Substituted pyrazoles as p38 kinase inhibitors

A compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the compound corresponds in structure to the following formula:
• as to R1:
• R1 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, arylalkyl, arylalkenyl, arylalkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkyl, alkenylthioalkyl, alkylthioalkenyl, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, alkyl amino alkyl, alkylsulfonylalkyl, acyl, acyloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonylalkyl, arylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylaryl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, alkylcarbonyloxyaryl, and arylcarbonyloxyaryl, or
• R1 corresponds in structure to the following formula:
• i is an integer from zero to 9;
• and
• R25 is selected from the group consisting of hydrogen, alkyl, arylalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkyl, and arylcarbonylalkyl;
• and
• R26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, alkoxycarbonylalkyl, and alkylaminoalkyl;
• and
• as to R27:
• R27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, arylalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylaryl, cycloalkylcycloalkyl, alkylaryl, alkylarylalkyl, arylalkylaryl, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxyalkoxyaryl, aryloxyaryl, arylalkoxyaryl, aryloxyalkoxyaryl, alkoxycarbonylalkyl, aminoalkyl, alkylaminoalkyl, arylaminocarbonylalkyl, alkoxyarylaminocarbonylalkyl, aminocarbonylalkyl, arylaminocarbonylalkyl, alkylaminocarbonylalkyl, arylcarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylaryloxycarbonylaryl, arylcarbonylaryl, alkylarylcarbonylaryl, alkoxycarbonylalkoxylaryl, alkylthioalkyl, cycloalkylthioalkyl, alkylthioaryl, arylalkylthioaryl, arylthioalkylaryl, arylsulfonylaminoalkyl, alkylsulfonylaryl, and alkylaminosulfonylaryl, wherein:
• the alkyl, cycloalkyl, arylalkyl, alkoxyaryl, aryloxyaryl, arylaminocarbonylalkyl, aryloxycarbonylaryl, arylcarbonylaryl, alkylthioaryl, arylthioalkylaryl, or alkylsulfonylaryl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or
• R27 is —CHR28R29;
• and
• R28 is alkoxycarbonyl;
• and
• R29 is selected from the group consisting of arylalkyl, arylalkoxyalkyl, alkoxycarbonylalkyl, alkylthioalkyl, and arylalkylthioalkyl, wherein:
• the arylalkyl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and nitro;
• and
• R2 is —R200-cyclohexyl, wherein the cyclohexyl may be optionally substituted with:
• one or more substituents independently selected from the group consisting of epoxyalkyl, amino(hydroxyalkyl), carboxy, aryloxy, arylalkoxy, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, arylsulfonyl, and arylalkylsulfonyl, or
• one or more R201 substituents;
• and
• R200 is selected from the group consisting of:
• —(C(R202)(R203))y—,
• —N(R202)—,
• —S—,
• —O—, and
• a bond;
• and
• each R201 is independently selected from the group consisting of selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, alkylcarbonyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxycarbonyl, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, alkoxyarylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkyl, amino, aminoalkyl, alkylamino, arylamino, arylalkylamino, alkylaminoalkyl, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, aminoalkylcarbonylaminocarbonylalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkyl, alkylimidocarbonyl, amidino, alkylamidino, arylalkylamidino, guanidino, guanidinoalkyl, and alkylsulfonylamino;
• and
• R202 and R203 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl;
• and
• y is selected from the group consisting of zero, 1, and 2;
• and
• R3 is selected from the group consisting of pyridinyl and pyrimidyl, wherein:
• the pyridinyl or pyrimidyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, keto, alkyl, arylalkyl, arylalkenyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, arylalkoxy, amino, alkylamino, haloarylalkyl, haloarylalkenyl, haloarylalkylamino, alkenylamino, alkynylamino, cycloalkylamino, hydroxycycloalkylamino, heterocyclylamino, heterocyclylalkylamino, cycloalkenylamino, arylamino, arylalkylheterocyclylamino, haloarylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylamino, alkoxyarylamino, alkoxyarylalkylamino, alkylsulfonylamino, alkylaminoalkylamino, hydroxyalkylamino, arylalkylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, haloalkylsulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and —NR44R45;
• and
• R44 is selected from the group consisting of alkylcarbonyl and amino;
• and
• R45 is selected from the group consisting of alkyl and arylalkyl;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfinylalkyl, arylsulfinylalkyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, arylalkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, and hydroxy.

A compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the compound corresponds in structure to the following formula:
• Z is selected from the group consisting of ═N— and ═C(H)—;
• and
• R1 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, and propargyl;
• and
• R2 is —R200-cyclohexyl, wherein:
• the cyclohexyl may be optionally substituted with one or more independently selected R201 substituents;
• and
• R200 is selected from the group consisting of:
• —(C(R202)(R203))y—,
• —N(R202)—,
• —S—,
• —O—, and
• a bond;
• and
• each R201 is independently selected from the group consisting of chloro, fluoro, bromo, iodo, hydroxy, carboxy, keto, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, butynyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, methoxy, ethoxy, propoxy, butoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, phenylcarbonyl, chlorophenylcarbonyl, fluorophenylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperdylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethyl, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, aminomethylcarbonylaminocarbonylmethyl, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, benzylamidino, guanidino, guanidinomethyl, guanidinoethyl, and methylsulfonylamino;
• and
• R202 and R203 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl;
• and
• y is selected from the group consisting of zero, 1, and 2;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, methoxy and ethoxy;
• and
• R5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, benzyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, dimethylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylamininoptylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl.

A compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the compound corresponds in structure to the following formula:
• Z is selected from the group consisting of ═N— and ═C(H)—;
• and
• R1 is hydrogen;
• and
• R2 is —R200-cyclohexyl, wherein:
• the cyclohexyl may be optionally substituted with one or more independently selected R201 substituents;
• and
• R200 is selected from the group consisting of:
• —C(H)2—,
• —N(R200)—,
• —S—,
• —O—, and
• a bond;
• and
• each R201 is independently selected from the group consisting of amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, aminomethylcarbonylaminocarbonylmethyl, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethyl, and ethoxycarbonylaminomethyl;
• and
• R202 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl;
• and
• R4 is phenyl, wherein the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, and methoxy;
• and
• R5 is selected from the group consisting of hydrogen, methylamino, dimethylamino, 2-methylbutylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino.

A compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the compound corresponds in structure to the following formula:
• Z is selected from the group consisting of ═N— and ═C(H)—;
• and
• R1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower arylalkyl, lower aminoalkyl and lower alkylaminoalkyl;
• and
• R2A is selected from the group consisting of lower alkylcarbonyl, lower alkylaminocarbonyl, lower alkoxyalkylcarbonyl, lower alkenyloxycarbonyl, lower cycloalkylcarbonyl, arylcarbonyl, lower arylalkylcarbonyl, arylaminocarbonyl, heterocyclylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower arylalkylsulfonyl, wherein:
• any aryl of R2A may be optionally substituted with one or more substituents independently selected from the group consisting of halo, lower alkyl, and lower alkoxy;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower arylalkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy;
• and
• R5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower arylalkyl, lower arylalkoxy, lower arylalkylamino, lower alkoxycarbonyl, lower alkylamino, lower haloarylalkyl, lower arylalkenyl, lower haloarylalkylamino, lower hydroxyalkylamino, lower alkylcarbonyl, lower arylalkenyl, carboxy, lower cycloalkylamino, lower hydroxycycloalkylamino, lower alkoxycarbonylamino, lower alkoxyarylalkylamino, lower alkylaminoalkylamino, lower alkylaminocarbonyl, lower alkoxyarylalkylamino, hydrazinyl, and lower alkylhydrazinyl, and —NR44R45;
• and
• R44 is selected from the group consisting of lower alkylcarbonyl and amino;
• and
• R45 is selected from the group consisting of lower alkyl and lower phenylalkyl.

A method for preparing a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the method comprises cyclizing an acyl hydrazone of the following formula:
• the compound corresponds in structure to the following formula:
• as to R1:
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, arylalkyl, arylalkenyl, arylalkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkyl, alkenylthioalkyl, alkylthioalkenyl, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, alkylaminoalkyl, alkylsulfonylalkyl, acyl, acyloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonylalkyl, arylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylaryl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, alkylcarbonyloxyaryl, and arylcarbonyloxyaryl, or
• R1 corresponds in structure to the following formula:
• i is an integer from zero to 9;
• and
• R25 is selected from the group consisting of hydrogen, alkyl, arylalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkyl, and arylcarbonylalkyl;
• and
• R26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, alkoxycarbonylalkyl, and alkylaminoalkyl;
• and
• as to R27:
• R27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, arylalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylaryl, cycloalkylcycloalkyl, alkylaryl, alkylarylalkyl, arylalkylaryl, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxyalkoxyaryl, aryloxyaryl, arylalkoxyaryl, aryloxyalkoxyaryl, alkoxycarbonylalkyl, aminoalkyl, alkylaminoalkyl, arylaminocarbonylalkyl, alkoxyarylaminocarbonylalkyl, aminocarbonylalkyl, arylaminocarbonylalkyl, alkylaminocarbonylalkyl, arylcarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylaryloxycarbonylaryl, arylcarbonylaryl, alkylarylcarbonylaryl, alkoxycarbonylalkoxylaryl, alkylthioalkyl, cycloalkylthioalkyl, alkylthioaryl, arylalkylthioaryl, arylthioalkylaryl, arylsulfonylaminoalkyl, alkylsulfonylaryl, and alkylaminosulfonylaryl, wherein:
• the alkyl, cycloalkyl, arylalkyl, alkoxyaryl, aryloxyaryl, arylaminocarbonylalkyl, aryloxycarbonylaryl, arylcarbonylaryl, alkylthioaryl, arylthioalkylaryl, or alkylsulfonylaryl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or
• R27 is —CHR28R29;
• and
• R28 is alkoxycarbonyl;
• and
• R29 is selected from the group consisting of arylalkyl, arylalkoxyalkyl, alkoxycarbonylalkyl, alkylthioalkyl, and arylalkylthioalkyl, wherein:
• the arylalkyl may be-optionally substituted with one or more substituents independently selected from the group consisting of alkyl and nitro;
• and
• R2 is —R200-cyclohexyl, wherein:
• the cyclohexyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, arylalkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and arylalkylsulfonyl;
• and
• R200 is selected from the group consisting of:
• —(C(R202)(R203))y—,
• N—(R202)—,
• —S—,
• —O—, and
• a bond;
• and
• R202 and R203 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl;
• and
• R3 is selected from the group consisting of pyridinyl and pyrimidyl, wherein:
• the pyridinyl or pyrimidyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, arylalkyl, arylalkenyl, haloarylalkyl, haloarylalkenyl, haloarylalkylamino, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, arylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylamino, alkoxyarylalkylamino, alkylaminoalkylamino, hydroxyalkylamino, arylalkylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and —NR44R45;
• and
• R44 is selected from the group consisting of alkylcarbonyl and amino;
• and
• R45 is selected from the group consisting of alkyl and arylalkyl;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfinylalkyl, arylsulfinylalkyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, arylalkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, and hydroxy.

