Inhibitors of histone deacetylase
View Patent ↗The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
1. A compound of structural formula (2a):
or a pharmaceutically acceptable salt thereof, wherein
Ar a is phenyl or thienyl;
R 6 is H, or C 1 -C 6 -alkyl;
Y and Z are —CH═;
W is (V′-L 4 ) t -V-L 3 -;
L 3 is a direct bond, —C 1 -C 6 -hydrocarbyl, —(C 1 -C 3 -hydrocarbyl) m1 -X′—(C 1 -C 3 -hydrocarbyl) m2 , —NH—(C 0 -C 3 -hydrocarbyl), (C 1 -C 3 - hydrocarbyl)-NH—, or —NH—(C 1 -C 3 -hydrocarbyl)-NH—;
m1 and m2 are independently 0 or 1;
X′ is —N(R 21 )—, —C(O)N(R 21 )—, N(R 21 )C(O)—, —O—, or —S—;
R 21 is —H, V″—(C 1 -C 6 -hydrocarbyl) c ;
L 4 is (C 1 -C 6 -hydrocarbyl) a -M-(C 1 -C 6 -hydrocarbyl) b ;
a and b are independently 0 or 1;
M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO 2 —, —NHSO 2 —, or —SO 2 NH—
V, V′, and V″ are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;
t is 0 or 1;
or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
wherein the A and Ar a rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.
2. The compound according to claim 1 wherein:
R 6 is H;
W is V-L 3 -;
L 3 is —NH—CH— or —CH—NH—;
V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C 1 -C 6 -hydrocarbyl, C 1 -C 6 -hydrocarbyl-oxy or -thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitroso, amino, sulfonamido, and cyano; and
Ar a is phenyl and the amino moieties to which it is bound are ortho to each other.
3. The compound according to claim 1 wherein V is an optionally substituted ring moiety selected from the group consisting of the following:
4. The compound according to claim 1 wherein W is selected from the group consisting of the following:
5. The compound according to claim 1 wherein the A and Ar a rings are not further substituted.
6. The compound according to claim 1 selected from the group consisting of the following combinations, in which, unless expressly displayed otherwise, Ar a is phenyl:
Cpd
W
Y
Z
R 6
481
CH
CH
H,
484
492
CH
CH
H,
493
CH
CH
H,
494
CH
CH
H,
495
CH
CH
H,
496
CH
CH
H,
497
CH
CH
H,
498
CH
CH
H,
499
CH
CH
H,
500
CH
CH
H,
501
CH
CH
H,
502
CH
CH
H,
503
CH
CH
H,
504
CH
CH
H,
505
CH
CH
H,
506
CH
CH
H,
507
CH
CH
H,
508
CH
CH
H,
509
CH
CH
H,
510
CH
CH
H,
511
CH
CH
H,
517
CH
CH
CH 3 ,
518
CH
CH
CH 3 ,
519
CH
CH
H,
520
CH
CH
H,
523
CH
CH
H,
526
CH
CH
H,
527
CH
CH
H,
528
CH
CH
H,
529
CH
CH
H,
530
CH
CH
H,
531
CH
CH
H,
532
CH
CH
H,
533
CH
CH
H,
534
CH
CH
H,
535
CH
CH
H,
536
CH
CH
H,
537
CH
CH
H,
538
CH
CH
H,
539
CH
CH
H,
540
CH
CH
H,
541
CH
CH
H,
542
CH
CH
H,
543
CH
CH
H,
544
CH
CH
H,
545
CH
CH
H,
546
CH
CH
H,
547
CH
CH
H,
548
CH
CH
H,
549
CH
CH
H,
550
CH
CH
H,
551
CH
CH
H,
552
CH
CH
H,
553
CH
CH
H,
554
CH
CH
H,
555
CH
CH
H,
556
CH
CH
H,
557
CH
CH
H,
558
CH
CH
H,
559
CH
CH
H,
560
561
562
CH
CH
H,
563
CH
CH
H,
564
565
CH
CH
H,
566
CH
CH
H,
567
568
and
570
7. The compound according to claim 6 wherein the amide nitrogen and the amino nitrogen bound to Ar a are ortho to each other.
8. The compound of formula (3b):
or pharmaceutically acceptable salt thereof, wherein Y and Z are CH and W is selected from the group consisting of:
F,
and
9. The compound according to claim 8 wherein Y, Z and W are one of the following combinations
Cpd
W
Y
Z
164
CH
CH,
166
CH
CH,
169
CH
CH,
170
CH
CH,
172
CH
CH,
179
CH
CH,
180
CH
CH,
181
CH
CH,
182
CH
CH,
or
183
CH
CH.
