Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 
1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein 
cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical 
evaluation for the treatment of mild to moderate and prodromal Alzheimer's 
disease. Although not selective over the closely related aspartyl protease 
BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl 
proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in 
rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we 
describe the discovery of 3, including design, validation, and selected SAR 
around the novel iminothiadiazinane dioxide core as well as aspects of its 
preclinical and Phase 1 clinical characterization.