Covalent inhibitors of kras G12C

Patent metadata

Field	Value
Publication number	US-10273207-B2
Application number	US-201815891304-A
Country	US
Kind code	B2
Filing date	Feb 7, 2018
Priority date	Mar 15, 2013
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

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 compound having the following structure (VI):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug 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 compound of claim 1 , wherein the compound has one of the following structures (VIa), (VIb), (VIc), (VId), (VIe), (VIf) or (VIg):

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

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

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

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

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

9. The compound of claim 1 , wherein n 3 is 2 and n 4 is 1.

10. The compound 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 compound 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 compound of claim 1 , wherein R 37a or R 37e is aryl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D205/04 Primary

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D237/04

  having less than three double bonds between ring members or between ring members and non-ring members · CPC title

• C07D285/16

  Thiadiazines; Hydrogenated thiadiazines · CPC title

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title