A series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones were synthesized and their anti-HIV-1 activities was evaluated. Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with EC₅₀ values in the range of 0.0038 to 0.4759 μmol/L. Among those compounds, I-11 had an EC₅₀ value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1. In vitro anti-HIV-1 activity and resistance profile studies suggested that compounds I-11 and I-12 displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC₅₀s range from 4.3 to 63.6 nmol/L and 18.9–219.3 nmol/L, respectively). On the other hand, it was observed that those two compounds were less effective with EC₅₀ values of 2.77 and 4.87 μmol/L for HIV-1A₁₇ (K103N+Y181C). The activity against reverse transcriptase (RT) was also evaluated for those compounds. Both I-11 and I-12 obtained sub-micromolar IC₅₀ values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound I-11 has acceptable pharmacokinetic properties and bioavailability. Preliminary structure–activity relationships and molecular modeling studies were also discussed.