WO2021249566A1

WO2021249566A1 - Benzo six-membered ring derivative and use thereof

Info

Publication number: WO2021249566A1
Application number: PCT/CN2021/100201
Authority: WO
Inventors: 李丹; 李洪林; 赵振江; 谢荣荣; 苏明波; 罗娜; 李诗良
Original assignee: 山东百极地长制药有限公司
Priority date: 2020-06-12
Filing date: 2021-06-15
Publication date: 2021-12-16
Also published as: CN113801088A; CN113801088B

Abstract

Provided are a benzo six-membered ring derivative for treating liver fibrosis and use thereof. Specifically, provided are a compound as shown in formula (I), a pharmaceutical composition containing the compound of formula (I), and use of the compound in preparing medicaments for treating diseases related to liver fibrosis.

Description

苯并六元环衍生物及其应用Benzo six-membered ring derivatives and their applications

技术领域Technical field

本发明涉及药物化学领域；具体地说，本发明涉及新型的苯并六元环衍生物，及其在制备肝纤维化相关疾病的药物中的应用。The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel benzo six-membered ring derivative and its application in the preparation of drugs for liver fibrosis-related diseases.

背景技术Background technique

肝纤维化是指由各种致病因子所致肝内***异常增生的病理生理过程。其发生于各种肝脏损伤后的肝脏修复愈合过程中，而长期的纤维化就会发展成肝硬化。有调查显示，70％的慢性肝病患者多伴有肝脏纤维化，10年中25％肝纤维化进一步发展为肝硬化，其中5％可发展为肝癌。其中非酒精性脂肪肝炎(non-alcoholic steatohepatitis，NASH))，是非酒精性脂肪性肝病(NAFLD)中进展最为迅速的一类疾病，是非嗜酒者发生的慢性肝炎。NASH组织学改变与酒精性肝病相似：脂肪变性，肝细胞损害，炎症细胞浸润，不同程度的纤维化，没有肝炎病毒感染；与单纯性脂肪肝最大的差别在于出现肝细胞损伤甚至纤维化，被认为是NAFLD一种进展性的亚型。NASH的发病常常与肥胖症、线粒体功能异常相关。此外，NASH与额外的心血管事件发生，肝脏及肿瘤相关的死亡率增加紧密相关。Liver fibrosis refers to the pathophysiological process of abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. It occurs in the healing process of the liver after various liver injuries, and long-term fibrosis will develop into cirrhosis. Investigations have shown that 70% of patients with chronic liver disease are often accompanied by liver fibrosis, and 25% of liver fibrosis will further develop into liver cirrhosis within 10 years, of which 5% may develop into liver cancer. Among them, non-alcoholic steatohepatitis (NASH) is the most rapidly progressing type of non-alcoholic fatty liver disease (NAFLD), and it is a chronic hepatitis that occurs in non-alcoholics. The histological changes of NASH are similar to those of alcoholic liver disease: steatosis, liver cell damage, inflammatory cell infiltration, varying degrees of fibrosis, no hepatitis virus infection; the biggest difference from simple fatty liver is that liver cell damage or even fibrosis occurs. Considered to be a progressive subtype of NAFLD. The incidence of NASH is often associated with obesity and abnormal mitochondrial function. In addition, NASH is closely related to the occurrence of additional cardiovascular events, liver and tumor-related mortality.

肝脏纤维化的病变过程中，多种因素造成的肝脏损伤会招募多种免疫细胞，产生包括TGFβ在内的多种细胞因子，在多种细胞因子的作用下，纤维母细胞会转化成成纤维细胞，而活化的肝脏星形细胞是这部分成纤维细胞的重要组成成份。活化的肝成纤维细胞会产生多种细胞外基质，以促进损伤后“愈合”的发生，此时若能及时消除损伤的成因，则肝脏损伤痊愈，恢复正常功能；而若不能及时去除损伤的成因，肝脏反复发生损伤，会导致细胞外基质产生与分解的失衡，肝脏内纤维***异常沉积，肝组织呈现出纤维化，最终致使肝硬化乃至肝癌的发生。纤维化病理过程复杂，涉及很多机制。现在已证明肝纤维化是可逆的。对其中的任何一个过程进行干预都将对肝纤维化的逆转起到积极作用。In the pathological process of liver fibrosis, liver damage caused by multiple factors will recruit a variety of immune cells and produce a variety of cytokines including TGFβ. Under the action of multiple cytokines, fibroblasts will be transformed into fibroblasts. Cells, and activated hepatic stellate cells are an important component of this part of fibroblasts. Activated liver fibroblasts will produce a variety of extracellular matrix to promote the occurrence of "healing" after injury. At this time, if the cause of the injury can be eliminated in time, the liver injury will be healed and normal function will be restored; and if the injury cannot be removed in time Causes: Repeated liver damage will result in an imbalance between the production and decomposition of extracellular matrix, abnormal deposition of fibrous connective tissue in the liver, and liver tissue showing fibrosis, which will eventually lead to liver cirrhosis and even liver cancer. The pathological process of fibrosis is complex and involves many mechanisms. It has now been proven that liver fibrosis is reversible. Intervention in any of these processes will have a positive effect on the reversal of liver fibrosis.

NASH及肝纤维化与肝脏的整体代谢失衡密切相关，目前众多与代谢相关的靶标正在被用于治疗NASH和肝纤维化。包括多种酶蛋白、细胞因子和受体类蛋白。在此过程中酶类分子靶点如AMPK、ACC、IBAT、ASBT、Ketohexokinase、Diglycerol Acyltransferase等，转录调节分子靶点如SREBP、CEBP等，受体拮抗类如Sphingosine 1-Phosphate Receptor、GLP-1Receptor、FXR、Mineralocorticoid Receptor等。NASH and liver fibrosis are closely related to the overall metabolic imbalance of the liver. At present, many metabolic-related targets are being used to treat NASH and liver fibrosis. Including a variety of enzyme proteins, cytokines and receptor proteins. In this process, molecular targets of enzymes such as AMPK, ACC, IBAT, ASBT, Ketohexokinase, Diglycerol Acyltransferase, etc., molecular targets of transcription regulation such as SREBP, CEBP, etc., receptor antagonists such as Sphingosine 1-Phosphate Receptor, GLP-1Receptor, FXR, Mineralocorticoid Receptor, etc.

目前靶向肝纤维化的药物研发进展的如火如荼。通过Biomedtrack数据库查询，发现NASH伴随肝纤维化研发管线中共70余个药物，进入临床研究的药物有30多个，其中一半以上药物处于临床II期及以上。国外临床试验进展最快的主要药物分别有GFT505、LJN452和GS9674,均已完成II期临床研究，其中GFT505于2019年4月获得FDA突破性疗法认定(Breakthrough Therapy Designation)，还有多个药物处于I/II期临床研究中。At present, the development of drugs targeting liver fibrosis is progressing in full swing. Through the Biomedtrack database query, it was found that there are more than 70 drugs in the NASH-associated liver fibrosis research and development pipeline, and more than 30 drugs have entered clinical studies, of which more than half of the drugs are in clinical phase II and above. The main drugs with the fastest progress in foreign clinical trials are GFT505, LJN452, and GS9674, which have completed phase II clinical studies. Among them, GFT505 was awarded FDA Breakthrough Therapy Designation in April 2019. There are also many drugs in Phase I/II clinical studies are in progress.

虽然国际上上跨国药企已将肝纤维化作为重点研发方向，加大相应研发力度。但是我国目前在肝纤维化的靶向治疗方面还刚起步，主要临床疗法还是以中药复方抗炎为主，因此急需新的靶向药物。Although multinational pharmaceutical companies have made liver fibrosis a key research and development direction in the world, they have increased corresponding research and development efforts. However, my country's current targeted therapy for liver fibrosis has just started, and the main clinical therapy is still Chinese medicine compound anti-inflammatory. Therefore, there is an urgent need for new targeted drugs.

发明内容Summary of the invention

本发明的目的在于提供具备全新结构的、高效、低毒、能够作为治疗肝纤维化的化合物，包括所述化合物的药物组合物、所述化合物的制备方法以及所述化合物在制备预防或治疗肝纤维化相关疾病的药物中的用途。The purpose of the present invention is to provide a compound with a novel structure, high efficiency, low toxicity, and capable of being used for the treatment of liver fibrosis, including a pharmaceutical composition of the compound, a preparation method of the compound, and preparation of the compound for preventing or treating liver fibrosis. Use in medicine for fibrosis-related diseases.

在第一方面，本发明提供通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物在制备预防或治疗肝纤维化的药物中的用途：In the first aspect, the present invention provides the use of a compound represented by general formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof in the preparation of a medicament for preventing or treating liver fibrosis :

式中：Where:

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

A是带有1-5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C _1-6烷基或被卤素、优选F，更优选1-5个F取代的C _1-6烷基、C1-6烷氧基或被卤素、优选F，更优选1-5个F取代的C _1-6烷氧基； A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl or substituted by halogen, preferably F, more preferably 1-5 F C _1-6 alkyl, C1-6 alkoxy or halogen, preferably F, and more preferably 1 to 5 F substituted C _1-6 alkoxy;

A环还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；Ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano, and boronic acid groups;

A杂环选自以下结构：A heterocycle is selected from the following structures:

环B、C不同时存在，Rings B and C do not exist at the same time,

环B选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，Ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

其取代基R独立选自H、卤素、氰基、羟基、C _1-6烷基或含1-5个F原子C _1-6烷基、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，n＝1-4， Which substituent group R is independently selected from H, halo, cyano, hydroxy, C _1-6 alkyl containing 1-5 F atoms or C _1-6 alkyl, C _1-6 alkoxy, or an 1-5 F atom C _1-6 alkoxy, n=1-4,

环C选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，Ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

其取代基R ₁独立选自H、卤素、任选取代的C _1-6烷基、氰基、任选取代的氨基、羰基、羟基、C _1-3羧基(优选COOH)、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，C _1-6氘代烷氧基或含1-5个F原子C _1-6氘代烷氧基，n＝1-4；或者 The substituent R _{1 is} independently selected from H, halogen, optionally substituted C _1-6 alkyl, cyano, optionally substituted amino, carbonyl, hydroxyl, C _1-3 carboxy (preferably COOH), C _1-6 an alkoxy group having 1 to 5 F atoms or C _1-6 alkoxy, C _1-6 alkoxy or deuterated having 1-5 C _1-6 F atoms deuterated alkoxy group, n = 1- 4; or

环C不存在时，R ₁直接与化合物主体相连， When ring C does not exist, R _{1 is} directly connected to the main body of the compound,

此时，R ₁为H、羰基、卤素、任选取代的苯基、氰基、任选取代的氨基、任选取代的含1-2个选自N或O的杂原子的5-6元杂环基、羟基、C _1-3羧基(优选COOH)、C _1-3羧酸酯基(优选甲酸甲酯基)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，m＝1-2。 In this case, R ₁ is H, carbonyl, halogen, optionally substituted phenyl, cyano, optionally substituted amino, optionally substituted 5-6 member containing 1-2 heteroatoms selected from N or O Heterocyclic group, hydroxyl group, C _1-3 carboxyl group (preferably COOH), C _1-3 carboxylate group (preferably methyl formate group), optionally substituted C _1-6 alkyl, optionally substituted C _{1- 10} Alkoxy (preferably C _1-6 alkoxy), optionally substituted C _2-10 alkoxy containing ethylenic or acetylenic bond, optionally substituted benzyloxy, optionally substituted C _1-10 Alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _{1-6 alkoxyformyl, carbamoyl} Acyl, amino, optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _{3-5 alkyllactam} , optionally substituted C _1-6 alkylsulfonamido, optionally substituted C _3-5 alkyl lactam sulfonyl group, mercapto group, optionally substituted C _1-5 alkyl mercapto group, optionally substituted C _1-5 alkylsulfonyl group, optionally substituted C _3-5 cycloalkylsulfonyl group Acyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m = 1-2.

在具体的实施方式中，所述化合物是通式(II)所示化合物：In a specific embodiment, the compound is a compound represented by the general formula (II):

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

A是带有1-5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、 C _1-6烷基或被卤素、优选F，更优选1-5个F取代的C _1-6烷基、C1-6烷氧基或被卤素、优选F，更优选1-5个F取代的C _1-6烷氧基； A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl or substituted by halogen, preferably F, more preferably 1-5 F C _1-6 alkyl, C1-6 alkoxy or halogen, preferably F, and more preferably 1 to 5 F substituted C _1-6 alkoxy;

R ₄独立选自H、羟基、F、氰基； R _{4 is} independently selected from H, hydroxyl, F, cyano;

R ₅为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，任选取代的苯基，q＝1-2。 R ₅ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted benzyloxy, optionally substituted C _1-10 alkylformyloxy, any Optional substituted C _1-3 alkoxy methoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _1-6 alkoxyformyl, carbamoyl, amino, NR ² R ³ , Optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _3-5 alkyl lactam, optionally substituted C _1-6 alkylsulfonamide, optionally substituted C _{3- 5} Alkyl lactamyl, mercapto, optionally substituted C _1-5 alkyl mercapto, optionally substituted C _1-5 alkylsulfonyl, optionally substituted C _3-5 cycloalkylsulfonyl, any Select substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q=1-2.

