The subject invention relates to novel P2X 3 receptor antagonists that play a critical role in treating disease states associated with pain, in particular peripheral pain, inflammatory pain, or tissue injury pain that can be treated using a P2X 3 receptor subunit modulator.
1. A compound of structural formula I:
or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:
X and Y independently represent N, or CR 1 ;
R 6 represents OH, (CH 2 ) n CF 3 , SO 2 R 2 , N(R 2 ) 2 , C(R 2 ) 2 OR 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, (CH 2 ) n C 6-10 aryl, (CH 2 ) n C 5-10 heterocyclyl, said alkyl substituted and said alkenyl, alkynyl, aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a , provided said heterocyclyl is not thiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, dihydro-isoxazolyl, or oxadiazolyl, provided that when R 6 is (CH 2 ) n C 5-10 heterocyclyl it is not tetrazolyl;
R 1 represents H, C 1-6 alkyl, halogen, (CH 2 ) n CF 3 , C 3-10 cycloalkyl, C(R 2 ) 2 OH, —O—, CN, (CH 2 ) n OR 2 , (CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, or C 1-6 alkoxy; said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of C 1-6 alkyl, halogen, hydroxyl, (CH 2 ) n CF 3 , or CN;
R 2 represents H, C 1-6 alkyl, CF 3 , OH;
R 3 represents —CR 2 R 4 R 5 , —(C(R 2 ) 2 ) n C 3-10 cycloalkyl, —(C(R 2 ) 2 ) n C 5-10 heterocycle, said cycloalkyl and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
or R 2 and R 3 can be combined with the nitrogen to which they are attached to form a C 5-10 heterocyclyl optionally substituted with 1 to 3 groups of R a ;
R 4 and R 5 independently represent H, (CH 2 ) n OR 2 , (CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n CF 3 , CHF 2 , CN, C(O) 1-2 R 2 , or C 1-6 alkyl; said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of R a , provided that when R 3 is —CR 2 R 4 R 5 and the R 4 is substituted by R a , the R a substituent is not N(R 4 ) 2 ;
R a represents C 1-6 alkyl, halogen, —CHF 2 , —(CH 2 ) n CF 3 , —O—, C 3-6 cycloalkyl, NR 2 C(O)R 2 , C(O)N(R 2 ) 2 , C(R 2 ) 2 OR 2 , C(O)R 2 , NO 2 , CN, N(R 2 ) 2 , C(O)OR 2 , SO 2 R 2 , OR 2 , (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 6-10 aryl, said alkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of C 1-6 alkyl, halogen, OR 2 , N(R 4 ) 2 , C(O)N(R 2 ) 2 , (CH 2 ) n CF 3 , or CN; and
n represents 0 to 4.
2. The compound according to claim 1 wherein one of X and Y is N and the other is CH.
3. The compound according to claim 2 wherein X is N and Y is CH.
4. The compound according to claim 1 wherein R 6 represents a substituted C 1-6 alkyl, substituted with 1 to 3 groups selected from N(R 2 ) 2 , CF 3 , OH, CHF 2 , CH 3 , phenyl and pyridyl.
5. The compound according to claim 1 wherein R 6 represents a (CH 2 ) n C 6-10 aryl, said aryl optionally substituted with 1 to 3 groups of R a .
6. The compound according to claim 1 wherein R 6 represents a (CH 2 ) n C 5-10 heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 groups of R a , provided said heterocyclyl is not oxazolyl, isoxazolyl, dihydro-isoxazolyl, or oxadiazolyl.
7. The compound according to claim 1 wherein X is N, Y is CH, R 3 is CR 2 R 4 R 5 , R 2 in CR 2 R 4 R 5 of R 3 is hydrogen, and one of R 4 and R 5 is C 1-6 alkyl and the other is (CH 2 ) n C 5-10 heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 groups of R a .
8. The compound according to claim 7 wherein R 6 represents a substituted C 1-6 alkyl, substituted with 1 to 3 groups of Ra.
9. The compound according to claim 8 wherein the alkyl is substituted with 1 to 3 groups selected from N(R 2 ) 2 , CF 3 , OH, CHF 2 , CH 3 , phenyl and pyridyl.
