Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition

We report the synthesis of a pyrimidinone library that targets anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase. This library was generated in three steps from a versatile commercially available starting material. Some compounds within this library showed single digit micromolar inhibition of ALK in vitro, while showing minimal inhibition of other homologous insulin receptor family kinases including the human insulin receptor kinase (IRK), at the highest concentrations investigated. We also present initial ALK structure–activity relationships for this library.

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► We report the synthesis of small pyrimidinone libraries that target anaplastic lymphoma kinase (ALK).
► Some compounds within these libraries exhibit single digit inhibition of ALK.
► None of these compounds inhibit the insulin receptor kinase (IRK), a kinase homologous to ALK.