WO2020034987A1

WO2020034987A1 - Prodrug containing glucuronide derivative of jak inhibitor, preparation method therefor, and uses thereof

Info

Publication number: WO2020034987A1
Application number: PCT/CN2019/100554
Authority: WO
Inventors: 高鹏; 曾蜜; 谭松良; 孙广俊; 包如迪
Original assignee: 江苏豪森药业集团有限公司; 上海翰森生物医药科技有限公司
Priority date: 2018-08-15
Filing date: 2019-08-14
Publication date: 2020-02-20
Also published as: CN111094314B; CN111094314A; TW202021977A

Abstract

Disclosed are a compound of formula I of a prodrug of a JAK inhibitor, a pharmaceutical composition thereof, a method for treating inflammatory diseases and tumors by using the compound, as well as a method and an intermediate for preparing the compound. The substituents in formula (I) are as defined in the description.

Description

含有葡糖苷酸衍生物JAK抑制剂的前药及其制备方法和应用Prodrug containing glucuronide derivative JAK inhibitor, preparation method and application thereof

技术领域Technical field

本发明属于药物合成领域，具体涉及一种含有葡糖苷酸衍生物JAK抑制剂的前药、其制备方法和应用。The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a prodrug containing a glucuronide derivative JAK inhibitor, a preparation method and application thereof.

背景技术Background technique

Janus激酶(JAK)是一种胞内非受体酪氨酸激酶，介导各种细胞因子的信号传导和激活。JAK激酶家族分为JAK1、JAK2、JAK3和TYK2四个亚型，各亚型分别介导不同类型的细胞因子信号通路，JAK-1、JAK-2和TYK-2在人体各组织细胞中均有表达，JAK-3主要表达于各造血组织细胞中。细胞因子受体的共同特点是受体本身不具有激酶活性，但受体胞内段具有酪氨酸激酶JAK的结合位点。当细胞因子受体与其配体结合后，激活受体偶联的JAKs，进而使受体被磷酸化，磷酸化的酪氨酸位点可与含有SH2结构域的STAT蛋白结合，从而使STAT被募集到受体并通过JAKs磷酸化，随后磷酸酪氨酸介导STAT二聚化，激活的STAT二聚体转移到细胞核内并激活其靶点基因转录，进而调控多种细胞的生长、活化、分化等多种功能。Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. The JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3, and TYK2. Each subtype mediates different types of cytokine signaling pathways. JAK-1, JAK-2, and TYK-2 are found in all tissue cells Expression, JAK-3 is mainly expressed in various hematopoietic cells. The common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. When the cytokine receptor binds to its ligand, it activates the receptor-coupled JAKs, which in turn causes the receptor to be phosphorylated. The phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain. Recruited to receptors and phosphorylated by JAKs, followed by phosphotyrosine-mediated STAT dimerization, activated STAT dimers are transferred to the nucleus and activate their target gene transcription, which in turn regulates the growth, activation, Different functions, such as differentiation.

JAK/STAT信号通路介导细胞内大多数细胞因子的信号传导，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。JAK/STAT信号通路功能广泛，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，与多种炎症性疾病如类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)等密切相关；同时JAK/STAT信号通路与肿瘤性疾病如骨髓纤维化、真性红细胞增多症及原发性血小板增多症密切相关，JAK分子自身的突变也会导致急性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)等肿瘤性疾病。The JAK / STAT signaling pathway mediates the signaling of most cytokines in cells and plays a key role in participating in biological processes such as immune regulation and immune cell proliferation. The JAK / STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation, and is associated with a variety of inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel Diseases (ulcerative colitis and Crohn's disease) are closely related; meanwhile, the JAK / STAT signaling pathway is closely related to tumor diseases such as myelofibrosis, polycythemia vera, and primary thrombocytosis, and mutations in the JAK molecule itself It can also cause tumor diseases such as acute myeloid cell leukemia (AML), acute lymphocytic leukemia (ALL), ductal carcinoma of the breast, and non-small cell lung cancer (NSCLC).

炎症性肠病是慢性肠道炎症性疾病，包括溃疡性结肠炎和克罗恩病。目前治疗炎症性肠病的药物主要有氨基水杨酸制剂、糖皮质激素、免疫抑制剂、抗生素等。UC的治疗以调节免疫反应、抑制炎症为主要原则。目前在临床上，柳氮磺胺吡啶主要用于治疗轻度至中度的UC。而中度至重度的UC目前常用的药物包括糖皮质激素类，但是因为风险大于益处，所以不会作为长期的治疗手段。单克隆抗体则存在药物，成本高昂、产生药物抗体影响药物安全性和有效性，以及静脉给药的方式不够方便等问题，该领域仍存在着远未满足的医疗需求。许多接受治疗的患者还没有得到缓解，高达80％的克罗恩病患者和30％的UC患者最终需要接受手术治疗。Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis and Crohn's disease. The current drugs for treating inflammatory bowel disease are aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics, etc. The main principle of UC treatment is to regulate the immune response and suppress inflammation. At present, sulfasalazine is mainly used in the treatment of mild to moderate UC. Moderate to severe UC currently used drugs include glucocorticoids, but because the risks outweigh the benefits, they will not be used as a long-term treatment. Monoclonal antibodies have problems such as high cost, the production of drug antibodies that affect the safety and effectiveness of drugs, and the inconvenient way of intravenous administration. There are still unmet medical needs in this field. Many patients who have received treatment have not yet responded, and up to 80% of Crohn's disease patients and 30% of UC patients eventually need surgery.

Tofacitinib(Xeljanz)是治疗中度至重度活动性UC成人患者的首个口服JAK 抑制剂，对JAK1、2、3亚型均有显著的抑制活性，其JAK2/JAK3选择性仅为20倍。JAK1和JAK2的活性增加了tofacitinib的疗效，但同时也带来了较为严重的副作用，不良反应包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib的上市背着诸多的黑框标识：严重感染(肺结核、细菌、真菌、病毒)和恶性肿瘤(淋巴瘤等)。由于JAK2活性与红系细胞分化以及脂代谢过程相关，上述部分不良反应被认为可能与Tofacitinib对JAK-3选择性不足相关，是该药物的非选择性抑制引起的。目前上市和在研的JAK抑制剂主要是竞争激酶结构域与ADP的结合而发挥作用，因此普遍存在选择性不高的问题，即使是对JAK某个亚型的选择性抑制剂同样存在严重的靶点相关副作用问题。Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of adult patients with moderate to severe active UC. It has significant inhibitory activity on JAK1, 2, 3 subtypes, and its JAK2 / JAK3 selectivity is only 20 times. The activities of JAK1 and JAK2 increase the efficacy of tofacitinib, but also bring more serious side effects. Adverse reactions include infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Tofacitinib's listing carries many black box signs: severe infections (tuberculosis, bacteria, fungi, viruses) and malignancies (lymphomas, etc.). Because JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of these adverse reactions are thought to be related to Tofacitinib's insufficient selectivity to JAK-3, which is caused by the non-selective inhibition of the drug. The JAK inhibitors currently on the market and under development mainly compete for the binding of the kinase domain and ADP, so there is a problem of low selectivity, even for selective inhibitors of a certain subtype of JAK. Target-related side effects.

介于JAK抑制剂的良好疗效和多种靶点相关性严重副作用，开发一种安全性更高的JAK抑制剂药物成为目前急需解决的问题。由于炎症性肠道疾病发生在胃肠道的肠腔表面，不需要药物进入血液***即可发挥作用，因此开发一种降低药物在血液循环中***暴露量而提高药物在炎症部位的局部暴露量的前药成为提高安全性的良好策略。国际申请WO2017091544(A1)报道了Theravance公司通过改造tofacitinib获得其前药的相关化合物，该类化合物表现出了良好的组织分布选择性，体现了该策略的可行性，具有重大的临床应用价值。Due to the good efficacy of JAK inhibitors and the serious side effects associated with multiple targets, the development of a JAK inhibitor drug with higher safety has become an urgent problem. Because inflammatory bowel disease occurs on the surface of the intestinal cavity of the gastrointestinal tract, it can function without the need for drugs to enter the blood system. Therefore, a system was developed to reduce the systemic exposure of the drug in the blood circulation and increase the local exposure of the drug to the site of inflammation. Prodrugs become a good strategy for improving safety. The international application WO2017091544 (A1) reports that Theravance Company obtained related compounds of its prodrugs by modifying tofacitinib. These compounds show good tissue distribution selectivity, reflecting the feasibility of this strategy and having great clinical application value.

发明内容Summary of the Invention

本发明的目的在于提供一种通式(IA)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：An object of the present invention is to provide a compound represented by the general formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:

其中：among them:

M、M ₁或M ₂为O、S或NH； M, M ₁ or M ₂ is O, S or NH;

L为键、-C(＝O)-或-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-； L is a bond, -C (= O)-or -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-;

G为JAK抑制剂，选自Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、Pf-04965842、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modified ruxolitinib analog、ATI-501、R-348、R-348、NS-018、SHR0302、Jaktinib hydrochloride、Jaktinib hydrochloride或KL-130008；G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-atin, Bertin PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride or KL-130008;

R为-CH ₂OH或-COOPg； R is -CH ₂ OH or -COOPg;

R ₁选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl with one or more substituents;

R ₂和R ₃各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基； R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

Pg为氢或羧基保护基，当Pg为羧基保护基时，选自-DMB、-Bn、-Allyl、-PfP、-Me、-PMB、-EM或t-Boc；Pg is hydrogen or a carboxy protecting group. When Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl, -PfP, -Me, -PMB, -EM, or t-Boc;

Pg ₁、Pg ₂和Pg ₃为氢或羟基保护基，当Pg ₁、Pg ₂和Pg ₃为羟基保护基时，各自独立的选自-CH ₃、-C(CH ₃) ₃、-CPh ₃、-CH ₂Ph、-CH ₂OCH ₃、-Si(CH ₃) ₃、-THP、-SiMe ₂(t-Bu)、-Ac或-COPh； Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protecting groups. When Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, each is independently selected from -CH ₃ , -C (CH ₃ ) ₃ , -CPh ₃ , -CH ₂ Ph, -CH ₂ OCH ₃ , -Si (CH ₃ ) ₃ , -THP, -SiMe ₂ (t-Bu), -Ac or -COPh;

n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and

x为0、1、2或3。x is 0, 1, 2 or 3.

本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：An object of the present invention is to provide a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:

其中：among them:

M为O、S或NH；M is O, S or NH;

G为JAK抑制剂，选自Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、Pf-04965842、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、 PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modified ruxolitinib analog、ATI-501、R-348、R-348、NS-018、SHR0302、Jaktinib hydrochloride、Jaktinib hydrochloride或KL-130008；优选SHR-0302；G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-atin, Bertin PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride or KL-130008; preferably SHR-0302;

R为-CH ₂OH或-COOPg R is -CH ₂ OH or -COOPg

Pg为氢或羧基保护基，当Pg为羧基保护基时，选自-DMB(2,4-二甲氧基苄基)、-Bn(苄基)、-Allyl(烯丙基)、-PfP(五氟代苯基)、-Me(甲基)、-PMB(对甲基苄基)、-EME(甲氧乙氧甲基)或t-Boc(叔丁氧羰基)；Pg is a hydrogen or carboxy protecting group. When Pg is a carboxy protecting group, it is selected from -DMB (2,4-dimethoxybenzyl), -Bn (benzyl), -Allyl (allyl), -PfP (Pentafluorophenyl), -Me (methyl), -PMB (p-methylbenzyl), -EME (methoxyethoxymethyl) or t-Boc (tert-butoxycarbonyl);

Pg ₁、Pg ₂和Pg ₃为氢或羟基保护基，当Pg ₁、Pg ₂和Pg ₃为羟基保护基时，各自独立的选自-CH ₃(甲基)、-C(CH ₃) ₃(叔丁基)、-CPh ₃(三苯基)、-CH ₂Ph(苄醚基)、-CH ₂OCH ₃(甲氧基甲基)、-Si(CH ₃) ₃(三甲基硅烷基)、-THP(四氢呋喃基)、-SiMe ₂(t-Bu)(叔丁基二甲硅烷基)、-Ac(乙酰基)或-COPh(苯甲酰基)； Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxy protecting groups. When Pg ₁ , Pg ₂ and Pg ₃ are hydroxy protecting groups, each is independently selected from -CH ₃ (methyl), -C (CH ₃ ) ₃ (Tert-butyl), -CPh ₃ (triphenyl), -CH ₂ Ph (benzyl ether), -CH ₂ OCH ₃ (methoxymethyl), -Si (CH ₃ ) ₃ (trimethylsilane) Group), -THP (tetrahydrofuryl), -SiMe ₂ (t-Bu) (tert-butyldisilyl), -Ac (acetyl) or -COPh (benzoyl);

n为0、1、2、3或4的整数；且n is an integer of 0, 1, 2, 3, or 4; and

x为0、1、2或3的整数；x is an integer of 0, 1, 2 or 3;

当M为O，Pg ₁、Pg ₂和Pg ₃为氢，R为-COOPg，Pg为氢，R ₁选自氢、氨基、硝基、卤素、甲基或甲氧基，R ₁位于的

邻位，L为-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-，R ₂和R ₃同时选自甲基，且x为1时，G不为Tofacitinib； When M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, R _{1 is} selected from hydrogen, amino, nitro, halogen, methyl or methoxy, and R ₁ is

In the ortho position, L is -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-, and R ₂ and R _{3 are} both selected from methyl, and when x is 1, G is not Tofacitinib;

当M为O，Pg ₁、Pg ₂和Pg ₃为氢，R为-COOPg，Pg为氢，R ₁为硝基，R ₁位于的

邻位，L为-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-，R ₂和R ₃同时选自甲基，且x为1时，G不为Ruxolitinib或Baricitinib。 When M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, R ₁ is nitro, and R ₁ is

Ortho position, L is -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-, R ₂ and R ₃ are selected from methyl at the same time, and when x is 1, G is not Ruxolitinib or Baricitinib .

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(II)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (II). Show:

其中：M、G、R～R ₃、Pg ₁～Pg ₃、n和x如通式(I)所述。 Among them: M, G, R to R ₃ , Pg ₁ to Pg ₃ , n and x are as described in the general formula (I).

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(IIA)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IIA). Show:

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(III)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (III) Show:

其中：M、G、R、R ₁、Pg ₁～Pg ₃和n如通式(I)所述。 Among them: M, G, R, R ₁ , Pg ₁ to Pg ₃ and n are as described in the general formula (I).

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(IV)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IV) Show:

其中：G、R ₁～R ₃、Pg、Pg ₁～Pg ₃和x如通式(I)所述。 Among them, G, R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x are as described in the general formula (I).

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(V)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (V). Show:

其中：M、G、R、R ₁和Pg ₁～Pg ₃如通式(I)所述。 Among them, M, G, R, R ₁ and Pg ₁ to Pg _{3 are} as described in the general formula (I).

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(VI)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VI) Show:

其中：R、R ₁～R ₃、Pg ₁～Pg ₃和x如通式(I)所述。 Among them, R, R ₁ to R ₃ , Pg ₁ to Pg ₃ and x are as described in the general formula (I).

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(VII)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VII) Show:

其中：R ₁～R ₃和x如通式(I)所述。 Among them, R ₁ to R ₃ and x are as described in the general formula (I).

本发明还涉及一个优选方案，所述的通式(IA)或(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(VIII)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (IA) or (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VIII). Show:

其中：among them:

R为-CH ₂OH或-COOH； R is -CH ₂ OH or -COOH;

G选自Tofacitinib或SHR-0302；G is selected from Tofacitinib or SHR-0302;

R ₁选自氢、卤素、氰基、硝基、氨基、C _1-6烷基、C _1-6卤代烷基、C _1-6烷氧基或C _1-6卤代烷氧基， R _{1 is} selected from hydrogen, halogen, cyano, nitro, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy,

优选氢、卤素、氰基、硝基、氨基、C _1-3烷基、C _1-3卤代烷基、C _1-3烷氧基或C _1-3卤代烷氧基；更优选氢、氟、氯、氰基、硝基、氨基、甲基、甲氧基或三氟甲基； Preferred are hydrogen, halogen, cyano, nitro, amino, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy; more preferred are hydrogen, fluorine, chlorine , Cyano, nitro, amino, methyl, methoxy or trifluoromethyl;

x选自0、1、2或3的整数，优选1；x is an integer selected from 0, 1, 2 or 3, preferably 1;

且，当x为1，G为Tofacitinib且R ₁选自硝基时，R为-CH ₂OH。 When x is 1, G is Tofacitinib, and R _{1 is} selected from nitro, R is -CH ₂ OH.

本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(IX)所示：The present invention also relates to a preferred embodiment. The compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further characterized by the general formula (IX):

其中：among them:

R ₁～R ₃和x如通式(I)所述。 R ₁ to R ₃ and x are as described in the general formula (I).

本发明还涉及一种通式(IB)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a compound represented by the general formula (IB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

其中：among them:

M ₁为O、S或NH； M ₁ is O, S or NH;

L ₁为键、-C(＝O)-或-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-； L ₁ is a bond, -C (= O)-or -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-;

G ₁为JAK抑制剂，选自Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、Pf-04965842、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modified ruxolitinib analog、ATI-501、R-348、R-348、NS-018、SHR0302、Jaktinib hydrochloride、Jaktinib hydrochloride或KL-130008； G ₁ is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-002, CID , PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride Or KL-130008;

R’为-CH ₂OH或-COOPg； R 'is -CH ₂ OH or -COOPg;

R ₁’选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ₁ ′ is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy Substituted with one or more substituents of aryl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Pg’为氢或羧基保护基，当Pg为羧基保护基时，选自-DMB(2,4-二甲氧基苄基)、-Bn(苄基)、-Allyl(烯丙基)、-PfP(五氟代苯基)、-Me(甲基)、-PMB(对甲基苄基)、-EME(甲氧乙氧甲基)或t-Boc(叔丁氧羰基)；Pg 'is hydrogen or a carboxy protecting group. When Pg is a carboxy protecting group, it is selected from -DMB (2,4-dimethoxybenzyl), -Bn (benzyl), -Allyl (allyl),- PfP (pentafluorophenyl), -Me (methyl), -PMB (p-methylbenzyl), -EME (methoxyethoxymethyl) or t-Boc (tert-butoxycarbonyl);

Pg ₁’、Pg ₂’和Pg ₃’为氢或羟基保护基，当Pg ₁、Pg ₂和Pg ₃为羟基保护基时，各自独立的选自-CH ₃(甲基)、-C(CH ₃) ₃(叔丁基)、-CPh ₃(三苯基)、-CH ₂Ph(苄醚基)、-CH ₂OCH ₃(甲氧基甲基)、-Si(CH ₃) ₃(三甲基硅烷基)、-THP(四氢呋喃基)、-SiMe ₂(t-Bu)(叔丁基二甲硅烷基)、-Ac(乙酰基)或-COPh(苯甲酰基)； Pg ₁ ′, Pg ₂ ′ and Pg ₃ ′ are hydrogen or hydroxy protecting groups. When Pg ₁ , Pg ₂ and Pg ₃ are hydroxy protecting groups, each is independently selected from the group consisting of -CH ₃ (methyl), -C (CH ₃ ) ₃ (tert-butyl), -CPh ₃ (triphenyl), -CH ₂ Ph (benzyl ether), -CH ₂ OCH ₃ (methoxymethyl), -Si (CH ₃ ) ₃ (tri (Methylsilyl), -THP (tetrahydrofuryl), -SiMe ₂ (t-Bu) (t-butyldisilyl), -Ac (acetyl) or -COPh (benzoyl);

n1为0、1、2、3或4的整数；且n1 is an integer of 0, 1, 2, 3, or 4; and

x为0、1、2或3的整数。x is an integer of 0, 1, 2 or 3.

本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中所述的G选自以下JAK抑制剂：The present invention also relates to a preferred embodiment, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the G is selected from the following JAK inhibitors:

其中，SHR0302为

Tofacitinib为

Among them, SHR0302 is

Tofacitinib is

本发明还涉及一个优选方案，任一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，The present invention also relates to a preferred embodiment, each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof described in any one of the features,

R ₁选自氢、卤素、氰基、硝基、氨基、C _1-6烷基、C _1-6卤代烷基、C _1-6烷氧基、C _1-6卤代烷氧基； R _{1 is} selected from hydrogen, halogen, cyano, nitro, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy;

R ₂、R ₃各自独立的选自C _1-6烷基或C _1-6卤代烷基。 R ₂ and R ₃ are each independently selected from a C _1-6 alkyl group or a C _1-6 haloalkyl group.

本发明还涉及一种制备所述的通式(VII)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，The present invention also relates to a method for preparing the compound represented by the general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,

通式(VII-1)脱保护，得到通式(VII)所示化合物或其立体异构体及其药学上可接受盐；Deprotection of general formula (VII-1) to obtain a compound represented by general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

其中：among them:

环R ₁～R ₃、Pg、Pg ₁～Pg ₃和x如通式(I)所述。 The rings R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x are as described in the general formula (I).

本发明还涉及一种制备所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，The invention also relates to a method for preparing the compound represented by the general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,

通式(VI-1)与通式(VII-2)反应，得到通式(VI)所示化合物或其立体异构体及其药学上可接受盐；Reacting the general formula (VI-1) with the general formula (VII-2) to obtain a compound represented by the general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

其中：among them:

环R ₁～R ₃、R、Pg ₁～Pg ₃和x如通式(I)所述。 The rings R ₁ to R ₃ , R, Pg ₁ to Pg ₃ and x are as described in the general formula (I).

本发明还涉及一种制备所述的通式(VI-2)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，The present invention also relates to a method for preparing the compound represented by the general formula (VI-2) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,

SHR-0302与通式(IX)反应，得到通式(VI-2)所示化合物或其立体异构体及其药学上可接受盐；SHR-0302 reacts with general formula (IX) to obtain a compound represented by general formula (VI-2) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

其中：among them:

X选自卤素。X is selected from halogen.

本发明还涉及一种制备通式(VII)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：The invention also relates to a method for preparing a compound represented by the general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:

本发明还涉及一种制备通式(IX)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：The invention also relates to a method for preparing a compound represented by the general formula (IX) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:

本发明还涉及一种药用组合物，其包括治疗有效剂量的任一项所示的通式 (I)化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention also relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmacological agents. Acceptable carrier, diluent or excipient.

本发明还涉及所述的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备JAK抑制剂药物中的应用，该应用包含JAK抑制剂中含有葡糖苷酸的前药，所述前药在所述应用中通过β-葡糖苷酸酶裂解而释放出JAK抑制剂，优选JAK1、JAK2、JAK3抑制剂。The invention also relates to the use of the compound of the general formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the use of the pharmaceutical composition in the preparation of a JAK inhibitor medicament, the application comprising JAK inhibition The agent contains a glucuronide prodrug, which in the application releases a JAK inhibitor, preferably a JAK1, JAK2, JAK3 inhibitor, by cleavage by β-glucuronidase.

本发明还涉及所述的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备含有葡糖苷酸衍生物JAK抑制剂前药的药物中的应用。The invention also relates to the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for preparing a medicine containing a glucuronide derivative JAK inhibitor prodrug Application.

本发明还涉及所述的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治疗炎症性疾病和肿瘤疾病相关药物中的应用。The invention also relates to the use of the compound of general formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a medicament for treating inflammatory diseases and tumor diseases.

本发明还涉及一种治疗炎症性疾病的方法和一种***疾病的方法，其包括向患者施用治疗有效剂量的药物组合物。The invention also relates to a method for treating inflammatory diseases and a method for treating tumor diseases, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical composition.

以上所述的炎症性疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)，所述的肿瘤性疾病选自骨髓纤维化、真性红细胞增多症及原发性血小板增多症、性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)，其中胃肠发炎疾病是慢性肠道炎症性疾病，进一步优选溃疡性结肠炎和克罗恩氏病。The inflammatory diseases mentioned above are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the tumor diseases are selected from bone marrow fibrosis and true disease. Polycythemia and primary thrombocytosis, myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ductal carcinoma of the breast, and non-small cell lung cancer (NSCLC), of which gastrointestinal inflammation is chronic intestinal For inflammatory diseases, ulcerative colitis and Crohn's disease are more preferred.

发明的详细说明Detailed description of the invention

除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.

术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、 3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms Alkyl, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Amyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Methyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, methyl, ethyl, isopropyl, tert-butyl, haloalkyl are preferred in the present invention , Deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH ₂-、“亚乙基”指-(CH ₂) ₂-、“亚丙基”指-(CH ₂) ₃-、“亚丁基”指-(CH ₂) ₄-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。 The term "alkylene" means that a hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH _2- , "ethylene" means-(CH ₂ ) _2- , "propylene" Means-(CH ₂ ) _3- , "butylene" means-(CH ₂ ) _4- , and the like. The term "alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.

术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基，更优选环丙基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 8 Carbon atoms, most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclocycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl base.

术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group that shares one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings have complete conjugation. Π electronic system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bisspirocycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：Spirocycloalkyl which also contains a single spirocycloalkyl and a heterocycloalkyl spiro atom, non-limiting examples include:

术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5- to 20-membered, each ring in the system that shares an adjacent pair of carbon atoms with other rings in the system. A full-carbon polycyclic group in which one or more rings may contain one or Multiple double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate π electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthalene Radical, benzocycloheptyl and the like. A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.

术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) _m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括氧杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选氧杂环丁基、四氢呋喃基、吡唑烷基、吗啉基、哌嗪基和吡喃基。更优选氧杂环丁基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of _m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, di Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl , Piperazinyl and pyranyl. More preferred is oxetanyl. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclic groups; the involved spiro, fused, and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further ring-connected to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

术语“螺杂环基”指3至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) _m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclyl" refers to a 3- to 20-membered monocyclic polycyclic heterocyclic group that shares one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spiroheterocyclyl is divided into monospiroheterocyclyl, bisspiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bisspiroheterocyclyl. More preferred are 3-membered / 5-membered, 4-membered 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) _m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/5元、4元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, but none of the rings have a completely conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) _m (where m is an integer from 0 to 2), and the remaining rings Atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 4-membered 5-membered, or 5-membered / 6-membered Bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) _m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a total A y-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls include:

所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

等。

Wait.

杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.

术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。An aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.

术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为***基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有选***基、吡咯基、噻吩基、噻唑基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.

术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.

“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclothio Radical, carboxyl or carboxylate.

“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" means (CH≡C-), wherein the alkynyl may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate.

“羟基”指-OH基团。"Hydroxy" refers to the -OH group.

“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.

“氨基”指-NH ₂。 "Amino" means -NH _2.

“氰基”指-CN。"Cyano" refers to -CN.

“硝基”指-NO ₂。 "Nitro" refers to -NO _2.

“羧基”指-C(O)OH。"Carboxy" refers to -C (O) OH.

“THF”指四氢呋喃。"THF" means tetrahydrofuran.

“EtOAc”指乙酸乙酯。"EtOAc" means ethyl acetate.

“MeOH”指甲醇。"MeOH" means methanol.

“DCM”指二氯甲烷。"DCM" means dichloromethane.

“DMF”指N、N-二甲基甲酰胺。"DMF" refers to N, N-dimethylformamide.

“DIPEA”指二异丙基乙胺。"DIPEA" means diisopropylethylamine.

“TFA”指三氟乙酸。"TFA" means trifluoroacetic acid.

“MeCN”指乙晴。"MeCN" means Yiqing.

“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N, N-dimethylacetamide.

“Et ₂O”指***。 "Et ₂ O" refers to diethyl ether.

“DCE”指1,2二氯乙烷。"DCE" refers to 1,2-dichloroethane.

“DIPEA”指N，N-二异丙基乙胺。"DIPEA" refers to N, N-diisopropylethylamine.

“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.

“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.

“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.

“Pd ₂(dba) ₃”指三(二亚苄基丙酮)二钯。 "Pd ₂ (dba) ₃ " refers to tris (dibenzylideneacetone) dipalladium.

“Dppf”指1,1’-双二苯基膦二茂铁。"Dppf" refers to 1,1'-bisdiphenylphosphine ferrocene.

“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.

“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.

“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamine.

“MeLi”指甲基锂。"MeLi" means methyl lithium.

“n-BuLi”指正丁基锂。"N-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃”指三乙酰氧基硼氢化钠。 "NaBH (OAc) ₃ " refers to sodium triacetoxyborohydride.

“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, or C" and other terms all express the same Meaning, meaning that X can be any one or several of A, B, and C.

本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atom according to the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the compound of the embodiment according to the present invention may also be replaced by a deuterium atom.

“立体异构”包含几何异构(顺反异构)、旋光异构、构象异构三类。"Stereoisomerism" includes three types of geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "an heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .

“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.

具体实施方式detailed description

以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below with reference to examples, but these examples do not limit the scope of the present invention.

实施例Examples

本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d ₆)，氘代甲醇(CD ₃OD)和氘代氯仿(CDCl ₃)，内标为四甲基硅烷(TMS)。 The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ). The internal standard was four. Methylsilane (TMS).

液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. For HPLC measurement, an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 × 4.6 mm column) were used.

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications adopted by TLC are 0.15mm ～ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ～ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.

在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.

实施例1Example 1

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并 [2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro -2H-pyran-2-carboxylic acid

第一步：(2S,3R,4S,5S,6S)-2-(4-甲酰基-2-硝基苯氧基)-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备First step: (2S, 3R, 4S, 5S, 6S) -2- (4-formyl-2-nitrophenoxy) -6- (methyl ester) tetrahydro-2H-pyran-3, Preparation of 4,5-triyltriacetate

往(2R,3R,4S,5S,6S)-2-溴-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(12.5g,31.5mmol)的乙腈溶液(200mL)中依次加入4-羟基-3-硝基苯(甲)醛(5.16g，30.9mmol)，Ag ₂O(9.30g,40.1mmol)，然后避光在室温下搅拌过夜。用硅藻土过滤除去不溶物，滤液浓缩，柱层析(EA:PE从0到1:1)得到标题化合物淡黄色固体11.8g，收率：79％。 To (2R, 3R, 4S, 5S, 6S) -2-bromo-6- (methyl ester) tetrahydro-2H-pyran-3,4,5-triyltriacetate (12.5g, 31.5mmol ) To an acetonitrile solution (200 mL), and 4-hydroxy-3-nitrobenzene (m) aldehyde (5.16 g, 30.9 mmol), Ag ₂ O (9.30 g, 40.1 mmol) were sequentially added, and then stirred at room temperature in the dark overnight. . The insoluble matter was removed by filtration through Celite, the filtrate was concentrated, and column chromatography (EA: PE from 0 to 1: 1) gave 11.8 g of the title compound as a pale yellow solid, yield: 79%.

¹H NMR(400MHz,CDCl ₃):δ2.05(s,3H),2.08(s,3H),2.14(s,3H),3.71(s,3H),4.32(d,J＝8.0Hz,1H),5.28-5.45(m,4H),7.51(d,J＝8.0Hz,1H),8.10(d,J＝8.0Hz,1H),8.32(s,1H),9.98(s,1H). ¹ H NMR (400MHz, CDCl ₃ ): δ 2.05 (s, 3H), 2.08 (s, 3H), 2.14 (s, 3H), 3.71 (s, 3H), 4.32 (d, J = 8.0Hz, 1H ), 5.28-5.45 (m, 4H), 7.51 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 9.98 (s, 1H).

第二步：(2S,3R,4S,5S,6S)-2-(4-(羟甲基)-2-硝基苯氧基)-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备Second step: (2S, 3R, 4S, 5S, 6S) -2- (4- (hydroxymethyl) -2-nitrophenoxy) -6- (methyl ester) tetrahydro-2H-pyran -3,4,5-Triyl triacetate

0℃下，往(2S,3R,4S,5S,6S)-2-(4-甲酰基-2-硝基苯氧基)-6-(甲酯基)四氢-2H- 吡喃-3,4,5-三基三乙酸酯(11.7g,24.2mmol)的DCM(110mL)和异丙醇(22mL)的混合溶液中，分三批加入NaBH ₄(550mg,14.5mmol)，然后继续在该温度下搅拌90分钟。加入冰水，分出有机相。水相用DCM萃取两次。合并有机相，用饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩，柱层析得到标题化合物8.0g，收率：68％。 At 0 ° C, (2S, 3R, 4S, 5S, 6S) -2- (4-formyl-2-nitrophenoxy) -6- (methyl ester) tetrahydro-2H-pyran-3 , 4,5-triyl triacetate (11.7 g, 24.2 mmol) in a mixed solution of DCM (110 mL) and isopropanol (22 mL), add NaBH ₄ (550 mg, 14.5 mmol) in three portions, and then continue Stir at this temperature for 90 minutes. Ice water was added and the organic phase was separated. The aqueous phase was extracted twice with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 8.0 g of the title compound. Yield: 68%.

¹H NMR(400MHz,CDCl ₃):δ2.04(s,3H),2.06(s,3H),2.12(s,3H),3.75(s,3H),4.20(d,J＝8.0Hz,1H),4.72(s,2H),5.19-5.38(m,4H),7.37(d,J＝8.0Hz,1H),7.75(dd,J＝8.0,2.0Hz,1H),7.81(d,J＝2.0Hz,1H). ¹ H NMR (400MHz, CDCl ₃ ): δ 2.04 (s, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 3.75 (s, 3H), 4.20 (d, J = 8.0Hz, 1H ), 4.72 (s, 2H), 5.19-5.38 (m, 4H), 7.37 (d, J = 8.0Hz, 1H), 7.75 (dd, J = 8.0, 2.0Hz, 1H), 7.81 (d, J = 2.0Hz, 1H).

第三步：(2S,3S,4S,5R,6S)-2-(甲酯基)-6-(4-((((2-(甲基氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备The third step: (2S, 3S, 4S, 5R, 6S) -2- (methyl ester) -6- (4-((((2- (methylamino) ethyl) carbamoyl) oxo) Preparation of methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyltriacetate

冰水浴下，往(2S,3R,4S,5S,6S)-2-(4-(羟甲基)-2-硝基苯氧基)-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(2.5g,5.15mmol)的DCM溶液(30mL)中加入N,N'-羰基二咪唑(CDI)(1.08g，6.70mmol)，然后在室温下搅拌3小时，TLC监测反应完全。In an ice water bath, go to (2S, 3R, 4S, 5S, 6S) -2- (4- (hydroxymethyl) -2-nitrophenoxy) -6- (methyl ester) tetrahydro-2H-pyridine N, N'-carbonyldiimidazole (CDI) (1.08 g, 6.70 mmol) was added to a DCM solution (30 mL) of tris-3,4,5-triyl triacetate (2.5 g, 5.15 mmol), and then After stirring at room temperature for 3 hours, the reaction was monitored by TLC for completion.

另在一圆底瓶中，加入N ₁,N ₂-二甲基乙烷-1,2-二胺(1.58g，18.0mmol)，DCM(20mL)，冰水浴下，一边搅拌，一边缓慢滴加入乙酸(1.08g，18.0mmol)，然后再缓慢滴加入上一步中间体的反应液。滴加完毕，在室温下搅拌3小时。加入冰水，分出有机相，有机相干燥后置于0-4℃冰箱中待用。 In a round-bottomed flask, add N ₁ , N ₂ -dimethylethane-1,2-diamine (1.58 g, 18.0 mmol), DCM (20 mL), and drop slowly while stirring in an ice-water bath. Add acetic acid (1.08 g, 18.0 mmol), and then slowly dropwise add the reaction solution of the previous intermediate. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours. Ice water was added to separate the organic phase. The organic phase was dried and placed in a refrigerator at 0-4 ° C until use.

MS m/z(ESI):600.2[M+H] ⁺. MS m / z (ESI): 600.2 [M + H] ⁺ .

第四步：(2S,3R,4S,5S,6S)-2-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备The fourth step: (2S, 3R, 4S, 5S, 6S) -2- (4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy- 1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -6- (methyl ester ) Preparation of tetrahydro-2H-pyran-3,4,5-triyl triacetate

冰水浴下，往对硝基苯基氯甲酸酯(190mg,0.94mmol)的乙腈溶液(7mL)中加入(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺(320mg，0.772mmol)，然后缓慢滴加入DIPEA(0.181mL，1.10mmol)，加毕，缓慢升至室温，并在室温下搅拌4小时。然后用冰水浴冷却后，缓慢滴加入(2S,3S,4S,5R,6S)-2-(甲酯基)-6-(4-((((2-(甲基氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的DCM溶液(7.4mL，约0.772mmol)。滴加完毕，缓慢升至室温，并在室温下继续搅拌1小时。用乙酸淬灭，再加入水和DCM，分出有机相，有机相用无水硫酸钠干燥，浓缩，柱层析，得到标题化合物290mg，收率：36％。To an acetonitrile solution (7 mL) of p-nitrophenyl chloroformate (190 mg, 0.94 mmol) in an ice-water bath, (3aR, 5s, 6aS) -N- (3-methoxy-1,2,4 -Thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) hexahydrocyclopentadieno [c] pyrrole-2 (1H ) -Formamide (320 mg, 0.772 mmol), then DIPEA (0.181 mL, 1.10 mmol) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature and stirred at room temperature for 4 hours. After cooling with an ice water bath, (2S, 3S, 4S, 5R, 6S) -2- (methylmethyl) -6- (4-((((2- (methylamino) ethyl) amino) Formyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate in DCM (7.4 mL, about 0.772 mmol). After the dropwise addition was completed, the temperature was slowly raised to room temperature, and stirring was continued at room temperature for 1 hour. It was quenched with acetic acid, and water and DCM were added to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound (290 mg, yield: 36%).

MS m/z(ESI):1040.3[M+H] ⁺. MS m / z (ESI): 1040.3 [M + H] ⁺ .

第五步：(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸的制备Step 5: (2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-((((2- (4-(((3aR, 5s, 6aS) -2 -((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino)- N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy ) Tetrahydro-2H-pyran-2-carboxylic acid

冰水浴下，往(2S,3R,4S,5S,6S)-2-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(50mg，0.048mmol)的THF溶液(2mL)中滴加入LiOH水溶液(1M,0.19mL)，然后在该温度下搅拌2小时，加入醋酸(0.2mL)，减压浓缩至干，用反向制备柱纯化得到标题化合物24mg，收率：56％。In an ice water bath, go to (2S, 3R, 4S, 5S, 6S) -2- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy -1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrole ([2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -6- (methyl ester Lithium) tetrahydro-2H-pyran-3,4,5-triyl triacetate (50 mg, 0.048 mmol) in a THF solution (2 mL) was added dropwise to an aqueous LiOH solution (1 M, 0.19 mL), and then at this temperature After stirring for 2 hours, acetic acid (0.2 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by a reverse preparation column to obtain 24 mg of the title compound. Yield: 56%.

