In the light of recent lines of evidence, 5-HT<sub>6</sub>R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT<sub>6</sub>R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT<sub>6</sub>R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K<sub>i</sub> < 100 nM) and selectivity towards 5-HT<sub>6</sub>R, with respect to 5-HT<sub>2A</sub>R, 5-HT<sub>7</sub>R and D<sub>2</sub>R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT<sub>6</sub>R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K<sub>i</sub> = 6 nM), very strong 5-HT<sub>6</sub>R antagonistic action (K<sub>B</sub> = 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research.