Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease

The medicinal chemistry and structure–activity
relationships
(SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds
as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed.
Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions
of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted
CAB which possessed a benzhydryl group on either the C-1 or the N-1
position. An N-3 substituent was found to be critical for the plasma
protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly,
compound 2v displayed significant efficacy in a mouse
model infected with influenza viruses.