Macrocyclic compounds, compositions, and methods of use thereof

Abstract

The present disclosure includes, inter alia, compounds of Formula I (I) as CFTR modulators, pharmaceutical compositions, and methods of making and using them. TIFF2025530153001720.tif58165

Claims

1. Formula I: or a pharmaceutically acceptable salt thereof, During the ceremony, L １ is optionally substituted C １～６ an alkylene chain, wherein one to three of the methylene units are optionally and independently —O—, —N(R ２ ), -C(O)-, -S-, -S(O)-, -S(O) ２ -, optionally substituted 3- to 6-membered carbocyclyl, Optionally substituted C ２ optionally substituted by alkenylene or optionally substituted 5- to 6-membered heteroaryl; L ２ is optionally substituted C １～６ an alkylene chain in which one to three of the methylene units are optionally and independently —C(CD ３ ) ２ -, -O-, -N(R ２ )-, —C(O)-, —S-, —S(O)-, optionally substituted 3- to 6-membered carbocyclyl, —S(O) ２ -, optionally substituted C ２ optionally substituted by alkenylene or optionally substituted 5- to 6-membered heteroaryl; Ring A is an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; Ring B is optionally substituted phenyl or optionally substituted 6-membered heteroaryl; Ring D is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl; X is —O—, —S—, —CH ２ -, -C(OH)H-, -CHCH ３ , -SO-, -CO-, -SO ２ -, -CFH-, -CF ２ - and -N(R ２ )- is selected from the group consisting of Each R Ａ are independently selected from halogen, cyano, optionally substituted C １ ~C ６ Aliphatic, optionally substituted C １ ~C ６ Alkoxy and -CD ３ is selected from the group consisting of Each R Ｂ are independently selected from halogen, cyano, —C(O)N(R ２ ) ２ , C(O)OR ２ , -OR ２ , -N(R ２ ) ２ , optionally substituted C １ ~C ６ Aliphatic and optionally substituted C １ ~C ６ alkoxy; Each R Ｃ are independently hydrogen, halogen, cyano, -(CH ２ ) ０～３ C(O)OH, optionally substituted C １ ~C ６ Aliphatic or optionally substituted C １ ~C ６ alkoxy; Each R Ｄ are independently selected from halogen, cyano, —C(O)N(R ２ ) ２ , -C(O)OR ２ , -OR ２ , -N(R ２ ) ２ , optionally substituted C １ ~C ６ Aliphatic, optionally substituted C １ ~C ３ alkoxy, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S; Ｄ But, R ｄ may be replaced by 1 to 6 instances of Here, R Ｄ two instances of may be taken together to form an optionally substituted 5- to 7-membered carbocyclic ring, an optionally substituted 5- to 6-membered heteroaryl, and an optionally substituted 3- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S; Each R ｄ are independently hydrogen, —OH, —CD ３ , -C(O)N(R ２ ) ２、 C(O)OR ２ , -OR ２ , -N(R ２ ) ２ , -S(O) ２ R ２ , optionally substituted C １ ~C ６ selected from the group consisting of aliphatic, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S; R １ is hydrogen, cyano, -OR ２ , -(CH ２ ) ０～３ N (R ２ ) ２ , optionally substituted C １ ~C ３ a 3- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of aliphatic, N, O, or S, and -CD ３ is selected from the group consisting of Each R ２ are independently hydrogen, optionally substituted C １ ~C ６ Aliphatic, -OH, C １ ~C ６ Alkoxy, —S(O) ２ (Optionally substituted C １ ~C ６ aliphatic), each Z is independently —CH═, —N═, or —NH—; n is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; r is 0, 1, 2, 3, 4 or 5; The compound or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein ring D is an optionally substituted phenyl or an optionally substituted pyridine.

3. Ring D is 3. The compound of claim 2, wherein:

4. Ring D is 10. A compound according to any one of the preceding claims, wherein

5. Ring D is 10. A compound according to any one of the preceding claims, wherein

6. 10. A compound according to any one of the preceding claims, wherein Ring B is an optionally substituted phenyl, an optionally substituted pyridine or an optionally substituted pyridone.

