Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, ester, stereoisomer, tautomer, solvate, hydrate, or combination thereof: which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).
1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:
wherein
is selected from
X 1 , X 2 and X 3 are each independently selected from N and C(R 5 );
R 3 , R 4 and R 5 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) NO 2 ;
4) Cyano;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted —C 3 -C 8 cycloalkyl;
7) Optionally substituted 3- to 8-membered heterocycloalkyl; and
8) Optionally substituted —C 1 -C 8 alkoxyl;
R is
R 1 is selected from the group consisting of:
R 2 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) Cyano;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted —C 2 -C 8 alkenyl;
7) Optionally substituted —C 2 -C 8 alkynyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted aryl;
10) Optionally substituted arylalkyl;
11) Optionally substituted 3- to 8-membered heterocycloalkyl;
12) Optionally substituted heteroaryl;
13) Optionally substituted heteroarylalkyl;
14) —N(R 6 )(R 7 );
15) —S(O) 2 N(R 6 )(R 7 );
16) —N(R 6 )C(O)(R 7 ); and
17) —N(R 6 )S(O) 2 (R 7 );
wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 15 alkyl; cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)—NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl; alternatively, R 7 and R 6 are taken together with the nitrogen atom to which they are attached to form a heterocyclic.
2. The compound of claim 1 , wherein R 2 is selected from the following:
wherein each of the above groups is optionally substituted.
3. The compound of claim 1 , wherein R 3 is selected from the following:
wherein each of the above groups is optionally substituted.
4. The compound of claim 1 , which is selected from compounds of Formula (IIa-1) or (IIb-1), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , and X 1 are as defined in claim 1 .
5. A compound selected from compounds of Formula (IVa-1) or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are delineated for each compound in Table 1,
TABLE 1
Entry
R 1
R 2
1
Me
2
Me
3
Me
4
Me
5
Me
6
Me
7
Me
8
Me
9
Me
10
Me
11
CF 3
12
CF 3
13
CF 3
14
CF 3
15
CF 3
16
CF 3
17
CF 3
18
CF 3
19
CF 3
20
CF 3
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
6. A compound selected from compounds of Formula (IVb-1), or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are delineated for each compound in Table 2,
TABLE 2
Entry
R 1
R 2
101
Me
102
Me
103
Me
104
Me
105
Me
106
Me
107
Me
108
Me
109
Me
110
Me
111
CF 3
112
CF 3
113
CF 3
114
CF 3
115
CF 3
116
CF 3
117
CF 3
118
CF 3
119
CF 3
120
CF 3
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
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
7. The compound of claim 1 , which is selected from compounds of Formula (Va-1), or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are delineated for each compound in Table 3,
TABLE 3
Entry
R 1
R 2
201
Me
202
Me
203
Me
204
Me
205
Me
206
Me
209
Me
210
Me
211
CF 3
212
CF 3
213
CF 3
214
CF 3
215
CF 3
216
CF 3
219
CF 3
220
CF 3
221
222
223
224
225
226
229
230
231
232
233
234
235
236
239
240
241
242
243
244
245
246
249
250
251
252
253
254
255
256
259
260
261
262
263
264
265
266
269
270
271
272
273
274
275
276
279
280
281
282
283
284
285
286
289
290
291
292
293
294
295
296
299
300
8. A compound selected from compounds of Formula (Vb-1), or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are delineated for each compound in Table 4,
TABLE 4
Compound
R 1
R 2
301
Me
302
Me
303
Me
304
Me
305
Me
306
Me
307
Me
308
Me
309
Me
310
Me
311
CF 3
312
CF 3
313
CF 3
314
CF 3
315
CF 3
316
CF 3
317
CF 3
318
CF 3
319
CF 3
320
CF 3
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
151
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
392
393
394
395
396
397
398
399
400
9. A compound selected from compounds of Formula (VIa-1), (VIa-2), (VIa-3), and (VIa-4), or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are delineated for each compound in Table 5,
TABLE 5
Entry
R 1
R 2
401
Me
402
Me
403
Me
404
Me
405
Me
406
Me
407
Me
408
Me
409
Me
410
Me
411
CF 3
412
CF 3
413
CF 3
414
CF 3
415
CF 3
416
CF 3
417
CF 3
418
CF 3
419
CF 3
420
421
422
423
424
425
426
427
428
429
430
430
432
433
434
435
436
437
438
439
440
441
442
443
444
445
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
10. A compound selected from compounds of Formula (VIb-1), (VIb-2), (VIb-3), and (VIb-4), or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are delineated for each compound in Table 6,
TABLE 6
Entry
R 1
R 2
501
Me
502
Me
503
Me
504
Me
505
Me
506
Me
507
Me
508
Me
509
Me
510
Me
511
CF 3
512
CF 3
513
CF 3
514
CF 3
515
CF 3
516
CF 3
517
CF 3
518
CF 3
519
CF 3
520
CF 3
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
11. A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
Structure
3a
4a
5a
6a
7a
8a
10a
11a
12a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
28a
30a
32a
33a
34a
35a
36a
40a
41a
42a
43a
44a
45a
46a
47a
49a
51a
53a
55a
58a
60a
61a
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
13. A method for treating an ASK-1 mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
14. The method according to claim 13 , wherein the ASK-1 mediated disease or condition is selected from the group consisting of an autoimmune disorder, a neurodegenerative disorder, an inflammatory disease, chronic kidney disease, renal disease, cardiovascular disease, a metabolic disease, or an acute or chronic liver disease.
15. The method according to claim 14 , wherein the disease or condition is selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, alpha 1-antitrypsin deficiency, diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, kidney fibrosis, polycystic kidney disease polycystic kidney disease, pyelonephritis, kidney fibrosis, glomerulonephritis, atherosclerosis, arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy, respiratory diseases, heart attacks, myocardial ischemia, insulin resistance, Type I and Type II diabetes, and obesity.
16. A method for treating a disease selected from the group consisting of glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, multiple sclerosis, or Sjoegren's syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
17. A method for treating a disease selected from the group consisting of ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, congestive heart failure, pathologic immune responses, and thrombin-induced platelet aggregation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
18. A method for treating a disease selected from the group consisting of osteoporosis, osteoarthritis, multiple myeloma-related bone disorder, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's disease, polyglutamine diseases, traumatic brain injury, ischemic and hemorrhaging stroke, cerebral ischemias or neurodegenerative disease, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .