Inhibitors of histone deacetylase

1. A compound having formula I:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

the moiety

 is of the formula:

U is selected from single bond and NR 2d ;

V is selected from C and N, provided that when V is N, one of R 2a , R 2b , or R 2c is absent;

each X is independently selected from hydrogen, deuterium, methyl, CF 3 , and halogen;

R 2a is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;

R 2b is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;

R 2c is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;

R 2d is selected from NH 2 and C 1 -C 8 alkyl;

provided that:

taken together two of R 2a , R 2b , and R 2c form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring containing 1, 2, 3, or 4 nitrogen atoms, and the remaining R 2a , R 2b , or R 2c is absent or selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl, further wherein:

said cycloalkyl ring formed by taking together two of R 2a , R 2b , and R 2c is substituted with two or more R x , wherein two R x are taken together to form a C 3 -C 8 cycloalkyl ring that is substituted with one or more R z or is unsubstituted, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkenyl ring and heterocyclic ring are unsubstituted or substituted with one or more R z , or to form an aromatic ring or heteroaromatic ring, further wherein said aromatic ring and heteroaromatic ring are monocyclic or bicyclic, and are unsubstituted or substituted with one or more R z ; and

said cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c , and heterocyclic ring formed by taking together two of R 2a , R 2b , and R 2c are unsubstituted or substituted with one or more R x ;

or taken together R 2d and one of R 2a , R 2b ,and R 2c form a 3 to 8 membered saturated or partially unsaturated heterocyclic ring, and: the remaining R 2a , R 2b , or R 2c is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl, or taken together two of the remaining R 2a , R 2b , and R 2c form ═O; further wherein said heterocyclic ring is unsubstituted or substituted with one or more R x ;

or taken together two of R 2a , R 2b , and R 2c form an aromatic or heteroaromatic ring and the remaining R 2a , R 2b , or R 2c is absent, provided that when two of R 2a , R 2b ,and R 2c form an aromatic or heteroaromatic ring and the remaining R 2a , R 2b , or R 2c is absent, U is not a single bond, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more R x ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R x ;

each R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -aromatic ring, (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 ′(CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 ; wherein the aromatic ring is monocyclic, bicyclic, or tricyclic, and the heterocyclic ring is 3 or 8 membered;

or taken together two R x attached to the same carbon atom of a cycloalkyl, cycloalkenyl or heterocyclic ring form ═O;

or taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkyl ring cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more R z ;

or taken together two R x form an aromatic ring or heteroaromatic ring, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z ;

each R z is independently selected from halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , and C(O)CH 3 ;

R 3 is C 1 -C 8 alkyl;

R 4 is selected from C 1 -C 8 alkyl and CF 3 ;

R 5 is selected from hydrogen, deuterium, halogen, OH, OCH 3 , CF 3 , CH 3 , and cyclopropyl;

t is selected from 0, 1, and

z is selected from 0, 1, 2, and 3.

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

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

the moiety

 is of the formula:

 and

U is a single bond.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl;

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and

d and d′ are each independently selected from 0, 1, 2, and 3, provided that the ring formed by taking together R 2a and R 2b is a 3 to 8 membered ring; and further provided that when J is C:

v is selected from 2, 3, 4, 5, 6, 7, and 8; and

taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkyl ring, cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more R z ;

or taken together two R x form an aromatic ring or heteroaromatic ring, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z .

4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, or thereof, wherein R 2a R 2b R 2c V is

wherein w is selected from 1, 2, and 3.

5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N, O, C, and S;

when J is N or C, R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ; and when J is O or S, R u is absent;

R 3a is C 1 -C 8 alkyl;

n is 1, 2, or 3; and

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;

provided that when J is C:

each R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 OCH 2 F, OCHF 2 , (CH 2 ) z -aromatic ring, (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 , wherein the aromatic ring is monocyclic, bicyclic, or tricyclic, and the heterocyclic ring is 3 to 8 membered;

or taken together two R x attached to the same carbon atomcycloalkyl, cycloalkenyl, or heterocyclic ring form ═O.

6. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U is selected from:

wherein: b is selected from 0, 1, 2, and 3; and a is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

7. The compound of claim 1 , selected from:

Compound No.

Structure

207

220

222

228

234

237

and pharmaceutically acceptable salts, hydrates, and solvates thereof.

8. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutical carrier, diluent, or excipient.

9. A kit containing one or more compounds of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5 is hydrogen.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein in the moiety

each X is hydrogen.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U is of the formula:

wherein:

taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered, saturated or partially unsaturated, heterocyclic ring;

a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

b is 0, 1, 2, or 3.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U is

wherein:

V is N or CH;

each T is independently CH, CR z , or N;

each R z is independently selected from halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , and C(O)CH 3 ;

each R 3 is C 1 -C 8 alkyl; and

b is 0, 1, 2, 3, or 4.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U is of the formula:

wherein:

V is N or CH;

each R z is independently halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , or C(O)CH 3 ;

each R 3 is C 1 -C 8 alkyl; and

b is 0, 1, 2, or 3.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U is of the formula:

wherein:

each R z is independently halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , or C(O)CH 3 ;

each R 3 is C 1 -C 8 alkyl; and

b is 0, 1, 2, 3, or 4.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3a ;

R 3a is C 1 -C 8 alkyl;

n is 1, 2, or 3; and

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl; and

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;

provided that when J is C:

v is selected from 2, 3, 4, 5, 6, 7, and 8; and

taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkyl ring, cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more R z ;

or taken together two R x form an aromatic ring or heteroaromatic ring, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z .

18. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl; and

v is selected from 0, 1, 2, 3, 4, 5, 6 or 7;

provided that when J is C:

v is selected from 2, 3, 4, 5, 6 or 7; and

taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkyl ring, cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more R z ;

or taken together two R x form an aromatic ring or heteroaromatic ring, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z .

19. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl; and

v is selected from 0, 1, 2, 3, 4 or 5;

provided that when J is C:

v is selected from 2, 3, 4 or 5; and

taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkyl ring, cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more R z ;

or taken together two R x form an aromatic ring or heteroaromatic ring, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z .

20. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

r and r′ are each independently selected from 0, 1, and 2, provided that the ring formed by taking together R 2a and R 2b is a 3 to 8 membered ring;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl; and

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

21. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl;

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;

v′ is selected from 0, 1, 2, 3, and 4; and

o and o′ are each independently selected from 0, 1, 2, and 3, provided that the ring formed by taking together R 2a and R 2b is a 3 to 8 membered ring.

22. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

R 2a R 2b R 2c V— is of the formula:

wherein:

J is selected from N and C;

R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;

R 3a is C 1 -C 8 alkyl;

v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;

v′ is selected from 0, 1, 2, 3, and 4; and

o and o′ are each independently selected from 0, 1, 2, and 3, provided that the ring formed by taking together R 2a and R 2b is a 3 to 8 membered ring.