Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C, S, or S(O);

Y 1 is N or CH;

Y 2 is N or CR 5 ;

Y 3 is N or CR 6 ;

Y 4 is N or CR 7 ;

R 1 is —OH;

R 2 is (C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 8 ;

R 4 and R 4′ are independently H;

R 5 is H;

R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 7 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ;

each R 8 is independently (C 1 -C 6 ) alkyl, halogen, or (C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three 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 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl, wherein alkyl or aryl are optionally substituted with one to three R 19 ;

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, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 14 is independently (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, or di(C 1 -C 6 ) alkylamino;

each R 15 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 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;

m is 0;

n is 1;

q is independently at each occurrence 0, 1, or 2; and

provided that

(a) when R 2 is optionally substituted (C 1 -C 6 ) alkyl, R 5 is H; and R 7 is H; then R 6 is not chloro;

(b) R 5 , R 6 , and R 7 are not all simultaneously H; and

(c) the compound is further characterized by any one or more of the following:

i. at least one of Y 1 , Y 2 , Y 3 , or Y 4 is N;

ii. at least one of R 6 or R 7 is an optionally substituted (C 6 -C 14 ) aryl;

iii. R 6 is (C 1 -C 6 ) alkyl, —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl of R 6 is substituted with a R 13 that is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

iv. R 6 is (C 1 -C 6 ) alkyl, —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl of R 6 is substituted with a R 13 that is (C 1 -C 6 ) alkyl or a 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is substituted with one to three R 15 ; or

v. R 7 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl of R 7 is substituted with a R 14 that is (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, or di(C 1 -C 6 ) alkylamino.

2. The compound of claim 1 , wherein:

R 2 is (C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to two R 8 ;

each R 8 is independently halogen or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 ; and

each R 9 is —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl.

3. The compound of claim 2 , wherein R 2 is (C 1 -C 6 ) alkyl substituted with one R 8 ; and R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl.

4. The compound of claim 2 , wherein R 2 is (C 6 -C 14 ) aryl.

5. The compound of claim 4 , wherein two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 .

6. The compound of claim 5 , wherein the (C 3 -C 8 )cycloalkyl formed by two R 8 together on adjacent atoms is substituted with one R 9 and R 9 is —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl.

7. The compound of claim 2 , wherein

R 6 is H;

is (C 1 -C 6 ) alkyl, C 6 -aryl, or —O—C 6 -aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ; and

each R 14 is independently (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 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino.

8. The compound of claim 7 , wherein R 14 is halogen.

9. The compound of claim 8 , wherein R 7 is C 6 -aryl.

10. The compound of claim 8 , wherein R 7 is —O—C 6 -aryl.

11. The compound of claim 2 , wherein

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 13 is independently (C 1 -C 6 ) alkyl or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 15 is independently (C 1 -C 6 ) alkyl; and

R 7 is H.

12. The compound of claim 11 , wherein R 6 is NHC(O)(C 1 -C 6 ) alkyl.

13. The compound of claim 1 , of formula (Ic):

or a pharmaceutically acceptable salt thereof; wherein:

R 2 is (C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 8 ;

R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 7 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ;

each R 8 is independently (C 1 -C 6 ) alkyl, halogen, or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three 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 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl, wherein alkyl and aryl are optionally substituted with one to three R 19 ;

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, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein in the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 14 is independently (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, or di(C 1 -C 6 ) alkylamino;

each R 15 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; and

each R 19 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.

14. The compound of claim 13 , wherein

R 2 is (C 1 -C 6 ) alkyl, optionally substituted with one R 8 ; and

R 8 is independently —(C 0 -C 4 )-alkylene-(C 6 ) aryl, wherein the aryl are optionally substituted with one to three R 9 .

15. The compound of claim 14 , wherein R 8 is not substituted with R 9 .

16. The compound of claim 15 , wherein

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ; and

R 7 is H.

17. The compound of claim 16 , wherein R 6 is (C 1 -C 6 ) alkyl, or —NH 2 , wherein the alkyl is optionally substituted with one to three R 13 .

18. The compound of claim 16 , wherein R 6 is —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl is optionally substituted with one to three R 13 .

19. The compound of claim 18 , wherein R 13 is a 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 15 .

20. The compound of claim 19 , wherein R 15 is (C 1 -C 6 ) alkyl.

21. The compound of claim 15 , wherein

R 6 is H; and

R 7 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 .

22. The compound of claim 21 , wherein R 7 is (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one R 14 .

23. The compound of claim 22 , wherein R 14 is halogen.

24. The compound of claim 1 , selected from formula (Id) or formula (Ie):

or a pharmaceutically acceptable salt thereof; wherein:

R 2 is (C 1 -C 6 ) alkyl, optionally substituted with R 8 ;

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 7 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 ;

R 8 is independently (C 1 -C 6 ) alkyl, halogen, or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ;

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, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein in the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 14 is independently (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, or di(C 1 -C 6 ) alkylamino;

each R 15 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; and

each R 19 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.

25. The compound of claim 24 , wherein R 2 is (C 1 -C 6 ) alkyl substituted with R 8 ; and R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl.

26. The compound of claim 25 , wherein:

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl is optionally substituted with one to three R 13 ; and

R 7 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, or —O—(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 14 .

27. The compound of claim 26 , of formula (Ie) wherein R 7 is (C 6 -C 14 ) aryl or —O—(C 6 -C 14 ) aryl, wherein the aryl is optionally substituted with one to three R 14 ; and each R 14 is independently (C 1 -C 6 ) alkyl or halogen.

28. The compound of claim 26 , of formula (Ie) wherein R 7 is (C 1 -C 6 ) alkyl.

29. A compound of formula (Id):

or a pharmaceutically acceptable salt thereof, wherein

R 6 is —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl is substituted with R 13 ; R 13 is 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is substituted with one to three R 15 ; and R 15 is (C 1 -C 6 ) alkyl;

R 2 is (C 1 -C 6 ) alkyl substituted with R 8 ; and R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the aryl in R 8 is substituted with one to three 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 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 19 ;

each R 19 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;

m is 0; and

n is 1.

30. The compound of claim 29 , wherein

R 6 is —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl of R 6 is substituted with R 13 , R 13 is piperazine substituted with one to three R 15 , and R 15 is (C 1 -C 6 ) alkyl; and

R 2 is (C 1 -C 6 ) alkyl substituted with one R 8 ; and R 8 is unsubstituted —(C 0 -C 4 )-alkylene-(C 6 ) aryl.