Heterocyclic Compounds Useful for Kinase Inhibition

• US 20160096824A1
• Filed: 12/10/2015
• Published: 04/07/2016
• Est. Priority Date: 03/24/2010
• Status: Active Grant

• Current Assignee: Amitech Therapeutic Solutions, Inc.
• Original Assignee: Amitech Therapeutic Solutions, Inc.
• Inventors: ARNOLD, Lee Daniel, MURPHY, Eric A.
• Granted Patent: US 10,214,513 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 249/14 Nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/22 : in which the condensed system contains four or more hetero rings
• CPC Class Codes: C12N 2501/48 : Regulators of apoptosis
• CPC Class Codes: C12N 5/0693 : Tumour cells; Cancer cells

Abstract

Provided herein are compounds useful for kinase inhibition.

Claims

1. A compound having the structure (I) or an N-oxide, N,N′

-dioxide, N,N′

,N″

-trioxide, or a pharmaceutically acceptable salt thereof;

2. The compound of claim 1, wherein Q is S.

3. The compound of claim 1 or claim 2, wherein n is 2.

4. The compound of claim 1 or claim 2 or claim 3, wherein Z₃ is O or S.

5. The compound of any one of claims 1-4, wherein W is C₃-C₁₀ heterocycle having 1-3 heteroatoms.

6. The compound of any one of claims 1-4, wherein W is C₆-C₁₂ aryl.

7. The compound of any one of claims 1-5, wherein

Z₃ is O or S;

and

each R₂ and R₃ are independently selected from a group consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally substituted C₁-C₆ alkyl, —

CF₃, halogen, —

CN, and —

CO₂R′

wherein R′

is hydrogen or C₁-C₆ alkyl;

or, optionally, R₂ and R₃ are joined to form a five to seven membered carbocycle.

8. The compound of claim 5, wherein W is selected from the group consisting of thiophene, pyridine, pyridazine, pyrimidine and pyrazine.

9. The compound of claim 6, wherein W is phenyl.

10. The compound of any one of claims 1-9, wherein R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms.

11. The compound of any one of claim 1-10, wherein R₁ is an unsubstituted or a substituted pyridine.

12. The compound of any one of claims 1-10, wherein R₁ is an unsubstituted or a substituted pyrimidine.

13. The compound of any one of claims 1-12, wherein R₄ is hydrogen.

14. The compound of claim 11, wherein R₁ is an unsubstituted pyridine or a C₁-C₆ alkyl substituted pyridine.

15. The compound of any one of claims 1-14, wherein each R₂ and R₃ are independently selected from a group consisting of a C₁-C₆ alkyl, —

CF₃, and halogen, wherein p is 0 or 1 or 2;

or, optionally, R₂ and R₃ are joined to form a five to seven membered carbocycle.

16. The compound of claim 5, wherein the compound is selected from the group consisting of:

17. The compound of claim 1, wherein the compound having structure (I) is selected from the group consisting of:

18. The compound of claim 1, wherein the compound having structure (I) is selected from the group consisting of:

19. The compound of claim 1, wherein the compound having structure (I) is selected from the group consisting of:

20. The compound of claim 1, having the structure (H)

21. The compound of claim 20, wherein

each R₂ and R₃ are independently selected from a group consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally substituted C₁-C₆ alkyl, —

CF₃, halogen, —

CN, and —

CO₂R′

wherein R′

is hydrogen or C_r C₆ alkyl;

or, optionally, R₂ and R₃ are joined to form a five to seven membered carbocycle.

22. The compound of claim 20 or claim 21, wherein R₄ is hydrogen.

23. The compound of any one of claims 20-22, wherein R₈ and R₉ are independently selected from the group consisting of optionally substituted C₁-C₆ alkoxy, —

NR₁₀R₁₁, and —

SO_mR₁₂, and m is 0-2.

24. The compound of any one of claims 20-23, wherein R₈ is C₁-C₆ alkoxy or —

SR₁₂.

