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.

1 . A deuterium-enriched compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         one of R 8 -R 8a  is —(CR 9 R 10 ) n A and the other is selected from H and D; 
         alternatively, R 8a  is —OR 12a , and R 8  is selected from H and D; 
         A is NR 11 R 12 ; 
         alternatively, when n=1, then A is selected from D, H, and NR 11 R 12 ; 
         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 11  is selected from H, D, and CH 3 ; 
         R 12  is selected from H, D, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, C(O)R 13 , C(S)R 13 , C(O)OR 14 , (C 1 -C 8 )alkyl-N(R 16 ) 2 , (C 1 -C 8 )alkyl-OR 15 , (C 1 -C 8 )alkyl-C(O)OR 15 , C(O)NHR 13 , C(S)NHR 13 , C(O)NR 13 R 13′ , C(S)NR 13 R 13′ , and (C 1 -C 8 )alkyl-O(CO)R 15 ; 
         provided that when n=0, R 12  is other than H or D; 
         R 12a  is selected from CH 2 —R a -R b -R c , H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, C(O)(C 1 -C 8 )alkyl, C(O)O(C 1 -C 8 )alkyl, C(O)NH(C 1 -C 8 )alkyl, C(O)N((C 1 -C 8 )alkyl) 2 , C(O)(C 3 -C 7 )cycloalkyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, C(O)aryl, C(O)(C 1 -C 6 )heterocycloalkyl, and C(O)(C 2 -C 9 )heteroaryl, and R 12a  is optionally substituted with 1-3 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 , C(O)NH(C 1 -C 8 )alkyl, C(O)N((C 1 -C 8 )alkyl) 2 , NO 2 , —CN, OH, halogen, and S(O) 2 (C 1 -C 8 )alkyl; 
         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 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 13  is selected from H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, (C 0 -C 8 )alkyl-N(R 16 ) 2 , (C 1 -C 8 )alkyl-OR 15 , (C 1 -C 8 )alkyl-C(O)OR 15 , (C 1 -C 8 )alkyl-O(CO)R 15 , and C(O)OR 15 ; 
         R 13′  is selected from (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, (C 0 -C 8 )alkyl-N(R 16 ) 2 , (C 1 -C 8 )alkyl-OR 15 , (C 1 -C 8 )alkyl-C(O)OR 15 , (C 1 -C 8 )alkyl-O(CO)R 15 , and C(O)OR 15 ; 
         R 14  is selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 15 , (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, and (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl; 
         R 15  is selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, and (C 2 -C 9 )heteroaryl; 
         R 16 , at each occurrence, is independently selected from H, D, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 2 -C 9 )heteroaryl, and (C 0 -C 8 )alkyl-C(O)OR 15 ; 
         alternatively, N(R 16 ) 2  forms a heterocycloalkyl group; 
         n, at each occurrence, is selected from 0, 1, 2, and 3; 
         the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with 1-3 R 17 ; 
         R 17 , at each occurrence, is independently selected from H, D, halogen, NO 2 , —CN, (C 1 -C 8 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )alkyenedioxy, —NHC(O)(C 1 -C 6 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , S—(C 1 -C 8 )alkyl, SO 2 (C 1 -C 8 )alkyl, S—(C 1 -C 8 )haloalkyl, SO 2 (C 1 -C 8 )haloalkyl, (C 0 -C 4 )alkyl-R 17a , (C 0 -C 4 )alkyl-R 18 , —O—(C 0 -C 4 )alkyl-R 18 , —(CH 2 —R 19 ) p —R 18 , OC(O)(CH 2 ) p NH 2 , and OC(O)(CH 2 ) p (C 1 -C 6 )heterocycloalkyl; 
         p, at each occurrence, is selected from 0, 1, and 2; 
         R 17a , at each occurrence, is independently selected from OH, NH 2 , and CO 2 R 20 ; 
         R 18 , at each occurrence, is independently selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl, wherein each aryl, heterocycloakyl, and heteroaryl is optionally substituted with 1-3 (C 1 -C 8 )alkyl; 
         R 19 , at each occurrence, is independently selected from CH 2 , NH, and O; 
         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:
 wherein:   R 8  is —(CR 9 R 10 )NR 11 R 12 ;   R 8a  is selected from H and D;   X is CH 2 ;   Y is 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 11  is selected from H and D;   R 12  is selected from C(O)R 13  and C(O)OR 14 ;   R 13  is selected from (C 1 -C 8 )alkyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, and (C 1 -C 6 )alkyl-C(O)OR 15 ;   R 14  is (C 1 -C 8 )alkyl;   R 15  is selected from H and (C 1 -C 8 )alkyl;   the aryl and heteroaryl groups are optionally substituted with 1-3 R 17 ;   R 17 , at each occurrence, is independently selected from H, D, halogen, (C 1 -C 8 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, S—(C 1 -C 8 )alkyl, and SO 2 (C 1 -C 8 )alkyl;   wherein a hydrogen atom is present in any of the substituents it is optionally replaced by deuterium.   
     
