Novel fak degrader compounds and uses thereof

Abstract

Provided herein are compounds and compositions thereof that reduce FAK protein levels. In some embodiments, the compounds have structures of Formula I: In some embodiments, the compounds and compositions are provided for treatment of FAK associated diseases such as cancer.

Description

This application provides compounds and compositions thereof that can reduce FAK protein levels. In some embodiments, the compounds have the structure shown in Formula I; in some embodiments, the compounds and compositions are used to treat FAK-related diseases, such as cancer. Abstract

Claims

CLAIMS What is claimed is:

1. A compound having a Formula (I),or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: ---- may be absent or a double bond; X is independently selected from C and N; Y is independently selected from C and N; YY is independently selected from C and N; Z is independently selected from C and N; ZZ is independently selected from C and N; R1is independently selected from hydrogen, halogen, and -C1-C6 alkyl; R2is independently selected from hydrogen, halogen, -(=O), -C1-C6 alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R9, -N(R9R10), and –OR9; R3is independently absent or selected from hydrogen and halogen; R4is independently absent or selected from hydrogen and -C1-C6alkyl; R5is independently absent or selected from hydrogen, halogen and -C1-C6alkyl; R6is independently selected from a 5 to 12 membered aryl and a 5 to 12 membered heteroaryl ring, wherein the aryl and heteroaryl may be optionally substituted with 1, 2, or 3 -R9, -N(R9R10), and -OR9; R7is hydrogen or halogen; R8is independently selected from -N(R9R10), and a 4 to 12 membered heterocyclic ring, wherein the heterocyclic ring may be optionally substituted with 1, 2 or 3 -R9, - N(R9R10), and -OR9;R9is independently selected from hydrogen, halogen, -OR10, -N(R10R10), -C1-C6 alkyl, - O-C1-C6 alkyl, -CN, a 3 to 12 membered cycloalkyl, and a 4 to 12 membered heterocyclic ring; wherein the alkyl, cycloalkyl, or heterocyclic ring in R9are each independently unsubstituted or substituted with 1, 2, or 3 R10substituents; R10in each instance is independently selected from hydrogen, -OH, -C1-C6alkyl, -C2-C6alkenyl, halogen, -O-(C1-C6alkyl)-, -N(R11R11), a 3 to 12 membered cycloalkyl, a 4 to 12 membered heterocyclic, a 5 to 12 membered aryl and a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R10are each independently unsubstituted or substituted with 1, 2, or 3 R11substituents; and R11is independently selected from hydrogen, halogen, -OH, and -C1-C6 alkyl, and further wherein the alkyl, heterocyclic and heteroaryl ring in each R6, R8, R9, and R10may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

2. The compound of claim 1, wherein ---- is a double bond.

3. The compound of claim 1, wherein ---- is absent.

4. The compound of any one of claims 1, 2 or 3, wherein X is C.

5. The compound of any one of claims 1-4, wherein Y is N.

6. The compound of any one of claims 1-4, wherein Y is C.

7. The compound of any one of claims 1-6, wherein YY is N.

8. The compound of any one of claims 1-6, wherein YY is C.

9. The compound of any one of claims 1-8, wherein Z is N.

10. The compound of any one of claims 1-8, wherein Z is C.

11. The compound of any one of claims 1-10, wherein ZZ is N.

12. The compound of any one of claims 1-10, wherein ZZ is C.

13. The compound of any one of claims 1-12, wherein R1is hydrogen.

14. The compound of any one of claims 1-12, wherein R2is hydrogen.

15. The compound of any one of claims 1-14, wherein R3is hydrogen.

16. The compound of any one of claims 1-15, wherein R4is absent.

17. The compound of any one of claims 1-15, herein R4is hydrogen.

18. The compound of any one of claims 1-15, wherein R4is -C1-C6 alkyl.

19. The compound of claim 18, wherein R4is -CH3.

20. The compound of claim 18, wherein R4is -CH2CH3.

21. The compound of any one of claims 1-20, wherein R5is hydrogen.

22. The compound of any one of claims 1-20, wherein R5is -C1-C6 alkyl.

23. The compound of claim 22, wherein R5is -CH3.

24. The compound of any one of claims 1-20, wherein R5is halogen.

25. A compound according to any one of claims 1-2, 4-5, 8, 10-11,13-15, and 21-24, having a Formula (Ia),or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R5is independently absent or selected from hydrogen, halogen or -C1-C6alkyl; R6is independently selected from a 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the aryl, and heteroaryl may be optionally substituted with 1, 2, or 3 -R9, -N(R9R10), or -OR9; R7is hydrogen or halogen; R8is independently selected from -N(R9R10), a 4 to 12 membered heterocyclic, ring, wherein the heterocyclic ring may be optionally substituted with 1, 2 or 3 -R9, -N(R9R10), or -OR9; R9is independently selected from hydrogen, halogen, -C1-C6 alkyl, -OR10, -N(R10R10), -CN, a 3 to 12 membered cycloalkyl, or a 4 to 12 membered heterocyclic ring; wherein the alkyl, cycloalkyl, or heterocyclic ring in R9are each independently unsubstituted or substituted with 1, 2, or 3 R10substituents; R10in each instance is independently selected from hydrogen, halogen, -OH, -C1-C6 alkyl, 3 to 12 membered cycloalkyl, and 4 to 12 membered heterocyclic ring; wherein the alkyl, cycloalkyl, and heterocyclic ring in R10are each independently unsubstituted or substituted with 1, 2, or 3 R11substituents; R11is independently hydrogen, halogen, -OH, and -C1-C6 alkyl, further wherein the cycloalkyl, heterocyclic and heteroaryl cyclic ring in each R6, R8, R9, and R10may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

26. The compound of claim 25, wherein R5is hydrogen.

27. The compound of claim 25, wherein R5is halogen.

28. The compound of claim 27, wherein R5is Cl or F.

29. The compound of claim 25, wherein R5is -C1-C6alkyl.

30. The compound of claim 29, wherein R5is -CH3.

31. The compound of any one of claims 25-30, wherein R6is selected from a 5 to 12 membered aryl ring, optionally substituted with 1, 2, or 3 -R9, -N(R9R10), or -OR9.

32. The compound of any one of claims 25-30, wherein R6is a 5 to 12 membered heteroaryl ring, optionally substituted with 1, 2, or 3 -R9, -N(R9R10), or -OR9.

33. The compound of any one of claims 25-32, wherein R7is hydrogen.

34. The compound of any one of claims 25-32, wherein R7is halogen.

35. The compound of claim 34, wherein the halogen is F or Cl.

36. The compound of any one of claims 25-34, wherein R8is independently selected from -N(R9R10), and a 4 to 12 membered heterocyclic ring.

37. The compound of claim 36, wherein R8is -N(R9R10).

38. The compound of claim 36, wherein R8is a 4 to 12 membered heterocyclic ring.

39. The compound of any one of claims 25-40, wherein R9is hydrogen.

40. The compound of any one of claims 25-40, wherein R9is halogen.

41. The compound of claim 42, wherein the halogen is selected from Cl and F.

42. The compound of claim 43, wherein the halogen is selected from Cl.

43. The compound of claim 43, wherein the halogen is selected from F.

44. The compound of any one of claims 25-38, having the Formula (Ia), wherein R9is - C1-C6alkyl.

45. The compound of claim 41, wherein the -C1-C6alkyl is selected from -CH3, -CH2CH3, -CH(CH3)2, and -C(CH3)3.

46. The compound of any one of claims 25-38, wherein R9is -OR10, -N(R10R10), -CN, a 3 to 12 membered cycloalkyl, or a 4 to 12 membered heterocyclic ring; wherein the alkyl, cycloalkyl, or heterocyclic ring in R9are each independently unsubstituted or substituted with 1, 2, or 3 R10substituents.

