Substituted quinolines as inhibitors of KRAS G12C

• US 10,370,386 B2
• Filed: 11/07/2017
• Issued: 08/06/2019
• 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:
  US15/805,716
• Publication Number:
  US 20180118757A1
• Time in Patent Office: 637 Days
• Field of Search: 514314, 546159
• 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′

) or (I″

);

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

);

3. The compound of claim 2, wherein:

R′

is R¹; and

R″

is R^2c.

4. The compound of claim 2, wherein:

R′

is H; and

R″

is R¹.

5. The compound of claim 1, wherein the compound has structure (I″

);

6. The compound of claim 5, wherein:

R′

is R¹; and

R″

is R^2c.

7. The compound of claim 5, wherein:

R′

is H; and

R″

is R¹.

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

C(═

O)—

.

9. The compound of claim 1, wherein

10. The compound of claim 1, wherein R¹ is substituted with one or more substituents.

11. The compound of claim 10, wherein the one or more substituents are selected from the group consisting of halo, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₂-C₆ alkenylcarbonylaminyl.

12. The compound of claim 10, wherein the one or more substituents are selected from the group consisting of fluoro, chloro, methyl and amino.

13. The compound of claim 1, wherein R¹ is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl, each optionally substituted.

14. The compound of claim 1, wherein R¹ is selected from the group consisting of:

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

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

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

18. The compound of claim 17, wherein R^2b is chloro or fluoro.

19. The compound of claim 1, wherein:

R^3a is H;

R^3b is H;

R^4a is H; and

R^4b is H.

20. The compound of claim 1, wherein at least one of R⁹ and R¹⁰ is H.

21. The compound of claim 20, wherein:

R⁹ is H; and

R¹⁰ is H.

22. The compound of claim 1, wherein the compound is selected from the group consisting of:

23. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier.

24. A method for inhibiting RAS-mediated signaling transduction in a subject, the method comprising administering to the subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

25. The method of claim 24, wherein the subject has cancer.

26. The method of claim 25, wherein the cancer is selected from the group consisting of MYH-associated polyposis, pancreatic cancer, colorectal cancer, lung cancer and a hematological cancer.

27. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

28. A method for inhibiting tumor metastasis in a subject, the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition of claim 23.

29. A method for regulating activity of a KRAS G12C, HRAS G12C or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C, HRAS G12C or NRAS G12C mutant protein with a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

30. A method for preparing a labeled KRAS G12C, HRAS G12C or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C, HRAS G12C or NRAS G12C mutant protein with a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.