SUBSTITUTED QUINAZOLINE COMPOUNDS AND METHODS OF USE THEREOF

• US 20160297774A1
• Filed: 04/08/2016
• Published: 10/13/2016
• Est. Priority Date: 04/10/2015
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Li, Liansheng, Feng, Jun, Long, Yun Oliver, Liu, Yuan, Wu, Tao, Ren, Pingda, Liu, Yi
• Granted Patent: US 10,246,424 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07D 239/74 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• 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 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R¹, R^2a, R^2b, R^2c, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁶, A, B, G¹, G², L¹, L², m¹, m², n, x, y, X and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

Claims

1. A compound having the following structure (I):

2. The compound of claim 1, wherein the compound has the following structure (I′

a);

3. The compound of claim 2, wherein the compound has one of the following structures (I′

b), (I′

c), (I′

d) or (I′

e);

4. The compound claim 1, wherein R¹ is aryl.

5. The compound of claim 4, wherein R¹ is phenyl or napthyl.

7. The compound of claim 4, wherein R¹ is substituted with one or more substituents.

8. The compound of claim 7, wherein R¹ is substituted with halo, amino, hydroxyl, C₁-C₆ alkyl, cyano, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, boronic acid, —

OC(═

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

9. The compound of claim 8, wherein R¹ is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropryl, trifluoromethyl or methoxy, or combinations thereof.

10. The compound of claim 1, wherein R¹ has one of the following structures:

11. The compound of claim 1, wherein R¹ is heteroaryl.

13. The compound of claim 11, wherein R¹ is indazolyl, indolyl, benzoimidazole, benzotriazole or quinolinyl.

14. The compound of claim 11, wherein R¹ is substituted with one or more substituents.

15. The compound of claim 14, wherein R¹ is substituted with hydroxyl, halo or C₁-C₆ alkyl, or combinations thereof.

16. The compound of claim 11, wherein R¹ has one of the following structures:

17. The compound of claim 1, wherein R^2c is H.

18. The compound of claim 1, wherein R^2a and R^2b are each independently halo, haloalkyl, alkyl, or alkoxy.

19. The compound of claim 1, wherein R^2a is fluoro, chloro or methoxy.

20. The compound of claim 1, wherein R^2b is chloro, fluoro or CF₃.

21. The compound of claim 1, wherein n is 0, X is a bond and R⁶ is heterocyclyl.

22. The compound of claim 21, wherein R⁶ is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

23. The compound of claim 21, wherein R⁶ is substituted.

24. The compound of claim 23, wherein R⁶ is substituted with C₁-C₆ alkyl, C₁-C₆ alkylaminyl, heterocyclyl or spiro-heterocyclyl, or combinations thereof.

25. The compound of claim 21, wherein R⁶ has one of the following structures:

26. The compound of claim 1, wherein n is an integer from 1 to 6, X is —

O— and

R⁶ is heterocyclyl or heteroaryl, provided that R⁶ is not morpholinyl, piperazinyl, pyrrolidinyl or imidazolyl when R¹ is indazolyl.

27. The compound of claim 26, wherein R⁶ is azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl, thiomorpholinyl, or an oxidized analogue thereof, dioxolanyl, or tetrahydropyranyl.

28. The compound of claim 26, wherein R⁶ is substituted.

29. The compound of claim 28, wherein R⁶ is substituted with oxo, cyano, halo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, heteroaryl, or combinations thereof.

30. The compound of claim 26, wherein R⁶ has one of the following structures:

31. The compound of claim 1, wherein n is an integer from 1 to 6, X is —

NR⁷— and

R⁶ is heterocyclyl or heteroaryl, provided that R⁶ is not N-methylimidazolyl when R¹ is indazolyl.

32. The compound of claim 31, wherein R⁶ is piperidinyl, pyridinyl, imidazolyl, pyrrolidinyl, pyrimidinyl, or azetidinyl.

