CYCLOALKYL CARBOXYLIC ACID 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, Y.sup.1, Y.sup.2, X.sup.1, X.sup.2, X.sup.3, Q.sup.1, and Ra are as defined elsewhere herein. Also provided herein 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): ##STR00222## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m is 0, or 1, and nis 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is: (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

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 ##STR00223##

3. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 0 and nis 1.

4. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1 and n is 0.

5. The compound of any one of claims 1-4, 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.

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 ##STR00224## of formula (I) is selected from the group consisting of ##STR00225##

7. The compound of any one of claims 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH.

8. The compound of any one of claim 1-4 or 7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ##STR00226## of formula (I) is selected from the group consisting of ##STR00227##

9. The compound of any one of claim 1-5, or 7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.1 and X.sup.2 are each independently H or F.

10. The compound of any one of claim 1-5, 7, or 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.3 is H, 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.

11. The compound of any one of claims 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl.

12. The compound of any one of claims 1-11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is ##STR00228##

13. The compound of any one of claims 1-10, 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 R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl.

14. The compound of any one of claim 1-10, or 13, 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 R.sup.b, wherein each R.sup.b is independently CH.sub.3, OCH.sub.3, NHC(O)NH.sub.2, NHC(O)-(3-6 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more CH.sub.3.

15. The compound of any one of claim 1-10, 13, or 14, 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 ##STR00229##

16. The compound of any one of claims 1-10, 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 or C.sub.1-6alkyl.

17. The compound of any one of claim 1-10, or 16, 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 ##STR00230##

18. The compound of any one of claims 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein 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.

19. The compound of any one of claim 1-10, or 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 ##STR00231##

20. The compound of any one of claims 1-19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.a is H, F, OH, or NHC(O)C.sub.1-4alkoxy.

21. The compound of any one of claims 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.a is H.

22. The compound of any one of claims 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.a is F.

23. The compound of any one of claim 1-10, 13, 15, or 20-22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A): ##STR00232## 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, C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more 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 3-3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-6alkyl, and wherein X.sup.3, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, oxo or C.sub.1-6alkyl, or 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, or more NH.sub.2; 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, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-6alkyl, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, oxo or C.sub.1-6alkyl, or 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, or NH.sub.2.

24. 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 one of X.sup.4-8 is C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl and the others of X.sup.4-8 are each independently H.

25. The compound of any one of claim 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-B): ##STR00233## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

26. The compound of any one of claim 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): ##STR00234## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, 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 or C.sub.1-6alkyl, or 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1.

27. 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 the compounds of Table 1.

28. A process for preparing a compound of any one of claims 1-27, 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): ##STR00235## 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; X.sup.3 is H, 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; and Q.sup.1 is: (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; with a compound of formula (I-2): ##STR00236## m is 0, or 1, and nis 0, 1, or 2, wherein m+n is an integer from 1 to 2; R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy; and PG is a protecting group; in the presence of a coupling reagent, to provide a compound of formula (I-3): ##STR00237## wherein m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is: (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-4alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy; and PG is a protecting group; followed by (b) contacting the compound of formula (I-3) with deprotecting agent to provide a compound of any one of claims 1-27.

29. A process for preparing a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the process comprises: reacting a compound of formula (I-1): ##STR00238## 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; X.sup.3 is H, 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; and Q.sup.1 is: (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; with a compound of formula (I-4): ##STR00239## wherein, m is 0, or 1, and nis 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is: (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy; in the presence of a coupling reagent to provide a compound of any one of claims 1-27.

30. A pharmaceutical composition comprising (i) a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

31. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30.

32. The method of claim 31, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

33. The method of claim 31 or claim 32, 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.

34. The method of any one of claims 31-33, wherein the disease, disorder, or condition is Pompe disease.

35. The method of claim 31, wherein the disease, disorder, or condition is cancer.

36. The method of claim 31 or claim 35, 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).

37. The method of claim 31, wherein the individual has a GAA mutation.

38. The method of claim 37, wherein the GAA mutation is a loss-of-function mutation.

39. A kit, comprising (i) a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

40. The kit of claim 39, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

41. The kit of claim 39 or claim 40, 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.

42. The kit of any one of claims 39-41, wherein the disease, disorder, or condition is Pompe disease.

43. The kit of claim 42, wherein the disease, disorder, or condition is cancer.

44. The kit of claim 39 or claim 43, 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).

45. The kit of claim 39, wherein the individual has a GAA mutation.

46. The kit of claim 45, wherein the GAA mutation is a loss-of-function mutation.

47. 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 of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30.

48. 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 of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30.

49. 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 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30.

50. 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 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30.

51. The method of claim 50, comprising subjecting the individual to glycogen substrate reduction therapy in combination with enzyme replacement therapy.

52. The method of claim 51, wherein the enzyme replacement therapy is selected from the group consisting of alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) Myozyme and Lumizyme.

53. The method of any one of claims 50-52, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

54. The method of any one of claims 50-53, 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.

55. The method of any one of claims 50-54, wherein the disease, disorder, or condition is Pompe disease.

56. The method of any one of claims 50-52, wherein the disease, disorder, or condition is cancer.

57. The method of any one of claim 50-52, or 56, 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).

58. The method of any one of claims 50-52, wherein the individual has a GAA mutation.

59. The method of claim 58, wherein the GAA mutation comprises a loss-of-function mutation.

60. The method of any one of claims 47-49 wherein the compound is selective for GYS1 over GYS2.

61. The method of claim 60, wherein the compound is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

62. The method of any one of claim 31-38 or 47-61, comprising reducing the level of glycogen in skeletal muscle.

63. A compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30, for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

64. A compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30, for use in modulating GYS1 in a cell.

65. A compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30, for use in inhibiting GYS1 in a cell.

66. A compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30, for use in reducing tissue glycogen stores in an individual in need thereof.

67. A compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30, for use in a glycogen substrate reduction therapy for treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

68. Use of a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30, in the manufacture of a medicament for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

69. Use of a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30, in the manufacture of a medicament for use in modulating GYS1 in a cell.

70. Use of a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30, in the manufacture of a medicament for use in inhibiting GYS1 in a cell.

71. Use of a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 30, in the manufacture of a medicament for use in reducing tissue glycogen stores in an individual in need thereof.

72. Use of a compound of any one of claims 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 30, 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

[0037] FIG. 1 depicts the pathway in which PPP1R3A Loss of Function (LoF) leads to reduction in muscle glycogen.

[0038] 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.

[0039] 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.

[0040] FIGS. 2E and 2F depict the association between PPP1R3A protein truncating variant (PTV) and PQ interval (ms) and QRS duration (ms) in UK Biobank.

[0041] 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

[0042] 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.

[0043] 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.

[0044] 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).

[0045] 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).

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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 encompassedfor 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.

[0053] 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.

[0054] 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.

[0055] 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. 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.3-8cycloalkyl). 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.

[0056] 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).

[0057] 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.

[0058] 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). 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.

[0059] The term oxo, as used herein, refers to a O moiety.

[0060] 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.

[0061] It is understood that aspects and embodiments described herein as comprising include consisting of and consisting essentially of embodiments.

[0062] 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.

[0063] 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, .sup.35S, .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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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##

[0069] Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds and the presence of a * symbol indicate that the composition is made up of at least 90%, by weight, of a single isomer with unknown stereochemistry, e.g.,

##STR00012##

[0070] 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.,

##STR00013##

[0071] 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.,

##STR00014##

[0072] 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.,

##STR00015##

Compounds

[0073] In one aspect, provided is a compound of formula (I):

##STR00016##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: [0074] m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; [0075] Y.sup.1 and Y.sup.2 are each CH, or [0076] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; [0077] X.sup.1 and X.sup.2 are each independently H or halo; [0078] X.sup.3 is H, 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; [0079] Q.sup.1 is: [0080] (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, [0081] (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, [0082] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0083] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and [0084] R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[0085] 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.

[0086] 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.

[0087] 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.3 is H, 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.3 is H, 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. In some embodiments, X.sup.3 is H, isopropyl, or cyclopropyl, wherein the cyclopropyl of X.sup.3 is optionally substituted with one or more methyl. In some embodiments, X.sup.3 is H. In some embodiments, X.sup.3 is isopropyl. In some embodiments, X.sup.3 is cyclopropyl, wherein the cyclopropyl of X.sup.3 is optionally substituted with one or more methyl. In some embodiments, X.sup.3 is cyclopropyl.

[0088] 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, X.sup.2, and X.sup.3 are each H.

[0089] 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.

[0090] 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, and X.sup.1, X.sup.2, and X.sup.3 are each H.

[0091] 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.

[0092] 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,

##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 selected from the group consisting of

##STR00022##

In some embodiments,

##STR00023##

of formula (I) is

##STR00024##

In some embodiments,

##STR00025##

of formula (I) is

##STR00026##

In some embodiments,

##STR00027##

of formula (I) is

##STR00028##

[0093] 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.