A method for preparing a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the method comprises cyclizing an acyl hydrazone of the following formula:
• the compound corresponds in structure to the following formula:
• as to R1:
• R1 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, arylalkyl, arylalkenyl, arylalkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkyl, alkenylthioalkyl, alkylthioalkenyl, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, alkylaminoalkyl, alkylsulfonylalkyl, acyl, acyloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonylalkyl, arylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylaryl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, alkylcarbonyloxyaryl, and arylcarbonyloxyaryl, or
• R1 corresponds in structure to the following formula:
• i is an integer from zero to 9;
• and
• R25 is selected from the group consisting of hydrogen, alkyl, arylalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkyl, and arylcarbonylalkyl;
• and
• R26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, arylalkyl, alkoxycarbonylalkyl, and alkylaminoalkyl;
• and
• as to R27;
• R27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, arylalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylaryl, cycloalkylcycloalkyl, alkylaryl, alkylarylalkyl, arylalkylaryl, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxyalkoxyaryl, aryloxyaryl, arylalkoxyaryl, aryloxyalkoxyaryl, alkoxycarbonylalkyl, aminoalkyl, alkylaminoalkyl, arylaminocarbonylalkyl, alkoxyarylaminocarbonylalkyl, aminocarbonylalkyl, arylaminocarbonylalkyl, alkylaminocarbonylalkyl, arylcarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylaryloxycarbonylaryl, arylcarbonylaryl, alkylarylcarbonylaryl, alkoxycarbonylalkoxylaryl, alkylthioalkyl, cycloalkylthioalkyl, alkylthioaryl, arylalkylthioaryl, arylthioalkylaryl, arylsulfonylaminoalkyl, alkylsulfonylaryl, and alkylaminosulfonylaryl, wherein:
• the alkyl, cycloalkyl, arylalkyl, alkoxyaryl, aryloxyaryl, arylaminocarbonylalkyl, aryloxycarbonylaryl, arylcarbonylaryl, alkylthioaryl, arylthioalkylaryl, or alkylsulfonylaryl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or
• R27 is —CHR28R29;
• and
• R28 is alkoxycarbonyl;
• and
• R29 is selected from the group consisting of arylalkyl, arylalkoxyalkyl, alkoxycarbonylalkyl, alkylthioalkyl, and arylalkylthioalkyl, wherein:
• the arylalkyl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and nitro;
• and
• R2 is —R200-cyclohexyl, wherein the cyclohexyl may be optionally substituted with:
• one or more substituents independently selected from the group consisting of epoxyalkyl, amino(hydroxyalkyl), carboxy, aryloxy, arylalkoxy, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, arylsulfonyl, and arylalkylsulfonyl, or one or more R201 substituents;
• and
• R200 is selected from the group consisting of:
• —(C(R202)(R203))y—,
• —N(R202)—,
• —S—,
• —O—, and
• a bond;
• and
• each R201 is independently selected from the group consisting of selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, alkylcarbonyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxycarbonyl, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, alkoxyarylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkyl, amino, aminoalkyl, alkylamino, arylamino, arylalkylamino, alkylaminoalkyl, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, aminoalkylcarbonylaminocarbonylalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkyl, alkylimidocarbonyl, amidino, alkylamidino, arylalkylamidino, guanidino, guanidinoalkyl, and alkylsulfonylamino;
• and
• R202 and R203 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl;
• and
• y is selected from the group consisting of zero, 1, and 2;
• and
• R3 is selected from the group consisting of pyridinyl and pyrimidyl, wherein:
• the pyridinyl or pyrimidyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, keto, alkyl, arylalkyl, arylalkenyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, arylalkoxy, amino, alkylamino, haloarylalkyl, haloarylalkenyl, haloarylalkylamino, alkenylamino, alkynylamino, cycloalkylamino, hydroxycycloalkylamino, heterocyclylamino, heterocyclylalkylamino, cycloalkenylamino, arylamino, arylalkylheterocyclylamino, haloarylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylamino, alkoxyarylamino, alkoxyarylalkylamino, alkylsulfonylamino, alkylaminoalkylamino, hydroxyalkylamino, arylalkylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, haloalkylsulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and —NR44R45;
• and
• R44 is selected from the group consisting of alkylcarbonyl and amino;
• and
• R45 is selected from the group consisting of alkyl and arylalkyl;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfinylalkyl, arylsulfinylalkyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, arylalkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, and hydroxy.

