Abstract: The present invention relates to novel therapeutic agents against hepatitis B virus (HBV) infection, particularly inhibitors of viral covalently closed circular DNA (cccDNA) which is the key barrier for HBV cure. Accordingly, the invention provides the pyrrolo[2,3-b]pyrazine compounds of formula (I), as described and defined herein, for use in the treatment of HBV infection. The compounds provided herein are highly potent against HBV infection and enable an improved therapy, particularly of chronic HBV infection and HBV rebound. The present invention further relates to a novel screening assay for the identification of therapeutic agents against HBV infection, particularly cccDNA inhibitors, which is performed in hepatocyte-like cells that recapitulate the complete HBV life cycle following infection with patient-derived HBV.