2',6'-DIOXO-3'-DEUTERO-PIPERDIN-3-YL-ISOINDOLINE COMPOUNDS
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:
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 .