     
         3 . A deuterium-enriched compound of  claim 1 , wherein:
 R 8  is selected from H and D;   R 8a  is —OR 12a      X is CH 2 ;   Y is 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 selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, C(O)(C 1 -C 8 )alkyl, C(O)O(C 1 -C 8 )alkyl, C(O)NH(C 1 -C 8 )alkyl, C(O)N((C 1 -C 8 )alkyl) 2 , C(O)(C 3 -C 7 )cycloalkyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, C(O)aryl, C(O)(C 1 -C 6 )heterocycloalkyl, and C(O)(C 2 -C 9 )heteroaryl, and R 12a  is optionally substituted with 1-3 groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, NR 20   2 , CO 2 R 20 , C(O)NH(C 1 -C 8 )alkyl, C(O)N((C 1 -C 8 )alkyl) 2 , NO 2 , —CN, OH, halogen, and S(O) 2 (C 1 -C 8 )alkyl;   R 20  is selected from H and (C 1 -C 8 )alkyl;   wherein a hydrogen atom is present in any of the substituents it is optionally replaced by deuterium.   
     
     
         4 . A deuterium-enriched compound of  claim 1 , 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 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;   wherein a hydrogen atom present in any of the substituents is optionally replaced by deuterium.   
     
     
         5 . A deuterium-enriched compound of  claim 1 , wherein:
 R 8  is —(CR 9 R 10 ) n NR 11 R 12 ;   R 8a  is selected from H and D;   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 11  is selected from H and D;   R 12  is selected from C(O)NHR 13  and C(O)NR 13 R 13′ ;   R 13  is selected from aryl;   R 13′  is (C 1 -C 8 )alkyl;   n, at each occurrence, is selected from 0, 1, 2, and 3;   the aryl group is substituted with 2 R 17 ;   R 17 , at each occurrence, is independently selected from H, halogen, NO 2 , (C 1 -C 8 )alkyl, —NHC(O)(C 1 -C 6 )alkyl, (C 0 -C 4 )alkyl-R 17a , (C 0 -C 4 )alkyl-R 18 , —O—R 18 , —(CH 2 —R 19 ) p —R 18 , OC(O)(CH 2 ) p NH 2 , and OC(O)(CH 2 ) p (C 1 -C 6 )heterocycloalkyl;   p, at each occurrence, is selected from 0, 1, and 2;   R 17a , at each occurrence, is independently selected from OH and NH 2 ;   R 18 , at each occurrence, is independently selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl, wherein each aryl, heterocycloakyl, and heteroaryl is optionally substituted with 1-3 (C 1 -C 8 )alkyl;   R 19 , at each occurrence, is independently selected from CH 2 , NH, and O;   wherein a hydrogen atom present in any of the substituents is optionally replaced by deuterium.   
     
     
         6 . A deuterium-enriched compound of  claim 1 , wherein:
 R 8  is selected from H and D;   R 8a  is —(CR 9 R 10 )A is NR 11 R 12 ;   X is CH 2 ;   Y is 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 11  is CH 3 ;   R 12  is selected from H, D, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, C(O)R 13 , C(S)R 13 , C(O)OR 14 , (C 1 -C 8 )alkyl-N(R 16 ) 2 , (C 1 -C 8 )alkyl-OR 15 , (C 1 -C 8 )alkyl-C(O)OR 15 , C(O)NHR 13 , C(S)NHR 13 , C(O)NR 13 R 13′ , C(S)NR 13 R 13′ , and (C 1 -C 8 )alkyl-O(CO)R 15 ;   R 13  is selected from H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, (C 0 -C 8 )alkyl-N(R 16 ) 2 , (C 1 -C 8 )alkyl-OR 15 , (C 1 -C 8 )alkyl-C(O)OR 15 , (C 1 -C 8 )alkyl-O(CO)R 15 , and C(O)OR 15 ;   R 13′  is selected from (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, (C 0 -C 8 )alkyl-N(R 16 ) 2 , (C 1 -C 8 )alkyl-OR 15 , (C 1 -C 8 )alkyl-C(O)OR 15 , (C 1 -C 8 )alkyl-O(CO)R 15 , and C(O)OR 15 ;   R 14  is selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 15 , (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, and (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl;   R 15  is selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, and (C 2 -C 9 )heteroaryl;   R 16 , at each occurrence, is independently selected from H, D, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 2 -C 9 )heteroaryl, and (C 0 -C 8 )alkyl-C(O)OR 15 ;   alternatively, N(R 16 ) 2  forms a heterocycloalkyl group;   n, at each occurrence, is selected from 0, 1, 2, and 3;   the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with 1-3 R 17 ;   R 17 , at each occurrence, is independently selected from H, D, halogen, NO 2 , (C 1 -C 8 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )alkyenedioxy; —NHC(O)(C 1 -C 6 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , S—(C 1 -C 8 )alkyl, SO 2 (C 1 -C 8 )alkyl, (C 0 -C 4 )alkyl-R 17a , (C 0 -C 4 )alkyl-R 18 , —O—(C 0 -C 4 )alkyl-R 18 , —(CH 2 —R 19 ) p —R 18 , OC(O)(CH 2 ) p NH 2 , and OC(O)(CH 2 ) p (C 1 -C 6 )heterocycloalkyl;   p, at each occurrence, is selected from 0, 1, and 2;   R 17a , at each occurrence, is independently selected from OH, NH 2 , and CO 2 R 20 ;   R 18 , at each occurrence, is independently selected from aryl, (C 1 -C 6 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl, wherein each aryl, heterocycloakyl, and heteroaryl is optionally substituted with 1-3 (C 1 -C 8 )alkyl;   R 19 , at each occurrence, is independently selected from CH 2 , NH, and O;   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.   
     
