Inhibitors of histone deacetylase

1. A histone deacetylase inhibitor of formula (2):

or a pharmaceutically acceptable salt thereof, wherein

Cy 2 is optionally substituted aryl;

X 1 is M 2 -L 2 wherein

L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene;

M 2 is selected from the group consisting of M 1 and heteroarylene, which heteroarylene ring is optionally substituted;

M 1 is selected from the group consisting of —O—, —N(R 7 )—, —S—, —S(O)—, S(O) 2 —, —S(O) 2 N(R 7 )—, —N(R 7 )—S(O) 2 —, —C(O)—, wherein R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

Ar 2 is optionally substituted arylene;

q is 0; and

Ay 2 is a phenyl, a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl substituted with an amino or hydroxy moiety and further optionally substituted;

provided that

(a) when Ay 2 is o-phenol optionally substituted by halo, nitro, or methyl, Ar 2 is optionally substituted phenyl, X 1 is —O—, —S—, —S—CH 2 —, —S(O)—, —S(O) 2 —, —C(O)—, or —OCH 2 —, then Cy 2 is not optionally substituted phenyl or naphthyl;

(b) when Ar 2 is amino or hydroxy substituted phenyl, X 1 is C 0 -C 8 -alkyl-X 1a —C 0 -C 8 -alkyl, wherein X 1a is —O—, —S—, —NH—, —C(O)—, then Cy 2 is not optionally substituted naphthyl or di- or -tetrahydronaphthalene.

2. The compound according to claim 1 wherein Ay 2 is phenyl or thienyl, each substituted with —OH or —NH 2 .

3. The compound according to claim 1 wherein the amino or hydroxy substituent is ortho to the nitrogen to which Ay 2 is attached.

4. The compound according to claim 1 wherein Ay 2 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl.

5. The compound according to claim 1 wherein Ar 2 has the formula

and wherein G, at each occurrence, is C, and C is optionally substituted.

6. The compound according to claim 5 wherein Ar 2 has the formula

7. The compound according to claim 1 wherein Ar 2 is phenylene.

8. The compound according to claim 1 wherein Cy 2 optionally substituted phenyl.

9. The compound according to claim 1 wherein Cy 2 has from one and three substituents independently selected from the group consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy.

10. The compound according to claim 1 wherein the Cy 2 substituents are selected from methyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl.

11. A compound of the formula (2b):

or a pharmaceutically acceptable salt thereof, wherein

Ay 2 is phenyl or thienyl, each substituted at the ortho position with —NH 2 or —OH and each further optionally substituted with one to three substituents independently selected from —NH 2 , —OH, and halo;

q is 0;

X 1 is selected from —CH 2 —, —NH—CH 2 —, and —S—CH 2 —;

Cy 2 is monocyclic or fused bicyclic aryl optionally substituted with one to three substituents selected from CH 3 —, CH 3 O—, phenyl optionally substituted with one to three CH 3 O—, morphylinyl, morphylinyl-C 1 -C 3 -alkoxy, cyano, and CH 3 C(O)NH—;

provided that when

Cy 2 is optionally substituted phenyl or naphthyl, X 1 is —CH 2 — or —S—CH 2 —, then Ay 2 is not o-phenyl optionally substituted by halo.

12. The compound according to claim 11 wherein Ay 2 is selected from:

13. The compound according to claim 11 wherein Cy 2 is phenyl, optionally substituted with one to three CH 3 O—.

14. The compound according to claim 11 wherein Cy 2 is phenyl substituted with one to three CH 3 O—.

15. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. A method of inhibiting histone deacetylase in a cell in vitro, the method comprising contacting a cell with a compound according to claim 1 .

17. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

18. A method of inhibiting histone deacetylase in a cell in vitro, the method comprising contacting a cell with a compound according to claim 11 .

19. A method of treating colon or lung cancer in a human patient, the method comprising administering an effective amount of a compound according to claim 1 to the patient.

20. A method of treating colon or lung cancer in a human patient, the method comprising administering an effective amount of a compound according to claim 11 to the patient.

21. A histone deacetylase inhibitor selected from the compounds listed in Tables 4b, and 5e-5f, or a pharmaceutically acceptable salt thereof:

TABLE 4b

Cpd

W

Y

329

CH

404

CH

TABLE 5e

Cpd

Structure

164

166

TABLE 5f

Cpd

Structure

277

289

290

296

297

301

305

352

366

367

386

393

394

395

397

400

401

402

403

404

406

407

409

410

412

413

414

415

416

417

422

423

424b

424c

425

426

427

428

429

430

434

437

438

441

450

453

454

457

571

572

574