Inhibitors of kras g12c mutant proteins

Patent metadata

Field	Value
Publication number	US-2016108019-A1
Application number	US-201514866147-A
Country	US
Kind code	A1
Filing date	Sep 25, 2015
Priority date	Sep 25, 2014
Publication date	Apr 21, 2016
Grant date	—

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, stereoisomer or prodrug thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , L, 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

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

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
G 1 and G 2 are each independently N or CH;
L is a bond, NR or alkylene;
X is a bond or CH 2 when G 1 is N; or X is a bond, NR or O when G 1 is CH;
R is H or C 1 -C 6 alkyl;
R 1 is aryl or heteroaryl;
R 2 is arylene or heteroarylene, wherein the aryl or heteroarylene is substituted with R 5 and R 6 ;
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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 3a and one R 3b join to form a carbocyclic or heterocyclic ring, and each remaining 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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 3b joins with one R 4b to form a carbocyclic or heterocyclic ring, and each R 3a and each remaining 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 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or one R 3b joins with one of R 5 or R 6 to form a carbocyclic or heterocyclic ring, and each R 3a and each remaining 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 alkynyl, hydroxylalkyl, aminoalkyl, 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 1 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 4a and one R 4b join to form a carbocyclic or heterocyclic ring, and each remaining 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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 4b joins with one R 3b to form a carbocyclic or heterocyclic ring, and each R 4a and each remaining 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 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 5 and R 6 are each independently H, —OH, —CN, halo, C 1 -C 6 alkyl or aminocarbonyl; or one of R 5 or R 6 joins with one R 3b to form a carbocyclic or heterocyclic ring, and the other of R 5 or R 6 is H, —OH, —CN, halo, C 1 -C 6 alkyl or aminocarbonyl;
m 1 and m 2 are each independently 1, 2 or 3; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein.

2 . The compound of claim 1 , wherein the compound has one of the following structures (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) or (Ij):

wherein:
R 5a and R 6a are each independently H, —NH 2 , —C(═O)NH 2 , —OH, —CN, halo, C 1 -C 6 alkyl or aminocarbonyl;
A and B are each independently O, NH, NHR′ or CHR5a, wherein R′ is C 1 -C 6 alkyl or aminylalkyl;
X and Y are each independently N, NH or CHR 5a ;
W is H, —NH 2 or oxo; and
are each independently a single or double bond such that all valences are satisfied.

3 . The compound of claim 2 , wherein the compound has one of the following structures (Ia′), (Ib′), (Ic′), (Id′), (Ie′), (If′), (Ig′), (Ih′), (Ii′):

wherein:
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 7 )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 7 is H, —OH, —CN or C 1 -C 6 alkyl;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxylalkyl 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 hydroxylalkyl.

4 . The compound of claim 3 , wherein the compound has one of the following structures (Ia″), (Ib″), (Ic″), (Id″), (Ie″), (If″), (Ig″); (Ih″) or (Ij′):

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

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

7 . The compound of claim 6 , wherein R 1 is substituted with —OH, halo, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.

8 . The compound of claim 7 , wherein the C 1 -C 6 alkyl is substituted with one or more halo.

9 . The compound of claim 7 wherein halo is chloro or fluoro.

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

11 . The compound of claim 10 , wherein R 1 is phenyl or napthyl.

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

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

14 . The compound of claim 13 , wherein R 1 comprises one or more nitrogen atoms.

15 . The compound of claim 14 , wherein R 1 is indazolyl.

16 . The compound of claim 15 , wherein R 1 has the following structure:

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

18 - 24 . (canceled)

25 . The compound of claim 3 , wherein at least one of R 9 or R 10 is H.

26 . The compound of claim 25 , wherein each of R 9 and R 10 are H.

27 - 32 . (canceled)

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

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

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

36 . The compound of claim 1 , wherein at least one R 3a or at least one R 4a is aminylcarbonyl.

37 . The compound of claim 36 , wherein aminylcarbonyl is

38 . The compound of claim 1 , wherein at least one R 3a or at least one R 4a is cyano.

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D295/10

  substituted by doubly bound oxygen or sulphur atoms · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title