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We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Urszula Tyrcha is the Chemical Synthesis Specialist at the company RECEPTON Sp. z o.o., Aleksandra Hec-Gałązka is the Chemical Synthesis Specialist at the company RECEPTON Sp. z o.o., Prof. Dr Tad Holak is the CSO of the company RECEPTON Sp. z o.o., Head of Drug Discovery Laboratory Dr Tomasz Sitar is the CEO of the company RECEPTON Sp. z o.o., Head of Protein Engineering Laboratory., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)