamide (SFC column: DAICEL CHIRALPAK AD, second eluting isomer) 324.2 325.2 34 [00236] (1S)-3-fluoro-N-((S)-(4- isopropylphenyl)(phenyl) methyl)cyclopentane-1- carboxamide 339.2 340.1 35 [00237] (1S)-3-hydroxy-N-((S)-(4- isopropylphenyl)(phenyl) methyl)cyclopentane-1- carboxamide 337.2 338.1 36 [00238] (1R,2S)-2-fluoro-N-((S)-(4- isopropylphenyl)(phenyl) methyl)cyclopropane-1- carboxamide 311.2 312.1 38 [00239] (1R,2S)-N-((S)-(4- isopropylphenyl)(phenyl) methyl)-2- ureidocyclopentane-1- carboxamide 379.2 380.3 39 [00240] (R)-N-((4- isopropylphenyl)(2- (methylamino)phenyl) methyl)cyclo- propanecarboxamide (SFC column: REGIS (s,s) WHELK-O1, first eluting isomer) 322.2 323.2 40 [00241] (S)-N-((4- cyclobutylphenyl)(phenyl) methyl)cyclo- propanecarboxamide 305.2 306.1 41 [00242] (S)-N-((4- cyclopropylphenyl) (phenyl)methyl) cyclopropanecarboxamide 291.2 292.1 42 [00243] (S)-1-acetyl-N-(2-((R)- cyclopropanecarboxamido (4- isopropylphenyl)methyl) phenyl)azetidine-2- carboxamide 433.2 434.3 43 [00244] (R)-N-((4- isopropylphenyl)(3- methyl-1H-pyrazol-4- yl)methyl)cyclo- propanecarboxamide (SFC column: REGIS (s,s) WHELK-O1, second eluting isomer) 297.2 298.2 44 [00245] (R)-N-((2-acetamido-5- fluorophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide (SFC column: DAICEL CHIRALPAK AD, first eluting isomer) 368.2 369.1 45 [00246] (S)-N-((5-isopropyl- pyridin-2- yl)(phenyl)methyl) cyclopropanecarboxamide 294.2 294.9 46 [00247] (S)-N-((2- acetamidophenyl)(5- isopropylpyridin-2- yl)methyl) cyclopropanecarboxamide 351.2 352.1 47 [00248] (S)-N-((5-isopropylpyridin- 2-yl)(o- tolyl)methyl)cyclopropane- carboxamide (SFC column: DAICEL CHIRALPAK AD, second eluting isomer) 308.2 309.2 49 [00249] (S)-N-(2-((R)- cyclopropanecarboxamido (4- isopropylphenyl)methyl) phenyl)azetidine-2- carboxamide 391.2 392.4 50 [00250] (R)-N-(2-((R)- cyclopropanecarboxamido (4- isopropylphenyl)methyl) phenyl)azetidine-2- carboxamide 391.2 392.4 51 [00251] (R)-N-((2-aminopyridin-3- yl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide (SFC column: DAICEL CHIRALPAK AD, first eluting isomer) 309.2 310.2 52 [00252] (S)-N-((3-fluoro-4- isopropylphenyl)(phenyl) methyl)cyclo- propanecarboxamid (SFC column: DAICEL CHIRALPAK AD, second eluting isomer) 311.2 312.2 53 [00253] (R)-N-((4- isopropylphenyl)(2-(3- methylureido)phenyl) methyl)cyclo- propanecarboxamide 365.2 366.2 54 [00254] (R)-N-((4- isopropylphenyl)(2- ureidophenyl)methyl) cyclopropanecarboxamide 351.2 352.2 55 [00255] (1R,2S)-2-acetamido-N- ((S)-(4- isopropylphenyl)(phenyl) methyl)cyclopentane-1- carboxamide 378.2 379.2 56 [00256] (R)-N-((4- isopropylphenyl)(1H- pyrazol-5-yl)methyl) cyclopropanecarboxamide 283.2 284.2 57 [00257] (R)-N-((4- isopropylphenyl)(2- (methylsulfonamido) phenyl)methyl) cyclopropanecarboxamide 386.2 387.2 58 [00258] (R)-N-((2-chlorophenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide (SFC column: REGIS (s,s) WHELK-O1, first eluting isomer) 327.1 328.1 59 [00259] (R)-N-((4- isopropylphenyl)(2- propionamidophenyl) methyl)cyclo- propanecarboxamide 364.2 365.4 60 [00260] (R)-N-(2- (cyclopropanecarboxamido (4- isopropylphenyl)methyl) phenyl)oxetane-3- carboxamide 392.2 393.3 61 [00261] (R)-N-(2- (cyclopropanecarboxamido (4-isopropylphenyl) methyl)phenyl) cyclopropanecarboxamide (SFC column: DAICEL CHIRALPAK AD, first eluting isomer) 376.2 377.2 63 [00262] (R)-N-((4- isopropylphenyl)(3- methoxy-2- methylphenyl)methyl) cyclopropanecarboxamide 337.2 338.2 65 [00263] (R)-N-((4- isopropylphenyl)(o- tolyl)methyl)cyclopropane- carboxamide (SFC column: Phenomenex- Cellulose-2, first eluting isomer) 307.2 308.3 66 [00264] (R)-N-((4- isopropylphenyl)(m- tolyl)methyl)cyclopropane- carboxamide (SFC column: REGIS (s,s) WHELK-O1, first eluting isomer) 307.2 308.2 67 [00265] (R)-N-((2- hydroxyphenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 309.2 310.1 68 [00266] (R)-N-((4- hydroxyphenyl)(4- isopropylphenyl)methyl) cyclopropanecarboxamide 309.2 310.1 69 [00267] (R)-N-((4- isopropylphenyl)(1- methyl-1H-pyrazol-5- yl)methyl)cyclo- propanecarboxamide (prep-HPLC column: DAICEL CHIRALPAK AS, first eluting isomer) 297.2 298.2 70 [00268] (R)-N-((4- isopropylphenyl)(3- methoxyphenyl)methyl) cyclopropanecarboxamide 323.2 324.1 71 [00269] (R)-N-((4- isopropylphenyl)(2- methoxyphenyl)methyl) cyclopropanecarboxamide (SFC column: Chiralpak AD-3, second eluting isomer) 323.2 324.2 72 [00270] (R)-N-((4- isopropylphenyl)(4- methoxyphenyl)methyl) cyclopropanecarboxamide 323.2 324.2 73 [00271] (S)-N-((4- isopropylphenyl)(phenyl) methyl)cyclo- propanecarboxamide 293.2 294.1

