Based on the detailed analysis of the binding mode of diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries of novel NNRTIs, with the aim to probe biologically relevant chemical space of solvent-exposed tolerant regions in NNRTIs binding pocket (NNIBP). The most potent compound 21a exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC50 = 2.44 nM; L100I, EC50 = 4.24 nM; Y181C, EC50 = 4.80 nM; F227L + V106A, EC50 = 17.8 nM) and 4-5-fold (K103N, EC50 = 1.03 nM; Y188L, EC50 = 7.16 nM; E138K, EC50 = 3.95 nM) more potent than the reference drug ETV. Furthermore, molecular simulation was conducted to understand the binding mode of interactions of these novel NNRTIs and to provide insights for the next optimization studies.