Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents

Inventors

Andrez, Jean-Christophe • Burford, Kristen Nicole • Dehnhardt, Christoph Martin • Focken, Thilo • GRIMWOOD, Michael Edward • Jia, Qi • Lofstrand, Verner Alexander • Sun, Shaoyi • Wesolowski, Steven Sigmund • Wilson, Michael Scott • Zenova, Alla Yurevna

Assignees

Xenon Pharmaceuticals Inc

Abstract

This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy and/or epileptic seizure disorders.

Core Innovation

The invention relates to treating a disease or a condition associated with aberrant Nav1.6 activity in a patient. The disease or condition is epilepsy, epileptic seizure disorder, or SCN8A developmental and epileptic encephalopathy (SCN8A-DEE). The method comprises administering to the patient a therapeutically effective amount of a compound of formula (Ie), including as an individual stereoisomer, enantiomer or tautomer, a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.

Compound formula (Ie) is defined by variable substituents, including R1 as phenyl optionally substituted by halo, —R8—N(R9)R10, and optionally substituted N-heterocyclylalkyl; R2 as an optionally substituted 5-membered or 6-membered N-heteroaryl; R3 and R4 as hydrogen or alkyl; R5 as independently alkyl, halo, haloalkyl, optionally substituted cycloalkyl, cyano or —OR7; and R7 as hydrogen, alkyl, or haloalkyl. R8 is an optionally substituted straight or branched alkylene chain, and R9 and R10 are each alkyl or together form a 4- to 6-membered ring when attached to the N.

The disclosure also provides examples of substituted heteroaryl sulfonamide compounds and intermediates, including fluorinated pyridine/benzylsulfonamide cores, thiazol-4-yl or isothiazol-3-yl sulfonamide motifs, and substituted azetidine, pyrrolidine, and azabicyclo-type amine substituents. The described examples include salt forms such as trifluoroacetic acid salt and formic acid salt, along with reported characterization for selected intermediates and final compounds.

Claims Coverage

The claim coverage centers on 4 inventive features: treating Nav1.6-associated epilepsy-related conditions, the compound of formula (Ie) with defined substituent framework, specific named formula (Ie) compound embodiment, and alternative specific named formula (Ie) compound embodiment. The inventive coverage includes stereoisomer, enantiomer, tautomer, mixture, and pharmaceutically acceptable salt or solvate forms.

Overall, the claims cover a Nav1.6-associated treatment method using compounds of formula (Ie) with the defined heteroaryl-substituted benzenesulfonamide substituent framework, including stereochemical and salt or solvate forms. Dependent claims narrow the indication and further specify particular compound embodiments.

Stated Advantages

Documented Applications