[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 of S(O) 2 , S(O), and S;

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 , —S(O) 2 R a , —C(O)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 —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, 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 —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 —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) 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 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 claim 1 , wherein R 1 is —(CH 2 ) n —R a .

7. The compound of claim 6 , wherein R a is optionally substituted aryl.

8. The compound of claim 6 , wherein n is 1.

9. The compound of claim 1 , wherein R 2 and R 2 ′ can combine with the carbon to form an oxo.

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

11. The compound of claim 1 , wherein R 4 is H and R 5 is —C(O)N(R 10 )(R 11 ).

12. The compound of claim 1 having the formula (IA):

13. The compound of claim 6 , wherein n is 1 and R a is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 3- to 8-membered heterocycle.

14. The compound of claim 6 , wherein n is 1 and R a is aryl 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 halo alkyl, —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.

15. The compound of claim 6 , wherein n is 1 and R a is heteroaryl 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.

16. The compound of claim 6 , wherein n is 1 and R a is 3- to 8-membered heterocycle 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.

17. The compound of claim 1 , having the formula IA-3a, IA-3b, IA-3c, IA-3d, IA-4a, IA-4b, IA-4c, or IA-4d:

18. The compound of claim 1 , having the formula IB-3a, IB-3b, IB-3c, IB-3d, IB-4a, IB-4b, IB-4c, or IB-4d:

19. A compound selected from:

N-hydroxy-4-(3-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide (I-15);

N-hydroxy-4-(1-(4-(methylsulfonyl)phenyl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide (I-16);

N-hydroxy-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide 1,1-dioxide (I-79);

N-hydroxy-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide-1,1-dioxide (I-80);

N-hydroxy-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide (I-81);

N-hydroxy-4-(4-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide (I-82);

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.