Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters 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
X 1 and X 2 are each independently C(R 8 ) or N;
X 3 is C(R 9 ) or N, wherein R 9 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy and halo;
R 1 is selected from
R 4 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;
R 2 , R 5 and R 8 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) Cyano;
5) Substituted or unsubstituted —C 1 -C 8 alkyl;
6) Substituted or unsubstituted —C 2 -C 8 alkenyl;
7) Substituted or unsubstituted —C 2 -C 8 alkynyl;
8) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
9) Substituted or unsubstituted aryl;
10) Substituted or unsubstituted arylalkyl;
11) Substituted or unsubstituted heterocycloalkyl;
12) Substituted or unsubstituted heteroaryl;
13) Substituted or unsubstituted 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 6 ;
R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, —C 1 -C 8 alkenyl, —C 1 -C 8 alkynyl, —C 3 -C 8 cycloalkyl, —C 3 -C 8 cycloalkyl-alkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, wherein the —C 1 -C 8 alkyl, —C 1 -C 8 alkenyl, —C 1 -C 8 alkynyl, —C 3 -C 8 cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, —C 3 -C 8 cycloalkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl; or R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
R 3 is selected from the group consisting of:
1) Hydrogen
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl;
10) Substituted or unsubstituted heteroarylalkyl;
11) —C(O)R 6 ;
12) —C(O)OR 6 ;
13) —C(O)N(R 6 )(R 7 ); and
14) —SO 2 R 6 ;
R 10 and R 11 are each independently selected from the group consisting of hydrogen, hydroxyl, and optionally substituted —C 1 -C 8 alkyl; or alternatively, R 10 and R 11 are taken together with the carbon atom to which they are attached to form C(O), spiro-C 3 -C 8 cycloalkyl, or spiro-3- to 8-membered heterocycloalkyl;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, halo, and optionally substituted —C 1 -C 8 alkyl; and
n is 0, 1 or 2.
2. The compound of claim 1 , represented by Formula II, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , X 2 , X 3 and n are as defined in claim.
3. The compound of claim 1 , represented by Formula III, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
4. The compound of claim 1 , represented by Formula IV, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 3 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula V, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
6. The compound of claim 1 , represented by Formula VI, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
7. The compound of claim 1 , represented by Formula VII, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
8. The compound of claim 1 , which is selected from compounds of Formula VIII, or a pharmaceutically acceptable salt thereof:
wherein X 3 , R 3 , and n are delineated for each compound in Table 1:
TABLE 1
Compound
R 3
X 3
n
1
H
C—H
0
2
Methyl
C—H
0
3
Ethyl
C—H
0
4
Propyl
C—H
0
5
Allyl
C—H
0
6
i-Propyl
C—H
0
7
C—H
0
8
i-Butyl
C—H
0
9
t-Butyl
C—H
0
10
C—H
0
11
C—H
0
12
C—H
0
13
C—H
0
14
C—H
0
15
C—H
0
16
C—H
0
17
C—H
0
18
C—H
0
19
C—H
0
20
C—H
0
21
C—H
0
22
C—H
0
23
C—H
0
24
C—H
0
25
C—H
0
26
C—H
0
27
C—H
0
28
C—H
0
29
C—H
0
30
C—H
0
31
C—H
0
32
C—H
0
33
C—H
0
34
C—H
0
35
C—H
0
36
C—H
0
37
C—H
0
38
C—H
0
39
C—H
0
40
C—H
0
41
C—H
0
42
C—H
0
43
C—H
0
44
C—H
0
45
C—H
0
46
C—H
0
47
C—H
0
48
C—H
0
49
C—H
0
50
C—H
0
51
H
C—F
0
52
Methyl
C—F
0
53
Ethyl
C—F
0
54
Propyl
C—F
0
55
Allyl
C—F
0
56
i-Propyl
C—F
0
57
C—F
0
58
i-Butyl
C—F
0
59
t-Butyl
C—F
0
60
C—F
0
61
C—F
0
62
C—F
0
63
C—F
0
64
C—F
0
65
C—F
0
66
C—F
0
67
C—F
0
68
C—F
0
69
C—F
0
70
C—F
0
71
C—F
0
72
C—F
0
73
C—F
0
74
C—F
0
75
C—F
0
76
C—F
0
77
C—F
0
78
C—F
0
79
C—F
0
80
C—F
0
81
C—F
0
82
C—F
0
83
C—F
0
84
C—F
0
85
C—F
0
86
C—F
0
87
C—F
0
88
C—F
0
89
C—F
0
90
C—F
0
91
C—F
0
92
C—F
0
93
C—F
0
94
C—F
0
95
C—F
0
96
C—F
0
97
C—F
0
98
C—F
0
99
C—F
0
100
C—F
0
101
H
N
0
102
Methyl
N
0
103
Ethyl
N
0
104
Propyl
N
0
105
Allyl
N
0
106
i-Propyl
N
0
107
N
0
108
i-Butyl
N
0
109
t-Butyl
N
0
110
N
0
111
N
0
112
N
0
113
N
0
114
N
0
115
N
0
116
N
0
117
N
0
118
N
0
119
N
0
120
N
0
121
N
0
122
N
0
123
N
0
124
N
0
125
N
0
126
N
0
127
N
0
128
N
0
129
N
0
130
N
0
131
N
0
132
N
0
133
N
0
134
N
0
135
N
0
136
N
0
137
N
0
138
N
0
139
N
0
140
N
0
141
N
0
142
N
0
143
N
0
144
N
0
145
N
0
146
N
0
147
N
0
148
N
0
149
N
0
150
N
0
151
H
C—H
1
152
Methyl
C—H
1
153
Ethyl
C—H
1
154
Propyl
C—H
1
155
Allyl
C—H
1
156
i-Propyl
C—H
1
157
C—H
1
158
i-Butyl
C—H
1
159
t-Butyl
C—H
1
160
C—H
1
161
C—H
1
162
C—H
1
163
C—H
1
164
C—H
1
165
C—H
1
166
C—H
1
167
C—H
1
168
C—H
1
169
C—H
1
170
C—H
1
171
C—H
1
172
C—H
1
173
C—H
1
174
C—H
1
175
C—H
1
176
C—H
1
177
C—H
1
178
C—H
1
179
C—H
1
180
C—H
1
181
C—H
1
182
C—H
1
183
C—H
1
184
C—H
1
185
C—H
1
186
C—H
1
187
C—H
1
188
C—H
1
189
C—H
1
190
C—H
1
191
C—H
1
192
C—H
1
193
C—H
1
194
C—H
1
195
C—H
1
196
C—H
1
197
C—H
1
198
C—H
1
199
C—H
1
200
C—H
1
201
H
C—F
1
202
Methyl
C—F
1
203
Ethyl
C—F
1
204
Propyl
C—F
1
205
Allyl
C—F
1
206
i-Propyl
C—F
1
207
C—F
1
208
i-Butyl
C—F
1
209
t-Butyl
C—F
1
210
C—F
1
211
C—F
1
212
C—F
1
213
C—F
1
214
C—F
1
215
C—F
1
216
C—F
1
217
C—F
1
218
C—F
1
219
C—F
1
220
C—F
1
221
C—F
1
222
C—F
1
223
C—F
1
224
C—F
1
225
C—F
1
226
C—F
1
227
C—F
1
228
C—F
1
229
C—F
1
230
C—F
1
231
C—F
1
232
C—F
1
233
C—F
1
234
C—F
1
235
C—F
1
236
C—F
1
237
C—F
1
238
C—F
1
239
C—F
1
240
C—F
1
241
C—F
1
242
C—F
1
243
C—F
1
244
C—F
1
245
C—F
1
246
C—F
1
247
C—F
1
248
C—F
1
249
C—F
1
250
C—F
1
251
H
N
1
252
Methyl
N
1
253
Ethyl
N
1
254
Propyl
N
1
255
Allyl
N
1
256
i-Propyl
N
1
257
N
1
258
i-Butyl
N
1
259
t-Butyl
N
1
260
N
1
261
N
1
262
N
1
263
N
1
264
N
1
265
N
1
266
N
1
267
N
1
268
N
1
269
N
1
270
N
1
271
N
1
272
N
1
273
N
1
274
N
1
275
N
1
276
N
1
277
N
1
278
N
1
279
N
1
280
N
1
281
N
1
282
N
1
283
N
1
284
N
1
285
N
1
286
N
1
287
N
1
288
N
1
289
N
1
290
N
1
291
N
1
292
N
1
293
N
1
294
N
1
295
N
1
296
N
1
297
N
1
298
N
1
299
N
1
300
N
1 .
9. The compound of claim 1 , represented by Formula IX, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
10. The compound of claim 1 , represented by Formula X, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
11. The compound of claim 1 , which is selected from compounds of Formula XI, or a pharmaceutically acceptable salt thereof:
wherein X 3 , R 3 , and n are delineated for each compound in Table 2:
TABLE 2
Compound
R 3
X 3
n
301
H
C—H
0
302
Methyl
C—H
0
303
Ethyl
C—H
0
304
Propyl
C—H
0
305
Allyl
C—H
0
306
i-Propyl
C—H
0
307
C—H
0
308
i-Butyl
C—H
0
309
t-Butyl
C—H
0
310
C—H
0
311
C—H
0
312
C—H
0
313
C—H
0
314
C—H
0
315
C—H
0
316
C—H
0
317
C—H
0
318
C—H
0
319
C—H
0
320
C—H
0
321
C—H
0
322
C—H
0
323
C—H
0
324
C—H
0
325
C—H
0
326
C—H
0
327
C—H
0
328
C—H
0
329
C—H
0
330
C—H
0
331
C—H
0
332
C—H
0
333
C—H
0
334
C—H
0
335
C—H
0
336
C—H
0
337
C—H
0
338
C—H
0
339
C—H
0
340
C—H
0
341
C—H
0
342
C—H
0
343
C—H
0
344
C—H
0
345
C—H
0
346
C—H
0
347
C—H
0
348
C—H
0
349
C—H
0
350
C—H
0
351
H
C—F
0
352
Methyl
C—F
0
353
Ethyl
C—F
0
354
Propyl
C—F
0
355
Allyl
C—F
0
356
i-Propyl
C—F
0
357
C—F
0
358
i-Butyl
C—F
0
359
t-Butyl
C—F
0
360
C—F
0
361
C—F
0
362
C—F
0
363
C—F
0
364
C—F
0
365
C—F
0
366
C—F
0
367
C—F
0
368
C—F
0
369
C—F
0
370
C—F
0
371
C—F
0
372
C—F
0
373
C—F
0
374
C—F
0
375
C—F
0
376
C—F
0
377
C—F
0
378
C—F
0
379
C—F
0
380
C—F
0
381
C—F
0
382
C—F
0
383
C—F
0
384
C—F
0
385
C—F
0
386
C—F
0
387
C—F
0
388
C—F
0
389
C—F
0
390
C—F
0
391
C—F
0
392
C—F
0
393
C—F
0
394
C—F
0
395
C—F
0
396
C—F
0
397
C—F
0
398
C—F
0
399
C—F
0
400
C—F
0
401
H
N
0
402
Methyl
N
0
403
Ethyl
N
0
404
Propyl
N
0
405
Allyl
N
0
406
i-Propyl
N
0
407
N
0
408
i-Butyl
N
0
409
t-Butyl
N
0
410
N
0
411
N
0
412
N
0
413
N
0
414
N
0
415
N
0
416
N
0
417
N
0
418
N
0
419
N
0
420
N
0
421
N
0
422
N
0
423
N
0
424
N
0
425
N
0
426
N
0
427
N
0
428
N
0
429
N
0
430
N
0
431
N
0
432
N
0
433
N
0
434
N
0
435
N
0
436
N
0
437
N
0
438
N
0
439
N
0
440
N
0
441
N
0
442
N
0
443
N
0
444
N
0
445
N
0
446
N
0
447
N
0
448
N
0
449
N
0
450
N
0
451
H
C—H
1
452
Methyl
C—H
1
453
Ethyl
C—H
1
454
Propyl
C—H
1
455
Allyl
C—H
1
456
i-Propyl
C—H
1
457
C—H
1
458
i-Butyl
C—H
1
459
t-Butyl
C—H
1
460
C—H
1
461
C—H
1
462
C—H
1
463
C—H
1
464
C—H
1
465
C—H
1
466
C—H
1
467
C—H
1
468
C—H
1
469
C—H
1
470
C—H
1
471
C—H
1
472
C—H
1
473
C—H
1
474
C—H
1
475
C—H
1
476
C—H
1
477
C—H
1
478
C—H
1
479
C—H
1
480
C—H
1
481
C—H
1
482
C—H
1
483
C—H
1
484
C—H
1
485
C—H
1
486
C—H
1
487
C—H
1
488
C—H
1
489
C—H
1
490
C—H
1
491
C—H
1
492
C—H
1
493
C—H
1
494
C—H
1
495
C—H
1
496
C—H
1
497
C—H
1
498
C—H
1
499
C—H
1
500
C—H
1
501
H
C—F
1
502
Methyl
C—F
1
503
Ethyl
C—F
1
504
Propyl
C—F
1
505
Allyl
C—F
1
506
i-Propyl
C—F
1
507
C—F
1
508
i-Butyl
C—F
1
509
t-Butyl
C—F
1
510
C—F
1
511
C—F
1
512
C—F
1
513
C—F
1
514
C—F
1
515
C—F
1
516
C—F
1
517
C—F
1
518
C—F
1
519
C—F
1
520
C—F
1
521
C—F
1
522
C—F
1
523
C—F
1
524
C—F
1
525
C—F
1
526
C—F
1
527
C—F
1
528
C—F
1
529
C—F
1
530
C—F
1
531
C—F
1
532
C—F
1
533
C—F
1
534
C—F
1
535
C—F
1
536
C—F
1
537
C—F
1
538
C—F
1
539
C—F
1
540
C—F
1
541
C—F
1
542
C—F
1
543
C—F
1
544
C—F
1
545
C—F
1
546
C—F
1
547
C—F
1
548
C—F
1
549
C—F
1
550
C—F
1
551
H
N
1
552
Methyl
N
1
553
Ethyl
N
1
554
Propyl
N
1
555
Allyl
N
1
556
i-Propyl
N
1
557
N
1
558
i-Butyl
N
1
559
t-Butyl
N
1
560
N
1
561
N
1
562
N
1
563
N
1
564
N
1
565
N
1
566
N
1
567
N
1
568
N
1
569
N
1
570
N
1
571
N
1
572
N
1
573
N
1
574
N
1
575
N
1
576
N
1
577
N
1
578
N
1
579
N
1
580
N
1
581
N
1
582
N
1
583
N
1
584
N
1
585
N
1
586
N
1
587
N
1
588
N
1
589
N
1
590
N
1
591
N
1
592
N
1
593
N
1
594
N
1
595
N
1
596
N
1
597
N
1
598
N
1
599
N
1
600
N
1 .
12. The compound of claim 1 , represented by Formula XII-a or Formula XII-b, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 10 , R 11 , R 12 , R 13 , X 3 and n are as defined in claim 1 .
13. The compound of claim 1 , represented by Formula XIII-a, Formula XIII-b, Formula XIV-a, Formula XIV-b, Formula XV-a, or Formula XV-b, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , and X 3 are as defined in claim 1 .
14. The compound of claim 1 , selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof:
Compound
Structure
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
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
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
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
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
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
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
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
183a
15. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable excipient or carrier.
16. A method for the treatment of 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 .
17. 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, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, multiple sclerosis, Sjoegren's syndrome, stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, congestive heart failure, pathologic immune responses, thrombin-induced platelet aggregation, 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 .
18. The method according to claim 16 , wherein the ASK-1 mediated disease is selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis, bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, 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, and alpha 1-antitrypsin deficiency.
19. The method according to claim 18 , wherein the ASK-1 mediated disease is selected from the group consisting of primary biliary cirrhosis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.
20. The method according to claim 16 , wherein the ASK-1 mediated disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis, hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, polycystic kidney disease, atherosclerosis, arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy, respiratory diseases, heart attacks, myocardial ischemia, insulin resistance, Type I and Type II diabetes, obesity, polycystic kidney disease, pyelonephritis, kidney fibrosis and glomerulonephritis.