USP7 inhibition
Disclosed herein are inhibitors of deubiquitinating (DUB) enzyme USP7 (Ubiquitin Specific Protease 7). Also provided are methods of treating a disease or disorder modulated by USP7.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring B is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
L 1 is —C(═O)alkyl-[NR 5 C(═O)-alkyl] p —NR 5 C(═O), wherein each alkyl is independently substituted with one or more R 7 ,
R 1 is H, —OR 5 , or —NR 5 R 6 ;
R 2 is
or absent;
L 3 is a bond, —NR 5 R 6 , alkyl, cycloalkyl, or heterocyclyl, wherein each alkyl is independently optionally substituted with one or more R 8 ,
Y is O;
each R E1 , R E2 , and R E3 is independently at each occurrence H, alkyl, —OR 11 , —NR 11 R 12 , cycloalkyl, —NR 5 C(═O) heterocyclyl, —C(═O)NR 5 alkyl, C(═O)NR cycloalkyl, or —C(═O) heterocyclyl;
each R 11 and R 12 is independently at each occurrence H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
R 11 and R 12 together form heterocyclyl or heteroaryl;
R 3 is alkyl, hydroxyl, CF 3 , halo-NR 5 C(═O)alkyl, —C(═O)NR 5 alkyl, —NR 5 R 6 , cycloalkyl, heteroaryl, or aryl;
R 4 is alkyl, —NR 5 C(═O)alkyl, —C(═O)NR 5 alkyl, or —NR 5 R 6 , wherein each alkyl is independently optionally substituted with one or more R 8 , wherein when R 4 is alkyl, it is optionally substituted with two R 8 substituents that, taken together, form cycloalkyl or heterocyclyl, wherein each cycloalkyl or heterocyclyl is independently optionally substituted with one or more R 9 ;
each R 5 and R 6 is independently H, alkenyl, or alkyl;
each R 7 is independently at each occurrence-NR 5 R 6 , alkylamine, cycloalkyl, carbocycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, wherein each amine, cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently optionally substituted with one or more R 10 ;
each R 8 is independently at each occurrence-NR 5 R 6 , cycloalkyl, or heterocyclyl;
each R 9 is independently at each occurrence H, alkenyl, or alkyl;
each R 10 is independently at each occurrence halogen, —OR 5 , —NR 5 R 6 , alkenyl, or alkyl;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, 3, or 4.
2 . The compound of claim 1 having the following structural formula:
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 having the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring B is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
L 1 is a —C(═O)alkyl-[NR 5 C(═O)-alkyl], —NR 5 C(═O), wherein each alkyl is independently optionally substituted with one or more R 7 ,
R 1 is H, —OR 5 , or —NR 5 R 6 ;
R 2 is
L 3 is a bond, —NR 5 R 6 , alkyl, cycloalkyl, or heterocyclyl, wherein each alkyl is independently optionally substituted with one or more R 8 ,
Y is O;
each R E1 , R E2 , and R E3 is independently at each occurrence H, alkyl, —OR 11 , —NR 11 R 12 , cycloalkyl, —NR 5 C(═O) heterocyclyl, —C(═O)NR 5 alkyl, C(═O)NR 5 cycloalkyl, or —C(═O) heterocyclyl;
each R 11 and R 12 is independently at each occurrence H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or
R 11 and R 12 together form heterocyclyl or heteroaryl;
R 3 is alkyl, —NR 5 C(═O)alkyl, —C(═O)NR 5 alkyl, or —NR 5 R 6 ,
R 4 is alkyl, —NR 5 C(═O)alkyl, —C(═O)NR 5 alkyl, or —NR 5 R 6 , wherein each alkyl is independently optionally substituted with one or more R 8 , wherein when R 4 is alkyl, it is optionally substituted with two R 8 substituents that, taken together, form cycloalkyl or heterocyclyl, wherein each cycloalkyl or heterocyclyl is independently optionally substituted with one or more R 9 ;
each R 5 and Re is independently H, alkenyl, or alkyl;
each R 7 is independently at each occurrence-NR 5 R 6 , alkylamine, cycloalkyl, carbocycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, wherein each amine, cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently optionally substituted with one or more R 10 ;
each R 8 is independently at each occurrence-NR 5 R 6 , cycloalkyl, or heterocyclyl;
each R 9 is independently at each occurrence H, alkenyl, or alkyl;
each R 10 is independently at each occurrence halogen, —OR 5 , —NR 5 R 6 , alkenyl, or alkyl;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, 3, or 4.
4 . The compound of claim 1 , having the following structural formula:
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , having the following structural formula:
or a pharmaceutically acceptable salt thereof,
wherein q is 1, 2, 3, 4, 5, or 6.
6 . The compound of claim 1 , wherein ring B is cycloalkyl, heterocyclyl, or heteroaryl.
7 . The compound of claim 1 , wherein each R 7 is independently at each occurrence aralkyl, heterocyclylalkyl, or heteroaralkyl.
8 . The compound of claim 7 , wherein each aryl, heterocyclyl, or heteroaryl of R 7 is substituted with one of more R 10 ; and R 10 is independently at each occurrence halogen, —OR 5 , —NR 5 R 6 , or alkyl.
9 . The compound of claim 1 , wherein R 2 is
10 . The compound of claim 9 , wherein each R E1 , R E2 , and R E3 is independently at each occurrence H or —NR 11 R 12 .
11 . The compound of claim 10 , wherein
each R 11 and R 12 is independently at each occurrence H, alkyl, cycloalkyl, or heterocyclyl;
or R 11 and R 12 together form heterocyclyl or heteroaryl.
12 . The compound of claim 9 , wherein L 3 is a bond, —NR 5 R 6 , or heterocyclyl.
13 . The compound of claim 1 , wherein R 1 is H or —OR 5 .
14 . The compound of claim 1 , wherein each R 3 is independently selected from CF 3 , alkyl, hydroxyl, cycloalkyl, heteroaryl, and aryl; and n is 1, 2, 3, or 4.
15 . The compound of claim 1 , wherein
Ring B is heterocyclyl or heteroaryl;
L 1 is —C(═O)alkyl-[NR 5 C(═O)-alkyl]—NR 5 C(═O), wherein each alkyl is independently substituted with one or more R 7 ;
R 1 is H or —OR 5 ;
R 2 is
L 3 is a bond;
Y is O;
each R E1 , R E2 , and R E3 is independently at each occurrence H, alkyl, —OR 11 , or —NR 11 R 12 ,
each R 11 and R 12 is independently at each occurrence H or alkyl; or
R 11 and R 12 together form heterocyclyl;
R 4 is alkyl, —NR 5 C(═O)alkyl, —C(═O)NR 5 alkyl, or —NR 5 R 6 , wherein each alkyl is independently optionally substituted with one or more R 8 , wherein when R 4 is alkyl, it is optionally substituted with two R 8 substituents that, taken together, form cycloalkyl or heterocyclyl, wherein each cycloalkyl or heterocyclyl is independently optionally substituted with one or more R 9 ;
each R 5 and Re is H;
each R 7 is independently at each occurrence carbocycloalkyl, aralkyl, heterocyclylalkyl, or heteroaralkyl;
each R 9 is independently at each occurrence H or alkyl;
n is 0; and
p is 0, 1, or 2.
16 . The compound of claim 1 , wherein R 4 is
17 . The compound of claim 1 , wherein ring B is heteroaryl.
18 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
Compound