WO2021228173A1

WO2021228173A1 - Azepine fused ring compounds and medical uses thereof

Info

Publication number: WO2021228173A1
Application number: PCT/CN2021/093499
Authority: WO
Inventors: 殷惠军; 闫旭; 沙汉明; 刘国标; 王国政; 李斌; 温俊歌; 路嘉伟
Original assignee: 中国医药研究开发中心有限公司
Priority date: 2020-05-14
Filing date: 2021-05-13
Publication date: 2021-11-18
Also published as: TW202144353A; CN115038707A

Abstract

The present invention relates to azepine fused ring compounds and their medical uses. Specifically, the present invention relates to an azepine fused ring compound represented by the general formula (I), a preparation method therefor, a pharmaceutical composition comprising same, and the use thereof as a receptor-interacting protein kinase 1 (RIP1) inhibitor in the treatment of diseases associated with RIP1 activity. The definition of each substituent in the general formula (I) is the same as the definition in the specification.

Description

氮杂卓类稠环化合物及其医药用途Azepine condensed ring compound and its medical use

技术领域Technical field

本发明涉及氮杂卓类稠环化合物及其医药用途。具体地，本发明涉及通式(I)所示的氮杂卓类稠环化合物，其制备方法，含有其的药物组合物，以及其作为受体相互作用蛋白激酶1(RIP1)抑制剂，用于治疗与RIP1活性相关的疾病的用途。The present invention relates to azazepine fused ring compounds and their medical uses. Specifically, the present invention relates to the azazepine fused ring compound represented by the general formula (I), its preparation method, a pharmaceutical composition containing it, and its use as a receptor-interacting protein kinase 1 (RIP1) inhibitor. For the treatment of diseases related to RIP1 activity.

背景技术Background technique

凋亡和坏死是细胞死亡的2种方式。环境因素引起的被动性细胞死亡、细胞坏死在炎症反应等病理和生理过程中发挥重要作用。RIP1处于多条炎症和细胞死亡相关信号通路交互点，参与调节TNF激活的NF-κB、凋亡、坏死等多条下游信号通路。Apoptosis and necrosis are two ways of cell death. Passive cell death and cell necrosis caused by environmental factors play an important role in pathological and physiological processes such as inflammation. RIP1 is at the interaction point of multiple inflammation and cell death-related signaling pathways, and participates in the regulation of TNF-activated NF-κB, apoptosis, necrosis and other downstream signaling pathways.

RIP1可通过介导NF-κB通路促进炎症反应，但值得注意的是，NF-κB通路的激活以及TNF诱导的细胞凋亡不需要RIP1的激酶活性，RIP1激酶抑制对TNF诱导的NF-κB通路激活没有影响。但是，RIP1的激酶活性也可通过细胞坏死、炎症小体、TNF产生等多条途径促进炎症的发生发展。RIP1 can promote inflammation by mediating the NF-κB pathway, but it is worth noting that the activation of the NF-κB pathway and TNF-induced apoptosis do not require the kinase activity of RIP1, and RIP1 kinase inhibits the NF-κB pathway induced by TNF Activation has no effect. However, the kinase activity of RIP1 can also promote the occurrence and development of inflammation through multiple pathways such as cell necrosis, inflammasome, and TNF production.

RIP1激酶介导的细胞坏死与炎症：发生凋亡的细胞可在细胞膜未破裂时就被机体快速清除，而坏死细胞清除较慢，细胞膜破裂后，细胞质内大量的危险内容物释放，并被机体视为病原体样物质，激活众多模式识别受体，严重增强炎症反应。细胞坏死也被认为是相关炎症疾病快速发展并发生严重症状的重要因素。Cell necrosis and inflammation mediated by RIP1 kinase: Apoptotic cells can be quickly cleared by the body when the cell membrane is not ruptured, while necrotic cells are cleared more slowly. After the cell membrane ruptures, a large amount of dangerous contents in the cytoplasm are released and are released by the body. Regarded as a pathogen-like substance, it activates many pattern recognition receptors and severely enhances the inflammatory response. Cell necrosis is also considered to be an important factor in the rapid development of related inflammatory diseases and the occurrence of severe symptoms.

RIP1激酶与炎症小体：同TNF-α一样，IL-1β也是关键的促炎症因子。例如，在RA的发生发展过程中，IL-1β通过作用于滑膜成纤维细胞和软骨细胞而加重软骨、骨组织以及关节周围软组织的破坏。IL-1β分泌需要2条通路协助：首先，TLR4和TNF等通路促IL-1β/IL-18前体表达；随后，形成的NLPR3等炎症小体平台促IL-1β/IL-18前体成熟。炎症小体与RA、银屑病等自身免疫性疾病的发生发展密切相关。炎症小体的活化依赖于RIP1和RIP3及其激酶活性。RIP1和RIP3可扩大IL-1β的表达，且该过程非依赖于细胞坏死。RIP1 kinase and inflammasome: Like TNF-α, IL-1β is also a key pro-inflammatory factor. For example, during the occurrence and development of RA, IL-1β acts on synovial fibroblasts and chondrocytes to aggravate the destruction of cartilage, bone tissue and soft tissues around joints. The secretion of IL-1β requires the assistance of two pathways: first, pathways such as TLR4 and TNF promote the expression of IL-1β/IL-18 precursors; then, the formation of NLPR3 and other inflammasome platforms promote the maturation of IL-1β/IL-18 precursors . Inflammasome is closely related to the occurrence and development of autoimmune diseases such as RA and psoriasis. The activation of inflammasomes depends on RIP1 and RIP3 and their kinase activities. RIP1 and RIP3 can expand the expression of IL-1β, and the process is independent of cell necrosis.

RIP1激酶依赖性介导IL-1α产生：蛋白酪氨酸磷酸酶SHP-1在免疫信号通路中扮演重要角色，SHP-1突变小鼠产生大量炎症因子伴随关节炎等炎症疾病，但机制未知。特定SHP-1突变小鼠可自发严重炎症，症状与人嗜中性皮肤病相似。在该模型中，RIP1激酶依赖促IL-1α产生，后者可介导和扩大炎症以及组织损伤，这些都非依赖于炎症小体、IL-1β和RIP3。RIP1激酶抑制可防止相关炎症和损伤的发生，NF-κB和ERK抑制可缓解RIP1介导的炎症因子产生。因此，SHP-1突变小鼠的炎症及组织损伤依赖RIP1激酶介导的IL-1α产生，机制与RIP1激酶调控NF-κB和ERK通路有关。RIP1 kinase-dependently mediates the production of IL-1α: protein tyrosine phosphatase SHP-1 plays an important role in the immune signaling pathway. SHP-1 mutant mice produce a large number of inflammatory factors associated with inflammatory diseases such as arthritis, but the mechanism is unknown. Certain SHP-1 mutant mice can spontaneously severe inflammation, with symptoms similar to human neutrophilic skin diseases. In this model, RIP1 kinase is dependent on the production of IL-1α, which can mediate and amplify inflammation and tissue damage, which are independent of inflammasome, IL-1β and RIP3. Inhibition of RIP1 kinase can prevent related inflammation and injury, and inhibition of NF-κB and ERK can alleviate the production of inflammatory factors mediated by RIP1. Therefore, inflammation and tissue damage in SHP-1 mutant mice depend on the IL-1α production mediated by RIP1 kinase, and the mechanism is related to the regulation of NF-κB and ERK pathways by RIP1 kinase.

RIP1激酶依赖性介导TNFα产生：cIAP可通过泛素化抑制RIP1活性，而Smac 等cIAP抑制剂可诱导TNFα产生和细胞死亡，但机制未知。TNFα抑制可防止半胱天冬酶抑制诱导的细胞死亡，说明半胱天冬酶e抑制可能诱导TNFα的产生。RIP1激酶抑制可防止半胱天冬酶抑制诱导的细胞死亡，因此，在半胱天冬酶抑制的情况下，RIP1可能作为TNFα产生的上游机制。近年研究表明，RIP1激酶可与EDD相互作用诱导JNK通路激活和TNFα产生，该通路特异性对应半胱天冬酶抑制，说明RIP1激酶活性不仅调控TNFR1下游的细胞坏死，而且在介导TNFα产生方面扮演重要角色。RIP1 kinase-dependently mediates TNFα production: cIAP can inhibit RIP1 activity through ubiquitination, while cIAP inhibitors such as Smac can induce TNFα production and cell death, but the mechanism is unknown. TNFα inhibition can prevent cell death induced by caspase inhibition, indicating that caspase e inhibition may induce the production of TNFα. Inhibition of RIP1 kinase can prevent cell death induced by caspase inhibition. Therefore, in the case of caspase inhibition, RIP1 may serve as an upstream mechanism for TNFα production. Recent studies have shown that RIP1 kinase can interact with EDD to induce JNK pathway activation and TNFα production. This pathway specifically corresponds to caspase inhibition, indicating that RIP1 kinase activity not only regulates cell necrosis downstream of TNFR1, but also mediates TNFα production. play an important role.

近年来，一些基因学证据(例如RIP1激酶失活突变)以及RIP1激酶抑制剂工具分子(例如Nec-1)的相关研究进一步证实RIP1激酶在一些炎症及多种组织损伤疾病的发生发展中扮演重要角色。RIP1激酶失活突变可完全防止多器官炎症表型，特别是皮肤炎症；RIP1激酶抑制可防止肾移植动物模型因缺血-再灌注导致的肾损伤；RIP1激酶抑制剂Nec-1防止心梗和心脏缺氧；RIP1激酶抑制剂Nec-1防止视锥细胞死亡，dsRNA导致的视网膜变性，以及色素性视网膜炎。In recent years, some genetic evidence (such as RIP1 kinase inactivation mutations) and related research on RIP1 kinase inhibitor tool molecules (such as Nec-1) have further confirmed that RIP1 kinase plays an important role in the occurrence and development of some inflammation and various tissue damage diseases. Role. RIP1 kinase inactivation mutations can completely prevent multiple organ inflammatory phenotypes, especially skin inflammation; RIP1 kinase inhibition can prevent kidney injury caused by ischemia-reperfusion in animal models of kidney transplantation; RIP1 kinase inhibitor Nec-1 prevents myocardial infarction and Heart hypoxia; RIP1 kinase inhibitor Nec-1 prevents cone cell death, dsRNA-induced retinal degeneration, and retinitis pigmentosa.

RIP1缺失导致动物死亡，与RIP1缺失不同，RIP1激酶失活突变小鼠可以正常存活，且抵抗坏死刺激，因此，RIP1缺失导致的死亡与激酶活性无关。Ripk1D138N/D138N和RipkK45A/K45A激酶失活突变小鼠没有明显改变的表型，说明RIP1激酶活性是相对比较安全的靶点。相比之下，RIP3激酶失活突变小鼠体重下降较快，且发生死亡。Deletion of RIP1 leads to death of animals. Unlike RIP1 deletion, RIP1 kinase inactivation mutant mice can survive normally and resist necrotic stimulation. Therefore, death caused by RIP1 deletion has nothing to do with kinase activity. The phenotype of Ripk1D138N/D138N and RipkK45A/K45A kinase inactivation mutant mice did not change significantly, indicating that RIP1 kinase activity is a relatively safe target. In contrast, mice with RIP3 kinase inactivation mutants lost more weight and died.

鉴于RIP1激酶在炎症发生发展中扮演的重要角色，RIP1激酶抑制剂用于炎症疾病治疗受到全球领先药企的一定关注。其中，GSK代表化合物GSK2982772已开始临床II期研究；Roche也有分子处于临床前研究阶段。但至今尚无RIP1激酶抑制剂上市，研发人员还需要开发更多的RIP1激酶抑制剂分子，以便选择更好的化合物用于相关疾病及炎症的治疗。In view of the important role that RIP1 kinase plays in the occurrence and development of inflammation, the use of RIP1 kinase inhibitors in the treatment of inflammatory diseases has received certain attention from leading global pharmaceutical companies. Among them, GSK represents the compound GSK2982772 has begun clinical phase II research; Roche also has molecules in the preclinical research stage. However, there is no RIP1 kinase inhibitor on the market so far, and researchers need to develop more RIP1 kinase inhibitor molecules in order to select better compounds for the treatment of related diseases and inflammation.

发明内容Summary of the invention

本发明人经过潜心研究，设计合成了一系列氮杂卓类稠环化合物，其显示出受体相互作用蛋白激酶1(RIP1)的抑制活性，可以被开发为预防或治疗与RIP1活性相关的疾病的药物。After painstaking research, the inventors designed and synthesized a series of azazepine fused ring compounds, which show the inhibitory activity of receptor-interacting protein kinase 1 (RIP1), and can be developed to prevent or treat diseases related to RIP1 activity. medicine.

因此，本发明的目的是提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，Therefore, the object of the present invention is to provide a compound represented by the general formula (I) or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its medicinal salt,

其中，in,

X选自-O-、-S(O) _m-、-NR ^a-、-CR’R”-； X is selected from -O-, -S(O) _m -, -NR ^a -, -CR'R"-;

Y ¹和Y ²各自独立地选自O或S； Y ¹ and Y ² are each independently selected from O or S;

Z ¹和Z ²各自独立地选自C或N原子； Z ¹ and Z ² are each independently selected from C or N atoms;

L选自单键、-O-、-S(O) _m-、-NR ^a-、-(CR ^aR ^b) _n-、-(CR ^aR ^b) _nO-、-(CR ^aR ^b) _nS-和-(CR ^aR ^b) _nNR ^a-； L is selected from single bond, -O-, -S(O) _m -, -NR ^a -, -(CR ^a R ^b ) _n -, -(CR ^a R ^b ) _n O-, -(CR ^a R ^b ) _n S- and -(CR ^a R ^b ) _n NR ^a -;

环A选自芳基、杂芳基、环烷基和杂环基，其中所述芳基、杂芳基、环烷基和杂环烷基任选进一步被一个或多个R ⁹取代； Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally further substituted with one or more R ⁹ ;

环B为芳环或芳杂环，其任选进一步被一个或多个R ⁸取代； Ring B is an aromatic ring or an aromatic heterocyclic ring, which is optionally further substituted by one or more R ⁸ ;

环C为含氮杂环，其任选进一步被一个或多个R ⁷取代； Ring C is a nitrogen-containing heterocyclic ring, which is optionally further substituted by one or more R ⁷ ;

R ¹和R ²与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，或者R ²和R ³与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，或者R ³和R ⁴与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，其中所述C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基任选进一步被一个或多个R ⁶取代；其中： R ¹ and R ² together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, or R ² and R ³ and The atoms to which they are connected together form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, or R ³ and R ⁴ together with the atoms to which they are connected form C _6-10 aryl, 6 to 10 membered heteroaryl, 6 to 10 membered heterocyclic group or C _6-10 cycloalkyl, wherein the C _6-10 aryl, 6 to 10 membered heteroaryl, 6 To 10-membered heterocyclyl or C _6-10 cycloalkyl is optionally further substituted with one or more R ⁶ ; wherein:

当R ¹和R ²与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基时，R ³和R ⁴各自独立地选自R ⁶；或者 When R ¹ and R ² together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, R ³ and R ⁴ Each independently selected from R ⁶ ; or

当R ²和R ³与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基时，R ¹和R ⁴各自独立地选自R ⁶；或者 When R ² and R ³ together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10-membered heteroaryl group, a 6 to 10-membered heterocyclic group or a C _6-10 cycloalkyl group, R ¹ and R ⁴ Each independently selected from R ⁶ ; or

当R ³和R ⁴与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基时，R ¹和R ²各自独立地选自R ⁶； When R ³ and R ⁴ together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, R ¹ and R ² Each independently selected from R ⁶ ;

R ⁵选自氢、烷基、卤代烷基、环烷基和卤代环烷基； R ^{5 is} selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

每个R ⁶各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和-P(O)(R ^a) ₂，其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{6 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, -NHS (O) m R a , and ^{-P (O) (R a)} 2, wherein the alkyl, alkoxy, cycloalkyl Alkyl, heterocyclic, aryl, heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy One or more group substitutions of group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

每个R ⁷各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{7 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

每个R ⁹各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{9 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

R’和R”各自独立地选自氢、卤素、烷基、卤代烷基；R'and R" are each independently selected from hydrogen, halogen, alkyl, haloalkyl;

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, One or more group substitutions of oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2；m is 0, 1 or 2;

n为0至3的整数。n is an integer from 0 to 3.

在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof , Or its pharmaceutically acceptable salt,

其中，in,

环D选自C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，优选苯基、6-8元杂芳基、6-8元杂环基、C _6-8环烷基，所述芳基、杂芳基、杂环基和环烷基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、 -NHS(O) _mR ^a和-P(O)(R ^a) ₂的一个或多个基团取代； Ring D is selected from C _6-10 _{aryl, 6-10 membered heteroaryl, 6-10} membered heterocyclic group or C 6-10 cycloalkyl, preferably phenyl, 6-8 membered heteroaryl, 6-8 Member heterocyclic group, C _6-8 cycloalkyl group, the aryl group, heteroaryl group, heterocyclic group and cycloalkyl group are optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo , Alkyl, -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^{_{a, -S (O) m R}} a, -S (O) m NR a R b, a -NHS (O) _m R ^a, and ^{-P (O) (R a)} 2 or more substituent groups;

R ¹和R ²各自独立地选自氢、卤素、烷基； R ¹ and R ² are each independently selected from hydrogen, halogen, and alkyl;

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, One or more group substitutions of ester group, oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

m为0、1或2；m is 0, 1 or 2;

X、Y ¹、Y ²、Z ¹、Z ²、L、环A、环B、环C、R ⁵如通式(I)所定义。 X, Y ¹ , Y ² , Z ¹ , Z ² , L, ring A, ring B, ring C, and R ^{5 are} as defined in the general formula (I).

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (III) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

其中，in,

环E选自C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，优选苯基、6-8元杂芳基、6-8元杂环基、C _6-8环烷基，所述芳基、杂芳基、杂环基和环烷基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和-P(O)(R ^a) ₂的一个或多个基团取代； Ring E is selected from C _6-10 _{aryl, 6-10 membered heteroaryl, 6-10} membered heterocyclic group or C 6-10 cycloalkyl, preferably phenyl, 6-8 membered heteroaryl, 6-8 Member heterocyclic group, C _6-8 cycloalkyl group, the aryl group, heteroaryl group, heterocyclic group and cycloalkyl group are optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo , Alkyl, -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^{_{a, -S (O) m R}} a, -S (O) m NR a R b, a -NHS (O) _m R ^a, and ^{-P (O) (R a)} 2 or more substituent groups;

R ¹和R ⁴各自独立地选自氢、卤素、烷基； R ¹ and R ⁴ are each independently selected from hydrogen, halogen, and alkyl;

m为0、1或2；m is 0, 1 or 2;

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (IV), or a meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

其中：in:

环F选自C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，优选苯基、6-8元杂芳基、6-8元杂环基、C _6-8环烷基，所述芳基、杂芳基、杂环基和环烷基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和-P(O)(R ^a) ₂的一个或多个基团取代； Ring F is selected from C _6-10 _{aryl, 6-10 membered heteroaryl, 6-10} membered heterocyclic group or C 6-10 cycloalkyl, preferably phenyl, 6-8 membered heteroaryl, 6-8 Member heterocyclic group, C _6-8 cycloalkyl group, the aryl group, heteroaryl group, heterocyclic group and cycloalkyl group are optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo , Alkyl, -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^{_{a, -S (O) m R}} a, -S (O) m NR a R b, a -NHS (O) _m R ^a, and ^{-P (O) (R a)} 2 or more substituent groups;

R ³和R ⁴各自独立地选自氢、卤素、烷基； R ³ and R ⁴ are each independently selected from hydrogen, halogen, and alkyl;

m为0、1或2；m is 0, 1 or 2;

在一个优选的实施方案中，根据通式(II)、(III)和(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In a preferred embodiment, according to the compounds represented by the general formulae (II), (III) and (IV) or their mesomers, racemates, enantiomers, diastereomers , Or its mixture form, or its pharmaceutically acceptable salt,

其中：in:

R ^a和R ^b各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基，其中所述烷基、烯基、炔基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl are optionally selected Further selected from one of halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl Or multiple group substitutions;

或者R ^a和R ^b与他们连接的原子一起形成5-7元含氮杂环基，所述5-7元含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Or R ^a and R ^b together with the atoms to which they are attached form a 5-7 membered nitrogen-containing heterocyclic group, the 5-7 membered nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, One or more groups of oxo group, hydroxyl group, mercapto group, carboxyl group, ester group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are substituted.

在另一个优选的实施方案中，根据通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, according to the compound represented by the general formula (II) or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its medicinal salt,

其中，环D选自C _6-8环烷基或6-8元杂环基，优选6元杂环基，更优选哌啶基、吗啉基、二噁英基；所述杂环基任选进一步被选自卤素、氰基、氧代基、C _1-6烷基、-C(O)R ^a、-C(O)NR ^aR ^b、-S(O) _mR ^a和-S(O) _mNR ^aR ^b的一个或多个基团取代； Among them, ring D is selected from a C _6-8 cycloalkyl group or a 6-8 membered heterocyclic group, preferably a 6-membered heterocyclic group, more preferably a piperidinyl group, a morpholinyl group, and a dioxin group; the heterocyclic group optionally is further selected from halogen, cyano, oxo, C _1-6 ^{alkyl, -C (O) R a,} -C (O) NR a R b, -S (O) m R a and -S ( O) One or more groups of _m NR ^a R ^{b are substituted;}

R ^a选自氢、C _1-6烷基、C _3-6环烷基、5-6元杂环基，其中所述C _1-6烷基、C _3-6环烷基、5-6元杂环基任选进一步被选自氘代、卤素、C _1-6烷基的一个或多个基团取代； R ^{a is} selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclic group, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 The membered heterocyclic group is optionally further substituted with one or more groups _{selected from deuterated, halogen, and C 1-6 alkyl;}

R ^b选自氢或C _1-6烷基； R ^{b is} selected from hydrogen or C _1-6 alkyl;

m为1或2。m is 1 or 2.

在另一个优选的实施方案中，根据通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, according to the compound represented by the general formula (III) or the meso, racemate, enantiomer, diastereomer, or mixture form thereof, or Its medicinal salt,

其中，in,

环E选自C _6-8环烷基或6-8元杂环基，优选6元环烷基或6元杂环基，更优选环己基、哌啶基、吗啉基、二噁英基；所述环烷基或杂环基任选进一步被选自卤素、氰基、氧代基、C _1-6烷基、-C(O)R ^a、-C(O)NR ^aR ^b、-S(O) _mR ^a和-S(O) _mNR ^aR ^b的一个或多个基团取代； Ring E is selected from C _6-8 cycloalkyl or 6-8 membered heterocyclic group, preferably 6-membered cycloalkyl or 6-membered heterocyclic group, more preferably cyclohexyl, piperidinyl, morpholinyl, dioxinyl; said cycloalkyl or heterocyclyl is optionally further substituted selected from halogen, cyano, oxo, C _1-6 ^{alkyl, -C (O) R a,} -C (O) NR a R b, - One or more groups of S(O) _m R ^a and -S(O) _m NR ^a R ^{b are substituted;}

m为1或2。m is 1 or 2.

在另一个优选的实施方案中，根据通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, according to the compound represented by the general formula (IV) or the meso, racemate, enantiomer, diastereomer, or mixture form thereof, or Its medicinal salt,

其中，in,

环F选自C _6-8环烷基或6-8元杂环基，优选6元环烷基或6元杂环基，更优选环己基、哌啶基、吗啉基、二噁英基；所述环烷基或杂环基任选进一步被选自卤素、氰基、氧代基、C _1-6烷基、-C(O)R ^a、-C(O)NR ^aR ^b、-S(O) _mR ^a和-S(O) _mNR ^aR ^b的一个或多个基团取代； Ring F is selected from C _6-8 cycloalkyl or 6-8 membered heterocyclic group, preferably 6-membered cycloalkyl or 6-membered heterocyclic group, more preferably cyclohexyl, piperidinyl, morpholinyl, dioxinyl; said cycloalkyl or heterocyclyl is optionally further substituted selected from halogen, cyano, oxo, C _1-6 ^{alkyl, -C (O) R a,} -C (O) NR a R b, - One or more groups of S(O) _m R ^a and -S(O) _m NR ^a R ^{b are substituted;}

m为1或2。m is 1 or 2.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，X为-O-。In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, X is -O-.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环C为5至8元含氮杂环，优选哌啶环、四氢吡咯环、哌嗪环、二氢吡咯环、四氢吡啶环或高哌嗪环，更优选哌啶环，其任选进一步被一个或多个R ⁷取代； In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein the ring C is a 5- to 8-membered nitrogen-containing heterocyclic ring, preferably a piperidine ring, a tetrahydropyrrole ring, a piperazine ring, a dihydropyrrole ring, a tetrahydropyridine ring or a high A piperazine ring, more preferably a piperidine ring, which is optionally further substituted by one or more R ⁷ ;

其中：in:

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, ring One or more group substitutions of alkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2。m is 0, 1, or 2.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R ⁸取代； In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, the ring B is a 6 to 10 membered aromatic ring or a 5 to 6 membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, and a pyrrole Ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring Ring, which is optionally further substituted with one or more R ⁸ ;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁸为卤素； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted; preferably R ⁸ is halogen;

其中：in:

m为0、1或2。m is 0, 1, or 2.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein

选自：

Selected from:

其中，in,

Y ²选自O或S； Y ^{2 is} selected from O or S;

环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R ⁸取代； Ring B is a 6 to 10 membered aromatic ring or a 5 to 6 membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, Thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further substituted by one or more R ⁸ replace;

每个R ⁷各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基；或者两个相邻的R ⁷与他们连接的原子一起形成杂环基或环烷基，其中所述烷基、烷氧基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁷为氢； Each R ^{7 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy; or two adjacent R ⁷ together with the atom to which they are attached A heterocyclic group or a cycloalkyl group is formed, wherein the alkyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, One or more groups of carboxyl group, ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are substituted; preferably R ⁷ is hydrogen;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁸为卤素； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; Wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , Ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; preferably R ⁸ is halogen;

p为0、1、2、3或4，优选0。p is 0, 1, 2, 3 or 4, preferably 0.

选自：

Selected from:

优选

Preferred

其中，in,

Y ²选自O或S； Y ^{2 is} selected from O or S;

q为0、1或2。q is 0, 1, or 2.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y ²为O。 In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, Y ² is O.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y ¹为O。 In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, Y ¹ is O.

在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

其中，in,

环A选自芳基和杂芳基，优选苯基，其中所述芳基或杂芳基任选进一步被一个或多个R ⁹取代， Ring A is selected from aryl and heteroaryl, preferably phenyl, wherein the aryl or heteroaryl is optionally further substituted with one or more R ⁹ groups,

每个R ⁹各自独立地选自氢、卤素、氰基、羟基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基，优选氢、卤素、烷基和烷氧基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Each R ^{9 is} independently selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, alkane And alkoxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, One or more groups of hydroxy, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.

其中，其中，L选自-NR ^a-和-(CR ^aR ^b) _n-，优选-(CR ^aR ^b) _n-； Wherein, L is selected from -NR ^a -and -(CR ^a R ^b ) _n -, preferably -(CR ^a R ^b ) _n -;

R ^a和R ^b各自独立地选自氢和C _1-6烷基； R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl;

n为0至3的整数，优选1；n is an integer from 0 to 3, preferably 1;

L更优选-CH ₂-； L is more preferably -CH ₂ -;

其中，R ⁵选自氢、C _1-6烷基和卤代C _1-6烷基，优选氢和C _1-6烷基。 Among them, R ^{5 is} selected from hydrogen, C _1-6 alkyl and halogenated C _1-6 alkyl, preferably hydrogen and C _1-6 alkyl.

