Isoxazole derivatives as FXR agonists and methods of use thereof
The present invention provides compounds of Formula I: pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated as FXR modulators. Specifically, the present invention relates to isoxazole derivatives useful as agonists for FXR, and methods for their preparation and use.
1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof:
wherein,
R 1 is hydrogen, halogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;
R 2 is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted C 3 -C 8 cycloalkyl;
is selected from the group consisting of
wherein the hydrogen at the 1-position is absent when N-attached,
n is 0 or 1;
is phenyl or a 5- or 6-membered heterocyclic or heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein said phenyl, heterocycle or heteroaryl is optionally substituted with one or two substituents independently selected from substituted or unsubstituted —C 1 -C 8 alkyl, halo, and haloalkyl,
R 3 is:
R 4 and R 5 are independently 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; and
5) Optionally substituted —C 3 -C 8 cycloalkyl;
R 6 is selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted aryl;
6) Optionally substituted arylalkyl;
7) Optionally substituted heterocycloalkyl;
8) Optionally substituted heteroaryl;
9) Optionally substituted heteroarylalkyl; and
10) NR 7 R 8 ; wherein, R 7 and R 8 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl, or R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring.
2. The compound of claim 1 , wherein R 2 is selected from the group consisting of:
3. The compound of claim 1 , represented by Formula (II) or (III), or a pharmaceutically acceptable salt thereof:
wherein, R 1 , R 2 ,
n,
and R 6 are as defined in claim 1 .
4. The compound of claim 1 , represented by Formula (IV) or (V), or a pharmaceutically acceptable salt thereof:
wherein, R 2 ,
n,
and R 6 are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula (VI) or (VII), or a pharmaceutically acceptable salt thereof:
wherein,
n,
and R 6 are as defined in claim 1 .
6. The compound of claim 1 , represented by Formula (VIII) or (IX), or a pharmaceutically acceptable salt thereof:
wherein,
n, and R 6 are as defined in claim 1 .
7. The compound of claim 1 , represented by one of Formulas (X) to (XV), or a pharmaceutically acceptable salt thereof:
wherein, R 6 is as defined in claim 1 , and the —NHC(O)NHS(O) 2 R 6 group in Formula (X), Formula (XII), and Formula (XIV), or the —C(O)NHS(O) 2 R 6 group in Formula (XI), Formula (XIII), and Formula (XV) is attached to phenyl at position 1, 2 or 3.
8. The compound of claim 1 , which is selected from:
(a) compounds of Formula (X)
wherein R 6 and the substitution position for the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 1,
TABLE 1
Compound
R 6
position
1
Methyl
1
2
Ethyl
1
3
Isopropyl
1
4
Butyl
1
5
t-Butyl
1
6
Propyl
1
7
Benzyl
1
8
Vinyl
1
9
Allyl
1
10
—CF 3
1
11
1
12
1
13
1
14
1
15
1
16
1
17
1
18
1
19
1
20
1
21
1
22
1
23
1
24
—NH 2
1
25
—NHCH 3
1
26
—N(CH 3 ) 2
1
27
1
28
1
29
1
30
Methyl
2
31
Ethyl
2
32
Isopropyl
2
33
Butyl
2
34
t-Butyl
2
35
Propyl
2
36
Benzyl
2
37
Vinyl
2
38
Allyl
2
39
—CF 3
2
40
2
41
2
42
2
43
2
44
2
45
2
46
2
47
2
48
2
49
2
50
2
51
2
52
2
53
—NH 2
2
54
—NHCH 3
2
55
—N(CH 3 ) 2
2
56
2
57
2
58
2
