Serine protease inhibitors comprising .alpha.-keto heterocycles

N-(Benzyloxycarbonyl)-L-valyl-N-[1-[3-[5-(3-trifluoromethyl benzyl)-1,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-N-benzylglycinamide

• N-Succinyl-L-valyl-N-[1-[3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]c arbonyl]-2-phenylethylenyl]-L-prolinamide;
• N-[4-(4-Morpholinylcarbonyl)benzoyl]-L-valyl-N-[1-[3-[5-(3-trifluoromethylb enzyl)-1,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide;
• or
• N-Acetyl-L-alanyl-N-[1-[3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]ca rbonyl]-2-(S)-methylpropyl]-L-prolinamide.

N-(Benzyloxycarbonyl)-L-valyl-N-[1-[2- [5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl]-1-methylethyl]-L-prolinamid e;

• N-(Benzyloxycarbonyl)-L-t-butylglycyl-N-[1-[3-[5-(3-trifluoromethylbenzyl)- 1,2,4-oxadiazolyl]carbonyl]-2-methylpropyl]-L-prolinamide;
• N-(Benzyloxycarbonyl)-L-Valyl-N-[1-[3-[5-(naphthyl-2-methylene)-1,2,4-oxadi azolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide;
• N-(Benzyloxycarbonyl)-L-TIC-N-[1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]c arbonyl]-2-Methylpropyl]-L-Prolinamide;
• N-(3-Pyridylcarbonyl)-L-Valyl-N-[1-[3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl ]carbonyl]-2-(S)-Methylpropyl]-L-Prolinamide;
• or
• N-(Methanesulfonyl)-L-valyl-N-[1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]c arbonyl]-2-(S)-methylpropyl]-L-prolinamide.

A method of inhibiting the enzymatic activity of a serine protease comprising contacting such protease with an inhibitory amount of a compound of formula (I):

• ##STR15## wherein AA.sub.2, AA.sub.3, AA.sub.4 and AA.sub.5 are independently an amino acid residue or amino acid residue mimetic, or a direct bond, and AA.sub.1 is represented by formula (IIIc):
• ##STR16## and wherein R.sub.2 and R".sub.2 are independently H;
• alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine;
• --RCOR', --RCOOR', --RNR'R"R.degree. or --RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R.degree. are independently H, alkyl, alkenyl, cycloalkyl or (C.sub.5 -C.sub.6)aryl;
• or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C.sub.5 -C.sub.12)aryl, (C.sub.5 -C.sub.12)arylalkyl or (C.sub.5 -C.sub.12)arylalkenyl optionally comprising 1-4 heteroatoms select from N, O and S, and optionally substituted with hydroxy, halo, cyano, keto, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C.sub.5 -C.sub.6)aryl, --O-(C.sub.5 -C.sub.6)aryl, arylcarboxamide, akylthio or haloalhylthio;
• Y and X are independently O, S or N, said N being optionally substituted with (a) alkyl or alkenyl, which alkyl or alkenyl is optionally substituted with 1-3 halo atoms;
• or (b) (C.sub.5 -C.sub.6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;
• R.sub.1 is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxy;
• alkylamino, dialkylamino, alkyldialkylamino;
• or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C.sub.5 -C.sub.12)aryl, (C.sub.5 -C.sub.12)arylalkyl or (C.sub.5 -C.sub.12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkylenedioxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C.sub.5 -C.sub.6)aryl, --O-(C.sub.5 -C.sub.6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
• R.sub.4 and R.sub.4 ' are independently --C(O)R.sub.5, --C(O)NHR.sub.5, --S(O).sub.2 R.sub.5, --C(O)OR.sub.5, --C(O)-(C.sub.5 -C.sub.6)aryl-C(O)--R.sub.5, --CH.sub.2 R.sub.5 or R.sub.5, where R.sub.5 is H, alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy or alkylcarboxamide;
• cycloalkyl, alkylcycloalkyl, (C.sub.5 -C.sub.12)aryl or (C.sub.5 -C.sub.12)arylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkyl, alkenyl, alkynyl or (C.sub.5 -C.sub.12)aryl;
• or absent;
• or together R.sub.4 and R.sub.4 ' form a ring comprising 5-7 atoms selected from C, N, S and O;
• and
• wherein at least one of Y or X is N;
• or a pharmaceutically acceptable salt of any of the above.

N-(Phenylsulfonyl)-L-valyl-N-[1 -[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-p rolinamide;

• N-(3-Pyridylcarbonyl)-L-valyl-N-[1-[3-[5-(3-trifluoromethylbenzyl)-1,2,4-ox adiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide;
• N-(4-Pyridylmethyleneoxycarbonyl)-L-valyl-N-[1-[3-[5-(3-trifluoromethylbenz yl)-1,2,4-oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide;
• N-(4-Pyridylmethyleneoxycarbonyl)-L-valyl-N-[1-[2-[5-(3-methylbenzyl)-1,3,4 -oxadiazolyl]carbonyl]-2-(S)-methylpropyl]-L-prolinamide;
• or
• N-(Pyrrolyl-2-carbonyl)-L-valyl-N-[1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazol yl]carbonyl]-2-(S)-methylpropyl]-N-(1-indanyl)glycinamide.