[0094] 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,

##STR00029##

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

##STR00030##

In some embodiments,

##STR00031##

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

##STR00032##

In some embodiments,

##STR00033##

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

##STR00034##

In some embodiments,

##STR00035##

of formula (I) is

##STR00036##

In some embodiments,

##STR00037##

of formula (I) is

##STR00038##

In some embodiments,

##STR00039##

of formula (I) is

##STR00040##

[0095] 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, Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl. In some embodiments, C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more methyl. In some embodiments Q.sup.1 is

##STR00041##

[0096] 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.3 is H, and Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, X.sup.3 is H, and C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl.

[0097] 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, 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 R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, Q.sup.1 is C.sub.6-10aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-4alkyl, C.sub.1-4alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-4alkyl. In some embodiments, Q.sup.1 is C.sub.6-10aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b.

[0098] 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, each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, each R.sup.b is independently C.sub.1-4alkyl, C.sub.1-4alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-4alkyl. In some embodiments, each R.sup.b is independently methyl, iso-propyl, sec-butyl, tert-butyl, methoxy, iso-propoxy, sec-butoxy, tert-butoxy, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-4alkyl.

[0099] 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, Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-4alkyl, C.sub.1-4alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-4alkyl.

[0100] 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, Q.sup.1 is selected from the group consisting of

##STR00042##

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

##STR00043##

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

##STR00044##

In some embodiments, Q.sup.1 is

##STR00045##

In some embodiments, Q.sup.1 is

##STR00046##

[0101] 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, 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 or C.sub.1-6alkyl. 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 selected from the group consisting of

##STR00047##

[0102] 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, 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, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1. 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, and wherein the 5-10 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1. 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. In some embodiments, Q.sup.1 is pyridinyl. In some embodiments, Q.sup.1 is thiophenyl. In some embodiments, Q.sup.1 is pyrazolyl.

[0103] 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, Q.sup.1 is selected from the group consisting of

##STR00048##

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

##STR00049##

[0104] 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.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy. In some embodiments, R.sup.a is H. In some embodiments, R.sup.a is halo. In some embodiments, R.sup.a is F. In some embodiments, R.sup.a is OH. In some embodiments, R.sup.a is NHC(O)C.sub.1-3alkoxy. In some embodiments, R.sup.a is OH. In some embodiments, R.sup.a is NHC(O)-tert-butoxy.

[0105] 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-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (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, X.sup.1, X.sup.2, X.sup.3, Y.sup.1, Y.sup.2, and R.sup.a, are as defined elsewhere herein.

[0106] 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-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (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, X.sup.1, X.sup.2, X.sup.3, Y.sup.1, and Y.sup.2, are as defined elsewhere herein.

[0107] 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; 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; X.sup.3 is H, 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; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-6 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-3alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy.

[0108] 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 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, or NHC(O)-(3-6 membered heterocyclyl); and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is methyl, or cyclopropyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently methyl, methoxy, or NHC(O) azetidinyl; and R.sup.a is H.

[0109] 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 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, or NHC(O)NH.sub.2; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is F; X.sup.3 is isopropyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently methyl, or NHC(O)NH.sub.2; and R.sup.a is H.

[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; and n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl; and R.sup.a is H. In some embodiments, m is 0; and n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is isopropyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently methyl; and R.sup.a is H.

[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, 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; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-3alkyl; and R.sup.a is H. 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 F; X.sup.3 is isopropyl; Q.sup.1 is phenyl wherein the phenyl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently oxazolyl or pyrazolyl, wherein the oxazolyl or pyrazolyl of R.sup.b is optionally substituted with one or more methyl; and R.sup.a is H.

[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, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy.

[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, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently halo; X.sup.3 is H, C.sub.1-3alkyl; Q.sup.1 is phenyl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently F; X.sup.3 is isopropyl; Q.sup.1 is phenyl; and R.sup.a is H.

[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, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; Y.sup.1 and Y.sup.2 are each CH; one of X.sup.1 and X.sup.2 is H and the other of X.sup.1 and X.sup.2 is independently H or halo; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy. In some embodiments, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; Y.sup.1 and Y.sup.2 are each CH; one of X.sup.1 and X.sup.2 is H and the other of X.sup.1 and X.sup.2 is independently H or halo; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy.

[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, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; Q.sup.1 is phenyl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is isopropyl, cyclopropyl, or cyclobutyl; Q.sup.1 is phenyl; and R.sup.a is H.

[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, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy. In some embodiments, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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 and the other of X.sup.1 and X.sup.2 is independently H or halo; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy.

[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, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy. In some embodiments, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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 and the other of X.sup.1 and X.sup.2 is independently H or halo; X.sup.3 is H, 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; Q.sup.1 is phenyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy.

[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, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.3-6cycloalkyl; Q.sup.1 is phenyl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is cyclopropyl; Q.sup.1 is phenyl; and R.sup.a is H.

[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, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 and X.sup.2 are each H; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; Q.sup.1 is phenyl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 and X.sup.2 are each H; X.sup.3 is isopropyl, cyclopropyl, or cyclobutyl; Q.sup.1 is phenyl; and R.sup.a is H.

[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, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; 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 C.sub.1-6alkyl, or (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is H, 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; 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 C.sub.1-3alkyl, or (ii) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more NH.sub.2; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-3alkoxy.

[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, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-6alkyl; 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 or C.sub.1-6alkyl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-3alkyl; 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 or C.sub.1-3alkyl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is indolinyl, dihydro-2H-benzo[d]imidazolyl, benzo[d]oxazolyl, or 3,4-dihydroquinolinyl, wherein the indolinyl, dihydro-2H-benzo[d]imidazolyl, benzo[d]oxazolyl, or 3,4-dihydroquinolinyl of Q.sup.1 is optionally substituted with one or more oxo; and R.sup.a is H.

[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, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.1-6alkyl; 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; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.1-3alkyl; 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; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 is CH; Y.sup.2 is N; X.sup.1 is H; X.sup.2 is F; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is dihydro-2H-benzo[d]imidazolyl, benzo[d]oxazolyl, wherein the dihydro-2H-benzo[d]imidazolyl of Q.sup.1 is optionally substituted with one or more oxo or methyl; and R.sup.a is H.

[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, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.1-6alkyl; Q.sup.1 is 5-20 membered heteroaryl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is halo; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is 5-20 membered heteroaryl; and R.sup.a is H. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 is H; X.sup.2 is F; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is 1H-benzo[d]imidazole; and R.sup.a is H.

[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, m is 0; n is 1, or 2; 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; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0; n is 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; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[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, m is 0; n is 2; 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; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[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, m is 0; n is 2; 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; X.sup.3 is C.sub.1-6alkyl; Q.sup.1 is 5-20 membered heteroaryl; and R.sup.a is H. In some embodiments, m is 0; n is 2; 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; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is 5-10 membered heteroaryl; and R.sup.a is H. In some embodiments, m is 0; n is 2; 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; X.sup.3 is isopropyl; Q.sup.1 is thiophenyl; and R.sup.a is H.

[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, 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; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[0128] 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; 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; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[0129] 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; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-6alkyl; Q.sup.1 is C.sub.6-20aryl; and R.sup.a is H. In some embodiments, m is 1; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is C.sub.1-3alkyl; Q.sup.1 is C.sub.6-10aryl; and R.sup.a is H. In some embodiments, m is 1; n is 0; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H; X.sup.3 is isopropyll; Q.sup.1 is phenyl; and R.sup.a is H.

[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, m is 1; n is 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; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[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, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl, (ii) C.sub.6-19aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl, or (iv) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[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 m is 0, and n is 1, wherein m+n is an integer from 1 to 2; Y.sup.1 and Y.sup.2 are each CH; one of X.sup.1 and X.sup.2 is H and the other of X.sup.1 and X.sup.2 is independently H or halo; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl, (ii) C.sub.6-19aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl, or (iv) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0, and n is 1, wherein m+n is an integer from 1 to 2; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; Q.sup.1 is (i) C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl, (ii) C.sub.6-19aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl, or (iv) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[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, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0; n is 1; Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are each independently H or halo; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl, (ii) C.sub.6-19aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl, or (iv) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[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, m is 0, and n is 1, wherein m+n is an integer from 1 to 2; 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 and the other of X.sup.1 and X.sup.2 is independently H or halo; X.sup.3 is H, 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; Q.sup.1 is (i) C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl, (ii) C.sub.6-19aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl, or (iv) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy. In some embodiments, m is 0, and n is 1, wherein m+n is an integer from 1 to 2; 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; X.sup.3 is C.sub.1-3alkyl, or C.sub.3-6cycloalkyl; Q.sup.1 is (i) C.sub.6-8cycloalkyl, wherein the C.sub.6-8cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-3alkyl, (ii) C.sub.6-19aryl, wherein the C.sub.6-10aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, (iii) 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-3alkyl, or (iv) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy.

[0135] 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: [0136] i. X.sup.4-8 are each independently H, C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl; or [0137] 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 [0138] 3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-6alkyl, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, oxo or C.sub.1-6alkyl, or [0139] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, or more-NH.sub.2; or [0140] 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 [0141] 3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-6alkyl, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, oxo or C.sub.1-6alkyl, or [0142] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, or NH.sub.2.

[0143] 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, C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, X.sup.4-8 are each independently H, C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently optionally substituted with one or more C.sub.1-3alkyl.

[0144] 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.

[0145] 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 X.sup.4-8 is C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl and the others of X.sup.4-8 are each independently H. In some embodiments, one of X.sup.4-8 is C.sub.1-3alkyl, C.sub.1-3lkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently optionally substituted with one or more C.sub.1-3alkyl and the others of X.sup.4-8 are each independently H. In some embodiments, one of X.sup.4-8 is selected from the group consisting of methyl, OCH.sub.3,

##STR00053##

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

[0146] 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 or C.sub.1-6alkyl, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, oxo or C.sub.1-6alkyl, or [0147] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1, and wherein X.sup.5, X.sup.7, and the other of X.sup.4 or X.sup.8 are each independently H, or more-NH.sub.2.

[0148] 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 or C.sub.1-6alkyl, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, oxo or C.sub.1-6alkyl, or [0149] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1, and wherein X.sup.4, X.sup.6, and the other of X.sup.5 or X.sup.8 are each independently H, or NH.sub.2.

[0150] 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 X.sup.4-8 is C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl and the others of X.sup.4-8 are each independently H. In some embodiments, one of X.sup.4-8 is C.sub.1-3alkyl, C.sub.1-3lkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently optionally substituted with one or more C.sub.1-3alkyl and the others of X.sup.4-8 are each independently H. In some embodiments, one of X.sup.4-8 is selected from the group consisting of methyl, OCH.sub.3,

##STR00054##

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

[0151] 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 or C.sub.1-6alkyl. In some embodiments, ring A is 5-6 membered heterocyclyl, wherein the 5-6 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.

[0152] 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 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-8 membered heteroaryl of ring A contains at least 1 annular N when m is 1. 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, and wherein the 5-8 membered heteroaryl of ring A contains at least 1 annular N when m is 1. In some embodiments, ring A is

##STR00056##

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

[0153] 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, C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, X.sup.4 is H, C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently optionally substituted with one or more C.sub.1-3alkyl.

[0154] 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, C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl is independently optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, X.sup.6 is H, C.sub.1-3alkyl, C.sub.1-3alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-10 membered heterocyclyl), or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently optionally substituted with one or more C.sub.1-3alkyl.

[0155] 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.

[0156] 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 X.sup.3 is H, 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.1 and X.sup.2 are independently H or F; and X.sup.3 is H, 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. 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 X.sup.3 is H, 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, one of X.sup.1 and X.sup.2 is H; the other of X.sup.1 and X.sup.2 is F; and X.sup.3 is H, 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.

[0157] 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 X.sup.3 is H, 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, Y.sup.1 and Y.sup.2 are each CH; X.sup.1 and X.sup.2 are independently H or F; and X.sup.3 is H, 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. 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 X.sup.3 is H, 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, 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 X.sup.3 is H, 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.

[0158] 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 X.sup.3 is H, 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, 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 X.sup.3 is H, 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. 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 X.sup.3 is H, 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, 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 X.sup.3 is H, 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.

[0159] 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):

##STR00060##

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

[0160] 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; 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.1 and X.sup.2 are independently 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.

[0161] 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):

##STR00061##

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

[0162] 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 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.

[0163] 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):

##STR00062##

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

[0164] 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, 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.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.

[0165] 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):

##STR00063##

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

[0166] 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):

##STR00064##

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

[0167] 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.

[0168] 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):

##STR00065##

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

[0169] 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, 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.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.

[0170] 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):

##STR00066##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is [0171] 3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0172] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1.

[0173] 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):

##STR00067##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is [0174] 3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0175] 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A is optionally substituted with one or more-NH.sub.2, and wherein the 5-14 membered heteroaryl of ring A contains at least 1 annular N when m is 1.

[0176] 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 or C.sub.1-3alkyl. In some embodiments, ring A is selected from the group consisting of

##STR00068##

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

[0177] 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 is optionally substituted with one or more NH.sub.2, and wherein the 5-8 membered heteroaryl of ring A contains at least 1 annular N when m is 1. 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, and wherein the 5-8 membered heteroaryl of ring A contains at least 1 annular N when m is 1. In some embodiments, ring A is

##STR00069##

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

[0178] 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):

##STR00070##

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

[0179] 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):

##STR00071##

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

[0180] 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):

##STR00072##

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

[0181] 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):

##STR00073##

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

[0182] 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):

##STR00074##

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

[0183] 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):

##STR00075##

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

[0184] 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):

##STR00076##

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

[0185] 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):

##STR00077##

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

[0186] 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):

##STR00078##

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

[0187] 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):

##STR00079##

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

[0188] 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):

##STR00080##

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

[0189] 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):

##STR00081##

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

[0190] 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):

##STR00082##

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

[0191] 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):

##STR00083##

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

[0192] 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):

##STR00084##

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

[0193] 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.

[0194] 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.

[0195] 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: [0196] Knime Analytics Platform 4.2.2 [0197] RDKit Knime Integration 4.0.1.v202006261025 (this extension includes the RDKit Canon SMILES node) [0198] ChemAxon/Infocom Marvin Extensions Feature 4.3.0v202100 (this extension includes the MolConverter node) [0199] 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 [00085] (1S,2R)-2-(((S)-(6-fluoro-5- isopropylpyridin-2-yl)(3-(1- methyl-1H-pyrazol-5- yl)phenyl)methyl)carbamoyl)cyclo- pentane-1-carboxylic acid 2 [00086] (1S,2R)-2-(((S)-(6-fluoro-5- isopropylpyridin-2-yl)(3-oxazol- 5- yl)phenyl)methyl)carbamoyl)cyclo- pentane-1-carboxylic acid 3 [00087] (1S,2R)-2-(((S)-(6-fluoro-5- isopropylpyridin-2-yl)(3- (isoxazol-5- yl)phenyl)methyl)carbamoyl)cyclo- pentane-1-carboxylic acid 4 [00088] (1S,2R)-2-(((S)-(3-(1H-pyrazol-5- yl)phenyl)(6-fluoro-5- isopropylpyridin-2- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 5 [00089] (1S,2R)-2-(((S)-(6-fluoro-5- isopropylpyridin-2-yl)(1H- indazol-6- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 6 [00090] (1S,2R)-2-(((S)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 7 [00091] (1S,2R)-2-(((R)-(3-fluoro-4- isopropylphenyl)(1-methyl-2-oxo- 2,3-dihydro-1H-benzo[b]imidazol- 4- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 8 [00092] (1S,2R)-2-(((S)-(3,5-difluoro-4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 9 [00093] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxo-2,3- dihydrobenzo[d]oxazol-7- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 10 [00094] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxo-2,3- dihydrobenzo[d]oxazol-4- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 11 [00095] (1S or 1R,2R or 2S,4R or 4S)-4- ((tert-butoxycarbonyl)amino)-2- (((S)-(4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 12 [00096] (1S,2R)-2-(((S)-(5- cyclpropylpyridin-2- yl)(phenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 13 [00097] (1S,2R)-2-(((R)-(2-(azetidine-3- carboxamido)phenyl)(4- isopropylphenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 14 [00098] (1S,2R)-2-(((S)-(4-(1- methylcyclopropyl)phenyl) (phenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 15 [00099] (1S,2R)-2-(((S)-(5- cyclobutylpyridin-2- yl)(phenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 16 [00100] (1S or 1R,2R or 2S,4R or 4S)-4- hydroxy-2-(((S)-(4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 17 [00101] (1S,2R)-2-(((S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 18 [00102] (1S,2R)-2-(((S)-(4-cyclobutyl-3- fluorophenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 19 [00103] (1S or 1R,2R or 2S)-2-(((R or S)- (4-isopropylphenyl)(2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 20 [00104] (1R or 1S,2S or 2R)-2-(((S or R)- (4-isopropylphenyl)(2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 21 [00105] (1S or 1R,2R or 2S,4S or 4R)-4- hydroxy-2-(((S)-(4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 22 [00106] (1S,2R)-2-(((S)-(5- isopropylpyridin-2-yl)(o- tolyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 23 [00107] (1S,2R)-2-(((R)-(3-fluoro-4- isopropylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 24 [00108] (1S,2R)-2-(((R)-(3-fluoro-4- isopropylphenyl)(2- ureidophenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 25 [00109] (1S or 1R,2R or 2S,4R or 4S)-4- fluoro-2-(((S)-(4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 26 [00110] (1S,2R)-2-(((R)-(4- cyclopropylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 27 [00111] (1S,2R)-2-(((R)-(3-fluoro-4- isopropylphenyl)(1H-pyrazol-5- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 28 [00112] (1S,2R)-2-(((R)-(4- cyclobutylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 29 [00113] (1S,2R)-2-(((R)-(2-aminopyridin- 3-yl)(4- isopropylphenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 30 [00114] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxoindolin-7- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 31 [00115] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxo-1,2,3,4- tetrahydroquinolin-8- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 32 [00116] (1S,2R)-2-(((R)-(4- isopropylphenyl)(1H-pyrazol-5- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 33 [00117] (1S or 1R,3R or 3S)-3-(((S)-(4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 34 [00118] (1S,2R)-2-(((S)-(4- cyclobutylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 35 [00119] (1S or 1R,2R or 2S)-2-(((R)-(6,6- dimethylspiro[3.3]heptan-2- yl)(phenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 36 [00120] (1S,2R)-2-(((S)-(5- isopropylpyridin-2- yl)(phenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 37 [00121] (1S,2R)-2-(((S)-(3-fluoro-4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 38 [00122] (1S,2R)-2-(((S)-(4- cyclopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 39 [00123] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2- methoxyphenyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 40 [00124] (1S,2R)-2-(((R)-(4- isopropylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1-carboxylic acid 41 [00125] (1S,2R)-2-(((S)-(4- isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 42 [00126] (1S,2R)-2-(((R)-(4- isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclohexane- 1-carboxylic acid 43 [00127] (1R or 1S,2S or 2R)-2-(((S or R)- (4-isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 44 [00128] (1R or 1S,2S or 2R)-2-(((R or S)- (4-isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 45 [00129] (1S,2R)-2-(((R)-(4- isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 46 [00130] (1S or 1R,2R or 2S)-2-(((S or R)- (4-isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid

[0200] 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, wherein 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: [0201] 2-({[4-(propan-2-yl)phenyl](thiophen-2-yl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0202] 2-({[4-(propan-2-yl)phenyl](thiophen-2-yl)methyl}carbamoyl)cyclohexane-1-carboxylic acid; [0203] 2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0204] 2-{[(2-methylphenyl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0205] 2-{[(2-methoxyphenyl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0206] 2-{[(4-cyclopropylphenyl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0207] 2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0208] 2-({phenyl[5-(propan-2-yl) pyridin-2-yl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0209] 2-[({6,6-dimethylspiro[3.3]heptan-2-yl}(phenyl)methyl) carbamoyl]cyclopentane-1-carboxylic acid; [0210] 3-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0211] 2-{[(4-cyclobutylphenyl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0212] 2-({[4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0213] 2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-8-yl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0214] 2-{[(2-oxo-2,3-dihydro-1H-indol-7-yl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0215] 2-{[(2-aminopyridin-3-yl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0216] 2-{[(4-cyclobutylphenyl)(2-methylphenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0217] 2-({[3-fluoro-4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0218] 2-{[(4-cyclopropylphenyl)(2-methylphenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0219] 4-fluoro-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0220] 2-({[2-(carbamoylamino)phenyl][3-fluoro-4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0221] 2-({[3-fluoro-4-(propan-2-yl)phenyl](2-methylphenyl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0222] 2-{[(2-methylphenyl) [5-(propan-2-yl) pyridin-2-yl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0223] 4-hydroxy-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0224] 2-{[(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0225] 2-{[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0226] 2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0227] 4-hydroxy-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0228] 2-{[(5-cyclobutylpyridin-2-yl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0229] 2-({[4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0230] 2-({[2-(azetidine-3-amido)phenyl][4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0231] 2-{[(5-cyclopropylpyridin-2-yl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0232] 4-{[(tert-butoxy) carbonyl]amino}-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0233] 2-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-4-yl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0234] 2-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl) [4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0235] 2-({[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0236] 2-({[3-fluoro-4-(propan-2-yl)phenyl](1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0237] 2-{[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]carbamoyl}cyclopentane-1-carboxylic acid; [0238] 2-({[6-fluoro-5-(propan-2-yl) pyridin-2-yl](1H-indazol-6-yl)methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0239] 2-({[6-fluoro-5-(propan-2-yl) pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0240] 2-({[6-fluoro-5-(propan-2-yl) pyridin-2-yl][3-(1,2-oxazol-5-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0241] 2-({[6-fluoro-5-(propan-2-yl) pyridin-2-yl][3-(1,3-oxazol-5-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; and [0242] 2-({[6-fluoro-5-(propan-2-yl) pyridin-2-yl][3-(1-methyl-1H-pyrazol-5-yl)phenyl]methyl}carbamoyl)cyclopentane-1-carboxylic acid; [0243] or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0244] 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, wherein 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: [0245] (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(1-methyl-1H-pyrazol-5-yl)phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0246] (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(oxazol-5-yl)phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0247] (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(isoxazol-5-yl)phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0248] (1S,2R)-2-(((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0249] (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0250] (1S,2R)-2-(((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0251] (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0252] (1S,2R)-2-(((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0253] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0254] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0255] (1S or 1R,2R or 2S,4R or 4S)-4-((tert-butoxycarbonyl)amino)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0256] (1S,2R)-2-(((S)-(5-cyclopropylpyridin-2-yl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0257] (1S,2R)-2-(((R)-(2-(azetidine-3-carboxamido)phenyl)(4-isopropylphenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0258] (1S,2R)-2-(((S)-(4-(1-methylcyclopropyl)phenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0259] (1S,2R)-2-(((S)-(5-cyclobutylpyridin-2-yl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0260] (1S or 1R,2R or 2S,4R or 4S)-4-hydroxy-2-(((S)-(4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0261] (1S,2R)-2-(((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0262] (1S,2R)-2-(((S)-(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0263] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0264] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0265] (1S or 1R,2R or 2S,4S or 4R)-4-hydroxy-2-(((S)-(4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0266] (1S,2R)-2-(((S)-(5-isopropylpyridin-2-yl)(o-tolyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0267] (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(o-tolyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0268] (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(2-ureidophenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; (1S or 1R,2R or 2S,4R or 4S)-4-fluoro-2-(((S)-(4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0269] (1S,2R)-2-(((R)-(4-cyclopropylphenyl)(o-tolyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0270] (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1H-pyrazol-5-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0271] (1S,2R)-2-(((R)-(4-cyclobutylphenyl)(o-tolyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0272] (1S,2R)-2-(((R)-(2-aminopyridin-3-yl)(4-isopropylphenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0273] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxoindolin-7-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0274] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-1,2,3,4-tetrahydroquinolin-8-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0275] (1S,2R)-2-(((R)-(4-isopropylphenyl)(1H-pyrazol-5-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0276] (1S or 1R,3R or 3S)-3-(((S)-(4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0277] (1S,2R)-2-(((S)-(4-cyclobutylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0278] (1S or 1R,2R or 2S)-2-(((R)-(6,6-dimethylspiro[3.3]heptan-2-yl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0279] (1S,2R)-2-(((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0280] (1S,2R)-2-(((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0281] (1S,2R)-2-(((S)-(4-cyclopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0282] (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-methoxyphenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0283] (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0284] (1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0285] (1S,2R)-2-(((R)-(4-isopropylphenyl)(thiophen-2-yl)methyl) carbamoyl)cyclohexane-1-carboxylic acid; [0286] (1R or 1S,2S or 2R)-2-(((S or R)-(4-isopropylphenyl)(thiophen-2-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0287] (1R or 1S,2S or 2R)-2-(((R or S)-(4-isopropylphenyl)(thiophen-2-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0288] (1S,2R)-2-(((R)-(4-isopropylphenyl)(thiophen-2-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; and [0289] (1S or 1R,2R or 2S)-2-(((S or R)-(4-isopropylphenyl)(thiophen-2-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid; [0290] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Methods of Treatment

[0291] 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

[0292] 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.

[0293] 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.

[0294] 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).

[0295] 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.

[0296] 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.

[0297] 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).

[0298] 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.

[0299] 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 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.

[0300] 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.

[0301] Provided herein is a method of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] In some embodiments of the foregoing, the administration is oral administration.

Kits

[0312] 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.

[0313] 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

[0314] Provided herein are kits, comprising (i) 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

[0315] 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

[0316] 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-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (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.

[0317] 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: [0318] (a) reacting a compound of formula (I-1):

##STR00131## [0319] or a salt thereof, wherein [0320] Y.sup.1 and Y.sup.2 are each CH, or [0321] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; [0322] X.sup.1 and X.sup.2 are each independently H or halo; [0323] X.sup.3 is H, 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; and [0324] Q.sup.1 is: [0325] (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, [0326] (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each RD is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, [0327] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0328] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, [0329] provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; [0330] with a compound of formula (I-2):

##STR00132## [0331] m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; [0332] R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy; [0333] and PG is a protecting group; [0334] in the presence of a coupling reagent, to provide a compound of formula (1-3):

##STR00133## [0335] wherein [0336] m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; [0337] Y.sup.1 and Y.sup.2 are each CH, or [0338] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; [0339] X.sup.1 and X.sup.2 are each independently H or halo;

[0340] X.sup.3 is H, 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; [0341] Q.sup.1 is: [0342] (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, [0343] (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, [0344] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0345] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; [0346] R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy; and [0347] PG is a protecting group: [0348] followed by, [0349] (b) contacting the compound of formula (I-3) with deprotecting agent to provide a compound of formula (I).

