Anti-fibrotic pyridinones
Disclosed are pyridinone compounds, method for preparing these compounds, and methods for treating fibrotic disorders.
1. A compound having the structure of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is 5-10 membered heteroaryl optionally substituted with one or more R 4 ;
R 2 is selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , and —C(O)R 8 ;
R 3 is selected from the group consisting of hydrogen, phenyl, —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 1 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
or R 6 and R 7 together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 1 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
each R 9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , —CN, and —NO 2 ;
each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —O—(CH 2 ) n —C 1-8 alkoxy, —C(O)R 8 , and optionally substituted C 1-6 alkoxy;
each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
Z is selected from oxygen and sulfur;
each n is independently an integer from 0 to 4; and
the bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond, provided that
when R 3 is H, then R 1 is selected from C 6-10 aryl optionally substituted with one or more R 4 , or 5-10 membered heteroaryl optionally substituted with one or more R 4 ;
when R 3 is a phenyl; R 2 is OR 5 or NR 6 R 7 ; then R 1 is not triazolyl;
when R 3 is 4-methyl phenyl, R 2 is morpholinyl, and Z is O; then R 1 is not methyl; and
when R 3 is 4-methyl phenyl, R 2 is —N(CH 3 ) 2 , Z is O; then R 1 is not methyl.
2. The compound of claim 1 , wherein
R 2 is selected from the group consisting of halogen, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ;
R 3 is selected from the group consisting of phenyl, —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ; and
each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy.
3. The compound of claim 1 , wherein R 1 is a pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .
4. The compound of claim 1 , wherein each R 4 is independently selected from halogen, or optionally substituted C 1-6 alkyl.
5. The compound of claim 4 , wherein R 4 is methyl.
6. The compound of claim 1 , wherein R 2 is —CN.
7. The compound of claim 1 , wherein R 2 is —OR 5 .
8. The compound of claim 7 , wherein R 5 is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, C 7-14 aralkyl optionally substituted with one or more R 11 , C 6-10 aryl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 .
9. The compound of claim 8 , wherein R 5 is optionally substituted C 1-6 alkyl.
10. The compound of claim 8 , wherein R 5 is C 6-10 aryl optionally substituted with one or more R 11 .
11. The compound of claim 8 , wherein R 5 is C 7-14 aralkyl optionally substituted with one or more R 11 .
12. The compound of claim 8 , wherein R 5 is optionally substituted C 2-8 alkoxyalkyl.
13. The compound of claim 12 , wherein R 5 is selected from —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OC 3 H 7 or —(CH 2 ) 2 O(CH 2 )OCH 3 .
14. The compound of claim 8 , wherein R 5 is —(CH 2 ) n -(5 or 6 membered heterocyclyl) optionally substituted with one or more R 10 .
15. The compound of claim 14 , wherein R 5 is selected from
each optionally substituted with one or more R 10 .
16. The compound of claim 1 , wherein R 2 is —NR 6 R 7 .
17. The compound of claim 16 , wherein each R 6 and R 7 is independently selected from hydrogen, C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , or —C(O)OR 5 .
18. The compound of claim 17 , wherein R 6 is hydrogen or C 1-6 alkyl.
19. The compound of claim 17 , wherein R 7 is C 1-6 alkyl.
20. The compound of claim 17 , wherein R 7 is C 6-10 aryl optionally substituted with one or more R 11 .
21. The compound of claim 18 , wherein R 7 is C 7-14 aralkyl optionally substituted with one or more R 11 .
22. The compound of claim 21 , wherein R 7 is benzyl or —(CH 2 ) 2 Ph, each optionally substituted with one or more R 11 .
23. The compound of claim 21 , wherein R 7 is unsubstituted benzyl or unsubstituted —(CH 2 ) 2 Ph.
24. The compound of claim 18 , wherein R 7 is (6 membered heteroaryl)alkyl optionally substituted with one or more R 11 .
25. The compound of claim 16 , wherein R 6 and R 7 together with the nitrogen to which they are attached form a 6-10 membered heterocyclyl optionally substituted with one or more R 10 .
26. The compound of claim 1 , wherein R 10 is C 1-6 alkyl.
27. The compound of claim 1 , wherein two geminal R 10 together are oxo.
28. The compound of claim 1 , wherein each R 11 is independently selected from —CN, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, —O—(CH 2 ) n —C 1-8 alkoxy, or —C(O) NR 12 R 13 .
29. The compound of claim 1 , wherein R 3 is -phenyl optionally substituted with one or more R 9 , and wherein n is 0.
30. The compound of claim 29 , wherein R 9 is selected from hydroxy, halogen, optionally substituted C 1-6 alkyl, —OR 5 , or —NR 14 R 15 .
31. The compound of claim 30 , wherein R 5 is selected from hydrogen, C 1-6 alkyl, halo substituted C 1-6 alkyl, or C 2-8 alkoxyalkyl.
32. The compound of claim 29 , wherein R 3 is unsubstituted.
33. The compound of claim 1 , wherein Z is oxygen.
34. The compound of claim 1 , wherein the bonds represented by a solid and dashed line are double bonds.
35. The compound of claim 1 , wherein the compound is selected from the group consisting of Compounds 120-162, 402-414, 523-535, 537-540, 542-545, 550, 664 and 696-707:
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
402
403
404
405
406
407
408
409
410
411
412
413
414
523
524
525
526
527
528
529
530
531
532
533
534
535
537
538
539
540
542
543
544
545
550
664
696
697
698
699
700
701
702
703
704
705
706
707
or pharmaceutically acceptable salts thereof.
36. A compound selected from the group consisting of Compounds 1-28, 64-84, 217-240, 244, 247, 253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434, 438-440, 442, 446-512, 513-522, 546-549, 558, 570 575, 585, 609, 610, 627, 628, 630, 632, 633, 639, 641, 656, 666-668, 708 and 709:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
244
247
253
256
257
262
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
285
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
431
433
434
438
439
440
442
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
546
547
548
549
558
570
571
572
573
574
575
585
609
610
627
628
630
632
633
639
641
656
666
667
668
708
709
or pharmaceutically acceptable salts thereof.
37. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.