Histone deacetylase inhibitors and compositions and methods of use thereof

1. A method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is —C(O)NH(OH) or —N(OH)C(O)R 9 ;

R 2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile;

A is aryl or heteroaryl;

R 3 is chosen from hydrogen, alkyl, halo, —NHSO 2 R 10 , C(O)NR 11 R 12 , NR 11 R 12 , nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino;

R 4 is absent or is chosen from hydrogen, alkyl, halo, —NHSO 2 R 10 , C(O)NR 11 R 12 , NR 11 R 12 , nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino;

for each occurrence, R 5 , R 6 , R 7 , and R 8 are independently chosen from hydrogen and lower alkyl;

R 9 is hydrogen or lower alkyl;

R 10 is lower alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 11 and R 12 are independently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyl and cycloalkyl, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and

m and m′ are independently chosen from 0, 1, 2, 3 and 4, provided that 2≤(m+m′)≤4.

2. The method of claim 1 , wherein said at least one histone deacetylase is HDAC4.

3. The method of claim 1 , wherein said condition or disorder involves a neurodegenerative pathology.

4. The method of claim 1 , wherein said condition or disorder is Huntington's disease.

5. The method of claim 1 , wherein the compound of Formula I is a compound of Formula II:

6. The method of claim 1 , wherein the compound of Formula I is a compound of Formula III:

7. The method of claim 1 , wherein the compound of Formula I is a compound of Formula VI:

8. The method of claim 1 , wherein the compound of Formula I is a compound of Formula VII:

9. The method of claim 1 , wherein the compound of Formula I is a compound of Formula IV:

10. The method of claim 1 , wherein the compound of Formula I is a compound of Formula V:

11. The method of claim 1 , wherein the compound of Formula I is a compound of Formula VIII:

12. A method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from:

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-2-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;

5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide; and 5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;

5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;

3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide;

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide;

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide;

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide;

(S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;

(R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;

(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;

(S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(R)-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;

(S)-6-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;

(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;

(R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;

(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;

(S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;

(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;

(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;

(S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;

(R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

E1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide;

E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide;

2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide;

2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide;

E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;

E2-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide; and

N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;

E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide;

E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide;

N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide;

(S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;

(R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;

(R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;

(R)-4-(3-fluoro-2-methylphenyl)-2-(2-fluorobenzyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide; and

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide.

13. The method of claim 9 , wherein said condition or disorder is Huntington's disease.

14. The method of claim 10 , wherein said condition or disorder is Huntington's disease.

15. The method of claim 11 , wherein said condition or disorder is Huntington's disease.

16. The method of claim 12 , wherein said condition or disorder is Huntington's disease.

17. The method of claim 10 , wherein m is 1 and m′ is 1.

18. The method of claim 10 , wherein, for each occurrence, R 5 , R 6 , R 7 , and R 8 are hydrogen.

19. The method of claim 10 , wherein R 2 is phenyl optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

20. The method of claim 19 , wherein R 2 is phenyl optionally substituted with 1 to 3 substituents independently chosen from halo and alkyl.