Fused-tricyclic inhibitors of KRAS and methods of use thereof

• US 10,428,064 B2
• Filed: 04/15/2016
• Issued: 10/01/2019
• Est. Priority Date: 04/15/2015
• 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): Carcanague, Daniel R
• Application Number:
  US15/566,648
• Publication Number:
  US 20180086753A1
• Time in Patent Office: 1,264 Days
• Field of Search: 514293
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 219/10 attached in position 9
• CPC Class Codes: C07D 219/12 Amino-alkylamino radicals attached in position 9
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/056 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):(I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A is a heterocyclic or heteroaryl ring, and R¹, R^2a, R^2b, R^2c, R^3a, R^3b, R^4a, R^4b, A, G¹, G², L¹, L², m¹, m², 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′

a);

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

b), (I′

c), (I'"'"'d) or (I′

e);

3. The compound of claim 1, wherein A is a 5, 6 or 7-membered heterocyclic or heteroaryl ring.

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

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

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

7. The compound of claim 5, 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.

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 is heteroaryl.

10. The compound of claim 9, wherein R¹ is indazolyl, indolyl, benzimidazolyl, benzotriazolyl or quinolinyl.

11. The compound of claim 9, wherein R¹ is substituted with hydroxyl, halo or C₁-C₆ alkyl, or combinations thereof.

12. The compound of claim 1, 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 Q is C(═

O)—

.

16. The compound of claim 1, wherein R⁹ and R¹⁰ are each H.

17. The compound of claim 1, wherein the moiety

18. The compound of claim 1, wherein the moiety has the following structure:

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

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

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

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

23. A substantially purified atropisomer of a compound according to claim 1.

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

25. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 24 to a subject in need thereof.

26. A method for regulating activity of a KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C mutant protein with the compound of claim 1.

27. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of claim 1.

28. A method for preparing a labeled KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS, HRAS or NRAS G12C mutant with a compound of claim 1, to result in the labeled KRAS, HRAS or NRAS G12C protein.