     
         7 . A deuterium-enriched compound of  claim 6 , wherein:
 R 12  is selected from C(O)R 13 , C(O)OR 14 , C(O)NHR 13 , and C(O)NR 13 R 13′ ;   R 13  is selected from H, (C 1 -C 8 )alkyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, and (C 0 -C 8 )alkyl-N(R 16 ) 2 ;   R 13′  is selected from (C 1 -C 8 )alkyl, (C 0 -C 4 )alkyl-aryl, and (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl;   R 14  is selected from (C 1 -C 8 )alkyl;   R 15  is (C 1 -C 8 )alkyl;   R 16 , at each occurrence, is independently selected from H, D, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 0 -C 4 )alkyl-aryl, (C 2 -C 9 )heteroaryl, and (C 0 -C 8 )alkyl-C(O)OR 15 ;   the aryl and heteroaryl groups are optionally substituted with 1-3 R 17 ;   R 17 , at each occurrence, is independently selected from halogen, (C 1 -C 8 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, and (C 1 -C 6 )alkyenedioxy;   wherein a hydrogen atom present in any of the substituents is optionally replaced by deuterium.   
     
     
         8 . A deuterium-enriched compound of  claim 1 , wherein:
 R 8  is —(CR 9 R 10 ) n NR 11 R 12 ;   R 8a  is selected from H and D;   X is CH 2 ;   Y is 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 11  is selected from H and D;   R 12  is selected from (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, C(O)R 13 , C(S)R 13 , C(O)OR 14 , C(O)NHR 13 , and C(S)NHR 13 ;   R 13  is selected from (C 1 -C 8 )alkyl, (C 0 -C 4 )alkyl-aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 9 )heteroaryl, and (C 1 -C 8 )alkyl-C(O)OR 15 ;   R 14  is selected from (C 1 -C 8 )alkyl;   R 15  is selected from H and (C 1 -C 8 )alkyl;   n, at each occurrence, is selected from 0 and 1;   the heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with 1-3 R 17 ;   R 17 , at each occurrence, is independently selected from halogen, —CN, (C 1 -C 8 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )alkyenedioxy, S—(C 1 -C 8 )alkyl, SO 2 (C 1 -C 8 )alkyl, S—(C 1 -C 8 )haloalkyl, and SO 2 (C 1 -C 8 )haloalkyl;   wherein a hydrogen atom present in any of the substituents is optionally replaced by deuterium.   
     
     
         9 . A deuterium-enriched compound of  claim 1 , wherein the compound is of formula Ia or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A deuterium-enriched compound of  claim 9 , wherein:
 X and Y are C═O;   n is 1;   R 12  is C(O)R 13 ; and   R 13  is selected from (C 1 -C 8 )alkyl and (C 3 -C 7 )cycloalkyl.   
     
     
         11 . A deuterium-enriched compound of  claim 1 , wherein the compound is of formula Ib or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         12 . (canceled) 
     
     
         13 . A deuterium-enriched compound of  claim 1 , wherein the compound is of formula II, or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 12a -R 12e  are independently selected from H and D. 
       
     
     
         14 . A deuterium-enriched compound of  claim 13 , wherein the compound is of formula IIa, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 12a -R 12e  are independently selected from H and D. 
       
     
     
         15 . A deuterium-enriched compound of  claim 13 , wherein the compound is of formula IIb, or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 12a -R 12e  are independently selected from H and D. 
       
     
     
         16 . A deuterium-enriched compound of  claim 1 , or stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 the abundance of deuterium in Z is selected from: (a) at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%.   
     
     
         17 . A deuterium-enriched compound of  claim 1 , wherein the compound is of formula II 1 , or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein the abundance of deuterium in Z is selected from: (a) at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%. 
       
     
     
         18 . A deuterium-enriched compound of  claim 1 , wherein the compound is of formula IIa 1 , or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein the abundance of deuterium in Z is selected from: (a) at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%. 
       
     
     
         19 . A deuterium-enriched compound of  claim 1 , wherein the compound is of formula IIb 1 , or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein the abundance of deuterium in Z is selected from: (a) at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%. 
       
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         24 . A method for treating myelodysplastic syndrome comprising: administering, to a patient in need thereof, a therapeutically effective amount of a compound of  claim 1 .