在具体的实施方式中，所述化合物是通式(III)所示化合物：In a specific embodiment, the compound is a compound represented by the general formula (III):

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₆为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苯基(优选甲磺酰基取代的苯基)、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基； R ₆ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted phenyl (preferably methanesulfonyl substituted phenyl), optionally substituted benzyloxy , Optionally substituted C _1-10 alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _{1 -6} alkoxyformyl, carbamoyl, amino, NR ² R ³ , optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _3-5 alkyl lactam, optionally substituted C _1-6 alkylsulfonamide group, optionally substituted C _3-5 alkyl lactamyl sulfonamide group, mercapto group, optionally substituted C _1-5 alkyl mercapto group, optionally substituted C _1-5 alkylsulfonyl group Acyl, optionally substituted C _3-5 cycloalkylsulfonyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano.

在具体的实施方式中，所述化合物是通式(IV)所示化合物：In a specific embodiment, the compound is a compound represented by the general formula (IV):

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₁₀为独立选自为氢、卤素、氰基、羟基、疏基、C _1-3羧基(优选COOH)、C _1-3羧酸甲酯基(优选甲酸甲酯基)、C _1-6烷基磺酰基、C _1-6烷基磺酰胺基或被卤素、优选F，更优选1-5个F取代的烷基磺酰胺基、C _1-6烷氧基、四唑基，r＝1-5； R ₁₀ is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, C _1-3 carboxyl (preferably COOH), C _1-3 methyl carboxylate (preferably methyl formate), C _1-6 Alkylsulfonyl, C _1-6 alkylsulfonamido or alkylsulfonamido substituted by halogen, preferably F, more preferably 1-5 F, C _1-6 alkoxy, tetrazolyl, r= 1-5;

在具体的实施方式中，所述化合物是通式(V)所示化合物：In a specific embodiment, the compound is a compound represented by general formula (V):

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₁₀独立选自为C _1-6氘代甲氧基、C _1-6烷氧基或被卤素、优选F，更优选1-5个F取代的烷氧基；R ₁₂独立选自为氰基。 R _{10 is} independently selected from C _1-6 deuterated methoxy, C _1-6 alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1-5 F; R _{12 is} independently selected from cyano base.

在第二方面，本发明提供选自下组的化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物在制备预防或治疗肝纤维化的药物中的用途：In the second aspect, the present invention provides the use of a compound selected from the following group or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof in the preparation of a medicine for preventing or treating liver fibrosis:

在优选的实施方式中，所述药物是适于口服的剂型,包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。In a preferred embodiment, the drug is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.

在第三方面，本发明提供通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：In the third aspect, the present invention provides a compound represented by general formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式中：Where:

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

环B、C不同时存在，Rings B and C do not exist at the same time,

其取代基R ₁独立选自H、卤素、氰基、羟基、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，n＝1-4；或者 Substituents R ₁ which is independently selected from H, halo, cyano, hydroxy, C _1-6 alkoxy group having 1 to 5 F atoms or C _1-6 alkoxy, n = 1-4; or

此时，R ₁为H、羰基、卤素、任选取代的苯基、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5 烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，m＝1-2。 At this time, R ₁ is H, carbonyl, halogen, optionally substituted phenyl, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _1-6 alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted benzyloxy, optionally substituted C _{1 -10} alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _1-6 alkoxyformyl, Carbamoyl, amino, optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _{3-5 alkyllactam} , optionally substituted C _1-6 alkylsulfonamido, optionally Substituted C _3-5 alkyl lactamyl, mercapto, optionally substituted C _1-5 alkyl mercapto, optionally substituted C _1-5 alkylsulfonyl, optionally substituted C _3-5 cycloalkane Group sulfonyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m = 1-2.

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₆为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苯基(优选甲磺酰基取代的苯基)、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基 OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基； R ₆ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted phenyl (preferably methanesulfonyl substituted phenyl), optionally substituted benzyloxy , Optionally substituted C _1-10 alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _{1 -6} alkoxyformyl, carbamoyl, amino, NR ² R ³ , optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _3-5 alkyl lactam, optionally substituted C _1-6 alkylsulfonamide group, optionally substituted C _3-5 alkyl lactamyl sulfonamide group, mercapto group, optionally substituted C _1-5 alkyl mercapto group, optionally substituted C _1-5 alkylsulfonyl group Acyl, optionally substituted C _3-5 cycloalkylsulfonyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

在具体的实施方式中，所述化合物是选自下组的化合物：In a specific embodiment, the compound is a compound selected from the following group:

在第四方面，本发明提供一种药物组合物，包含第三方面所述的化合物。In the fourth aspect, the present invention provides a pharmaceutical composition comprising the compound described in the third aspect.

应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them one by one here.

具体实施方式detailed description

发明人经过广泛而深入的研究，发现一批结构全新的苯并六元环衍生物，这些衍生物能够抑制肝纤维化，在此基础上完成了本发明。After extensive and in-depth research, the inventor found a batch of benzo six-membered ring derivatives with brand-new structures, which can inhibit liver fibrosis, and completed the present invention on this basis.

术语定义Definition of Terms

本文中涉及到的一些基团定义如下：Some groups involved in this article are defined as follows:

本文中，“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链或环烷基，优选的烷基包括长1-5个、1-2个、1-6个、1-4个、3-8个碳原子不等的烷基。烷基的例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。烷基可以被1个或多个取代基取代，例如被卤素或卤代烷基取代。例如，烷基可以是被1-4个氟原子取代的烷基，或者烷基可以是被氟代烷基取代的烷基。As used herein, "alkyl" refers to a saturated branched or straight chain or cyclic alkyl group with a carbon chain length of 1-10 carbon atoms. Preferred alkyl groups include 1-5, 1-2, 1-6. One, 1-4, 3-8 alkyl groups with varying carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl and the like. The alkyl group may be substituted by one or more substituents, for example by halogen or haloalkyl. For example, the alkyl group may be an alkyl group substituted with 1-4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

本文中，“链烯基”通常表示具有至少一个双键的单价烃基，通常含有2-8个碳原子，优选含有2-6个碳原子，可以是直链或支链。链烯基的例子包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、己烯基等等。Herein, "alkenyl" generally means a monovalent hydrocarbon group with at least one double bond, usually containing 2-8 carbon atoms, preferably containing 2-6 carbon atoms, and may be straight or branched. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

本文中，“酯基”通常表示具有至少一个酯基的羧酸衍生物，通常含有3-8个碳原子，优选含有3-6个碳原子，可以是直链或支链。酯基的例子包括但不限于甲酸甲酯、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯等等。In this context, "ester group" generally refers to a carboxylic acid derivative having at least one ester group, usually containing 3-8 carbon atoms, preferably containing 3-6 carbon atoms, and may be linear or branched. Examples of ester groups include, but are not limited to, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, and the like.

本文中，“羟基”指碳链长度为1-10个碳原子的支链或直链醇，通常含有1-10个碳原子，优选含有1-6个碳原子，可以是直链或支链。酯羟基的例子包括但不限于1-羟基正丁基、1-羟基异丁基等等。In this context, "hydroxyl" refers to a branched or straight chain alcohol with a carbon chain length of 1-10 carbon atoms, usually containing 1-10 carbon atoms, preferably containing 1-6 carbon atoms, and can be straight or branched. . Examples of ester hydroxyl groups include, but are not limited to, 1-hydroxyn-butyl, 1-hydroxyisobutyl, and the like.

本文中，“酰氨基”指结构式为“-R’-NH-C(O)-R”的基团，其中，R’可选自氢或烷基，R可选自烷基、链烯基、炔基、被NR _cR _d取代的烷基、被NR _cR _d取代的链烯基和NR _cR _d取代的炔基、被卤素取代的烷基、被氰基取代的链烯基，其中，R _c和R _d可选自烷基和链烯基。 In this context, "amido" refers to a group with the structural formula "-R'-NH-C(O)-R", wherein R'can be selected from hydrogen or alkyl, and R can be selected from alkyl and alkenyl , alkynyl, NR _c R _d is substituted alkyl, NR _c R _d is substituted alkenyl and NR _c R _d group substituted alkynyl, halogen substituted alkyl, alkenyl substituted with cyano group, Among them, R _c and R _{d can be} selected from alkyl and alkenyl groups.

本文中，“芳基”指含有6到14个碳原子的单环、双环或三环芳族基团，包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。芳基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C _1-4醛基、C _1-6烷基、氰基、硝基、氨基、酰胺基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C _1-4烷氧基、乙氧甲酰基、N(CH ₃)和C _1-4酰基等、杂环基或杂芳基等。 As used herein, "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, indenyl, stilbene, tetralin Base, indanyl, etc. The aryl group may be optionally substituted with 1-5 (for example, 1, 2, 3, 4, or 5) substituents selected from the group consisting of halogen, C _1-4 aldehyde, C _1-6 alkyl, cyano Group, nitro, amino, amido, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxyl, C _1-4 Alkoxy, ethoxyformyl, N(CH ₃ ) and C _1-4 acyl, etc., heterocyclic group or heteroaryl group, etc.

本文中，“杂环基”包括但不限于含有1-3个选自O、S或N的杂原子的5元或6 元杂环基团，包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、***基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基等。As used herein, "heterocyclyl" includes but is not limited to 5-membered or 6-membered heterocyclic groups containing 1-3 heteroatoms selected from O, S or N, including but not limited to furyl, thienyl, pyrrolyl , Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, etc.

本文中，“芳杂环基”是指含有5-14个环原子，并且有6个、10个或14个电子在环体系上共用。而且所含环原子是碳原子和从氧、氮、硫中任选的1-3个杂原子。有用的芳杂环基包括哌嗪基、吗啉基、哌啶基、吡咯烷基、噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、吡啶基、包括但不限制于嘧啶基等。芳杂环基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C _1-4醛基、C _1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C _1-4烷氧基、乙氧甲酰基、N(CH ₃)和C _1-4酰基。 In this context, "aromatic heterocyclic group" means that it contains 5-14 ring atoms and has 6, 10, or 14 electrons shared in the ring system. Moreover, the ring atoms contained are carbon atoms and optionally 1-3 heteroatoms from oxygen, nitrogen, and sulfur. Useful aromatic heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to In pyrimidinyl and so on. The aromatic heterocyclic group may be optionally substituted with 1-5 (for example, 1, 2, 3, 4, or 5) substituents selected from the group consisting of halogen, C _1-4 aldehyde, C _1-6 straight chain Or branched chain alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxyl, C _1-4 alkoxy, ethoxyformyl, N(CH ₃ ) and C _1-4 acyl.

本文中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基，更优选为长1-3个碳原子的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、丙氧基等。烷氧基可以被1个或多个取代基取代，例如被卤素或卤代烷基取代。例如，烷氧基可以是被1-4个氟原子取代的烷基，或者烷基可以是被氟代烷基取代的烷基。As used herein, "alkoxy" refers to an oxy group substituted by an alkyl group. Preferred alkoxy groups are alkoxy groups having 1 to 6 carbon atoms in length, more preferably alkoxy groups having 1 to 3 carbon atoms in length. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy and the like. The alkoxy group may be substituted by one or more substituents, for example by halogen or haloalkyl. For example, the alkoxy group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

本文中，“卤素”指氟、氯、溴或碘。As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

本文中，“任选取代的”指其所修饰的取代基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C _1-4醛基、C _1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C _1-4烷氧基、乙氧甲酰基、N(CH ₃)和C _1-4酰基。 As used herein, "optionally substituted" means that the modified substituent may be optionally substituted with 1-5 (for example, 1, 2, 3, 4, or 5) substituents selected from the following: halogen, C _1-4 aldehyde groups, C _1-6 straight or branched chain alkyl groups, cyano groups, nitro groups, amino groups, hydroxyl groups, hydroxymethyl groups, halogen-substituted alkyl groups (e.g. trifluoromethyl), halogen-substituted alkoxy groups Group (e.g. trifluoromethoxy), carboxy, C _1-4 alkoxy, ethoxyformyl, N(CH ₃ ) and C _1-4 acyl.

本发明的化合物Compound of the present invention

本发明的化合物具备肝纤维化的治疗活性。具体地说，本发明提供通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：The compound of the present invention possesses the therapeutic activity of liver fibrosis. Specifically, the present invention provides a compound represented by general formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式I中的取代基各自如上文所述。The substituents in Formula I are each as described above.

在优选的实施方式中，本发明提供通式(II)所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：In a preferred embodiment, the present invention provides a compound represented by general formula (II), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式II中的取代基各自如上文所述。The substituents in Formula II are each as described above.

在优选的实施方式中，本发明提供通式(III)所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：In a preferred embodiment, the present invention provides a compound represented by the general formula (III), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式III中的取代基各自如上文所述。The substituents in Formula III are each as described above.