10. The compound according to claim 8 wherein Y, Z and W are one of the following combinations
Cpd
W
Y
Z
187
CH
CH,
188
CH
CH,
189
CH
CH,
190
CH
CH,
193
CH
CH,
194
CH
CH,
195
CH
CH,
196
CH
CH,
320
CH
CH,
321
CH
CH,
322
CH
CH,
323
CH
CH,
325
CH
CH,
326
CH
CH,
327
CH
CH,
328
CH
CH,
329
CH
CH,
330
CH
CH,
331
CH
CH,
332
CH
CH,
333
CH
CH,
334
CH
CH,
335
CH
CH,
336
CH
CH,
337
CH
CH,
338
CH
CH,
339
CH
CH,
340
CH
CH,
341
CH
CH,
342
CH
CH,
343
CH
CH,
344
CH
CH,
345
CH
CH,
346
CH
CH,
347
CH
CH,
348
CH
CH,
349
CH
CH,
350
CH
CH,
351
CH
CH,
356
CH
CH,
357
CH
CH,
358
CH
CH,
359
CH
CH,
360
CH
CH,
361
CH
CH,
362
CH
CH,
363
CH
CH,
364
CH
CH,
365
CH
CH,
366
CH
CH,
368
CH
CH,
369
CH
CH,
370
CH
CH,
375
CH
CH,
377
CH
CH,
378
CH
CH,
379
CH
CH,
381
CH
CH,
382
CH
CH,
383
CH
CH,
384
CH
CH,
385
CH
CH,
386
CH
CH,
387
CH
CH,
388
CH
CH,
389
CH
CH,
390
CH
CH,
391
CH
CH,
392
CH
CH,
393
CH
CH,
394
CH
CH,
395
CH
CH,
396
CH
CH,
397
CH
CH,
399
CH
CH,
400
CH
CH,
401
CH
CH,
402
CH
CH,
403
CH
CH,
404
CH
CH,
405
CH
CH,
406
CH
CH,
407
CH
CH,
408
CH
CH,
409
CH
CH,
410
CH
CH,
411
CH
CH,
412
CH
CH,
413
CH
CH,
414
CH
CH,
415
CH
CH,
416
CH
CH,
417
CH
CH,
418
CH
CH,
419
CH
CH,
420
CH
CH,
421
CH
CH,
422
CH
CH,
423
CH
CH,
424b
CH
CH,
425
CH
CH,
426
CH
CH,
427
CH
CH,
428
CH
CH,
429
CH
CH,
430
CH
CH,
431
CH
CH,
432
CH
CH,
433
CH
CH,
434
CH
CH,
435
CH
CH,
436
CH
CH,
437
CH
CH,
438
CH
CH,
439
CH
CH,
440
CH
CH,
441
CH
CH,
442
CH
CH,
443
CH
CH,
444
CH
CH,
447
CH
CH,
448
CH
CH,
449
CH
CH,
450
CH
CH,
451
F
CH
CH,
452
CH
CH,
453
454
455
CH
CH,
456
CH
CH,
457
458
CH
CH,
459
CH
CH,
461
CH
CH,
462
CH
CH,
465
CH
CH,
466
CH
CH,
467
CH
CH,
or
468
CH
CH.
11. A compound selected from the group consisting of the following and their pharmaceutically acceptable salts:
12. A histone deacetylase inhibitor selected from the group consisting of the following compounds and their pharmaceutically acceptable salts:
N-(2-Amino-phenyl)-4-(quinolin-2-
ylsulfanylmethyl)-benzamide,
N-(2-Amino-phenyl)-4-(4,6-dimethyl-
pyrimidin-2-ylsulfanylmethyl)-benzamide,
N-(2-Amino-phenyl)-4-(4-trifluoromethyl-
pyrimidin-2-ylsulfanylmethyl)-benzamide,
Biphenyl-4,4′-dicarboxylic acid bis-[(2-
amino-phenyl)-amide],
N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-
dihydro-2H-thieno[3,2-d]pyrimidin-3-
ylmethyl)-benzamide,
N-(2-Amino-phenyl)-4-[bis-(3-
trifluoromethoxy-benzyl)-amino]-
benzamide, and
N-(2-Amino-phenyl)-3-(4-{[1-(3-benzyl-
7-chloro-4-oxo-3,4-dihydro-quinazolin-2-
yl)-ethylamino]-methyl}-phenyl)-
acrylamide.
13. A composition comprising a compound according to any one of claim 1 - 7 or 8 - 10 and a pharmaceutically acceptable carrier.
14. A method of treating or inhibiting colon cancer, the method comprising administering to a patient in need thereof a effective amount of a compound according to any one of claims 1 - 7 and 8 - 12 , or a pharmaceutical composition thereof.
15. A method of treating or inhibiting colon cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of structural formula (2a):
or a pharmaceutically acceptable salt thereof, said compound optionally administered together with a pharmaceutically acceptable carrier, wherein
Ar a is phenyl or thienyl;
R 6 is H, or C 1 -C 6 -alkyl;
Y and Z are —CH═;
W is halo;
or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
wherein the A and Ar a rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.