Bicycloheteroaryl compounds as P2X
View Patent ↗Bicycloheteroaryl compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.
1. A bicycloheteroaryl compound having a formula:
wherein
B and Y are independently selected from CR 2a ;
W, W′ and Z are each independently CR 4 ;
L 1 is substituted or unsubstituted C 1 C 5 alkylene;
n is 1, 2, 3 or 4;
R 1 is selected from a substituted or unsubstituted heterocycloalkyl, aryl and heteroaryl ring;
each of R 2a , R 2′ and R 2″ is independently selected from hydrogen, halo, and substituted or unsubstituted C 1 -C 6 alkyl; or any of R 2′ and R 2″ join together to form a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;
R 3 is hydrogen or a functional group selected from acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, nitro, and thio;
provided that R 3 is other than hydrogen bond donor group;
R 4 is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio;
and the dotted bond is a double bond;
or a pharmaceutically acceptable salt thereof;
and stereoisomers, isotopic variants and tautomers thereof.
2. A compound according to claim 1 wherein each of B and Y is CH; and the dotted bond is a double bond.
3. A compound according to claim 1 wherein each of R 2′ and R 2″ is H.
4. A compound according to claim 1 wherein one of R 2′ and R 2″ is independently Me and the other is H.
5. A compound according to claim 1 wherein R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
6. A compound according to claim 1 wherein R 1 is substituted or unsubstituted phenyl, pyridyl, quinoline, or benzodioxole, benzodioxane, benzofuran, benzothiophene, and benzodioxepine.
7. A compound according to claim 1 wherein the compound is according to formula III or IV:
wherein
W is CR 4 ; Z is CR 4 ;
L 1 , R 1 , R 2′ , R 2″ , R 3 and R 4 are as in claim 1 ;
and R 5 is selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, arylalkyl, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio;
or a pharmaceutically acceptable salt thereof;
and stereoisomers, isotopic variants and tautomers thereof.
8. A compound according to claim 1 wherein the compound is according to formula IX or X:
wherein
W is CR 4 ; Z is CR 4 ;
L 1 , R 3 and R 4 are as in claim 1 ;
R 5 is selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, arylalkyl, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; R 2′ is H or Me;
each R 4a is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; and m is selected from 0-5;
or a pharmaceutically acceptable salt thereof;
and stereoisomers, isotopic variants and tautomers thereof.
9. A compound according to any one of claims 1 , 7 and 8 , wherein L 1 is a C 1 -C 5 alkylene unsubstituted or substituted by one or more substituents independently selected from alkyl and oxo.
10. A compound according to any one of claims 1 , 7 and 8 , wherein R 3 is selected from alkyl, dialkylamino, acyloxy, alkoxy, and —SO 2 -alkyl.
11. A compound according to any one of claims 1 , 7 and 8 , wherein R 3 is selected from t-Bu, NMe 2 , SO 2 Me, OMe, and OCOMe.
12. A compound according to any one of claims 1 , 7 and 8 , wherein R 3 is substituted or unsubstituted aryl, heteroaryl, cycloalkyl or cycloheteroalkyl.
13. A compound according to any one of claims 1 , 7 and 8 , wherein R 3 is substituted or unsubstituted phenyl, pyridyl, pyran, tetrahydropyran, piperidine, morpholine, pyrrolidine, pyrrolidinone and benzodioxane.
14. A compound according to any one of claims 1 , 7 and 8 , wherein the group -L 1 -R 3 is selected from
15. A compound according to claim 1 wherein the compound is according to formula XIa, XIb, XIc, XId, XIe, XIf, XIg, XIh or XIj:
wherein
each R 4a is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; m is selected from 0-5; and R 5 is selected from H, alkyl, or halo.
16. A compound according to any one of claims 8 and 15 , wherein m is 1 or 2; and each R 4a is independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF 3 , CHF 2 , OCF 3 , i-Pr, i-Bu, t-Bu, SMe, CH═CH—CO 2 H, SOMe, SO 2 Me, SO 3 H, SO 3 Me, and pyridyl.
17. A compound according to any one of claims 1 , 7 and 8 , wherein each of W and Z is independently CH.
18. A compound according to any one of claims 7 , 8 and 15 , wherein R 5 is H, Me, Cl, F, or CF 3 .
19. A compound according to claim 1 wherein the compound is selected from table below:
ID
Structure
1001
1002
1003
1004
1005
1009
1010
1011
1016
1017
1018
1019
1020
1021
1022
1023
1027
1028
1031
1032
1036
1037
1038
1041
1042
1045
1046
1048
1049
1050
1051
1054
1055
1057
1058
1062
1064
1065
1066
1069
1070
1075
1076
1077
1079
1080
1093
1094
1095
1097
1099
1100
1101
1102
1103
1104
1105
1106
1107
1108
1110
1111
1119
1121
1123
1125
1126
1127
1130
1134
1135
1148
1149
1150
1152
1154
1155
1156
1157
1158
1159
1160
1161
1163
1164
1171
1173
1176
1177
1178
1181
1185
1186
1200
1201
1202
1203
1204
1205
1206
1207
1208
1209
1210
1211
1212
1213
1214
1215
1217
1218
1226
1228
1230
1232
1233
1234
1237
1241
1242
1247
1248
1250
1252
1253
1254
1255
1256
1257
1258
1259
1260
1261
1262
1263
1265
1266
1274
1276
1278
1280
1281
1284
1286
1287
1292
1293
1294
1295
1296
1297
1298
1299
1301
1307
1309
1311
1313
1314
1315
1316
1317
1318
1319
1321
1322
1329
1331
1333
1335
1336
1337
1338
1341
1342
1347
1348
1349
1350
1351
1352
1353
1354
1355
1356
1357
1359
1360
1365
1366
1367
1369
1374
1376
1377
1378
1380
1381
1382
1383
1384
1385
1386
1387
1391
1392
1396
1399
1400
1401
1404
1406
1409
1417
1422
1423
1431
1432
1433
1435
1436
1437
1438
1439
1449
1450
1453
1455
1457
1459
1466
1467
1468
1470
1472
1473
1474
1475
1477
1482
1484
1485
1488
1491
1492
1495
1497
1498
1499
1501
1502
1517
1518
1519
1520
1521
1522
1523
1524
1525
1527
1528
1531
1535
1537
1538
1539
1542
1546
1547
1550
1552
1553
1554
1557
1558
1570
1571
1572
1573
1575
1576
1577
1578
1579
1580
1581
1582
1583
1584
1585
1586
1588
1589
1597
1599
1601
1603
1604
1605
1606
1609
1610
1611
1612
1613
1614
1615
1616
1617
1618
1620
1621
1623
1624
1626
1627
1628
1630
1631
1632
1633
1634
1635
1636
1637
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .
21. The pharmaceutical composition of claim 20 , wherein the carrier is a parenteral, oral or topical carrier.