USP7 inhibitors for treating multiple myeloma
The present disclosure relates to inhibitors of USP7 useful in the treatment of cancers, and other USP7 mediated diseases, having the Formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are described herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, —NO 2 , —NH 2 , CN, —NR 7 C(═O)alkyl, —C(═O)NR 7 alkyl, or —NR 7 R 8 , wherein each alkyl is independently optionally substituted with one or more R 9 ;
R 2 is —NR 7 C(═O)alkyl or —C(═O)NR 7 alkyl and each alkyl of R 2 is substituted with one or more R 9 ;
R 3 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, —NH 2 , —NO 2 , CN, —NR 7 C(═O)alkyl, —C(═O)NR 7 alkyl, or —NR 7 R 8 ; wherein each alkyl is independently optionally substituted with one or more R 9 ;
R 4 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, —NO 2 , —NH 2 , CN, —NR 7 C(═O)alkyl, —C(═O)NR 7 alkyl, or —NR 7 R 8 ; wherein each alkyl is independently optionally substituted with one or more R 9 ; wherein R 1 , R 2 , R 3 and R 4 are not simultaneously H;
R 5 is H, halogen, —CN, —OR 7 , or —NR 7 R 8 ;
R 6 is alkyl, —C(═O)R 10 , —C(═S)R 10 , —C(O)NR 7 R 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are each independently optionally substituted with one or more R 11 ; and wherein the alkyl is substituted with one or more R 12 ;
each R 7 and R 8 is independently H, acyl, alkylacyl, alkenyl, alkenylacyl, or alkyl;
each R 9 is independently at each occurrence azido, —NR 7 R 8 , alkoxy, —(OCH 2 CH 2 ) m alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from alkoxy, haloalkoxy, halogen, and —OH; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, —N 3 , and —OH;
R 10 is alkyl, alkenyl, alkynyl, —NR 7 R 8 , cycloalkyl, heterocycloalkyl, aryl, amino, heteroalkyl, alkylamino, aminoalkyl or heteroaryl, wherein the alkyl, alkenyl, and alkynyl are each independently optionally substituted with one or more R 13 ; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R 12 ;
each R 11 is independently at each occurrence alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, —NO 2 , or —OH;
each R 12 is independently at each occurrence aryl or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and —OH;
each R 13 is independently at each occurrence —OH, alkoxy, heteroalkyl, aryloxy, —NH 2 , arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —O-heteroaryl, —NR 7 aryl, —NR 7 heteroaryl, or —NR 7 C(═O)R 14 , wherein the cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, and heteroaryl are each independently optionally substituted with one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, —NO 2 , and —OH;
R 14 is alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted with one or more R 15 ; and wherein the alkyl, alkenyl, and alkynyl are each independently optionally substituted with one or more substituents selected from halogen and —OH;
each R 15 is independently at each occurrence halogen, alkyl, CN, —C(═O)alkyl, or —C(═O)alkenyl, wherein the alkyl and alkenyl is each independently substituted with one or more substituents selected from halogen and —OH;
m is 1, 2, or 3; and
n is 0 or 1.
2. The compound of claim 1 , wherein R 1 is H, —NR 7 C(═O)alkyl, or —NR 7 R 8 .
3. The compound of claim 1 , wherein R 3 is H, —NO 2 , or —NR 7 R 8 .
4. The compound of claim 1 , wherein R 4 is H.
5. The compound of claim 1 , wherein each R 9 is independently at each occurrence —NR 7 R 8 , alkoxy, —(OCH 2 CH 2 ) m alkyl, heterocycloalkyl, or heteroaryl, wherein the heterocycloalkyl or heteroaryl are each independently optionally substituted with one or more substituents selected from alkyl, alkoxy, and —N 3 .
6. The compound of claim 1 , wherein the compound has a structure of Formula (Ia):
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein R 2 is —NR 7 C(═O)alkyl.
8. The compound of claim 1 , wherein R 2 is —NR 7 C(═O)alkyl or —C(═O)NR 7 alkyl; the alkyl of R 2 is substituted with one R 9 ; R 9 is azido, —NR 7 R 8 , heterocycloalkyl or heteroaryl; and R 8 is H.
9. The compound of claim 1 , wherein R 2 is —NR 7 C(═O)alkyl or —C(═O)NR 7 alkyl; the alkyl of R 2 is substituted with one R 9 ; and R 7 is acyl, alkylacyl, or alkenylacyl.
10. The compound of claim 1 , wherein the compound has a structure of Formula (Ib):
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein R 5 is H, CN, —OH, or —NR 7 R 8 .
12. The compound of claim 1 , wherein R 7 and R 8 are each H or alkyl.
13. The compound of claim 1 , wherein R 6 is alkyl, —C(═O)R 10 , —C(═S)R 10 , aryl, or heteroaryl.
14. The compound of claim 13 , wherein R 10 is alkyl, alkenyl, amino, alkylamino, alkynyl, cycloalkyl, heteroalkyl, heteroaryl, or aminoalkyl, each optionally substituted with one or more R 13 .
15. The compound of claim 1 , wherein R 10 is alkyl, alkenyl, alkynyl, —NR 7 R 8 , cycloalkyl, or heterocycloalkyl, each optionally substituted with one or more R 13 ; and each R 13 is independently at each occurrence —OH, alkoxy, aryloxy, —NH 2 , arylalkyl, cycloalkyl, aryl, heteroaryl, or —NR 7 C(═O)R 14 .
16. The compound of claim 15 , wherein each R 14 is independently at each occurrence alkyl, haloalkyl, arylalkyl, alkenyl, heterocyclyl, or heteroaryl.
17. The compound of claim 6 , wherein:
R 2 is —NR 7 C(═O)alkyl, wherein the alkyl of R 2 is substituted with one or more R 9 ;
R 6 is —C(═O)R 10 ; and
R 10 is alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl, wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R 13 ; and wherein the cycloalkyl and heterocycloalkyl are each optionally substituted with one or more R 12 .
18. A compound selected from:
Compound
10
11
12
13
14
15
16
17
47
48
49
63
106
108
109
110
111
112
116
and
117
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method of treating a disease or disorder modulated by USP7 comprising, administering to a subject in need thereof a compound of claim 1 or a pharmaceutically acceptable salt thereof.
21. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 1 or a pharmaceutically acceptable salt thereof.