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A series of non\u2010nucleoside HCMV DNA polymerase inhibitors with various substitution groups at 2\u2010postition of the novel pyrido[2,3\u2010<jats:italic>b<\/jats:italic>]pyrazine core was synthesized and investigated. The study focused on optimizing HCMV polymerase inhibition while minimizing off\u2010target inhibition of human ether\u2010\u00e0\u2010go\u2010go (hERG) ion channel. Several compounds exhibited strong antiviral activity against HCMV (typical EC<jats:sub>50<\/jats:sub>&lt;1\u2005\u03bcM), with favorable cytotoxicity profiles. A potent lead compound, <jats:bold>27<\/jats:bold>, with an EC<jats:sub>50<\/jats:sub> of 0.33\u2005\u03bcM and improved aqueous solubility was identified. 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