[6,6] fused bicyclic HDAC8 inhibitors

1. A compound of Formula (I):

or pharmaceutically acceptable salts thereof,

wherein:

Y 1 , Y 2 , Y 3 , and Y 4 are each independently C or CR 3 , provided that when bonded to —C(O)NHOH any of Y 1 , Y 2 , Y 3 , or Y 4 is C;

X is selected from the group consisting C(═O) and C(R 4 )(R 5 );

W is C(R 4 )(R 5 );

R 1 is C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, —(CH 2 ) n —R a , —(CH 2 ) n —O—(CH 2 ) p —R a , or —C(O)N(R a )(R b ), wherein each alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more of —OH, halogen, oxo, —NO 2 , —NH 2 , —CN, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, heterocycle, aryl, heteroaryl, or R 4 ;

R a is, independently at each occurrence, halogen, OH, NH 2 , C 2 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or —C(O)N(R 10 )(R 11 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle is optionally substituted with one or more of —OH, R 4′ , R 5′ , halogen, oxo, (CH 2 ) n OR 6 , —NO 2 , —OR 6 , —N(R 6 )(R 7 ), C(O)OR 6 , —C(O)N(R 6 )(R 7 ), —S(O) 2 R 6 , —S(O)R 6 , —S(R 6 ), —C(O)R 6 , —S(O) 2 N(R 6 )(R 7 ), —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl, and wherein each aryl is optionally substituted with one or more of —OH, R 4′ , R 5′ , halogen, oxo, (CH 2 ) n OR 6 , —OR 6 , —N(R 6 )(R 7 ), C(O)OR 6 , —C(O)N(R 6 )(R 7 ), —S(O) 2 R 6 , —S(O)R 6 , —S(R 6 ), —C(O)R 6 , —S(O) 2 N(R 6 )(R 7 ), —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl;

R b is at each occurrence, hydrogen, halogen, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or —C(O)N(R 10 )(R 11 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, R 4′ , R 5′ , halogen, oxo, (CH 2 ) n OR 6 , —NO 2 , —OR 6 , —N(R 6 )(R 7 ), C(O)OR 6 , —C(O)N(R 6 )(R 7 ), —S(O) 2 R 6 , —S(O)R 6 , —S(R 6 ), —C(O)R 6 , —S(O) 2 N(R 6 )(R 7 ), —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl;

or R a and R b can combine with the carbon or nitrogen to which they are attached to form a C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycle optionally substituted with one or more substituents selected from R 4′ and R 5′ , wherein R 4′ and R 5′ independently at each occurrence are H or —C 1 -C 6 alkyl;

R 2 and R 2 ′ are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OH, halogen, —NO 2 , —NH 2 , —CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or 3- to 8-membered heterocycle, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —NH 2 , —CN, —C 1 -C 6 alkyl, or —C 1 -C 6 alkoxy; or

R 2 and R 2 ′ can combine with the carbon to which they are attached to form an oxo group, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycle;

R 3 is independently, at each occurrence, hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;

each R 4 or R 5 is each independently, at each occurrence, hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or —C(O)N(R 10 )(R 11 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, R 4′ , R 5′ , halogen, oxo, (CH 2 ) n OR 6 , —NO 2 , —OR 6 , —N(R 6 )(R 7 ), C(O)OR 6 , —C(O)N(R 6 )(R 7 ), —S(O)R 6 , —S(R 6 ), S(O) 2 N(R 6 )(R 7 ), —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl, and wherein aryl is optionally substituted with one or more —OH, R 4′ , R 5′ , halogen, oxo, (CH 2 ) n OR 6 , —OR 6 , —N(R 6 )(R 7 ), C(O)OR 6 , —C(O)N(R 6 )(R 7 ), —S(O) 2 R 6 , —S(O)R 6 , —S(R 6 ), —C(O)R 6 , —S(O) 2 N(R 6 )(R 7 ), —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl; or

R 4 and R 5 can combine with the carbon or nitrogen to which they are attached to form an oxo group, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycle optionally substituted with one or more substituents selected from R 4′ and R 5′ ;