33. The compound of claim 31, wherein R⁶ is substituted.

34. The compound of claim 33, wherein R⁶ is substituted with halo, hydroxyl, C₁-C₆ alkyl C₃-C₈ cycloalkyl, or combinations thereof.

35. The compound of claim 31, wherein R⁶ has one of the following structures:

36. The compound of claim 1, wherein n is 0, X is —

O— and

R⁶ is cycloalkyl, heterocyclyl or heteroaryl, provided that R⁶ is not tetrahydropyranyl or tetrahydrofuranyl when R^2a is H and provided that R⁶ is not N-methylpyrazolyl when R¹ is indazolyl.

37. The compound of claim 36, wherein R⁶ is cyclohexyl, oxetanyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, azetidinyl, or piperidinyl.

38. The compound of claim 36, wherein R⁶ is substituted.

39. The compound of claim 38, wherein R⁶ is substituted with hydroxyl, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkylcarbonyl, heterocyclyl, or combinations thereof.

40. The compound of claim 36, wherein R⁶ has one of the following structures:

41. The compound of claim 1, wherein n is 0, X is —

NR⁷— and

R⁶ is a 3, 4, 6, 7 or 8-membered heterocyclyl or 3, 4, 6 or 7-membered heteroaryl, provided that R⁶ is not tetrahydropyranyl or N-methylpiperidinyl when R¹ is indazolyl;

or n is 0, X is —

NR⁷— and

R⁶ is a 5-membered, oxygen-containing heterocyclyl and R¹ is aryl.

42. The compound of claim 41, wherein R⁶ is piperidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, or an oxidized analogue thereof, azabicyclo[3.2.1]octanyl, or tetrahydropyranyl.

43. The compound of claim 41, wherein R⁶ is substituted.

44. The compound of claim 43, wherein R⁶ is substituted with hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl, cycloalkylalky, heterocyclyl, C₁-C₆ alkylcarbonyl, heteroaryl, or combinations thereof.

45. The compound of claim 41, wherein R⁶ has one of the following structures:

46. The compound of claim 1, wherein R⁶ is substituted alkyl, and R⁶ is substituted with one substituent selected from the group consisting of alkylaminylcarbonyl, C₂-C₆ dialkylaminyl, halo, C₁-C₆ monoalkylaminyl, heteroarylamino, heteroarylalkyloxy and alkylsulfonyl, and wherein R⁶ optionally comprises one or more additional substituent.

47. The compound of claim 46, wherein R⁶ has one of the following structures:

48. The compound of claim 1, wherein R⁶ is alkyl substituted with at least one hydroxyl and X is —

O—

.

49. The compound of claim 1, wherein R⁶ is alkyl substituted with at least one hydroxyl and R¹ is aryl or heteroaryl.

50. The compound of claim 1, wherein R⁶ is substituted C₂-C₆ alkyl, X is a bond and n is 0.

51. The compound of claim 50, wherein R⁶ is substituted with dialkylaminyl.

52. The compound of claim 1, wherein R⁶ is cyano.

53. The compound of claim 1, wherein R⁶ is amino, C₁-C₆ alkylphosphoryl, C₁-C₆ alkylphosphorylaminyl or perhalomethyl.

54. The compound of claim 53, wherein R⁶ has one of the following structures:

80. The compound of claim 2, wherein Q is —

C(═

O)—

.

81. The compound of claim 1, wherein E has one of the following structures:

84. The compound of claim 1, wherein R^3a, R^3b, R^4a and R^4b are each H.

85. The compound of claim 1, wherein the compound has one of the following structures:

88. A substantially purified atropisomer according to claim 1.

89. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

92. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 89 to a subject in need thereof.

6. (canceled)

12. (canceled)

55. A compound having the following structure (II):

56-67. -67. (canceled)

68. A compound having the following structure (III):

69-79. -79. (canceled)

82-83. -83. (canceled)

86-87. -87. (canceled)

90-91. -91. (canceled)

93-102. -102. (canceled)