TRPM8 antagonists and their use in treatments

摘要

Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure:;
where the definitions of the variables are provided herein.

主权项

1. A compound of Formula I having the structure:or a pharmaceutically-acceptable salt thereof, a tautomer thereof, a pharmaceutically-acceptable salt of the tautomer, a stereoisomer thereof, or a mixture thereof, wherein:
m is 0; n is 0 or 1; X1 is CH; X2 is N; Y is NH; Z is O; R1 isand the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule;
R2 is F or CF3; R3 is CF3 or OCF3; R4 is F or H; R5 is independently, in each instance, Cl, Br, F, CH3, CF3, or ORa; R6 is F, CF3, C1-6alk, or ORa; Ra is independently, at each instance, H or Rb; and Rb is independently, at each instance, phenyl, benzyl or C1-6alk, the phenyl, benzyl and C1-6alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, C1-4alk, C1-3haloalk, —OC1-4alk, —OH, —NH2, —OC1-4alk, —OC1-4haloalk, —NHC1-4alk, and —N(C1-4alk)C1-4alk.