Bicyclic compounds for ketohexokinase inhibition

Abstract

Disclosed herein are methods for inhibiting ketohexokinase (KHK) in a biological sample or subject, and methods for treating or preventing a disease or disorder (e.g., a disease or disorder related to KHK dysregulation), comprising administering to the biological sample or subject an effective amount of a compound represented by formula (I) or a compound in Table A, or a pharmaceutically acceptable salt thereof. JPEG2026520434000114.jpg4243

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, X １ and X ２ Each of these independently determines N or CR ４ And, Z is N or CR ５ And, R １ However, it is either H or OH, R ２ However, C １－６ Alkyl or C １－６ It is a haloalkyl, R ３ is H, C １－６ alkyl, C １－６ haloalkyl, or C １－６ alkoxy, and R ４ However, H, Haro, C １－６ Alkyl, C １－６ Haloalkyl, or C ３－１０ It is a cycloalkyl, R ５ However, H, Haro, C １－６ Alkyl, or C １－６ It is a haloalkyl, Y is combined or C １－６ It is alkylene-C(O), A is a 5 or 6-membered heteroaryl having 1 to 3 ring nitrogen atoms, and the heteroaryl has 1 or 2 R ６ It is replaced by an optional selection, B is a 4- to 8-membered heterocycloalkyl having one or two ring nitrogen atoms, and the heterocycloalkyl has one or two R ６ It is replaced by an optional selection, Each R ６ However, independently, OH, Halo, CN, -N(R) ａ ) (Caution ｂ ), C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, or C １－６ It is an alkoxy, R ａ and R ｂ However, independently, H or C １－３ A compound that is alkyl, or a pharmaceutically acceptable salt thereof.

2. Formula II: 【Chemistry 2】 It has the structure, in the formula C Ａ and C Ｂ The compound or salt according to claim 1, wherein each of these represents a carbon stereocenter.

3. C Ａ However, it is a carbon in the R configuration, C Ｂ The compound or salt according to claim 2, wherein the carbon is in an R configuration.

4. C Ａ However, it is a carbon in the R configuration, C Ｂ The compound or salt according to claim 2, wherein the carbon is in an S configuration.

5. Formula III: 【Transformation 3】 It has the structure, in the formula C Ａ , C Ｂ , C Ｄ and C Ｅ The compound or salt according to claim 1, wherein each of these represents a carbon stereocenter.

6. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in the R configuration, C Ｄ and C Ｅ The compound or salt according to claim 5, wherein the carbon is in the R configuration.

7. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in the R configuration, C Ｄ and C Ｅ The compound or salt according to claim 5, wherein the carbon is in an S configuration.

8. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in the R configuration, C Ｄ However, it is a carbon in the R configuration, C Ｅ The compound or salt according to claim 5, wherein the carbon is in an S configuration.

9. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in the R configuration, C Ｄ However, it is a carbon in an S configuration, C Ｅ The compound or salt according to claim 5, wherein the carbon is in the R configuration.

10. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in an S configuration, C Ｄ and C Ｅ The compound or salt according to claim 5, wherein the carbon is in the R configuration.

11. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in an S configuration, C Ｄ and C Ｅ The compound or salt according to claim 5, wherein the carbon is in an S configuration.

12. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in an S configuration, C Ｄ However, it is a carbon in the R configuration, C Ｅ The compound or salt according to claim 5, wherein the carbon is in an S configuration.

13. C Ａ However, it is a carbon in the R configuration, C Ｂ However, it is a carbon in an S configuration, C Ｄ However, it is a carbon in an S configuration, C Ｅ The compound or salt according to claim 5, wherein the carbon is in the R configuration.

14. X １ and X ２ One of them is N, and the other is CR ４ The compound or salt according to any one of claims 1 to 13.

15. X １ However, N is X ２ However, CR ４ The compound or salt according to claim 14.

16. X １ However, CR ４ X ２ The compound or salt according to claim 14, wherein N is present.

17. R ４ However, H, Haro, C １－６ Alkyl, or C １－６ A compound or salt according to any one of claims 1 to 16, which is a haloalkyl compound.