25. The compound of any one of claims 20-24, wherein each R₂ and R₃ are independently selected from a group consisting of a C₁-C₆ alkyl, —

CF₃, and halogen wherein p is 0 or 1 or 2;

or, optionally, R₂ and R₃ are joined to form a five to seven membered carbocycle.

26. The compound of claim 20, wherein the compound having structure (II) is selected from the group consisting of

27. The compound of claim 20, therein the compound having structure (II) is selected from the group consisting of

28. The compound of claim 20, therein the compound having structure (II) is selected from the group consisting of

29. The compound of claim 1, having the structure (III) or an N-oxide, N,N′

-dioxide, N,N′

,N″

-trioxide, or a pharmaceutically acceptable salt thereof;

30. The compound of claim 29, wherein Z₃ is O or S.

31. The compound of claim 29 or claim 30, wherein

each R₂ and R₃ are independently selected from a group consisting of a C₁-C₆ alkyl, —

CF₃, and halogen wherein p is 0 or 1 or 2;

or, optionally, R₂ and R₃ are joined to form a five to seven membered carbocycle.

32. The compound of any one of claims 29-31, wherein R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms.

33. The compound of any one of claim 29-32, wherein R₁ is an unsubstituted or a substituted pyridine.

34. The compound of any one of claims 29-32, wherein R₁ is an unsubstituted or a substituted pyrimidine.

35. The compound of any one of claims 29-34, wherein R₄ is hydrogen.

36. The compound of claim 33, wherein R₁ is an unsubstituted pyridine or a C₁-C₆ alkyl substituted pyridine.

37. The compound of claim 29, wherein the compound having structure (III) is selected from the group consisting of

38. The compound of claim 29, wherein the compound is

46. A pharmaceutical composition comprising a compound as set forth in any of the preceding claims, in a pharmaceutically acceptable carrier.

47. A method for suppressing, preventing or inhibiting lymphangiogenesis, neovascularization, recruitment of periendothelial cells, angiogenesis, hyderproliferative disorder, fibrotic lesion, ocular disorder and/or growth of a tumor, which comprises contacting the tumor with the pharmaceutical composition of claim 46 or a compound of any of the preceding claims 1-45.

48. A method for treating cancer, restenosis, intimal hyperplasia, fibrotic diseases or angiogenesis-dependent disorder in a human subject comprising administering to a patient in need the pharmaceutical composition of claim 46 or a compound according to any one of claims 1-45.

49. A method for preventing inhibition of ASK1-mediated apoptosis in a cell, sensitizing a cell to an extrinsic stress, or inhibiting MEK1/2- and/or ERK1/2-mediated cellular proliferation or migration comprising contacting the cell with the pharmaceutical composition of claim 46 or a compound according to any one of claims 1-45.

50. A method for inhibiting phosphorylation of S338 of CRAF and/or RAF dimerization comprising contacting the cell with the pharmaceutical composition of claim 46 or a compound according to any one of claims 1-45.

51. A method of inhibiting a protein kinase comprising contacting the protein kinase with an inhibitory concentration of a compound according to any one of claims 1-45.

52. The method of claim 51, wherein the protein kinase is selected from A-RAF, B-RAF and C-RAF.

53. A method of inhibiting RAF kinase mediated signaling in a cell comprising contacting the cell with an inhibitory concentration of a compound according to any one of claims 1-45.

54. The method of claim 53 wherein the cell is characterized by increased activity of the RAS-RAF-MEK-ERK pathway compared to a non-transformed cell.

55. The method of claim 53, wherein the cell is characterized by an A-RAF, B-RAF, or C-RAF gain-of-function mutation.

56. The method of any one of claims 47-55, wherein the compound is a selective type II inhibitor of a PDGF receptor or RAF kinase.

57. The method of any one of claims 47-50, wherein the compound inhibits the heterodimerization of B-RAF with C-RAF or C-RAF with C-RAF.