[0350] In some embodiments, the protecting group is an alkyl protecting group. In some embodiments, the protecting group is a tert-butoxy group. In some embodiments, the protecting group is an allyl protecting group. In some embodiments, the protecting group is a propenyl group.

[0351] In some embodiments, the coupling reagent comprises EDCCI, TCFH, or T3P. In some embodiments, the process further comprises the presence of a base. In some embodiments, the base comprises an amine. In some embodiments, the amine is DMAP, NMM, or a trialkylamine. In some embodiments, the coupling reagent is N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (TFCH).

[0352] In some embodiments, the deprotecting agent comprises an acid. In some embodiments the acid is HCl, TFA, or barbituric acid. In some embodiments, the deprotecting agent comprises tetrakis(triphenylphosphine) palladium (0). In some embodiments, the deprotecting agent comprises tetrakis(triphenylphosphine) palladium (0) and barbituric acid.

[0353] 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: [0354] reacting a compound of formula (1-1):

##STR00134## [0355] or a salt thereof, wherein [0356] Y.sup.1 and Y.sup.2 are each CH, or [0357] one of Y.sup.1 and Y.sup.2 is N and the other of Y.sup.1 and Y.sup.2 is CH; [0358] X.sup.1 and X.sup.2 are each independently H or halo; [0359] X.sup.3 is H, 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; and [0360] Q.sup.1 is: [0361] (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, [0362] (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, [0363] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0364] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, [0365] provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; [0366] with a compound of formula (I-4):

##STR00135## [0367] wherein, [0368] m is 0, or 1, and n is 0, 1, or 2, wherein m+n is an integer from 1 to 2; [0369] 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; [0370] X.sup.1 and X.sup.2 are each independently H or halo; [0371] X.sup.3 is H, 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; [0372] Q.sup.1 is: [0373] (i) C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl, [0374] (ii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of Q.sup.1 is optionally substituted with one or more R.sup.b, wherein each R.sup.b is independently C.sub.1-6alkyl, C.sub.1-6alkoxy, NHC(O)NH.sub.2, NHC(O)-(3-15 membered heterocyclyl), or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.b is optionally substituted with one or more C.sub.1-6alkyl, [0375] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo or C.sub.1-6alkyl, or [0376] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more-NH.sub.2, and wherein the 5-20 membered heteroaryl of Q.sup.1 contains at least 1 annular N when m is 1, [0377] provided that, when X.sup.3 is H, then Q.sup.1 is C.sub.6-10cycloalkyl, wherein the C.sub.6-10cycloalkyl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl; and [0378] R.sup.a is H, halo, OH, or NHC(O)C.sub.1-6alkoxy; [0379] in the presence of a coupling reagent to provide a compound of formula (I).

[0380] In some embodiments, the coupling reagent comprises 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 DIEA, or a trialkylamine.

EXAMPLES

[0381] 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.

[0382] 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.

[0383] 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

[0384] 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

##STR00136##

[0385] Compounds of formula S1-4 can be prepared as outlined in general Scheme 1. Amide coupling of a mono-protected carboxylic acid S1-1 with amine S1-2 using a coupling reagent such as N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (TFCH) and a base such as N-methylimidazole (NMI) in an aprotic solvent such as acetonitrile gives amide S1-3. Removal of the allyl protecting group with a metal catalyst such as tetrakis(triphenylphosphine) palladium (0) and barbituric acid in a solvent such as DCM gives compounds of formula S1-4. If desired, compounds of formula S1-4 may be further purified by chiral SFC.

##STR00137##

[0386] Compounds of formulae S2-3, S2-4, S2-5, and S2-6 can be prepared as outlined in general Scheme 2. Reaction of anhydride S2-1 with amine S2-2 using a tertiary amine base such as DIEA in an aprotic solvent such as THE gives rise to compounds of formulae S2-3, S2-4, S2-5, and S2-6. These compounds may be further purified using a method such as chiral SFC to provide compounds as single stereoisomers.

[0387] 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, 75th Ed. The following examples are intended to be illustrative only and not limiting in any way.

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

Intermediate A-1: Synthesis of (R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl) methanaminium chloride

##STR00138##

[0388] Step a: To a solution of 3-fluoro-4-isopropylbenzaldehyde (700 mg, 4.21 mmol, 1 eq) and 2-methylpropane-2-sulfinamide (816 mg, 6.74 mmol, 1.6 eq) in DCM (20 mL) was added Cs.sub.2CO.sub.3 (4.12 g, 12.6 mmol, 3 eq). The resulting mixture was then warmed to 40 C. and stirred for 2 h. The reaction mixture was then filtered and diluted with water, and the filtrate was extracted with DCM (320 mL). The combined organic extracts were washed with H.sub.2O (30 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (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 270.2.

[0389] Step b: To a solution of 4-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.00 g, 4.40 mmol, 1 eq) in THF (20 mL) at 65 C. under N.sub.2 atmosphere was added n-BuLi (2.50 M in hexanes, 7.05 mL, 4 eq) in a dropwise manner. The resulting mixture was stirred for 3 h at 65 C. A solution of (E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (2.37 g, 8.81 mmol, 2 eq) in THF (5 mL) was then added in a dropwise manner to the reaction mixture at 65 C. The resulting mixture was then allowed to warm to 25 C. and stirred at for 2 h. The reaction mixture was then cooled to 0 C. and quenched by addition of saturated aqueous NH.sub.4Cl solution (20 mL). The resulting mixture was then allowed to warm to room temperature before it was diluted with water (10 mL). The resulting biphasic mixture was extracted with EtOAc (330 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 N-((3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-2-methylpropane-2-sulfinamide as a mixture of isomers. These isomers were separated by prep-HPLC (column: Phenomenex Luna C18) to give N((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-2-methylpropane-2-sulfinamide as the first eluting isomer. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.22H.sub.28FN.sub.3O.sub.2S: 418.2. found 418.2.

[0390] Step c: To a mixture of N((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (120 mg, 287 mol, 1.00 eq) in EtOAc (1 mL) at 0 C. was added HCl/EtOAc (5 mL). The resulting mixture was then stirred at 0 C. for 1 h. The reaction mixture was then filtered, and the filter cake was washed with MTBE (35 mL). The solid obtained was dried under reduced pressure to give (R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl) methanaminium chloride.

Intermediate A-2: Synthesis of (3-fluoro-4-isopropylphenyl)(o-tolyl) methanaminium chloride

##STR00139##

[0391] Step a: To a solution of (E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (1.5 g, 5.57 mmol, 1 eq) in DCM (15 mL) at 0 C. under N.sub.2 atmosphere was added o-tolylmagnesium bromide (0.9 M in diethyl ether, 15.4 mL, 2.5 eq) in a dropwise manner. The resulting mixture was warmed to 20 C. and stirred for 2 h. The reaction solution was then quenched with H.sub.2O (30 mL), and the resulting biphasic mixture was extracted with EtOAc (330 mL). The organic extracts were combined and dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give N-((3-fluoro-4-isopropylphenyl)(o-tolyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.28FNOS: 362.2. found 362.2.

[0392] Step b: To a solution of N-((3-fluoro-4-isopropylphenyl)(o-tolyl)methyl)-2-methylpropane-2-sulfinamide (2.6 g, 7.19 mmol, 1 eq) in EtOAc (5 mL) at 0 C. was added HCl/EtOAc (10 mL). The resulting mixture was warmed to 20 C. and stirred for 1.5 h. The reaction was then concentrated under reduce pressure to give (3-fluoro-4-isopropylphenyl)(o-tolyl) methanaminium chloride. LC-MS (ESI): m/z: [MH.sub.3].sup.+ calculated for C.sub.17H.sub.20FN: 241.1. found 241.2.

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

##STR00140##

[0393] 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.

[0394] 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 N.sub.2. The resulting mixture was then degassed and placed under an N.sub.2 atmosphere. The reaction mixture was then warmed to 100 C. and stirred for 2 h under N.sub.2. 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.

[0395] 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.

[0396] 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.

[0397] Step e: To a solution of 6-bromo-2-fluoro-3-isopropylpyridine (665 mg, 3.05 mmol, 1.5 eq) in THF (5 mL) at 78 C. under N.sub.2 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 THF (5 mL) cooled to 78 C. under N.sub.2 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.

[0398] 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: [MNH.sub.3].sup.+ calculated for C.sub.16H.sub.17FN.sub.4: 268.1. found 268.2.

Intermediate A-4: Synthesis of (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride

##STR00141##

[0399] 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 N.sub.2 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.26FNOS: 415.2. found 415.2.

[0400] 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 mol, 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-5: Synthesis of(S)-(3-fluoro-4-isopropylphenyl)(phenyl) methanaminium chloride

##STR00142##

[0401] 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.

[0402] 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.

[0403] 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. 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.

[0404] 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 THF (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.

[0405] 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-6: Synthesis of(S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride

##STR00143##

[0406] 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.

[0407] 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).sub.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.

[0408] 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.

[0409] Step d: To a mixture of 6-bromo-3-cyclopropyl-2-fluoropyridine (90 g, 416 mmol, 1 eq) and trifluoro (vinyl)-24-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.

[0410] Step e: To a mixture of 3-cyclopropyl-2-fluoro-6-vinylpyridine (47 g, 288 mmol, 1 eq) in THF (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.

[0411] 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.

[0412] 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.

[0413] 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-7: Synthesis of(S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(1-methyl-1H-pyrazol-5-yl)phenyl) methanaminium chloride

##STR00144##

[0414] Step a: In two parallel reactions, a solution of 6-bromo-2-fluoro-3-isopropylpyridine (5 g, 22.9 mmol, 1 eq) in THF (25 mL) was cooled to 0 C. under N.sub.2. To this solution was added i-PrMgCl.Math.LiCl (1.3 M in THF, 26.5 mL, 1.5 eq) in a dropwise manner. The reaction mixture was then allowed to warm to 25 C. and stirred for 2 h. At this time, the reaction mixture was cooled to 0 C., and DMF (5.3 mL, 68.8 mmol, 3 eq) was added in a dropwise manner. After the addition was complete, the reaction mixture was allowed to warm to 25 C. and stirred for 1 h. At this time, the two separate reactions were combined for work up. The combined reaction mixture was quenched with NH.sub.4Cl (70 mL), and the resulting biphasic mixture was extracted with ethyl acetate (250 mL). The combined organic extracts were washed with brine (250 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-fluoro-5-isopropylpicolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.10FNO: 168.1. found 168.2.

[0415] Step b: In two parallel reactions, Cs.sub.2CO.sub.3 (3.64 g, 11.2 mmol, 1.1 eq) was added to a mixture of 6-fluoro-5-isopropylpicolinaldehyde (1.70 g, 10.1 mmol, 1 eq) and(S)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol, 1.1 eq) in DCM (20 mL). The resulting mixture was warmed to 40 C. under N.sub.2 and stirred for 2 h. At this time, the two parallel reactions were concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (S,E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.19FN.sub.2OS: 271.1. found 271.1.

[0416] Step c: To a solution of 1-bromo-3-iodo-benzene (5.22 g, 18.5 mmol, 2 eq) in THF (8 mL) at 0 C. under N.sub.2 was added i-PrMgCl.Math. LiCl (1.3 M in THF, 10 mL, 1.4 eq) in a dropwise manner. The resulting mixture was warmed to 25 C. and stirred for 2 h. At this time, the reaction mixture was cooled to 65 C., and a solution of (S,E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (2.5 g, 9.25 mmol, 1 eq) in DCM (30 mL) was added in a dropwise manner. The resulting mixture was the stirred at 65 C. for 3 h under N.sub.2. The reaction mixture was then quenched with NH.sub.4Cl (70 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2100 mL). The combined organic extracts were washed with brine (250 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography. This material was further purified by prep-HPLC (column: Phenomenex Titank C18) to give(S)N((S)-(3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide as the second eluting isomer. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.24BrFN.sub.2OS: 427.1. found 427.0.

[0417] Step d: To a mixture of (S)N((S)-(3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (550 mg, 1.29 mmol, 1 eq) and (1-methyl-1H-pyrazol-5-yl) boronic acid (324 mg, 2.57 mmol, 2 eq) in dioxane (2.5 mL) and H.sub.2O (2.5 mL) was added K.sub.2CO.sub.3 (534 mg, 3.86 mmol, 3 eq) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (105 mg, 129 mol, 0.1 eq). The resulting mixture was then warmed to 90 C. and stirred for 2 h. The reaction mixture was then quenched with H.sub.2O (10 mL) and extracted with ethyl acetate (210 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 to give(S)N((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(1-methyl-1H-pyrazol-5-yl)phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.23H.sub.29FN.sub.4OS: 429.2. found 429.3.

[0418] Step e: To a solution of(S)N((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(1-methyl-1H-pyrazol-5-yl)phenyl)methyl)-2-methylpropane-2-sulfinamide in ethyl acetate (1 mL) at 0 C. was added HCl/EtOAc (4 M, 15 mL), and the resulting mixture was stirred at 0 C. for 1 h. The reaction was then concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (10 mL) to give(S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(1-methyl-1H-pyrazol-5-yl)phenyl) methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.21FN.sub.4: 325.2. found 325.2.

[0419] The following compounds in Table B-1 were synthesized using procedures similar to Intermediates A-1 through A-7 using the appropriate starting materials and reagents.

TABLE-US-00003 TABLE B-1 Exact Intermediate mass LCMS, Found No. Structure IUPAC (g/mol) [M + H].sup.+ B-1-1 [00145] (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 [00146] (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 [00147] (3-fluoro-4-isopropylphenyl)(2- uriedophenyl) methanaminium chloride 301.2 B-1-4 [00148] (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 [00149] (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 [00150] (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 [00151] (4-isopropylphenyl)(2- oxoindolin-7- yl)methanaminium chloride 280.2 264.3 [M NH.sub.3].sup.+ B-1-8 [00152] tert-butyl (3-(amino(4- isopropylphenyl)methyl)pyridin- 2-yl)carbamate 341.2 342.2 B-1-9 [00153] (R)-(4-isopropylphenyl)(o- tolyl)methanaminium chloride 239.2 223.2 [M NH.sub.3].sup.+ B-1-10 [00154] (4-isopropylphenyl)(1H- pyrazol-5-yl)methanaminium chloride 215.1 199.1 [M NH.sub.3].sup.+ B-1-11 [00155] (R)-(4-isopropylphenyl)(2- methoxyphenyl)methanaminium chloride 255.2 239.1 [M NH.sub.3].sup.+ B-1-12 [00156] (S)-(4- isopropylphenyl)(phenyl) methanaminium chloride 225.1 209.1 [M NH.sub.3].sup.+ B-1-13 [00157] (3-fluoro-4- isopropylphenyl)(1H-pyrazol- 5-yl)methanaminium chloride 233.1 217.1 [M NH.sub.3].sup.+ B-1-14 [00158] (5-isopropylpyridin-2-yl)(o- tolyl)methanaminium chloride 240.2 241.1 B-1-15 [00159] (6-fluoro-5-isopropylpyridin-2- yl)(3-(oxazol-5- yl)phenyl)methanaminium chloride 311.1 294.9 [M NH.sub.3].sup.+ B-1-16 [00160] (6-fluoro-5-isopropylpyridin-2- yl)(3-(isoxazol-5- yl)phenyl)methanaminium chloride 311.1 312.2 B-1-17 [00161] (S)-(3,5-difluoro-4- isopropylphenyl)(phenyl) methanaminium chloride 261.1 B-1-18 [00162] (5-cyclopropylpyridin-2- yl)(phenyl)methanaminium chloride 224.1 225.1 B-1-19 [00163] (S)-(4-(1- methylcyclopropyl)phenyl) (phenyl)methanaminium chloride 237.1 B-1-20 [00164] (5-cyclobutylpyridin-2- yl)(phenyl)methanaminium chloride 238.1 B-1-21 [00165] (S)-(4-cyclopropyl-3- fluorophenyl)(phenyl) methanaminium chloride 241.1 B-1-22 [00166] (S)-(4-cyclobutyl-3- fluorophenyl)(phenyl) methanaminium chloride 255.1 B-1-23 [00167] (4-cyclopropylphenyl)(o- tolyl)methanaminium chloride 237.1 B-1-24 [00168] (4-cyclobutylphenyl)(o- tolyl)methanaminium chloride 251.2 B-1-25 [00169] (4- cyclobutylphenyl)(phenyl) methanaminium chloride 237.1 B-1-26 [00170] (R)-(6,6- dimethylspiro[3.3]heptan-2- yl)(phenyl)methanaminium chloride 229.2 B-1-27 [00171] (S)-(5-isopropylpyridin-2- yl)(phenyl)methanaminium chloride 226.1 227.2 B-1-28 [00172] (4- cyclopropylphenyl)(phenyl) methanaminium chloride 223.1 B-1-29 [00173] (4-isopropylphenyl)(thiophen- 2-yl)methanaminium chloride 231.1 B-1-30 [00174] (2-(1-(tert- butoxycarbonyl)azetidine-3- carboxamido)phenyl)(4- isopropylphenyl) methanaminium chloride 423.2 424.2

Intermediate A-9: Synthesis of (1R,2S)-2-((allyloxy)carbonyl)cyclopentane-1-carboxylic acid

##STR00175##

[0420] Step a: To a mixture of cis-tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (6.25 g, 44.6 mmol, 1 eq) and (DHQD).sub.2AQN (CAS: 176298-44-5, 3.06 g, 3.57 mmol, 0.08 eq) in toluene (1.7 L) at 30 C. was added allyl alcohol (25.9 g, 446 mmol, 30 mL, 10 eq). The resulting mixture was stirred at 30 C. for 170 h. The reaction was then quenched by addition of aqueous HCl (1 M, 1 L), and the resulting biphasic mixture was extracted with EtOAc (21 L). The organic extracts were combined, 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 (1R,2S)-2-((allyloxy) carbonyl)cyclopentane-1-carboxylic acid.