BIOLOGICAL EXAMPLES

Example B-1

[0498] The GYS1 coupled enzyme assay is a kinetic biochemical assay that indirectly quantifies the rate of glycogen synthesis by coupling the conversion of GYS1 substrate UDP-glucose into UDP with downstream enzymatic reactions. UDP is released from UDP-glucose as glucose monomers are linked into the growing glycogen strand by GYS1. The coupled assay then proceeds with pyruvate kinase utilizing UDP and phospho(enol)pyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH into lactate and NAD+. Oxidation of NADH to NAD+ can be measured continuously with a plate reader by quantifying the decrease in NADH absorbance at 340 nm over time.

[0499] Compounds that inhibit the hGYS1 enzyme and, subsequently, the downstream conversion of NADH to NAD+, were tested using assay ready plates (black, clear bottom 384 well plates) in a final DMSO reaction volume of 2.5% DMSO. The Assay Buffer contained 50 mM Tris pH 7.5, 2 mM MgCl.sub.2, and 100 mM KCl. Fresh stocks of BSA at a final concentration of 0.02% and TCEP at 1 mM were added before splitting buffer into hGYS1 buffer and substrate buffer. To the hGYS1 buffer, rabbit liver glycogen was added at a final concentration of 0.2% glycogen. Glucose-6-Phosphate was added at 1 mM, recombinant hGYS1/GN1 protein was added at 50 nM to the substrate buffer, phosphoenolpyruvate (PEP) was added at 2 mM, UDP-Glucose was added at 0.8 mM, NADH) was added at 0.6 mM, and Pyruvate Kinase/Lactate Dehydrogenase was added at 20 units/mL. The reaction was initiated by mixing hGYS1 buffer and substrate buffer at a 1:1 ratio. Both buffers were plated using a liquid dispensing device with hGYS1 buffer plated first followed by the substrate buffer. Plates were spun briefly to eliminate air bubbles and are immediately read in continuous mode at an absorbance of 340 nm, for 10 time points in one-minute increments, for a total of 10 minutes. The slope from these 10 time points was normalized to the positive and negative control wells. The duplicate % inhibition values are then averaged and fit to a Hill equation for dose response according to the Levenberg-Marquardt algorithm with the Hill equation maximum set to 100 and the minimum set to 0.

