Inhibitors of histone deacetylase

1. A compound of formula (1):

or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug thereof, or a racemic or scalemic mixture, diastereomer, enantiomer or tautomer thereof, wherein

T is NH 2 or OH;

A is selected from the group consisting of arylene, heteroarylene, cycloalkylene and heterocyclylene, each of which is optionally substituted; and

X is

(a)

 wherein

Y=N or CH,

n 1 =0-4 and

Z 1 is selected from the group consisting of R 9 —, R 13 —C(O)—, R 13 —C(S)—, R 7 —N(R 2 )—, R 6 —O—, R 10 —S—, R 13 —S(O) 1-2 , R 5 —C(O)—O—, R 15 —O—C(O)—, R 15 —C(O)—S—, R 15 —S—C(O)—, R 11 —C(O)—N(R 2 )—, R 13 —N(R 2 )—C(O)—, R 15 —C(S)—O—, R 15 —O—C(S)—, R 15 —C(S)—S—, R 15 —S—C(S)—, R 15 —C(S)—N(R 2 )—, R 15 —N(R 2 )—C(S)—, R 5 —O—C(O)—O—, R 15 —O—C(O)—S—, R 15 —S—C(O)—O—, R 12 —O—C(O)—N(R 2 )—, R 8 —N(R 2 )—C(O)—O—, R 5 —O—C(S)—O—, R 15 —O—C(S)—S—, R 15 —S—C(S)—O—, R 15 —O—C(S)—N(R 2 )—, R 15 —N(R 2 )—C(S)—O—, R 15 —S—C(O)—S—, R 15 —S—C(O)—N(R 2 )—, R 15 —N(R 2 )—C(O)—S—, R 15 —S—C(S)—S—, R 5 —N(R 2 )—C(O)—N(R 2 )—, R 5 —N(R2)—C(S)—N(R 2 )—, R 15 —N(R 2 )—C(S)—S—, R 15 —S—C(S)—N(R 2 )—, R 5 —NH—C(N(R 2 ))—NH—, R 5 —S(O) 0-2 —N(R 2 )—, R 5 —N(R 2 )—S(O) 0-2 — and R 15 —N(R 2 )—S(O) 0-2 —N(R 2 )—;

with the proviso that if n 1 is 1 or 2 and Z 1 is R 9 —, R 13 —C(O)—, R 7 —N(R 2 )—, R 6 —O—, R 10 —S—, R 13 —S(O) 1-2 , R 15 —C(O)—O—, R 15 —O—C(O)—, R 11 —C(O)—N(R 2 )—, R 13 —N(R 2 )—C(O)—, R 12 —O—C(O)—N(R 2 )—, R 8 —N(R 2 )—C(O)—O—, R 5 —S(O) 2 —N(R 2 )— or R 5 —N(R 2 )—S(O) 2 —, then A is not thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl, triazinyl or tetrazinyl;

in which

each R 2 is independently selected from the group consisting of hydrogen, (C 1 -C 5 alkyl, Hca-(C 0 -C 4 alkyl)-, Cak-(C 0 -C 4 alkyl)-, R 14 —CO—, R 14 —SO2-, R 14 —CO—NH— and R 14 —CO—O—, in which each alkyl is optionally substituted;

each R 5 is independently selected from the group consisting of H-, optionally substituted (C 1 -C 6 hydrocarbyl)-, Ar—(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

each R 6 is independently selected from the group consisting of H—, substituted (C 1 -C 6 hydrocarbyl)- with the proviso that if the (C 1 -C 6 hydrocarbyl) has only one substituent, it is not halo or amino, Hca-(C 0 -C 1 or C 3 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

each R 7 is independently selected from the group consisting of H, optionally substituted (C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 1 or C 3 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

each R 8 is independently selected from the group consisting of optionally substituted (C 1 -C 6 hydrocarbyl)-, Ar-(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-, with the proviso that R 8 is not 2(morpholin-4-yl)ethyl;

each R 9 is independently selected from the group consisting of Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-; each R m is independently selected from the group consisting of H-, Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

each R 11 is independently selected from the group consisting of H—, (C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

each R 12 is independently selected from the group consisting of optionally substituted (C 1 -C 6 hydrocarbyl)-, Ar—(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)-, Cak-(C 0 -C 6 hydrocarbyl)-;

each R 13 is independently selected from the group consisting of H—, optionally substituted (C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

each R 14 is independently selected from the group consisting of Ar— and optionally substituted (C 1 -C 6 hydrocarbyl)-; and

each R 15 is independently selected from the group consisting of H—, optionally substituted (C 1 -C 6 hydrocarbyl)-, Ar—(C 0 -C 6 hydrocarbyl)-, Het-(C 0 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- and Cak-(C 0 -C 6 hydrocarbyl)-;

in which any (C 1 -C 6 hydrocarbyl)- moiety is optionally substituted, and each Ar is independently an optionally substituted aryl, each Het is independently an optionally substituted heteroaryl, each Hca is independently an optionally substituted heterocycloalkyl, and each Cak is independently an optionally substituted cycloalkyl.

2. The compound according to claim 1 , wherein T is NH 2 .

3. The compound according to claim 1 , wherein A is unsubstituted or optionally-substituted phenyl, thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or tetrazinyl.

4. The compound according to claim 1 , wherein A is a 6-membered ring and the X— and carbonyl moieties are arranged in a 1,4- manner relative to one another on the ring.

5. The compound according to claim 1 , wherein A is unsubstituted or optionally-substituted arylene.

6. The compound according to claim 1 , wherein A is unsubstituted phenylene.

7. The compound according to claim 1 , wherein Z 1 is R 5 —C(O)—O—, R 12 —O—C(O)—N(R 2 )—, R 11 —C(O)—N(R 2 )—, R 15 —C(S)—N(R 2 )—, R 15 —S—C(O)—N(R 2 )—, R 5 —N(R 2 )—C(O)—N(R 2 ), R 5 —N(R 2 )—C(S)—N(R 2 )—, R 8 —N(R 2 )—C(O)—O—, R 15 —O—C(S)—N(R 2 )—, R 15 —S—C(S)—N(R 2 )—, R 5 —N(R 2 )—C(S)—O—, R 5 —O—C(S)—N(R 2 )—, R 5 —S(O) 0-2 —N(R 2 )— or R 5 —N(R 2 )—S(O) 0-2 —.

8. The compound according to claim 1 , wherein Z 1 is R 5 —C(O)—O—, R 12 —O—C(O)—N(R 2 )—, R 11 —C(O)—N(R 2 )—, R 5 —N(R 2 )—C(O)—N(R 2 ), R 5 —N(R 2 )—C(S)—N(R 2 )—, R 8 —N(R 2 )—C(O)—O—, R 5 —N(R 2 )—C(S)—O—, R 5 —O—C(S)—N(R 2 )—, R 6 —O— or R 7 —N(R 2 )—.

9. The compound according to claim 1 , wherein Z 1 is R 12 —O—C(O)—N(R 2 )—.

10. The compound according to claim 1 , wherein Z 1 is (C 1 -C 6 hydrocarbyl)—O—C(O)—N(R 2 )—, and the (C 1 -C 6 hydrocarbyl) is optionally substituted.

11. A compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug or a racemic mixture, diastereomer, enantiomer or tautomer thereof, according to claim 10 , wherein Z 1 is R 16 —O—C(O)—N(R 2 )—, in which R 16 is optionally-substituted (C 1 -C 6 hydrocarbyl)-, optionally-substituted Ar—(C 1 -C 2 hydrocarbyl)-, optionally-substituted Het-(C 1 -C 2 hydrocarbyl)-, optionally-substituted Hca-(C 0 -C 2 hydrocarbyl)- or optionally-substituted Cak-(C 0 -C 2 hydrocarbyl).

12. The compound according to claim 1 , wherein n 1 =1.

13. The compound according to claim 12 , wherein the compound has an (S)-stereochemical configuration at the carbon to which Z 1 is connected.

14. The compound according to claim 1 , wherein,

T is —NH 2 ;

A is phenyl; and

X is

15. The compound according to claim 1 , wherein,

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is selected from the group consisting of R 7 —N(R 2 )—, R 6 —O—, R 11 —C(O)—N(R 2 )—, R 15 —C(S)—N(R 2 )—, R 12 —O—C(O)—N(R 2 )—, R 8 —N(R 2 )—C(O)—O—, R 15 —N(R 2 )—C(S)—O—, R 5 —N(R 2 )—C(O)—N(R 2 )—, R 5 —N(R 2 )—C(S)—N(R 2 )—, R 15 —O—C(S)—N(R 2 )— and R 5 —S(O) 0-2 —N(R 2 )—.

