Starting from lead compound , the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF group delivered an excellent pharmacological profile with a p of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent -(3-((3,6)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide (), able to reduce significantly A levels in mice, rats, and dogs in acute and chronic treatment regimens.