Isoxazole analogs 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 optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 3 -C 12 cycloalkyl or optionally substituted 3- to 12-membered heterocycloalkyl;
is selected from the group consisting of:
R 3 is independently selected from group consisting of halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; m is 0, 1, or 2; n is 0, 1, 2, or 3;
Z is selected from the group consisting of:
is phenyl, 3- to 8-membered heterocycloalkyl, or heteroaryl wherein said phenyl, 3- to 8-membered heterocycloalkyl, or heteroaryl is optionally substituted with one or two groups independently selected from OH, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 3 -C 6 cycloalkyl, N(R b )SO 2 C 1 -C 6 alkyl, —C(O)R b , and NHC(O)R b ;
R b is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 3 -C 6 cycloalkenyl;
R 4 is:
R 5 and R 6 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 7 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 12 cycloalkyl;
5) Optionally substituted —C 3 -C 12 cycloalkenyl;
6) Optionally substituted aryl;
7) Optionally substituted arylalkyl;
8) Optionally substituted 3- to 12-membered heterocycloalkyl;
9) Optionally substituted heteroaryl;
10) Optionally substituted heteroarylalkyl; and
11) NR 9 R 10 ; wherein R 9 and R 10 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 arylalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl; alternatively, R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring;
R 8 is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocycloalkyl;
4) Optionally substituted aryl;
5) Optionally substituted arylalkyl;
6) Optionally substituted heteroaryl;
7) Optionally substituted heteroarylalkyl; and
8) NR 12 R 13 ; wherein R 12 and R 13 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 arylalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, alternatively, R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring; provided that at least one of R 12 and R 13 is not hydrogen.
2. The compound of claim 1 , represented by Formula II or III, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , , Z, , R 7 and R 8 are as defined in claim 1 .
3. The compound of claim 1 , represented by Formula IV or V, or a pharmaceutically acceptable salt thereof:
wherein R 2 , , Z, , R 7 and R 8 are as defined in claim 1 .
4. The compound of claim 1 , represented by Formula VI or VII, or a pharmaceutically acceptable salt thereof:
wherein , Z, , R 7 and R 8 are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula VIII or IX, or a pharmaceutically acceptable salt thereof:
wherein Z, , R 7 and R 8 are as defined in claim 1 .
6. The compound of claim 1 , represented by Formula X, XI, XII, XIII, XIV, XV, XVI or XVII, or a pharmaceutically acceptable salt thereof:
wherein , R 7 and R 8 are as defined in claim 1 .
7. The compound of claim 1 , which is selected from:
(a) compounds of Formula (X),
wherein R 7 and are delineated for each compound in Table 1:
TABLE 1
Com- pound
R 7
1
Methyl
2
Ethyl
3
Isopropyl
4
Butyl
5
t-Butyl
6
Propyl
7
Benzyl
8
Vinyl
9
Allyl
10
—CF 3
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
—NH 2
28
—NHCH 3
29
—N(CH 3 ) 2
30
31
32
33
34
35
Methyl
36
Ethyl
37
Isopropyl
38
Butyl
39
t-Butyl
40
Propyl
41
Benzyl
42
Vinyl
43
Allyl
44
—CF 3
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
—NH 2
62
—NHCH 3
63
—N(CH 3 ) 2
64
65
66
67
68
69
Methyl
70
Ethyl
71
Isopropyl
72
Butyl
73
t-Butyl
74
Propyl
75
Benzyl
76
Vinyl
77
Allyl
78
—CF 3
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
—NH 2
96
—NHCH 3
97
—N(CH 3 ) 2
98
99
100
101
102
and
(b) compounds of Formula (XI),
wherein R 8 and are delineated for each compound in Table 2:
TABLE 2
Com- pound
R 8
103
104
105
106
107
108
109
110
Benzyl
111
112
113
114
115
116
117
118
119
120
123
—N(CH 3 ) 2
124
125
126
127
128
129
130
131
132
133
134
Benzyl
135
136
137
138
139
140
141
142
143
144
147
—N(CH 3 ) 2
148
149
150
151
152
153
154
155
156
157
158
Benzyl
159
160
161
162
163
164
165
166
167
168
171
—N(CH 3 ) 2
172
173
174
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , which is selected from:
(a) compounds of Formula (XII),
wherein R 7 and are delineated for each compound in Table 3:
TABLE 3
Com- pound
R 7
175
Methyl
176
Ethyl
177
Isopropyl
178
Butyl
179
t-Butyl
180
Propyl
181
Benzyl
182
Vinyl
183
Allyl
184
—CF 3
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
—NH 2
202
—NHCH 3
203
—N(CH 3 ) 2
204
205
206
207
208
209
Methyl
210
Ethyl
211
Isopropyl
212
Butyl
213
t-Butyl
214
Propyl
215
Benzyl
216
Vinyl
217
Allyl
218
—CF 3
