2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof

• US 10,414,757 B2
• Filed: 11/16/2016
• Issued: 09/17/2019
• Est. Priority Date: 11/16/2015
• 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
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/353,402
• Publication Number:
  US 20170197945A1
• Time in Patent Office: 1,035 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):

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, G¹, G², L¹, L², m¹, m², n, X and E are as defined herein and, wherein at least one of R^3a, R^3b, R^4a or R^4b is not H. 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 of claim 1, wherein R¹ is aryl.

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

6. The compound of claims 4, wherein R¹ is substituted with one or more substituents.

7. The compound of claim 6, wherein R¹ is substituted with 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 or —

OC(═

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

8. The compound of claim 7, wherein R¹ is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.

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

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

11. The compound of claim 10, wherein R¹ is substituted with cyano, nitro, —

NH₂, —

(C═

O)NH₂, hydroxyl, hydroxylalkyl, halo or C₁-C₆ alkyl, or combinations thereof.

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

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

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

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

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

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

18. The compound of claim 17, wherein R⁶ is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

19. The compound of claim 17, wherein R⁶ is substituted.

20. The compound of claim 19, wherein R⁶ is substituted with C₁-C₆ alkyl, C₁-C₆ alkylaminyl, heterocyclyl or spiro-heterocyclyl, or combinations thereof.

21. The compound of claim 17, wherein R⁶ has one of the following structures:

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

O—

and R⁶ is heterocyclyl or heteroaryl.

23. The compound of claim 22, wherein R⁶ is azetidinyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl, pyridinonyl, pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl, thiomorpholinyl, pyrrolopyridinyl, imidazolyl, benzoimidazolyl, or an oxidized analogue thereof, dioxolanyl, or tetrahydropyranyl.

24. The compound of claim 22, wherein R⁶ is substituted.

25. The compound of claim 24, wherein R⁶ is substituted with oxo, cyano, halo, C₁-C₆ alkyl, C₁-C₆ alkylaminyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, heteroaryl, or combinations thereof.

26. The compound of claim 22, wherein R⁶ has one of the following structures:

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

NR⁷—

and R⁶ is heterocyclyl or heteroaryl.

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

O—

and R⁶ is cycloalkyl, heterocyclyl or heteroaryl.

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

NR⁷ —

and R⁶ is heterocyclyl or heteroaryl.

30. The compound of claim 1, wherein X is —

O—

, n is an integer from 1 to 6 and R⁶ is heterocyclyl, heteroarylalkylaminyl, cyano, amino or —

NR^aR^b.

31. The compound of claim 1, wherein X is a bond, n is 0 and R⁶ is amino, cyano or hydroxyl.

32. The compound of claim 1, wherein X is a bond, n is an integer from 1 to 3 and R⁶ is heteroarylalkyloxy or heteroarylalkylaminyl.

33. The compound of claim 1, wherein at least two of R^3a, R^3b, R^4a and R^4b are not H.

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

35. The compound of claim 1, wherein one of R^3a, R^3b, R^4a or R^4b is C₁-C₆ alkyl.

36. The compound of claim 1, wherein two of R^3a, R^3b, R^4a and R^4b are C₁-C₆ alkyl.

37. The compound of claim 35 , wherein C₁-C₆ alkyl is methyl.

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

C(═

O)—

.

39. The compound of claim 2, wherein each of R⁹ and R¹⁰ are H.

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

41. The compound of claim 40, wherein E is

42. The compound of claim 1, wherein L¹ is a bond.

43. The compound of claim 1, wherein L² is a bond.

44. The compound of claim 1, wherein A is N.

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

46. A substantially purified atropisomer of the compound of claim 1.

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

48. A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 47 to a subject in need thereof.

49. The method of claim 48, wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.