Substituted quinazolines as inhibitors of KRAS G12C

Patent metadata

Field	Value
Publication number	US-9840516-B2
Application number	US-201414511425-A
Country	US
Kind code	B2
Filing date	Oct 10, 2014
Priority date	Oct 10, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

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, tautomer, prodrug or stereoisomer thereof, wherein R 1 , R 2a , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , A, B, W, X, Y, Z 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, tautomer, or stereoisomer thereof, wherein:
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 —;
Y is CR 6 ;
X is N;
Z is N;
L 1 is a bond;
L 2 is a bond or alkylene;
R′ is R 1 and R″ is R 2c ; or R′ is H and R″ is R 1 ;
R 1 is heterocyclyl, heteroaryl or aryl;
R 2a , R 2b and R 2c are each independently H, halo, —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 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 2 -C 6 alkynyl, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
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, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 6 is H, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —CO 2 NR a R b , alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl or arylalkyloxy;
R a and R b are each independently H or C 1 -C 6 alkyl; or
R a and R b join to form a carbocyclic or heterocyclic ring;
R 8 is H, C 1 -C 6 alkyl or hydroxyalkyl;
R 8′ is H, —OH, cyano or C 1 -C 6 alkyl;
indicates a double bond;
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxy, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxyalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic 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 hydroxyalkyl,
provided that at least one of R 2a , R 2b or R 2c is not H when R 1 is pyridyl, and wherein each alkylene, heterocyclyl, heteroaryl, aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkynyl, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, carbocyclic ring, heterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, quanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryloxy, arylaminyl, arylalkylaminyl and arylalkyloxy is optionally substituted with one or more substituents selected from the group consisting of aminyl, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C 1 -C 12 alkyl, C 1 -C 6 alkylaminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, C 1 -C 12 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, cyanoC 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 1 -C 6 alkylhetercycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenylcarbonylaminyl, C 1 -C 6 thioalkyl, aryl, aralkyl, C 3 -C 8 cycloalkyl optionally substituted with cyano, C 3 -C 8 cycloalkylalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 fused cycloalkyl, heterocycyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl.

2. The compound of claim 1 , wherein the compound has the following structure (I′f):

3. The compound of claim 1 , wherein the compound has the following structure (I′j):

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

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

6. The compound of claim 5 , wherein R 1 is substituted with one or more substituents.

7. The compound of claim 6 , wherein the substituents are selected from the group consisting of halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfonyl, aminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 cycloalkylalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl and heteroaryl.

8. The compound of claim 7 , wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, cyano, hydroxy, hydroxymethyl, methoxy, methoxymethyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl and cyclopropyl.

9. The compound of claim 1 , wherein R 1 is aryl substituted with one or more substituents selected from the group consisting of halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfonyl, aminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 cycloalkylalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl and heteroaryl, and each of R a , R b , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 6 , R 8 , R 8′ , R 9 , R 10 and L 2 are unsubstituted.

10. The compound of claim 5 , wherein R 1 is phenyl.

11. The compound of claim 5 , wherein R 1 has one of the following structures:

12. The compound of claim 1 , wherein R 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl.

13. The compound of claim 12 , wherein R 1 is substituted with one or more substituents.

14. The compound of claim 13 , wherein the substituents are selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 2 -C 6 alkenylcarbonylaminyl.

15. The compound of claim 13 , wherein the substituents are selected from the group consisting of fluoro, chloro, amino and methyl.

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/517 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D237/28

  Cinnolines · CPC title