Substituted pyrazoles as p38 kinase inhibitors

• US 6,617,324 B1
• Filed: 04/02/2002
• Issued: 09/09/2003
• Est. Priority Date: 05/22/1997
• Status: Expired due to Fees

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Naraian, Ashok S., Xi, Xiangdong, Hanson, Gunnar J., Flynn, Daniel L., Geng, Lifeng, Hanau, Cathleen E., Yu, Yi, Huang, He, Talley, John Jeffrey, Hartmann, Susan J., Vazquez, Michael L., Devraj, Rajesh, Koszyk, Francis J., Liao, Shuyuan, Weier, Richard M., Metz, Suzanne, Hepperle, Michael, Graneto, Matthew J., Khanna, Ish K., Clare, Michael, Stealey, Michael A., Collins, Paul W., Partis, Richard A., South, Michael S., Selness, Shaun Raj, Perry, Thao D., Rao, Shashidhar N., Crich, Joyce Zuowu
• Primary Examiner(s): Solola, T. A.
• Application Number:
  US10/114,297
• Time in Patent Office: 525 Days
• Field of Search: 514/253.01, 514/254.05, 514/235.8, 514/319, 514/341, 544/124, 544/364, 546/206, 546/256, 546/275.4
• US Class Current: 514/235.8
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 473/00 : Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

A class of pyrazole derivatives described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula IA

wherein R¹, R², R³ and R⁴ are as described in the specification.

Claims

1. 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, 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(R²⁰⁰)(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, arninocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, and hydroxy.

2. A compound, salt, or tautomer according to claim 1, wherein R¹ is hydrogen.

3. A compound, salt, or tautomer according to claim 1, wherein R²⁰⁰ is a bond.

4. A compound, salt, or tautomer according to claim 1, wherein:

as to R¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkyl, lower haloalkyl, lower hydroxyalkyl, lower arylalkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkyl, amino, lower alkylamino, lower arylamino, and lower alkylaminoalkyl, or

R¹ corresponds in structure to the following formula;

i is selected from the group consisting of zero, 1, and 2; and

R²⁵ is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower alkoxyalkyl, lower phenoxyalkyl, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkyl, and lower phenoxycarbonylalkyl; and

R²⁶ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkyl, lower phenylalkyl, lower alkoxycarbonylalkyl, and lower alkylaminoalkyl; and

as to R²⁷;

R²⁷ is selected from the group consisting of lower alkyl, lower cycloalkyl, lower alkynyl, phenyl, biphenyl, naphthyl, lower phenylalkyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, lower cycloalkylaryl, lower cycloalkylcycloalkyl, lower alkylphenyl, lower alkylphenylalkyl, lower phenylalkylphenyl, lower alkoxyalkyl, lower alkoxyphenyl, lower alkoxyphenylalkyl, lower alkoxyalkoxyphenyl, lower phenoxyphenyl, lower phenylalkoxyphenyl, lower phenoxyalkoxyphenyl, lower alkoxycarbonylalkyl, lower aminoalkyl, lower alkylaminoalkyl, lower phenylaminocarbonylalkyl, lower alkoxyphenylaminocarbonylalkyl, lower aminocarbonylalkyl, arylaminocarbonylalkyl, lower alkylaminocarbonylalkyl, lower phenylcarbonylalkyl, lower alkoxycarbonylphenyl, lower phenoxycarbonylphenyl, lower alkylphenoxycarbonylphenyl, lower phenylcarbonylphenyl, lower alkylphenylcarbonylphenyl, lower alkoxycarbonylalkoxylphenyl, lower alkylthioalkyl, cycloalkylthioalkyl, lower alkylthiophenyl, lower phenylalkylthiophenyl, lower phenylthioalkylphenyl, lower phenylsulfonylaminoalkyl, lower alkylsulfonylphenyl, and lower alkylaminosulfonylphenyl, wherein;

the lower alkyl, lower cycloalkyl, phenyl, biphenyl, naphthyl, lower phenylalkyl, lower alkoxyphenyl, lower phenoxyphenyl, lower phenylaminocarbonylalkyl, lower phenoxycarbonylphenyl, lower phenylcarbonylphenyl, lower alkylthiophenyl, lower phenylthioalkylphenyl, or lower alkylsulfonylphenyl may be optionally substituted with one or more substituents independently selected from the group consisting of lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano, or

R²⁷ is —

CHR²⁸R²⁹; and

R²⁸ is lower alkoxycarbonyl; and

R²⁹ is selected from the group consisting of lower phenylalkyl, lower phenylalkoxyalkyl, lower alkoxycarbonylalkyl, lower alkylthioalkyl, and lower phenylalkylthioalkyl, wherein;

the phenylalkyl may be optionally substituted with one or more substituents independently selected from the group consisting of lower 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, lower alkyl, lower alkynyl, phenyl, heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkylaminoalkylamino, lower alkynylamino, lower amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, and phenylsulfonyl; 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 lower alkylthio, halo, lower alkyl, lower arylalkyl, lower phenylalkenyl, carboxy, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower arylalkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, 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; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of lower alkylthio, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower arylalkoxy, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy.

5. A compound, salt, or tautomer according to claim 4, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, benzyl, phenylethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and

R²is —

R²⁰⁰-cycloehexyl, wherein;

the cyclohexyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1-dimethylethylcarbonyl; 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 methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phthylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, (1-ethyl-2-hydroxy)ethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylhydrazinyl, and —

NR⁴⁴R⁴⁵; and

R⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and

R⁴⁵ is selected from the group consisting of methyl, ethyl and phenylmethyl; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy.

6. A compound, salt, or tautomer according to claim 5, wherein:

R¹ is selected from the group consisting of hydrogen and methyl; 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 fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phthyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phthylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and

R⁴ is selected from phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy.

7. A compound, salt, or tautomer according to claim 5, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, and diethylaminoethyl; and

R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl; 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 fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phthyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phthylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy.

8. A compound, salt, or tautomer according to claim 7, wherein:

R¹ is selected from the group consisting of hydrogen and methyl; and

R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl; 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 fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phthyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phthylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and

R⁴ is selected from the group consisting of phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy.

9. A compound, salt, or tautomer according to claim 4, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, benzyl, phenylethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; 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 methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phthylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, (1-ethyl-2-hydroxy)ethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, and —

NR⁴⁴R⁴⁵; and

R⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and

R⁴⁵ is selected from the group consisting of methyl, ethyl and phenylmethyl; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy.

10. A compound, salt, or tautomer according to claim 9, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, and diethylaminoethyl; 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 fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phthyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phthylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy.

11. A compound, salt, or tautomer according to claim 1, 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

R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl may be optionally substituted with one or more substituents independently selected from the group consisting of halo, lower alkyl, keto, arylalkyl, carboxy, lower haloalkyl, lower alkoxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl; 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 halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower arylalkyl, lower haloarylalkyl, lower haloarylalkenyl, lower hydroxyalkylamino, lower alkynylamino, lower haloarylalkylamino, lower arylalkoxy, lower arylalkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower arylalkenyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyarylalkylamino, lower alkylaminoalkylamino, lower alkylaminocarbonyl, lower alkoxyarylalkylamino, hydrazinyl, 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.

12. A compound, salt, or tautomer according to claim 11, wherein Z is ═

N—

.

13. A compound, salt, or tautomer according to claim 11, wherein Z is ═

C(H)—

.

14. A compound, salt, or tautomer according to claim 11, wherein R¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl.

15. A compound, salt, or tautomer according to claim 11, wherein R¹ is hydrogen.

16. A compound, salt, or tautomer according to claim 11, wherein R¹ is lower alkyl.

17. A compound, salt, or tautomer according to claim 11, wherein R¹ is selected from the group consisting of hydrogen, methyl, and ethyl.

18. A compound, salt, or tautomer according to claim 11, wherein R¹ is selected from the group consisting of methyl and ethyl.

19. A compound, salt, or tautomer according to claim 11, wherein:

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 substituents independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and

R⁵ is selected from the group consisting of fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methylhydrazinyl, and —

NR⁴⁴R⁴⁵; and

R⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and

R⁴⁵ is selected from the group consisting of methyl and benzyl.

20. A compound, salt, or tautomer according to claim 11, wherein:

R¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl; and

R⁵ is selected from the group consisting of halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower arylalkyl, lower haloarylalkyl, lower haloarylalkenyl, lower hydroxyalkylamino, lower alkynylamino, lower haloarylalkylamino, lower arylalkoxy, lower arylalkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyarylalkylamino, lower alkylaminoalkylamino, lower alkylaminocarbonyl, lower alkoxyarylalkylamino, hydrazinyl, lower alkylhydrazinyl, and —

NR⁴⁴R⁴⁵.

