Substituted quinazoline compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10351550-B2
Application number	US-201815916075-A
Country	US
Kind code	B2
Filing date	Mar 8, 2018
Priority date	Jul 22, 2015
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

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, stereoisomer or prodrug thereof, wherein:
A is N;
B is oxo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, amino, alkylamino, arylamino, —CO 2 H, —CONH 2 , aminylcarbonyl, aminylcarbonylalkyl, heteroarylamino, halo, haloalkyl, alkoxy, haloalkoxy, aryl 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, halo, haloalkyl, hydroxyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, —CO 2 H, —CONH 2 , aminylcarbonyl, 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, cyano, 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, heterocyclylalkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
is a single bond such that all valences are satisfied; and
E is:

wherein:
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 or hydroxylalkyl;
R 8 ′ is H, —OH, —CN or C 1 -C 6 alkyl; and
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.

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 B is oxo.

5. The compound of claim 4 , 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a and R 3b join to form oxo, 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 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a and R 4b join to form oxo, 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 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.

6. The compound of claim 5 , wherein the compound has one of the following structures (IEa), (IEb), (IEc) or (IEd):

7. The compound of claim 5 , wherein the compound has one of the following structures (IEe), (IEf), (IEg), (IEh), (IEi), (IEj), (IEk) or (IEl):

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

9. The compound of claim 8 , wherein R 1 is phenyl or naphthyl.

10. The compound of claim 8 , wherein R 1 is substituted with one or more substituents.

11. The compound of claim 10 , wherein R 1 is substituted with halo, amino, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylaminyl, cycloalkylaminyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —OC(═O)R or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.

12. The compound of claim 11 , wherein R 1 is substituted with fluoro, chloro, cyclopropyl, cyclobutyl, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl or methoxy, or combinations thereof.

13. The compound of claim 8 , wherein R 1 has one of the following structures:

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

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

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

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

18. The compound of claim 1 , wherein R 2a is fluoro, chloro or methoxy.

19. The compound of claim 1 , wherein R 2b is chloro, fluoro, amino, hydroxyl or CF 3 .

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

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

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

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

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

25. A substantially purified atropisomer of the compound according to claim 1 .

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

27. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 26 to a subject in need thereof.

28. A method for regulating activity of a KRAS, HRAS or NRAS G12C mutant protein, the

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• C07D403/04 Primary

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

• C07D239/88

  Oxygen atoms · CPC title

• C07D215/46

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

• C07D401/04

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

• G01N33/532

  Production of labelled immunochemicals · CPC title