Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic β (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.