Structure-Based Design and Synthesis of 3‑Amino-1,5-dihydro‑4H‑pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1–3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.

本文报道了3-氨基-1,5-二氢-4H-吡唑并吡啶-4-酮类酪氨酸激酶2（TYK2）抑制剂的发现与优化过程。通过针对TYK2与Janus激酶1-3（JAK1-3）的高通量筛选，获得氨基吲唑衍生物1作为命中化合物。对该氨基吲唑母核进行骨架跃迁，发现了3-氨基-1,5-二氢-4H-吡唑并吡啶-4-酮衍生物3，这是一类新型的TYK2抑制剂化学骨架。有趣的是，初始构效关系（SAR）研究表明，该骨架可能存在垂直翻转的结合模式，这促使我们在7位引入取代基，作为朝向溶剂暴露区域的官能团。在7位引入1-甲基-3-吡唑基官能团后，TYK2抑制活性得到显著提升，经过进一步优化得到化合物20。化合物20在大鼠药效动力学（PD）试验中可抑制白细胞介素23（IL-23）诱导的白细胞介素22（IL-22）生成，同时在人类外周血单个核细胞（PBMC）中可阻断IL-23信号通路。此外，相较于粒细胞-巨噬细胞集落刺激因子（GM-CSF）信号通路，化合物20对IL-23信号通路抑制具有选择性，体现了该新型TYK2抑制剂独特的细胞因子选择性。