Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
The present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and m are as defined herein, pharmaceutical compositions comprising these compounds and methods of use of these compounds for treating a TGR5 mediated disease or condition.
1. A compound represented by Formula I:
or a pharmaceutically acceptable salt, ester, solvate, or combination thereof, wherein:
L is absent or —NR 11 CHR 12 C(O)—, wherein R 11 and R 12 are independently selected from R 3 ;
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted aryl;
8) Substituted or unsubstituted alkylaryl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted alkylheteroaryl; and
12) —NR 9 R 10 ; wherein, R 9 and R 10 are independently selected from hydrogen,substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, Substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or R 9 and R 10 are taken together with the nitrogen they attached to form a heterocyclic ring;
provided that when L is absent, R 1 is not halogen or hydroxyl;
R 2 is hydrogen or substituted or unsubstituted —C 1 -C 8 alkyl;
R 3 is independently selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted alkylaryl; and
6) Substituted or unsubstituted aryl;
m is selected from 0, 1, 2 and 3;
R 4 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ,
R 5 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− ,
—SR 2 or —NHR 2 ;
or R 4 and R 5 are taken together with the carbons they attached to form —CH═CH— or cycloalkyl ring or heterocycloalkyl ring;
R 6 and R 7 are each independently hydrogen or a hydroxyl protecting group; and
R 8 is ethyl.
2. The compound of claim 1 , represented by Formula II-A or Formula II-B:
or a pharmaceutically acceptable salt, ester, solvate, or combination thereof, wherein, R 1 , R 3 , R 4 , R 5 , R 8 , R 12 and m are as defined in claim 1 .
3. The compound of claim 1 , represented by Formula III-A or Formula III-B:
or a pharmaceutically acceptable salt, ester, solvate, or combination thereof, wherein, R 1 , R 3 , R 4 , R 8 and m are as defined in claim 1 .
4. The compound of claim 1 , represented by one of formulas (III-1) to (III-18),
or a pharmaceutically acceptable salt, ester, solvate or combination thereof, wherein R 1 , R 8 , and m are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula IV-A or Formula IV-B:
or a pharmaceutically acceptable salt, ester, solvate, or combination thereof, wherein, R 1 , and m are as defined in claim 1 .
6. The compound according to claim 1 , which is selected from:
(a) Compounds according to Formula IV-A wherein, R 1 and m are delineated for each compound in Table 1:
TABLE 1
Compound
m
R 1
1
0
Methyl
2
0
Ethyl
3
0
Isopropyl
4
0
Butyl
5
0
t-Butyl
6
0
Propyl
7
0
Benzyl
8
0
Vinyl
9
0
Allyl
10
0
CF 3
11
0
12
0
13
0
14
0
15
0
16
0
17
0
NH 2
18
0
19
0
20
0
21
0
22
0
23
0
24
0
26
1
Methyl
27
1
Ethyl
28
1
Isopropyl
29
1
Butyl
30
1
t-Butyl
31
1
Propyl
32
1
Benzyl
33
1
Vinyl
34
1
Allyl
35
1
CF 3
36
1
37
1
38
1
39
1
40
1
41
1
42
1
NH 2
43
1
44
1
45
1
46
1
47
1
48
1
49
1
51
2
Methyl
52
2
Ethyl
53
2
Isopropyl
54
2
Butyl
55
2
t-Butyl
56
2
Propyl
57
2
Benzyl
58
2
Vinyl
59
2
Allyl
60
2
CF 3
61
2
62
2
63
2
64
2
65
2
66
2
67
2
NH 2
68
2
69
2
70
2
71
2
72
2
73
2
74
2
(b) Compounds according to Formula IV-B wherein, R 1 and m are delineated for each compound in Table 2:
TABLE 2
Compound
m
R 1
76
0
Methyl
77
0
Ethyl
78
0
Isopropyl
79
0
Butyl
80
0
t-Butyl
81
0
Propyl
82
0
Benzyl
83
0
Vinyl
84
0
Allyl
85
0
CF 3
86
0
87
0
88
0
89
0
90
0
91
0
92
0
NH 2
93
0
94
0
95
0
96
0
97
0
98
0
99
0
100
0
F
101
1
Methyl
102
1
Ethyl
103
1
Isopropyl
104
1
Butyl
105
1
t-Butyl
106
1
Propyl
107
1
Benzyl
108
1
Vinyl
109
1
Allyl
110
1
CF 3
111
1
112
1
113
1
114
1
115
1
116
1
117
1
NH 2
118
1
119
1
120
1
121
1
122
1
123
1
124
1
125
1
F
126
2
Methyl
127
2
Ethyl
128
2
Isopropyl
129
2
Butyl
130
2
t-Butyl
131
2
Propyl
132
2
Benzyl
133
2
Vinyl
134
2
Allyl
135
2
CF 3
136
2
137
2
138
2
139
2
140
2
141
2
142
2
NH 2
143
2
144
2
145
2
146
2
147
2
148
2
149
2
150
2
F
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
7. The compound of claim 1 , represented by Formula V-A or Formula V-B:
wherein m and R 1 are as set forth in claim 1 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
8. The compound according to claim 1 , which is selected from:
