Covalent inhibitors of KRas G12C

Patent metadata

Field	Value
Publication number	US-10919850-B2
Application number	US-201916355258-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Mar 15, 2013
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

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.

First claim

The invention claimed is:

1. A method for treating a cancer mediated by a K-Ras G12C, H-Ras G12C or N-Ras G12C mutation, the method comprising administering an effective amount of a compound having the following structure (VI):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, to a subject in need thereof, wherein:
A is CR 37b , N or NR 38a ;
B is CR 37c , N, NR 38b or S;
C is CR 37d , N, NR 38c or S;
G 3 and G 4 are each independently N or CR, wherein R is H, cyano, halo or C 1 -C 6 alkyl;
L 1a is a bond, —NH—, alkylene or heteroalkylene;
L 2 is a bond or alkylene;
R 32a and R 32b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, cyano, cyanoalkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32a is H, —OH, —NH 2 , —CO 2 H, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring;
R 33a and R 33b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, cyano, cyanoalkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33a is H, —OH, —NH 2 , —CO 2 H, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;
R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 aminoalkyl, heterocyclyl or aryl;
R 38a , R 38b and R 38c are each independently H, C 1 -C 6 alkyl or aryl;
n 3 and n 4 are each independently 1, 2 or 3;
m is 0 or 1;
is a single or double bond such that all valences are satisfied; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

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

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

wherein:
Q is C(═O)—, NR 34 C(═O)—, —S(═O) 2 — or —NR 34 S(═O) 2 —;
R 34 is H, C 1 -C 6 alkyl or hydroxylalkyl;
is a carbon-carbon double bond or a carbon-carbon triple bond; and
R 35 and R 36 are each independently H, cyano, C 1 -C 6 alkyl, aminoalkyl, alkylaminoalkyl, or hydroxylalkyl or R 35 and R 36 join to form a carbocyclic or heterocyclic ring when is a double bond; or R 35 is absent and R 36 is H, C 1 -C 6 alkyl, aminoalkyl, alkylaminoalkyl or hydroxylalkyl when is a triple bond.

4. The method of claim 1 , wherein G 3 is N and G 4 is CR.

5. The method of claim 1 , wherein G 3 is CR and G 4 is N.

6. The method of claim 1 , wherein G 3 is N and G 4 is N.

7. The method of claim 1 , wherein n 3 is 2 and n 4 is 2.

8. The method of claim 1 , wherein n 3 is 1 and n 4 is 1.

9. The method of claim 1 , wherein n 3 is 2 and n is 1.

10. The method of claim 1 , wherein R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, —OH, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, heterocyclyl or aryl.

11. The method 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 method of claim 1 , wherein R 37a or R 37e is aryl.

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

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

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

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

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

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

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

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

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

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

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

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

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

26. The method of claim 3 , wherein Q is —C(═O)—.

27. The method of claim 3 , wherein each of R 35 and R 36 are H.

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

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

30. The method of claim 1 , wherein L 2 is a bond.

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

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

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

34. The method of claim 1 , wherein the compound is formulated in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

35. The method of claim 34 , wherein the pharmaceutical composition is formulated for oral administration.

36. The method of claim 34 , wherein the pharmaceutical composition is formulated for injection.

37. The method of claim 1 , further comprising administering an additional anticancer agent to the subject.

38. The me

Assignees

• Araxes Pharma Llc

Inventors

• Ren Pingda
• Liu Yi
• Li Liansheng
• Feng Jun
• Wu Tao

Classifications

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D285/16

  Thiadiazines; Hydrogenated thiadiazines · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D295/16

  acylated on ring nitrogen atoms · CPC title