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

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is CR 1 R 2 ;

X 2 is NR 3 ;

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 ;

Y 2 and Y 3 are each independently N or CR 1 when not bonded to C(O)NHOH and Y 2 and Y 3 are C when bonded to C(O)NHOH;

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 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 5 -C 12 spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —OR 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 , heterocyclyl, aryl, and 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 N, S, P, or O, —OH, halogen, —NO 2 , —CN, —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, —CO 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, or (CHR 5 )—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, and heteroaryl containing 1-5 heteroatoms selected from N, S, P, or O;

R 3 and R 4 are independently, and at each occurrence, —H, —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 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, and —(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 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 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 , heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selected from N, S, P, or O;

R 5 is independently, and at each occurrence, —H, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH, halogen, —NO 2 , —CN, —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 X 1 , X 3 , X 4 , and X 5 are each CH 2 .

3. The compound of claim 1 , wherein the compound is of the Formula IA:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of the Formula IB:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 selected from:

N-hydroxy-5-methyl-2-phenyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

2-benzyl-N-hydroxy-5-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

2-benzoyl-N-hydroxy-5-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

2-(cyclohexanecarbonyl)-N-hydroxy-5-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

N-hydroxy-5-methyl-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

N8-hydroxy-5-methyl-N2-phenyl-3,4,5,6-tetrahydrobenzo[f][1,4]diazocine-2,8(1H)-dicarboxamide;

N-hydroxy-5-methyl-2-(N-phenylsulfamoyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

N-hydroxy-2-methyl-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

5-benzyl-N-hydroxy-2-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

5-benzoyl-N-hydroxy-2-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

5-(cyclohexanecarbonyl)-N-hydroxy-2-methyl-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

N-hydroxy-2-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide;

N9-hydroxy-5-methyl-N2-phenyl-3,4,5,6-tetrahydrobenzo[f][1,4]diazocine-2,9(1H)-dicarboxamide; or

N-hydroxy-2-methyl-5-(N-phenylsulfamoyl)-1,2,3,4,5,6-hexahydrobenzo[f][1,4]diazocine-8-carboxamide.

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

7. The compound of claim 1 , wherein Y 1 , Y 3 , and Y 4 are each CR 1 and Y 2 is C.

8. The compound of claim 1 , wherein Y 1 , Y 2 , and Y 4 are each CR 1 and Y 3 is C.

9. The compound of claim 1 , wherein X 2 is N(CH 3 ).

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

11. The compound of claim 10 , wherein R is aryl.

12. The compound of claim 10 , wherein R is heterocyclyl.

13. The compound of claim 10 , wherein R is —C 3 -C 8 cycloalkyl.

14. The compound of claim 10 , wherein L is a bond, —CH 2 —, —C(O)—, —C(O)NH—, or —S(O) 2 NH—.

15. The compound of claim 14 , wherein L is a bond.

16. The compound of claim 14 , wherein L is —CH 2 —.

17. The compound of claim 14 , wherein L is —C(O)—.

18. The compound of claim 14 , wherein L is —C(O)NH—.

19. The compound of claim 14 , wherein L is —S(O) 2 NH—.