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1. WO2020117635 - IRE1 SMALL MOLECULE INHIBITORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:


wherein,

Y1, Y2, Y3, and Y4 are each independently selected from N and CR8; Z1 is independently selected from N and CR7; Z2 is independently selected from N and CR7A; and Z3 is independently selected from N and CR7B; wherein at least one of Y1, Y2, Y3, Y4, Z1, Z2 and Z3 are N and not more than two of Y1, Y2, Y3, and Y4 are N;

X1, X2, and X3 are each independently selected from N and CR4;

R1 is halogen, -CN, -OR10, optionally substituted Ci-C4alkyl, optionally substituted Ci- C4fluoroalkyl, or optionally substituted Ci-C4heteroalkyl;

R2 is hydrogen, -CN, -OR10, -SR10, optionally substituted Ci-C4alkyl, optionally

substituted Ci-C4fluoroalkyl, optionally substituted -0-Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted -0-C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted -0-C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R3 is H, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cyclooalkylalkyl, optionally substituted C2- Cioheterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R4 is independently H, halogen, -CN, -OR10, -SR10, -S(=0)R9, -S(=0)2R9, - S(=0)2N(RU)2, -NR10S(=O)2R9, -C(=0)R9, -0C(=0)R9, -C(=0)OR10, -0C(=0)0R9, -N(RU)2, -0C(=0)N(RU)2, -NR10C(=O)R9, -NR10C(=O)OR9, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted Ci- C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R5 is H, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cyclooalkylalkyl, optionally substituted C2- Cioheterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R6 is independently halogen, -CN, -OR10, -SR10, -S(=0)R9, -S(=0)2R9, - S(=0)2N(RU)2, -NR10S(=O)2R9, -C(=0)R9, -0C(=0)R9, -C(=0)OR10, -0C(=0)0R9, -N(RU)2, -0C(=0)N(RU)2, -NR10C(=O)R9, -NR10C(=O)OR9, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted Ci- C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R7, R7A, and R7B are independently H, -CN, halogen, -OR9, optionally substituted Ci- C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci- C4fluoroalkyl, or optionally substituted aryl;

each R8 is independently H, halogen, -CN, -OR10, -SR10, -N(RU)2, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted Ci- C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2- Cioheterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R9 is independently optionally substituted Ci-C4alkyl, optionally substituted Ci- C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3- C6cycloalkyl, optionally substituted C2-Cioheterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R10 is independently H, optionally substituted Ci-C4alkyl, optionally substituted Ci- C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3- C6cycloalkyl, optionally substituted C2-Cioheterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R11 is independently H, optionally substituted Ci-C4alkyl, optionally substituted Ci- C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3- C6cycloalkyl, optionally substituted C2-Cioheterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or two R11 are taken together with the N atom to which they are attached to form an

optionally substituted heterocycle; and

q is 0, 1, 2, 3, or 4.

2. The compound of claim 1 having Formula (la), or a pharmaceutically acceptable salt or solvate thereof:

Formula (la);

wherein Y1, Y2, Y3, and Y4 are each independently selected from N and CR8, and wherein one or two of Y1, Y2, Y3, and Y4 are N;

3. The compound of claim 1 having Formula (lb), or a pharmaceutically acceptable salt or solvate thereof:


Formula (lb);

wherein Z1 is independently selected from N and CR7, Z2 is independently selected from N and CR7A, and Z3 is independently selected from N and CR7B ; and wherein at least one of Z1, Z2 and Z3 are N.

4. The compound of claim 1 having Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:


Formula (Ic);

wherein Z1 is independently selected from N and CR7, Z2 is independently selected from N and CR7A, and Z3 is independently selected from N and CR7B.

5. The compound of claim 4, or a pharmaceutically acceptable salt, or solvate thereof, wherein Z1 is CR7, Z2 is CR7A, and Z3 is CR7B.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7 is H, halogen, -CN, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, or optionally substituted Ci-C4fluoroalkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7 is H, halogen, -CN, or optionally substituted Ci-C4alkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7 is H, fluorine, chlorine, -CN, or unsubstituted Ci-C4alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7 is H.

10. The compound of claim 1 having Formula (Id) or a pharmaceutically acceptable salt or solvate thereof:


Formula (Id);

wherein Y1, Y2, Y3, and Y4 are each independently selected from N and CR8, and wherein not more than two of Y1, Y2, Y3, and Y4 are N.

