Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is O;

X 2 , X 3 , X 4 and X 5 are each CR 1 R 2 ;

Y 1 and Y 4 are each independently N or CR 1 ;

one of Y 2 and Y 3 is C bonded to C(O)NHOH and the other of Y 2 and Y 3 is N or CR 1 ;

L is a bond, —(CR 1 R 2 ) n —, —C(O)—, —C(O)O—, —C(O)NR 3 —, —S(O) 2 —, —S(O) 2 NR 3 —, —S(O)—, —S(O)NR 3 —, —C(O)(CR 1 R 2 ) n O—, or —C(O)(CR 1 R 2 ) n —;

R is independently, and at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 5 -C 12 spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —CO 2 R 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , —NR 3 S(O)R 1 , heterocycle, aryl, or heteroaryl, with the proviso that when L is —C(O)— the spiroheterocyclyl is not bound to L via a nitrogen atom;

R 1 and R 2 are independently, and at each occurrence, —H, R 3 , R 4 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, —OH, halogen, —NO 2 , —CN, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 C 6 alkyl)S(O) 2 R 5 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), or —(CHR 5 ) n NR 3 R 4 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 N(R 3 ) 2, —S(O) 2 R 5 , —C(O)R 5 , —CO 2 R 5 , —NR 3 S(O) 2 R 5 , —S(O)R 5 , —S(O)NR 3 R 4 , —NR 3 S(O)R 5 , heterocyclyl, aryl, or heteroaryl;

R 3 and R 4 are independently, and at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —CO 2 C 1 -C 6 alkyl, or —(CHR 5 ) n N(C 1 -C 6 alkyl) 2 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkly) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —C(O)C 1 -C 6 alkyl, —CO 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocycle, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O;

R 5 is independently, and at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 3 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH, halogen, —NO 2 , —CN, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —C(O)C 1 -C 6 alkyl, —CO 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl) or (CH 2 ) n N(C 1 -C 6 alkyl) 2 ; and

n is independently and at each occurrence an integer from 0 to 6.

2. The compound of claim 1 , wherein L is CH 2.

3. The compound of claim 2 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, or aryl.

4. The compound of claim 1 , wherein L is —C(O)—.

5. The compound of claim 4 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, or aryl.

6. The compound of claim 1 , wherein L is a bond.

7. The compound of claim 6 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, or aryl.

8. The compound of claim 1 , wherein L is —S(O) 2 —.

9. The compound of claim 8 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, or aryl.

10. The compound of claim 1 , wherein L is —C(O)NR 3 —.

11. The compound of claim 10 , wherein R 3 is —H.

12. The compound of claim 10 , wherein R is —C 3 -C 8 cycloalkyl, heterocyclyl, or aryl.

13. The compound of claim 1 , wherein each R 1 and R 2 is —H.

14. The compound of claim 1 wherein the compound is of Formula IIA:

15. The compound of claim 1 wherein the compound is of Formula II-B:

16. The compound of claim 1 selected from:

N-hydroxy-4-phenyl-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;

4-benzyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;

4-benzoyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;

4-(cyclohexanecarbonyl)-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;

N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;

N-hydroxy-4-(phenylsulfonyl)-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;

N9-hydroxy-N4-phenyl-2,3,5,6-tetrahydro-4H-benzo[g][1,4]oxazocine-4,9-dicarboxamide;

N-hydroxy-4-phenyl-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;

4-benzyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;

4-benzoyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;

4-(cyclohexanecarbonyl)-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;

N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3 ,4, 5 ,6-tetrahydro-2H-benzo [g][1,4]oxazocine-8-carboxamide;

N-hydroxy-4-(phenyl sulfonyl)-3 ,4, 5, 6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide; and

N8-hydroxy-N4-phenyl-2,3,5,6-tetrahydro-4H-benzo[g][1,4]oxazocine-4,8-dicarboxamide.

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