Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization

β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer’s disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine <b>6</b>, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in <b>24</b> with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency