Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R1 attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R2. The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.