Substituted quinazoline compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10246424-B2
Application number	US-201615093951-A
Country	US
Kind code	B2
Filing date	Apr 8, 2016
Priority date	Apr 10, 2015
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

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

The invention claimed is:

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

or a pharmaceutically acceptable salt or stereoisomer or thereof, wherein:
A is N;
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 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 2 -C 6 alkynyl, C 2 -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 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 3 -C 8 cycloalkyl, heterocyclylalkyl, 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 3 -C 8 cycloalkyl, heterocyclylalkyl, 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 3 -C 8 cycloalkyl, heterocyclylalkyl, 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;
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 heteroaryl; 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, heterocyclyl, alkenyl, 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, the optional substituents being selected from the group consisting of aminyl, cyano, hydroxyl, 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 alkylheterocycloalkyl, 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, C 3 -C 8 cycloalkylalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, and
wherein: i) each aryl comprises a 6- to 18-membered carbocyclic aromatic ring radical; ii) each heterocyclyl comprises a 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and iii) each heteroaryl comprises a 5- to 14-membered ring radical comprising hydrogen atoms, one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.

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

7. The compound of claim 6 , 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.

8. The compound of claim 7 , wherein R 1 is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropryl, trifluoromethyl or methoxy, or combinations thereof.

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

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

11. The compound of claim 10 , wherein R 1 is indazolyl, indolyl, benzoimidazole, benzotriazole or quinolinyl.

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

13. The compound of claim 12 , wherei

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

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D401/04

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

• C07D491/10

  Spiro-condensed systems · CPC title