After identification of lead compound , 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to (), an inhibitor with a p of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3,6)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide (, ), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.