47. The compound of any one of claims 25-46, wherein R10in each instance is independently selected from hydrogen, halogen, -OH, -C1-C6alkyl, -N(R11R11), a 3 to 12 membered cycloalkyl, a 4 to 12 membered heterocyclic, ring; wherein the alkyl, cycloalkyl, heterocyclic ring in R10are each independently unsubstituted or substituted with 1, 2, or 3 R11substituents.

48. The compound of any one of claims 25-47, wherein R11is independently hydrogen, halogen, -OH, or -C1-C6 alkyl.

49. The compound of any one of claims 1, and 25-48, wherein R6is independently selected from:

50. The compound of any one of claims 1, and 25-49, wherein R8is independently selected from:

51. A compound of claim 1, having a Formula (Ib),or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein:

52. A compound of claim 1, having a Formula (Ic),or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: X is C or N; R4is independently selected from hydrogen or -C1-C6alkyl; R6is independently selected fromR8is independently selected fromor -N(CH3CH3).

53. The compound of claim 52, wherein R4is hydrogen.

54. The compound of claim 52, wherein R4is -C1-C6alkyl.

55. The compound of claim 54, wherein -C1-C6 alkyl is -CH3.

56. The compound of any one of claims 52-55, wherein R6is57. The compound of any one of claims 52-55, wherein R6is58. The compound of any one of claims 52-57, wherein R8is -N(CH3CH3).

59. The compound of any one of claims 52-57, wherein R8is60. The compound of any one of claims 52-59, wherein X is C.

61. The compound of any one of claims 52-59, wherein X is N.

62. A compound of claim 1, having a Formula (Id),or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R4is independently selected from hydrogen or -C1-C6 alkyl; R6is independently selected from R8is independently selected from63. A compound of claim 1, having a Formula (Ie),or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R6is; and R8is -N(CH3CH3).

64. A compound, selected fromor a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharmaceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the foregoing, or a mixture thereof.

65. A method for reducing FAK protein levels, the method comprising contacting a cell with an effective amount of a compound of any one of claims 1-64 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

66. The method of claim 65, wherein the cell is in a subject.

67. A method of preventing or treating cancer in a subject comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-66 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

68. The method according to claim 67, where the cancer is selected from gastric, lung, pancreatic, ovarian, breast, skin, colon, neuroblastoma, osteosarcoma, uterine, rectal, and kidney cancer.

69. The method according to claim 68, wherein the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high grade serous ovarian cancer, triple negative breast cancer, uterine serous carcinoma, Ewing’s sarcoma, melanoma, colon, and clear cell renal cell carcinoma (ccRCC).

70. A compound of any one of claims 1-64 for use as a medicament.

71. A compound of any one of claims 1-64 and 70 for use in a method of treating cancer, comprising administering to a mammal having cancer a therapeutically effective amount of the compound.

72. The use of a compound of any one of claims 1-64 and 70-71 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in the manufacture of a medicament for reducing FAK protein levels.

73. The use of a compound of any one of claims 1-64 and 70-71 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in the manufacture of a medicament for the prevention or treatment of cancer.

74. The compound for use according to claim 72, wherein the cancer is selected from gastric, lung, pancreatic, ovarian, breast, skin, colon, neuroblastoma, osteosarcoma, uterine, rectal, and kidney cancer.

75. The compound for use according to claim 72, wherein the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high grade serous ovarian cancer, triple negative breast cancer, uterine serous carcinoma, Ewing’s sarcoma, melanoma, colon, and clear cell renal cell carcinoma (ccRCC).

76. The compound for use according to any one of claims 70-75, wherein the use further comprises administering a therapeutically effective amount of another second active agent or a support care therapy, wherein the other second active agent is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid or a pharmacologically active mutant or derivative thereof. ***********************