Cycloalkyl-containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts 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
R 1 is selected from the following:
wherein R 4 is selected from the group consisting of:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl;
5) Optionally substituted —C 3 -C 8 cycloalkyl;
6) Optionally substituted aryl;
7) Optionally substituted arylalkyl;
8) Optionally substituted heterocycloalkyl;
9) Optionally substituted heteroaryl; and
10) Optionally substituted heteroarylalkyl;
is selected from
wherein
X 2 and X 3 are each independently selected from N or C(R 5 );
R 5 and R 6 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; and
7) Optionally substituted 3- to 8-membered heterocycloalkyl;
X 1 is N or C(R 11 ), R 11 is hydrogen, halogen or optionally substituted alkoxy;
is selected from —C 3 -C 8 cycloalkyl and —C 4 -C 8 cycloalkenyl, each of which, is optionally substituted with one or more substituents, which are not R 3 ;
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 7 )(R 8 );
15) —S(O) 2 N(R 7 )(R 8 );
16) —N(R 7 )C(O)(R 8 ); and
17) —N(R 7 )S(O)2(R 8 );
R 3 is selected from the group consisting of:
1) —NO 2 ;
2) Cyano;
3) —N(R 7 )(R 8 );
4) —N(R 9 )C(O)N(R 7 )(R 8 );
5) —N(R 7 )C(O)(R 8 );
6) —N(R 7 )C(O) 2 (R 8 );
7) —N(R 9 )S(O) 2 N(R 7 )(R 8 );
8) —N(R 7 )S(O) 2 (R 8 );
9) —C(O) 2 (R 7 );
10) —C(O)N(R 7 )(R 8 );
11) —C(O)N(R 7 )S(O) 2 (R 8 );
12) —CH 2 (O)C(O) 2 (R 7 );
13) —CH 2 (O)C(O)N(R 7 )(R 8 );
14) Optionally substituted —C 1 -C 8 alkyl;
15) Optionally substituted —C 2 -C 8 alkenyl;
16) Optionally substituted —C 2 -C 8 alkynyl;
17) Optionally substituted —C 3 -C 8 cycloalkyl;
18) Optionally substituted aryl;
19) Optionally substituted arylalkyl;
20) Optionally substituted 3- to 8-membered heterocycloalkyl;
21) Optionally substituted heteroaryl; and
22) Optionally substituted heteroarylalkyl;
wherein R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, —CN, alkoxy, —CF 3 , aryl, and heteroaryl;
alternatively, R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a heterocyclic.
2. The compound of claim 1 , wherein
s selected from the following:
wherein each of the above shown groups is optionally substituted.
3. The compound of claim 1 , which is represented by Formula (VIIa), (VIIb), or (VIIc), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , and X 1 are as defined in claim 1 .
4. The compound of claim 1 , which is represented by Formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 ,
and X 1 are as defined in claim 1 .
5. The compound of claim 1 , which is represented by Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt thereof:
wherein R 2 , R 3 , R 4 , and X 1 are as defined in claim 1 .
6. The compound of claim 1 , which represented by Formula (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are as defined in claim 1 .
7. The compound of claim 1 , which is selected from compounds of Formula (IIIa) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are delineated for each compound in Table 1,
TABLE 1
com-
pound
R 3
R 4
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
8. The compound of claim 1 , which is selected from compounds of Formula (IIIb) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are delineated for each compound in table 2,
TABLE 2
com-
pound
R 3
R 4
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
9. The compound of claim 1 , which is selected from compounds of Formula (IVa) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are delineated for each compound in Table 3,
TABLE 3
com-
pound
R 3
R 4
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
10. The compound of claim 1 , which is selected from compounds of Formula (IVb) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are delineated for each compound in Table 4,
TABLE 4
com-
pound
R 3
R 4
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
11. The compound of claim 1 , which is selected from compounds of Formula (Va) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are delineated for each compound in Table 5,
TABLE 5
com-
pound
R 3
R 4
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
12. The compound of claim 1 , which is selected from compounds of Formula (Vb) or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 4 are delineated for each compound in Table 6,
TABLE 6
com-
pound
R 3
R 4
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
13. 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
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
15. A method of treating a disease or condition 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, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver transplant associated graft versus host disease, congenital hepatic fibrosis, choledocholithiasis, diabetic nephropathy, focal segmental glomerulosclerosis, hypertensive nephrosclerosis, chronic transplant glomerulopathy, chronic interstitial nephritis, cardiac hypertrophy, heart attack, myocardial ischemia pyelonephritis, kidney fibrosis and glomerulonephritis, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .