Covalent inhibitors of kras G12C

• US 10,273,207 B2
• Filed: 02/07/2018
• Issued: 04/30/2019
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Ren, Pingda, Liu, Yi, Li, Liansheng, Feng, Jun, Wu, Tao
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US15/891,304
• Publication Number:
  US 20180162812A1
• Time in Patent Office: 447 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 237/04 having less than three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 285/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 285/16 Thiadiazines; Hydrogenated thiadiazines
• CPC Class Codes: C07D 295/16 acylated on ring nitrogen atoms
• 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 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 419/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: G01N 33/58 : involving labelled substances G01N33/53 takes precedence

Abstract

Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.

Claims

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

2. The compound of claim 1, wherein the compound has one of the following structures (VIa), (VIb), (VIc), (VId), (VIe), (VIf) or (VIg):

3. The compound of claim 1, wherein the compound has one of the following structures (VIa′

), (VIb′

), (VIc′

), (VId′

), (VIe′

), (VIf′

) or (VIg′

);

4. The compound of claim 1, wherein G³ is N and G⁴ is CR.

5. The compound of claim 1, wherein G³ is CR and G⁴ is N.

6. The compound of claim 1, wherein G³ is N and G⁴ is N.

7. The compound of claim 1, wherein n³ is 2 and n⁴ is 2.

8. The compound of claim 1, wherein n³ is 1 and n⁴ is 1.

9. The compound of claim 1, wherein n³ is 2 and n⁴ is 1.

10. The compound of claim 1, wherein R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, —

OH, halo, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, heterocyclyl or aryl.

11. The compound of claim 10, wherein R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, —

OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl.

12. The compound of claim 1, wherein R^37a or R^37e is aryl.

13. The compound of claim 12, wherein aryl is phenyl.

14. The compound of claim 12, where the aryl is substituted with one or more halo substituents.

15. The compound of claim 14, wherein the halo substituents are selected from fluoro and chloro.

16. The compound of claim 1, wherein R^37a is heteroaryl.

17. The compound of claim 16, wherein the heteroaryl is thiophenyl.

18. The compound of claim 1, wherein R^37a or R^37e, or both, is halo.

19. The compound of claim 18, wherein halo is chloro, bromo or iodo.

20. The compound of claim 1, wherein R^37a or R^37e has one of the following structures:

21. The compound of claim 1, wherein R^38a, R^38b and R^38c are each independently H or aryl.

22. The compound of claim 21, wherein R^38a, R^38b and R^38c are each independently H.

23. The compound of claim 1, wherein R^38c is aryl.

24. The compound of claim 23, wherein the aryl is substituted with one or more halo substituents.

25. The compound of claim 24, wherein halo is chloro.

26. The compound of claim 3, wherein Q is —

C(═

O)—

.

27. The compound of claim 3, wherein each of R³⁵ and R³⁶ are H.

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

29. The compound of claim 1, wherein L^1a is a bond.

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

31. The compound of claim 1, wherein at least one of R^32a, R^32b, R^33a or R^33b is H.

32. The compound of claim 1, wherein each of R^32a, R^32b, R^33a or R^33b is H.

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

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