Substituted quinazoline compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016297774-A1
Application number	US-201615093951-A
Country	US
Kind code	A1
Filing date	Apr 8, 2016
Priority date	Apr 10, 2015
Publication date	Oct 13, 2016
Grant date	—

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , A, B, G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , n, x, y, X 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, stereoisomer or prodrug thereof, wherein:
A is N or CR′;
G 1 and G 2 are each independently N or CH;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R′ is H, cyano, alkyl, cycloalkyl, amino, aminylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, aminylalkoxy, alkylaminylalkoxy, alkylaminyl, alkylaminylalkyl, aminylalkylaminyl, carboxyalkyl, alkylcarbonylaminyl, aminylcarbonyl, alkylaminylcarbonyl or aminylcarbonylalkyl;
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, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 1 -C 6 alkynyl, C 1 -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 1 -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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 1 -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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 1 -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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 1 -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;
R 5a and R 5b are, at each occurrence, independently H, hydroxyl, halo or C 1 -C 6 alkyl, or R 5a and R 5b join to form oxo;
R 6 is amino, cyano, substituted alkyl or substituted or unsubstituted: haloalkyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 alkylphosphoryl, C 1 -C 6 alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyloxy or heteroarylalkylaminyl when R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroarylaryl; or R 6 is methyl when R 1 is substituted aryl or substituted or unsubstituted heteroaryl;
R 7 is, at each occurrence, independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or heterocyclyl;
m 1 and m 2 are each independently 1, 2 or 3;
n is an integer from 0 to 6;
X is a bond, —O—, —NR 7 — or —S—; 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,
wherein each occurrence of alkyl, alkylene, aryl, heteroaryl, alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, alkylphosphoryl, alkylphosphorylaminyl, aminylcarbonyl, alkylaminyl, haloalkyl, alkoxy, haloalkoxy; cycloalkyl, heterocyclylalkyl, heteroarylalkyloxy, heteroarylalkylaminyl and carbocyclic and heterocyclic rings is optionally substituted with one or more substituents unless otherwise specified.

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

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 —;
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.

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

4 . The compound claim 1 , wherein R 1 is aryl.

5 . The compound of claim 4 , wherein R 1 is phenyl or napthyl.

6 . (canceled)

7 . The compound of claim 4 , wherein R 1 is substituted with one or more substituents.

8 . The compound of claim 7 , 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.

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

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

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

12 . (canceled)

13 . The compound of claim 11 , wherein R 1 is indazolyl, indolyl, benzoimidazole, benzotriazole or quinolinyl.

14 . The compound of claim 11 , wherein R 1 is substituted with one or more substituents.

15 . The compound of claim 14 , wherein R 1 is substituted with hydroxyl, halo or C 1 -C 6 alkyl, or combinations thereof.

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

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

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

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

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

21 . The compound of claim 1 , wherein n is 0, X is a bond and R 6 is heterocyclyl.

22 . The compound of claim 21 , wherein R 6 is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

23 . The compound of claim 21 , wherein R 6 is substituted.

24 . The compound of claim 23 , whe

Assignees

• Araxes Pharma Llc

Inventors

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

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/04

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

• C07D405/12

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

• C07D239/74 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring · CPC title