10. The compound according to claim 6 wherein R 6 is imidazolyl, triazolyl, pyrazolyl, piperazinyl, pyridyl, morpholinyl, and oxazinyl optionally substituted with 1 to 3 groups of Ra, one of X and Y is nitrogen and the other is CH, the R2 in CR 2 R 4 R 5 of R3 is hydrogen, and one of R4 and R5 is C1-6 alkyl or hydrogen and the other is C5-10 heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 groups of Ra.
11. The compound according to claim 6 wherein R 6 is imidazolyl, triazolyl, pyrazolyl, piperazinyl, pyridyl, morpholinyl, and oxazinyl optionally substituted with 1 to 3 groups of R a , X and Y are CH, the R 2 in CR 2 R 4 R 5 of R 3 is hydrogen, and one of R 4 and R 5 is C 1-6 alkyl or hydrogen and the other is (CH 2 ) n C 5-10 heterocyclyl, said heterocylyl optionally substituted with 1 to 3 groups of R a .
12. The compound according to claim 1 wherein R 6 is substituted C 1-6 alkyl, X and Y are CH, the R 2 in CR 2 R 4 R 5 of R 3 is hydrogen, and one of R 4 and R 5 is C 1-6 alkyl or hydrogen and the other is (CH 2 ) n C 5-10 heterocyclyl, said heterocylyl optionally substituted with 1 to 3 groups of R a .
13. The compound according to claim 1 wherein R 3 is —(C(R 2 ) 2 ) n C 3-10 cycloalkyl, said cycloalkyl optionally substituted with 1 to 3 groups of R a .
14. The compound according to claim 1 wherein R 3 is —(C(R 2 ) 2 ) n C 5-10 heterocycle, said heterocylyl optionally substituted with 1 to 3 groups of R a .
15. The compound according to claim 14 wherein the heterocycle is selected from the group consisting of triazolyl, pyridyl, pyrimidinyl, oxazolyl, pyrazolyl and oxadiazolyl, optionally substituted by 1 to 3 groups of R a .
16. A compound of Tables 1-7 or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof:
TABLE 1
EX
Structure
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
1.10
1.11
1.12
1.13
1.14
1.15
1.16
1.17
1.18
1.19
1.20
1.21
1.22
1.23
1.24
1.25
1.26
1.27
1.28
1.29
1.30
1.31
1.32
1.33
1.34
1.35
1.36
1.37
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
1.58
1.59
1.60
1.61
1.62
1.63
1.64
1.65
1.66
1.67
1.68
1.69
1.70
1.71
1.72
1.73
1.74
1.75
1.76
1.77
1.78
1.79
1.80
1.81
1.82
1.83
1.84
1.85
1.86
1.87
1.88
1.89
1.90
1.91
1.92
1.93
1.94
1.95
1.96
1.97
1.98
1.99
1.100
1.101
1.102
1.103
1.104
TABLE 2
EX
Structure
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
2.11
2.12
2.13
2.14
TABLE 3
EX
Structure
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13
3.14
3.15
3.16
3.17
3.18
3.19
3.20
3.21
TABLE 4
Example
R 1
R 2
R 3
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.11
4.12
4.13
4.14
4.15
4.16
4.17
4.18
4.19
4.20
4.21
4.22
4.23
4.24
4.25
4.26
4.27
4.28
4.29
4.30
4.31
4.32
4.33
4.34
4.35
4.36
4.37
4.38
4.39
4.40
4.41
4.42
4.43
4.44
4.45
4.46
4.47
4.48
4.49
4.50
4.51
4.52
4.53
4.54
4.55
4.56
4.57
4.58
4.59
4.60
4.61
4.62
4.63
4.64
4.65
4.66
4.67
4.68
4.69
4.70
4.71
4.72
4.73
4.74
4.75
4.76
4.77
4.78
4.79
4.80
4.81
4.82
4.83
4.84
4.85
4.86
4.87
4.88
4.89
4.90
4.91
4.92
4.93
4.94
4.95
4.96
4.97
4.98
4.99
4.100
4.101
4.102
4.103
4.104
4.105
