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 or optionally substituted heteroarylalkyl;
X 1 , X 2 , X 3 , and X 4 are independently selected from N and C(Y); wherein Y is selected from hydrogen, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, and haloalkoxy;
is aryl, heterocyclic, heteroaryl, bicyclic fused arylheterocyclic or bicyclic fused heteroarylheterocyclic, wherein said aryl, heterocyclic, heteroaryl, bicyclic fused arylheterocyclic or bicyclic fused heteroarylheterocyclic is optionally substituted with one or two substituents independently selected from optionally substituted —C 1 -C 8 alkyl, halo, and halo-C 1 -C 8 -alkyl; or
is
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 3- to 8-membered 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 arylalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or R 7 and R 8 are taken together with the nitrogen atom which they are attached to form an optionally substituted heterocyclic ring; provided that when R 3 is
R 6 is NR 7 R 8 .
2. The compound of claim 1 , represented by Formula II or III or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , X 1 , X 2 , X 3 , X 4 ,
and R 6 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 , X 1 , X 2 , X 3 , X 4 ,
and R 6 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 X 1 , X 2 , X 3 , X 4 ,
and R 6 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
and R 6 are as defined in claim 1 .
6. The compound of claim 1 , which is selected from
(a) compounds of Formula (X),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of 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 of Formula (XI),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 2,
TABLE 2
Compound
R 6
Position
88
—NH 2
1
89
—NHCH 3
1
90
—N(CH 3 ) 2
1
91
1
92
1
93
1
94
—NH 2
2
95
—NHCH 3
2
96
—N(CH 3 ) 2
2
97
2
98
2
99
2
100
—NH 2
3
101
—NHCH 3
3
102
—N(CH 3 ) 2
3
103
3
104
3
105
3.
7. The compound of claim 1 , which is selected from (a) compounds of Formula (XII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 3,
TABLE 3
Compound
R 6
Position
106
Methyl
1
107
Ethyl
1
108
Isopropyl
1
109
Butyl
1
110
t-Butyl
1
111
Propyl
1
112
Benzyl
1
113
Vinyl
1
114
Allyl
1
115
—CF 3
1
116
1
117
1
118
1
119
1
120
1
121
1
122
1
123
1
124
1
125
1
126
1
127
1
128
1
129
—NH 2
1
130
—NHCH 3
1
131
—N(CH 3 ) 2
1
132
1
133
1
134
1
135
Methyl
2
136
Ethyl
2
137
Isopropyl
2
138
Butyl
2
139
t-Butyl
2
140
Propyl
2
141
Benzyl
2
142
Vinyl
2
143
Allyl
2
144
—CF 3
2
145
2
146
2
147
2
148
2
149
2
150
2
151
2
152
2
153
2
154
2
155
2
156
2
157
2
158
—NH 2
2
159
—NHCH 3
2
160
—N(CH 3 ) 2
2
161
2
162
2
163
2
164
Methyl
3
165
Ethyl
3
166
Isopropyl
3
167
Butyl
3
168
t-Butyl
3
169
Propyl
3
170
Benzyl
3
171
Vinyl
3
172
Allyl
3
173
—CF 3
3
174
3
175
3
176
3
177
3
178
3
179
3
180
3
181
3
182
3
183
3
184
3
185
3
186
3
187
—NH 2
3
188
—NHCH 3
3
189
—N(CH 3 ) 2
3
190
3
191
3
192
3
and
(b) compounds of Formula (XIII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 4,
TABLE 4
Compound
R 6
Position
193
—NH 2
1
194
—NHCH 3
1
195
—N(CH 3 ) 2
1
196
1
197
1
198
1
199
—NH 2
2
200
—NHCH 3
2
201
—N(CH 3 ) 2
2
202
2
203
2
204
2
205
—NH 2
3
206
—NHCH 3
3
207
—N(CH 3 ) 2
3
208
3
209
3
210
3.
