Pyrimidines as sodium channel blockers

摘要

The present disclosure provides substituted pyrimidine compounds of Formula (I), and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein A1, X, A2, W1, W2, E, Z, and R4 are defined as set forth in the specification. The present disclosure 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 disclosure are especially useful for treating pain.;

主权项

1. A compound having Formula I:or a pharmaceutically acceptable salt, or solvate thereof,wherein:
W1 and W2 are N and W3 is CR3; or W1 and W3 are N and W2 is CR3; or W2 and W3 are N and W1 is CR3;A1 is selected from the group consisting of:
a) optionally substituted aryl; b) optionally substituted heteroaryl; c) optionally substituted cycloalkyl; d) optionally substituted heterocyclo; and e) aralkyl;X is
—O—;A2 is selected from the group consisting of:
a) optionally substituted aryl; b) optionally substituted heteroaryl; c) optionally substituted heterocyclo; and d) optionally substituted cycloalkyl; orA2 is absent;E is selected from the group consisting of:
a) hydroxy; b) alkoxy; and c) —NR1R2;R1 is selected from the group consisting of:
a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;R2 is selected from the group consisting of hydrogen and alkyl; or
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;R3 selected from the group consisting of:
a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; and m) alkoxyalkyl; Z is selected from the group consisting of —NR5— and —O—;R4 is selected from the group consisting of: c) hydroxyalkyl; d) hydroxy(cycloalkyl)alkyl; and e) (heterocyclo)alkyl;each R10a, R10b, R10c, and R10d is independently selected from the group consisting of:
a) hydrogen; b) hydroxy; c) optionally substituted alkyl; d) aralkyl; e) (heterocyclo)alkyl; f) (heteroaryl)alkyl; g) (amino)alkyl; h) (alkylamino)alkyl; i) (dialkylamino)alkyl; j) (carboxamido)alkyl; k) (cyano)alkyl; l) alkoxyalkyl; m) hydroxyalkyl; n) heteroalkyl; o) optionally substituted cycloalkyl; p) optionally substituted aryl; q) optionally substituted heterocyclo; and r) optionally substituted heteroaryl; or R10a and R10b taken together with the carbon atom to which they are attached form a 3- to 8-membered optionally substituted cycloalkyl or a 3- to 8-membered optionally substituted heterocyclo;r is 1, 2, or 3;s is 1, 2, or 3;R11 is selected from the group consisting of:
a) hydroxy; b) alkoxy; and c) —NR1aR2a; R1a is selected from the group consisting of: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl; R2a is selected from the group consisting of hydrogen and alkyl; or R1a and R2a taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo; R12 is selected from the group consisting of: a) hydrogen; b) optionally substituted alkyl; c) (amino)alkyl; d) (alkylamino)alkyl; e) (dialkylamino)alkyl; f) (carboxamido)alkyl; g) (cyano)alkyl; h) alkoxyalkyl; i) hydroxyalkyl; and j) heteroalkyl;R5 is selected from the group consisting of:
a) hydrogen b) alkyl; c) hydroxyalkyl; and d) alkylsulfonyl; or R4 and R5 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo; with the proviso that when R4 and R5 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo, then R1 is selected from the group consisting of: a) hydrogen; b) (heterocyclo)alkyl; c) (heteroaryl)alkyl; d) (amino)alkyl; e) (alkylamino)alkyl; f) (dialkylamino)alkyl; g) (carboxamido)alkyl; h) (cyano)alkyl; i) alkoxyalkyl; j) hydroxyalkyl; and k) heteroalkyl.