Thienopyridine carboxamides as ubiquitin-specific protease inhibitors

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof,

wherein:

X is N or CR 7 ;

R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —CN, or —NR 9 R 10 ;

R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 11 R 12 ;

R 3 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 13 R 14 ;

wherein at least one of R 1 , R 2 , or R 3 is not H;

or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ;

or R 2 and R 3 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ;

R 4 is H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;

R 5 is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;

R 5′ is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl; or

R 4 and R 5 together with the carbon atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring;

R 6 is —(C 0 -C 3 ) alkylene-C(O)OH, —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 3 ) alkylene-heteroaryl or —N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 16 ;

each R 7 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl is optionally substituted with one or more (C 1 -C 6 ) alkoxy or —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 17 ; or

R 6 and R 7 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 18 ; or R 6 and R 7 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 18 ; R 6 and R 7 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 18 ; or R 6 and R 7 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 18 ; or

two R 7 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring; or two R 7 together when on adjacent atoms form a heterocycloalkyl ring; two R 7 together when on adjacent atoms form an aryl ring; or two R 7 together when on adjacent atoms form a heteroaryl ring;

R 8 is H or (C 1 -C 6 ) alkyl;

each R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently H, (C 1 -C 6 ) alkyl, or —C(O)(C 1 -C 6 ) alkyl;

each R 15 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, or —OH;

each R 16 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, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —C(O)NR 21 R 22 , —S(O) 2 (C 1 -C 6 ) alkyl, —OH, or —NR 19 R 20 , wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy, OH, and heterocycloalkyl; or

two R 16 together when attached to the same carbon can form —C═(O) when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or

—N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl; or two R 16 together when attached to the same atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 23 when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or

—N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl; or two R 16 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl optionally substituted with one or more R 23 when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or

—N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl; or two R 16 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 23 ; or two R 16 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 23 ; or two R 16 together with the atoms to which they are attached can form a bridged heterocycloalkyl ring optionally substituted with one or more R 23 when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or —N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl;

each R 17 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, cycloalkyl, heterocycloalkyl, or

—C(O)-heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy and —OH;

each R 18 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, —CN, —C(O)OH, or —C(O)O(C 1 -C 6 ) alkyl;

each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, —CH 2 C(O)NH 2 , —S(O) 2 (C 1 -C 6 ) alkyl, —S(O) 2 (C 6 -C 10 ) aryl or —C(O)(C 1 -C 6 ) alkyl;

each R 21 and R 22 is independently H or (C 1 -C 6 ) alkyl;

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, or halogen; or

two R 23 together when attached to the same carbon form —C═(O);

m is 1 or 2; and

n is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein R 1 is (C 1 -C 6 ) alkyl, R 2 is H or (C 1 -C 6 ) alkyl, or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ; and R 3 is H.

3. The compound of claim 1 , having the structure of Formula (Id):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

4. The compound of claim 1 , wherein R 4 , R 5 , and R 5′ are each independently chosen from H or (C 1 -C 6 ) alkyl.

5. The compound of claim 1 , wherein R 4 and R 5 are each independently chosen from H or CH 3 , and R 5′ is H.

6. The compound of claim 1 , wherein R 6 is —(C 0 -C 3 ) alkylene -heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 17 .

7. The compound of claim 1 , wherein X is CH.

8. The compound of claim 3 , wherein R 1 is (C 1 -C 6 ) alkyl, R 2 is H or (C 1 -C 6 ) alkyl, or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ; R 3 is H; R 4 , R 5 , and R 5′ are each independently chosen from H or (C 1 -C 6 ) alkyl; and R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 17 .

9. The compound of claim 8 , wherein R 1 is CH 3 , R 2 is H; R 3 is H; R 4 , R 5 , and R 5′ are each independently chosen from H or CH 3; and R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 17 .

10. The compound of claim 9 , wherein R 4 , R 5 , and R 5′ are each H.

11. The compound of claim 9 , wherein R 6 is piperazinyl ring.

12. The compound of claim 3 , wherein R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 , wherein R 15 is independently at each occurrence (C 1 -C 6 ) alkyl, halogen, or —OH; R 3 is H; R 4 , R 5 , and R 5′ are each independently chosen from H or (C 1 -C 6 ) alkyl; and R 6 is —(C 0 ) alkylene -heterocycloalkyl.

13. The compound of claim 12 , wherein R 1 and R 2 together form a (C 5 ) cycloalkyl substituted with one R 15 that is —OH; and R 4 , R 5 , and R 5′ are each H.

14. The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

15. The compound of claim 1 , selected from

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

16. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof,

wherein:

X is CR 7 ;

R 1 is H, or (C 1 -C 6 ) alkyl;

R 2 is H, or (C 1 -C 6 ) alkyl;

R 3 is H, or (C 1 -C 6 ) alkyl;

wherein at least one of R 1 , R 2 , or R 3 is not H;

or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ;

R 4 , R 5 , and R 5′ are each H;

R 6 is a —(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 16 ;

each R 7 is independently at each occurrence H or halogen;

each R 15 is independently at each occurrence (C 1 -C 6 ) alkyl, halogen, or —OH;

each R 16 is independently at each occurrence (C 1 -C 6 ) alkyl, or halogen;

m is 1; and

n is 0, 1, 2, or 3.

17. The compound of claim 16 , wherein R 1 is a (C 1 -C 6 ) alkyl; R 2 is H; R 3 is H; and R 6 is a —(C 0 ) alkylene-heterocycloalkyl.

18. The compound of claim 16 , wherein R 1 and R 2 together form a (C 5 ) cycloalkyl substituted with one R 15 ; R 3 is H; R 6 is a —(C 0 ) alkylene-heterocycloalkyl; and R 15 is —OH.

19. A composition comprising a compound of claim 14 , and a pharmaceutically acceptable carrier.

20. A composition comprising a pharmaceutically acceptable carrier and a compound selected from

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.