WO2014114186A1

WO2014114186A1 - Jnk inhibitors

Info

Publication number: WO2014114186A1
Application number: PCT/CN2014/000089
Authority: WO
Inventors: 李丽; 张艳; 钱林艺; 张敏
Original assignee: 山东亨利医药科技有限责任公司
Priority date: 2013-01-24
Filing date: 2014-01-24
Publication date: 2014-07-31
Also published as: CN104903331A

Abstract

The present invention belongs to the field of pharmaceutical techniques, and in particular relates to JNK inhibitors as shown by general formulae (I), (1a) or (1b), pharmaceutically acceptable salts or stereoisomers thereof, the preparation method of these compounds, pharmaceutical preparations containing these compounds, and use of these compounds in the preparation of drugs for treating and/or preventing ischemia reperfusion injury, diabetes, neurodegenerative disorders, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or liver cirrhosis.

Description

JNK抑制剂技术领域 JNK inhibitors

本发明属于医药技术领域，具体涉及 JNK抑制剂、其药学上可接受的盐或其立体异构体，这些化合物的制备方法，含有这些化合物的药物制剂，以及这些化合物在制备治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症、肺纤维化、肝纤维化、脂肪肝或肝硬化的药物中的用途。 The invention belongs to the technical field of medicine, and particularly relates to a JNK inhibitor, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a preparation method of the compound, a pharmaceutical preparation containing the same, and a preparation and treatment of the compound and/or prevention thereof Use in drugs for ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.

背景技术 Background technique

JNK 又被称为应激活化蛋白激酶（ stress-activated kinases, SAPK ),是 1990年«现的促***原活化蛋白激酶，为 MAPK 家族的主要成员之一。促 ***原活化蛋白激醉 (m itogen-activated protein kinase, MAPK；)是哺 L动物细胞内广泛存在的一类丝氨酸 /苏氨酸蛋白激酶，目前已鉴定出 4种家族成员，分别为细！包外信号调节激酶（ extracellular signal-regu lated kinase 1/2, ERK 1/2)、 c-Jun J ^末端激酶 (c-Jun N-terminal kinase, JNK：)、 p38及 ERK5。 JNK基因有 3个亚型，即 JNK1, JNK2和 JNK3，经过选择性剪切形成。 JNK1和 JNK2 在组织中广泛表达，而 JNK3 仅在脑、心和睾丸中表达。每个 JNKL^因都可以编码 46和 54 kD的蛋白产物。 3种 JNK异构体通过不同的方式激活、结合和磷酸化不同的蛋白底物。 JNK, also known as stress-activated kinases (SAPK), was a mitogen-activated protein kinase in 1990 and is one of the major members of the MAPK family. The mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase widely found in the cells of L-like animals. Four family members have been identified, respectively! Extracellular signal-regu lated kinase 1/2 (ERK 1/2), c-Jun N-terminal kinase (JNK:), p38 and ERK5. The JNK gene has three subtypes, JNK1, JNK2 and JNK3, which are formed by selective shearing. JNK1 and JNK2 are widely expressed in tissues, while JNK3 is expressed only in the brain, heart and testis. Each JNKL can encode a protein product of 46 and 54 kD. The three JNK isoforms activate, bind and phosphorylate different protein substrates in different ways.

JNK信号通路可被细胞因子 [如肿瘤坏死因子 a( tumor necrosis factor α, TNFa)、白介素 1 (interleukin 1， IL- 1 )、表皮生长因子（ epidermal growth factor, EGF) ]、某些 G蛋白偶联受体、应激 (如电离辐射、渗透压、热休克和氧化损伤)等多种因素激活，参与细胞增殖与分化、细胞形态维持、细胞骨架构建、细胞凋亡和细胞恶变等多种生物学反应。 JNK信号通路功能失调可造成缺血再灌注损伤、慢性炎症、神经退行性变、糖尿病和肿瘤等多种疾病。 The JNK signaling pathway can be mediated by cytokines [such as tumor necrosis factor α (TNFa), interleukin 1, IL-1, epidermal growth factor (EGF)], and some G protein pairs. Recombinant receptors, stress (such as ionizing radiation, osmotic pressure, heat shock and oxidative damage) and other factors activate, participate in cell proliferation and differentiation, cell morphology maintenance, cytoskeletal construction, apoptosis and cell malignant transformation Learn the reaction. Dysfunction of the JNK signaling pathway can cause ischemia, reperfusion injury, chronic inflammation, neurodegenerative changes, diabetes and tumors.

典型的促***原活化的蛋白激酶 (MAPK)信号通路包括 3个连续的酶促反应，即 MAPKKKs→MAPKKs→MAPKs。 JNKs 的直接上游激酶 MAPKKs目前确认的只有 MKK4和 MKK7，TXY序列是 MKK活化 JNK 的双磷酸化位点， MKK4和 MKK⁷通过磷酸化 TXY序列的第 183位苏氨酸残基（ Thrl83 )和第 185位酪氨酸残基（Tyrl85)激活 JNK, 引起细胞增殖与分化、细胞凋亡和细胞恶变等多种生物学反应。 A typical mitogen-activated protein kinase (MAPK) signaling pathway includes three consecutive enzymatic reactions, namely MAPKKKs→MAPKKs→MAPKs. JNKs MAPKKs directly upstream kinases MKK4 and currently recognized only MKK7, TXY sequence MKK activation of JNK dual phosphorylation sites, MKK4 and ^{MKK. 7} of threonine residue 183 (Thrl83) by phosphorylation sequence and TXY The 185 tyrosine residue (Tyrl85) activates JNK, causing various biological responses such as cell proliferation and differentiation, apoptosis and malignant transformation.

信号通路的调节是个极其复杂的***， JN 信号通路的调节主要有两种不同的机制，一是识别 MKKK和 MKK 以及 MKK和 MAPK 间的序列；二是支架蛋白使 MKKK-MKK-MAPK模块组装成蛋白复合物。 MAPK通过保守序列与特异性上游分子 MKK和底物（如 c-Jun， ATF2 等）实现对接。在所有 MAPK中（包括 J K )，有一组带负电荷的羧基端氛基酸连接到激酶的结构域序列，这个位点被称为共同对接域（ common dock ing doma in, CD ), 用于 ΜΚΚ,ΜΑΡΚ,特异性底物以及支架蛋白的对接。另一个保守序列称为谷氨酸- 天冬氨酸域，同样用于 MAPK 的对接。 MKK,底物， MAPK及支架蛋白中的对接位点具有一个共同的保守序列 R/K-X4A-0A-X- 0B(0A和 0B是亮氨酸、异亮氨酸和缬氨酸的疏水残基)。当对接位点（ docking doma in, DD ) 中的碱性残基与 MAPK的 CD 域的酸性残基结合时，疏水残基位于对接槽内，使得 0A-X-0B疏水序列与 DD序列结合。这些对接位点间的相互作用在 MAPK的特异性结合和活化中扮演重要角色。除了 MAPK与 MKK、底物和调节因子间的对接作用，还有特异性序列调控 MKKK和 MKK 间的相互作用。研究发现, 在一些 MKK 中，包括调节 JNK的 MKK4 /7,存在一种多功能对接域，被称为多功能对接位点（ doma in for versatile dock ing, DVD), DVD位点位于 MKK 的羧基端，连接 MKKK [ 包括 MEKK 1, MEKK4 (MTK 1)， ASK1, Tao2 和 Takl], 所有这些都可以激活 JNK信号通路。 MKKK 内的 N形激酶结合域与 MKK 的 DVD位点结合。 The regulation of the signaling pathway is an extremely complex system. There are two different mechanisms for the regulation of the JN signaling pathway. One is to identify the sequence between MKKK and MKK and between MKK and MAPK. The second is that the scaffold protein assembles the MKKK-MKK-MAPK module into Protein complex. MAPK by conservative order The column is docked with a specific upstream molecule MKK and a substrate such as c-Jun, ATF2, and the like. In all MAPKs (including JK), a group of negatively charged carboxy terminal amino acids are linked to the domain sequence of the kinase, which is called the common docking domain (CD) for ΜΚΚ , ΜΑΡΚ, specific substrate and docking protein binding. Another conserved sequence, called the glutamate-aspartate domain, is also used for the docking of MAPK. The docking sites in MKK, substrate, MAPK and scaffold proteins share a common conserved sequence R/K-X4A-0A-X- 0B (0A and 0B are hydrophobic for leucine, isoleucine and valine) Residues). When the basic residue in the docking doma in (DD) binds to the acidic residue of the CD domain of the MAPK, the hydrophobic residue is located in the docking groove such that the 0A-X-0B hydrophobic sequence binds to the DD sequence. The interaction between these docking sites plays an important role in the specific binding and activation of MAPK. In addition to the docking between MAPK and MKK, substrates and regulatory factors, there is also a specific sequence that regulates the interaction between MKKK and MKK. It has been found that in some MKKs, including MKK4/7, which regulates JNK, there is a multifunctional docking domain called doma in for versatile docking (DVD), and the DVD site is located in the carboxyl group of MKK. End, connect MKKK [including MEKK 1, MEKK4 (MTK 1), ASK1, Tao2 and Takl], all of which activate the JNK signaling pathway. The N-shaped kinase binding domain within MKKK binds to the DVD site of MKK.

控制 J K信号通路的另一方面是通过支架蛋白组合信号通路复合物。支架蛋白本身没有催化功能，但是能编码对接位点，连接 MAPK模块成员 MKKK, MKK和 MAPK。一般情况下，支架蛋白通过和 SH2, SH3， PTB等结合域相互作用与其他蛋白结合，而这些结构域使得细胞中的 MAPK信号通路复合物定位至不同位点。不同的激活物使得支架蛋白和特异性 MKKK选择性活化 MAPK, 并具有时空动态性。在不同的支架蛋白中， JNK相互作用蛋白 ( J K-interacting prote ins, JIPs)结合特异性驱动蛋白和 MKKK ό々混合谱系激酶（ m ixed lineage k inase,MLK )族；抑制蛋白 β-arrestin为 G蛋白偶联受体嶙酸化的辅助因子；多结合域蛋白 POSH ( plenty of SH3s)含有多个 SH3结构域, 参与哺乳动物和果蝇细胞凋亡中的 JNK信号通路；接头蛋白 C rk II通过黏附因子与 JNK信号通路结合。此夕卜， MEKK1不仅能与 MKK4结合，还能与 JNK1 /2结合，这表明它本身具有类似支架蛋白的作用。 Another aspect that controls the JK signaling pathway is the combination of signaling pathway complexes via scaffold proteins. The scaffold protein itself has no catalytic function, but can encode docking sites and link MAPK module members MKKK, MKK and MAPK. In general, scaffold proteins interact with other proteins by interacting with SH2, SH3, PTB and other binding domains, which allow the MAPK signaling pathway complex in cells to localize to different sites. Different activators allow scaffold proteins and specific MKKK to selectively activate MAPK with spatiotemporal dynamics. Among the different scaffold proteins, JK-interacting prote ins (JIPs) binds to specific kinesin and MKKK m mixed lineage k inase (MLK); inhibitory protein β-arrestin is A cofactor for the phosphorylation of the G protein-coupled receptor; the multi-binding domain protein POSH (the majority of SH3s) contains multiple SH3 domains involved in the JNK signaling pathway in mammalian and Drosophila cell apoptosis; the adaptor protein C rk II is passed Adhesion factors bind to the JNK signaling pathway. Furthermore, MEKK1 not only binds to MKK4, but also binds to JNK1/2, indicating that it itself has a scaffold-like effect.

敲除小鼠模型中目标同源重组基因，使得不同的 JNK或其上游调节分子表达缺失，从而影响其在生理和疾病中发挥作用，通过 JNK抑制剂也进一步证明了 JNK信号通路在不同疾病中的重要作用。 JNK抑制剂可抑制由缺血及其他应激诱导凋亡反应导致的细胞死亡，这显示出了巨大的治疗潜力。已有文献证明 JNK抑制剂可以用于治疗或预防呼吸***疾病（如肺纤维化）、脂肪肝、肝纤维化、肝硬化、缺血 /再灌注损伤、慢性炎症性疾病、神经退行性疾病、糖尿病及肿瘤等。 Knockout of the target homologous recombination gene in the mouse model, resulting in the loss of expression of different JNK or its upstream regulatory molecules, thereby affecting its role in physiology and disease. JNK signaling pathway is further demonstrated by JNK inhibitors in different diseases. The important role. JNK inhibitors inhibit cell death caused by ischemia and other stress-induced apoptosis, which shows great therapeutic potential. JNK inhibitors have been shown to be useful in the treatment or prevention of respiratory diseases (eg pulmonary fibrosis), lipids Fatty liver, liver fibrosis, cirrhosis, ischemia/reperfusion injury, chronic inflammatory diseases, neurodegenerative diseases, diabetes and tumors.

研究较多的 JNK抑制剂主要是多肽和小分子类化合物， WO2005025567 和 WO2006076595中，均才艮道了新型 JNK小分子类抑制剂在多个治疗领域的作用。目前，暂无 JNK抑制剂类药物上市，因此，需要研发更多的 JNK抑制剂结构类型，选择有效性和安全性较好的化合物，用于呼吸***疾病、脂肪肝、肝纤维化、肝硬化、慢性炎症性疾病的治疗。 The most studied JNK inhibitors are mainly polypeptides and small molecule compounds. WO2005025567 and WO2006076595 have all justified the role of novel JNK small molecule inhibitors in various therapeutic fields. At present, there are no JNK inhibitors listed on the market. Therefore, it is necessary to develop more JNK inhibitor structure types, and select compounds with good efficacy and safety for respiratory diseases, fatty liver, liver fibrosis, and cirrhosis. , the treatment of chronic inflammatory diseases.

AS-602801是 Merck公司开发的用于治疗纤维化的药物，目前正处于临床 II 到了该化合物，结构式如下：

AS-602801 is a drug developed by Merck for the treatment of fibrosis and is currently in clinical phase II. The structural formula is as follows:

发明内容 Summary of the invention

本发明提供了下述技术方案 The invention provides the following technical solutions

1、通式（ I )、（ l a )或（ l b )所示的化合物、其药学上可接受的盐或其立体异构体：

A compound represented by the formula (I), (la) or (lb), a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

(I) (la) (lb) (I) (la) (lb)

其中， among them,

X、 Y分别独立地为 N或 CR¹, 其中 X、 Y至少有 1个为 N; X and Y are each independently N or CR ¹ , wherein at least one of X and Y is N;

Z、 W、 U、 G分别独立地为 N或 CR¹, 其中 Z、 W、 U、 G至少有 1个为 N; Z, W, U, G are independently N or CR ¹ , wherein at least one of Z, W, U, G is N;

R¹, R²分别独立的为氢、磺酰基、卤素、 C_1-6烷基、卤代 C 烷基、 C_1-6 烷氧基、氨基、、羟基、 C₂-₆烯基、 C_2-6炔基、 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基； R ¹ and R ² are each independently hydrogen, sulfonyl, halogen, C _1-6 alkyl, halo C alkyl, C _1-6 alkoxy, amino, hydroxy, C ₂ - ₆ alkenyl, C _2-6 alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl;

n选自 0, 1 , 2或 3; n is selected from 0, 1, 2 or 3;

L为 C_1-6烷基、 C_1-6烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基、 7-12元螺环基、 7-12元桥环基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2 个环烷基、杂环烷基、芳基或杂芳基稠合； O L is a C _1-6 alkyl group, a C _1-6 alkoxy group, -N(R ^a R ^b ), a 6-14 membered aryl group which is unsubstituted or substituted with at least one R ³ , and a 5-14 membered heteroaryl group. a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, a 7-12 membered spirocyclic group, a 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or a heteroaryl group can be fused to an additional 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups; O

_R3为/^！^或 ^：、 _r4，其中 m选自 0, 1， 2或 3， _R 3 is /^! ^ or ^:, _r4 , where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C_1-6烷基、卤代 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 C_1-6烷氧基、氨基、氰基、羟基、 C_2-6烯基、 C₂_₆炔基、未被取代或至少被一个 R⁵取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基、 7-12元螺环基、 7-12元桥环基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合， 3-14元杂环烷基的任意 CH₂可被 C(O)取代； R ⁴ is sulfonyl, halogen, C _1-6 alkyl, halo C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 Alkoxy, amino, cyano, hydroxy, C _2-6 alkenyl, C ₂ _-6 alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl unsubstituted or substituted by at least one R ⁵ a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, a 7-12 membered spirocyclic group, a 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heterocyclic group The aryl group may be fused to another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, and any CH _{2 of the} 3-14 membered heterocycloalkyl group may be substituted by C(O);

R⁵为磺酰基、卤素、 C_1-6烷基、卤代 C ₆烷基、 _₆烷氧基、 -C(0)-0-Ci_-6 烷基、 - C -Cw烷基、 -(CHz C -O-Cw烷基、 -(CH p-O-C^烷基、 -(C¾)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、、、羟基、 C₂_₆烯基、 C_2-6炔基、 3-14元环烷基、 6-14元芳基或 3-14元杂环烷基； R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halo C ₆ alkyl, _-6 alkoxy, -C(0)-0-Ci _-6 alkyl, -C-Cw alkyl, - (CHz C -O-Cw alkyl, -(CH pOC^alkyl, -(C3⁄4) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , , hydroxy, C ₂ _-6 alkenyl, C _2-6 alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl or 3-14 membered heterocycloalkyl;

R^a、 R^b分别独立的为氢、 d.₆烷基、 -(C¾)_p-OC_1-6烷基或 6-14元芳基 C^₆ 烷基， R ^a and R ^b are each independently hydrogen, d. ₆ alkyl, -(C 3⁄4) _p -OC _1-6 alkyl or 6-14 member aryl C ₆ alkyl.

p选自 1， 2， 3或 4。 p is selected from 1, 2, 3 or 4.

2、如前述技术方案中任一项所述的化合物、其药学上可接受的盐或其立体异构体： 2. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， among them,

X、 Y分别独立地为 N或 CR¹ , 其中 X、 Y至少有 1个为 N; X and Y are each independently N or CR ¹ , wherein at least one of X and Y is N;

Z、 W、 U、 G分别独立地为 N或 CR¹ , 其中 Z、 W、 U、 G至少有 1个为 N; Z, W, U, G are independently N or CR ¹ , wherein at least one of Z, W, U, G is N;

R¹ , R²分别独立的为氢、磺酰基、卤素、 d_₆烷基、 C_1-6烷氧基、氰基、羟基、 C₂_₆烯基、 C₂_₆炔基、 6-14元芳基； R ¹ and R ² are each independently hydrogen, sulfonyl, halogen, d- ₆ alkyl, C _1-6 alkoxy, cyano, hydroxy, C ₂ _-6 alkenyl, C ₂ _-6 alkynyl, 6- 14-membered aryl;

n选自 0, 1 , 2或 3; n is selected from 0, 1, 2 or 3;

L为 d.₆烷基、 d.₆烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合； L is d. ₆ alkyl, d. ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³ 6-14 membered aryl, 5-14 membered heteroaryl, a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be bonded to another 1-2 cycloalkyl groups, heterocycloalkyl groups , aryl or heteroaryl fused;

0 其中 m选自 0， 1， 2或 3， R⁴为磺酰基、卤素、 C_1-6烷基、卤代 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 d_₆烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基、 7-12元螺环基、 7-12 元桥环基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合， 3-14元杂环烷基的任意 CH₂可被 C(O) 取代； 0 where m is selected from 0, 1, 2 or 3, R ⁴ is a sulfonyl group, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), d_ ₆ alkoxylate a 6-14 membered aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkane, which is unsubstituted or substituted with at least one R ⁵ group, amino group, cyano group, hydroxy group a 7-12 membered spiro group, a 7-12 membered bridged ring group, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can be combined with another 1-2 cycloalkyl groups, heterocycloalkanes a aryl, aryl or heteroaryl fused, any CH _{2 of a} 3-14 membered heterocycloalkyl group may be substituted by C(O);

R⁵为磺酰基、卤素、 C_1-6烷基、卤代 C^₆烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6 烷基、 -C O C^烷基、 -(CH₂)_p-C(0)-0-C_1-6烷基、 -(CH₂)_p-0-C_1-6烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、氨基、氰基、羟基、 C_2-6烯基、 C₂.₆炔基、 3-14元环烷基、 6-14元芳基或 3-14元杂环烷基； R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halo C ₆ alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -COC alkane , -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0) ^{^{N (R a R b),}} -. (CH 2) p -OH, amino, cyano, hydroxy, C _2-6 alkenyl group, C ₂ ₆ alkynyl group, a 3-14 membered cycloalkyl, 6-14 membered Aryl or 3-14 membered heterocycloalkyl;

R^A、 R^B分别独立的为氢、 C ₆烷基、 -(CH₂)_P-OC_1-6烷基、苯基 C_1-6烷基， p选自 1， 2， 3或 4。 R ^A and R ^B are each independently hydrogen, C ₆ alkyl, -(CH ₂ ) _P -OC _1-6 alkyl, phenyl C _1-6 alkyl, and p is selected from 1, 2, 3 or 4.

3、如前述技术方案中任一项所述的化合物、其药学上可接受的盐或其立体异构体： 3. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， among them,

R¹, R²分别独立的为氢、磺酰基、卤素、 d.₆烷基、 C^₆烷氧基、氨基、氰基、羟基； R ¹ and R ² are each independently hydrogen, sulfonyl, halogen, d. ₆ alkyl, C ₆ alkoxy, amino, cyano, hydroxy;

n选自 0, 1， 2或 3; n is selected from 0, 1, 2 or 3;

L为 d_₆烷基、 d-6烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 5-6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； L is d- ₆ alkyl, d-6 alkoxy, -N(R ^a R ^b ), unsubstituted or at least substituted with one R ³ phenyl, quinolyl, 5-6 membered heteroaryl, 3 -8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

0 0

R³为^" ^ 或/ R⁴ , R ³ is ^" ^ or / R ⁴ ,

其中 m选自 0， 1 , 2或 3, Where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C_1-6烷基、卤代 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合， 3-14元杂环烷基的任意 C¾可被 C(O)取代； R ⁴ is a sulfonyl group, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), an alkoxy group, Amino, cyano, hydroxy, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, unsubstituted or substituted with at least one R ⁵ , Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be fused to an additional 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, 3-14 membered heterocycloalkane Any C3⁄4 of the base may be replaced by C(O);

R⁵为磺酰基、卤素、 _₆烷基、卤代 d.₆烷基、 C_1-6烷氧基、 -C(0)-0-Ci_-6 烷基、 -ccc -c^烷基、 -(CH₂)_p-C(0)-0- d.₆烷基、 -(CH₂)_p-0-C_1-6烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、氨基、、羟基、 C_2-6烯基、 C_2-6炔基、 3-14元环烷基、 6-14元芳基或 3-14元杂环烷基； R ⁵ is sulfonyl, halogen, _-6 alkyl, halogenated d. ₆ alkyl, C _1-6 alkoxy, -C(0)-0-Ci _-6 Alkyl, -ccc -c^alkyl, -(CH ₂ ) _p -C(0)-0-d. ₆ alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino, hydroxy, C _2-6 alkenyl, C _2-6 alkynyl, 3-14-membered naphthenic a 6-14 membered aryl group or a 3-14 membered heterocycloalkyl group;

R^a、 R^b分别独立的为氢、 ^₆烷基、 -(CH^p-OCw烷基、苄基或苯基乙基， p选自 1 , 2， 3或 4。 R ^a and R ^b are each independently hydrogen, ^ ₆ alkyl, -(CH^p-OCw alkyl, benzyl or phenylethyl, and p is selected from 1, 2, 3 or 4.

4、如前述技术方案中任一项所述的化合物、其药学上可接受的盐或其立体异构体： 4. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， among them,

R¹, R²分别独立的为氢、烷基； R ¹ and R ² are each independently hydrogen or alkyl;

n选自 0， 1 , 2或 3; n is selected from 0, 1, 2 or 3;

L为 d_₆烷基、 C^₆烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 5-6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； L is d- ₆ alkyl, C^ ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least substituted with one R ³ phenyl, quinolyl, 5-6 membered heteroaryl, 3 -8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

o o

_R3为/ 或/ C、_R4 , 其中 m选自 0， 1 , 2或 3， _R 3 is / or / C, _R4 , wherein m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 d_₆烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的苯基、 5-6元杂芳基、 3-8元环烷基、 3-8元杂环烷基，其中所述环烷基、杂环烷基、苯基或杂芳基可与另外 1个环烷基、杂环烷基、苯基或杂芳基稠合， 3-8元杂环烷基的任意 CH₂可被 C(O)取代； R ⁴ is sulfonyl, halogen, C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), d- ₆ alkoxy, amino, cyano, hydroxy, a phenyl group, a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group which is unsubstituted or substituted with at least one R ⁵ , wherein the cycloalkyl group, heterocycloalkyl group a phenyl or heteroaryl group may be fused to another cycloalkyl, heterocycloalkyl, phenyl or heteroaryl group, and any CH _{2 of the} 3-8 membered heterocycloalkyl group may be substituted by C(O);

R⁵为 C_1-6烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6烷基、 -C(0)-C_1-6烷基、 -(CH₂)_p-C(0)-0-C_1-6 烷基、 - (C¾)_p-0-C_1-6 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(C¾)_p-OH、氨基、氰基、羟基、 3-8元环垸基、苯基、 3- 8元杂环垸基；R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(C3⁄4) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ) -(C3⁄4) _p- OH, amino group, cyano group, hydroxy group, 3-8 membered ring fluorenyl group, phenyl group, 3- 8 membered heterocyclic fluorenyl group;

R^A、 R^B分别独立的为氢、 C 烷基、 -(C¾)_P-OC_1-6烷基、苄基或苯基乙基； p选自 1， 2， 3或 4。 R ^A and R ^B are each independently hydrogen, C alkyl, -(C3⁄4) _P -OC _1-6 alkyl, benzyl or phenylethyl; p is selected from 1, 2, 3 or 4.

