Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors

A method of treating pancreatitis, thrombosis, ischemia, stroke, restenosis, emphysema or inflammation in a mammal, comprising administering to the mammal an effective amount of a compound having the Formula VII:

• or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein:
• R1 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle or heterocycloalkyl, any of which may be optionally substituted;
• Z is —SO2—, —OCO—, —CO—,
• where R2 is hydrogen, alkyl, aralkyl, aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
• Het is selected from the group consisting of
• where
• R3 and R5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, carboxymethyl, alkoxycarbonylmethyl, —CO2Rx, —CH2ORx or —ORx,
• where Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
• R6 is hydrogen, alkyl, aralkyl, aryl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, or carboxyalkyl;
• R7 is hydrogen, C1-4alkyl, or C2-4 alkenyl;
• R8 is hydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
• R12, R13, R14 and R15 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
• or R12 and R13 are taken together to form —(CH2)y—, where y is 2 to 7, while R14 and R15 are defined as above;
• or R14 and R15 are taken together to form —(CH2)q—, where q is 2 to 7, while R12 and R13 are defined as above;
• or R12 and R14 are taken together to form —(CH2)r—, where r is 0 or 1 to 7, while R13 and R15 are defined as above;
• X is oxygen or NR9,
• where R9 is hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
• Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw, where
• Rw is alkyl, cycloalkyl, phenyl, benzyl,
• where Rd and Rc are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
• n is from zero to 8;
• and
• m is from zero to 6.

A method of treating thrombosis, comprising administering to the mammal an effective amount of a compound having the Formula VII:

• or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein:
• R1 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle or heterocycloalkyl, any of which may be optionally substituted;
• Z is —SO2—, —OCO—, —CO—,
• where R2 is hydrogen, alkyl, aralkyl, aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
• Het is selected from the group consisting of
• where
• R3 and R5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, carboxymethyl, alkoxycarbonylmethyl, —CO2Rx, —CH2ORx or —ORx,
• where Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
• R6 is hydrogen, alkyl, aralkyl, aryl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, or carboxyalkyl;
• R7 is hydrogen, C1-4alkyl, or C2-4 alkenyl;
• R8 is hydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino (C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
• R12, R13, R14 and R15 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
• or R12 and R13 are taken together to form —(CH2)y—, where y is 2 to 7, while R14 and R15 are defined as above;
• or R14 and R15 are taken together to form —(CH2)q—, where q is 2 to 7, while R12 and R13 are defined as above;
• or R12 and R14 are taken together to form —(CH2)r—, where r is 0 or 1 to 7, while R13 and R15 are defined as above;
• X is oxygen or NR9,
• where R9 is hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
• Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw, where
• Rw is alkyl, cycloalkyl, phenyl, benzyl,
• where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
• n is from zero to 8;
• and
• m is from zero to 6.