¹H NMR(400MHz,DMSO-d ⁶)δ1.84(m,4H),2.42-2.45(m,6H),2.46-2.56(m,1H),2.61-3.13(m,12H),3.44-3.68(m,5H),3.76-3.94(m,4H),4.51-5.72(m,6H),6.67(s,1H),6.96-7.03(m,1H),7.31-7.38(m,1H),7.56-7.62(m,1H),7.81(s,1H),8.07-8.10(m,1H),11.55(s,1H)； ¹ H NMR (400MHz, DMSO-d ⁶ ) δ1.84 (m, 4H), 2.42-2.45 (m, 6H), 2.46-2.56 (m, 1H), 2.61-3.13 (m, 12H), 3.44-3.68 (m, 5H), 3.76-3.94 (m, 4H), 4.51-5.72 (m, 6H), 6.67 (s, 1H), 6.96-7.03 (m, 1H), 7.31-7.38 (m, 1H), 7.56 -7.62 (m, 1H), 7.81 (s, 1H), 8.07-8.10 (m, 1H), 11.55 (s, 1H)

¹³C NMR(100MHz,DMSO-d ⁶)δ31.88,34.49,52.67,55.48,56.35,65.22,71.66,73.26,75.83,76.37,100.48,102.91,104.52,117.47,124.49,131.61,133.88,140.39,149.19,150.80,152.35,152.57,153.25,157.57,167.79,170.44,178.41(代表性 ¹³C信号)； ¹³ C NMR (100MHz, DMSO-d ⁶ ) , 150.80, 152.35, 152.57, 153.25, 157.57, 167.79, 170.44, 178.41 (representative ¹³ C signals);

MS m/z(ESI):900.3[M+H] ⁺. MS m / z (ESI): 900.3 [M + H] ⁺ .

实施例2Example 2

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy- 1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- 2H-pyran-2-carboxylic acid

(2S,3R,4S,5S,6S)-2-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-6-(甲酯基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(50mg，0.048mmol)、Pd(OH) ₂/C(20wt％,10mg)混合于乙醇(2mL)中，在氢气氛中，常温常压，搅拌3天，用硅藻土过滤除去不溶物，滤液浓缩至干。 (2S, 3R, 4S, 5S, 6S) -2- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2, 4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3 -d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -6- (methyl ester) tetrahydro- 2H-pyran-3,4,5-triyl triacetate (50 mg, 0.048 mmol), Pd (OH) ₂ / C (20 wt%, 10 mg) were mixed in ethanol (2 mL), and in a hydrogen atmosphere, Stir for 3 days at room temperature and pressure, filter through celite to remove insolubles, and concentrate the filtrate to dryness.

往上述残余物中，加入MeOH(1mL)，THF(1mL)和水(1mL)的混合溶剂溶解，然后加入一水氢氧化锂固体(11mg，0.27mmol)，在室温下搅拌1小时，加入乙酸淬灭，减压浓缩至干，用反向制备柱纯化得到标题化合物13mg，收率：31％。To the above residue, a mixed solvent of MeOH (1 mL), THF (1 mL) and water (1 mL) was added to dissolve, and then lithium hydroxide monohydrate solid (11 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added It was quenched, concentrated to dryness under reduced pressure, and purified by a reverse preparation column to obtain 13 mg of the title compound in a yield of 31%.

MS m/z(ESI):870.3[M+H] ⁺. MS m / z (ESI): 870.3 [M + H] ⁺ .

实施例3Example 3

(2S,3S,4S,5R,6S)-3,4,5-三乙酰氧基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-triacetoxy-6- (4-((((2- (4-(((3aR, 5s, 6aS) -2- ( (3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N- Methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) tetrahydro-2H- Pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三乙酰氧基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-triacetoxy-6- (4-((((2- (4-(((3aR, 5s, 6aS) -2- ( (3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N- Methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) tetrahydro-2H- For the preparation of pyran-2-carboxylic acid, refer to Example 1.

MS m/z(ESI):981.3[M+H] ⁺. MS m / z (ESI): 981.3 [M + H] ⁺ .

实施例4Example 4

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) tetrahydro-2H-pyran -2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) tetrahydro-2H-pyran For the preparation of -2-carboxylic acid, refer to Example 1.

MS m/z(ESI):855.3[M+H] ⁺. MS m / z (ESI): 855.3 [M + H] ⁺ .

实施例5Example 5

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并 [2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-甲基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-methylphenoxy) tetrahydro -2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-甲基苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-methylphenoxy) tetrahydro Preparation of -2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):869.3[M+H] ⁺. MS m / z (ESI): 869.3 [M + H] ⁺ .

实施例6Example 6

(2S,3S,4S,5R,6S)-6-(2-氯-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-chloro-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy- 1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- 2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氯-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (2-chloro-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy- 1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- For the preparation of 2H-pyran-2-carboxylic acid, refer to Example 1.

MS m/z(ESI):889.3[M+H] ⁺. MS m / z (ESI): 889.3 [M + H] ⁺ .

实施例7Example 7

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(2-甲氧基-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (2-methoxy-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino ) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) tetra Hydrogen-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(2-甲氧基-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (2-methoxy-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino ) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) tetra The preparation of hydrogen-2H-pyran-2-carboxylic acid is described in Example 1.

MS m/z(ESI):885.3[M+H] ⁺. MS m / z (ESI): 885.3 [M + H] ⁺ .

实施例8Example 8

(2S,3S,4S,5R,6S)-6-(2-氟-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-fluoro-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy- 1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- 2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氟-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (2-fluoro-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy- 1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- For the preparation of 2H-pyran-2-carboxylic acid, refer to Example 1.

MS m/z(ESI):873.3[M+H] ⁺. MS m / z (ESI): 873.3 [M + H] ⁺ .

实施例9Example 9

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-(三氟甲基)苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2- (trifluoromethyl) phenoxy ) Tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-(三氟甲基)苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2- (trifluoromethyl) phenoxy Group) Preparation of tetrahydro-2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):923.3[M+H] ⁺. MS m / z (ESI): 923.3 [M + H] ⁺ .

实施例10Example 10

(2S,3S,4S,5R,6S)-6-(2-氰基-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-cyano-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy -1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrole ([2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro -2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氰基-4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (2-cyano-4-((((2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy -1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrole ([2,3-d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro Preparation of -2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):880.3[M+H] ⁺. MS m / z (ESI): 880.3 [M + H] ⁺ .

实施例11Example 11

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基(2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酸酯3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy Substituted) benzyl (2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octa Hydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl ) (Meth) carbamate

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基(2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酸酯的制备参照实施例1。3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy Substituted) benzyl (2- (4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octa Hydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl ) (Meth) carbamate was prepared as described in Example 1.

MS m/z(ESI):886.3[M+H] ⁺. MS m / z (ESI): 886.3 [M + H] ⁺ .

实施例12Example 12

(2S,3S,4S,5R,6R)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-噻喃-2-羧酸(2S, 3S, 4S, 5R, 6R) -3,4,5-trihydroxy-6- (4-((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro -2H-thian-2-carboxylic acid

(2S,3S,4S,5R,6R)-3,4,5-三羟基-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-噻喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6R) -3,4,5-trihydroxy-6- (4-((((2- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro -2H-thiathio-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):916.3[M+H] ⁺. MS m / z (ESI): 916.3 [M + H] ⁺ .

实施例13Example 13

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((3-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)丙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((3- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) propyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro -2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((3-(4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)丙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((((3- (4-(((3aR, 5s, 6aS) -2-((3 -Methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -N-methyl -7H-pyrrolo [2,3-d] pyrimidine-7-carbooxamido) propyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro Preparation of -2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):914.3[M+H] ⁺. MS m / z (ESI): 914.3 [M + H] ⁺ .

实施例14Example 14

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-(二氟甲氧基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) (Oxo) methyl) -2- (difluoromethoxy) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-(二氟甲氧基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) Oxo) methyl) -2- (difluoromethoxy) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):819.3[M+H] ⁺. MS m / z (ESI): 819.3 [M + H] ⁺ .

实施例15Example 15

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-(三氟甲氧基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) (Oxo) methyl) -2- (trifluoromethoxy) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-(三氟甲氧基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) Oxo) methyl) -2- (trifluoromethoxy) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):837.3[M+H] ⁺. MS m / z (ESI): 837.3 [M + H] ⁺ .

实施例16Example 16

(2S,3S,4S,5R,6S)-6-(4-((((3-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)丙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-((((((3- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) propyl) (methyl) carbamoyl) (Oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((3-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)丙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-((((((3- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) propyl) (methyl) carbamoyl) Oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):812.3[M+H] ⁺. MS m / z (ESI): 812.3 [M + H] ⁺ .

实施例17Example 17

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(丙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (propyl) carbamoyl) (Oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(丙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (propyl) carbamoyl) Oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):826.3[M+H] ⁺. MS m / z (ESI): 826.3 [M + H] ⁺ .

实施例18Example 18

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-丙基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-propyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) (Oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-丙基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-propyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) Oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):826.3[M+H] ⁺. MS m / z (ESI): 826.3 [M + H] ⁺ .

实施例19Example 19

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)硫代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) (Thio) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)硫代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine Pyridin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) Refer to Example 1 for the preparation of thio) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI):814.3[M+H] ⁺. MS m / z (ESI): 814.3 [M + H] ⁺ .

实施例20Example 20

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(1-((R)-2-氰基-1-环戊基乙基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((((2- (4- (1-((R) -2-cyano-1-cyclopentylethyl ) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) oxy ) Methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(1-((R)-2-氰基-1-环戊基乙基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((((2- (4- (1-((R) -2-cyano-1-cyclopentylethyl ) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) (methyl) carbamoyl) oxy Substitution) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 2.

MS m/z(ESI):762.3[M+H] ⁺. MS m / z (ESI): 762.3 [M + H] ⁺ .

实施例21Example 21

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(1-(3-(氰基甲基)-1-(乙基磺酰)吖丁啶-3-基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (4- (1- (3- (cyanomethyl) -1--1-ethylsulfonyl ) Azetidin-3-yl) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl) ( (Methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(1-(3-(氰基甲基)-1-(乙基磺酰)吖丁啶-3-基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (4- (1- (3- (cyanomethyl) -1--1-ethylsulfonyl ) Azetidin-3-yl) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl) ( For the preparation of methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, refer to Example 2.

MS m/z(ESI):827.3[M+H] ⁺. MS m / z (ESI): 827.3 [M + H] ⁺ .

实施例22Example 22

(2S,3S,4S,5R,6S)-6-(4-((((2-(5-氨基甲酰-4-(((1R,2S,5S,7S)-5-羟基金刚烷-2-基)氨基)-N-甲基-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (5-carbamoyl-4-(((1R, 2S, 5S, 7S) -5-hydroxyadamantane- 2-yl) amino) -N-methyl-1H-pyrrolo [2,3-b] pyridine-1-carbooxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) (2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(5-氨基甲酰-4-(((1R,2S,5S,7S)-5-羟基金刚烷-2-基)氨基)-N-甲基-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (5-carbamoyl-4-(((1R, 2S, 5S, 7S) -5-hydroxyadamantane- 2-yl) amino) -N-methyl-1H-pyrrolo [2,3-b] pyridine-1-carbooxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):812.3[M+H] ⁺. MS m / z (ESI): 812.3 [M + H] ⁺ .

实施例23Example 23

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(5-氨基甲酰-4-(((1R,2S,5S,7S)-5-羟基金刚烷-2-基)氨基)-N-甲基-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (5-carbamoyl-4-(((1R, 2S, 5S, 7S) -5- Hydroxyadamantane-2-yl) amino) -N-methyl-1H-pyrrolo [2,3-b] pyridine-1-carbooxalamido) ethyl) (methyl) carbamoyl) oxo ) Methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(5-氨基甲酰-4-(((1R,2S,5S,7S)-5-羟基金刚烷-2-基)氨基)-N-甲基-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (5-carbamoyl-4-(((1R, 2S, 5S, 7S) -5- Hydroxyadamantane-2-yl) amino) -N-methyl-1H-pyrrolo [2,3-b] pyridine-1-carbooxalamido) ethyl) (methyl) carbamoyl) oxo ) Methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 2.

MS m/z(ESI):782.3[M+H] ⁺. MS m / z (ESI): 782.3 [M + H] ⁺ .

实施例24Example 24

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-((3S,4R)-1-(2-氰基乙酰基)-3-甲基-1,6-二氮杂螺[3.4]辛烷-6-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-((3S, 4R) -1- (2-cyanoacetyl) -3-methyl-1 , 6-diazaspiro [3.4] octane-6-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl) (methyl ) Carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-((3S,4R)-1-(2-氰基乙酰基)-3-甲基-1,6-二氮杂螺[3.4]辛烷-6-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4-((3S, 4R) -1- (2-cyanoacetyl) -3-methyl-1 , 6-diazaspiro [3.4] octane-6-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl) (methyl ) Preparation of carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):796.3[M+H] ⁺. MS m / z (ESI): 796.3 [M + H] ⁺ .

实施例25Example 25

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-((3S,4R)-1-(2-氰基乙酰基)-3-甲基-1,6-二氮杂螺[3.4]辛烷-6-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (4-((3S, 4R) -1- (2-cyanoacetyl) -3- Methyl-1,6-diazaspiro [3.4] octane-6-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl ) (Meth) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-((3S,4R)-1-(2-氰基乙酰基)-3-甲基-1,6-二氮杂螺[3.4]辛烷-6-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (4-((3S, 4R) -1- (2-cyanoacetyl) -3- Methyl-1,6-diazaspiro [3.4] octane-6-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl ) (Meth) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 2.