5、如前述技术方案中任一项所述的化合物、其药学上可接受的盐或其立体异构体： 5. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， X、 Y分别独立地为 N或 CR¹, 其中 X、 Y至少有 1个为 N; Z、 W、 U、 G分别独立地为 N或 CR¹ , 其中 Z、 W、 U、 G至少有 1个为 N; among them, X and Y are each independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are each independently N or CR ¹ , wherein Z, W, U, G have at least 1 N is N;

R¹, R²分别独立的为氢、 C^₆烷基； R ¹ and R ² are each independently hydrogen and C ₆ alkyl;

n选自 0, 1， 2或 3; n is selected from 0, 1, 2 or 3;

1^为（^₆烷基、 ₆烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； 1^ is (^ ₆ alkyl, ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³ phenyl, quinolyl, 6-membered heteroaryl, 3-8 a cycloalkyl group or a 3-8 membered heterocycloalkyl group;

R³为

R ³ is

其中 m选自 0， 1， 2或 3， Where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、（^-₃烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 C_1-6烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的苯基、 5-6元杂芳基、 3-8元环烷基、 3-8元杂环烷基或 1，2，3,4-四氢异喹啉 -2-基，其中 3-8元杂环烷基的任意 CH₂可被 C(O)取代； R ⁴ is a sulfonyl group, a halogen, (^- ₃ alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), a C _1-6 alkoxy group, an amino group, a cyano group, a hydroxy group, a phenyl group which is unsubstituted or substituted with at least one R ⁵ , a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group or a 1,2,3,4-tetra Hydrogen isoquinolin-2-yl, wherein any CH _{2 of a} 3-8 membered heterocycloalkyl group may be substituted by C(O);

R⁵为 c_1-6烷基、 c_1-6烷氧基、 -c(o)-o-c_1-6烷基、 -c ^-c^烷基、

烷基、 -(CH₂)_p-0-C_1-6 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、氨基、氰基或羟基； R ⁵ is c _1-6 alkyl, c _1-6 alkoxy, -c(o)-oc _1-6 alkyl, -c ^-c^alkyl,

Alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino, cyanide Base or hydroxyl group;

R^A、 R^B分别独立的为氢、 C 烷基、 -(CH₂)_P-OC_1-3烷基或苄基， p选自 1， 2或 3。 R ^A and R ^B are each independently hydrogen, C alkyl, -(CH ₂ ) _P -OC _1-3 alkyl or benzyl, and p is selected from 1, 2 or 3.

6、如前述技术方案中任一项所述的化合物、其药学上可接受的盐或其立体异构体： 6. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， among them,

R¹, R²分别独立的为氢、 d.₆烷基； R ¹ , R ² are independently hydrogen, d. ₆ alkyl;

n选自 0, 1， 2或 3; n is selected from 0, 1, 2 or 3;

！^为。^烷基、 d.₆烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； ! ^为为. ^alkyl, d. ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³ phenyl, quinolyl, 6-membered heteroaryl, 3-8-membered naphthenic Or a 3-8 membered heterocycloalkyl group;

0 0

_R3为^ _R4或， _R 3 is ^ _R4 or,

其中 m选自 0， 1， 2或 3， R⁴为磺酰基、卤素、 C_1-3烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 C_1-6烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的 5-6元杂芳基、 3-8元杂环烷基或 1 ,2,3,4-四氢异喹啉 -2-基，其中 3-8元杂环烷基的任意 CH₂可被 C(O)取代； Where m is selected from 0, 1, 2 or 3, R ⁴ is a sulfonyl group, a halogen, a C _1-3 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), a C _1-6 alkoxy group, an amino group, a cyano group, a 5-6 membered heteroaryl group, a 3-8 membered heterocycloalkyl group or a 1,2,3,4-tetrahydroisoquinolin-2-yl group which is unsubstituted or substituted with at least one R ⁵ , wherein 3 Any CH ₂ of an 8- to 8-membered heterocycloalkyl group may be substituted by C(O);

R⁵为 Ci_-3烷基、 Ci_-6烷氧基、 -C(0)-0-Ci.₆烷基、 -C(0)-Ci_-3烷基、 -(CH₂)p-C(0)-0-Ci.₃ 烷基、 -(CH₂)_p-0-C_1-3 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、氨基、 ^J^或羟基； R ⁵ is Ci _-3 alkyl, Ci _-6 alkoxy, -C(0)-0-Ci. ₆ alkyl, -C(0)-Ci _-3 alkyl, -(CH ₂ )pC(0 -0-Ci. ₃ alkyl, -(CH ₂ ) _p -0-C _1-3 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p- OH, amino, ^J^ or hydroxy;

R^a、 R^b分别独立的为氢、（^₆烷基、 -(CH₂)_p-OCw烷基或苄基， R ^a and R ^b are each independently hydrogen, (^ ₆ alkyl, -(CH ₂ ) _p -OCw alkyl or benzyl,

p选自 1 , 2或 3。 p is selected from 1, 2 or 3.

7、如前述技术方案中任一项所述的化合物、其药学上可接受的盐或其立体异构体： 7. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

其中， among them,

R¹ , R²分别独立的为氢、甲基或乙基； R ¹ and R ² are each independently hydrogen, methyl or ethyl;

n选自 0， 1 , 2或 3 ; n is selected from 0, 1 , 2 or 3 ;

L为烷基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、吡啶基、嘧啶基、环己烷基、哌啶基、四氢吡喃基、哌嗪基或吗啉基； L is alkyl, -N(R ^a R ^b ), unsubstituted or substituted with at least one R ³ phenyl, quinolyl, pyridyl, pyrimidinyl, cyclohexane, piperidinyl, tetrahydropyridyl Meryl, piperazinyl or morpholinyl;

0 0

_R3为^ R₄或 ^e、_R4， _R 3 is ^ R ₄ or ^e , _R4 ,

其中 m选自 0或 1 , Where m is selected from 0 or 1

R⁴为磺酰基、卤素、 C_1-3烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、未被取代或至少被一个 R⁵取代的吡啶基、吡唑基、咪唑基、嘧啶基、 1,2，3,4-四氢异喹啉-2- 基、吗啉基、哌啶基、哌嗪基、四氢吡咯 2-酮基； R ⁴ is a sulfonyl group, a halogen, a C _1-3 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), a pyridyl group which is unsubstituted or substituted with at least one R ⁵ , pyrazolyl, imidazolyl, pyrimidinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrole 2-keto;

R⁵为 C_1-3烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6烷基、 -C(0)-C_1-3烷基、 -(CH₂)p-C(0)-0-C₁_₃ 烷基、 -(CH₂)_p-0-C_1-3 烷基、 -(C¾)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH; R ⁵ is C _1-3 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-3 alkyl, -(CH ₂ ) pC(0)-0-C ₁ _ ₃ alkyl, -(CH ₂ ) _p -0-C _1-3 alkyl, -(C3⁄4) _p -C(0)N(R ^a R ^b ), - (CH ₂ ) _p -OH;

R^a、 R^b分别独立的为氢、 C_1-6烷基、 -(CH^-OCw烷基或苄基， R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, -(CH^-OCw alkyl or benzyl,

p选自 1， 2或 3。 p is selected from 1, 2 or 3.

8. 如技术方案 1-7中任一项所述的化合物、其药学上可接受的盐或其立体异构体， 8. The compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Isomers,

其中 X和 Y中的一个是 N，另一个是 0 ¹。 One of X and Y is N and the other is 0 ¹ .

9. 如技术方案 1-8中任一项所述的化合物、其药学上可接受的盐或其立体异构体， 9. The compound according to any one of claims 1-8, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

其中 Z代表 CH， W代表 CH; Where Z stands for CH and W stands for CH;

U代表 N， G代表 N。 U stands for N and G stands for N.

10、选自以下的化合物、其药学上可接受的盐或其立体异构体: 10. A compound selected from the group consisting of a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

01 01

M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

II II

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680

680

n n

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98i / 0Z OAV 680000/M0ZN3/X3d 98i / 0Z OAV

91 91

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

LI LI

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

81 81

680000/1-lOiN3/X3d 98\m/noz OAV 680000/1-lOiN3/X3d 98\m/noz OAV

61 61

680000/ίΊ01Μ3/Χ3<Ι 98ΐ Ϊ/Π0ε ΟΛ\ 680000/ίΊ01Μ3/Χ3<Ι 98ΐ Ϊ/Π0ε ΟΛ\

oz Oz

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

11、选自以下的化合物、其药学上可接受的盐或其立体异构体，所述化合物选自： 11. A compound selected from the group consisting of a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the compound being selected from the group consisting of:

12、一种药物组合物，其包括技术方案 1 ~ 11任一项所述的化合物、其药学上可接受的盐或其立体异构体与一种或多种药用载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

13、技术方案 1 ~ 11任一项所述的化合物、其药学上可接受的盐或其立体异构体或技术方案 12的药物组合物在制备治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症（如过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼）、肺纤维化、肝纤维化、脂肪肝或肝硬化的药物中的用途。 13. The compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 12, for the preparation of a medicament for treating and/or preventing ischemia-reperfusion injury, diabetes , neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma), lung Use in drugs for fibrosis, liver fibrosis, fatty liver or cirrhosis.

14、一种治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症（如过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼）、肺纤维化、肝纤维化、脂肪肝或肝硬化的方法，包括给予需要其的患者治疗有效量的技术方案 1 - 12任一项所述的化合物、其药学上可接受的盐或其立体异构体或技术方案 13的药物组合物。 15、用于治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症（如过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼）、肺纤维化、肝纤维化、脂肪肝或肝硬化的技术方案 1 ~ 12任一项所述的化合物、其药学上可接受的盐或其立体异构体或技术方案 13的药物组合物。具体实施方式 14. A treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, Methods of allergic keratitis, dry eye, retinopathy, glaucoma, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis, including administering a therapeutically effective amount of a technical solution to a patient in need thereof 1 - 12 A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of claim 13. 15. For the treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or A stereoisomer thereof or a pharmaceutical composition of claim 13. detailed description

在本发明中，术语"卤素，，指氟原子、氯原子、溴原子或碘原子。 In the present invention, the term "halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

在本发明中 , 术语 "C^₆烷基"指含有 1-6个碳原子的直链或支链的烷基，其中包括例如 "d_₅烷基"、 "CM烷基"、 "Cw烷基"等；其实例包括但不限于例如甲基、乙基、正丙基、异丙基、正丁基、 2-甲基丙基、 1-曱基丙基、 1，1-二曱基乙基、正戊基、 3-甲基丁基、 2-甲基丁基、 1-曱基丁基、 1-乙基丙基、正己基、 4-曱基戊基、 3-甲基戊基、 2-甲基戊基、 1-甲基戊基、 3，3-二曱基丁基、 2，2-二甲基丁基、 1,1-二甲基丁基、 1,2-二甲基丁基、 1，3-二甲基丁基、 2,3-二曱基丁基、 2-乙基丁基、 1 ,2-二曱基丙基等。术语" C_1-5烷基"、 "CM烷基"、 "C_1-3 烷基"指上述实例中的分别含有 1-5个碳原子、 1-4个碳原子、 1-3个碳原子的具体实例。 In the present invention, the term "C ^ ₆ alkyl" refers to straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example "d_ ₅ alkyl", "the CM alkyl", "alkoxy Cw of Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-mercaptopropyl, 1,1-didecyl Ethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-mercaptobutyl, 1-ethylpropyl, n-hexyl, 4-decylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 3,3-dimercaptobutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 1,3-dimethylbutyl, 2,3-didecylbutyl, 2-ethylbutyl, 1,2-dimercaptopropyl, and the like. The terms "C _1-5 alkyl", "CM alkyl", "C _1-3 alkyl" mean that the above examples contain 1-5 carbon atoms, 1-4 carbon atoms, 1-3 carbons, respectively. Specific examples of atoms.

在本发明中，术语" <^₆烯基"指含有双键的碳原子数为 2〜6的直链或支链或环状的烃基，其中包括例如 "C_2-5烯基"、 "CM烯基"、 "C_2-3烯基"、 "C_3-6环烯基，，等；其实例包括但不限于例如乙烯基、 1-丙浠基、 2-丙烯基、 1-曱基乙烯基、 1-丁烯基、 2-丁烯基、 3-丁烯基、 1-曱基 -1-丙婦基、 2-甲基小丙烯基、In the present invention, the term "< _{6 6} alkenyl" means a straight or branched or cyclic hydrocarbon group having 2 to ₆ carbon atoms containing a double bond, and includes, for example, "C _2-5 alkenyl group", CM alkenyl", "C _2-3 alkenyl", "C _3-6 cycloalkenyl, and the like; examples thereof include, but are not limited to, for example, vinyl, 1-propenyl, 2-propenyl, 1-indole Vinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-decyl-1-propanyl, 2-methylpropenyl,

1-曱基 -2-丙蜂基、 2-甲基 -2-丙烯基、 1-戊烯基、 2-戊烯基、 3-戊烯基、 4-戊烯基、 1-曱基小丁烯基、 2-甲基 -1-丁烯基、 3-甲基 -1-丁烯基、 1-曱基 -2-丁烯基、1-mercapto-2-propanyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-decyl Butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-indolyl-2-butenyl,

₂—曱基 _₂_丁烯基、 3-甲基 -2-丁烯基、 1-曱基 -3-丁烯基、 2-曱基 -3-丁烯基、 3- 曱基 -3-丁烯基、 1,1-二甲基 -2-丙烯基、 1 ,2-二甲基 -1-丙烯基、 1，2-二曱基 -2- 丙烯基、乙基 -1-丙烯基、 1-乙基 -2-丙烯基、 1-己烯基、 2-己烯基、 3-己烯基、 4-己烯基、 5-己烯基、 1-甲基 -1-戊婦基、 2-曱基 -1-戊烯基、 3-甲基 -1-戊烯基、 4-曱基 -1-戊烯基、 1-曱基 -2-戊烯基、 2-甲基 -2-戊烯基、 3-甲基 -2-戊烯基、 4- 甲基 -2-戊烯基、 1-甲基 -3-戊婦基、 2-曱基 -3-戊烯基、 3-甲基 -3-戊烯基、 4-甲基 -3-戊烯基、 1-曱基 -4-戊烯基、 2-甲基 -4-戊烯基、 3-曱基 -4-戊烯基、 4-曱基 -4-戊晞基、 1 ,1-二甲基 -2-丁烯基、 1,1-二甲基 -3-丁烯基、 1，2-二曱基 -1-丁婦基、 1,2-二甲基 -2-丁烯基、 1 ,2-二甲基 -3-丁烯基、 1，3-二甲基 -1-丁烯基、 1，3-二甲基 -2-丁烯基、 1 ,3-二曱基 -3-丁烯基、 2,2-二甲基 -3-丁浠基、 2，3-二甲基小丁烯基、 2,3-二曱基 -2-丁烯基、 2,3-二曱基 -3-丁烯基、 3,3-二甲基 -1-丁烯基、 3，3- 二曱基 -2-丁浠基、 1-乙基 -1-丁烯基、 1-乙基 -2-丁烯基、 1-乙基 -3-丁烯基、 2- 乙基 -1-丁烯基、 2-乙基 -2-丁烯基、 2-乙基 -3-丁烯基、 1,1,2-三甲基 -2-丙烯基、 1-乙基 -1-甲基 -2-丙烯基、 1-乙基 -2-曱基 -1-丙烯基、 1-乙基 -2-甲基 -2-丙烯基、 1,3-丁二烯、 1,3-戊二烯、 1，4-戊二烯、 1，4-己二烯等；所述" C₃_₆环烯基 "其实例包括但不限于例如环丙烯基、环丁烯基、环戊烯基、 1,3-环戊二烯基、环己浠基、 1,4-环己二烯基等。 ₂ —fluorenyl _ ₂ _butenyl, 3-methyl-2-butenyl, 1-fluorenyl-3-butenyl, 2-mercapto-3-butenyl, 3-mercapto-3 -butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimercapto-2-propenyl, ethyl-1-propene , 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentyl Glycosyl, 2-mercapto-1-pentenyl, 3-methyl-1-pentenyl, 4-decyl-1-pentenyl, 1-decyl-2-pentenyl, 2-methyl 2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentyl, 2-mercapto-3-pentene , 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-decyl-4-pentenyl, 2-methyl-4-pentenyl, 3-fluorenyl -4-pentenyl, 4-mercapto-4-pentanyl, 1 ,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2- Dimercapto-1-butanyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butene Base, 1,3-dimethyl-2-butenyl, 1, 3-dimercapto-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3- Small methyl butene , 2,3-dimercapto-2-butenyl, 2,3-dimercapto-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-diindole 2-butanyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butene Base, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2 -propenyl, 1-ethyl-2-mercapto-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; examples of the "C ₃ _-6 cycloalkenyl group" include, but are not limited to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, 1 , 3-cyclopentadienyl, cyclohexyldecyl, 1,4-cyclohexadienyl and the like.

在本发明中，术语" 炔基"指含有三键的碳原子数为 3-6的直链或支链的烃基，其中包括例如 "( ₂_₅炔基"、 "Cw炔基"、 "C₂_₃炔基"等；其实例包括但不限于例如乙炔基、 2-丙炔基、 2-丁炔基、 3-丁炔基、 1-曱基 -2-丙炔基、 2-戊炔基、 3-戊炔基、 4-戊炔基、 1-甲基 -2-丁炔基、 1-曱基 -3-丁炔基、 2-甲基 -3- 丁炔基、 1,1-二曱基 -2-丙炔基、 1-乙基 -2-丙炔基、 2-己炔基、 3-己炔基、 4-己炔基、 5-己炔基、 1-甲基 -2-戊炔基、 1-甲基 -3-戊炔基、 1-曱基 -4-戊炔基、 2- 甲基 -3-戊炔基、 2-曱基 -4-戊炔基、 3-曱基 -4-戊炔基、 4-甲基 -2-戊炔基、 1,1- 二甲基 -2-丁炔基、 1,1-二甲基 -3-丁炔基、 1,2-二曱基 -3-丁炔基、 2,2-二曱基 -3- 丁炔基、 1-乙基 -2-丁炔基、 1-乙基 -3-丁炔基、 2-乙基 -3-丁炔基、 1-乙基小曱基 -2-丙炔基等。 In the present invention, the term "alkynyl" means a straight or branched hydrocarbon group having 3 to 3 carbon atoms, and includes, for example, "( ₂ _ ₅ alkynyl group), "Cw alkynyl group", C ₂ _ ₃ alkynyl group "and the like; examples thereof include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-propynyl Yue-2-yl, 2- Pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-indolyl-3-butynyl, 2-methyl-3-butynyl, 1 , 1-dimercapto-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1- Methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-indolyl-4-pentynyl, 2-methyl-3-pentynyl, 2-indolyl-4-pentyl Alkynyl, 3-mercapto-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butene Alkynyl, 1,2-dimercapto-3-butynyl, 2,2-dimercapto-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butyl Alkynyl, 2-ethyl-3-butynyl, 1-ethylberyl-2-propynyl, and the like.

在本发明中，术语" C_1-6烷氧基 "指" C_1-6烷基 -0-"基团，其中" Q_₆烷基"如前文所定义，其中包括例如 "Cw烷氧基"、 "CM烷氧基"、 "Cw烷氧基 "等；其实例包括但不限于例如曱氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、仲丁氧基、戊氧基、新戊氧基、己氧基等。 In the present invention, the term " _C1-6 alkoxy" means a " _C1-6 alkyl-0-" group, wherein "Q- ₆ alkyl" is as defined above, including, for example, "Cw alkoxy"","CMalkoxy","Cwalkoxy",etc.; examples thereof include, but are not limited to, decyloxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.

在本发明中，术语" 3-14元环烷基"指具有 3-14个碳原子的环烷基基团，其中包括例如 "3-12元环烷基"、 "3-10元环烷基"、 "3-8元环烷基"、 "3-6元环烷基"、 "5-10元环烷基"、 "5-8元环烷基"、 "5-10元环烷基"、 "4-6元环烷基" 等；也包括 "3-8元单环环烷基 "和" 6-14元稠环环烷基"。 In the present invention, the term "3-14 membered cycloalkyl group" means a cycloalkyl group having 3 to 14 carbon atoms, and includes, for example, "3-12 membered cycloalkyl group" and "3-10 membered cycloalkane". "", "3-8 membered cycloalkyl", "3-6 membered cycloalkyl", "5-10 membered cycloalkyl", "5-8 membered cycloalkyl", "5-10 membered cycloalkane" "", "4-6 membered cycloalkyl", etc.; also includes "3-8 membered monocyclic cycloalkyl group" and "6-14 membered fused ring cycloalkyl group".

所述" 3-8元单环环烷基"指具有 3-8个碳原子的单环环烷基，其中包括例如" 3-6元单环环烷基"、 "5-8元单环环烷基"、 "5-6元单环环烷基 "等；其实例包括但不限于：环丙烷基、环丁烷基、环戊垸基、环己烷基、环庚烷基、环辛烷基等；所述" 3-8元单环环烷基，，还可以进一步被 C 烷基取代，包括但不限于：曱基环丙烷基、二甲基环丙烷基、甲基环丁烷基、二曱基环丁烷基、曱基环戊烷基、二甲基环戊烷基、曱基环己烷基、二曱基环己烷基等。 The "3-8 membered monocyclic cycloalkyl group" means a monocyclic cycloalkyl group having 3 to 8 carbon atoms, and includes, for example, "3-6 membered monocyclic cycloalkyl group", "5-8 membered single ring" Cycloalkyl", "5-6 membered monocyclic cycloalkyl", etc.; examples thereof include, but are not limited to: cyclopropyl, cyclobutane, cyclopentanyl, cyclohexane, cycloheptyl, ring Octyl or the like; the "3-8 membered monocyclic cycloalkyl group, which may be further substituted by a C alkyl group, including but not limited to: nonylcyclopropane group, dimethylcyclopropane group, methylcyclobutene Alkyl, dinonylcyclobutane, decylcyclopentyl, dimethylcyclopentanyl, nonylcyclohexane, dinonylcyclohexane, and the like.

所述" 6-14元稠环环烷基 "指该稠环由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的稠环环烷基基团，其中包括例如 "6-12元稠环环烷基"、 "8-12元稠环环烷基"、 "7-10元稠环环烷基 "等；其实例包括但不限于：二环 [3.1.0]己烷基、二环 [4.1.0]庚烷基、二环 [2.2.0]己烷基、二环 [3.2.0]庚烷基、二环 [4.2.0]辛烷基、八氢茚基、十氢化萘基、十四氢菲基等。 The "6-14 membered fused ring cycloalkyl group" means a fused ring cycloalkyl group formed by the two or more cyclic structures sharing two adjacent carbon atoms with each other, including, for example, "6-12 yuan fused ring naphthenic ",""8-12 membered fused ring cycloalkyl group", "7-10 membered fused ring cycloalkyl group", etc.; examples thereof include, but are not limited to: bicyclo[3.1.0]hexane group, bicyclo[4.1 .0]heptyl, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydroindenyl, decahydronaphthyl, Tetrahydrophenanthyl and the like.

在本发明中，术语" 6-14元芳基"指具有 6-14个碳原子的芳香基团，其中包括例如" 6-10元芳基"；也包括 "6-8元单环芳基"和" 8-14元稠环芳基"。 In the present invention, the term "6-14 membered aryl" means an aromatic group having 6 to 14 carbon atoms, including, for example, "6-10 membered aryl group"; also includes "6-8 membered monocyclic aryl group" "And" 8-14 yuan fused ring aryl".

所述" 6-8元单环芳基，，包括例如苯基。 The "6-8 membered monocyclic aryl group" includes, for example, a phenyl group.

所述" 8-14元稠环芳基"是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的具有 8-14个碳原子且至少一个环为芳香性的稠环基团，其中包括 10-14元全部环为芳环的稠环芳基，例如萘、菲等。 The "8-14 membered fused ring aryl group" means that 8 to 14 carbon atoms and at least one ring are aromatic by two or more ring structures sharing two adjacent carbon atoms with each other. A fused ring group comprising 10-14 members of a fused ring aryl group in which all rings are aromatic rings, such as naphthalene, phenanthrene, and the like.