16. The compound according to claim 1 , wherein,

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is selected from the group consisting of R 7 —N(R 2 )—, R 6 —O—, R 11 —C(O)—N(R 2 )—, R 15 —C(S)—N(R 2 )—, R 12 —O—C(O)—N(R 2 )—, R 8 —N(R 2 )—C(O)—O—, R 15 —N(R 2 )—C(S)—O—, R 5 —N(R 2 )—C(O)—N(R 2 )—, R 5 —N(R 2 )—C(S)—N(R 2 )—, R 15 —O—C(S)—N(R 2 )— and R 5 —S(O) 0-2 —N(R 2 )—; wherein

R 2 is H, optionally substituted (C 1 -C 5 alkyl)-, or optionally substituted Het-(C 0 -C 4 alkyl)-;

R 5 is optionally substituted Het-(C 1 -C 0 hydrocarbyl)-;

R 6 is H;

R 7 is H or optionally substituted (C 1 -C 6 hydrocarbyl)-;

R 8 is optionally substituted (C 1 -C 0 hydrocarbyl)-;

R 11 is optionally substituted Hca-(C 0 -C 6 hydrocarbyl)- or optionally substituted (C 1 -C 6 hydrocarbyl)-;

R 12 is (C 1 -C 6 hydrocarbyl)-, Ar—(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- or Cak-(C 0 -C 6 hydrocarbyl)-, each of which is optionally substituted; and

R 15 is optionally substituted (C 1 -C 6 hydrocarbyl)- or optionally substituted Hca-(C 0 -C 6 hydrocarbyl)-.

17. The compound according to claim 1 , wherein,

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is selected from the group consisting of R 7 —N(R 2 )—, R 11 —C(O)—N(R 2 )— and R 12 —O—C(O)—N(R 2 )—.

18. The compound according to claim 1 , wherein,

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is selected from the group consisting of R 7 —N(R 2 )—, R 11—C(O)—N(R 2 )— and R 12 —O—C(O)—N(R 2 )—; wherein

R 2 is H, optionally substituted (C 1 -C 5 alkyl)-, or optionally substituted Het-(C 0 -C 4 alkyl)-;

R 7 is H or optionally substituted (C 1 -C 6 hydrocarbyl)-;

R 11 is optionally substituted Hca-(C 0 -C 6 hydrocarbyl)- or optionally substituted (C 1 -C 6 hydrocarbyl)-; and

R 12 is (C 1 -C 6 hydrocarbyl)-, Ar—(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- or Cak-(C 0 -C 6 hydrocarbyl)-, each of which is optionally substituted.

19. The compound according to claim 1 , wherein

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is R 12 —O—C(O)—N(R 2 )—; wherein

R 2 is H or optionally substituted Het-(C 0 -C 4 alkyl)-; and

R 12 (C 1 -C 6 hydrocarbyl)-, Ar—(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- or Cak-(C 0 -C 6 hydrocarbyl)-, each of which is optionally substituted.

20. The compound according to claim 1 , wherein

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is R 12 —O—C(O)—N(R 2 )—; wherein

R 2 is H or optionally substituted Het-(C 0 -C 4 alkyl)-; and

R 12 is (C 1 -C 6 hydrocarbyl)-, Ar—(C 1 -C 6 hydrocarbyl)-, Het-(C 1 -C 6 hydrocarbyl)-, Hca-(C 0 -C 6 hydrocarbyl)- or Cak-(C 0 -C 6 hydrocarbyl)-, each of which is optionally substituted with a substituent selected from the group consisting of alkyl, amino, alkylamino, di-alkylamino, alkoxy, —CF 3 and halo.

21. The compound according to claim 1 , wherein

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is R 12 —O—C(O)—N(R 2 )—; wherein

R 2 is H or optionally substituted Het-(C 0 -C 4 alkyl)-; and

R 12 is (C 1 -C 6 hydrocarbyl)- optionally substituted with a substituent selected from the group consisting of alkyl, amino, alkylamino, di-alkylamino, alkoxy, -CF 3 and halo.