21. A compound, salt, or tautomer according to claim 20, wherein:

R¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl, and propargyl; and

R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl; and

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and

R⁵ is selected from the group consisting of fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methylhydrazinyl, and —

NR⁴⁴R⁴⁵; and

R⁴⁴ is selected from methylcarbonyl and amino; and

R⁴⁵ is selected from methyl and benzyl.

22. A compound, salt, or tautomer according to claim 21, wherein R⁵ is selected from the group consisting of fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methylhydrazinyl, and —

NR⁴⁴R⁴⁵.

63. A pharmaceutical composition comprising:

a therapeutically-effective amount of a compound, tautomer, or salt recited in claim 1, and

a pharmaceutically acceptable carrier.

68. A method for treating a tumor necrosis factor mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 1.

69. The method according to claim 68, wherein the tumor necrosis factor mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

70. A method for treating a p38 kinase mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 1.

71. The method according to claim 70, wherein the p38 kinase mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

72. A method for treating inflammation, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 1.

73. A method for treating arthritis, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 1.

74. A method for treating asthma, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 1.

75. A method for treating a tumor necrosis factor mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 1.

76. The method according to claim 75, wherein the tumor necrosis factor mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

23. 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.

24. A compound, salt, or tautomer according to claim 23, wherein:

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

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, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkyl, amino, aminoalkyl, alkylamino, arylalkylamino, alkylaminoalkyl, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkyl, alkylimidocarbonyl, amidino, alkylamidino, arylalkylamidino, guanidino, guanidinoalkyl, and alkylsulfonylamino; 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, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, 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.

25. A compound, salt, or tautomer according to claim 23, wherein R²⁰⁰ is a bond.

26. A compound, salt, or tautomer according to claim 23, wherein R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl is 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.

27. A compound, salt, or tautomer according to claim 26, wherein 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, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, 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.

28. A compound, salt, or tautomer according to claim 23, wherein:

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, arylamino, aminoalkylcarbonylaminocarbonylalkyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkyl, amino, aminoalkyl, alkylamino, arylalkylamino, alkylaminoalkyl, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkyl, alkylimidocarbonyl, amidino, alkylamidino, arylalkylamidino, guanidino, guanidinoalkyl, and alkylsulfonylamino; 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, hydroxycycloalkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, 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.

29. A compound, salt, or tautomer according to claim 23, 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

R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl may be optionally substituted with one or more independently selected R²⁰¹ substituents; and

each R²⁰¹ is independently selected from the group consisting of halogen, hydroxy, carboxy, keto, lower alkyl, lower hydroxyalkyl, lower haloalkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, aryl, heterocyclyl, lower arylalkyl, lower heterocyclylalkyl, lower alkylcarbonyl, lower hydroxyalkylcarbonyl, lower cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, lower alkoxy, lower alkoxyalkyl, lower alkoxyaryl, lower alkoxycarbonyl, lower carboxyalkylcarbonyl, lower alkoxyalkylcarbonyl, lower alkoxyarylcarbonyl, arylamino, lower aminoalkylcarbonylaminocarbonylalkyl, lower heterocyclylalkylcarbonyl, lower alkylsulfonyl, lower alkylsulfonylalkyl, amino, lower aminoalkyl, lower alkylamino, lower arylalkylamino, lower alkylaminoalkyl, aminocarbonyl, lower alkylcarbonylamino, lower alkylcarbonylaminoalkyl, lower alkylaminoalkylcarbonyl, lower alkylaminoalkylcarbonylamino, lower aminoalkylcarbonylaminoalkyl, lower alkoxycarbonylamino, lower alkoxyalkylcarbonylamino, lower alkoxycarbonylaminoalkyl, lower alkylimidocarbonyl, amidino, lower alkylamidino, lower arylalkylamidino, guanidino, lower guanidinoalkyl, and lower alkylsulfonylamino; 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.

30. A compound, salt, or tautomer according to claim 29, wherein R²⁰⁰ is a bond.

31. A compound, salt, or tautomer according to claim 29, wherein Z is ═

N—

.

32. A compound, salt, or tautomer according to claim 29, wherein Z is ═

C(H)—

.

33. A compound, salt, or tautomer according to claim 32, wherein R²⁰⁰ is a bond.

34. A compound, salt, or tautomer according to claim 33, wherein the compound corresponds in structure to a formula selected from the group consisting of the following:

35. A compound, salt, or tautomer according to claim 32, wherein R²⁰⁰ is —

C(H)₂—

.

36. A compound, salt, or tautomer according to claim 35, wherein the compound corresponds in structure to a formula selected from the group consisting of the following:

37. A compound, salt, or tautomer according to claim 29, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl and propargyl; 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, piperidinylmethyl, piperazinylmethyl, 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, 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

R⁴ is phenyl, wherein;

the phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of methylthio, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and

R⁵ is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, benzyl, fluorophenylethyl, fluorophenylethenyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethyl amino, hydroxyethylamino, hydroxypropyl amino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, ethylcarbonyl, hydrazinyl, 1-methylhydrazinyl, and —

NR⁴⁴R⁴⁵; and

R⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and

R⁴⁵ is selected from the group consisting of methyl and benzyl.

38. A compound, salt, or tautomer according to claim 37, wherein:

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, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl.

39. A compound, salt, or tautomer according to claim 38, wherein:

each R²⁰¹ is independently selected from the group consisting of chloro, fluoro, hydroxy, carboxy, keto, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, fluoromethyl, fluoroethyl, fluoropropyl, phenyl, benzyl, piperidinyl, piperazinyl, piperidinylmethyl, piperazinylmethyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethyl, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, N-benzylamino, methylaminomethyl, aminocarbonyl, methoxycarbonylamino, ethoxycarbonylamino, and methylsulfonylamino; and

R⁵ is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, hydroxyethylaamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl.

40. A compound, salt, or tautomer according to claim 38, wherein:

each R²⁰¹ is independently selected from the group consisting of chloro, fluoro, bromo, hydroxy, carboxy, keto, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, phenyl, benzyl, piperidinyl, piperazinyl, piperidinylmethyl, piperazinylmethyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, ethoxyethyl, methoxyphenyl, ethoxyphenyl, 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, 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, and methylsulfonylamino; and

R⁵ is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl.

41. A compound, salt, or tautomer according to claim 29, wherein:

R¹ is hydrogen; and

each R²⁰¹ is independently selected from the group consisting of hydroxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, methylsulfonyl, ethylsulfonyl, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, N-benzylamino, methylaminomethyl, aminocarbonyl, methoxycarbonylamino, and ethoxycarbonylamino; 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.

42. A compound, salt, or tautomer according to claim 41, wherein:

each R²⁰¹ is independently selected from the group consisting of methyl, methoxyethyl, methylcarbonyl, hydroxymethylcarbonyl, methoxymethylcarbonyl, methylsulfonyl, amino, N,N-dimethylamino, and N,N-diethylamino; and

R⁵ is selected from the group consisting of hydrogen, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino.

43. A compound, salt, or tautomer according to claim 29, wherein:

R¹ is hydrogen; and

each R²⁰¹ is independently selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, propargyl, phenyl, benzyl, piperidinyl, and piperazinyl; 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, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino.

44. A compound, salt, or tautomer according to claim 43, wherein:

each R²⁰¹ is independently selected from the group consisting of methyl, cyclopropyl, propargyl, and benzyl; and

R⁵ is selected from the group consisting of hydrogen, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino.

64. A pharmaceutical composition comprising:

a therapeutically-effective amount of a compound, tautomer, or salt recited in claim 23, and

a pharmaceutically acceptable carrier.

77. A method for treating a p38 kinase mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 23.

78. The method according to claim 77, wherein the p38 kinase mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

79. A method for treating inflammation, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound,or salt of claim 77.

80. A method for treating arthritis, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 77.

81. A method for treating asthma, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 23.

45. 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.

46. A compound, salt, or tautomer according to claim 45, wherein R²⁰⁰ is a bond.

47. A compound, salt, or tautomer according to claim 45, wherein Z is ═

N—

.

48. A compound, salt, or tautomer according to claim 45, wherein Z is ═

C(H)—

.

49. A compound, salt, or tautomer according to claim 45, wherein:

each R²⁰¹ is independently selected from the group consisting of chloro, fluoro, bromo, hydroxy, carboxy, keto, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, methoxy, ethoxy, propoxy, 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, and ethoxycarbonylaminomethyl; and

R²⁰² and R²⁰³ are independently selected from the group consisting of hydrogen, methyl, ethyl, phenyl and benzyl; and

R⁵ is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl.

65. A pharmaceutical composition comprising:

a therapeutically-effective amount of a compound, tautomer, or salt recited in claim 45, and

a pharmaceutically acceptable carrier.

82. A method for treating a tumor necrosis factor mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 45.

83. The method according to claim 82, wherein the tumor necrosis factor mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

84. A method for treating a p38 kinase mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 45.

86. A method for treating inflammation, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 45.

87. A method for treating arthritis, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 45.

88. A method for treating arthritis, the method comprising treating a subject having or susceptible to asthma with a therapeutically-effective amount of a compound or salt of claim 45.

50. 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.

51. A compound, salt, or tautomer according to claim 50, wherein R²⁰⁰ is a bond.

52. A compound, salt, or tautomer according to claim 50, wherein Z is ═

N—

.

53. A compound, salt, or tautomer according to claim 50, wherein Z is ═

C(H)—

.

54. A compound, salt, or tautomer according to claim 50, wherein:

R² is —

R²⁰⁰-cyclohexyl, wherein;

the cyclohexyl is substituted with one or more independently selected R²⁰¹ substituents; and

each R²⁰¹ is independently selected from the group consisting of amino, aminomethyl, N,N-dimethylamino, and N-isopropylamino; and

R²⁰² is selected from the group consisting of hydrogen and methyl; and

R⁵ is selected from the group consisting of hydrogen, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino.

66. A pharmaceutical composition comprising:

a therapeutically-effective amount of a compound, tautomer, or salt recited in claim 50, and

a pharmaceutically acceptable carrier.

89. A method for treating a tumor necrosis factor mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 50.

90. The method according to claim 89, wherein the tumor necrosis factor mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

91. A method for treating a p38 kinase mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 50.

92. The method according to claim 91, wherein the p38 kinase mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

93. A method for treating inflammation, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 50.

94. A method for treating arthritis, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 50.

95. A method for treating arthritis, the method comprising treating a subject having or susceptible to asthma with a therapeutically-effective amount of a compound or salt of claim 50.

55. 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

R^2A 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 R^2A 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.

56. A compound, salt, or tautomer according to claim 55, wherein Z is ═

N—

.

57. A compound, salt, or tautomer according to claim 55, wherein Z is ═

C(H)—

.

58. A compound, salt, or tautomer according to claim 55, wherein R²⁰⁰ is a bond.

59. A compound, salt, or tautomer according to claim 58, wherein R^2A corresponds in structure to a formula selected from the group consisting of:

60. A compound, salt, or tautomer according to claim 59, wherein R¹ is hydrogen.

61. A compound, salt, or tautomer according to claim 60, R⁴ is phenyl optionally substituted with halo.

62. A compound, salt, or tautomer according to claim 60, R⁴ corresponds in structure to the following formula:

67. A pharmaceutical composition comprising:

a therapeutically-effective amount of a compound, tautomer, or salt recited in claim 55, and

a pharmaceutically acceptable carrier.

96. A method for treating a tumor necrosis factor mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 55.

97. The method according to claim 96, wherein the tumor necrosis factor mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

98. A method for treating a p38 kinase mediated disorder, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 55.

99. The method according to claim 98, wherein the p38 kinase mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

100. A method for treating inflammation, the method comprising treating a subject having or susceptible to inflammation with a therapeutically-effective amount of a compound or salt of claim 55.

101. A method for treating arthritis, the method comprising treating a subject having or susceptible to arthritis with a therapeutically-effective amount of a compound or salt of claim 55.

102. A method for treating arthritis, the method comprising treating a subject having or susceptible to asthma with a therapeutically-effective amount of a compound or salt of claim 55.

85. The method according to claim wherein the p38 kinase mediated disorder comprises a disorder selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disorder state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disorder, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn'"'"'s disorder, ulcerative colitis, inflammatory bowel disorder, and cachexia.

103. 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.

104. The process of claim 103, wherein:

the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide; and

the ketone corresponds in structure to the following formula;

the acyl hydrazide corresponds in structure to the following formula;

105. 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.

106. The process of claim 105, wherein:

the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide; and

the ketone corresponds in structure to the following formula;

the acyl hydrazide corresponds in structure to the following formula;

107. 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.

108. The process of claim 107, wherein:

the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide; and

the ketone corresponds in structure to the following formula;

the acyl hydrazide corresponds in structure to the following formula;

109. 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.

110. The process of claim 109, wherein:

the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide; and

the ketone corresponds in structure to the following formula;

the acyl hydrazide corresponds in structure to the following formula;

111. 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

R^2A 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 R^2A 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.

112. The process of claim 111, wherein:

the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide; and

the ketone corresponds in structure to the following formula;

the acyl hydrazide corresponds in structure to the following formula;