18. R ４ However, H, C １－６ Alkyl or C １－６ The compound or salt according to claim 17, which is a haloalkyl compound.

19. R ４ is H, methyl or CF ３ and is a compound or salt according to claim 17 or 18.

20. R ４ The compound or salt according to claim 17, which is a halo.

21. R ４ The compound or salt according to claim 20, wherein it is fluoro.

22. R ４ However, C ３－１０ A compound or salt according to any one of claims 1 to 16, which is a cycloalkyl compound.

23. R ４ The compound or salt according to claim 22, wherein the compound is cyclopropyl.

24. A compound or salt according to any one of claims 1 to 23, wherein Z is N.

25. Z is CR ５ The compound or salt according to any one of claims 1 to 23, wherein Z is CR

26. R １ The compound or salt according to any one of claims 1 or 14 to 25, wherein H is present.

27. R １ The compound or salt according to any one of claims 1 to 25, wherein the compound is an OH group.

28. R ２ However, C １－６ A compound or salt according to any one of claims 1 to 27, wherein the compound is alkyl.

29. R ２ The compound or salt according to claim 28, wherein the compound is methyl.

30. R ２ However, C １－６ A compound or salt according to any one of claims 1 to 27, which is a haloalkyl compound.

31. R ２ However, CHF ２ or CF ３ The compound or salt according to claim 30.

32. R ３ However, H or C １－６ A compound or salt according to any one of claims 1 to 31, wherein the compound is alkyl.

33. R ３ The compound or salt according to claim 32, wherein the compound is H or methyl.

34. A is a 5-membered heteroaryl having 1 to 3 ring nitrogen atoms, and 1 or 2 R ６ A compound or salt according to any one of claims 1 to 33, which is optionally substituted by [the specified compound].

35. A is pyrazolyl, imidazolyl, or triazolyl, and one or two R ６ The compound or salt according to claim 34, which is optionally substituted.

36. The compound or salt according to claim 34 or 35, wherein A is unsubstituted.

37. A, 【Chemistry 4】 and each ＊ However, A indicates a bonding site to the rest of the compound, and A is one or two R ６ A compound or salt according to any one of claims 34 to 36, which is optionally substituted by [the specified compound].

38. A compound or salt according to any one of claims 1 to 37, wherein Y is a bond.

39. Y is C １－６ The compound or salt according to any one of claims 1 to 37, which is alkylene-C(O).

40. Y is C １ The compound or salt according to claim 39, which is alkylene-C(O).

41. B is a 4- to 8-membered heterocycloalkyl having one or two ring nitrogen atoms, and one or two R ６ A compound or salt according to any one of claims 1 to 40, which is optionally substituted with [the specified compound].

42. B is a 4-6 member heterocycloalkyl having one or two ring nitrogen atoms, and one or two R ６ A compound or salt according to any one of claims 1 to 4 or 14 to 41, which is optionally substituted by [the specified compound or salt].

43. B is azetidinil, pyrrolidinil, piperazinil, or diazepinil, and one or two R ６ The compound or salt according to claim 42, which is optionally substituted.

44. B is azetidinil or piperazinil, and one or two R ６ The compound or salt according to claim 43, which is optionally substituted.

45. A compound or salt according to any one of claims 1 to 4 and 14 to 44, wherein B is unsubstituted.

46. B has one R ６ A compound or salt according to any one of claims 1 to 44, which is substituted with

47. B has two R ６ A compound or salt according to any one of claims 1 to 44, which is substituted with

48. B, 【Transformation 5】 And, ＊ The compound or salt according to any one of claims 1 to 4 or 14 to 41, wherein it indicates a bonding site to the remaining portion of the compound.

49. at least one R ６ However, C １－６ A compound or salt according to any one of claims 46 to 48, wherein it is alkyl.

50. at least one R ６ The compound or salt according to claim 49, wherein the compound is methyl.

51. B, 【Transformation 6】 The compound or salt according to claim 48.

52. Formula (IV): 【Transformation 7】 It has the structure, and in the formula, R ４ However, H, chloro, fluoro, or C １－２ It is alkyl, R ２ However, trifluoromethyl or C １－２ It is alkyl, R ３ However, H or C １－２ It is alkyl, Y is combined or C １ It is alkylene-C(O), B, 【Transformation 8】 And, R ６ However, C １２ A compound or salt according to any one of claims 1 to 4, 26, and 27, wherein the compound is alkyl.