7. Ring B is and During the ceremony, W is -CH=, -C(R Ｂ )= or -N=, V is -CH=, -C(R Ｂ )= or -N=; A compound according to any one of the preceding claims.

8. Ring B is 10. A compound according to any one of the preceding claims, wherein

9. Ring B is 10. A compound according to any one of the preceding claims, wherein

10. Ring B is 10. A compound according to any one of the preceding claims, wherein

11. R Ｂ is halogen or optionally substituted C １ ~C ３ 10. A compound according to any one of the preceding claims, which is alkyl.

12. R Ｂ 10. A compound according to any one of the preceding claims, wherein is a halogen.

13. R Ｂ 10. A compound according to any one of the preceding claims, wherein is fluoro.

14. The compound has formula (Ia), (Ib), (Ic) or (Id): or a pharmaceutically acceptable salt thereof, During the ceremony, Y is C or N; A compound according to any one of the preceding claims.

15. Formula (I-a1), (I-a2), (I-a3), (I-a4) or (I-a5):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

16. Formula (I-d1), (I-d2), (I-d3), (I-d4) or (I-d5):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

17. 10. A compound according to any one of the preceding claims, wherein Ring C is selected from optionally substituted indole, optionally substituted indazole, optionally substituted benzimidazole, optionally substituted 6-azaindole and optionally substituted 7-azaindole.

18. 10. A compound according to any one of the preceding claims, wherein Ring C is an optionally substituted indole.

19. R Ｄ At least one instance of and During the ceremony, Each R ｄ are independently hydrogen, optionally substituted methyl, —OH, —OMe, or —CD ３ is selected from Here, two instances R ｄ together with the atoms to which they are attached can form a cyclopropyl ring, m is 0, 1, 2 or 3; A compound according to any one of the preceding claims.

20. Each R ｄ are independently hydrogen, methyl, or —CF ３ , -CF ２ H or -CFH ２ 17. The compound of claim 16, selected from:

21. Each R ｄ 18. The compound of claim 17, wherein is independently selected from hydrogen and methyl.

22. R Ｄ At least one instance of 10. A compound according to any one of the preceding claims selected from the group consisting of:

23. R Ｄ At least one instance of 20. The compound of claim 19 selected from the group consisting of:

24. R Ｄ but, 21. The compound of claim 20, wherein:

25. R Ｄ but, 22. The compound of claim 21, wherein:

26. R Ｄ but, 22. The compound of claim 21, wherein:

27. 10. A compound according to any one of the preceding claims, wherein Ring A is selected from the group consisting of imidazole, pyrazole, tetrazole, oxazole, thiazole and 1,2,4 triazole.

28. Each R Ａ are independently hydrogen, methyl and -CD ３ 10. A compound according to any one of the preceding claims, selected from:

29. Formula (I-e):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

30. L １ is optionally substituted C １～６ is an alkylene chain, and L ２ is optionally substituted C １～６ an alkylene chain, where L ２ 10. A compound according to any one of the preceding claims, wherein one of the methylene units of

31. L １ C substituted with 1 to 3 instances of methyl １～６ is an alkylene chain, and L ２ But C １～６ an alkylene chain, where L ２ One of the methylene units of L may be replaced by —O—; ２ 10. A compound according to any one of the preceding claims, wherein is optionally substituted with 1 to 3 instances of methyl.

32. L １ is unsubstituted C ２ 10. A compound according to any one of the preceding claims, which is an alkylene chain.

33. L ２ But C ５ an alkylene chain, where L ２ One of the methylene units of L may be replaced by —O—; ２ 10. A compound according to any one of the preceding claims, wherein is optionally substituted with 1 to 3 instances of methyl.

34. L ２ But C ５ an alkylene chain, where L ２ 10. A compound according to any one of the preceding claims, wherein is optionally substituted with 1 to 3 instances of methyl.

