In this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration of the structure–activity relationship through the introduction of spirocyclic scaffolds based on the reported selective TYK2 inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on TYK2/JAK1 kinases with IC₅₀ values of 6 and 37 nM, respectively, and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more potent anti-inflammatory efficacy than tofacitinib in acute ulcerative colitis models. Moreover, the excellent anti-inflammatory effect of compound 48 was mediated by regulating the expression of related TYK2/JAK1-regulated genes, as well as the formation of Th1, Th2, and Th17 cells. Taken together, these findings suggest that compound 48 is a selective dual TYK2/JAK inhibitor, deserving to be developed as a clinical candidate.

中文翻译：

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鉴定一种新型 2,8-Diazaspiro[4.5]decan-1-one 衍生物作为治疗炎症性肠病的有效和选择性双 TYK2/JAK1 抑制剂

在这项研究中，我们描述了一系列 2,8-diazaspiro[4.5]decan-1-one 衍生物作为选择性 TYK2/JAK1 抑制剂。通过引入基于报道的选择性 TYK2 抑制剂14l的螺环支架系统探索结构-活性关系导致发现了优越的衍生化合物48。化合物48对 TYK2/JAK1 激酶表现出优异的效力，IC ₅₀值分别为 6 和 37 nM，对 JAK2 的选择性超过 23 倍。化合物48在急性溃疡性结肠炎模型中，还表现出比托法替尼更好的代谢稳定性和更有效的抗炎功效。此外，化合物48优异的抗炎作用是通过调节相关 TYK2/JAK1 调节基因的表达以及 Th1、Th2 和 Th17 细胞的形成来介导的。总之，这些发现表明化合物48是一种选择性的 TYK2/JAK 双重抑制剂，值得开发为临床候选药物。