Pyrrolidine amide compounds as histone demethylase inhibitors

Patent metadata

Field	Value
Publication number	US-10022354-B2
Application number	US-201715482584-A
Country	US
Kind code	B2
Filing date	Apr 7, 2017
Priority date	Oct 10, 2014
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

The present invention relates to compounds useful as inhibitors of one or more histone demethylases, such as KDM5. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

First claim

We claim:

1. A compound of formula (I):

or a salt thereof, wherein:
A is selected from the group consisting of:

R 1 is halo, —N(R x ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, C 1-6 alkoxy, 5-10 membered aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, wherein said C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, 3-8 membered carbocyclyl, C 1-6 alkoxy, 5-10 membered aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, hydroxy, halo, C 1-3 alkoxy, 3-8 membered carbocyclyl, 5-10 membered aryl, —N(R x ) 2 , —N(R x )C(O)R x , and C 1-3 alkyl;
each R x is independently selected from the group consisting of H and C 1-6 alkyl, that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, and C 1-3 alkoxy;
R 2 is 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl, —OR a , —C(O)N(R a ) 2 , or NR a R b , wherein each 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 5-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with one or more groups R d ;
R a and R b are each independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl —C(O)R c , —CO 2 R c , —C(O)N(R c ) 2 , —C(O)SR c , and —C(O)C(O)R c , wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, —OR c , —SR c , —N(R c ) 2 , —C(O)R c , —C(O)N(R c ) 2 , —C(O)SR c , —C(O)C(O)R c , —S(O)R c , —SO 2 N(R c ) 2 , —N(R c )C(O)R c , —N(R c )C(O)N(R c ) 2 , —N(R c )SO 2 R c , —N(R c )SO 2 N(R c ) 2 , —N(R c )N(R c ) 2 , —N(R c )C(═N(R c ))N(R c ) 2 , —C(═N)N(R c ) 2 , —C═NOR c , and —C(═N(R c ))N(R c ) 2 ;
each R c is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with one or more groups R h ;
each R d is independently selected from the group consisting of halo, nitro, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl, —OR e , —SR e , —N(R e ) 2 , —C(O)R e , —CO 2 R e , —C(O)N(R e ) 2 , —C(O)SR e , —C(O)C(O)R e , —S(O)R e , —SO 2 R e , —SO 2 N(R e ) 2 , —N(R e )C(O)R e , —N(R e )C(O)N(R e ) 2 , —N(R e )SO 2 R e , —N(R e )SO 2 N(R e ) 2 , —N(R e )N(R e ) 2 , —N(R e )C(═N(R e ))N(R e ) 2 , —C(═N)N(R e ) 2 , —C═NOR e , and —C(═N(R e ))N(R e ) 2 , wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from R f ;
each R e is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl;
each R f is independently selected from the group consisting of halo, nitro, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, —OR g , —SR g , —N(R g ) 2 , —C(O)R g , —CO 2 R g , —C(O)N(R g ) 2 , —C(O)SR g , —C(O)C(O)R g , —S(O)R g , —SO 2 R g , —SO 2 N(R g ) 2 , —N(R g )C(O)R g , —N(R g )C(O)N(R g ) 2 , —N(R g )SO 2 R g , —N(R g )SO 2 N(R g ) 2 , —N(R g )N(R g ) 2 , —N(R g )C(═N(R g ))N(R g ) 2 , —C(═N)N(R g ) 2 , and —C═NOR g , —C(═N(R g ))N(R g ) 2 , wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and 3-8 membered carbocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, oxo, 3-8 membered carbocyclyl, —OR g , —N(R g ) 2 , —C(O)R g , —CO 2 R g , —C(O)N(R g ) 2 , —SO 2 R g , —SO 2 N(R g ) 2 , and —N(R g )C(O)R g ;
each R g is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl; and
each R h is independently selected from the group consisting of halo, nitro, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl, —N(R k ) 2 , and, —OR k , wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, 5-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, C 1-4 alkoxy, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, and 5-10 membered aryl;
each R k is independently selected from the group consisting of H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, and 5-10 membered aryl wherein any C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-8 membered carbocyclyl, and 5-10 membered aryl carbocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, oxo hydroxy, and 3-8 membered carbocyclyl; and
R 3 is H or C 1-6 alkyl;
R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or 3-8 membered carbocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 3-8 membered carbocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, C 1-6 alkoxy, and 3-8 membered carbocyclyl; and
R 5 is H, halo, or C 1-6 alkyl, and R 6 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, or 3-8 membered carbocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 3-8 membered carbocyclyl, is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, C 1-6 alkoxy, and 3-8 membered carbocyclyl; or R 5 and R 6 taken together with the atom to which they are attached form a 3-8 membered carbocyclyl or a 3-8 membered heterocyclyl, which 3-8 membered carbocyclyl and 3-8 membered heterocyclyl are optionally substitutes with one or more groups ind

Assignees

• Genentech Inc
• Constellation Pharmaceuticals Inc
• Constellation Pharmaceuticals Inc

Inventors

• Lai Kwong Wah
• Liang Jun
• Zhang Birong
• Labadie Sharada
• ORTWINE Daniel
• DRAGOVICH Peter
• Kiefer James
• Gehling Victor S
• Harmange Jean-Christophe

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title