ABSTRACT
A novel series of non-nucleoside HCV NS5B polymerase inhibitors was prepared from a (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid template. Solution and solid phase analog synthesis focused on the northern region of the template combined with structure based design led to the discovery of several potent and orally bioavailable lead compounds.
Subject(s)
Acrylates/chemistry , Acrylates/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitorsABSTRACT
Potassium tert-butoxide triggers the chemoselective cyclization between nitrile anions and remote, enolizable carbonyl groups, despite the acidity difference favoring enolate formation and addition to the nitrile group. Domino deprotonation, cyclization, and dehydration efficiently transform a diverse array of omega-oxonitriles into carbocyclic and heterocyclic five- and six-membered alkenenitriles in a single synthetic operation.