4.106
4.107
4.108
4.109
4.110
4.111
4.112
4.113
4.114
4.115
4.116
4.117
4.118
4.119
4.120
4.121
4.122
4.123
4.124
4.125
4.126
4.127
4.128
4.129
4.130
4.131
4.132
4.133
4.134
4.135
4.136
4.137
4.138
4.139
4.140
4.141
4.142
4.143
4.144
4.145
4.146
4.147
4.148
4.149
4.150
4.151
4.152
4.153
4.154
4.155
4.156
4.157
4.158
4.159
4.160
4.161
4.162
4.163
4.164
4.165
4.166
4.167
4.168
4.169
4.170
4.171
4.172
4.173
4.174
4.175
4.176
4.177
4.178
4.179
4.180
4.181
4.182
4.183
4.184
4.185
4.186
4.187
4.188
4.189
4.190
4.191
4.192
4.193
4.194
4.195
4.196
4.197
4.198
4.199
4.200
4.201
4.202
4.203
4.204
4.205
4.206
4.207
4.208
4.209
4.210
4.211
4.212
4.213
4.214
4.215
4.216
4.217
4.218
4.219
4.220
4.221
4.222
4.223
4.224
4.225
4.226
4.227
4.228
4.229
4.230
4.231
4.232
4.233
4.234
4.235
4.236
4.237
4.238
4.239
4.240
4.241
4.242
4.243
4.244
4.245
4.246
4.247
4.248
4.249
4.250
4.251
4.252
4.253
4.254
4.255
4.256
4.257
4.258
4.259
4.260
4.261
4.262
4.263
4.264
4.265
4.266
4.267
4.268
4.269
4.270
4.271
4.272
4.273
4.274
4.275
4.276
4.277
4.278
4.279
4.280
4.281
4.282
4.283
4.284
4.285
4.286
4.287
4.288
4.289
4.290
4.291
4.292
4.293
4.294
4.295
4.296
4.297
4.298
4.299
4.300
4.301
4.302
4.303
4.304
4.305
4.306
4.307
4.308
4.309
4.310
4.311
4.312
4.313
4.314
4.315
4.316
4.317
4.318
4.319
4.320
4.321
4.322
4.323
4.324
4.325
4.326
4.327
4.328
4.329
4.330
4.331
4.332
4.333
4.334
4.335
4.336
4.337
4.338
4.339
4.340
4.341
4.342
4.343
4.344
4.345
4.346
4.347
4.348
4.349
4.350
4.351
4.352
4.353
4.354
4.355
4.356
4.357
4.358
4.359
4.360
4.361
4.362
4.363
4.364
4.365
4.366
4.367
4.368
4.369
4.370
4.371
4.372
4.373
4.374
4.375
4.376
4.377
4.378
4.379
4.380
4.381
4.382
4.383
4.384
4.385
4.386
4.387
4.388
4.389
4.390
4.391
4.392
4.393
4.394
4.395
4.396
4.397
4.398
4.399
4.400
4.401
4.402
4.403
4.404
4.405
4.406
4.407
4.408
4.409
4.410
4.411
4.412
4.413
4.414
4.415
4.416
4.417
4.418
4.419
4.420
4.421
4.422
4.423
4.424
4.425
4.426
4.427
4.428
4.429
4.430
4.431
4.432
4.433
4.434
4.435
4.436
4.437
4.438
4.439
4.440
4.441
4.442
4.443
4.444
4.445
4.446
4.447
4.448
4.449
4.450
4.451
4.452
4.453
4.454
4.455
4.456
4.457
4.458
4.459
4.460
4.461
4.462
4.463
4.464
4.465
4.466
4.467
4.468
4.469
4.470
4.471
4.472
4.473
4.474
4.475
4.476
4.477
4.478
4.479
4.480
4.481
4.482
4.483
4.484
4.485
4.486
4.487
4.488
4.489
4.490
4.491
4.492
4.493
4.494
4.495
4.496
4.497
4.498
4.499
4.500
4.501
4.502
4.503
4.504
4.505
4.506
4.507
4.508
4.509
4.510
4.511
4.512
4.513
4.514
4.515
4.516
4.517
4.518
4.519
4.520
4.521
4.522
4.523
4.524
4.525
4.526
4.527
4.528
4.529
4.530
4.531
4.532
4.533
4.534
4.535
4.536
4.537
4.538
4.539
4.540
4.541
4.542
4.543
4.544
4.545
4.546
4.547
4.548
4.549
4.550
4.551
4.552
4.553
4.554
4.555
4.556
4.557
4.558
4.559
4.560
4.561
4.562
4.563
4.564
4.565
4.566
4.567
4.568
4.569
4.570
4.571
4.572
4.573
4.574
4.575
4.576
4.577
4.578
4.579
4.580
4.581
4.582
4.583
4.584
4.585
4.586
4.587
4.588
4.589
4.590
4.591
4.592
4.593
4.594
4.595
4.596
4.597
4.598
4.599
4.600
4.601
4.602
4.603
4.604
4.605
4.606
4.607
4.608
4.609
4.610