MS m/z(ESI):766.3[M+H] ⁺. MS m / z (ESI): 766.3 [M + H] ⁺ .

实施例26Example 26

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-(((甲基(2-(N-甲基-4-(甲基((1s,3s)-3-(丙基磺酰氨基)环丁基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((methyl (2- (N-methyl-4- (methyl ((1s, 3s ) -3- (propylsulfonylamino) cyclobutyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) carbamoyl) oxo) formyl ) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-(((甲基(2-(N-甲基-4-(甲基((1s,3s)-3-(丙基磺酰氨基)环丁基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((methyl (2- (N-methyl-4- (methyl ((1s, 3s ) -3- (propylsulfonylamino) cyclobutyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) carbamoyl) oxo) formyl The preparation of the group) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid is described in Example 1.

MS m/z(ESI):809.3[M+H] ⁺. MS m / z (ESI): 809.3 [M + H] ⁺ .

实施例27Example 27

(2S,3S,4S,5R,6S)-6-(2-氨基-4-(((甲基(2-(N-甲基-4-(甲基((1s,3s)-3-(丙基磺酰氨基)环丁基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((methyl (2- (N-methyl-4- (methyl ((1s, 3s) -3- ( Propylsulfonylamino) cyclobutyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) carbamoyl) oxo) methyl) phenoxy ) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-(((甲基(2-(N-甲基-4-(甲基((1s,3s)-3-(丙基磺酰氨基)环丁基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((methyl (2- (N-methyl-4- (methyl ((1s, 3s) -3- ( Propylsulfonylamino) cyclobutyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-7-carbosalylamino) ethyl) carbamoyl) oxo) methyl) phenoxy ) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 2.

MS m/z(ESI):779.3[M+H] ⁺. MS m / z (ESI): 779.3 [M + H] ⁺ .

实施例28Example 28

(2S,3S,4S,5R,6S)-6-(4-((((2-(8-((3R,4S)-4-乙基-1-((2,2,2-三氟乙基)氨基甲酰)吡咯烷-3-基)-N-甲基-3H-咪唑并[1,2-a]吡咯并[2,3-e]吡嗪-3-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (8-((3R, 4S) -4-ethyl-1-((2,2,2-trifluoro Ethyl) carbamoyl) pyrrolidin-3-yl) -N-methyl-3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazine-3-carboxamidoamino ) Ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(8-((3R,4S)-4-乙基-1-((2,2,2-三氟乙基)氨基甲酰)吡咯烷-3-基)-N-甲基-3H-咪唑并[1,2-a]吡咯并[2,3-e]吡嗪-3-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (8-((3R, 4S) -4-ethyl-1-((2,2,2-trifluoro Ethyl) carbamoyl) pyrrolidin-3-yl) -N-methyl-3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazine-3-carboxamidoamino ) Ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):866.3[M+H] ⁺. MS m / z (ESI): 866.3 [M + H] ⁺ .

实施例29Example 29

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(8-((3R,4S)-4-乙基-1-((2,2,2-三氟乙基)氨基甲酰)吡咯烷-3-基)-N-甲基-3H-咪唑并[1,2-a]吡咯并[2,3-e]吡嗪-3-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (8-((3R, 4S) -4-ethyl-1-((2,2, 2-trifluoroethyl) carbamoyl) pyrrolidin-3-yl) -N-methyl-3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazine-3-carbon Weedylamino) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(8-((3R,4S)-4-乙基-1-((2,2,2-三氟乙基)氨基甲酰)吡咯烷-3-基)-N-甲基-3H-咪唑并[1,2-a]吡咯并[2,3-e]吡嗪-3-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (8-((3R, 4S) -4-ethyl-1-((2,2, 2-trifluoroethyl) carbamoyl) pyrrolidin-3-yl) -N-methyl-3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazine-3-carbon Weanylamino) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid实施例 2。 Example 2.

MS m/z(ESI):836.3[M+H] ⁺. MS m / z (ESI): 836.3 [M + H] ⁺ .

实施例30Example 30

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(1-(3-(氰基甲基)-1-(1-(3-氟-2-(三氟甲基)异尼古丁酰)哌啶-4-基)吖丁啶-3-基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4- (1- (3- (cyanomethyl) -1- (1- (3-fluoro-2 -(Trifluoromethyl) isonicotyryl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3 -d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro -2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(1-(3-(氰基甲基)-1-(1-(3-氟-2-(三氟甲基)异尼古丁酰)哌啶-4-基)吖丁啶-3-基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (4- (1- (3- (cyanomethyl) -1- (1- (3-fluoro-2 -(Trifluoromethyl) isonicotyryl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3 -d] pyrimidine-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro Preparation of -2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):1039.3[M+H] ⁺. MS m / z (ESI): 1039.3 [M + H] ⁺ .

实施例31Example 31

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(1-(3-(氰基甲基)-1-(1-(3-氟-2-(三氟甲基)异尼古丁酰)哌啶-4-基)吖丁啶-3-基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H- 吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((((2- (4- (1- (3- (cyanomethyl) -1--1- (1- (3 -Fluoro-2- (trifluoromethyl) isonicotyryl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- 2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(4-(1-(3-(氰基甲基)-1-(1-(3-氟-2-(三氟甲基)异尼古丁酰)哌啶-4-基)吖丁啶-3-基)-1H-吡唑-4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((((2- (4- (1- (3- (cyanomethyl) -1--1- (1- (3 -Fluoro-2- (trifluoromethyl) isonicotyryl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro- For the preparation of 2H-pyran-2-carboxylic acid, refer to Example 2.

MS m/z(ESI):1009.3[M+H] ⁺. MS m / z (ESI): 1009.3 [M + H] ⁺ .

实施例32Example 32

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-(((甲基(2-(N-甲基-3-(4-(((R)-2-甲基-1-羰基-1-((2,2,2-三氟乙基)氨基)丁烷-2-基)氨基)嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((methyl (2- (N-methyl-3- (4-(((R) 2-methyl-1-carbonyl-1-((2,2,2-trifluoroethyl) amino) butane-2-yl) amino) pyrimidin-2-yl) -1H-pyrrolo [2, 3-b) pyridine-1-carbooxamido) ethyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-(((甲基(2-(N-甲基-3-(4-(((R)-2-甲基-1-羰基-1-((2,2,2-三氟乙基)氨基)丁烷-2-基)氨基)嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((methyl (2- (N-methyl-3- (4-(((R) 2-methyl-1-carbonyl-1-((2,2,2-trifluoroethyl) amino) butane-2-yl) amino) pyrimidin-2-yl) -1H-pyrrolo [2, 3-b) pyridine-1-carbooxamido) ethyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):778.3[M+H] ⁺. MS m / z (ESI): 778.3 [M + H] ⁺ .

实施例33Example 33

(2S,3S,4S,5R,6S)-6-(2-氨基-4-(((甲基(2-(N-甲基-3-(4-(((R)-2-甲基-1-羰基-1-((2,2,2-三氟乙基)氨基)丁烷-2-基)氨基)嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((methyl (2- (N-methyl-3- (4-(((R) -2-methyl -1-carbonyl-1-((2,2,2-trifluoroethyl) amino) butane-2-yl) amino) pyrimidin-2-yl) -1H-pyrrolo [2,3-b] pyridine 1-Carbonoxalamido) ethyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-(((甲基(2-(N-甲基-3-(4-(((R)-2-甲基-1-羰基-1-((2,2,2-三氟乙基)氨基)丁烷-2-基)氨基)嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-1-碳杂草酰氨基)乙基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-(((methyl (2- (N-methyl-3- (4-(((R) -2-methyl -1-carbonyl-1-((2,2,2-trifluoroethyl) amino) butane-2-yl) amino) pyrimidin-2-yl) -1H-pyrrolo [2,3-b] pyridine 1-Carbonoxalamido) ethyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid实施例 2。 Example 2.

MS m/z(ESI):848.3[M+H] ⁺. MS m / z (ESI): 848.3 [M + H] ⁺ .

实施例34Example 34

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-丙烯酰-6-甲基哌啶-3-基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-((((2- (4-(((3R, 6S) -1-acryloyl-6-methylpiperidin-3-yl) Amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitro Phenylphenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-丙烯酰-6-甲基哌啶-3-基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-((((2- (4-(((3R, 6S) -1-acryloyl-6-methylpiperidin-3-yl) Amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitro Phenylphenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid was prepared as described in Example 1.

MS m/z(ESI):771.3[M+H] ⁺. MS m / z (ESI): 771.3 [M + H] ⁺ .

实施例35Example 35

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-丙烯酰-6-甲基哌啶-3-基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-氨基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-((((2- (4-(((3R, 6S) -1-acryloyl-6-methylpiperidin-3-yl) (Amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-amino (Phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-丙烯酰-6-甲基哌啶-3-基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-氨基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (4-((((2- (4-(((3R, 6S) -1-acryloyl-6-methylpiperidin-3-yl) (Amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-amino Reference Example 2 for the preparation of phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI):741.3[M+H] ⁺. MS m / z (ESI): 741.3 [M + H] ⁺ .

实施例36Example 36

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-甲基-7-((R)-2-(4-甲基哌嗪-1-基)丙酰氨基)-1H-吲哚-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-((((2- (3- (2-((3-methoxy-1-methyl -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N-methyl-7-((R) -2- (4-methylpiperazin-1-yl) propionamido)- 1H-indole-1-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxyl acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-((((2-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-甲基-7-((R)-2-(4-甲基哌嗪-1-基)丙酰氨基)-1H-吲哚-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-((((2- (3- (2-((3-methoxy-1-methyl -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N-methyl-7-((R) -2- (4-methylpiperazin-1-yl) propionamido)- 1H-indole-1-carbooxamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxyl For the preparation of the acid, refer to Example 1.

MS m/z(ESI):975.4[M+H] ⁺. MS m / z (ESI): 975.4 [M + H] ⁺ .

实施例37Example 37

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-甲基-7-((R)-2-(4-甲基哌嗪-1-基)丙酰氨基)-1H-吲哚-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (3- (2-((3-methoxy-1-methyl-1H-pyrazole -4-yl) amino) pyrimidin-4-yl) -N-methyl-7-((R) -2- (4-methylpiperazin-1-yl) propionamido) -1H-indole- 1-Carbonoxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-甲基-7-((R)-2-(4-甲基哌嗪-1-基)丙酰氨基)-1H-吲哚-1-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (3- (2-((3-methoxy-1-methyl-1H-pyrazole -4-yl) amino) pyrimidin-4-yl) -N-methyl-7-((R) -2- (4-methylpiperazin-1-yl) propionamido) -1H-indole- 1-Carbonoxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid The preparation is described in Example 2.

MS m/z(ESI):945.4[M+H] ⁺. MS m / z (ESI): 945.4 [M + H] ⁺ .

实施例38Example 38

(2S,3S,4S,5R,6S)-6-(4-((((2-(3-(4-((1R,5S)-8-((S)-2,2-二氟环丙烷-1-羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)嘧啶-2-基)-1-甲基-3-(1-甲基-1H-吡唑-4-基)脲基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (3- (4-((1R, 5S) -8-((S) -2,2-difluoro ring Propane-1-carbonyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) pyrimidin-2-yl) -1-methyl-3- (1-methyl-1H- Pyrazol-4-yl) ureido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H- Pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(3-(4-((1R,5S)-8-((S)-2,2-二氟环丙烷-1-羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)嘧啶-2-基)-1-甲基-3-(1-甲基-1H-吡唑-4-基)脲基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((((2- (3- (4-((1R, 5S) -8-((S) -2,2-difluoro ring Propane-1-carbonyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) pyrimidin-2-yl) -1-methyl-3- (1-methyl-1H- Pyrazol-4-yl) ureido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxytetrahydro-2H- For the preparation of pyran-2-carboxylic acid, refer to Example 1.

MS m/z(ESI):875.3[M+H] ⁺. MS m / z (ESI): 875.3 [M + H] ⁺ .

实施例39Example 39

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(3-(4-((1R,5S)-8-((S)-2,2-二氟环丙烷-1-羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)嘧啶-2-基)-1-甲基-3-(1-甲基-1H-吡唑-4-基)脲基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (3- (4-((1R, 5S) -8-((S) -2,2 -Difluorocyclopropane-1-carbonyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) pyrimidin-2-yl) -1-methyl-3- (1-methyl -1H-pyrazol-4-yl) ureido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyridine Ran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-氨基-4-((((2-(3-(4-((1R,5S)-8-((S)-2,2-二氟环丙烷-1-羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)嘧啶-2-基)-1-甲基-3-(1-甲基-1H-吡唑-4-基)脲基)乙基)(甲基)氨基甲酰)氧代)甲基)苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例2。(2S, 3S, 4S, 5R, 6S) -6- (2-amino-4-((((2- (3- (4-((1R, 5S) -8-((S) -2,2 -Difluorocyclopropane-1-carbonyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) pyrimidin-2-yl) -1-methyl-3- (1-methyl -1H-pyrazol-4-yl) ureido) ethyl) (methyl) carbamoyl) oxo) methyl) phenoxy) -3,4,5-trihydroxytetrahydro-2H-pyridine For the preparation of -2-ancarboxylic acid, refer to Example 2.