11. The compound of claim 10 wherein Y1, Y2, Y3, and Y4 are each independently selected from CR8.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7B is H, halogen, -CN, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, or optionally substituted Ci-C4fluoroalkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7B is H, halogen, -CN, or optionally substituted Ci-C4alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7B is H, fluorine, chlorine, -CN, or unsubstituted Ci-C4alkyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7B is unsubstituted Ci-C4alkyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7B is ethyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7A is H, halogen, -CN, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, or optionally substituted Ci-C4fluoroalkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7A is H, halogen, -CN, or optionally substituted Ci-C4alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7A is H, fluorine, chlorine, -CN, or unsubstituted Ci-C4alkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7A is H.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, or


23. The compound of claim 22, or a pharmaceutically acceptable salt, or solvate thereof, wherein:


24. The compound of any one of claims 1-23 wherein each R4 is independently H, halogen, -CN, -OR8, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4fluoroalkyl, or optionally substituted Ci-C4heteroalkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R4 is independently H, halogen, -CN, or optionally substituted Ci-C4alkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R4 is independently H, fluorine, chlorine, -CN, or unsubstituted Ci-C4alkyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R4 is H.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, or solvate thereof, wherein R2 is -CN, -OR10, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, or optionally substituted -0-C3-C6cycloalkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt, or solvate thereof, wherein R2 is optionally substituted Ci-C4alkyl or optionally substituted -0-Ci-C4alkyl.

30. The compound of claim 29, or a pharmaceutically acceptable salt, or solvate thereof, wherein R2 is methyl or methoxy.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is halogen, -CN, -OR8, optionally substituted Ci-C4alkyl, or optionally substituted Ci-C4fluoroalkyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is halogen or optionally substituted Ci-C4alkyl.

33. The compound of claim 32, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is chlorine, fluorine, or unsubstituted Ci-C4alkyl.

34. The compound of claim 33 or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is chlorine.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R8 is independently H, halogen, -CN, -OR10, -SR10, -N(RU)2, optionally substituted Ci-C4alkyl, or optionally substituted Ci-C4fluoroalkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R8 is independently H, halogen, -CN, or optionally substituted Ci-C4alkyl.

37. The compound of claim 36, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R8 is independently H, fluorine, chlorine, -CN, or unsubstituted Ci-C4alkyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R8 is H.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R6 is independently halogen, -OR10, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, or optionally substituted Ci-C4fluoroalkyl.

40. The compound of claim 39, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R6 is independently halogen, -OH, or optionally substituted Ci-C4alkyl.

41. The compound of claim 40, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R6 is fluorine, -OH, or unsubstituted Ci-C4alkyl.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is 1 or 2.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is 1.

44. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is zero.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is H, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3-C6cyclooalkyl, or optionally substituted C3-C6cycloalkylalkyl.

46. The compound of claim 45, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is H or optionally substituted Ci-C4alkyl.

47. The compound of claim 46, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is H, methyl, or ethyl.

48. The compound of claim 47, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is H.

49. The compound of claim 47, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is methyl or ethyl.

50. The compound of claim 49, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is methyl.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, or solvate thereof, wherein R5 is H, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3-C6cyclooalkyl, or optionally substituted C3-C6cycloalkylalkyl.

52. The compound of claim 51, or a pharmaceutically acceptable salt, or solvate thereof, wherein R5 is H or optionally substituted Ci-C4alkyl.

53. The compound of claim 52, or a pharmaceutically acceptable salt, or solvate thereof, wherein R5 is H, methyl, or ethyl.

54. The compound of claim 53, or a pharmaceutically acceptable salt, or solvate thereof, wherein R5 is H.

55. The compound of claim 53, or a pharmaceutically acceptable salt, or solvate thereof, wherein R5 is methyl or ethyl.

56. The compound of claim 55, or a pharmaceutically acceptable salt, or solvate thereof, wherein R5 is methyl.

57. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein

R1 is chlorine, fluorine, or unsubstituted Ci-C4alkyl;

R2 is unsubstituted Ci-C4alkyl or unsubstituted -0-Ci-C4alkyl;

R3 is hydrogen or unsubstituted Ci-C4alkyl;

each R4 is independently selected from hydrogen, fluorine, chlorine, -CN, or

unsubstituted Ci-C4alkyl;

R5 is hydrogen or unsubstituted Ci-C4alkyl;

each R6 is independently selected from fluorine, -OH, or unsubstituted Ci-C4alkyl and q is 0, 1, or 2;

Z1 is N or CR7 wherein R7 is hydrogen, fluorine, chlorine, -CN, or unsubstituted Ci- C4alkyl;

Z2 is N or CR7A wherein R7A is hydrogen, fluorine, chlorine, -CN, or unsubstituted Ci- C4alkyl;

Z3 is N or CR7B wherein R7B is hydrogen, fluorine, chlorine, -CN, or unsubstituted Ci- C4alkyl;

Y1 is N or CR8;

Y2 is N or CR8;

Y3 is N or CR8;

Y4 is N or CR8;

each R8 is independently selected from hydrogen, fluorine, chlorine, -CN, and

unsubstituted Ci-C4alkyl ;

X1 is N or CR4;

X2 is N or CR4; and

X3 is N or CR4; wherein at least one of Y1, Y2, Y3, Y4, Z1, Z2, and Z3 are N and not more than two of Y1, Y2, Y3, and Y4 are N.

