WO2017020428A1

WO2017020428A1 - Novel compounds for use as jak inhibitors

Info

Publication number: WO2017020428A1
Application number: PCT/CN2015/091451
Authority: WO
Inventors: 陈亦林; 彭红; 钱进; 陶琳; 赵岩; 张晓丽; 赵银鹰; 邹阳
Original assignee: 南昌弘益科技有限公司; 南昌弘益药业有限公司
Priority date: 2015-08-03
Filing date: 2015-10-08
Publication date: 2017-02-09
Also published as: CN106397432A; CN106397432B

Abstract

The present invention relates to novel compounds for use as Janus kinase (JAK) inhibitors. The compounds are compounds of Formula I and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and pharmaceutical compositions comprising the compounds. The compositions may be used for the prevention or treatment of diseases and symptoms associated with JAK in human or mammalian patients, and may be applied as JAK inhibitors in experiments in medicine, pharmacy, biology, physiology, biochemistry, etc.

Description

作为JAK抑制剂的一类新化合物A new class of compounds that act as JAK inhibitors

技术领域Technical field

本发明涉及作为JAK抑制剂的一类新化合物，包括其药学上可接受的盐、前药、代谢物、同位素衍生物和溶剂合物，其可用于通过调节蛋白激酶活性来调节细胞活性如信号转导、增殖和细胞因子分泌。此外，本发明涉及包含所述化合物的药物组合物，可用于预防或治疗Janus激酶(JAK)相关疾病的JAK抑制剂，并可作为Janus激酶(JAK)抑制剂应用在医学、药学、生物学、生理学、生化学等实验中。所述JAK相关疾病包括炎性疾病、自身免疫性疾病、增殖性疾病、增生性疾病等。The present invention relates to a novel class of compounds which are JAK inhibitors, including pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, which are useful for modulating cellular activity such as signaling by modulating protein kinase activity. Transduction, proliferation and secretion of cytokines. Further, the present invention relates to a pharmaceutical composition comprising the compound, which is useful for preventing or treating a JAK inhibitor of a Janus kinase (JAK)-related disease, and can be used as a Janus kinase (JAK) inhibitor in medicine, pharmacy, biology, Physiology, biochemistry and other experiments. The JAK-related diseases include inflammatory diseases, autoimmune diseases, proliferative diseases, proliferative diseases, and the like.

背景技术Background technique

蛋白激酶(PK)是调控多种重要生物过程的一组酶，所述生物过程尤其包括细胞激酶催化蛋白质、脂质、糖、核苷和其他细胞代谢物的磷酸化并在真核细胞生理学的所有方面起关键作用。特别地，蛋白激酶和脂质激酶参与信号传导事件，该事件控制对细胞外调节物或刺激物(如生长因子、细胞因子或趋化因子)响应的细胞的激活、生长、分化和存活。Protein kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, including, inter alia, cellular kinases that catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites in physiology of eukaryotic cells. All aspects play a key role. In particular, protein kinases and lipid kinases are involved in signaling events that control the activation, growth, differentiation and survival of cells that respond to extracellular regulators or stimuli such as growth factors, cytokines or chemokines.

Janus激酶(Janus kinase,JAK)是一类非跨膜型非受体型蛋白酪氨酸激酶家族，在细胞因子信号传递过程中起重要作用。JAK激酶既能磷酸化与其相结合的细胞因子受体，又能磷酸化多个含特定Src同源2结构域(Src homology 2 domain，SH2)的信号分子。目前有四种已知的哺乳动物JAK家族成员：JAK1、JAK2、JAK3和TYK2。它们在结构上有7个JAK同源结构域(JAK homology domain,JH)，其中JH1结构域为激酶区，功能是编码激酶蛋白；JH2结构域是“假”激酶区，对JH1的活性起调节作用；JH3-JH7组成一个四合一结构域，调节JAK与受体的结合。JAK3分布于骨髓和淋巴***中，而JAK1、JAK2、TYK2广泛分布于多种组织细胞中。JAK激酶参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。Janus kinase (JAK) is a family of non-transmembrane non-receptor protein tyrosine kinases that play an important role in cytokine signaling. JAK kinase can phosphorylate both its cytokine receptor and phosphorylation of multiple signal molecules containing a specific Src homology 2 domain (SH2). There are currently four known mammalian JAK family members: JAK1, JAK2, JAK3, and TYK2. They are structurally composed of seven JAK homology domains (JH), in which the JH1 domain is a kinase domain and functions to encode a kinase protein; the JH2 domain is a "pseudo" kinase domain that regulates the activity of JH1. Role; JH3-JH7 constitutes a four-in-one domain that regulates the binding of JAK to the receptor. JAK3 points It is distributed in the bone marrow and lymphatic system, while JAK1, JAK2, and TYK2 are widely distributed in various tissue cells. JAK kinase is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.

信号转导子和转录激活子(signal transducer and activator of transcription，STAT)是JAK的底物。信号转导和转录激活(STATs)蛋白家族中包括STAT1，STAT2，STAT3，STAT4，STAT5a，STAT5b及STAT6等7个成员。JAKs与STATs之间的相互作用在细胞因子受体信号通路中起着重要作用(O'SULLIVAN LA,LIONGUE C,LEWIS RS,et al.Cytokine receptor signaling through the Jak Stat pathway in disease[J].MolImmunol,2007,44{10)：2497-2506.)。当细胞因子与其靶细胞上的特异性受体结合后可使JAK活化，继而催化受体上的酪氨酸残基发生磷酸化,并形成相应的STAT与受体复合物结合的“停泊位点”(docking site)。最后JAK激酶催化STAT蛋白磷酸化,活化的STAT形成同源或异源二聚体后进人细胞核内与特定的靶基因结合，调控目的蛋白表达(LVASHKIV LB,HU XY.Signaling by STATs[J].Arthritis Res Ther,2004,6(4):159-168.),此途径即JAK/STAT信号通路。JAK/STAT信号转导途径的异常活化与肿瘤、白血病等多种疾病的发生、发展和预后密切相关。Signal transducers and activator of transcription (STAT) are substrates for JAK. The signal transduction and transcriptional activation (STATs) protein family includes seven members including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. The interaction between JAKs and STATs plays an important role in the cytokine receptor signaling pathway (O'SULLIVAN LA, LIONGUE C, LEWIS RS, et al. Cytokine receptor signaling through the Jak Stat pathway in disease [J]. MolImmunol , 2007, 44{10): 2497-2506.). When a cytokine binds to a specific receptor on its target cell, it activates JAK, which in turn catalyzes the phosphorylation of the tyrosine residue on the receptor and forms a corresponding "parking site for STAT binding to the receptor complex. "(docking site)." Finally, JAK kinase catalyzes the phosphorylation of STAT protein. The activated STAT forms a homologous or heterodimer and then binds to a specific target gene in the human nucleus to regulate the expression of the target protein (LVASHKIV LB, HU XY. Signaling by STATs [J]. Arthritis Res Ther, 2004, 6(4): 159-168.), this pathway is the JAK/STAT signaling pathway. Abnormal activation of JAK/STAT signal transduction pathway is closely related to the occurrence, development and prognosis of various diseases such as tumor and leukemia.

JAK/STAT信号通路是近年来新发现的一条与细胞因子密切相关的细胞内信号转导通路，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生理学过程，对机体免疫应答、免疫细胞分化发育及炎症反应等有重要影响，在肿瘤、炎症及多种自身免疫等疾病的发生、发展中起重要作用。JAK/STAT信号通路的异常激活与多种肿瘤发生和发展密切相关。JAK/STAT signaling pathway is a newly discovered intracellular signal transduction pathway closely related to cytokines in recent years. It is involved in many important physiological processes such as cell proliferation, differentiation, apoptosis and immune regulation, and immune response and immunity to the body. Cell differentiation and inflammatory response have important effects, and play an important role in the occurrence and development of tumors, inflammation and various autoimmune diseases. Abnormal activation of the JAK/STAT signaling pathway is closely related to multiple tumorigenesis and development.

JAK/STAT信号通路是一条由多种细胞因子受体刺激的信号转导通路，这些因子包括白介素类(如IL-2～7，IL-9，IL-10，IL-15，IL-21等)、干扰素类(包括IFN-α，IFN-β，IFN-γ等)、***(EPO)、粒细胞和巨噬细胞集落刺激因子(GM-CSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)、血小板衍生因子(PDGF)以及表皮细胞生长因子(EGF)等，其在参与免疫调节、免疫细胞增殖等生物学过程中起关键作用(GHORESCHI K，LAURENCE A,O'SHEA JJ.Janus kinases in immune cell signaling[J].Immunol Rev,2009,228(1)：273-287.)。不同受体可激活不同亚型的JAK激酶，从而表现差异化的生物学功能。The JAK/STAT signaling pathway is a signal transduction pathway stimulated by a variety of cytokine receptors, including interleukins (eg IL-2-7, IL-9, IL-10, IL-15, IL-21, etc.). ), Interferons (including IFN-α, IFN-β, IFN-γ, etc.), erythropoietin (EPO), granulocyte and macrophage colony-stimulating factor (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), platelet-derived factor (PDGF), and epidermal growth factor (EGF), which play a key role in biological processes such as immune regulation and immune cell proliferation (GHORESCHI K, LAURENCE A, O'SHEA JJ. Janus kinases in immune cell signaling [J]. Immunol Rev, 2009, 228(1): 273-287.). Different receptors activate JAK kinases of different subtypes to express differential biological functions.

在小鼠模型上的JAK1基因敲除实验表明该酶在调节上述多种细胞因子受体的生物学效应中起着关键作用(KISSELEVA T,BHATTACHARYA S，BRAUNSTEIN J，et al.Signaling through the JAK/STAT pathway,recent advances and future challenges[J].Gene,2002,285(1-2):1-24.)。JAK1 knockout experiments on mouse models indicate that this enzyme plays a key role in regulating the biological effects of the various cytokine receptors described above (KISSELEVA T, BHATTACHARYA S, BRAUNSTEIN J, et al. Signaling through the JAK/ STAT pathway, recent advances and future challenges [J]. Gene, 2002, 285(1-2): 1-24.).

在小鼠模型中敲除JAK2可导致贫血引起的动物死亡(SCHINDLER C，LEVY DE，DECKER T.JAK-STAT signaling：from interferons to cytokines[J].J Biol Chem,2007,282(28):20059-20063.)。人体中的JAK2基因上的一个碱基突变JAK2V617F,其与骨髓增生性疾病中的真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓纤维化(IMF)、慢性粒细胞白血病(CML)等的发生密切相关(GHORESCHI K，LAURENCE A,O'SHEA JJ.Janus kinases in immune cell signaling[J].Immunol Rev,2009,228(1)：273-287.)。JAK2抑制剂已描述适用于骨髓增殖性疾病(Santos等人,Blood,2010,115:1131；Barosi G.和Rosti V.，Curr.Opin.Hematol.,2009,16:129；Atallah E.和Versotvsek S.，2009Exp.Rev.Anticancer Ther.9:663)。Knocking out JAK2 in a mouse model can lead to animal death caused by anemia (SCHINDLER C, LEVY DE, DECKER T. JAK-STAT signaling: from interferons to cytokines [J]. J Biol Chem, 2007, 282(28): 20059 -20063.). A base mutation in JAK2 gene in human body JAK2V617F, which is associated with polycythemia (PV), idiopathic thrombocytosis (ET), idiopathic myelofibrosis (IMF), chronic in myeloproliferative diseases The occurrence of granulocyte leukemia (CML) and the like is closely related (GHORESCHI K, LAURENCE A, O'SHEA JJ. Janus kinases in immune cell signaling [J]. Immunol Rev, 2009, 228(1): 273-287.). JAK2 inhibitors have been described for use in myeloproliferative disorders (Santos et al, Blood, 2010, 115: 1131; Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16: 129; Atallah E. and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9: 663).

JAK3缺陷首次在患有常染色体隐性重度联合免疫缺陷(SCID)的人中被识别(Macchi等，1995.Nature377(6544)：65-68)。JAK3敲除小鼠也显示SCID但未显示非免疫性缺陷，表明JAK3抑制剂作为免疫抑制剂将在体内具有相关效应并因此成为用于免疫抑制的有前景的药物(Papageorgiou和Wikman2004，Trends in Pharmacological Sciences25(11)：558-62)。酪氨酸激酶JAK3的抑制剂已被描述适用作免疫抑制剂(例如美国专利6,313,129；Borie等人,Curr.Opin.Investigational Drugs，2003，4:1297)。JAK3 defects are first recognized in people with autosomal recessive severe combined immunodeficiency (SCID) (Macchi et al, 1995. Nature 377 (6544): 65-68). JAK3 knockout mice are also The SCID is shown but does not show non-immune defects, indicating that the JAK3 inhibitor as an immunosuppressive agent will have a relevant effect in vivo and thus become a promising drug for immunosuppression (Papageorgiou and Wikman 2004, Trends in Pharmacological Sciences 25(11): 558 -62). Inhibitors of the tyrosine kinase JAK3 have been described as useful as immunosuppressive agents (e.g., U.S. Patent No. 6,313,129; Borrie et al., Curr. Opin. Investigational Drugs, 2003, 4:1297).

TYK2是JAK家族中的第1个成员，其可被IF-Ns，IL-10,IL-6，IL-12，IL-23，IL-27等多种受体激活。在小鼠中，TYK2功能缺失会引起多种细胞因子受体的信号通路发生缺陷，进而导致病毒感染、抗菌免疫功能下降并增加了肺部感染的可能性等(KISSELEVA T,BHATTACHARYA S,BRAUNSTEIN J,et al.Signaling through the JAK/STAT pathway,recent advances and future challenges[J].Gene,2002,285(1-2):1-24.)。另外,Lamer AC小组的研究表明TYK2可有助于抑制乳腺癌的生长和转移(ZHANG Q,STURGILL JL,KMIECIAK M et al.The role of Tyk2in regulation of breast cancer growth[J].J Intetferon Cytokine Res,2011,31(9)：671-677.)TYK2 is the first member of the JAK family and is activated by a variety of receptors such as IF-Ns, IL-10, IL-6, IL-12, IL-23, IL-27. In mice, loss of TYK2 function causes defects in the signaling pathways of various cytokine receptors, leading to viral infection, decreased immune function, and increased likelihood of pulmonary infection (KISSELEVA T, BHATTACHARYA S, BRAUNSTEIN J , et al. Signaling through the JAK/STAT pathway, recent advances and future challenges [J]. Gene, 2002, 285(1-2): 1-24.). In addition, studies by the Lamer AC team have shown that TYK2 can help inhibit breast cancer growth and metastasis (ZHANG Q, STURGILL JL, KMIECIAK M et al. The role of Tyk2in regulation of breast cancer growth [J]. J Intetferon Cytokine Res, 2011, 31(9): 671-677.)

综上所述，JAK激酶的水平上阻断信号转导有望开发治疗或预防Janus激酶(JAK)相关疾病，如免疫、炎症、自身免疫、增殖性疾病如癌症、增生性疾病、过敏病症或疾病、移植排斥或移植物抗宿主病、干眼症等。In summary, blocking signal transduction at the level of JAK kinase is expected to develop treatment or prevention of Janus kinase (JAK)-related diseases such as immunity, inflammation, autoimmunity, proliferative diseases such as cancer, proliferative diseases, allergic diseases or diseases. , transplant rejection or graft versus host disease, dry eye syndrome, etc.

目前美国辉瑞(Pfizer)公司研发的JAK抑制剂Tofacitinib能选择性抑制JAK3激酶，于2012年11月6日被FDA批准用于治疗成人活动期及对甲氨蝶呤反应不佳的中至重度类风湿性关节炎(RA)。Tofacitinib的主要副作用有严重感染率和低密度脂蛋白水平提高，最常见的不良反应为上呼吸道感染、头痛、腹泻、鼻充血、咽喉痛和鼻咽炎。除肝脂肪变性、周围水肿外，Tofacitinib的其他大部分不良反应，单抗类药物也都存在。Tofacitinib作为免疫抑制剂，批准说明书中的警告和注意事项与抗TNF单抗药物基本相同。由于部分抑制了Jak2活性并干扰红细胞生成素和集落刺激因子等细胞因子发挥效应，因而也有临床研究报道，Tofacitinib可引起贫血和中性粒细胞减少症等副作用。此外，临床试验显示，Tofacitinib并不会致使T淋巴细胞总数减少，但会导致CD8+T细胞减少及自然杀伤细胞(NK细胞)轻微减少，因此服用Tofacitinib时还存在某些不确定的风险。[用于治疗类风湿性关节炎的JAK抑制剂，薛锋，刘飞，吴刚，尤启冬，《药学进展》2014，38(4)：264－273]At present, the FAK inhibitor Tofacitinib developed by Pfizer in the United States can selectively inhibit JAK3 kinase. It was approved by the FDA on November 6, 2012 for the treatment of adult active and moderate to severe grades with poor response to methotrexate. Rheumatoid arthritis (RA). The main side effects of Tofacitinib are severe infection rate and elevated LDL levels. The most common adverse reactions are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat and nasopharyngitis. In addition to liver steatosis, surrounding water Exogenous, most of the other adverse reactions of Tofacitinib, monoclonal drugs are also present. Tofacitinib acts as an immunosuppressant, and the warnings and precautions in the approved instructions are essentially the same as those of the anti-TNF monoclonal antibody. Due to partial inhibition of Jak2 activity and interference with cytokines such as erythropoietin and colony stimulating factor, clinical studies have also reported that Tofacitinib can cause side effects such as anemia and neutropenia. In addition, clinical trials have shown that Tofacitinib does not reduce the total number of T lymphocytes, but it leads to a decrease in CD8+ T cells and a slight decrease in natural killer cells (NK cells), so there are some uncertain risks when taking Tofacitinib. [JAK inhibitors for the treatment of rheumatoid arthritis, Xue Feng, Liu Fei, Wu Gang, You Qidong, Progress in Pharmacy 2014, 38(4): 264-273]

尽管目前已公开了一系列的JAK激酶抑制剂，但这些已上市或正处于研究阶段的JAK激酶抑制剂在疗效和安全性方面还有改进的空间，仍需要开发更好药效和安全性的新化合物。本发明的化合物作为Janus激酶(JAK)抑制剂，表现出良好的活性和安全性。Although a series of JAK kinase inhibitors have been published, these JAK kinase inhibitors that are on the market or in the research stage still have room for improvement in efficacy and safety, and there is still a need to develop better efficacy and safety. New compound. The compounds of the present invention, as inhibitors of Janus kinase (JAK), exhibit good activity and safety.

发明内容Summary of the invention

本发明涉及作为JAK抑制剂的一类新化合物，该化合物为式(I)化合物及其药学上可接受的盐、前药、代谢物、同位素衍生物和溶剂合物，及包含所述化合物的药物组合物，可用于预防或治疗在人体患者、哺乳动物患者中与Janus激酶(JAK)相关的疾病和病症；及其可作为Janus激酶(JAK)抑制剂应用在医学、药学、生物学、生理学、生化学等实验中。The present invention relates to a novel class of compounds which are JAK inhibitors, which are compounds of formula (I), and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and compositions comprising the same A pharmaceutical composition for preventing or treating diseases and disorders associated with Janus kinase (JAK) in human patients, mammalian patients; and for use as a Janus kinase (JAK) inhibitor in medicine, pharmacy, biology, physiology , biochemistry and other experiments.

一种式(I)的新化合物：A new compound of formula (I):

包括其药学上可接受的盐、前药、代谢物、同位素衍生物和溶剂合物，其中：Including pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, wherein:

环A为C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基、C_11-15三元环基，其中环A任选被一个或多个相同或不同的R、R₁所取代；Ring A is C _3-7 cycloalkyl, C _5-7 aromatic ring group, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group, C _11-15 three a cyclic group wherein ring A is optionally substituted by one or more of the same or different R, R ₁ ;

R、R₁是H、卤素、苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R, R ₁ is H, halogen, benzene, C _3-7 cycloalkyl, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group, wherein these rings are Optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, The C _2-8 alkynyl group is optionally substituted by one or more of the same or different R ₆ ;

B₁是H、CH₃、CN、NO₂、CF₃、卤素；B ₁ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

B₂是H、CH₃、CN、NO₂、CF₃、卤素；B ₂ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

X是H、CH₃、CN、NO₂、CF₃、C(O)NH₂、卤素；X is H, CH ₃ , CN, NO ₂ , CF ₃ , C(O)NH ₂ , halogen;

R₂是H、CH₃、CN、NO₂、CF₃、卤素；R ₂ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

R₃是H、CH₃、CN、NO₂、CF₃、卤素；R ₃ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

R₄是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2- ₈炔基任选被一个或多个相同或不同的R₆取代；R ₄ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _{a 5-7} aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl , C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, C _2- ₈ alkynyl group optionally substituted by one or more identical or different substituents R ₆ ;

R₅是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2- ₈炔基任选被一个或多个相同或不同的R₆取代； R ₅ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _{a 5-7} aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl , C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, C _2- ₈ alkynyl group optionally substituted by one or more identical or different substituents R ₆ ;

R₆是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₆ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _{a 5-7} aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally substituted by one or more of the same or different R ₆ ;

R₇是苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₇ is benzene, C _3-7 cycloalkyl, C _5-7 aromatic heterocyclic, C _7-11 aromatic bicyclic, C _7-11 aromatic heterobicyclic, wherein these rings are optionally one or more Substituted or substituted by R ₅ ; C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl Optionally substituted with one or more identical or different R ₆ ;

R₈、R_8’分别是H、CN、NO₂、CF₃、COOR₇、CONR₈R_8’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₈ and R _{8 '} are H, CN, NO ₂ , CF ₃ , COOR ₇ , CONR ₈ R _{8 '} , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _5-7 An aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl, C _{2 An} alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group is optionally substituted by one or more of the same or different R ₆ ;

R₉、R_9’分别是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈R_8’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₉ and R _{9 '} are H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _{8 '} , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _{5 a -7} aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally substituted by one or more of the same or different R ₆ ;

R₁₀是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代； R ₁₀ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _{a 5-7} aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally substituted by one or more of the same or different R ₆ ;

R₁₁是H、苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₁₁ is H, benzene, C _3-7 cycloalkyl, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group, wherein these rings are optionally one or Multiple identical or different R ₅ substitutions; C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, C _2-8 An alkynyl group is optionally substituted by one or more of the same or different R ₆ ;

Y是(CR₁₂R₁₃)n；Y is (CR ₁₂ R ₁₃ )n;

n是0或1；n is 0 or 1;

R₁₂、R₁₃是R₅；R ₁₂ and R ₁₃ are R ₅ ;

Z₁、Z₂可以分别选自C(R₁₄)或N(R₁₄)；Z ₁ , Z ₂ may be respectively selected from C(R ₁₄ ) or N(R ₁₄ );

R₁₄是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；苯、C_3-7环烷基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代。R ₁₄ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; benzene, C _3-7 cycloalkyl, C _{a 5-7} aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally substituted by one or more of the same or different R ₆ .

本发明的含义内，如下使用术语：Within the meaning of the present invention, the terms are used as follows:

“卤素”是指F、Cl、Br、I、At。"Halogen" means F, Cl, Br, I, At.

“C_3-7环烷基”是指具有3-7个碳原子的环烷基链，例如环丙基、环丁基、环戊基、环己基、环己烯基、环庚基。环烷基碳的每个氢可被进一步规定的取代基替换。"C _3-7 cycloalkyl" refers to a cycloalkyl chain having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of the cycloalkyl carbon can be replaced by a further defined substituent.

“C_5-7芳香杂环基”是指具有具有5-7个碳原子的芳香杂环基，例如咪唑、噻唑、吡唑、吡啶、嘧啶等。芳香杂环基的每个氢可被进一步规定的取代基替换。The "C _5-7 aromatic heterocyclic group" means an aromatic heterocyclic group having 5 to 7 carbon atoms, such as imidazole, thiazole, pyrazole, pyridine, pyrimidine or the like. Each hydrogen of the aromatic heterocyclic group may be replaced by a further defined substituent.

“C_7-11芳香双环基”是指具有具有7-11个碳原子的芳香双环基，例如萘、茚等。芳香双环基的每个氢可被进一步规定的取代基替换。 The "C _7-11 aromatic bicyclic group" means an aromatic bicyclic group having 7 to 11 carbon atoms, such as naphthalene, anthracene or the like. Each hydrogen of the aromatic bicyclic group can be replaced by a further defined substituent.

“C_7-11芳香杂双环基”是指具有具有7-11个碳原子的芳香杂双环基，例如喹啉、异喹啉、苯并噻唑等。芳香杂双环基的每个氢可被进一步规定的取代基替换。The "C _7-11 aromatic heterobicyclic group" means an aromatic heterobicyclic group having 7 to 11 carbon atoms, such as quinoline, isoquinoline, benzothiazole or the like. Each hydrogen of the aromatic heterobicyclic group can be replaced by a further defined substituent.

“C_l-8烷基”是指具有1-8个碳原子的烷基链，例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。C_l-8烷基碳的每个氢可被进一步规定的取代基替换。"C _l-8 alkyl" means an alkyl chain having from 1 to 8 carbon atoms, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl. Each hydrogen of the C _8-8 alkyl carbon can be replaced by a further defined substituent.

“C_2-8烯基”是指具有2-8个碳原子的烯基链，例如：-CH＝CH，，一CH＝CH-CH₃，-CH₂-CH＝CH₂，-CH＝CH-CH₂-CH₃，-CH＝CH-CH＝CH₂。C_2-8烯基碳的每个氢可被进一步规定的取代基替换。"C _2-8 alkenyl" means an alkenyl chain having 2-8 carbon atoms, for example: -CH=CH, -CH=CH-CH ₃ , -CH ₂ -CH=CH ₂ , -CH= CH-CH ₂ -CH ₃ , -CH=CH-CH=CH ₂ . Each hydrogen of the C _2-8 alkenyl carbon may be replaced by a further defined substituent.

“C_2-8炔基”是指具有2-8个碳原子的炔基链，例如：-C-CH，-CH.,-C-CH，CH2-CH2-C三CH，CH2-C-C-CH3。C_2-6炔基碳的每个氢可被进一步规定的取代基替换。"C _2-8 alkynyl" means an alkynyl chain having 2-8 carbon atoms, for example: -C-CH, -CH., -C-CH, CH2-CH2-CTri-CH, CH2-CC- CH3. Each hydrogen of the C _2-6 alkynyl carbon can be replaced by a further defined substituent.

Tofacitinib：Tofacitinib:

Decernotinib：Decernotinib:

Filgotinib： Filgotinib:

对于式(I)化合物，本发明还包括所有比例的所有互变异构体和立体异构体形式及其混合物，及其药学上可接受的盐、前药、代谢物、同位素衍生物和溶剂合物，及包含所述化合物的药物组合物。For the compounds of formula (I), the invention also includes all tautomeric and stereoisomeric forms and mixtures thereof, and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvents thereof, in all ratios. And a pharmaceutical composition comprising the compound.

式(I)化合物的药学可接受的盐，包含一个或多个碱性或酸性基团，本发明还包括其相应的药学上或毒理学上可接受的盐，特别是其药学上可利用的盐。因此，包含酸性基团的式(I)化合物能根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更精确的实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺如乙胺、乙醇胺、三乙醇胺或氨基酸的盐。可存在并可根据本发明以其与无机酸或有机酸的加成盐的形式使用包含一个或多个碱性基团，即能被质子化的基团的式(I)化合物。适当酸的实例包括盐酸、硫酸、磷酸、硝酸、甲磺酸、乳酸、苹果酸、马来酸、苯甲酸、酒石酸、草酸、对甲苯磺酸等以及本领域技术人员已知的其他酸。如果式(I)化合物在分子内同时包含酸性和碱性基团，本发明还包括除了提及的盐形式之外的内盐或内铵盐(两性离子)。式(I)的各个盐能由本领域技术人员已知的常规方法获得，例如通过使这些与有机或无机酸或碱在溶剂或分散剂中接触获得，或通过与其他盐进行阴离子交换或阳离子交换获得。本发明还包括式(I)化合物的所有盐，其由于低生理学相容性不直接适用于药物，但是其可例如用作化学反应的中间体或用于制备药学上可接受的盐。 A pharmaceutically acceptable salt of a compound of formula (I), which comprises one or more basic or acidic groups, the invention also includes its corresponding pharmaceutically or toxicologically acceptable salts, in particular pharmaceutically acceptable salt. Thus, compounds of the formula (I) which comprise an acidic group can be used according to the invention, for example as an alkali metal salt, an alkaline earth metal salt or as an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the formula (I) which comprise one or more basic groups, ie groups which can be protonated, can be used in the form of their addition salts with inorganic or organic acids according to the invention. Examples of suitable acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, as well as other acids known to those skilled in the art. If the compound of the formula (I) contains both acidic and basic groups in the molecule, the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned. The individual salts of formula (I) can be obtained by conventional methods known to those skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. obtain. The invention also includes all salts of the compounds of formula (I) which are not directly suitable for use in medicine due to their low physiological compatibility, but which may, for example, be used as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

在本发明中，术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地，该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。In the present invention, the term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to a human. Preferably, the term refers to a mammalian preferred person certified by a regulatory agency such as CFDA (China), EMEA (Europe), FDA (United States), and the like.

“前药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本发明化合物的衍生物。The "prodrug" means a derivative which is converted into a compound of the present invention by a reaction with an enzyme, a gastric acid or the like under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis or the like which is each carried out under an enzyme catalysis.

“代谢物”是指在细胞或有机体优选人中源自本发明任意化合物的所有分子。"metabolite" refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

“同位素衍生物”是指与构成化合物之一或多个原子处以非天然比例含有同位素的所述的化合物。例如氘(2H或D)、碳-13(13C)、氮-15(15N)等。"Isotopic derivative" means a compound which contains an isotope in an unnatural ratio to one or more of the constituent compounds. For example, hydrazine (2H or D), carbon-13 (13C), nitrogen-15 (15N), and the like.

“溶剂合物”是指通常通过溶剂分解反应与溶剂物理结合的化合物形式。此物理结合包含氢键结合。常规溶剂包含水、乙醇、甲醇、乙酸等。式(I)化合物可以结晶形式制备且可呈溶剂合物形式(例如水合形式)。适宜溶剂合物包含药学可接受的溶剂合物(例如水合物)，且进一步包含化学计量溶剂合物及非化学计量溶剂合物。在某些情形下，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂合物将能够解离。“溶剂合物”涵盖溶液相及可解离溶剂合物。代表性溶剂合物包含水合物、乙醇合物及甲醇合物等。"Solvate" means a form of the compound which is usually physically associated with a solvent by a solvolysis reaction. This physical bond involves hydrogen bonding. Conventional solvents include water, ethanol, methanol, acetic acid, and the like. The compound of formula (I) can be prepared in crystalline form and can be in the form of a solvate (for example, in hydrated form). Suitable solvates comprise pharmaceutically acceptable solvates (e.g., hydrates), and further comprise stoichiometric solvates and non-stoichiometric solvates. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of dissociating. "Solvate" encompasses both solution and dissociable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

式(I)化合物可以晶体或无定形形式存在。此外，式(I)化合物的某些晶体形式可以多晶型形式存在，其包括在本发明范围内。可以使用许多常规分析技术包括但不限于X-射线粉末衍射(XRPD)图、红外(IR)光谱、拉曼光谱、差示扫描量热法(DSC)、热重分析(TGA)和固体核磁共振(ssNMR)表征来区分式(I)化合物的多晶型。 The compound of formula (I) may exist in crystalline or amorphous form. Furthermore, certain crystalline forms of the compounds of formula (I) may exist in polymorphic form and are included within the scope of the invention. Many conventional analytical techniques can be used including, but not limited to, X-ray powder diffraction (XRPD), infrared (IR), Raman, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state nuclear magnetic resonance. (ssNMR) characterization to distinguish polymorphs of the compounds of formula (I).

“药物组合物”在用作药物时，本发明式I化合物及式I化合物的盐、同位素衍生物、代谢物、前药、溶剂合物与具有生物活性和或不具有生物活性物质组成的组合物作为JAK抑制剂在治疗或预防免疫、自身免疫性或变应性病症、增生疾病或增殖性疾病、炎症、过敏病症、移植排斥、免疫介导中的应用。A "pharmaceutical composition" when used as a medicament, a salt, an isotopic derivative, a metabolite, a prodrug, a solvate of a compound of the formula I according to the invention and a compound of the formula I in combination with a composition having biological activity and or no biologically active substance The use of a JAK inhibitor as a JAK inhibitor in the treatment or prevention of an immune, autoimmune or allergic condition, a proliferative or proliferative disease, inflammation, an allergic condition, transplant rejection, immune mediated.

本发明的药物组合物可以含有一种或多种药学上可接受的载体，可用作制成注射和非注射给药途径的药物制剂和药物剂型。所述载体包括药学领域所有的可用于制成注射和非注射给药途径的药物制剂，例如稀释剂、润湿剂、填充剂、粘合剂、湿滑剂、崩解剂、吸收促进剂、表面活性剂、阻滞剂、吸附剂、助悬剂、絮凝剂、反絮凝剂、乳化剂、常用基质、增溶剂、助溶剂、潜溶剂、防腐剂、矫味剂、着色剂、抗氧剂、缓冲剂、抑菌剂、等渗调节剂、PH调节剂、金属离子络合剂、硬化剂、增稠剂、吸收促进剂等。The pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable carriers for use as pharmaceutical formulations and pharmaceutical dosage forms for administration by injection and non-injection. The carrier includes all pharmaceutical preparations which can be used in the pharmaceutical field for the preparation of injection and non-injection routes, such as diluents, wetting agents, fillers, binders, slip agents, disintegrating agents, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants, deflocculating agents, emulsifiers, common substrates, solubilizers, solubilizers, latent solvents, preservatives, flavoring agents, colorants, antioxidants A buffer, a bacteriostatic agent, an isotonicity adjusting agent, a pH adjusting agent, a metal ion complexing agent, a hardening agent, a thickening agent, an absorption enhancer, and the like.

本发明式(I)化合物和药物组合物可制成注射或非注射给药途径的药物制剂和药物剂型。适于皮下注射、肌肉注射、静脉注射、口服、肺部(鼻或口腔吸入)、直肠、局部、肠胃外、关节内、眼部、鼻腔给药等，虽然在任意给定情况下最适当的途径将依赖于要治疗的疾病状态的性质和严重程度以及活性成分性质。它们可以方便地存在于单一剂型中，并且由药学领域公知的任意方法制备。The compounds of the formula (I) and pharmaceutical compositions of the invention may be formulated into pharmaceutical preparations and pharmaceutical dosage forms for administration by injection or non-injection. Suitable for subcutaneous injection, intramuscular injection, intravenous injection, oral administration, pulmonary (nasal or oral inhalation), rectal, topical, parenteral, intra-articular, ocular, nasal administration, etc., although most appropriate in any given case The route will depend on the nature and severity of the disease state being treated and the nature of the active ingredient. They can conveniently be presented in a single dosage form and are prepared by any methods known in the art of pharmacy.

本发明中Janus激酶(JAK)相关的疾病和病症为免疫、炎症、自身免疫、增殖性疾病如癌症、增生性疾病、过敏病症或疾病、移植排斥或移植物抗宿主病、干眼症等。The diseases and conditions associated with Janus kinase (JAK) in the present invention are immune, inflammatory, autoimmune, proliferative diseases such as cancer, proliferative diseases, allergic conditions or diseases, transplant rejection or graft versus host disease, dry eye, and the like.

自身免疫疾病为至少部分由身体对抗自身组分例如蛋白质、脂质或DNA的免疫反应引发的疾病。器官特异性自身免疫病症的实例为影响胰腺的胰岛素依赖性糖尿病(I型)、影响甲状腺的桥本甲状腺炎和格雷夫斯病、影响胃的恶性贫血、影响肾上腺的库欣病和爱迪生氏病、影响肝的慢性活动性肝炎；***(PCOS)、乳糜泻、牛皮癣、炎性肠病(IBD)和强直性脊柱炎。非器官特异性自身免疫病症的实例为类风湿性关节炎、多发性硬化、***性红斑狼疮和重症肌无力。Autoimmune diseases are diseases that are caused, at least in part, by the body's immune response against its own components, such as proteins, lipids or DNA. Examples of organ-specific autoimmune disorders are insulin-dependent diabetes (type I) affecting the pancreas, Hashimoto's thyroiditis affecting the thyroid gland, and Graves Disease, malignant anemia affecting the stomach, Cushing's disease and Edison's disease affecting the adrenal gland, chronic active hepatitis affecting the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and rigidity Spondylitis. Examples of non-organ specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and myasthenia gravis.

炎症性肠病(IBD)是一组免疫介导的慢性非特异性肠道炎症性疾病，主要包括溃疡性结肠炎(UC)和克罗恩病(CD),是胃肠道炎症性疾病的重要类型之一。克罗恩病最常涉及末端回肠和结肠，并且是透壁的和不连续的。相反，在溃疡性结肠炎中，炎症是连续的并且限于直肠和结肠粘膜层。在限定至回肠和结肠的大约10％的情况下，克罗恩病或溃疡性结肠炎的确定分类不能被做出，并且被称为“不确定的结肠炎”。两种疾病都包括皮肤、眼睛或关节的肠外炎症。中性粒细胞诱导的伤害可通过使用中性粒细胞迁移抑制剂而预防(Asakura等，2007，World J Gastroenterol.13(15)：2145-9)。Inflammatory bowel disease (IBD) is a group of immune-mediated chronic non-specific intestinal inflammatory diseases, including ulcerative colitis (UC) and Crohn's disease (CD), which are important for inflammatory diseases of the gastrointestinal tract. One of the types. Crohn's disease most often involves the terminal ileum and colon, and is transmural and discontinuous. In contrast, in ulcerative colitis, inflammation is continuous and is limited to the rectal and colonic mucosal layers. A defined classification of Crohn's disease or ulcerative colitis cannot be made, and is referred to as "indeterminate colitis", limited to about 10% of the ileum and colon. Both diseases include extraintestinal inflammation of the skin, eyes or joints. Neutrophil-induced damage can be prevented by the use of neutrophil migration inhibitors (Asakura et al, 2007, World J Gastroenterol. 13(15): 2145-9).

***性红斑狼疮(SLE)是由T-细胞介导的B-细胞激活产生的慢性炎性疾病，其导致血管球性肾炎和肾衰竭。人SLE在早期的特征为持久的自身反应性CD4+记忆细胞的扩张(D'Cruzetal.,2007,Lancet 369(9561):587-596)。Systemic lupus erythematosus (SLE) is a chronic inflammatory disease caused by T-cell mediated B-cell activation that causes glomerulonephritis and renal failure. The early stage of human SLE is characterized by the expansion of persistent autoreactive CD4+ memory cells (D'Cruzetal., 2007, Lancet 369 (9561): 587-596).

类风湿关节炎(RA)是一种以对称性、多关节炎为主要表现的慢性、全身性自身免疫疾病，病变主要累及关节的滑膜关节和关节外的表现广泛而多变，最终导致关节结构破坏、功能丧失致残率较高。Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by symmetry and polyarthritis. The lesions mainly involve the synovial joints of the joints and the extra-articular manifestations are extensive and variable, eventually leading to joints. Structural damage, loss of function and high disability rate.

多发性硬化(Multiple sclerosis，MS)是中枢神经***白质炎症性脱髓鞘性自身免疫性疾病，髓鞘脱失与浸润的淋巴细胞(CD4⁺T)介导的细胞免疫有关。SOCS1能抑制JAK2诱导的STAT3的磷酸化,使用JAK2抑制剂(AG490)可以模拟SOCS1对JAK2-STAT3的抑制作用。(SOCS1-JAK2- STAT3信号通路在C57BL/6小鼠实验性自身免疫性脑脊髓炎模型中作用机制探讨，董梅等，中国免疫学杂志，2014，30(4)：459～463)。Multiple sclerosis (MS) is a central nervous system leukocytic inflammatory demyelinating autoimmune disease associated with infiltration of lymphocytes (CD4 ⁺ T)-mediated cellular immunity. SOCS1 inhibits JAK2-induced phosphorylation of STAT3, and JAK2 inhibitor (AG490) can be used to mimic the inhibitory effect of SOCS1 on JAK2-STAT3. (The mechanism of action of SOCS1-JAK2-STAT3 signaling pathway in experimental autoimmune encephalomyelitis model of C57BL/6 mice, Dong Mei et al., Chinese Journal of Immunology, 2014, 30(4): 459-463).

I型糖尿病由自身反应性T细胞对分泌胰岛素的胰岛β细胞的选择性进攻而继发。在这种疾病中以JAK3为靶标是基于这样的观察：已知通过JAK途径传导信号的多种细胞因子参与β细胞的T细胞介导的自身免疫性损伤。事实上，JAK3抑制剂，JANEX-1在I型糖尿病的NOD小鼠模型中显示预防自发的自身免疫性糖尿病的发展。Type I diabetes is secondary to the selective attack of insulin-producing islet beta cells by autoreactive T cells. Targeting JAK3 in this disease is based on the observation that various cytokines known to transmit signals through the JAK pathway are involved in T cell-mediated autoimmune damage of beta cells. In fact, the JAK3 inhibitor, JANEX-1, has been shown to prevent the development of spontaneous autoimmune diabetes in a NOD mouse model of type I diabetes.

本发明的另一方面为本发明的化合物或其药学上可接受的盐用于治疗或预防增生疾病尤其是癌症的方法。癌症包含一组特征在于异常细胞的失控生长和扩散的疾病。通常，癌症分类为实体瘤的癌症(如，***癌、肾癌、肝癌、胰腺癌、胃癌、结直肠癌、乳腺癌、***、肺癌、头颈部癌、甲状腺癌、胶质母细胞瘤、卡波济氏肉瘤、卡斯特莱曼病、黑色素瘤等)，血液癌症(如，淋巴瘤、白血病，诸如急性成淋巴细胞性白血病、急性髓细胞性白血病(AML)或多发性骨髓瘤)，皮肤癌(诸如皮肤T细胞淋巴瘤(CTCL)和皮肤B细胞淋巴瘤以及示例性皮肤T细胞)，淋巴瘤(包括塞泽里综合征(Sezary syndrome)和蕈样肉芽肿病)等。Another aspect of the invention is a method of using a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a proliferative disease, particularly cancer. Cancer contains a group of diseases characterized by uncontrolled growth and spread of abnormal cells. Generally, cancer is classified as a solid tumor (eg, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, colorectal cancer, breast cancer, cervical cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma). , Kaposi's sarcoma, Castellmann's disease, melanoma, etc.), blood cancer (eg, lymphoma, leukemia, such as acute lymphoblastic leukemia, acute myeloid leukemia (AML) or multiple myeloma ), skin cancer (such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma and exemplary skin T cells), lymphoma (including Sezary syndrome and mycosis fungoides).

移植排斥(同种异体移植排斥)包括但不限于例如肾、心脏、肝、肺、骨髓、皮肤和角膜的移植之后的急性和慢性同种异体排斥。已知T细胞在同种异体排斥的特异性免疫反应中起关键作用。超急性、急性和慢性器官移植排斥可以治疗。超急性排斥发生在移植的几分钟内。急性排斥通常发生在移植的六至十二个月之内。超急性和急性排斥通常是可逆的，其中用免疫抑制剂治疗。特征为器官功能的逐渐损失的慢性排斥是移植接受者持续关心的，因为其可在移植后的任何时间发生。Transplant rejection (allogene rejection) includes, but is not limited to, acute and chronic allogeneic rejection following transplantation of, for example, kidney, heart, liver, lung, bone marrow, skin, and cornea. T cells are known to play a key role in the specific immune response to allogeneic rejection. Hyperacute, acute and chronic organ transplant rejection can be treated. Hyperacute rejection occurs within a few minutes of transplantation. Acute rejection usually occurs within six to twelve months of transplantation. Hyperacute and acute rejection are usually reversible, with immunosuppressive therapy. Chronic rejection characterized by a gradual loss of organ function is of continuing concern to the transplant recipient as it can occur at any time after transplantation.

移植物抗宿主病(GVDH)是异源骨髓移植(BMT)的主要并发症。GVDH由识别组织相容性复杂***中的接受者差异并且对其作出反应的供体T细胞引起，这导致了显著的发病率和死亡率。JAK3在诱导GVHD中起关键作用，用JAK3押制剂JANEX-1进行治疗显示出削弱GVHD严重性(综述在Cetkovic-Cvrlje and Ucken，2004)。Graft-versus-host disease (GVDH) is a major complication of heterologous bone marrow transplantation (BMT). GVDH is a donor T cell that recognizes and responds to receptor differences in a complex system of histocompatibility Caused, this led to significant morbidity and mortality. JAK3 plays a key role in the induction of GVHD, and treatment with the JAK3 formulation JANEX-1 has been shown to attenuate the severity of GVHD (reviewed in Cetkovic-Cvrlje and Ucken, 2004).

干眼症(DES，也称为干燥性角膜结膜炎)是眼科医生治疗的最常见问题之一。有时DES被称为泪液功能不全综合征(Jackson，2009.Canadian Journal Ophthalmology44(4)，385-394)。DES影响最高达10％的年龄在20至45岁之间的人口，且百分比随年龄增长。尽管可利用许多种类的人工泪液产品，但这些产品仅提供症状的暂时缓解。因此，需要治疗干眼的制剂、组合物和治疗方法。干眼有时也称为干燥性角膜结膜炎，干眼症的治疗包括改善干眼症的特定症状，如眼部不适、视觉障碍、泪膜不稳定、眼泪高渗透压和眼球表面的炎症。Dry eye syndrome (DES, also known as dry keratoconjunctivitis) is one of the most common problems treated by ophthalmologists. Sometimes DES is called tear dysfunction syndrome (Jackson, 2009. Canadian Journal Ophthalmology 44 (4), 385-394). DES affects up to 10% of the population between the ages of 20 and 45, and the percentage increases with age. Although many types of artificial tear products are available, these products only provide temporary relief of symptoms. Therefore, there is a need for formulations, compositions, and methods of treatment for dry eye. Dry eye is sometimes referred to as dry keratoconjunctivitis, and treatment for dry eye includes improving specific symptoms of dry eye, such as eye discomfort, visual impairment, tear film instability, high tear pressure on the eye, and inflammation of the surface of the eye.

因此，本发明的另一方面为本发明的化合物及其药学上可接受的盐、前药、代谢物、同位素衍生物和溶剂合物，及包含所述化合物的药物组合物，用于预防或治疗免疫、炎症、自身免疫、增殖性疾病如癌症、增生性疾病、过敏病症或疾病、移植排斥或移植物抗宿主病、干眼症等的方法。Accordingly, another aspect of the invention is a compound of the invention, and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and pharmaceutical compositions comprising the compounds, for use in prophylaxis or A method of treating immunity, inflammation, autoimmunity, proliferative diseases such as cancer, proliferative diseases, allergic conditions or diseases, transplant rejection or graft versus host disease, dry eye, and the like.

本发明有益的效果Advantageous effects of the present invention

通过本发明技术方案的实施，结果表明本发明所述的化合物(式I)具有良好的抑制JAK活性和药代动力学性质，与Tofacitinib具有生物相似性，无细胞毒性，大鼠单次口服灌胃给药未见明显毒性。Through the practice of the technical scheme of the present invention, the results show that the compound (Formula I) of the present invention has good inhibition of JAK activity and pharmacokinetic properties, has biosimilarity with Tofacitinib, has no cytotoxicity, and is administered by a single oral administration in rats. No significant toxicity was observed in gastric administration.

具体实施方式Detailed ways

实施例1：2-(2-{5-氟-4-[(吡啶并[2,3-d]嘧啶-6-亚甲基)-胺]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 1: 2-(2-{5-Fluoro-4-[(pyrido[2,3-d]pyrimidin-6-methylene)-amine]-pyrimidin-2-ylamino}-imidazole-1 -base)-ethanol

化合物结构： Compound structure:

合成路线：synthetic route:

合成方法：resolve resolution:

取一定量的2,4-二氯-5-氟嘧啶放置到三口烧瓶中，加1～5倍量的二异丙基乙胺和异丙醇混合溶剂，搅拌均匀，将嘧啶并吡啶-6-甲基氨基溶于1～10倍量异丙醇的溶液，然后慢慢加入到三口烧瓶中，加完后，-10℃至30℃反应1小时～10小时，自然升至室温，产生产生大量沉淀，加二氯甲烷至固体全部溶解，然后以饱和食盐水洗涤有机物。有机物用无水硫酸镁干燥后，滤去干燥剂蒸干，柱色谱提纯得白色产物(2-氯-5-氟嘧啶-4-基)-吡啶并[2,3-d]嘧啶-6-甲基胺，产率50％～70％。Take a certain amount of 2,4-dichloro-5-fluoropyrimidine into a three-necked flask, add 1 to 5 times the amount of diisopropylethylamine and isopropanol mixed solvent, stir evenly, pyrimidopyridine-6 - Methylamino is dissolved in a solution of 1 to 10 times the amount of isopropanol, and then slowly added to a three-necked flask. After the addition, the reaction is carried out at -10 ° C to 30 ° C for 1 hour to 10 hours, and naturally rises to room temperature to produce A large amount of precipitate was added, methylene chloride was added until the solid was completely dissolved, and then the organic matter was washed with saturated brine. The organics were dried over anhydrous magnesium sulfate, and then filtered and evaporated to dryness, and purified to afford white product (2-chloro-5-fluoropyrimidin-4-yl)-pyrido[2,3-d]pyrimidine-6- Methylamine, the yield is 50% to 70%.

取一定量的(2-氯-5-氟嘧啶-4-基)-吡啶并[2,3-d]嘧啶-6-甲基胺，放置到三口烧瓶中，加1～5倍量的异丙醇，搅拌均匀，通过双排管技术排空反应体系的空气，并充以氮气；将1-羟乙基、2-氨基咪唑溶于 1～10倍量异丙醇的溶液，加入到反应体系中，50℃至150℃反应5小时～24小时，冷却后，加入乙酸乙酯和饱和碳酸氢钠混合溶液，搅拌30分钟后，分出有机相，水相用乙酸乙酯萃取，饱和食盐水洗涤有机相和萃取相。无水硫酸镁干燥。滤去干燥剂蒸干，柱色谱纯化得白色产物2-(2-{5-氟-4-[(吡啶并[2,3-d]嘧啶-6-亚甲基)-胺]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇，产率50％～80％。Take a certain amount of (2-chloro-5-fluoropyrimidin-4-yl)-pyrido[2,3-d]pyrimidine-6-methylamine, place it in a three-necked flask, add 1 to 5 times the amount of difference Propyl alcohol, stir evenly, empty the air of the reaction system through double-row tube technology, and fill with nitrogen; dissolve 1-hydroxyethyl, 2-aminoimidazole A solution of 1 to 10 times the amount of isopropanol is added to the reaction system, and the reaction is carried out at 50 ° C to 150 ° C for 5 hours to 24 hours. After cooling, a mixed solution of ethyl acetate and saturated sodium hydrogencarbonate is added, and the mixture is stirred for 30 minutes. The organic phase was taken, the aqueous phase was extracted with ethyl acetate, and brine and brine were washed and evaporated. Dry over anhydrous magnesium sulfate. The desiccant was evaporated to dryness and purified by column chromatography to yield white product 2-(2-{5-fluoro-4-[(pyrido[2,3-d]pyrimidin-6-methylene)-amine]-pyrimidine- 2-Baseamino}-imidazol-1-yl)-ethanol in a yield of 50% to 80%.

1H-NMR(400MHZ,CDCl3,TMS,ppm):1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.88(1H),δ8.75(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ8.78(1H),δ9.26(1H)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.88(1H), δ8.75(1H), δ7.0( 1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ8.78(1H), δ9.26(1H)

实施例2：5-氟-N2-(1-甲基-1H-咪唑-2-基)-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-嘧啶-2,4-二胺Example 2: 5-Fluoro-N2-(1-methyl-1H-imidazol-2-yl)-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-pyrimidine -2,4-diamine

化合物结构：Compound structure:

合成路线： synthetic route:

合成方法：resolve resolution:

取一定量的2,4-二氯-5-氟嘧啶放置到三口烧瓶中，加1～5倍量的二异丙基乙胺和异丙醇混合溶剂，搅拌均匀，将3-(1-甲基-1H-吡唑-4-基)苄胺溶于1～10倍量异丙醇的溶液，然后慢慢加入到三口烧瓶中，加完后，－10℃至30℃反应1小时～10小时，自然升至室温，产生产生大量沉淀，加二氯甲烷至固体全部溶解，然后以饱和食盐水洗涤有机物。有机物用无水硫酸镁干燥后，滤去干燥剂蒸干，柱色谱提纯得白色产物(2-氯-5-氟-嘧啶-4-基)-[3-(1-甲基-1H-吡唑-4-基)-苄]-胺，产率55％～80％。Take a certain amount of 2,4-dichloro-5-fluoropyrimidine into a three-necked flask, add 1 to 5 times the amount of diisopropylethylamine and isopropanol mixed solvent, stir evenly, 3-(1- Methyl-1H-pyrazol-4-yl)benzylamine is dissolved in a solution of 1 to 10 times the amount of isopropanol, and then slowly added to a three-necked flask. After the addition, the reaction is carried out at -10 ° C to 30 ° C for 1 hour. After 10 hours, it naturally rose to room temperature, and a large amount of precipitate was produced. Methylene chloride was added until the solid was completely dissolved, and then the organic matter was washed with saturated brine. The organics were dried over anhydrous magnesium sulfate, and then filtered and evaporated to dryness, and purified by column chromatography to give white product (2-chloro-5-fluoro-pyrimidin-4-yl)-[3-(1-methyl-1H-pyridin Zyridin-4-yl)-benzyl]-amine, yield 55% to 80%.

取一定量的(2-氯-5-氟-嘧啶-4-基)-[3-(1-甲基-1H-吡唑-4-基)-苄]-胺，放置到三口烧瓶中，加1～5倍量的异丙醇，搅拌均匀，通过双排管技术排空反应体系的空气，并充以氮气；将1-甲基、2-氨基咪唑溶于1～10倍量异丙醇的溶液，加入到反应体系中，50℃至150℃反应5小时～24小时，冷却后，加入乙酸乙酯和饱和碳酸氢钠混合溶液，搅拌30分钟后，分出有机相，水相用乙酸乙酯萃取，饱和食盐水洗涤有机相和萃取相。无水硫酸镁干燥。滤去干燥剂蒸干，柱色谱纯化得白色产物5-氟- N2-(1-甲基-1H-咪唑-2-基)-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-嘧啶-2,4-二胺，产率50％～70％。Take a certain amount of (2-chloro-5-fluoro-pyrimidin-4-yl)-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-amine and place it in a three-necked flask. Add 1 to 5 times the amount of isopropanol, stir evenly, evacuate the air of the reaction system by double-tube technology, and fill with nitrogen; dissolve 1-methyl and 2-aminoimidazole in 1~10 times of isopropyl The alcohol solution is added to the reaction system, and reacted at 50 ° C to 150 ° C for 5 hours to 24 hours. After cooling, a mixed solution of ethyl acetate and saturated sodium hydrogencarbonate is added, and after stirring for 30 minutes, the organic phase is separated, and the aqueous phase is separated. The organic phase and the extract phase were washed with ethyl acetate and brine. Dry over anhydrous magnesium sulfate. The desiccant is filtered off and evaporated to dryness, and purified by column chromatography to yield white product 5-fluoro- N2-(1-methyl-1H-imidazol-2-yl)-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-pyrimidine-2,4-diamine, The yield is 50% to 70%.

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ6.9(1H),δ3.63(3H),δ8.34(1H),δ8.20(1H),δ3.80(3H)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ7.0(1H), δ6.9(1H), δ3.63(3H), δ8.34(1H), δ8.20(1H), δ3.80(3H )

实施例3：2-(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-氨基}-咪唑-1-基)-乙醇Example 3: 2-(2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidine-2-amino}-imidazole-1 -base)-ethanol

合成方法参照实施例2。The synthesis method is referred to in Example 2.

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.02(2H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ8.20(1H),δ8.34(1H),δ3.8(3H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.02(2H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ8.20(1H), δ8.34(1H), δ3.8(3H), δ7.0(1H), δ7.0(1H), δ3.92(2H ), δ4.01(2H), δ2.0(1-OH)

实施例4：2-(2-{5-氯-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-氨基}-咪唑-1-基)-乙醇 Example 4: 2-(2-{5-Chloro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidine-2-amino}-imidazole-1 -base)-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.97(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ8.20(1H),δ8.34(1H),δ3.8(3H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(92H),δ2.0(1-OH)Δ7.97(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ8.20(1H), δ8.34(1H), δ3.8(3H), δ7.0(1H), δ7.0(1H), δ3.92(2H ), δ4.01 (92H), δ2.0 (1-OH)

实施例5：2-(2-{4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-5-三氟甲基-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 5: 2-(2-{4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-5-trifluoromethyl-pyrimidin-2-ylamino} -imidazol-1-yl)-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.52(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ8.40(1H),δ8.40(1H),δ13.7(1NH),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH) Δ7.52(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ8.40(1H), δ8.40(1H), δ13.7(1NH), δ7.0(1H), δ7.0(1H), δ3.92(2H ), δ4.01(2H), δ2.0(1-OH)

实施例6：2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-5-腈Example 6: 2-[1-(2-Hydroxy-ethyl)-1H-imidazol-2-ylamino]-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl Amino]-pyrimidine-5-carbonitrile

MS：415.19MS: 415.19

实施例7：2-(2-{5-氟-4-[3-氟-5-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 7: 2-(2-{5-Fluoro-4-[3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino }-Imidazol-1-yl)-ethanol

MS：426.17MS: 426.17

实施例8：2-(2-{4-[3-(1-乙基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇 Example 8: 2-(2-{4-[3-(1-ethyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl) -ethanol

MS：404.21MS: 404.21

实施例9：2-(2-{4-[(1H-苯并咪唑-5-亚甲基)-胺]-5-氟-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 9: 2-(2-{4-[(1H-Benzimidazole-5-methylene)-amine]-5-fluoro-pyrimidin-2-ylamino}-imidazol-1-yl)-ethanol

合成方法参照实施例1。The synthesis method is referred to in Example 1.

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(1H),δ7.50(1H),δ7.58(1H),δ7.06(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ8.08(1H),δ5.0(1NH)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(1H), δ7.50(1H), δ7.58(1H), δ7.06( 1H), δ7.0(1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ8.08(1H), δ5.0 (1NH)

实施例10：2-(2-{4-[(6,9-二氢-嘌呤-1-亚甲基)-胺]-5-氟-嘧啶-2-基氨基}-咪唑-1-基)-乙醇 Example 10: 2-(2-{4-[(6,9-Dihydro-inden-1-methylene)-amine]-5-fluoro-pyrimidin-2-ylamino}-imidazol-1-yl )-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ3.81(92H),δ7.50(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ7.4(1H),δ13.4(1NH)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ3.81(92H), δ7.50(1H), δ7.0( 1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ7.4(1H), δ13.4(1NH)

实施例11：2-(2-{5-氟-4-[(9-羟基甲基-6,9-二氢-嘌呤-1-亚甲基)-胺]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 11: 2-(2-{5-Fluoro-4-[(9-hydroxymethyl-6,9-dihydro-inden-1-methylene)-amine]-pyrimidin-2-ylamino} -imidazol-1-yl)-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ3.75(92H),δ7.50(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ7.2(1H),δ5.97(2H),δ2.0(1-OH)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ3.75(92H), δ7.50(1H), δ7.0( 1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ7.2(1H), δ5.97(2H), δ2.0 (1-OH)

实施例12：2-[2-(5-氟-4-{1-[3-(1-甲基-1H-吡唑-4-基)-苯基]-乙胺基}-嘧啶-2-基氨基)-咪唑-1-基]-乙醇 Example 12: 2-[2-(5-Fluoro-4-{1-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethylamino}-pyrimidine-2 -ylamino)-imidazol-1-yl]-ethanol

MS：422.20MS: 422.20

实施例13：2-(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苯胺基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 13: 2-(2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-anilino]-pyrimidin-2-ylamino}-imidazole-1 -base)-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ6.42(1H),δ7.07(1H),δ6.84(1H),δ6.68(1H),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ4.0(1-NH)Δ7.44(1H), δ4.0(1-NH), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ6.42( 1H), δ7.07(1H), δ6.84(1H), δ6.68(1H), δ8.34(1H), δ8.20(1H), δ3.80(3H), δ4.0(1 -NH)

实施例14：2-(2-{5-氟-4-[3-氟-5-(1-甲基-1H-吡唑-4-基)-苯胺基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇 Example 14: 2-(2-{5-Fluoro-4-[3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-anilino]-pyrimidin-2-ylamino} -imidazol-1-yl)-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ6.13(1H),δ6.55(1H),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ4.0(1-NH)Δ7.44(1H), δ4.0(1-NH), δ7.0(1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1- OH), δ6.13(1H), δ6.55(1H), δ8.34(1H), δ8.20(1H), δ3.80(3H), δ4.0(1-NH)

实施例15：2-(2-{4-[3-(1-乙基-1H-吡唑-4-基)-苯胺基]-5-氟-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 15: 2-(2-{4-[3-(1-ethyl-1H-pyrazol-4-yl)-anilino]-5-fluoro-pyrimidin-2-ylamino}-imidazole-1 -base)-ethanol

MS：408.18MS: 408.18

实施例16：2-{2-[4-(1H-苯并咪唑-5-基氨基)-5-氟-嘧啶-2-基氨基]-咪唑-1-基}-乙醇 Example 16: 2-{2-[4-(1H-benzimidazol-5-ylamino)-5-fluoro-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ6.90(1H),δ7.45(1H),δ6.46(1H),δ4.0(1-NH),δ8.08(1H),δ5.0(1-NH)Δ7.44(1H), δ4.0(1-NH), δ7.0(1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1- OH), δ 6.90 (1H), δ 7.45 (1H), δ 6.46 (1H), δ 4.0 (1-NH), δ 8.08 (1H), δ 5.0 (1-NH)

实施例17：2-{2-[5-氟-4-(吡啶并[2,3-d]嘧啶-6-基氨基)-嘧啶-2-基氨基]-咪唑-1-基}-乙醇Example 17: 2-{2-[5-fluoro-4-(pyrido[2,3-d]pyrimidin-6-ylamino)-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol

MS：367.13MS: 367.13

实施例18：2-{2-[4-(6,9-二氢-嘌呤-1-基氨基)-5-氟-嘧啶-2-基氨基]-咪唑-1-基}-乙醇 Example 18: 2-{2-[4-(6,9-Dihydro-indol-1-ylamino)-5-fluoro-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol

MS：358.14MS: 358.14

实施例19：2-{2-[5-氟-4-(9-羟基甲基-6,9-二氢-嘌呤-1-基氨基)-嘧啶-2-基氨基]-咪唑-1-基}-乙醇Example 19: 2-{2-[5-Fluoro-4-(9-hydroxymethyl-6,9-dihydro-indol-1-ylamino)-pyrimidin-2-ylamino]-imidazole-1- Base}-ethanol

MS：388.15MS: 388.15

实施例20：2-[2-(5-氟-4-{甲基-[3-(1-甲基-1H-吡唑-4-基)-苯基]-胺}-嘧啶-2-基氨基)-咪唑-1-基]-乙醇 Example 20: 2-[2-(5-Fluoro-4-{methyl-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-amine}-pyrimidine-2- Base amino)-imidazol-1-yl]-ethanol

MS：408.18MS: 408.18

实施例21：2-{2-[(5-氟-4-{甲基-[3-(1-甲基-1H-吡唑-4-基)-苄]-胺}-嘧啶-2-基)-甲基-胺]-咪唑-1-基}-乙醇Example 21: 2-{2-[(5-Fluoro-4-{methyl-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-amine}-pyrimidine-2- Base)-methyl-amine]-imidazol-1-yl}-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1OH),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ2.47(3H),δ2.47(3H)Δ7.44(1H), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29(1H), δ7.28(1H), δ7.0(1H), δ7 .0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1OH), δ8.34(1H), δ8.20(1H), δ3.80(3H), δ2. 47(3H), δ2.47(3H)

实施例22：2-[2-({5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基}-甲基-胺)-咪唑-1-基]-乙醇 Example 22: 2-[2-({5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-yl}-methyl -amine)-imidazol-1-yl]-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ2.47(3H)Δ7.44(1H), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29(1H), δ7.28(1H) , δ7.0(1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ8.34(1H), δ8.20(1H ), δ3.80 (3H), δ2.47 (3H)

实施例23：2-[2-(5-氟-4-{甲基-[3-(1-甲基-1H-吡唑-4-基)-苄]-胺}-嘧啶-2-基氨基)-咪唑-1-基]-乙醇Example 23: 2-[2-(5-Fluoro-4-{methyl-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-amine}-pyrimidin-2-yl Amino)-imidazol-1-yl]-ethanol

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(91H),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ2.47(3H)Δ7.44(91H), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29(1H), δ7.28(1H) , δ7.0(1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ8.34(1H), δ8.20(1H ), δ3.80 (3H), δ2.47 (3H)

实施例24：1-{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]-吡唑-1-基}-乙酮Example 24: 1-{4-[3-({5-fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}- Methyl)-phenyl]-pyrazol-1-yl}-ethanone

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4,32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ7.0(1H),δ3.92(2H),δ4.01(2H),δ2.0(1-OH),δ8.4(1H),δ8.4(1H),δ2.20(3H)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4,32(2H), δ7.02(1H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ7.0(1H), δ7.0(1H), δ3.92(2H), δ4.01(2H), δ2.0(1-OH), δ8.4 (1H), δ8.4 (1H), δ2.20 (3H)

实施例25：{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]-吡唑-1-基}-甲基磺酰胺 Example 25: {4-[3-({5-Fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl )-phenyl]-pyrazol-1-yl}-methylsulfonamide

MS：487.16MS: 487.16

实施例26：{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]-吡唑-1-基}-乙酸Example 26: {4-[3-({5-Fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl )-phenyl]-pyrazol-1-yl}-acetic acid

MS：452.17MS: 452.17

实施例27：{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]吡唑-1-基}-乙酸甲基酯 Example 27: {4-[3-({5-Fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl )-phenyl]pyrazol-1-yl}-acetic acid methyl ester

MS：466.19MS: 466.19

实施例28：2-(2-{5-氟-4-[3-(1-羟基甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇Example 28: 2-(2-{5-Fluoro-4-[3-(1-hydroxymethyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazole -1-yl)-ethanol

MS：424.18MS: 424.18

实施例29：(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-甲基磺酰胺 Example 29: (2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazole-1- Methylsulfonamide

MS：457.14MS: 457.14

实施例30：(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙酸Example 30: (2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazole-1- Base)-acetic acid

MS：422.16MS: 422.16

实施例31：(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙酸甲基酯 Example 31: (2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazole-1- Methyl acetate

MS：436.18MS: 436.18

实施例32：(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-甲醇Example 32: (2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazole-1- Base)-methanol

MS：394.17MS: 394.17

实施例33：5-氟-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-N2-(4-甲基-4H-[1,2,4]***-3-基)-嘧啶-2,4-二胺 Example 33: 5-Fluoro-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-N2-(4-methyl-4H-[1,2,4]3 Zyrid-3-yl)-pyrimidine-2,4-diamine

MS：379.17MS: 379.17

实施例34：(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-甲基磺酰胺Example 34: (3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-4-yl)-methylsulfonamide

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ6.9(1H),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ5.85(2H),δ2.0(2-NH) Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ7.0(1H), δ6.9(1H), δ8.34(1H), δ8.20(1H), δ3.80(3H), δ5.85(2H ), δ2.0(2-NH)

实施例35：(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-乙酸Example 35: (3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-4-yl)-acetic acid

¹H-NMR(400MHZ,CDCl₃,TMS,ppm): ¹ H-NMR (400 MHZ, CDCl ₃ , TMS, ppm):

δ7.44(1H),δ4.0(1-NH),δ4.0(1-NH),δ4.32(2H),δ7.02(1H),δ7.20(1H),δ7.29(1H),δ7.28(1H),δ7.0(1H),δ6.9(1H),δ8.34(1H),δ8.20(1H),δ3.80(3H),δ4.67(2H),δ11.0(1-OH)Δ7.44(1H), δ4.0(1-NH), δ4.0(1-NH), δ4.32(2H), δ7.02(1H), δ7.20(1H), δ7.29( 1H), δ7.28(1H), δ7.0(1H), δ6.9(1H), δ8.34(1H), δ8.20(1H), δ3.80(3H), δ4.67(2H ), δ11.0(1-OH)

实施例36：(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-乙酸甲基酯Example 36: (3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-4-yl)-acetic acid methyl ester

合成方法参照实施例2。 The synthesis method is referred to in Example 2.

MS：437.17MS: 437.17

实施例37：(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-甲醇Example 37: (3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-4-yl)-methanol

MS：395.16MS: 395.16

实施例38：5-氟-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-N2-(2-甲基-2H-[1,2,4]***-3-基)-嘧啶-2,4-二胺Example 38: 5-Fluoro-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-N2-(2-methyl-2H-[1,2,4]3 Zyrid-3-yl)-pyrimidine-2,4-diamine

MS：379.17 MS: 379.17

实施例39：(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-甲基磺酰胺Example 39: (5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-1-yl)-methylsulfonamide

MS：458.14MS: 458.14

实施例40：(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-乙酸Example 40: (5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-1-yl)-acetic acid

MS：423.16 MS: 423.16

实施例41：(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-乙酸甲基酯Example 41: (5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-1-yl)-acetic acid methyl ester

MS：437.17MS: 437.17

实施例42：(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-甲醇Example 42: (5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2 , 4] triazol-1-yl)-methanol

MS：395.16MS: 395.16

实施例43：与JAK3靶标的结合试验 Example 43: Binding assay with JAK3 target

将本发明实施例1～42所列的化合物、Tofacitinib和Decernotinib分别与JAK3进行分子对接，观察其与JAK3靶标的结合情况。结果见表1。The compounds listed in Examples 1 to 42 of the present invention, Tofacitinib and Decernotinib were molecularly docked with JAK3, respectively, and their binding to the JAK3 target was observed. The results are shown in Table 1.

表1 与JAK3靶标的结合实验结果Table 1 Experimental results of binding to JAK3 target

化合物Compound	与JAK3靶标的结合度Degree of binding to the JAK3 target
本发明实施例1化合物Inventive Example 1 Compound	CC
本发明实施例2化合物Inventive Example 2 Compound	AA
本发明实施例3化合物Inventive Example 3 Compound	BB
本发明实施例4化合物Inventive Example 4 Compound	BB
本发明实施例5化合物Inventive Example 5 Compound	BB
本发明实施例6化合物Inventive Example 6 compound	CC
本发明实施例7化合物Inventive Example 7 Compound	BB
本发明实施例8化合物Inventive Example 8 Compound	DD
本发明实施例9化合物Inventive Example 9 compound	BB
本发明实施例10化合物Inventive Example 10 Compound	BB
本发明实施例11化合物Inventive Example 11 Compound	CC
本发明实施例12化合物Inventive Example 12 Compound	BB
本发明实施例13化合物Inventive Example 13 compound	BB
本发明实施例14化合物Inventive Example 14 Compound	BB
本发明实施例15化合物Inventive Example 15 Compound	BB
本发明实施例16化合物Inventive Example 16 Compound	BB
本发明实施例17化合物Inventive Example 17 Compound	BB
本发明实施例18化合物Inventive Example 18 Compound	CC
本发明实施例19化合物Inventive Example 19 Compound	CC
本发明实施例20化合物Inventive Example 20 Compound	AA
本发明实施例21化合物Inventive Example 21 Compound	AA
本发明实施例22化合物Inventive Example 22 Compound	AA
本发明实施例23化合物Inventive Example 23 Compound	AA
本发明实施例24化合物Inventive Example 24 Compound	BB
本发明实施例25化合物Inventive Example 25 Compound	DD
本发明实施例26化合物Inventive Example 26 Compound	DD
本发明实施例27化合物Inventive Example 27 Compound	CC
本发明实施例28化合物Inventive Example 28 Compound	DD
本发明实施例29化合物Inventive Example 29 Compound	DD
本发明实施例30化合物Inventive Example 30 Compound	BB
本发明实施例31化合物Inventive Example 31 Compound	DD
本发明实施例32化合物Inventive Example 32 Compound	BB
本发明实施例33化合物Inventive Example 33 Compound	DD
本发明实施例34化合物Inventive Example 34 Compound	DD
本发明实施例35化合物Inventive Example 35 Compound	DD
本发明实施例36化合物Inventive Example 36 Compound	BB
本发明实施例37化合物Inventive Example 37 Compound	BB
本发明实施例38化合物Inventive Example 38 Compound	AA
本发明实施例39化合物Inventive Example 39 Compound	DD
本发明实施例40化合物Inventive Example 40 Compound	CC
本发明实施例41化合物Inventive Example 41 Compound	BB

本发明实施例42化合物Inventive Example 42 Compound	BB
TofacitinibTofacitinib	BB
DecernotinibDecernotinib	BB

注：1.(A)80＜与JAK3靶标的结合度＜100；Note: 1. (A) 80 < binding degree to JAK3 target <100;

2.(B)100＜与JAK3靶标的结合度＜120；2. (B) 100 < degree of binding to the JAK3 target <120;

3.(C)120＜与JAK3靶标的结合度＜140；3. (C) 120 < degree of binding to the JAK3 target <140;

4.(D)与JAK3靶标的结合度＞140。4. (D) The degree of binding to the JAK3 target is >140.

实施例44：与STAT3靶标的结合试验Example 44: Binding assay to STAT3 target

将本发明实施例1～42所列的化合物、Tofacitinib、Filgotinib和Decernotinib分别与STAT3进行分子对接，观察其与STAT3靶标的结合情况。结果见表2。The compounds listed in Examples 1 to 42 of the present invention, Tofacitinib, Filgotinib and Decernotinib were molecularly docked with STAT3, respectively, and their binding to the STAT3 target was observed. The results are shown in Table 2.

表2 与STAT3靶标的结合实验结果Table 2 Experimental results of binding to STAT3 target

化合物Compound	与STAT3靶标的结合度Degree of binding to STAT3 targets
本发明实施例1化合物Inventive Example 1 Compound	BB
本发明实施例2化合物Inventive Example 2 Compound	BB
本发明实施例3化合物Inventive Example 3 Compound	CC
本发明实施例4化合物Inventive Example 4 Compound	CC
本发明实施例5化合物Inventive Example 5 Compound	BB
本发明实施例6化合物Inventive Example 6 compound	BB
本发明实施例7化合物Inventive Example 7 Compound	BB
本发明实施例8化合物Inventive Example 8 Compound	DD
本发明实施例9化合物Inventive Example 9 compound	CC
本发明实施例10化合物Inventive Example 10 Compound	BB
本发明实施例11化合物Inventive Example 11 Compound	CC
本发明实施例12化合物Inventive Example 12 Compound	AA
本发明实施例13化合物Inventive Example 13 compound	CC
本发明实施例14化合物Inventive Example 14 Compound	BB
本发明实施例15化合物Inventive Example 15 Compound	BB
本发明实施例16化合物Inventive Example 16 Compound	CC
本发明实施例17化合物Inventive Example 17 Compound	BB
本发明实施例18化合物Inventive Example 18 Compound	AA
本发明实施例19化合物Inventive Example 19 Compound	BB
本发明实施例20化合物Inventive Example 20 Compound	CC
本发明实施例21化合物Inventive Example 21 Compound	CC
本发明实施例22化合物Inventive Example 22 Compound	BB
本发明实施例23化合物Inventive Example 23 Compound	BB
本发明实施例24化合物Inventive Example 24 Compound	BB
本发明实施例25化合物Inventive Example 25 Compound	DD
本发明实施例26化合物Inventive Example 26 Compound	CC
本发明实施例27化合物Inventive Example 27 Compound	DD

本发明实施例28化合物Inventive Example 28 Compound	BB
本发明实施例29化合物Inventive Example 29 Compound	DD
本发明实施例30化合物Inventive Example 30 Compound	DD
本发明实施例31化合物Inventive Example 31 Compound	DD
本发明实施例32化合物Inventive Example 32 Compound	CC
本发明实施例33化合物Inventive Example 33 Compound	BB
本发明实施例34化合物Inventive Example 34 Compound	CC
本发明实施例35化合物Inventive Example 35 Compound	CC
本发明实施例36化合物Inventive Example 36 Compound	BB
本发明实施例37化合物Inventive Example 37 Compound	CC
本发明实施例38化合物Inventive Example 38 Compound	CC
本发明实施例39化合物Inventive Example 39 Compound	CC
本发明实施例40化合物Inventive Example 40 Compound	BB
本发明实施例41化合物Inventive Example 41 Compound	DD
本发明实施例42化合物Inventive Example 42 Compound	CC
TofacitinibTofacitinib	AA
DecernotinibDecernotinib	AA
FilgotinibFilgotinib	BB

注：1.(A)80＜与STAT3靶标的结合度＜100；Note: 1. (A) 80 < binding degree to STAT3 target <100;

2.(B)100＜与STAT3靶标的结合度＜120；2. (B) 100 < binding degree to STAT3 target <120;

3.(C)120＜与STAT3靶标的结合度＜140；3. (C) 120 < degree of binding to the STAT3 target <140;

4.(D)与STAT3靶标的结合度＞140。4. (D) The degree of binding to the STAT3 target is >140.

实施例45：对JAK的抑制作用Example 45: Inhibition of JAK

研究化合物对纯化的重组JAK活性的影响,是从酶学水平研究化合物对JAK的抑制活性。其实验原理为采用一种发光法激酶检测方法，用于检测JAK与底物Poly(4:1Glu,Tyr)肽反应产生的ADP含量：ADP转化为ATP后，ATP即可作为Ultra-Glo荧光素酶催化反应的底物，产生光信号。发光信号与ADP的量和激酶活性正相关。因此，通过观察化合物对JAK与底物反应产生的发光信号来确定其对重组的JAK的抑制效果，用IC₅₀表示。The effect of the study compound on the activity of purified recombinant JAK was to study the inhibitory activity of the compound against JAK at the enzymatic level. The experimental principle is to use a luminescent kinase assay to detect the ADP content produced by the reaction of JAK with the substrate Poly (4:1Glu, Tyr) peptide: ADP can be used as Ultra-Glo fluorescein after ADP is converted to ATP. The enzyme catalyzes the substrate of the reaction, producing an optical signal. The luminescent signal is positively correlated with the amount of ADP and kinase activity. Therefore, the inhibitory effect on the recombinant JAK was determined by observing the luminescence signal produced by the reaction of the compound with JAK and the substrate, and it was expressed by IC ₅₀ .

实验方法：10个不同浓度的化合物分别在37℃与JAK1、JAK2和JAK3孵育60分钟，然后加入底物及ATP混合，37℃反应50分钟后加入25μlADP-Glo^TM混合2分钟，室温反应50分钟。再加入50μl检测试剂混合2分钟，室温孵育50分钟，用化学发光仪检测。结果见表3。 Experimental method: 10 different concentrations of compounds were incubated with JAK1, JAK2 and JAK3 for 60 minutes at 37 ° C, then added with substrate and ATP, reacted at 37 ° C for 50 minutes, then added with 25 μl of ADP-Glo ^TM for 2 minutes, and reacted at room temperature for 50 minutes. . Further, 50 μl of the detection reagent was added and mixed for 2 minutes, and incubated at room temperature for 50 minutes, and detected by a chemiluminometer. The results are shown in Table 3.

表3 对JAK的抑制作用实验结果Table 3 Experimental results of inhibition of JAK

注：1.(A)20nM或更小；Note: 1. (A) 20nM or less;

2.(B)>20nM至100nM；2. (B) > 20nM to 100nM;

3.(C)>100nM3.(C)>100nM

实施例46：对p-STAT5的抑制作用Example 46: Inhibition of p-STAT5

JAK-STAT信号传递通路主要发生在白细胞中，因此参与免疫调节。IL-3激活细胞膜上的受体后导致JAK2发生自身磷酸化并激活。STAT蛋白结合在磷酸化的受体上并被JAK磷酸化。磷酸化的STAT与另外一个磷酸化的STAT蛋白结合形成二聚体并向细胞核转移。在细胞核，STAT与DNA结合并促进基因转录，引起免疫反应。因此，通过观察化合物对IL-3介导的STAT5(如下表所示)的磷酸化来确定其对JAK2的抑制效果。The JAK-STAT signaling pathway occurs mainly in white blood cells and is therefore involved in immune regulation. Activation of the receptor on the cell membrane by IL-3 results in autophosphorylation and activation of JAK2. The STAT protein binds to the phosphorylated receptor and is phosphorylated by JAK. Phosphorylated STAT binds to another phosphorylated STAT protein to form a dimer and transfer to the nucleus. In the nucleus, STAT binds to DNA and promotes gene transcription, causing an immune response. Therefore, its inhibitory effect on JAK2 was determined by observing the phosphorylation of IL-3 mediated STAT5 (shown in the following table).

实验方法：将化合物按照11个不同浓度用DMSO稀释，取200μl稀释后的化合物加入24孔板；将TF-1细胞(ATCC TIB-202)用0.5％的血清饥饿过夜，然后将其调整到2×10⁶/ml，取200μl细胞加入到上述已经加入化合物的24孔板中，混匀后，37℃细胞培养箱孵育60分钟；60分钟后，每孔加入12ng的IL-3，37℃细胞培养箱再刺激60分钟；刺激60分钟后，2％PFA室温固定30分钟；将固定后的细胞加入到BD流式管中，4℃水平离心，1500rpm,5分钟；加入500μl甲醇，4℃孵育60分钟穿膜；4℃水平离心，1500rpm,5分钟；加入2mlFACS buffer，4℃水平离心，1500rpm,5分钟；加入2mlFACS buffer，4℃水平离心，1500rpm,5分钟；每管加入5μl STAT5(pY694)抗体(562077)，室温避光孵育60分钟；加入2mlFACS buffer，4℃水平离心，1500rpm，5分钟；每管加入300μlFACS buffer重悬，用流式细胞仪检测，观察化合物对p-STAT5的抑制作用，用IC₅₀表示。结果见表4。Experimental method: Compounds were diluted with DMSO at 11 different concentrations, and 200 μl of the diluted compound was added to a 24-well plate; TF-1 cells (ATCC TIB-202) were starved with 0.5% serum overnight, and then adjusted to 2 ×10 ⁶ /ml, 200 μl of the cells were added to the above-mentioned 24-well plate to which the compound had been added, and after mixing, the cells were incubated at 37 ° C for 60 minutes; after 60 minutes, 12 ng of IL-3 was added to each well, and the cells were 37 ° C. The incubator was stimulated for another 60 minutes; after 60 minutes of stimulation, 2% PFA was fixed at room temperature for 30 minutes; the fixed cells were added to a BD flow tube, centrifuged at 4 ° C for 1500 rpm for 5 minutes; 500 μl of methanol was added, and incubation was carried out at 4 ° C. 60 minutes through the membrane; 4 ° C horizontal centrifugation, 1500 rpm, 5 minutes; add 2ml FACS buffer, 4 ° C horizontal centrifugation, 1500 rpm, 5 minutes; add 2ml FACS buffer, 4 ° C horizontal centrifugation, 1500 rpm, 5 minutes; add 5μl STAT5 per tube (pY694 Antibody (562077), incubate at room temperature for 60 minutes in the dark; add 2 ml of FACS buffer, centrifuge at 4 °C, 1500 rpm for 5 minutes; resuspend in 300 μl of FACS buffer per tube, and observe the inhibition of p-STAT5 by flow cytometry. Function, using IC ₅₀ table Show. The results are shown in Table 4.

表4 对p-STAT5的抑制作用实验结果Table 4 Experimental results of inhibition of p-STAT5

化合物Compound	对p-STAT5的抑制作用IC50(nM)Inhibition of p-STAT5 IC50 (nM)
本发明实施例1化合物Inventive Example 1 Compound	AA

本发明实施例2化合物Inventive Example 2 Compound	AA
本发明实施例3化合物Inventive Example 3 Compound	BB
本发明实施例4化合物Inventive Example 4 Compound	AA
本发明实施例5化合物Inventive Example 5 Compound	BB
本发明实施例6化合物Inventive Example 6 compound	BB
本发明实施例7化合物Inventive Example 7 Compound	AA
本发明实施例8化合物Inventive Example 8 Compound	AA
本发明实施例9化合物Inventive Example 9 compound	BB
本发明实施例10化合物Inventive Example 10 Compound	AA
本发明实施例11化合物Inventive Example 11 Compound	BB
本发明实施例12化合物Inventive Example 12 Compound	BB
本发明实施例13化合物Inventive Example 13 compound	BB
本发明实施例14化合物Inventive Example 14 Compound	AA
本发明实施例15化合物Inventive Example 15 Compound	BB
本发明实施例16化合物Inventive Example 16 Compound	AA
本发明实施例17化合物Inventive Example 17 Compound	BB
本发明实施例18化合物Inventive Example 18 Compound	AA
本发明实施例19化合物Inventive Example 19 Compound	BB
本发明实施例20化合物Inventive Example 20 Compound	AA
本发明实施例21化合物Inventive Example 21 Compound	AA
本发明实施例22化合物Inventive Example 22 Compound	BB
本发明实施例23化合物Inventive Example 23 Compound	AA
本发明实施例24化合物Inventive Example 24 Compound	AA
本发明实施例25化合物Inventive Example 25 Compound	BB
本发明实施例26化合物Inventive Example 26 Compound	BB
本发明实施例27化合物Inventive Example 27 Compound	BB
本发明实施例28化合物Inventive Example 28 Compound	BB
本发明实施例29化合物Inventive Example 29 Compound	AA
本发明实施例30化合物Inventive Example 30 Compound	BB
本发明实施例31化合物Inventive Example 31 Compound	BB
本发明实施例32化合物Inventive Example 32 Compound	BB
本发明实施例33化合物Inventive Example 33 Compound	BB
本发明实施例34化合物Inventive Example 34 Compound	BB
本发明实施例35化合物Inventive Example 35 Compound	BB
本发明实施例36化合物Inventive Example 36 Compound	AA
本发明实施例37化合物Inventive Example 37 Compound	BB
本发明实施例38化合物Inventive Example 38 Compound	BB
本发明实施例39化合物Inventive Example 39 Compound	AA
本发明实施例40化合物Inventive Example 40 Compound	BB
本发明实施例41化合物Inventive Example 41 Compound	BB
本发明实施例42化合物Inventive Example 42 Compound	BB
TofacitinibTofacitinib	AA
DecernotinibDecernotinib	BB

注：1.(A)200nM或更小；Note: 1. (A) 200nM or less;

2.(B)>200nM至2000nM；2. (B) > 200nM to 2000nM;

实施例47：对p-STAT6的抑制作用 Example 47: Inhibition of p-STAT6

IL-4诱导STAT6的磷酸化是检测抑制剂在JAK1-JAK3通路的细胞水平活性的关键实验。Induction of phosphorylation of STAT6 by IL-4 is a key assay to detect inhibitors at the cellular level of the JAK1-JAK3 pathway.

实验方法：将化合物按照11个不同浓度用DMSO稀释，取200μl稀释后的化合物加入24孔板；将THP1细胞(ATCC TIB-202)调整到2×10⁶/ml，取200μl细胞加入到上述已经加入化合物的24孔板中，混匀后，37℃细胞培养箱孵育60分钟；60分钟后，每孔加入8ng的IL-4，37℃细胞培养箱再刺激60分钟；刺激60分钟后，用2％PFA室温固定30分钟；将固定后的细胞加入到BD流式管中，4℃水平离心，1500rpm,5分钟；加入500μl甲醇，4℃孵育60分钟穿膜；4℃水平离心，1500rpm,5分钟；加入2mlFACS buffer，4℃水平离心，1500rpm,5分钟；加入2mlFACS buffer，4℃水平离心，1500rpm,5分钟；每管加入5μlSTAT6(pY641)抗体(562078)，室温避光孵育60分钟；加入2mlFACS buffer，4℃水平离心，1500rpm,5分钟；每管加入300μlFACS buffer重悬，用流式细胞仪检测，观察化合物对p-STAT6的抑制作用，用IC₅₀表示。结果见表5。Experimental method: The compound was diluted with DMSO at 11 different concentrations, 200 μl of the diluted compound was added to a 24-well plate; THP1 cells (ATCC TIB-202) were adjusted to 2×10 ⁶ /ml, and 200 μl of cells were added to the above. Add the compound to a 24-well plate, mix and incubate for 60 minutes at 37 ° C in a cell culture incubator; after 60 minutes, add 8 ng of IL-4 per well, and stimulate for another 60 minutes at 37 ° C in a cell culture incubator; after 60 minutes of stimulation, use 2% PFA was fixed at room temperature for 30 minutes; the fixed cells were added to a BD flow tube, centrifuged at 4 ° C horizontally, 1500 rpm, 5 minutes; 500 μl of methanol was added, and the membrane was incubated at 4 ° C for 60 minutes; 4 ° C horizontal centrifugation, 1500 rpm, 5 minutes; add 2ml FACS buffer, 4°C horizontal centrifugation, 1500rpm, 5 minutes; add 2ml FACS buffer, centrifuge at 4°C, 1500rpm, 5 minutes; add 5μl STAT6 (pY641) antibody (562078) per tube, incubate at room temperature for 60 minutes in the dark; 2 ml of FACS buffer was added, and centrifuged horizontally at 4 ° C, 1500 rpm for 5 minutes; each tube was resuspended by adding 300 μl of FACS buffer, and the inhibitory effect of the compound on p-STAT6 was observed by flow cytometry, and expressed by IC ₅₀ . The results are shown in Table 5.

表5 对p-STAT6的抑制作用实验结果Table 5 Experimental results of inhibition of p-STAT6

化合物Compound	对p-STAT6的抑制作用IC50(nM)Inhibition of p-STAT6 IC50(nM)
本发明实施例1化合物Inventive Example 1 Compound	BB
本发明实施例2化合物Inventive Example 2 Compound	BB
本发明实施例3化合物Inventive Example 3 Compound	BB
本发明实施例4化合物Inventive Example 4 Compound	BB
本发明实施例5化合物Inventive Example 5 Compound	BB
本发明实施例6化合物Inventive Example 6 compound	AA
本发明实施例7化合物Inventive Example 7 Compound	BB
本发明实施例8化合物Inventive Example 8 Compound	BB
本发明实施例9化合物Inventive Example 9 compound	BB
本发明实施例10化合物Inventive Example 10 Compound	BB
本发明实施例11化合物Inventive Example 11 Compound	AA
本发明实施例12化合物Inventive Example 12 Compound	BB
本发明实施例13化合物Inventive Example 13 compound	BB
本发明实施例14化合物Inventive Example 14 Compound	BB
本发明实施例15化合物Inventive Example 15 Compound	BB
本发明实施例16化合物Inventive Example 16 Compound	BB

本发明实施例17化合物Inventive Example 17 Compound	BB
本发明实施例18化合物Inventive Example 18 Compound	BB
本发明实施例19化合物Inventive Example 19 Compound	BB
本发明实施例20化合物Inventive Example 20 Compound	AA
本发明实施例21化合物Inventive Example 21 Compound	AA
本发明实施例22化合物Inventive Example 22 Compound	BB
本发明实施例23化合物Inventive Example 23 Compound	AA
本发明实施例24化合物Inventive Example 24 Compound	AA
本发明实施例25化合物Inventive Example 25 Compound	BB
本发明实施例26化合物Inventive Example 26 Compound	AA
本发明实施例27化合物Inventive Example 27 Compound	BB
本发明实施例28化合物Inventive Example 28 Compound	AA
本发明实施例29化合物Inventive Example 29 Compound	BB
本发明实施例30化合物Inventive Example 30 Compound	AA
本发明实施例31化合物Inventive Example 31 Compound	AA
本发明实施例32化合物Inventive Example 32 Compound	BB
本发明实施例33化合物Inventive Example 33 Compound	AA
本发明实施例34化合物Inventive Example 34 Compound	AA
本发明实施例35化合物Inventive Example 35 Compound	AA
本发明实施例36化合物Inventive Example 36 Compound	AA
本发明实施例37化合物Inventive Example 37 Compound	BB
本发明实施例38化合物Inventive Example 38 Compound	AA
本发明实施例39化合物Inventive Example 39 Compound	BB
本发明实施例40化合物Inventive Example 40 Compound	AA
本发明实施例41化合物Inventive Example 41 Compound	BB
本发明实施例42化合物Inventive Example 42 Compound	AA
TofacitinibTofacitinib	AA
DecernotinibDecernotinib	AA

注：1.(A)200nM或更小；Note: 1. (A) 200nM or less;

2.(B)>200nM至2000nM；2. (B) > 200nM to 2000nM;

实施例48：对胶原蛋白诱发的小鼠类风湿关节炎的影响Example 48: Effect on collagen-induced rheumatoid arthritis in mice

在胶原蛋白诱发的小鼠类风湿关节炎(CIA)模型中，研究选择的化合物的抑制活性。Ⅱ型胶原蛋白(CII)大多存在于关节软骨中，是一种与免疫***隔绝的蛋白质，但在病理条件下可作为一种自身抗体呈现出来，50％类风湿关节炎(RA)患者血清中存在抗CII的自身抗体，这表明CII可诱导产生关节炎性质的自身免疫反应。The inhibitory activity of selected compounds was investigated in a collagen-induced mouse rheumatoid arthritis (CIA) model. Type II collagen (CII) is mostly found in articular cartilage and is a protein isolated from the immune system, but it can be presented as an autoantibody under pathological conditions, in 50% of patients with rheumatoid arthritis (RA). The presence of autoantibodies against CII suggests that CII can induce an autoimmune response that produces arthritic properties.

用10周龄雄性DBA-1小鼠进行二次免疫，初次免疫(在第0日)：酒精棉球消毒小鼠尾根部皮肤，于小鼠尾根部2-3cm处皮下注射乳化好的胶原蛋白100μl(CII与CFA体积比为1:1)(含CII 150μg和热灭活的分枝杆菌50μg)；二次免疫(在第21日)：酒精棉球消毒小鼠尾根部皮肤，于小鼠尾根部2-3cm处皮下注射乳化好的胶原蛋白50μl(CII与IFA体积比为1:1)(含CII 75μg)。二次免疫后小鼠随机分组，分为对照组(助溶剂组)和试验组。试验组将化合物悬浮于1％甲基纤维素的水悬浮液，在第23日开始给药至第41日结束给药，药物剂量为30mg/kg，每次灌胃200μl，每天2次；对照组同法给予助溶剂。每日测评临床炎症症状分数。评分标准如下：0分：无红斑和水肿；1分：两只足小趾关节红斑水肿；2分：全部趾关节或前脚掌红斑水肿；3分：踝关节以下延伸到趾关节红斑水肿；4分：踝关节至全爪红肿或关节畸形。每只小鼠四肢评分相加总评分为小鼠关节炎指数，总分为16分。分别观测对照组和试验组小鼠炎症症状，计算临床炎症症状分值，采用双侧、非配对t-检验法比较试验组与对照组的临床炎症症状分值，评价化合物对胶原蛋白诱发的小鼠类风湿关节炎的影响，用P值表示。结果见表6。Secondary immunization with 10 weeks old male DBA-1 mice, primary immunization (on day 0): alcohol cotton ball disinfected the skin of the tail of the mouse, subcutaneously injected with emulsified collagen at 2-3 cm of the tail of the mouse 100μl (CII to CFA volume ratio is 1:1) (containing CII 150μg and heat inactivated Mycobacteria 50μg); secondary immunization (on the 21st day): alcohol cotton ball disinfection of the skin of the tail of the mouse, subcutaneous injection of 50μl of emulsified collagen at the root of the mouse at 2-3cm (the volume ratio of CII to IFA is 1:1) (containing CII 75μg). After secondary immunization, mice were randomly divided into control group (cosolvent group) and experimental group. The test group suspended the compound in an aqueous suspension of 1% methylcellulose, and started the administration on the 23rd day until the end of the 41st day. The drug dose was 30 mg/kg, 200 μl per administration twice a day; The co-solvent is given by the same method. The clinical inflammatory symptom score was measured daily. The scoring criteria are as follows: 0 points: no erythema and edema; 1 point: erythema edema of the two small toe joints; 2 points: erythema edema of all toe joints or forefoot; 3 points: erythema edema extending to the toe joint below the ankle joint; 4 Points: ankle to full paw redness or joint deformity. The total score of the limbs of each mouse was scored as the mouse arthritis index with a total score of 16 points. The inflammatory symptoms of the control group and the experimental group were observed respectively, and the clinical inflammatory symptom scores were calculated. The clinical inflammatory symptom scores of the test group and the control group were compared by double-sided and unpaired t-test, and the compounds were evaluated for collagen-induced small scores. The effect of rheumatoid arthritis in rats is indicated by the P value. The results are shown in Table 6.

表6 对胶原蛋白诱发的小鼠类风湿关节炎的影响Table 6 Effect on collagen-induced rheumatoid arthritis in mice

化合物Compound	试验组与对照组临床炎症症状分值统计学分析比较PStatistical analysis of clinical inflammatory symptom scores between the experimental group and the control group
本发明实施例1化合物Inventive Example 1 Compound	＜0.05<0.05
本发明实施例2化合物Inventive Example 2 Compound	＜0.05<0.05
本发明实施例3化合物Inventive Example 3 Compound	＜0.05<0.05
本发明实施例4化合物Inventive Example 4 Compound	＜0.05<0.05
本发明实施例5化合物Inventive Example 5 Compound	＜0.05<0.05
本发明实施例6化合物Inventive Example 6 compound	＜0.01<0.01
本发明实施例7化合物Inventive Example 7 Compound	＜0.05<0.05
本发明实施例8化合物Inventive Example 8 Compound	＜0.01<0.01
本发明实施例9化合物Inventive Example 9 compound	＜0.05<0.05
本发明实施例10化合物Inventive Example 10 Compound	＜0.05<0.05
本发明实施例11化合物Inventive Example 11 Compound	＜0.05<0.05
本发明实施例12化合物Inventive Example 12 Compound	＜0.01<0.01
本发明实施例13化合物Inventive Example 13 compound	＜0.05<0.05
本发明实施例14化合物Inventive Example 14 Compound	＜0.01<0.01
本发明实施例15化合物Inventive Example 15 Compound	＜0.05<0.05
本发明实施例16化合物Inventive Example 16 Compound	＜0.05<0.05
本发明实施例17化合物Inventive Example 17 Compound	＜0.01<0.01
本发明实施例18化合物Inventive Example 18 Compound	＜0.05<0.05
本发明实施例19化合物Inventive Example 19 Compound	＜0.05<0.05
本发明实施例20化合物Inventive Example 20 Compound	＜0.05<0.05

本发明实施例21化合物Inventive Example 21 Compound	＜0.01<0.01
本发明实施例22化合物Inventive Example 22 Compound	＜0.05<0.05
本发明实施例23化合物Inventive Example 23 Compound	＜0.05<0.05
本发明实施例24化合物Inventive Example 24 Compound	＜0.01<0.01
本发明实施例25化合物Inventive Example 25 Compound	＜0.05<0.05
本发明实施例26化合物Inventive Example 26 Compound	＜0.05<0.05
本发明实施例27化合物Inventive Example 27 Compound	＜0.05<0.05
本发明实施例28化合物Inventive Example 28 Compound	＜0.01<0.01
本发明实施例29化合物Inventive Example 29 Compound	＜0.05<0.05
本发明实施例30化合物Inventive Example 30 Compound	＜0.05<0.05
本发明实施例31化合物Inventive Example 31 Compound	＜0.01<0.01
本发明实施例32化合物Inventive Example 32 Compound	＜0.05<0.05
本发明实施例33化合物Inventive Example 33 Compound	＜0.01<0.01
本发明实施例34化合物Inventive Example 34 Compound	＜0.01<0.01
本发明实施例35化合物Inventive Example 35 Compound	＜0.01<0.01
本发明实施例36化合物Inventive Example 36 Compound	＜0.05<0.05
本发明实施例37化合物Inventive Example 37 Compound	＜0.01<0.01
本发明实施例38化合物Inventive Example 38 Compound	＜0.05<0.05
本发明实施例39化合物Inventive Example 39 Compound	＜0.05<0.05
本发明实施例40化合物Inventive Example 40 Compound	＜0.05<0.05
本发明实施例41化合物Inventive Example 41 Compound	＜0.01<0.01
本发明实施例42化合物Inventive Example 42 Compound	＜0.05<0.05
TofacitinibTofacitinib	＜0.01<0.01
DecernotinibDecernotinib	＜0.05<0.05

注：1.P＜0.05，试验组与对照组小鼠临床炎症症状分值统计学分析比较Note: 1.P<0.05, statistical analysis of clinical inflammatory symptom scores between experimental group and control group

差异有显著性；The difference is significant;

2.P＜0.01，试验组与对照组小鼠临床炎症症状分值统计学分析比较2.P<0.01, statistical analysis of clinical inflammatory symptom scores between experimental group and control group

差异有极显著性。The difference is extremely significant.

实施例49：对人肿瘤细胞体外增殖的抑制作用Example 49: Inhibition of proliferation of human tumor cells in vitro

取人胃癌细胞SNU-5、肝癌细胞Hep-G2、肺癌细胞EBC-1、胃癌细胞BGC-823、脑星形胶质母细胞瘤U87MG、***细胞Hela、乳腺癌细胞Bcap-37，将化合物用DMSO配制成20mM的溶液，将系列化合物和紫杉醇(储液0.2mM)用DMSO 3倍梯度稀释(10个浓度)；分别取5μl梯度稀释好的化合物溶液和紫杉醇加入到495μl含有10％FBS的培养基中，配制成2X待测化合物。Human gastric cancer cell line SNU-5, liver cancer cell Hep-G2, lung cancer cell EBC-1, gastric cancer cell BGC-823, brain astroglioma U87MG, cervical cancer cell line Hela, breast cancer cell Bcap-37, compound Prepare a 20 mM solution in DMSO, and serially dilute the series of compounds and paclitaxel (reservoir 0.2 mM) with DMSO in 3 folds (10 concentrations); add 5 μl of the gradient diluted compound solution and paclitaxel to 495 μl of 10% FBS. In the medium, 2X test compound was formulated.

取100μl含2X待测化合物、紫杉醇加到96孔板相应孔中，二氧化碳细胞培养箱培养72小时。 100 μl of the compound containing 2X and paclitaxel were added to the corresponding wells of a 96-well plate, and cultured in a carbon dioxide cell incubator for 72 hours.

去除培养基，每孔加入XTT工作液(0.3mg/ml XTT；0.00265mg/ml PMS)150μl，二氧化碳培养箱中放置2小时，微孔板振荡器震荡5分钟，酶标仪450nm读取吸光值，计算化合物对人肿瘤细胞的抑制率(％)，求得IC₅₀值(μM)。结果见表7。The medium was removed, 150 μl of XTT working solution (0.3 mg/ml XTT; 0.00265 mg/ml PMS) was added to each well, and placed in a carbon dioxide incubator for 2 hours, the microplate oscillator was shaken for 5 minutes, and the absorbance was read by a microplate reader at 450 nm. The inhibition rate (%) of the compound against human tumor cells was calculated, and the IC ₅₀ value (μM) was determined. The results are shown in Table 7.

表7 对人肿瘤细胞体外增殖的抑制作用(IC₅₀，μM)Table 7 Inhibition of proliferation of human tumor cells in vitro (IC ₅₀ , μM)

化合物Compound	SNU-SSNU-S	EBC-1EBC-1	BGC-823BGC-823	HepG2HepG2	U87-MGU87-MG	HeleHele	Bcap-37Bcap-37
本发明实施例1化合物Inventive Example 1 Compound	0.9810.981	1.2131.213	1.7251.725	1.6041.604	1.3231.323	0.2890.289	0.4110.411
本发明实施例2化合物Inventive Example 2 Compound	0.8220.822	1.5161.516	1.8911.891	1.9241.924	2.1032.103	0.6230.623	0.7110.711
本发明实施例3化合物Inventive Example 3 Compound	1.1041.104	2.3252.325	1.9561.956	1.3461.346	1.8461.846	1.0211.021	0.4150.415
本发明实施例4化合物Inventive Example 4 Compound	2.3842.384	1.1161.116	1.7561.756	2.5342.534	1.3211.321	0.6960.696	0.7930.793
本发明实施例5化合物Inventive Example 5 Compound	1.8121.812	1.0361.036	2.3112.311	3.1563.156	2.0012.001	1.1711.171	1.0121.012
本发明实施例6化合物Inventive Example 6 compound	0.6550.655	1.1981.198	3.0253.025	1.6971.697	1.7861.786	0.4530.453	0.5210.521
本发明实施例7化合物Inventive Example 7 Compound	0.9210.921	2.3112.311	1.6941.694	2.3162.316	1.0781.078	0.6610.661	0.8150.815
本发明实施例8化合物Inventive Example 8 Compound	1.3291.329	1.0101.010	1.3561.356	1.8491.849	0.9850.985	0.7890.789	0.7730.773
本发明实施例9化合物Inventive Example 9 compound	2.1152.115	2.3042.304	1.4961.496	1.1051.105	1.2131.213	0.8910.891	0.7820.782
本发明实施例10化合物Inventive Example 10 Compound	0.7680.768	1.3241.324	1.1351.135	1.7561.756	0.8230.823	0.5780.578	0.6420.642
本发明实施例11化合物Inventive Example 11 Compound	1.1411.141	1.3241.324	1.0961.096	1.7481.748	1.2971.297	0.3690.369	0.5250.525
本发明实施例12化合物Inventive Example 12 Compound	0.7460.746	1.5371.537	1.7381.738	1.0221.022	0.9560.956	0.4830.483	0.9640.964
本发明实施例13化合物Inventive Example 13 compound	0.8450.845	1.7211.721	1.3241.324	1.3691.369	1.0351.035	0.5840.584	0.7330.733
本发明实施例14化合物Inventive Example 14 Compound	1.0211.021	1.3291.329	1.1251.125	1.8761.876	2.3692.369	1.0221.022	0.8670.867
本发明实施例15化合物Inventive Example 15 Compound	0.7330.733	0.9260.926	0.8380.838	1.0691.069	1.2111.211	1.2361.236	0.4570.457
本发明实施例16化合物Inventive Example 16 Compound	1.9691.969	1.0291.029	1.3841.384	1.3421.342	1.8751.875	1.0311.031	0.9240.924
本发明实施例17化合物Inventive Example 17 Compound	2.3962.396	1.9261.926	1.3541.354	1.4591.459	1.6871.687	1.8461.846	1.0211.021
本发明实施例18化合物Inventive Example 18 Compound	1.0111.011	1.2131.213	3.8143.814	1.1051.105	1.4691.469	0.9680.968	0.6880.688
本发明实施例19化合物Inventive Example 19 Compound	3.2423.242	2.3542.354	1.9691.969	0.8760.876	1.0211.021	1.0311.031	0.9010.901
本发明实施例20化合物Inventive Example 20 Compound	1.2251.225	1.8691.869	2.1342.134	0.9860.986	1.0231.023	1.3331.333	0.7670.767
本发明实施例21化合物Inventive Example 21 Compound	1.0221.022	1.3231.323	1.0651.065	1.3281.328	2.1112.111	1.9561.956	1.6871.687
本发明实施例22化合物Inventive Example 22 Compound	2.3692.369	1.6981.698	1.3421.342	1.0961.096	1.7771.777	0.9690.969	0.6860.686
本发明实施例23化合物Inventive Example 23 Compound	1.1341.134	0.9280.928	1.0111.011	1.2151.215	1.3451.345	0.8790.879	0.5370.537
本发明实施例24化合物Inventive Example 24 Compound	0.5450.545	0.9670.967	1.2351.235	0.8790.879	1.0101.010	0.9220.922	0.3540.354

本发明实施例25化合物Inventive Example 25 Compound	0.6960.696	0.8790.879	1.0211.021	1.3241.324	0.9670.967	1.0231.023	0.7860.786
本发明实施例26化合物Inventive Example 26 Compound	1.0331.033	0.8860.886	1.0541.054	1.2331.233	1.3761.376	1.6961.696	1.0101.010
本发明实施例27化合物Inventive Example 27 Compound	2.6152.615	1.8691.869	1.9671.967	1.5431.543	1.8491.849	1.0111.011	0.6790.679
本发明实施例28化合物Inventive Example 28 Compound	1.2221.222	1.3211.321	1.0231.023	1.0101.010	1.8221.822	0.9650.965	0.7690.769
本发明实施例29化合物Inventive Example 29 Compound	0.7860.786	0.9680.968	0.7820.782	1.0831.083	1.3841.384	1.0221.022	0.5760.576
本发明实施例30化合物Inventive Example 30 Compound	0.6630.663	1.0231.023	1.2311.231	0.9670.967	1.0281.028	0.6960.696	0.7590.759
本发明实施例31化合物Inventive Example 31 Compound	1.0211.021	0.8790.879	0.8940.894	1.2551.255	1.3851.385	0.8790.879	0.6660.666
本发明实施例32化合物Inventive Example 32 Compound	1.8861.886	1.2331.233	1.2841.284	2.3422.342	1.8951.895	1.0691.069	0.9670.967
本发明实施例33化合物Inventive Example 33 Compound	3.2483.248	2.3692.369	1.9681.968	1.6891.689	1.1141.114	1.2331.233	1.0211.021
本发明实施例34化合物Inventive Example 34 Compound	1.8651.865	1.3211.321	1.0391.039	0.9980.998	1.0221.022	1.5471.547	1.0191.019
本发明实施例35化合物Inventive Example 35 Compound	2.8312.831	3.8693.869	5.9495.949	7.4287.428	3.1633.163	2.2992.299	3.3223.322
本发明实施例36化合物Inventive Example 36 Compound	2.3112.311	3.1043.104	5.1565.156	7.2177.217	3.2833.283	2.6932.693	3.4553.455
本发明实施例37化合物Inventive Example 37 Compound	1.3571.357	2.3262.326	4.3694.369	3.8643.864	2.1122.112	1.8781.878	2.1342.134
本发明实施例38化合物Inventive Example 38 Compound	0.7330.733	0.9630.963	1.0321.032	1.2391.239	1.3351.335	0.3690.369	0.4290.429
本发明实施例39化合物Inventive Example 39 Compound	0.8690.869	0.8370.837	1.3791.379	1.6981.698	1.4451.445	0.9680.968	0.5210.521
本发明实施例40化合物Inventive Example 40 Compound	0.9350.935	1.0311.031	1.2161.216	1.3341.334	1.0291.029	0.6900.690	0.7330.733
本发明实施例41化合物Inventive Example 41 Compound	1.0221.022	1.2311.231	1.7961.796	1.0011.001	1.2121.212	0.3460.346	0.4780.478
本发明实施例42化合物Inventive Example 42 Compound	2.0122.012	3.3353.335	4.3294.329	3.2163.216	1.6971.697	3.5743.574	1.0121.012

实施例50：药代动力学及生物利用度试验Example 50: Pharmacokinetics and Bioavailability Test

取化合物，健康小鼠单次口服灌胃给药，剂量为30mg/kg，取小鼠血清，测定相关药代动力学参数，并与Tofacitinib比较，计算相对生物利用度F。结果见表8。Compounds were administered to healthy mice by single oral gavage at a dose of 30 mg/kg. Mouse serum was taken and the relevant pharmacokinetic parameters were determined. The relative bioavailability F was calculated by comparison with Tofacitinib. The results are shown in Table 8.

