IP Library › Granted Patent US 9,763,922

Granted Patent B2

US 9,763,922 · App. 14/952,821 · Granted Sep 19, 2017

Therapeutic compounds and uses thereof

Inventors: Marc Adler (South San Francisco, CA); Brian K. Albrecht (Cambridge, MA); Sarah Bronner (South San Francisco, CA); Kevin X. Chen (Shanghai, CN); Alexandre Côté (Cambridge, MA); Terry Crawford (South San Francisco, CA); Patrick Cyr (South San Francisco, CA); Jackson Egen (South San Francisco, CA); Steven Kauder (South San Francisco, CA); Kwong Wah Lai (Shanghai, CN); Jiangpeng Liao (Shanghai, CN); Steven Magnuson (South San Francisco, CA); Jeremy Murray (South San Francisco, CA); Richard Pastor (South San Francisco, CA); F. Anthony Romero (South San Francisco, CA); Alexander M. Taylor (Cambridge, MA); Vickie Hsiao-Wei Tsui (South San Francisco, CA); Fei Wang (Shanghai, CN); Bing-Yan Zhu (South San Francisco, CA)

Assignees: GENENTECH, INC.; CONSTELLATION PHARMACEUTICALS, INC.

A61K31/437 A61K31/4375 A61K31/4709 A61K31/4725 A61K31/496 A61K31/498 A61K31/506 A61K31/538 A61K31/5377 A61K31/5415 A61K31/55 A61K45/06 C07D471/04 C07D519/00

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Quick Facts

Patent No.: US 9,763,922
App. No.: 14/952,821
Granted: Sep 19, 2017
Kind: B2

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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.

Claims (74)

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 g )—S(O)—R g , N(R g )—S(O) 2 —R g , 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 g ) 2 , —O—R g , heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C 1-6 alkyl;

each R g 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 g 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 h of Formula (I) is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo; and

R 1 of Formula (II) is selected from 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), 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 2 of Formula (II) 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 2 is optionally substituted with one or more groups R b ;

R 3 of Formula (II) 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 e ) 2 , —S(O)—N(R e ) 2 , —S(O) 2 —N(R e ) 2 , —C(O)—R e , —C(O)—O—R e , —S(O)—R e , or —S(O) 2 —R e , 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 e ) 2 , —S(O)—N(R e ) 2 , —S(O) 2 —N(R e ) 2 , —O—R e , —S—R e , —O—C(O)—R e , —O—C(O)—O—R e , —C(O)—R e , —C(O)—O—R e , —S(O)—R e , —S(O) 2 —R e , —O—C(O)—N(R e ) 2 , —N(R e )—C(O)—OR e , —N(R e )—C(O)—N(R e ) 2 , —N(R e )—C(O)—R e , —N(R e )—S(O)—R e , —N(R e )—S(O) 2 —R e , —N(R e )—S(O)—N(R e ) 2 , and —N(R e )—S(O) 2 —N(R e ) 2 ;

each R a of Formula (II) 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 (II) 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 , —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 , —C(O)—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 (II) 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 , —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 (II) 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; and

each R e of Formula (II) is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo; provided that R 1 is not unsubstituted phenyl, when R 2 is carboxymethyl or 2-carboxyethyl.

2. The compound of claim 1 , where the compound is of formula (I):

or a salt thereof, wherein:

R 1 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 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 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 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 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 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 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)—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)—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 , —C(O)—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 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 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 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,

each R f 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 g )—S(O)—R g , N(R g )—S(O) 2 —R g , 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 g ) 2 , —O—R g , heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C 1-6 alkyl;

each R g 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 g 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; and

each R h is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo.

3. The compound of claim 2 wherein R 1 is:

4. The compound of claim 2 wherein R 2 is phenyl optionally substituted with one or more substituent groups independently selected from R c , and R 3 is methyl or phenyl, wherein each methyl and phenyl of R 3 is optionally substituted with one or more groups R e .

5. The compound of claim 2 wherein R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e .

6. The compound of claim 2 wherein R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e ; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring.

7. The compound of claim 2 wherein —NR 2 R 3 taken together is selected from the group consisting of:

8. The compound of claim 2 wherein R 4 is selected from the group consisting of:

9. The compound of claim 2 wherein:

R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b ;

—NR 2 R 3 taken together is selected from the group consisting of:

and

R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.

10. The compound of claim 2 selected from the group consisting of:

and salts thereof.

11. The compound of claim 1 , wherein the compound is of formula (II):

or a salt thereof, wherein:

R 1 is selected from 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), 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 and —N(R a )—S(O) 2 —N(R a ) 2 ;

R 2 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 2 is optionally substituted with one or more groups R b ;

R 3 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 e ) 2 , —S(O)—N(R e ) 2 , —S(O) 2 —N(R e ) 2 , —C(O)—R e , —C(O)—O—R e , —S(O)—R e , or —S(O) 2 —R e , 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 e ) 2 , —S(O)—N(R e ) 2 , —S(O) 2 —N(R e ) 2 , —O—R e , —S—R e , —O—C(O)—R e , —O—C(O)—O—R e , —C(O)—R e , —C(O)—O—R e , —S(O)—R e , —S(O) 2 —R e , —O—C(O)—N(R e ) 2 , —N(R e )—C(O)—OR e , —N(R e )—C(O)—N(R e ) 2 , —N(R e )—C(O)—R e , —N(R e )—S(O)—R e , —N(R e )—S(O) 2 —R e , —N(R e )—S(O)—N(R e ) 2 , and —N(R e )—S(O) 2 —N(R e ) 2 ;

each R a 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 IV 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 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—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 , —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 e is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo; provided that R 1 is not unsubstituted phenyl, when R 2 is carboxymethyl or 2-carboxyethyl.

12. The compound of claim 11 wherein R 1 is selected from:

13. The compound of claim 11 wherein R 2 is:

14. The compound of claim 11 wherein R 3 is selected from the group consisting of:

15. The compound of claim 11 selected from:

and salts thereof.

16. A composition comprising a compound of formula (I) or formula (II) as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

17. A method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof as described in claim 1 , to the animal, wherein the treating does not include preventing the disorder.

18. A method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as described in claim 1 .

19. A method of extending the duration of response to a cancer therapy in an animal, comprising administering to an animal undergoing the cancer therapy a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, as described in claim 1 , wherein the duration of response to the cancer therapy when the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is administered is extended over the duration of response to the cancer therapy in the absence of the administration of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof.

20. A method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as described in claim 1 , and (b) a cytotoxic agent, wherein the treating does not include preventing the cancer.

Assignments (5)