Antiviral heterocyclic compounds
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Human Respiratory Syncytial Virus (HRSV) or Human Metapneumovirus (HMPV) inhibitors. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HRSV or HMPV infection. The invention also relates to methods of treating an HRSV or HMPV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of:
1) Optionally substituted aryl; and
2) Optionally substituted heteroaryl;
E is selected from the group consisting of:
1) Optionally substituted aryl; and
2) Optionally substituted heteroaryl;
R 1 and R 2 are each independently selected from the group consisting of:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) optionally substituted —C 3 -C 8 cycloalkyl;
4) Optionally substituted 3- to 8-membered heterocycloalkyl;
5) Optionally substituted aryl;
6) Optionally substituted arylalkyl;
7) Optionally substituted heteroaryl; and
8) Optionally substituted heteroarylalkyl;
alternatively, Rand R 2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocyclic ring;
R 3 is hydroxy or fluorine; and
R 4 is selected from the group consisting of:
1) Optionally substituted aryl;
2) Optionally substituted arylalkyl;
3) optionally substituted heteroaryl; and
4) Optionally substituted heteroarylalkyl.
2. The compound of claim 1 , wherein R 4 selected from the groups set forth below:
wherein R 31 is halogen, —CN, —OR 33 , —CO 2 R 33 , —SO 2 R 33 , —SO 2 NR 33 R 34 , —NR 33 R 34 , optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 6 alkenyl, or optionally substituted —C 3 -C 8 cycloalkyl; n is 0, 1 or 2; R 33 and R 34 are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
3. A compound selected from the compounds set forth in the table below, or a pharmaceutically acceptable salt thereof,
Compound
Structure
9
12
13
14
15
16
17
18
19
25
26
41
42
43
44
45
79
80
81
82
83
84
85
86
87
88
89
90
93
94
95
96
97
98
99
100
101
102
109
110
113
115
117
118
130
131
132
237
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
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
210
213
216
217
219
220
221
222
223
224
227
228
229
230
231
232
233
234
241
242
243
244
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
307
308
311
312
313
314
315
305
331
332
333
334
335
336
337
339
340
342
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
466
397
398
399
400
405
406
463
464
467
468
469
470
471
472
474
475
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
.
4. The compound of claim 3 , selected from the compounds set forth in the table below, or a pharmaceutically acceptable salt thereof:
Example #
Structure
85
155
170
187
258
259
262
266
269
275
277
280
286
291
5. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
6. A method of treating or preventing an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .
7. The method of claim 6 , further comprising the step of administering to the subject an additional anti-RSV agent.
8. The method of claim 6 , further comprising administering to the subject a steroid anti-inflammatory compound.
9. A method of treating an RSV infection and influenza in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 and a therapeutically effective amount of an anti-influenza agent.
10. The method of claim 7 , wherein the compound and the additional anti-RSV agent are co-formulated.
11. The method of claim 7 , wherein the compound and the additional anti-RSV agent are co-administered.
12. The method of claim 7 , wherein administering the compound allows for administering of the additional anti-RSV agent at a lower dose or frequency as compared to the administering of the additional anti-RSV agent alone that is required to achieve similar results in prophylactically treating an RSV infection in a subject in need thereof.
13. A method of treating or preventing an HMPV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .
14. The method of claim 13 , further comprising the step of administering to the subject an additional anti-HMPV agent.
15. The method of claim 14 , wherein the compound and the additional anti-HMPV agent are co-formulated.
16. The method of claim 14 , wherein the compound and the additional anti-HMPV agent are co-administered.