Quinazoline compounds as sodium channel blockers

A method of modulating sodium channels in a mammal,

• comprising administering to the mammal at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof:
• wherein:
• R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonylamino, (alkylsulfonylamino)alkyl, ureido, (aminocarbonyl)alkylamino, and (carboxyalkyl)amino;
• G is G1, G2, G3, or G4, wherein
• G1 is —NR5R6, wherein
• R5 is H, alkyl, or NH2,
• R6 is
• a) H,
• b) alkyl,
• c) hydroxyalkyl,
• d) (aminocarbonyl)alkyl,
• e) (aminocarbonyl)(hydroxy)alkyl;
• f) aminoalkyl,
• g) alkylaminoalkyl,
• h) dialkylaminoalkyl,
• i) cycloalkyl, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• j) (cycloalkyl)alkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• k) aryl, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• l) arylalkyl, wherein the aryl group is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• m) heteroaryl, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• n) heteroarylalkyl, wherein the heteroaryl group is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• o) heterocyclo, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• or
• p) heterocycloalkyl, wherein the heterocyclo is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• or
• R5 and R6 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring having carbon atoms and 1 or 2 nitrogen atoms, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of oxo, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• G2 is
• p is 0, 1or 2;
• R7 is
• a) —(CH2)qOH, wherein q is 0, 1, 2, 3, 4, or 5;
• or
• b) selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, and alkoxy;
• and
• R8 is hydrogen or a bond;
• G3 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, wherein the heteroaryl is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• and
• G4 is —OR9, wherein R9 is alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl are unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, carboxy, alkoxycarbonyl, and cyano;
• A is
• wherein
• A1 is aryl or heteroaryl, any of which is optionally substituted;
• X is —O—, —S—, —SO—, —SO2—, —CH2—, or —NH—;
• and
• R13 and R14 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl;
• with the proviso that when G is G1, where R5 is hydrogen or alkyl and R6 is hydrogen, alkyl or cycloalkyl, and X is —O—, then no two of R1, R2, R3 and R4 are alkoxy at the same time.