本发明的典型化合物，包括但不限于：Typical compounds of the present invention include but are not limited to:

其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。The meso, racemate, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof.

本发明进一步提供一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：The present invention further provides a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or mixture form thereof , Or its pharmaceutically acceptable salt preparation method, which comprises the following steps:

在催化剂的存在下，将化合物Il发生分子内关环反应得到通式(I)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound Il undergoes an intramolecular ring-closure reaction to obtain a compound of general formula (I), and the catalyst is preferably trimethylaluminum;

其中，X、Y ¹、Y ²、Z ¹、Z ²、L、环A、环B、环C、R ¹、R ²、R ³、R ⁴、R ⁵如通式(I)所定义。 Wherein, X, Y ¹ , Y ² , Z ¹ , Z ² , L, ring A, ring B, ring C, R ¹ , R ² , R ³ , R ⁴ , and R ^{5 are} as defined in the general formula (I).

本发明进一步提供一种药物组合物，其包含根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体或赋形剂。The present invention further provides a pharmaceutical composition comprising the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, or diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物在制备受体相互作用蛋白激酶1(RIP1)抑制剂中的用途。The present invention further relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its pharmaceutically acceptable salt or pharmaceutical composition containing it in the preparation of receptor-interacting protein kinase 1 (RIP1) inhibitors.

本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物在制备预防或治疗与受体相互作用蛋白激酶1活性相关的疾病的药物中的用途，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The present invention further relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for the prevention or treatment of a disease related to the activity of receptor-interacting protein kinase 1, the disease is preferably an inflammatory disease, an autoimmune disease or a neurological disease , The inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, Crohn’s disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, Spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, autoimmunity Hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome , Allergic diseases, asthma, atopic skin diseases, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme related fever syndrome, Chronic obstructive pulmonary disease, tumor necrosis factor receptor related syndrome, or periodontitis; the neurological disease such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.

本发明进一步涉及一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物，其用作受体相互作用蛋白激酶1(RIP1)抑制剂。The present invention further relates to a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or mixture form thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a receptor-interacting protein kinase 1 (RIP1) inhibitor.

本发明进一步涉及一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物，其用于预防或治疗与受体相互作用蛋白激酶1活性相关的疾病，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The present invention further relates to a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or mixture form thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used to prevent or treat a disease related to the activity of receptor-interacting protein kinase 1, the disease is preferably an inflammatory disease, an autoimmune disease or a neurological disease, The inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spine Arthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjogren’s syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, autoimmune hepatitis , Autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, Allergic diseases, asthma, atopic skin diseases, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme related fever syndrome, lung Chronic obstructive disease, tumor necrosis factor receptor related syndrome or periodontitis; the neurological disease such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.

本发明进一步涉及一种抑制受体相互作用蛋白激酶1(RIP1)的方法，其包括向有需要的患者施用有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或包含其的药物组合物。The present invention further relates to a method for inhibiting receptor-interacting protein kinase 1 (RIP1), which comprises administering to a patient in need an effective amount of the compound represented by the general formula (I) according to the present invention or its internal elimination Rotate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

本发明进一步涉及一种预防或治疗与受体相互作用蛋白激酶1活性相关的疾病的方法，其包括向有需要的患者施用预防或治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或包含其的药物组合物；其中，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The present invention further relates to a method for preventing or treating diseases related to the activity of receptor-interacting protein kinase 1, which comprises administering to a patient in need a preventive or therapeutically effective amount of the formula (I) according to the present invention The shown compound or its mesosome, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same; wherein, The disease is preferably an inflammatory disease, an autoimmune disease or a nervous system disease, such as rheumatoid arthritis, ulcerative colitis, Crohn’s disease, psoriasis, retinal detachment, pigment Retinitis, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis , Osteoarthritis, non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organs Ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic disease, asthma, atopic skin disease, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, white Serum’s disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related syndrome or periodontitis; the neurological diseases such as Huntington’s disease, Alzheimer’s disease, Pa Kingson’s disease or amyotrophic lateral sclerosis.

按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。According to conventional methods in the field of the present invention, the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base. The bases include inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.

含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. For example, water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethyl cellulose, cellulose acetate butyrate can be used.

也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin can also be used, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil solvent such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide oral preparations.

水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和***胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents, which can be natural Produced phospholipids such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as seventeen-carbon ethyleneoxy whale Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweeteners. Flavoring agents such as sucrose, saccharin or aspartame.

油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oil suspensions can be formulated by suspending the active ingredients in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersing or wetting agent for mixing, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation of the partial esters and ethylene oxide Products such as polyethylene oxide sorbitol monooleate. The emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Syrups and elixirs formulated with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. Then the oil solution is added to the mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.

本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。The pharmaceutical composition of the present invention may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of the present invention can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、***的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。Those skilled in the art know that the dosage of drugs depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient’s age, the patient’s weight, the patient’s health, the patient’s clothing, and the patient’s The diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc. In addition, the best treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.

本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与酪氨酸激酶活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。The present invention may contain a compound represented by general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions and the like. The compound of the present invention can be used as the sole active ingredient, and can also be used in combination with other drugs for the treatment of diseases related to tyrosine kinase activity. Combination therapy is achieved by administering each treatment component simultaneously, separately or sequentially.

发明的详细说明Detailed description of the invention

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

术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms Atom of the alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group, or a carboxylate group.

术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.

术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.

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

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

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

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

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

术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) _m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spiro, condensed, and bridged heterocyclic groups.

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

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

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

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

等。

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

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

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

术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably Pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

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

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

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

术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.

术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“氨基”指-NH ₂。 The term "amino" refers to -NH ₂ .

术语“氰基”指-CN。The term "cyano" refers to -CN.

术语“硝基”指-NO ₂。 The term "nitro" refers to -NO ₂ .

术语“氧代基”指＝O。The term "oxo" refers to =O.

术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.

术语“巯基”指-SH。The term "mercapto" refers to -SH.

术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。The term "ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to a compound containing a -C(O)R group, where R is an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.

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

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

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

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

本发明化合物的合成方法Synthetic method of the compound of the present invention

为了完成本发明的目的，本发明采用如下合成方案制备本发明的通式(I)化合物。In order to accomplish the purpose of the present invention, the present invention adopts the following synthetic scheme to prepare the compound of general formula (I) of the present invention.

当X为-O-，Y ¹和Y ²为O，L为-CH ₂-，环C为哌啶环，环B为氯代吡唑环时，按照方案1合成通式(I)的化合物： When X is -O-, Y ¹ and Y ² are O, L is -CH ₂ -, ring C is a piperidine ring, and ring B is a chloropyrazole ring, the compound of general formula (I) is synthesized according to Scheme 1. :

方案1plan 1

步骤1：在催化剂的存在下，将化合物Ia与氨基保护的丝氨酸甲酯反应得到化合物Ib，所述催化剂优选三苯基膦和DIAD，所述保护基优选Boc和Trt；Step 1: In the presence of a catalyst, compound Ia is reacted with amino-protected serine methyl ester to obtain compound Ib, the catalyst is preferably triphenylphosphine and DIAD, and the protecting group is preferably Boc and Trt;

步骤2：在催化剂的存在下，将化合物Ib发生氢化反应得到化合物Ic，所述催化剂优选钯碳；Step 2: In the presence of a catalyst, the compound Ib is hydrogenated to obtain the compound Ic, and the catalyst is preferably palladium on carbon;

步骤3：在催化剂的存在下，将化合物Ic发生分子内关环反应得到化合物Id，所述催化剂优选三甲基铝；Step 3: In the presence of a catalyst, the compound Ic undergoes an intramolecular ring-closure reaction to obtain the compound Id, and the catalyst is preferably trimethylaluminum;

步骤4：在碱性条件下，将化合物Id与R ⁵I反应得到化合物Ie，所述碱性条件优选碳酸铯； Step 4: Under basic conditions, compound Id is reacted with R ⁵ I to obtain compound Ie, and the basic conditions are preferably cesium carbonate;

步骤5：在酸性条件下，将化合物Ie发生脱保护基反应得到化合物If，所述酸性条件优选三氟乙酸；Step 5: Under acidic conditions, the compound Ie is subjected to deprotection reaction to obtain the compound If, and the acidic conditions are preferably trifluoroacetic acid;

步骤6：在碱性条件下，将丁炔二酸二乙酯与肼类化合物Ig反应得到化合物Ih，所述碱性条件优选碳酸钾；Step 6: Under alkaline conditions, reacting diethyl butynedioate with hydrazine compound Ig to obtain compound Ih, and the alkaline conditions are preferably potassium carbonate;

步骤7：在催化剂的存在下，将化合物Ih发生维尔斯迈尔-哈克反应并氯化得到化合物Ii，所述催化剂优选DMF和三氯氧磷；Step 7: In the presence of a catalyst, the compound Ih is subjected to the Wellsmeier-Hacker reaction and chlorinated to obtain the compound Ii. The catalyst is preferably DMF and phosphorus oxychloride;

步骤8：在碱性条件下，将化合物Ii与wittig试剂反应得到化合物Ij，所述碱性条件优选叔丁醇钾；Step 8: Under alkaline conditions, react compound Ii with wittig reagent to obtain compound Ij, and the alkaline conditions are preferably potassium tert-butoxide;

步骤9：在酸性条件下，将化合物Ij发生水解反应得到化合物Ik，所述酸性条件优选盐酸；Step 9: Under acidic conditions, subject compound Ij to a hydrolysis reaction to obtain compound Ik, and the acidic conditions are preferably hydrochloric acid;

步骤10：在催化剂条件下，将化合物Ik与化合物If发生还原氨化反应得到化合物Il，所述催化剂优选2-甲基吡啶硼烷复合物；Step 10: Under the condition of a catalyst, the compound Ik and the compound If undergo a reductive amination reaction to obtain the compound Il, and the catalyst is preferably a 2-picoline borane complex;

步骤11：在催化剂的存在下，将化合物Il发生分子内关环反应得到通式(I)化合物，所述催化剂优选三甲基铝；Step 11: In the presence of a catalyst, the compound 11 undergoes an intramolecular ring-closure reaction to obtain a compound of general formula (I), and the catalyst is preferably trimethylaluminum;

其中，Z ¹、Z ²、环A、R ¹、R ²、R ³、R ⁴、R ⁵如通式(I)所定义。 Among them, Z ¹ , Z ² , ring A, R ¹ , R ² , R ³ , R ⁴ , and R ^{5 are} as defined in the general formula (I).

具体实施方式Detailed ways

进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。Further examples are used to understand the compounds of the present invention and their preparation. These examples illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。The compound of the present invention is prepared by using convenient starting materials and general preparation procedures. The present invention provides typical or inclined reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. Optimal conditions may vary with the use of specific reactants or solvents, but under normal circumstances, reaction optimization steps and conditions can be determined.

另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。In addition, some protecting groups may be used in the present invention to protect certain functional groups to avoid unnecessary reactions. The protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, "Protecting Groups in Organic Preparation" by T.W. Greene and G.M. Wuts (3rd edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protective groups.

化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层板色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。The separation and purification of compounds and intermediates adopt appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods. For the specific method of use, please refer to the examples described in the present invention. Of course, other similar separation and purification methods can also be used. It can be characterized using conventional methods including physical constants and spectral data.

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 ^-6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d ₆)，氘代氯仿(CDCl ₃)，氘代甲醇(CD ₃OD)，内标为四甲基硅烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts are given in units of ^{10 -6 (ppm).} NMR was measured by Brukerdps 300 nuclear magnetometer, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl -Based silane (TMS).

MS的测定用LC(Waters 2695)/MS(Quattro Premier xE)质谱仪(生产商：沃特世)(Photodiode Array Detector)。LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector) is used for MS measurement.

制备液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为 DaisogelC18 10μm 100A(30mm×250mm)，流动相：乙腈/水。The lc6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng) was used for the preparative liquid chromatography. The chromatographic column is Daisogel C18 10μm 100A (30mm×250mm), mobile phase: acetonitrile/water.

薄层色谱法(TLC)使用青岛海洋化工GF254硅胶板，反应监测用薄层色谱法使用的硅胶板采用的规格是0.20mm～0.25mm，分离纯化用薄层色谱法使用的硅胶板采用的规格是0.5mm。Thin layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plate, the size of the silica gel plate used for reaction monitoring is 0.20mm～0.25mm, and the size of the silica gel plate used for separation and purification is used. It is 0.5mm.

硅胶柱层析色谱法使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。Silica gel column chromatography uses Qingdao Marine Silica Gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得等公司。The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from the network store, Beijing coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Companies such as Anaiji Chemical, Shanghai Bide, etc.

实施例中无特殊说明，反应能够均在氮气氛下进行。There are no special instructions in the examples, and the reactions can all be carried out under a nitrogen atmosphere.

氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

反应溶剂，有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、***、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。The reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , Dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. There is no special description in the examples, and the solution refers to an aqueous solution.

本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。The chemical reaction described in the present invention is generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and complete within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent system used in the reaction includes: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.

纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和三氟乙酸等碱性或酸性试剂进行调节。The eluent system of column chromatography and the developing solvent system of thin layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on the compound It can be adjusted for different polarities, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.

除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the content described can be applied to the method of the present invention.

实施例Example

实施例1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢萘并[2,3-b][1,4]氧杂卓-4(5H)-酮(1)的制备。Example 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-2,3,7,8,9,10-hexahydronaphtho[2,3-b][1,4]oxazepine-4(5H)-one(1 ) Preparation.

步骤1：3-硝基-5,6,7,8-四氢萘-2-醇(1a)的制备Step 1: Preparation of 3-nitro-5,6,7,8-tetrahydronaphthalene-2-ol (1a)

于0℃，将5,6,7,8-四氢萘-2-醇(10.00g，67.5mmol)加入到氯仿(80mL)和乙酸(80mL)混合溶剂中，搅拌10分钟后，向其中缓慢滴加硝酸(5.20g，81mmol)。将反应液升温至室温，搅拌半小时后，倾入碎冰中，用二氯甲烷(50mL)萃取，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝20:1-10:1)，得黄色固体状的标题化合物4.00g，收率：30.7％。At 0°C, 5,6,7,8-tetrahydronaphthalene-2-ol (10.00g, 67.5mmol) was added to the mixed solvent of chloroform (80mL) and acetic acid (80mL), and after stirring for 10 minutes, slowly added to it Nitric acid (5.20 g, 81 mmol) was added dropwise. The reaction solution was warmed to room temperature, stirred for half an hour, poured into crushed ice, extracted with dichloromethane (50 mL), the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ EA=20:1-10:1) to obtain 4.00 g of the title compound as a yellow solid, yield: 30.7%.

LC-MS：m/z 194.24[M+H] ⁺。 LC-MS: m/z 194.24 [M+H] ⁺ .

步骤2：(3-硝基-5,6,7,8-四氢萘-2-基)-N-三苯甲基-L-丝氨酸甲酯(1b)的制备Step 2: Preparation of (3-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)-N-trityl-L-serine methyl ester (1b)

将三苯基磷(6.56g，25mmol)溶于30mL THF中，于0℃，氮气氛下，向其中滴加DIAD(5.04g，25mmol)，继续搅拌10分钟后，加入L-Trt-丝氨酸甲酯(8.80g，22.8mmol)，继续搅拌10分钟后，加入3-硝基-5,6,7,8-四氢萘-2-醇(4.00g，20.8mmol)。于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝150:1-100:1)，得浅黄色固体状的标题化合物3.90g，收率：35.7％。Dissolve triphenylphosphonium (6.56g, 25mmol) in 30mL THF, add DIAD (5.04g, 25mmol) dropwise to it at 0°C under nitrogen atmosphere, continue stirring for 10 minutes, add L-Trt-serine methyl Ester (8.80g, 22.8mmol), after stirring for 10 minutes, 3-nitro-5,6,7,8-tetralin-2-ol (4.00g, 20.8mmol) was added. After stirring overnight at room temperature, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=150:1-100:1) to obtain 3.90g of the title compound as a pale yellow solid, yield : 35.7%.

LC-MS：m/z 537.74[M+H] ⁺。 LC-MS: m/z 537.74 [M+H] ⁺ .

步骤3：(3-硝基-5,6,7,8-四氢萘-2-基)-L-丝氨酸甲酯(1c)的制备Step 3: Preparation of (3-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)-L-serine methyl ester (1c)

将(3-硝基-5,6,7,8-四氢萘-2-基)-N-三苯甲基-L-丝氨酸甲酯(3.90g，7.3mmol)溶解于10mL饱和盐酸乙酸乙酯溶液中，于室温搅拌1小时后过滤。将滤液调节pH至10后，用乙酸乙酯(20mL)萃取。有机相减压浓缩，得白色固体状的标题化合物1.80g，收率：83.8％。Dissolve (3-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)-N-trityl-L-serine methyl ester (3.90g, 7.3mmol) in 10mL saturated hydrochloric acid ethyl acetate The ester solution was stirred at room temperature for 1 hour and then filtered. After adjusting the pH of the filtrate to 10, it was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain 1.80 g of the title compound as a white solid, yield: 83.8%.

LC-MS：m/z 295.41[M+H] ⁺。 LC-MS: m/z 295.41 [M+H] ⁺ .

步骤4：N-(叔丁氧基羰基)-O-(3-硝基-5,6,7,8-四氢萘-2-基)-L-丝氨酸甲酯(1d)的制备Step 4: Preparation of N-(tert-butoxycarbonyl)-O-(3-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)-L-serine methyl ester (1d)

将(3-硝基-5,6,7,8-四氢萘-2-基)-L-丝氨酸甲酯(1.80g，6mmol)溶解于10mL二氯甲烷中，加入DIPEA(1.55g，12mmol)，再分批加入Boc酸酐(2.60g，12mmol)。于室温搅拌1小时后，用水(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体状的标题化合物2.30g，收率97.3％。Dissolve (3-nitro-5,6,7,8-tetrahydronaphthalene-2-yl)-L-serine methyl ester (1.80g, 6mmol) in 10mL of dichloromethane, add DIPEA (1.55g, 12mmol) ), and then add Boc anhydride (2.60 g, 12 mmol) in batches. After stirring for 1 hour at room temperature, it was washed with water (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.30 g of the title compound as a yellow solid with a yield of 97.3%.

LC-MS：m/z 395.76[M+H] ⁺。 LC-MS: m/z 395.76 [M+H] ⁺ .

步骤5：O-(3-氨基-5,6,7,8-四氢萘-2-基)-N-(叔丁氧基羰基)-L-丝氨酸甲酯(1e)的制备Step 5: Preparation of O-(3-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (1e)

于室温，将N-(叔丁氧基羰基)-O-(3-硝基-5,6,7,8-四氢萘-2-基)-L-丝氨酸甲酯(2.3g，5.84mmol)溶于甲醇(15mL)中，加入钯碳(100mg)，在氢气氛下搅拌3小时，过滤，滤液减压浓缩，得棕色油状的标题化合物2.1g，收率98.8％。At room temperature, N-(tert-butoxycarbonyl)-O-(3-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)-L-serine methyl ester (2.3g, 5.84mmol ) Was dissolved in methanol (15 mL), added palladium on carbon (100 mg), stirred under a hydrogen atmosphere for 3 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.1 g of the title compound as a brown oil with a yield of 98.8%.

LC-MS：m/z 365.20[M+H] ⁺。 LC-MS: m/z 365.20 [M+H] ⁺ .

步骤6：(S)-(4-氧代-2,3,4,5,7,8,9,10-八氢萘并[2,3-b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(1f)的制备Step 6: (S)-(4-oxo-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-b][1,4]oxazepine-3 -Yl) preparation of tert-butyl carbamate (1f)

将O-(3-氨基-5,6,7,8-四氢萘-2-基)-N-(叔丁氧基羰基)-L-丝氨酸甲酯(2.1g，5.8mmol)溶于20mL氯仿中，于0℃，氮气氛下，滴加2M三甲基铝甲苯溶液(3mL)。氮气氛将混合物升温至60℃，搅拌2小时。然后，向反应液中加入10mL乙醇，继续搅拌10分钟，滤去不溶物，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相PE/EA＝10:1)，得白色固体状的标题化合物1.2g，收率62.3％。Dissolve O-(3-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (2.1g, 5.8mmol) in 20mL In chloroform, under a nitrogen atmosphere at 0°C, a 2M trimethylaluminum toluene solution (3 mL) was added dropwise. The mixture was heated to 60°C under a nitrogen atmosphere and stirred for 2 hours. Then, 10 mL of ethanol was added to the reaction solution, stirring was continued for 10 minutes, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=10:1) to obtain 1.2 g of the title compound as a white solid with a yield of 62.3%.

LC-MS：m/z 332.17[M+H] ⁺。 LC-MS: m/z 332.17 [M+H] ⁺ .

步骤7：(S)-(5-甲基-4-氧代-2,3,4,5,7,8,9,10-八氢萘并[2,3-b][1,4]氧氮杂卓-3-基)氨基甲酸叔丁酯(1g)的制备Step 7: (S)-(5-Methyl-4-oxo-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-b][1,4] Preparation of oxazepine-3-yl) tert-butyl carbamate (1g)

于室温，将(S)-(4-氧代-2,3,4,5,7,8,9,10-八氢萘并[2,3-b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯化合物(0.8g，2.4mmol)和碳酸铯(1.7g，5.28mmol)，溶于10mL DMF中。向其中滴加碘甲烷(0.16mL，2.4mmol)，搅拌2小时。然后加入30mL水和30mL EA，有机层用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得淡黄色固体状的标题化合物470mg，收率56.7％。At room temperature, add (S)-(4-oxo-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-b][1,4]oxazepine- 3-yl) tert-butyl carbamate compound (0.8g, 2.4mmol) and cesium carbonate (1.7g, 5.28mmol), dissolved in 10mL DMF. Methyl iodide (0.16 mL, 2.4 mmol) was added dropwise thereto, and the mixture was stirred for 2 hours. Then 30 mL of water and 30 mL of EA were added, the organic layer was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 470 mg of the title compound as a pale yellow solid with a yield of 56.7%.

LC-MS：m/z 347.19[M+H] ⁺。 LC-MS: m/z 347.19 [M+H] ⁺ .

步骤8：(S)-3-氨基-5-甲基-2,3,7,8,9,10-六氢萘并[2,3-b][1,4]氧氮杂卓-4(5H)-酮(1h)的制备Step 8: (S)-3-Amino-5-methyl-2,3,7,8,9,10-hexahydronaphtho[2,3-b][1,4]oxazepine-4 Preparation of (5H)-ketone (1h)

于室温，将(S)-(5-甲基-4-氧代-2,3,4,5,7,8,9,10-八氢萘并[2,3-b][1,4]氧氮杂卓-3-基)氨基甲酸叔丁酯(0.47g，1.36mmol)溶解于5mL TFA中，搅拌1小时后，加入15mL饱和碳酸氢钠溶液和20mL EA，有机相减压浓缩，残余物通过TLC分离(展开剂PE/EA＝10:1)，得灰白色固体状标题化合物320mg，收率95.6％。At room temperature, (S)-(5-methyl-4-oxo-2,3,4,5,7,8,9,10-octahydronaphtho[2,3-b][1,4 ]Oxazepine-3-yl) tert-butyl carbamate (0.47g, 1.36mmol) was dissolved in 5mL TFA. After stirring for 1 hour, 15mL saturated sodium bicarbonate solution and 20mL EA were added, and the organic phase was concentrated under reduced pressure. The residue was separated by TLC (developing solvent PE/EA=10:1) to obtain 320 mg of the title compound as an off-white solid with a yield of 95.6%.

LC-MS：m/z247.14[M+H] ⁺。 LC-MS: m/z247.14 [M+H] ⁺ .

步骤9：1-苄基-5-羟基-1H-吡唑-3-羧酸乙酯(1i)的制备Step 9: Preparation of 1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (1i)

于0℃，将丁炔二酸二乙酯(4.4g，25.6mmol)、苄基肼二盐酸盐(5g,25.6mmol)和无水碳酸钾(8.8g，64mmol)加入到160mL无水乙醇中，加热回流搅拌过夜。将反应液降至室温并继续反应液搅拌5小时。加入6N的盐酸调节PH值至3。加入300mL水与150mL乙酸乙酯，有机层用饱和食盐水100mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用10mL乙腈打浆，得到黄色固体状的标题化合物2.2g，收率35％。At 0°C, add diethyl butynedioate (4.4g, 25.6mmol), benzylhydrazine dihydrochloride (5g, 25.6mmol) and anhydrous potassium carbonate (8.8g, 64mmol) to 160mL of absolute ethanol In the middle, heating under reflux and stirring overnight. The reaction solution was lowered to room temperature and the reaction solution was continued to be stirred for 5 hours. Add 6N hydrochloric acid to adjust the pH to 3. 300 mL of water and 150 mL of ethyl acetate were added, the organic layer was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with 10 mL of acetonitrile to obtain 2.2 g of the title compound as a yellow solid with a yield of 35%.

LC-MS：m/z 247.10[M+H] ⁺。 LC-MS: m/z 247.10 [M+H] ⁺ .

步骤10：1-苄基-5-氯-4-甲酰基-1H-吡唑-3-羧酸乙酯(1j)的制备Step 10: Preparation of 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1j)

于室温，将1-苄基-5-羟基-1H-吡唑-3-羧酸乙酯(0.5g，2.1mmol)加入到DMF0.65mL中，滴入三氯氧磷(1.6mL，16mmol)，升温至90℃搅拌4小时。将反应液缓慢倾入到冰的饱和碳酸氢钠溶液中，加入30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-5:1)，得白色固体状的标题化合物300mg，收率48.9％。At room temperature, ethyl 1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylate (0.5g, 2.1mmol) was added to 0.65mL of DMF, and phosphorus oxychloride (1.6mL, 16mmol) was added dropwise The temperature was raised to 90°C and stirred for 4 hours. The reaction solution was slowly poured into a saturated sodium bicarbonate solution on ice, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=10:1-5:1) to obtain 300 mg of the title compound as a white solid, with a yield of 48.9%.

LC-MS：m/z 293.06[M+H] ⁺。 LC-MS: m/z 293.06 [M+H] ⁺ .

步骤11：1-苄基-5-氯-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(1k)的制备Step 11: Preparation of 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1k)

于室温，将(甲氧基甲基)三苯基氯化鏻(1.6g，4.8mmol)溶于20mL无水四氢呋喃中，于0℃，滴入叔丁醇钾(0.5g，4.4mmol)溶于10mL无水四氢呋喃的溶液，搅拌10分钟后，滴入1-苄基-5-氯-4-甲酰基-1H-吡唑-3-羧酸乙酯(0.3g，1.1mmol)的10mL无水四氢呋喃溶液中。继续搅拌30分钟后升至室温并搅拌过夜。向反应液加入60mL水与40mL乙酸乙酯，有机相用饱和食盐水50mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝5:1-2:1)，得黄色固体状标题化合物200mg,收率56.8％。At room temperature, dissolve (methoxymethyl)triphenylphosphonium chloride (1.6g, 4.8mmol) in 20mL of anhydrous tetrahydrofuran. Add potassium tert-butoxide (0.5g, 4.4mmol) at 0°C. In 10mL of anhydrous tetrahydrofuran solution, after stirring for 10 minutes, add dropwise 10mL of ethyl 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylate (0.3g, 1.1mmol) Water in tetrahydrofuran solution. Stirring was continued for 30 minutes, then warmed to room temperature and stirred overnight. 60 mL of water and 40 mL of ethyl acetate were added to the reaction solution, the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=5:1-2:1) to obtain 200 mg of the title compound as a yellow solid, with a yield of 56.8%.

LC-MS：m/z 321.09[M+H] ⁺。 LC-MS: m/z 321.09 [M+H] ⁺ .

步骤12：1-苄基-5-氯-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(1l)的制备Step 12: Preparation of 1-benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1l)

于室温，将1-苄基-5-氯-4-(2-甲氧基乙烯基)-1H-吡唑-3-羧酸乙酯(0.2g，0.63mmol)溶于10mL THF中，加入2mL 6N盐酸，升温至60℃。搅拌30钟。将反应液倾入到20mL饱和碳酸氢钠溶液中，加入30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得无色油状标题化合物190mg，收率98.6％。At room temperature, dissolve 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.2g, 0.63mmol) in 10mL THF, add 2mL 6N hydrochloric acid, heat up to 60°C. Stir for 30 minutes. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 190 mg of the title compound as a colorless oil. The yield was 98.6%.

LC-MS：m/z 307.08[M+H] ⁺。 LC-MS: m/z 307.08 [M+H] ⁺ .

步骤13：(S)-1-苄基-5-氯-4-(2-((5-甲基-4-氧代-2,3,4,5,7,8,9,10-八氢萘并[2,3-b][1,4]氧氮杂卓-3-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(1m)的制备Step 13: (S)-1-Benzyl-5-chloro-4-(2-((5-methyl-4-oxo-2,3,4,5,7,8,9,10-octa Preparation of Hydronaphtho[2,3-b][1,4]oxazepine-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1m)

于室温，将1-苄基-5-氯-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(0.19g,0.6mmol)和(S)-3-氨基-5-甲基-2,3,7,8,9,10-六氢萘并[2,3-b][1,4]氧氮杂卓-4(5H)-酮(1h)(0.15 g，0.6mmol)溶于15mL甲醇，加入1mL乙酸，搅拌10分钟后，加入2-甲基吡啶硼烷复合物(0.1g，0.84mmol)，继续搅拌小时。向反应液中加入20mL水与30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用TLC分离(PE/EA＝1:1)，得黄色固体状标题化合物210mg，收率65.3％。At room temperature, combine 1-benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.19g, 0.6mmol) and (S)-3-amino -5-methyl-2,3,7,8,9,10-hexahydronaphtho[2,3-b][1,4]oxazepine-4(5H)-one(1h)(0.15 g, 0.6 mmol) was dissolved in 15 mL of methanol, 1 mL of acetic acid was added, and after stirring for 10 minutes, 2-picoline borane complex (0.1 g, 0.84 mmol) was added, and stirring was continued for an hour. 20mL of water and 30mL of ethyl acetate were added to the reaction solution, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by TLC (PE/EA=1:1), 210 mg of the title compound was obtained as a yellow solid with a yield of 65.3%.

LC-MS：m/z 537.22[M+H] ⁺。 LC-MS: m/z 537.22 [M+H] ⁺ .

步骤14：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基2,3,7,8,9,10-六氢萘并[2,3-b][1,4]氧氮杂卓-4(5H)-酮(化合物1)的制备Step 14: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-5-methyl 2,3,7,8,9,10-hexahydronaphtho[2,3-b][1,4]oxazepine-4(5H)-one (compound 1 ) Preparation

于室温，将(S)-1-苄基-5-氯-4-(2-((5-甲基-4-氧代-2,3,4,5,7,8,9,10-八氢萘并[2,3-b][1,4]氧氮杂卓-3-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(0.21g，0.4mmol)溶解于5mL甲苯中。在氮气氛下，加入0.8mL三甲基铝正己烷溶液。升温至90℃搅拌2小时。向反应液加入30mL水和30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：30％-80％)，得55mg白色固体状标题化合物，收率28.1％。At room temperature, (S)-1-benzyl-5-chloro-4-(2-((5-methyl-4-oxo-2,3,4,5,7,8,9,10- Octahydronaphtho[2,3-b][1,4]oxazepine-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.21g, 0.4mmol) dissolved In 5mL toluene. Under a nitrogen atmosphere, 0.8 mL of trimethylaluminum n-hexane solution was added. The temperature was raised to 90°C and stirred for 2 hours. 30 mL of water and 30 mL of ethyl acetate were added to the reaction solution, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 55 mg of the title compound as a white solid, yield 28.1%.

LC-MS：m/z 491.18[M+H] ⁺。 LC-MS: m/z 491.18 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ7.38-7.17(m,6H),6.92(s,1H),5.55(dd,J＝11.8,7.9Hz,1H),5.43(s,2H),4.81-4.71(m,1H),4.30-4.20(m,1H),4.01(d,J＝7.0Hz,1H),3.61(s,1H),3.26(s,3H),2.73(s,6H),1.74(td,J＝6.3,3.4Hz,4H)。 ¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.38-7.17 (m, 6H), 6.92 (s, 1H), 5.55 (dd, J = 11.8, 7.9 Hz, 1H), 5.43 (s, 2H), 4.81-4.71(m,1H), 4.30-4.20(m,1H), 4.01(d,J=7.0Hz,1H), 3.61(s,1H), 3.26(s,3H), 2.73(s,6H) , 1.74 (td, J = 6.3, 3.4 Hz, 4H).

实施例2：(S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-10-甲基-2,3,7,8-四氢-[1,4]二噁英并[2'3':4,5]苯并[1,2-b][1,4]氧氮杂卓-9(10H)-酮(2)的制备。Example 2: (S)-8-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-10-methyl-2,3,7,8-tetrahydro-[1,4]dioxino[2'3':4,5]benzo[1,2-b][ 1,4] Preparation of oxazepine-9(10H)-one (2).

与实施例1的制备方法相同，除了用2,2-二氢苯并[b][1,4]二噁英-6-醇代替步骤1中的5,6,7,8-四氢萘-2-醇，制得标题化合物2。The preparation method is the same as in Example 1, except that 2,2-dihydrobenzo[b][1,4]dioxin-6-ol is used instead of 5,6,7,8-tetralin in step 1. -2-ol to obtain the title compound 2.

LC-MS：m/z 495.14[M+H] ⁺。 LC-MS: m/z 495.14 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ7.35-7.32(m,3H),7.19-7.16(m,2H),7.07(s,1H),6.79(s,1H),5.58-5.56(m,1H),5.45(s,2H),4.81-4.67(m,1H),4.31-4.28(m,5H),4.10-3.95(m,1H),3.71-3.55(m,1H),3.24(s,3H),2.92-2.74(m,1H),2.74-2.63(m,1H)。 ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.35-7.32 (m, 3H), 7.19-7.16 (m, 2H), 7.07 (s, 1H), 6.79 (s, 1H), 5.58-5.56 (m ,1H),5.45(s,2H),4.81-4.67(m,1H),4.31-4.28(m,5H),4.10-3.95(m,1H),3.71-3.55(m,1H),3.24(s , 3H), 2.92-2.74 (m, 1H), 2.74-2.63 (m, 1H).

实施例3：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6- 基)-1,7-二甲基-1,3,4,7,9,10-六氢-[1,4]氧氮杂卓并[3,2-g]喹啉-2,8-二酮(3)的制备Example 3: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1,7-dimethyl-1,3,4,7,9,10-hexahydro-[1,4]oxazepine[3,2-g]quinoline-2, Preparation of 8-diketone (3)

与实施例1的制备方法相同，除了用7-羟基-1-甲基-3,4-二氢喹啉-2(1H)-酮代替步骤1中的5,6,7,8-四氢萘-2-醇，制得标题化合物3。The preparation method is the same as in Example 1, except that 7-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one is used instead of 5,6,7,8-tetrahydro in step 1. Naphthalene-2-ol to obtain the title compound 3.

LC-MS：m/z 520.99[M+H] ⁺。 LC-MS: m/z 520.99 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.44-7.29(m,4H),7.21(d,2H),7.00(s,1H),5.67-5.54(m,1H),5.45(s,2H),4.85(t,1H),4.45-4.32(m,1H),4.11-3.98(m,1H),3.73-3.58(m,1H),3.28(d,6H),2.96-2.89(m,2H),2.85-2.78(m,1H),2.73-2.59(m,3H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.44-7.29 (m, 4H), 7.21 (d, 2H), 7.00 (s, 1H), 5.67-5.54 (m, 1H), 5.45 (s, 2H) ), 4.85(t,1H),4.45-4.32(m,1H),4.11-3.98(m,1H),3.73-3.58(m,1H),3.28(d,6H),2.96-2.89(m,2H) ), 2.85-2.78 (m, 1H), 2.73-2.59 (m, 3H).

实施例4：(S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-4,10-二甲基-2,3,4,7,8,10-六氢-9H-[1,4]噁嗪并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-9-酮(4)的制备Example 4: (S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-4,10-dimethyl-2,3,4,7,8,10-hexahydro-9H-[1,4]oxazino[2',3':4,5]benzene Preparation of and [1,2-b][1,4]oxazepine-9-one (4)

步骤1：6-甲氧基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮(4a)的制备Step 1: Preparation of 6-methoxy-2H-benzo[b][1,4]oxazine-3-(4H)-one (4a)

于室温，将2-氨基-4-甲氧基苯酚(1.80g，12.9mmol)溶于乙腈(30mL)，加入碳酸钾(5.36g，38.8mmol)，于0℃加入氯乙酰氯(2.19g，19.4mmol)，80℃搅拌过夜。加入20mL水淬灭，EA萃取(20mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-5:1)，得棕色固体的标题化合物2.49g(粗品)。At room temperature, 2-amino-4-methoxyphenol (1.80g, 12.9mmol) was dissolved in acetonitrile (30mL), potassium carbonate (5.36g, 38.8mmol) was added, and chloroacetyl chloride (2.19g, 19.4mmol), stirred at 80°C overnight. It was quenched by adding 20mL water, extracted with EA (20mLx3), washed with saturated brine (20mLx1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ EA=100:1-5:1) to obtain 2.49g (crude) of the title compound as a brown solid.

LC-MS：m/z 180.06[M+H] ⁺。 LC-MS: m/z 180.06 [M+H] ⁺ .

步骤2：6-甲氧基-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(4b)的制备Step 2: Preparation of 6-methoxy-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (4b)

于室温，将6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(12.0g，67.0mmol)溶于 AcOH(36ml)中。于0℃，缓慢加入HNO ₃(67％，12ml)，搅拌30分钟。将反应液加冰水淬灭，过滤并收集固体，干燥，得到9g绿色固体状标题化合物，收率60％。 At room temperature, 6-methoxy-2H-benzo[b][1,4]oxazine-3(4H)-one (12.0g, 67.0mmol) was dissolved in AcOH (36ml). At 0°C, slowly add HNO ₃ (67%, 12 ml) and stir for 30 minutes. The reaction solution was quenched with ice water, filtered and collected the solid, and dried to obtain 9 g of the title compound as a green solid with a yield of 60%.

LC-MS：m/z 225.04[M+H] ⁺。 LC-MS: m/z 225.04 [M+H] ⁺ .

步骤3：6-甲氧基-7-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪(4c)的制备Step 3: Preparation of 6-methoxy-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4c)

于室温，将6-甲氧基-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(8.00g，35.4mmol)溶于THF(150ml)中。氮气氛下，于0℃，加入BH ₃-THF(35.4ml,70.8mmol，2M)。将反应液升温至65℃搅拌1小时。将反应液加水淬灭，用EA(50mLx3)萃取，合并有机相用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得7.5g绿色固体状标题化合物，收率99％。 At room temperature, 6-methoxy-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (8.00g, 35.4mmol) was dissolved in THF (150ml) . Under a nitrogen atmosphere, at 0°C, BH ₃ -THF (35.4 ml, 70.8 mmol, 2M) was added. The reaction solution was heated to 65°C and stirred for 1 hour. The reaction solution was quenched with water, extracted with EA (50mLx3), the combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase : PE/EA=2:1) to obtain 7.5 g of the title compound as a green solid, with a yield of 99%.

LC-MS：m/z 211.06[M+H] ⁺。 LC-MS: m/z 211.06 [M+H] ⁺ .

步骤4：6-甲氧基-4-甲基-7-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪(4d)的制备Step 4: Preparation of 6-methoxy-4-methyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4d)

于室温，将6-甲氧基-7-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪(4.40g，20.9mmol)溶于DMF(70ml)。氮气氛下，于0℃，分批加入NaH(1.26g，30.4mmol，60％)，搅拌0.5小时，加入碘甲烷(5.95g，41.9mmol)。将反应液升至室温搅拌过夜。将反应液加水淬灭，EA(80mLx3)萃取，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得淡棕色固体状标题化合物4g，收率84.7％。At room temperature, 6-methoxy-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.40g, 20.9mmol) was dissolved in DMF (70ml). Under a nitrogen atmosphere, NaH (1.26 g, 30.4 mmol, 60%) was added in batches at 0°C, stirred for 0.5 hours, and methyl iodide (5.95 g, 41.9 mmol) was added. The reaction solution was raised to room temperature and stirred overnight. The reaction solution was quenched with water, extracted with EA (80mLx3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1), 4 g of the title compound was obtained as a light brown solid, with a yield of 84.7%.

LC-MS：m/z 225.08[M+H] ⁺。 LC-MS: m/z 225.08 [M+H] ⁺ .

步骤5：4-甲基-7-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-醇(4e)的制备Step 5: Preparation of 4-methyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-ol (4e)

于室温，将6-甲氧基-4-甲基-7-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪(3.80g，16.9mmol)溶于DCM(100mL)中。氮气氛下，于-78℃滴加BBr ₃的DCM溶液(50.89ml，50.89mmol，1M)。于-20℃搅拌2小时。于-20℃加水淬灭，用DCM(50mLx3)萃取，无水Na ₂SO ₄干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)得棕色固体状标题化合物1.5g，收率42.2％。 At room temperature, dissolve 6-methoxy-4-methyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (3.80g, 16.9mmol) DCM (100 mL). Under a nitrogen atmosphere, a solution of BBr ₃ in DCM (50.89ml, 50.89mmol, 1M) was added dropwise at -78°C. Stir at -20°C for 2 hours. It was quenched with water at -20°C, extracted with DCM (50 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 1.5 g of the title compound as a brown solid, with a yield of 42.2%.

LC-MS：m/z 211.06[M+H] ⁺。 LC-MS: m/z 211.06 [M+H] ⁺ .

其它步骤与实施例1的制备方法相同，除了用4-甲基-7-硝基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-醇(4e)代替步骤2中的3-硝基-5,6,7,8-四氢萘-2-醇(1a)，制得标题化合物4。The other steps are the same as the preparation method of Example 1, except that 4-methyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-ol (4e ) Instead of 3-nitro-5,6,7,8-tetrahydronaphthalen-2-ol (1a) in step 2, the title compound 4 is prepared.

LC-MS：m/z 508.17[M+H] ⁺。 LC-MS: m/z 508.17 [M+H] ⁺ .

1H NMR(400MHz,DMSO-d ₆)δ7.34-7.30(m,4H),7.28(s,1H),6.64(s,1H),6.47(s,1H),5.96-5.91(m,1H),5.41(s,2H),4.60-4.57(m,1H),4.42-4.27(m,5H),3.56-3.53(m,2H),3.32(s,3H),3.12-3.04(m,2H),2.93(s,3H)。 1H NMR (400MHz, DMSO-d ₆ ) δ 7.34-7.30 (m, 4H), 7.28 (s, 1H), 6.64 (s, 1H), 6.47 (s, 1H), 5.96-5.91 (m, 1H) ,5.41(s,2H),4.60-4.57(m,1H),4.42-4.27(m,5H),3.56-3.53(m,2H),3.32(s,3H),3.12-3.04(m,2H) ,2.93(s,3H).

实施例5：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6- 基)-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(5)的制备Example 5: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-8-(2,2,2-trifluoroacetyl)-2,3,7,8,9,10-hexahydro-[1,4]oxazepine Preparation of [2,3-g]isoquinoline-4(5H)-one (5)

步骤1：2,2,2-三氟-1-(6-甲氧基-3,4-二氢异喹啉-2-(1H-基)乙-1-酮(5a)的制备Step 1: Preparation of 2,2,2-trifluoro-1-(6-methoxy-3,4-dihydroisoquinoline-2-(1H-yl)ethan-1-one (5a)

于室温，将6-甲氧基-1,2,3,4-四氢异喹啉盐酸盐(5.00g，25.0mmol)溶于DCM(100ml)中，加入TEA(7.58g，75.0mmol)。氮气氛下，于0℃，向反应液中加入TFAA(7.87g，37.5mmol)，将反应液升至室温搅拌2小时。加水淬灭，用DCM(120mLx2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝4:1)，得无色透明液体状标题化合物6.5g，收率99.9％。At room temperature, 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.00g, 25.0mmol) was dissolved in DCM (100ml), and TEA (7.58g, 75.0mmol) was added . Under a nitrogen atmosphere, TFAA (7.87 g, 37.5 mmol) was added to the reaction solution at 0° C., and the reaction solution was raised to room temperature and stirred for 2 hours. It was quenched with water, extracted with DCM (120 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=4:1) to obtain 6.5 g of the title compound as a colorless transparent liquid with a yield of 99.9%.

LC-MS：m/z 260.08[M+H] ⁺。 LC-MS: m/z 260.08 [M+H] ⁺ .

步骤2：2,2,2-三氟-1-(6-甲氧基-7-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(5b)的制备Step 2: 2,2,2-Trifluoro-1-(6-methoxy-7-nitro-3,4-dihydroisoquinolin-2-(1H)-yl)ethan-1-one ( 5b) Preparation

将2,2,2-三氟-1-(6-甲氧基-3,4-二氢异喹啉-2-(1H-基)乙-1-酮(6.50g，25.1mmol)溶于MeCN(90mL)中，加入NaNO ₃(2.14g，25.1mmol)，氮气氛下，于0℃，向反应液中滴加TFAA(8.44g，40.2mmol)，将反应液升至室温搅拌过夜。将反应液加水淬灭，EA(120mLx2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得淡黄色固体状标题化合物4g，收率52.4％。 2,2,2-Trifluoro-1-(6-methoxy-3,4-dihydroisoquinoline-2-(1H-yl)ethan-1-one (6.50g, 25.1mmol) was dissolved in To MeCN (90 mL), NaNO ₃ (2.14 g, 25.1 mmol) was added, and TFAA (8.44 g, 40.2 mmol) was added dropwise to the reaction solution at 0° C. under nitrogen atmosphere, and the reaction solution was raised to room temperature and stirred overnight. The reaction solution was quenched with water, extracted with EA (120mLx2), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=3:1) to obtain 4 g of the title compound as a pale yellow solid, with a yield of 52.4%.

LC-MS：m/z 305.07[M+H] ⁺。 LC-MS: m/z 305.07 [M+H] ⁺ .

步骤3：2,2,2-三氟-1-(6-羟基-7-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(5c)的制备Step 3: 2,2,2-Trifluoro-1-(6-hydroxy-7-nitro-3,4-dihydroisoquinoline-2-(1H)-yl)ethan-1-one (5c) Preparation

将2,2,2-三氟-1-(6-甲氧基-7-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(3.00g， 9.87mmol)溶于DCM(50ml)中，氮气氛下，于0℃，向反应液中滴加BBr ₃(4.87g，19.7mmol)，继续搅拌1.5小时。加水淬灭，DCM(60mLx2)萃取，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得淡黄色固体油状标题化合物2.7g，收率94.4％。 2,2,2-Trifluoro-1-(6-methoxy-7-nitro-3,4-dihydroisoquinoline-2-(1H)-yl)ethan-1-one (3.00g _{, 9.87mmol) was dissolved in DCM (50ml), BBr 3} (4.87g, 19.7mmol) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirring was continued for 1.5 hours. It was quenched with water, extracted with DCM (60 mL×2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.7 g of the title compound as a pale yellow solid oil, with a yield of 94.4%.

LC-MS：m/z 291.05[M+H] ⁺。 LC-MS: m/z 291.05 [M+H] ⁺ .

步骤4：O-(7-硝基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-N-三苯甲基-L-丝氨甲酯(5d)的制备Step 4: O-(7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-trityl Preparation of methyl-L-serine methyl ester (5d)

于室温，将2,2,2-三氟-1-(6-羟基-7-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(2.70g,9.31mmol)和三苯甲基-L-丝氨酸甲酯(5.04g,14.0mmol)溶于50mL THF中，加入三苯基膦(4.90g,18.6mmol)。氮气氛下，于冰浴，向反应液中加入偶氮二甲酸二异丙酯(DIAD)(3.76g,18.6mmol)。将反应液升至室温搅拌过夜。加入水稀释，用EA萃取(50mLx2)，饱和NaCl洗涤(50mLx2)，无水Na ₂SO ₄干燥，过滤，滤液减压浓缩。得棕色油状标题化合物5g，收率：84.7％。 At room temperature, 2,2,2-trifluoro-1-(6-hydroxy-7-nitro-3,4-dihydroisoquinolin-2-(1H)-yl)ethan-1-one (2.70 g, 9.31 mmol) and trityl-L-serine methyl ester (5.04 g, 14.0 mmol) were dissolved in 50 mL THF, and triphenylphosphine (4.90 g, 18.6 mmol) was added. Under a nitrogen atmosphere, in an ice bath, diisopropyl azodicarboxylate (DIAD) (3.76 g, 18.6 mmol) was added to the reaction solution. The reaction solution was raised to room temperature and stirred overnight. It was diluted with water, extracted with EA (50 mL×2), washed with saturated NaCl (50 mL× ₂ ), dried over anhydrous Na 2 SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. 5g of the title compound was obtained as a brown oil, yield: 84.7%.

LC-MS：m/z 634.62[M+H] ⁺。 LC-MS: m/z 634.62 [M+H] ⁺ .

步骤5：O-(7-硝基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-L-丝氨酸甲酯(5e)制备Step 5: O-(7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-L-serine methyl ester (5e) Preparation

于室温，将O-(7-硝基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-N-三苯甲基-L-丝氨酸甲酯(5.00g,7.89mmol)溶于60mL DCM中，向反应液中加入HCl的二氧六环溶液(15ml)。室温搅拌过夜。加入饱和NaHCO ₃溶液调节pH值至碱性，用EA萃取(90mLx3)，饱和NaCl洗涤(150mLx2)，无水Na ₂SO ₄干燥，过滤，滤液减压浓缩。得棕色油状标题化合物3.6g，收率99％。 At room temperature, O-(7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-triphenyl Methyl-L-serine methyl ester (5.00 g, 7.89 mmol) was dissolved in 60 mL DCM, and a dioxane solution of HCl (15 mL) was added to the reaction solution. Stir at room temperature overnight. Saturated NaHCO ₃ solution was added to adjust the pH to alkaline, extracted with EA (90 mL×3), washed with saturated NaCl (150 mL× ₂ ), dried with anhydrous Na 2 SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. 3.6 g of the title compound was obtained as a brown oil with a yield of 99%.

LC-MS：m/z 392.30[M+H] ⁺。 LC-MS: m/z 392.30 [M+H] ⁺ .

步骤6：N-(叔丁氧基羰基)-O-(7-硝基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-L-丝氨酸甲酯(5f)的制备Step 6: N-(tert-butoxycarbonyl)-O-(7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline- Preparation of 6-yl)-L-serine methyl ester (5f)

于室温，将O-(7-硝基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-L-丝氨酸甲酯(3.64g,9.31mmol)溶于DCM(50ml)中，向反应液中加入DIEA(3.60g,27.9mmol)和Boc ₂O(3.05g,14.0mmol)。于室温搅拌过夜。加水稀释，DCM萃取(3x60ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1),得黄色固体状标题化合物4.5g，收率98％。 At room temperature, O-(7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-L-serine methyl The ester (3.64 g, 9.31 mmol) was dissolved in DCM (50 ml), DIEA (3.60 g, 27.9 mmol) and Boc ₂ O (3.05 g, 14.0 mmol) were added to the reaction solution. Stir overnight at room temperature. Dilute with water, extract with DCM (3x60ml), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1) to obtain a yellow solid The title compound was 4.5 g, and the yield was 98%.

LC-MS：m/z 492.42[M+H] ⁺。 LC-MS: m/z 492.42 [M+H] ⁺ .

步骤7：O-(7-氨基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-N-(叔丁氧基羰基)-L-丝氨酸甲酯(5g)的制备Step 7: O-(7-amino-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(tert-butoxy Preparation of methyl carbonyl)-L-serine (5g)

于室温，将N-(叔丁氧基羰基)-O-(7-硝基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-L-丝氨酸甲酯(4.50g，9.16mmol)溶于80mL EA中，向反应液中加入Pd/C(10wt％，1g)，于氢气氛下，室温搅拌过夜。将反应液通过硅藻土过滤，加EA，MeOH洗涤滤饼，滤液减压浓缩，得灰黑色固体状的标题化合物4g，收率94.5％。At room temperature, N-(tert-butoxycarbonyl)-O-(7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline -6-yl)-L-serine methyl ester (4.50g, 9.16mmol) was dissolved in 80mL EA, Pd/C (10wt%, 1g) was added to the reaction solution, and stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered through Celite, EA and MeOH were added to wash the filter cake, and the filtrate was concentrated under reduced pressure to obtain 4 g of the title compound as a gray-black solid with a yield of 94.5%.

LC-MS：m/z 462.44[M+H] ⁺。 LC-MS: m/z 462.44 [M+H] ⁺ .

步骤8：(S)-(4-氧代-8-(2,2,2-三氟乙酰基)-2,3,4,5,7,8,9,10-八氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-3-基)氨基甲酸叔丁酯(5h)的制备Step 8: (S)-(4-oxo-8-(2,2,2-trifluoroacetyl)-2,3,4,5,7,8,9,10-octahydro-[1, 4] Preparation of tert-butyl oxazepine [2,3-g]isoquinolin-3-yl)carbamate (5h)

将O-(7-氨基-2-(2,2,2-三氟乙酰基)-1,2,3,4-四氢异喹啉-6-基)-N-(叔丁氧基羰基)-L-丝氨酸甲酯(500mg,1.08mmol)溶于氯仿(11mL)中，氮气氛下，于冰浴，加入三甲基铝(1.08ml，2M，2.17mmol)，将反应液升至室温搅拌2h。加入水淬灭，硅藻土过滤，DCM洗涤滤饼，DCM萃取(2x50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体状标题化合物330mg，收率70.8％。O-(7-amino-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-(tert-butoxycarbonyl) )-L-serine methyl ester (500mg, 1.08mmol) was dissolved in chloroform (11mL), under nitrogen atmosphere, in an ice bath, added trimethylaluminum (1.08ml, 2M, 2.17mmol), and the reaction solution was raised to room temperature Stir for 2h. It was quenched by adding water, filtered through Celite, the filter cake was washed with DCM, extracted with DCM (2×50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 330 mg of the title compound as a yellow solid with a yield of 70.8%.

LC-MS：m/z 430.40[M+H] ⁺。 LC-MS: m/z 430.40 [M+H] ⁺ .

