Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus

Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo­[1,5-a]­pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos­(t)­ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.