58. The method of any one of claims 47-50, wherein the compound inhibits the phosphorylation of S338 of C-RAF.

59. The method of any one of claims 47-50, wherein said compound is an allosteric inhibitor of PDGFRα

, PDGFRβ

, Flt3, A-RAF, B-RAF, C-RAF and/or c-Kit.

60. The method of claim 48, wherein the cancer is resistant, refractory or non-responsive to a type I inhibitor of the protein kinase.

61. The method of claim 48, wherein the cancer is resistant, refractory or non-responsive to a pan-RAF kinase drug or an ATP-competitive inhibitor.

62. The method of claim 48, wherein the cancer is resistant, refractory or non-responsive to a drug selected from Sorafenib, PLX4032, XL281, RAF265, 885-A, ZM336372, L-779450, AZ628, AAL881, LBT613, MCP110, 17-DMAG, CI1040, AZD6244/ARRY142886, PD0325901, SB590885, DP3346, and DP2514.

63. The method of claim 48, wherein the cancer is resistant, refractory or non-responsive to a VEGF-targeted therapy.

64. The method of claim 48, wherein the cancer is associated with a mutant form of RAF kinase.

65. The method of claim 64, wherein the mutant form of RAF kinase is a B-RAF kinase selected from mutant T529I, T529N, G464A, G464E, G464V, G466A, G466E, G466V, G469A, G469E, N581S, E586K, F595L, G596R, L597V, L597R, T599I, V600E, and K601E.

66. The method of claim 64, wherein the mutant form of RAF kinase is C-RAF gatekeeper mutant selected from T421N, and T421I.

67. The method of claim 48 wherein the cancer is selected from melanoma, breast cancer, colon cancer, pancreatic cancer, lung cancer, kidney cancer, and colon cancer.

68. The method of claim 48, wherein the cancer is characterized by stroma rich tumors.

69. The method of claim 48, wherein the cancer has a mutant or aberration selected from N-RAS, H-RAS, K-RAS, B-RAF(V600E), B-RAF/Ras, HER1, p53, PTEN, and P13K.

70. The method of claim 48, wherein the cancer exhibits up-regulation of the RAF-MEK-ERK pathway.

71. The method of claim 48, wherein the compound is administered orally to the patient in need.

72. The method of claim 48, wherein the human subject is also provided with a therapy selected from anti-angiogenic therapy, chemotherapy or radiation therapy.

73. The method of claim 48, wherein the response of the patient to the compound is monitored by inhibition of the phosphorylation of S338 of C-RAF.

74. The method of claim 49 wherein the stress is selected from hypoxia, chemotherapy, radiotherapy or glucose/nutrient starvation.

75. The method of claim 49, wherein the compound blocks VEGF- and/or FGF-stimulated endothelial responses in tumor angiogenesis.

76. The method of claim 48 wherein the restenosis is intimal hyperplasia-driven restenosis after vascular injury.

77. The method of claim 48, wherein the fibrosis is pulmonary fibrosis.

78. The method of claim 48, wherein the fibrosis is liver fibrosis.

79. The method of claim 48, wherein the fibrosis is cardiac fibrosis.

80. The compound according to any one of claims 1 to 45, wherein said compound is deuterium-enriched by replacing at least one hydrogen atom with deuterium atom.

81. The compound of claim 80, wherein deuterium enrichment is at least about 1%.

82. The compound of claim 80, wherein said compound is selected from the group consisting of:

39. A compound having the structure (IV) or an N-oxide, N,N′

-dioxide, N,N′

,N″

-trioxide, or a pharmaceutically acceptable salt thereof;

40. The compound of claim 39, wherein n is 2.

41. The compound of claim 39 or claim 40, wherein Z₃ is O or S.

42. The compound of claim 39, wherein the compound having structure (IV) is selected from the group consisting of

43. A compound having the structure (V) or an N-oxide, N,N′

-dioxide, N,N′

,N″

-trioxide, or a pharmaceutically acceptable salt thereof;

44. The compound of claim 43, wherein n is 2.

45. The compound of claim 43, the compound having structure (V) is selected from the group consisting of