35. L ２ But C ５ an alkylene chain, where L ２ 10. A compound according to any one of the preceding claims, wherein is optionally substituted with 1 to 3 instances of methyl.

36. The compound has the formula (If): or a pharmaceutically acceptable salt thereof, During the ceremony, Z １ But -CH ２ - or -O-, Z ２ But -CH ２ - or -O-; A compound according to any one of the preceding claims.

37. Formula (Ig):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

38. Formula (I-g1) or (I-g2):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

39. Formula (Ih):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

40. Formula (I-i):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

41. Formula (I-j):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

42. Formula (Ik):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

43. Formula (Im):

10. The compound of any one of the preceding claims, which is: or a pharmaceutically acceptable salt thereof.

44. Z １ is —O—, and Z ２ But -CH ２ 10. A compound according to any one of the preceding claims, wherein

45. Z １ But -CH ２ - and Z ２ A compound according to any one of the preceding claims, wherein is -O-.

46. Z １ But -CH ２ - and Z ２ But -CH ２ 10. A compound according to any one of the preceding claims, wherein

47. R １ is optionally substituted C １ ~C ３ 10. A compound according to any one of the preceding claims which is aliphatic.

48. R １ is optionally substituted methyl or -CD ３ 10. A compound according to any one of the preceding claims, wherein

49. Each R ｄ are independently hydrogen or optionally substituted C １ ~C ３ 10. A compound according to any one of the preceding claims which is aliphatic.

50. At least one R ｄ is optionally substituted C １ ~C ３ 10. A compound according to any one of the preceding claims which is aliphatic.

51. At least one R ｄ 10. A compound according to any one of the preceding claims, wherein is methyl.

52. Each R Ａ are independently optionally substituted C １ ~C ３ 10. A compound according to any one of the preceding claims which is aliphatic.

53. Each R Ａ are independently methyl or -CD ３ 10. A compound according to any one of the preceding claims, wherein

54. R Ｃ 10. A compound according to any one of the preceding claims, wherein is a halogen.

55. R Ｃ 4. A compound according to any one of the preceding claims, wherein is independently fluoro or chloro.

56. R Ｄ A compound according to any one of the preceding claims, wherein is -COOH.

57. R Ｄ 10. A compound according to any one of the preceding claims, wherein is a halogen.

58. R Ｄ 10. A compound according to any one of the preceding claims, wherein is fluoro.

59. R Ｃ 10. A compound according to any one of the preceding claims, wherein is hydrogen.

60. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

62. 62. A method of treating a CFTR-mediated disease or disorder, comprising administering to a patient in need thereof a compound of any one of claims 1 to 60 or a pharmaceutical composition of claim 61.

63. The disease or condition may be cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, sinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary pulmonary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, familial hypercholesterolemia, type 1 cholangiocarcinoma, or type 2 cholangiocarcinoma. Micronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidosis, Sandhoff / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal ( Neurophysial DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Peritzeus-Merzbach disease, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies, Huntington's disease, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian corpora, myotonic dystrophy, spongiform encephalopathy, hereditary Creutzfeldt-Jakob disease, Fabry disease, Strauss- 63. The method of claim 62, wherein the condition is selected from Scheinker syndrome, COPD, dry eye disease, Sjogren's disease, osteoporosis, osteopenia, bone healing and growth, bone repair, bone regeneration, reduced bone resorption, increased bone deposition, Gorham syndrome, chloride channelopathy, myotonia congenita, Bartter syndrome type III, Dent's disease, hyperalgesia, epilepsy, hyperalgesia, lysosomal storage disease, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus, and ciliary aplasia.

64. 64. The method of claim 62 or 63, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent or chronic pancreatitis, generalized bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomicronemia, mild lung disease, lipid processing deficiency, hereditary angioedema type 1, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-associated metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

65. 65. The method of any one of claims 62 to 64, wherein the disease or condition is cystic fibrosis.

66. 62. A method of treating cystic fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 60 or a pharmaceutical composition of claim 61.

67. 67. The method of claim 66, wherein the subject is a human.

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