Heteroaryl containing bile acid analogs as FXR/TGR5 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 by FXR and/or TGR5.
1. A compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof:
wherein:
ring A is a five membered heteroaromatic ring comprising three heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally further substituted;
R 1 is 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 aryl; and
6) Substituted or unsubstituted arylalkyl;
m is selected from 0, 1, 2 and 3;
R 2 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 3 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 1 or —NHR 1 ; alternatively, R 2 and R 3 are taken together with the carbon atoms to which they are attached to form —CH═CH— or a cycloalkyl ring or heterocycloalkyl ring;
R 4 and R 5 are each independently selected from hydrogen and hydroxyl protecting group;
R 6 is ethyl;
R 7 is selected from the group consisting of:
1) Substituted or unsubstituted —C 3 -C 8 heterocycloalkyl;
2) Substituted or unsubstituted aryl;
3) Substituted or unsubstituted heteroaryl;
4) Substituted or unsubstituted arylalkyl;
5) —NR 8 R 9 ;
6) —N(R 10 )C(O)R 11 ;
7) —N(R 10 )C(O)OR 11 ;
8) —N(R 10 )C(O)NR 8 R 9 ;
9) —N(R 10 )SO 2 NR 8 R 9 ;
10) —N(R 10 )SO 2 R 11 ;
11) —N(R 10 )C(O)N(R 8 )SO 2 R 11 ; and
12) —N(R 10 )C(O)N(R 8 )SO 2 NR 8 R 9;
R 8 , R 9 , R 10 , and R 11 are each 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, substituted or unsubstituted —C 3 -C 8 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzyl; alternatively, R 8 and R 9 or R 8 and R 10 are taken together with the atoms to which they are attached to form an optionally substituted heteroaryl ring.
2. The compound of claim 1 , wherein A-R 7 is selected from groups (I-1) to (I-11):
wherein R a is 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 —C 3 -C 8 cycloalkyl;
6) —C(O)R 11 ;
7) —C(O)OR 11 ;
8) —C(O)NR 8 R 9 ;
9) —SO 2 R 11 ; and
10) —C(O)N(R 8 )SO 2 R 11 ; and
R b is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) CF 3 ;
4) CN;
5) Substituted or unsubstituted —C 1 -C 8 alkyl;
6) Substituted or unsubstituted —C 2 -C 8 alkenyl;
7) Substituted or unsubstituted —C 2 -C 8 alkynyl;
8) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
9) Substituted or unsubstituted —C 3 -C 8 heterocycloalkyl;
10) Substituted or unsubstituted aryl;
11) Substituted or unsubstituted heteroaryl;
12) Substituted or unsubstituted arylalkyl;
13) —C(O)R 11 ;
14) —C(O)OR 11 ;
15) —C(O)NR 8 R 9 ; and
16) —C(O)N(R 8 )SO 2 R 11 ;
wherein R 7 is as defined in claim 1 .
3. The compound of claim 1 , represented by Formula II or a pharmaceutically acceptable salt or ester thereof:
wherein ring A, R 1 , R 2 , R 3 , R 6 , R 7 and m are as defined in claim 1 .
4. The compound of claim 1 , represented by Formula III or a pharmaceutically acceptable salt or ester thereof:
wherein ring A, R 1 , R 2 , R 6 , R 7 and m are as defined in claim 1 .
5. The compound of claim 1 , represented by formula (III-1˜III-12), or a pharmaceutically acceptable salt or ester thereof,
wherein R 6 , R 7 and m are as defined in claim 1 .
6. The compound of claim 1 , represented by Formula IV or a pharmaceutically acceptable salt or ester thereof:
wherein R 7 and m are as defined in claim 1 .
7. The compound according to claim 6 selected from compounds of Formula IV wherein R 7 and m are delineated for each compound in Table 1:
TABLE 1
compound
m
R 7
4
0
5
0
6
0
—NH 2
7
0
—NMe 2
8
0
9
0
10
0
11
0
12
0
13
0
14
0
15
0
16
0
17
0
18
0
19
0
20
0
21
0
22
0
23
0
24
0
25
0
26
0
27
0
28
0
33
1
34
1
35
1
—NH 2
36
1
—NMe 2
37
1
38
1
39
1
40
1
41
1
42
1
43
1
44
1
45
1
46
1
47
1
48
1
49
1
50
1
51
1
52
1
53
1
54
1
55
1
56
1
57
1
62
2
63
2
64
2
—NH 2
65
2
—NMe 2
66
2
67
2
68
2
69
2
70
2
71
2
72
2
73
2
74
2
75
2
76
2
77
2
78
2
79
2
80
2
81
2
82
2
83
2
84
2
85
2
86
2
or a pharmaceutically acceptable salt or ester thereof.
8. The compound of claim 1 , represented by Formula V, or a pharmaceutically acceptable salt or ester thereof:
wherein R 7 and m are as defined in claim 1 .
9. The compound according to claim 8 , selected from compounds of Formula V wherein R 7 and m are delineated for each compound in Table 2:
TABLE 2
compound
m
R 7
91
0
92
0
93
0
—NH 2
94
0
—NMe 2
95
0
96
0
97
0
98
0
99
0
100
0
101
0
102
0
103
0
104
0
105
0
106
0
107
0
108
0
109
0
110
0
111
0
112
0
113
0
114
0
115
0
120
1
121
1
122
1
—NH 2
123
1
—NMe 2
124
1
125
1
126
1
127
1
128
1
129
1
130
1
131
1
132
1
133
1
134
1
135
1
136
1
137
1
138
1
139
1
140
1
141
1
142
1
143
1
144
1
149
2
150
2
151
2
—NH 2
152
2
—NMe 2
153
2
154
2
155
2
156
2
157
2
158
2
159
2
160
2
161
2
162
2
163
2
164
2
165
2
166
2
167
2
168
2
169
2
170
2
171
2
172
2
173
2
or a pharmaceutically acceptable salt or ester thereof.
10. The compound of claim 1 , represented by Formula VI or a pharmaceutically acceptable salt or ester thereof:
wherein R 7 and m are as defined in claim 1 .
11. The compound of claim 10 , selected from compounds of Formula VI wherein R 7 and m are delineated for each compound in Table 3:
TABLE 3
compound
m
R 7
178
0
179
0
180
0
—NH 2
181
0
—NMe 2
182
0
183
0
184
0
185
0
186
0
187
0
188
0
189
0
190
0
191
0
192
0
193
0
194
0
195
0
196
0
197
0
198
0
199
0
200
0
201
0
202
0
207
1
208
1
209
1
—NH 2
210
1
—NMe 2
211
1
212
1
213
1
214
1
215
1
216
1
217
1
218
1
219
1
220
1
221
1
222
1
223
1
224
1
225
1
226
1
227
1
228
1
229
1
230
1
231
1
236
2
237
2
238
2
—NH 2
239
2
—NMe 2
240
2
241
2
242
2
243
2
244
2
245
2
246
2
247
2
248
2
249
2
250
2
251
2
252
2
253
2
254
2
255
2
256
2
257
2
258
2
259
2
260
2
or a pharmaceutically acceptable salt or ester thereof.
12. The compound of claim 1 , represented by Formula VII or a pharmaceutically acceptable salt or ester thereof:
wherein R 7 and m are previously defined in claim 1 .
13. The compound of claim 12 , selected from compounds of Formula VII wherein R 7 and m are delineated for each compound in Table 4:
TABLE 4
compound
m
R 7
265
0
266
0
267
0
—NH 2
268
0
—NMe 2
269
0
270
0
271
0
272
0
273
0
274
0
275
0
276
0
277
0
278
0
279
0
280
0
281
0
282
0
283
0
284
0
285
0
286
0
287
0
288
0
289
0
294
1
295
1
296
1
—NH 2
297
1
—NMe 2
298
1
299
1
300
1
301
1
302
1
303
1
304
1
305
1
306
1
307
1
308
1
309
1
310
1
311
1
312
1
313
1
314
1
315
1
316
1
317
1
318
1
323
2
324
2
325
2
—NH 2
326
2
—NMe 2
327
2
328
2
329
2
330
2
331
2
332
2
333
2
334
2
335
2
336
2
337
2
338
2
339
2
340
2
341
2
342
2
343
2
344
2
345
2
346
2
347
2
or a pharmaceutically acceptable salt or ester thereof.
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
15. 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 of a compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof:
wherein:
ring A is a five membered heteroaromatic ring comprising three heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally further substituted;
R 1 at each occurrence 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 aryl; and
6) Substituted or unsubstituted arylalkyl;
m is selected from 0, 1, 2 and 3;
R 2 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 3 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 1 or —NHR 1 ; alternatively, R 2 and R 3 are taken together with the carbon atoms to which they are attached to form —CH═CH— or a cycloalkyl ring or heterocycloalkyl ring;
R 4 and R 8 are each independently selected from hydrogen and hydroxyl protecting group;
R 6 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
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; and
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl; and
R 7 is selected from the group consisting of:
1) Substituted or unsubstituted —C 3 -C 8 heterocycloalkyl;
2) Substituted or unsubstituted aryl;
3) Substituted or unsubstituted heteroaryl;
4) Substituted or unsubstituted arylalkyl;
5) —NR 8 R 9 ;
6) —N(R 10 )C(O)R 11 ;
7) —N(R 10 )C(O)OR 11 ;
8) —N(R 10 )C(O)NR 8 R 9 ;
9) —N(R 10 )SO 2 NR 8 R 9 ;
10) —N(R 10 )SO 2 R 11 ;
11) —N(R 10 )C(O)N(R 8 )SO 2 R 11 ; and
12) —N(R 10 )C(O)N(R 8 )SO 2 NR 8 R 9
R 8 , R 9 , R 10 , and R 11 are each 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, substituted or unsubstituted —C 3 -C 8 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzyl; alternatively, R 8 and R 9 or R 8 and R 10 are taken together with the atoms to which they are attached to form an optionally substituted heteroaryl ring.
16. The method of claim 15 , wherein the disease or condition is primary biliary cirrhosis.
17. The method of claim 15 , wherein the disease or condition is nonalcoholic steatohepatitis.
18. The method of claim 15 , wherein the disease or condition is nonalcoholic fatty liver disease.