# US 10,246,483 B2 · Bile acid analogs as FXR/TGR5 agonists and methods of use thereof

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- Number: US 10,246,483 B2
- Document ID: US10246483B2
- Status: Granted
- Kind: B2
- Application number: 15/041,811
- Filed: 2016-02-11
- Published: 2016-08-11
- Granted: 2019-04-02
- Earliest claimed: 2015-02-11
- Assignees: Enanta Pharmaceuticals, Inc.
- Applicants: Enanta Pharmaceuticals, Inc.
- Inventors: Ruichao Shen; Yat Sun Or; Guoqiang Wang
- Web page: https://patentgrep.com/patent/US10246483B2

## CPC

- C07J 41/0061: {one of the carbon atoms being part of an amide group}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/12: of the kidneys
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07J 43/003: {not condensed}
- C07J 9/005: {containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton}
- C07J: STEROIDS (seco-steroids C07C)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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.

## Claims

### Claim 1

A compound represented by Formula I:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein:
R1 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C1-C8 alkyl;
3) Substituted or unsubstituted —C2-C8 alkenyl;
4) Substituted or unsubstituted —C2-C8 alkynyl;
5) Substituted or unsubstituted —C3-C8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;
Ra, Rb, and Rc are each independently selected from R1; or Ra and Rb, or Ra and Rc, or Rb and Rc are taken together with the two nitrogen atoms to which they are attached and the intervening carbon atom to form a heterocyclic, heteroaryl or heterocycloalkenyl ring;
R2 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C1-C8 alkyl;
4) Substituted or unsubstituted —C2-C8 alkenyl;
5) Substituted or unsubstituted —C2-C8 alkynyl;
6) Substituted or unsubstituted arylalkyl; and
7) Substituted or unsubstituted aryl;
m is 0, 1, 2 or 3;
R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —PPO3H2 or —OPO32−;
R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2, —OPO32−, —SR2 or —NHR2, or R3 and R4 are taken together with the carbons to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R5 and R6 are each independently hydrogen or hydroxyl protecting group; and
R7 is ethyl.

### Claim 2 (depends on 1)

The compound of claim 1 represented by Formula II:
or a pharmaceutically acceptable salt, solvate, or ester thereof,
wherein R1, Ra, Rb, Rc, R2, R3, R4, R7 and m are as defined in claim 1.

### Claim 3 (depends on 1)

The compound of claim 1 represented by Formula III:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1, Ra, Rb, Rc, R2, R3, R7 and m are as defined in claim 1.

### Claim 4 (depends on 1)

The compound of claim 1, represented by one of formulas (III-1) to (III-9),
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1, Ra, Rb, Rc, R2, R3, R7 and m are as defined in claim 1.

### Claim 5 (depends on 1)

The compound of claim 1, represented by Formula IV:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1, Ra, Rb, Rc, and m are as defined in claim 1.

### Claim 6 (depends on 1)

A compound of claim 1, represented by Formula V:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1 and m are as defined in claim 1.

### Claim 7 (depends on 1)

The compound of claim 1, selected from compounds of Formula V, wherein R1 and m are delineated for each compound in Table 1:
TABLE 1
(V)
Compound
m
R1
Compound
M
R1
Compound
m
R1
1
0
H
26
1
H
51
2
H
2
0
Methyl
27
1
Methyl
52
2
Methyl
3
0
Ethyl
28
1
Ethyl
53
2
Ethyl
4
0
Isopropyl
29
1
Isopropyl
54
2
Isopropyl
5
0
Butyl
30
1
Butyl
55
2
Butyl
6
0
t-Butyl
31
1
t-Butyl
56
2
t-Butyl
7
0
Propyl
32
1
Propyl
57
2
Propyl
8
0
Benzyl
33
1
Benzyl
58
2
Benzyl
9
0
Allyl
34
1
Allyl
59
2
Allyl
10
0
CF3
35
1
CF3
60
2
CF3
11
0
36
1
61
2
12
0
37
1
62
2
13
0
38
1
63
2
14
0
39
1
64
2
15
0
40
1
65
2
16
0
41
1
66
2
17
0
42
1
67
2
18
0
43
1
68
2
19
0
44
1
69
2
20
0
45
1
70
2
21
0
46
1
71
2
22
0
47
1
72
2
23
0
48
1
73
2
24
0
49
1
74
2
25
0
50
1
75
2
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 8 (depends on 1)

The compound of claim 1, represented by Formula VI:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1 and m are as defined in claim 1.