22. The compound according to claim 1 , wherein

T is —NH 2 ;

A is phenyl; and

X is

 wherein

n 1 =1 and

Z 1 is R 7 —N(R 2 )—; wherein

R 2 is optionally substituted Het-(C 0 -C 4 alkyl)-; and

R 7 is H or optionally substituted (C 0 -C 6 hydrocarbyl)-.

23. A compound selected from the group consisting of:

(S)-2-(Dimethylamino)ethyl-1-(4-(2-aminophenylcarbamoyl)-phenyl)pyrrolidin-3-ylcarbamate;

(S)-Methyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Ethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-tert-Butyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Isobutyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Benzyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-N-(1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl)morpholine-4-carboxamide;

((S)-Pyridin-3-ylmethyl-1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-N-(2-Aminophenyl)-4-(3-(3-(pyridin-3-ylmethyl)ureido)pyrro lidin- 1 -yl) benzamide;

(S)-2-Methoxyethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(R)-2-Methoxyethyl 1-(5-(2-aminophenylcarbamoyl)pyridin-2-yl)pyrrolidin-3-yl carbamate;

(S)-N-(2-Aminophenyl)-4-(3-(3-(pyridin-3-ylmethyl)thioureido)pyrrolidin- 1-yl) benzamide;

(S)-O-Methyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamothioate;

(S)-2,2,2-Trifluoroethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)-pyrrolidin-3-ylcarbamate;

(S)-N-(2-Aminophenyl)-4-(3-(2-(dimethylamino) acetamido) pyrrolidin-1-yl)benzamide;

(S)-Pyridin-4-ylmethyl 1-(4-(2-aminophenyl carbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Pyridin-2-ylmethyl 1-(4-(2-aminophenyl carbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-3-(Dimethyl amino)propyl 1-(4-(2-amino phenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Furan-3-ylmethyl1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(R)-1-Methylpyrrolidin-3-yl (S)-1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl acetate;

(S)-N-(2-Aminophenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide;

(S)-1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl ethyl carbamate;

(S)-O-1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl 2-morpholinoethylcarbamothioate;

(S)-N-(2-Aminophenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)benzamide;

(S)-N-(2-Aminophenyl)-4-(3-(phenylmethylsulfonamido)pyrrolidin-1-yl)benzamide;

(S)-2-morpholinoethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate;

(S)-methyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl(pyridin-3-ylmethyl) carbamate;

(S)-benzyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl(3,4,5-trimethoxybenzyl) carbamate;

(S)-isopropyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate;

(S)-cyclopropylmethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate;

(S)-tetrahydro-2H-pyran-4-yl 1-(4-(2-aminophenylcarb amoyl)phenyl)pyrro lidin-3-ylcarbamate, and

(R)-N-(2-Aminophenyl)-4-(3-hydroxypyrro lidin-1-yl)benzamide.

24. The compound according to claim 1 , selected from the group consisting of:

(S)-Ethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-2-Methoxyethyl-1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate; and

(S)-N-(2-Aminophenyl)-4-(3-(pyridin-2-ylamino)pyrrolidin-1-yl)benzamide.

25. A composition comprising a compound according to claim 1 present in at least about 30% enantiomeric or diastereomeric excess.

26. The composition according to claim 25 wherein the compound is present in at least about 50% enantiomeric or diastereomeric excess.

27. The compositionaccording to claim 25 wherein the compound is present in at least 80% enantiomeric or diastereomeric excess.

28. The composition according to claim 25 wherein the compound is present in at least 90% enantiomeric or diastereomeric excess.

29. A composition comprising a compound according to claim 1 present as a substantially racemic mixture.

30. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable, diluent, carrier or excipient.

31. A method of inhibiting histone deacetylase in a cell, the method comprising contacting the cell with one or more compounds according to claims 1 , or a composition thereof.

32. A method for treating a cell proliferative disease or condition in an animal in need of such treatment, the method comprising administering to the animal a therapeutically effective amount of one or more compounds according to claim 1 or a composition thereof, wherein said cell proliferative disease or condition is selected from one or more of the group consisting of cancer, restenosis, and psoriasis.

33. The method according to claim 32 wherein the animal is a human.