在本发明中，术语" 3-14元杂环烷基"指含有 3-14个环原子（其中至少含有一个杂原子）的环状基团，其中包括例如 "3-10元杂环烷基"、 "4-12元杂环烷基"、 "3-8元杂环烷基"、 "5-10元杂环烷基"、 "5-8元杂环烷基"、 "5-6元杂环烷基 "等，也包括 "3-8元单环杂环烷基"和" 6-14元稠环杂环烷基"，所述的杂原子有氮、氧和硫等，环原子为 CH₂时可以被氧代。 In the present invention, the term "3-14 membered heterocycloalkyl" means a cyclic group having 3 to 14 ring atoms (having at least one hetero atom), including, for example, "3-10 membered heterocycloalkyl"","4-12 membered heterocycloalkyl", "3-8 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "5-8 membered heterocycloalkyl", "5-6 a heterocycloalkyl group "etc., also includes "3-8 membered monocyclic heterocycloalkyl group" and "6-14 membered fused ring heterocycloalkyl group", and the hetero atom has nitrogen, oxygen, sulfur, etc., ring When the atom is CH ₂ , it can be substituted by oxo.

所述" 3-8元单环杂环烷基"，是指含有 3-8个环原子（其中至少含有一个杂原子）的单环杂环烷基，其中包括例如 "5-8元单环杂环烷基"、 "5-6元单环杂环烷基"、 "3-6元饱和单环杂环烷基 "等；其具体实例包括但不仅限于：氮杂环丙烷基、氮杂环丁烷基、硫杂环丁烷基、四氢呋喃基、四氢吡咯基、咪唑烷基、吡唑烷基、四氢呋喃基、 1，4-二氧杂环己烷基、 1,3-二氧杂环己烷基、 1,3-二硫杂环己烷基、哌啶基、吗啉基、哌嗪基等；进一步，环原子为 CH₂ 时可以被氧代，例如哌啶 -2-酮等。 The "3-8 membered monocyclic heterocycloalkyl group" means a monocyclic heterocycloalkyl group having 3 to 8 ring atoms (having at least one hetero atom), including, for example, a "5-8 membered monocyclic ring". a heterocycloalkyl group, a "5-6 membered monocyclic heterocycloalkyl group", a "3-6 membered saturated monocyclic heterocycloalkyl group", etc.; specific examples thereof include, but are not limited to: aziridine group, aza Cyclobutane, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl, 1,3-dioxo a heterocyclohexane group, a 1,3-dithiacyclohexane group, a piperidinyl group, a morpholinyl group, a piperazinyl group or the like; further, when the ring atom is CH ₂ , it may be substituted with oxo, for example, piperidine-2- Ketones, etc.

所述" 6-14元稠环杂环烷基"是指含有 6-14个环原子（其中至少含有一个杂原子）由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的稠环杂环烷基团，其中包括例如 "8-12元稠环杂环烷基"、 "7-10元稠环杂环烷基"、 "9-10元稠环杂环烷基"、 "9-12元稠环杂环烷基，，等；其具体实例包括但不仅限于：环丁烷并四氢吡咯基、环戊烷并四氢吡咯基、氮杂环丁烷并咪唑烷基等。 The "6-14 membered fused ring heterocycloalkyl group" means that 6 to 14 ring atoms (having at least one hetero atom) are bonded to each other by two or more ring structures. a fused ring heterocycloalkyl group formed, which includes, for example, "8-12 membered fused ring heterocycloalkyl group", "7-10 membered fused ring heterocycloalkyl group", "9-10 membered fused ring heterocycloalkane" "," 9-12 membered fused ring heterocycloalkyl, and the like; specific examples thereof include, but are not limited to, cyclobutanetetrahydropyrrolyl, cyclopentahydrotetrahydropyrrolyl, azetidine Imidazolidinyl and the like.

本发明所述的 "5-14元杂芳基"，其环原子除了碳原子外，还包括一个或多个杂原子，所述"杂原子 "包括但不限于氧原子、氮原子和 <原子。杂芳基可通过碳或杂环原子键合。包括 5-8元单环杂芳基和 8-14元稠杂环芳基。 The "5-14 membered heteroaryl group" of the present invention has a ring atom including one or more hetero atoms in addition to a carbon atom, and the "hetero atom" includes but is not limited to an oxygen atom, a nitrogen atom and an < atom . The heteroaryl group may be bonded through a carbon or a hetero atom. It includes a 5-8 membered monocyclic heteroaryl group and a 8-14 membered fused heterocyclic aryl group.

"5-8元单环杂芳基 "是指芳香性的含有杂原子的环状基团，其中包括例如" 5-6元单环杂芳基"、 "5-7元单环杂芳基 "等；其具体实例包括但不仅限于呋喃基、噻¹¹分基、吡咯基、咪唑基、噻唑基、 1,2，3-噻二唑基、 1，2，4-噻二唑基、 1，3,4-噻二唑基、吡唑基、 1，2,3-***基、 1，2,4-***基、吡啶基、噁唑基、异噁唑基、异噻唑基、 1,2，3-噁二唑基、 1,2,4-噁二唑基、 1,2,5-噁二唾基、 1,2,3- 三嗪基、 1，2，4-三嗪基、四唑基、噁***基、 2H-1,2-噁嗪基、 4H-1，2-噁嗪基、 6H-1,2-噁嗪基、 2H-1，3-噁嗪基、 4H-1,3-噁嗪基、 611-1，3-噁基、 2H-1，4-噁嗪基、 4H-1,4-噁嗪基、异噁嗪基、 1，3，5-三嗪基、 1,2,4，5-四嗪基、哒嗪基、嘧啶基和吡噪基。 The "5-8 membered monocyclic heteroaryl group" means an aromatic hetero atom-containing cyclic group including, for example, "5-6 membered monocyclic heteroaryl group" and "5-7 membered monocyclic heteroaryl group". "Equivalent examples include, but are not limited to, furyl, thia- ¹¹ , pyrrolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, oxazolyl, isoxazolyl, isothiazolyl 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadisyl, 1,2,3-triazinyl, 1,2,4- Triazinyl, tetrazolyl, oxatriazole, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3- Zinyl, 4H-1,3-oxazinyl, 611-1,3-oxa, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, isoxazinyl, 1,3 , 5-triazinyl, 1,2,4,5-tetraazinyl, pyridazinyl, pyrimidinyl and pyranyl.

所述" 8-14元稠杂环芳基 "是指全部的环均为芳香性环的稠杂环基团，其中包括例如" 8-12元稠杂环芳基"、 "9-10元稠杂环芳基"、 "10-14元稠杂环芳基"等，如苯并 5-8元单环杂芳基形成的稠杂环芳基， 5-8元单环杂芳基并 5-8 元单环杂芳基形成的稠杂环芳基等，其具体实例包括但不限于：苯并呋喃基、苯并异呋喃基、苯并噻吟基、吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、会淋基、异会啉基、吡，定并吡唑基、吡¹定并吡洛基、嘧¹定并吡唑基、嘧¹定并吡咯基、 p达，秦并吡唑基、。秦并吡咯基、吖¹⁷定基、菲啶基、苯并哒。秦基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、异吲哚、异吲哚基、吲嗪基、苯并二嗪基、苯并异噁唑基、苯并噁嗪基、吡唑并 [3，4-b]吡啶基等。 The "8-14 membered fused heterocyclic aryl group" means a fused heterocyclic group in which all of the rings are aromatic rings, and includes, for example, "8-12 membered fused heterocyclic aryl group" and "9-10 member". A fused heterocyclic aryl group, a "10-14 membered fused heterocyclic aryl group", or the like, a fused heterocyclic aryl group formed by a benzo-5-8 membered monocyclic heteroaryl group, a 5-8 membered monocyclic heteroaryl group A fused heterocyclic aryl group formed by a 5-8 membered monocyclic heteroaryl group, and the like, and specific examples thereof include, but are not limited to, benzofuranyl group, benzisofuranyl group, benzothiazepine group, fluorenyl group, benzoxanthene oxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, will leaching group, isopentyl group will morpholine, pyridine, and given pyrazolyl, pyrazolyl-pyrazole and ¹ set Rocky, ethyl and ^1-pyrazolyl given , pyrimidine ¹ and pyrrolyl, p-dar, and pyrazolyl,. Qinlopyrrolyl, 吖¹⁷ -decyl, phenanthryl, benzopyrene. Chalylene, pyridazinyl, quinazolinyl, quinoxalinyl, phenolzinyl, acridinyl, fluorenyl, isoindole, isodecyl, pyridazinyl, benzodiazinyl, benzo Oxazolyl, benzoxazinyl, pyrazolo[3,4-b]pyridyl and the like.

在本发明中，术语" 7-12元桥环基"是指任意两个环共用两个不直接相连的原子形成的含有 7-12个环原子的脂肪烃基，所述环原子可以全部为碳原子或含有杂原子，所述的杂原子有氮、氧和硫等。所述" 7-12元桥环 "包括 "7-12 元饱和桥环基 "和" 7-12元不饱和桥环基"。 In the present invention, the term "7-12 membered bridged ring group" means an aliphatic hydrocarbon group having 7 to 12 ring atoms formed by any two rings sharing two atoms which are not directly connected, and the ring atoms may all be carbon. The atom or contains a hetero atom, and the hetero atom includes nitrogen, oxygen, sulfur, and the like. The "7-12 yuan bridge ring" includes "7-12 yuan saturated bridge ring base" and "7-12 yuan unsaturated bridge ring base".

所述" 7-12元饱和桥环基"，是指该桥环中的所有环均为饱和的环状基团， The "7-12 dollar saturated bridged ring group" refers to a cyclic group in which all rings in the bridge ring are saturated.

"7-10元饱和桥环基"、 "7-8元饱和桥环基 "等，其具体实例包括 "7-10 yuan saturated bridge ring base", "7-8 yuan saturated bridge ring base", etc., specific examples thereof include

所述" 7-12元不饱和桥环基，，，是指该桥环基中有至少有一个环为不饱和的环状基团，其中包括例如" 7-10元不饱和桥环基"、 "7-8元不饱和桥环基"等，其具体实例包括但不限于：

The "7-12 member unsaturated bridged ring group," means a cyclic group having at least one ring in the bridged ring group which is unsaturated, including, for example, "7-10 member unsaturated bridged ring group". , "7-8 yuan unsaturated bridge ring base", etc. Specific examples include, but are not limited to:

在本发明中，术语" 7-12元螺环基"是指一类由至少两个环共享一个原子形成的含有 7-12个环原子的脂肪烃基，所述环原子可以全部为碳原子或含有杂原子，所述的杂原子选自氮、氧和硫等。其中包括例如" 7-11元螺环基"、 "8-11 元螺环基"、 "9-10元螺环基"等，也包括 "7-12元饱和螺环基 "和" 7-12元不饱和螺环基"。 In the present invention, the term "7-12 membered spirocyclic group" means a type of aliphatic hydrocarbon group having 7 to 12 ring atoms formed by sharing at least two rings with one atom, and the ring atoms may all be carbon atoms or Containing a hetero atom, the hetero atom is selected from the group consisting of nitrogen, oxygen, sulfur, and the like. These include, for example, "7-11 element spiro group", "8-11 element spiro group", "9-10 element spiro group", etc., including "7-12 yuan saturated spiro group" and "7- 12-membered unsaturated spiro ring base."

所述" 7-12元饱和螺环基"，是指该螺环基中的所有环均为饱和环，其中包括例如" 7-11元饱和螺环基"、 "8- "、 "9-10元饱 " The "7-12-membered saturated spirocyclic group" means that all of the rings in the spirocyclic group are saturated rings, including, for example, "7-11-membered saturated spiro group", "8-", "9-" 10 yuan full"

所述" 7-12元不饱和螺环基"，是指该螺环基中至少有一个环为不饱和的环，其中包括例如 "7-11元不饱和螺环基"、 "8-11元不饱和螺环基"、 "9-10元 The "7-12 member unsaturated spiro group" means that at least one ring of the spiro group is an unsaturated ring, including, for example, "7-11 member unsaturated spiro group", "8-11" Unsaturated spiro ring base", "9-10 yuan

在本发明中，杂原子是指 0， N， S， SO和 SO: In the present invention, a hetero atom means 0, N, S, SO and SO:

本发明的部分化合物： Some of the compounds of the invention:

结构式结构式

Structural structure

HZ HZ

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

98Ϊ Ϊ/ 0Ζ OAV 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

It It

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

3/X3d 98Ϊ Ϊ/ 0Ζ OAV 3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OW 680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OW

6£ 6 £

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

中间体 2 原料 3 式（ I )所示化合物

Intermediate 2 Starting material 3 Compound of formula (I)

(la) (lb) (la) (lb)

反应步骤 Reaction step

( 1 )将原料 1和丙二睛混合于无水乙醇中，加入冰乙酸，升温， 30-100。C 反应 5-24小时，反应液浓缩，硅胶柱层析 (石油醚→石油醚:乙酸乙酯 =1:0.5-2) 得到黄色固体； (1) Mixing raw material 1 and propylene diacetate in absolute ethanol, adding glacial acetic acid, and heating, 30-100. C reaction 5-24 hours, the reaction liquid was concentrated, and silica gel column chromatography ( petroleum ether: petroleum ether: ethyl acetate = 1:0.5-2)

( 2 )将中间体 1溶于四氢呋喃中，氮气保护，緩慢加入氢化钠， 0-30。C 下搅拌 10-120分钟，加入原料 2， 0-30。C下反应 5-24小时，加水，用盐酸调成弱酸性，析出固体，过滤，滤饼水洗，干燥滤饼，得到固体，直接用于下一步； (2) Dissolve Intermediate 1 in tetrahydrofuran, protect with nitrogen, and slowly add sodium hydride, 0-30. Stir at C for 10-120 minutes and add the starting material 2, 0-30. The reaction under C is carried out for 5-24 hours, water is added, the acidity is adjusted with hydrochloric acid, the solid is precipitated, filtered, the filter cake is washed with water, and the filter cake is dried to obtain a solid, which is directly used in the next step;

( 3 )将氢化钠加入到 A^V-二甲基乙酰胺中，加入原料 3， 0-30°C反应 10-120分钟后加入中间体 2, 之后升温至 50-150°C反应 3-15小时，旋干反应液，硅胶柱层析 (二氯甲烷→二氯曱烷:曱醇 =20:0.1- 5), 得式（I )所示化合物。 (3) Add sodium hydride to A^V-dimethylacetamide, add the raw material at 3, 0-30 ° C for 10 to 120 minutes, then add intermediate 2, then warm to 50-150 ° C reaction 3- After 15 hours, the reaction mixture was dried and purified by silica gel column chromatography (dichloromethane:dichlorohexane:methanol = 20:0.1 - 5) to give the compound of formula (I).

上反应方程式中的 X、 Y、 G、 U、 Z、 W、 L、 R¹, R²和 n如前文所定义，式（ I )所示化合物可以是它的异构体例如式（ I &)或（ I b)所示化合物。必要时，可用常规的保护剂对需要保护的官能团进行保护，此后通过常规方法脱去保护基团；必要时，也可对某些化合物进行制备，例如原料 1的制备。 X, Y, G, U, Z, W, L, R ¹ , R ² and n in the upper reaction equation are as defined above, and the compound of formula (I) may be an isomer thereof such as formula (I & Or a compound represented by (I b). If necessary, the functional group to be protected may be protected by a conventional protective agent, after which the protecting group is removed by a conventional method; if necessary, some compounds may also be prepared, for example, the preparation of the starting material 1.

本发明要求保护式（ I )、（ l a )或（ l b )所示化合物的"药学上可接受的盐，，，包括碱金属盐，如钠盐、钾盐、锂盐等；碱土金属盐，如钙盐、镁盐等；其他金属盐，如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等；无机碱盐，如铵盐；有机碱盐，如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、 N-曱基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、 Ν,Ν'-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、 Ν-苄基-苯乙基胺盐、哌嗪盐、四曱基胺盐、三 (羟曱基)胺基甲烷盐；氢卤酸盐，如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等；无机酸盐，如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等；低级烷横酸盐，如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等；芳基磺酸盐，如苯磺酸盐、对苯磺酸盐等；有机酸盐，如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等；氨基酸盐，如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。 The present invention claims "a pharmaceutically acceptable salt of a compound of the formula (I), (la) or (lb), including an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt or the like; an alkaline earth metal salt, Such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic alkali salts, such as ammonium salts; organic alkali salts, such as tert-octylamine salts , dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-decyl glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt , dicyclohexylamine salt, hydrazine, Ν'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, Ν-benzyl-phenethylamine salt, piperazine Salt, tetradecylamine salt, tris(hydroxyindenyl)aminomethane salt; hydrohalide salt, Such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkylate salts, such as methylsulfonate Acid salts, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonates such as besylate, p-benzenesulfonate, etc.; organic acid salts such as acetate, malate, Fumar Acid salts, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts such as glycinate, trimethylglycine, arginine, ornithine, glutamic acid Salt, aspartate, etc.

本发明要求保护式（ I )、（ l a )或（ l b )所示化合物的 "立体异构体"，当化合物结构中存在一个或多个不对称碳原子时，会产生对映异构体；当化合物含有烯基或者环状结构时，会产生顺 /反异构体；当化合物存在有酮或者肟时，会产生互变异构体等等。所有这些异构体及混合物都本发明的范畴。 The present invention claims a "stereoisomer" of a compound of formula (I), (la) or (lb) which, when one or more asymmetric carbon atoms are present in the structure of the compound, will give rise to the enantiomer; When the compound contains an alkenyl group or a cyclic structure, a cis/trans isomer is produced; when a compound has a ketone or an anthracene, a tautomer or the like is produced. All such isomers and mixtures are within the scope of the invention.

本发明式（ I )、（ l a )或（ l b )所示化合物、其药学上可接受的盐或其立体异构体可以与一种或多种药用载体制成药物制剂。所述药物制剂指临床上使用的常规制剂 , 可以口服或肠胃外给药等方式施用于需要这种治疗的患者。如片剂、颗粒、胶嚢、粉末、注射剂、吸入剂、舌下给药制剂、糖浆、凝胶、油膏、栓剂、洗剂、鼻腔滴剂、滴眼剂、喷雾剂、透皮制剂等。这些制剂可以通过常规方法，添加药用载体如赋形剂、黏合剂、增湿剂、崩解剂、增稠剂等制备而成。 The compound of the formula (I), (l a ) or ( l b ), a pharmaceutically acceptable salt thereof or a stereoisomer thereof of the present invention may be formulated into a pharmaceutical preparation together with one or more pharmaceutically acceptable carriers. The pharmaceutical preparation refers to a conventional preparation for clinical use, which can be administered orally or parenterally to a patient in need of such treatment. Such as tablets, granules, capsules, powders, injections, inhalants, sublingual preparations, syrups, gels, ointments, suppositories, lotions, nasal drops, eye drops, sprays, transdermal preparations, etc. . These preparations can be prepared by a conventional method, by adding a pharmaceutically acceptable carrier such as an excipient, a binder, a moisturizer, a disintegrating agent, a thickener or the like.

本发明式（ I )、（ l a )或（ l b )所示化合物、其药学上可接受的盐或其立体异构体可以用于治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症、肺纤维化、肝纤维化、脂肪肝或肝硬化等的疾病。 The compound of the formula (I), (la) or (lb) of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof can be used for the treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegenerative Diseases such as pathology, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.

慢性炎症包括过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼。 Chronic inflammation includes allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma.

在本文中，以下缩写具有下述含义： In this article, the following abbreviations have the following meanings:

HOAc: 乙酸 HOAc: Acetic acid

THF: 四氢呋喃 THF: tetrahydrofuran

DMA: N，N-二甲基乙醜胺 DMA: N,N-dimethylethyl acetamide

TLC: 薄层色谱 TLC: thin layer chromatography

DCM: 二氯甲烷 DCM: Dichloromethane

MeOH: 甲醇 MeOH: methanol

DMSO: 二甲基亚砜 DMSO: dimethyl sulfoxide

Ac: 乙酰基 Ac: acetyl

Me: 曱基 Me: 曱基

PE: 石油醚 EA: 乙酸乙酯 PE: petroleum ether EA: ethyl acetate

HATU: 2-(7-偶氮苯并三氮唑) -N，N，N，,N，-四曱基脲六氟磷酸酯 HATU: 2-(7-azobenzotriazole) -N,N,N,,N,-tetradecylurea hexafluorophosphate

TBS: 叔丁基二曱基硅基 TBS: tert-butyl bismuthyl silicon

TBSC1: 叔丁基二甲基氯硅烷 TBSC1: tert-butyldimethylchlorosilane

DIPEA: N，N-二异丙基乙胺 DIPEA: N,N-diisopropylethylamine

Boc: 叔丁氧羰基 Boc: tert-butoxycarbonyl

Hepes: 4-羟乙基哌嗪乙磺酸 Hepes: 4-Hydroxyethylpiperazineethanesulfonic acid

Brij-35: 十二烷基聚乙二醇醚 Brij-35: Dodecyl Polyglycol Ether

DTT: 二^ Τυ苏糖醇 DTT: Disaccharide

FAM: 羧基荧光素 FAM: Carboxyfluorescein

ΑΤΡ: 三磷酸腺苷 ΑΤΡ: adenosine triphosphate

ALT: 谷丙转氨酶 ALT: alanine aminotransferase

AST: 谷草转氨酶 AST: Aspartate aminotransferase

以下通过本发明化合物的体外酶学活性进一步阐述本发明化合物的有益效果，本发明其他化合物与试验中所列举的本发明化合物具有相同的有益效果，但不应将此理解为本发明化合物仅具有下列有益效果。 The beneficial effects of the compounds of the invention are further illustrated by the in vitro enzymatic activity of the compounds of the invention, and the other compounds of the invention have the same beneficial effects as the compounds of the invention recited in the tests, but it should not be construed that the compounds of the invention have only The following benefits.

实验例 1 本发明化合物的体外药理活性 Experimental Example 1 In vitro pharmacological activity of the compound of the present invention

供试品：本发明部分化合物，按照实施例方法制备；对照药 AS-602801 , 自制。 Test sample: Part of the compound of the present invention was prepared according to the method of the example; the reference drug AS-602801 was prepared.

实验方法：酶学实验 ( enzyme assay ) Experimental method: enzyme assay

Caliper Mobility- Shift J K2 Assay: Caliper Mobility- Shift J K2 Assay:

准确称取供试品，加入 DMSO溶解，充分混匀，配成 10 mM。用 DMSO 将其稀释至 50倍终浓度。转移 ΙΟΟμΙ化合物至％孔板中，进行 3倍系列稀释，共 10个浓度。转移 ΙΟμΙ化合物至新的 96孔板中，再向该 96孔板每孔加入 90ul激酶緩冲液（ 50mM Hepes pH 7.5, 10 mM MgCl₂, 0.0015% Brij-35, 2mM DTT ) 。化合物的终浓度最大为 10μΜ。转移 5ul至 384孔板中后，加入 ΙΟμΙ 包含 JNK2 的激酶緩冲液，室温孵育 30min后，加入 ΙΟμΙ 包含 FAM-labeled peptide和 ATP的肽緩冲液， 28°C孵育特定时间后，加入 25μ1 的终止液，终止反应。电泳分离检测底物和产物， Caliper's Reviewer软件计算转化率，通过以下公式计算抑制率，抑制率用 Prism 5.0计算 IC₅Q值。 The test sample was accurately weighed, dissolved in DMSO, and thoroughly mixed to prepare 10 mM. It was diluted to a final concentration of 50 times with DMSO. The ΙΟΟμΙ compound was transferred to a % well plate and serially diluted 3 times for a total of 10 concentrations. The ΙΟμΙ compound was transferred to a new 96-well plate, and 90 ul of kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl ₂ , 0.0015% Brij-35, 2 mM DTT) was added to each well of the 96-well plate. The final concentration of the compound is at most 10 μΜ. After transferring 5 ul to 384-well plate, add ΙΟμΙ kinase buffer containing JNK2, incubate for 30 min at room temperature, add ΙΟμΙ peptide buffer containing FAM-labeled peptide and ATP, incubate at 28 °C for a specific time, add 25μ1 Stop the solution and stop the reaction. The substrate and product were separated by electrophoresis, and the conversion was calculated by Caliper's Reviewer software. The inhibition rate was calculated by the following formula. The inhibition rate was calculated using Prism 5.0 to calculate the IC ₅ Q value.

抑制率 = [转化率 (ZPE)-转化率 (样品 )]χ 100/ [转化率 (ZPE)-转化率 (HPE)] 注： ΗΡΕ: 不加酶的空白对照； ΖΡΕ: 不加化合物的空白对照。 Inhibition rate = [conversion rate (ZPE) - conversion rate (sample)] χ 100 / [conversion rate (ZPE) - conversion rate (HPE)] Note: ΗΡΕ: blank control without enzyme; ΖΡΕ: blank without compound Control.