MS m/z(ESI):845.3[M+H] ⁺. MS m / z (ESI): 845.3 [M + H] ⁺ .

实施例40Example 40

(2S,3S,4S,5R,6S)-6-(4-(((4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羰基)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -6- (4-(((4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine-3- (Methyl) amino) -7H-pyrrolo [2,3-d] pyrimidine-7-carbonyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxy Tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-(((4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羰基)氧代)甲基)-2-硝基苯氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -6- (4-(((4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidine-3- (Methyl) amino) -7H-pyrrolo [2,3-d] pyrimidine-7-carbonyl) oxo) methyl) -2-nitrophenoxy) -3,4,5-trihydroxy Refer to Example 1 for the preparation of tetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI):684.2[M+H] ⁺. MS m / z (ESI): 684.2 [M + H] ⁺ .

实施例41Example 41

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸酯3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy A) benzyl 4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2 , 3-d] pyrimidine-7-carboxylic acid ester

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸酯的制备参照实施例1。3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy A) benzyl 4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2 Refer to Example 1 for the preparation of, 3-d] pyrimidine-7-carboxylic acid ester.

MS m/z(ESI):670.2[M+H] ⁺. MS m / z (ESI): 670.2 [M + H] ⁺ .

实施例42Example 42

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基(2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酸酯3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy Substituted) benzyl (2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -N- Methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxamido) ethyl) (methyl) carbamate

第一步：(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-甲酰基-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备First step: (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-formyl-2-nitrophenoxy) tetrahydro-2H-pyran- Preparation of 3,4,5-triyl triacetate

往(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-溴四氢-2H-吡喃-3,4,5-三基三乙酸酯(8.00g,19.5mmol)的乙腈溶液(140mL)里依次加入4-羟基-3-硝基苯(甲)醛(3.19g,19.1mmol)，Ag ₂O(5.75g)，然后室温下，避光，搅拌过夜。用硅藻土滤除不溶物，滤液减压浓缩有机溶剂，柱层析分离得到标题化合物9.00g，收率：95％。 To (2R, 3R, 4S, 5R, 6R) -2- (acetoxymethyl) -6-bromotetrahydro-2H-pyran-3,4,5-triyltriacetate (8.00g, 19.5 mmol) of acetonitrile solution (140 mL) was added 4-hydroxy-3-nitrobenzene (m) aldehyde (3.19 g, 19.1 mmol), Ag ₂ O (5.75 g) in order, and then stirred overnight at room temperature, protected from light. . The insoluble matter was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The organic solvent was separated by column chromatography to obtain the title compound (9.00 g, yield: 95%).

MS m/z(ESI):498.1[M+H] ⁺. MS m / z (ESI): 498.1 [M + H] ⁺ .

第二步：(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-(羟甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备Second step: (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4- (hydroxymethyl) -2-nitrophenoxy) tetrahydro-2H- Preparation of pyran-3,4,5-triyltriacetate

冰水浴下，往(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-甲酰基-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(2.00g,4.02mmol)的二氯甲烷(20mL)和异丙醇(5mL)的混合溶液里，加入NaBH ₄(91.3mg,2.41mmol)，然后继续在冰水浴下搅拌2小时。加入冰水淬灭，用二氯甲烷萃取两次，合并有机相，用饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤后浓缩有机溶剂，柱层析分离得到标题化合物1.30g,收率：65％。 Go to (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-formyl-2-nitrophenoxy) tetrahydro-2H-pyran under ice water bath -3,4,5-triyl triacetate (2.00 g, 4.02 mmol) in a mixed solution of dichloromethane (20 mL) and isopropanol (5 mL), added NaBH ₄ (91.3 mg, 2.41 mmol), Stirring was continued for 2 hours in an ice water bath. It was quenched by the addition of ice water, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, the organic phases were separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated after filtration, and the title compound was isolated by column chromatography to obtain 1.30 g, Yield: 65%.

MS m/z(ESI):500.1[M+H] ⁺. MS m / z (ESI): 500.1 [M + H] ⁺ .

第三步：(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-(((甲基(2-(甲基氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备The third step: (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-(((methyl (2- (methylamino) ethyl) carbamoyl ) Oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyltriacetate

往(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-(羟甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(637mg，1.28mmol)的二氯甲烷溶液(6mL)中加入CDI(269mg,1.66mmol)，然后在室温下搅拌2小时。To (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4- (hydroxymethyl) -2-nitrophenoxy) tetrahydro-2H-pyran- To a solution of 3,4,5-triyltriacetate (637 mg, 1.28 mmol) in dichloromethane (6 mL) was added CDI (269 mg, 1.66 mmol), followed by stirring at room temperature for 2 hours.

另一圆底瓶中，配好N1,N2-二甲基乙烷-1,2-二胺(0.490mL，4.46mmol)的二氯甲烷溶液(4mL)，在冰水浴里，一边搅拌，一边依次往该溶液里滴加入冰醋酸(0.255mL，4.46mmol)，以及上面步骤中的反应液。滴加完毕，缓慢升至室温，并在室温下搅拌3小时。In another round-bottomed flask, mix a solution of N1, N2-dimethylethane-1,2-diamine (0.490mL, 4.46mmol) in dichloromethane (4mL), and stir in an ice-water bath while stirring To this solution were sequentially added dropwise glacial acetic acid (0.255 mL, 4.46 mmol) and the reaction solution in the above step. After the dropwise addition was completed, the temperature was slowly raised to room temperature and stirred at room temperature for 3 hours.

用二氯甲烷稀释反应液，然后用饱和食盐水洗涤反应液，分离有机相并用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物255mg，收率：33％。The reaction solution was diluted with dichloromethane, and then the reaction solution was washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and the title compound was separated by column chromatography to obtain 255 mg, yield: 33%.

MS m/z(ESI):614.2[M+H] ⁺. MS m / z (ESI): 614.2 [M + H] ⁺ .

第四步：(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯的制备The fourth step: (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-((((2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbon weed Amido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate preparation

冰水浴下，往托法替尼(130mg，0.416mmol)，二(对硝基苯基)碳酸酯(139mg，0.458mmol)的乙腈溶液(5mL)里滴加入DIPEA(0.089mL，0.451mmol)，然后缓慢升至室温，并在室温下继续搅拌2小时。To a solution of tofacitinib (130 mg, 0.416 mmol), di (p-nitrophenyl) carbonate (139 mg, 0.458 mmol) in acetonitrile (5 mL) under ice-water bath was added DIPEA (0.089 mL, 0.451 mmol) dropwise. The temperature was then slowly raised to room temperature and stirring was continued at room temperature for 2 hours.

再将反应液置于冰水浴下，逐滴加入(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-(((甲基(2-(甲基氨基)乙基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(255mg，0.416mmol)的二氯甲烷溶液(2mL)，然后在室温下搅拌2小时。The reaction solution was placed in an ice-water bath, and (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-(((methyl (2- (methyl Propylamino) ethyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyltriacetate (255mg, 0.416mmol ) In dichloromethane (2 mL), and then stirred at room temperature for 2 hours.

加入冰醋酸(1mL)淬灭，用二氯甲烷稀释反应液，然后该溶液依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，有机相再用无水硫酸钠干燥，减压浓缩有机溶剂，柱层析分离得到标题化合物130mg，收率：33％。Add glacial acetic acid (1 mL) to quench, dilute the reaction solution with dichloromethane, and then the solution was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution in sequence, and the organic phase was dried over anhydrous sodium sulfate. Chromatographic separation gave 130 mg of the title compound in a yield of 33%.

MS m/z(ESI):952.4[M+H] ⁺. MS m / z (ESI): 952.4 [M + H] ⁺ .

第五步：3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基(2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酸酯的制备Step 5: 3-nitro-4-(((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 -Yl) oxo) benzyl (2- (4-(((3R, 4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino ) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carbooxalamido) ethyl) (methyl) carbamate

冰水浴下，往(2R,3R,4S,5R,6S)-2-(乙酰氧基甲基)-6-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基)乙基)(甲基)氨基甲酰)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(35mg，0.037mmol)的四氢呋喃溶液(5mL)里，滴加入LiOH.H ₂O(6.2mg,0.15mmol)的水溶液(2mL)，加毕，缓慢升至室温，再在室温下搅拌过夜。向反应液中加入两滴醋酸，减压除去有机溶剂，用二氯甲烷萃取两次。合并有机相并用无水硫酸钠干燥，减压浓缩有机溶剂，用反向制备柱分离纯化得到标题化合物9mg，收率：31％。 In an ice water bath, go to (2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -6- (4-((((2- (4-(((3R, 4R) -1 -(2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-7-carba Oxalamido) ethyl) (methyl) carbamoyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyltriacetate (35 mg, 0.037 mmol) in a tetrahydrofuran solution (5 mL) was added dropwise an aqueous solution (2 mL) of LiOH.H ₂ O (6.2 mg, 0.15 mmol). After the addition was completed, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature overnight. Two drops of acetic acid were added to the reaction solution, the organic solvent was removed under reduced pressure, and extraction was performed twice with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and separated and purified by a reverse preparation column to obtain 9 mg of the title compound. Yield: 31%.

¹H NMR(400MHz,CD ₃OD):δ1.10(d,J＝8.4Hz,3H)，1.71-2.03(m,3H),2.47(m,2H),2.85-3.56(m,20H),3.63-3.98(m,6H),6.73(s,1H),6.78(s,1H),7.74(m,1H),7.65(m,1H),8.17(m,2H),8.41(br s,1H)； ¹ H NMR (400MHz, CD ₃ OD): δ1.10 (d, J = 8.4Hz, 3H), 1.72-2.03 (m, 3H), 2.47 (m, 2H), 2.85-3.56 (m, 20H), 3.63-3.98 (m, 6H), 6.73 (s, 1H), 6.78 (s, 1H), 7.74 (m, 1H), 7.65 (m, 1H), 8.17 (m, 2H), 8.41 (br s, 1H );

MS m/z(ESI):784.2[M+H] ⁺. MS m / z (ESI): 784.2 [M + H] ⁺ .

实施例43Example 43

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-(((4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羰基)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((4-(((3aR, 5s, 6aS) -2-((3-methoxy -1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -7H-pyrrolo [2,3 -d] pyrimidine-7-carbonyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(4-(((4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羰基)氧代)甲基)-2-硝基苯氧基)四氢-2H-吡喃-2-羧酸的制备参照实施例1。(2S, 3S, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (4-(((4-(((3aR, 5s, 6aS) -2-((3-methoxy -1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentadieno [c] pyrrole-5-yl) (methyl) amino) -7H-pyrrolo [2,3 -d] Preparation of pyrimidine-7-carbonyl) oxo) methyl) -2-nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid Refer to Example 1.

MS m/z(ESI):786.2[M+H] ⁺. MS m / z (ESI): 786.2 [M + H] ⁺ .

实施例44Example 44

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸酯3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy Substituted) benzyl 4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentane Eno [c] pyrrole-5-yl) (methyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-7-carboxylic acid ester

3-硝基-4-(((2S,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧代)苯甲基4-(((3aR,5s,6aS)-2-((3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酰)八氢环戊二烯并[c]吡咯-5-基)(甲基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸酯的制备参照实施例1。3-nitro-4-((((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy Substituted) benzyl 4-(((3aR, 5s, 6aS) -2-((3-methoxy-1,2,4-thiadiazol-5-yl) carbamoyl) octahydrocyclopentane The preparation of the eno [c] pyrrolo-5-yl) (meth) amino) -7H-pyrrolo [2,3-d] pyrimidin-7-carboxylic acid ester is described in Example 1.

MS m/z(ESI):772.2[M+H] ⁺. MS m / z (ESI): 772.2 [M + H] ⁺ .

生物学测试评价Evaluation of biological tests

以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The present invention is further described below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

测试例1、本发明化合物对JAK激酶活性抑制作用的测定Test Example 1. Determination of the inhibitory effect of the compound of the present invention on the activity of JAK kinase

实验目的：该测试例的目的是测试化合物对JAK激酶活性抑制的活性。Experimental purpose: The purpose of this test case is to test the compound's inhibitory activity on JAK kinase activity.

实验仪器：laboratory apparatus:

离心机(5702R)购自Eppendorf公司；The centrifuge (5702R) was purchased from Eppendorf;

移液器购自Eppendorf或Rainin公司；Pipettes were purchased from Eppendorf or Rainin;

酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。The microplate reader was purchased from BioTek, USA, and the model is SynergyH1 full-function microplate reader.

实验方法：本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对JAK激酶活性的抑制作用，并得出化合物对JAK激酶活性的半数抑制浓度IC ₅₀。 Experimental Method: The inhibitory effect of test fluorescence resonance energy transfer (TR-FRET) method of test compounds on the JAK kinase activity, and compounds obtained half JAK kinase activity inhibitory concentration IC _50.

具体实验操作如下：The specific experimental operation is as follows:

激酶反应在白色384孔板(PerkinElmer)中进行，每孔加入1-5μL用DMSO和ddH ₂O稀释的不同浓度的化合物，阳性对照孔加入1-5μL相应溶媒，然后每孔加入1-5μL用激酶缓冲液(HEPES 50-250mM，MgCl ₂ 5-20mM等)稀释的0.1-20nM JAK激酶溶液，阴性对照孔加入1-5μL的激酶缓冲液，加入1～5μL包含多肽底物和ATP的底物混合液，室温孵育0.5～5小时，加入10μL EDTA和含标记抗体的检测液，室温孵育2～24小时，用BioTek Synergy H1酶标仪测定各板孔的约615nm和665nm荧光信号值，通过荧光信号值计算抑制率。根据不同浓度的抑制率通过曲线拟合得出化合物的IC ₅₀。 The kinase reaction was performed in a white 384-well plate (PerkinElmer). Add 1-5 μL of different concentrations of compounds diluted with DMSO and ddH ₂ O to each well, add 1-5 μL of the corresponding solvent to the positive control well, and then add 1-5 μL to each well. 0.1-20nM JAK kinase solution diluted with kinase buffer (HEPES 50-250mM, MgCl ₂ 5-20mM, etc.), add 1-5μL of kinase buffer to the negative control well, and add 1 ～ 5μL of substrate containing peptide substrate and ATP The mixed solution was incubated at room temperature for 0.5 to 5 hours, 10 μL of EDTA and a detection solution containing a labeled antibody were added, and the mixture was incubated at room temperature for 2 to 24 hours. The fluorescence signal values of approximately 615 nm and 665 nm in each well were measured with a BioTek Synergy H1 microplate reader. The signal value calculates the suppression rate. The obtained compound IC ₅₀ inhibition rate of different concentration by curve fitting.

实验数据处理方法：Experimental data processing method:

通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC ₅₀值，通过以上方案得出本发明所示的实施例化合物在JAK激酶活性试验中显示出如下表1的生物活性。 Calculate the percentage inhibition data of the wells treated with the compound from the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate (% inhibition rate = 100-[(test compound value-negative control value)] / (Positive control value-negative control value) x 100}. GraphPad prism was used to fit the data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC ₅₀ value. According to the above scheme, it was obtained that the compound of the embodiment shown in the present invention was shown in the JAK kinase activity test as shown in Table 1 below. Biological activity.

表1：本发明中化合物JAK激酶活性抑制IC ₅₀ Table 1: Compounds of the invention JAK kinase activity inhibit IC ₅₀

测试例2、本发明化合物对细胞JAK1/TYK2-STAT信号通路抑制作用的测定Test Example 2. Determination of the inhibitory effect of the compound of the present invention on cellular JAK1 / TYK2-STAT signaling pathway

实验目的：该测试例的目的是测试化合物对细胞JAK1/TYK2-STAT信号通路的抑制活性。Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound on the cell JAK1 / TYK2-STAT signal pathway.

实验仪器：微孔板振荡器(88880024)购自Thermo Scientific ^TM公司，离心机(5702R)购自Eppendorf公司，移液器购自Eppendorf公司，酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。 Experimental instruments: Microplate shaker (88880024) was purchased from Thermo Scientific ^TM company, centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, microplate reader was purchased from American BioTek company, and the model was SynergyH1. Microplate reader.

实验方法：本实验采用U266细胞系，通过INF-刺激激活JAK1/TYK2-STAT信号通路，检测化合物对其下游STAT3磷酸化的抑制活性，并得到化合物对JAK1/TYK2-STAT信号通路活性的半数抑制浓度IC ₅₀。 Experimental method: In this experiment, U266 cell line was used to activate the JAK1 / TYK2-STAT signaling pathway through INF-stimulation, to detect the inhibitory activity of the compound on its downstream STAT3 phosphorylation, and to obtain a half inhibition of the activity of the compound on JAK1 / TYK2-STAT signaling pathway concentration IC _50.

具体实验操作如下：The specific experimental operation is as follows:

384孔检测板中铺入U266细胞3-12μL，每孔细胞个数为100-300K，加入2μL梯度稀释的化合物溶液，室温350rpm震荡孵育2小时。2小时后加入2μL INF-α，INF-α终浓度1000U/mL，室温震荡15min。加入2-5μL(5X)LANCE Ultra Lysis Buffer 2溶液，室温震荡2h。2h后加入5μL终浓度为0.5nM的LANCE Ultra Eu-labeled Anti-STAT3 Antibody(PerkinElmer)和终浓度为5nM的LANCE Ultra ULight-labeled Anti-STAT3 Antibody(PerkinElmer)溶液，室温孵育过夜。酶标仪测定各板孔的665nm荧光信号值，通过荧光信号值计算抑制率，根据不同浓度的抑制率通过曲线拟合得出化合物的IC ₅₀。 Put 3-12 μL of U266 cells into a 384-well detection plate, the number of cells in each well is 100-300K, add 2 μL of a gradient diluted compound solution, and incubate with shaking at 350 rpm for 2 hours at room temperature. After 2 hours, 2 μL of INF-α was added, and the final concentration of INF-α was 1000 U / mL, followed by shaking at room temperature for 15 min. Add 2-5 μL (5X) LANCE Ultra Lysis Buffer 2 solution and shake at room temperature for 2h. After 2 h, 5 μL of a LANCE Ultra Eu-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 0.5 nM and a LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 5 nM were added and incubated at room temperature overnight. The microplate reader measures the 665nm fluorescence signal value of each plate well, calculates the inhibition rate based on the fluorescence signal value, and obtains the IC _{50 of the} compound by curve fitting according to the inhibition rate of different concentrations.

实验数据处理方法：Experimental data processing method:

通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不加细胞)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC ₅₀值，本实施例化合物对U266细胞JAK1/TYK2-STAT信号通路抑制活性试验中显示出如下表2的生物活性： Calculate the percentage inhibition data of the wells treated with the compound from the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate (% inhibition rate = 100-[(test compound value-negative control value)] / (Positive control value-negative control value) x 100}. GraphPad prism was used to fit different concentration and corresponding percentage inhibition rate data to a 4-parameter non-linear logic formula to calculate the IC ₅₀ value. The compound of this example has an inhibitory activity test on U266 cells JAK1 / TYK2-STAT signal pathway as shown in Table 2 below. Biological activity:

表2：Table 2:

化合物Compound	U266(IC ₅₀nM) U266 (IC ₅₀ nM)
实施例1Example 1	>1000> 1000
实施例42Example 42	>1000> 1000

测试例3、本发明化合物在β-葡萄糖醛酸酶溶液中的稳定性Test Example 3. Stability of the compound of the present invention in β-glucuronidase solution

实验目的：该测试例的目的是检测化合物是否被β-葡萄糖醛酸酶酶切，以及完全酶切的时间。Experimental purpose: The purpose of this test case is to detect whether the compound is cleaved by β-glucuronidase and the time for complete digestion.

实验仪器：laboratory apparatus:

离心机(5702R)购自Eppendorf公司，移液器购自Eppendorf或Rainin公司，LC/MS/MS分析仪器：AB Sciex API 4000。The centrifuge (5702R) was purchased from Eppendorf, and the pipette was purchased from Eppendorf or Rainin. LC / MS / MS analysis instrument: AB Sciex API 4000.

实验方法：experimental method:

A.酶切反应A. Enzymatic digestion reaction

酶切反应在96孔板(Corning)中进行。每孔加入50μL的β-葡萄糖醛酸酶(sigma)溶液，此溶液含有10U的酶，再在对应孔加入10nmol的化合物共同孵育0，5，10，20，30min，在对应的时间点加入100μL的ACN终止反应。The digestion reaction was performed in a 96-well plate (Corning). Add 50 μL of β-glucuronidase (sigma) solution to each well. This solution contains 10 U of enzyme. Add 10 nmol of compound to the corresponding wells and incubate for 0, 5, 10, 20, 30 min. Add 100 μL at the corresponding time point. ACN stopped the reaction.

B.LC-MS分析B. LC-MS analysis

取A步骤酶切终止后的溶液40μL，加入160μL乙腈沉淀，混合后4000rpm离心10分钟。然后取处理后的上清溶液100μL进行LC/MS/MS分析待测化合物的浓度。Take 40 μL of the solution after the digestion in step A, add 160 μL of acetonitrile to precipitate, mix and centrifuge at 4000 rpm for 10 minutes. Then 100 μL of the treated supernatant solution was taken for LC / MS / MS analysis of the concentration of the test compound.

LC-MS/MS分析条件：液相条件：Shimadzu LC-20AD泵；质谱条件:AB Sciex API 4000质谱仪；色谱柱：phenomenex Gemiu 5um C18 50×4.6mm；流动相：A液为0.1％甲酸水溶液，B液为乙腈，流速：0.8mL/min，洗脱时间：0-4分钟梯度洗脱。LC-MS / MS analysis conditions: liquid phase conditions: Shimadzu LC-20AD pump; mass spectrometric conditions: AB Sciex API 4000 mass spectrometer; chromatographic column: phenomenex Gemiu 5um C18 50 × 4.6mm; mobile phase: A liquid is 0.1% formic acid aqueous solution , B liquid is acetonitrile, flow rate: 0.8mL / min, elution time: 0-4 minutes gradient elution.

如表3所示，本发明优选实施例前药(实施例1)的活性代谢物(JAK抑制剂SHR0302)能快速被β-葡萄糖醛酸酶酶切下来，释放出SHR0302。酶切的机理如上图所示。As shown in Table 3, the active metabolite (JAK inhibitor SHR0302) of the prodrug (Example 1) of the preferred embodiment of the present invention can be quickly cut by β-glucuronidase to release SHR0302. The mechanism of enzyme digestion is shown in the figure above.

表3：本发明实施例1酶切实验结果Table 3: Results of the enzyme digestion experiment in Example 1 of the present invention

实施例42的结构中糖部分是葡萄糖结构，与实施例1结构中糖部分的葡萄糖酸不同，所以在相同实验条件下，β-葡萄糖醛酸酶酶切实施例42进而释放出活性药Tofacitinib的速率极慢，不能有效释放。但实施例42可被β-D-葡萄糖苷酶酶切快速释放出活性药Tofacitinib，酶切机理如下图所示：The sugar part of the structure of Example 42 is a glucose structure, which is different from the gluconic acid of the sugar part of the structure of Example 1. Therefore, under the same experimental conditions, β-glucuronidase digests Example 42 and releases the active drug Tofacitinib. The rate is extremely slow and cannot be effectively released. However, Example 42 can be quickly digested by β-D-glucosidase to release the active drug Tofacitinib. The mechanism of the digestion is shown in the following figure:

测试例4、本发明化合物在小鼠的药代动力学分析测定Test Example 4. Pharmacokinetic analysis of the compound of the present invention in mice

实验目的：进行本发明优选实施例在小鼠的血液和胃肠道组织药物代谢动力学测试分析Experimental purpose: To perform a pharmacokinetic test and analysis of blood and gastrointestinal tissues in mice according to a preferred embodiment of the present invention

实验仪器：laboratory apparatus:

离心机(5702R)购自Eppendorf公司，The centrifuge (5702R) was purchased from Eppendorf,

移液器购自Eppendorf或Rainin公司，Pipettes were purchased from Eppendorf or Rainin.

LC/MS/MS分析仪器：AB Sciex API 4000。LC / MS / MS analysis instrument: AB Sciex API 4000.

实验动物：采用BALB/c小鼠，购自上海杰思捷实验动物有限公司。Experimental animals: BALB / c mice were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.

实验方法：取BALB/c小鼠，每组3只，单次灌胃给予实施例化合物，给药剂量为5毫克/10毫升/千克，于给药后0.5、1、2、4、6、8和24小时静脉采血及分离收集胃肠道组织。血液置于K ₂EDTA试管中，室温1000～3000×g离心5～20min分离血浆，胃肠道组织取下后用缓冲液漂洗，加入匀浆缓冲液后进行组织匀浆后冻存或检测，血浆和组织匀浆样品处理后进行LC/MS/MS分析待测化合物的浓度。所得药代数据如下表4所示，其中AUC _0-t为AUC _0-8小时： Experimental method: BALB / c mice, 3 mice in each group, were administered the compound of the example in a single intragastric administration at a dose of 5 mg / 10 ml / kg, and 0.5, 1, 2, 4, 6, and At 8 and 24 hours, venous blood was collected and the gastrointestinal tissue was collected. The blood was placed in a K ₂ EDTA test tube, and the plasma was separated by centrifugation at 1000-3000 × g for 5-20 minutes at room temperature. The gastrointestinal tissue was removed and rinsed with buffer. The homogenized buffer was added and the tissue was homogenized and frozen or tested. Plasma and tissue homogenate samples were processed by LC / MS / MS to analyze the concentration of test compounds. The obtained pharmacokinetic data are shown in Table 4 below, where AUC _0-t is AUC _{0-8 hours} :

表4：小鼠药代实验结果Table 4: Results of pharmacokinetic experiments in mice

实验结论：Experimental results:

本发明优选前药实施例42的活性代谢物(Tofacitinib)在小鼠的血液暴露量小于单次灌胃给予Tofacitinib的血液暴露量；实施例42的活性代谢物(Tofacitinib)在肠道组织暴露量大于单次灌胃给予Tofacitinib的肠道组织暴露量；实施例1的活性代谢产物SHR0302在血液暴露量极低，而在肠道组织中具有较高的暴露量。The blood exposure of the active metabolite (Tofacitinib) of the preferred prodrug Example 42 in the present invention is less than that of a single intragastric administration of Tofacitinib; the exposure of the active metabolite (Tofacitinib) of Example 42 in intestinal tissues Greater than the amount of intestinal tissue exposure given to Tofacitinib in a single gavage; the active metabolite SHR0302 of Example 1 had extremely low blood exposure and a higher exposure in intestinal tissue.

根据相关文献报道，实施例42在小鼠灌胃给药后，由β-D-葡萄糖苷酶酶切，释放出活性药Tofacitinib。前药实施例1和实施例42的分子量比对应的活性代谢物分子量大，如果小鼠灌胃给药相同摩尔比的前药和对应的活性代谢物，前药(实施例1和实施例42)可实现活性药物在靶器官(回、结肠)的富集，并能极大的减少对应活性代谢物(SHR0302和Tofacitinib)在血液的暴露量。According to relevant literature reports, Example 42 was digested by β-D-glucosidase after administration to mice by intragastric administration, and the active drug Tofacitinib was released. The molecular weight of Prodrug Examples 1 and 42 is larger than the molecular weight of the corresponding active metabolite. If mice are administered intragastrically with the same molar ratio of prodrug and the corresponding active metabolite, the prodrug (Example 1 and Example 42) ) Can achieve the enrichment of active drugs in target organs (back, colon), and can greatly reduce the exposure of the corresponding active metabolites (SHR0302 and Tofacitinib) in the blood.

Claims

一种通式(IA)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by the general formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

其中：among them:

M、M ₁或M ₂为O、S或NH； M, M ₁ or M ₂ is O, S or NH;

L为键、-C(＝O)-或-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-； L is a bond, -C (= O)-or -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-;

G为JAK抑制剂，选自Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、Pf-04965842、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modified ruxolitinib analog、ATI-501、R-348、R-348、NS-018、SHR0302、Jaktinib hydrochloride、Jaktinib hydrochloride或KL-130008；G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-atin, Bertin PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride or KL-130008;

R为-CH ₂OH或-COOPg； R is -CH ₂ OH or -COOPg;

R ₁选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy Substituted with one or more substituents of aryl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₂和R ₃各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基； R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

Pg为氢或羧基保护基，当Pg为羧基保护基时，选自-DMB、-Bn、-Allyl、-PfP、-Me、-PMB、-EM或t-Boc；Pg is hydrogen or a carboxy protecting group. When Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl, -PfP, -Me, -PMB, -EM, or t-Boc;

Pg ₁、Pg ₂和Pg ₃为氢或羟基保护基，当Pg ₁、Pg ₂和Pg ₃为羟基保护基时，各自独立的选自-CH ₃、-C(CH ₃) ₃、-CPh ₃、-CH ₂Ph、-CH ₂OCH ₃、-Si(CH ₃) ₃、-THP、-SiMe ₂(t-Bu)、-Ac或-COPh； Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protecting groups. When Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, each is independently selected from -CH ₃ , -C (CH ₃ ) ₃ , -CPh ₃ , -CH ₂ Ph, -CH ₂ OCH ₃ , -Si (CH ₃ ) ₃ , -THP, -SiMe ₂ (t-Bu), -Ac or -COPh;

n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and

x为0、1、2或3。x is 0, 1, 2 or 3.
一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

其中：among them:

M为O、S或NH；M is O, S or NH;

L为键、-C(＝O)-或-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-； L is a bond, -C (= O)-or -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-;

G为JAK抑制剂，选自Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、Pf-04965842、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modified ruxolitinib analog、ATI-501、R-348、R-348、NS-018、SHR0302、Jaktinib hydrochloride、Jaktinib hydrochloride或KL-130008；优选SHR-0302；G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-002, Cer PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride or KL-130008; preferably SHR-0302;

R为-CH ₂OH或-COOPg； R is -CH ₂ OH or -COOPg;

R ₁选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy Substituted with one or more substituents of aryl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₂和R ₃各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基； R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

Pg为氢或羧基保护基，当Pg为羧基保护基时，选自-DMB、-Bn、-Allyl、-PfP、-Me、-PMB、-EM或t-Boc；Pg is hydrogen or a carboxy protecting group. When Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl, -PfP, -Me, -PMB, -EM, or t-Boc;

Pg ₁、Pg ₂和Pg ₃为氢或羟基保护基，当Pg ₁、Pg ₂和Pg ₃为羟基保护基时，各自独立的选自-CH ₃、-C(CH ₃) ₃、-CPh ₃、-CH ₂Ph、-CH ₂OCH ₃、-Si(CH ₃) ₃、-THP、 -SiMe ₂(t-Bu)、-Ac或-COPh； Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protecting groups. When Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, each is independently selected from -CH ₃ , -C (CH ₃ ) ₃ , -CPh ₃ , -CH ₂ Ph, -CH ₂ OCH ₃ , -Si (CH ₃ ) ₃ , -THP, -SiMe ₂ (t-Bu), -Ac or -COPh;

n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and

x为0、1、2或3。x is 0, 1, 2 or 3.
根据权利要求2所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，The compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 2, wherein:

当M为O，Pg ₁、Pg ₂和Pg ₃为氢，R为-COOPg，Pg为氢，R ₁选自氢、氨基、硝基、卤素、甲基或甲氧基，R ₁位于的
邻位，L为-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-，R ₂和R ₃同时选自甲基，且x为1时，G不为Tofacitinib； When M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, R _{1 is} selected from hydrogen, amino, nitro, halogen, methyl or methoxy, and R ₁ is
In the ortho position, L is -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-, and R ₂ and R _{3 are} both selected from methyl, and when x is 1, G is not Tofacitinib;

当M为O，Pg ₁、Pg ₂和Pg ₃为氢，R为-COOPg，Pg为氢，R ₁为硝基，R ₁位于的
邻位，L为-C(＝O)NR ₂(CH ₂) _xNR ₃C(＝O)-，R ₂和R ₃同时选自甲基，且x为1时，G不为Ruxolitinib或Baricitinib。 When M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, R ₁ is nitro, and R ₁ is
Ortho position, L is -C (= O) NR ₂ (CH ₂ ) _x NR ₃ C (= O)-, R ₂ and R ₃ are selected from methyl at the same time, and when x is 1, G is not Ruxolitinib or Baricitinib .
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(II)所示：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by the general formula (II):

其中：M、G、R～R ₃、Pg ₁～Pg ₃、n和x如权利要求2所述。 Wherein: M, G, R to R ₃ , Pg ₁ to Pg ₃ , n and x are as described in claim 2.
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(III)所示：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by the general formula (III):

其中：M、G、R、R ₁、Pg ₁～Pg ₃和n如权利要求2所述。 Wherein: M, G, R, R ₁ , Pg ₁ to Pg ₃ and n are as described in claim 2.
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(IIA)所示：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by the general formula (IIA):
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(IV)所示：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by the general formula (IV):

其中：G、R ₁～R ₃、Pg、Pg ₁～Pg ₃和x如权利要求2所述。 Among them, G, R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x are as described in claim 2.
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(V)所示：The compound of the general formula according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, further characterized by the general formula (V):

其中：G、R、R ₁、Pg ₁～Pg ₃如权利要求2所述。 Wherein, G, R, R ₁ , and Pg ₁ to Pg _{3 are} as described in claim 2.
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(VI)所示：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by the general formula (VI):

其中：R、R ₁～R ₃、Pg ₁～Pg ₃和x如权利要求2所述。 Wherein: R, R ₁ to R ₃ , Pg ₁ to Pg ₃ and x are as described in claim 2.
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(VII)所示：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, further characterized by the general formula (VII):

其中：R ₁～R ₃和x如权利要求2所述。 Wherein: R ₁ to R ₃ and x are as described in claim 2.
根据权利要求1或2所述的通式化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步为通式(VIII)所示：The compound of general formula according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, further characterized by the general formula (VIII):

其中：among them:

R为-CH ₂OH或-COOH； R is -CH ₂ OH or -COOH;

G选自Tofacitinib或SHR-0302；G is selected from Tofacitinib or SHR-0302;

R ₁选自氢、卤素、氰基、硝基、氨基、C _1-6烷基、C _1-6卤代烷基、C _1-6烷氧基或C _1-6卤代烷氧基， R _{1 is} selected from hydrogen, halogen, cyano, nitro, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy,

优选氢、卤素、氰基、硝基、氨基、C _1-3烷基、C _1-3卤代烷基、C _1-3烷氧基或C _1-3卤代烷氧基；更优选氢、氟、氯、氰基、硝基、氨基、甲基、甲氧基或三氟甲基； Preferred are hydrogen, halogen, cyano, nitro, amino, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy; more preferred are hydrogen, fluorine, chlorine , Cyano, nitro, amino, methyl, methoxy or trifluoromethyl;

x选自0、1、2或3的整数，优选1；x is an integer selected from 0, 1, 2 or 3, preferably 1;

且，当x为1，G为Tofacitinib且R ₁选自硝基时，R为-CH ₂OH。 When x is 1, G is Tofacitinib, and R _{1 is} selected from nitro, R is -CH ₂ OH.
根据权利要求1～8以及11所述的通式化合物、其立体异构体或其药学上可接受盐，其中所述的G选自以下JAK抑制剂：The compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claims 1 to 8, and 11, wherein the G is selected from the following JAK inhibitors:
根据权利要求1～12中任一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，Each general formula according to any one of claims 1 to 12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

R ₁选自氢、卤素、氰基、硝基、氨基、C _1-6烷基、C _1-6卤代烷基、C _1-6烷氧基或C _1-6卤代烷氧基； R _{1 is} selected from hydrogen, halogen, cyano, nitro, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

R ₂、R ₃各自独立的选自C _1-6烷基或C _1-6卤代烷基。 R ₂ and R ₃ are each independently selected from a C _1-6 alkyl group or a C _1-6 haloalkyl group.
根据权利要求1～13中任一项所述的通式化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound of general formula according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:
一种制备权利要求10所述的通式(VII)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：A method for preparing a compound represented by general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof according to claim 10, comprising the following steps:

通式(VII-1)脱保护，得到通式(VII)所示化合物或其立体异构体及其药学上可接受盐；Deprotection of general formula (VII-1) to obtain a compound represented by general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

其中：among them:

环R ₁～R ₃、Pg、Pg ₁～Pg ₃和x如权利要求2所述。 The rings R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x are as described in claim 2.
一种制备权利要求9所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：A method for preparing a compound represented by general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof according to claim 9, comprising the following steps:

通式(VI-1)与通式(VII-2)反应，得到通式(VI)所示化合物或其立体异构体及其药学上可接受盐；Reacting the general formula (VI-1) with the general formula (VII-2) to obtain a compound represented by the general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

其中：among them:

环R ₁～R ₃、R、Pg ₁～Pg ₃和x如权利要求2所述。 The rings R ₁ to R ₃ , R, Pg ₁ to Pg ₃ and x are as described in claim 2.
一种制备权利要求16所述的通式(VI-2)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤，A method for preparing a compound represented by the general formula (VI-2) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof according to claim 16, comprising the following steps,

SHR-0302与通式(X)反应，得到通式(VI-2)所示化合物或其立体异构体及其药学上可接受盐；SHR-0302 reacts with the general formula (X) to obtain a compound represented by the general formula (VI-2) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

其中：among them:

X选自卤素。X is selected from halogen.
一种药用组合物，其包括治疗有效剂量的权利要求1～14中任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Carrier, diluent or excipient.
根据权利要求1～14中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求18所述的药物组合物在制备JAK抑制剂药物中的应用，该应用包含JAK抑制剂中含有葡糖苷酸的前药，所述前药在所述应用中通过β-葡糖苷酸酶裂解而释放出JAK抑制剂，优选JAK1、JAK2、JAK3和TYK2抑制剂。The compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to claim 18 in the preparation of a JAK inhibitor medicament, the A prodrug comprising a glucuronide in a JAK inhibitor is used, said prodrug in said application releasing β-glucuronidase cleavage to release a JAK inhibitor, preferably a JAK1, JAK2, JAK3 and TYK2 inhibitor.
根据权利要求1～14中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求18所述的药物组合物在制备含有葡糖苷酸衍生物JAK抑制剂前药的药物中的应用。The compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a JAK inhibitor containing a glucuronide derivative Application of prodrugs in medicine.
根据权利要求1～14中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求18所述的药物组合物在制备治疗炎症性疾病和肿瘤疾病相关药物中的应用，其中所述的炎症性疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病，所述的肿瘤性疾病选自骨髓纤维化、真性红细胞增多症及原发性血小板增多症、性骨髓细胞性白血病、急性淋巴细胞性白血病、乳腺导管癌及非小细胞肺癌，其中胃肠发炎疾病是慢性肠道炎症性疾病，进一步优选溃疡性结肠炎和克罗恩氏病。The compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating inflammatory diseases and tumor diseases Application, wherein the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease, and the tumorous disease is selected from bone marrow fibrosis, polycythemia vera, and primary Thrombocytosis, sexual myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma of the breast, and non-small cell lung cancer, among which gastrointestinal inflammation is a chronic intestinal inflammatory disease, and ulcerative colitis and Crohn's disease are further preferred .