Methods using HDAC11 inhibitors

1. A compound of Formula II-A or a pharmaceutically acceptable salt thereof:

wherein:

X 1 and X 2 are each independently, at each occurrence —CR 4 R 2 —;

Y 1 , Y 2 , and Y 3 are each independently CR 1 ;

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

R is independently —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 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 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;

R 1 and R 2 are independently, 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 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, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —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 , —C(O)OR 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, or heteroaryl;

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

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

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

R 3 and R 4 are independently, 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 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, —C(O)OC 1 -C 6 alkyl, or —(CHR 5 ) p 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, —C(O)OC 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;

R 5 is independently, 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 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 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 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 ) p N(C 1 -C 6 alkyl) 2 ;

p is 0, 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

q is 1 or 2;

r is 1 or 2;

wherein the sum q+r≤3 and

wherein the sum m+n≤4.

2. The compound according to claim 1 , wherein L is selected from a bond, —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —C(O)—, —C(O)NR 3 —, or —C(O)CH 2 —.

3. The compound according to claim 1 , wherein L is selected from —CH 2 — or —C(O)—.

4. The compound according to claim 1 , wherein R is hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, C 3 -C 8 cycloalkyl, heterocyclyl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O.

5. The compound according to claim 1 , wherein R is hydrogen or an optionally substituted group selected from phenyl, C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, or morpholinyl.

6. The compound according to claim 1 , wherein R is phenyl optionally substituted with one or more independent occurrences of halogen, CF 3 , —SO 2 CH 3 , phenyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, pyridyl, —OCF 3 or —OCH 2 phenyl.

7. The compound according to claim 3 , wherein R is hydrogen or an optionally substituted group selected from phenyl, C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, or morpholinyl.

8. The compound according to claim 3 , R is phenyl optionally substituted with one or more independent occurrences of halogen, CF 3 , —SO 2 CH 3 , phenyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, pyridyl, —OCF 3 or —OCH 2 phenyl.

9. The compound according to claim 1 , wherein the compound is of formula II-A-i,

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 , wherein L is selected from a bond, —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —C(O)—, —C(O)NR 3 —, or —C(O)CH 2 —.

11. The compound according to claim 9 , wherein L is selected from —CH 2 — or —C(O)—.

12. The compound according to claim 9 , wherein R is hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl, aryl, C 3 -C 8 cycloalkyl, heterocyclyl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O.

13. The compound according to claim 9 , wherein R is hydrogen or an optionally substituted group selected from phenyl, C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, or morpholinyl.

14. The compound according to claim 9 , wherein R is phenyl optionally substituted with one or more independent occurrences of halogen, CF 3 , —SO 2 CH 3 , phenyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, pyridyl, —OCF 3 or —OCH 2 phenyl.

15. The compound according to claim 11 , wherein R is hydrogen or an optionally substituted group selected from phenyl, C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, or morpholinyl.

16. The compound according to claim 11 , wherein R is phenyl optionally substituted with one or more independent occurrences of halogen, CF 3 , —SO 2 CH 3 , phenyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, pyridyl, —OCF 3 or —OCH 2 phenyl.

17. The compound of claim 1 , wherein the compound is selected from:

1 (4-chlorobenzyl)-N-hydroxy 2-oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-1);

N-hydroxy-1 methyl 2-oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-2);

(R)-1 (4-chloro-3-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-3);

(S)-1 (4-chloro-3-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide;

1 (3-fluoro-4-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-5);

N-hydroxy-2 oxo-1 (4-(trifluoromethyl)benzyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-6);

1 (4-fluorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-7);

N-hydroxy-1 (4-(methylsulfonyl)benzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-8);

1 cyclopropyl-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-9);

1 cyclobutylmethyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-10);

N-hydroxy-2 oxo-1 (4-(trifluoromethyl)phenyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-11);

N-hydroxy-2 oxo-1 (3-(trifluoromethyl)phenyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-12);

N-hydroxy-2 oxo-1 (2-(trifluoromethyl)phenyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-13);

1 benzyl-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-14);

N-hydroxy-2 oxo-1 (3-phenylpropyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-15);

1 ([1,1 biphenyl]-4-ylmethyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-16);

N-hydroxy-1 (3-methylbenzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-17);

1 ([1,1 biphenyl]-3-ylmethyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-18);

N-hydroxy-1 (4-methoxybenzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-19);

N-hydroxy-1 (3-methoxybenzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-20);

1 (2,6-dichlorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-21);

1 (2,3-dichlorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-22);

N-hydroxy-1 (2-methylbenzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-23);

N-hydroxy-2 oxo-1 (pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-24);

1 (2-chlorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-25);

1 (3-fluorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-26);

N-hydroxy-2 oxo-1 (4-(trifluoromethoxy)benzyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-27);

1 (3,5-difluorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-28);

N-hydroxy-2 oxo-1 (2-(trifluoromethyl)benzyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-29);

1 (3-chlorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-30);

N-hydroxy-2 oxo-1 (3-(trifluoromethyl)benzyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-31);

N-hydroxy-2 oxo-1 (2-(trifluoromethoxy)benzyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-32);

1 (3-bromobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-33);

N-hydroxy-2 oxo-1 ((2-phenylthiazol-4-yl)methyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-34);

1 (2,4-difluorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-35);

N-hydroxy-1 (2-methoxybenzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-36);

1 ([1,1 biphenyl]-2-ylmethyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-37);

1 (3,4-dichlorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 -pyrrolidine]-4-carboxamide (II-38);

1 (3,4-dimethylbenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 -pyrrolidine]-4-carboxamide (II-39);

1 (3,5-dimethoxybenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 -pyrrolidine]-4-carboxamide (II-40);

1 (4-(benzyloxy)benzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 -pyrrolidine]-4-carboxamide (II-41);

N-hydroxy-2 oxo-1 (3-(trifluoromethoxy)benzyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-42);

1 (2-fluoro-3-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-43);

1 (cyclohexylmethyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-44);

1 (2,5-dichlorobenzyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-45);

N-hydroxy-2 oxo-1 ((3-phenylisoxazol-5-yl)methyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-46);

1 ((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-47);

N-hydroxy-2 oxo-1 ((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-48);

N-hydroxy-2 oxo-1 ((5-(tetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-3-yl)methyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-49);

1 ((3,5-dimethylisoxazol-4-yl)methyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-50);

N-hydroxy-2 oxo-1 ((6-(trifluoromethyl)pyridin-2-yl)methyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-51);

N-hydroxy-1 (2-morpholinoethyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-52);

N-hydroxy-2 oxo-1 ((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-53);

N-hydroxy-1 (4-(methylsulfonyl)benzyl)-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-54);

1 (cyclopropylmethyl)-N-hydroxy-2 oxo-1,3-dihydrospiro[indene-2,3 pyrrolidine]-4-carboxamide (II-55);

1 (4-chloro-3-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-67);

1 (3-fluoro-4-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-68);

1 (4-chlorobenzyl)-N-hydroxy-2 oxo-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-69);

N-hydroxy-2 oxo-1 (4-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-70);

N-hydroxy-2 oxo-1 (4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-71);

N-hydroxy-2 oxo-1 (3-(trifluoromethyl)phenyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-72);

N-hydroxy-2 oxo-1 (2-(trifluoromethyl)phenyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-8-carboxamide (II-73);

1 (4-chloro-3-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-84);

N-hydroxy-2 oxo-1 (4-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-85);

1 (3-fluoro-4-(trifluoromethyl)benzyl)-N-hydroxy-2 oxo-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-86);

1 (4-chlorobenzyl)-N-hydroxy-2 oxo-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-87);

N-hydroxy-2 oxo-1 (4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-88);

N-hydroxy-2 oxo-1 (3-(trifluoromethyl)phenyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-89);

N-hydroxy-2 oxo-1 (2-(trifluoromethyl)phenyl)-3,4-dihydro-1H-spiro[naphthalene-2,3 pyrrolidine]-5-carboxamide (II-90);

or a pharmaceutically acceptable salt thereof.

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

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