IP Library › Patent Application 15722187

Patent Application

App. No. 15/722,187

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

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App. No.: 15/722,187

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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.

Claims (170)

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 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 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 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;

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 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;

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:

19 . A deuterium-enriched compound of claim 1 , wherein the compound is of formula IIb 1 , or pharmaceutically acceptable salt thereof:

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 .