Discovery of Benzoazepine­quinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors

A novel benzoazepine­qunoline
(BAQ) series was discovered
as RSV fusion inhibitors. BAQ series originated from compound 2, a hit from similarity-based virtual screening. In SAR exploration,
benzoazepine allowed modifications in the head moiety. Benzylic sulfonyl
on benzoazepine and 6-Me on quinoline were crucial for good anti-RSV
activity. Although the basic amine in the head portion was crucial
for anti-RSV activity, the attenuated basicity was required to reduce Vss. Introducing oxetane to the head portion
led to discovery of compound 1, which demonstrated single-digit
nM anti-RSV activity against different RSV strains, reasonable oral
exposure in plasma, and 78-fold higher exposure in lung. Compound 1 also displayed 1 log viral reduction in a female BALB/c
mice RSV model by b.i.d. oral dosing at 12.5 mg/kg. A single resistant
mutant at L138F in fusion protein proved compound 1 to
be a RSV fusion inhibitor.