[0500] The results are shown in Table 3 below, which reports the IC.sub.50 of each compound. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least 2 assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1.

[0501] Note that, in Table 3, the compounds are referred to by the corresponding Compound No. in Table 1, which is also referred to in the synthetic examples.

TABLE-US-00006 TABLE 3 GYS1 PK/LDH Cmpd IC.sub.50 No. (M) 1 0.285 2 1.145 3 0.055 4 0.156 5 0.131 6 0.737 7 1.141 8 0.295 9 0.956 10 0.194 11 0.145 12 1.637 13 1.043 14 0.891 15 0.883 16 1.742 17 2.216 18 0.964 19 0.304 20 2.979 21 1.527 22 1.283 23 1.213 24 1.200 25 1.143 26 1.188 27 0.598 28 2.973 29 0.169 30 1.395 31 1.224 32 2.004 33 1.423 34 0.778 35 1.134 36 0.418 37 1.061 38 1.915 39 0.502 40 1.331 41 2.061 42 1.477 43 2.444 44 0.378 45 2.493 46 1.422 47 1.811 48 1.063 49 1.793 50 1.791 51 0.735 52 0.591 53 1.231 54 0.346 55 2.423 56 0.372 57 2.169 58 1.378 59 0.441 60 0.521 61 0.710 62 0.376 63 1.427 64 0.404 65 0.514 66 2.098 67 0.293 68 0.663 69 1.823 70 0.786 71 0.397 72 2.675 73 0.706

Example B-2

[0502] The GYS1 cell based assay is a bioluminescent assay that quantifies the glucose resulting from glycogen digestion; the quantified glucose is an indirect measure of GYS1 glycogen synthesis. Newly synthesized glycogen is digested using Glucoamylase; the resulting glucose is quantified by using the Glucose-glo assay kit from Promega. Glucose-glo works by coupling glucose oxidation and NADH production with a bioluminescent system that is activated with NADH. Glucose is oxidized by Glucose dehydrogenase and the reaction reduces NAD+ to NADH; NADH activates Reductase which reduces a pro-luciferin Reductase Substrate to luciferin. Luciferin is detected in a luciferase reaction using Ultra-Glo rLuciferase and ATP, and the luminesce produced is proportional to the glucose in the sample. The luminescence is measured as a single point read in a plate reader.

[0503] Compounds that inhibit the hGYS1 enzyme and, subsequently, the glycogen synthesis in cells, were tested using assay ready plates (white, clear bottom 384 well plates) in a final DMSO reaction volume of 1% DMSO. Compounds in the assay ready plates were mixed with media with no additives, except for 20 mM glucose prior to cell addition. HeLa cells were starved in media with no additives, except for 1 Glutamax for 24 h. Starved HeLa cells were plated, in a 1:1 ratio to the media in the assay ready plate and incubated for 24 h at 37 C. and 5% CO.sub.2. Cells were washed in 1PBS buffer and lysed in lysis buffer containing 50% 1PBS and 25% 0.3 N HCl of the final volume in the well or reaction volume; cells were incubated with lysis buffer for 10 minutes and quenched with the remaining 25% of the reaction volume that consisted of 450 mM Tris pH 8.0. Lysates were mixed in a 1:1 ratio with Glucoamylase in 100 mM Sodium Acetate buffer, pH 5.3; the mixture was incubated for 1 h at 37 C. The digested lysate was mixed in a 1:1 ratio with Glucose-glo detection mixture as per vendor recommendations (Luciferase detection buffer, Reductase, Reductase substrate, Glucose dehydrogenase, and NAD) in read-out plates (solid white 384-well plates) and incubated for 1 h at RT. The plates were read using a plate reader with luminescence capabilities. Each compound concentration Relative Luminescence Unit (RLU) was averaged and normalized to the average RLU of the positive and negative controls to obtain a percentage inhibition. The normalized data vs. concentration was plotted; to determine the half-maximal concentration (IC.sub.50), the Levenberg-Marquardt algorithm was used to fit a Hill equation to the dose response data.

