Substituted quinazoline compounds and methods of use thereof

• US 10,351,550 B2
• Filed: 03/08/2018
• Issued: 07/16/2019
• Est. Priority Date: 07/22/2015
• 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): Seaman, D Margaret M
• Application Number:
  US15/916,075
• Publication Number:
  US 20180194748A1
• Time in Patent Office: 495 Days
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 239/88 Oxygen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: G01N 33/532 Production of labelled immunochemicals

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 R, R¹, R^2a, R^2b, R^2c, A, B, L¹ 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 B is cycloalkyl, heterocyclyl or heteroaryl.

3. The compound of claim 1, wherein L¹ is alkylene or absent.

4. The compound of claim 1, wherein B is oxo.

5. The compound of claim 4, wherein the compound has the following structure (IE):

6. The compound of claim 5, wherein the compound has one of the following structures (IEa), (IEb), (IEc) or (IEd):

7. The compound of claim 5, wherein the compound has one of the following structures (IEe), (IEf), (IEg), (IEh), (IEi), (IEj), (IEk) or (IEl):

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

9. The compound of claim 8, wherein R¹ is phenyl or naphthyl.

10. The compound of claim 8, wherein R¹ is substituted with one or more substituents.

11. The compound of claim 10, wherein R¹ is substituted with halo, amino, hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylaminyl, cycloalkylaminyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —

OC(═

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

12. The compound of claim 11, wherein R¹ is substituted with fluoro, chloro, cyclopropyl, cyclobutyl, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl or methoxy, or combinations thereof.

13. The compound of claim 8, wherein R¹ has one of the following structures:

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

15. The compound of claim 14, wherein R¹ has one of the following structures:

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

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

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

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

20. The compound of claim 1, wherein R is H.

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

C(═

O)—

.

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

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

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

25. A substantially purified atropisomer of the compound according to claim 1.

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

27. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 26 to a subject in need thereof.

28. 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.

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

30. A method for treating a disorder mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation in a subject in need thereof, the method comprising:

determining if the subject has a KRAS, HRAS or NRAS G12C mutation; and

if the subject is determined to have the KRAS, HRAS or NRAS G12C mutation, then administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 26.

31. 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.

32. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of claim 26 to a subject in need thereof.