53. Compounds listed in Table A, or their pharmaceutically acceptable salts.

54. (2S,3R)-1-{3-chloro-5-[1-(1-methyl-3-azetidinyl)-4-pyrazolyl]-1,3a,6-triaza-7-indenyl}-2-methyl-3-azetidinol (A18), 7-[(R)-2-(trifluoromethyl)-1-azetidinyl]-4-methyl-5-[1-(1-methyl-3-azetidinyl)-4-pyrazolyl]-1,3a,6-triazaidene (A11), 7-[(S)-2-methyl-1-azetidinyl]-4-methyl-5-[1-(1-methyl-3-azetidinyl)-4-pyrazolyl]-1,3a,6-triazaidene(A9), 7-[(R)-2-(trifluoromethyl)-1-azetidinyl]-3-methyl-5-[1-(1-methyl-3-azetidinyl)-4-pyrazolyl]-1,3a,6-triazaidene (A21), 2-(4-{7-[(R)-2-(trifluoromethyl)-1-azetidinyl]-3-chloro-1,3a,6-triaza-5-indenyl}-1-pyrazolyl)-1-(1-piperazinyl)-1-ethanone (A29), 7-[(S)-2-methyl-1-azetidinyl]-3-methyl-5-[1-(1-methyl-3-azetidinyl)-4-pyrazolyl]-1,3a,6-triazaidene (A49), 2-(4-{7-[(S)-2-methyl-1-azetidinyl]-3-chloro-1,3a,6-triaza-5-indenyl}-1-pyrazolyl)-1-(1-piperazinyl)-1-ethanone (A60), and A compound selected from 7-[(R)-2-(trifluoromethyl)-1-azetidinyl]-4-methyl-5-[1-(1-methyl-3-azetidinyl)-4-pyrazolyl]-1,3,3a,6-tetraazaidene (A89), or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 54 and a pharmaceutically acceptable excipient.

56. A method for inhibiting ketohexokinase (KHK) in cells, comprising contacting the cells with a compound or salt according to any one of claims 1 to 54, or a pharmaceutical composition according to claim 55.

57. A method for treating or preventing a disease or disorder related to abnormal ketohexohinase (KHK) activity in a subject, comprising administering to the subject a therapeutic amount of a compound or salt according to any one of claims 1 to 54, or a pharmaceutical composition according to claim 55.

58. The method according to claim 57, wherein the disease or disorder is related to KHK dysregulation.

59. The method according to claim 57 or 58, wherein the disease or disorder is a metabolic syndrome, hypertriglyceridemia, hypercholesterolemia, non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-related fatty liver disease (MASLD), MASLD with increased alcohol intake (MetALD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-related fatty liver disease (MASH), type 2 diabetes mellitus (T2D), diabetic nephropathy (DKD), alcoholic steatohepatitis (ASH), alcohol-related liver disease (ALD), hepatic fibrosis or cirrhosis, liver disease caused by hepatocyte stress, hereditary fructose intolerance, hyperuricemia, gout, toxic craving, neurodegenerative disease, or cancer.

60. The method according to claim 59, wherein the disease or disorder is NASH or MASH.

61. The method according to any one of claims 56 to 60, further comprising administering to the subject an additional therapeutically effective amount of a therapeutic agent.

62. The method according to claim 61, wherein the additional therapeutic agent comprises metformin, a fructose transporter inhibitor, an aldose reductase inhibitor, a xanthine oxidase inhibitor, a thyroid hormone beta receptor agonist, an incretin hormone receptor agonist or modulator, or a sodium / glucose transporter inhibitor.

63. The method according to claim 62, wherein the incretin hormone receptor agonist or modulator is semaglutide, dulaglutide, liraglutide, tilzepatide, sulvodutide, letatoltide, pembidutide, VK2735, olfoglipron, caglilintide / semaglutide, danuglipron, maridebaatcafraglutide, RGT-075, PF-0695422, NN9487, NN9541, CT-388, CT-868, CT-996, efinopegdutide, efosipegdoltide, AZD9550, DR10624, NLY01, ECC5004, mazdutide, exenatide, TERN-601, echnoglutide, or XW-004.

64. The method according to claim 63, wherein the fructose transporter inhibitor is an inhibitor of GLUT2, GLUT5, or both.

65. The method according to claim 63, wherein the aldose reductase inhibitor is AT-001, AT-003, gaborestat, ranirestat, epalrestat, fidarestat, imirestat, tollestat, or risarestat.

66. A method for treating or preventing metabolic syndrome, hypertriglyceridemia, hypercholesterolemia, non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-related fatty liver disease (MASLD), MASLD with increased alcohol intake (MetALD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-related fatty liver disease (MASH), type 2 diabetes mellitus (T2D), diabetic nephropathy (DKD), alcoholic steatohepatitis (ASH), alcohol-related liver disease (ALD), hepatic fibrosis or cirrhosis, liver disease caused by hepatocyte stress, hereditary fructose intolerance, hyperuricemia, gout, toxic craving, neurodegenerative disease, or cancer, comprising administering to the subject a therapeutic dose of a compound or salt according to any one of claims 1 to 54, or a pharmaceutical composition according to claim 55.

67. The method according to claim 66, wherein the disease or disorder is NASH or MASH.

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