3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative diseases. Following previous studies, we have designed JNK3 inhibitors to reduce the molecular weight and successfully identified a lead compound that exhibits equipotent activity towards JNK3. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases. Among the derivatives, the IC50 value of 8a, (R)-2-(1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetonitrile exhibited 227 nM, showing the highest inhibitory activity against JNK3.

中文翻译：

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发现3-烷基-5-芳基-1-嘧啶基-1H-吡唑衍生物作为JNK3的新型选择性抑制剂支架。

设计并合成了3-烷基-5-芳基-1-嘧啶基-1H-吡唑衍生物，作为JNK3的选择性抑制剂，JNK3是神经退行性疾病的治疗靶标。经过先前的研究，我们设计了JNK3抑制剂以降低分子量，并成功鉴定出对JNK3具有同等活性的先导化合物。激酶谱分析结果还显示了在38种激酶中对JNK3的高度选择性。在衍生物中，IC50值为8a，（R）-2-（1-（2-（（（（（1-（环丙烷羰基）吡咯烷-3-基）氨基）嘧啶-4-基）-5-（3,4 -二氯苯基）-1H-吡唑-3-基）乙腈显示227 nM，显示出对JNK3的最高抑制活性。