Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
The disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: where R 1 , R 2 , R 3 , R 5 , R 5′ , X 1 , X 2 , n, and m are described herein.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is C;
X 2 is
R 1 is —OH;
R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
R 4 is (C 1 -C 6 ) alkyl or (C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one or more R 12 ;
R 5 and R 5 ′ are H;
R 7 is H;
each R 8 is independently (C 1 -C 6 ) alkyl, halogen, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —C(O)R 21 , wherein the alkyl, alkylene, aryl, and heteroaryl are optionally substituted with one or more R 9 ;
each R 9 is independently (C 1 -C 6 ) alkyl, halogen, or —NR 23 S(O) q R 24 ;
each R 12 is independently (C 6 -C 14 ) aryl, —O—(C 3 -C 8 )cycloalkyl, and halogen, wherein in the aryl and cycloalkyl are optionally substituted with one or more R 13 ;
each R 13 is halogen;
each R 21 is (C 2 -C 6 ) alkenyl;
each R 23 and R 24 is independently H or (C 2 -C 6 ) alkenyl;
m is 0;
n is 1; and
q is 2.
2. The compound of claim 1 , wherein R 4 is (C 6 -C 14 ) aryl, optionally substituted with one or more R 12 .
3. The compound of claim 2 , wherein R 12 is (C 6 -C 14 ) aryl.
4. The compound of claim 3 , wherein R 2 is heterocycloalkyl, optionally substituted with one or more R 8 .
5. The compound of claim 4 , wherein R 8 is —C(O)R 21 and R 21 is (C 2 -C 6 ) alkenyl.
6. The compound of claim 2 , wherein R 12 is halogen.
7. The compound of claim 6 , wherein R 2 is (C 1 -C 6 ) alkyl, optionally substituted with one or more R 8 .
8. The compound of claim 7 , wherein each R 8 is independently selected from heteroaryl and halogen, wherein heteroaryl is substituted with one or more R 9 , and wherein R 9 is halogen.
9. The compound of claim 6 , wherein R 2 is (C 3 -C 8 ) cycloalkyl, optionally substituted with one or more R 8 .
10. The compound of claim 9 , wherein R 8 is O-heteroaryl, wherein heteroaryl is substituted with one or more R 9 , and wherein R 9 is (C 1 -C 6 ) alkyl.
11. The compound of claim 2 , wherein R 12 is —O—(C 3 -C 8 )cycloalkyl, optionally substituted with one or more R 13 , and wherein R 13 is halogen.
12. The compound of claim 11 , wherein R 2 is (C 3 -C 8 ) cycloalkyl, optionally substituted with one or more R 8 .
13. The compound of claim 12 , wherein R 8 is (C 1 -C 6 ) alkyl.
14. The compound of claim 1 , wherein R 4 is (C 1 -C 6 ) alkyl.
15. The compound of claim 14 , wherein R 2 is (C 6 -C 14 ) aryl, optionally substituted with one or more R 8 .
16. The compound of claim 15 , wherein:
R 8 is aryl, optionally substituted with one or more R 9 ;
R 9 is —NR 23 S(O) q R 24 ;
R 23 is H; and
R 24 is (C 2 -C 6 ) alkenyl.