SUBSTITUTED PYRIDINES AS SODIUM CHANNEL BLOCKERS

摘要

The invention relates to substituted pyridine and pyrimidine compounds of Formula (I) and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein R1, R2a, R2b, A1, A2, X, and Z are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.;

主权项

1. A compound having Formula I:wherein:
A1 is selected from the group consisting of optionally substituted C4-8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; X is selected from the group consisting of —O—, —S—, —SO—, —SO2—, and —(CR2dR2e)m—;wherein:
each R2d and R2e, which can be identical or different, are selected from the group consisting of hydrogen, halo, and optionally substituted alkyl; or each R2d and R2e taken together with the carbon atom to which they are attached form a 3- to 8-membered optionally substituted cycloalkyl or optionally substituted heterocyclo; m is 1, 2, or 3; A2 is selected from the group consisting of optionally substituted C4-8 cycloalkyl, optionally substituted C4-8 cycloalkenyl, optionally substituted phenyl, optionally substituted 4- to 12-membered heterocyclo, and optionally substituted 5- or 6-membered heteroaryl; Z is selected from the group consisting of N and CR2c; R1 is selected from the group consisting of: R2a, R2b, and R2c, which can be identical or different, are selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, (amino)alkyl, and (diamino)alkyl; and R3 is dihydroxyalkyl; R4 is selected from the group consisting of —NR6aR6b and —OR7; R6a and R6b are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, monohydroxyalkyl, dihydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl; or R6a and R6b taken together with the carbon atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo; R7 is selected from the group consisting of hydrogen, alkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; or a pharmaceutically acceptable salt or solvate thereof.