Example S-1

TABLE-US-00004 TABLE 2 Exact Observed Cmpd Mass Mass No. Cmpd Name (g/mol) (M + H) 1 (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(1- 464.2 465.1 methyl-1H-pyrazol-5- yl)phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 2 (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(oxazol- 451.2 452.1 5-yl)phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 3 (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3- 451.2 452.2 (isoxazol-5-yl)phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 4 (1S,2R)-2-(((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5- 450.2 451.1 isopropylpyridin-2-yl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 5 (1S,2R)-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(1H- 424.2 425.1 indazol-6-yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 6 (1S,2R)-2-(((S)-(5-cyclopropyl-6-fluoropyridin-2- 382.2 383.1 yl)(phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 7 (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo- 453.2 454.1 2,3-dihydro-1H-benzo[d]imidazol-4- yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 8 (1S,2R)-2-(((S)-(3,5-difluoro-4- 401.2 402.2 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 9 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3- 422.2 423.1 dihydrobenzo[d]oxazol-7-yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 10 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3- 422.2 423.2 dihydrobenzo[d]oxazol-4-yl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 11 (1S or 1R,2R or 2S,4R or 4S)-4-((tert-butoxycarbonyl)amino)- 480.3 481.5 2-(((S)-(4- isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 12 (1S,2R)-2-(((S)-(5-cyclopropylpyridin-2- 364.2 365.2 yl)(phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 13 (1S,2R)-2-(((R)-(2-(azetidine-3-carboxamido)phenyl)(4- 463.2 464.1 isopropylphenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 14 (1S,2R)-2-(((S)-(4-(1- 377.2 378.2 methylcyclopropyl)phenyl)(phenyl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 15 (1S,2R)-2-(((S)-(5-cyclobutylpyridin-2- 378.2 379.2 yl)(phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 16 (1S or 1R,2R or 2S,4R or 4S)-4-hydroxy-2-(((S)-(4- 381.2 382.4 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 17 (1S,2R)-2-(((S)-(4-cyclopropyl-3- 381.2 382.1 fluorophenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 18 (1S,2R)-2-(((S)-(4-cyclobutyl-3- 395.2 396.2 fluorophenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 19 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3-dihydro-1H- 421.2 422.1 benzo[d]imidazol-4-yl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 20 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-2,3-dihydro-1H- 421.2 422.1 benzo[d]imidazol-4-yl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 21 (1S or 1R,2R or 2S,4S or 4R)-4-hydroxy-2-(((S)-(4- 381.2 382.4 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 22 (1S,2R)-2-(((S)-(5-isopropylpyridin-2-yl)(o- 380.2 381.2 tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 23 (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(o- 397.2 398.2 tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 24 (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(2- 441.2 442.1 ureidophenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 25 (1S or 1R,2R or 2S,4R or 4S)-4-fluoro-2-(((S)-(4- 383.2 382.2 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- (M H) carboxylic acid 26 (1S,2R)-2-(((R)-(4-cyclopropylphenyl)(o- 377.2 378.1 tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 27 (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1H-pyrazol-5- 373.2 374.2 yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 28 (1S,2R)-2-(((R)-(4-cyclobutylphenyl)(o- 391.2 392.2 tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 29 (1S,2R)-2-(((R)-(2-aminopyridin-3-yl)(4- 381.2 382.1 isopropylphenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 30 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxoindolin-7- 420.2 421.1 yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 31 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2-oxo-1,2,3,4- 434.2 435.2 tetrahydroquinolin-8-yl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 32 (1S,2R)-2-(((R)-(4-isopropylphenyl)(1H-pyrazol-5- 355.2 356.2 yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 33 (1S or 1R,3R or 3S)-3-(((S)-(4- 365.2 366.2 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 34 (1S,2R)-2-(((S)-(4- 377.2 378.2 cyclobutylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 35 (1S or 1R,2R or 2S)-2-(((R)-(6,6-dimethylspiro[3.3]heptan-2- 369.2 370.2 yl)(phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 36 (1S,2R)-2-(((S)-(5-isopropylpyridin-2- 366.2 367.1 yl)(phenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 37 (1S,2R)-2-(((S)-(3-fluoro-4- 383.2 384.2 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 38 (1S,2R)-2-(((S)-(4- 363.2 364.2 cyclopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane- 1-carboxylic acid 39 (1S,2R)-2-(((R)-(4-isopropylphenyl)(2- 395.2 396.3 methoxyphenyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 40 (1S,2R)-2-(((R)-(4-isopropylphenyl)(o- 379.2 380.3 tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 41 (1S,2R)-2-(((S)-(4- 365.2 366.2 isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentane-1- carboxylic acid 42 (1S,2R)-2-(((R)-(4-isopropylphenyl)(thiophen-2- 385.2 386.1 yl)methyl)carbamoyl)cyclohexane-1-carboxylic acid 43 (1R or 1S,2S or 2R)-2-(((S or R)-(4- 371.2 372.2 isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 44 (1R or 1S,2S or 2R)-2-(((R or S)-(4- 371.2 372.2 isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 45 (1S,2R)-2-(((R)-(4-isopropylphenyl)(thiophen-2- 371.2 372.2 yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid 46 (1S or 1R,2R or 2S)-2-(((S or R)-(4- 371.2 372.2 isopropylphenyl)(thiophen-2- yl)methyl)carbamoyl)cyclopentane-1-carboxylic acid

Example S-2: Synthesis of (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid (Compound 7)

##STR00176##

[0421] Step a: A mixture of (R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl) methanaminium chloride (80.0 mg, 255 mol, 1.00 eq) and (1R,2S)-2-((allyloxy) carbonyl)cyclopentane-1-carboxylic acid (60.7 mg, 306 mol, 1.20 eq), N-methylimidazole (62.9 mg, 766 mol, 3.00 eq) in CH.sub.3CN (5.00 mL) at 20 C. was added chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (85.9 mg, 306 mol, 1.20 eq), and the resulting mixture was warmed to 0 C. and stirred for 1 h. The reaction mixture was then quenched by addition of H.sub.2O (5 mL) at 0 C., and the resulting biphasic mixture was extracted with DCM (310 mL). The combined organic extracts were washed with brine (350 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 allyl(1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.28H.sub.32FN.sub.3O.sub.4: 494.2. found 494.3.

[0422] Step b: To a solution of (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylate (130 mg, 263 mol, 1.00 eq) in DCM (5.00 mL) at 30 C. under N.sub.2 was added Pd(PPh.sub.3).sub.4 (91.3 mg, 79.0 mol, 0.3 eq) and barbituric acid (202 mg, 1.58 mmol, 6.00 eq). The resulting mixture was stirred at 30 C. for 1 h under N.sub.2 atmosphere. The reaction mixture was then warmed to 0 C. and quenched by addition of H.sub.2O (5.0 mL), and the resulting biphasic mixture was extracted with DCM (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 (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl) carbamoyl)cyclopentane-1-carboxylic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.28FN.sub.3O.sub.4: 454.2. found 454.2.

Example S-3: Synthesis of (1S,2R)-2-(((R)-(3-fluoro-4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (Compound 23)

##STR00177##

[0423] Step a: To a solution of (3-fluoro-4-isopropylphenyl)(o-tolyl) methanaminium chloride (500 mg, 1.70 mmol, 1 eq) and cis-tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (262 mg, 1.87 mmol, 1.1 eq) in THF (4 mL) was added DIPEA (659 mg, 5.11 mmol, 3 eq). The resulting mixture was stirred at 20 C. for 2 h. The reaction mixture was then diluted with H.sub.2O (10 mL) and extracted with EtOAc (220 mL). The organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtrated, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give a mixture of diastereomers. This mixture was separated using chiral SFC (column: DAICEL CHIRALPAK AD) to give (1S,2R)-2-(((R)-(3-fluoro-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.28FNO.sub.3: 398.2. found 398.2.

[0424] The following compounds in Table T-1 were synthesized using procedures similar to Examples S-2 and S-3 using the appropriate starting materials.