在优选的实施方式中，本发明提供通式(IV)所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：In a preferred embodiment, the present invention provides a compound represented by the general formula (IV), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式IV中的取代基各自如上文所述。The substituents in formula IV are each as described above.

在优选的实施方式中，本发明提供通式(V)所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：In a preferred embodiment, the present invention provides a compound represented by the general formula (V), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式V中的取代基各自如上文所述。The substituents in formula V are each as described above.

在具体的实施方式中，本发明提供选自下组的化合物或其药学上可接受的盐或前药：In a specific embodiment, the present invention provides a compound selected from the following group or a pharmaceutically acceptable salt or prodrug thereof:

在本发明的化合物的基础上，本发明提供一种药物组合物，该组合物含有治疗有效量的本发明的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。On the basis of the compound of the present invention, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient .

本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS，胺丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts, such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, and maleate , Fumarate, mandelate and oxalate; and inorganic and alkalis such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine Organic alkali salt.

本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成用于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药的形式，用于***和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。The pharmaceutical composition of the present invention can be formulated into a formulation suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, and cranial use. In the form of internal, nasal or external route of administration, it is used to treat tumors and other diseases. The dosage is the amount of medicine that is effective to improve or eliminate one or more conditions. For the treatment of a specific disease, an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease. Such a dose can be administered as a single dose, or it can be administered according to an effective treatment regimen. The dosage may cure the disease, but the administration is usually to improve the symptoms of the disease. Generally, repeated administration is required to achieve the desired symptom improvement. The dosage of the medicine will be determined according to the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired treatment benefit.

本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类。The pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention. The most important of these mammals is humans.

本发明的化合物或其药物组合物可用于治疗和预防肝纤维化相关的疾病。The compound of the present invention or its pharmaceutical composition can be used to treat and prevent diseases related to liver fibrosis.

本发明的药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。The pharmaceutical preparation of the present invention can be manufactured in a known manner. For example, it is manufactured by traditional mixing, granulating, ingoting, dissolving, or freeze-drying processes. When manufacturing oral preparations, solid excipients and active compounds can be combined to selectively grind the mixture. After adding an appropriate amount of additives if needed or necessary, the granule mixture is processed to obtain tablets or dragee cores.

合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有***树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。Suitable auxiliary materials are especially fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or dibasic calcium phosphate; and binders, such as starch pastes, including corn starch , Wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone. If necessary, disintegrating agents can be added, such as the starch mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt, such as sodium alginate. Auxiliary agents are especially flow regulators and lubricants, for example, silica, talc, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycol. If necessary, the tablet core can be provided with a suitable coating that can resist gastric juices. For this purpose, concentrated sugar solutions can be used. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture. In order to prepare a coating resistant to gastric juice, a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used. Dyestuffs or pigments can be added to the coating of tablets or lozenge cores. For example, to identify or to characterize combinations of active ingredient doses.

给药方法包括但不限于本领域周知的各种给药方法，可根据患者的实际情况加以确定。这些方法包括但不限于肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药。The administration method includes, but is not limited to, various administration methods known in the art, which can be determined according to the actual condition of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal or topical routes of administration.

本发明的优点：The advantages of the present invention:

1.本发明提供的化合物是一种结构全新抗肝纤维化结构；1. The compound provided by the present invention is a novel anti-hepatic fibrosis structure;

2.本发明提供的化合物对肝纤维化具有优异的抑制活性；2. The compound provided by the present invention has excellent inhibitory activity on liver fibrosis;

3.本发明提供的化合物为开发能抑制靶向肝纤维化药物奠定了基础，具备极大的产业化和商品化前景以及市场价值，经济效益显著。3. The compound provided by the present invention lays a foundation for the development of drugs capable of inhibiting targeted liver fibrosis, has great industrialization and commercialization prospects and market value, and has significant economic benefits.

以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The technical solution of the present invention will be further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute a limitation to the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention belong to the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

材料与方法Materials and Methods

2-(2,4,5-三氟苯基)-3,4-二氢-2H-苯并[h]色满-3-胺衍生物合成路线Synthetic route of 2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-benzo[h]chroman-3-amine derivative

试剂和条件：(a)1,1-Dichlorodimethyl Ether,AgOTf,DCM,-78℃to r.t.,N ₂，55.3％；(b)1,1-Dichlorodimethyl Ether,TiCl ₄,0℃to r.t.,22.5％-79.0％；(c)AlCl ₃,DCM,0℃to 40℃,40.5％-66.5％；(d)L-Pipecolinic,Toluene,120℃,N ₂,10.2％-42.5％；(e)1)NaBH ₄,THF/CH ₃OH,r.t.；2)DIPEA,EtOH,r.t.；(f)Zn,HCl,EtOH,r.t.,10.8％-25.9％；(g)CH ₃SO ₂Na,L-Proline,NaOH,CuI,DMSO,130℃,N ₂,88.8％；(h)CH ₃OH,H ₂SO ₄,70℃,95.0％；(i)CH ₃SO ₂Cl,pyridine,DCM,0℃to r.t.,45.0％；(j)Tf ₂O,Et ₃N,DCM,-78℃to r.t.,68.1％；(k)(1)(3,6-Dihydro-2H-pyran-4-yl)-boronic acid pinacol ester,Pd(PPh ₃) ₄,Cs ₂CO ₃,DMF/H ₂O,90℃,N ₂；(2)Pd/C,H ₂,MeOH,r.t.,73.3％for two steps；(l)(3-(methylsulfonyl)phenyl)boronic acid,Pd(PPh ₃) ₄,Cs ₂CO ₃,DMF/H ₂O,95℃,N ₂,73.0％；(m)morpholine,Pd ₂(dba) ₃,BINAP；t-BuOK,Toluene,100℃,N ₂,49.0％；(n)NaOH,MeOH/H ₂O,50℃,50.0％；(o)POCl ₃,DMF,0℃to r.t.,69.6％. Reagents and conditions: (a) 1,1-Dichlorodimethyl Ether, AgOTf, DCM, -78℃to rt, N ₂ , 55.3%; (b) 1,1-Dichlorodimethyl Ether,TiCl ₄ ,0℃to rt, 22.5% -79.0%; (c) AlCl ₃ , DCM, 0℃to 40℃, 40.5%-66.5％; (d) L-Pipecolinic, Toluene, 120℃, N ₂ , 10.2%-42.5%; (e)1) NaBH ₄ ,THF/CH ₃ OH,rt; 2) DIPEA, EtOH, rt; (f) Zn, HCl, EtOH, rt, 10.8%-25.9%; (g) CH ₃ SO ₂ Na, L-Proline, NaOH ,CuI,DMSO,130℃,N ₂ ,88.8%; (h)CH ₃ OH,H ₂ SO ₄ ,70℃,95.0%; (i)CH ₃ SO ₂ Cl,pyridine,DCM,0℃to rt, 45.0%; (j) Tf ₂ O, Et ₃ N, DCM, -78℃to rt, 68.1%; (k)(1)(3,6-Dihydro-2H-pyran-4-yl)-boronic acid pinacol ester,Pd(PPh ₃ ) ₄ ,Cs ₂ CO ₃ ,DMF/H ₂ O,90℃,N ₂ ;(2)Pd/C,H ₂ ,MeOH,rt,73.3% for two steps; (l)( 3-(methylsulfonyl)phenyl)boronic acid,Pd(PPh ₃ ) ₄ ,Cs ₂ CO ₃ ,DMF/H ₂ O,95℃,N ₂ ,73.0%; (m)morpholine,Pd ₂ (dba) ₃ ,BINAP ;T-BuOK,Toluene,100℃,N ₂ ,49.0%; (n)NaOH,MeOH/H ₂ O,50℃,50.0%; (o)POCl ₃ ,DMF,0℃to rt,69.6%.

2-(2,4,5-三氟苯基)-6-苯基-3,4-二氢-2H-色满-3-胺衍生物的合成路线Synthetic route of 2-(2,4,5-trifluorophenyl)-6-phenyl-3,4-dihydro-2H-chroman-3-amine derivative

试剂和条件：(a)Cs ₂CO ₃,PdCl ₂(dppf) ₂,DMF/H ₂O,100℃,N ₂,31.0-60.0％；(b) L-Pipecolinic,Toluene,120℃,N ₂,23.0％-70.0％；(c)1)NaBH ₄,THF/CH ₃OH,r.t.；2)DIPEA,EtOH,r.t.；(d)Zn,HCl,EtOH,r.t.,10.0％-69.0％. Reagents and conditions: (a) Cs ₂ CO ₃ , PdCl ₂ (dppf) ₂ , DMF/H ₂ O, 100℃, N ₂ , 31.0-60.0%; (b) L-Pipecolinic, Toluene, 120℃, N ₂ , 23.0%-70.0%; (c) 1) NaBH ₄ , THF/CH ₃ OH, rt; 2) DIPEA, EtOH, rt; (d) Zn, HCl, EtOH, rt, 10.0% -69.0%.

2-(2,4,5-三氟苯基)-3,4-二氢-2H-苯并[f]色满-3-胺衍生物合成路线Synthetic route of 2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-benzo[f]chroman-3-amine derivative

试剂和条件：(a)BBr ₃,DCM,-78℃to r.t.,77.6％；(b)CD ₃I or CH ₃CH ₂I,K ₂CO ₃,MeCN,40℃～50℃,45.5％；(c)Zn,HCl,EtOH,r.t.,30.5％；(d)Optical resolution. Reagents and conditions: (a) BBr ₃ , DCM, -78℃to rt, 77.6%; (b) CD ₃ I or CH ₃ CH ₂ I, K ₂ CO ₃ , MeCN, 40℃～50℃, 45.5%; (c) Zn, HCl, EtOH, rt, 30.5%; (d) Optical resolution.

2-苯基-3,4-二氢-2H-苯并[f]色满-3-胺的合成路线Synthetic route of 2-phenyl-3,4-dihydro-2H-benzo[f]chroman-3-amine

试剂和条件：(a)1,1-Dichlorodimethyl Ether,TiCl ₄,0℃to r.t.,74.5％；(b)AlCl ₃,DCM,0℃to 40℃,70.0％；(c)L-Pipecolinic,Toluene,120℃,N ₂,25％；(d)1)NaBH ₄,THF/CH ₃OH,r.t.；2)DIPEA,EtOH,r.t.,23％；(e)Zn,HCl,EtOH,r.t.,13％；(f)Optical resolution. Reagents and conditions: (a) 1,1-Dichlorodimethyl Ether, TiCl ₄ , 0℃to rt, 74.5%; (b) AlCl ₃ ,DCM, 0℃to 40℃, 70.0%; (c) L-Pipecolinic, Toluene , 120℃, N ₂ , 25%; (d) 1) NaBH ₄ , THF/CH ₃ OH, rt; 2) DIPEA, EtOH, rt, 23%; (e) Zn, HCl, EtOH, rt, 13% ;(F)Optical resolution.

实施例1.具体合成方法Example 1. Specific synthesis method

1-甲氧基-萘衍生物(8c、8e、8g-j)的合成Synthesis of 1-methoxy-naphthalene derivatives (8c, 8e, 8g-j)

1-甲氧基-4-甲磺酰基萘(8c)1-Methoxy-4-methylsulfonyl naphthalene (8c)

将1-碘-4-甲氧基萘酚(100.00mg,0.35mmol)、甲基亚磺酸钠(50.00mg，0.42mmol)，碘化亚铜(7.00mg,0.10mmol),L-脯氨酸(10.00mg,0.07mmol)，氢氧化钠(2.80mg,0.07mmol),无水DMSO(5mL)加入到25mL三口反应瓶中，氮气保护，升温至130℃搅拌，TLC监测反应进度。待反应结束后，冷却至室温，向反应体系中加入水10mL，然后用乙酸乙酯(10mL×3)萃取，有机相用卤水洗涤，再加入无水Na ₂SO ₄干燥，硅胶柱层析纯化分离(PE:EA＝10:1)，得淡黄色产品73.01mg,收率为87.9％。 ¹H NMR(400MHz,CDCl ₃)δ8.60(dd,J＝40.4,26.8Hz,1H),8.39(d,J＝8.4Hz,1H),8.28(d,J＝8.3Hz,1H),7.71(t,J＝7.7Hz,1H),7.59(t,J＝7.6Hz,1H),6.87(d,J＝8.4Hz,1H),4.07(s,3H),3.18(s,3H).LC-MS(ESI)m/z 237.05[M+H] ⁺. Combine 1-iodo-4-methoxynaphthol (100.00mg, 0.35mmol), sodium methanesulfinate (50.00mg, 0.42mmol), cuprous iodide (7.00mg, 0.10mmol), L-proline Acid (10.00mg, 0.07mmol), sodium hydroxide (2.80mg, 0.07mmol), and anhydrous DMSO (5mL) were added to a 25mL three-necked reaction flask, protected by nitrogen, heated to 130°C for stirring, and TLC monitored the progress of the reaction. After the reaction is over, cool to room temperature, add 10 mL of water to the reaction system, then extract with ethyl acetate (10 mL×3), wash the organic phase with brine, add anhydrous Na ₂ SO _{4 to} dry, and purify by silica gel column chromatography After separation (PE:EA=10:1), 73.01 mg of light yellow product was obtained, and the yield was 87.9%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.60 (dd, J = 40.4, 26.8 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 7.71 (t,J=7.7Hz,1H),7.59(t,J=7.6Hz,1H), 6.87(d,J=8.4Hz,1H),4.07(s,3H),3.18(s,3H).LC -MS(ESI)m/z 237.05[M+H] ⁺ .

4-甲氧基-1-萘甲酸甲酯(8e)Methyl 4-methoxy-1-naphthoate (8e)

将4-甲氧基-1-萘甲酸(1.00g，4.95mmol)加入单50mL两口反应瓶中，加入10mL甲醇溶解，冰浴下搅拌，然后缓慢滴加浓硫酸1mL,滴加完毕后，升温至70℃加热回流4小时。待原料完全转化，搅拌停止，待反应液冷却至室温，减压旋干反应液，加入10mL水，乙酸乙酯(3×10mL)萃取，有机相用饱和NaHCO ₃和卤水分别洗涤，无水Na ₂SO ₄干燥，硅胶柱层析纯化(PE:EA＝20:1)，得白色油状产品1.01g,收率为95.3％。 ¹H NMR(400MHz,CDCl ₃)δ9.03(d,J＝8.7Hz,1H),8.31(t,J＝11.3Hz,1H),8.24(d,J＝8.3Hz,1H),7.63(t,J＝8.4Hz,1H),7.52(t,J＝8.1Hz,1H),6.81(d,J＝8.3Hz,1H),4.06(s,3H),3.97(s,3H).LC-MS(ESI)m/z 271.01[M+H] ⁺. Add 4-methoxy-1-naphthoic acid (1.00g, 4.95mmol) into a single 50mL two-necked reaction flask, add 10mL of methanol to dissolve, stir under ice bath, then slowly add 1mL of concentrated sulfuric acid dropwise. After the addition is complete, warm up Heat to reflux at 70°C for 4 hours. When the raw materials are completely transformed, the stirring is stopped. When the reaction solution is cooled to room temperature, the reaction solution is spin-dried under reduced pressure. 10mL of water is added and extracted with ethyl acetate (3×10mL). The organic phase is washed with saturated NaHCO ₃ and brine, respectively, anhydrous Na ₂ SO _{4 was} dried and purified by silica gel column chromatography (PE:EA=20:1) to obtain 1.01 g of a white oily product with a yield of 95.3%. ¹ H NMR(400MHz,CDCl ₃ )δ9.03(d,J=8.7Hz,1H), 8.31(t,J=11.3Hz,1H), 8.24(d,J=8.3Hz,1H), 7.63(t ,J=8.4Hz,1H),7.52(t,J=8.1Hz,1H),6.81(d,J=8.3Hz,1H),4.06(s,3H),3.97(s,3H).LC-MS (ESI)m/z 271.01[M+H] ⁺ .

N-(4-甲氧基萘1-基)甲磺酰胺(8g)N-(4-methoxynaphthalene 1-yl)methanesulfonamide (8g)

取4-甲氧基萘-1胺(1.57g，9.06mmol)，吡啶(0.80mL，9.97mmol)于100mL反应瓶中，冰浴下逐滴滴加甲磺酰氯(1.14mL,9.06mmol)，控制温度在5℃以下， TLC监测反应。待反应结束后，加入3N NaOH溶液，然后二氯甲烷萃取，再有机相用饱和食盐水洗涤，无水Na ₂SO ₄干燥，最后用硅胶柱层析纯化(PE:EA＝8:1)。得淡黄色产品1.02g，产率为44.7％。 ¹H NMR(400MHz,DMSO-d6):δ9.47(s,1H),8.20(dd,J＝13.8,4.9Hz,2H),7.72-7.57(m,1H),7.56-7.50(m,1H),7.45(d,J＝8.2Hz,1H),6.98(d,J＝8.3Hz,1H),3.99(s,3H),2.98(s,3H).LC-MS(ESI)m/z 250.06[M-H] ^-. Take 4-methoxynaphthalene-1amine (1.57g, 9.06mmol) and pyridine (0.80mL, 9.97mmol) in a 100mL reaction flask, add methanesulfonyl chloride (1.14mL, 9.06mmol) dropwise under ice bath, Control the temperature below 5°C and TLC monitor the reaction. After the reaction is over, 3N NaOH solution is added, then extracted with dichloromethane, the organic phase is washed with saturated brine, dried with anhydrous Na ₂ SO ₄ , and finally purified by silica gel column chromatography (PE:EA=8:1). 1.02 g of light yellow product was obtained, and the yield was 44.7%. ¹ H NMR (400MHz, DMSO-d6): δ9.47 (s, 1H), 8.20 (dd, J = 13.8, 4.9 Hz, 2H), 7.72-7.57 (m, 1H), 7.56-7.50 (m, 1H) ),7.45(d,J=8.2Hz,1H),6.98(d,J=8.3Hz,1H),3.99(s,3H),2.98(s,3H).LC-MS(ESI)m/z 250.06 [MH] ^- .

1,1,1-三氟-N-(4-甲氧基萘-1-基)甲磺酰胺(8h)1,1,1-Trifluoro-N-(4-methoxynaphthalene-1-yl)methanesulfonamide (8h)

取4-甲氧基萘-1胺(1.00g，5.78mmol)，三乙胺(1.78mL，11.20mmol),二氯甲烷(15mL)于100mL反应瓶中，-78℃下逐滴滴加三氟甲磺酸酐(0.97mL，5.78mmol)，然后移至室温搅拌，TLC监测反应。待原料转化完全后，向反应瓶加入水淬灭，二氯甲烷萃取三次，有机相用饱和NaCl溶液洗涤，无水Na ₂SO ₄干燥，硅胶柱层析纯化(PE:EA＝10:1)，得产品1.20g，产率为68.2％。 ¹H NMR(400MHz,DMSO-d6)δ11.79(s,1H),8.23(d,J＝8.3Hz,1H),8.04(d,J＝8.4Hz,1H),7.71(t,J＝7.2Hz,1H),7.60(t,J＝7.3Hz,1H),7.46(d,J＝8.3Hz,1H),7.02(d,J＝8.3Hz,1H),4.01(s,3H).LC-MS(ESI)m/z 304.03[M-H] ^-. Take 4-methoxynaphthalene-1amine (1.00g, 5.78mmol), triethylamine (1.78mL, 11.20mmol), dichloromethane (15mL) in a 100mL reaction flask, and add three dropwise drops at -78°C. Fluoromethanesulfonic anhydride (0.97 mL, 5.78 mmol) was then moved to room temperature and stirred, and the reaction was monitored by TLC. After the conversion of the raw materials is complete, add water to the reaction flask to quench, extract with dichloromethane three times, wash the organic phase with saturated NaCl solution, dry with anhydrous Na ₂ SO ₄ , and purify by silica gel column chromatography (PE:EA=10:1) , The product is 1.20g, and the yield is 68.2%. ¹ H NMR(400MHz,DMSO-d6)δ11.79(s,1H), 8.23(d,J=8.3Hz,1H), 8.04(d,J=8.4Hz,1H), 7.71(t,J=7.2 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.01 (s, 3H). LC- MS(ESI)m/z 304.03[MH] ^- .

4-(4-甲氧基萘-1-基)四氢-2H-吡喃(8i)4-(4-methoxynaphthalene-1-yl)tetrahydro-2H-pyran (8i)

将1-溴-4-甲氧基萘酚(100.00mg,0.42mmol)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(79.60mg,0.50mmol)、四三苯基膦钯(97.00mg,0.08mmol),碳酸铯(410.00mg,1.26mmol)，DMF 2mL,水0.5mL，氮气置换三次，90℃搅拌，TLC监测。反应结束后，待体系冷却至室温，用乙酸乙酯(10mL×3)萃取，有机相用饱和NaCl洗涤，无水硫酸钠干燥，得到粗产品待下一步还原。Combine 1-bromo-4-methoxynaphthol (100.00mg, 0.42mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl Base-1,3,2-dioxaborane (79.60mg, 0.50mmol), palladium tetrakistriphenylphosphine (97.00mg, 0.08mmol), cesium carbonate (410.00mg, 1.26mmol), DMF 2mL, water 0.5 mL, replaced with nitrogen three times, stirred at 90°C, monitored by TLC. After the reaction, the system was cooled to room temperature and extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated NaCl and dried over anhydrous sodium sulfate to obtain a crude product to be reduced in the next step.

取上一步粗产品4-(4-甲氧基萘-1-基)-3,6-二氢-2H-吡喃，加入Pd/C(10％),适量甲醇溶解，体系氢气条件下(1个大气压)常温搅拌，TLC监测。待反应结束后，加水淬灭反应，用乙酸乙酯(10mL×3)萃取，有机相用卤水洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EA＝10:1)，得产品70.00mg，两步反应总收率为51.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.33(dd,J＝8.3,1.1Hz,1H),8.04(d,J＝8.4Hz,1H), 7.60-7.41(m,2H),7.27(d,J＝8.0Hz,1H),6.77(d,J＝8.0Hz,1H),4.20-4.06(m,2H),3.96(s,3H),3.75-3.59(m,2H),3.56-3.37(m,1H),2.02-1.79(m,4H).LC-MS(ESI)m/z 243.13[M+H] ⁺. Take the crude product 4-(4-methoxynaphthalen-1-yl)-3,6-dihydro-2H-pyran from the previous step, add Pd/C (10%), dissolve an appropriate amount of methanol, and the system under hydrogen conditions ( 1 atmosphere) stirring at room temperature and monitoring by TLC. After the reaction is over, add water to quench the reaction, extract with ethyl acetate (10mL×3), wash the organic phase with brine, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (PE:EA=10:1) to obtain the product 70.00mg, the total yield of the two-step reaction is 51.1%. ¹ H NMR(400MHz,CDCl ₃ )δ8.33(dd,J=8.3,1.1Hz,1H), 8.04(d,J=8.4Hz,1H), 7.60-7.41(m,2H), 7.27(d, J = 8.0Hz, 1H), 6.77 (d, J = 8.0Hz, 1H), 4.20-4.06 (m, 2H), 3.96 (s, 3H), 3.75-3.59 (m, 2H), 3.56-3.37 (m ,1H),2.02-1.79(m,4H).LC-MS(ESI)m/z 243.13[M+H] ⁺ .

1-甲氧基-4-(3-(甲磺酰基)苯基)萘(8j)1-Methoxy-4-(3-(methylsulfonyl)phenyl)naphthalene (8j)

称取1-溴-4甲氧基萘(0.20g，0.84mmol)，(3-(甲磺酰基)苯基)苯硼酸(0.20g，1.00mmol),碳酸铯(274.00mg，2.52mmol)，四三苯基膦钯(48.50mg,0.05mmol)，无水DMF 10mL，水3mL于50mL反应瓶中，氮气保护，升温至95℃充分搅拌，TLC监测。待原料基本转化完全，用水和乙酸乙酯萃取三次，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，硅胶柱层析纯化(PE:EA＝8:1)，得产品0.19g，产率为73.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.36(d,J＝8.2Hz,1H),8.06(s,1H),7.96(t,J＝9.7Hz,1H),7.82-7.71(m,2H),7.66(t,J＝7.7Hz,1H),7.57-7.41(m,2H),7.35(t,J＝8.6Hz,1H),6.88(d,J＝7.9Hz,1H),4.05(s,3H),3.11(s,3H).LC-MS(ESI)m/z 313.08[M+H] ⁺ Weigh 1-bromo-4methoxynaphthalene (0.20g, 0.84mmol), (3-(methylsulfonyl)phenyl)phenylboronic acid (0.20g, 1.00mmol), cesium carbonate (274.00mg, 2.52mmol), Tetratriphenylphosphine palladium (48.50 mg, 0.05 mmol), 10 mL of anhydrous DMF, 3 mL of water in a 50 mL reaction flask, protected by nitrogen, heated to 95° C. and stirred well, monitored by TLC. When the raw material is basically converted completely, it is extracted three times with water and ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=8:1) to obtain 0.19g of product. The yield was 73.1%. ¹ H NMR(400MHz,CDCl ₃ )δ8.36(d,J=8.2Hz,1H),8.06(s,1H),7.96(t,J=9.7Hz,1H),7.82-7.71(m,2H) ,7.66(t,J=7.7Hz,1H),7.57-7.41(m,2H),7.35(t,J=8.6Hz,1H),6.88(d,J=7.9Hz,1H),4.05(s, 3H),3.11(s,3H).LC-MS(ESI)m/z 313.08[M+H] ⁺

1-甲氧基-2-萘甲醛衍生物(9a-h)的合成Synthesis of 1-methoxy-2-naphthaldehyde derivative (9a-h)

4-溴-1-甲氧基-2-萘甲醛(9a)4-bromo-1-methoxy-2-naphthaldehyde (9a)

1,1-二氯甲基甲醚(0.73g，6.35mmol)，TiCl ₄(2.00g,10.60mmol)，CH ₂Cl ₂ 5mL加入到100mL三口反应瓶中，冰浴条件下搅拌16min，逐滴滴加1-溴4-甲氧基萘(1.00g,4.24mmol)的二氯甲烷(5mL)溶液，常温下继续搅拌，TLC监测。反应结束后，加入1mol/L的盐酸溶液，然后用CH ₂Cl ₂萃取三次，有机相用饱和NaCl溶液洗涤，无水硫酸钠干燥，减压蒸发溶剂，硅胶柱层析纯化(PE:EA＝5:1)，得白色粉末500.00mg，产率为22.4％。 ¹H NMR(400MHz,CDCl ₃)δ10.26(s,1H),9.22(d,J＝8.5Hz,1H),8.22(d,J＝8.4Hz,1H),8.11(s,1H),7.78-7.69(m,1H),7.66(dd,J＝11.2,4.1Hz,1H),4.09(s,3H).LC-MS(ESI)m/z 266.11[M+H] ⁺. 1,1-Dichloromethyl methyl ether (0.73g, 6.35mmol), TiCl ₄ (2.00g, 10.60mmol), CH ₂ Cl ₂ 5mL were added to a 100mL three-necked reaction flask, stirred for 16min under ice bath conditions, dropwise A solution of 1-bromo 4-methoxynaphthalene (1.00 g, 4.24 mmol) in dichloromethane (5 mL) was added dropwise, and stirring was continued at room temperature, monitored by TLC. After the reaction, 1mol/L hydrochloric acid solution was added, and then extracted with CH ₂ Cl ₂ three times. The organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (PE:EA= 5:1), 500.00 mg of white powder is obtained, and the yield is 22.4%. ¹ H NMR (400MHz, CDCl ₃ ) δ10.26 (s, 1H), 9.22 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.78 -7.69(m,1H),7.66(dd,J=11.2,4.1Hz,1H),4.09(s,3H).LC-MS(ESI)m/z 266.11[M+H] ⁺ .

1-甲氧基-4-甲磺酰基-2-萘甲醛(9b)1-Methoxy-4-methanesulfonyl-2-naphthaldehyde (9b)

向50mL三颈反应瓶中加入化合物1-甲氧基-4-(甲磺酰基)萘(0.50g，2.12mmol)、三氟甲烷磺酸银(1.63g，6.36mmol)、二氯甲烷10mL，反应体系氮气置换三次，-78℃下搅拌。再将1,1二氯甲基甲醚(0.73g，6.36mmol)滴加到上述反应液，十分钟后转移至室温搅拌，TLC监测。反应结束后，冰浴下缓慢加入饱和NaHCO ₃溶液，减压抽滤，滤液用乙酸乙酯(10mL)萃取三次，有机相用卤水洗涤，无水Na ₂SO ₄干燥，200-300目硅胶柱纯化(PE:EA＝5:1)，得到白色固体0.31g，收率为55.3％。 ¹H NMR(400MHz,CDCl ₃)δ10.57(s,1H),8.79(d,J＝8.6Hz,1H),8.75(s,1H),8.43(d,J＝8.4Hz,1H),7.96-7.83(m,1H),7.76(t,J＝7.7Hz,1H),4.24(s,3H),3.22(s,3H).LC-MS(ESI)m/z 265.04[M+H] ⁺. Add the compound 1-methoxy-4-(methylsulfonyl)naphthalene (0.50g, 2.12mmol), silver trifluoromethanesulfonate (1.63g, 6.36mmol), 10mL of dichloromethane to a 50mL three-necked reaction flask, The reaction system was replaced with nitrogen three times and stirred at -78°C. Then 1,1 dichloromethyl methyl ether (0.73 g, 6.36 mmol) was added dropwise to the above reaction solution, and after ten minutes, it was transferred to room temperature and stirred, monitored by TLC. After the reaction, slowly add saturated NaHCO ₃ solution under ice bath, filter under reduced pressure, extract the filtrate with ethyl acetate (10 mL) three times, wash the organic phase with brine, dry with anhydrous Na ₂ SO ₄ , 200-300 mesh silica gel column Purified (PE:EA=5:1) to obtain 0.31 g of a white solid with a yield of 55.3%. ¹ H NMR(400MHz,CDCl ₃ )δ10.57(s,1H), 8.79(d,J=8.6Hz,1H), 8.75(s,1H), 8.43(d,J=8.4Hz,1H),7.96 -7.83(m,1H),7.76(t,J=7.7Hz,1H),4.24(s,3H),3.22(s,3H).LC-MS(ESI)m/z 265.04[M+H] ⁺ .

3-甲酰基-4-甲氧基-1-萘甲酸甲酯(9c)Methyl 3-formyl-4-methoxy-1-naphthoate (9c)

合成步骤参照9a，得淡黄色固体2.28g，收率为70.7％。 ¹H NMR(400MHz,CDCl ₃)δ10.58(s,1H),9.02(d,J＝8.6Hz,1H),8.61(d,J＝4.0Hz,1H),8.61(s,1H),7.87-7.67(m,1H),7.65-7.58(m,1H),4.19(s,3H),4.00(s,3H).LC-MS(ESI)m/z 245.07[M+H] ⁺. The synthesis step refers to 9a, and 2.28 g of a light yellow solid is obtained, and the yield is 70.7%. ¹ H NMR (400MHz, CDCl ₃ ) δ10.58 (s, 1H), 9.02 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 4.0 Hz, 1H), 8.61 (s, 1H), 7.87 -7.67(m,1H),7.65-7.58(m,1H),4.19(s,3H),4.00(s,3H).LC-MS(ESI)m/z 245.07[M+H] ⁺ .

N-(3-甲酰基-4-甲氧基萘-1-基)甲磺酰胺(9d)N-(3-formyl-4-methoxynaphthalen-1-yl)methanesulfonamide (9d)

合成步骤参照9a，得白色粉末1.50g，产率58.1％. ¹H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.81(s,1H),8.37-8.27(m,2H),7.87-7.78(m,1H),7.76-7.70(m,2H),4.14(s,3H),3.03(s,3H).LC-MS(ESI)m/z 278.05[M-H] ^-. For the synthesis step refer to 9a, 1.50g of white powder was obtained, and the yield was 58.1%. ¹ H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.81(s,1H),8.37-8.27(m,2H) ,7.87-7.78(m,1H),7.76-7.70(m,2H),4.14(s,3H),3.03(s,3H).LC-MS(ESI)m/z 278.05[MH] ^- .

1,1,1-三氟-N-(3-甲酰基-4-甲氧基萘甲醛-1-基)甲磺酰胺(9e)1,1,1-Trifluoro-N-(3-formyl-4-methoxynaphthaldehyde-1-yl)methanesulfonamide (9e)

合成步骤参照9a，得淡黄色固体1.31g,产率33.1％。 ¹H NMR(400MHz, CDCl3)δ10.43(s,1H),8.23(d,J＝8.3Hz,1H),8.06(t,J＝7.9Hz,1H),7.84(s,1H),7.80-7.68(m,1H),7.65-7.56(m,1H),4.09(s,3H).LC-MS(ESI)m/z 332.02[M-H] ^-. Refer to 9a for the synthesis step to obtain 1.31 g of a light yellow solid with a yield of 33.1%. ¹ H NMR(400MHz, CDCl3)δ10.43(s,1H), 8.23(d,J=8.3Hz,1H), 8.06(t,J=7.9Hz,1H), 7.84(s,1H), 7.80- 7.68(m,1H),7.65-7.56(m,1H),4.09(s,3H).LC-MS(ESI)m/z 332.02[MH] ^- .

1-甲氧基-4-(四氢-2H-吡喃-4-基)-2-萘甲醛(9f)1-Methoxy-4-(tetrahydro-2H-pyran-4-yl)-2-naphthaldehyde (9f)

合成步骤参照9a，得淡黄色固体3.01g，收率79.1％。 ¹H NMR(400MHz,CDCl ₃)δ10.60(s,1H),8.32(dd,J＝8.3,0.8Hz,1H),8.14(d,J＝8.5Hz,1H),7.78(s,1H),7.75-7.65(m,1H),7.63-7.58(m,1H),4.27-4.00(m,5H),3.69(td,J＝11.7,2.1Hz,2H),3.55-3.45(m,1H),2.08-1.86(m,4H).LC-MS(ESI)m/z 271.12[M+H] ⁺. For the synthesis step, refer to 9a to obtain 3.01 g of light yellow solid, with a yield of 79.1%. ¹ H NMR(400MHz,CDCl ₃ )δ10.60(s,1H), 8.32(dd,J=8.3,0.8Hz,1H), 8.14(d,J=8.5Hz,1H),7.78(s,1H) ,7.75-7.65(m,1H),7.63-7.58(m,1H), 4.27-4.00(m,5H), 3.69(td,J=11.7,2.1Hz,2H),3.55-3.45(m,1H) ,2.08-1.86(m,4H).LC-MS(ESI)m/z 271.12[M+H] ⁺ .

1-甲氧基-4-(3-(甲基磺酰基)苯基)-2-萘甲醛(9g)1-Methoxy-4-(3-(methylsulfonyl)phenyl)-2-naphthaldehyde (9g)

合成步骤参照9a，得淡黄色固体2.33g，产率55.2％. ¹H NMR(400MHz,CDCl3)δ10.65(s,1H),8.43-8.32(m,1H),8.06(d,J＝1.2Hz,1H),8.03(t,J＝1.5Hz,1H),7.82(s,1H),7.80-7.75(m,2H),7.72(t,J＝7.5Hz,1H),7.69-7.62(m,2H),4.22(s,3H),3.14(s,3H).LC-MS(ESI)m/z 341.07[M+H] ⁺. For the synthesis step refer to 9a, 2.33g of light yellow solid was obtained, and the yield was 55.2%. ¹ H NMR (400MHz, CDCl3) δ 10.65 (s, 1H), 8.43-8.32 (m, 1H), 8.06 (d, J = 1.2 Hz, 1H), 8.03 (t, J = 1.5 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.69-7.62 (m ,2H),4.22(s,3H),3.14(s,3H).LC-MS(ESI)m/z 341.07[M+H] ⁺ .

1-甲氧基-4-吗啉-1-萘甲醛(9h)1-Methoxy-4-morpholine-1-naphthaldehyde (9h)

将化合物4-溴-1-甲氧基-2-萘甲醛(200.00mg,0.76mmol)，吗啉(0.08mL,0.906mmol)，Pd ₂(dba) ₃(3.68mg,0.5％mol),BINAP(4.70mg,0.01mmol)，叔丁醇钾(143.36mg,1.28mmol)加入到25mL三口反应瓶中,氮气保护后加入甲苯10mL，升温至100℃搅拌，TLC监测。反应结束后，冷却至室温，用乙酸乙酯(10mL)萃取三次，有机相用卤水洗涤，无水Na ₂SO ₄干燥，200-300目硅胶柱纯化(PE:EA＝ 5:1)。得淡黄色固体100.00mg，产率48.8％。 ¹H NMR(400MHz,CDCl ₃)δ10.58(s,1H),8.36-8.20(m,2H),7.75-7.70(m,1H),7.65-7.58(m,1H),7.47(s,1H),4.12(s,3H),3.98(dd,J＝15.8,11.1Hz,4H),3.22-3.04(m,4H).LC-MS(ESI)m/z 272.12[M+H] ⁺. The compound 4-bromo-1-methoxy-2-naphthaldehyde (200.00mg, 0.76mmol), morpholine (0.08mL, 0.906mmol), Pd ₂ (dba) ₃ (3.68mg, 0.5% mol), BINAP (4.70 mg, 0.01 mmol), potassium tert-butoxide (143.36 mg, 1.28 mmol) was added to a 25 mL three-necked reaction flask, 10 mL of toluene was added after nitrogen protection, and the temperature was raised to 100° C. for stirring, and TLC monitoring. After the reaction, it was cooled to room temperature, extracted three times with ethyl acetate (10 mL), the organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , and purified by 200-300 mesh silica gel column (PE:EA=5:1). 100.00 mg of light yellow solid was obtained, and the yield was 48.8%. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.58 (s, 1H), 8.36-8.20 (m, 2H), 7.75-7.70 (m, 1H), 7.65-7.58 (m, 1H), 7.47 (s, 1H) ),4.12(s,3H),3.98(dd,J=15.8,11.1Hz,4H),3.22-3.04(m,4H).LC-MS(ESI)m/z 272.12[M+H] ⁺ .

