Therapeutic compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9763922-B2
Application number	US-201514952821-A
Country	US
Kind code	B2
Filing date	Nov 25, 2015
Priority date	Nov 27, 2014
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention relates to compounds of formula (I) or formula (II):

and to salts thereof, wherein R 1 -R 4 of formula (I) and R 1 -R 3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.

First claim

We claim:

1. A compound of formula (I) or formula (II):

or a salt thereof, wherein:
R 1 of Formula (I) is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 1 is optionally substituted with one or more groups R b ;
R 2 of Formula (I) is selected from C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), —(C 1 -C 20 heteroaryl)-(C 6 -C 20 aryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —C(O)—R a , —C(O)—O—R a , —S(O)—R a , —S(O) 2 —R a , —O—C(O)—N(R a ) 2 , —N(R a )—C(O)—OR a , —N(R a )—C(O)—N(R a ) 2 , —N(R a )—C(O)—R a , —N(R a )—S(O)—R a , —N(R a )—S(O) 2 —R a , —N(R a )—S(O)—N(R a ) 2 , and —N(R a )—S(O) 2 —N(R a ) 2 ;
R 3 of Formula (I) is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 3 is optionally substituted with one or more groups R e ; or
R 2 and R 3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R e ;
R 4 of Formula (I) is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R h ) 2 , —S(O)—N(R h ) 2 , —S(O) 2 —N(R h ) 2 , —C(O)—R h , —C(O)—O—R h , —S(O)—R h , or

—S(O) 2 —R h , wherein any C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R h ) 2 , —S(O)—N(R h ) 2 , —S(O) 2 —N(R h ) 2 , —O— R h , —S—R h , —O—C(O)—R h , —O—C(O)—O—R h , —C(O)—R h , —C(O)—O—R h , —S(O)—R h , —S(O) 2 —R h , —O—C(O)—N(R h ) 2 , —N(R h )—C(O)—OR h , —N(R h )—C(O)—N(R h ) 2 , —N(R h )—C(O)—R a , —N(R h )—S(O)—R h , —N(R h )—S(O) 2 —R h , —N(R h )—S(O)—N(R h ) 2 , and —N(R h )—S(O) 2 —N(R h ) 2 ;
each R a of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R a are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
each R b of Formula (I) is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—O—R c , —O—C(O)—O—R c , —C(O)—R c , —C(O)—O—R c , —S(O)—R c , —S(O) 2 —R c , —O—C(O)—N(R c ) 2 , —N(R c )—C(O)—OR c , —N(R c )—C(O)—N(R c ) 2 , —N(R c )—C(O)—R c , —N(R c )—S(O)—R c , —N(R c )—S(O) 2 —R c , —N(R c )—S(O)—N(R c ) 2 , and —N(R c )—S(O) 2 —N(R c ) 2 , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—R c , —C(O)—R c , —S(O)—R c , —S(O) 2 —R c , —C(O)—N(R c ) 2 , —N(R c )—C(O)—R c , —N(R c )—S(O)—R c , —N(R c )—S(O) 2 —R c and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
each R c of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —S(O)—N(R d ) 2 , —S(O) 2 —N(R d ) 2 , —O—R d , —S—R d , —O—C(O)—R d , —C(O)—R d , —C(O)—O—R d , —S(O)—R d , —S(O) 2 —R d , —C(O)—N(R d ) 2 , —N(R d )—C(O)—R d , —N(R d )—S(O)—R d , N(R d )—S(O) 2 —R d , and C 1-6 alkyl, which carbocyclyl and C 1-6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C 1-6 alkyl, cyano, —N(R d ) 2 , —O—R d , heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C 1-6 alkyl;
each R d of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R d are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
each R e of Formula (I) is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R f ) 2 , —CN, —C(O)—N(R f ) 2 , —S(O)—N(R f ) 2 , —S(O) 2 —N(R f ) 2 , —O—R f , —S—R f , —O—C(O)—R f , —O—C(O)—O—R f , —C(O)—R f , —C(O)—O—R f , —S(O)—R f , —S(O) 2 —R f , —O—C(O)—N(R f ) 2 , —N(R f )—C(O)—OR f , —N(R f )—C(O)—N(R f ) 2 , —N(R f )—C(O)—R f , —N(R f )—S(O)—R f , —N(R f )—S(O) 2 —R f , —N(R f )—S(O)—N(R f ) 2 , and —N(R f )—S(O) 2 —N(R f ) 2 , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo,

halo, —NO 2 , —N(R f ) 2 , —CN, —C(O)—N(R f ) 2 , —S(O)—N(R f ) 2 , —S(O) 2 —N(R f ) 2 , —O—R f , —S—R f , —O—C(O)—R f , —C(O)—R f , —C(O)—O—R f , —S(O)—R f , —S(O) 2 —R f , —C(O)—N(R f ) 2 , —N(R f )—C(O)—R f , —N(R f )—S(O)—R f , —N(R f )—S(O) 2 —R f , carbocycle, and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
each R f of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R g ) 2 , —CN, —C(O)—N(R g ) 2 , —S(O)—N(R g ) 2 , —S(O) 2 —N(R g ) 2 , —O—R g , —S—R g , —O—C(O)—R g , —C(O)—R g , —C(O)—O—R g , —S(O)—R g , —S(O) 2 —R g , —C(O)—N(R g ) 2 , —N(R g )—C(O)—R g , —N(R

Assignees

• Genentech Inc
• Constellation Pharmaceuticals Inc

Inventors

• Adler Marc
• Albrecht Brian K
• Bronner Sarah
• Chen Kevin X
• Côté Alexandre
• Crawford Terry
• Cyr Patrick
• Egen Jackson
• Kauder Steven
• Lai Kwong Wah
• Liao Jiangpeng
• Magnuson Steven
• Murray Jeremy
• Pastor Richard
• Romero F Anthony
• Taylor Alexander M
• Tsui Vickie Hsiao-Wei
• Wang Fei
• Zhu Bing-Yan

Classifications

• A61K31/5415

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title