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In this study, a novel series of diarylpyrimidine derivatives with Fsp3‐enriched spirocycles were designed and synthesized to further explore the chemical space of the hydrophobic channel of the NNRTI‐binding pocket. The biological evaluation results showed that most of the compounds displayed effective inhibitory potency against the HIV‐1 wild‐type strain, with EC50 values ranging from micromolar to submicromolar levels. Among them, TT6 turned out to be the most effective inhibitor with an EC50 value of 0.17 μM, demonstrating up to 47 times more active than that of reference drug 3TC (EC50 = 8.01 μM). More encouragingly, TT6 was found to potently inhibit the HIV‐1 mutant strain K103N with an EC50 value of 0.69 μM, being about 6‐fold more potent than 3TC (EC50 = 3.68 μM) and NVP (EC50 = 4.62 μM). Furthermore, TT6 exhibited the most potent inhibitory activity toward HIV‐1 reverse transcriptase with an IC50 value of 0.33 μM. Additionally, molecular simulation studies were conducted to investigate the binding modes between TT6 and NNRTI‐binding pocket, which may provide valuable clues for the follow‐up structural optimizations. [ABSTRACT FROM AUTHOR]