1-羟基-2-萘甲醛衍生物(11a-j)的合成Synthesis of 1-hydroxy-2-naphthaldehyde derivatives (11a-j)

1-羟基-2-萘甲醛(11a)1-hydroxy-2-naphthaldehyde (11a)

合成步骤参照9a,得黄色油状产物2.33g，产率30.3％。 ¹H NMR(400MHz,CDCl ₃)δ11.70(s,1H),9.00(s,1H),7.47(d,J＝8.0Hz,1H),6.81(d,J＝8.2Hz,1H),6.69(t,J＝7.5Hz,1H),6.58(t,J＝7.6Hz,1H),6.52(d,J＝8.6Hz,1H),6.40(d,J＝8.6Hz,1H).LC-MS(ESI)m/z 173.10[M+H] ⁺. For the synthesis procedure referring to 9a, 2.33 g of yellow oily product was obtained, with a yield of 30.3%. ¹ H NMR(400MHz,CDCl ₃ )δ11.70(s,1H),9.00(s,1H),7.47(d,J=8.0Hz,1H), 6.81(d,J=8.2Hz,1H), 6.69 (t,J=7.5Hz,1H), 6.58(t,J=7.6Hz,1H), 6.52(d,J=8.6Hz,1H), 6.40(d,J=8.6Hz,1H).LC-MS (ESI)m/z 173.10[M+H] ⁺ .

1-羟基-4-甲氧基-2-萘甲醛(11b)1-hydroxy-4-methoxy-2-naphthaldehyde (11b)

合成步骤参照9a，得淡黄色油状产物2.01g，产率50.2％。 ¹H NMR(400MHz,CDCl ₃)δ12.37(s,1H),9.91(s,1H),8.42(d,J＝8.2Hz,1H),8.21(d,J＝8.4Hz,1H),7.74-7.62(m,1H),7.60-7.55(m,1H),6.72(s,1H),3.99(s,3H).LC-MS(ESI)m/z 203.06[M+H] ⁺. The synthesis procedure is referred to 9a, and 2.01 g of a pale yellow oily product is obtained, with a yield of 50.2%. ¹ H NMR(400MHz,CDCl ₃ )δ12.37(s,1H),9.91(s,1H),8.42(d,J=8.2Hz,1H), 8.21(d,J=8.4Hz,1H),7.74 -7.62(m,1H),7.60-7.55(m,1H),6.72(s,1H),3.99(s,3H).LC-MS(ESI)m/z 203.06[M+H] ⁺ .

4-溴-1-羟基-2-萘甲醛(11c)4-bromo-1-hydroxy-2-naphthaldehyde (11c)

将化合物4-溴-1甲氧基2-萘甲醛(200.00mg,0.76mmol)，二氯甲烷5mL加入到50mL三口瓶中,冰浴下搅拌10分钟，缓慢加入三氯化铝(301.25mg,2.27mmol),升至40℃加热，TLC监测。反应结束后，冷却至室温，加入稀盐酸淬灭反应，用CH ₂Cl ₂(20mL)萃取三次，有机相卤水洗涤，无水Na ₂SO ₄干燥，硅胶柱纯化(PE:EA＝5:1)，得淡黄色固体125.22mg，收率为66.4％。 ¹H NMR(400MHz,CDCl ₃)δ12.51(s,1H),9.82(s,1H),8.38(dd,J＝8.3,0.5Hz,1H),8.09(d,J＝8.5Hz,1H),7.83-7.70(m,1H),7.67(s,1H),7.63-7.48(m,1H).LC-MS(ESI)m/z 251.10[M+H] ⁺. The compound 4-bromo-1methoxy-2-naphthaldehyde (200.00mg, 0.76mmol), 5mL of dichloromethane was added to a 50mL three-necked flask, stirred under ice bath for 10 minutes, slowly added aluminum trichloride (301.25mg, 2.27mmol), heated to 40°C, monitored by TLC. After the reaction, cool to room temperature, add dilute hydrochloric acid to quench the reaction, _{extract three times with CH 2} Cl ₂ (20 mL), wash the organic phase with brine, dry with anhydrous Na ₂ SO ₄ , and purify on a silica gel column (PE:EA=5:1 ), 125.22 mg of light yellow solid was obtained, and the yield was 66.4%. ¹ H NMR(400MHz,CDCl ₃ )δ12.51(s,1H),9.82(s,1H),8.38(dd,J=8.3,0.5Hz,1H), 8.09(d,J=8.5Hz,1H) ,7.83-7.70(m,1H),7.67(s,1H),7.63-7.48(m,1H).LC-MS(ESI)m/z 251.10[M+H] ⁺ .

1-羟基-4-甲磺酰基-2-萘甲醛(11d)1-Hydroxy-4-methylsulfonyl-2-naphthaldehyde (11d)

合成步骤参考11c，得淡黄色固体2.50g，收率为60.5％。 ¹H NMR(400MHz,DMSO)δ10.33(s,1H),8.59(d,J＝8.6Hz,1H),8.54(d,J＝8.5Hz,1H),8.49(s,1H),7.90-7.87(m,1H),7.80-7.72(m,1H),4.10(s,1H),3.34(s,3H).LC-MS(ESI)m/z 251.10[M+H] ⁺. For the synthesis procedure referring to 11c, 2.50 g of a pale yellow solid was obtained with a yield of 60.5%. ¹ H NMR (400MHz, DMSO) δ 10.33 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.49 (s, 1H), 7.90- 7.87(m,1H),7.80-7.72(m,1H),4.10(s,1H),3.34(s,3H).LC-MS(ESI)m/z 251.10[M+H] ⁺ .

3-甲酰基-4-羟基-1-萘甲酸甲酯(11e)Methyl 3-formyl-4-hydroxy-1-naphthoate (11e)

合成步骤参考11c，得淡黄色固体1.50g，收率为65.5％。 ¹H NMR(400MHz DMSO)δ10.25(s,1H),8.93(d,J＝8.6Hz,1H),8.48(s,1H),8.45(d,J＝8.2Hz,1H),7.98-7.78(m,1H),7.69(t,J＝7.4Hz,1H),3.94(d,J＝10.9Hz,3H).LC-MS(ESI)m/z 231.05[M+H] ⁺. For the synthesis procedure referring to 11c, 1.50 g of light yellow solid was obtained, and the yield was 65.5%. ¹ H NMR(400MHz DMSO)δ10.25(s,1H), 8.93(d,J=8.6Hz,1H), 8.48(s,1H), 8.45(d,J=8.2Hz,1H),7.98-7.78 (m,1H),7.69(t,J=7.4Hz,1H),3.94(d,J=10.9Hz,3H).LC-MS(ESI)m/z 231.05[M+H] ⁺ .

N-(3-甲酰基-4-羟基萘-1-基)甲磺酰胺(11f)N-(3-formyl-4-hydroxynaphthalene-1-yl)methanesulfonamide (11f)

合成步骤参考11c，得淡黄色固体1.22g，收率为60.1％。 ¹H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.24(s,1H),9.59(s,1H),8.51-8.33(m,1H),8.26(d,J＝8.4Hz,1H),7.87-7.77(m,1H),7.73(s,1H),7.70-7.56(m,1H),3.04(s,3H).LC-MS(ESI)m/z 264.04[M-H] ^-. For the synthesis procedure referring to 11c, 1.22 g of a pale yellow solid was obtained, and the yield was 60.1%. ¹ H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.24(s,1H),9.59(s,1H),8.51-8.33(m,1H),8.26(d,J=8.4Hz ,1H),7.87-7.77(m,1H),7.73(s,1H),7.70-7.56(m,1H),3.04(s,3H).LC-MS(ESI)m/z 264.04[MH] ^- .

1,1,1-三氟-N-(3-甲酰基-4-羟基萘-1-基)甲磺酰胺(11g)1,1,1-Trifluoro-N-(3-formyl-4-hydroxynaphthalene-1-yl)methanesulfonamide (11g)

合成步骤参考11c，得淡黄色固体1.01g，收率为50.1％。 ¹H NMR(400MHz,DMSO-d6)δ12.31(s,1H),10.28(s,1H),8.45(d,J＝8.4Hz,1H),8.08(d,J＝8.4Hz,1H),7.90(t,J＝7.7Hz,1H),7.80-7.65(m,2H).LC-MS(ESI)m/z 318.01[M-H] ^-. For the synthesis procedure referring to 11c, 1.01 g of light yellow solid was obtained, and the yield was 50.1%. ¹ H NMR(400MHz,DMSO-d6)δ12.31(s,1H), 10.28(s,1H), 8.45(d,J=8.4Hz,1H), 8.08(d,J=8.4Hz,1H), 7.90(t,J=7.7Hz,1H),7.80-7.65(m,2H).LC-MS(ESI)m/z 318.01[MH] ^- .

1-羟基-4-(四氢-2H-吡喃-4-基)-2-萘甲醛(11h)1-Hydroxy-4-(tetrahydro-2H-pyran-4-yl)-2-naphthaldehyde (11h)

合成步骤参考11c，得淡黄色固体2.53g，收率为55.3％。 ¹H NMR(400MHz,CDCl ₃)δ12.54(s,1H),9.96(d,J＝9.6Hz,1H),8.52(d,J＝7.6Hz,1H),8.04(d,J＝8.6Hz,1H),7.78-7.67(m,1H),7.56(dt,J＝19.0,5.9Hz,1H),7.36(s,1H),4.17(dt,J＝11.1,2.7Hz,2H),3.84-3.59(m,2H),3.45(m,1H),2.14-1.75(m,4H).LC-MS(ESI)m/z 257.10[M+H] ⁺. For the synthesis procedure referring to 11c, 2.53 g of a pale yellow solid was obtained, and the yield was 55.3%. ¹ H NMR(400MHz, CDCl ₃ )δ12.54(s,1H), 9.96(d,J=9.6Hz,1H), 8.52(d,J=7.6Hz,1H), 8.04(d,J=8.6Hz , 1H), 7.78-7.67 (m, 1H), 7.56 (dt, J = 19.0, 5.9 Hz, 1H), 7.36 (s, 1H), 4.17 (dt, J = 11.1, 2.7 Hz, 2H), 3.84 3.59(m,2H),3.45(m,1H),2.14-1.75(m,4H).LC-MS(ESI)m/z 257.10[M+H] ⁺ .

1-羟基-4-吗啉-2-萘甲醛(11i)1-Hydroxy-4-morpholine-2-naphthaldehyde (11i)

合成步骤参考11c，得淡黄色产品0.80g，产率为40.0％。 ¹H NMR(400MHz,CDCl ₃)δ12.50(s,1H),9.95(s,1H),8.59-8.14(m,2H),7.86-7.52(m,2H),7.19(d,J＝57.8Hz,1H),3.98(m,4H),3.06(m,4H).LC-MS(ESI)m/z 258.10[M+H] ⁺. The synthesis step refers to 11c, and 0.80 g of light yellow product is obtained, and the yield is 40.0%. ¹ H NMR (400MHz, CDCl ₃ ) δ 12.50 (s, 1H), 9.95 (s, 1H), 8.59-8.14 (m, 2H), 7.86-7.52 (m, 2H), 7.19 (d, J = 57.8 Hz,1H),3.98(m,4H),3.06(m,4H).LC-MS(ESI)m/z 258.10[M+H] ⁺ .

1-羟基-4-(3-(甲基磺酰基)苯基)-2-萘甲醛(11j)1-Hydroxy-4-(3-(methylsulfonyl)phenyl)-2-naphthaldehyde (11j)

合成步骤参考11c，得淡黄色固体1.50g，收率为66.1％。 ¹H NMR(400MHz,CDCl ₃)δ12.71(s,1H),10.01(s,1H),8.57(dd,J＝8.1,0.9Hz,1H),8.20-8.10(m,1H),8.05-7.88(m,1H),7.78(dt,J＝7.6,1.4Hz,1H),7.72(dd,J＝8.3,6.8Hz,2H),7.67(dt,J＝3.0,1.5Hz,1H),7.64(dd,J＝4.7,1.6Hz,1H),7.61(dt,J＝11.1,2.9Hz,1H),7.47(s,1H),3.14(s,3H).LC-MS(ESI)m/z 327.06[M+H] ⁺. For the synthesis procedure referring to 11c, 1.50 g of light yellow solid was obtained, and the yield was 66.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ 12.71 (s, 1H), 10.01 (s, 1H), 8.57 (dd, J = 8.1, 0.9 Hz, 1H), 8.20-8.10 (m, 1H), 8.05 7.88(m,1H),7.78(dt,J=7.6,1.4Hz,1H),7.72(dd,J=8.3,6.8Hz,2H),7.67(dt,J=3.0,1.5Hz,1H),7.64 (dd,J=4.7,1.6Hz,1H),7.61(dt,J=11.1,2.9Hz,1H),7.47(s,1H),3.14(s,3H).LC-MS(ESI)m/z 327.06[M+H] ⁺ .

