Substituted quinazoline compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10144724-B2
Application number	US-201615217304-A
Country	US
Kind code	B2
Filing date	Jul 22, 2016
Priority date	Jul 22, 2015
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

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, stereoisomer or prodrug thereof, wherein R, R 1 , R 2a , R 2b , R 2c , A, B, L 1 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):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A is N or C;
B is oxo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl or —X-L 2 -R a ;
X is NR b — or —O—;
L 1 is alkylene, cycloalkylene, heterocyclylene or absent;
L 2 is alkylene or absent;
R is H, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl or C 1 -C 6 alkoxy;
R a is cycloalkyl, heterocyclyl, heteroaryl, —(C═O)OH, —(C═O)NH 2 or —(C═O)NHOH;
R b is, at each occurrence, independently H or C 1 -C 6 alkyl;
R 1 is aryl or heteroaryl;
R 2a , R 2b and R 2c are each independently H, amino, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, —NR b (C═O)R b , C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;
is a single or double bond such that all valences are satisfied; and
E has the following structure:

wherein:
Q is —C(═O)— or —NR 8 C(═O)—;
R 8 is H or C 1 -C 6 alkyl; and
R 9 and R 10 are each independently H or C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein B is cycloalkyl, heterocyclyl or heteroaryl.

3. The compound of claim 1 , wherein L 1 is alkylene or absent.

4. The compound of claim 1 , wherein the compound has the following structure (IA):

wherein:
G 1 is N or CH;
G 2 is NR c or CHR c ;
R c is H, alkyl, alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl or heteroarylcarbonyl;

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 2 -C 6 alkynyl, hydroxylalkly, 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 2 -C 6 alkynyl, hydroxylalkly, 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 2 -C 6 alkynyl, hydroxylalkly, 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 2 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
m 1 and m 2 are each independently 1, 2 or 3; and
n is an integer from 0 to 5.

5. The compound of claim 4 , wherein the compound has the following structure (IAa) or (IAb):

wherein p 1 is an integer from 0 to 3.

6. The compound of claim 4 , wherein the compound has one of the following structures (IAc), (IAd) or (IAe):

7. The compound of claim 4 , wherein R c is alkylcarbonyl, aminocarbonyl, alkylcarbonylaminyl, aminocarbonylaminyl or heteroarylcarbonyl.

8. The compound of claim 7 , wherein alkylcarbonyl is substituted with aminocarbonyl, hydroxylaminocarbonyl, hydroxyl or amino.

9. The compound of claim 4 , wherein R c has one of the following structures:

wherein p 2 is an integer from 1 to 3.

10. The compound of claim 1 , wherein B is oxo.

11. The compound of claim 10 , wherein the compound has the following structure (IE):

wherein:
G 1 is CH;
G 2 is N or CH;
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 2 -C 6 alkynyl, hydroxylalkly, 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 2 -C 6 alkynyl, hydroxylalkly, 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 2 -C 6 alkynyl, hydroxylalkly, 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 2 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring; and
m 1 and m 2 are each independently 1, 2 or 3.

12. The compound of claim 11 , wherein the compound has one of the following structures (IEa), (IEb), (IEc) or (IEd):

13. The compound of claim 11 , wherein the compound has one of the following structures (IEe), (IEf), (IEg), (IEh) or (IEi):

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

15. The compound of claim 14 , wherein R 1 is phenyl or naphthyl.

16. The compound of claim 14 , wherein R 1 is substituted with one or more substituents.

17. The compound of claim 16 , wherein R 1 is substituted with halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylcarbonyloxy, or combinations thereof.

18. The compound of claim 17 , wherein R 1 is substituted with fluoro, hydroxyl, methyl, isopropyl, trifluoromethyl or methoxy, or combinations thereof.

19. The compound of claim 14 , wherein R 1 has one of the following structures:

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

21. The compound of claim 20 , wherein R 1 has one of the following structures:

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

23. The compound of claim 1 , wherein R 2a and R 2b are each halo.

24. The compound of claim 1 , wherein R 2a is fluoro.

25. The compound of claim 1 , wherein R 2b is chloro.

26. The compound of claim 1 , wherein R is H.

27. The compound of claim 1 , wherein Q is —C

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• C07D401/04

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

• C07D239/88

  Oxygen atoms · CPC title

• G01N33/532

  Production of labelled immunochemicals · CPC title

• C07D215/46

  with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms · CPC title

• C07D403/04 Primary

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