A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT<sub>4</sub>R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT<sub>4</sub>R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT<sub>4</sub>R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, <b>12l</b>). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.