4-羟基-1H-吲哚-5-甲醛的合成(17)Synthesis of 4-hydroxy-1H-indole-5-carbaldehyde (17)

量取5mL DMF于250mL三口反应瓶中，加入三氯氧磷(3.45g,22.56mmol)，冰浴下搅拌。再称取4-羟基吲哚(1.00g，7.52mmol)，用5mL DMF溶解，逐滴滴加到上述反应体系中,TLC监测反应进度。待原料转化完全后，加入冰水，用乙酸乙酯(10mL)萃取三次，有机相用卤水洗涤，无水Na ₂SO ₄干燥，200-300目硅胶柱纯化(PE:EA＝8:1)，得到目标产物0.80g，收率为69.6％。 ¹H NMR(400MHz,DMSO-d6)δ11.79(s,1H),11.62(s,1H),10.03(s,1H),7.38(d,J＝8.5Hz,1H),7.36-7.33(m,1H),7.04(d,J＝8.5Hz,1H),6.72(m,1H).LC-MS(ESI)m/z 162.05[M+H] ⁺. Measure 5mL DMF into a 250mL three-necked reaction flask, add phosphorus oxychloride (3.45g, 22.56mmol), and stir under ice bath. Then 4-hydroxyindole (1.00 g, 7.52 mmol) was weighed, dissolved in 5 mL DMF, and added dropwise to the above reaction system, and the progress of the reaction was monitored by TLC. After the conversion of the raw materials is complete, add ice water, extract three times with ethyl acetate (10 mL), wash the organic phase with brine, dry with anhydrous Na ₂ SO ₄ , and purify by 200-300 mesh silica gel column (PE:EA=8:1) 0.80 g of the target product was obtained, and the yield was 69.6%. ¹ H NMR(400MHz,DMSO-d6)δ11.79(s,1H),11.62(s,1H),10.03(s,1H),7.38(d,J=8.5Hz,1H),7.36-7.33(m ,1H),7.04(d,J=8.5Hz,1H),6.72(m,1H).LC-MS(ESI)m/z 162.05[M+H] ⁺ .

2-(2,4,5-三氟苯基)-3-硝基-2H-苯并[h]色满衍生物(13a-j)的合成Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-2H-benzo[h]chroman derivatives (13a-j)

2-(2,4,5-三氟苯基)-3-硝基-2H-苯并[h]色满(13a)2-(2,4,5-trifluorophenyl)-3-nitro-2H-benzo[h]chroman(13a)

称取1-羟基-2-萘甲醛(150.00mg，0.86mmol)，20mL甲苯，2,4,5-三氟苯硝基乙烯(174.70mg，0.86mmol)，L-哌啶甲酸(110.90mg，0.86mmol)加入到125mL三口瓶，氮气保护，120℃过夜搅拌，溶液由淡黄色逐渐变为暗红色。冷却至室温，二氯甲烷萃取三次，无水Na ₂SO ₄干燥，减压蒸发多余的甲苯，二氯甲烷溶解，拌入硅胶粉，最后使用硅胶柱层析分离纯化(PE:EA＝4:1)，得橙红色目标产物90.00mg，收率为28.9％。 ¹H NMR(400MHz,CDCl ₃)δ8.27(s,1H),8.11(d,J＝8.3Hz,1H),7.76(d,J＝8.1Hz,1H),7.60-7.52(m,1H),7.52-7.44(m,2H),7.35(d,J＝8.5Hz,1H),7.10(s,1H),6.98-6.95(m,2H). Weigh 1-hydroxy-2-naphthaldehyde (150.00mg, 0.86mmol), 20mL of toluene, 2,4,5-trifluorophenylnitroethylene (174.70mg, 0.86mmol), L-piperidinecarboxylic acid (110.90mg, 0.86mmol) was added to a 125mL three-neck flask, protected by nitrogen, and stirred overnight at 120°C. The solution gradually changed from light yellow to dark red. Cool to room temperature, extract with dichloromethane three times, dry with anhydrous Na ₂ SO ₄ , evaporate excess toluene under reduced pressure, dissolve in dichloromethane, stir in silica gel powder, and finally use silica gel column chromatography to separate and purify (PE:EA=4: 1), 90.00 mg of the orange-red target product was obtained, and the yield was 28.9%. ¹ H NMR(400MHz,CDCl ₃ )δ8.27(s,1H), 8.11(d,J=8.3Hz,1H), 7.76(d,J=8.1Hz,1H), 7.60-7.52(m,1H) ,7.52-7.44(m,2H), 7.35(d,J=8.5Hz,1H), 7.10(s,1H), 6.98-6.95(m,2H).

2-(2,4,5-三氟苯基)-3-硝基-6-甲氧基-2H-苯并[h]色满(13b)2-(2,4,5-Trifluorophenyl)-3-nitro-6-methoxy-2H-benzo[h]chroman(13b)

合成方法参照13a，得橙红色固体1.55g，收率为30.2％。 ¹H NMR(400MHz,CDCl ₃)δ8.24(s,1H),8.19(t,J＝9.6Hz,1H),8.06(t,J＝9.2Hz,1H),7.63-7.45(m,2H),7.06-6.95(m,2H),6.62(s,1H),5.30(s,1H),4.00(s,3H). The synthesis method refers to 13a, and 1.55 g of orange-red solid is obtained, and the yield is 30.2%. ¹ H NMR(400MHz,CDCl ₃ )δ8.24(s,1H), 8.19(t,J=9.6Hz,1H), 8.06(t,J=9.2Hz,1H), 7.63-7.45(m,2H) ,7.06-6.95(m,2H), 6.62(s,1H), 5.30(s,1H), 4.00(s,3H).

2-(2,4,5-三氟苯基)-3-硝基-6-溴-2H-苯并[h]色满(13c)2-(2,4,5-Trifluorophenyl)-3-nitro-6-bromo-2H-benzo[h]chroman(13c)

合成方法参照13a，得橙红色固体1.21g，收率为29.5％。 ¹H NMR(400MHz,CDCl ₃)δ8.20(s,1H),8.14(dd,J＝8.8,2.2Hz,1H),7.95(d,J＝13.8Hz,1H),7.67(d,J＝5.8Hz,1H),7.63(s,1H),7.59-7.51(m,1H),7.40-7.31(m,1H),7.13-6.98(m,2H). The synthesis method refers to 13a, and 1.21 g of orange-red solid is obtained, and the yield is 29.5%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 8.14 (dd, J = 8.8, 2.2 Hz, 1H), 7.95 (d, J = 13.8 Hz, 1H), 7.67 (d, J = 5.8Hz, 1H), 7.63 (s, 1H), 7.59-7.51 (m, 1H), 7.40-7.31 (m, 1H), 7.13-6.98 (m, 2H).

2-(2,4,5-三氟苯基)-3-硝基-6-甲磺酰基-2H-苯并[h]色满(13d)2-(2,4,5-Trifluorophenyl)-3-nitro-6-methanesulfonyl-2H-benzo[h]chroman(13d)

合成方法参照13a，得暗红色固体1.02g，收率为10.5％。 ¹H NMR(400MHz,CDCl ₃)δ8.70-8.60(m,1H),8.30(s,1H),8.26(d,J＝8.2Hz,2H),7.80(dd,J＝11.4,4.2Hz,1H),7.63(dd,J＝13.0,5.8Hz,1H),7.18(s,1H),7.15-6.99(m,2H),3.22(s,3H). The synthesis method refers to 13a, and 1.02 g of dark red solid is obtained, and the yield is 10.5%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.70-8.60 (m, 1H), 8.30 (s, 1H), 8.26 (d, J = 8.2 Hz, 2H), 7.80 (dd, J = 11.4, 4.2 Hz, 1H), 7.63(dd,J=13.0,5.8Hz,1H), 7.18(s,1H), 7.15-6.99(m,2H), 3.22(s,3H).

2-(2,4,5-三氟苯基)-3-硝基-6-甲酸甲酯基-2H-苯并[h]色满(13e)2-(2,4,5-Trifluorophenyl)-3-nitro-6-methyl carboxylate-2H-benzo[h]chroman(13e)

合成方法参照13a，得橙红色固体2.55g，收率为41.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.98(t,J＝7.3Hz,1H),8.28(s,1H),8.21(s,1H),8.18(d,J＝8.4Hz,1H),7.70(t,J＝8.5Hz,1H),7.57-7.51(m,1H),7.15(s,1H),7.09-6.97(m,2H),4.01(s, 3H). The synthesis method refers to 13a, and 2.55 g of orange-red solid is obtained, and the yield is 41.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.98 (t, J = 7.3Hz, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.70 (t,J=8.5Hz,1H), 7.57-7.51 (m, 1H), 7.15 (s, 1H), 7.09-6.97 (m, 2H), 4.01 (s, 3H).

2-(2,4,5-三氟苯基)-3-硝基-6-甲磺酰胺基-2H-苯并[h]色满(13f)2-(2,4,5-Trifluorophenyl)-3-nitro-6-methanesulfonamido-2H-benzo[h]chroman(13f)

合成方法参照13a，得暗红色固体1.55g，收率为42.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.25(s,1H),8.18(d,J＝8.4Hz,1H),8.01(d,J＝8.5Hz,1H),7.69(t,J＝7.7Hz,1H),7.57(dd,J＝9.5,5.3Hz,2H),7.12(s,1H),7.11-6.97(m,2H),6.77(s,1H),3.04(s,3H).LC-MS(ESI)m/z 449.015[M-H] ^-. The synthesis method refers to 13a, and 1.55 g of dark red solid is obtained, and the yield is 42.1%. ¹ H NMR(400MHz,CDCl ₃ )δ8.25(s,1H), 8.18(d,J=8.4Hz,1H), 8.01(d,J=8.5Hz,1H), 7.69(t,J=7.7Hz ,1H),7.57(dd,J=9.5,5.3Hz,2H),7.12(s,1H),7.11-6.97(m,2H),6.77(s,1H),3.04(s,3H).LC- MS(ESI)m/z 449.015[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-(1,1,1-三氟甲基)磺酰胺基-2H-苯并[h]色满(13g)2-(2,4,5-trifluorophenyl)-3-nitro-6-(1,1,1-trifluoromethyl)sulfonamido-2H-benzo[h]chroman (13g)

合成方法参照13a，得暗红色固体1.05g，收率为32.0％。 ¹H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.05(dd,J＝15.8,7.0Hz,2H),7.82-7.75(m,1H),7.73-7.67(m,2H),7.62(dd,J＝16.5,9.2Hz,2H),7.17(s,1H).LC-MS(ESI)m/z 503.10[M-H] ^-. The synthesis method refers to 13a, and 1.05 g of dark red solid is obtained, and the yield is 32.0%. ¹ H NMR(400MHz,DMSO-d6)δ8.64(s,1H), 8.05(dd,J=15.8,7.0Hz,2H),7.82-7.75(m,1H),7.73-7.67(m,2H) ,7.62(dd,J=16.5,9.2Hz,2H),7.17(s,1H).LC-MS(ESI)m/z 503.10[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-(四氢-2H-吡喃-4-基)-2H-苯并[h]色满(13h)2-(2,4,5-Trifluorophenyl)-3-nitro-6-(tetrahydro-2H-pyran-4-yl)-2H-benzo[h]chroman(13h)

合成方法参照13a，得橙红色固体1.55g，收率为42.9％。 ¹H NMR(400MHz,CDCl ₃)δ8.29(s,1H),8.18(d,J＝7.8Hz,1H),8.04(dd,J＝21.0,6.9Hz,1H),7.69-7.56(m,1H),7.50(t,J＝7.6Hz,1H),7.24(s,1H),7.10(s,1H),7.09-6.96(m,2H),4.41-3.92(m,2H),3.88-3.54(m,3H),3.50-3.34(m,1H),2.00-1.85(m,4H). The synthesis method refers to 13a, and 1.55 g of orange-red solid is obtained, and the yield is 42.9%. ¹ H NMR(400MHz,CDCl ₃ )δ8.29(s,1H), 8.18(d,J=7.8Hz,1H), 8.04(dd,J=21.0,6.9Hz,1H), 7.69-7.56(m, 1H),7.50(t,J=7.6Hz,1H),7.24(s,1H),7.10(s,1H),7.09-6.96(m,2H),4.41-3.92(m,2H),3.88-3.54 (m,3H),3.50-3.34(m,1H),2.00-1.85(m,4H).

2-(2,4,5-三氟苯基)-3-硝基-6-吗啉基-2H-苯并[h]色满(13i)2-(2,4,5-Trifluorophenyl)-3-nitro-6-morpholino-2H-benzo[h]chroman(13i)

合成方法参照13a，得橙红色固体2.01g，收率为40.2％。 ¹H NMR(400MHz,CDCl ₃)δ8.24(d,J＝16.2Hz,1H),8.16(d,J＝8.4Hz,1H),8.12(d,J＝8.2Hz,1H),7.65-7.55(m,1H),7.50(t,J＝7.2Hz,1H),7.08(d,J＝6.7Hz,1H),7.07-6.99(m,2H),6.96(s,1H),4.29-3.63(m,4H),3.30-2.85(m,4H).LC-MS(ESI)m/z 443.10[M+H] ⁺. The synthesis method refers to 13a, and 2.01 g of orange-red solid is obtained, and the yield is 40.2%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.24 (d, J = 16.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.65-7.55 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 6.7 Hz, 1H), 7.07-6.99 (m, 2H), 6.96 (s, 1H), 4.29-3.63 ( m,4H),3.30-2.85(m,4H).LC-MS(ESI)m/z 443.10[M+H] ⁺ .