58. The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R1 is chlorine;

R2 is unsubstituted Ci-C4alkyl or unsubstituted -0-Ci-C4alkyl;

R3 is hydrogen or unsubstituted Ci-C4alkyl;

R4 is hydrogen;

R5 is hydrogen or unsubstituted Ci-C4alkyl;

R6 is absent as q is zero;

Z1 is N or CR7 wherein R7 is H;

Z2 is N or CR7A wherein R7A is H;

Z3 is N or CR7B wherein R7B is unsubstituted Ci-C4alkyl;

Y1 is N or CR8;

Y2 is N or CR8;

Y3 is N or CR8;

Y4 is N or CR8;

R8 is hydrogen;

X1 is N or CR4;

X2 is N or CR4; and

X3 is N or CR4; wherein at least one of Y1, Y2, Y3, Y4, Z1, Z2, and Z3 are N and not more than two of Y1, Y2, Y3, and Y4 are N.

59. The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R1 is chlorine;

R2 is methyl or methoxy;

R3 is hydrogen or methyl;

R4 is hydrogen;

R5 is hydrogen or methyl;

R6 is absent as q is zero;

Z1 is N or CR7 wherein R7 is H;

Z2 is N or CR7A wherein R7A is H;

Z3 is N or CR7B wherein R7B is ethyl;

Y1 is N or CR8;

Y2 is N or CR8;

Y3 is N or CR8;

Y4 is N or CR8;

R8 is hydrogen;

X1 is N or CR4;

X2 is N or CR4; and

X3 is N or CR4; with the proviso that at least one of Y1, Y2, Y3, Y4, Z1, Z2, and Z3 are N and not more than two of Y1, Y2, Y3, and Y4 are N.

60. The compound of any one of claims 57-59, or a pharmaceutically acceptable salt, or

solvate thereof, wherein


61. The compound of claim 60, or a pharmaceutically acceptable salt, or solvate thereof, wherein:


62. The compound of any one of claims 57-61 wherein Z1 is CR7, Z2 is CR7A, and Z3 is CR7B, wherein one or two of Y1, Y2, Y3, and Y4 are N.

63. The compound of any one of claims 57-61 wherein Y1 is CR8; Y2 is CR8; Y3 is CR8; and Y4 is CR8, wherein at least one of Z1, Z2, and Z3 are N.

64. The compound of any one of claims 57-61 wherein Y1 is CR8; Y2 is CR8; Y3 is N; Y4 is CR8, Z1 is N or CR7; Z2 is N or CR7A; and Z3 is N or CR7B.

65. The compound of any one of claims 57-61 wherein Y1 is CR8; Y2 is CR8; Y3 is N, Y4 is CR8, Z1 is CR7; Z2 is CR7A; and Z3 is CR7B.

66. The compound of any one of claims 57-61 wherein, Y1 is N or CR8; Y2 is N or CR8; Y3 is N or CR8; Y4 is N or CR8, Z1 is N; Z2 is CR7A; and Z3 is CR7B.

67. The compound of any one of claims 57-61 wherein Y1 is CR8; Y2 is CR8; Y3 is CR8; Y4 is CR8, Z1 is N; Z2 is CR7A; and Z3 is CR7B.

68. The compound of any one of claims 62-67, wherein and at least one of X1, X2, and X3 are N.

69. The compound of any one of claims 62-67, wherein X1, X2, and X3 are CR4.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R9 is independently optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, or optionally substituted C2-Cioheterocycloalkyl and each R10 is independently H, optionally substituted Ci-C4alkyl, optionally substituted Ci-C4heteroalkyl, optionally substituted Ci-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, or optionally substituted C2-C loheterocy cloalkyl .

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, or solvate thereof, wherein optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -C02(Ci-C4alkyl), -CH2NH2, -C(=0)NH2, -C(=0)NH(Ci-C4alkyl), -C(=0)N(Ci-C4alkyl)2, -S(=0)2NH2, -S(=0)2NH(Ci-C4alkyl), -S(=0)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=0)Ci-C4alkyl, and -S(=0)2Ci-C4alkyl.

72. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, or solvate thereof, wherein optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CHS, -CH2CH3, -CH2NH2, -CF3, -0CH3, and -OCF3.

73. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt or solvate thereof, wherein there are no optional substituents.

74. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: 4-chloro-N-(5-(2-(((lr,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)pyridine-3 -sulfonamide; and

2-chloro-N-(5-(2-(((lr,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylpyrido[3,2-d]pyrimidin-6-yl)-6-methylpyri din-2 -yl)benzenesulfonamide.

75. A pharmaceutical composition comprising a compound according to any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

76. A method for treating or ameliorating the effects of a disease associated with altered IRE1 signaling, the method comprising administering to a subject in need thereof a compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, or a

pharmaceutical composition of claim 75.

77. The method of claim 76, wherein the disease is cancer.

78. The method of claim 77, wherein the cancer is a solid cancer or a hematologic cancer.

79. The method of claim 77, wherein the cancer is an ovarian cancer, a bladder cancer, a breast cancer, or a lung cancer.

80. The method of claim 79, wherein the breast cancer is triple negative breast cancer (TNBC).

81. The method of claim 77, wherein the cancer is a leukemia, lymphoma, or multiple myeloma.

82. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 75, for use as a medicament.

83. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 75, for use in the treatment of cancer.