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
—NH 2
236
—NHCH 3
237
—N(CH 3 ) 2
238
239
240
241
242
243
Methyl
244
Ethyl
245
Isopropyl
246
Butyl
247
t-Butyl
248
Propyl
249
Benzyl
250
Vinyl
251
Allyl
252
—CF 3
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
—NH 2
270
—NHCH 3
271
—N(CH 3 ) 2
272
273
274
275
276
and
(b) compounds of Formula XIII,
wherein R 8 and are delineated for each compound in Table 4:
TABLE 4
Com- pound
R 8
277
278
279
280
281
282
283
284
Benzyl
285
286
287
288
289
290
291
292
293
294
297
—N(CH 3 ) 2
298
299
300
301
302
303
304
305
306
307
308
Benzyl
309
310
311
312
313
314
315
316
317
318
321
—N(CH 3 ) 2
322
323
324
325
326
327
328
329
330
331
332
Benzyl
333
334
335
336
337
338
339
340
341
342
345
—N(CH 3 ) 2
346
347
348
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , which is selected from:
(a) compounds of Formula (XIV),
wherein R 7 and are delineated for each compound in Table 5:
TABLE 5
Com- pound
R 7
349
Methyl
350
Ethyl
351
Isopropyl
352
Butyl
353
t-Butyl
354
Propyl
355
Benzyl
356
Vinyl
357
Allyl
358
—CF 3
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
—NH 2
376
—NHCH 3
377
—N(CH 3 ) 2
378
379
380
381
382
383
Methyl
384
Ethyl
385
Isopropyl
386
Butyl
387
t-Butyl
388
Propyl
389
Benzyl
390
Vinyl
391
Allyl
392
—CF 3
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
—NH 2
410
—NHCH 3
411
—N(CH 3 ) 2
412
413
414
415
416
417
Methyl
418
Ethyl
419
Isopropyl
420
Butyl
421
t-Butyl
422
Propyl
423
Benzyl
424
Vinyl
425
Allyl
426
—CF 3
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
—NH 2
444
—NHCH 3
445
—N(CH 3 ) 2
446
447
448
449
450
and
(b) compounds of Formula (XV),
wherein R 8 and are delineated for each compound in Table 6:
TABLE 6
Com- pound
R 8
451
452
453
454
455
456
457
458
Benzyl
459
460
461
462
463
464
465
466
467
468
471
—N(CH 3 ) 2
472
473
474
475
476
477
478
479
480
481
482
Benzyl
483
484
485
486
487
488
489
490
491
492
495
—N(CH 3 ) 2
496
497
498
499
500
501
502
503
504
505
506
Benzyl
507
508
509
510
511
512
513
514
515
516
519
—N(CH 3 ) 2
520
521
522
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , which is selected from:
(a) compounds of Formula (XVI),
wherein R 7 and are delineated for each compound in Table 7:
TABLE 7
Com- pound
R 7
523
Methyl
524
Ethyl
525
Isopropyl
526
Butyl
527
t-Butyl
528
Propyl
529
Benzyl
530
Vinyl
531
Allyl
532
—CF 3
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
—NH 2
550
—NHCH 3
551
—N(CH 3 ) 2
552
553
554
555
556
557
Methyl
558
Ethyl
559
Isopropyl
560
Butyl
561
t-Butyl
562
Propyl
563
Benzyl
564
Vinyl
565
Allyl
566
—CF 3
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
—NH 2
584
—NHCH 3
585
—N(CH 3 ) 2
586
587
588
589
590
591
Methyl
592
Ethyl
593
Isopropyl
594
Butyl
595
t-Butyl
596
Propyl
597
Benzyl
598
Vinyl
599
Allyl
600
—CF 3
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
—NH 2
618
—NHCH 3
619
—N(CH 3 ) 2
620
621
622
623
624
and
(b) compounds of Formula (XVII)
wherein R 8 and are delineated for each compound in Table 8:
TABLE 8
Com- pound
R 8
625
626
627
628
629
630
631
632
Benzyl
633
634
635
636
637
638
639
640
641
642
645
—N(CH 3 ) 2
646
647
648
649
650
651
652
653
654
655
656
Benzyl
657
658
659
660
661
662
663
664
665
666
669
—N(CH 3 ) 2
670
671
672
673
674
675
676
677
678
679
680
Benzyl
681
682
683
684
685
686
687
688
689
690
693
—N(CH 3 ) 2
694
695
696
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , selected from the compounds set forth below,
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
13. A method for treating an FXR-mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) according to claim 1 .
14. The method according to claim 13 , wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, fibrotic diseases, and metabolic disease.
15. The method according to claim 14 , wherein the fibrotic disease is selected from primary biliary cirrhosis, primary sclerosing cholangitis, pulmonary fibrosis, renal fibrosis, and liver fibrosis.
16. The method according to claim 14 , wherein the chronic liver 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.
17. The method according to claim 14 , wherein the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis, hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.
18. The method according to claim 14 , wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.
19. The method according to claim 14 , wherein the metabolic disease is selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.
20. The method of claim 14 , wherein the disease or condition is selected from primary biliary cirrhosis, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.