# US 2014/0193363 A1 · Novel benzimidazole derivatives

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- Number: US 2014/0193363 A1
- Document ID: US20140193363A1
- Status: Published application
- Kind: A1
- Application number: 14/155,653
- Filed: 2014-01-15
- Published: 2014-07-10
- Earliest claimed: 2009-02-27
- Assignees: Enanta Pharmaceuticals, Inc.
- Applicants: Enanta Pharmaceuticals, Inc.
- Inventors: Yao-Ling Qiu; Ce Wang; Xiaowen Peng; Lu Ying; Yat Sun Or
- Web page: https://patentgrep.com/patent/US20140193363A1

## CPC

- C07D 403/14: containing three or more hetero rings
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4245: Oxadiazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 38/19: Cytokines; Lymphokines; Interferons
- A61K 38/21: Interferons {[IFN]}
- A61K 38/212: {IFN-alpha}
- A61K 38/215: {IFN-beta}
- A61K 38/217: {IFN-gamma}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/08: Bridged systems
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

## Claims

### Claim 1

A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
D and Z are are each independently absent or optionally substituted linear aliphatic group comprising zero to eight carbons;
A and E are are each independently absent or a cyclic group; wherein said each cyclic group is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, each optionally substituted;
T is absent or an optionally substituted aliphatic group;
Wherein one to four of A, D, E, T and Z is absent;
Ring B is a five-membered heteroaryl, wherein said heteroaryl is optionally substituted;
R1 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C4 alkyl, —O—R11, —NRaRb, —C(O)R11, —CO2R11, and —C(O)NRaRb;
R11 at each occurrence is independently hydrogen or optionally substituted C1-C8 alkyl;
Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C2-C8 alkenyl; or Ra and Rb can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
u is independently 1, 2, or 3;
Q and J are each independently selected from:
R3 and R4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C3-C8 cycloalkyl; or alternatively, R3 and R4 can be taken together with the carbon atom to which they are attached to form optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic;
R5 at each occurrence is independently hydrogen, optionally substituted C1-C8 alkyl, or optionally substituted C3-C8 cycloalkyl;
R6 is selected from the group consisting of —C(O)—R12, —C(O)—C(O)—R12, —S(O)2—R12, and —C(S)—R12;
R12 at each occurrence is independently selected from the group consisting of —O—R11, —NRaRb, —R13, and —NRcRd; wherein
R13 at each occurrence is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; and
Rc and Rd at each occurrence are each independently selected from the group consisting of hydrogen, —R13, —C(O)—R13, —C(O)—OR13, —S(O)2—R13, —C(O)N(R13)2, and —S(O)2N(R13)2;
m is 0, 1, or 2;
n is 1, 2, 3, or 4;
X at each occurrence is independently selected from O, S, S(O), SO2, and C(R7)2; provided that when m is 0, X is C(R7)2; and
R7 at each occurrence is independently selected from the group consisting of: hydrogen, halogen, cyano, —O—R11, —NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted —C1-C4 alkyl; or two vicinal R7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring; or alternatively two geminal R7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Q and J are each independently selected from:
wherein X is independently CH2, CF2, CHF, or CH(OH); or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Ring B is selected from imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and isoxazolyl; and Ring B is C-attached to J and C-attached to one of Z, E, T, A and D; or a pharmaceutically acceptable salt.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Q and J are each independently
R1 is each independently hydrogen; Ring B is selected from imidazolyl, pyrazolyl, 1,3,4-triazolyl, and 1,3,4-oxadiazolyl; and Ring B is C-attached to J and C-attached to one of Z, E, T, A and D; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein each of D, A, E, and Z are absent and T is present; or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein each of D, E, T, and Z are absent, and A is present; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein each of D, E, and Z are absent and each of A and T are present; or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein each of D, A, and Z are absent and each of T and E are present; or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein each of D, T, and Z are absent and A and E are each present; or a pharmaceutically acceptable salt thereof

### Claim 10 (depends on 1)

The compound of claim 1, wherein each of E and Z are absent and D, A, and T are each present; or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, wherein each of D and A are absent and T, E, and Z are present or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein each of D and Z are absent and A, T, and E are present; or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, wherein D is absent and A, T, E, and Z are are each present; or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Z is absent and D, A, T, and E are each present; or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1, wherein each of D, A, E, and Z are absent and T is an aliphatic group comprising one or more of an olefinic double bond, an alkynic triple bond, O, N(R11), C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(R11)C(O)N(R11), N(R11)C(O)N(R11), N(R11)S(O)2N(R11), C(O)N(R11)S(O)2 and C(O)N(R11)S(O)2N(R11); or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound according to claim 1, selected from the group of compounds 1-1, 2-1, 2-2, and 1-440 shown below, or a pharmaceutically acceptable salt thereof:
Compounds 1-219
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
Compounds 220-229
Entry
R
R′
R″
X
220
Me
H
H
CH2
221
H
H
H
CF2
222
Me
H
H
S
223
H
H
H
224
Me
H
H
O
225
H
H
H
226
H
Ph
H
CH2
227
H
H
H
228
H
H
Ph
CH2
229
H
H
H
Compounds 234-243
Entry
R
R′
R″
234
Me
Me
H
235
H
Me
H
236
Me
H
Me
237
cyclopropyl
Me
H
238
Me
Me
Me
239
Me
cyclopropyl
H
240
Me
Allyl
H
241
Et
Me
H
242
Me
CHMe2
H
243
Me
Et
H
Compounds 244-263
Entry
R
R′
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
Compounds 264-273
Entry
R
R′
R″
R′′′
264
F
H
H
H
265
F
F
H
H
266
Me
H
H
H
267
Me
Me
H
H
268
H
H
Me
Me
269
H
H
Et
Et
270
CF3
H
H
H
271
CF3
H
CF3
H
272
Cl
H
H
H
273
Cl
H
Cl
H
Compounds 274-299
Entry
R
R′
R″
R′′′
274
Me
H
H
H
275
H
CO2H
H
H
276
H
F
H
H
277
H
H
CO2H
H
278
H
H
F
H
279
H
H
H
CO2H
280
H
H
H
F
281
H
CO2Me
H
H
282
H
Cl
H
H
283
H
H
CO2Me
H
284
H
H
Cl
H
285
H
H
H
CO2Me
286
H
H
H
Cl
287
H
CONH2
H
H
288
H
Me
H
H
289
H
H
CONH2
H
290
H
H
Me
H
291
H
H
H
CONH2
292
H
H
H
Me
293
H
OMe
H
H
294
H
CF3
H
H
295
H
H
OMe
H
296
H
H
CF3
H
297
H
H
H
OMe
298
H
H
H
CF3
299
CO2Me
H
H
H
Compounds 300-434
Entry
Aa
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
Compounds 435-440
Entry
Bb
435
436
437
438
439
440

