Aminoguanidines and alkoxyguanidines as protease inhibitors

A compound having the formula:

• 66
• or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof:
• wherein
• R21 is one of phenyl, naphthyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, methoxy, trifluoromethyl, cyano, nitro, amino or dimethylamino;
• and when R21 is phenyl, said phenyl can be optionally substituted by C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, N-morpholinosulfonyl, or R22R23NSO2—, where R22 and R23 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C1-4)alkyl, hydroxy(C1-4)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, or R22 and R23 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally N′ substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4)alkoxycarbonyl(C1-4)alkyl, cyano(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
• R24 is hydrogen or C1-4 alkyl;
• Y′ is one of O, NR10 or a covalent bond hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino(C1-8)alkyl;
• and
• a and b are 0, 1 or 2;
• X′ is O or NR29;
• and
• R29 is hydrogen or C1-4 alkyl.

A compound having the formula:

• 67
• or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof;
• wherein
• R21 is one of phenyl, naphthyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, methoxy, trifluoromethyl, cyano, nitro, amino or dimethylamino;
• and when R21 is phenyl, said phenyl can be optionally substituted by C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, N-morpholinosulfonyl, or R22R23NSO2—, where R22 and R23 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C1-4)alkyl, hydroxy(C1-4)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, or R22 and R23 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally N′ substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4)alkoxycarbonyl(C1-4)alkyl, cyano(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
• R24 is hydrogen or C1-4 alkyl;
• X′ is O or NR29;
• and
• R29 is hydrogen or C1-4 alkyl;
• Y′ is one of O, NR10 or a covalent bond hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino(C1-8)alkyl;
• and
• b is 0, 1, or 2.

A compound having the Formula I:

• 68
• or a solvate, hydrate or pharmaceutically acceptable salt thereof;
• wherein:
• R1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
• Z is one of —NR10SO2—, —SO2NR10—, —NR10C(RyRz)—, —C(RyRz)NR10—, —OSO2—, —SO2O—, —OC(RyRz)—, —C(RyRz)O—, —NR10CO— or —CONR10—;
• Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
• R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of —CH═CH—CH═CH— or —(CH2)q—, where q is from 2 to 6, and R4 is defined as above;
• 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;
• Y is one of —O—, —NR10—, —S—, —CHR10— or a covalent bond;
• Rw is alkyl, cycloalkyl, phenyl, benzyl,
• 69
• 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;
• and:
• A. R7 and R12 are taken together to form —(CH2)o—, where o is 1, 2 or 3;
• R11 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
• R8 is hydrogen;
• Ra, Rb and Rc are hydrogen, hydroxy,
• 70
• where Rh is benzyl or t-butyl, and where Rf is hydrogen or methyl;
• and
• R6 is hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2-8)alkyl;
• or
• B. R7 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
• R8 and R12 are taken together to form —CH2—CH2—(CH2)p—, where p is 1, 2 or 3;
• R7 is hydrogen;
• and
• Ra, Rb and Rc are hydrogen, hydroxy,
• 71
• where Rh is benzyl or t-butyl, and where Rf is hydrogen or methyl;
• and
• R6 is hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2-8)alkyl;
• or
• C. R6 and Rb are taken together to form ═CH—N═CH—NH— or —CH2—(CH2)r—, where r is 1, 2 or 3;
• Ra is hydrogen or hydroxy;
• Rc is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or —CO2Rw—, where Rw is as defined above;
• R7 and R8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form —(CH2)y—, where y is zero, 1 or 2;
• R11 is hydrogen;
• and R12 is one of 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;
• or
• D. Ra and Rc are taken together to form —CH2—(CH2)s—, where s is 1 or 2;
• and
• R6 is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw—, where Rw is as defined above;
• R7 and R8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form —(CH2)y—, where y is zero, 1 or 2;
• R11 is hydrogen;
• and R12 is one of 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.

A compound having Formula IX:

• 72
• wherein
• R1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
• Z is one of —NR10SO2—, —SO2NR10—, —NR10C(RyRz)—, —C(RyRz)NR10—, —OSO2—, —SO2O—, —OC(RyRz)—, —C(RyRz)O—, —NR10CO— or —CONR10—;
• Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
• R2, R3 and R4 are each independently one of hydrogen, alkyl. cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms. R2 and R3 may also be taken together to form one of —CH═CH—CH═CH— or —(CH2)q—, where q is from 2 to 6, and R4 is defined as above;
• 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;
• Y is one of —O—, —NR10—, —S—, —CHR10— or a covalent bond;
• R7, R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkyllaminoalkyl or carboxyalkyl;
• or R7 and R8 are taken together to form —(CH2)y—, where q is zero (a bond), 1 or 2, while R11 and R12 are defined as above;
• or R7 and R12 are defined as above;
• or R8 and R11 are taken together to form —(CH2)r—, where r is 2-8, while R7 and R12 are defined as above;
• R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl, carboxyalkyl or alkoxycarbonylalkyl;
• n is from zero to 8;
• and
• m is from zero to 4.