Modulators of methyl modifying enzymes, compositions and uses thereof

Abstract

Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.

1 . A compound having the structural Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is CH or N; 
         R 1a  is selected from —C 1 -C 2  alkyl and —O—(C 1 -C 2  alkyl), wherein R 1a  is optionally substituted with one or more fluoro; 
         R 4a  is selected from 1-substituted-pipieridin-4-yl, C 3 -C 6  cycloalkyl optionally substituted with one or more fluoro, and tetrahydropyranyl; and 
         R 13  is selected from hydrogen, halo, phenyl, pyridinyl, and —O—(C 1 -C 4  alkyl). 
       
     
     
         2 . The compound of  claim 1 , wherein R 1a  is selected from —OCH 3 , —CH 3 , —OCHF 2 , and —CH 2 CH 3 . 
     
     
         3 . The compound of  claim 2 , wherein the 1-substituted-pipieridin-4-yl is a 1-halo(C 1 -C 3 )alkyl-piperidin-4-yl. 
     
     
         4 . The compound of  claim 3 , wherein R 4a  is selected from -4,4-difluorocyclohexyl, cyclopropyl, tetrayhyrdopyran-4-yl, 1-(t-butoxycarbonyl)-piperidin-4-yl, 1-(isobutoxycarbonyl)-piperidin-4-yl, 1-(isopropoxycarbonyl)-piperidin-4-yl, 1-(2-fluoroethyl)-piperidin-4-yl, 1-(2,2-difluoroethyl)-piperidin-4-yl, 1-(2,2,2-trifluoroethyl)-piperidin-4-yl, 1-(2-hydroxyisobutyl)-piperidin-4-yl, 1-(hydroxyisopropylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonylmethyl)-piperidin-4-yl, 1-(isopropylcarbonyl)-piperidin-4-yl, 1-methylpiperidin-4-yl, 1-(methylsulfonyl)-piperidin-4-yl, 1-(ethylsulfonyl)-piperidin-4-yl, 1-(isopropylsulfonyl)-piperidin-4-yl, 1-(phenyl)-piperidin-4-yl, 1-(oxetan-3-yl)piperidin-4-yl, 1-(pyridin-2-yl)-piperidin-4-yl, and 1-(pyrimidin-2-yl)-piperidin-4-yl. 
     
     
         5 . The compound of  claim 4 , wherein R 13  is selected from hydrogen, chloro, fluoro, —OCH(CH 3 ) 2 , phenyl, and pyridin-2-yl. 
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         7 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 7 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A pharmaceutical composition comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.