Serine protease inhibitors-keto and di-keto containing ring systems

A compound of the formula:

• ##STR19## wherein X and Y are O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxy;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, (C.sub.5 -C.sub.6)aryl, --O--(C.sub.5 -C.sub.6)aryl, arylcarboxamido, alkylthio or haloalkylthio;
• R.sub.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• A is a direct bond, --C(O)--, --NH--C(O)--, --S(O).sub.2 --, --OC(O)--, --OC(O)NH--, --CH.sub.2 -- or --NH--;
• R.sub.13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
• and
• R.sub.14 is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylcarboxamido, alkylthio or haloalkylthio;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula:

• ##STR20## wherein X and Y are O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxy;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, (C.sub.5 -C.sub.6)aryl, --O--(C.sub.5 -C.sub.6)aryl, arylcarboxamido, alkylthio or haloalkylthio;
• R.sub.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• A is a direct bond, --C(O)--, --NH--C(O)--, --S(O).sub.2 --, --OC(O)--, --OC(O)NH--, --CH.sub.2 --, --NH-- or alkylamino;
• R.sub.13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
• and
• R.sub.14 is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylcarboxamido, alkylthio or haloalkylthio;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula:

• ##STR21## wherein X and Y are O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxy;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, (C.sub.5 -C.sub.6)aryl, --O--(C.sub.5 -C.sub.6)aryl, arylcarboxamido, alkylthio or haloalkylthio;
• R.sub.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• A is a direct bond, --C(O)--, or --CH.sub.2 --;
• R.sub.13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
• and
• R.sub.14 is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylcarboxamido, alkylthio or haloalkylthio;
• and
• R.sub.15 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula:

• ##STR24## wherein X and Y is O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxyl;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, 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.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• W is S, SO or CH.sub.2 ;
• n is 0, 1 or 2;
• R.sub.13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
• R.sub.14 is H, alkyl, alkenyl or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio or haloalkylthio;
• and
• G is --NHC(O)--, --C(O)--, --OC(O)NH--, --NHS(O).sub.2 -- or a direct bond;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula:

• ##STR25## wherein X and Y is O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxyl;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, 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.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R.sub.13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
• or .dbd.CHR.sub.15 or R.sub.15 where R.sub.15 is pyridinyl, phenyl or benzyl optionally substituted with halo, dialkylamino, or --C(O)OCH.sub.3 ;
• R.sub.14 and R'.sub.14 are independently or together H, alkyl, alkenyl, CH.sub.3 C(O)-- or cycloalkyl, aryl, arylalkyl or fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamido, aryl, arylcarboxamido, alkylthio or haloalkylthio;
• and
• R.sub.16, R.sub.17, R'.sub.16 and R'.sub.17 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula:

• ##STR27## wherein X and Y are O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxy;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, (C.sub.5 -C.sub.6)aryl, --O--(C.sub.5 -C.sub.6)aryl, arylcarboxamido, alkylthio or haloalkylthio;
• R.sub.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• V is N or C;
• and U, W and Y are independently or together N, C, C(O), N(R.sub.13) where R.sub.13 is H, alkyl, halo, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N, and S, and optionally substituted with halo or alkyl;
• N(R.sub.14) where R.sub.14 is H, alkyl, alkenyl, or cycloalkyl, aryl, arylalkyl or fused arylcycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylcarboxamide, alkylthio or haloalkylthio;
• or C(R.sub.16)(R.sub.17) where R.sub.16 and R.sub.17 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine.

A compound of the formula ##STR28## wherein X and Y are O, N or S where at least one of X or Y is N;

• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxy;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, (C.sub.5 -C.sub.6)aryl, --O--(C.sub.5 -C.sub.6)aryl, arylcarboxamido, alkylthio or haloalkylthio;
• R.sub.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• and
• R.sub.11, R.sub.12 and E together form a monocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, S and O;
• said ring containing 1 or more keto groups;
• and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, alkylthio, haloalkylthio, cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C.sub.5 -C.sub.12)aryl, (C.sub.5 -C.sub.12)arylalkyl, ((C.sub.5 -C.sub.12)arylalkyl)OC(O)NH-- or (C.sub.5 -C.sub.12)arylalkenyl optionally comprising one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, --C(O)O(alkyl), --C(O)(alkyl), alkylcarboxamido, alkylthio or haloalkylthio;
• or
• a pharmaceutically acceptable salt thereof.

A compound of the formula:

• ##STR29## wherein X and Y is O, N or S where at least one of X or Y is N;
• R.sub.1 is alkyl or alkenyl, optionally substituted with halo or hydroxyl;
• alkynyl, alkyl-C(O)OCH.sub.3, 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 one or more heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with halo, cyano, nitro, 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.2 and R.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• R'.sub.2 and R'.sub.3 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• U and V are independently or together N, C, N(R.sub.13) where R.sub.13 is H, alkyl, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N, and S, and optionally substituted with halo or alkyl;
• or C(R.sub.16)(R.sub.17) where R.sub.16 and R.sub.17 are independently or together H, alkyl, alkylthio, alkylthioalkyl or cycloalkyl, alkylcycloalkyl, phenyl or phenyl alkyl optionally substituted with guanidine, carboalkoxy, hydroxy, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine;
• and
• n is 1 or 2;
• or a pharmaceutically acceptable salt thereof.