IP Library › Patent Application 10985023

Patent Application

App. No. 10/985,023

Certain imidazo[1,2-a]pyrazin-8-ylamines, method of making, and method of use thereof

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App. No.: 10/985,023

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Abstract

At least one chemical entity chosen from compounds of Formula 1 and pharmaceutically acceptable pharmaceutically acceptable salts, hydrates, solvates, crystal forms, diastereomers, and prodrugs thereof. Methods of treating or preventing disorders in which aberrant kinase activity is implicated, pharmaceutically compositions, and methods for detecting the presence kinases in cells or biological preparations and for identifying kinases of therapeutic interest.

Claims (399)

1 . At least one chemical entity chosen from compounds of Formula I:

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

A is chosen from 0 and 1;

Z 1 is chosen from

wherein

each occurrence of R 4 and R 5 is independently chosen from hydrogen, C 1 -C 6 alkyl, sulfonamido, and halo;

m is chosen from 0, 1, 2, and 3; and

R 6 is chosen from

hydrogen,

C 1 -C 6 alkyl,

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substitutents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, and amino(C 1 -C 6 alkyl),

heteroaryl, and

substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substitutents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, and amino(C 1 -C 6 alkyl);

R 1 is chosen from

hydrogen,

C 1 -C 7 alkyl,

C 1 -C 6 alkoxy,

C 3 -C 7 cycloalkyl,

(C 3 -C 7 cycloalkyl)methyl,

heterocycloalkyl,

(heterocycloalkyl)C 1 -C 2 alkyl,

sulfonamido,

(C 1 -C 6 alkoxy)C 1 -C 6 alkoxy,

mono-(C 1 -C 6 alkyl)amino,

di-(C 1 -C 6 alkyl)amino,

mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl),

di(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl),

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

phenyl fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms chosen from N, O, and S,

substituted phenyl fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms chosen from N, O, and S, or heteroaryl, chosen from mono-, di-, and tri-substituted phenyl fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms chosen from N, O, and S, or heteroaryl, wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

heteroaryl, and

substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl, wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl;

Z 2 is chosen from

substituted phenylene chosen from mono-, di-, and tri-substituted phenylene with substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl),

pyridylidene,

substituted pyridylidene chosen from mono-, di-, and tri-substituted pyridylidene with substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl), and

substituted naphthylidene chosen from mono-, di-, and tri-substituted naphthylene with substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl);

Q is chosen from

wherein

each occurrence of R 7 and R 8 is independently chosen from C 1 -C 6 alkyl, sulfonamido, and halo;

n is chosen from 0, 1, 2, and 3; and

R 9 -R 12 are each independently chosen from

hydrogen,

C 1 -C 6 alkyl,

phenyl,

heteroaryl, and

substituted heteroaryl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkyloxy)C 1 -C 6 alkoxy, C 1 -C 6 perfluoroalkyl, C 1 -C 6 perfluoroalkoxy, mono-(C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, and amino(C 1 -C 6 alkyl);

R 2 is chosen from

C 1 -C 7 alkyl,

substituted C 1 -C 7 alkyl chosen from mono-, di-, and tri-substituted C 1 -C 7 alkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 3 -C 7 cycloalkyl,

substituted C 3 -C 7 cycloalkyl chosen from mono-, di-, and tri-substituted C 3 -C 7 cycloalkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl, wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy, wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

aryloxy,

substituted aryloxy chosen from mono-, di-, and tri-substituted aryloxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

heteroaryl, and

substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl; and

R 3 is chosen from hydrogen, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C 1 -C 2 alkyl, heterocycloalkyl, and (heterocycloalkyl)C 1 -C 2 alkyl.

2 . At least one chemical entity of claim 1 wherein R 2 -Q- is halo-C 1 -C 4 alkyl.

3 . At least one chemical entity of claim 1 wherein R 2 -Q- is chosen from

phenoxy and

substituted phenoxy chosen from mono-, di-, and tri-substituted phenoxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

4 . At least one chemical entity of claim 1 wherein

R 6 is chosen from hydrogen, C 1 -C 6 alkyl, and phenyl;

R 1 is chosen from

phenyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl,

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyrimidinyl, and

substituted pyrimidinyl chosen from mono-, di-, and tri-substituted pyrimidinyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl;

Z 2 is chosen from

pyridylidene,

R 2 -Q- is chosen from

chloro-C 1 -C 4 alkyl,

phenoxy, and

5 . At least one chemical entity of claim 1 wherein

R 6 is chosen from hydrogen, C 1 -C 6 alkyl, and phenyl;

