Serine protease inhibitors containing substituted oxadiazole, thiadiazole and triazole peptide derivatives

摘要

The pyrrole derivative has the formula (I) wherein: X is O and Y is N; R1 is isopropyl, n-butyl, tert-butyl, or is alkyl substituted with one or more carboxyl, carboalkoxy, amino, alkylamino or dialkylamino groups or is alkyl fused aryl, alkyl fused arylcycloalkyl, alkyl(aryl)2 or a,a-dialkyl-arylalkyl optionally comprising 1-4 heteroatoms selected from O, S and N, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, aryl, -O-aryl, arylcarboxamide, alkylthio or haloalkylthio or R1 is aryl or arylalkyl substituted with alkyl, amino, alkylamino, dialkylamino, optionally substituted aryl or aryloxy or is aryl or arylalkyl substituted with two more halo, cyano, nitro, hydroxyl, haloalkyl, amino, amino alkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio, arylcarboxamide or optionally substituted aryl or -O-aryl or R1 is aryl or arylalkyl comprising one or more heteroatoms selected from O, S and N or cycloalkyl or alkylcycloalkyl optionally comprising one or more heteroatoms selected from O, S and N; R2 and R3 are independently or together H, alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine or are -RCOR', RCOOR', -RNR'R"R" or -RC(O)NR'R"; R is alkyl or alkenyl; R', R" and R" are independently H, alkyl, alkenyl, cycloalkyl or aryl or are cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyloxyaryl, alkylthioaryl, alkylaminoaryl, aryl, arylalkyl or (cs-cl2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, aryl, -O-aryl, arylcarboxamide, alkylthio or haloalkylthio; A is a direct bond, -NHC(O) or is proline, isoleucine, cyclohexylalanine, optionally substituted cysteine, phenylalanine, homophenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid, optionally substituted tetrahydrosioquinoline-2-carboxylic acid, tryptophan, tyrosine, serine, threonine, histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid, asparagine, glutamine, ornithine or lysine and R4 is benzyl. A pharmaceutical composition thereof is useful for inhibiting serine proteases.