CONJUGATES OF CEREBLON BINDING COMPOUNDS AND G12C MUTANT KRAS, HRAS OR NRAS PROTEIN MODULATING COMPOUNDS AND METHODS OF USE THEREOF

• US 20180015087A1
• Filed: 07/13/2017
• Published: 01/18/2018
• Est. Priority Date: 07/13/2016
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Liu, Yi, Li, Liansheng, Ren, Pingda
• Granted Patent: US 10,646,488 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence

Abstract

Conjugates of a cereblon-binding compound and compounds having modulatory activity against G12C mutant KRAS, HRAS or NRAS G12C proteins are provided. Methods associated with preparation and use of such conjugates, pharmaceutical compositions comprising such conjugates and methods to modulate the activity of G12C mutant KRAS, HRAS or NRAS G12C proteins for treatment of disorders, such as cancer, are also provided.

Claims

1. A conjugate having the formula (I):

X—

Y—

Z 

 

(I)

or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein;

X is an indolinone or bridged cycloalkyl radical;

Y is direct bond or a linker connecting X to Z; and

Z is a G12C mutant KRAS, HRAS, or NRAS G12C protein modulating compound capable of forming a covalent bond with the cysteine residue at position 12 of the G12C mutant KRAS, HRAS or NRAS protein.

3. The conjugate of claim 1, having the following structure (IA):

7. The conjugate of claim 1, having the following structure (IA′

);

10. The conjugate of claim 1, wherein X has the following structure (IB):

12. The conjugate of claim 10, having the following structure (IB′

);

15. The conjugate of claim 1, wherein Y has one of the following structures:

16. The conjugate of claim 1, wherein Z has the structure of formula (II):

17. The conjugate of claim 16, wherein Z has the structure of formula (III):

18. The conjugate of claim 17, wherein Z has the following structure (IIIA):

19. The conjugate of claim 18, wherein Z has one of the following structures (IIIB), (IIIC), (IIID) or (IIIE):

21. The conjugate of claim 16, wherein R¹ is phenyl or naphthyl.

23. The conjugate of claim 21, wherein R¹ is substituted with —

Y—

X, halo, amino, hydroxyl, C₁-C₆ alkyl, cyano, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —

OC(═

O)R or C₁-C₆ alkylcarbonyloxy, or combinations thereof, wherein R is C₁-C₆ alkyl.

25. The conjugate of claim 16, wherein R¹ has one of the following structures:

28. The conjugate of claim 16, wherein R¹ is indazolyl, indolyl, benzoimidazole, benzotriazole or quinolinyl.

30. The conjugate of claim 28, wherein R¹ is substituted with —

Y—

X, halo, hydroxyl, C₁-C₆ alkyl or C₁-C₆ alkoxy, or a combination thereof.

31. The conjugate of claim 16, wherein R¹ has one of the following structures:

33. The conjugate of claim 16, wherein R^2a and R^2b are each independently halo, haloalkyl, C₁-C₆ alkyl or C₁-C₆ alkoxy.

36. The conjugate of claim 16, wherein n is 0, Q is a bond, and R⁹ is heterocyclyl optionally substituted with —

Y—

X, one or more substituents, or combinations thereof.

37. The conjugate of claim 36, wherein R⁹ is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl, each of which is optionally substituted with —

Y—

X, one or more substituents, or combinations thereof.

39. The conjugate of claim 37, wherein R⁹ is substituted with —

Y—

X, C₁-C₆ alkyl, C₁-C₆ alkylamino, heterocyclyl or spiro-heterocyclyl, or combinations thereof.

40. The conjugate of claim 36, wherein R⁹ has one of the following structures:

41. The conjugate of claim 16, wherein n is an integer from 1 to 6, Q is —

O— and

R⁹ is heterocyclyl or heteroaryl, each of which is optionally substituted with —

Y—

X, one or more substituents, or combinations thereof.

46. The conjugate of claim 16, wherein n is an integer from 1 to 6, Q is —

NR¹⁰— and

R⁹ is heterocyclyl or heteroaryl, each of which is optionally substituted with —

Y—

X, one or more substituents, or combinations thereof.

51. The conjugate of claim 16, wherein n is 0, Q is —

O— and

R⁹ is cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally substituted with —

Y—

X, one or more substituents, or combinations thereof.

56. The conjugate of claim 16, wherein n is 0, Q is —

NR¹⁰— and

R⁹ is heterocyclyl or heteroaryl, each of which is optionally substituted with —

Y—

X, one or more substituents, or combinations thereof.

61. The conjugate of claim 16, wherein R⁹ is C₁-C₆ alkyl, and R⁹ is substituted with one or more substituent selected from the group consisting of —

Y—

X, alkylaminocarbonyl, C₁-C₆ dialkylamino, halo, C₁-C₆ monoalkylamino, heteroarylamino and alkylsulfonyl.

68. The conjugate of claim 1, wherein Z has one of the following structures:

69. The conjugate of claim 68, wherein R⁹ is amino, C₁-C₆ alkyl, haloalkyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C₁-C₆ alkylphosphoryl, C₁-C₆ alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyloxy or heteroarylalkylaminyl substituted with —

Y—

X.

70. The conjugate of claim 69, wherein Q is a bond and n is 0.

71. The conjugate of claim 68, wherein R⁹ is heterocyclyl.

74. The conjugate of claim 16, wherein R^3a, R^3b, R^4a and R^4b are each H.

75. The conjugate of claim 16, wherein one or two of R^3a, R^3b, R^4a and R^4b are C₁-C₆ alkyl.

77. The conjugate of claim 75, wherein C₁-C₆ alkyl is methyl.

78. The conjugate of claim 16, wherein one of R^3a, R^3b, R^4a and R^4b is —

Y—

X.

79. The conjugate of claim 18, wherein Q¹ is —

C(═

O)—

.

84. The conjugate of claim 16, wherein E has one of the following structures:

87. The conjugate of claim 1, wherein the conjugate has one of the following structures:

88. The conjugate of claim 87, wherein B⁴ is N or C—

CN.

89. The conjugate of claim 87, wherein R¹ has one of the following structures:

90. The conjugate of claim 1, wherein the conjugate is selected from one of the following compounds:

91. A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable carrier.

94. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 91 to a subject in need thereof.

103. The conjugate of claim 1, having one of the following structures:

2. (canceled)

4-6. -6. (canceled)

8-9. -9. (canceled)

11. (canceled)

13-14. -14. (canceled)

20. (canceled)

22. (canceled)

24. (canceled)

26-27. -27. (canceled)

29. (canceled)

32. (canceled)

34-35. -35. (canceled)

38. (canceled)

42-45. -45. (canceled)

47-50. -50. (canceled)

52-55. -55. (canceled)

57-60. -60. (canceled)

62-67. -67. (canceled)

72-73. -73. (canceled)

76. (canceled)

80-83. -83. (canceled)

85-86. -86. (canceled)

92-93. -93. (canceled)

95-102. -102. (canceled)