2',6'-dioxo-3'-deutero-piperdin-3-yl-isoindoline compounds

Abstract

The present application describes 2-(2′,6′-dioxo-3′-deutero-piperidin-3′-yl)isoindoles, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treating using the same.

What is claimed is: 
     
         1 . A deuterium-enriched compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 8  is selected from H and D; 
         R 8a  is —OR 12a ; 
         one of X and Y is C═O and the other is selected from CH 2 , CHD, CD 2 , and C═O; 
         Z is H or D, provided that the abundance of deuterium in Z is at least 30%; 
         R 1 -R 7  and R 9 -R 10  are independently selected from H and D; 
         R 12a  is CH 2 —R a -R b -R c ; 
         R a  is a bond, alternatively, R a  is selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl, wherein R a  is optionally substituted with 1-3 halogen; 
         R b  is selected from (CH 2 ) m , O(CH 2 ) m , and (CH 2 ) m O; 
         m is selected from 0-3; 
         R c  is selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl, and R c  is substituted with 0-2 groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, ═O, NR 20   2 , CO 2 R 20 , —CN, OH, halogen, S(O) 2 (C 1 -C 8 )alkyl, aryl substituted with 0-2 R d , and (C 2 -C 9 )heteroaryl substituted with 0-2 R d ; 
         R d  is selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, CONR 20   2 , CO 2 (C 1 -C 6 )alkyl, and CO 2 (C 1 -C 6 )haloalkyl; 
         R 20  is selected from H and (C 1 -C 8 )alkyl; 
         wherein a hydrogen atom present in any of the substituents is optionally replaced by deuterium. 
       
     
     
         2 . A deuterium-enriched compound of  claim 1 , wherein:
 R a  is selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl, wherein R a  is optionally substituted with 1-3 halogen.   
     
     
         3 . A deuterium-enriched compound of  claim 1 , wherein:
 R a  is selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl.   
     
     
         4 . A deuterium-enriched compound of  claim 1 , wherein:
 R a  is aryl.   
     
     
         5 . A deuterium-enriched compound of  claim 1 , wherein:
 R b  is (CH 2 ) m .   
     
     
         6 . A deuterium-enriched compound of  claim 5 , wherein:
 m is 1.   
     
     
         7 . A deuterium-enriched compound of  claim 1 , wherein:
 R c  is (C 1 -C 6 )heterocycloalkyl substituted with 0-2 groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, ═O, NR 20   2 , CO 2 R 20 , —CN, OH, halogen, or S(O) 2 (C 1 -C 8 )alkyl.   
     
     
         8 . A deuterium-enriched compound of  claim 1 , wherein:
 R c  is (C 1 -C 6 )heterocycloalkyl.   
     
     
         9 . A deuterium-enriched compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 8  is selected from H and D; 
         R 8a  is —OR 12a ; 
         one of X and Y is C═O and the other is selected from CH 2 , CHD, CD 2 , and C═O; 
         Z is H or D, provided that the abundance of deuterium in Z is at least 30%; 
         R 1 -R 7  and R 9 -R 10  are independently selected from H and D; 
         R 12a  is CH 2 —R a -R b -R c ; 
         R a  is aryl; 
         R b  is CH 2 ; 
         R c  is (C 1 -C 6 )heterocycloalkyl; 
         wherein a hydrogen atom present in any of the substituents is optionally replaced by deuterium. 
       
     
     
         10 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         11 . A method for treating myelodysplastic syndrome comprising: administering, to a patient in need thereof, a therapeutically effective amount of a compound of  claim 1 . 
     
     
         12 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 9 . 
     
     
         13 . A method for treating myelodysplastic syndrome comprising: administering, to a patient in need thereof, a therapeutically effective amount of a compound of  claim 9 .