R 1 is chosen from

phenyl,

benzo[d]1,3-dioxolyl,

pyridyl,

pyrimidinyl, and

Z 2 is chosen from

pyridylidene,

Q is chosen from

wherein

each occurrence of R 7 and R 8 is independently chosen from C 1 -C 6 alkyl, sulfonamido, and halo, and n is chosen from 0, 1, 2, and 3; and

R 9 -R 12 are each independently chosen from hydrogen, C 1 -C 6 alkyl, and phenyl;

R 2 is chosen from

C 3 -C 7 cycloalkyl,

substituted C 3 -C 7 cycloalkyl chosen from mono-, di-, and tri-substituted C 3 -C 7 cycloalkyl wherein the substituents are independently chosen from hydroxy, cyano, amino, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 4 alkyl)amino, and di-(C 1 -C 4 alkyl)amino,

(C 3 -C 7 cycloalkyl)methyl,

substituted (C 3 -C 7 cycloalkyl)methyl chosen from mono-, di-, and tri-substituted (C 3 -C 7 cycloalkyl)methyl wherein the substituents are independently chosen from hydroxy, cyano, amino, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 4 alkyl)amino, and di-(C 1 -C 4 alkyl)amino,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl, wherein the substituents are independently chosen from hydroxy, cyano, amino, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 4 alkyl)amino, and di-(C 1 -C 4 alkyl)amino,

(heterocycloalkyl)C 1 -C 2 alkyl,

substituted (heterocycloalkyl)C 1 -C 2 alkyl chosen from mono-, di-, and tri-substituted (heterocycloalkyl)C 1 -C 2 alkyl, wherein the substituents are independently chosen from hydroxy, cyano, amino, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 4 alkyl)amino, and di-(C 1 -C 4 alkyl)amino,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy, wherein the substituents are independently chosen from hydroxy, cyano, amino, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 4 alkyl)amino, and di-(C 1 -C 4 alkyl)amino,

aryloxy,

substituted aryloxy chosen from mono-, di-, and tri-substituted aryloxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

pyridyl,

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

pyrimidinyl, and

substituted pyrimidinyl chosen from mono-, di-, and tri-substituted pyrimidinyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

6 . At least one chemical entity of claim 1 wherein Q is chosen from

wherein

each occurrence of R 7 and R 8 is independently chosen from C 1 -C 6 alkyl, sulfonamido, and halo; and n is chosen from 1 and 2; and

R 9 -R 12 are each independently chosen from hydrogen, C 1 -C 6 alkyl, and phenyl.

7 . At least one chemical entity of claim 1 chosen from compounds of Formula 2:

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

R 20 represents 1, 2, or 3 substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

8 . At least one chemical entity of claim 7 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

9 . At least one chemical entity of claim 7 wherein R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

10 . At least one chemical entity of claim 7 chosen from compounds of Formula 3

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0, 1, 2 and 3;

R 21 represents 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

11 . At least one chemical entity of claim 10 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

12 . At least one chemical entity of claim 7 chosen from compounds of Formula 4

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof

13 . At least one chemical entity of claim 12 wherein R 20 represents 1 substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

14 . At least one chemical entity of claim 12 chosen from compounds of Formula 5

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0, 1, 2 and 3;

R 21 represents 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl, and

R 2 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl.

15 . At least one chemical entity of claim 14 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

16 . At least one chemical entity of claim 12 chosen from compounds of Formula 6

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

X, Y, and Z are chosen from nitrogen and CH, wherein one and only one of X, Y, and Z is nitrogen;

R 21 represents 0, 1, 2, or 3 substituents independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl;

R 2 is chosen from

C 1 -C 6 alkyl,

substituted C 1 -C 6 alkyl chosen from mono-, di-, and tri-substituted C 1 -C 6 alkyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 3 -C 7 cycloalkyl,

substituted C 3 -C 7 cycloalkyl alkyl chosen from mono-, di-, and tri-substituted C 3 -C 7 cycloalkyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

aryloxy,

substituted aryloxy chosen from mono-, di-, and tri-substituted aryloxy wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

heteroaryl, and

substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl.

17 . At least one chemical entity of claim 16 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

18 . At least one chemical entity of claim 16 wherein

R 2 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl.

19 . At least one chemical entity of claim 7 chosen from compounds of Formula 7

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof wherein

R 1 is chosen from

C 3 -C 7 cycloalkyl,

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl;

R 22 represents 0 to 4 substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

20 . At least one chemical entity of claim 19 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

21 . At least one chemical entity of claim 19 chosen from compounds of Formula 8

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0 and 1.

