Asymmetric synthesis of potent and orally bioavailable thiophene-based EZH2 inhibitors

Abstract

An efficient synthesis of 6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one bearing 3-methyl-2-(R)-(1-(piperidin-4-yl)ethyl) substituents (3), a pivotal intermediate for the development of EZH2 inhibitors, is described. The key steps include a highly enantioselective iridium-catalyzed hydrogenation of a 1,1-disubstituted alkene, cyanomethylation of a bromo thiophene using the Suzuki coupling-isoxazole fragmentation protocol, and subsequent tandem nitrile reduction/lactamization. Potent and orally bioavailable EZH2 inhibitors, such as 25 and 26, were discovered from 3 by optimizing substitutions at the piperidine ring.