(a) compounds according to Formula V-A wherein, R 1 and m are delineated for each compound in Table 3:
TABLE 3
Compound
m
R 1
151
0
Methyl
152
0
Ethyl
153
0
Isopropyl
154
0
Butyl
155
0
t-Butyl
156
0
Propyl
157
0
Benzyl
158
0
Vinyl
159
0
Allyl
160
0
CF 3
161
0
162
0
163
0
164
0
165
0
166
0
167
0
NH 2
168
0
169
0
170
0
171
0
172
0
173
0
174
0
176
1
Methyl
177
1
Ethyl
178
1
Isopropyl
179
1
Butyl
180
1
t-Butyl
181
1
Propyl
182
1
Benzyl
183
1
Vinyl
184
1
Allyl
185
1
CF 3
186
1
187
1
188
1
189
1
190
1
191
1
192
1
NH 2
193
1
194
1
195
1
196
1
197
1
198
1
199
1
201
2
Methyl
202
2
Ethyl
203
2
Isopropyl
204
2
Butyl
205
2
t-Butyl
206
2
Propyl
207
2
Benzyl
208
2
Vinyl
209
2
Allyl
210
2
CF 3
211
2
212
2
213
2
214
2
215
2
216
2
217
2
NH 2
218
2
219
2
220
2
221
2
222
2
223
2
224
2
(b) Compounds according to Formula V-B wherein, R 1 and m are delineated for each compound in Table 4:
TABLE 4
Compound
m
R 1
226
0
Methyl
227
0
Ethyl
228
0
Isopropyl
229
0
Butyl
230
0
t-Butyl
231
0
Propyl
232
0
Benzyl
233
0
Vinyl
234
0
Allyl
235
0
CF 3
236
0
237
0
238
0
239
0
240
0
241
0
242
0
NH 2
243
0
244
0
245
0
246
0
247
0
248
0
249
0
250
0
F
251
1
Methyl
252
1
Ethyl
253
1
Isopropyl
254
1
Butyl
255
1
t-Butyl
256
1
Propyl
257
1
Benzyl
258
1
Vinyl
259
1
Allyl
260
1
CF 3
261
1
262
1
263
1
264
1
265
1
266
1
267
1
NH 2
268
1
269
1
270
1
271
1
272
1
273
1
274
1
275
1
F
276
2
Methyl
277
2
Ethyl
278
2
Isopropyl
279
2
Butyl
280
2
t-Butyl
281
2
Propyl
282
2
Benzyl
283
2
Vinyl
284
2
Allyl
285
2
CF 3
286
2
287
2
288
2
289
2
290
2
291
2
292
2
NH 2
293
2
294
2
295
2
296
2
297
2
298
2
299
2
300
2
F
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
9. The compound according to claim 1 , represented by Formula VI-A or Formula VI-B:
wherein R 1 and m have the meanings set forth in claim 1 , or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
10. The compound according to claim 1 , which is selected from:
(a) Compounds according to Formula VI-A wherein, R 1 and m are delineated for each compound in Table 5,
TABLE 5
Compound
m
R 1
301
0
Methyl
302
0
Ethyl
303
0
Isopropyl
304
0
Butyl
305
0
t-Butyl
306
0
Propyl
307
0
Benzyl
308
0
Vinyl
309
0
Allyl
310
0
CF 3
311
0
312
0
313
0
314
0
315
0
316
0
317
0
NH 2
318
0
319
0
320
0
321
0
322
0
323
0
324
0
326
1
Methyl
327
1
Ethyl
328
1
Isopropyl
329
1
Butyl
330
1
t-Butyl
331
1
Propyl
332
1
Benzyl
333
1
Vinyl
334
1
Allyl
335
1
CF 3
336
1
337
1
338
1
339
1
340
1
341
1
342
1
NH 2
343
1
344
1
345
1
346
1
347
1
348
1
349
1
351
2
Methyl
352
2
Ethyl
353
2
Isopropyl
354
2
Butyl
355
2
t-Butyl
356
2
Propyl
357
2
Benzyl
358
2
Vinyl
359
2
Allyl
360
2
CF 3
361
2
362
2
363
2
364
2
365
2
366
2
367
2
NH 2
368
2
369
2
370
2
371
2
372
2
373
2
374
2
and
(b) Compounds according to Formula VI-B wherein, R 1 and m are delineated for each compound in Table 6,
TABLE 6
Compound
m
R 1
376
0
Methyl
377
0
Ethyl
378
0
Isopropyl
379
0
Butyl
380
0
t-Butyl
381
0
Propyl
382
0
Benzyl
383
0
Vinyl
384
0
Allyl
385
0
CF 3
386
0
387
0
388
0
389
0
390
0
391
0
392
0
NH 2
393
0
394
0
395
0
396
0
397
0
398
0
399
0
400
0
F
401
1
Methyl
402
1
Ethyl
403
1
Isopropyl
404
1
Butyl
405
1
t-Butyl 430
406
1
Propyl
407
1
Benzyl
408
1
Vinyl
409
1
Allyl
410
1
CF 3
411
1
412
1
413
1
414
1
415
1
416
1
417
1
NH 2
418
1
419
1
420
1
421
1
422
1
423
1
424
1
425
1
F
426
2
Methyl
427
2
Ethyl
428
2
Isopropyl
429
2
Butyl
430
2
t-Butyl
431
2
Propyl
432
2
Benzyl
433
2
Vinyl
434
2
Allyl
435
2
CF 3
436
2
437
2
438
2
439
2
440
2
441
2
442
2
NH 2
443
2
444
2
445
2
446
2
447
2
448
2
449
2
450
2
F
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
11. The compound according to claim 1 selected from the compounds shown in the tables below:
Compound
R
451
452
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
481
482
483
484
Compound
Structure
485
486
487
488
489
490
491
492
or a pharmaceutically acceptable salt, ester, solvate or combination thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
13. A method for ameliorating a disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
14. A method of ameliorating primary biliary cirrhosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
15. A method of ameliorating nonalcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
16. A method of ameliorating nonalcoholic fatty liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .