JAK激酶抑制剂药物广泛应用于类风湿性关节炎、银屑病、骨髓纤维化、克罗恩病、系统性红斑狼疮等难治的免疫性疾病的治疗，JAK激酶抑制剂药物的开发在临床上有着极为重要的应用价值。然而现阶段JAK激酶抑制剂药物却由于低的JAK亚型选择性而导致在用药过程中会产生高风险感染和血液方面的毒副作用，这极大限制了JAK激酶抑制剂药物的临床适用性范围并严重威胁着患者的健康。在本项目中，为了克服这些严重的毒副作用，申请人拟在前期研究中发现的强效的选择性JAK3激酶抑制剂的结构基础上，通过合理的药物设计策略，开发结构新颖的高选择性JAK3激酶抑制剂和JAK-PROTAC分子。通过对这两类分子的结构优化和构效关系的研究，并进行免疫相关的体内外活性评价及机制研究，同时改善先导化合物的类药性，最终发明结构新颖、成药性良好、安全性高且具有自主知识产权的选择性JAK3激酶抑制剂和JAK-PROTAC分子。

JAK inhibitors are widely applied in the treatment of rheumatoid arthritis, psoriasis, myelofibrosis, Crohn's disease, systemic lupus erythematosus and other refractory immunological disorders. The development of JAK inhibitors is of great clinical value. However, due to the low selectivity of the JAK subtype, high risk of infection and side effects in blood occur during the course of medication, which greatly limits the clinical applicability and seriously threatens the health of patients. In this project, in order to overcome these serious adverse effects, based on the structure of selective JAK3 inhibitors found in the previous study, the applicant intends to develop novel and highly selective JAK3 inhibitors and JAK-PROTAC molecules through reasonable drug design strategies. Through the study of the structure optimization and structure-activity relationship, the in vitro and in vivo activity evaluation and mechanism research related to immunity, at the same time to improve the drug-like property of the lead compound, the highly selective JAK3 inhibitors and JAK-PROTAC molecules with novel structure, good drug-like property, high safety and proprietary intellectual property rights are finally invented.