4.611
4.612
4.613
4.614
4.615
4.616
4.617
4.618
4.619
4.620
4.621
4.622
4.623
4.624
4.625
4.626
4.627
4.628
4.629
4.630
4.631
4.632
4.633
4.634
4.635
4.636
4.637
4.638
4.639
4.640
4.641
4.642
4.643
TABLE 5
EX
Structure
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
5.10
TABLE 6
EX
Structure
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
6.9
TABLE 7
EX
Structure
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
17. A compound according to claim 16 which is:
N-[(1R)-1-(5-Fluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-[(R/S)-2,2,2-trifluoro-1-hydroxyethyl]benzamide;
4′-Methyl-N-(2,2,2-trifluoroethyl)-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxamide;
3-(5-Fluoropyridin-2-yl)-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}-5-[(R/S)-2,2,2-trifluoro-1-hydroxyethyl]benzamide;
4′-Methyl-5-[2,2,2-trifluoro-1-hydroxy-(trifluoromethyl)ethyl]-N-{(1R)-1-[2-(trifluoromethyl)-pyrimidine-5-yl]ethyl}biphenyl-3-carboxamide
4′-Methyl-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridyn-3-yl]ethyl}-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]biphenyl-3-carboxamide;
N-[(1R)-1-(4-Fluorophenyl)ethyl]-3-(5-methylpyridin-2-yl)-5-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]benzamide;
2′-Fluoro-5-[hydroxy(phenyl)methyl]-N-isopropyl-4′-methylbiphenyl-3-carboxamide;
3-(5-Cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-5-(5-methylpyridin-2-yl)benzamide;
3-(5-Cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-N-[(1R)-1-(3,5-difluoropyridin-2-yl)ethyl]-5-(5-methylpyridin-2-yl)benzamide;
3-(5-Methylpyridin-2-yl)-5-(4-methyl-4H-1,2,4-triazol-3-yl)-N-{(1R)-1-[5-(trifluoromethyl)pyridin-2-yl]ethyl}benzamide;
N-[(1R)-1-(3,5-Difluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-(1-methyl-1H-1,2,3-triazol-5-yl)benzamide;
2′,4′-Difluoro-5-piperazin-1-yl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}biphenyl-3-carboxamide;
2′-Fluoro-4′-methyl-5-morpholin-4-yl-N-[(1R)-1-(1H-1,2,4-triazol-3-yl)ethyl]biphenyl-3-carboxamide;
3-(3-Fluoropyridin-2-yl)-N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-5-(5-methylpyridin-2-yl)benzamide;
3-(3-Fluoropyridin-2-yl)-N-[(1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]-5-(5-methylpyridin-2-yl)benzamide;
3-(5-Chloropyridin-2-yl)-5-(1-hydroxy-1-methylethyl)-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide;
N-[(1R)-1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-(2-methylpyrimidin-5-yl)benzamide;
3-Isopropyl-5-(5-methylpyridin-2-yl)-N-[(1S)-1-(4H-1,2,4-triazole-3-yl)ethyl]benzamide;
3-(1-Hydroxy-1-methylethyl)-5-(5-methylpyridin-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; or
2′,4′-Difluoro-5-(1-hydroxy-1-methylethyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]biphenyl-3-carboxamide;
or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof.
18. A compound according to claim 17 which is 3-(5-Chloropyridin-2-yl)-5-(1-hydroxy-1-methylethyl)-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof.
19. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .