Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors

A diagnost composition composition useful for in vivo imaging of thrombi in a mammal comprising compound having Formula VIII:

• or a solvate, hydrate of pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent;
• wherein
• Z′ is —OCO—, —CO—, —SO2—, —NHCO—, or a covalent bond;
• R21 is:
• R22(CH2)k, where k is 0–4, (R22)(OR22)CH(CH2)p, where p is 1–4,
• (R22)2CH(CH2)k, where k is 0–4 and R22 can be the same or different, and wherein (R22)2 can also be a ring substituent on CH represented by C3-7 cycloalkyl, C7-12 bicyclic alkyl, or a 5- to 7-membered mono- or 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S, and
• R22O(CH2)p, wherein p is 1–4;
• R22 is hydrogen;
• phenyl, unsubstituted or substituted with one or more of C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, hydroxy, COOH, or CONH2;
• naphthyl;
• biphenyl;
• a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S;
• C1-4 alkyl;
• C3-7 cycloalkyl, or C7-12 bicyclic alkyl;
• R25 is hydrogen;
• C1-4 alkyl;
• C3-7 cycloalkyl, or trifluoromethyl;
• Ra, Rb and Rc are independently hydrogen, hydroxy, or cyano;
• R32, R33, R34 and R35 are independently one of hydrogen, C1-6 alkyl, C2-10 carboxyalkyl or C2-10 hydroxyalkyl, or R32 and R33 are taken together to form —(CH2)y—, where y is 2 to 5, while R34 and R35 are defined as above;
• or R34 and R35 are taken together to form —(CH2)q—, where q is 2 to 5, while R32 and R33 are defined as above;
• or R32 and R34 are taken together to form —(CH2)r—, where r is 0 (a bond) or 1–4, while R33 and R35 are defined as above;
• R28 is hydrogen, C1-4 alkyl or C6-10 aryl (C1-4)alkyl
• X′ is O;
• n is from zero to 4;
• m is zero to 2;
• and
• wherein said compound is capable of being detected outside the body;
• and a pharmaceutically acceptable carrier or diluent.

A method for in vivo imaging of a thrombus in a mammal, comprising:

• (a) administering to said mammal a diagnostically-effective amount of a composition comprising 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—, —NR2CO— or a covalent bond,
• 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
• where
• R3, R4 and R5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, alkoxycarbonylmethyl, carboxymethyl, —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;
• 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 (a bond) 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;
• m is from zero to 6;
• and
• wherein said compound is capable of being detected outside the body;
• and a pharmaceutically acceptable carrier or diluent;
• and
• (b) detecting said thrombus.