步骤9：(S)-(5-甲基-4-氧代-8-(2,2,2-三氟乙酰基)-2,3,4,5,7,8,9,10-八氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-3-基)氨基甲酸叔丁酯(5i)的制备Step 9: (S)-(5-Methyl-4-oxo-8-(2,2,2-trifluoroacetyl)-2,3,4,5,7,8,9,10-A Preparation of tert-butyl hydrogen-[1,4]oxazepine[2,3-g]isoquinolin-3-yl)carbamate (5i)

将(S)-(4-氧代-8-(2,2,2-三氟乙酰基)-2,3,4,5,7,8,9,10-八氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-3-基)氨基甲酸叔丁酯(330mg，0.769mmol)溶于DMF(6ml)，加入碳酸铯(376mg，1.15mmol)，氮气氛下，加入碘甲烷(131ml，0.923mmol)。于室温搅拌2h。加水稀释，EA萃取(2x15ml)，用饱和食盐水洗涤有机相(3x 50ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备薄层色谱法分离纯化(展开剂：PE/EA＝4:1)，得淡黄色固体状标题化合物90mg，收率26.4％。(S)-(4-oxo-8-(2,2,2-trifluoroacetyl)-2,3,4,5,7,8,9,10-octahydro-[1,4] Oxazepine [2,3-g]isoquinolin-3-yl) tert-butyl carbamate (330mg, 0.769mmol) was dissolved in DMF (6ml), cesium carbonate (376mg, 1.15mmol) was added, and nitrogen atmosphere Next, iodomethane (131ml, 0.923mmol) was added. Stir at room temperature for 2h. Dilute with water, extract with EA (2x15ml), wash the organic phase (3x 50ml) with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative thin-layer chromatography (developing solvent: PE/ EA=4:1), 90 mg of the title compound was obtained as a pale yellow solid, with a yield of 26.4%.

LC-MS：m/z 444.42[M+H] ⁺。 LC-MS: m/z 444.42 [M+H] ⁺ .

步骤10：(S)-3-氨基-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4-(5H)-酮(5j)的制备Step 10: (S)-3-amino-5-methyl-8-(2,2,2-trifluoroacetyl)-2,3,7,8,9,10-hexahydro-[1,4 Preparation of ]oxazepine[2,3-g]isoquinoline-4-(5H)-one (5j)

于室温，将(S)-(5-甲基-4-氧代-8-(2,2,2-三氟乙酰基)-2,3,4,5,7,8,9,10-八氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-3-基)氨基甲酸叔丁酯(90.0mg,0.203mmol)溶于4mL DCM中，向反应液中加入HCl的二氧六环溶液(1ml)。室温搅拌过夜。加入饱和NaHCO ₃溶液调节pH至碱性，用DCM萃取(100mLx3)，无水Na ₂SO ₄干燥，过滤，滤液减压浓缩。得棕色固体状标题化合物69mg，收率99％。 At room temperature, add (S)-(5-methyl-4-oxo-8-(2,2,2-trifluoroacetyl)-2,3,4,5,7,8,9,10- Tert-butyl octahydro-[1,4]oxazepine[2,3-g]isoquinolin-3-yl)carbamate (90.0mg, 0.203mmol) was dissolved in 4mL DCM and added to the reaction solution A solution of HCl in dioxane (1 ml) was added. Stir at room temperature overnight. Saturated NaHCO ₃ solution was added to adjust the pH to alkaline, extracted with DCM (100 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. 69 mg of the title compound was obtained as a brown solid with a yield of 99%.

LC-MS：m/z 344.31[M+H] ⁺。 LC-MS: m/z 344.31 [M+H] ⁺ .

其它步骤与实施例1的制备方法相同，除了用(S)-3-氨基-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4-(5H)-酮(5j)代替步骤9中的(S)-3-氨基-5-甲基-2,3,7,8,9,10-六氢萘并[2,3-b][1,4]氧氮杂卓-4(5H)-酮(1h)，制得标题化合物5。The other steps are the same as the preparation method of Example 1, except that (S)-3-amino-5-methyl-8-(2,2,2-trifluoroacetyl)-2,3,7,8,9 ,10-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4-(5H)-one (5j) instead of (S)-3-amino- in step 9 5-methyl-2,3,7,8,9,10-hexahydronaphtho[2,3-b][1,4]oxazepine-4(5H)-one (1h), prepared Title compound 5.

LC-MS：m/z 588.15[M+H] ⁺。 LC-MS: m/z 588.15 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.47-7.45(m,1H),7.37-7.27(m,3H),7.20-7.17(m,2H),7.10(s,1H),5.58-5.53(m,1H),5.42(s,2H),4.84-4.78(m,1H),4.32-4.27(m,1H),4.09-4.00(m,1H),3.88-3.79(m,2H),3.65-3.58(m,1H),3.28(s,3H),2.94-2.90(m,2H),2.84-2.76(m,1H),2.71-2.66(m,1H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.47-7.45 (m, 1H), 7.37-7.27 (m, 3H), 7.20-7.17 (m, 2H), 7.10 (s, 1H), 5.58-5.53 (m, 1H), 5.42 (s, 2H), 4.84-4.78 (m, 1H), 4.32-4.27 (m, 1H), 4.09-4.00 (m, 1H), 3.88-3.79 (m, 2H), 3.65 -3.58 (m, 1H), 3.28 (s, 3H), 2.94-2.90 (m, 2H), 2.84-2.76 (m, 1H), 2.71-2.66 (m, 1H).

实施例6：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4-(5H)-酮(6)的制备Example 6: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4-(5H )-Preparation of ketone (6)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4-(5H)-酮(6)的制备Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4-(5H) -Preparation of ketone (6)

于室温，将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4-(5H)-酮(50.0mg,0.0850mmol)溶于MeOH/H ₂O(2ml/0.5ml)中，向反应液中加入碳酸钾(24.0mg,0.171mmol)。于室温搅拌过夜。加水稀释，用EA萃取(10mLx2)，无水硫酸钠干燥，过滤，减压浓缩。残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得类白色固体状标题化合物5mg，收率11.9％。 At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-8-(2,2,2-trifluoroacetyl)-2,3,7,8,9,10-hexahydro-[1,4]oxazepine [2,3-g]isoquinoline-4-(5H)-one (50.0mg, 0.0850mmol) was dissolved in MeOH/H ₂ O (2ml/0.5ml), potassium carbonate (24.0mg , 0.171mmol). Stir overnight at room temperature. Dilute with water, extract with EA (10 mL×2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by high-pressure preparative liquid phase separation and purification (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min) to obtain 5 mg of the title compound as an off-white solid , The yield is 11.9%.

LC-MS：m/z 492.17[M+H] ⁺。 LC-MS: m/z 492.17 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.36-7.29(m,3H),7.20-7.17(m,3H),6.95(s,1H),5.57-5.52(m,1H),5.42(s,2H),4.73-4.79(m,1H),4.28-4.24(m,1H),4.09-4.00(m,1H),3.94-3.89(m,2H),3.25(s,3H),3.10-2.96(m,3H),2.80-2.71(m,5H)。 ¹ H NMR(400MHz, DMSO-d ₆ )δ7.36-7.29(m,3H), 7.20-7.17(m,3H), 6.95(s,1H), 5.57-5.52(m,1H), 5.42(s ,2H),4.73-4.79(m,1H),4.28-4.24(m,1H),4.09-4.00(m,1H),3.94-3.89(m,2H), 3.25(s,3H), 3.10-2.96 (m, 3H), 2.80-2.71 (m, 5H).

实施例7：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5,8-二甲基-2,3,7,8,9,1-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(7)的制备Example 7: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5,8-dimethyl-2,3,7,8,9,1-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4 Preparation of (5H)-ketone (7)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5,8- 二甲基-2,3,7,8,9,1-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(7)的制备Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Base)-5,8-dimethyl-2,3,7,8,9,1-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4( Preparation of 5H)-ketone (7)

于室温，将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,1-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(50.0mg，0.102mmol)溶于乙腈(3mL)中，向反应液中加入甲醛(38％在水中)(102mg，1.02mmol)、醋酸(0.3ml)，搅拌30分钟，加入NaBH ₃CN(64.0mg，1.016mmol)，继续搅拌2小时。向反应液中加入饱和NaHCO ₃溶液，用EA(10mLx2)萃取，无水Na ₂SO ₄干燥。过滤，滤液减压浓缩。残留物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得到5.2mg淡黄色固体状标题化合物，收率12.1％。 At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-2,3,7,8,9,1-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4(5H) -Ketone (50.0mg, 0.102mmol) was dissolved in acetonitrile (3mL), formaldehyde (38% in water) (102mg, 1.02mmol) and acetic acid (0.3ml) were added to the reaction solution, stirred for 30 minutes, and NaBH ₃ CN was added (64.0mg, 1.016mmol), continue to stir for 2 hours. _{A saturated NaHCO 3} solution was added to the reaction solution, extracted with EA (10 mL×2), and dried with anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by high-pressure preparation liquid phase separation and purification (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min) to obtain 5.2 mg of the title as a pale yellow solid Compound, the yield is 12.1%.

LC-MS：m/z 506.19[M+H] ⁺。 LC-MS: m/z 506.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.32-7.28(m,4H),7.26(s,1H),7.01(s,1H),6.96(s,1H),5.91-5.88(m,1H),5.42(s,2H),4.66-4.61(m,1H),4.42-4.38(m,1H),4.30-4.25(m,1H),4.02-3.97(m,2H),3.58-3.53(m,2H),3.37(s,3H),3.12-3.05(m,4H),2.89(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 7.32-7.28 (m, 4H), 7.26 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 5.91-5.88 (m, 1H), 5.42(s,2H),4.66-4.61(m,1H),4.42-4.38(m,1H),4.30-4.25(m,1H),4.02-3.97(m,2H),3.58-3.53(m,2H) ), 3.37 (s, 3H), 3.12-3.05 (m, 4H), 2.89 (s, 3H).

实施例8：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-8-(甲磺酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(12)的制备Example 8: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-8-(methylsulfonyl)-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g] Preparation of isoquinolin-4(5H)-one (12)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-8-(甲基磺酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(8)的制备Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-5-methyl-8-(methylsulfonyl)-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g] Preparation of isoquinolin-4(5H)-one (8)

于室温，将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(55.0mg，0.0915mmol)溶于DCM(2ml)中，向反应液中加入DIEA(17.3mg，0.134mmol)。于0℃，加入甲磺酰氯(15.3mg，0.134mmol)，继续搅拌1小时。向反应液中加入饱和碳酸氢钠溶液，用DCM(15mLx3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％， 30min)，得类白色固体状标题化合物7.50mg，收率11.1％。At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4(5H) -Ketone (55.0mg, 0.0915mmol) was dissolved in DCM (2ml), DIEA (17.3mg, 0.134mmol) was added to the reaction solution. At 0°C, methanesulfonyl chloride (15.3 mg, 0.134 mmol) was added, and stirring was continued for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM (15mLx3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high pressure liquid phase separation and purification (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min), the title compound was obtained as an off-white solid 7.50mg, with a yield of 11.1%.

LC-MS：m/z 570.15[M+H] ⁺。 LC-MS: m/z 570.15 [M+H] ⁺ .

¹HNMR(400MHz,DMSO-d ₆)δ7.37-7.28(m,4H),7.20-7.18(m,2H),7.06(br,1H),5.58-5.53(m,1H),5.43(br,2H),4.81(t,1H),4.40(br,2H),4.29(t,1H),4.05-3.99(m,1H),3.65-3.59(m,1H),3.46-3.42(m,2H),3.27(br,3H),2.96(br,3H),2.93-2.90(m,2H),2.81-2.77(m,1H),2.71-2.66(m,1H)。 ¹ HNMR (400MHz, DMSO-d ₆ ) δ 7.37-7.28 (m, 4H), 7.20-7.18 (m, 2H), 7.06 (br, 1H), 5.58-5.53 (m, 1H), 5.43 (br, 2H), 4.81 (t, 1H), 4.40 (br, 2H), 4.29 (t, 1H), 4.05-3.99 (m, 1H), 3.65-3.59 (m, 1H), 3.46-3.42 (m, 2H) , 3.27 (br, 3H), 2.96 (br, 3H), 2.93-2.90 (m, 2H), 2.81-2.77 (m, 1H), 2.71-2.66 (m, 1H).

实施例9：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-N,N,5-三甲基-4-氧代-2,3,4,5,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-8(7H)-磺酰胺(9)的制备Example 9: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-N,N,5-trimethyl-4-oxo-2,3,4,5,9,10-hexahydro-[1,4]oxazepine[2,3- g) Preparation of isoquinoline-8(7H)-sulfonamide (9)

与实施例8的制备方法相同，除了用二甲基氨磺酰氯代替甲磺酰氯，制得标题化合物9。The preparation method was the same as in Example 8, except that dimethylsulfamoyl chloride was used instead of methanesulfonyl chloride to obtain the title compound 9.

LC-MS：m/z 599.18[M+H] ⁺。 LC-MS: m/z 599.18 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.37-7.30(m,4H),7.20-7.18(m,2H),7.06(s,1H),5.58-5.52(m,1H),5.43(s,2H),4.80(t,1H),4.41(br,2H),4.29(t,1H),4.04-3.99(m,1H),3.64-3.61(m,1H),3.49(t,2H),3.27(s,3H),2.93-2.90(m,2H),2.79(s,6H),2.72-2.68(m,2H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.37-7.30 (m, 4H), 7.20-7.18 (m, 2H), 7.06 (s, 1H), 5.58-5.52 (m, 1H), 5.43 (s , 2H), 4.80 (t, 1H), 4.41 (br, 2H), 4.29 (t, 1H), 4.04-3.99 (m, 1H), 3.64-3.61 (m, 1H), 3.49 (t, 2H), 3.27 (s, 3H), 2.93-2.90 (m, 2H), 2.79 (s, 6H), 2.72-2.68 (m, 2H).

实施例10：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-4-氧代-2,3,4,5,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-8(7H)-甲腈(10)的制备Example 10: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-4-oxo-2,3,4,5,9,10-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline Preparation of -8(7H)-carbonitrile (10)

与实施例8的制备方法相同，除了用溴化氰代替甲磺酰氯，制得标题化合物10。The preparation method was the same as in Example 8, except that cyanogen bromide was used instead of methanesulfonyl chloride to obtain the title compound 10.

LC-MS：m/z 517.18[M+H] ⁺。 LC-MS: m/z 517.18 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.32-7.23(m,5H),6.96(s,1H),6.91(s,1H),5.92-5.86(m,1H),5.39(s,2H),4.80(t,1H),4.33-4.23(m,3H),4.26-4.22(m,1H),3.57-3.48(m,3H),3.35(s,3H),3.05-2.95(m,3H),2.69-2.64(m,1H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.32-7.23 (m, 5H), 6.96 (s, 1H), 6.91 (s, 1H), 5.92-5.86 (m, 1H), 5.39 (s, 2H) ), 4.80(t,1H),4.33-4.23(m,3H),4.26-4.22(m,1H),3.57-3.48(m,3H),3.35(s,3H),3.05-2.95(m,3H) ), 2.69-2.64 (m, 1H).

实施例11：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-8-(环丙烷甲酰基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(11)的制备Example 11: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-8-(cyclopropaneformyl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ] Preparation of isoquinolin-4(5H)-one (11)

与实施例8的制备方法相同，除了用环丙烷甲酰氯代替甲磺酰氯，制得标题化合物11。The preparation method was the same as in Example 8, except that cyclopropanecarbonyl chloride was used instead of methanesulfonyl chloride to obtain the title compound 11.

LC-MS：m/z 560.00[M+H] ⁺。 LC-MS: m/z 560.00 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.31-7.29(m,5H),6.99-6.96(m,2H),5.90(t,1H),5.39(br,2H),4.92-4.87(m,1H),4.62-4.54(m,1H),4.36(t,1H),4.28-4.22(m,1H),3.84(br,1H),3.57-3.51(m,1H),3.35(br,3H),3.08-3.01(m,1H),2.94-2.83(m,2H),2.68-2.61(m,1H),1.86-1.79(m,1H),1.74-1.61(m,1H),1.45-1.54(m,1H),0.92-0.83(m,4H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ7.31-7.29 (m, 5H), 6.99-6.96 (m, 2H), 5.90 (t, 1H), 5.39 (br, 2H), 4.92-4.87 (m, 1H) ), 4.62-4.54(m,1H), 4.36(t,1H), 4.28-4.22(m,1H), 3.84(br,1H), 3.57-3.51(m,1H), 3.35(br,3H), 3.08-3.01(m,1H),2.94-2.83(m,2H),2.68-2.61(m,1H),1.86-1.79(m,1H),1.74-1.61(m,1H),1.45-1.54(m ,1H),0.92-0.83(m,4H).

实施例12：(8S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4c]吡啶-6-基)-10-甲基-9-氧代-2,3,7,8,9,10-六氢-[1,4]二噁英并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-2-甲腈(12)的制备Example 12: (8S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4c]pyridine-6- Group)-10-methyl-9-oxo-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2',3':4,5]benzo Preparation of [1,2-b][1,4]oxazepine-2-carbonitrile (12)

步骤1：4,5-二甲氧基-2-硝基苯酚(12a)的制备Step 1: Preparation of 4,5-dimethoxy-2-nitrophenol (12a)

于室温，将4,5-二甲氧基-2-硝基苯甲醛(5.00g，23.7mmol)溶于100mL DCM。于0℃，加入间氯过氧苯甲酸(m-CPBA)(10.9g，63.4mmol)，氮气氛下，于0℃加入TFA(1.76mL)。升至室温搅拌过夜。于0℃，加入饱和硫代硫酸钠溶液淬灭，过滤，DCM洗涤滤饼，有机相用饱和碳酸氢钠溶液洗涤(100mLx1)，饱和食盐水洗涤(100mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。At room temperature, 4,5-dimethoxy-2-nitrobenzaldehyde (5.00 g, 23.7 mmol) was dissolved in 100 mL of DCM. At 0°C, m-chloroperoxybenzoic acid (m-CPBA) (10.9 g, 63.4 mmol) was added, and under a nitrogen atmosphere, TFA (1.76 mL) was added at 0°C. Warm to room temperature and stir overnight. At 0°C, add saturated sodium thiosulfate solution to quench, filter, DCM wash filter cake, organic phase washed with saturated sodium bicarbonate solution (100mLx1), saturated brine (100mLx1), dried with anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to obtain a crude product.

粗品溶于70mL甲醇中，加入2mol/L的NaOH溶液(30mL)，于室温搅拌1小时。1mol/L的盐酸调节PH至3-4，过滤，甲醇洗涤滤饼，收集滤饼，干燥得黄色固体的标题化合物3.25g，收率：69.0％。The crude product was dissolved in 70 mL methanol, 2 mol/L NaOH solution (30 mL) was added, and the mixture was stirred at room temperature for 1 hour. Adjust the pH to 3-4 with 1mol/L hydrochloric acid, filter, wash the filter cake with methanol, collect the filter cake, and dry to obtain 3.25 g of the title compound as a yellow solid, yield: 69.0%.

LC-MS：m/z 200.05[M+H] ⁺。 LC-MS: m/z 200.05 [M+H] ⁺ .

步骤2：O-(4,5-二甲氧基-2-硝基苯基)-N-三苯甲基-L-丝氨酸甲酯(12b)的制备Step 2: Preparation of O-(4,5-Dimethoxy-2-nitrophenyl)-N-trityl-L-serine methyl ester (12b)

于室温，将4,5-二甲氧基-2-硝基苯酚(3.25g，12.3mmol)、甲基三苯甲基-L-丝氨酸(6.64g，18.4mmol)和三苯基膦(6.45g，24.5mmol)溶于150mL THF中。氮气氛下，于0℃，加入偶氮二甲酸二异丙酯(DIAD)(4.95g，24.5mmol)，升至室温搅拌过夜。加入100mL水淬灭，EA萃取(100mLx3)，饱和食盐水洗涤(150mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-2:1)，得黄色油状标题化合物13.2g(粗品)。At room temperature, 4,5-dimethoxy-2-nitrophenol (3.25g, 12.3mmol), methyltrityl-L-serine (6.64g, 18.4mmol) and triphenylphosphine (6.45 g, 24.5mmol) dissolved in 150mL THF. Under a nitrogen atmosphere, at 0°C, add diisopropyl azodicarboxylate (DIAD) (4.95 g, 24.5 mmol), raise to room temperature and stir overnight. It was quenched by adding 100mL water, extracted with EA (100mLx3), washed with saturated brine (150mLx1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ EA=100:1-2:1) to obtain 13.2 g (crude) of the title compound as a yellow oil.

步骤3：O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(12c)的制备Step 3: Preparation of O-(4,5-Dimethoxy-2-nitrophenyl)-L-serine methyl ester (12c)

将O-(4,5-二甲氧基-2-硝基苯基)-N-三苯甲基-L-丝氨酸甲酯(13.2g，21.7mmol) 溶于100ml DCM中，加入4mol/L的盐酸/二氧六环溶液(20mL)，室温搅拌过夜。减压浓缩，打浆三次(EA/PE＝3:1)，过滤，滤饼干燥，得浅黄色固体标题化合物3.05g，收率：46.8％。Dissolve O-(4,5-Dimethoxy-2-nitrophenyl)-N-trityl-L-serine methyl ester (13.2g, 21.7mmol) in 100ml DCM, add 4mol/L The hydrochloric acid/dioxane solution (20 mL) was stirred overnight at room temperature. Concentration under reduced pressure, beating three times (EA/PE=3:1), filtering, and drying the filter cake to obtain 3.05 g of the title compound as a pale yellow solid, yield: 46.8%.

LC-MS：m/z 301.10[M+H] ⁺。 LC-MS: m/z 301.10 [M+H] ⁺ .

步骤4：N-(叔丁氧基羰基)-O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(12d)的制备Step 4: Preparation of N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (12d)

将O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(3.05g，10.2mmol)溶于50mL DCM中，加入DIEA(3.93g，30.5mmol)，室温搅拌20分钟。于0℃，分批加入Boc ₂O(3.32g，15.2mmol)，室温搅拌过夜。加入100mL水，用DCM萃取(50mLx2)，饱和食盐水洗涤(100mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物5.01g(粗品)。 Dissolve O-(4,5-Dimethoxy-2-nitrophenyl)-L-serine methyl ester (3.05g, 10.2mmol) in 50mL DCM, add DIEA (3.93g, 30.5mmol), room temperature Stir for 20 minutes. At 0°C, Boc ₂ O (3.32 g, 15.2 mmol) was added in batches, and the mixture was stirred at room temperature overnight. Add 100 mL of water, extract with DCM (50 mL×2), wash with saturated brine (100 mL×1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 5.01 g (crude) of the title compound as a yellow oil.

LC-MS：m/z 401.15[M+H] ⁺。 LC-MS: m/z 401.15 [M+H] ⁺ .

步骤5：O-(2-氨基-4,5-二甲氧基苯基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(12e)的制备Step 5: Preparation of O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (12e)

将N-(叔丁氧基羰基)-O-(4,5-二甲氧基-2-硝基苯基)-L-丝氨酸甲酯(5.01g，12.5mmol)溶于50ml MeOH中，加入钯碳(10wt％，2.50g)，氢气氛下，室温搅拌过夜。过滤，甲醇洗涤滤饼(10mLx3)，滤液减压浓缩，得黑色油状标题化合物4.75g(粗品)。Dissolve N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (5.01g, 12.5mmol) in 50ml MeOH, add Palladium on carbon (10wt%, 2.50g), stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filter cake (10 mL×3) was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 4.75 g (crude) of the title compound as a black oil.

LC-MS：m/z 371.17[M+H] ⁺。 LC-MS: m/z 371.17 [M+H] ⁺ .

步骤6：(S)-(7,8-二甲氧基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)氨基甲酸叔丁酯(12f)的制备Step 6: (S)-(7,8-Dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl ) Preparation of tert-butyl carbamate (12f)

将O-(2-氨基-4,5-二甲氧基苯基)-N-(叔丁氧羰基)-L-丝氨酸甲酯(4.75g，12.5mmol)溶于CHCl ₃(80ml)中。氮气氛下，于0℃向反应液中加入三甲基铝溶液(2.7mL，2mol/L)。50℃搅拌3小时。加入甲醇淬灭，减压浓缩，残余物用DCM/MeOH＝5:1(10mLx5)打浆，过滤，收集滤液，减压浓缩，得黑色油状标题化合物2.65g，收率：62.8％。 O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (4.75 g, 12.5 mmol) was dissolved in CHCl ₃ (80 ml). Under a nitrogen atmosphere, trimethylaluminum solution (2.7 mL, 2 mol/L) was added to the reaction solution at 0°C. Stir at 50°C for 3 hours. It was quenched by adding methanol, concentrated under reduced pressure, the residue was slurried with DCM/MeOH=5:1 (10 mL×5), filtered, the filtrate was collected, and concentrated under reduced pressure to obtain 2.65 g of the title compound as a black oil, yield: 62.8%.

LC-MS：m/z 339.15[M+H] ⁺。 LC-MS: m/z 339.15 [M+H] ⁺ .

步骤7：(S)-(7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢-苯并[b][1,4]氧氮杂卓-3-基)氨基甲酸叔丁基(12g)的制备Step 7: (S)-(7,8-Dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]oxynitrogen Preparation of tert-butyl azol-3-yl) carbamate (12g)

将(S)-(7,8-二甲氧基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)氨基甲酸叔丁酯(2.65g，7.84mmol)溶于35mL DMF，加入碳酸铯(3.83g，11.7mmol)，室温搅拌30分钟。于0℃加入碘甲烷(1.11g，7.82mmol)，于室温搅拌2小时。加入50mL水，EA萃取(30mLx3)，饱和食盐水洗涤(30mLx2)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-3:1),得黄色油状标题化合物650mg，收率：23.6％。(S)-(7,8-Dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)amino Tert-butyl formate (2.65 g, 7.84 mmol) was dissolved in 35 mL DMF, cesium carbonate (3.83 g, 11.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Add methyl iodide (1.11 g, 7.82 mmol) at 0°C, and stir at room temperature for 2 hours. Add 50 mL of water, extract with EA (30 mL×3), wash with saturated brine (30 mL×2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-3:1) to obtain 650 mg of the title compound as a yellow oil, yield: 23.6%.

LC-MS：m/z 353.16[M+H] ⁺。 LC-MS: m/z 353.16 [M+H] ⁺ .

步骤8：(S)-3-氨基-7,8-二甲氧基-5-甲基-2,3-二氢-苯并[b][1,4]氧氮杂卓-4(5H)-酮(12h)的制备Step 8: (S)-3-amino-7,8-dimethoxy-5-methyl-2,3-dihydro-benzo[b][1,4]oxazepine-4(5H )-Ketone (12h) preparation

将 (S)-(7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢-苯并[b][1,4]氧氮杂卓-3-基)氨基甲酸叔丁基(650mg,1.85mmol)溶于DCM(10ml)中，向反应液中加入4mol/L的盐酸/二氧六环溶液(3mL)，于室温搅拌过夜。加入10mL饱和碳酸氢钠溶液，DCM萃取(10mLx3)，饱和食盐水洗涤(15mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色半固体标题化合物380mg，收率：81.7％。 ( S)-(7,8-Dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]oxazepine Tert-butyl -3-yl)carbamic acid (650 mg, 1.85 mmol) was dissolved in DCM (10 ml), 4 mol/L hydrochloric acid/dioxane solution (3 mL) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Add 10 mL of saturated sodium bicarbonate solution, extract with DCM (10 mL×3), wash with saturated brine (15 mL×1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 380 mg of yellow semi-solid title compound, yield: 81.7%.

LC-MS：m/z 253.27[M+H] ⁺。 LC-MS: m/z 253.27 [M+H] ⁺ .

步骤9：(S)-1-苄基-5-氯-4-(2-((7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(12i)的制备Step 9: (S)-1-Benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5- Preparation of tetrahydrobenzo[b][1,4]oxazepine-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (12i)

将(S)-3-氨基-7,8-二甲氧基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(360mg，1.43mmol)、1-苄基-5-氯-4-(2-氧代乙基)-1H-吡唑-3-羧酸乙酯(1l)(612mg，2.00mmol)溶于10mL甲醇，加入1mL冰醋酸和2-甲基吡啶硼烷(214mg，2.00mmol)，室温搅拌2小时。加入20mL饱和碳酸氢钠溶液，用DCM萃取(10mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-2:3)，得红棕色色固体标题化合物400mg，收率：51.6％。(S)-3-amino-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (360mg, 1.43mmol), 1-benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1l) (612mg, 2.00mmol) dissolved in 10mL Methanol, 1 mL of glacial acetic acid and 2-picoline borane (214 mg, 2.00 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was added, extracted with DCM (10 mL×3), washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-2:3) to obtain 400 mg of the title compound as a reddish-brown solid, yield: 51.6%.

LC-MS：m/z 543.19[M+H] ⁺。 LC-MS: m/z 543.19 [M+H] ⁺ .

步骤10：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二甲氧基-5-甲基-2,3-二氢-苯并[b][1,4]氧氮杂卓-4(5H)-酮(12j)的制备Step 10: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-7,8-dimethoxy-5-methyl-2,3-dihydro-benzo[b][1,4]oxazepine-4(5H)-one(12j) preparation

将(S)-1-苄基-5-氯-4-(2-((7,8-二甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)氨基)乙基)-1H-吡唑-3-羧酸乙酯(350mg,0.644mmol)溶于5ml甲苯中，氮气氛下，于0℃，加入Al(CH ₃) ₃的甲苯溶液(0.97mL，2mol/L)，于90℃搅拌3小时。加10mL水淬灭，EA萃取(10mLx3)，饱和食盐水洗涤(10mLx1)，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-1:1)，得浅红色固体标题化合物330mg(粗品)。 The (S)-1-benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydro Benzo[b][1,4]oxazepine-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (350mg, 0.644mmol) dissolved in 5ml toluene, nitrogen atmosphere Then, at 0°C, _{a toluene solution of Al(CH 3} ) ₃ (0.97 mL, 2 mol/L) was added, and the mixture was stirred at 90°C for 3 hours. It was quenched by adding 10mL water, extracted with EA (10mLx3), washed with saturated brine (10mLx1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA) =100:1-1:1) to obtain 330 mg (crude product) of the title compound as a light red solid.

LC-MS：m/z 496.29[M+H] ⁺。 LC-MS: m/z 496.29 [M+H] ⁺ .

步骤11：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二羟基-5-甲基-2,3-二氢-苯并[b][1,4]氧氮杂卓-4(5H)-酮(12k)的制备Step 11: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-7,8-dihydroxy-5-methyl-2,3-dihydro-benzo[b][1,4]oxazepine-4(5H)-one (12k)

于室温，将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二甲氧基-5-甲基-2,3-二氢-苯并[b][1,4]氧氮杂卓-4(5H)-酮(250mg，0.503mmol)溶于6mL二氯甲烷，于0℃加入三溴化硼的二氯甲烷溶液(1M，3mL)，于室温搅拌2小时。于0℃滴加甲醇淬灭，DCM萃取(10mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得红棕色固体标题化合物270mg(粗品)。At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-7,8-dimethoxy-5-methyl-2,3-dihydro-benzo[b][1,4]oxazepine-4(5H)-one (250mg, 0.503mmol) was dissolved in 6mL of dichloromethane, a dichloromethane solution (1M, 3mL) of boron tribromide was added at 0°C, and stirred at room temperature for 2 hours. It was quenched with methanol dropwise at 0°C, extracted with DCM (10 mL×3), washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 270 mg (crude) of the title compound as a reddish brown solid.

LC-MS：m/z 469.12[M+H] ⁺。 LC-MS: m/z 469.12 [M+H] ⁺ .

步骤12：(8S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4c]吡啶-6-基)-10-甲基-9-氧代-2,3,7,8,9,10-六氢-[1,4]二噁英并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-2-甲腈(12)的制备Step 12: (8S)-8-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4c]pyridin-6-yl )-10-methyl-9-oxo-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2',3':4,5]benzo[ Preparation of 1,2-b][1,4]oxazepine-2-carbonitrile (12)

将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-7,8-二羟基-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂卓-4(5H)-酮(100mg，0.214mmol)溶于3ml乙腈中，加入碳酸钾(88.5mg，0.641mg)和2,3-二溴丙烷腈(59.2mg，0.278mmol)，于75℃搅拌过夜。加10mL水淬灭，EA萃取(10mLx3)，饱和食盐水洗涤(10mLx1)，无水硫酸钠干燥，过滤，减压浓缩，残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm×250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得浅黄色固体状标题化合物10.0mg，收率：9.01％。(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl )-7,8-Dihydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (100mg, 0.214mmol) dissolved in 3ml To acetonitrile, potassium carbonate (88.5 mg, 0.641 mg) and 2,3-dibromopropane nitrile (59.2 mg, 0.278 mmol) were added, and the mixture was stirred at 75°C overnight. Quench with 10mL water, extract with EA (10mLx3), wash with saturated brine (10mLx1), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by high-pressure preparative liquid phase separation and purification (column model: Daisogei 30mm×250mm , C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), to obtain 10.0 mg of the title compound as a pale yellow solid, yield: 9.01%.

LC-MS：m/z 520.13[M+H] ⁺。 LC-MS: m/z 520.13 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ:7.38-7.19(m,6H),7.00-6.94(m,1H),5.88-5.81(m,1H),5.62-5.52(m,1H),5.45(br,2H),4.84-4.74(m,1H),4.72-4.62(m,1H),4.55-4.35(m,2H),4.09-3.98(m,1H),3.71-3.56(m,1H),3.32-3.23(m,4H),2.87-2.77(m,1H),2.75-2.65(m,H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.38-7.19 (m, 6H), 7.00-6.94 (m, 1H), 5.88-5.81 (m, 1H), 5.62-5.52 (m, 1H), 5.45 (br ,2H),4.84-4.74(m,1H),4.72-4.62(m,1H),4.55-4.35(m,2H),4.09-3.98(m,1H),3.71-3.56(m,1H),3.32 -3.23 (m, 4H), 2.87-2.77 (m, 1H), 2.75-2.65 (m, H).

实施例13：(8S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6吡唑并[3,4c]吡啶-6-基)-10-甲基-9-氧代-2,3,7,8,9,10-六氢-[1,4]二噁英并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-2-羧酰胺(13)的制备Example 13: (8S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6pyrazolo[3,4c]pyridin-6-yl )-10-methyl-9-oxo-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2',3':4,5]benzo[ Preparation of 1,2-b][1,4]oxazepine-2-carboxamide (13)

将(8S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4c]吡啶-6-基)-10-甲基-9-氧代-2,3,7,8,9,10-六氢-[1,4]二噁英并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-2-甲腈(120mg，0.231mmol)溶于3ml DMSO中，于0℃加入碳酸钾(3.18mg，0.0230mg)，双氧水(1mL，30％)，于室温搅拌1小时。加15mL饱和亚硫酸钠溶液淬灭，EA萃取(10mLx3)，饱和食盐水洗涤(10mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得浅黄色固体状标题化合物7.0mg，收率：5.64％。Add (8S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4c]pyridin-6-yl)- 10-Methyl-9-oxo-2,3,7,8,9,10-hexahydro-[1,4]dioxino[2',3':4,5]benzo[1, 2-b][1,4]oxazepine-2-carbonitrile (120mg, 0.231mmol) dissolved in 3ml DMSO, add potassium carbonate (3.18mg, 0.0230mg), hydrogen peroxide (1mL, 30%) at 0℃ ), stirred at room temperature for 1 hour. Add 15mL saturated sodium sulfite solution to quench, EA extraction (10mLx3), saturated brine washing (10mLx1), anhydrous sodium sulfate drying, filtration, filtrate concentrated under reduced pressure, the residue was separated by high pressure preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), to obtain 7.0 mg of the title compound as a pale yellow solid, yield: 5.64%.

LC-MS：m/z 538.14[M+H] ⁺。 LC-MS: m/z 538.14 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ:7.62-7.49(m,2H),7.42-7.25(m,3H),7.24-7.16(m,2H),7.12(s,1H),6.85(s,1H)，5.62-5.51(m,1H),5.43(s,2H)，4.89-4.82(m,1H),4.79-4.69(m,1H),4.40-4.24(m,3H),4.08-3.97(m,1H),3.68-3.56(m,1H),3.23(s,3H),2.90-2.75(m,1H),2.72-2.62(m,1H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.62-7.49 (m, 2H), 7.42-7.25 (m, 3H), 7.24-7.16 (m, 2H), 7.12 (s, 1H), 6.85 (s, 1H) ), 5.62-5.51(m,1H), 5.43(s,2H), 4.89-4.82(m,1H), 4.79-4.69(m,1H), 4.40-4.24(m,3H),4.08-3.97(m , 1H), 3.68-3.56 (m, 1H), 3.23 (s, 3H), 2.90-2.75 (m, 1H), 2.72-2.62 (m, 1H).

实施例14：(S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-4-异丙基-10-甲基-4,7,8,10-四氢-2H-[1,4]噁嗪并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-3,9-二酮(14)的制备Example 14: (S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-4-isopropyl-10-methyl-4,7,8,10-tetrahydro-2H-[1,4]oxazino[2',3':4,5]benzo Preparation of [1,2-b][1,4]oxazepine-3,9-dione (14)

步骤1：6-甲氧基-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(14a)的制备Step 1: Preparation of 6-methoxy-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (14a)

于室温，将6-甲氧基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮溶于9ml冰醋酸中。于0℃，加入浓硝酸(3mL)，于0℃搅拌1小时。反应液倒入冰水中，过滤，水洗滤饼(5mLx3)，干燥，得黄色固体的标题化合物2.99g，收率：97.7％。At room temperature, 6-methoxy-2H-benzo[b][1,4]oxazine-3-(4H)-one was dissolved in 9ml of glacial acetic acid. At 0°C, concentrated nitric acid (3mL) was added and stirred at 0°C for 1 hour. The reaction solution was poured into ice water, filtered, and the filter cake (5 mL×3) was washed with water and dried to obtain 2.99 g of the title compound as a yellow solid, yield: 97.7%.

LC-MS：m/z 225.04[M+H] ⁺。 LC-MS: m/z 225.04 [M+H] ⁺ .

步骤2：4-异丙基-6-甲氧基-7-硝基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮(14b)的制备Step 2: Preparation of 4-isopropyl-6-methoxy-7-nitro-2H-benzo[b][1,4]oxazine-3-(4H)-one (14b)

于室温，将6-甲氧基-7-硝基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮(2.40g，10.7mmol)溶于35mL DMF。于0℃，加入NaH(1.28g，32.0mmol)。于室温搅拌30分钟。于0℃，加入碘代异丙烷(5.46g，32.1mmol)。封管80℃搅拌2小时。加入30mL饱和氯化铵溶液淬灭，EA萃取(30mLx3)，饱和食盐水洗涤(30mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-3:1)，得浅红棕色固体的标题化合物710mg，收率：24.9％。At room temperature, 6-methoxy-7-nitro-2H-benzo[b][1,4]oxazine-3-(4H)-one (2.40g, 10.7mmol) was dissolved in 35mL DMF. At 0°C, NaH (1.28 g, 32.0 mmol) was added. Stir at room temperature for 30 minutes. At 0°C, iodoisopropane (5.46 g, 32.1 mmol) was added. The tube was sealed and stirred at 80°C for 2 hours. It was quenched by adding 30mL saturated ammonium chloride solution, extracted with EA (30mLx3), washed with saturated brine (30mLx1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile Phase: PE/EA=100:1-3:1) to obtain 710 mg of the title compound as a light reddish brown solid, yield: 24.9%.

LC-MS：m/z 267.09[M+H] ⁺。 LC-MS: m/z 267.09 [M+H] ⁺ .

步骤3：6-羟基-4-异丙基-7-硝基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮(14c)的制备Step 3: Preparation of 6-hydroxy-4-isopropyl-7-nitro-2H-benzo[b][1,4]oxazine-3-(4H)-one (14c)

于室温，将4-异丙基-6-甲氧基-7-硝基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮(300mg，1.13mmol)溶于5ml二氯甲烷中。氮气氛下，于0℃，加入1mol/L的BBr ₃溶液(2.26mL)。于室温搅拌1小时。于0℃加入甲醇淬灭，加入10mL水，DCM萃取(10mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得浅黄色固体的标题化合物310mg(粗品)。 At room temperature, dissolve 4-isopropyl-6-methoxy-7-nitro-2H-benzo[b][1,4]oxazine-3-(4H)-one (300mg, 1.13mmol) In 5ml dichloromethane. Under a nitrogen atmosphere, at 0°C, a 1 mol/L BBr ₃ solution (2.26 mL) was added. Stir at room temperature for 1 hour. It was quenched by adding methanol at 0°C, adding 10mL water, extracting with DCM (10mLx3), washing with saturated brine (20mLx1), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 310mg (crude) of the title compound as a light yellow solid .

LC-MS：m/z 253.1[M+H] ⁺。 LC-MS: m/z 253.1 [M+H] ⁺ .

其他步骤与实施例1的制备方法相同，除了用6-羟基-4-异丙基-7-硝基-2H-苯并[b][1,4]噁嗪-3-(4H)-酮(14c)代替步骤2中的3-硝基-5,6,7,8-四氢萘-2-醇(1a)，制得标题化合物14。The other steps are the same as the preparation method of Example 1, except that 6-hydroxy-4-isopropyl-7-nitro-2H-benzo[b][1,4]oxazine-3-(4H)-one is used (14c) Instead of 3-nitro-5,6,7,8-tetrahydronaphthalen-2-ol (1a) in step 2, the title compound 14 was prepared.

LC-MS：m/z 550.18[M+H] ⁺。 LC-MS: m/z 550.18 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.37-7.29(m,3H),7.28-7.24(m,2H),6.97(s,1H),6.89(s,1H),6.02-5.91(m,1H),5.43(s,2H),4.75-4.59(m,2H),4.58-4.53(m,2H),4.47-4.39(m,1H),4.32-4.23(m,1H),3.62-3.52(m,1H),3.35(s,3H),3.14-3.04(m,1H),2.74-2.64(m,1H),1.70-1.58(m,6H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 7.37-7.29 (m, 3H), 7.28-7.24 (m, 2H), 6.97 (s, 1H), 6.89 (s, 1H), 6.02-5.91 (m, 1H) ), 5.43 (s, 2H), 4.75-4.59 (m, 2H), 4.58-4.53 (m, 2H), 4.47-4.39 (m, 1H), 4.32-4.23 (m, 1H), 3.62-3.52 (m , 1H), 3.35 (s, 3H), 3.14-3.04 (m, 1H), 2.74-2.64 (m, 1H), 1.70-1.58 (m, 6H).

实施例15：(S)-8-(环丙烷羰基)-3-(2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)酮(15)的制备Example 15: (S)-8-(cyclopropanecarbonyl)-3-(2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ] Preparation of isoquinolin-4(5H)one (15)

步骤1：1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(15a)的制备Step 1: Preparation of 1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (15a)

将1H-吡唑-3-羧酸乙酯(2.00g，14.3mmol)溶于25mL四氢呋喃中，于0℃加入NaH(686mg，17.1mmol)，搅拌20分钟，加入1-(溴甲基)-2-氟苯(2.97g，15.7mmol)，于室温流搅拌过夜。饱和氯化铵溶液淬灭，加入30mL水与15mL乙酸乙酯，有机层用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-15:1)，得到浅黄色油状的标题化合物2.78g，收率78.5％。Dissolve 1H-pyrazole-3-carboxylic acid ethyl ester (2.00g, 14.3mmol) in 25mL tetrahydrofuran, add NaH (686mg, 17.1mmol) at 0°C, stir for 20 minutes, add 1-(bromomethyl)- 2-Fluorobenzene (2.97g, 15.7mmol), stirred at room temperature overnight. The saturated ammonium chloride solution was quenched, 30 mL of water and 15 mL of ethyl acetate were added, the organic layer was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-15:1) to obtain 2.78 g of the title compound as a pale yellow oil with a yield of 78.5%.

LC-MS：m/z 249.1[M+H] ⁺。 LC-MS: m/z 249.1 [M+H] ⁺ .

步骤2：4-溴-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(15b)的制备Step 2: Preparation of 4-bromo-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (15b)

于室温，将1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(2.68g，10.8mmol)溶于DMF35mL中，滴入NBS(2.12g，11.9mmol)，于室温搅拌过夜。将反应液缓慢倾入水中，加入30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得红棕色固体状的标题化合物4.25g(粗品)。At room temperature, 1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (2.68g, 10.8mmol) was dissolved in 35mL of DMF, and NBS (2.12g, 11.9mmol) was added dropwise at room temperature. Stir overnight. The reaction solution was slowly poured into water, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4.25 g (crude) of the title compound as a reddish brown solid.

LC-MS：m/z 327.0[M+H] ⁺。 LC-MS: m/z 327.0 [M+H] ⁺ .

步骤3：(E)-4-(2-乙氧基乙烯基)-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(15c)的制备Step 3: Preparation of (E)-4-(2-ethoxyvinyl)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (15c)

于室温，将4-溴-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(4.25g，10.8mmol)和(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷溶于56mL DME和7mL水中，加入碳酸铯(8.80g，27.0mmol)和Pd(dppf) ₂Cl ₂(789mg，1.08mmol)，于90℃搅拌过夜。向反应液加入60mL水与40mL乙酸乙酯，有机相用饱和食盐水50mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-3:1)，得黄色油状标题化合物3.08g，收率74.6％。 At room temperature, 4-bromo-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (4.25g, 10.8mmol) and (E)-2-(2-ethoxyethylene Base)-4,4,5,5-tetramethyl-1,3,2-dioxaborane dissolved in 56mL DME and 7mL water, add cesium carbonate (8.80g, 27.0mmol) and Pd(dppf) ₂ Cl ₂ (789mg, 1.08mmol), stirred at 90°C overnight. 60 mL of water and 40 mL of ethyl acetate were added to the reaction solution, the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE /EA=100:1-3:1), 3.08 g of the title compound was obtained as a yellow oil, with a yield of 74.6%.

LC-MS：m/z 319.1[M+H] ⁺。 LC-MS: m/z 319.1 [M+H] ⁺ .

步骤4：1-(2-氟苄基)-4-(2-氧乙基)-1H-吡唑-3-羧酸乙酯(15d)的制备Step 4: Preparation of 1-(2-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (15d)

于室温，将(E)-4-(2-乙氧基乙烯基)-1-(2-氟苄基)-1H-吡唑-3-羧酸乙酯(500mg，1.57mmol)溶于10mL THF中，加入5mL 6N盐酸。于室温搅拌2.5小时。将反应液倾入至20mL饱和碳酸氢钠溶液中，加入30mL乙酸乙酯，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得无色油状标题化合物270mg，收率59.2％。At room temperature, dissolve (E)-4-(2-ethoxyvinyl)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (500mg, 1.57mmol) in 10mL Add 5mL 6N hydrochloric acid to THF. Stir at room temperature for 2.5 hours. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 270 mg of the title compound as a colorless oil. The yield was 59.2%.

LC-MS：m/z 291.1[M+H] ⁺。 LC-MS: m/z 291.1 [M+H] ⁺ .

步骤5：(S)-1-(2-氟苄基)-4-(2-((5-甲基-4-氧代-8-(2,2,2-三氟乙酰基)-2,3,4,5,7，8,9,10-八氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-3-基)氨基)乙基)-1H-吡唑-3-羧酸甲酯(15e)制备Step 5: (S)-1-(2-fluorobenzyl)-4-(2-((5-methyl-4-oxo-8-(2,2,2-trifluoroacetyl)-2 ,3,4,5,7,8,9,10-Octahydro-[1,4]oxazepine[2,3-g]isoquinolin-3-yl)amino)ethyl)-1H -Pyrazole-3-carboxylic acid methyl ester (15e) preparation

于室温，将(S)-3-氨基-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(5j)(140mg，0.271mmol)、1-(2-氟苄基)-4-(2-氧乙基)-1H-吡唑-3-羧酸乙酯(94.3mg，0.325mmol)溶于3mL甲醇，向反应液中加入AcOH(0.3ml)和2-甲基吡啶硼烷(40.6mg，0.379mmol)，室温搅拌2小时。加入饱和NaHCO ₃溶液，用EA萃取(15mL x 3)，饱和食盐水洗涤(20mL x1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得淡黄色固体状标题化合物80.0mg，收率32.5％。 At room temperature, add (S)-3-amino-5-methyl-8-(2,2,2-trifluoroacetyl)-2,3,7,8,9,10-hexahydro-[1, 4] Oxazepine [2,3-g]isoquinolin-4(5H)-one(5j) (140mg, 0.271mmol), 1-(2-fluorobenzyl)-4-(2-oxy Ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (94.3mg, 0.325mmol) was dissolved in 3mL methanol, AcOH (0.3ml) and 2-picoline borane (40.6mg, 0.379 mmol), stirring at room temperature for 2 hours. Add saturated NaHCO ₃ solution, extract with EA (15mL x 3), wash with saturated brine (20mL x 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 80.0 mg of the title compound as a pale yellow solid, yield 32.5 %.

LC-MS：m/z 604.21[M+H] ⁺。 LC-MS: m/z 604.21 [M+H] ⁺ .

步骤6：(S)-3-(2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(15f)的制备Step 6: (S)-3-(2-(2-Fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-8-(2,2,2-trifluoroacetyl)-2,3,7,8,9,10-hexahydro-[1,4]oxazepine Preparation of [2,3-g]isoquinoline-4(5H)-one (15f)

于室温，将化合物15e(80.0mg,0.130mmol)溶于4ml氯仿中，氮气氛下，于0℃向反应液中加入Al(CH ₃) ₃(2M)(0.19ml，0.389mmol)。于50℃搅拌2小时。加水淬灭，用硅藻土过滤，加EA洗涤滤饼。滤液加水稀释，EA萃取(20mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用薄层色谱法分离纯化(PE/EA＝4:1)，得淡黄色固体状标题化合物100.0mg(粗品)。 At room temperature, compound 15e (80.0 mg, 0.130 mmol) was dissolved in 4 ml of chloroform, and Al(CH ₃ ) ₃ (2M) (0.19 ml, 0.389 mmol) was added to the reaction solution at 0° C. under a nitrogen atmosphere. Stir at 50°C for 2 hours. Add water to quench, filter with diatomaceous earth, and add EA to wash the filter cake. The filtrate was diluted with water, extracted with EA (20mLx3), washed with saturated brine (20mLx1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by thin layer chromatography (PE/EA=4:1), 100.0 mg (crude) of the title compound was obtained as a pale yellow solid.

LC-MS：m/z 572.18[M+H] ⁺。 LC-MS: m/z 572.18 [M+H] ⁺ .

步骤7：(S)-3-(2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(15g)的制备Step 7: (S)-3-(2-(2-Fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4(5H) -Preparation of ketone (15g)

于室温，将化合物15f(100mg,0.175mmol)溶于MeOH/H ₂O(3ml/0.7ml)中，向反应液中加入碳酸钾(36.2mg,0.262mmol)，于室温搅拌过夜。加水稀释，DCM萃取(20mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得浅黄色固体状标题化合物90.0mg(粗品)。 At room temperature, compound 15f (100 mg, 0.175 mmol) was dissolved in MeOH/H ₂ O (3 ml/0.7 ml), potassium carbonate (36.2 mg, 0.262 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Dilute with water, extract with DCM (20 mL×3), wash with saturated brine (20 mL×1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 90.0 mg (crude) of the title compound as a pale yellow solid.

LC-MS：m/z 476.20[M+H] ⁺。 LC-MS: m/z 476.20 [M+H] ⁺ .

步骤8：(S)-8-(环丙烷羰基)-3-(2-(2-氟苄基)-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)酮(15)的制备Step 8: (S)-8-(cyclopropanecarbonyl)-3-(2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[ 3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g] Preparation of isoquinolin-4(5H)one (15)

于室温，将化合物15g(80.0mg，0.168mmol)溶于DCM(2ml)中，向反应液中加入DIEA(43.4mg，0.336mmol)。于0℃，加入环丙烷碳酰氯(35.3mg，0.336mmol)。然后于室温搅拌过夜。加10ml饱和碳酸氢钠溶液，DCM萃取(15mLx3)，饱和食盐水洗涤(20mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得类白色固体状标题化合物10.0mg，收率10.9％。At room temperature, compound 15g (80.0mg, 0.168mmol) was dissolved in DCM (2ml), and DIEA (43.4mg, 0.336mmol) was added to the reaction solution. At 0°C, cyclopropanecarbonyl chloride (35.3 mg, 0.336 mmol) was added. Then it was stirred overnight at room temperature. Add 10 ml of saturated sodium bicarbonate solution, extract with DCM (15 mL×3), wash with saturated brine (20 mL×1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min), and the title compound was obtained as an off-white solid 10.0mg, yield 10.9%.

LC-MS：m/z 544.23[M+H] ⁺。 LC-MS: m/z 544.23 [M+H] ⁺ .

¹HNMR(400MHz,DMSO-d ₆)δ:7.74(s,1H),7.43-7.32(m,2H),7.26-7.14(m,3H),7.07(s,1H),5.62-5.52(m,1H),5.42(s,2H),4.93(s,1H),4.78(t,1H),4.64(d,1H),4.26(t,1H),4.08-3.86(m,3H),3.78-3.49(m,3H),3.47-3.29(m,5H),1.31-1.19(m,3H),0.78-0.75(m,2H)。 ¹ HNMR(400MHz,DMSO-d ₆ )δ:7.74(s,1H),7.43-7.32(m,2H),7.26-7.14(m,3H),7.07(s,1H),5.62-5.52(m, 1H), 5.42 (s, 2H), 4.93 (s, 1H), 4.78 (t, 1H), 4.64 (d, 1H), 4.26 (t, 1H), 4.08-3.86 (m, 3H), 3.78-3.49 (m, 3H), 3.47-3.29 (m, 5H), 1.31-1.19 (m, 3H), 0.78-0.75 (m, 2H).

实施例16：(S)-8-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-10-甲基-4-(甲基-d3)-4,7,8,10-四氢-2H-[1,4]噁嗪并[2',3':4,5]苯并[1,2-b][1,4]氧氮杂卓-3,9-二酮(16)的制备Example 16: (S)-8-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-10-methyl-4-(methyl-d3)-4,7,8,10-tetrahydro-2H-[1,4]oxazino[2',3':4,5 ]Benzo[1,2-b][1,4]oxazepine-3,9-dione (16)

步骤1：6-甲氧基-4-(甲基-d3)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(16a)的制备Step 1: Preparation of 6-methoxy-4-(methyl-d3)-2H-benzo[b][1,4]oxazine-3(4H)-one (16a)

于室温，将6-甲氧基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(1.91g，10.7mmol)溶于30mL DMF。于0℃，加入NaH(1.02g，25.5mmol)。于室温搅拌30分钟。于0℃，加入氘代碘甲烷(2.47g，17.0mmol)。封管80℃搅拌2小时。加入30mL饱和氯化铵溶液淬灭，EA萃取(30mLx3)，饱和食盐水洗涤(30mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100:1-3:1),得类白色固体的标题化合物1.33g，收率：63.6％。At room temperature, dissolve 6-methoxy-2H-benzo[b][1,4]oxazine-3(4H)-one (1.91g, 10.7mmol) in 30mL DMF. At 0°C, NaH (1.02 g, 25.5 mmol) was added. Stir at room temperature for 30 minutes. At 0°C, deuterated methyl iodide (2.47 g, 17.0 mmol) was added. The tube was sealed and stirred at 80°C for 2 hours. It was quenched by adding 30mL saturated ammonium chloride solution, extracted with EA (30mLx3), washed with saturated brine (30mLx1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile Phase: PE/EA=100:1-3:1), to obtain 1.33 g of the title compound as an off-white solid, yield: 63.6%.

LC-MS：m/z 197.09[M+H] ⁺。 LC-MS: m/z 197.09 [M+H] ⁺ .

步骤2：6-甲氧基-4-(甲基-d3)-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(16b)的制备Step 2: Preparation of 6-methoxy-4-(methyl-d3)-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (16b)

于室温，将6-甲氧基-4-(甲基-d3)-2H-苯并[b][1,4]噁嗪-3(4H)-酮溶于12ml冰醋酸中。于0℃，加入浓硝酸(3mL)。于0℃搅拌1小时。反应液倒入冰水中，过滤，水洗滤饼(5mLx3)，干燥，得黄色固体的标题化合物1.58g(粗品)。At room temperature, 6-methoxy-4-(methyl-d3)-2H-benzo[b][1,4]oxazine-3(4H)-one was dissolved in 12ml of glacial acetic acid. At 0°C, concentrated nitric acid (3 mL) was added. Stir at 0°C for 1 hour. The reaction solution was poured into ice water, filtered, and the filter cake (5 mL×3) was washed with water and dried to obtain 1.58 g (crude) of the title compound as a yellow solid.

LC-MS：m/z 242.08[M+H] ⁺。 LC-MS: m/z 242.08 [M+H] ⁺ .

步骤3：6-羟基-4-(甲基-d3)-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(16c)的制备Step 3: Preparation of 6-hydroxy-4-(methyl-d3)-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (16c)

于室温，将6-甲氧基-4-(甲基-d3)-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(1.35g，5.60mmol)溶于20ml二氯甲烷中。氮气氛下，于0℃，加入1mol/L的BBr ₃溶液(11.2mL)。于室温搅拌1小时。于0℃加入甲醇淬灭，加入50mL水，DCM萃取(50mLx3)，饱和食盐水洗涤(100mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体的标题化合物1.34g(粗品)。 At room temperature, 6-methoxy-4-(methyl-d3)-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (1.35g, 5.60 mmol) was dissolved in 20 ml of dichloromethane. Under a nitrogen atmosphere, at 0°C, a 1 mol/L BBr ₃ solution (11.2 mL) was added. Stir at room temperature for 1 hour. It was quenched by adding methanol at 0°C, 50mL of water was added, DCM extraction (50mLx3), saturated brine washing (100mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.34g (crude) of the title compound as a yellow solid .

LC-MS：m/z 228.06[M+H] ⁺。 LC-MS: m/z 228.06 [M+H] ⁺ .

与实施例1的制备方法相同，除了用6-羟基-4-(甲基-d3)-7-硝基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(16c)代替步骤2中的3-硝基-5,6,7,8-四氢萘-2-醇(1a)，制得标题化合物16。The preparation method is the same as in Example 1, except that 6-hydroxy-4-(methyl-d3)-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one is used (16c) Instead of 3-nitro-5,6,7,8-tetrahydronaphthalen-2-ol (1a) in step 2, the title compound 16 was prepared.

LC-MS：m/z 525.17[M+H] ⁺。 LC-MS: m/z 525.17 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d6)δ:7.38-7.28(m,3H),7.23-7.16(m,3H),7.09(s,1H),5.63-5.54(m,1H),5.43(br,2H),4.84-4.76(m,1H),4.74-4.64(m,2H),4.38-4.29 (m,1H),4.08-3.97(m,1H),3.68-3.58(m,1H),3.26(s,3H),2.87-2.75(m,1H),2.72-2.64(m,1H)。 ¹ H NMR (400MHz, DMSO-d6) δ: 7.38-7.28 (m, 3H), 7.23-7.16 (m, 3H), 7.09 (s, 1H), 5.63-5.54 (m, 1H), 5.43 (br, 2H), 4.84-4.76 (m, 1H), 4.74-4.64 (m, 2H), 4.38-4.29 (m, 1H), 4.08-3.97 (m, 1H), 3.68-3.58 (m, 1H), 3.26 ( s, 3H), 2.87-2.75 (m, 1H), 2.72-2.64 (m, 1H).

实施例17：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(2,2,2-三氟乙酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(17)的制备Example 17: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-9-(2,2,2-trifluoroacetyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine Preparation of [3,2-f]isoquinoline-2(1H)-one (17)

步骤1：2,2,2-三氟-1-(6-甲氧基-5-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(17a)的制备Step 1: 2,2,2-Trifluoro-1-(6-methoxy-5-nitro-3,4-dihydroisoquinolin-2-(1H)-yl)ethan-1-one ( 17a) Preparation

将2,2,2-三氟-1-(6-甲氧基-3,4-二氢异喹啉-2-(1H-基)乙-1-酮(5a)(6.50g，25.1mmol)溶于MeCN(90mL)中，加入NaNO ₃(2.14g，25.1mmol)，氮气氛下，于0℃，向反应液中滴加TFAA(8.44g，40.2mmol)，将反应液升至室温搅拌过夜。将反应液加水淬灭，EA(120mLx2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得淡黄色固体状标题化合物3g，收率39.3％。 2,2,2-Trifluoro-1-(6-methoxy-3,4-dihydroisoquinoline-2-(1H-yl)ethan-1-one (5a) (6.50g, 25.1mmol ) Was dissolved in MeCN (90mL), NaNO ₃ (2.14g, 25.1mmol) was added, and TFAA (8.44g, 40.2mmol) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and the reaction solution was raised to room temperature and stirred Overnight. The reaction solution was quenched with water, extracted with EA (120mLx2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=3:1 ) To obtain 3 g of the title compound as a pale yellow solid, with a yield of 39.3%.

LC-MS：m/z 305.07[M+H] ⁺。 LC-MS: m/z 305.07 [M+H] ⁺ .

其他步骤与实施例5的制备方法相同，除了用2,2,2-三氟-1-(6-甲氧基-5-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(17a)代替2,2,2-三氟-1-(6-甲氧基-7-硝基-3,4-二氢异喹啉-2-(1H)-基)乙-1-酮(5b)，制得标题化合物17。The other steps are the same as the preparation method of Example 5, except that 2,2,2-trifluoro-1-(6-methoxy-5-nitro-3,4-dihydroisoquinoline-2-(1H )-Yl)ethan-1-one (17a) instead of 2,2,2-trifluoro-1-(6-methoxy-7-nitro-3,4-dihydroisoquinoline-2-(1H )-Yl)ethan-1-one (5b) to obtain the title compound 17.

LC-MS：m/z 588.15[M+H] ⁺。 LC-MS: m/z 588.15 [M+H] ⁺ .

¹HNMR(400MHz,DMSO-d ₆)δ7.37-7.28(m,4H),7.20-7.17(m,3H),5.55-5.50(m,1H),5.43(br,2H),5.04-4.58(m,3H),4.21(t,1H),4.12-4.06(m,2H),3.65-3.50(m,2H),3.13(br,3H),3.03-2.94(m,1H),2.81-2.75(m,2H),2.71-2.66(m,1H)。 ¹ HNMR (400MHz, DMSO-d ₆ ) δ 7.37-7.28 (m, 4H), 7.20-7.17 (m, 3H), 5.55-5.50 (m, 1H), 5.43 (br, 2H), 5.04-4.58 ( m,3H),4.21(t,1H),4.12-4.06(m,2H),3.65-3.50(m,2H),3.13(br,3H),3.03-2.94(m,1H),2.81-2.75( m, 2H), 2.71-2.66 (m, 1H).

实施例18：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(18)的制备Example 18: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]isoquinoline-2(1H) -Preparation of ketone (18)

与实施例6的制备方法相同，除了用(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(2,2,2-三氟乙酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(17)代替(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-8-(2,2,2-三氟乙酰基)-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4-(5H)-酮(5)，制得标题化合物18。The preparation method is the same as in Example 6, except that (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-1-methyl-9-(2,2,2-trifluoroacetyl)-3,4,8,9,10,11-hexahydro-[1, 4] Oxazepine [3,2-f]isoquinoline-2(1H)-one (17) instead of (S)-3-(2-benzyl-3-chloro-7-oxo-2 ,4,5,7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(2,2,2-trifluoroacetyl)-2 ,3,7,8,9,10-Hexahydro-[1,4]oxazepine[2,3-g]isoquinoline-4-(5H)-one(5) to obtain the title compound 18.

LC-MS：m/z 492.17[M+H] ⁺。 LC-MS: m/z 492.17 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ8.30(br,1H),7.37-7.28(m,3H),7.19-7.17(m,2H),7.06(br,2H),5.51-5.46(m,1H),5.43(br,2H),4.73-4.68(m,1H),4.19-4.15(m,1H),4.11-4.05(m,1H),3.95(br,2H),3.65-3.58(m,2H),3.20-3.16(m,1H),3.11(br,3H),2.84-2.75(m,3H),2.71-2.61(m,1H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.30 (br, 1H), 7.37-7.28 (m, 3H), 7.19-7.17 (m, 2H), 7.06 (br, 2H), 5.51-5.46 (m ,1H),5.43(br,2H),4.73-4.68(m,1H),4.19-4.15(m,1H),4.11-4.05(m,1H),3.95(br,2H),3.65-3.58(m ,2H), 3.20-3.16(m,1H), 3.11(br,3H), 2.84-2.75(m,3H), 2.71-2.61(m,1H).

实施例19：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-9-(环丙基磺酰基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(19)的制备Example 19: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-9-(cyclopropylsulfonyl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2- f) Preparation of isoquinoline-2(1H)-one (19)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6基)-9-(环丙基磺酰基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]噁嗪并[3,2-f]异喹啉-2(1H)-酮(19)的制备。Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 Yl)-9-(cyclopropylsulfonyl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazino[3,2-f]isoquine Preparation of lin-2(1H)-one (19).

于室温，将(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(30.0mg,0.0610mmol)溶于DCM(2ml)中，向反应液中加入DIEA(15.7mg,0.122mmol)。于0℃，加入环丙烷磺酰氯(10.3mg,0.0729mmol)。室温搅拌过夜。加5ml水，DCM萃取(5mLx3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm×250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得白色固体状标题化合物10.0mg，收率27.8％。At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]isoquinoline-2(1H) -Ketone (30.0mg, 0.0610mmol) was dissolved in DCM (2ml), DIEA (15.7mg, 0.122mmol) was added to the reaction solution. At 0°C, cyclopropanesulfonyl chloride (10.3 mg, 0.0729 mmol) was added. Stir at room temperature overnight. Add 5ml of water, extract with DCM (5mLx3), wash with saturated brine (10mL x 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by high-pressure preparation liquid phase (column model: Daisogei 30mm× 250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min), to obtain 10.0 mg of the title compound as a white solid, with a yield of 27.8%.

LC-MS：m/z 596.17[M+H] ⁺。 LC-MS: m/z 596.17 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.38-7.28(m,3H),7.28-7.17(m,2H),7.11-7.00(m,2H),5.90-5.80(m,1H),5.41(s,2H),4.80-4.75(m,1H),4.62-4.51(m,1H),4.49-4.20(m,4H),4.10-4.00(m,1H),3.68-3.45(m,2H),3.21(s,3H),3.19-2.91(m,4H),2.88-2.61(m,3H),2.41-2.31(m,1H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 7.38-7.28 (m, 3H), 7.28-7.17 (m, 2H), 7.11-7.00 (m, 2H), 5.90-5.80 (m, 1H), 5.41 (s , 2H), 4.80-4.75 (m, 1H), 4.62-4.51 (m, 1H), 4.49-4.20 (m, 4H), 4.10-4.00 (m, 1H), 3.68-3.45 (m, 2H), 3.21 (s, 3H), 3.19-2.91 (m, 4H), 2.88-2.61 (m, 3H), 2.41-2.31 (m, 1H).

实施例20：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(吡咯烷-1-基磺酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(20)的制备Example 20: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-9-(pyrrolidin-1-ylsulfonyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3 ,2-f) Preparation of isoquinoline-2(1H)-one (20)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(吡咯烷-1-基磺酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(20)的制备Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-1-methyl-9-(pyrrolidin-1-ylsulfonyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3, Preparation of 2-f]isoquinoline-2(1H)-one (20)

于室温，将化合物18(30.0mg,0.0610mmol)溶于DCM(2ml)中，向反应液中加入DIEA(15.7mg,0.122mmol)。于0℃，加入吡咯烷-1-磺酰氯(12.4mg,0.0729mmol)。室温搅拌过夜。加5ml水，DCM萃取(5mLx3)，饱和食盐水洗涤(10mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm×250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得白色固体状标题化合物8.00mg，收率21.0％。At room temperature, compound 18 (30.0 mg, 0.0610 mmol) was dissolved in DCM (2 ml), and DIEA (15.7 mg, 0.122 mmol) was added to the reaction solution. At 0°C, pyrrolidine-1-sulfonyl chloride (12.4 mg, 0.0729 mmol) was added. Stir at room temperature overnight. Add 5ml of water, extract with DCM (5mLx3), wash with saturated brine (10mLx1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by high-pressure preparative liquid phase separation and purification (column model: Daisogei 30mm×250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min) to obtain the title compound as a white solid, 8.00mg , The yield is 21.0%.

LC-MS：m/z 625.19[M+H] ⁺。 LC-MS: m/z 625.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.38-7.29(m,3H),7.28-7.24(m,2H),7.10-7.02(m, 2H),5.92-5.84(m,1H),5.41(s,2H),4.72-4.54(m,2H),4.40-4.27(m,3H),4.04-3.95(m,1H),3.62-3.52(m,1H),3.45-3.35(m,4H),3.23(s,3H),3.19-2.94(m,3H),2.82-2.63(m,2H),2.01-1.91(m,4H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 7.38-7.29 (m, 3H), 7.28-7.24 (m, 2H), 7.10-7.02 (m, 2H), 5.92-5.84 (m, 1H), 5.41 (s ,2H),4.72-4.54(m,2H),4.40-4.27(m,3H),4.04-3.95(m,1H),3.62-3.52(m,1H),3.45-3.35(m,4H),3.23 (s, 3H), 3.19-2.94 (m, 3H), 2.82-2.63 (m, 2H), 2.01-1.91 (m, 4H).

实施例21：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-N,N,1-三甲基-2-氧代-1,2,3,4,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-9(8H)-羧酰胺(21)的制备Example 21: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-N,N,1-trimethyl-2-oxo-1,2,3,4,10,11-hexahydro-[1,4]oxazepine[3,2- f) Preparation of isoquinoline-9(8H)-carboxamide (21)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-N,N,1-三甲基-2-氧代-1,2,3,4,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-9(8H)-羧酰胺(21)的制备Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-N,N,1-trimethyl-2-oxo-1,2,3,4,10,11-hexahydro-[1,4]oxazepine[3,2-f ] Preparation of isoquinoline-9(8H)-carboxamide (21)

于室温，将化合物18(30.0mg，0.0610mmol)溶于DCM(2ml)中，向反应液中加入DIEA(15.7mg，0.122mmol)。于0℃，加入二甲基氨基甲酰氯(7.90mg，0.0731mmol)。室温搅拌过夜。加5ml水，DCM萃取(5mLx3)，饱和食盐水洗涤(10mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得白色固体状标题化合物8.00mg，收率23.5％。At room temperature, compound 18 (30.0 mg, 0.0610 mmol) was dissolved in DCM (2 ml), and DIEA (15.7 mg, 0.122 mmol) was added to the reaction solution. At 0°C, dimethylcarbamoyl chloride (7.90 mg, 0.0731 mmol) was added. Stir at room temperature overnight. Add 5ml of water, extract with DCM (5mLx3), wash with saturated brine (10mLx1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by high-pressure preparation liquid phase separation and purification (column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min) to obtain the title compound as a white solid, 8.00mg , The yield is 23.5%.

LC-MS：m/z 563.21[M+H] ⁺。 LC-MS: m/z 563.21 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.39-7.28(m,3H),7.24-7.16(m,3H),7.14-7.10(m,1H),5.54-5.47(m,1H),5.43(s,2H),4.79-4.68(m,1H),4.54-4.30(m,2H),4.25-4.05(m,2H),3.84-3.73(m,1H),3.68-3.56(m,1H),3.13(s,3H),3.07-2.92(m,2H),2.1(s,3H),2.72-2.62(m,1H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.39-7.28 (m, 3H), 7.24-7.16 (m, 3H), 7.14-7.10 (m, 1H), 5.54-5.47 (m, 1H), 5.43 (s, 2H), 4.79-4.68 (m, 1H), 4.54-4.30 (m, 2H), 4.25-4.05 (m, 2H), 3.84-3.73 (m, 1H), 3.68-3.56 (m, 1H) , 3.13 (s, 3H), 3.07-2.92 (m, 2H), 2.1 (s, 3H), 2.72-2.62 (m, 1H).

实施例22：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(吗啉代磺酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(22)的制备Example 22: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-9-(morpholinosulfonyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2- f) Preparation of isoquinoline-2(1H)-one (22)

步骤1：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(吗啉代磺酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(22)的制备Step 1: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6 -Yl)-1-methyl-9-(morpholinosulfonyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f ] Preparation of isoquinolin-2(1H)-one (22)

于室温，将化合物18(30.0mg，0.0610mmol)溶于DCM(2ml)中，向反应液中加入DIEA(15.7mg，0.122mmol)。于0℃，加入吗啉-4-磺酰氯(13.6mg，0.0731mmol)，室温搅拌过夜。加5ml水，DCM萃取(5mLx3)，饱和食盐水洗涤(10mLx1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过高压制备液相分离纯化(色谱柱型号：Daisogei 30mm×250mm，C18，10um 100A，流动相：乙腈/水，梯度：10％-30％，30min)，得白色固体状标题化合物6.00mg，收率15.4％。At room temperature, compound 18 (30.0 mg, 0.0610 mmol) was dissolved in DCM (2 ml), and DIEA (15.7 mg, 0.122 mmol) was added to the reaction solution. At 0°C, morpholine-4-sulfonyl chloride (13.6 mg, 0.0731 mmol) was added, and the mixture was stirred at room temperature overnight. Add 5ml of water, extract with DCM (5mLx3), wash with saturated brine (10mLx1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by high-pressure preparative liquid phase separation and purification (column model: Daisogei 30mm×250mm, C18, 10um 100A, mobile phase: acetonitrile/water, gradient: 10%-30%, 30min) to obtain the title compound as a white solid 6.00mg , The yield was 15.4%.

LC-MS：m/z 641.19[M+H] ⁺。 LC-MS: m/z 641.19 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.38-7.29(m,3H),7.26-7.22(m,1H),7.20-7.14(m,3H),5.53-5.47(m,1H),5.43(s,2H),4.77-4.70(m,1H),4.59-4.53(m,1H),4.47-4.41(m,1H),4.26-4.16(m,2H),4.13-4.01(m,2H),3.88-3.81(m,1H)，3.67-3.58(m,5H)，3.20-3.15(m,4H)，3.13(s,3H),3.19-2.91(m,4H),2.73-2.63(m,3H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.38-7.29 (m, 3H), 7.26-7.22 (m, 1H), 7.20-7.14 (m, 3H), 5.53-5.47 (m, 1H), 5.43 (s,2H),4.77-4.70(m,1H),4.59-4.53(m,1H),4.47-4.41(m,1H),4.26-4.16(m,2H),4.13-4.01(m,2H) ,3.88-3.81(m,1H), 3.67-3.58(m,5H), 3.20-3.15(m,4H), 3.13(s,3H), 3.19-2.91(m,4H),2.73-2.63(m, 3H).

实施例23：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(甲磺酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(23)的制备Example 23: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-9-(methylsulfonyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f] Preparation of isoquinolin-2(1H)-one (23)

与实施例8的制备方法相同，除了用(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H- 吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(18)代替(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(6)，制得标题化合物23。The preparation method is the same as in Example 8, except that (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]iso Quinoline-2(1H)-one (18) instead of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ]Isoquinolin-4(5H)-one (6) to obtain the title compound 23.

LC-MS：m/z 570.15[M+H] ⁺。 LC-MS: m/z 570.15 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.33-7.31(m,3H),7.30-7.27(m,2H),7.11-7.06(m,2H),5.88(t,1H),5.43(br,2H),5.41(s,2H),4.78(d,1H),4.56(t,1H),4.24-4.31(m,3H),4.06-4.08(m,1H),3.58-3.54(m,1H),3.24(s,3H),3.06-3.02(m,3H),2.84(s,3H),2.80-2.71(m,1H),2.69-2.67(m,1H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ7.33-7.31 (m, 3H), 7.30-7.27 (m, 2H), 7.11-7.06 (m, 2H), 5.88 (t, 1H), 5.43 (br, 2H) ), 5.41 (s, 2H), 4.78 (d, 1H), 4.56 (t, 1H), 4.24-4.31 (m, 3H), 4.06-4.08 (m, 1H), 3.58-3.54 (m, 1H), 3.24 (s, 3H), 3.06-3.02 (m, 3H), 2.84 (s, 3H), 2.80-2.71 (m, 1H), 2.69-2.67 (m, 1H).

实施例24：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-9-(环丙烷甲酰基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(24)的制备Example 24: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-9-(cyclopropaneformyl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f ] Preparation of isoquinolin-2(1H)-one (24)

与实施例11的制备方法相同，除了用(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(18)代替(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(6)，制得标题化合物24。The preparation method is the same as in Example 11, except that (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]iso Quinoline-2(1H)-one (18) instead of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ] Isoquinolin-4(5H)-one (6) to obtain the title compound 24.

LC-MS：m/z 570.20[M+H] ⁺。 LC-MS: m/z 570.20 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ7.38-7.33(m,3H),7.32-7.30(m,1H),7.32-7.21(m,3H),5.56-5.43(m,1H),5.43(br,2H),4.97-4.91(m,1H),4.78-4.71(m,1H),4.42-4.37(m,1H),4.28-4.22(m,1H),4.24-4.18(m,1H),4.11-4.07(m,1H),3.65-362(m,1H),3.12(br,3H),2.84-2.76(m,1H),2.71-2.65(m,4H),2.11-2.08(m,1H),0.78-0.75(m,4H)。 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.38-7.33 (m, 3H), 7.32-7.30 (m, 1H), 7.32-7.21 (m, 3H), 5.56-5.43 (m, 1H), 5.43 (br, 2H), 4.97-4.91 (m, 1H), 4.78-4.71 (m, 1H), 4.42-4.37 (m, 1H), 4.28-4.22 (m, 1H), 4.24-4.18 (m, 1H) ,4.11-4.07(m,1H),3.65-362(m,1H),3.12(br,3H),2.84-2.76(m,1H),2.71-2.65(m,4H),2.11-2.08(m, 1H), 0.78-0.75 (m, 4H).

实施例25：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-2-氧代-1,2,3,4,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-9(8H)-腈(25)的制备Example 25: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-2-oxo-1,2,3,4,10,11-hexahydro-[1,4]oxazepine[3,2-f]isoquinoline Preparation of -9(8H)-nitrile (25)

与实施例10的制备方法相同，除了用(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(18)代替(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(6)，制得标题化合物25。The preparation method is the same as in Example 10, except that (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]iso Quinoline-2(1H)-one (18) instead of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ]Isoquinolin-4(5H)-one (6) to obtain the title compound 25.

LC-MS：m/z 517.17[M+H] ⁺。 LC-MS: m/z 517.17 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.32-7.23(m,5H),7.10-7.07(m,1H),7.02-6.99(m,1H),5.85(t,1H),5.39(s,2H),4.61-4.48(m,3H),4.34-4.25(m,2H),3.78-3.74(m,1H),3.58-3.55(m,1H),3.34-3.27(m,1H),3.03-2.99(m,3H),2.77-2.70(m,2H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 7.32-7.23 (m, 5H), 7.10-7.07 (m, 1H), 7.02-6.99 (m, 1H), 5.85 (t, 1H), 5.39 (s, 2H) ),4.61-4.48(m,3H),4.34-4.25(m,2H),3.78-3.74(m,1H),3.58-3.55(m,1H),3.34-3.27(m,1H),3.03-2.99 (m, 3H), 2.77-2.70 (m, 2H).

实施例26：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1,9-二甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(26)的制备Example 26: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1,9-dimethyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]isoquinoline-2 Preparation of (1H)-ketone (26)

与实施例7的制备方法相同，除了用(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(18)代替(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(6)，制得标题化合物26。The preparation method is the same as in Example 7, except that (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]iso Quinoline-2(1H)-one (18) instead of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ]Isoquinolin-4(5H)-one (6), to obtain the title compound 26.

LC-MS：m/z 506.17[M+H] ⁺。 LC-MS: m/z 506.17 [M+H] ⁺ .

1H NMR(400MHz,CDCl ₃)δ7.29-7.26(m,3H),7.23(s,2H),5.88-5.83(m,1H),5.39(s,2H),4.57-4.51(s,1H),4.30-4.25(m,1H),4.02(s,2H),3.56-3.51(m,3H),3.21(s,3H),3.10-3.00(m,2H),2.69-2.64(m,3H),2.64-2.58(m,3H)。 1H NMR (400MHz, CDCl ₃ ) δ 7.29-7.26 (m, 3H), 7.23 (s, 2H), 5.88-5.83 (m, 1H), 5.39 (s, 2H), 4.57-4.51 (s, 1H) , 4.30-4.25 (m, 1H), 4.02 (s, 2H), 3.56-3.51 (m, 3H), 3.21 (s, 3H), 3.10-3.00 (m, 2H), 2.69-2.64 (m, 3H) ,2.64-2.58(m,3H).

实施例27：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-N,N,1-三甲基-2-氧代-1,2,3,4,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-9(8H)-磺酰胺(27)的制备Example 27: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-N,N,1-trimethyl-2-oxo-1,2,3,4,10,11-hexahydro-[1,4]oxazepine[3,2- f) Preparation of isoquinoline-9(8H)-sulfonamide (27)

与实施例9的制备方法相同，除了用(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H- 吡唑并[3,4-c]吡啶-6-基)-1-甲基-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(18)代替(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-5-甲基-2,3,7,8,9,10-六氢-[1,4]氧氮杂卓并[2,3-g]异喹啉-4(5H)-酮(6)，制得标题化合物27。The preparation method is the same as in Example 9, except that (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3 ,4-c]pyridin-6-yl)-1-methyl-3,4,8,9,10,11-hexahydro-[1,4]oxazepine[3,2-f]iso Quinoline-2(1H)-one (18) instead of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridin-6-yl)-5-methyl-2,3,7,8,9,10-hexahydro-[1,4]oxazepine[2,3-g ]Isoquinolin-4(5H)-one (6), to obtain the title compound 27.

LC-MS：m/z 598.12[M+H] ⁺。 LC-MS: m/z 598.12 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d6)δ7.40-7.27(m,3H),7.26-7.08(m,4H),5.55-5.34(m,3H),4.72(t,J＝10.9Hz,1H),4.60-4.32(m,2H),4.18(t,J＝9.2Hz,1H),4.13-4.00(m,1H),3.89-3.73(m,1H),3.68-3.50(m,1H),3.24-3.05(m,5H),3.04-2.85(m,1H),2.78(s,7H),2.73-2.57(m,2H)。 ¹ H NMR(300MHz,DMSO-d6)δ7.40-7.27(m,3H),7.26-7.08(m,4H),5.55-5.34(m,3H),4.72(t,J=10.9Hz,1H) , 4.60-4.32 (m, 2H), 4.18 (t, J = 9.2 Hz, 1H), 4.13-4.00 (m, 1H), 3.89-3.73 (m, 1H), 3.68-3.50 (m, 1H), 3.24 -3.05 (m, 5H), 3.04-2.85 (m, 1H), 2.78 (s, 7H), 2.73-2.57 (m, 2H).

实施例28：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(四氢-2H-吡喃-4-甲酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(28)的制备Example 28: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-9-(tetrahydro-2H-pyran-4-formyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine Preparation of Zolo[3,2-f]isoquinoline-2(1H)-one (28)

与实施例23的制备方法相同，除了用四氢-2H-吡喃-4-甲酰氯代替甲磺酰氯，制得标题化合物28。The preparation method was the same as in Example 23, except that tetrahydro-2H-pyran-4-carboxylic acid chloride was used instead of methanesulfonyl chloride to obtain the title compound 28.

LC-MS：m/z 604.22[M+H] ⁺。 LC-MS: m/z 604.22 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ7.35-7.28(m,3H),7.25-7.19(m,2H),7.16-7.01(m,2H),5.91-5.85(m,1H),5.39(br,2H),5.12-5.07(m,1H),4.75-4.51(m,2H),4.46-4.41(m,1H),4.38-4.24(m,2H),4.13-4.00(m,2H),3.62-3.42(m,3H),3.21(br,3H),3.13-2.97(m,1H),2.92-2.59(m,4H),2.11-1.84(m,2H),1.80-1.68(m,2H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ7.35-7.28 (m, 3H), 7.25-7.19 (m, 2H), 7.16-7.01 (m, 2H), 5.91-5.85 (m, 1H), 5.39 (br ,2H),5.12-5.07(m,1H),4.75-4.51(m,2H),4.46-4.41(m,1H),4.38-4.24(m,2H),4.13-4.00(m,2H),3.62 -3.42(m,3H),3.21(br,3H),3.13-2.97(m,1H),2.92-2.59(m,4H),2.11-1.84(m,2H),1.80-1.68(m,2H) .

实施例29：(S)-3-(2-苄基-3-氯-7-氧代-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶-6-基)-1-甲基-9-(4-甲基哌嗪-1-甲酰基)-3,4,8,9,10,11-六氢-[1,4]氧氮杂卓并[3,2-f]异喹啉-2(1H)-酮(29)的制备Example 29: (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-yl)-1-methyl-9-(4-methylpiperazine-1-formyl)-3,4,8,9,10,11-hexahydro-[1,4]oxazepine Preparation of bi[3,2-f]isoquinoline-2(1H)-one (29)

与实施例23的制备方法相同，除了用4-甲基哌嗪-1-甲酰氯代替甲磺酰氯，制得标题化合物29。The preparation method was the same as in Example 23, except that 4-methylpiperazine-1-formyl chloride was used instead of methanesulfonyl chloride to obtain the title compound 29.

LC-MS：m/z 517.17[M+H] ⁺。 LC-MS: m/z 517.17 [M+H] ⁺ .

¹H NMR(400MHz,CDCl ₃)δ8.31(br,1H),7.32-7.29(m,3H),7.25-7.21(m,2H),7.04(s,2H),5.90-5.83(m,1H),5.41(br,2H),4.56-4.41(m,2H),4.31-4.25(m,2H),3.94-3.91(m,1H),3.62-3.34(m,7H),3.21(s,3H),3.15-2.84(m,3H),2.75-2.62(m,5H),2.47(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ8.31 (br, 1H), 7.32-7.29 (m, 3H), 7.25-7.21 (m, 2H), 7.04 (s, 2H), 5.90-5.83 (m, 1H) ), 5.41(br,2H),4.56-4.41(m,2H),4.31-4.25(m,2H),3.94-3.91(m,1H),3.62-3.34(m,7H),3.21(s,3H) ), 3.15-2.84 (m, 3H), 2.75-2.62 (m, 5H), 2.47 (s, 3H).

生物学试验Biological test

试验例1：本发明化合物体外抑制U937细胞坏死活性的分析Test Example 1: In Vitro Inhibition of U937 Cell Necrosis Activity by the Compounds of the Invention

受体相互作用蛋白激酶1(RIP1)活化可诱导人类单核细胞性白血病U937细胞坏死，因此，本发明化合物的活性利用人类单核细胞性白血病U937细胞(CBP60277，CoBioer)，通过体外细胞坏死测定实验来测试。Receptor-interacting protein kinase 1 (RIP1) activation can induce necrosis of human monocytic leukemia U937 cells. Therefore, the activity of the compounds of the present invention utilizes human monocytic leukemia U937 cells (CBP60277, CoBioer) by in vitro cell necrosis assay Experiment to test.

ATP腺嘌呤核苷三磷酸参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态。向细胞培养基中加入相应体积的CellTiter-Glo ^TM试剂(Promega)，测量发光值，发光值与ATP量成正比，而ATP又与活细胞数正相关，通过检测ATP含量从而测定细胞活力。 ATP adenine nucleoside triphosphate participates in a variety of enzymatic reactions in organisms and is an indicator of living cell metabolism. Its content directly reflects the number of cells and cell state. Add a corresponding volume of CellTiter-Glo ^TM reagent (Promega) to the cell culture medium to measure the luminescence value. The luminescence value is proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Cell viability is determined by detecting the ATP content.

试验方法：experiment method:

a.细胞培养在补充有10％胎牛血清(10099141，Gibco)、100U/mL青霉素和100μg/mL链霉素(15140122，Invitrogen)的RPMI 1640培养基(31800-500，Solarbio)中。测定时，将细胞以5×10 ⁵个细胞/mL悬浮于补充有1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基内。将细胞悬液加入384孔板(3570，Corning)中，每孔35μL，即U937细胞17500个/孔。 a. Cells are cultured in RPMI 1640 medium (31800-500, Solarbio) supplemented with 10% fetal bovine serum (10099141, Gibco), 100 U/mL penicillin and 100 μg/mL streptomycin (15140122, Invitrogen). During the measurement, the cells were suspended in RPMI 1640 medium supplemented with 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin ^{at 5×10 5 cells/mL.} The cell suspension was added to a 384-well plate (3570, Corning), 35 μL per well, that is, 17,500 U937 cells/well.

b.将10mM QVD(Q-VD-OPh)(货号：551476，EMD Millipore Corp)储液(QVD溶于100％的DMSO配制成10mM储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基稀释40倍至250μM，取5μL QVD加入相应的细胞孔中，反应终体系为50μL，QVD的终浓度为25μM。b. The 10mM QVD (Q-VD-OPh) (Cat. No.: 551476, EMD Millipore Corp) stock solution (QVD is dissolved in 100% DMSO to make a 10mM stock solution) with 1% fetal bovine serum, 100U/mL penicillin, 100μg/mL streptomycin RPMI 1640 medium was diluted 40 times to 250μM, and 5μL QVD was added to the corresponding cell well. The final reaction system was 50μL, and the final concentration of QVD was 25μM.

c.将10mM本发明化合物储液作为起始浓度(本发明化合物溶于100％的DMSO配制成10mM储液)，在96孔稀释板中(249944，Nunc)以1：3进行等比稀释，化合物的梯度浓度为10000μM、3333.33μM、1111.11μM、370.37μM、123.46μM、41.15μM、13.72μM、4.57μM、0μM。c. Take the 10mM stock solution of the present invention as the starting concentration (the compound of the present invention is dissolved in 100% DMSO to prepare a 10mM stock solution), and dilute it in a 96-well dilution plate (249944, Nunc) at a ratio of 1:3, The gradient concentrations of the compounds were 10000μM, 3333.33μM, 1111.11μM, 370.37μM, 123.46μM, 41.15μM, 13.72μM, 4.57μM, 0μM.

d.将上述经过100％DMSO等比稀释的化合物用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基稀释100倍。d. Dilute the above-mentioned compound diluted with 100% DMSO equal ratio with RPMI 1640 medium containing 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin 100 times.

e.取步骤d中经过稀释的化合物5μL加入384孔板的细胞中，化合物的终浓度为10000nM、3333.33nM、1111.11nM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、0nM。e. Take 5 μL of the diluted compound in step d and add it to the cells of the 384-well plate. The final concentration of the compound is 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, 0 nM.

f.在37℃，5％CO ₂培养箱中培养30分钟。 f. Incubate for 30 minutes in a 37°C, 5% CO _{2 incubator.}

g.培养后，将TNFα(PHC3016，Gibco)储液(TNFα溶于无菌水配制成100μg/mL储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的RPMI 1640培养基稀释100倍至1μg/mL，取5μL TNFα加入相应的细胞孔中，反应终体系为 50μL，TNFα的终浓度为100ng/mL。g. After incubation, TNFα (PHC3016, Gibco) stock solution (TNFα is dissolved in sterile water to make a 100μg/mL stock solution) with RPMI containing 1% fetal bovine serum, 100U/mL penicillin, and 100μg/mL streptomycin The 1640 medium was diluted 100 times to 1μg/mL, and 5μL of TNFα was added to the corresponding cell well. The final reaction system was 50μL, and the final concentration of TNFα was 100ng/mL.

h.将细胞培养板放置培养箱中，37℃，5％CO ₂培养过夜。 h. Place the cell culture plate in an incubator, and incubate overnight at _{37°C with 5% CO 2.}

i.将384孔板细胞取出，室温平衡30分钟。i. Take the cells out of the 384-well plate and equilibrate for 30 minutes at room temperature.

j.向每个试验孔中加入30μLCellTiter-Glo ^TM试剂，振荡混匀，室温孵育10分钟。 j. Add 30 μL of CellTiter-Glo ^TM reagent to each test well, shake and mix, and incubate at room temperature for 10 minutes.

k.用Cytation 3检测化学发光信号。k. Use Cytation 3 to detect the chemiluminescence signal.

用GraphPad Prism 5软件，利用以下非线性拟合公式得到化合物的IC ₅₀： _{Using GraphPad Prism 5 software, the IC 50 of the} compound was obtained using the following nonlinear fitting formula:

Y＝Bottom+(Top–Bottom)/(1+10^((Log EC ₅₀–X)×Hillslope))， Y=Bottom+(Top-Bottom)/(1+10^((Log EC ₅₀ -X)×Hillslope)),

其中，X为化合物浓度的对数值，Y为化合物抑制细胞坏死的效能；Top和Bottom为曲线最高及最低平台期的Y值；Hillslope为希尔常数。Among them, X is the logarithmic value of the compound concentration, Y is the compound's efficacy in inhibiting cell necrosis; Top and Bottom are the Y values at the highest and lowest plateau of the curve; Hillslope is the Hill constant.

本发明化合物抑制U937细胞坏死的活性见下表1。The activity of the compounds of the present invention in inhibiting necrosis of U937 cells is shown in Table 1 below.

在表1中，A是指化合物抑制细胞坏死的IC ₅₀<10nM；B是指10nM<IC ₅₀<100nM；C是指100nM<IC ₅₀<500nM；D是指IC ₅₀>500nM。 In Table 1, A refers to a compound to inhibit cell necrosis IC ₅₀ <10nM; B refers to 10nM <IC ₅₀ <100nM; C refers 100nM <IC ₅₀ <500nM; D refers IC _50> 500nM.

表1 本发明化合物抑制U937细胞坏死的IC ₅₀值 _{Table 1 The IC 50} value of the compounds of the present invention for inhibiting necrosis of U937 cells

结论：本发明化合物能够有效抑制U937细胞坏死。Conclusion: The compound of the present invention can effectively inhibit the necrosis of U937 cells.

试验例2：本发明化合物对受体相互作用蛋白激酶1(RIP1)活性的抑制分析Test Example 2: Inhibition analysis of the compound of the present invention on the activity of receptor-interacting protein kinase 1 (RIP1)

本发明化合物对受体相互作用蛋白激酶1(RIP1)活性的抑制作用可以利用ADP-Glo ^TM激酶分析来检测。ADP-Glo ^TM激酶分析为发光法的激酶检测分析，RIP1自磷酸化过程中产生ADP，ADP被转化成ATP，然后ATP再被Ultra-Glo萤光素酶转化成光，通过检测光信号定量ADP，从而通过定量酶反应期间所产生的ADP量来测量酶活性。所述分析分两个步骤进行：首先，在激酶反应后，向其中加入一份与激酶反应体系等体积的ADP-Glo试剂，使反应终止，并消耗完剩余的ATP；其次，加入激酶检测试剂，其在使ADP转化成ATP的同时，还使用偶联的萤光素酶/萤光素反应来检测新合成的ATP。 The inhibitory effect of the compounds of the present invention on the activity of receptor-interacting protein kinase 1 (RIP1) can ^{be detected by ADP-Glo TM} kinase assay. ADP-Glo ^TM kinase analysis is a kinase detection analysis of luminescence method. ADP is produced during autophosphorylation of RIP1, ADP is converted into ATP, and then ATP is converted into light by Ultra-Glo luciferase, and ADP is quantified by detecting light signal , Thereby measuring the enzyme activity by quantifying the amount of ADP produced during the enzyme reaction. The analysis is carried out in two steps: first, after the kinase reaction, add a portion of ADP-Glo reagent equal in volume to the kinase reaction system to terminate the reaction and consume the remaining ATP; secondly, add the kinase detection reagent It not only converts ADP into ATP, but also uses a coupled luciferase/luciferin reaction to detect newly synthesized ATP.

试验方法：experiment method:

a.将10mM本发明化合物储液作为起始浓度(本发明化合物溶于100％的DMSO配制成10mM储液)，在化合物稀释板中(781201-906，Greiner)以1：3进行等比稀释，化合物的梯度浓度为10000μM、3333.33μM、1111.11μM、370.37μM、123.46μM、41.15μM、13.72μM、4.57μM、1.52μM、0.51μM、0μM。a. Take the 10mM stock solution of the present invention as the starting concentration (dissolve the compound of the present invention in 100% DMSO to prepare a 10mM stock solution), and dilute 1:3 in a compound dilution plate (781201-906, Greiner) The gradient concentration of the compound is 10000μM, 3333.33μM, 1111.11μM, 370.37μM, 123.46μM, 41.15μM, 13.72μM, 4.57μM, 1.52μM, 0.51μM, 0μM.

b.将上述经过100％DMSO等比稀释的化合物用Echo 550(LABCYTE)从化合物稀释板转移至白色OptiPlate-384F板(6007290，PE)中，每孔10nL，再加入90nL DMSO稀释10倍，阳性对照孔和阴性对照孔各转移100nL DMSO。反应终体系为10μL，化合物的终浓度为10000nM、3333.33nM、1111.11nM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、1.52nM、0.51nM、0nM。b. Use Echo 550 (LABCYTE) to transfer the above-mentioned compound diluted in 100% DMSO from the compound dilution plate to the white OptiPlate-384F plate (6007290, PE), 10nL per well, and then add 90nL DMSO to dilute 10-fold, positive Transfer 100 nL DMSO to the control wells and the negative control wells. The final reaction system is 10 μL, and the final concentration of the compound is 10000nM, 3333.33nM, 1111.11nM, 370.37nM, 123.46nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0nM.

c.配制反应缓冲液。用去离子水配制终浓度为50mM HEPES(PH 7.5)(H3375，Sigma)、0.02％CHAPS(C3023，Sigma)、50mM氯化钠(7647-14-5，Sigma)、30mM氯化镁(M1028-100mL，Sigma)、1mM二硫苏糖醇(43816-50mL，Sigma)、0.05％BSA(CR84-100，Sigma)的缓冲液。c. Prepare the reaction buffer. Use deionized water to prepare the final concentration of 50mM HEPES (PH 7.5) (H3375, Sigma), 0.02% CHAPS (C3023, Sigma), 50mM sodium chloride (7647-14-5, Sigma), 30mM magnesium chloride (M1028-100mL, Sigma), 1mM dithiothreitol (43816-50mL, Sigma), 0.05% BSA (CR84-100, Sigma) buffer.

d.将0.794μM GST-RIPK1储液(R07-11G，SignalChem)用上述反应缓冲液稀释至40nM。每孔加入5μL RIP1酶溶液，反应终体系为10μL，RIP1酶终浓度为20nM。25℃温箱预孵育30分钟。d. Dilute 0.794μM GST-RIPK1 stock solution (R07-11G, SignalChem) with the above reaction buffer to 40nM. Add 5μL of RIP1 enzyme solution to each well, the final reaction system is 10μL, and the final concentration of RIP1 enzyme is 20nM. Pre-incubate for 30 minutes in a 25°C incubator.

e.将10mM ADP-Glo试剂盒中的ATP储液(V915B，Promega)用上述反应缓冲液稀释至100μM。除阴性对照孔外每孔加入5μL ATP溶液，阴性对照孔每孔加入5μL反应缓冲液。反应终体系为10μL，ATP终浓度为50μM。25℃温箱孵育4小时。e. Dilute the ATP stock solution (V915B, Promega) in the 10mM ADP-Glo kit with the above reaction buffer to 100μM. Add 5μL of ATP solution to each well except the negative control well, and add 5μL of reaction buffer to each well of the negative control well. The final reaction system is 10 μL, and the final concentration of ATP is 50 μM. Incubate for 4 hours in an incubator at 25°C.

f.每孔加入10μLADP-Glo试剂盒(V9102，Promega)中的ADP-Glo Reagent，25℃温箱孵育40分钟。f. Add 10 μL of ADP-Glo Reagent in the LADP-Glo kit (V9102, Promega) to each well, and incubate for 40 minutes in an incubator at 25°C.

g.每孔加入20μLADP-Glo试剂盒的Detection reagent，25℃温箱孵育30分钟。g. Add 20μ LADP-Glo detection reagent to each well, and incubate for 30 minutes in a 25°C incubator.

h.使用Envision(2014，PE)读取化学发光值。h. Use Envision (2014, PE) to read the chemiluminescence value.

使用如下公式计算化合物抑制率(抑制％)：Use the following formula to calculate the compound inhibition rate (inhibition %):

S待测化合物：加入化合物样品孔的读值S compound to be tested: the reading value of the added compound sample hole

S阳性对照：加入GST-RIPK1酶和底物孔的读值S positive control: add the reading value of GST-RIPK1 enzyme and substrate well

S阴性对照：加入不含GST-RIP1酶的反应缓冲液和底物孔的读值S negative control: add the reaction buffer without GST-RIP1 enzyme and the reading value of the substrate well

以抑制％作为纵坐标，化合物的浓度作为横坐标，使用XLfit拟合剂量-效应曲线，得到化合物的IC ₅₀，公式如下： Using the% inhibition as the ordinate and the concentration of the compound as the abscissa, use XLfit to fit the dose-response curve to obtain the IC _{50 of the} compound. The formula is as follows:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀-X)*HillSlope)) Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

其中，X为化合物浓度的对数值，Y为化合物抑制激酶的效能；Top和Bottom为曲线最高及最低平台期的Y值；Hillslope为希尔常数。Among them, X is the logarithmic value of the compound concentration, Y is the potency of the compound to inhibit kinase; Top and Bottom are the Y values of the highest and lowest plateau of the curve; Hillslope is the Hill constant.

本发明化合物抑制RIP1活性见下表2。The compounds of the present invention inhibit RIP1 activity as shown in Table 2 below.

在表2中，A是指化合物抑制RIP1的IC ₅₀<10nM；B是指10nM<IC ₅₀<100nM；C是指100nM<IC ₅₀<500nM；D是指IC ₅₀>500nM。 In Table 2, A means that the compound inhibits RIP1 with IC ₅₀ <10 nM; B means 10 nM <IC ₅₀ <100 nM; C means 100 nM <IC ₅₀ <500 nM; D means IC ₅₀ > 500 nM.

表2 本发明化合物抑制RIP1的IC ₅₀值 _{Table 2 The IC 50} value of the compounds of the present invention for inhibiting RIP1

结论：本发明化合物能够有效抑制RIP1活性。Conclusion: The compound of the present invention can effectively inhibit the activity of RIP1.

试验例3：本发明化合物体外抑制L929细胞坏死活性的分析Test Example 3: Analysis of the in vitro inhibitory activity of the compound of the present invention on L929 cell necrosis

本发明化合物的作用可以利用L929细胞(南京科佰)，通过体外细胞坏死测定实验来测试。ATP腺嘌呤核苷三磷酸参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态。向细胞培养基中加入相应体积的promega公司的CellTiter-Glo ^TM试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，通过检测ATP含量从而测定细胞活力。 The effects of the compounds of the present invention can be tested by using L929 cells (Nanjing Kebai) through in vitro cell necrosis assays. ATP adenine nucleoside triphosphate participates in a variety of enzymatic reactions in organisms and is an indicator of living cell metabolism. Its content directly reflects the number of cells and cell state. Add a corresponding volume of Promega's CellTiter-Glo ^TM reagent to the cell culture medium to measure the luminescence value. The luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Cell viability can be determined by detecting the ATP content.

试验方法：experiment method:

a.细胞培养在补充有10％胎牛血清(10099141，Gibco)、100U/mL青霉素和100μg/mL链霉素(15140122，invitrogen)的MEM培养基(11095-080， Invitrogen)中。测定时，将细胞以5×10 ⁴个细胞/mL悬浮于补充有1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基内。将细胞悬液加入384孔板(3570，Corning)中，每孔35μL，即L929细胞1750个/孔。 a. Cells are cultured in MEM medium (11095-080, Invitrogen) supplemented with 10% fetal bovine serum (10099141, Gibco), 100 U/mL penicillin and 100 μg/mL streptomycin (15140122, invitrogen). During the measurement, the cells ^{were suspended at 5×10 4} cells/mL in a MEM medium supplemented with 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. The cell suspension was added to a 384-well plate (3570, Corning), 35 μL per well, that is, 1750 L929 cells/well.

b.将30mM本发明化合物储液作为起始浓度(本发明化合物溶于100％的DMSO配制成30mM储液)在96孔稀释板中(249944，Nunc)以1：3进行等比稀释，化合物的梯度浓度为30000μM、10000μM、3333.33μM、1111.11μM、370.37μM、123.46μM、41.15μM、13.72μM、4.57μM、0μM。b. Use 30 mM stock solution of the present invention as the starting concentration (the present compound is dissolved in 100% DMSO to prepare a 30 mM stock solution) in a 96-well dilution plate (249944, Nunc) at a ratio of 1:3 to dilute the compound. The gradient concentrations are 30000μM, 10000μM, 3333.33μM, 1111.11μM, 370.37μM, 123.46μM, 41.15μM, 13.72μM, 4.57μM, 0μM.

c.将上述经过100％DMSO等比稀释的化合物用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基稀释100倍。c. Dilute the above-mentioned compound diluted with 100% DMSO equal ratio with MEM medium containing 1% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin 100 times.

d.取c步骤经过稀释的化合物5μL加入384孔板的细胞中，反应总体系为50μL，化合物的终浓度为30000nM、10000nM、3333.33nM、1111.11nM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、0nM。d. Take 5μL of the diluted compound in step c and add it to the cells in the 384-well plate. The total reaction system is 50μL, and the final concentration of the compound is 30000nM, 10000nM, 3333.33nM, 1111.11nM, 370.37nM, 123.46nM, 41.15nM, 13.72nM , 4.57nM, 0nM.

e.在37℃，5％CO ₂培养箱中培养30分钟。 e. Incubate for 30 minutes in a 37°C, 5% CO _{2 incubator.}

f.将10mM QVD(551476，EMD)储液(QVD溶于100％的DMSO配制成10mM储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基稀释40倍至250μM。f. Dilute the 10mM QVD (551476, EMD) stock solution (QVD is dissolved in 100% DMSO to prepare a 10mM stock solution) with MEM medium containing 1% fetal bovine serum, 100U/mL penicillin, and 100μg/mL streptomycin 40 times to 250μM.

g.将mTNFα(50349-MNAE，义翘神州)储液(TNFα溶于无菌水配制成590μg/mL储液)用含1％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基稀释590倍至1μg/mL。g. Use mTNFα (50349-MNAE, Yiqiao Shenzhou) stock solution (TNFα is dissolved in sterile water to prepare 590μg/mL stock solution) with 1% fetal bovine serum, 100U/mL penicillin, 100μg/mL streptomycin MEM medium was diluted 590 times to 1μg/mL.

h.将中间稀释的QVD和mTNFα以1：1混合均匀。h. Mix the intermediately diluted QVD and mTNFα at a ratio of 1:1.

i.取10μlQVD和mTNFα的混合物加入相应的细胞孔中。反应终体系为50μl，QVD终浓度为25μM，mTNFα终浓度为100ng/mL。i. Take 10μl of QVD and mTNFα mixture and add it to the corresponding cell well. The final reaction system is 50μl, the final concentration of QVD is 25μM, and the final concentration of mTNFα is 100ng/mL.

j.将细胞培养板放置培养箱中，37℃，5％CO ₂培养48h。 j. Place the cell culture plate in an incubator, and incubate at 37°C and 5% CO _{2 for} 48 hours.

k.将384孔板细胞取出，室温平衡30分钟。k. Take the cells out of the 384-well plate and equilibrate for 30 minutes at room temperature.

l.向每个试验孔加入30μL CellTiter-Glo ^TM试剂，振荡混匀，室温孵育10分钟。 1. Add 30μL CellTiter-Glo ^TM reagent to each test well, shake and mix, and incubate at room temperature for 10 minutes.

m.用Cytation 3检测化学发光信号。m. Use Cytation 3 to detect the chemiluminescence signal.

n.用GraphPad Prism 5软件，利用以下非线性拟合公式来得到化合物的EC50：n. Using GraphPad Prism 5 software, use the following nonlinear fitting formula to obtain the EC50 of the compound:

本发明化合物抑制L929细胞坏死的活性见下表3。See Table 3 below for the activity of the compounds of the present invention in inhibiting necrosis of L929 cells.

在表3中，A是指化合物抑制细胞坏死的IC ₅₀<50nM；B是指50nM<IC ₅₀<100nM；C是指100nM<IC ₅₀<500nM；D是指IC ₅₀>500nM。 In Table 3, A refers to a compound to inhibit cell necrosis IC ₅₀ <50nM; B refers to 50nM <IC ₅₀ <100nM; C refers 100nM <IC ₅₀ <500nM; D refers IC _50> 500nM.

表3 本发明化合物抑制L929细胞坏死的IC ₅₀值 _{Table 3 The IC 50} value of the compound of the present invention for inhibiting L929 cell necrosis

结论：本发明化合物能够抑制L929细胞坏死。Conclusion: The compound of the present invention can inhibit the necrosis of L929 cells.

试验例4：本发明化合物在wistar大鼠和ICR小鼠体内药代动力学评价Test Example 4: Evaluation of the pharmacokinetics of the compound of the present invention in wistar rats and ICR mice

对雄性6周龄wistar大鼠和雄性7周龄ICR小鼠(北京市维通利华实验动物技术有限公司)口服给予本发明化合物。分别于给药前和给药后，在0、0.167、0.25、0.50、1.00、2.00、4.00、6.00、8.00和24.00h进行眼眶采血。血液经乙二胺四乙酸二钾抗凝，于4℃，3500rpm离心10分钟，获取血浆并在-20℃保存直至测试。取血浆样品50μL于1.5mL EP管中，加入400μL含有5ng/mL盐酸维拉帕米(内标)的乙腈工作液，涡旋1分钟充分混匀，10000rpm离心10分钟。移取上清液0.2mL，用0.22μM有机膜(AS081320-T，Agela Technologies)过滤后，加入进样小瓶中，经LC/MS(Waters，Waters UPLC I Class、TQ-S micro)分析得出血药浓度，并通过DAS软件3.3.0分析药代动力学参数。The compound of the present invention was orally administered to male 6-week-old wistar rats and male 7-week-old ICR mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.). Before and after administration, blood was collected from the orbit at 0, 0.167, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00h. The blood was anticoagulated with dipotassium edetate, centrifuged at 4°C and 3500 rpm for 10 minutes, and plasma was obtained and stored at -20°C until testing. Take 50μL of plasma sample into 1.5mL EP tube, add 400μL of acetonitrile working solution containing 5ng/mL verapamil hydrochloride (internal standard), vortex for 1 minute to mix well, and centrifuge at 10000rpm for 10 minutes. Pipette 0.2mL of the supernatant, filter it with a 0.22μM organic membrane (AS081320-T, Agela Technologies), add it to the sample vial, and analyze the bleeding by LC/MS (Waters, Waters UPLC I Class, TQ-S micro) Drug concentration, and analyze the pharmacokinetic parameters by DAS software 3.3.0.

本发明化合物口服给药后药代动力学实验数据见表4。The pharmacokinetic experimental data of the compound of the present invention after oral administration are shown in Table 4.

在表4中，A是指化合物的AUC _0-t(μg/L*h)<500；B是指500<AUC _0-t(μg/L*h)<1000；C是指1000<AUC _0-t(μg/L*h)<5000；D是指5000<AUC _0-t(μg/L*h)<10000。 In Table 4, A refers to the compound's AUC _0-t (μg/L*h)<500; B refers to 500<AUC _0-t (μg/L*h)<1000; C refers to 1000<AUC _{0 -t} (μg/L*h)<5000; D means 5000<AUC _0-t (μg/L*h)<10000.

表4 单次口服给予雄性wistar大鼠和雄性ICR小鼠本发明化合物的药动学参数Table 4 The pharmacokinetic parameters of the compound of the invention in a single oral administration to male wistar rats and male ICR mice

结论：本发明化合物口服给予大鼠和小鼠有较好的体内药代动力学性质。Conclusion: The compound of the present invention has better in vivo pharmacokinetic properties when administered orally to rats and mice.

试验例5：本发明化合物在C57BL/6J小鼠体内血脑屏障透过率测试Test Example 5: Test of the blood-brain barrier permeability of the compound of the present invention in C57BL/6J mice

对雄性6周龄C57BL/6小鼠(北京市维通利华实验动物技术有限公司)口服给予本发明化合物。分别于给药前和给药后，在0、0.25、1.00和4.00h采集小鼠血液和脑组织。取脑组织前，从小鼠左心室灌流10mL生理盐水。血液样品经乙二胺四乙酸二钾抗凝，于4℃，3500rpm离心10分钟，获取血浆并在-20℃保存直至测试。脑组织用生理盐水冲洗干净后，称量干重，转移至10mL EP管中。根据体重加生理盐水匀浆(脑重：生理盐水体积＝1:2)，匀浆后统一定容至2mL，保证整个过程在低温下进行。精密量取脑组织匀浆液样品50μL，转移至1.5mL EP管中，向其中加入400μL含有5ng/mL盐酸维拉帕米(内标)的乙腈工作液，涡旋剧烈震荡1min，16000rpm离心10min。取上清液，用0.22μm有机膜(AS081320-T，Agela Technologies)过滤，加入进样小瓶中待测。经LC/MS(Waters，Waters UPLC I Class、TQ-S micro)分析得出血药浓度和脑组织药物浓度。The compound of the present invention was orally administered to male 6-week-old C57BL/6 mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.). The blood and brain tissues of the mice were collected at 0, 0.25, 1.00 and 4.00 hours before and after administration, respectively. Before taking the brain tissue, 10 mL of normal saline was perfused from the left ventricle of the mouse. The blood samples were anticoagulated with dipotassium ethylenediaminetetraacetate, centrifuged at 4°C and 3500 rpm for 10 minutes, and plasma was obtained and stored at -20°C until testing. After the brain tissue is rinsed with normal saline, the dry weight is weighed and transferred to a 10 mL EP tube. Homogenize with normal saline according to body weight (brain weight: normal saline volume = 1:2), and uniformly dilute the volume to 2 mL after homogenization to ensure that the whole process is carried out at low temperature. Accurately measure 50μL of brain tissue homogenate sample, transfer it to a 1.5mL EP tube, add 400μL of acetonitrile working solution containing 5ng/mL verapamil hydrochloride (internal standard) to it, vortex vigorously for 1min, and centrifuge at 16000rpm for 10min. Take the supernatant, filter it with a 0.22μm organic membrane (AS081320-T, Agela Technologies), and add it to the sample vial to be tested. After LC/MS (Waters, Waters UPLC I Class, TQ-S micro) analysis, hemorrhage drug concentration and brain tissue drug concentration are obtained.

本发明化合物口服给药后血脑屏障透过率见表5。The blood-brain barrier permeability after oral administration of the compound of the present invention is shown in Table 5.

表5 单次口服给予雄性C57BL/6J小鼠本发明化合物的血脑屏障透过率。Table 5 The blood-brain barrier permeability of a single oral administration of the compound of the present invention to male C57BL/6J mice.

化合物Compound	C _b/C _p@1h C _b /C _p @1h
实施例2Example 2	>1>1
实施例14Example 14	<1<1

注：C _b(ng/g)：脑组织中药物浓度，C _p(ng/mL)：血浆中药物浓度。 Note: C _b (ng/g): drug concentration in brain tissue, C _p (ng/mL): drug concentration in plasma.

从上述实验结果可以看出，本发明实施例2在脑组织中药物浓度大于血浆中药物浓度，而实施例14在血浆中药物浓度大于脑组织中药物浓度。It can be seen from the above experimental results that the concentration of the drug in brain tissue in Example 2 of the present invention is greater than that in plasma, while the concentration of drug in plasma in Example 14 is greater than that in brain tissue.

Claims

一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，A compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中，in,

X选自-O-、-S(O) _m-、-NR ^a-、-CR’R”-； X is selected from -O-, -S(O) _m -, -NR ^a -, -CR'R"-;

Y ¹和Y ²各自独立地选自O或S； Y ¹ and Y ² are each independently selected from O or S;

Z ¹和Z ²各自独立地选自C或N原子； Z ¹ and Z ² are each independently selected from C or N atoms;

L选自单键、-O-、-S(O) _m-、-NR ^a-、-(CR ^aR ^b) _n-、-(CR ^aR ^b) _nO-、-(CR ^aR ^b) _nS-和-(CR ^aR ^b) _nNR ^a-； L is selected from single bond, -O-, -S(O) _m -, -NR ^a -, -(CR ^a R ^b ) _n -, -(CR ^a R ^b ) _n O-, -(CR ^a R ^b ) _n S- and -(CR ^a R ^b ) _n NR ^a -;

环A选自芳基、杂芳基、环烷基和杂环基，其中所述芳基、杂芳基、环烷基和杂环烷基任选进一步被一个或多个R ⁹取代； Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally further substituted with one or more R ⁹ ;

环B为芳环或芳杂环，其任选进一步被一个或多个R ⁸取代； Ring B is an aromatic ring or an aromatic heterocyclic ring, which is optionally further substituted by one or more R ⁸ ;

环C为含氮杂环，其任选进一步被一个或多个R ⁷取代； Ring C is a nitrogen-containing heterocyclic ring, which is optionally further substituted by one or more R ⁷ ;

R ¹和R ²与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，或者R ²和R ³与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，或者R ³和R ⁴与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，其中所述C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基任选进一步被一个或多个R ⁶取代； R ¹ and R ² together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, or R ² and R ³ and The atoms to which they are connected together form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, or R ³ and R ⁴ together with the atoms to which they are connected form C _6-10 aryl, 6 to 10 membered heteroaryl, 6 to 10 membered heterocyclic group or C _6-10 cycloalkyl, wherein the C _6-10 aryl, 6 to 10 membered heteroaryl, 6 To 10-membered heterocyclyl or C _6-10 cycloalkyl is optionally further substituted with one or more R ⁶ ;

其中：in:

当R ¹和R ²与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基时，R ³和R ⁴各自独立地选自R ⁶；或者 When R ¹ and R ² together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, R ³ and R ⁴ Each independently selected from R ⁶ ; or

当R ²和R ³与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基时，R ¹和R ⁴各自独立地选自R ⁶；或者 When R ² and R ³ together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10-membered heteroaryl group, a 6 to 10-membered heterocyclic group or a C _6-10 cycloalkyl group, R ¹ and R ⁴ Each independently selected from R ⁶ ; or

当R ³和R ⁴与他们连接的原子一起形成C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基时，R ¹和R ²各自独立地选自R ⁶； When R ³ and R ⁴ together with the atoms to which they are attached form a C _6-10 aryl group, a 6 to 10 membered heteroaryl group, a 6 to 10 membered heterocyclic group or a C _6-10 cycloalkyl group, R ¹ and R ² Each independently selected from R ⁶ ;

R ⁵选自氢、烷基、卤代烷基、环烷基和卤代环烷基； R ^{5 is} selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

每个R ⁶各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和 -P(O)(R ^a) ₂，其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{6 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, -NHS (O) m R a , and ^{-P (O) (R a)} 2, wherein the alkyl, alkoxy, cycloalkyl Alkyl, heterocyclic, aryl, heteroaryl are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy One or more group substitutions of group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

每个R ⁷各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{7 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

每个R ⁹各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{9 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

R’和R”各自独立地选自氢、卤素、烷基、卤代烷基；R'and R" are each independently selected from hydrogen, halogen, alkyl, haloalkyl;

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, One or more group substitutions of oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2；m is 0, 1 or 2;

n为0至3的整数。n is an integer from 0 to 3.
根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its meso, racemate, enantiomer, diastereomer, or a mixture form thereof, or a pharmaceutically acceptable compound thereof Salt for use, which is a compound represented by the general formula (II) or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

其中，in,

环D选自C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，优选苯基、6-8元杂芳基、6-8元杂环基、C _6-8环烷基；所述芳基、杂芳基、杂环基和环烷基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和-P(O)(R ^a) ₂的一个或多个基团取代； Ring D is selected from C _6-10 _{aryl, 6-10 membered heteroaryl, 6-10} membered heterocyclic group or C 6-10 cycloalkyl, preferably phenyl, 6-8 membered heteroaryl, 6-8 Membered heterocyclic group, C _6-8 cycloalkyl; the aryl, heteroaryl, heterocyclic and cycloalkyl are optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo , Alkyl, -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^{_{a, -S (O) m R}} a, -S (O) m NR a R b, a -NHS (O) _m R ^a, and ^{-P (O) (R a)} 2 or more substituent groups;

R ¹和R ²各自独立地选自氢、卤素、烷基； R ¹ and R ² are each independently selected from hydrogen, halogen, and alkyl;

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, One or more group substitutions of ester group, oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2；m is 0, 1 or 2;

X、Y ¹、Y ²、Z ¹、Z ²、L、环A、环B、环C、R ⁵如权利要求1所定义。 X, Y ¹ , Y ² , Z ¹ , Z ² , L, ring A, ring B, ring C, and R ^{5 are} as defined in claim 1.
根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its meso, racemate, enantiomer, diastereomer, or a mixture form thereof, or a pharmaceutically acceptable compound thereof Salt for use, which is a compound represented by the general formula (III) or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

其中，in,

环E选自C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，优选苯基、6-8元杂芳基、6-8元杂环基、C _6-8环烷基，所述芳基、杂芳基、杂环基和环烷基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和-P(O)(R ^a) ₂的一个或多个基团取代； Ring E is selected from C _6-10 _{aryl, 6-10 membered heteroaryl, 6-10} membered heterocyclic group or C 6-10 cycloalkyl, preferably phenyl, 6-8 membered heteroaryl, 6-8 Member heterocyclic group, C _6-8 cycloalkyl group, the aryl group, heteroaryl group, heterocyclic group and cycloalkyl group are optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo , Alkyl, -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^{_{a, -S (O) m R}} a, -S (O) m NR a R b, a -NHS (O) _m R ^a, and ^{-P (O) (R a)} 2 or more substituent groups;

R ¹和R ⁴各自独立地选自氢、卤素、烷基； R ¹ and R ⁴ are each independently selected from hydrogen, halogen, and alkyl;

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, One or more group substitutions of oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2；m is 0, 1 or 2;

X、Y ¹、Y ²、Z ¹、Z ²、L、环A、环B、环C、R ⁵如权利要求1所定义。 X, Y ¹ , Y ² , Z ¹ , Z ² , L, ring A, ring B, ring C, and R ^{5 are} as defined in claim 1.
根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its meso, racemate, enantiomer, diastereomer, or a mixture form thereof, or a pharmaceutically acceptable compound thereof Salt for use, which is a compound represented by the general formula (IV) or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

其中：in:

环F选自C _6-10芳基、6至10元杂芳基、6至10元杂环基或C _6-10环烷基，优选苯基、6-8元杂芳基、6-8元杂环基、C _6-8环烷基，所述芳基、杂芳基、杂环基和环烷基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、-NHS(O) _mR ^a和-P(O)(R ^a) ₂的一个或多个基团取代； Ring F is selected from C _6-10 _{aryl, 6-10 membered heteroaryl, 6-10} membered heterocyclic group or C 6-10 cycloalkyl, preferably phenyl, 6-8 membered heteroaryl, 6-8 Member heterocyclic group, C _6-8 cycloalkyl group, the aryl group, heteroaryl group, heterocyclic group and cycloalkyl group are optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo , Alkyl, -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^{_{a, -S (O) m R}} a, -S (O) m NR a R b, a -NHS (O) _m R ^a, and ^{-P (O) (R a)} 2 or more substituent groups;

R ³和R ⁴各自独立地选自氢、卤素、烷基； R ³ and R ⁴ are each independently selected from hydrogen, halogen, and alkyl;

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, One or more group substitutions of oxo group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2；m is 0, 1 or 2;

X、Y ¹、Y ²、Z ¹、Z ²、L、环A、环B、环C、R ⁵如权利要求1所定义。 X, Y ¹ , Y ² , Z ¹ , Z ² , L, ring A, ring B, ring C, and R ^{5 are} as defined in claim 1.
根据权利要求2至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 2 to 4, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein

R ^a和R ^b各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基，其中所述烷基、烯基、炔基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl are optionally selected Further selected from one of halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl Or multiple group substitutions;

或者R ^a和R ^b与他们连接的原子一起形成5-7元含氮杂环基，所述5-7元含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Or R ^a and R ^b together with the atoms to which they are attached form a 5-7 membered nitrogen-containing heterocyclic group, the 5-7 membered nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, One or more groups of oxo group, hydroxyl group, mercapto group, carboxyl group, ester group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are substituted.
根据权利要求2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 2 or its mesomer, racemate, enantiomer, diastereomer, or a mixture form thereof, or a medicine thereof With salt,

其中，环D选自C _6-8环烷基或6-8元杂环基，优选6元杂环基，更优选哌啶基、吗啉基、二噁英基；所述杂环基任选进一步被选自卤素、氰基、氧代基、C _1-6烷基、-C(O)R ^a、-C(O)NR ^aR ^b、-S(O) _mR ^a和-S(O) _mNR ^aR ^b的一个或多个基团取代； Among them, ring D is selected from a C _6-8 cycloalkyl group or a 6-8 membered heterocyclic group, preferably a 6-membered heterocyclic group, more preferably a piperidinyl group, a morpholinyl group, and a dioxin group; the heterocyclic group optionally is further selected from halogen, cyano, oxo, C _1-6 ^{alkyl, -C (O) R a,} -C (O) NR a R b, -S (O) m R a and -S ( O) One or more groups of _m NR ^a R ^{b are substituted;}

R ^a选自氢、C _1-6烷基、C _3-6环烷基、5-6元杂环基，其中所述C _1-6烷基、C _3-6环烷基、5-6元杂环基任选进一步被选自氘代、卤素、C _1-6烷基的一个或多个基团取代； R ^{a is} selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclic group, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 The membered heterocyclic group is optionally further substituted with one or more groups _{selected from deuterated, halogen, and C 1-6 alkyl;}

R ^b选自氢或C _1-6烷基； R ^{b is} selected from hydrogen or C _1-6 alkyl;

m为1或2。m is 1 or 2.
根据权利要求3所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 3, or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof With salt,

其中，in,

环E选自C _6-8环烷基或6-8元杂环基，优选6元环烷基或6元杂环基，更优选环己基、哌啶基、吗啉基、二噁英基；所述环烷基或杂环基任选进一步被选自卤素、氰基、氧代基、C _1-6烷基、-C(O)R ^a、-C(O)NR ^aR ^b、-S(O) _mR ^a和-S(O) _mNR ^aR ^b的一个或多个基团取代； Ring E is selected from C _6-8 cycloalkyl or 6-8 membered heterocyclic group, preferably 6-membered cycloalkyl or 6-membered heterocyclic group, more preferably cyclohexyl, piperidinyl, morpholinyl, dioxinyl; said cycloalkyl or heterocyclyl is optionally further substituted selected from halogen, cyano, oxo, C _1-6 ^{alkyl, -C (O) R a,} -C (O) NR a R b, - One or more groups of S(O) _m R ^a and -S(O) _m NR ^a R ^{b are substituted;}

R ^a选自氢、C _1-6烷基、C _3-6环烷基、5-6元杂环基，其中所述C _1-6烷基、C _3-6 环烷基、5-6元杂环基任选进一步被选自氘代、卤素、C _1-6烷基的一个或多个基团取代； R ^{a is} selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclic group, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 The membered heterocyclic group is optionally further substituted with one or more groups _{selected from deuterated, halogen, and C 1-6 alkyl;}

R ^b选自氢或C _1-6烷基； R ^{b is} selected from hydrogen or C _1-6 alkyl;

m为1或2。m is 1 or 2.
根据权利要求4所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 4, or a meso, racemate, enantiomer, diastereomer, or a mixture form thereof, or a medicine thereof With salt,

其中，in,

环F选自C _6-8环烷基或6-8元杂环基，优选6元环烷基或6元杂环基，更优选环己基、哌啶基、吗啉基、二噁英基；所述环烷基或杂环基任选进一步被选自卤素、氰基、氧代基、C _1-6烷基、-C(O)R ^a、-C(O)NR ^aR ^b、-S(O) _mR ^a和-S(O) _mNR ^aR ^b的一个或多个基团取代； Ring F is selected from C _6-8 cycloalkyl or 6-8 membered heterocyclic group, preferably 6-membered cycloalkyl or 6-membered heterocyclic group, more preferably cyclohexyl, piperidinyl, morpholinyl, dioxinyl; said cycloalkyl or heterocyclyl is optionally further substituted selected from halogen, cyano, oxo, C _1-6 ^{alkyl, -C (O) R a,} -C (O) NR a R b, - One or more groups of S(O) _m R ^a and -S(O) _m NR ^a R ^{b are substituted;}

R ^a选自氢、C _1-6烷基、C _3-6环烷基、5-6元杂环基，其中所述C _1-6烷基、C _3-6环烷基、5-6元杂环基任选进一步被选自氘代、卤素、C _1-6烷基的一个或多个基团取代； R ^{a is} selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclic group, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 The membered heterocyclic group is optionally further substituted with one or more groups _{selected from deuterated, halogen, and C 1-6 alkyl;}

R ^b选自氢或C _1-6烷基； R ^{b is} selected from hydrogen or C _1-6 alkyl;

m为1或2。m is 1 or 2.
根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，X为-O-。The compound represented by the general formula (I) according to any one of claims 1 to 8, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
根据权利要求1至9中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 9 or its meso, racemate, enantiomer, diastereomer, or mixture thereof Form, or its pharmaceutically acceptable salt,

其中，环C为5至8元含氮杂环，优选哌啶环、四氢吡咯环、哌嗪环、二氢吡咯环、四氢吡啶环或高哌嗪环，更优选哌啶环，其任选进一步被一个或多个R ⁷取代； Among them, ring C is a 5- to 8-membered nitrogen-containing heterocyclic ring, preferably a piperidine ring, a tetrahydropyrrole ring, a piperazine ring, a dihydropyrrole ring, a tetrahydropyridine ring or a homopiperazine ring, and more preferably a piperidine ring, which Optionally further substituted by one or more R ⁷ ;

每个R ⁷各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Each R ^{7 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic group, aryl group and heteroaryl group;

其中：in:

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, ring One or more group substitutions of alkyl, heterocyclyl, aryl, and heteroaryl;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2。m is 0, 1, or 2.
根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 10, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

其中，环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R ⁸取代； Among them, ring B is 6 to 10 membered aromatic ring or 5 to 6 membered aromatic heterocyclic ring, preferably benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole Ring, thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further substituted by one or more R ⁸ replaced;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR ^aR ^b、-C(O)R ^a、-O(O)CR ^a、-C(O)OR ^a、-C(O)NR ^aR ^b、-NHC(O)R ^a、-S(O) _mR ^a、-S(O) _mNR ^aR ^b、和-NHS(O) _mR ^a；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁸为卤素； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -NR ^a R ^b , -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a ,- _{^{S (O) m R a,}} -S (O) m NR a R b, and -NHS (O) _m R ^a; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, an aryl group, Heteroaryl groups are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more groups of cyclic group, aryl group and heteroaryl group are substituted; preferably R ⁸ is halogen;

其中：in:

R ^a和R ^b各自独立地选自氢、卤素、羟基、硝基、氰基、氧代、烷基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, ring Alkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, ring One or more group substitutions of alkyl, heterocyclyl, aryl, and heteroaryl;

或者R ^a和R ^b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代； Or R ^a and R ^b together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more groups of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m为0、1或2。m is 0, 1, or 2.
根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 10, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, in which,

选自：
Selected from:

其中，in,

Y ²选自O或S； Y ^{2 is} selected from O or S;

Z ¹和Z ²各自独立地选自C或N原子； Z ¹ and Z ² are each independently selected from C or N atoms;

环B为6至10元芳环或5至6元芳杂环，优选苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环、噁唑环、噻唑环、异噁唑环、异噻唑环、噁二唑环、噻二唑环、***环，更优选吡唑环、咪唑环、***环，其任选进一步被一个或多个R ⁸取代； Ring B is a 6 to 10 membered aromatic ring or a 5 to 6 membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, Thiazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, triazole ring, more preferably pyrazole ring, imidazole ring, triazole ring, which are optionally further substituted by one or more R ⁸ replace;

每个R ⁷各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基；或者两个相邻的R ⁷与他们连接的原子一起形成杂环基或环烷基，其中所述烷基、烷氧基、环烷基、杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁷为氢； Each R ^{7 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy; or two adjacent R ⁷ together with the atom to which they are attached A heterocyclic group or a cycloalkyl group is formed, wherein the alkyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, One or more groups of carboxyl group, ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are substituted; preferably R ⁷ is hydrogen;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁸为卤素； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; Wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , Ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; preferably R ⁸ is halogen;

p为0、1、2、3或4，优选0。p is 0, 1, 2, 3 or 4, preferably 0.
根据权利要求1至12中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 12, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, in which,

选自：
Selected from:

优选

Preferred

其中，in,

Y ²选自O或S； Y ^{2 is} selected from O or S;

每个R ⁸各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；优选R ⁸为卤素； Each R ^{8 is} independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl ; Wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl , Ester group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups; preferably R ⁸ is halogen;

q为0、1或2。q is 0, 1, or 2.
根据权利要求1至13中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y ²为O。 The compound represented by the general formula (I) according to any one of claims 1 to 13, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein Y ² is O.
根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y ¹为O。 The compound represented by the general formula (I) according to any one of claims 1 to 14, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein Y ¹ is O.
根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 15 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

其中，in,

环A选自芳基和杂芳基，优选苯基，其中所述芳基或杂芳基任选进一步被一个或多个R ⁹取代， Ring A is selected from aryl and heteroaryl, preferably phenyl, wherein the aryl or heteroaryl is optionally further substituted with one or more R ⁹ groups,

每个R ⁹各自独立地选自氢、卤素、氰基、羟基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基，优选氢、卤素、烷基和烷氧基；其中所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 Each R ^{9 is} independently selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, alkane And alkoxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, oxo, One or more groups of hydroxy, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.
根据权利要求1至16中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 16 or its meso, racemate, enantiomer, diastereomer, or mixture thereof Form, or its pharmaceutically acceptable salt,

其中，L选自-NR ^a-和-(CR ^aR ^b) _n-，优选-(CR ^aR ^b) _n-； Wherein, L is selected from -NR ^a -and -(CR ^a R ^b ) _n -, preferably -(CR ^a R ^b ) _n -;

R ^a和R ^b各自独立地选自氢和C _1-6烷基； R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl;

n为0至3的整数，优选1；n is an integer from 0 to 3, preferably 1;

L更优选-CH ₂-。 L is more preferably -CH ₂ -.
根据权利要求1至17中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to any one of claims 1 to 17, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

其中，R ⁵选自氢、C _1-6烷基和卤代C _1-6烷基，优选氢和C _1-6烷基。 Among them, R ^{5 is} selected from hydrogen, C _1-6 alkyl and halogenated C _1-6 alkyl, preferably hydrogen and C _1-6 alkyl.
根据权利要求1至18中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中所述化合物选自：The compound represented by the general formula (I) according to any one of claims 1 to 18, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
一种根据权利要求1至19中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：A compound represented by the general formula (I) according to any one of claims 1 to 19, or its mesogen, racemate, enantiomer, diastereomer, or The preparation method of its mixture form or its pharmaceutically acceptable salt includes the following steps:

在催化剂的存在下，将化合物Il发生分子内关环反应得到通式(I)化合物，所述催化剂优选三甲基铝；In the presence of a catalyst, the compound Il undergoes an intramolecular ring-closure reaction to obtain a compound of general formula (I), and the catalyst is preferably trimethylaluminum;

其中，X、Y ¹、Y ²、Z ¹、Z ²、L、环A、环B、环C、R ¹、R ²、R ³、R ⁴、R ⁵如权利要求1所定义。 Wherein, X, Y ¹ , Y ² , Z ¹ , Z ² , L, ring A, ring B, ring C, R ¹ , R ² , R ³ , R ⁴ , and R ^{5 are} as defined in claim 1.
一种药物组合物，其包含根据权利要求1至19中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体或赋形剂。A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 19, or a meso, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients.
根据权利要求1至19中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求21所述的药物组合物在制备受体相互作用蛋白激酶1(RIP1)抑制剂中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 19, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition according to claim 21 in the preparation of receptor-interacting protein kinase 1 (RIP1) inhibitors.
根据权利要求1至19中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求21所述的药物组合物在制备预防或治疗与受体相互作用蛋白激酶1活性相关的疾病的药物中的用途，所述疾病优选炎症疾病、自身免疫性疾病或神经***疾病，所述炎症疾病和自身免疫性疾病例如类风湿性关节炎、溃疡性结肠炎、克罗恩病、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、幼年特发性关节炎、***性红斑狼疮、干燥综合征、***性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫性血小板减少性紫癜、移植排斥反应、实体器官缺血再灌注损伤、脓毒症、全身炎症反应综合征、***反应性疾病、哮喘、特应性皮肤病、多发性硬化、I型糖尿病、眶坏死性肉芽肿病、肺结节病、白塞病、白细胞介素-1转换酶相关发热综合征、肺慢性阻塞性疾病、肿瘤坏死因子受体相关综合征或牙周炎；所述神经***疾病例如亨廷顿病、阿尔茨海默病、帕金森氏症或肌萎缩侧索硬化。The compound represented by the general formula (I) according to any one of claims 1 to 19, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition according to claim 21 in the preparation of a medicament for the prevention or treatment of diseases related to the activity of receptor-interacting protein kinase 1, the diseases are preferably inflammatory diseases, self Immune diseases or neurological diseases such as rheumatoid arthritis, ulcerative colitis, Crohn’s disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreas Inflammation, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjogren’s syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic Steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis Syndrome, systemic inflammatory response syndrome, allergic disease, asthma, atopic skin disease, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 Converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related syndrome, or periodontitis; the neurological diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral cord hardening.