To explore the potential chemical space using C-H alkylation, 125 hit molecules featuring N -heteroaromatic scaffolds and known MAGL inhibitory activity were selected. These molecules were combined with 211 carboxylic acid fragments characterized by high sp 3 content, spanning a virtual library of 26,375 potential products. The compounds were subsequently evaluated using a multi-dimensional optimization (MDO) strategy including protein-ligand template docking, synthetic feasibility assessment using reaction prediction, as well as physicochemical and ADME property prediction (lipophilicity calculated as LogD values, kinetic solubility assay (LYSA), P-glycoprotein (P-gp) apparent permeability, and Parallel artificial membrane permeability assay (PAMPA)). For MAGL, an intracellular target, the cellular permeability of inhibitors is a crucial factor for successful drug development. This MDO approach allowed for the simultaneous evaluation of diverse criteria, ensuring the identification of compounds balancing potency, synthesizability, and properties that impact their pharmacokinetic profiles. Figure illustrates how the applied computational filtering process enabled prioritization and selection of compounds with predicted increased inhibitor potency and synthetic accessibility compared to the original hits.