A series of novel heteroaromatic biphenyl-methyl-pyrimidine analogues were designed via hybridization of privileged structures of two HIV-1 inhibitors. Among them, compound 7a containing 4-pyridinyl-phenyl and methyl-pyrimidine fragments revealed excellent wild-type HIV-1 inhibitory activity with low cytotoxicity. 7a had favorable solubility and liver microsome stability; moreover, no apparent CYP enzymatic inhibitory activity or acute toxicity was observed. However, its inhibitory activity toward mutant strains and the pharmacokinetic (PK) profiles were still unsatisfactory. Further optimizations resulted in a highly potent compound 9d without methyl on the pyrimidine but a heteroaromatic dimethyl-biphenyl on the left rings of difluoro-pyridinyl-diarylpyrimidines (DAPYs). A broad-spectrum activity (EC50 = 2.0-57 nM) of 9d against resistant strains was revealed. This compound also exhibited good solubility and safety profiles and a good PK profile with an oral bioavailability of 59% in rats. Collectively, these novel heteroaromatic dimethyl-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.