Substituted quinazolines as inhibitors of KRAS G12C

• US 9,840,516 B2
• Filed: 10/10/2014
• Issued: 12/12/2017
• Est. Priority Date: 10/10/2013
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Li, Liansheng, Feng, Jun, Wu, Tao, Ren, Pingda, Liu, Yi, Liu, Yuan, Long, Yun Oliver
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/511,425
• Publication Number:
  US 20150239900A1
• Time in Patent Office: 1,159 Days
• Field of Search: 5142662, 544293, 544359
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 217/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 239/84 Nitrogen atoms
• 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 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-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, tautomer, prodrug or stereoisomer thereof, wherein R¹, R^2a, R^3a, R^3b, R^4a, R^4b, G¹, G², L¹, L², m¹, m², A, B, W, X, Y, Z 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′

f);

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

j);

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

5. The compound of claim 1, wherein R¹ is optionally substituted aryl.

6. The compound of claim 5, wherein R¹ is substituted with one or more substituents.

7. The compound of claim 6, wherein the substituents are selected from the group consisting of halo, cyano, cyanoC₁-C₆ alkyl, cyanoC₃-C₈ cycloalkyl, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkylcycloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylaminyl, C₁-C₆ alkylcarbonylaminyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, aminylsulfonyl, aminylcarbonyl, aminylcarbonylC₁-C₆alkyl, aminylcarbonylC₃-C₈ cycloalkyl, C₁-C₆ alkylaminylcarbonyl, C₃-C₈ cycloalkylaminylcarbonyl, C₃-C₈ cycloalkylalkyl, C₃-C₈ cycloalkyl, C₃-C₈ fused cycloalkyl and heteroaryl.

8. The compound of claim 7, wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, cyano, hydroxy, hydroxymethyl, methoxy, methoxymethyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl and cyclopropyl.

9. The compound of claim 1, wherein R¹ is aryl substituted with one or more substituents selected from the group consisting of halo, cyano, cyanoC₁-C₆ alkyl, cyanoC₃-C₈ cycloalkyl, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkylcycloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylaminyl, C₁-C₆ alkylcarbonylaminyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, aminylsulfonyl, aminylcarbonyl, aminylcarbonylC₁-C₆ alkyl, aminylcarbonylC₃-C₈ cycloalkyl, C₁-C₆ alkylaminylcarbonyl, C₃-C₈ cycloalkylaminylcarbonyl, C₃-C₈ cycloalkylalkyl, C₃-C₈ cycloalkyl, C₃-C₈ fused cycloalkyl and heteroaryl, and each of R^a, R^b, R^2a, R^2b, R^2c, R^3a, R^3b, R^4a, R^4b, R⁶, R⁸, R^8′

, R⁹, R¹⁰ and L² are unsubstituted.

10. The compound of claim 5, wherein R¹ is phenyl.

11. The compound of claim 5, wherein R¹ has one of the following structures:

12. The compound of claim 1, wherein R¹ is optionally substituted heterocyclyl or optionally substituted heteroaryl.

13. The compound of claim 12, wherein R¹ is substituted with one or more substituents.

14. The compound of claim 13, wherein the substituents are selected from the group consisting of halo, C₁-C₆ alkyl, C₁-C₆alkoxy and C₂-C₆ alkenylcarbonylaminyl.

15. The compound of claim 13, wherein the substituents are selected from the group consisting of fluoro, chloro, amino and methyl.

16. The compound of claim 1, wherein R¹ is heteroaryl substituted with one or more substituents selected from the group consisting of halo, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₂-C₆ alkenylcarbonylaminyl, and each of R^a, R^b, R^2a, R^2b, R^2c, R^3a, R^3b, R^4a, R^4b, R⁶, R⁸, R^8′

, R⁹, R¹⁰ and L² are unsubstituted.

17. The compound of claim 12, wherein R¹ is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.

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

19. The compound of claim 1, wherein R^2a is halo.

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

21. The compound of claim 1, wherein R^2b is halo.

22. The compound of claim 21, wherein R^2b is chloro or fluoro.

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

24. The compound of claim 1, wherein R⁶ is heterocyclylaminyl.

25. The compound of claim 1, wherein R⁶ is H.

26. The compound of claim 1, wherein Q is —

C(═

O)—

.

27. The compound of claim 1, wherein at least one of R⁹ or R¹⁰ is H.

28. The compound of claim 27, wherein each of R⁹ and R¹⁰ are H.

29. The compound of claim 1, wherein

30. The compound of claim 1, wherein

31. The compound of claim 1, wherein each of R^a, R^b, R¹, R^2a, R^2b, R^2c, R^3a, R^3b, R^4a, R^4b, R⁶, R⁸, R^8′

, R⁹, R¹⁰ and L² are unsubstituted.

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

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