实验结果和结论：表 1 本发明化合物对 JNK2的 IC₅₀值 Experimental results and conclusions: Table 1 IC ₅₀ values of the compounds of the invention against JNK2

化合物 JNK2酶学抑制活性 IC₅Q ( nM )Compound JNK2 enzymatic inhibitory activity IC ₅ Q ( nM )

AS-602801 320 AS-602801 320

化合物 1 177 Compound 1 177

化合物 2 309 Compound 2 309

结论：由表 1可见，本发明化合物对 JNK2酶具有一定程度的抑制活性。实验例 2 本发明化合物的体外药理活性 Conclusion: It can be seen from Table 1 that the compound of the present invention has a certain inhibitory activity against JNK2 enzyme. Experimental Example 2 In vitro pharmacological activity of the compound of the present invention

供试品：本发明部分化合物，按照实施例方法制备；对照药 AS-602801 , 根据 WO2003047570的方法自制。 Test sample: A part of the compound of the present invention was prepared according to the method of the example; the reference drug AS-602801 was prepared according to the method of WO2003047570.

实验方法：醉学实验（enzyme assay ) Experimental method: Enzyme assay

HTRF JNK2 Assay (均相时间分辨荧光技术测定 JNK2酶的活性实验）：本实验采用 HTRF方法（ Cisbio )测定化合物对 JNK2的抑制活性。准确称取供试品，加入 DMSO溶解，充分混匀，配成 10 mM。用 DMSO将其稀释至 50倍终浓度。转移 30μ1化合物至 96孔板中，进行 4倍系列稀释，共 7 个浓度。再分别取 2μ1转移至含有 38μ1 Kinase buffer 中，得到终浓度最大为 HTRF JNK2 Assay (Standard time-resolved fluorescence technique for the determination of JNK2 enzyme activity): This experiment used the HTRF method (Cisbio) to determine the inhibitory activity of compounds on JNK2. Accurately weigh the test sample, add it to DMSO, mix well, and mix it into 10 mM. It was diluted with DMSO to a final concentration of 50 times. Transfer 30 μl of the compound to a 96-well plate and perform a 4-fold serial dilution for a total of 7 concentrations. Then transfer 2μ1 to 38μ1 Kinase buffer to get the maximum concentration.

25μΜ的工作液。将该化合物分别加至 384孔板中，每孔 4μ1。再加入浓度为25μΜ working solution. This compound was separately added to a 384-well plate at 4 μl per well. Add the concentration to

0.04n^l 的 JNK2激酶 2μ1，孵育 lOmin后，加入 ATP和底物 ATF-2 ( Cell0.04n^l of JNK2 kinase 2μ1, after incubation for 10 min, add ATP and substrate ATF-2 ( Cell

Signaling )混合液 4μ1。 25°C孵育 30min后，加入 Anti-GST-XL665单克隆抗体（Cisbio )和抗 phospho ATF2 Antibody-Cryptate ( Cisbio )混合液。 25 °C 孵育 lh后，用酶标仪分别检测检测样品在 615nm和 665nm处的荧光值。数据处理如下： Signaling ) Mix 4μ1. After incubating for 30 min at 25 °C, a mixture of Anti-GST-XL665 monoclonal antibody (Cisbio) and anti-phospho ATF2 Antibody-Cryptate (Cisbio) was added. After incubation at 25 °C for 1 h, the fluorescence values of the samples at 615 nm and 665 nm were detected by a microplate reader. The data is processed as follows:

Ratio= ( 665nm荧光值 /615nm荧光值 ) ΐθ⁴ Ratio= (665nm fluorescence value / 615nm fluorescence value) ΐθ ⁴

, ，， Ratio ( Positive ) -Ratio ( Sample ) , ,, Ratio ( Positive ) -Ratio ( Sample )

%抑制率 = —— - ^ -—— xl 00% % inhibition rate = —— - ^ -—— xl 00%

Ratio ( Positive ) -Ratio ( negative ) Ratio ( Positive ) -Ratio ( negative )

STDEV ( Positive ) +STDEV ( negative ) STDEV ( Positive ) +STDEV ( negative )

Z'=l-3x Z'=l-3x

AVERAGE ( Positive ) - AVERAGE ( negative ) AVERAGE ( Positive ) - AVERAGE ( negative )

采用 GraphPad 5.0软件进行曲线拟合，拟合方程为 Curve fitting was performed using GraphPad 5.0 software, and the fitting equation was

Y=Bottom + (Top-Bottom)/(l+10^A((LogIC₅₀-X)*HillSlope)), 得出 IC₅₀值' 表 2 本发明化合物对 JNK2的 IC₅o值 Y=Bottom + (Top-Bottom)/(l+10 ^A ((LogIC ₅₀ -X)*HillSlope)), gives the IC ₅₀ value' Table 2 IC ₅ o values of the compounds of the invention against JNK2

化合物 Compound

AS-602801 995 AS-602801 995

化合物 3 539 化合物 5 275 Compound 3 539 Compound 5 275

化合物 29 214 Compound 29 214

化合物 31 881 Compound 31 881

化合物 93 844 Compound 93 844

化合物 89 358 Compound 89 358

化合物 119 231 Compound 119 231

化合物 217 527.6 Compound 217 527.6

化合物 222 810.8 Compound 222 810.8

结论：由表 2可见，本发明化合物对 JNK2具有较好的抑制活性均好于对照药 AS-602801。 Conclusion: It can be seen from Table 2 that the compound of the present invention has better inhibitory activity against JNK2 than the reference drug AS-602801.

实验例 3 本发明化合物的大鼠体内药物动力学特征 Experimental Example 3 Pharmacokinetic characteristics of the compound of the present invention in rats

供试品：本发明部分化合物，按照实施例方法制备 Test sample: part of the compound of the invention, prepared according to the method of the example

实脸方法：大鼠体内 PK实验 ( in vivo PK evaluation in rats ) Real face method: PK experiment in rats ( in vivo PK evaluation in rats )

1.动物实验 Animal experiment

正常 SD大鼠，静脉推注给药 (iv)和灌胃给药 (po)， 3只 /给药途径。供试品给药剂量分别为 2 mg/kg和 4 mg/kg,给药浓度都为 1 mg/ml，给药体积分别为 2 ml/kg和 4 ml/kg。 iv (静脉推注）给药的 SD大鼠，于给药后 0.083h, 0.25h, 0.5h, lh, 2h, 4h, 6h, 8h, 24h 由尾静脉采血； po (口服）给药的 SD大鼠，于给药后 0.17h， 0.5h, lh, 2h, 4h， 6h， 8h, 24h由尾静脉采血。所得到的全血置于肝素化试管中。低速离心（3500转 /分） 8 min后分离血浆，乎 4。C避光保存。待实验完成后，所有血桨样品置于 -70。C冰箱保存。 Normal SD rats, intravenous bolus (iv) and intragastric administration (po), 3 / route of administration. The test doses were 2 mg/kg and 4 mg/kg, respectively, at a concentration of 1 mg/ml, and the doses were 2 ml/kg and 4 ml/kg, respectively. Iv (intravenous bolus) SD rats were administered with blood from the tail vein at 0.083h, 0.25h, 0.5h, lh, 2h, 4h, 6h, 8h, 24h after administration; po (oral) dosed SD Rats were bled from the tail vein at 0.17 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration. The resulting whole blood was placed in a heparinized test tube. Plasma was separated after 8 min of low-speed centrifugation (3500 rpm). C is protected from light. After the experiment was completed, all blood paddle samples were placed at -70. C refrigerator to save.

2.样品分析 2. Sample analysis

从水箱（-70°C) 中取出待测样品，室温自然融化后涡旋 3 min。精密移取 20 μΐ样品至 1.5 ml离心管中。加入 200 μΐ含内标溶液（ AS-602801 50ng/ml 曱醇溶液）涡旋 3 min后，离心 5 min ( 12000转 /分钟）。精密移取 50 μΐ上清液加入 150μ1水，涡旋 3 min后进 LC-MS/MS***进行样品分析。受试物浓度使用 AB公司的 Analyst 1.6.1输出结果。 Microsoft Excel计算均值、标准差、变异系数等参数（Analyst 1.6.1直接输出的不用计算）， PK参数采用 Pharsight Phoenix 6.2软件非房室模型 (NCA)计算。 3. 实验结果 The sample to be tested was taken out from the water tank (-70 ° C), and naturally fused at room temperature and vortexed for 3 min. Precision transfer of 20 μΐ sample into a 1.5 ml centrifuge tube. After adding 200 μM of internal standard solution (AS-602801 50 ng/ml sterol solution) for 3 min, centrifuge for 5 min (12,000 rpm). The 50 μΐ supernatant was accurately transferred to 150 μl of water, vortexed for 3 min, and then analyzed by LC-MS/MS system. The concentration of the test substance was output using AB's Analyst 1.6.1. Microsoft Excel calculates parameters such as mean, standard deviation, coefficient of variation, etc. (Analyst 1.6.1 direct output is not calculated), and PK parameters are calculated using Pharsight Phoenix 6.2 software non-compartmental model (NCA). 3. Experimental results

表 3 本发明化合物在大鼠体内的 PK参数总结 Table 3 Summary of PK parameters of the compounds of the present invention in rats

tl/2_iv (h)/ AUC_inflv(h*ng/ml)/ Tl/2 _iv (h)/ AUC _inflv (h*ng/ml)/

化合物 F% Compound F%

tl/2_po (h) AUC_infpo(h*ng/ml) _Tl /2 _po (h) AUC _infpo (h*ng/ml)

1.19±0.12 2422士 310 1.19±0.12 2422士 310

AS-602801 68±12 AS-602801 68±12

1.32±0.55 3277士 603 1.32±0.55 3277士 603

1.08±0.10 5305±357 1.08±0.10 5305±357

化合物 5 78±42 Compound 5 78±42

2.97±1.16 8228士 4424 2.97±1.16 8228士 4424

6.75±4.88 11411士 1155 6.75±4.88 11411士 1155

化合物 29 119±56 Compound 29 119±56

4.17±0.67 26345±12318 4.17±0.67 26345±12318

2.65±0.97 6230±1162 2.65±0.97 6230±1162

化合物 89 83±14 Compound 89 83±14

8.17±1.24 8.17±1.24

3.52±0.16 11986士 1525 3.52±0.16 11986士 1525

化合物 93 109±18 Compound 93 109±18

3.00±0.18 3.00±0.18

3.27±0.60 100340士 16494 3.27±0.60 100340士 16494

化合物 217 97±7 Compound 217 97±7

2.75±0.23 2.75±0.23

2.30±0.56 11893±4267 2.30±0.56 11893±4267

化合物 218 100±21 Compound 218 100±21

4.95士 1.65 4.95 士 1.65

备注： tl/2为半衰期， AUC为暴露量， F%为生物利用度。 Remarks: tl/2 is the half-life, AUC is the exposure, and F% is the bioavailability.

本发明化合物 5的半衰期在 iv给药时，半衰期跟 AS-602801相当，而在 po给药时，半衰期是 AS-602801的两倍多，本发明化合物 5的暴露量及生物利用度均好于 AS-602801 , 本发明化合物 29的半衰期、暴露量及生物利用度军好于 AS-602801 , 因此本发明化合物跟 AS-602801相比在 PK方面具有较强的优势。 The half-life of the compound 5 of the present invention is equivalent to that of AS-602801 when administered iv, and the half-life is more than twice that of AS-602801 when po is administered, and the exposure amount and bioavailability of the compound 5 of the present invention are better than those of the compound 5 of the present invention. AS-602801, the half-life, exposure and bioavailability of the compound 29 of the present invention are better than AS-602801, so the compound of the present invention has a strong advantage in PK compared with AS-602801.

实验例 4 本发明化合物的体内药理活性 Experimental Example 4 In vivo pharmacological activity of the compound of the present invention

实验方法：刀豆蛋白诱导的急性肝炎模型 Experimental method: Concanavalin-induced acute hepatitis model

C57BL/6小鼠在 SPF级动物房适应 1周后，按照体重随机分为模型组和各给药组；试验前采用记号笔在小鼠尾部进行标记，并在笼具上标注试验编号，组别和试验日期；模型组动物给予溶媒 30min后（10ml/kg )，尾静脉给予刀豆蛋白（ Concanavalin A， ConA, 15mg/kg )；各给药组给药 30min后尾静脉给予相同剂量 ConA, 给予 ConA 7h后，小鼠由戊巴比妥钠麻醉（腹腔内注射 45mg/kg ), 眼内眦静脉窦取血 30(^1 ( SOP-DS-200024-A )，置于 1.5ml 不加抗凝剂的离心管中 ,室温静置 lh,血样采用 eppendorf 5424R离心机离心，离心条件为 3500rpm, 4°C , lOmin, 之后提取血清，其中 ΙΟΟμΙ血清采用全自动生化分析仪测定 ALT和 AST的含量，其余血清保存至 -80°C冰箱。 C57BL/6 mice were randomly divided into model group and each drug-administered group according to body weight after 1 week of adaptation in SPF-class animal room. Marks were used to mark the tail of the mouse before the test, and the test number was marked on the cage. Do not compare with the test date; the model group animals were given vehicle for 30 min (10 ml/kg), and the tail vein was given Concanavalin A (ConA, 15 mg/kg); after 30 minutes of administration, the same dose of ConA was given to the tail vein. After 7 days of ConA administration, the mice were anesthetized with sodium pentobarbital (45 mg/kg intraperitoneally), and 30 (^1 (SOP-DS-200024-A) was taken from the iliac sinus of the eye. The anticoagulant was centrifuged at room temperature for 1 h, and the blood sample was centrifuged using an eppendorf 5424R centrifuge. After centrifugation conditions were 3500 rpm, 4 ° C, lOmin, serum was extracted, and ΙΟΟμΙ serum was measured by automatic biochemical analyzer for ALT and AST content, and the remaining serum was stored in a -80 °C refrigerator.

表 4化合物对 ConA诱导的急性肝炎模型中小鼠血清 ALT和 AST的抑制作用 Inhibition of serum ALT and AST in mice induced by ConA-induced acute hepatitis in Table 4

化合物 ALT 7h降低⁰ /₀ AST 7h降低⁰ /₀ Compound ALT 7h decreased by ⁰ / ₀ AST 7h decreased by ⁰ / ₀

AS-602801 59 67 化合物 119 79 74 结论:本发明化合物能够显著降低急性肝炎模型小鼠 ALT和 AST的水平，且效果好于 AS-602801。 AS-602801 59 67 Compound 119 79 74 Conclusion: The compounds of the present invention can significantly reduce the levels of ALT and AST in acute hepatitis model mice, and the effect is better than AS-602801.

以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。实施例 1: 2-(2-(4- (吗啉代甲基)苄氧基)嘧啶 -4-基) -2- (噻唑并【5，4-W吡啶 -2-基)乙腈（化合物 1 )的制备 The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. The techniques implemented based on the above aspects of the present invention are all within the scope of the present invention. Example 1: 2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-Wpyridin-2-yl)acetonitrile (compound) Preparation of 1)

( 1 ) 2- (噻唑并 [5,4- ]吡啶 -2-基）乙腈的制备 (1) Preparation of 2-(thiazolo[5,4-]pyridin-2-yl)acetonitrile

干燥的圆底烧瓶内，分别加入 10 mL乙醇， 1.26 g ( 10 mmol ) 比啶 -1-疏醇， 660 mg ( 10 mmol ) 丙二腈， 720 mg ( 12 mmol )冰乙酸，加热回流反应 15 h, TLC监测反应结束。旋干溶剂，柱层析（DCM:MeOH=500:l )，得到黄色固体 1.01 g，收率 57.7%。In a dry round bottom flask, add 10 mL of ethanol, 1.26 g (10 mmol) of pyridin-1-ol, 660 mg (10 mmol) of malononitrile, 720 mg (12 mmol) of glacial acetic acid, and heat reflux. h, TLC monitors the end of the reaction. The solvent was evaporated to dryness (mjqqqqqq

-(2-氯嘧啶 -4-基) -2- (噻唑并 [5，4-6]吡啶 -2-基）乙腈的制备

Of (2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

干燥的反应瓶中，分别加入 20 mL THF, 1.01 g ( 5.77 mmol ) 2- (噻唑并 [5,4- )]吡啶 -2-基）乙腈， 346 mg ( 8.66 mmol ) 60%的 NaH， 860 mg ( 5.77 mmol ) 2，4-二氯嘧啶，室温下反应 15 h。加入冰水淬灭，加入稀盐酸调节至弱酸性，析出固体，抽滤，分别用水、曱醇、乙酸乙酯洗涤滤饼，干燥，得到黄色固体 860 mg, 收率 51.8%。 In a dry reaction flask, add 20 mL THF, 1.01 g ( 5.77 mmol) 2-(thiazolo[5,4- )]pyridin-2-yl)acetonitrile, 346 mg ( 8.66 mmol) 60% NaH, 860 Mg ( 5.77 mmol ) 2,4-Dichloropyrimidine, reacted at room temperature for 15 h. It was quenched by the addition of ice water, diluted with dilute hydrochloric acid to adjust to a weak acid, and the solid was precipitated, and filtered, and the filter cake was washed with water, decyl alcohol and ethyl acetate, and dried to give a yellow solid 860 mg, yield 51.8%.

( 3 ) 2-(2-(4- (吗啉代曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基) 乙腈 (3) 2-(2-(4-(morpholinoguanidino)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridine-2-yl)acetonitrile

将 1.24 g( 6 mmol )4- (吗啉代曱基)苄醇溶于 20 mL DMA中，加入 480 mg ( 12 mmol ) 60%的 NaH, 室温搅拌 1 h, 再加入 860 mg ( 2.99 mmol ) 2-(2- 氯嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈，加热至 100°C反应 15 h。将反应液倒入水水中，加入稀盐酸调节至酸性，析出固体粗品，抽滤，柱层析纯化（DCM:MeOH=20:l )，得到黄色固体 600 mg, 收率 43.8%。 1.24 g (6 mmol) of 4-(morpholinoindenyl)benzyl alcohol was dissolved in 20 mL of DMA, 480 mg (12 mmol) of 60% NaH was added, stirred at room temperature for 1 h, then 860 mg ( 2.99 mmol) was added. 2-(2-Chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, heated to 100 ° C for 15 h. The reaction mixture was poured into water, and the mixture was diluted with EtOAc (EtOAc) (EtOAc)

分子式： C₂₄H₂₂N₆0₂S; 分子量： 458.15; 质谱 (M+H): 458.9Molecular formula: C ₂₄ H ₂₂ N ₆ 0 ₂ S; Molecular weight: 458.15; Mass spectrum (M+H): 458.9

400 MHz): δ 11.70 (IH, br s), 8.29 (IH, d), 7.99 (1H， d)_: 7.79 (IH, d), 7.59 (2H, d), 7.50 (2H, d), 7.37 (IH, dd), 6.64 (IH, m), 5.70 (2H, s)， 4.15-3.93 (2H, m), 3.77-3.62 (4H, m), 2.93-2.77 (4H， m)。

400 MHz): δ 11.70 (IH, br s), 8.29 (IH, d), 7.99 (1H, d) _: 7.79 (IH, d), 7.59 (2H, d), 7.50 (2H, d), 7.37 ( IH, dd), 6.64 (IH, m), 5.70 (2H, s), 4.15-3.93 (2H, m), 3.77-3.62 (4H, m), 2.93-2.77 (4H, m).

实施例 2: 2-(2-(4- (吗啉代曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [4，5-c】吡啶 -2- 基) Example 2: 2-(2-(4-(morpholinoguanidino)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)

3-氨基吡啶 -4-硫醇的制备

Preparation of 3-aminopyridine-4-thiol

称取 4-氯 -3-硝基吡啶 (4.74 g, 30.0 mmol)和硫氢化钠 (5.04 g, 90.0 mmol)溶于 300 mL无水乙醇溶液中，室温下搅拌反应 1小时，之后加入保险粉 (sodium dithionite)(15.66 g, 90.0 mmol)的水溶液溶液 100 mL, 升温至 80°C反应 12小时，过滤，滤液浓缩，硅胶柱层析 (石油醚→石油醚:乙酸乙酯 =3:1)得到黄绿色固体 3.3 g, 收率 87%。 Weigh 4-chloro-3-nitropyridine (4.74 g, 30.0 mmol) and sodium hydrosulfide (5.04 g, 90.0 mmol) in 300 mL of absolute ethanol solution, stir at room temperature for 1 hour, then add the powder. 100 mL of an aqueous solution of (sodium dithionite) (15.66 g, 90.0 mmol), warmed to 80 ° C for 12 hours, filtered, and concentrated with silica gel column chromatography ( petroleum ether: petroleum ether: ethyl acetate = 3:1) Get yellow green The color solid was 3.3 g, and the yield was 87%.

( 2 ) 2- (噻唑并 [4,5-c]吡啶 -2-基）乙腈的制备 (2) Preparation of 2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

将 3- J^比啶 -4-硫醇 (2.52 g, 20.0 mmol)和丙二睛 (1.32 g, 20.0 mmol)混合于 150 mL无水乙醇中，加入 2.0 mL冰乙酸，升温至 80。C反应 12小时，反应液浓缩，硅胶柱层析 (石油瞇→石油醚:乙酸乙酯 =1 :1)得到黄色固体 2.6 g, 收率 74%。3-J^pyridin-4-thiol (2.52 g, 20.0 mmol) and propylene diacetate (1.32 g, 20.0 mmol) were mixed in 150 mL of absolute ethanol, and 2.0 mL of glacial acetic acid was added and the mixture was warmed to 80. The reaction was carried out for 12 hours, and the mixture was concentrated to silica gel column chromatography (eluent: petroleum oil: ethyl acetate = 1:1) to afford 2.6 g of a yellow solid.

-(2-氯嘧啶 -4-基) -2- (噻唑并 [4,5-c]吡啶 -2-基)乙腈的制备

Of 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

称取 2- (噻唑并 [4,5-c]吡啶 -2-基）乙腈 (1.75 g， 10.0 mmol)溶于 15 mL干燥的四氢呋喃中，氮气保护，緩慢加入氢化钠 (60%， 0.8 g， 20 mmol), 室温下搅拌半小时，之后加入 2，4-二氯嘧啶 (1.49 g, 10.0 mmol), 室温下反应 12小时，加水，用 1N的盐酸调成弱酸性，析出固体，过滤，滤饼水洗，干燥滤饼，得到固体 3.0 g, 直接用于下一步。 2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (1.75 g, 10.0 mmol) was weighed and dissolved in 15 mL of dry tetrahydrofuran, protected with nitrogen, slowly added sodium hydride (60%, 0.8 g , 20 mmol), stir at room temperature for half an hour, then add 2,4-dichloropyrimidine (1.49 g, 10.0 mmol), react at room temperature for 12 hours, add water, adjust to weak acidity with 1N hydrochloric acid, precipitate solid, filter, The filter cake was washed with water and the filter cake was dried to give a solid, 3.0 g, which was used directly in the next step.

( 4 ) 2-(2-(4- (吗啉代甲基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [4,5-c]吡啶 -2-基) 乙腈 (4) 2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

称取氢化钠 (60%， 0.4 g, 10 mmol)加入到 5 mL A^N-二甲基乙酰胺中，加入 4- (吗啉代曱基)苄醇 (1.04 g， 5.0 mmol), 室温反应 1小时后加入 2-(2-氯嘧啶 -4- 基) -2- (噻唑并 [4,5-c]吡啶 -2-基)乙腈 (0.719 g， 2.5 mmol), 之后升温至 100。C反应 8小时，旋干反应液，硅胶柱层析 (二氯甲烷→二氯甲烷:甲醇 =20:1)，得到产物 0.6 g, 收率 52.4%。 Sodium hydride (60%, 0.4 g, 10 mmol) was weighed into 5 mL of A^N-dimethylacetamide, and 4-(morpholinoguanidino)benzyl alcohol (1.04 g, 5.0 mmol) was added at room temperature. After 1 hour of reaction, 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (0.719 g, 2.5 mmol) was added, and then warmed to 100. After reacting for 8 hours, the reaction mixture was evaporated to silica gel column chromatography (dichloromethane: methylene chloride:methanol = 20:1) to yield product (yield: 52.4%).

分子式： C₂₄H₂₂N₆0₂S; 分子量： 458.15; 质谱 (M+H): 458.9 Molecular formula: C ₂₄ H ₂₂ N ₆ 0 ₂ S; Molecular weight: 458.15; Mass spectrum (M+H): 458.9

^-NMRiDMSO-^, 400 MHz): δ 8.89 (1Η, s), 8.22 (1H, m), 7.99 (1H, m), 7.84 (1H, m)， 7.55 (2H, d), 7.42 (2H, d), 6.63 (1H, m)， 5.61 (2H, s)， 3.81 (2H, s)， 3.67-3.58 (4H, m), 2.72-2.58 (4H， m)。 ^-NMRiDMSO-^, 400 MHz): δ 8.89 (1Η, s), 8.22 (1H, m), 7.99 (1H, m), 7.84 (1H, m), 7.55 (2H, d), 7.42 (2H, d), 6.63 (1H, m), 5.61 (2H, s), 3.81 (2H, s), 3.67-3.58 (4H, m), 2.72-2.58 (4H, m).

