Fused-tricyclic inhibitors of KRAS and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10428064-B2
Application number	US-201615566648-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Apr 15, 2015
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):(I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A is a heterocyclic or heteroaryl ring, and R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , A, G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , 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.

First claim

The invention claimed is:

1. A compound having the following structure (I′a):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:
A is a carbocyclic, heterocyclic or heteroaryl ring;
G 1 and G 2 are each independently N or CH;
L 1 is a bond or NR 5 ;
L 2 is a bond or alkylene;
R 1 is aryl or heteroaryl;
R 2a , R 2b and R 2c are each independently H, amino, halo, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a and R 3b join to form a carbocyclic or heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a and R 4b join to form a carbocyclic or heterocyclic ring; or R 4a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 5 is, at each occurrence, independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or heterocycloalkyl;
m 1 and m 2 are each independently 1, 2 or 3;
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 8′ )—, NR 8 C(═O)—, —S(═O) 2 — or NR 8 S(═O) 2 ;
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8 cycloalkyl or heterocycloalkyl;
R 8′ is H, —OH, —CN or C 1 -C 6 alkyl;
when is a double bond then R 9 and R 10 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R 9 and R 10 join to form a carbocyclic, heterocyclic or heteroaryl ring; and
when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 , alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

2. The compound of claim 1 , wherein the compound has one of the following structures (I′b), (I′c), (I'd) or (I′e):

3. The compound of claim 1 , wherein A is a 5, 6 or 7-membered heterocyclic or heteroaryl ring.

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

wherein:
R 6 is, at each occurrence, independently H, halo, amino, cyano, arayl, heteroaryl, C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, heterocycloalkyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, arylalkyl or heteroarylalkyl;
X is O or CH 2 ; and
n is 0, 1 or 2.

5. The compound of claim 1 , wherein R 1 is aryl.

6. The compound of claim 5 , wherein R 1 is phenyl or naphthyl.

7. The compound of claim 5 , wherein R 1 is substituted with halo, amino hydroxyl, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, boronic acid, —OC(═O)R, phosphate, phosphoalkoxy or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.

8. The compound of claim 7 , wherein R 1 is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.

9. The compound of claim 1 , wherein R 1 is heteroaryl.

10. The compound of claim 9 , wherein R 1 is indazolyl, indolyl, benzimidazolyl, benzotriazolyl or quinolinyl.

11. The compound of claim 9 , wherein R 1 is substituted with hydroxyl, halo or C 1 -C 6 alkyl, or combinations thereof.

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

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

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

15. The compound of claim 1 , wherein Q is C(═O)—.

16. The compound of claim 1 , wherein R 9 and R 10 are each H.

17. The compound of claim 1 , wherein the moiety

has one of the following structures:

18. The compound of claim 1 , wherein the moiety has the following structure:

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

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

21. The compound of claim 1 , wherein R 3a , R 3b , R 4a and R 4b are each H.

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

23. A substantially purified atropisomer of a compound according to claim 1 .

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

25. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 24 to a subject in need thereof.

Assignees

• Araxes Pharma Llc

Inventors

• Li Liansheng
• Feng Jun
• Long Yun Oliver
• Liu Yuan
• Wu Tao
• Ren Pingda
• Liu Yi

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title