We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4′-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, modifications of the 6-isopropylaminoindazole substituent were explored to improve selectivity over PIM3 while maintaining potent CSNK2A inhibition. The 6-isopropoxyindole analogue 6c was identified as a nanomolar CSNK2A inhibitor with 30-fold selectivity over PIM3 in cells. Replacement of the 6-isopropoxyindole by isosteric ortho-methoxy anilines, such as 7c, generated analogues with selectivity for CSNK2A over PIM3 and improved the kinome-wide selectivity. The optimized 2,6-disubstituted pyrazines showed inhibition of viral replication consistent with their CSNK2A activity.

中文翻译：

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鉴定 4-(6-((2-甲氧基苯基)氨基)吡嗪-2-基)苯甲酸作为 CSNK2A 抑制剂，具有抗病毒活性并比 PIM3 具有更高的选择性

我们报道了 2,6-二取代吡嗪的合成，作为有效的细胞活性 CSNK2A 抑制剂。发现 4'-羧基苯基是 CSNK2A 活性的最佳 2-吡嗪取代基，对额外修饰的耐受性很小。在 6 位，对 6-异丙氨基吲唑取代基的修饰进行了探索，以提高对 PIM3 的选择性，同时保持有效的 CSNK2A 抑制作用。6-异丙氧基吲哚类似物 6c 被鉴定为纳摩尔 CSNK2A 抑制剂，在细胞中的选择性是 PIM3 的 30 倍。用等排邻甲氧基苯胺（例如 7c）替换 6-异丙氧基吲哚，生成的类似物对 CSNK2A 的选择性高于 PIM3，并提高了激酶组范围内的选择性。优化的 2,6-二取代吡嗪表现出与 CSNK2A 活性一致的病毒复制抑制作用。