59
Methyl
3
60
Ethyl
3
61
Isopropyl
3
62
Butyl
3
63
t-Butyl
3
64
Propyl
3
65
Benzyl
3
66
Vinyl
3
67
Allyl
3
68
—CF 3
3
69
3
70
3
71
3
72
3
73
3
74
3
75
3
76
3
77
3
78
3
79
3
80
3
81
3
82
—NH 2
3
83
—NHCH 3
3
84
—N(CH 3 ) 2
3
85
3
86
3
87
3
and
(b) compounds according to Formula (XI),
wherein R 6 and the substitution position for the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 2,
TABLE 2
Compound
R 6
position
88
Methyl
1
89
Ethyl
1
90
Isopropyl
1
91
Butyl
1
92
t-Butyl
1
93
Propyl
1
94
Benzyl
1
95
Vinyl
1
96
Allyl
1
97
—CF 3
1
98
1
99
1
100
1
101
1
102
1
103
1
104
1
105
1
106
1
107
1
108
1
109
1
110
1
111
—NH 2
1
112
—NHCH 3
1
113
—N(CH 3 ) 2
1
114
1
115
1
116
1
117
Methyl
2
118
Ethyl
2
119
Isopropyl
2
120
Butyl
2
121
t-Butyl
2
122
Propyl
2
123
Benzyl
2
124
Vinyl
2
125
Allyl
2
126
—CF 3
2
127
2
128
2
129
2
130
2
131
2
132
2
133
2
134
2
135
2
136
2
137
2
138
2
139
2
140
—NH 2
2
141
—NHCH 3
2
142
—N(CH 3 ) 2
2
143
2
144
2
145
2
146
Methyl
3
147
Ethyl
3
148
Isopropyl
3
149
Butyl
3
150
t-Butyl
3
151
Propyl
3
152
Benzyl
3
153
Vinyl
3
154
Allyl
3
155
—CF 3
3
156
3
157
3
158
3
159
3
160
3
161
3
162
3
163
3
164
3
165
3
166
3
167
3
168
3
169
—NH 2
3
170
—NHCH 3
3
171
—N(CH 3 ) 2
3
172
3
173
3
174
3
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , which is selected from:
(a) compounds of Formula XII,
wherein R 6 and the substitution position for the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 3,
TABLE 3
Compound
R 6
position
175
Methyl
1
176
Ethyl
1
177
Isopropyl
1
178
Butyl
1
179
t-Butyl
1
180
Propyl
1
181
Benzyl
1
182
Vinyl
1
183
Allyl
1
184
—CF 3
1
185
1
186
1
187
1
188
1
189
1
190
1
191
1
192
1
193
1
194
1
195
1
196
1
197
1
198
—NH 2
1
199
—NHCH 3
1
200
—N(CH 3 ) 2
1
201
1
202
1
203
1
204
Methyl
2
205
Ethyl
2
206
Isopropyl
2
207
Butyl
2
208
t-Butyl
2
209
Propyl
2
210
Benzyl
2
211
Vinyl
2
212
Allyl
2
213
—CF 3
2
214
2
215
2
216
2
217
2
218
2
219
2
220
2
221
2
222
2
223
2
224
2
225
2
226
2
227
—NH 2
2
228
—NHCH 3
2
229
—N(CH 3 ) 2
2
230
2
231
2
232
2
233
Methyl
3
234
Ethyl
3
235
Isopropyl
3
236
Butyl
3
237
t-Butyl
3
238
Propyl
3
239
Benzyl
3
240
Vinyl
3
241
Allyl
3
244
—CF 3
3
245
3
246
3
247
3
248
3
249
3
250
3
251
3
252
3
253
3
254
3
255
3
256
3
257
3
258
—NH 2
3
259
—NHCH 3
3
260
—N(CH 3 ) 2
3
261
3
262
3
263
3
and
(b) compounds according to Formula XIII,
wherein R 6 and the substitution position for the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 4,
TABLE 4
Compound
R 6
position
264
Methyl
1
265
Ethyl
1
266
Isopropyl
1
267
Butyl
1
268
t-Butyl
1
269
Propyl
1
270
Benzyl
1
271
Vinyl
1
272
Allyl
1
273
—CF 3
1
274
1
275
1
276
1
277
1
278
1
279
1
280
1
281
1
282
1
283
1
284
1
285
1
286
1
287
—NH 2
1
288
—NHCH 3
1
289
—N(CH 3 ) 2
1
290
1
291
1
292
1
293
Methyl
2
294
Ethyl
2
295
Isopropyl
2
296
Butyl
2
297
t-Butyl
2
298
Propyl
2
299
Benzyl
2
300
Vinyl
2
301
Allyl
2
302
—CF 3
2
303
2
304
2
305
2
306
2
307
2
308
2
309
2
310
2
311
2
312
2
313
2
314
2
315
2
316
—NH 2
2
317
—NHCH 3
2
318
—N(CH 3 ) 2
2
319
2
320
2
321
2
322
Methyl
3
323
Ethyl
3
324
Isopropyl
3
325
Butyl
3
326
t-Butyl
3
327
Propyl
3
328
Benzyl
3
329
Vinyl
3
330
Allyl
3
331
—CF 3
3
332
3
333
3
334
3
335
3
336
3
337
3
338
3
339
3
340
3
341
3
342
3
343
3
344
3
345
—NH 2
3
346
—NHCH 3
3
347
—N(CH 3 ) 2
3
348
3
349
3
350
3
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , which is selected from:
(a) compounds of Formula (XIV),
wherein R 6 and the substitution position for the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 5,
TABLE 5
Compound
R 6
position
351
Methyl
1
352
Ethyl
1
353
Isopropyl
1
354
Butyl
1
355
t-Butyl
1
356
Propyl
1
357
Benzyl
1
358
Vinyl
1
359
Allyl
1
360
—CF 3
1
361
1
362
1
363
1
364
1
365
1
366
1
367
1
368
1
369
1
370
1
371
1
372
1
373
1
374
—NH 2
1
375
—NHCH 3
1
376
—N(CH 3 ) 2
1
377
1
378
1
379
1
380
Methyl
2
381
Ethyl
2
382
Isopropyl
2
383
Butyl
2
384
t-Butyl
2
385
Propyl
2
386
Benzyl
2
387
Vinyl
2
388
Allyl
2
389
—CF 3
2
390
2
391
2
392
2
393
2
394
2
395
2
396
2
397
2
398
2
399
2
400
2
401
2
402
2
403
—NH 2
2
404
—NHCH 3
2
405
—N(CH 3 ) 2
2
406
2
407
2
408
2
409
Methyl
3
410
Ethyl
3
411
Isopropyl
3
412
Butyl
3
413
t-Butyl
3
414
Propyl
3
415
Benzyl
3
416
Vinyl
3
417
Allyl
3
418
—CF 3
3
419
3
420
3
421
3
422
3
423
3
424
3
425
3
426
3
427
3
428
3
429
3
430
3
431
3
432
—NH 2
3
433
—NHCH 3
3
434
—N(CH 3 ) 2
3
435
3
436
3
437
3
and
compounds according to Formula XV,
wherein R 6 and the substitution position for the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 6,
TABLE 6
Compound
R 6
position
438
Methyl
1
439
Ethyl
1
440
Isopropyl
1
441
Butyl
1
442
t-Butyl
1
443
Propyl
1
444
Benzyl
1
445
Vinyl
1
446
Allyl
1
447
—CF 3
1
448
1
449
1
450
1
451
1
452
1
453
1
454
1
456
1
457
1
458
1
459
1
460
1
461
1
462
—NH 2
1
463
—NHCH 3
1
464
—N(CH 3 ) 2
1
465
1
466
1
467
1
468
Methyl
2
469
Ethyl
2
470
Isopropyl
2
471
Butyl
2
472
t-Butyl
2
473
Propyl
2
474
Benzyl
2
475
Vinyl
2
476
Allyl
2
477
—CF 3
2
478
2
479
2
480
2
481
2
482
2
483
2
484
2
485
2
486
2
487
2
488
2
489
2
490
2
491
—NH 2
2
492
—NHCH 3
2
493
—N(CH 3 ) 2
2
494
2
495
2
496
2
497
Methyl
3
498
Ethyl
3
499
Isopropyl
3
500
Butyl
3
501
t-Butyl
3
502
Propyl
3
503
Benzyl
3
504
Vinyl
3
505
Allyl
3
506
—CF 3
3
507
3
508
3
509
3
510
3
511
3
512
3
513
3
514
3
515
3
516
3
517
3
518
3
519
3
520
—NH 2
3
521
—NHCH 3
3
522
—N(CH 3 ) 2
3
523
3
524
3
525
3
or a pharmaceutically acceptable salt thereof.
11. A method for treating disease or condition selected from primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, insulin resistance, Type I and Type II diabetes and obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
12. The method according to claim 11 , wherein the disease or condition is selected from primary biliary cirrhosis and primary sclerosing cholangitis.
13. The method according to claim 11 , wherein the disease or condition is selected from the group consisting of primary biliary cirrhosis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.
14. The method according to claim 11 , wherein the disease or condition is selected from the group consisting of atherosclerosis, hypercholesterolemia, and hypertriglyceridemia.
15. The method according to claim 11 , wherein the disease or condition is selected from the group consisting of Type I diabetes, Type II diabetes, and obesity.
16. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. The method according to claim 11 , wherein the disease or condition is primary biliary cirrhosis.
18. The method according to claim 11 , wherein the disease or condition is nonalcoholic steatohepatitis.
19. The method according to claim 11 , wherein the disease or condition is nonalcoholic fatty liver disease.