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However, the long\u2010term administration of antiviral drugs promotes HBV for potential drug resistance. To overcome this problem, combination therapies are administered, but HBV progressively altered mutations remain a threat. Therefore, optimally designed NAs are urgently needed to treat drug\u2010resistant HBV. Herein, 2\u2032\u2010fluoro\u20106\u2032\u2010methylene carbocyclic adenosine (FMCA) and its phosphoramidate (FMCAP) have been discovered, which may be utilized in combination therapies for curing drug\u2010resistant chronic hepatitis B. In preclinical studies, these carbocyclic NAs demonstrated potential anti\u2010HBV activity against adefovir, as well as lamivudine (LMV\/LAM) drug\u2010resistant mutants. In vitro, these molecules have demonstrated significant activity against LMV\/entecavir (ETV) triple mutants (L180M + S202G + M204V). Also, preliminary studies of FMCA\/FMCAP in chimeric mice and female Non\u2010obese diabetic\/severe combined immunodeficiency (NOD\/SCID) mouse models having the LMV\/ETV triple mutant have shown a high rate of reduction of HBV DNA levels compared to ETV. 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