8. The compound of claim 1 , which is selected from (a) compounds of Formula (XIV),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 5,
TABLE 5
Compound
R 6
Position
211
Methyl
1
212
Ethyl
1
213
Isopropyl
1
214
Butyl
1
215
t-Butyl
1
216
Propyl
1
217
Benzyl
1
218
Vinyl
1
219
Allyl
1
220
—CF 3
1
221
1
222
1
223
1
224
1
225
1
226
1
227
1
228
1
229
1
230
1
231
1
232
1
233
1
234
—NH 2
1
235
—NHCH 3
1
236
—N(CH 3 ) 2
1
237
1
238
1
239
1
240
Methyl
2
241
Ethyl
2
242
Isopropyl
2
243
Butyl
2
244
t-Butyl
2
245
Propyl
2
246
Benzyl
2
247
Vinyl
2
248
Allyl
2
249
—CF 3
2
250
2
251
2
252
2
253
2
254
2
255
2
256
2
257
2
258
2
259
2
260
2
261
2
262
2
263
—NH 2
2
264
—NHCH 3
2
265
—N(CH 3 ) 2
2
266
2
267
2
268
2
269
Methyl
3
270
Ethyl
3
271
Isopropyl
3
272
Butyl
3
273
t-Butyl
3
274
Propyl
3
275
Benzyl
3
276
Vinyl
3
277
Allyl
3
278
—CF 3
3
279
3
280
3
281
3
282
3
283
3
284
3
285
3
286
3
287
3
288
3
289
3
290
3
291
3
292
—NH 2
3
293
—NHCH 3
3
294
—N(CH 3 ) 2
3
295
3
296
3
297
3
and
(b) compounds of Formula (XV),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 6,
TABLE 6
Compound
R 6
Position
298
—NH 2
1
299
—NHCH 3
1
300
—N(CH 3 ) 2
1
301
1
302
1
303
1
304
—NH 2
2
305
—NHCH 3
2
306
—N(CH 3 ) 2
2
307
2
308
2
309
2
310
—NH 2
3
311
—NHCH 3
3
312
—N(CH 3 ) 2
3
313
3
314
3
315
3.
9. The compound of claim 1 , which is selected from (a) compounds of Formula (XVI),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 7,
TABLE 7
Compound
R 6
Position
316
Methyl
1
317
Ethyl
1
318
Isopropyl
1
319
Butyl
1
320
t-Butyl
1
321
Propyl
1
322
Benzyl
1
323
Vinyl
1
324
Allyl
1
325
—CF 3
1
326
1
327
1
328
1
329
1
330
1
331
1
332
1
333
1
334
1
335
1
336
1
337
1
338
1
339
—NH 2
1
340
—NHCH 3
1
341
—N(CH 3 ) 2
1
342
1
343
1
344
1
345
Methyl
2
346
Ethyl
2
347
Isopropyl
2
348
Butyl
2
349
t-Butyl
2
350
Propyl
2
351
Benzyl
2
352
Vinyl
2
353
Allyl
2
354
—CF 3
2
355
2
356
2
357
2
358
2
359
2
360
2
361
2
362
2
363
2
364
2
365
2
366
2
367
2
368
—NH 2
2
369
—NHCH 3
2
370
—N(CH 3 ) 2
2
371
2
372
2
373
2
374
Methyl
3
375
Ethyl
3
376
Isopropyl
3
377
Butyl
3
378
t-Butyl
3
379
Propyl
3
380
Benzyl
3
381
Vinyl
3
382
Allyl
3
383
—CF 3
3
384
3
385
3
386
3
387
3
388
3
389
3
390
3
391
3
392
3
393
3
394
3
395
3
396
3
397
—NH 2
3
398
—NHCH 3
3
399
—N(CH 3 ) 2
3
400
3
401
3
402
3
and
(b) compounds of Formula (XVII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 8,
TABLE 8
Compound
R 6
Position
403
—NH 2
1
404
—NHCH 3
1
405
—N(CH 3 ) 2
1
406
1
407
1
408
1
409
—NH 2
2
410
—NHCH 3
2
411
—N(CH 3 ) 2
2
412
2
413
2
414
2
415
—NH 2
3
416
—NHCH 3
3
417
—N(CH 3 ) 2
3
418
3
419
3
420
3.