取化合物，健康小鼠单次静脉注射给药，剂量为5mg/kg，取小鼠血清，测定相关药代动力学参数，并与Tofacitinib比较，计算相对生物利用度F。结果见表9。Compounds were administered to healthy mice in a single intravenous dose at a dose of 5 mg/kg. Mouse serum was taken and the relevant pharmacokinetic parameters were determined. The relative bioavailability F was calculated in comparison with Tofacitinib. The results are shown in Table 9.

在实施例48中试验结束日最后一次给药后1小时取小鼠血清，测定相关药代动力学参数，并与Tofacitinib比较，计算相对生物利用度F。结果见表10。Mouse sera were taken 1 hour after the last administration on the end of the experiment in Example 48, and the relevant pharmacokinetic parameters were determined and compared with Tofacitinib to calculate the relative bioavailability F. The results are shown in Table 10.

表8 健康小鼠单次口服灌胃给药相对生物利用度测定结果 Table 8 Relative bioavailability determination results of single oral gavage in healthy mice

化合物Compound	与Tofacitinib比较相对生物利用度FRelative bioavailability F with Tofacitinib
本发明实施例1化合物Inventive Example 1 Compound	AA
本发明实施例2化合物Inventive Example 2 Compound	BB
本发明实施例3化合物Inventive Example 3 Compound	AA
本发明实施例4化合物Inventive Example 4 Compound	AA
本发明实施例5化合物Inventive Example 5 Compound	BB
本发明实施例6化合物Inventive Example 6 compound	BB
本发明实施例7化合物Inventive Example 7 Compound	AA
本发明实施例8化合物Inventive Example 8 Compound	AA
本发明实施例9化合物Inventive Example 9 compound	BB
本发明实施例10化合物Inventive Example 10 Compound	AA
本发明实施例11化合物Inventive Example 11 Compound	AA
本发明实施例12化合物Inventive Example 12 Compound	AA
本发明实施例13化合物Inventive Example 13 compound	BB
本发明实施例14化合物Inventive Example 14 Compound	BB
本发明实施例15化合物Inventive Example 15 Compound	AA
本发明实施例16化合物Inventive Example 16 Compound	BB
本发明实施例17化合物Inventive Example 17 Compound	AA
本发明实施例18化合物Inventive Example 18 Compound	AA
本发明实施例19化合物Inventive Example 19 Compound	AA
本发明实施例20化合物Inventive Example 20 Compound	AA
本发明实施例21化合物Inventive Example 21 Compound	BB
本发明实施例22化合物Inventive Example 22 Compound	BB
本发明实施例23化合物Inventive Example 23 Compound	AA
本发明实施例24化合物Inventive Example 24 Compound	BB
本发明实施例25化合物Inventive Example 25 Compound	AA
本发明实施例26化合物Inventive Example 26 Compound	BB
本发明实施例27化合物Inventive Example 27 Compound	BB
本发明实施例28化合物Inventive Example 28 Compound	AA
本发明实施例29化合物Inventive Example 29 Compound	AA
本发明实施例30化合物Inventive Example 30 Compound	AA
本发明实施例31化合物Inventive Example 31 Compound	AA
本发明实施例32化合物Inventive Example 32 Compound	BB
本发明实施例33化合物Inventive Example 33 Compound	AA
本发明实施例34化合物Inventive Example 34 Compound	BB
本发明实施例35化合物Inventive Example 35 Compound	BB
本发明实施例36化合物Inventive Example 36 Compound	AA
本发明实施例37化合物Inventive Example 37 Compound	BB
本发明实施例38化合物Inventive Example 38 Compound	AA
本发明实施例39化合物Inventive Example 39 Compound	AA
本发明实施例40化合物Inventive Example 40 Compound	AA
本发明实施例41化合物Inventive Example 41 Compound	BB
本发明实施例42化合物Inventive Example 42 Compound	AA

注：1.(A)与Tofacitinib比较相对生物利用度为90％～100％；Note: 1. (A) compared with Tofacitinib relative bioavailability is 90% ~ 100%;

2.(B)与Tofacitinib比较相对生物利用度为100％～120％。2. (B) Relative bioavailability compared to Tofacitinib is 100% to 120%.

表9 健康小鼠单次静脉注射给药相对生物利用度测定结果 Table 9 Relative bioavailability measurement results of single intravenous administration of healthy mice

化合物Compound	与Tofacitinib比较相对生物利用度FRelative bioavailability F with Tofacitinib
本发明实施例1化合物Inventive Example 1 Compound	AA
本发明实施例2化合物Inventive Example 2 Compound	AA
本发明实施例3化合物Inventive Example 3 Compound	BB
本发明实施例4化合物Inventive Example 4 Compound	BB
本发明实施例5化合物Inventive Example 5 Compound	AA
本发明实施例6化合物Inventive Example 6 compound	AA
本发明实施例7化合物Inventive Example 7 Compound	AA
本发明实施例8化合物Inventive Example 8 Compound	AA
本发明实施例9化合物Inventive Example 9 compound	BB
本发明实施例10化合物Inventive Example 10 Compound	BB
本发明实施例11化合物Inventive Example 11 Compound	AA
本发明实施例12化合物Inventive Example 12 Compound	AA
本发明实施例13化合物Inventive Example 13 compound	AA
本发明实施例14化合物Inventive Example 14 Compound	BB
本发明实施例15化合物Inventive Example 15 Compound	BB
本发明实施例16化合物Inventive Example 16 Compound	BB
本发明实施例17化合物Inventive Example 17 Compound	AA
本发明实施例18化合物Inventive Example 18 Compound	BB
本发明实施例19化合物Inventive Example 19 Compound	AA
本发明实施例20化合物Inventive Example 20 Compound	AA
本发明实施例21化合物Inventive Example 21 Compound	AA
本发明实施例22化合物Inventive Example 22 Compound	BB
本发明实施例23化合物Inventive Example 23 Compound	AA
本发明实施例24化合物Inventive Example 24 Compound	AA
本发明实施例25化合物Inventive Example 25 Compound	AA
本发明实施例26化合物Inventive Example 26 Compound	AA
本发明实施例27化合物Inventive Example 27 Compound	BB
本发明实施例28化合物Inventive Example 28 Compound	BB
本发明实施例29化合物Inventive Example 29 Compound	AA
本发明实施例30化合物Inventive Example 30 Compound	AA
本发明实施例31化合物Inventive Example 31 Compound	BB
本发明实施例32化合物Inventive Example 32 Compound	BB
本发明实施例33化合物Inventive Example 33 Compound	AA
本发明实施例34化合物Inventive Example 34 Compound	AA
本发明实施例35化合物Inventive Example 35 Compound	BB
本发明实施例36化合物Inventive Example 36 Compound	BB
本发明实施例37化合物Inventive Example 37 Compound	BB
本发明实施例38化合物Inventive Example 38 Compound	AA
本发明实施例39化合物Inventive Example 39 Compound	BB
本发明实施例40化合物Inventive Example 40 Compound	AA
本发明实施例41化合物Inventive Example 41 Compound	AA
本发明实施例42化合物Inventive Example 42 Compound	AA

表10 胶原蛋白诱发的类风湿关节炎小鼠相对生物利用度测定结果 Table 10 Results of relative bioavailability of collagen-induced rheumatoid arthritis mice

化合物Compound	与Tofacitinib比较相对生物利用度FRelative bioavailability F with Tofacitinib
本发明实施例1化合物Inventive Example 1 Compound	BB
本发明实施例2化合物Inventive Example 2 Compound	BB
本发明实施例3化合物Inventive Example 3 Compound	BB
本发明实施例4化合物Inventive Example 4 Compound	AA
本发明实施例5化合物Inventive Example 5 Compound	AA
本发明实施例6化合物Inventive Example 6 compound	AA
本发明实施例7化合物Inventive Example 7 Compound	BB
本发明实施例8化合物Inventive Example 8 Compound	BB
本发明实施例9化合物Inventive Example 9 compound	AA
本发明实施例10化合物Inventive Example 10 Compound	BB
本发明实施例11化合物Inventive Example 11 Compound	BB
本发明实施例12化合物Inventive Example 12 Compound	BB
本发明实施例13化合物Inventive Example 13 compound	AA
本发明实施例14化合物Inventive Example 14 Compound	AA
本发明实施例15化合物Inventive Example 15 Compound	AA
本发明实施例16化合物Inventive Example 16 Compound	AA
本发明实施例17化合物Inventive Example 17 Compound	BB
本发明实施例18化合物Inventive Example 18 Compound	BB
本发明实施例19化合物Inventive Example 19 Compound	BB
本发明实施例20化合物Inventive Example 20 Compound	AA
本发明实施例21化合物Inventive Example 21 Compound	AA
本发明实施例22化合物Inventive Example 22 Compound	AA
本发明实施例23化合物Inventive Example 23 Compound	AA
本发明实施例24化合物Inventive Example 24 Compound	BB
本发明实施例25化合物Inventive Example 25 Compound	BB
本发明实施例26化合物Inventive Example 26 Compound	BB
本发明实施例27化合物Inventive Example 27 Compound	BB
本发明实施例28化合物Inventive Example 28 Compound	BB
本发明实施例29化合物Inventive Example 29 Compound	AA
本发明实施例30化合物Inventive Example 30 Compound	AA
本发明实施例31化合物Inventive Example 31 Compound	AA
本发明实施例32化合物Inventive Example 32 Compound	AA
本发明实施例33化合物Inventive Example 33 Compound	AA
本发明实施例34化合物Inventive Example 34 Compound	AA
本发明实施例35化合物Inventive Example 35 Compound	AA
本发明实施例36化合物Inventive Example 36 Compound	BB
本发明实施例37化合物Inventive Example 37 Compound	AA
本发明实施例38化合物Inventive Example 38 Compound	AA
本发明实施例39化合物Inventive Example 39 Compound	AA
本发明实施例40化合物Inventive Example 40 Compound	BB
本发明实施例41化合物Inventive Example 41 Compound	AA
本发明实施例42化合物Inventive Example 42 Compound	AA

实施例51：细胞毒性试验 Example 51: Cytotoxicity test

实验原理：CCK8中的wst-8在电子耦合试剂存在的情况下，可以被线粒体内的脱氢酶还原生成高度水溶性的橙黄色的甲臜产物(formazan)。颜色的深浅与细胞的增殖成正比，与细胞毒性成反比。使用酶标仪在450nm波长处测定OD值，间接反映活细胞的数量，用于测定化合物的细胞毒性。Experimental principle: Wst-8 in CCK8 can be reduced by dehydrogenase in mitochondria to form a highly water-soluble orange-yellow formazan product (formazan) in the presence of an electron coupling reagent. The depth of color is directly proportional to the proliferation of cells and inversely proportional to cytotoxicity. The OD value was measured at a wavelength of 450 nm using a microplate reader, indirectly reflecting the number of viable cells, and was used to determine the cytotoxicity of the compound.

实验方法：根据实验过程中流式细胞仪及显微镜的形态观察，各化合物毒性非常小。为了进一步定量确认化合物毒性，用CCK-8的方法检测了HELA细胞的增殖，详细方法如下：将化合物按照10个不同浓度用DMSO稀释，取100ml稀释后的化合物加入96孔板；将HELA细胞调整到2×10⁵/ml，取100ml细胞加入到上述已经加入化合物的96孔板中，混匀后，37℃细胞培养箱孵育24小时；向每孔加入20μl CCK溶液；将培养板在培养箱内孵育4小时；用酶标仪测定在450nm处的吸光度。Experimental method: According to the morphology of flow cytometry and microscope during the experiment, the toxicity of each compound was very small. In order to further quantitatively confirm the toxicity of the compound, the proliferation of HELA cells was detected by CCK-8 method. The detailed method was as follows: the compound was diluted with DMSO at 10 different concentrations, and 100 ml of the diluted compound was added to a 96-well plate; the HELA cells were adjusted. To 2 × 10 ⁵ /ml, 100 ml of cells were added to the 96-well plate to which the compound had been added, and after mixing, incubate in a 37 ° C cell incubator for 24 hours; add 20 μl of CCK solution to each well; and incubate the plate in an incubator Incubate for 4 hours; measure the absorbance at 450 nm with a microplate reader.

实验结果：各化合物均没有浓度依赖性地改变细胞数量，表明这些化合物对HELA细胞无毒性。结果见表11。Experimental results: Each compound did not change the number of cells in a concentration-dependent manner, indicating that these compounds were not toxic to HELA cells. The results are shown in Table 11.

表11 细胞毒性实验结果Table 11 Cytotoxicity test results

化合物Compound	细胞毒性Cytotoxicity
本发明实施例1化合物Inventive Example 1 Compound	无no
本发明实施例2化合物Inventive Example 2 Compound	无no
本发明实施例3化合物Inventive Example 3 Compound	无no
本发明实施例4化合物Inventive Example 4 Compound	无no
本发明实施例5化合物Inventive Example 5 Compound	无no
本发明实施例6化合物Inventive Example 6 compound	无no
本发明实施例7化合物Inventive Example 7 Compound	无no
本发明实施例8化合物Inventive Example 8 Compound	无no
本发明实施例9化合物Inventive Example 9 compound	无no
本发明实施例10化合物Inventive Example 10 Compound	无no
本发明实施例11化合物Inventive Example 11 Compound	无no
本发明实施例12化合物Inventive Example 12 Compound	无no
本发明实施例13化合物Inventive Example 13 compound	无no
本发明实施例14化合物Inventive Example 14 Compound	无no
本发明实施例15化合物Inventive Example 15 Compound	无no
本发明实施例16化合物Inventive Example 16 Compound	无no
本发明实施例17化合物Inventive Example 17 Compound	无no
本发明实施例18化合物Inventive Example 18 Compound	无no

本发明实施例19化合物Inventive Example 19 Compound	无no
本发明实施例20化合物Inventive Example 20 Compound	无no
本发明实施例21化合物Inventive Example 21 Compound	无no
本发明实施例22化合物Inventive Example 22 Compound	无no
本发明实施例23化合物Inventive Example 23 Compound	无no
本发明实施例24化合物Inventive Example 24 Compound	无no
本发明实施例25化合物Inventive Example 25 Compound	无no
本发明实施例26化合物Inventive Example 26 Compound	无no
本发明实施例27化合物Inventive Example 27 Compound	无no
本发明实施例28化合物Inventive Example 28 Compound	无no
本发明实施例29化合物Inventive Example 29 Compound	无no
本发明实施例30化合物Inventive Example 30 Compound	无no
本发明实施例31化合物Inventive Example 31 Compound	无no
本发明实施例32化合物Inventive Example 32 Compound	无no
本发明实施例33化合物Inventive Example 33 Compound	无no
本发明实施例34化合物Inventive Example 34 Compound	无no
本发明实施例35化合物Inventive Example 35 Compound	无no
本发明实施例36化合物Inventive Example 36 Compound	无no
本发明实施例37化合物Inventive Example 37 Compound	无no
本发明实施例38化合物Inventive Example 38 Compound	无no
本发明实施例39化合物Inventive Example 39 Compound	无no
本发明实施例40化合物Inventive Example 40 Compound	无no
本发明实施例41化合物Inventive Example 41 Compound	无no
本发明实施例42化合物Inventive Example 42 Compound	无no

实施例52：大鼠急性毒性试验Example 52: Acute toxicity test in rats

取化合物，观察大鼠单次口服灌胃给药急性毒性，计算LD₅₀。结果见表12。Compounds were taken and acute toxicity was observed by single oral gavage in rats, and LD _{50 was} calculated. The results are shown in Table 12.

表12 大鼠单次口服灌胃给药急性毒性实验结果Table 12 Results of acute toxicity test of single oral gavage in rats

化合物Compound	大鼠单次口服灌胃给药急性毒性LD₅₀(nM)Acute oral toxicity of LD ₅₀ (nM) in rats after single oral administration
本发明实施例1化合物Inventive Example 1 Compound	FF
本发明实施例2化合物Inventive Example 2 Compound	DD
本发明实施例3化合物Inventive Example 3 Compound	DD
本发明实施例4化合物Inventive Example 4 Compound	DD
本发明实施例5化合物Inventive Example 5 Compound	BB
本发明实施例6化合物Inventive Example 6 compound	DD
本发明实施例7化合物Inventive Example 7 Compound	FF
本发明实施例8化合物Inventive Example 8 Compound	DD
本发明实施例9化合物Inventive Example 9 compound	FF
本发明实施例10化合物Inventive Example 10 Compound	FF
本发明实施例11化合物Inventive Example 11 Compound	FF
本发明实施例12化合物Inventive Example 12 Compound	CC
本发明实施例13化合物Inventive Example 13 compound	EE
本发明实施例14化合物Inventive Example 14 Compound	FF

本发明实施例15化合物Inventive Example 15 Compound	EE
本发明实施例16化合物Inventive Example 16 Compound	FF
本发明实施例17化合物Inventive Example 17 Compound	FF
本发明实施例18化合物Inventive Example 18 Compound	FF
本发明实施例19化合物Inventive Example 19 Compound	FF
本发明实施例20化合物Inventive Example 20 Compound	EE
本发明实施例21化合物Inventive Example 21 Compound	DD
本发明实施例22化合物Inventive Example 22 Compound	EE
本发明实施例23化合物Inventive Example 23 Compound	FF
本发明实施例24化合物Inventive Example 24 Compound	EE
本发明实施例25化合物Inventive Example 25 Compound	FF
本发明实施例26化合物Inventive Example 26 Compound	EE
本发明实施例27化合物Inventive Example 27 Compound	FF
本发明实施例28化合物Inventive Example 28 Compound	FF
本发明实施例29化合物Inventive Example 29 Compound	FF
本发明实施例30化合物Inventive Example 30 Compound	EE
本发明实施例31化合物Inventive Example 31 Compound	EE
本发明实施例32化合物Inventive Example 32 Compound	EE
本发明实施例33化合物Inventive Example 33 Compound	DD
本发明实施例34化合物Inventive Example 34 Compound	FF
本发明实施例35化合物Inventive Example 35 Compound	EE
本发明实施例36化合物Inventive Example 36 Compound	EE
本发明实施例37化合物Inventive Example 37 Compound	FF
本发明实施例38化合物Inventive Example 38 Compound	DD
本发明实施例39化合物Inventive Example 39 Compound	FF
本发明实施例40化合物Inventive Example 40 Compound	EE
本发明实施例41化合物Inventive Example 41 Compound	EE
本发明实施例42化合物Inventive Example 42 Compound	FF
TofacitinibTofacitinib	BB
DecernotinibDecernotinib	FF

注：1.(A)LD₅₀＜10mg/kg；Note: 1. (A) LD ₅₀ <10mg/kg;

2.(B)10mg/kg＜LD₅₀＜50mg/kg；2. (B) 10 mg / kg < LD ₅₀ <50mg / kg;

3.(C)50mg/kg＜LD₅₀＜100mg/kg；3. (C) 50 mg / kg < LD ₅₀ <100 mg / kg;

4.(D)100mg/kg＜LD₅₀＜500mg/kg；4. (D) 100 mg / kg < LD ₅₀ <500 mg / kg;

5.(E)500mg/kg＜LD₅₀＜1000mg/kg；5. (E) 500 mg / kg < LD ₅₀ <1000 mg / kg;

6.(F)LD₅₀＞1000mg/kg。6. (F) LD ₅₀ >1000 mg/kg.

以上所述仅是本发明的优选实施方式，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。 The above description is only a preferred embodiment of the present invention, and those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. These improvements and retouchings should also be considered as The scope of protection of the present invention.

Claims

一种式(I)的新化合物：A new compound of formula (I):

包括其药学上可接受的盐、前药、代谢物、同位素衍生物和溶剂合物，其中：Including pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, wherein:

环A为C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基、C_11-15三元环基，其中环A任选被一个或多个相同或不同的R、R₁所取代；Ring A is C _3-7 cycloalkyl, C _5-7 aromatic ring group, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group, C _11-15 three a cyclic group wherein ring A is optionally substituted by one or more of the same or different R, R ₁ ;

R、R₁是H、卤素、C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R, R ₁ is H, halogen, C _3-7 cycloalkyl, C _5-7 aromatic ring group, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group Wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl is optionally substituted by one or more of the same or different R ₆ ;

B₁是H、CH₃、CN、NO₂、CF₃、卤素；B ₁ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

B₂是H、CH₃、CN、NO₂、CF₃、卤素；B ₂ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

X是H、CH₃、CN、NO₂、CF₃、C(O)NH₂、卤素；X is H, CH ₃ , CN, NO ₂ , CF ₃ , C(O)NH ₂ , halogen;

R₂是H、CH₃、CN、NO₂、CF₃、卤素；R ₂ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

R₃是H、CH₃、CN、NO₂、CF₃、卤素；R ₃ is H, CH ₃ , CN, NO ₂ , CF ₃ , halogen;

R₄是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈ R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₄ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _{5- a 7-} aromatic cyclic group, a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; a C _1-8 alkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same by one or more Or a different R ₆ substitution;

R₅是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈ R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₅ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _{5- a 7-} aromatic cyclic group, a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; a C _1-8 alkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same by one or more Or a different R ₆ substitution;

R₆是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈ R_8’、SONR₉ R_9’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₆ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _{5- a 7-} aromatic cyclic group, a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; a C _1-8 alkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same by one or more Or a different R ₆ substitution;

R₇是C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₇ is C _3-7 cycloalkyl, C _5-7 aromatic ring group, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group, wherein these rings are Optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 alkenyl, The C _2-8 alkynyl group is optionally substituted by one or more of the same or different R ₆ ;

R₈、R_8’分别是H、CN、NO₂、CF₃、COOR₇、CONR₈ R_8’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₈ and R _{8 '} are H, CN, NO ₂ , CF ₃ , COOR ₇ , CONR ₈ R _{8 '} , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _5-7 aromatic ring a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; C _{1- An} aryl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same or different one or more R ₆ substitution;

R₉、R_9’分别是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈ R_8’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₉ and R _{9 '} are H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _{8 '} , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _5-7 An aromatic ring group, a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; _{a 1-8} alkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same or one or more Different R ₆ substitutions;

R₁₀是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈ R_8’、SONR₉ R_9’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₁₀ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _{5- a 7-} aromatic cyclic group, a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; a C _1-8 alkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same by one or more Or a different R ₆ substitution;

R₁₁是H、C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代；R ₁₁ is H, C _3-7 cycloalkyl, C _5-7 aromatic ring group, C _5-7 aromatic heterocyclic group, C _7-11 aromatic bicyclic group, C _7-11 aromatic heterobicyclic group, wherein these rings Optionally substituted by one or more of the same or different R ₅ ; C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, wherein C _1-8 alkyl, C _2-8 olefin a C _2-8 alkynyl group is optionally substituted by one or more of the same or different R ₆ ;

Y是(CR₁₂R₁₃)n；Y is (CR ₁₂ R ₁₃ )n;

n是0或1；n is 0 or 1;

R₁₂、R₁₃是R₅；R ₁₂ and R ₁₃ are R ₅ ;

Z₁、Z₂可以分别选自C(R₁₄)或N(R₁₄)；Z ₁ , Z ₂ may be respectively selected from C(R ₁₄ ) or N(R ₁₄ );

R₁₄是H、CN、NO₂、CF₃、COOH、COOR₇、CONR₈ R_8’、SONR₉R_9’、COR₁₀、R₁₁OH、卤素；C_3-7环烷基、C_5-7芳香环基、C_5-7芳香杂环基、C_7-11芳香双环基、C_7-11芳香杂双环基，其中这些环上任选被一个或多个相同或不同的R₅取代；C_1-8烷基、C_2-8烯基、C_2-8炔基，其中C_1-8烷基、C_2-8烯基、C_2-8炔基任选被一个或多个相同或不同的R₆取代。R ₁₄ is H, CN, NO ₂ , CF ₃ , COOH, COOR ₇ , CONR ₈ R _8' , SONR ₉ R _9' , COR ₁₀ , R ₁₁ OH, halogen; C _3-7 cycloalkyl, C _{5- a 7-} aromatic cyclic group, a C _5-7 aromatic heterocyclic group, a C _7-11 aromatic bicyclic group, a C _7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R ₅ ; a C _1-8 alkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, wherein the C _1-8 alkyl group, the C _2-8 alkenyl group, the C _2-8 alkynyl group are optionally the same by one or more Or different R ₆ substitutions.
如权利要求1所述的化合物，其中所述化合物选自：The compound of claim 1 wherein said compound is selected from the group consisting of:

2-(2-{5-氟-4-[(吡啶并[2,3-d]嘧啶-6-亚甲基)-胺]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{5-fluoro-4-[(pyrido[2,3-d]pyrimidin-6-methylene)-amine]-pyrimidin-2-ylamino}-imidazol-1-yl)- Ethanol

5-氟-N2-(1-甲基-1H-咪唑-2-基)-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-嘧啶-2,4-二胺； 5-fluoro-N2-(1-methyl-1H-imidazol-2-yl)-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-pyrimidine-2,4 -diamine;

2-(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-氨基}-咪唑-1-基)-乙醇；2-(2-{5-fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidine-2-amino}-imidazol-1-yl)- Ethanol

2-(2-{5-氯-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-氨基}-咪唑-1-基)-乙醇；2-(2-{5-chloro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidine-2-amino}-imidazol-1-yl)- Ethanol

2-(2-{4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-5-三氟甲基-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-imidazole-1 -base)-ethanol;

2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-5-腈；2-[1-(2-Hydroxy-ethyl)-1H-imidazol-2-ylamino]-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]- Pyrimidine-5-nitrile;

2-(2-{5-氟-4-[3-氟-5-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{5-fluoro-4-[3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazole- 1-yl)-ethanol;

2-(2-{4-[3-(1-乙基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{4-[3-(1-ethyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl)-ethanol;

2-(2-{4-[(1H-苯并咪唑-5-亚甲基)-胺]-5-氟-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{4-[(1H-benzimidazole-5-methylene)-amine]-5-fluoro-pyrimidin-2-ylamino}-imidazol-1-yl)-ethanol;

2-(2-{4-[(6,9-二氢-嘌呤-1-亚甲基)-胺]-5-氟-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{4-[(6,9-dihydro-inden-1-methylene)-amine]-5-fluoro-pyrimidin-2-ylamino}-imidazol-1-yl)-ethanol;

2-(2-{5-氟-4-[(9-羟基甲基-6,9-二氢-嘌呤-1-亚甲基)-胺]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{5-fluoro-4-[(9-hydroxymethyl-6,9-dihydro-inden-1-methylene)-amine]-pyrimidin-2-ylamino}-imidazole-1 -base)-ethanol;

2-[2-(5-氟-4-{1-[3-(1-甲基-1H-吡唑-4-基)-苯基]-乙胺基}-嘧啶-2-基氨基)-咪唑-1-基]-乙醇；2-[2-(5-fluoro-4-{1-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethylamino}-pyrimidin-2-ylamino) -imidazol-1-yl]-ethanol;

2-(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苯胺基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{5-fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-anilino]-pyrimidin-2-ylamino}-imidazol-1-yl)- Ethanol

2-(2-{5-氟-4-[3-氟-5-(1-甲基-1H-吡唑-4-基)-苯胺基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇； 2-(2-{5-fluoro-4-[3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-anilino]-pyrimidin-2-ylamino}-imidazole-1 -base)-ethanol;

2-(2-{4-[3-(1-乙基-1H-吡唑-4-基)-苯胺基]-5-氟-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{4-[3-(1-ethyl-1H-pyrazol-4-yl)-anilino]-5-fluoro-pyrimidin-2-ylamino}-imidazol-1-yl)- Ethanol

2-{2-[4-(1H-苯并咪唑-5-基氨基)-5-氟-嘧啶-2-基氨基]-咪唑-1-基}-乙醇；2-{2-[4-(1H-benzimidazol-5-ylamino)-5-fluoro-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol;

2-{2-[5-氟-4-(吡啶并[2,3-d]嘧啶-6-基氨基)-嘧啶-2-基氨基]-咪唑-1-基}-乙醇；2-{2-[5-fluoro-4-(pyrido[2,3-d]pyrimidin-6-ylamino)-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol;

2-{2-[4-(6,9-二氢-嘌呤-1-基氨基)-5-氟-嘧啶-2-基氨基]-咪唑-1-基}-乙醇；2-{2-[4-(6,9-dihydro-indol-1-ylamino)-5-fluoro-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol;

2-{2-[5-氟-4-(9-羟基甲基-6,9-二氢-嘌呤-1-基氨基)-嘧啶-2-基氨基]-咪唑-1-基}-乙醇；2-{2-[5-fluoro-4-(9-hydroxymethyl-6,9-dihydro-indol-1-ylamino)-pyrimidin-2-ylamino]-imidazol-1-yl}-ethanol ;

2-[2-(5-氟-4-{甲基-[3-(1-甲基-1H-吡唑-4-基)-苯基]-胺}-嘧啶-2-基氨基)-咪唑-1-基]-乙醇；2-[2-(5-fluoro-4-{methyl-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-amine}-pyrimidin-2-ylamino)- Imidazolyl-1-yl]-ethanol;

2-{2-[(5-氟-4-{甲基-[3-(1-甲基-1H-吡唑-4-基)-苄]-胺}-嘧啶-2-基)-甲基-胺]-咪唑-1-基}-乙醇；2-{2-[(5-fluoro-4-{methyl-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-amine}-pyrimidin-2-yl)-- Base-amine]-imidazol-1-yl}-ethanol;

2-[2-({5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基}-甲基-胺)-咪唑-1-基]-乙醇；2-[2-({5-fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-yl}-methyl-amine)- Imidazolyl-1-yl]-ethanol;

2-[2-(5-氟-4-{甲基-[3-(1-甲基-1H-吡唑-4-基)-苄]-胺}-嘧啶-2-基氨基)-咪唑-1-基]-乙醇；2-[2-(5-fluoro-4-{methyl-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-amine}-pyrimidin-2-ylamino)-imidazole -1-yl]-ethanol;

1-{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]-吡唑-1-基}-乙酮；1-{4-[3-({5-fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl)- Phenyl]-pyrazol-1-yl}-ethanone;

{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]-吡唑-1-基}-甲基磺酰胺；{4-[3-({5-fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl)-phenyl) ]-pyrazol-1-yl}-methylsulfonamide;

{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]-吡唑-1-基}-乙酸； {4-[3-({5-fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl)-phenyl) ]-pyrazol-1-yl}-acetic acid;

{4-[3-({5-氟-2-[1-(2-羟基-乙基)-1H-咪唑-2-基氨基]-嘧啶-4-基氨基}-甲基)-苯基]吡唑-1-基}-乙酸甲基酯；{4-[3-({5-fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino}-methyl)-phenyl) Pyrazol-1-yl}-acetic acid methyl ester;

2-(2-{5-氟-4-[3-(1-羟基甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙醇；2-(2-{5-fluoro-4-[3-(1-hydroxymethyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl )-ethanol;

(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-甲基磺酰胺；(2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl)- Sulfonamide

(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙酸；(2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl)-acetic acid ;

(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-乙酸甲基酯；(2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl)-acetic acid Methyl ester

(2-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-咪唑-1-基)-甲醇；(2-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-imidazol-1-yl)-methanol ;

5-氟-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-N2-(4-甲基-4H-[1,2,4]***-3-基)-嘧啶-2,4-二胺；5-fluoro-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-N2-(4-methyl-4H-[1,2,4]triazole-3- -pyrimidine-2,4-diamine;

(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-甲基磺酰胺；(3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4]3 Zin-4-yl)-methylsulfonamide;

(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-乙酸；(3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4]3 Zin-4-yl)-acetic acid;

(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-乙酸甲基酯；(3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4]3 Zin-4-yl)-acetic acid methyl ester;

(3-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-4-基)-甲醇；(3-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4]3 Zin-4-yl)-methanol;

5-氟-N4-[3-(1-甲基-1H-吡唑-4-基)-苄]-N2-(2-甲基-2H-[1,2,4]***-3-基)-嘧啶-2,4-二胺； 5-fluoro-N4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-N2-(2-methyl-2H-[1,2,4]triazole-3- -pyrimidine-2,4-diamine;

(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-甲基磺酰胺；(5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4] Zin-1-yl)-methylsulfonamide;

(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-乙酸；(5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4] Zin-1-yl)-acetic acid;

(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-乙酸甲基酯；(5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4] Zin-1-yl)-acetic acid methyl ester;

(5-{5-氟-4-[3-(1-甲基-1H-吡唑-4-基)-苄基氨基]-嘧啶-2-基氨基}-[1,2,4]***-1-基)-甲醇。(5-{5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino}-[1,2,4] Zin-1-yl)-methanol.
如权利要求1或2所述的化合物，其是各类晶型，包括但不限于结晶、无定形及其他各类晶型。The compound of claim 1 or 2 which is a variety of crystalline forms including, but not limited to, crystalline, amorphous, and other types of crystalline forms.
一种药物组合物，包括权利要求1-3中任一项所述的化合物或其可药用盐、前药、代谢物、同位素衍生物和溶剂合物以及可药用载体或赋型剂，任选与一种或多种其他药物组合物结合。A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, prodrug, metabolite, isotopic derivative and solvate thereof, and a pharmaceutically acceptable carrier or excipient, Optionally, in combination with one or more other pharmaceutical compositions.
如权利要求1-3中任一项所述的化合物或如权利要求4所述的药物组合物，其可制成注射或非注射给药途径的药物制剂和药物剂型。A compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 which can be formulated into a pharmaceutical preparation and a pharmaceutical dosage form for administration by injection or non-injection.
用作药物的如权利要求1-3中任一项所述的化合物或如权利要求4或5所述的药物组合物。A compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 or 5 for use as a medicament.
如权利要求1-3中任一项所述的化合物或如权利要求4或5所述的药物组合物，其用于在人体患者中预防或治疗与Janus激酶(JAK)相关的疾病和病症。A compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 or 5 for use in the prevention or treatment of diseases and conditions associated with Janus kinase (JAK) in a human patient.
如权利要求1-3中任一项所述的化合物或如权利要求4或5所述的药物组合物，其用于在哺乳动物患者中预防或治疗与Janus激酶(JAK)相关的疾病和病症。A compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 or 5 for use in the prevention or treatment of diseases and conditions associated with Janus kinase (JAK) in a mammalian patient .
如权利要求6或7所述的化合物或药物组合物，其中所述与Janus激酶(JAK)相关的疾病和病症选自：免疫、炎症、自身免疫、增殖性疾病如癌症、增生性疾病、过敏病症或疾病、移植排斥或移植物抗宿主病、干眼症。The compound or pharmaceutical composition according to claim 6 or 7, wherein the diseases and conditions associated with Janus kinase (JAK) are selected from the group consisting of: immunity, inflammation, autoimmunity, proliferative diseases Such as cancer, proliferative diseases, allergic diseases or diseases, transplant rejection or graft versus host disease, dry eye syndrome.
如权利要求1-3中任一项所述的化合物或如权利要求4或5所述的药物组合物，其可作为Janus激酶(JAK)抑制剂应用在医学、药学、生物学、生理学、生化学等实验中。The compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 or 5, which can be used as a Janus kinase (JAK) inhibitor in medicine, pharmacy, biology, physiology, health In experiments such as chemistry.
一种如权利要求1-3中任一项所述的化合物或其可药用盐、前药、代谢物、同位素衍生物和溶剂合物，或如权利要求4或5所述的药物组合物用于治疗与Janus激酶(JAK)相关的疾病和病症的方法。A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, prodrug, metabolite, isotopic derivative or solvate thereof, or a pharmaceutical composition according to claim 4 or 5 A method for treating diseases and conditions associated with Janus kinase (JAK).
如权利要求11所述的方法，其中所述与Janus激酶(JAK)相关的疾病和病症选自：免疫、炎症、自身免疫、增殖性疾病如癌症、增生性疾病、过敏病症或疾病、移植排斥或移植物抗宿主病、干眼症。 The method of claim 11, wherein the diseases and conditions associated with Janus kinase (JAK) are selected from the group consisting of: immunity, inflammation, autoimmunity, proliferative diseases such as cancer, proliferative diseases, allergic conditions or diseases, transplant rejection Or graft versus host disease, dry eye syndrome.