### Claim 17 (depends on 1)

A compound of claim 1, represented by Formula (II), or a pharmaceutically acceptable salt thereof:

### Claim 18 (depends on 17)

A compound of claim 17, wherein m is 1; n is 1 or 2; u is 1 or 2; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; T is absent or optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl; R1 at each occurrence is independently hydrogen or halogen; X at each occurrence is each independently CH2, CHF, CH(OH), CHMe, CF2, or C(R7)2; wherein R7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R7 groups are taken together with the carbon to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl; or yet alternatively, two vicinal R7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-C8 cycloalkyl; and R12 at each occurrence is independently optionally substituted C1-C8 alkyl; or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A compound of claim 1, represented by Formula (III-a), (III-b), (III-c) or (III-d):
wherein n is 1 or 2; X at each occurrence is independently CH2, CHF, CH(OH), CHMe, CF2, or C(R7)2; wherein R7 at each occurrence is independently hydrogen or methyl; alternatively, two geminal R7 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal R7 groups are taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R12 at each occurrence is independently C1-C8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(C1-C4 alkyl); or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

The compound of claim 1, wherein
is selected from the group listed below, or a pharmaceutically acceptable salt thereof:

### Claim 21 (depends on 1)

A compound according to claim 1 selected from the group of compounds 441-545 shown below, or a pharmaceutically acceptable salt thereof:

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound or a combination of compounds according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.

### Claim 23 (depends on 1)

A method of inhibiting the replication of an RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

A method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The method of claim 24, wherein the RNA-containing virus is hepatitis C virus.

### Claim 26 (depends on 24)

The method of claim 24, further comprising the step of co-administering one or more agents selected from the group consisting of a host immune modulator and an antiviral agent, or a combination thereof.

### Claim 27 (depends on 26)

The method of claim 26, wherein the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, consensus interferon, a cytokine, and a vaccine.

### Claim 28 (depends on 26)

The method of claim 26, wherein the antiviral agents inhibit replication of HCV by inhibiting host cellular functions associated with viral replication.

### Claim 29 (depends on 26)

The method of claim 26, wherein the antiviral agents inhibit the replication of HCV by targeting proteins of the viral genome.

### Claim 30 (depends on 26)

The method of claim 26, wherein said antiviral agent is an inhibitor of a HCV viral protein, a replication process or a combination thereof, wherein said targeting protein or replication process is selected from the group consisting of helicase, protease, polymerase, metalloprotease, NS4A, NS4B, NS5A, assembly, entry, and IRES.

### Claim 31 (depends on 24)

The method of claim 24, further comprising the step of co-administering an agent or combination of agents that treat or alleviate symptoms of HCV infection selected from cirrhosis and inflammation of the liver.

### Claim 32 (depends on 24)

The method of claim 24, further comprising the step of co-administering one or more agents that treat patients for disease caused by hepatitis B (HBV) infection.

### Claim 33 (depends on 24)

The method of claim 24, further comprising the step of co-administering one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection.

### Claim 34 (depends on 22)

The pharmaceutical composition of claim 22, further comprising an agent selected from interferon, pegylated interferon, ribavirin, amantadine, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internal ribosome entry site inhibitor.

### Claim 35 (depends on 22)

The composition of claim 22, further comprising a cytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 35)

The composition of claim 35, wherein the cytochrome P450 mooxygenase inhibitor is ritonavir.

### Claim 37 (depends on 1)

A method of treating hepatitis C infection in a subject in need thereof comprising co-administering to said subject a cytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptable salt thereof, and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 1)

A process of making a compound of claim 1 comprising the steps of:
i) preparing a compound of Formula (II-a):
via a transition-metal catalyzed cross-coupling reaction;
wherein:
E is optionally substituted aryl or optionally substituted heteroaryl; T, X, n, u, R1, and R7 are as defined in claim 1;
Za and Zb are each independently an amino protecting group or —C(O)—R12; R12 is C1-C8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(C1-C4 alkyl);
ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (II-b):
wherein Zc is hydrogen, an amino protecting group or —C(O)—R12;
iii) capping the released amino group of a compound of Formula (II-b) with LG-C(O)—R12, wherein LG is a leaving group; to give the compound of Formula (II-c):
wherein Zd is an amino protecting group —C(O)—R12; and
iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (II-d):