10. The compound of claim 1 , which is selected from
(a) compounds of Formula (XVIII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 9,
TABLE 9
Compound
R 6
Position
421
Methyl
1
422
Ethyl
1
423
Isopropyl
1
424
Butyl
1
425
t-Butyl
1
426
Propyl
1
427
Benzyl
1
428
Vinyl
1
429
Allyl
1
430
—CF 3
1
431
1
432
1
433
1
434
1
435
1
436
1
437
1
438
1
439
1
440
1
441
1
442
1
443
1
444
—NH 2
1
445
—NHCH 3
1
446
—N(CH 3 ) 2
1
447
1
448
1
449
1
450
Methyl
2
451
Ethyl
2
452
Isopropyl
2
453
Butyl
2
454
t-Butyl
2
455
Propyl
2
456
Benzyl
2
457
Vinyl
2
458
Allyl
2
459
—CF 3
2
460
2
461
2
462
2
463
2
464
2
465
2
466
2
467
2
468
2
469
2
470
2
471
2
472
2
473
—NH 2
2
474
—NHCH 3
2
475
—N(CH 3 ) 2
2
476
2
477
2
478
2
479
Methyl
3
480
Ethyl
3
481
Isopropyl
3
482
Butyl
3
483
t-Butyl
3
484
Propyl
3
485
Benzyl
3
486
Vinyl
3
487
Allyl
3
488
—CF 3
3
489
3
490
3
491
3
492
3
493
3
494
3
495
3
496
3
497
3
498
3
499
3
500
3
501
3
502
—NH 2
3
503
—NHCH 3
3
504
—N(CH 3 ) 2
3
505
3
506
3
507
3
and
(b) compounds of Formula (XIX),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 10,
TABLE 10
Compound
R 6
Position
508
—NH 2
1
509
—NHCH 3
1
510
—N(CH 3 ) 2
1
511
1
512
1
513
1
514
—NH 2
2
515
—NHCH 3
2
516
—N(CH 3 ) 2
2
517
2
518
2
519
2
520
—NH 2
3
521
—NHCH 3
3
522
—N(CH 3 ) 2
3
523
3
524
3
525
3.
11. The compound of claim 1 , which is selected from
(a) compounds of Formula (XX),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 11,
TABLE 11
Compound
R 6
Position
526
Methyl
1
527
Ethyl
1
528
Isopropyl
1
529
Butyl
1
530
t-Butyl
1
531
Propyl
1
532
Benzyl
1
533
Vinyl
1
534
Allyl
1
535
—CF 3
1
536
1
537
1
538
1
539
1
540
1
541
1
542
1
543
1
544
1
545
1
546
1
547
1
548
1
549
—NH 2
1
550
—NHCH 3
1
551
—N(CH 3 ) 2
1
552
1
553
1
554
1
555
Methyl
2
556
Ethyl
2
557
Isopropyl
2
558
Butyl
2
559
t-Butyl
2
560
Propyl
2
561
Benzyl
2
562
Vinyl
2
563
Allyl
2
564
—CF 3
2
565
2
566
2
567
2
568
2
569
2
570
2
571
2
572
2
573
2
574
2
575
2
576
2
577
2
578
—NH 2
2
579
—NHCH 3
2
580
—N(CH 3 ) 2
2
581
2
582
2
583
2
584
Methyl
3
585
Ethyl
3
586
Isopropyl
3
587
Butyl
3
588
t-Butyl
3
589
Propyl
3
590
Benzyl
3
591
Vinyl
3
592
Allyl
3
593
—CF 3
3
594
3
595
3
596
3
597
3
598
3
599
3
600
3
601
3
602
3
603
3
604
3
605
3
606
3
607
—NH 2
3
608
—NHCH 3
3
609
—N(CH 3 ) 2
3
610
3
611
3
612
3
and
(b) compounds of Formula (XXI),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 12,
TABLE 12
Compound
R 6
Position
613
—NH 2
1
614
—NHCH 3
1
615
—N(CH 3 ) 2
1
616
1
617
1
618
1
619
—NH 2
2
620
—NHCH 3
2
621
—N(CH 3 ) 2
2
622
2
623
2
624
2
625
—NH 2
3
626
—NHCH 3
3
627
—N(CH 3 ) 2
3
628
3
629
3
630
3.
