Tetrahydrothieno[2,3-b]quinolines and related compounds and their preparation, pharmaceutical composition, and use for inhibiting KSP kinesin activity and treatment of proliferative diseases.

Abstract

The invention provides compds. of formula I. (wherein R1, R3, X, W, Z and ring Y are as defined herein). The invention also provides compns. comprising these compds. that are useful for treating cellular proliferative diseases or disorders assocd. with KSP kinesin activity and for inhibiting KSP kinesin activity. Compds. of formula I wherein Y is a 5- to 7-membered ring consisting of (un)substituted cycloalkyl, (un)substituted cycloalkenyl, (un)substituted heterocyclyl, and (un)substituted heterocyclenyl; W is N and CR12; X is N and N-oxide; Z is S, SO, and SO2; R1 is H, alkyl, alkoxy, HO, halo, CN, S-alkyl, SO-alkyl, SO2-alkyl, etc.; R3 is H, halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, (hetero)aryl, CO2H and derivs, etc.; R12 is is H, halo, alkyl, cycloalkyl, heterocyclyl(alkyl), (hetero)aryl, (hetero)aralkyl, CO2H and derivs, etc.; and their pharmaceutically acceptable salts, solvates and esters thereof are claimed. Example compd. II was prepd. by hydrolysis of 6-tert-butyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carbonitrile. All the invention compds. were evaluated for their KSP kinesin inhibitory activity. From the assay, it was detd. that Compd. II exhibited and IC50 value of less than 100 nM. [on SciFinder(R)]