22 . At least one chemical entity of claim 21 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

23 . At least one chemical entity of claim 19 chosen from compounds of Formula 9

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

24 . At least one chemical entity of claim 23 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

25 . At least one chemical entity of claim 7 chosen from compounds of Formula 10

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

R 2 is chosen from

C 1 -C 6 alkyl,

substituted C 1 -C 6 alkyl chosen from mono-, di-, and tri-substituted C 1 -C 6 alkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 3 -C 7 cycloalkyl,

substituted C 3 -C 7 cycloalkyl alkyl chosen from mono-, di-, and tri-substituted C 3 -C 7 cycloalkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

aryloxy,

substituted aryloxy chosen from mono-, di-, and tri-substituted aryloxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

heteroaryl, and

substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl

26 . At least one chemical entity of claim 25 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

27 . At least one chemical entity of claim 25 chosen from compounds of Formula 11

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0, 1, 2, and 3; and

28 . At least one chemical entity of claim 27 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

29 . At least one chemical entity of claim 25 chosen from compounds of Formula 12

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0, 1, 2, and 3;

X, Y, and Z are chosen from nitrogen and CH, wherein one and only one of X, Y, and Z is nitrogen; and

R 2 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl

30 . At least one chemical entity of claim 29 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

31 . At least one chemical entity of claim 7 chosen from compounds of Formula 13

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

R 2 is chosen from

C 1 -C 6 alkyl,

substituted C 1 -C 6 alkyl chosen from mono-, di-, and tri-substituted C 1 -C 6 alkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 3 -C 7 cycloalkyl,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

aryloxy,

phenyl,

heteroaryl, and

32 . At least one chemical entity of claim 31 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

33 . At least one chemical entity of claim 31 wherein R 2 is chosen from

phenyl substituted with at least one branched C 3 -C 6 alkyl, and further substituted with 0 to 2 substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl, and

pyridyl substituted with at least one branched C 3 -C 6 alkyl, and further substituted with 0 to 2 substituents independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, piperidinyl, piperazinyl, and morpholinyl.

34 . At least one chemical entity of claim 31 chosen from compounds of Formula 14

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0 and 1.

35 . At least one chemical entity of claim 34 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

36 . At least one chemical entity of claim 34 wherein R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

37 . At least one chemical entity of claim 31 chosen from compounds of Formula 15

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0 and 1.

38 . At least one chemical entity of claim 37 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

39 . At least one chemical entity of claim 37 wherein, R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo [d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

40 . At least one chemical entity of claim 7 chosen from compounds of Formula 16

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

R 2 is chosen from

C 1 -C 6 alkyl,

substituted C 1 -C 6 alkyl chosen from mono-, di-, and tri-substituted C 1 -C 6 alkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 3 -C 7 cycloalkyl,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

aryloxy,

phenyl,

heteroaryl, and

41 . At least one chemical entity of claim 40 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

42 . At least one chemical entity of claim 40 chosen from compounds of Formula 17

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

); and

a is chosen from 0 and 1.

43 . At least one chemical entity of claim 42 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

44 . At least one chemical entity of claim 42 wherein R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

45 . At least one chemical entity of claim 40 chosen from compounds of Formula 18

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0 and 1.

46 . At least one chemical entity of claim 45 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

47 . At least one chemical entity of claim 44 wherein R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

48 . At least one chemical entity of claim 7 chosen from compounds of Formula 19

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

R 2 is chosen from

C 1 -C 6 alkyl,

substituted C 1 -C 6 alkyl chosen from mono-, di-, and tri-substituted C 1 -C 6 alkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 3 -C 7 cycloalkyl,

heterocycloalkyl,

substituted heterocycloalkyl chosen from mono-, di-, and tri-substituted heterocycloalkyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

C 1 -C 6 alkoxy,

substituted C 1 -C 6 alkoxy chosen from mono-, di-, and tri-substituted C 1 -C 6 alkoxy wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and heterocycloalkyl,

aryloxy,

phenyl,

heteroaryl, and

49 . At least one chemical entity of claim 48 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

50 . At least one chemical entity of claim 48 chosen from compounds of Formula 20

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0 and 1.

51 . At least one chemical entity of claim 50 wherein R 20 represents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

52 . At least one chemical entity of claim 50 wherein R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkox

53 . At least one chemical entity of claim 48 chosen from compounds of Formula 21

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof, wherein

a is chosen from 0 and 1.

54 . At least one che mical entity of claim 53 wherein R 20 r epresents one substituent chosen from hydroxy, nitro, cyano, amino, halo, C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkoxy, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, and amino(C 1 -C 4 alkyl).

55 . At least one chemical entity of claim 53 wherein R 1 is chosen from

phenyl,

substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

benzo[d]1,3-dioxolyl,

substituted benzo[d]1,3-dioxolyl chosen from mono-, di-, and tri-substituted benzo[d]1,3-dioxolyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl,

pyridyl, and

substituted pyridyl chosen from mono-, di-, and tri-substituted pyridyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, carboxy, amino, sulfonamido, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, mono-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), di-(C 1 -C 6 alkyl)amino(C 1 -C 6 alkyl), C 2 -C 6 alkanoyl, and C 1 -C 6 alkoxycarbonyl.

56 . At least one chemical entity of claim 1 chosen from

4-{6-[3-(4-tert-Butyl-benzoylamino)-4-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid;

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid;

4-{6-[5-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid;

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid ethyl ester;

4-tert-Butyl-N-{2-methyl-5-[8-(4-sulfamoyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;

and pharmaceutically acceptable salts, solvates, crystal forms, diastereomers, and prodrugs thereof.

57 . At least one chemical entity according to claim 1 , wherein in an in vitro assay of kinase modulation, the at least one chemical entity exhibits an IC 50 value less than or equal to 25 micromolar.

58 . At least one chemical entity according to claim 1 , wherein in an in vitro assay of modulation of soft agar growth, the at least one chemical entity exhibits a IC 50 value less than or equal to 25 micromolar.

59 . At least one chemical entity according to claim 1 , wherein in an in vitro assay of modulation of cell growth in soft agar, the at least one chemical entity exhibits an IC 50 value less than or equal to 25 micromolar, wherein the cells are chosen from HCT-15, MiaPaca-2, MCF-7, OVCAR-4, and A549 cells, the at least one chemical entity exhibits an IC 50 value less than or equal to 25 micromolar.

60 . A pharmaceutical composition comprising at least one chemical entity according to claim 1; and at least one pharmaceutically acceptable carrier or excipient.

61 . A method of treating a kinase-implicated condition in a mammal having a kinase-implicated condition, comprising administering to the mammal a therapeutically effective amount of at least one chemical entity of claim 1 .

62 . The method of claim 61 , wherein the mammal is a human.

63 . The method of claim 61 , wherein the mammal is chosen from cats and dogs.

64 . A method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity according to claim 1 .

65 . A method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity according to claim 1 and a therapeutically effective amount of at least one antitumor therapeutic.

66 . The method of claim 65 , wherein treatment with the at least one antitumor therapeutic follows treatment with the at least one chemical entity of claim 1 .

67 . The method of claim 65 , wherein the at least one antitumor therapeutic is at least one other chemotherapeutic agent.

68 . The method of claim 67 , wherein the at least one chemotherapeutic agent is chosen from mitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide, and doxorubicin.

69 . The method of claim 65 , wherein the at least one antitumor therapeutic is at least one radiotherapeutic agent.

70 . The method of claim 65 , wherein the mammal is a human.

71 . The method of claim 65 , wherein the mammal is chosen from cats and dogs.

72 . A method for identifying a kinase, comprising contacting an organism, cell, or preparation comprising the kinase with at least one chemical entity according to claim 1 , and detecting modulation of an activity of a kinase, whereby the kinase is identified.

73 . A method of treating a Btk-implicated condition in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one chemical entity according to claim 1 .

74 . The method of claim 73 wherein an additional kinase is implicated in the condition.

75 . The method of claim 73 wherein the mammal is a human.

76 . The method of claim 73 wherein the mammal is chosen from cats and dogs.

77 . A method for identifying Btk, comprising

contacting an organism, cell, or preparation comprising the kinase with at least one chemical entity according to claim 1 , whereby

detecting modulation of an activity of Btk, whereby Btk is identified.

78 . A method of treating a Btk-implicated autoimmune/inflammatory condition in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one chemical entity according to claim 1 .

79 . The method of claim 78 , wherein the mammal is a human.

80 . The method of claim 78 wherein the mammal is chosen from cats and dogs.

81 - 83 . (canceled)

Assignments (2)

CHANGE OF NAME Recorded Sep 27, 2005

From: CELLULAR GENOMICS INC.

To: CGI PHARMACEUTICALS, INC.

Reel/Frame 016843/0224 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 4, 2005

From: CURRIE, KEVIN S.; DESIMONE, ROBERT W.; PIPPIN, DOUGLAS A.; DARROW, JAMES W.; MITCHELL, SCOTT A.

To: CELLULAR GENOMICS, INC.

Reel/Frame 015842/0273 →