新型选择性TYK2/JAK1小分子抑制剂的设计、合成及其在炎症性肠病（IBD）治疗中的活性研究

自身免疫性疾病IBD已成为全球范围内的公共卫生挑战。将JAKs抑制剂应用于IBD治疗的研究持续受到关注，但目前已上市JAKs抑制剂中仅有Tofacitinib获批准适用于UC的治疗。随着对IBD的发病机制和JAKs的深入研究发现，通过选择性调控与IBD发病密切相关的IL-12、IL-13和IL-23等细胞因子通路的TYK2/JAK1选择性抑制剂可以实现低毒、高效的治疗效果。选择性TYK2/JAK1抑制剂研究成为JAKs抑制剂的研究热点之一。前期研究发现含螺环结构的嘧啶类化合物13可以实现选择性抑制TYK2/JAK1，IC50分别为6和17nM，且对DSS诱导的小鼠急性肠炎模型具有优异的治疗效果。本项目拟基于此，设计、合成化合物13的系列新型类似物，通过药理、药代、药效及安全性评价研究以期获得选择性TYK2/JAK1抑制剂候选分子应用于IBD治疗研究。

The autoimmune disease IBD has become a global public health challenge. The application of JAKs inhibitors in the treatment of IBD continues to receive attention, but Tofacitinib is the only JAKs inhibitor currently on the market that is approved for the treatment of UC. With the in-depth study on the pathogenesis of IBD and JAKs, it has been found that by selectively regulating the cytokine pathways such as IL-12, IL-13 and IL-23, which are closely related to the pathogenesis of IBD, the TYK2/JAK1 selective inhibitors can achieve low toxicity and high efficiency therapeutic effect. Selective TYK2/JAK1 inhibitors have become one of the research hotspots of JAKs inhibitors. Previous studies have found that compound 13, which contain spiral-ring and pyrimidine structure, can selectively inhibit TYK2/JAK1, with IC50 of 6 and 17nM, and have excellent therapeutic effects on DSS-induced acute IBD model in mice. Based on this, this project intends to design and synthesize a series of novel analogues of compound 13, and to obtain the candidate molecules of selective TYK2/JAK1 inhibitor for the treatment of IBD through the evaluation of pharmacology, PK, efficacy and safety evaluation.