We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC₅₀: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 μM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC₅₀ of 60 nM.

我们在此报告了被设计为潜在激酶抑制剂的 4,7-二取代吡啶并[3,2- d ]嘧啶的原始集合的合成和生物学评价。该集合由单一起始材料 4,7-二氯吡啶并[3,2 -d ]嘧啶产生，经过两个步骤提供最终化合物：连续或一锅序列，包括C -4 中的选择性交叉偶联反应，随后是C -7 中的第二次交叉耦合。在C -4位，Suzuki-Miyaura型反应产生单取代衍生物，而在C -7位，使用市售或未描述的硼衍生物通过Suzuki或Buchwald型反应实现合成。 V 形家族的生物活性通过蛋白激酶测定进行测量。构效关系（SAR）显示，一些化合物选择性抑制 DYRK1A 和 CDK5，而不影响 GSK3。对接研究提供了与 SAR 数据相关的可能解释。对两个生物靶标最活跃的化合物是27 ，其表现出以下 IC ₅₀ ：CDK5 为 110 nM，DYRK1A 为 24 nM，GSK3 仅 1.2 μM。在C -7 氨基亚家族中，最好的衍生物无疑是化合物48 ，它对DYRK1A 具有近乎选择性的作用，IC ₅₀高达60 nM。