[0504] The results are shown in Table 4 below, which reports the IC.sub.50 of each compound. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least 2 assay runs on separate days. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate.

TABLE-US-00007 TABLE 4 Cellular Cmpd IC.sub.50 No. (M) 2 6.52 3 1.51 4 2.79 5 1.06 11 3.28

Example B-3

[0505] The GYS2 coupled enzyme assay is a kinetic biochemical assay that indirectly quantifies the rate of glycogen synthesis by coupling the conversion of GYS2 substrate UDP-glucose into UDP with downstream enzymatic reactions. UDP is released from UDP-glucose as glucose monomers are linked into the growing glycogen strand by GYS2. The coupled assay then proceeds with pyruvate kinase utilizing UDP and phospho(enol)pyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH into lactate and NAD+. Oxidation of NADH to NAD+ can be measured continuously with a plate reader by quantifying the decrease in NADH absorbance at 340 nm over time.

[0506] Compounds that inhibit the hGYS2 enzyme and, subsequently, the downstream conversion of NADH to NAD+, were tested using assay ready plates (black, clear bottom 384 well plates) in a final DMSO reaction volume of 2.5% DMSO. The Assay Buffer contained 50 mM Tris pH 7.5, 2 mM MgCl.sub.2, and 100 mM KCl. Fresh stocks of BSA at a final concentration of 0.02% and TCEP 1 mM were added before splitting buffer into hGYS2 buffer and substrate buffer. To the hGYS2 buffer, rabbit liver glycogen was added at a final concentration of 0.2% glycogen. Glucose-6-Phosphate was added at 2 mM, recombinant hGYS2/GN1 protein was added at 200 nM to the substrate buffer, phosphoenolpyruvate (PEP) was added at 2 mM, UDP-Glucose was added at 2 mM, NADH was added at 0.6 mM, and Pyruvate Kinase/Lactate Dehydrogenase was added at 20 units/mL. The reaction was initiated by mixing hGYS2 buffer and substrate buffer at a 1:1 ratio. Both buffers were plated using a liquid dispensing device with hGYS2 buffer plated first followed by the substrate buffer. Plates were spun briefly to eliminate air bubbles and are immediately read in continuous mode at an absorbance of 340 nm, for 10 time points in one-minute increments, for a total of 10 minutes. The slope from these 10 time points was normalized to the positive and negative control wells. The duplicate % inhibition values are then averaged and fit to a Hill equation for dose response according to the Levenberg-Marquardt algorithm with the Hill equation maximum set to 100 and the minimum set to 0.

[0507] The results are shown in Table 5 below, which reports the IC.sub.50 of each compound. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least 2 assay runs on separate days. As shown in the table below, the compounds of the present invention are not potent inhibitors of human GYS2. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate.

TABLE-US-00008 TABLE 5 GYS2 PK/LDH Cmpd IC.sub.50 No. (M) 1 >100.0 9 >100.0 10 >100.0 11 >100.0 13 >100.0 14 >100.0 15 >100.0 18 >100.0 19 >100.0 26 >100.0 27 >100.0 29 >100.0 36 >100.0 37 >100.0 39 >100.0 44 >100.0 46 >100.0 48 >100.0 51 >100.0 52 >100.0 53 >100.0 54 >100.0 56 >100.0 57 >100.0 58 >100.0 59 >100.0 60 >100.0 61 >100.0 62 >100.0 63 >100.0 64 >100.0 65 >100.0 66 >100.0 67 >100.0 68 >97.44 69 >100.0 70 >100.0 71 >100.0 72 >100.0 73 >100.0

Example B-4

[0508] Pompe disease is a glycogen storage disease caused by mutations in the enzyme acid alpha-glucosidase resulting in pathological accumulation of glycogen. Glycogen can accumulate in virtually all tissues, but the primary pathology affects skeletal and cardiac muscle. Inhibiting the synthesis of muscle glycogen could reduce the pathologic build-up of glycogen by acting as a substrate reduction therapy. Savage et. al. identified a predicted protein truncating variant (PTV) in the PPP1R3A gene (a regulator of glycogen metabolism) in 0.5% of Europeans, which results in 65% reduction in muscle glycogen (Savage et. al., A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice. PLoS Medicine. 2008; herein incorporated by reference in its entirety). PPP1R3A functions as a key activator of muscle glycogen synthase 1 (GYS1) by dephosphorylating the enzyme and maximizing activity. FIG. 1 demonstrates the pathway in which PPP1R3A (loss of function) LoF leads to reduction in muscle glycogen.

[0509] Large biobanks enable investigation of the consequences of genetic variation on many health-related phenotypes. To assess the consequences of a predicted 65% loss of muscle glycogen, association study was performed in the UK Biobank comparing phenotypes between PPP1R3A PTV carriers and non-carriers. Genetic association studies were performed using REGENIE (Mbatchou, J., Barnard, L., Backman, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet 53, 1097-1103, 2021), adjusted for age, sex, and the first 10 principal components of ancestry. Quantitative traits were normalized using an inverse rank normal transformation.

[0510] With regards to FIGS. 2A-2H, the association between PPP1R3A PTV and the quantitative phenotypes of left ventricular ejection (LVEF) (%) (FIG. 2A), left ventricle wall thickness (mm) (FIG. 2B), exercise output (watts) (FIG. 2C), max heart rate (HR) exercise (bpm) (FIG. 2D), PQ interval (ms) (FIG. 2E), QRS duration (ms) (FIG. 2F), QT interval (ms) (FIG. 2G), and serum glucose (mmol/L) (FIG. 2H), are depicted. Phenotype values are plotted by PPP1R3A dosage for UK Biobank participants. No association between PPP1R3A PTV and the quantitative phenotypes in the UK Biobank was identified.

[0511] Table 6 below lists the P-value and number of participants (N) for the results depicted in FIGS. 2A-H. No associations between PPP1R3A PTV and cardiac parameters, including left ventricular ejection fraction (p=0.871) and wall thickness (p=0.168) were identified. There was no evidence of changes in EKG cardiac conduction intervals nor in any muscle performance measurements (n=49,616), including maximum heart rate (p=0.444) and maximum workload during an exercise test (p=0.100). Further, no changes in serum glucose (p=0.71) or any other members of a panel of 170 serum metabolites were observed.

TABLE-US-00009 TABLE 6 Phenotype P-value N LVEF 0.871 27,716 LV Wall Thickness 0.168 27,579 Exercise Output 0.100 49,616 Max HR Exercise 0.444 49,603 QRS Duration 0.527 29,507 PQ Interval 0.366 16,694 QT Interval 0.222 17,574 Serum Glucose 0.477 294,042

[0512] As shown in Table 7 below, no association between PPP1R3A PTV and key health outcomes was also observed. In addition to the phenotypes in Table 7, no phenome-wide significant associations between PPP1R3A PTV and rates of any ICD10 code with over 100 occurrences in UK Biobank was observed.

TABLE-US-00010 TABLE 7 Disease Effect (SE) P-value N Cases Type 2 Diabetes 0.094 (0.073) 0.200 18,868 Liver Cirrhosis 0.041 (0.273) 0.880 1,325 Heart Failure 0.061 (0.127) 0.630 6,117

[0513] After performing an extensive Phenome-wide association study in UK Biobank, no significant associations between any key outcomes or phenotypes and loss of function of PPP1R3A were found. The results provided herein demonstrate that loss of function variants in the PPP1R3A gene are not associated with adverse health outcomes in a large biobank population. This suggests that partial reduction in muscle glycogen (65%) from birth is well tolerated and supports the potential safety of pharmacologic reduction of muscle glycogen.

[0514] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually.

[0515] It is to be understood that, while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.