12. The compound of claim 1 , which is selected from
(a) compounds of Formula (XXII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 13,
TABLE 13
Compound
R 6
Position
631
Methyl
1
632
Ethyl
1
633
Isopropyl
1
634
Butyl
1
635
t-Butyl
1
636
Propyl
1
637
Benzyl
1
638
Vinyl
1
639
Allyl
1
640
—CF 3
1
641
1
642
1
643
1
644
1
645
1
646
1
647
1
648
1
649
1
650
1
651
1
652
1
653
1
654
—NH 2
1
655
—NHCH 3
1
656
—N(CH 3 ) 2
1
657
1
658
1
659
1
660
Methyl
2
661
Ethyl
2
662
Isopropyl
2
663
Butyl
2
664
t-Butyl
2
665
Propyl
2
666
Benzyl
2
667
Vinyl
2
668
Allyl
2
669
—CF 3
2
670
2
671
2
672
2
673
2
674
2
675
2
676
2
677
2
678
2
679
2
680
2
681
2
682
2
683
—NH 2
2
684
—NHCH 3
2
685
—N(CH 3 ) 2
2
686
2
687
2
688
2
689
Methyl
3
690
Ethyl
3
691
Isopropyl
3
692
Butyl
3
693
t-Butyl
3
694
Propyl
3
695
Benzyl
3
696
Vinyl
3
697
Allyl
3
698
—CF 3
3
699
3
700
3
701
3
702
3
703
3
704
3
705
3
706
3
707
3
708
3
709
3
710
3
711
3
712
—NH 2
3
713
—NHCH 3
3
714
—N(CH 3 ) 2
3
715
3
716
3
717
3
and
(b) compounds of Formula (XXIII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 14,
TABLE 14
Compound
R 6
Position
718
—NH 2
1
719
—NHCH 3
1
720
—N(CH 3 ) 2
1
721
1
722
1
723
1
724
—NH 2
2
725
—NHCH 3
2
726
—N(CH 3 ) 2
2
727
2
728
2
729
2
730
—NH 2
3
731
—NHCH 3
3
732
—N(CH 3 ) 2
3
733
3
734
3
735
3.
13. The compound of claim 1 , which is selected from
(a) compounds of Formula (XXIV),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 15,
TABLE 15
Compound
R 6
Position
736
Methyl
1
737
Ethyl
1
738
Isopropyl
1
739
Butyl
1
740
t-Butyl
1
741
Propyl
1
742
Benzyl
1
743
Vinyl
1
744
Allyl
1
745
—CF 3
1
746
1
747
1
748
1
749
1
750
1
751
1
752
1
753
1
754
1
755
1
756
1
757
1
758
1
759
—NH 2
1
760
—NHCH 3
1
761
—N(CH 3 ) 2
1
762
1
763
1
764
1
765
Methyl
2
766
Ethyl
2
767
Isopropyl
2
768
Butyl
2
769
t-Butyl
2
770
Propyl
2
771
Benzyl
2
772
Vinyl
2
773
Allyl
2
774
—CF 3
2
775
2
776
2
777
2
778
2
779
2
780
2
781
2
782
2
783
2
784
2
785
2
786
2
787
2
788
—NH 2
2
789
—NHCH 3
2
790
—N(CH 3 ) 2
2
791
2
792
2
793
2
794
Methyl
3
795
Ethyl
3
796
Isopropyl
3
797
Butyl
3
798
t-Butyl
3
799
Propyl
3
800
Benzyl
3
801
Vinyl
3
802
Allyl
3
803
—CF 3
3
804
3
805
3
806
3
807
3
808
3
809
3
810
3
811
3
812
3
813
3
814
3
815
3
816
3
817
—NH 2
3
818
—NHCH 3
3
819
—N(CH 3 ) 2
3
820
3
821
3
822
3
and
(b) compounds of Formula (XXV),
and pharmaceutically acceptable salt thereof wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 16,
TABLE 16
Compound
R 6
Position
823
—NH2
1
824
—NHCH3
1
825
—N(CH3)2
1
826
1
827
1
828
1
829
—NH2
2
830
—NHCH3
2
831
—N(CH3)2
2
832
2
833
2
834
2
835
—NH2
3
836
—NHCH3
3
837
—N(CH3)2
3
838
3
839
3
840
3.
14. The compound of claim 1 , which is selected from
(a) compounds of Formula (XXVI),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —NHC(O)NHS(O) 2 R 6 group are delineated for each compound in Table 17,
TABLE 17
Compound
R 6
Position
841
Methyl
1
842
Ethyl
1
843
Isopropyl
1
844
Butyl
1
845
t-Butyl
1
846
Propyl
1
847
Benzyl
1
848
Vinyl
1
849
Allyl
1
850
—CF3
1
851
1
852
1
853
1
854
1
855
1
856
1
857
1
858
1
859
1
860
1
861
1
862
1
863
1
864
—NH2
1
865
—NHCH3
1
866
—N(CH3)2
1
867
1
868
1
869
1
870
Methyl
2
871
Ethyl
2
872
Isopropyl
2
873
Butyl
2
874
t-Butyl
2
875
Propyl
2
876
Benzyl
2
877
Vinyl
2
878
Allyl
2
879
—CF3
2
880
2
881
2
882
2
883
2
884
2
885
2
886
2
887
2
888
2
889
2
890
2
891
2
892
2
893
—NH2
2
894
—NHCH3
2
895
—N(CH3)2
2
896
2
897
2
898
2
899
Methyl
3
900
Ethyl
3
901
Isopropyl
3
902
Butyl
3
903
t-Butyl
3
904
Propyl
3
905
Benzyl
3
906
Vinyl
3
907
Allyl
3
908
—CF3
3
909
3
910
3
911
3
912
3
913
3
914
3
915
3
916
3
917
3
918
3
919
3
920
3
921
3
922
—NH2
3
923
—NHCH3
3
924
—N(CH3)2
3
925
3
926
3
927
3
and
(b) compounds of Formula (XXVII),
and pharmaceutically acceptable salts thereof, wherein R 6 and the substitution position of the —C(O)NHS(O) 2 R 6 group are delineated for each compound in Table 18,
TABLE 18
Compound
R 6
Position
928
—NH 2
1
929
—NHCH 3
1
930
—N(CH 3 ) 2
1
931
1
932
1
933
1
934
—NH 2
2
935
—NHCH 3
2
936
—N(CH 3 ) 2
2
937
2
938
2
939
2
940
—NH 2
3
941
—NHCH 3
3
942
—N(CH 3 ) 2
3
943
3
944
3
945
3.
15. 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 .
16. The method according to claim 15 , wherein the disease or condition is selected from primary biliary cirrhosis and primary sclerosing cholangitis.
17. The method according to claim 15 , wherein the disease or condition is selected from the group consisting of atherosclerosis, hypercholesterolemia, and hypertriglyceridemia.
18. The method according to claim 15 , wherein the disease or condition is selected from the group consisting of Type I diabetes, Type II diabetes, and obesity.
19. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
20. The method according to claim 15 , wherein the disease or condition is primary biliary cirrhosis.
21. The method according to claim 15 , wherein the disease or condition is nonalcoholic steatohepatitis.
22. The method according to claim 15 , wherein the disease or condition is nonalcoholic fatty liver disease.