实施例 3: 2-(2-(4-((2，6-二曱基吗啉代)曱基)苄嘧啶 -4-基) -2- (噻唑并【5，4-W吡啶 -2-基）乙腈（化合物 3 )的制备 Example 3: 2-(2-(4-((2,6-Dimercaptomorpholino)indolyl)benzylpyrimidin-4-yl)-2-(thiazolo[5,4-Wpyridine-2 -base) preparation of acetonitrile (compound 3)

-二曱基吗啉代)甲基)苯曱酸曱酯的制备 Of bis-mercapto-morpholino)methyl)benzoic acid oxime ester

干燥的反应瓶中，分别加入 30mL甲醇， 576 mg (5.0 mmol) 2,6-二曱基吗啉， 2.46 g( 15 mmol)对甲酰基苯甲酸曱酯， lmL冰乙酸， 40°C反应 18h。再緩慢加入 4.24 g ( 20 mmol )三乙酰氧基硼氢化钠 , 继续反应 10 h。旋干溶剂 , 柱层析 ( PE:EA=10:1-5:1 ), 得到粗品 1.9 g白色固体。 In a dry reaction flask, add 30 mL of methanol, 576 mg (5.0 mmol) of 2,6-dimercaptomorpholine, 2.46 g (15 mmol) of p-formylbenzoate, 1 mL of glacial acetic acid, and react at 40 ° C for 18 h. . 4.24 g (20 mmol) of sodium triacetoxyborohydride was added slowly and the reaction was continued for 10 h. The solvent was sonicated and purified by column chromatography (PE: EA = 10: 1-5:1) to afford crude 1.9 g of white solid.

甲基吗啉代)曱基)苯基)曱醇的制备

Preparation of methylmorpholino)indenyl)phenyl) decyl alcohol

将上步得到的 1.9 g粗品溶于 40 mL四氢呋喃中，緩慢分批加入 760 mg ( 20 mmol )四氢铝锂，室温反应 1 h。加入氯化铵水溶液淬灭，硅藻土抽滤，曱醇洗涤滤饼，旋干滤液，制备液相色谱纯化（甲醇:水 =50:50w/w)得到白色固体 700 mg, 以上两步收率 59.5%。 The crude 1.9 g obtained in the previous step was dissolved in 40 mL of tetrahydrofuran, and 760 mg (20 mmol) of lithium aluminum hydride was slowly added in portions, and reacted at room temperature for 1 h. After quenching with aqueous ammonium chloride solution, diatomaceous earth was suction filtered, and the filter cake was washed with decyl alcohol. The filtrate was dried and purified by liquid chromatography (methanol: water = 50:50 w/w) to obtain a white solid, 700 mg. The rate is 59.5%.

( 3 ) 2-(2-(4-((2,6-二曱基吗啉代）曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [5,⁴- (3) 2- (2- (4 - ((2,6-Yue-yl morpholino) Yue-yl) benzyloxy) pyrimidin-4-yl) -2- (thiazolo [5, ⁴ -

将 470 mg (2 mmol) (4-((2，6-二甲基吗啉代)曱基)苯基)曱醇溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH，室温搅拌 1 h, 加入 288 mg ( 1 mmol)2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5，4-?]吡啶 -2-基）乙腈， Ν₂保护， 100°C 反应 18 h。加水，用稀盐酸调至中性，二氯曱烷萃取，水洗，干燥，旋干，柱层析（DCM→DCM:MeOH=100:l ), 得到黄色固体 140 mg，将其溶于 4mL 二氯甲烷中，緩慢加入 8mL***，析出固体，离心，得到黄色固体 40mg, 收率 8.2% 470 mg (2 mmol) of 4-((2,6-dimethylmorpholino)indolyl) decyl alcohol was dissolved in 10 mL of DMA, and 160 mg (4 mmol) of 60% NaH was added. Stir at room temperature for 1 h, add 288 mg (1 mmol) of 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-?]pyridin-2-yl)acetonitrile, Ν ₂ protected, 100 °C reaction for 18 h. Add water, adjust to neutral with dilute hydrochloric acid, dichloromethane extract, water wash, dry, spin dry, column chromatography (DCM: DCM: MeOH = 100:1) to give a yellow solid, 140 mg, dissolved in 4mL In methyl chloride, 8 mL of diethyl ether was slowly added to precipitate a solid, which was centrifuged to obtain 40 mg of a yellow solid, yield 8.2%.

分子式： C₂₆H₂₆N₆0₂S; 分子量： 486.2; 质镨 (M+H): 486.9 'H-NM CDMSO-^, 400 MHz): δ 8.25 (IH, d), 7.95 (1H， d), 7.80 (IH, d), 7.55 (2H, d), 7.42 (2H, d), 7.34 (1H， dd), 6.63 (IH, s)， 5.66 (2H， s)， 3.80 (2H， s), 3.68-3.55 (2H, m)， 2.94-2.83 (2H, m)， 2.15-1.98 (2H, m)， 1.02 (6H, d)。 Molecular formula: C ₂₆ H ₂₆ N ₆ 0 ₂ S; Molecular weight: 486.2; 镨 (M+H): 486.9 'H-NM CDMSO-^, 400 MHz): δ 8.25 (IH, d), 7.95 (1H, d), 7.80 (IH, d), 7.55 (2H, d), 7.42 (2H, d), 7.34 ( 1H, dd), 6.63 (IH, s), 5.66 (2H, s), 3.80 (2H, s), 3.68-3.55 (2H, m), 2.94-2.83 (2H, m), 2.15-1.98 (2H, m), 1.02 (6H, d).

实施例 4: 2-(2-(4- (哌啶 -1-基甲基)苄嘧啶 -4-基) -2- (噻唑并【5,4-6】吡啶 -2- Example 4: 2-(2-(4-(piperidin-1-ylmethyl)benzylpyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-

( 1 ) 4- (哌啶 -1-基甲基)苯甲酸甲酯的制备 (1) Preparation of methyl 4-(piperidin-1-ylmethyl)benzoate

^CQzMe 干燥的反应瓶中，分别加入 30 mL曱醇， 852 mg ( 10 mmol )哌啶， 1.64 g ( lO mmol )对甲酰基苯甲酸甲酯， I mL冰乙酸， 40°C反应 18 h。再緩慢加入 2.54 g ( 12 mmol )三乙酰氧基硼氢化钠，继续反应 10 h。旋干，柱层析 ( PE:EA=5:1→100%EA )，得到粗品 1.4 g白色固体。 ^CQzMe In a dry reaction flask, add 30 mL of sterol, 852 mg (10 mmol) of piperidine, 1.64 g (10 mmol) of methyl p-formylbenzoate, 1 mL of glacial acetic acid, and react at 40 ° C for 18 h. Further, 2.54 g (12 mmol) of sodium triacetoxyborohydride was added slowly, and the reaction was continued for 10 h. Spin dry, column chromatography (PE: EA = 5:1 - >

( 2 ) (4- (哌啶小基甲基)苯基)甲醇的制备 (2) Preparation of (4-(piperidinylmethyl)phenyl)methanol

将上步得到的 1.4 g粗品溶于 40 mL四氢呋喃中，緩慢分批加入 600 mg ( 15.8 mmol )四氢铝锂，室温反应 1 h。加入氯化铵水溶液淬灭，硅藻土抽滤，曱醇洗涤滤饼，旋干滤液，制备液相色谱纯化（甲醇：水 =50:50w/w )得到白色固体 850 mg, 以上两步收率 41.4%。 1.4 g of the crude product obtained in the previous step was dissolved in 40 mL of tetrahydrofuran, and 600 mg (1. 8 mmol) of lithium tetrahydrogenate was slowly added in portions, and reacted at room temperature for 1 h. After quenching with aqueous ammonium chloride solution, diatomaceous earth was suction filtered, and the filter cake was washed with decyl alcohol, and the filtrate was evaporated to give a liquid chromatograph (methanol: water = 50:50 w/w) to give 850 mg of white solid. The rate is 41.4%.

( 3 ) 2-(2-(4- (哌啶 -1-基曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [5，4-6]吡啶 -2- 基) (3) 2-(2-(4-(piperidin-1-ylindenyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)

将 410 mg ( 2 mmol ) (4- (哌啶 -1-基甲基)苯基)曱醇溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH，室温搅拌 1 h, 加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至中性，抽滤，干燥滤饼，柱层析 ( DCM→DCM:MeOH=10:l )，得到黄色固体 220 mg, 收率 48.2%。 410 mg ( 2 mmol ) (4-(piperidin-1-ylmethyl)phenyl) decyl alcohol was dissolved in 10 mL DMA, 160 mg (4 mmol) 60% NaH was added, stirred at room temperature for 1 h, added 288 mg (1 mmol) 2- ( 2- chloro-pyrimidin-4-yl) -2- (thiazolo [5,4-6] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, adjust to neutral with dilute hydrochloric acid, suction filtration, dry filter cake, column chromatography (DCM -> DCM: MeOH = 10:1).

分子式： C₂₅H₂₄N₆OS; 分子量： 456.2; 质谱 (M+H 456.9 Molecular formula: C ₂₅ H ₂₄ N ₆ OS; Molecular weight: 456.2; Mass spectrometry (M+H 456.9

^- MR (DMSO-i 6+D₂0, 400 MHz): δ 8.32 (IH, d), 8.03 (1H， d), 7.73 (IH, d), 7.62 (2H, d), 7.54 (2H, d), 7.40 (IH, dd), 6.66 (IH, d)， 5.75 (2H, s), 4.24 (2H, s), 3.30-3.20 (2H， m), 2.88-2.76 (2H, m)， 1.82-1.47 (4H, m), 1.35-1.21 (2H, m)。 ^- MR (DMSO-i 6+D ₂ 0, 400 MHz): δ 8.32 (IH, d), 8.03 (1H, d), 7.73 (IH, d), 7.62 (2H, d), 7.54 (2H, d), 7.40 (IH, dd), 6.66 (IH, d), 5.75 (2H, s), 4.24 (2H, s), 3.30-3.20 (2H, m), 2.88-2.76 (2H, m), 1.82 -1.47 (4H, m), 1.35-1.21 (2H, m).

实施例 5: 2-(2-(4-((2-氧代吡咯烷 -1-基)甲基)苄氧基)嘧啶 -4-基) -2- (噻唑并 Example 5: 2-(2-(4-((2-oxopyrrolidin-1-yl)methyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolidine)

[5，4- -2-基)乙腈（化合物 29 )的制备 Preparation of [5,4--2-yl)acetonitrile (Compound 29)

-((2-氧代吡咯烷 -1-基)曱基)苯甲酸曱酯的制备

Preparation of bis((2-oxopyrrolidin-1-yl)indolyl) benzoate

将吡咯烷酮（ 1.7 g, 20 mmol )，加到 10 mL的 DMA中，加入 60%的 NaH (800 mg, 20 mmol), 室温下搅拌 1 h, 再加入对溴甲基苯甲酸甲酯（ 2.28 g, 9.95 mmol ), 室温反应 3 h。将体系倒入 100 mL水中，稀盐酸中和至中性，乙酸乙酯萃取三次，水洗，干燥，旋干，柱层析（PE:EA=5:1→1:2 )，得到产物 1.11 g，收率： 47.8%。 Add pyrrolidone (1.7 g, 20 mmol) to 10 mL of DMA, add 60% NaH (800 mg, 20 mmol), stir at room temperature for 1 h, then add methyl p-bromomethylbenzoate ( 2.28 g , 9.95 mmol), react at room temperature for 3 h. The system was poured into 100 mL of water, neutralized to neutral with dilute hydrochloric acid, extracted three times with ethyl acetate, washed with water, dried, dried, and purified by column chromatography (PE: EA=5:1→1:2) to give the product 1.11 g , Yield: 47.8%.

-(4- (羟曱基)苄基)吡咯烷 -2-酮的制备

Preparation of -(4-(hydroxyindolyl)benzyl)pyrrolidin-2-one

将 4-((2-氧代吡咯烷 -1-基)甲基)苯曱酸曱酯（ 1.11 g， 4.76 mmol )加到 10 mL的 THF中， -25°C下緩' ft滴入 2.5 mol/L的四氢铝锂 1.9 mL反应 3 h。向体系滴入 180 mg水， 180 mg的 10% NaOH溶液后充分搅拌，抽滤，滤液旋干，制备液相色谱纯化（甲醇：水 =50:50w/w )得到产物 230 mg，收率： 23.5%。 Add 4-((2-oxopyrrolidin-1-yl)methyl)benzoic acid decyl ester (1.11 g, 4.76 mmol) to 10 mL of THF and slowly add ft to 2.5 at -25 °C. Mol/L lithium tetrahydrogenate 1.9 mL was reacted for 3 h. To the system, 180 mg of water and 180 mg of 10% NaOH solution were added dropwise, and the mixture was stirred well. After suction filtration, the filtrate was spin-dried and purified by liquid chromatography (methanol: water = 50:50 w/w) to obtain product 230 mg. Yield: 23.5%.

( 3 ) 2-(2-(4-((2-氧代吡咯烷 -1-基）曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [5,4- ]吡啶 -2-基）乙腈的制备 (3) 2-(2-(4-((2-Oxopyrrolidin-1-yl)indolyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-]pyridine Preparation of -2-yl)acetonitrile

将 l-(4- (羟曱基)苄基)吡咯烷 -2-酮 ( 230 mg, 1.12 mmol )溶于 2 mL的 DMA中，加入 60%的 NaH (90 mg, 2.25 mmol), 加毕，室温下搅拌 2 h。再将 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5 ,4-6]吡啶 -2-基）乙腈（161 mg, 0.56 mmol ) 加入， N₂保护下升温至 100°C反应 16 h。将体系倒入水中，稀盐酸调节 pH至中性，将体系旋干，制备液相色谱纯化（甲醇：水 =60:40w/w )得到产物 40 mg，收率： 15.6%。

Dissolve l-(4-(hydroxyindenyl)benzyl)pyrrolidin-2-one (230 mg, 1.12 mmol) in 2 mL of DMA and add 60% NaH (90 mg, 2.25 mmol). Stir at room temperature for 2 h. Then 2- (2-chloro-4-yl) -2- (thiazolo [5, 4-6] pyridin-2-yl) acetonitrile (161 mg, 0.56 mmol) was added, heated to 100 under N ₂ °C reaction for 16 h. The system was poured into water, and the pH was adjusted to neutral with dilute hydrochloric acid. The system was spin-dried and purified by liquid chromatography (methanol: water = 60:40 w/w) to give the product 40 mg, yield: 15.6%.

分子式： C₂₄H₂₀N₆O₂S; 分子量： 456.14; 质谱 (M+H): 457.1 Molecular formula: C ₂₄ H ₂₀ N ₆ O ₂ S; Molecular weight: 456.14; Mass spectrometry (M+H): 457.1

^]H-NMR (OMSO-d₆, 400 MHz): δ 8.19 (1Η, d)， 7.87 (1H, d), 7.82 (1H， d), ^{] H-NMR (OMSO-d} 6, 400 MHz): δ 8.19 (1Η, d), 7.87 (1H, d), 7.82 (1H, d),

7.50 (2H, d)， 7.30 (1H, dd), 7.25 (2H， d), 6.59 (1H, m)， 5.58 (2H, s)， 4.36 (2H, s),7.50 (2H, d), 7.30 (1H, dd), 7.25 (2H, d), 6.59 (1H, m), 5.58 (2H, s), 4.36 (2H, s),

3.20 (2H, t)， 2.27 (2H, t)， 1.89 (2H, t)。 3.20 (2H, t), 2.27 (2H, t), 1.89 (2H, t).

实施例 6 2-(2-(4-((1 -吡唑 -1-基）曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 Example 6 2-(2-(4-((1-pyrazol-1-yl)indolyl)benzyloxy)pyrimidin-4-yl)-2-(thiazole)

【5，4- -2-基）乙腈（化合物 31 )的制备 Preparation of [5,4--2-yl)acetonitrile (Compound 31)

-((1//-吡唑小基)曱基)苯甲酸曱酯的制备

-((1//-pyrazolyl)indenyl) benzoic acid oxime ester preparation

将对溴曱基苯甲酸曱酯（3.42 g， 14.9 mmol ), 吡唑（2.04 g, 30 mmol ), 碳酸钾 ( 4.14 g， 30 mmol )分别加到 30 mL的 DMA中 , 50°C反应 16 h。将体系倒入 100 mL 水中，乙酸乙酯萃取三次，水洗，干燥，旋干，柱层析 ( PE:EA=5: 1→1 :1 ), 得到产物 2.5 g, 收率： 77.9%。 Ethyl p-bromomethyl benzoate (3.42 g, 14.9 mmol), pyrazole (2.04 g, 30 mmol), potassium carbonate (4.14 g, 30 mmol) were added to 30 mL of DMA, respectively, and reacted at 50 °C. h. The system was poured into 100 mL of water, extracted with ethyl acetate three times, washed with water, dried, dried, and then purified by column chromatography (PE: EA = 5: 1 → 1:1) to give product 2.5 g, yield: 77.9%.

-((li7-吡唑 -1-基)甲基)苯基)甲醇的制备

Preparation of ((li7-pyrazol-1-yl)methyl)phenyl)methanol

将 4-((1/ -吡唑 -1-基)曱基)苯甲酸曱酯 ( 2.16 g, 9.99 mmol )加到 20 mL 的 THF中，緩' I"曼加入四氢铝锂 ( 0.76 g, 20 mmol )室温反应 3 h。向体系滴入 0.76 g水， 0.76 mL的 10%NaOH溶液，充分搅拌，抽滤，滤饼用 THF洗两次，滤液旋干，柱层析（PE:EA=5:1→100%EA ), 得到产物 1.03 g，收率： 54.8%。 Add 4-((1/-pyrazol-1-yl)indolyl benzoate oxime ester ( 2.16 g, 9.99 mmol) to 20 mL of THF, and slowly add I. , 20 mmol) at room temperature for 3 h. Add 0.76 g of water, 0.76 mL of 10% NaOH solution to the system, stir well, suction filter, filter cake twice with THF, spin dry, column chromatography (PE: EA = 5:1→100% EA ), the product was obtained in the form of 1.03 g, yield: 54.8%.

( 3 ) 2-(2-(4-((1 -吡唑 -1-基)曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2- (3) 2-(2-(4-((1-pyrazol-1-yl)indolyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin Acridine -2-

将 (4-((1/ -吡唑 -1-基)甲基)苯基)甲醇（ 188 mg， 1 mmol )溶于 2 mL的 DMA 中，加入 60%的 NaH (80 mg, 2 mmol), 加毕，室温下搅拌 2 h。再将 2-(2- 氯嘧啶 -4-基) -2- (噻唑并 [5,4- ]吡啶 -2-基）乙腈（ 144 mg, 0.5 mmol )加入， N₂ 保护下升温至 100°C反应 16 h。将体系倒入水中，稀盐酸调节 pH至中性，将体系旋干，制备液相色谱纯化（曱醇：水 =60:40 w/w )得到产物 20 mg，收率： 9.1%。 (4-((1/1/pyrazol-1-yl)methyl)phenyl)methanol (188 mg, 1 mmol) was dissolved in 2 mL of DMA and 60% NaH (80 mg, 2 mmol) , add, and stir at room temperature for 2 h. Add 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-]pyridin-2-yl)acetonitrile (144 mg, 0.5 mmol), and warm to 100 ° under N ₂ C reaction for 16 h. The system was poured into water, and the pH was adjusted to neutral with dilute hydrochloric acid. The system was spin-dried and purified by preparative liquid chromatography (methanol: water = 60:40 w/w) to give product 20 mg, yield: 9.1%.

分子式： C₂₃H₁₇N₇OS; 分子量： 439.12; 质谱 (M+H): 440.1 Molecular formula: C ₂₃ H ₁₇ N ₇ OS; Molecular weight: 439.12; Mass spectrometry (M+H): 440.1

^-NMR (DMSO- 400 MHz): δ 12.82 (1H， s), 8.34 (1Η， d), 8.06 (IH, d), ^-NMR (DMSO-400 MHz): δ 12.82 (1H, s), 8.34 (1Η, d), 8.06 (IH, d),

7.81 (1H， d), 7.74 (1H， m), 7.53 (2H, d), 7.45 (IH, dd), 7.41 (IH, dd), 7.25 (2H, d)7.81 (1H, d), 7.74 (1H, m), 7.53 (2H, d), 7.45 (IH, dd), 7.41 (IH, dd), 7.25 (2H, d)

6.63 (1H， d), 6.26 (1H， t), 5.68 (2H， s), 5.35 (2H, s)。 6.63 (1H, d), 6.26 (1H, t), 5.68 (2H, s), 5.35 (2H, s).

实施例 7: 2-(2-(4-乙基苄氧基)嘧啶 -4-基) -2- (噻唑并【5，4-b】吡啶 -2-基)乙腈 (化合物 37 )的制备 Example 7 Preparation of 2-(2-(4-ethylbenzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (Compound 37)

将 272 mg( 2 mmol H-乙基苄醇溶于 10 ml DMA中，加入 160 mg( 4 mmol ) 60%的 NaH，室温搅拌 1 h，加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，干燥滤饼，滤饼进一步柱层析（DCM--DCM:MeOH=500:l ), 得到黄色固体 240 mg, 收率 61.9%。 272 mg (2 mmol H-ethylbenzyl alcohol) was dissolved in 10 ml DMA, 160 mg (4 mmol) 60% NaH was added, stirred at room temperature for 1 h, and 288 mg (1 mmol) 2-(2-chloropyrimidine was added. -4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, protected with N ₂ , reacted at 100 ° C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, The filter cake was dried, and the residue was purified (jjjjjjjjjjj

分子式： C₂₁H₁₇N₅OS; 分子量： 387.12; 质谱 (M+H): 388.1 Molecular formula: C ₂₁ H ₁₇ N ₅ OS; Molecular weight: 387.12; Mass spectrometry (M+H): 388.1

丽 R(DMSO-i ₆， 400 MHz): δ 12.83 (IH, s), 8.37 (1H， dd), 8.11 (IH, d), 7.69 (1H， s), 7.49 (2H, d), 7.43 (IH, dd), 7.27 (2H, d), 6.64 (IH, d), 5.70 (2H, s)， 2.61 (2H, q), 1.17 (3H, t)。 R (DMSO-i ₆ , 400 MHz): δ 12.83 (IH, s), 8.37 (1H, dd), 8.11 (IH, d), 7.69 (1H, s), 7.49 (2H, d), 7.43 ( IH, dd), 7.27 (2H, d), 6.64 (IH, d), 5.70 (2H, s), 2.61 (2H, q), 1.17 (3H, t).

实施例 8: 2-(2- (环己基甲氧基)嘧啶 -4-基) -2- (噻唑并〖5,4-bl吡啶 -2-基）乙腈（化合物 89 )的制备

Example 8 Preparation of 2-(2-(cyclohexylmethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-blpyridin-2-yl)acetonitrile (Compound 89)

将 228 mg ( 2 mmol )环己基甲醇溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH, 室温搅拌 1 h，加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4- 基) -2- (噻唑并 [5，4- >]吡啶 -2-基)乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，二氯曱烷萃取，水洗，干燥，旋干，柱层析 ( DCM→DCM:MeOH=500:l ), 得到黄色固体 210 mg, 收率 57.5%。 228 mg (2 mmol) of cyclohexylmethanol was dissolved in 10 mL of DMA, 160 mg (4 mmol) of 60% NaH was added, stirred at room temperature for 1 h, and 288 mg (1 mmol) of 2-(2-chloropyrimidine-4) was added. -yl)-2-(thiazolo[5,4->]pyridin-2-yl)acetonitrile, protected with N ₂ and reacted at 100 ° C for 18 h. Water was added, and the mixture was diluted with dilute hydrochloric acid to give a weak acid. EtOAc (EtOAc m.).

分子式： C₁₉H₁₉N₅OS; 分子量： 365.13; 质讲 (M+H): 366.1 Molecular formula: C ₁₉ H ₁₉ N ₅ OS; Molecular weight: 365.13; Quality (M+H): 366.1

'H-NMRiDMSO-^, 400 MHz): δ 12.77 (IH, s)， 8.37 (1H， d), 8.09 (IH, d), 7.68 (1H， s), 7.43 (1H， dd), 6.60 (IH, d)， 4.50 (2H， d), 1.92-1.79 (3H， m)， 1.77-1.59 (4H， m), 1.32-1.05 (4H， m)。 'H-NMRiDMSO-^, 400 MHz): δ 12.77 (IH, s), 8.37 (1H, d), 8.09 (IH, d), 7.68 (1H, s), 7.43 (1H, dd), 6.60 (IH , d), 4.50 (2H, d), 1.92-1.79 (3H, m), 1.77-1.59 (4H, m), 1.32-1.05 (4H, m).

实施例 9: 2-(2- ((四氢 -2 吡喃 -4-基)曱氧基)嘧啶 -4-基) -2- (噻唑并【5，4-b】吡啶 -2- 乙腈（化合物 93 )的制备

Example 9: 2-(2-((tetrahydro-2-pyran-4-yl)decyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridine-2-acetonitrile Preparation of (Compound 93)

将 228 mg (2 mmol) (四氢 -2 -吡喃 -4-基)曱醇溶于 10 mL DMA中，加入 160 mg (4 mmol) 60%的 NaH, 室温搅拌 1 h，加入 288 mg (1 mmol) 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5，4-6]吡啶 -2-基）乙腈， N₂保护， 100 °C反应 18 h。加水，用稀盐酸调至弱酸性，二氯曱烷萃取，水洗，干燥有机相，旋干，柱层析 ( DCM→DCM:MeOH=100:l ), 得到黄色固体 230 mg，收率 62.6%. 228 mg (2 mmol) of (tetrahydro-2-pyran-4-yl) decyl alcohol was dissolved in 10 mL of DMA, 160 mg (4 mmol) of 60% NaH was added, stirred at room temperature for 1 h, and added 288 mg ( 1 mmol) 2- (2- chloro-pyrimidin-4-yl) -2- (thiazolo [5,4-6] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, dilute hydrochloric acid to weak acidity, dichloromethane extraction, water washing, dry organic phase, spin dry, column chromatography (DCM: DCM: MeOH = 100:1) to give a yellow solid 230 mg, yield 62.6% .

分子式 ·· C₁₈H₁₇N₅0₂S; 分子量： 367.11 ; 质谱 (M+H): 368.1 Molecular Formula · · C ₁₈ H ₁₇ N ₅ 0 ₂ S; Molecular Weight: 367.11 ; Mass Spectrum (M+H): 368.1

^- MRiCDCls, 400 MHz): δ 14.55 (IH, s), 8.44 (IH, dd), 7.98-7.90 (2H, m), 7.37 (1H， dd), 6.81 (IH, d)， 4.35 (2H, d), 4.06 (2H, dd), 3.53-3.42 (2H, m), 2.26-2.11 (lH, m), 1.81-1.72 (2H, m), 1.56-1.45 (2H，m)。 ^- MRiCDCls, 400 MHz): δ 14.55 (IH, s), 8.44 (IH, dd), 7.98-7.90 (2H, m), 7.37 (1H, dd), 6.81 (IH, d), 4.35 (2H, d), 4.06 (2H, dd), 3.53-3.42 (2H, m), 2.26-2.11 (lH, m), 1.81-1.72 (2H, m), 1.56-1.45 (2H, m).

实施例 10: 2-(5-甲基噻唑并 [5,4-6]吡啶 -2-基) -2-(2-(4- (吗啉代甲基)苄 lJ 嘧啶 4-基)乙腈（化合物 119 )的制备

Example 10: 2-(5-Methylthiazolo[5,4-6]pyridin-2-yl)-2-(2-(4-(morpholinomethyl)benzyl lJ pyrimidin-4-yl)acetonitrile Preparation of (Compound 119)

( 1 ) 3-氨基 -6-曱基吡啶 -2-硫醇的制备 (1) Preparation of 3-amino-6-mercaptopyridine-2-thiol

'ΝΗ₂ 'ΝΗ ₂

SH SH

称取 2-氯 -6-曱基 -3-硝基吡啶 (6.90 g， 40.0 mmol)和硫氢化钠 (6.61 g， 0.12 mol)溶于 500 mL无水乙醇溶液中，室温下搅拌反应 1小时，之后加入保险粉 (20.89 g, 0.12 mol)的水溶液溶液 150 mL, 升温至 80°C反应 12小时，过滤，滤液浓缩，硅胶柱层析 (100%石油醚→石油醚：乙酸乙酯 =2:1)得到黄色固体 1.95 g, 收率 34.8%。 2-Chloro-6-mercapto-3-nitropyridine (6.90 g, 40.0 mmol) and sodium hydrosulfide (6.61 g, 0.12 mol) were weighed and dissolved in 500 mL of absolute ethanol, and the reaction was stirred at room temperature for 1 hour. Then, 150 mL of an aqueous solution of insurance powder (20.89 g, 0.12 mol) was added, and the mixture was heated to 80 ° C for 12 hours, filtered, and the filtrate was concentrated, and silica gel column chromatography (100% petroleum ether → petroleum ether: ethyl acetate = 2) :1) A yellow solid 1.95 g was obtained in a yield of 34.8%.

( 2 ) 2-(5-甲基噻唑并 [5，4-6]吡啶 -2-基）乙腈的制备 (2) Preparation of 2-(5-methylthiazolo[5,4-6]pyridin-2-yl)acetonitrile

.CN 将 3-氨基 -6-曱基吡啶 -2-硫醇 (1.95 g, 13.9 mmol)和丙二睛 (0.92 g, 13.9 mmol)混合于 50 mL无水甲醇中，加入 20 mL冰乙酸，升温至 90。C反应 12 小时，将反应液浓缩，乙酸乙酯溶解，饱和碳酸氢钠溶液、饱和氯化钠溶液分别洗一次，有目干燥、浓缩得到黄色固体 1.45 g, 收率 55.1%。 .CN Mix 3-amino-6-mercaptopyridine-2-thiol (1.95 g, 13.9 mmol) and propylene diacetate (0.92 g, 13.9 mmol) in 50 mL of anhydrous methanol and add 20 mL of glacial acetic acid. Warm up to 90. After reacting for 12 hours, the reaction mixture was concentrated, ethyl acetate was dissolved, and saturated sodium bicarbonate solution and saturated sodium chloride solution were washed once, dried and concentrated to give a white solid 1.45 g, yield 55.1%.

-(2-氯嘧啶 -4-基) -2-(5-曱基噻唑并 [5，4- >]吡啶 -2-基)乙腈的制备

Of (2-chloropyrimidin-4-yl)-2-(5-mercaptothiazolo[5,4->]pyridin-2-yl)acetonitrile

称取 2-(5-甲基噻唑并 [5,4-6]吡啶 -2-基）乙腈 (1.45 g, 7.66 mmol)溶于 20 mL 干燥的四氢呋喃中，氮气保护，緩慢加入氢化钠 (60%, 0.612 g， 15.3 mmol), 室温下搅拌半小时，之后加入 2,4-二氯嘧啶 (1.141 g， 7.66 mmol), 室温下反应 12小时，加水，用 1N的盐酸调成弱酸性，析出固体，过滤，滤饼水洗，干燥滤饼，得到黄色固体 2.3 g, 收率： 99.5%。 2-(5-Methylthiazolo[5,4-6]pyridin-2-yl)acetonitrile (1.45 g, 7.66 mmol) was weighed and dissolved in 20 mL of dry tetrahydrofuran. %, 0.612 g, 15.3 mmol), stirred at room temperature for half an hour, then added 2,4-dichloropyrimidine (1.141 g, 7.66 mmol), reacted at room temperature for 12 hours, added water, adjusted to weak acidity with 1N hydrochloric acid, precipitated The solid was filtered, the cake was washed with water and dried, and then filtered to give a yellow solid (2.3 g, yield: 99.5%).

( 4 ) 2-(5-甲基噻唑并 [5，4-6]吡啶 -2-基) -2-(2-(4- (吗啉代甲基)苄氧基)嘧啶 -4-基)乙腈的制备

(4) 2-(5-Methylthiazolo[5,4-6]pyridin-2-yl)-2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl Preparation of acetonitrile

称取氢化钠 (60%, 0.2 g， 5.0 mmol)加入到 5 mL A^V-二曱基乙酰胺中 , 加入 4- (吗啉代甲基)苄醇 (0.52 g, 2.51 mmol), 室温反应 1小时后加入 2-(2-氯嘧啶 -4-基) -2-(5-甲基噻唑并 [5，4- >]吡啶 -2-基）乙腈 (0.377 g, 1.25 mmol),之后升温至 100°C反应 8小时，旋干反应液，硅胶柱层析 (二氯曱烷→二氯曱烷:曱醇 =20:1), 得到产物 0.32 g, 收率 54.2%。 Sodium hydride (60%, 0.2 g, 5.0 mmol) was weighed into 5 mL of A^V-dimercaptoacetamide, and 4-(morpholinomethyl)benzyl alcohol (0.52 g, 2.51 mmol) was added at room temperature. After 1 hour of reaction, 2-(2-chloropyrimidin-4-yl)-2-(5-methylthiazolo[5,4->]pyridin-2-yl)acetonitrile (0.377 g, 1.25 mmol) was added, then The mixture was heated to 100 ° C for 8 hours, and the reaction mixture was dried with a silica gel column chromatography (dichloromethane:dichloromethane:decanol = 20:1) to give the product 0.32 g, yield 54.2%.

分子式： C₂₅H₂₄N₆0₂S; 分子量： 472.17; 质语 (M+H): 473.2 Molecular formula: C ₂₅ H ₂₄ N ₆ 0 ₂ S; Molecular weight: 472.17; slang (M+H): 473.2

^-NMR (CDCl₃, 400 MHz): δ 14.41 (1Η, s)， 7.95 (1H, d), 7.79 (1H, d)， 7.46 (2H, d), 7.40 (2H, d), 7.19 (1H, d)， 6.81 (1H， d), 5.50 (2H, s), 3.72 (4H, t)， 3.53 (2H, s), 2.64 (3H， s), 2.47 (4H, t)。 ^-NMR (CDCl ₃ , 400 MHz): δ 14.41 (1Η, s), 7.95 (1H, d), 7.79 (1H, d), 7.46 (2H, d), 7.40 (2H, d), 7.19 (1H , d), 6.81 (1H, d), 5.50 (2H, s), 3.72 (4H, t), 3.53 (2H, s), 2.64 (3H, s), 2.47 (4H, t).

实施例 11: 2-(4-((4- (氰基 (噻唑并 [5,4-b】吡啶 -2-基)甲基)嘧啶 -2-基氧基) 甲基 -Λ^ν-二甲基乙酰胺（化合物 39 )的制备 Example 11: 2-(4-((4-(Cyano(thiazolo[5,4-b]pyridin-2-yl)methyl)pyrimidin-2-yloxy)methyl-Λ^ν- Preparation of dimethylacetamide (compound 39)

-(4-(曱氧基羰基)苯基)乙酸的制备

Preparation of -(4-(decyloxycarbonyl)phenyl)acetic acid

将 4-(2-甲氧基 -2-氧代乙基)苯曱酸曱酯（4 g, 19.2 mmol )、一水合氢氧化锂（ 847 mg, 20.17 mmol )溶于四氢呋喃 /甲醇 /水的混合溶剂（ 60 mL, 4: 1 :1 ) 中，室温下搅拌 24 h，减压浓缩掉大部分有机溶剂后，冰浴下调 pH 3 , 析出沉淀，抽滤，固体干燥，得到白色固体 3.4 g，收率 91.2%。 Ethyl 4-(2-methoxy-2-oxoethyl)benzoate (4 g, 19.2 mmol), lithium hydroxide monohydrate (847 mg, 20.17 mmol) dissolved in tetrahydrofuran / methanol / water In a mixed solvent (60 mL, 4:1:1), stir at room temperature for 24 h, concentrate most of the organic solvent under reduced pressure, then adjust pH 3 in an ice bath, precipitate, precipitate, and dry to give a white solid 3.4 g , the yield was 91.2%.

( 2 ) 4-(2- (二曱氨基) -2-氧代乙基)苯曱酸曱酯的制备将 2-(4- (曱氧基欺基)苯基)乙酸（2.89 g, 14.88 mmol )溶于二氯曱烷（40 mL ), 加入 3 滴 A^V "二甲基曱酰胺，冰浴下慢慢滴加草酰氯（5.67 g, 44.64 mmol ), 滴毕，室温下搅拌 2 h, 减压浓缩后溶于 20 mL二氯曱烷中备用。 (2) Preparation of 4-(2-(diamino)-2-oxoethyl)benzoic acid decyl ester 2-(4-(decyloxy)phenyl)acetic acid (2.89 g, 14.88 mmol) was dissolved in dichloromethane (40 mL), 3 drops of A^V "dimethyl phthalamide, ice bath Oxalyl chloride (5.67 g, 44.64 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h, concentrated under reduced pressure and dissolved in 20 mL of dichloromethane.

将二曱胺盐酸盐（ 4.85 g, 59.51 mmol )和三乙胺（ 9.04 g， 89.3 mmol )溶于二氯甲烷（ lOO mL ), 在冰浴下' I"曼慢滴加到上述酰氯的溶液中，滴毕，室温下搅拌 2 h，减压浓缩后所得固体经水洗后干燥，得到黄色固体 2.82 g，收率 85.7%。 Diammonium hydrochloride ( 4.85 g, 59.51 mmol) and triethylamine ( 9.04 g, 89.3 mmol) were dissolved in dichloromethane (100 mL) and added to the above acid chloride in an ice bath. The solution was added dropwise, and the mixture was stirred at room temperature for 2 hr.

-(4- (羟甲基)苯基) -A^V-二甲基乙酰胺的制备

-(4-(Hydroxymethyl)phenyl)-A^V-dimethylacetamide preparation

将 4-(2- (二甲氨基) -2-氧代乙基)苯甲酸甲酯（ 2.82 g， 12.7 mmol )溶于四氢呋喃（80 mL )，加入硼氢化钠（4.82 g, 127 mmol ), 加热回流反应 36 h，减压浓缩掉大部分溶剂后，加入水，乙酸乙酯萃取，有机相干燥，浓缩，硅胶柱层析（石油醚:乙酸乙酯 =1:1 )，得到白色固体 1.05 g, 收率 42.5%。 Methyl 4-(2-(dimethylamino)-2-oxoethyl)benzoate (2.82 g, 12.7 mmol) was dissolved in tetrahydrofuran (80 mL) and sodium borohydride (4.82 g, 127 mmol). The mixture was heated to reflux for 36 h. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. g, yield 42.5%.

-(4- (氯甲基)苯基) -A^ -二甲基乙酰胺的制备

-(4-(Chloromethyl)phenyl)-A^-dimethylacetamide preparation

将 2-(4- (羟甲基)苯基) -A^V-二曱基乙酰胺（0.41 g， 2.12 mmol )溶于二氯亚砜（10 mL )，室温下搅拌 2 h。减压浓缩后直接用于下一步。 2-(4-(Hydroxymethyl)phenyl)-A^V-dimercaptoacetamide (0.41 g, 2.12 mmol) was dissolved in dichloromethane (10 mL). It was concentrated under reduced pressure and used directly in the next step.

-(2-羟基嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈的制备

Of (2-hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

将 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5,4-b]吡啶 -2-基）乙腈（ 863 mg, 3 mmol )、氢氧化钠（ 1.2 g， 30 mmol )加入水中（20 mL ), 90°C下反应 6 h, 冷却，调 pH至 6 - 7,析出黄色固体，抽滤，干燥后硅胶柱层析（二氯甲烷:曱醇 =10:1 )，得到黄色固体 595 mg，收率 73.6%。 2-(2-Chloropyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (863 mg, 3 mmol), sodium hydroxide (1.2 g, 30 mmol Adding water (20 mL), reacting at 90 ° C for 6 h, cooling, adjusting the pH to 6 - 7, precipitating a yellow solid, suction filtration, drying and silica gel column chromatography (dichloromethane: decyl alcohol = 10:1) , 595 mg of a yellow solid was obtained, yield 73.6%.

( 6 ) 2-(4-((4- (氰基 (噻唑并 [5,4-b]吡啶 -2-基）甲基)嘧啶 -2-基氧基）曱基) 苯基二甲基乙酰胺的制备 (6) 2-(4-((4-(Cyano(thiazolo[5,4-b]pyridin-2-yl)methyl)pyrimidin-2-yloxy)indolyl)phenyl dimethyl Preparation of acetamide

将 2-(2-羟基嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈（380 mg, 1.41 mmol )、 2-(4- (氯甲基)苯基) - N-二甲基乙酰胺（448 mg, 2.12 mmol )、碳酸铯 ( 1378 mg, 4.23 mmol )、碘化钾（ 24 mg, 0.141 mmol )加入 V，N "二曱基乙酰胺中（20 mL )， 70°C下反应 16 h，冷却，倒入冰水中，析出黄色固体，抽滤，干燥后硅胶柱层析 (二氯曱烷:曱醇 =10: 1 )，得到黄色固体 147 mg，收率 23.5%。 2-(2-Hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile (380 mg, 1.41 Methyl), 2-(4-(chloromethyl)phenyl)-N-dimethylacetamide (448 mg, 2.12 mmol), cesium carbonate (1378 mg, 4.23 mmol), potassium iodide (24 mg, 0.141 mmol) Add V, N "dimercaptoacetamide (20 mL), react at 70 ° C for 16 h, cool, pour into ice water, precipitate a yellow solid, suction filtration, dry and silica gel column chromatography (dichloromethane: Furfuryl alcohol = 10: 1 ) gave 147 mg of a yellow solid, yield 23.5%.

分子式： C₂₃H_2QN₆0₂S; 分子量： 444.1 ; 质谱 (M+H): 445.1 Molecular formula: C ₂₃ H _2Q N ₆ 0 ₂ S; Molecular weight: 444.1 ; Mass spectrum (M+H): 445.1

^-NMR^-DMSO, 400 MHz): δ 12.96 (IH, s), 8.49 (IH, d), 8.25 (IH, d), ^-NMR^-DMSO, 400 MHz): δ 12.96 (IH, s), 8.49 (IH, d), 8.25 (IH, d),

7.94 (1H， d)， 7.55 (IH, dd), 7.29 (2H, d), 7.20 (2H, d), 6.30 (IH, d), 4.98 (2H, s)，7.94 (1H, d), 7.55 (IH, dd), 7.29 (2H, d), 7.20 (2H, d), 6.30 (IH, d), 4.98 (2H, s),

3.66 (2H, s), 2.97 (3H, s)， 2.79 (3H, s)。 3.66 (2H, s), 2.97 (3H, s), 2.79 (3H, s).

实施例 12: 2-(2-(4-((6-曱基吡啶 -3-基)曱基)苄 |Λ)嘧啶 -4-基) -2- (噻唑并 Example 12: 2-(2-(4-((6-Mercaptopyridine-3-yl)indolyl)benzyl)pyridin-4-yl)-2-(thiazolidine)

【5，4- -2-基)乙腈（化合物 27 )的制备 Preparation of [5,4--2-yl)acetonitrile (Compound 27)

( 1 ) (4-碘苄氧基)二曱基叔丁基硅烷的制备 (1) Preparation of (4-iodobenzyloxy)didecyl tert-butylsilane

将对碘苄醇（9.9 g， 42.3 mmol ), 咪唑（5.76 g， 84.6 mmol )溶于 20 mL DMF中，然后慢慢加入 TBSC1 ( 7.20 g， 47.3 mmol ), 在常温下搅拌 14 h, 然后在 0°CH曼慢滴加到 100 mL水中，所得的溶液过滤，用 250 mL水分三次洗涤滤饼， 45°C烘干滤饼得白色固体 12.1 g，收率： 82%。Isobenzyl alcohol (9.9 g, 42.3 mmol), imidazole (5.76 g, 84.6 mmol) was dissolved in 20 mL of DMF, then TBSC1 ( 7.20 g, 47.3 mmol) was added slowly, stirred at room temperature for 14 h, then 0 °CHman slow drop was added to 100 mL of water, and the resulting solution was filtered, and the filter cake was washed three times with 250 mL of water, and the filter cake was dried at 45 ° C to obtain 12.1 g of a white solid. Yield: 82%.

-甲氧基 -ΛΓ，6-二甲基烟酰胺的制备

-Methoxy-oxime, preparation of 6-dimethylnicotinamide

将 6-曱基烟酸（2.00 g, 14.59 mmol ), ΛζΟ-二甲基羟胺盐酸盐（ 1.706 g， 17.51 mmol ), DIPEA ( 4.05 g, 31.7 mmol ), HATU ( 6.665 g， 17.51 mmol )溶于 100 mL二氯曱烷，溶液搅拌过夜，然后加入 100 mL水，二氯曱烷萃取，有机相，干燥，浓缩，过硅胶柱（PE/EA=4: 1 )得淡红色固体 2.40 g, 收率： 91.4% 6-Mercaptonicotinic acid (2.00 g, 14.59 mmol), hydrazine-dimethylhydroxylamine hydrochloride ( 1.706 g, 17.51 mmol), DIPEA (4.05 g, 31.7 mmol), HATU ( 6.665 g, 17.51 mmol) After stirring in 100 mL of dichloromethane, the solution was stirred overnight, then 100 mL of water, extracted with dichloromethane, organic phase, dried, concentrated, and purified by silica gel column (PE/EA = 4:1) to give a red solid 2.40 g. Yield: 91.4%

( 3 ) (4- ((叔丁基二曱基硅氧基)曱基)苯基 )(6-甲基吡啶 -3-基)曱酮的制备

(3) Preparation of (4-((tert-butyldimethylsilyloxy)indenyl)phenyl)(6-methylpyridin-3-yl)anthone

取 250 mL三口瓶，将 (4-碘苄氧基)二曱基叔丁基硅烷（ 6.960 g, 20 mmol ) 用 50 mL THF溶解，用氮气置换三次，然后在 -30°C向该溶液中慢慢加入 2.4 N 的正丁基锂己烷溶液（4.2 mL, 10.08 mmol ), 在 -30°C搅拌 30 min, 冷却到 -78° (：。然后将 iV-甲氧基二曱基烟酰胺（1.8 g， 10 mmol )的 25 mL无水 THF溶液慢慢滴加上述反应液中，搅拌 120 min, TLC监测原料消失，加入 50 mL氯化铵水溶液，用 100 mL乙酸乙酯萃取 2次，将有机相干燥，过滤，旋干，过硅胶柱（PE:EA=4:1 )，得无色油状物 1.40 g，收率： 41.1% A 250 mL three-necked flask was used to dissolve (4-iodobenzyloxy)didecyl tert-butylsilane (6.960 g, 20 mmol) in 50 mL of THF, three times with nitrogen, and then at -30 ° C to the solution. Slowly add 2.4 N n-butyllithium hexane solution (4.2 mL, 10.08 mmol), stir at -30 ° C for 30 min, cool to -78 ° (:. Then iV-methoxy bis-nicotinamide (1.8 g, 10 mmol) of 25 mL of anhydrous THF solution was slowly added dropwise to the above reaction solution, stirred for 120 min, TLC was used to monitor the disappearance of the material, 50 mL of ammonium chloride aqueous solution was added, and extracted with 100 mL of ethyl acetate twice. The organic phase was dried, filtered, dried and dried over silica gel (PE: EA = 4:1) to give a colorless oil 1.40 g, yield: 41.1%

-甲基吡啶 -3-基)曱基)苯基)甲醇的制备

Of -methylpyridin-3-yl)indolyl)phenyl)methanol

将 (4- ((叔丁基二甲基硅氧基)曱基)苯基 )(6-甲基吡啶 -3-基)曱酮（1.40 g， 4.11 mmol )溶于 20 mL二缩三乙二醇中，然后加入 5 mL 40%的水合肼，溶液在 110°C敞口搅拌 1 h,然后加入 KOH( 0.690 g， 12.35 mmol ),溶液在 140°C 时搅拌 2小时，然后冷却至室温，加入 100 mL乙酸乙酯和 50 mL水，萃取，将有机相干燥，旋干，过硅胶柱（ PE:EA=2:1 )得无色油状物 0.54 g,收率 61.6%。 (4-((tert-Butyldimethylsilyloxy) decyl)phenyl)(6-methylpyridin-3-yl)anthone (1.40 g, 4.11 mmol) was dissolved in 20 mL of triethyl In the diol, 5 mL of 40% hydrazine hydrate was added, and the solution was stirred at 110 ° C for 1 h, then KOH (0.690 g, 12.35 mmol) was added, and the solution was stirred at 140 ° C for 2 hours, then cooled to room temperature. After adding 100 mL of ethyl acetate and 50 mL of water, the mixture was extracted, and the organic phase was dried, dried, and then passed through a silica gel column (PE: EA = 2:1) to give a colorless oil of 0.54 g.

-(4- (氯甲基)苄基) -2-甲基吡啶的制备

Preparation of -(4-(chloromethyl)benzyl)-2-methylpyridine

将 (4-((6-曱基吡啶 -3-基)曱基)苯基)曱醇（0.54 g， 2.53 mmol )溶于 20 mL 二氯甲烷中，然后慢慢滴加 l mL二氯亚砜，溶液常温搅拌 2小时，旋干得无色油状物 0.58 g，收率 98.8% (4-((6-Mercaptopyridin-3-yl)indolyl)phenyl) decyl alcohol (0.54 g, 2.53 mmol) was dissolved in 20 mL of dichloromethane, then 1 mL of dichloro The sulfone solution was stirred at room temperature for 2 hours and dried to give a colorless oil of 0.58 g, yield 98.8%.

( 6 ) 2-(2-(4-((6-甲基吡啶 -3-基)曱基)苄氧基)嘧啶 -4-基) -2- (噻唑并 [5,4-6] 吡啶 -基)乙腈的制备 (6) 2-(2-(4-((6-methylpyridin-3-yl)indolyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridine -base) preparation of acetonitrile

将 2-(2-羟基嘧啶 -4-基) -2- (噻唑并 [5，4-b]吡啶 -2-基）乙腈（0.326 g， 1.212 mmol ), 5-(4- (氯曱基)苄基) -2-曱基吡啶（0.42 g, 1.818 mmol ),碳酸铯（1.184 g, 3.636 mmol ) 碘化钾（ 20 mg, 0.121 mmol )加入 A ^-二曱基乙酰胺中（20 mL ), 60 °C下反应 46 h, 冷却，倒入冰水中，析出黄色固体，抽滤，干燥，硅胶柱层析（二氯甲烷:甲醇 =15:1 ), 得到黄色固体 57 mg, 收率 10.1%。 2-(2-Hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (0.326 g, 1.212 mmol), 5-(4-(chlorophenyl) Benzyl)-2-mercaptopyridine (0.42 g, 1.818 mmol), cesium carbonate (1.184 g, 3.636 mmol) potassium iodide (20 mg, 0.121 mmol) was added to A^-dimercaptoacetamide (20 mL). The reaction was carried out at 60 ° C for 46 h, cooled, poured into ice water, and then evaporated, evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjj .

分子式： C₂₆H₂。N₆OS; 分子量： 464.1 ; 质谱 (M+H): 465.1 O-NMR^-DMSO, 400 MHz): δ 12.95 (IH, s)， 8.50 (IH, d)， 8.33 (IH, d), 8.26 (IH, d), 7.92 (IH, d)， 7.59-7.50 (IH, m)， 7.47 (IH, dd)， 7.29 (2H, d), 7.23 (2H, d), 7.13 (IH, d), 6.29 (IH, d), 4.96 (2H, s)， 3.89 (2H, s)， 2.38 (3H， s)。 Molecular formula: C ₂₆ H ₂ . N ₆ OS; Molecular Weight: 464.1 ; Mass Spectrum (M+H): 465.1 O-NMR^-DMSO, 400 MHz): δ 12.95 (IH, s), 8.50 (IH, d), 8.33 (IH, d), 8.26 (IH, d), 7.92 (IH, d), 7.59-7.50 (IH, m), 7.47 (IH, dd), 7.29 (2H, d), 7.23 (2H, d), 7.13 (IH, d), 6.29 (IH, d), 4.96 (2H, s), 3.89 ( 2H, s), 2.38 (3H, s).

实施例 13: 2-(2- (环己基曱 M 嘧啶 -4-基) -2- (噻唑并【4，5-c】吡啶 -2-基）乙腈（ Example 13: 2-(2-(cyclohexyl曱 M pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (

( 1 ) 2-(2- (环己基甲氧基)嘧啶 -4-基) -2- (噻唑并 [4,5-c]吡啶 -2-基）乙腈的制备

(1) Preparation of 2-(2-(cyclohexylmethoxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

称取氢化钠 (60%, 0.320 g, 8.0 mmol)加入到 6 mL A^V "二甲基乙酰胺中，加入环己基甲醇 (0.457 g, 4.0 mmol), 室温反应 1小时后加入 2-(2-氯嘧啶 -4- 基) -2- (噻唑并 [4，5-c]吡啶 -2-基）乙腈 (0.575 g， 2.0 mmol), 之后升温至 100。C反应 4 小时，旋干反应液，硅胶柱层析 (二氯甲烷→二氯甲烷:曱醇 =100:1)，得到产物 0.311 g，收率 42.5%。 Sodium hydride (60%, 0.320 g, 8.0 mmol) was weighed into 6 mL of A^V "dimethylacetamide, and cyclohexylmethanol (0.457 g, 4.0 mmol) was added. After reacting for 1 hour at room temperature, 2-( 2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (0.575 g, 2.0 mmol), then warmed to 100 ° C for 4 h, spin-drying Liquid, silica gel column chromatography (dichloromethane: methylene chloride: methanol: 100:1) afforded the product 0.311 g, yield 42.5%.

分子式： C₁₉H₁₉N₅OS; 分子量： 365.1; 质谱 (M+H): 366.1Molecular formula: C ₁₉ H ₁₉ N ₅ OS; Molecular weight: 365.1; Mass spectrometry (M+H): 366.1

-NMR (^-DMSO, 400 MHz): δ 9.02 (1Η， s), 8.32 (1Η， d), 8.05 (IH, d), 7.72 (IH, d), 6.61 (IH, d)， 4.46 (2H, d), 1.93-1.60 (5H, m), 1.34-1.05 (6H, m)。 -NMR (^-DMSO, 400 MHz): δ 9.02 (1Η, s), 8.32 (1Η, d), 8.05 (IH, d), 7.72 (IH, d), 6.61 (IH, d), 4.46 (2H , d), 1.93-1.60 (5H, m), 1.34-1.05 (6H, m).

实施例 14: 2-(2- (哌啶 -4-基甲氧基)嘧啶 -4-基) -2- (噻唑并〖5，4-W吡啶 -2-基) 乙腈（化合物 91

Example 14: 2-(2-(piperidin-4-ylmethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-Wpyridin-2-yl)acetonitrile (compound 91

( 1 ) 4-((4- (氰基 (噻唑并 [5,4-6]吡啶 -2-基)曱基)嘧啶 -2-基氧基)曱基)哌啶 •1-

(1) 4-((4-(Cyano(thiazolo[5,4-6]pyridin-2-yl)indolyl)pyrimidin-2-yloxy)indolyl)piperidine•1-

将 300 mg( 2 mmol )4- (羟基甲基)哌啶 -1-甲酸叔丁酯溶于 lO mL DMA中, 加入 160 mg ( 4 mmol ) 60%的 NaH，室温搅拌 1 h，加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，滤饼用高压液相制备色语提纯得到黄色固体 220 mg，收率 47.2%。 Dissolve 300 mg (2 mmol) of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate in 10 mL DMA, add 160 mg (4 mmol) of 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2- (2- chloro-pyrimidin-4-yl) -2- (thiazolo [5,4-6] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, filter cake purified by high pressure liquid phase to obtain a yellow solid 220 mg, yield 47.2%.

( 2 ) 2-(2- (哌啶 -4-基甲氧基)嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈的制

(2) Preparation of 2-(2-(piperidin-4-ylmethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

将 220 mg ( 0.47 mmol ) 4-((4- (噻唑并 [5，4-6]吡啶-2-基)曱基)嘧啶-2- 基氧基)曱基)哌啶- 1 -甲酸叔丁酯溶于 20 mL二氯曱烷和 1 mL曱醇的混合溶剂中，冰浴下通入干燥的 HC1气体反应 2 h, TLC监测反应结束。抽滤，干燥滤饼，得到黄色固体 160 mg, 收率 93.6%。 220 mg (0.47 mmol) 4-((4-(thiazolo[5,4-6]pyridin-2-yl)indolyl)pyrimidin-2-yloxy)indolyl)piperidine-1-carboxylic acid Butyl ester was dissolved in a mixture of 20 mL of dichloromethane and 1 mL of decyl alcohol. The reaction was carried out by passing dry HCl gas for 2 h in an ice bath. The reaction was terminated by TLC. After suction filtration, the filter cake was dried to give a yellow solid, 160 mg, yield 93.6%.

分子式： C₁₈H₁₈N₆OS; 分子量： 366.1 ; 质谱 (M+H): 367.1 Molecular formula: C ₁₈ H ₁₈ N ₆ OS; Molecular weight: 366.1 ; Mass spectrum (M+H): 367.1

^-NMRiDMSO-^, 400 MHz): δ 9.06 (IH, d), 8.80-8.65 (IH, m)， 8.43 (IH, d)， 8.17 (1H， d), 7.74 (IH, d)， 7.50 (IH, dd), 6.65 (IH, d), 4.58 (2H， d), 3.36-3.25 (2H, d), 2.90 (2H, dd), 2.28-2.15 (1H， m), 1.95 (2H, d), 1.56 (2H, dd)。 ^-NMRiDMSO-^, 400 MHz): δ 9.06 (IH, d), 8.80-8.65 (IH, m), 8.43 (IH, d), 8.17 (1H, d), 7.74 (IH, d), 7.50 ( IH, dd), 6.65 (IH, d), 4.58 (2H, d), 3.36-3.25 (2H, d), 2.90 (2H, dd), 2.28-2.15 (1H, m), 1.95 (2H, d) , 1.56 (2H, dd).

实施例 15: 2-(4- (环己基甲嘧啶 -2-基) -2- (噻唑并 [5，4-b】吡啶 -2-基)乙腈（

Example 15: 2-(4-(cyclohexylpyrimidin-2-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (

制备方法参考实施例 8, 柱层析后通过高压液相制备色谱分离即得。 The preparation method is as described in Reference Example 8. After column chromatography, it is obtained by high pressure liquid phase preparative chromatography.

分子式： C₁₉H₁₉N₅OS; 分子量： 365.1 ; 质语 (M+H): 366.1 Molecular formula: C ₁₉ H ₁₉ N ₅ OS; Molecular weight: 365.1 ; Qualifier (M+H): 366.1

^-NMRCDMSO-^, 400 MHz): δ 13.87 (IH, s), 8.35 (IH, dd), 8.03 (IH, dd), ^-NMRC DMSO-^, 400 MHz): δ 13.87 (IH, s), 8.35 (IH, dd), 8.03 (IH, dd),

8.32-8.26 (IH, m), 7.47 (IH, dd), 6.45 (IH, d), 4.25 (2H, d), 1.87-1.60 (7H, m),8.32-8.26 (IH, m), 7.47 (IH, dd), 6.45 (IH, d), 4.25 (2H, d), 1.87-1.60 (7H, m),

1.18-0.99 (4H， m)。 1.18-0.99 (4H, m).

实施例 16: 2-(2-((6-曱基吡啶 -3-基）甲氧基)嘧啶 4-基) -2- (噻唑并【5，4-b】吡啶 - -基)乙腈（化合物 216 )的制备 Example 16: 2-(2-((6-Mercaptopyridin-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-yl)acetonitrile ( Preparation of compound 216)

( 1 ) (6-甲基吡啶 -3-基)甲醇的制备

(1) Preparation of (6-methylpyridin-3-yl)methanol

将 1.51 g ( 10 mmol ) 6-曱基烟酸甲酯溶于 50 ml THF中，冰浴下緩慢加入 570 mg ( 15 mmol )四氢铝锂，室温反应 lh, TLC监测反应结束。加入十水结晶硫酸钠，抽滤，旋干滤液，柱层析（PE:EA=3:1→1:1 )得到浅绿色液体 1.1 g, 收率 89.4%。 1.51 g (10 mmol) of 6-mercaptonicotinic acid methyl ester was dissolved in 50 ml of THF, and 570 mg (15 mmol) of lithium tetrahydrogenate was slowly added thereto under ice-cooling, and reacted at room temperature for 1 hour, and the reaction was terminated by TLC. Sodium sulfate dehydrated sodium sulfate was added thereto, and the mixture was filtered under suction, and the filtrate was evaporated to dryness, and column chromatography (PE: EA = 3:1 → 1:1) to obtain a pale green liquid of 1.1 g, yield of 89.4%.

- (氯曱基) -2-甲基吡啶的制备

- Preparation of (chloroindolyl)-2-methylpyridine

将 246 mg ( 2 mmol ) (6-曱基吡啶 -3-基)甲醇加入到 5 mL氯化亚砜中，室温搅拌 5 h, 直接旋干溶剂用于下步反应。 246 mg (2 mmol) of (6-decylpyridin-3-yl)methanol was added to 5 mL of thionyl chloride, stirred at room temperature for 5 h, and the solvent was directly dried to the next step.

( 3 ) 2-(2-((6-曱基吡啶 -3-基)甲氧基)嘧啶 -4-基) -2- (噻唑并 [5,4-b]吡啶 -2- 基)

(3) 2-(2-((6-Mercaptopyridin-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)

将 260 mg ( 0.97 mmol ) 2-(2-羟基嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基) 乙腈溶于 10 mL DMA中，加入 1.3 g ( 4 mmol )碳酸铯和 5- (氯甲基) -2-曱基吡啶（约 2 mmol )，最后加入 20 mg ( 0.12 mmol )碘化钾， 70°C反应 18 h。加水，用稀盐酸调至弱酸性，二氯甲烷萃取，水洗，干燥，浓缩，柱层析 ( DCM:MeOH=500:l→ 100:1 ), 得黄色固体 105 mg, 收率 28.9% 260 mg (0.97 mmol) of 2-(2-hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile was dissolved in 10 mL of DMA and added 1.3 g ( 4 mmol) cesium carbonate and 5-(chloromethyl)-2-mercaptopyridine (about 2 mmol), finally added 20 mg (0.12 mmol) of potassium iodide, and reacted at 70 ° C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, extract with methylene chloride, wash with water, dry, and concentrate, column chromatography (DCM: MeOH = 500: l → 100:1) to give a yellow solid 105 mg, yield 28.9%

分子式： C₁₉H₁₄N₆OS; 分子量： 374.1 ; 质谱 (M+H): 375.1 Molecular formula: C ₁₉ H ₁₄ N ₆ OS; Molecular weight: 374.1 ; Mass spectrum (M+H): 375.1

^-NMRCDMSO-^, 400 MHz): δ 12.95 (IH, s)， 8.52-8.47 (2H, m)， 8.26 (1H， d)， 7.98 (1H， d), 7.68 (IH, dd), 7.55 (IH, dd), 7.25 (1H， d), 6.31 (1H， d), 5.00 (2H, s)， 2.44 (3H, s)。 ^-NMRC DMSO-^, 400 MHz): δ 12.95 (IH, s), 8.52-8.47 (2H, m), 8.26 (1H, d), 7.98 (1H, d), 7.68 (IH, dd), 7.55 ( IH, dd), 7.25 (1H, d), 6.31 (1H, d), 5.00 (2H, s), 2.44 (3H, s).

实施例 17: 2-(2- (环己氧基)嘧啶 -4-基) -2- (噻唑并 [5，4-b】吡啶 -2-基）乙腈（化合物

Example 17: 2-(2-(Cyclohexyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (compound)

将 200 mg ( 2 mmol )环己醇溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH，室温搅拌 1 h，加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5 ,4- ]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，滤饼用高压液相制备色谱分离得到黄色固体 160 mg, 收率 45.5% 分子式： C₁₈H₁₇N₅OS; 分子量： 351.1 ; 质谱 (M+H): 352.1Dissolve 200 mg (2 mmol) of cyclohexanol in 10 mL of DMA, add 160 mg (4 mmol) of 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2-(2-chloropyrimidine-4 - yl) -2- (thiazolo [5, 4] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, filter cake separated by high pressure liquid chromatography to obtain yellow solid 160 mg, yield 45.5% Molecular formula: C ₁₈ H ₁₇ N ₅ OS; Molecular weight: 351.1 ; Mass spectrum (M+H): 352.1

-醒 R (DMSO- ， 400 MHz): δ 12.67 (1Η, br s), 8.38 (1H, dd)， 8.10 (1H, d)， 7.69-7.60 (1H, m), 7.43 (1H, dd), 6.59 (1H, d), 5.44-5.32 (1H, m), 2.25-2.15 (2H，m), 1.87-1.76 (2H, m), 1.70-1.42 (5H，m)， 1.38-1.25 (1H, m)。 - wake up R (DMSO- , 400 MHz): δ 12.67 (1Η, br s), 8.38 (1H, dd), 8.10 (1H, d), 7.69-7.60 (1H, m), 7.43 (1H, dd), 6.59 (1H, d), 5.44-5.32 (1H, m), 2.25-2.15 (2H, m), 1.87-1.76 (2H, m), 1.70-1.42 (5H, m), 1.38-1.25 (1H, m ).

实施例 18: 2-(2-(2-环己基乙氧基)嘧啶 -4-基) -2- (噻唑并〖5，4-b]吡啶 -2-基) 乙腈

Example 18: 2-(2-(2-Cyclohexylethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile

将 256 mg ( 2 mmol )环己基乙醇溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH, 室温搅拌 1 h，加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4- 基) -2- (噻唑并 [5 ,4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，滤饼用高压液相制备色谱分离得到黄色固体 180 mg，收率 47.4% 256 mg (2 mmol) of cyclohexylethanol was dissolved in 10 mL of DMA, 160 mg (4 mmol) of 60% NaH was added, stirred at room temperature for 1 h, and 288 mg (1 mmol) of 2-(2-chloropyrimidine-4) was added. - yl) -2- (thiazolo [5, 4-6] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, filter cake separated by high pressure liquid chromatography to obtain yellow solid 180 mg, yield 47.4%

分子式： C20H21N5OS; 分子量: 379.1；质谱 (M+H): 380.2ο Molecular formula: C20H21N5OS; Molecular weight: 379.1; Mass spectrometry (M+H): 380.2ο

^-NMRCDMSO-^, 400 MHz): δ 12.72 (1Η, s), 8.38 (1H, d), 8.09 (1H， d)， ^-NMRCDMSO-^, 400 MHz): δ 12.72 (1Η, s), 8.38 (1H, d), 8.09 (1H, d),

7.70-7.61 (1H， m), 7.42 (1H, dd), 6.59 (1H, d)， 4.71 (2H， t), 1.82-1.58 (8H, m),7.70-7.61 (1H, m), 7.42 (1H, dd), 6.59 (1H, d), 4.71 (2H, t), 1.82-1.58 (8H, m),

1.31-1.10 (4H， m), 1.07-0.95 (1H, m)。 1.31-1.10 (4H, m), 1.07-0.95 (1H, m).

实施例 19: 2-(2-(2-环己基乙嘧啶 -4-基) -2- (噻唑并【4，5-c】吡啶 -2-基) 乙腈

Example 19: 2-(2-(2-Cyclohexylethylpyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

( 1 ) 2-(2-(2-环己基乙氧基)嘧啶 -4-基) -2- (噻唑并 [4,5-c]吡啶 -2-基）乙腈的制备

(1) Preparation of 2-(2-(2-cyclohexylethoxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

称取氢化钠 (60%， 0.211 g, 5.28 mmol)加入到 5 mL TV^N-二曱基乙酰胺中，加入 2-环己基乙醇 (0.338 g, 2.64 mmol),室温反应 1小时后加入 2-(2-氯嘧啶 -4- 基) -2- (噻唑并 [4,5-c]吡啶 -2-基）乙腈 (0.38 g, 1.32 mmol), 之后升温至 100。C反应 8 小时，旋干反应液，硅胶柱层析 (二氯曱烷→二氯曱烷:甲醇 =100:1), 得到产物 0.254 g，收率 50.7%。 Sodium hydride (60%, 0.211 g, 5.28 mmol) was weighed into 5 mL of TV^N-dimercaptoacetamide, and 2-cyclohexylethanol (0.338 g, 2.64 mmol) was added, and reacted at room temperature for 1 hour, then added 2 -(2-Chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (0.38 g, 1.32 mmol), then warmed to 100. After reacting for 8 hours, the reaction mixture was evaporated to silica gel column chromatography (dichloromethane:dichloromethane:methanol =100:1) to give the product 0.254 g, yield 50.7%.

分子式： C₂。H₂₁N₅OS; 分子量： 379.1 ; 质谱 (M+H): 380.2 ^-NMR (d₆-OMSO, 400 MHz): δ 9.00 (1H, s)， 8.31 (1H, d), 7.98 (1H， d), 7.72 (1H, d), 6.60 (1H, d), 4.68 (2H, t), 1.82-1.34 (8H, m), 1.32-0.92 (5H, m)。 Molecular formula: C ₂ . H ₂₁ N ₅ OS; Molecular Weight: 379.1 ; Mass Spectrum (M+H): 380.2 ^-NMR (d ₆ -OMSO, 400 MHz): δ 9.00 (1H, s), 8.31 (1H, d), 7.98 (1H, d), 7.72 (1H, d), 6.60 (1H, d), 4.68 (2H, t), 1.82-1.34 (8H, m), 1.32-0.92 (5H, m).

实施例 20: 2-(2-((l-甲基 -1H-吡唑 -3-基)甲氧基)嘧啶 -4-基) -2- (噻唑 [5，4-W 吡啶 -2-基)乙 Example 20: 2-(2-((l-Methyl-1H-pyrazol-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazole [5,4-W pyridine-2- Base) B

-曱基吡唑 -3-曱酸曱酯的制备

-Preparation of mercaptopyrazole-3-decanoic acid decyl ester

将 1.26 g ( 10 mmol ) 1-曱基吡唑 -3-曱酸加入到 30 mL无水甲醇中，冰浴下加入 2.38 g ( 20 mmol )氯化亚砜，移至室温反应 18 h, 旋干溶剂，得到白色固体直接用于下步反应。 Add 1.26 g (10 mmol) of 1-decylpyrazole-3-furic acid to 30 mL of anhydrous methanol, add 2.38 g (20 mmol) of thionyl chloride under ice bath, and move to room temperature for 18 h. The solvent was dried to give a white solid which was used directly to the next step.

-曱基吡唑 -3-基)曱醇的制备

Preparation of -mercaptopyrazole-3-yl)nonanol

将上步产物（约 10 mmol )加入到 40 mL四氢呋喃中，冰浴下緩慢加入 570 mg ( 15 mmol )四氢铝锂，加毕移至室温反应 3h，加入十水结晶硫酸钠，抽滤，旋干滤液，柱层析（PE:EA=3: 1→1 : 1 ), 得到无色油状物 800 mg, 以上两步收率 71.4%。 The above product (about 10 mmol) was added to 40 mL of tetrahydrofuran, and 570 mg (15 mmol) of lithium aluminum hydride was slowly added in an ice bath, and the mixture was added to room temperature for 3 hours, added with sodium sulfate decahydrate, and suction filtered. The filtrate was dried and purified by column chromatography (PE: EA = 3: 1 <RTI ID=0.0>>

( 3 ) 2-(2-((1-曱基 -177-吡唑 -3-基)甲氧基)嘧啶 -4-基) -2- (噻唑 [5,4-b]吡啶 -2-基)乙腈的制备

(3) 2-(2-((1-Mercapto-177-pyrazol-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazole[5,4-b]pyridine-2- Preparation of acetonitrile

将 2²4 mg ( 2 mmol ) (1-甲基 -li/-吡唑 -3-基)甲醇溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH，室温搅拌 1 h,加入 288 mg ( 1 mmol ) 2-(2- 氯嘧啶 -4-基) -2- (噻唑并 [5,4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，滤饼用高压液相制备色谱分离得不纯品， DMSO重结晶得到黄色固体 20 mg，收率 5.5% 分子式： C₁₇H₁₃N₇OS; 分子量： 363.1 ; 质谱 (M+H): 364.1 2 ² 4 mg ( 2 mmol ) of (1-methyl-li/-pyrazol-3-yl)methanol was dissolved in 10 mL of DMA, and 160 mg (4 mmol) of 60% NaH was added and stirred at room temperature for 1 h. Add 288 mg (1 mmol) of 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, protected with N ₂ and react at 100 ° C for 18 h . Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, filter cake separated by high pressure liquid chromatography to obtain impurities, DMSO recrystallization to obtain a yellow solid 20 mg, yield 5.5% Molecular formula: C ₁₇ H ₁₃ N ₇ OS; Molecular weight: 363.1 ; Mass spectrum (M+H): 364.1

^-NMRCDMSO-^, 400 MHz): δ 12.81 (1H， br s)， 8.37 (IH, d), 8.14-8.07 ^-NMRCDMSO-^, 400 MHz): δ 12.81 (1H, br s), 8.37 (IH, d), 8.14-8.07

(IH, m), 7.74-7.62 (2H, m)， 7.43 (IH, dd), 6.68-6.60 (IH, m), 6.42 (1H， d), 5.66(IH, m), 7.74-7.62 (2H, m), 7.43 (IH, dd), 6.68-6.60 (IH, m), 6.42 (1H, d), 5.66

(2H， s), 3.85 (3H, s)。 (2H, s), 3.85 (3H, s).

实施例 21: ²-(2-(²_(²_氧代吡咯烷 -1-基）乙氧基)嘧啶 _⁴_基) -2- (噻唑并Example 21: ² -(2-( ² _( ² _Oxopyrrolidin-1-yl)ethoxy)pyrimidin- ⁴ -yl)-2-(thiazolyl)

【5，4- -2-基）乙腈（化合物 221 )的制备

Preparation of [5,4--2-yl)acetonitrile (Compound 221)

将 258 mg ( 2 mmol ) 1-(2-羟基乙基)吡咯烷 -2-酮溶于 10 mL DMA中，加入 160 mg ( 4 mmol ) 60%的 NaH, 室温搅拌 1 h,加入 288 mg ( 1 mmol ) 2-(2- 氯嘧啶 -4-基) -2- (噻唑并 [5 ,4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，滤饼用高压液相制备色谱分离得到黄色固体 160 mg，收率 42.1% 258 mg ( 2 mmol ) of 1-(2-hydroxyethyl)pyrrolidin-2-one was dissolved in 10 mL of DMA, 160 mg (4 mmol) of 60% NaH was added, and stirred at room temperature for 1 h, 288 mg ( 1 mmol) 2- (2- chloro-pyrimidin-4-yl) -2- (thiazolo [5, 4-6] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, filter cake separated by high pressure liquid chromatography to obtain yellow solid 160 mg, yield 42.1%

分子式： C₁₈H₁₆N₆0₂S; 分子量： 380.42; 质谱 (M+H): 381.1 Molecular formula: C ₁₈ H ₁₆ N ₆ 0 ₂ S; Molecular weight: 380.42; Mass spectrum (M+H): 381.1

^-NMRCDMSO-^, 400 MHz): δ 8.39 (IH, dd), 8.10 (IH, d), 7.73-7.66 (IH, m), 7.44 (IH, dd), 6.62 (1H， d)， 4.78 (2H, t)， 3.70 (2H， t)， 3.49 (2H, t), 2.22 (2H, t) 1.92 (2H, quintet)。 ^-NMRC DMSO-^, 400 MHz): δ 8.39 (IH, dd), 8.10 (IH, d), 7.73-7.66 (IH, m), 7.44 (IH, dd), 6.62 (1H, d), 4.78 ( 2H, t), 3.70 (2H, t), 3.49 (2H, t), 2.22 (2H, t) 1.92 (2H, quintet).

实施例 22: 2-(2-((4，4-二氟环己基)甲氧基)嘧啶 -4-基) -2- (噻唑并【5,4-b】吡啶 -2-基)乙腈（ Example 22: 2-(2-((4,4-Difluorocyclohexyl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (

( 1 ) (4，4-二氟环己基)曱醇的制备 (1) Preparation of (4,4-difluorocyclohexyl) decyl alcohol

将 1.92 g ( 10 mmol ) 4，4-二氟环己基甲酸乙酯加入到 40 mL四氢呋喃中，冰浴下緩慢加入 570 mg ( 15 mmol )四氢铝锂，加毕移至室温反应 3 h, 加入十水结晶硫酸钠，抽滤，旋干滤液。加水，乙酸乙酯萃取，干燥，旋干得到浅黄色油状物 1.1 g，收率 73.3%。 1.92 g (10 mmol) of ethyl 4,4-difluorocyclohexylcarboxylate was added to 40 mL of tetrahydrofuran, and 570 mg (15 mmol) of lithium tetrahydrogenate was slowly added in an ice bath, and the mixture was added to room temperature for 3 h. Sodium sulfate decahydrate was added, suction filtered, and the filtrate was dried. Water was added, extracted with ethyl acetate, dried and evaporated to dryness to affordd of pale yellow oil 1.1 g, yield 73.3%.

( 2 ) 2-(2-((4，4-二氟环己基）曱氧基)嘧啶 -4-基) -2- (噻唑并 [5，4-6]吡啶 -2- 基)乙腈的制备

(2) 2-(2-((4,4-Difluorocyclohexyl)decyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile preparation

将3000¾(2 01)(4，4-二氟环己基)曱醇溶于 lOmLDMA中，加入 160 mg ( 4 mmol ) 60%的 NaH，室温搅拌 1 h, 加入 288 mg ( 1 mmol ) 2-(2-氯嘧啶 -4-基) -2- (噻唑并 [5，4-6]吡啶 -2-基）乙腈， N₂保护， 100°C反应 18 h。加水，用稀盐酸调至弱酸性，抽滤，滤饼千燥用 DMSO溶解，加入少量曱醇，析出黄色固体 140mg, 收率 34.9% 30003⁄4(2 01)(4,4-difluorocyclohexyl) decyl alcohol was dissolved in 10 mL DMA, 160 mg (4 mmol) 60% NaH was added, stirred at room temperature for 1 h, and 288 mg (1 mmol) 2-( 2-chloro-pyrimidin-4-yl) -2- (thiazolo [5,4-6] pyridin-2-yl) acetonitrile, N ₂ protection, 100 ° C reaction was 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, suction filtration, filter cake dried in DMSO, add a small amount of sterol, precipitate yellow solid 140mg, yield 34.9%

分子式: Ci₉H₁₇F₂N₅OS; 分子量： 401.1; 质谱 (M+H): 402.1 Molecular formula: Ci ₉ H ₁₇ F ₂ N ₅ OS; Molecular weight: 401.1; Mass spectrometry (M+H): 402.1

^-NMRCDMSO-^, 400 MHz): δ 12.79 (1Η, s 8.38 (1H， d), 8.09 (1H, d), 7.68 (1H， s), 7.43 (1H， dd), 6.69-6.55 (1H， m), 4.59 (2H, d), 2.14-1.74 (9H, m ^-NMRC DMSO-^, 400 MHz): δ 12.79 (1Η, s 8.38 (1H, d), 8.09 (1H, d), 7.68 (1H, s), 7.43 (1H, dd), 6.69-6.55 (1H, m), 4.59 (2H, d), 2.14-1.74 (9H, m

Claims

权利要求书 Claim

1、通式（ I )、（ l a )或（ l b )所示的化合物、其药学上可接受的盐或 A compound represented by the formula (I), (l a ) or ( l b ), a pharmaceutically acceptable salt thereof or

(I) (la) (!b) (I) (la) (!b)

其中， among them,

R¹ , R²分别独立的为氢、磺酰基、卤素、烷基、卤代 _₆烷基、 d.6 烷氧基、氨基、氰基、羟基、 C_2-6烯基、 C₂_₆炔基、 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基； R ¹ and R ² are each independently hydrogen, sulfonyl, halogen, alkyl, halo- ₆ alkyl, d.6 alkoxy, amino, cyano, hydroxy, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl;

n选自 0, 1， 2或 3; n is selected from 0, 1, 2 or 3;

！^为。^烷基、烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的! ^为为. ^alkyl, alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³

6- 14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基、 7-12元螺环基、 7-12元桥环基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2 个环烷基、杂环烷基、芳基或杂芳基稠合；

6- 14-membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 7-12 membered spiro group, 7-12 membered bridged ring group, The cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be fused to an additional 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups;

其中 m选自 0, 1 , 2或 3， Where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C^₆烷基、卤代 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 ^₆烷氧基、氨基、氰基、羟基、 C^₆烯基、 C^₆炔基、未被取代或至少被一个 R⁵取代的 6-14元芳基、 5-14元杂芳基、 3- 14元环烷基、 3-14元杂环烷基、R ⁴ is a sulfonyl group, a halogen, a C ₆ alkyl group, a halogenated C _1-6 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), ^ ₆ alkoxy group , amino, cyano, hydroxy, C^ ₆ alkenyl, C^ ₆ alkynyl, unsubstituted or substituted by at least one R ⁵ 6-14 membered aryl, 5-14 membered heteroaryl, 3- 14 Cycloalkyl, 3-14 membered heterocycloalkyl,

7- 12元螺环基、 7-12元桥环基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合， 3-14元杂环烷基的任意 CH₂可被 C(O)取代； a 7- to 12-membered spirocyclic group, a 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be bonded to another 1-2 cycloalkyl groups, heterocycloalkyl groups, An aryl or heteroaryl group fused, any CH _{2 of a} 3-14 membered heterocycloalkyl group may be substituted by C(O);

R⁵为磺酰基、卤素、 C_1-6烷基、卤代 C!— ₆烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6 烷基、 -C(0)-C_1-6烷基、 -(CH₂)_p-C(0)-0-C_1-6烷基、 -(CH₂)_p-0-C_1-6烷基、 -(C¾)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、氨基、羟基、 C_2-6烯基、 C_2-6炔基、 3-14元环烷基、 6-14元芳基或 3-14元杂环基； R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halo C! _-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C( 0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(C3⁄4 _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino group, hydroxyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, a 3-14 membered cycloalkyl group, a 6-14 membered aryl group or a 3-14 membered heterocyclic group;

R^a、 R^b分别独立的为氢、 C_1-6烷基、 -(C¾)_p-OC_1-6烷基或 6-14元芳基 C_1-6 烷基， R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, -(C 3⁄4) _p -OC _1-6 alkyl or 6-14 member aryl C _1-6 alkyl,

p选自 1 , 2, 3或 4。 p is selected from 1, 2, 3 or 4.

2、如权利要求 1所述的化合物、其药学上可接受的盐或其立体异构体：其中， 2. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1 wherein:

R¹, R²分别独立的为氢、磺酰基、卤素、（^₆垸基、 d.₆烷氧基、氨基、 fj^. 羟基、 C_2-6烯基、 C_2-6炔基、 6-14元芳基； R ¹ and R ² are each independently hydrogen, sulfonyl, halogen, (^ ₆ fluorenyl, d. ₆ alkoxy, amino, fj^. hydroxy, C _2-6 alkenyl, C _2-6 alkynyl, 6-14 member aryl;

n选自 0, 1 , 2或 3; n is selected from 0, 1, 2 or 3;

L为 C_1-6垸基、 d_6烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合； L is a C _1-6 fluorenyl group, a d_6 alkoxy group, -N(R ^a R ^b ), a 6-14 membered aryl group which is unsubstituted or substituted with at least one R ³ , a 5-14 membered heteroaryl group, 3 a 14-membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be bonded to another 1-2 cycloalkyl groups, heterocycloalkyl groups, An aryl or heteroaryl group is fused;

0 0

R³为或 ^e、R⁴ , R ³ is or ^e , R ⁴ ,

其中 m选自 0， 1， 2或 3 , Where m is selected from 0, 1, 2 or 3

R⁴为磺酰基、卤素、烷基、卤代 d.₆烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 C_1-6烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基、 7-12元螺环基、 7-12 元桥环基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稠合， 3-14元杂环烷基的任意 CH₂可被 C(O) 取代； R ⁴ is a sulfonyl group, a halogen, an alkyl group, a halogenated d. ₆ alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), a C _1-6 alkoxy group, an amino group a cyano group, a hydroxy group, a 6-14 membered aryl group which is unsubstituted or substituted by at least one R ⁵ , a 5-14 membered heteroaryl group, a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, 7 a -12 membered spirocyclic group, a 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be bonded to another 1-2 cycloalkyl groups, heterocycloalkyl groups, and aromatic groups. a aryl or heteroaryl fused, any CH _{2 of a} 3-14 membered heterocycloalkyl group may be substituted by C(O);

R⁵为磺酰基、卤素、 C_1-6烷基、卤代 C_1-6烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6 烷基、 -C(0)-C_1-6烷基、 -(CH₂)_p-C(0)-0-C_1-6烷基、 -(CH₂)_p-0-C_1-6烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、、、羟基、 C_2-6烯基、 C_2-6炔基、 3-14元环烷基、 6-14元芳基或 3-14元杂环基； R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C( 0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , , hydroxy, C _2-6 alkenyl, C _2-6 alkynyl, 3-14 membered cycloalkyl a 6-14 membered aryl group or a 3-14 membered heterocyclic group;

R^a、 R^b分别独立的为氢、 C_1-6烷基、 -(CH₂)_p-OC_1-6烷基、苯基 C_1-6烷基， p选自 1， 2， 3或 4。 3、如权利要求 2所述的化合物、其药学上可接受的盐或其立体异构体：其中， R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, -(CH ₂ ) _p -OC _1-6 alkyl, phenyl C _1-6 alkyl, and p is selected from 1, 2, 3 or 4. 3. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 2: wherein

R¹ , R²分别独立的为氢、磺酰基、卤素、 d_₆烷基、 C_1-6烷氧基、氨基、氛基、择基 R ¹ and R ² are each independently hydrogen, sulfonyl, halogen, d- ₆ alkyl, C _1-6 alkoxy, amino, aryl, alkoxy

n选自 0, 1， 2或 3; n is selected from 0, 1, 2 or 3;

！^为^^烷基、烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹淋基、 5-6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； ! ^ is alkyl, alkoxy, -N(R ^a R ^b ), unsubstituted or at least substituted with one R ³ phenyl, quinolyl, 5-6 membered heteroaryl, 3-8 member a cycloalkyl group or a 3-8 membered heterocycloalkyl group;

0 0

_R3为/^ _R4或/ e、_R4 , 其中 m选自 0， 1 , 2或 3， _R 3 is /^ _R4 or / e, _R4 , wherein m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C_1-6烷基、卤代 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的 6-14元芳基、 5-14元杂芳基、 3-14元环烷基、 3-14元杂环烷基，其中所述环烷基、杂环烷基、芳基或杂芳基可与另外 1-2个环烷基、杂环烷基、芳基或杂芳基稍合， 3-14元杂环烷基的任意 CH₂可被 C(O)取代； R ⁴ is a sulfonyl group, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), an alkoxy group, Amino, cyano, hydroxy, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, unsubstituted or substituted with at least one R ⁵ , Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be slightly combined with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, 3-14 membered heterocycloalkane Any CH _{2 of the} group may be substituted by C(O);

R⁵为磺酰基、卤素、 C_1-6烷基、卤代 C_1-6烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6 烷基、 -C(0)-C_1-6烷基、 -(CH₂)_p-C(0)-0-C_1-6烷基、 -(CH₂)_p-0-C_1-6烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、、、羟基、 C₂_₆烯基、 C_2-6炔基、 R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C( 0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , , hydroxy, C ₂ _-6 alkenyl, C _2-6 alkynyl,

3-14元环烷基、 6-14元芳基或 3-14元杂环基； a 3-14 membered cycloalkyl group, a 6-14 membered aryl group or a 3-14 membered heterocyclic group;

R^a、 R^b分别独立的为氢、 C_1-6烷基、 -(C¾)_p-OC_1-6烷基、苄基或苯基乙基， p选自 1 , 2， 3或 4。 R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, -(C 3⁄4) _p -OC _1-6 alkyl, benzyl or phenylethyl, and p is selected from 1, 2, 3 or 4.

4、如权利要求 3所述的化合物、其药学上可接受的盐或其立体异构体：其中， 4. A compound according to claim 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof: wherein

R¹, R²分别独立的为氢、 d_₆烷基； R ¹ and R ² are each independently hydrogen and d ₆ alkyl;

n选自 0， 1 , 2或 3; n is selected from 0, 1, 2 or 3;

L为 ^₆烷基、（^₆烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 5-6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； L is ^ ₆ alkyl, (^ ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³ a phenyl group, a quinolyl group, a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group;

0 0

_R3为/^ 或/^：、 _r4，其中 m选自 0, 1， 2或 3， _R 3 is /^ or /^:, _r4 , where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C_1-6烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 ₆烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的苯基、 5-6元杂芳基、 3-8元环烷基、 3-8元杂环烷基，其中所述环烷基、杂环烷基、苯基或杂芳基可与另外 1个环烷基、杂环烷基、苯基或杂芳基稠合， 3-8元杂环烷基的任意 CH₂可被 C(O)取代； R ⁴ is sulfonyl, halogen, C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), ₆ alkoxy, amino, cyano, hydroxy, un a phenyl group substituted with or substituted with at least one R ⁵ , a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group, wherein the cycloalkyl group, heterocycloalkyl group, A phenyl or heteroaryl group may be fused to another 1 cycloalkyl, heterocycloalkyl, phenyl or heteroaryl group, and any CH _{2 of a} 3-8 membered heterocycloalkyl group may be substituted by C(O);

R⁵为 C_1-6烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6烷基、 -C(0)-C_1-6烷基、 -(CH₂)_p-C(0)-0-C_1-6 烷基、 -(CH₂)_p-0-C_1-6 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH、氨基、氰基、羟基、 3-8元环烷基、苯基、 3-8元杂环基； R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b , -(CH ₂ ) _p -OH, amino, cyano, hydroxy, 3-8 membered cycloalkyl, phenyl, 3-8 membered heterocyclic;

R^a、 R^b分别独立的为氢、 C_1-6烷基、 -(CH₂)_p-OC_1-6烷基、苄基或苯基乙基； p选自 1， 2， 3或 4。 R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, -(CH ₂ ) _p -OC _1-6 alkyl, benzyl or phenylethyl; p is selected from 1, 2, 3 or 4 .

5、如权利要求 4所述的化合物、其药学上可接受的盐或其立体异构体：其中， The compound according to claim 4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof: wherein

R¹, R²分别独立的为氢、 C 烷基； R ¹ and R ² are each independently hydrogen and C alkyl;

n选自 0, 1， 2或 3; n is selected from 0, 1, 2 or 3;

！^为^— ₆烷基、 d.6烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； ! ^ is ₆ - alkyl, d. ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³ phenyl, quinolyl, 6-membered heteroaryl, 3- 8-membered cycloalkyl or 3-8 membered heterocycloalkyl;

0 0

R³为^^ 或/ ^e、R⁴ , Or R ³ is ^^ / ^e, R ^4,

其中 m选自 0, 1， 2或 3， Where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 ₃烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 C_1-6烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的苯基、 5-6元杂芳基、 3-8元环烷基、 3-8元杂环烷基或哌啶并苯基，其中 3-8元杂环烷基的任意 CH₂ 可被 C(O)取代； R ⁴ is sulfonyl, halogen, ₃ alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 alkoxy, amino, cyano, hydroxy, un a phenyl group substituted with or substituted with at least one R ⁵ , a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group or a piperidinylphenyl group, wherein 3-8 members are hetero Any CH _{2 of a} cycloalkyl group may be substituted by C(O);

R⁵为 d.₆烷基、 C_1-6烷氧基、 -c c -o-c^烷基、 -C ^-C^烷基、 -(CH₂)_p-C(0)-0-C_1-6 烷基、 -(C¾)_p-0-C_1-6 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(C¾)_P-OH、氨基、氰基或羟基； R ⁵ is d. ₆ alkyl, C _1-6 alkoxy, -cc -oc^alkyl, -C ^-C^alkyl, -(CH ₂ ) _p -C(0)-0-C _{1 -6} alkyl, -(C3⁄4) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(C3⁄4) _P- OH, amino, cyano or hydroxy;

R^A、 R^B分别独立的为氢、 d_₆烷基、 -(CH^-OC 烷基或苄基， p选自 1 , 2或 3。 R ^A and R ^B are each independently hydrogen, d ₆ alkyl, -(CH^-OC alkyl or benzyl, and p is selected from 1, 2 or 3.

6、如权利要求 5所述的化合物、其药学上可接受的盐或其立体异构体：其中， 6. A compound according to claim 5, a pharmaceutically acceptable salt thereof or a stereoisomer thereof: wherein

R¹ , R²分别独立的为氢、烷基； R ¹ and R ² are each independently hydrogen or alkyl;

n选自 0， 1， 2或 3; n is selected from 0, 1, 2 or 3;

为 ^烷基、 ^₆烷氧基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、 6元杂芳基、 3-8元环烷基或 3-8元杂环烷基； Is a phenyl group, a ₆ alkoxy group, a -N(R ^a R ^b ), a phenyl group which is unsubstituted or substituted with at least one R ³ , a quinolyl group, a 6-membered heteroaryl group, a 3-8 membered naphthenic ring. Or a 3-8 membered heterocycloalkyl group;

0 0

R³为或、 R⁴， R ³ is or R ⁴ ,

其中 m选自 0, 1 , 2或 3 , Where m is selected from 0, 1, 2 or 3,

R⁴为磺酰基、卤素、 C_1-3烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、 C_1-6烷氧基、氨基、氰基、羟基、未被取代或至少被一个 R⁵取代的 5-6元杂芳基、 3-8元杂环烷基或哌啶并苯基，其中 3-8元杂环烷基的任意 CH₂可被 C(O)取代；R ⁴ is a sulfonyl group, a halogen, a C _1-3 alkyl group, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), a C _1-6 alkoxy group, an amino group, a cyano group, a 5-6 membered heteroaryl group, a 3-8 membered heterocycloalkyl group or a piperidinophenyl group which is unsubstituted or substituted with at least one R ⁵ , wherein any CH _{2 of the} 3-8 membered heterocycloalkyl group may be Replaced by C(O);

R⁵为 d_₃烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6烷基、 -C(0)-Cw烷基、 -(CH₂)_p-C(0)-0-C_1-3 烷基、 -(CH p-O-Cw 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH, 、或羟基； R ⁵ is d_ ₃ alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-Cw alkyl, -(CH ₂ ) _p -C( 0)-0-C _1-3 alkyl, -(CH pO-Cw alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , Or hydroxyl group;

R^a、 R^b分别独立的为氢、 C_1-6烷基、 -(CH₂)_p-OCw烷基或苄基， p选自 1 , 2或 3。 R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, -(CH ₂ ) _p -OCw alkyl or benzyl, and p is selected from 1, 2 or 3.

7、如权利要求 6所述的化合物、其药学上可接受的盐或其立体异构体：其中， The compound according to claim 6, a pharmaceutically acceptable salt thereof or a stereoisomer thereof: wherein

n选自 0, 1 , 2或 3; n is selected from 0, 1, 2 or 3;

L为 d_₆烷基、 -N(R^aR^b)、未被取代或至少被一个 R³取代的苯基、喹啉基、吡啶基、嘧啶基、环己烷基、哌啶基、四氢吡喃基、哌嗪基或吗啉基； L is d- ₆ alkyl, -N(R ^a R ^b ), unsubstituted or substituted with at least one R ³ phenyl, quinoline a pyridyl group, a pyridyl group, a cyclohexane group, a piperidinyl group, a tetrahydropyranyl group, a piperazinyl group or a morpholinyl group;

0 0

_R3为/ ( R₄或 ^e、_R4 , _R 3 is / ( R ₄ or ^e , _R 4 ,

其中 m选自 0或 1， Where m is selected from 0 or 1,

R⁴为磺酰基、卤素、 C_1-3烷基、 -C(0)N(R^aR^b)、 -N(R^aR^b)、未被取代或至少被一个 R⁵取代的吡¹¹定基、吡唑基、咪唑基、嘧⁵¹定基、哌啶并苯基、吗啉基、哌¹¹定基、哌。秦基、四氢吡咯 2-酮基； R ⁴ is sulfonyl, halogen, C _1-3 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), unsubstituted or substituted with at least one R ⁵ pyr ¹¹ Stationary, pyrazolyl, imidazolyl, pyrimidine ⁵¹ , piperidinyl phenyl, morpholinyl, piperidine ¹¹ , piperazine. Qinji, tetrahydropyrrole 2-keto group;

R⁵为 Ci_-3烷基、 C_1-6烷氧基、 -C(0)-0-C_1-6烷基、 -C(0)-C_1-3烷基、 -(CH₂)_p-C(0)-0-C_1-3 烷基、 -(CH p-O-Cw 烷基、 -(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH; R ⁵ is Ci _-3 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-3 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-3 alkyl, -(CH pO-Cw alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH;

R^a、 R^b分别独立的为氢、 ₆烷基、 -(CH p-OCw烷基或苄基， R ^a and R ^b are each independently hydrogen, ₆ alkyl, -(CH p-OCw alkyl or benzyl,

p选自 1 , 2或 3。 p is selected from 1, 2 or 3.

8.如权利要求 1-7中任一项所述的化合物、其药学上可接受的盐或其立体异构体， The compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

其中 X和 Y中的一个是 N，另一个是 CR Where one of X and Y is N and the other is CR

9.如权利要求 1-8中任一项所述的化合物、其药学上可接受的盐或其立体异构体， The compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

其中 Z代表 CH, W代表 CH; Where Z stands for CH and W stands for CH;

U代表 N， G代表 N。 U stands for N and G stands for N.

10. 选自以下的化合物、其药学上可接受的盐或其立体异构体： 10. A compound selected from the group consisting of a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

9L 9L

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

LL LL

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

08 08

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

18 18

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

C8 C8

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV 680000/M0ZN3/X3d 98Ϊ Ϊ / 0Ζ OAV

12、一种药物组合物，其包括权利要求 1 ~ 11任一项所述的化合物、其药学上可接受的盐或其立体异构体与一种或多种药用载体。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

13、权利要求 1 11任一项所述的化合物、其药学上可接受的盐或其立体异构体或权利要求 12的药物组合物在制备治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症（如过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼）、肺纤维化、肝纤维化、脂肪肝或肝硬化的药物中的用途。 13. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the treatment and/or prevention of ischemia-reperfusion injury, diabetes, Neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma), lung fiber Use in drugs for liver, liver fibrosis, fatty liver or cirrhosis.

14、一种治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症（如过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼）、肺纤维化、肝纤维化、脂肪肝或肝硬化的方法，包括给予需要其的患者治疗有效量的权利要求 1 ~ 12任一项所述的化合物、其药学上可接受的盐或其立体异构体或权利要求 13的药物组合物。 14. A treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, A method of allergic keratitis, dry eye, retinopathy, glaucoma, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis comprising administering to a patient in need thereof a therapeutically effective amount of any one of claims 1 to 12 A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutical composition according to claim 13.

15、用于治疗和 /或预防缺血再灌注损伤、糖尿病、神经退行性病变、慢性炎症（如过敏、哮喘、类风湿类关节炎、骨关节炎、动脉粥样硬化、过敏性结膜炎、过敏性角膜炎、干眼症、视网膜病变、青光眼）、肺纤维化、肝纤维化、脂肪肝或肝硬化的权利要求 1 ~ 12任一项所述的化合物、其药学上可接受的盐或其立体异构体或权利要求 13的药物组合物。 15. For the treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, A compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a liver sclerosing Its stereoisomer or the pharmaceutical composition of claim 13.