R 4′ and R 5′ are, independently at each occurrence, H or —C 1 -C 6 alkyl; or

R 4′ and R 5′ together when attached to the same atom form a C 3 -C 8 spirocycloalkyl ring; or

R 4′ and R 5′ together when attached to the same atom form a C 3 -C 8 spiroheterocycloalkyl ring; or

R 4′ and R 5′ together when attached to adjacent atoms form an aryl ring, a heteroaryl ring, a C 3 -C 8 cycloalkyl, or a 3- to 8-membered heterocycle, wherein the spirocycloalkyl, spiroheterocycloalkyl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with one or more groups selected from OH, halogen, —C 1 -C 6 alkyl and C(O)OR 6 ;

R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, heterocycle, —S(O) 2 NR 8 R 9 , —S(O) 2 R 8 , —C(O)R 8 , —CO 2 R 8 , —S(O)R 8 , and —S(O)NR 8 R 9 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —NH 2 , —CN, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, heterocycle, aryl, or heteroaryl; or

R 6 and R 7 together with the atom to which they are attached form a C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocycle, wherein the cycloalkyl or the heterocycle is optionally substituted with one or more groups selected from halogen, oxo and C 1 -C 6 alkyl;

R 8 and R 9 are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heteroaryl, or 3- to 8-membered heterocycle, wherein each is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —NH 2 , —CN, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 hydroxyalkyl, heterocycle, aryl, or heteroaryl;

R 10 and R 11 are each independently hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl or 3- to 8-membered heterocycle, wherein aryl, alkylaryl and heterocycle are optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; or

R 10 and R 11 can combine to form a 3- to 8-membered heterocycle optionally substituted with one or more R 12 ;

R 12 is H or C 1 -C 6 alkyl or two adjacent R 12 can combine to form an aryl or heteroaryl group;

n is an integer from 1 to 6; and

p is an integer from 0 to 2.

2. The compound of claim 1 , wherein Y 1 , Y 2 , and Y 3 are CR 3 .

3. The compound of claim 1 , wherein Y 1 , Y 2 , and Y 4 are CR 3 .

4. The compound of claim 1 , wherein Y 1 , Y 3 , and Y 4 are CR 3 .

5. The compound of claim 1 , wherein Y 2 , Y 3 , and Y 4 are CR 3 .

6. The compound of claim 1 , wherein R 1 is heteroaryl, 3- to 8-membered heterocycle, wherein each heteroaryl or heterocycle is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —NH 2 , —CN, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, heterocycle, aryl, heteroaryl, or R 4 .

7. The compound of claim 1 , wherein W is CH 2 .

8. The compound of claim 1 , having the formula (IA) or (IB):

9. The compound of claim 1 , having the formula Ia-2a, IA-2b, IA-2c, IA-2d:

10. The compound of claim 1 , having the formula IB-2b:

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

12. The compound of claim 10 , wherein R 2 and R 2 ′ are each hydrogen.

13. The compound of claim 12 , wherein R 1 is heteroaryl optionally substituted with one or more —C 1 -C 6 alkoxy.

14. The compound of claim 12 , wherein R 1 is 3- to 8-membered heterocycle optionally substituted with one or more —C 1 -C 6 alkoxy.

15. The compound of claim 1 , having the formula IB-2a, IB-2b, IB-2c, or IB-2d:

16. The compound of claim 1 , having the formula IB-2b:

17. The compound of claim 16 , wherein R 2 and R 2 ′ are each hydrogen.

18. The compound of claim 17 , wherein R 1 is heteroaryl optionally substituted with one or more —C 1 -C 6 alkoxy.

19. The compound of claim 17 , wherein R 1 is 3- to 8-membered heterocycle optionally substituted with one or more —C 1 -C 6 alkoxy.

20. A compound of claim 1 , wherein the compound is selected from:

1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-7-carboxamide (I-106);

1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-6-carboxamide (I-107);

N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxamide (I-110); and

N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (I-111),

or a pharmaceutically acceptable salt thereof.