TABLE-US-00005 TABLE T-1 Exact LCMS, Cmpd. mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 1 [00178] (1S,2R)-2-(((S)-(6- fluoro-5- isopropylpyridin-2- yl)(3-(1-methyl-1H- pyrazol-5- yl)phenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 464.2 465.1 2 [00179] (1S,2R)-2-(((S)-(6- fluoro-5- isopropylpyridin-2- yl)(3-(oxazol-5- yl)phenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 451.2 452.1 3 [00180] (1S,2R)-2-(((S)-(6- fluoro-5- isopropylpyridin-2- yl)(3-isoxazol-5- yl)phenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 451.2 452.2 4 [00181] (1S,2R)-2-(((S)-(3-(1H- pyrazol-5-yl)phenyl)(6- fluoro-5- isopropylpyridin-2- yl)methyl)carbamoyl) cyclopentane-1- carboxylic acid 450.2 451.1 5 [00182] (1S,2R)-2-(((S)-(6- fluoro-5- isopropylpyridin-2- yl)(1H-indazol-6- yl)methyl)carbamoyl) cyclopentane-1- carboxylic acid 424.2 425.1 6 [00183] (1S,2R)-2-(((S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 382.2 383.1 8 [00184] (1S,2R)-2-(((S)-(3,5- difluoro-4- isopropylphenyl) (phenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 401.2 402.2 9 [00185] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxo- 2,3-dihydrobenzo[d] oxazol-7-yl)methyl) carbamoyl)cyclopentane- carboxylic acid 422.2 423.1 10 [00186] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxo- 2,3-dihydrobenzo[d] oxazol-4-yl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, first eluting isomer 422.2 423.2 11 [00187] (1S or 1R,2R or 2S,4R or 4S)-4-((tert- butoxycarbonyl)amino)- 2-(((S)-4- isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid 480.3 481.5 12 [00188] (1S,2R)-2-(((S)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 364.2 365.2 13 [00189] (1S,2R)-2-(((R)-(2- (azetidine-3- carboxamido)phenyl)(4- isopropylphenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 463.2 464.1 14 [00190] (1S,2R)-2-(((S)-(4-(1- methylcyclopropyl) phenyl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 377.2 378.2 15 [00191] (1S,2R)-2-(((S)-(5- cyclobutylpyridin-2- yl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK AD, fourth eluting isomer 378.2 379.2 16 [00192] (1S or 1R,2R or 2S,4R or 4S)-4-hydroxy-2- (((S)-(4- isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid 381.2 382.4 17 [00193] (1S,2R)-2-(((S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 381.2 382.1 18 [00194] (1S,2R)-2-(((S)-(4- cyclobutyl-3- fluorophenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 395.2 396.2 19 [00195] (1S or 1R,2R or 2S)-2- (((R or S)-(4- isopropylphenyl)(2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-4- yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, first eluting isomer 421.2 422.1 20 [00196] (1R or 1S,2S or 2R)-2- (((S or R)-(4- isopropylphenyl)(2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-4- yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 421.2 422.1 21 [00197] (1S or 1R,2R or 2S,4S or 4R)-4-hydroxy-2-(((S)- (4- isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid 381.2 382.4 22 [00198] (1S,2R)-2-(((S)-(5- isopropylpyridin-2- yl)(o- tolyl)methyl)carbamoyl) cyclopentane-1- carboxylic acid, SFC column: REGIS (s,s) WHELK-O1, first eluting isomer 380.2 381.2 24 [00199] (1S,2R)-2-(((R)-(3- fluoro-4- isopropylphenyl)(2- ureidophenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK IC, second eluting isomer 441.2 442.1 25 [00200] (1S or 1R,2R or 2S,4R or 4S)-4-fluoro-2-(((S)- (4-isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid 383.2 382.2 (M H) 26 [00201] (1S,2R)-2-(((R)-(4- cyclopropylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 377.2 378.1 27 [00202] (1S,2R)-2-(((R)-(3- fluoro-4- isopropylphenyl)(1H- pyrazol-5- yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC SFC column: REGIS (s,s) WHELK- O1), second eluting isomer 373.2 374.2 28 [00203] (1S,2R)-2-(((R)-(4- cyclobutylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 391.2 392.2 29 [00204] (1S,2R)-2-(((R)-(2- aminopyridin-3-yl)(4- isopropylphenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK IC, second eluting isomer 381.2 382.1 30 [00205] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2- oxoindolin-7- yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK IC, second eluting isomer 420.2 421.1 31 [00206] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2-oxo- 1,2,3,4- tetrahydroquinolin-8- yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 434.2 435.2 32 [00207] (1S,2R)-2-(((R)-(4- isopropylphenyl)(1H- pyrazol-5- yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, prep-HPLC column: Phenomenex Luna C18, second eluting isomer 355.2 356.2 33 [00208] (1S or 1R,3R or 3S)-3- (((S)-(4- isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: Chiralcel OX-H, third eluting isomer 365.2 366.2 34 [00209] (1S,2R)-2-(((S)-(4- cyclobutylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 377.2 378.2 35 [00210] (1S or 1R,2R or 2S)-2- (((R)-(6,6- dimethylspiro[3.3]heptan- 2-yl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 369.2 370.2 36 [00211] (1S,2R)-2-(((S)-(5- isopropylpyridin-2- yl)(phenyl)methyl) carbamoyl)cyclopentane-1- carboxylic acid 366.2 367.1 37 [00212] (1S,2R)-2-(((S)-(3- fluoro-4- isopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, first eluting isomer 383.2 384.2 38 [00213] (1S,2R)-2-(((S)-(4- cyclopropylphenyl)(phenyl) methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 363.2 364.2 39 [00214] (1S,2R)-2-(((R)-(4- isopropylphenyl)(2- methoxyphenyl)methyl) carbamoyl)cyclopentane- 1-carboxylic acid 395.2 396.3 40 [00215] (1S,2R)-2-(((R)-(4- isopropylphenyl)(o- tolyl)methyl)carbamoyl) cyclopentane-1- carboxylic acid, SFC column: DAICEL CHIRALPAK AD, second eluting isomer 379.2 380.3 41 [00216] (1S,2R)-2-(((S)-(4- isopropylphenyl)(phenyl) methyl)carbamoyl)cyclo- pentane-1-carboxylic acid 365.2 366.2 42 [00217] (1S,2R)-2-(((R)-(4- isopropylphenyl)(thiophen- 2-yl)methyl)carbamoyl) cyclohexane-1-carboxylic acid, SFC column: (S,S) Whelk O-1, second eluting isomer 385.2 386.1 43 [00218] (1R or 1S,2S or 2R)-2- (((S or R)-(4- isopropylphenyl)(thiophen- 2-yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: Chiralpak AD-H, fourth eluting isomer 371.2 372.2 44 [00219] (1R or 1S,2S or 2R)-2- (((R or S)-(4- isopropylphenyl)(thiophen- 2-yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: Chiralpak AD-H, third eluting isomer 371.2 372.2 45 [00220] (1S,2R)-2-(((R)-(4- isopropylphenyl)(thiophen- 2-yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: Chiralpak AD-H, second eluting isomer 371.2 372.2 46 [00221] (1S or 1R,2R or 2S)-2- (((S or R)-(4- isopropylphenyl)(thiophen- 2-yl)methyl)carbamoyl) cyclopentane-1-carboxylic acid, SFC column: Chiralpak AD-H, first eluting isomer 371.2 372.2

BIOLOGICAL EXAMPLES

Example B-1

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 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 Cmpd PK/LDH No. IC50 (M) 1 1.442 2 0.426 3 0.630 4 0.178 5 0.084 6 0.272 7 0.884 8 0.239 9 0.879 10 2.934 11 1.945 12 1.731 13 2.362 14 1.005 15 0.497 16 0.836 17 1.582 18 0.384 19 0.228 20 2.378 21 1.956 22 1.265 23 0.166 24 2.823 25 1.147 26 0.795 27 1.478 28 0.224 29 1.516 30 1.606 31 1.086 32 2.392 33 3.128 34 0.426 35 2.395 36 0.837 37 0.236 38 1.129 39 3.405 40 0.390 41 0.637 42 0.961 43 19.750 44 12.870 45 0.364 46 >99.88

Example B-2

[0429] 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.

[0430] 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.

[0431] 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 No. IC.sub.50 (M) 7 >10.00 8 3.93 9 >100.00 10 >100.00 11 >100.00 12 >65.78 13 >68.62 14 >60.78 15 8.49 16 >100.00 17 27.3 18 16.57 19 20.68 20 >100.00 21 >100.00 22 13.9 23 5.36 24 91.97 25 24.48 26 21.57 27 46.29 28 15.77 29 65.58 30 31.32 31 12.26 32 >100.00 37 3.69 39 41.28 45 6.6

Example B-3

[0432] 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.

[0433] 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.

[0434] 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 No. IC.sub.50 (M) 8 >100.0 15 >100.0 17 >100.0 18 28.6 19 >100.0 22 66.73 23 8.483 26 15.49 27 >100.0 28 7.797 31 >100.0 34 67.07 36 >100.0 37 72.75 39 66.4 40 10.78 41 >87.06 42 >77.60 43 >250.0 44 11.69 45 97.96 46 >250.0

Example B-4

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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

[0439] 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

[0440] 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.

[0441] 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.

[0442] 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.