A method for preparing a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the method comprises cyclizing an acyl hydrazone corresponding in structure to the following formula:
• the compound corresponds in structure to the following formula:
• Z is selected from the group consisting of ═N— and ═C(H)—;
• and
• R1 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, and propargyl;
• and
• R2 is —R200-cyclohexyl, wherein:
• the cyclohexyl may be optionally substituted with one or more independently selected R201 substituents;
• and
• R200 is selected from the group consisting of:
• —(C(R202)(R203))y—,
• —N(R202)—,
• —S—,
• —O—, and
• a bond;
• and
• each R201 is independently selected from the group consisting of chloro, fluoro, bromo, iodo, hydroxy, carboxy, keto, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, butynyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, methoxy, ethoxy, propoxy, butoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, phenylcarbonyl, chlorophenylcarbonyl, fluorophenylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethyl, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, aminomethylcarbonylaminocarbonylmethyl, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, benzylamidino, guanidino, guanidinomethyl, guanidinoethyl, and methylsulfonylamino;
• and
• R202 and R203 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl;
• and
• y is selected from the group consisting of zero, 1, and 2;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, methoxy and ethoxy;
• and
• R5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, benzyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl.

A method for preparing a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the method comprises cyclizing an acyl hydrazone corresponding in structure to the following formula:
• the compound corresponds in structure to the following formula:
• Z is selected from the group consisting of ═N— and ═C(H)—;
• and
• R1 is hydrogen;
• and
• R2 is —R200-cyclohexyl, wherein:
• the cyclohexyl may be optionally substituted with one or more independently selected R201 substituents;
• and
• R200 is selected from the group consisting of:
• —C(H)2—,
• —N(R202)—,
• —S—,
• —O—, and
• a bond;
• and
• each R201 is independently selected from the group consisting of amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, aminomethylcarbonylaminocarbonylmethyl, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethyl, and ethoxycarbonylaminomethyl;
• and
• R202 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl;
• and
• R4 is phenyl, wherein the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, methyl, and methoxy;
• and
• R5 is selected from the group consisting of hydrogen, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino.

A method for preparing a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein:

• the method comprises cyclizing an acyl hydrazone corresponding in structure to the following formula:
• the compound corresponds in structure to the following formula:
• Z is selected from the group consisting of ═N— and ═C(H)—;
• and
• R1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower arylalkyl, lower aminoalkyl and lower alkylaminoalkyl;
• and
• R2A is selected from the group consisting of lower alkylcarbonyl, lower alkylaminocarbonyl, lower alkoxyalkylcarbonyl, lower alkenyloxycarbonyl, lower cycloalkylcarbonyl, arylcarbonyl, lower arylalkylcarbonyl, arylaminocarbonyl, heterocyclylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower arylalkylsulfonyl, wherein:
• any aryl of R2A may be optionally substituted with one or more substituents independently selected from the group consisting of halo, lower alkyl, and lower alkoxy;
• and
• R4 is phenyl, wherein:
• the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower arylalkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy;
• and
• R5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower arylalkyl, lower arylalkoxy, lower arylalkylamino, lower alkoxycarbonyl, lower alkylamino, lower haloarylalkyl, lower arylalkenyl, lower haloarylalkylamino, lower hydroxyalkylamino, lower alkylcarbonyl, lower arylalkenyl, carboxy, lower cycloalkylamino, lower hydroxycycloalkylamino, lower alkoxycarbonylamino, lower alkoxyarylalkylamino, lower alkylaminoalkylamino, lower alkylaminocarbonyl, lower alkoxyarylalkylamino, hydrazinyl, and lower alkylhydrazinyl, and —NR44R45;
• and
• R44 is selected from the group consisting of lower alkylcarbonyl and amino;
• and
• R45 is selected from the group consisting of lower alkyl and lower phenylalkyl.