Synthesis and SAR of Imidazo[1,5-a]pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition. Introduction of isopropyl group at third position of imidazo[1,5-a]pyridine dramatically changed the activity from antagonist to agonist towards 5-HT4 receptor. [Display omitted] •Novel series of imidazo[1,5-a]pyridine derivatives were reported as 5-HT4R agonists.•Reported compounds have potent in vitro potency.•Selected compounds showed acceptable ADME properties.•Compound 5a showed efficacy in cognition models.•Compound 5a is selective over 5-HT3 and 5-HT2B receptors.