### Claim 9 (depends on 1)

The compound of claim 1, selected from compounds of Formula VI, wherein R1 and m are delineated for each compound in Table 2:
TABLE 2
(VI)
Compound
m
R1
76
0
H
77
0
Methyl
78
0
Ethyl
79
0
Isopropyl
80
0
Butyl
81
0
t-Butyl
82
0
Propyl
83
0
Benzyl
84
0
Allyl
85
0
CF3
86
0
87
0
88
0
89
0
90
0
91
0
92
0
93
0
94
0
95
0
96
0
97
0
98
0
99
0
100
0
101
1
H
102
1
Methyl
103
1
Ethyl
104
1
Isopropyl
105
1
Butyl
106
1
t-Butyl
107
1
Propyl
108
1
Benzyl
109
1
Allyl
110
1
CF3
111
1
112
1
113
1
114
1
115
1
116
1
117
1
118
1
119
1
120
1
121
1
122
1
123
1
124
1
125
1
126
2
H
127
2
Methyl
128
2
Ethyl
129
2
Isopropyl
130
2
Butyl
131
2
t-Butyl
132
2
Propyl
133
2
Benzyl
134
2
Allyl
135
2
CF3
136
2
137
2
138
2
139
2
140
2
141
2
142
2
143
2
144
2
145
2
146
2
147
2
148
2
149
2
150
2
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 10 (depends on 1)

The compound of claim 1, represented by Formula VII:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1 and m are as defined in claim 1.

### Claim 11 (depends on 1)

The compound of claim 1, selected from compounds of Formula VII, wherein R1 and m are delineated for each compound in Table 3:
TABLE 3
(VII)
Compound
m
R1
151
0
H
152
0
Methyl
153
0
Ethyl
154
0
Isopropyl
155
0
Butyl
156
0
t-Butyl
157
0
Propyl
158
0
Benzyl
159
0
Allyl
160
0
CF3
161
0
162
0
163
0
164
0
165
0
166
0
167
0
168
0
169
0
170
0
171
0
172
0
173
0
174
0
175
0
176
1
H
177
1
Methyl
178
1
Ethyl
179
1
Isopropyl
180
1
Butyl
181
1
t-Butyl
182
1
Propyl
183
1
Benzyl
184
1
Allyl
185
1
CF3
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
1
199
1
200
1
201
2
H
202
2
Methyl
203
2
Ethyl
204
2
Isopropyl
205
2
Butyl
206
2
t-Butyl
207
2
Propyl
208
2
Benzyl
209
2
Allyl
210
2
CF3
211
2
212
2
213
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
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 12 (depends on 1)

The compound of claim 1, represented by Formula VIII:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R1 and m are as defined in claim 1.

### Claim 13 (depends on 1)

The compound of claim 1, selected from compounds of Formula VIII, wherein R1 and m are delineated for each compound in Table 4:
TABLE 4
(VIII)
Compound
m
R1
226
0
H
227
0
Methyl
228
0
Ethyl
229
0
Isopropyl
230
0
Butyl
231
0
t-Butyl
232
0
Propyl
233
0
Benzyl
234
0
Allyl
235
0
CF3
236
0
237
0
238
0
239
0
240
0
241
0
242
0
243
0
244
0
245
0
246
0
247
0
248
0
249
0
250
0
251
1
H
252
1
Methyl
253
1
Ethyl
254
1
Isopropyl
255
1
Butyl
256
1
t-Butyl
257
1
Propyl
258
1
Benzyl
259
1
Allyl
260
1
CF3
261
1
262
1
263
1
264
1
265
1
266
1
267
1
268
1
269
1
270
1
271
1
272
1
273
1
274
1
275
1
276
2
H
277
2
Methyl
278
2
Ethyl
279
2
Isopropyl
280
2
Butyl
281
2
t-Butyl
282
2
Propyl
283
2
Benzyl
284
2
Allyl
285
2
CF3
286
2
287
2
288
2
289
2
290
2
291
2
292
2
293
2
294
2
295
2
296
2
297
2
298
2
299
2
300
2
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

### Claim 15

A method for ameliorating an FXR-mediated 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 represented by Formula I:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein:
R1 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C1-C8 alkyl;
3) Substituted or unsubstituted —C2-C8 alkenyl;
4) Substituted or unsubstituted —C2-C8 alkynyl;
5) Substituted or unsubstituted —C3-C8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;
Ra, Rb, and Rc are each independently selected from R1; or Ra and Rb, or Ra and Rc, or Rb and Rc are taken together with the two nitrogen atoms to which they are attached and the intervening carbon atom to form a heterocyclic, heteroaryl or heterocycloalkenyl ring;
R2 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C1-C8 alkyl;
4) Substituted or unsubstituted —C2-C8 alkenyl;
5) Substituted or unsubstituted —C2-C8 alkynyl;
6) Substituted or unsubstituted arylalkyl; and
7) Substituted or unsubstituted aryl;
m is 0, 1, 2 or 3;
R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —PPO3H2 or —OPO32−;
R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2, —OPO32−, —SR2 or —NHR2, or R3 and R4 are taken together with the carbons to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R5 and R6 are each independently hydrogen or hydroxyl protecting group; and
R7 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C1-C8 alkyl;
4) Substituted or unsubstituted —C2-C8 alkenyl;
5) Substituted or unsubstituted —C2-C8 alkynyl; and
6) Substituted or unsubstituted —C2-C8 cycloalkyl.

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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.

### Claim 18 (depends on 1)

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.

### Claim 19 (depends on 18)

The method of claim 18, wherein the disease or condition is primary biliary cirrhosis.

### Claim 20 (depends on 18)

The method of claim 18, wherein the disease or condition is nonalcoholic steatohepatitis.

### Claim 21 (depends on 18)

The method of claim 18, wherein the disease or condition is nonalcoholic fatty liver disease.