Substituted pyridines as apoptosis signal-regulating kinase 1 inhibitors
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:
A is heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl or heteroaryl is optionally substituted;
X 1 is CR 6 ;
X 2 is CR 6 ;
X 3 is CR 7 or N;
R 2 is H, halogen, NO 2 , CN, C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, NR 4 R 5 , NR 4 C(O)R 5 , NR 4 S(O) 2 R 5 , S(O) 2 NR 4 R 5 , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
R 3 is H, C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C(O)R 4 , C(O)NR 4 R 5 , C(O)OR 4 , S(O) 2 R 4 , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
R 4 is H, C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, CF 3 , alkyl, C(O)heterocycloalkyl, NHalkyl, N(alkyl) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, OH, Oalkyl, ═O, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R 5 is H, C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, CF 3 , alkyl, C(O)heterocycloalkyl, NHalkyl, N(alkyl) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, OH, Oalkyl, ═O, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or
R 4 and R 5 , taken together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted;
R 6 is H, halogen, NO 2 , CN, C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, NR 4 R 5 , NR 4 C(O)R 5 , NR 4 S(O) 2 R 5 , S(O) 2 NR 4 R 5 , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 8 alkyl, arylalkyl, heteroarylalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
R 7 is H, halogen, C 1 -C 8 alkyl, or OC 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl or OC 1 -C 8 alkyl is optionally substituted;
R 8 is H, C 1 -C 8 alkyl, or OH, wherein the C 1 -C 8 alkyl is optionally substituted;
R 9 is H, C 1 -C 8 alkyl, or OH, wherein the C 1 -C 8 alkyl is optionally substituted; or
R 8 and R 9 , taken together with the carbon atom to which they are attached, form C(O), a spirocyclic C 3 -C 8 cycloalkyl, or a spirocyclic 3- to 8-membered heterocycloalkyl;
R 10 is H, halogen, or C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl is optionally substituted;
R 11 is H, halogen, or C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl is optionally substituted; and
n is 0, 1, or 2;
wherein each optionally substituted group of A, R 2 , R 3 , the heterocycloalkyl formed by R 4 and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, F, C 1 , Br, I, CN, NO 2 , C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 haloalkenyl, C 2 -C 12 alkynyl, C 2 -C 12 haloalkynyl, NH 2 , NHC(O)OC(CH 3 ) 3 , NHC(O)OCH 2 Ph, NHC(O)OCH 2 -(9-fluorenyl), N 3 , OH, Oalkyl, OCH 2 OCH 3 , OC(O)CH 3 , OC(O)CH 2 Ph, OSi(CH 3 ) 3 , OSi(CH 2 CH 3 ) 3 , Salkyl, and C 3 -C 12 halocycloalkyl.
2. The compound of claim 1 , wherein the compound is represented by Formula II:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is represented by Formula III:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is represented by Formula V:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is represented by Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of:
wherein each of the above shown groups is optionally substituted.
7. The compound of claim 1 , wherein the compound is selected from the compounds set forth in Table 1:
TABLE 1
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
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
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
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound is selected from the compounds set forth in Table 2:
TABLE 2
compound
Structure
97
98
99
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
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
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
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound is selected from the compounds set forth in Table 3:
TABLE 3
compound
Structure
193
194
195
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
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
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
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is selected from the compounds set forth in Table 4:
TABLE 4
compound
Structure
289
290
291
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
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
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
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is selected from the compounds set forth in Table 5:
TABLE 5
compound
Structure
385
386
387
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
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
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the compound is selected from the compounds set forth in Table 6:
TABLE 6
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
19
20
21
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
14. A compound selected from the compounds set forth in the table below:
Compound
Structure
4
36
68
100
132
164
196
228
260
292
324
356
388
420
452
or a pharmaceutically acceptable salt thereof.