COVALENT INHIBITORS OF KRAS G12C

• US 20160159738A1
• Filed: 11/05/2015
• Published: 06/09/2016
• 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
• Granted Patent: US 9,926,267 B2
• Time in Patent Office: 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 (V):

2. The compound of claim 1, wherein the compound has the following structure (Va):

3. The compound of claim 2, wherein the compound has the following structure (Vb):

4. The compound of claim 3, wherein the compound is selected from the group consisting of (Vc), (Vd), (Ve) and (Vf):

5. The compound of claim 3, wherein the compound is selected from the group consisting of (Vg), (Vh), (Vi) and (Vj):

6. The compound of claim 3, wherein the compound is selected from the group consisting of (Vk), (Vl), (Vm), (Vn);

(Vo) and (Vp);

10. The compound of claim 1, wherein R¹ is naphthyl.

12. The compound of claim 1, wherein the R¹ is phenyl.

15. The compound of claim 1, wherein the aryl is substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, aminocarbonyl, formyl, C₁-C₆alkyl, C₁-C₆alkylsulfonyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, C₁-C₆alkoxy, C₁-C₆hydroxylalkyl, C₁-C₆alkoxyalkyl, C₁-C₆aminoalkyl, aliphatic heterocyclyl, heteroaryl and aryl.

16. The compound of claim 15, wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methylsulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluorethyl, cyclobutyl, cyclopropyl and phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, halo, hydroxyl and cyano.

17. The compound of claim 16, wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, methyl, ethyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C₁-C₆alkyl, halo, hydroxyl and cyano.

18. The compound of claim 17, wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, halo, hydroxyl and cyano.

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

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

21. The compound of claim 20, wherein the heteroaryl is bicyclic.

22. The compound of claim 21, wherein the heteroaryl is a fused bicyclic heteroaryl.

23. The compound of claim 20, wherein the heteroaryl is monocyclic.

24. The compound of claim 20, wherein the heteroaryl comprises nitrogen, sulfur or a combination thereof.

25. The compound of claim 20, wherein the heteroaryl is selected from the group consisting of dihydroquinoxalinyl, indoleyl, benzoimidazolyl, pyridinyl and thiazolyl.

26. The compound of claim 20, wherein the heteroaryl is unsubstituted.

27. The compound of claim 20, wherein the heteroaryl is substituted with one or more substituents.

28. The compound of claim 27, wherein the substituents are selected from the group consisting of C₁-C₆alkyl, halo and oxo.

29. The compound of claim 28, wherein the substituents are selected from the group consisting of ethyl and chloro.

30. The compound of any one of claims 20-29, wherein R¹ is selected from the group consisting of:

31. The compound of claim 30, wherein R¹ is selected from the group consisting of:

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

C(═

O)—

.

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

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

88. The compound of claim 2, wherein L^1a is alkylene or alkenylene.

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

106. The compound of claim 1, wherein each of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is H.

107. The compound of claim 1, wherein at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is hydroxylalkyl.

110. The compound of claim 1, wherein at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a Or R^33b is C₁-C₆alkyl.

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

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

7-9. -9. (canceled)

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