Carboxamide Derivatives and Use Thereof

摘要

The present disclosure provides substituted pyridyl-, pyrimidinyl-, pyrazinyl-, pyridazinyl-, and triazinyl-based carboxamides of Formula I-A: R10 Z-HET-E I-A and the pharmaceutically acceptable salts and solvates thereof, wherein Z, HET, R10 and E are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I-A 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:
Z-HET-E  Ior a pharmaceutically acceptable salt or solvate thereof, wherein:
Z is: HET is a 6-membered nitrogen-containing heteroaryl selected from the group consisting of E is selected from the group consisting of: X is selected from the group consisting of N and CR1; R1 is selected from the group consisting of:
a) hydrogen;b) optionally substituted heteroaryl;c) heteroalkyl;d) (aralkylamino)alkyle) (heterocyclo)alkyl;f) optionally substituted aryl;g) (heterocycloalkylamino)alkyl;h) (heterocycloamino)alkyl;i) alkanolamine;j) hydroxyalkyl;k) (amino)alkyl;l) (alkylamino)alkyl;m) (dialkylamino)alkyl;n) (cycloalkylamino)alkyl;o) (nitro)alkyl;p) (carboxamido)alkyl; andq) (haloalkylamino)alkyl; R2 is selected from the group consisting of:
a) hydrogen;b) optionally substituted heteroaryl;c) heteroalkyl;d) (aralkylamino)alkyle) (heterocyclo)alkyl;f) optionally substituted aryl;g) (heterocycloalkylamino)alkyl;h) (heterocycloamino)alkyl;i) alkanolamine;j) hydroxyalkyl;k) (amino)alkyl;l) (alkylamino)alkyl;m) (dialkylamino)alkyl;n) (cycloalkylamino)alkyl;o) (nitro)alkyl;p) (carboxamido)alkyl; andq) (haloalkylamino)alkyl;with the proviso that at least one of R1 and R2 is hydrogen;
R3 is selected from the group consisting of:
a) hydrogen;b) halo;c) cyano;d) haloalkyl;e) C1-C4 alkyl;f) C1-4 haloalkyl;g) C1-4 haloalkoxy; andh) C1-4 alkoxy; R4 is selected from the group consisting of:
a) hydrogen;b) chloro;c) cyano;d) C1-4 haloalkyl;e) arylamino;f) (arylamino)alkyl;g) (aryloxy)alkyl;h) (dialkylamino)alkyl;i) alkoxyalkyl;j) (heterocyclo)alkyl;k) optionally substituted aryl; andl) optionally substituted heteroaryl; R5 is selected from the group consisting of:
a) hydrogen;b) chloro;c) cyano;d) C1-4 haloalkyl;e) arylamino;f) (arylamino)alkyl;g) (aryloxy)alkyl;h) (dialkylamino)alkyl;i) alkoxyalkyl;j) (heterocyclo)alkyl;k) optionally substituted aryl; andl) optionally substituted heteroaryl,with the provisos:
1) when X is CR1 and R1 is hydrogen or hydroxyalkyl, then: i) R2 is selected from the group consisting of optionally substituted heteroaryl; heteroalkyl; (aralkylamino)alkyl(heterocyclo)alkyl; optionally substituted aryl; (heterocycloalkylamino)alkyl; (heterocycloamino)alkyl; alkanolamine; hydroxyalkyl; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl; (cycloalkylamino)alkyl; (nitro)alkyl; (carboxamido)alkyl; and (haloalkylamino)alkyl; or ii) R4 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or iii) R5 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or 2) when X is CR1 and R2 is hydrogen, then: i) R1 is selected from the group consisting of optionally substituted heteroaryl; heteroalkyl; (aralkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; (heterocycloalkylamino)alkyl; (heterocycloamino)alkyl; alkanolamine; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl; (cycloalkylamino)alkyl; (nitro)alkyl; (carboxamido)alkyl; and (haloalkylamino)alkyl; or ii) R4 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or iii) R5 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl.