Heterocyclic compounds as RSV inhibitors
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV infection. The invention also relates to methods of treating an RSV 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:
each of which is optionally substituted with 1 or 2 substituents independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —SO 2 CH 3 , —CH 2 N(CH 3 ) 2 , and —C(O)CH 3 , and wherein in the bicyclic groups,
denotes the bond to L and
denotes the bond to R 1 ;
L is —CH 2 —, —CO—, or —SO 2 —;
B is aryl or heteroaryl, each of which is optionally substituted with one or two substituents selected from halogen, cyano and nitro;
R 1 is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocycloalkyl;
4) Optionally substituted aryl;
5) Optionally substituted heteroaryl;
6) —C(O)R 12 ;
7) —C(O)NR 11 S(O) 2 R 12 ;
8) —S(O) 2 NR 13 R 14 ;
9) —NR 13 R 14 ;
10) —NR 11 S(O) 2 R 12 ;
11) —NR 11 C(O)NR 13 R 14 ; and
12) —NR 11 C(O)NHS(O) 2 R 12 ;
R 2 is selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkoxy;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl;
5) Optionally substituted —C 3 -C 12 cycloalkyl;
6) Optionally substituted —C 3 -C 12 cycloalkenyl;
7) Optionally substituted 3- to 12-membered heterocycloalkyl;
8) —C(O)R 12 ;
9) —C(O)NR 13 R 14 ;
10) —C(O)NR 11 S(O) 2 R 12 ;
11) —S(O) 2 NR 13 R 14 ;
12) —NR 13 R 14 ;
13) —NR 11 S(O) 2 R 12 ;
14) —NR 11 C(O)R 12 ;
15) —NR 11 C(O)NR 13 R 14 ; and
16) —NR 11 C(O)NHS(O) 2 R 12 ;
Each R 3 is independently selected from halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, and optionally substituted —C 1 -C 8 alkyl-O—C 1 -C 8 alkoxy;
R 12 at each occurrence is independently selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkoxy;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl;
5) Optionally substituted —C 3 -C 8 cycloalkyl;
6) Optionally substituted —C 3 -C 8 cycloalkenyl;
7) Optionally substituted 3- to 8-membered heterocycloalkyl;
8) Optionally substituted aryl;
9) Optionally substituted arylalkyl;
10) Optionally substituted heteroaryl; and
11) Optionally substituted heteroarylalkyl;
R 11 , R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 5 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered heterocyclic ring; and
n is 0, 1, 2, 3 or 4.
2. The compound of claim 1 , wherein L is —CO—.
3. The compound of claim 1 , wherein R 2 is —C(O)NR 13 R 14 , and R 13 and R 14 are as defined in claim 1 .
4. The compound of claim 1 , wherein R 1 is selected from one of the following groups by removal of one hydrogen atom, wherein each of the groups is optionally substituted:
5. The compound of claim 1 , represented by one of Formulas (IIIa)-(IIIh), or a pharmaceutically acceptable salt thereof:
wherein A, L, R 1 , R 2 , R 3 , and n are as defined in claim 1 .
6. A compound of claim 1 , represented by one of Formulas (IVa)-(IVc), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , and n are as defined in claim 1 , and R a is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, or —CN.
7. The compound of claim 1 , represented by one of Formulas (Va)-(Vc), or a pharmaceutically acceptable salt thereof, wherein:
wherein R 1 , R 3 , R 13 , R 14 , and n are as defined in claim 1 , and R a is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, or —CN.
8. A compound of claim 1 , represented by one of Formulas (VIa)-(VIc) and (VIe)-(VIg), or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 13 , R 14 , and n are as defined in claim 1 ; R a is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, or —CN; each U is independently selected from N, C and CH; W is C or N; each V is independently selected from N, NH, O, S, C and CH; R a and R b are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and —CN; and R c is hydrogen, optionally substituted alkyl or selected from one of the following groups by removal of one hydrogen atom, and each group is optionally substituted:
9. A compound selected from the compounds set forth in the table below or a pharmaceutically acceptable salt thereof:
Entry
Compound
2
4
5
6
7
9
10
11
12
13
14
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
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
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
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
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
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
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
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
10. A pharmaceutical composition comprising a compound according to claim 1 , in combination with a pharmaceutically acceptable carrier, diluent or excipient.
11. A method of treating 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 .
12. The method of claim 11 , further comprising the step of administering to the subject an additional anti-RSV agent.
13. The method of claim 11 , further comprising administering to the individual a steroid anti-inflammatory compound.
14. A method of treating RSV 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.
15. The method of claim 12 , wherein the compound and the additional anti-RSV agent are co-formulated.
16. The method of claim 12 , wherein the compound and the additional anti-RSV agent are co-administered.
17. The compound of claim 1 , wherein A is
18. The compound of claim 1 , wherein R 1 is —R 13 R 14 .
19. The compound of claim 17 , wherein R 1 is —NR 13 R 14 .
20. The compound of claim 18 , wherein R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclic.