A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles

Described herein is a new approach to mitigate CYP3A4
induction.
In this unconventional approach, a fine-tuning of the dihedral angle
between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydro­pyrimidine
(HAP) class of capsid inhibitors successfully altered the structure–activity−relationships
(SARs) of the unwanted CYP3A4 induction and the desired HBV capsid
inhibition to more favorable values. This eventually led to the discovery
of a new capsid inhibitor with significantly reduced CYP3A4 induction,
excellent anti-HBV activity, favorable preclinical PK/PD profiles,
and no early safety flags.