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The adenosine A_2A receptor (A_2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A_2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine <b>1</b> (<i>K_i</i> (<i>h</i>A_2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound <b>5m</b> showed a high affinity for <i>h</i>A_2AR with a <i>K_i</i> value of 5 nM and demonstrated antagonist activity with an IC₅₀ of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (<b>9x</b>, <i>K_i</i> = 21 nM; <b>10d</b>, <i>K_i</i> = 15 nM) and functional antagonist activities (<b>9x</b>, IC₅₀ = 9 µM; <b>10d</b>, IC₅₀ = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A_2AR antagonists for therapeutic applications.