Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors

1. A compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof,

wherein

X 1 is C;

R 1 is OH;

R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or NR 10 R 11 , wherein the alkyl and aryl 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 alkyl and aryl are optionally substituted with one or more R 12 ;

R 5 and R 5′ are independently H;

R 6 is H;

each R 8 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —CN, —C(O)R 19 , —CO(O)R 19 , —C(O)NR 19 R 20 , —S(O) q R 19 , —S(O) q NR 19 R 20 , —NR 19 S(O) q R 20 , —(C 0 -C 3 )-alkylene-NR 19 R 20 , —NR 19 C(O)R 20 , —NR 19 C(O)C(O)R 20 , —NR 19 C(O)NR 19 R 20 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 19 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or

two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or

two R 8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or

two R 8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or

two R 8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 9 ;

each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —NH 2 , OH, CN, —C(O)R 21 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , oxo, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 24 ;

R 10 and R 11 are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or

R 10 and R 11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 ;

each R 12 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 25 R 26 , —S(O) q NR 25 R 26 , —NR 25 R 26 , —NR 25 C(O)NR 25 R 26 , —NR 25 C(O)OR 26 , —NR 25 S(O) q R 26 , —NR 25 C(O)R 26 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or

two R 12 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or

two R 12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or

two R 12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or

two R 12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 13 ;

each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 27 ;

each R 16 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 17 ;

each R 17 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;

each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;

each R 21 and R 22 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;

each R 23 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN;

each R 24 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 25 C(O)R 26 , —NR 25 S(O) q R 26 , —C(O)R 25 , —C(O)NR 25 R 26 , —NR 25 R 26 , —S(O) q R 25 , —S(O) q NR 25 R 26 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN;

each R 25 and R 26 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl;

each R 27 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;

m is 0;

n is 1; and

q is independently at each occurrence 0, 1, or 2.

2. The compound of claim 1 , wherein R 2 is (C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one or more R 8 .

3. The compound of claim 2 , wherein R 2 is (C 6 -C 14 ) aryl, wherein the aryl is substituted with halogen.

4. The compound of claim 3 , wherein R 2 is (C 6 -C 14 ) aryl, wherein the aryl is substituted with fluorine.

5. The compound of claim 2 , wherein R 2 is phenyl, wherein the phenyl is optionally substituted with one or more R 8 .

6. The compound of claim 5 , wherein R 8 is halogen.

7. The compound of claim 6 , wherein R 8 is fluorine.

8. The compound of claim 7 , wherein R 4 is (C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one or more R 12 .

9. The compound of claim 8 , wherein R 4 is (C 6 -C 14 ) aryl, wherein the aryl is substituted with (C 1 -C 6 ) alkoxy.

10. The compound of claim 9 , wherein R 4 is (C 6 -C 14 ) aryl, wherein the aryl is substituted with methoxy.

11. The compound of claim 8 , wherein R 4 is phenyl, wherein the phenyl is optionally substituted with one or more R 12 .

12. The compound of claim 11 , wherein R 4 is phenyl, wherein the phenyl is substituted with (C 1 -C 6 ) alkoxy.

13. The compound of claim 12 , wherein R 4 is phenyl, wherein the phenyl is substituted with methoxy.

14. The compound of claim 1 , wherein the compound is 6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7Hpyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically accepted salt thereof, and a pharmaceutically accepted carrier.

16. A pharmaceutical composition comprising a compound of claim 14 , or a pharmaceutically accepted salt thereof, and a pharmaceutically accepted carrier.