Therapeutic compounds and uses thereof

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.

We claim: 
     
         1 . A method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a CBP and/or EP300 inhibitor, or a pharmaceutically acceptable salt thereof, to the animal. 
     
     
         2 . The method of  claim 1  wherein the CBP and/or EP300-mediated disorder is a fibrotic disease. 
     
     
         3 . The method of  claim 2  wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis and arthro fibrosis. 
     
     
         4 . The method of  claim 1  wherein the CBP and/or EP300-mediated disorder is a fibrotic lung disease. 
     
     
         5 . The method of  claim 4  wherein the fibrotic lung disease is selected from the group consisting of idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), and pulmonary arterial hypertension. 
     
     
         6 . The method of  claim 5  wherein the fibrotic lung disease is idiopathic pulmonary fibrosis. 
     
     
         7 . The method of  claim 1  wherein the CBP and/or EP300 inhibitor is a compound of formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is NH, O, S, or —C(R a ) 2 —; 
 each R a  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl; 
 ring A is a 6 membered heteroaryl ring or a benzo ring, wherein ring A is optionally substituted with one or more groups R b  that are independently selected from the group consisting of R c , —F, —Cl, —Br, —I, —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 , —O—C(O)—O—R d , —C(O)—R d , —C(O)—O—R d , —S(O)—R d , —S(O) 2 —R d , —O—C(O)—N(R d ) 2 , —N(R d )—C(O)—OR d , —N(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 , —N(R d )—S(O)—N(R d ) 2 , —CH═C(R e ) 2 , and —N(R d )—S(O) 2 —N(R d ) 2 ; 
 
         each R c  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R f ;
 each R f  is independently selected from the group consisting of oxo, 3-20 membered carbocyclyl, 3-20 membered 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 , —Si(R h ) 3 , —N(R g )—C(O)—O—R g , —N(R g )—S(O)—R g , N(R g )—S(O) 2 —R g , and C 1-6 alkyl, which 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1-6 alkyl are optionally substituted with one or more groups R i , 
 each R g  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R j , or two R g  are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; 
 each R h  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl; 
 each R j  is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R k ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo; 
 each R k  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl; 
 each R i  is independently selected from the group consisting of oxo, halo, C 1-6 alkyl, cyano, —N(R 1 ) 2 , —O—R 1 , —S(O)—R 1 , —S(O) 2 —R 1 , —S(O)—N(R 1 ) 2 , —S(O) 2 —N(R 1 ) 2 , —N(R 1 )—S(O)—R 1 , —N(R 1 )—C(O)—R 1 , —N(R 1 )—C(O)—O—R 1 , —N(R 1 )—S(O) 2 —R 1 , 3-20 membered heterocyclyl, and 3-20 membered carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, and C 1-6 alkyl; 
 each R 1  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R m ; or two R 1  are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; and 
 each R m  is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R n ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo; 
 each R n  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl; 
 each R d  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R o , or two R d  are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; 
 each R o  is independently selected from the group consisting of oxo, halo, amino, hydroxyl, cyano, —O—R p , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl, wherein any C 1 -C 6  alkyl, 3-20 membered carbocyclyl and 3-20 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4  alkyl, —O—R q , and halo; 
 each R p  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R r , 
 each R r  is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R s ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo; 
 each R s  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl; 
 each R q  is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R t , 
 each R t  is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R u ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6  alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo; 
 each R u  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl; and 
 two R e  groups taken together with the carbon to which they are attached form a 3-20 membered carbocyclyl; 
 
         or a salt thereof. 
       
     
     
         8 . The method of  claim 1  wherein the CBP and/or EP300 inhibitor is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.