Pyridinyl derivatives as sodium channel activators

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):

• wherein:
• X, Y, and Z are each independently N or CR1b, provided that at least one and no more than two of X, Y, and Z are N;
• L is a direct bond, —NR4C(═O)—, or —C(═O)NR4—;
• R1 is methoxy, —R5N(R6)2, alkenyl, or has one of the following structures:
• wherein:
• each is independently a single or double bond such that all valences are satisfied;
• each R1a is independently alkyl, halo, haloalkyl, —R5OR6, —R5N(R6)2, —R5OC(═O)R6, optionally substituted cycloalkyl, or —R5C(═O)OR6;
• A is O, N, or C;
• each R1b is independently hydrogen, halo, alkyl, or haloalkyl;
• R2a and R2b, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
• or R2a is hydrogen or alkyl and R2b is an optionally substituted heterocyclyl or an optionally substituted cycloalkyl;
• or R2a and R2b are both alkyl;
• or R2a is alkyl and R2b is haloalkoxy;
• R3 is alkyl, cyanoalkyl, —R5OR6, —R5N(R6)2, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocyclylalkyl;
• R4 is hydrogen or alkyl;
• each R5 is independently a direct bond or an optionally substituted alkylene chain;
• each R6 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl;
• or two R6's, together with the nitrogen to which they are both attached, form an optionally substituted heterocyclyl;
• and
• n is 0, 1, 2, 3, 4, or 5,
• as a stereoisomer, enantiomer, or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

A method of treating a disease or condition in a mammal modulated by a voltage-gated sodium channel, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I):

• wherein:
• X, Y, and Z are each independently N or CR1b, provided that at least one and no more than two of X, Y, and Z are N;
• L is a direct bond, —NR4C(═O)—, or —C(═O)NR4—;
• R1 is methoxy, —R5N(R6)2, alkenyl, or has one of the following structures:
• wherein:
• each is independently a single or double bond such that all valences are satisfied;
• each R1a is independently alkyl, halo, haloalkyl, —R5OR6, —R5N(R6)2, —R5OC(═O)R6, optionally substituted cycloalkyl, or —R5C(═O)OR6;
• A is O, N, or C;
• each R1b is independently hydrogen, halo, alkyl, or haloalkyl;
• R2a and R2b, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
• or R2a is hydrogen or alkyl and R2b is an optionally substituted heterocyclyl or an optionally substituted cycloalkyl;
• or R2a and R2b are both alkyl;
• or R2a is alkyl and R2b is haloalkoxy;
• R3 is alkyl, cyanoalkyl, —R5OR6, —R5N(R6)2, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocyclylalkyl;
• R4 is hydrogen or alkyl;
• each R5 is independently a direct bond or an optionally substituted alkylene chain;
• each R6 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl;
• or two R6's, together with the nitrogen to which they are both attached, form an optionally substituted heterocyclyl;
• and
• n is 0, 1, 2, 3, 4, or 5,
• as a stereoisomer, enantiomer, or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt, solvate, isotopologue, or prodrug thereof.