3-aryl-4-amido-bicyclic [4,5,0] 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 , or C═O;

X 2 and X 4 are each independently CR 1 R 2 , CO═S(O) or SO 2 ;

X 3 is CR 1′ R 2′ ; wherein X 4 , X 2 , and X 1 are not all simultaneously CR 1 R 2 ;

Y 1 and Y 4 are not bonded to —C(O)NHOH and 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 selected from the group consisting of —C(O)—, —C(O)(CR 1 R 2 ) m —, and —C(O)(CR 1 R 2 ) m O—, wherein L is bonded to the ring nitrogen through the carbonyl group;

R is independently, and at each occurrence, selected from the group consisting of —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 spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —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 , heterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O with the proviso that R is not bonded to L via a nitrogen atom;

each R 1 and R 2 is independently, at each occurrence, selected from the group consisting of —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 to 5 heteroatoms selected from the group consisting of N, S, P, and O, —OH, halogen, —NO 2, —CN, —NHC 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, —CO 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, and —(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 the group consisting of —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 to 5 heteroatoms selected from the group consisting of N, S, P, and O;

or R 1 and R 2 can combine with the atom to which they are both attached to form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;

or R 1 and R 2 , when on adjacent atoms, can combine to form a heterocycle, cycloalkyl, cycloalkenyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;

or R 1 and R 2 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl, cycloalkenyl, or heterocycloalkyl;

each R 1′ and R 2′ arc each is independently, at each occurrence, selected from the group consisting of H, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO 2, oxo, —CN, —R 3 , —R 5 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 N(R 3 ) 2, —S(O)2R 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 , heterocycle, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein at least one of R 1′ or R 2′ is not H;

each R 3 and R 4 is independently, at each occurrence, selected from the group consisting of —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 to 5 heteroatoms selected from the group consisting of N, S, P, and 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, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO 2, oxo, —CN, —R 5 , —O(C 1 -C 6 ) alkyl, —NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 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 , heterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;

R 5 is independently, at each occurrence, selected from the group consisting of —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 to 5 heteroatoms selected from the group consisting of N, S, P, and O, —OH, halogen, —NO 2, —CN, —NHC 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 -C6 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) and —(CH 2 ) n N(C 1 -C 6 alkyl)2;

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

each m is independently and at each occurrence an integer from 1 to 6.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein one of R 1 ′ and R 2 ′ is optionally substituted aryl and the other of R 1′ and R 2′ is H.

5. The compound of claim 4 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.

6. The compound of claim 5 , wherein R is optionally substituted heterocyclyl.

7. The compound of claim 1 , wherein one of R 1′ and R 2′ is optionally substituted heteroaryl and the other of R 1′ and R 2′ is H.

8. The compound of claim 7 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

9. The compound of claim 8 , wherein R is optionally substituted heterocyclyl.

10. The compound of claim 2 , wherein one of R 1′ and R 2′ is optionally substituted aryl and the other of R 1′ and R 2′ is H.

11. The compound of claim 10 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.

12. The compound of claim 2 , wherein one of R 1′ and R 2′ is optionally substituted heteroaryl and the other of R 1′ and R 2′ is H.

13. The compound of claim 12 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

14. The compound of claim 3 , wherein one of R 1′ and R 2′ is optionally substituted aryl and the other of and R 2′ is H.

15. The compound of claim 14 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.

16. The compound of claim 3 , wherein one of R 1′ and R 2′ is optionally substituted heteroaryl and the other of R 1′ and R 2′ is H.

17. The compound of claim 16 , wherein L is —C(O)— and R is an optionally substituted group selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

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