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(甲基磺酰基)苯基)-2H-苯并[h]色满(13j)2-(2,4,5-Trifluorophenyl)-3-nitro-6-(3-(methylsulfonyl)phenyl)-2H-benzo[h]chroman(13j)

合成方法参照13a，得产物1.55g，收率为38.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.29(s,1H),8.26-8.19(m,1H),8.04(dd,J＝7.0,1.3Hz,2H),7.80-7.65(m,3H),7.61-7.49(m,2H),7.34(s,1H),7.15(s,1H),7.13-6.99(m,2H),3.14(s,3H). The synthesis method refers to 13a, and the product is 1.55g, and the yield is 38.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.26-8.19 (m, 1H), 8.04 (dd, J = 7.0, 1.3 Hz, 2H), 7.80-7.65 (m, 3H), 7.61-7.49 (m, 2H), 7.34 (s, 1H), 7.15 (s, 1H), 7.13-6.99 (m, 2H), 3.14 (s, 3H).

(9)2-(2,4,5-三氟苯基)-3-硝基-2,7-二氢吡喃并[2,3-e]吲哚的合成(18)(9) Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-2,7-dihydropyrano[2,3-e]indole (18)

合成方法参照13a，得橙红色固体1.95g，收率为55.3％。 ¹H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.54(s,1H),7.75-7.55(m,1H),7.47-7.38(m,1H),7.33-7.28(m,2H),7.13(d,J＝8.4Hz,1H),6.99(s,1H),6.45-6.34(s,1H).LC-MS(ESI)m/z 345.01[M+H] ⁺. The synthesis method refers to 13a, and 1.95 g of orange-red solid is obtained, and the yield is 55.3%. ¹ H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.54(s,1H),7.75-7.55(m,1H),7.47-7.38(m,1H),7.33-7.28(m, 2H),7.13(d,J=8.4Hz,1H),6.99(s,1H),6.45-6.34(s,1H).LC-MS(ESI)m/z 345.01[M+H] ⁺ .

2-(2,4,5-三氟苯基)-3-硝基-3,4-二氢-2H-苯并[h]色满衍生物(14a-j)的合成Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-3,4-dihydro-2H-benzo[h]chroman derivative (14a-j)

2-(2,4,5-三氟苯基)-3-硝基-3,4-二氢-2H-苯并[h]色满(14a)2-(2,4,5-trifluorophenyl)-3-nitro-3,4-dihydro-2H-benzo[h]chroman(14a)

将化合物2-(2,4,5-三氟苯基)-3-硝基-2H-苯并[h]色烯(500.00mg,1.40mmol),四氢呋喃5mL，甲醇0.5mL加入到25mL三口瓶中，冰浴下搅拌，缓慢加入NaBH ₄粉末(266.00mg，7.00mmol)，TLC监测反应进度，反应结束后，加入饱和NH ₄Cl溶液，乙酸乙酯(10mL)萃取三次，有机相用无水Na ₂SO ₄干燥，减压蒸发除去溶剂。然后用乙醇5mL将上述粗品溶解，加入DIPEA0.25mL,常温搅拌，TLC监测。反应结束后，乙酸乙酯(10mL)萃取三次，有机相用卤水洗涤，无水Na ₂SO ₄干燥，减压蒸发除去溶剂，得反式消旋体产品，待投下一步锌粉还原反应。 Add the compound 2-(2,4,5-trifluorophenyl)-3-nitro-2H-benzo[h]chromene (500.00mg, 1.40mmol), tetrahydrofuran 5mL, methanol 0.5mL into a 25mL three-necked flask After stirring under ice bath, NaBH ₄ powder (266.00 mg, 7.00 mmol) was slowly added, and the progress of the reaction was monitored by TLC. After the reaction was completed, saturated NH ₄ Cl solution was added and extracted three times with ethyl acetate (10 mL). The organic phase was washed with anhydrous It was _{dried over Na 2} SO ₄ and evaporated under reduced pressure to remove the solvent. Then dissolve the above crude product with 5 mL of ethanol, add 0.25 mL of DIPEA, stir at room temperature, and monitor by TLC. After the completion of the reaction, ethyl acetate (10 mL) was extracted three times, the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure to remove the solvent to obtain the trans racemate product, which is to be cast in the next step of zinc powder reduction reaction.

14b-j的合成方法参照14a，粗品直接用于下一步反应。The synthesis method of 14b-j refers to 14a, and the crude product is directly used in the next reaction.

2-(2,4,5-三氟苯基)-3-硝基-2,3,4,7-四氢吡喃并[2,3-e]吲哚的合成(19)Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-2,3,4,7-tetrahydropyrano[2,3-e]indole (19)

合成方法参照14a，粗品直接用于下一步反应。The synthesis method refers to 14a, and the crude product is directly used in the next reaction.

trans-2-(2,4,5-三氟苯基)-3,4-二氢-2H-苯并[h]色满-3-胺衍生物(15a-j)的合成Synthesis of trans-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-benzo[h]chroman-3-amine derivative (15a-j)

trans-2-(2,4,5-三氟苯基)-3,4-二氢-2H-苯并[h]色满-3-胺(15a)trans-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-benzo[h]chroman-3-amine(15a)

称取化合物trans-2-(2,4,5-三氟苯基)-3-硝基-3,4-二氢-2H-苯并[h]色满(325.00mg,0.90mmol),锌粉(585.00mg,9.00mmol),6N盐酸2.4mL加入到25mL三口反应瓶中，常温下搅拌，TLC监测，反应结束后，加入饱和碳酸氢钠溶液调节PH到弱碱性(7-8)，减压抽滤，滤液用乙酸乙酯和水洗涤，有机用相卤水洗涤，无水硫酸钠干燥，硅胶柱层析(200-300)纯化(PE:EA＝1:1)，得白色固体75.00mg，收率为25.3％。熔点：300.1-301.5℃。 ¹H NMR(400MHz,DMSO-d6)δ7.95(d,J＝7.7Hz,1H),7.85(dd,J＝8.6,7.3Hz,1H),7.77-7.57(m,2H),7.51-7.39(m,3H),7.26(d,J＝8.4Hz,1H),5.03(d,J＝9.1Hz,1H),3.37(td,J＝9.5,5.4Hz,1H),3.18-2.99(m,1H),2.97-2.79(m,1H),2.03-1.44(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.43,149.46,148.76,146.83,133.20,128.18,127.90,126.23,125.90,124.41,124.17,121.41,120.52,117.73,116.07,106.58,77.46,48.65,34.97.HRMS(EI):calcd for C ₁₉H ₁₄F ₃NO[M] ⁺m/z 329.1027；found,329.1028. Weigh the compound trans-2-(2,4,5-trifluorophenyl)-3-nitro-3,4-dihydro-2H-benzo[h]chroman (325.00mg, 0.90mmol), zinc Powder (585.00mg, 9.00mmol), 2.4mL of 6N hydrochloric acid was added to a 25mL three-necked reaction flask, stirred at room temperature and monitored by TLC. After the reaction, saturated sodium bicarbonate solution was added to adjust the pH to weakly alkaline (7-8). Vacuum filtration under reduced pressure, the filtrate was washed with ethyl acetate and water, the organic phase was washed with brine, dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (200-300) (PE:EA=1:1) to obtain a white solid 75.00 mg, the yield was 25.3%. Melting point: 300.1-301.5°C. ¹ H NMR (400MHz, DMSO-d6) δ 7.95 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 8.6, 7.3 Hz, 1H), 7.77-7.57 (m, 2H), 7.51-7.39 (m, 3H), 7.26 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 9.1 Hz, 1H), 3.37 (td, J = 9.5, 5.4 Hz, 1H), 3.18-2.99 (m, 1H), 2.97-2.79 (m, 1H), 2.03-1.44 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.43,149.46,148.76,146.83,133.20,128.18,127.90,126.23,125.90,124.41 ,124.17,121.41,120.52,117.73,116.07,106.58,77.46,48.65,34.97. HRMS(EI): calcd for C ₁₉ H ₁₄ F ₃ NO[M] ⁺ m/z 329.1027; found, 329.1028.

trans-2-(2,4,5-三氟苯基)-6-甲氧基-3,4-二氢-2H-苯并[h]色满-3-胺(15b)trans-2-(2,4,5-trifluorophenyl)-6-methoxy-3,4-dihydro-2H-benzo[h]chroman-3-amine (15b)

合成方法参照15a，得白色固体22.20mg，收率20.1％。熔点：346.1-347.8℃。 ¹H NMR(400MHz,DMSO-d6)δ8.14-8.01(m,1H),7.95-7.85(m,1H),7.76-7.54(m,2H),7.52-7.38(m,2H),6.71(s,1H),4.95(d,J＝9.0Hz,1H),3.93(s,3H),3.40-3.36(m,1H),3.05(dd,J＝16.7,5.4Hz,1H),2.86(dd,J＝16.6,10.1Hz,1H),1.61(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.38,149.35,149.15,146.82, 142.53,126.54,125.65,125.12,124.75,124.37,121.86,121.36,117.65,115.57,106.54,105.94,77.26,56.11,48.89,35.40.HRMS(EI):calcd for C ₂₀H ₁₆F ₃NO ₂[M] ⁺m/z 359.1133；found,359.1132. The synthesis method refers to 15a to obtain 22.20 mg of white solid, with a yield of 20.1%. Melting point: 346.1-347.8°C. ¹ H NMR (400MHz, DMSO-d6) δ8.14-8.01 (m, 1H), 7.95-7.85 (m, 1H), 7.76-7.54 (m, 2H), 7.52-7.38 (m, 2H), 6.71 ( s, 1H), 4.95 (d, J = 9.0 Hz, 1H), 3.93 (s, 3H), 3.40-3.36 (m, 1H), 3.05 (dd, J = 16.7, 5.4 Hz, 1H), 2.86 (dd , J = 16.6, 10.1 Hz, 1H), 1.61 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.38,149.35,149.15,146.82,142.53,126.54,125.65,125.12,124.75,124.37,121.86, 121.36,117.65,115.57,106.54,105.94,77.26,56.11,48.89,35.40. HRMS(EI): calcd for C ₂₀ H ₁₆ F ₃ NO ₂ [M] ⁺ m/z 359.1133; found, 359.1132.

trans-2-(2,4,5-三氟苯基)-6-溴-3,4-二氢-2H-苯并[h]色满-3-胺(15c)trans-2-(2,4,5-trifluorophenyl)-6-bromo-3,4-dihydro-2H-benzo[h]chroman-3-amine(15c)

合成方法参照15a，得白色固体20.05mg，收率24.1％。熔点：372.5-373.9℃。 ¹H NMR(400MHz,DMSO-d6)δ8.02(dd,J＝10.0,9.1Hz,2H),7.73-7.68(m,1H),7.67(s,1H),7.66-7.60(m,2H),7.54(t,J＝8.1Hz,1H),5.05(d,J＝9.1Hz,1H),3.41-3.36(m,1H),3.09(dd,J＝16.7,5.2Hz,1H),2.99-2.79(m,1H),1.66(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.47,149.55,148.84,146.91,131.58,130.85,128.01,126.94,126.62,125.66,123.72,122.15,117.79,117.63,112.53,106.62,77.58,48.36,34.43.HRMS(EI):calcd for C ₁₉H ₁₃BrF ₃NO[M] ⁺m/z 407.0133；found,407.0134. For the synthesis method, refer to 15a to obtain 20.05 mg of white solid, with a yield of 24.1%. Melting point: 372.5-373.9°C. ¹ H NMR(400MHz,DMSO-d6)δ8.02(dd,J=10.0,9.1Hz,2H),7.73-7.68(m,1H),7.67(s,1H),7.66-7.60(m,2H) ,7.54(t,J=8.1Hz,1H),5.05(d,J=9.1Hz,1H),3.41-3.36(m,1H),3.09(dd,J=16.7,5.2Hz,1H),2.99- 2.79 (m, 1H), 1.66 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.47,149.55,148.84,146.91,131.58,130.85,128.01,126.94,126.62,125.66,123.72,122.15,117.79, 117.63,112.53,106.62,77.58,48.36,34.43. HRMS(EI): calcd for C ₁₉ H ₁₃ BrF ₃ NO[M] ⁺ m/z 407.0133; found, 407.0134.

trans-2-(2,4,5-三氟苯基)-6-甲磺酰基-3,4-二氢-2H-苯并[h]色满-3-胺(15d)trans-2-(2,4,5-trifluorophenyl)-6-methanesulfonyl-3,4-dihydro-2H-benzo[h]chroman-3-amine(15d)

合成方法参照15a，得白色固体15.10mg，收率11.5％。熔点：323.9-325.0℃。 ¹H NMR(400MHz,DMSO-d6)δ8.60(d,J＝8.6Hz,1H),8.18(d,J＝7.9Hz,1H),8.08(s,1H),7.84-7.79(m,2H),7.75-7.64(m,2H),5.23(d,J＝9.1Hz,1H),3.35(s,3H),3.21(dd,J＝10.5,5.2Hz,1H),3.00(dd,J＝16.5,10.3Hz,1H),1.80(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.54,153.81,149.66,146.86,132.33,128.82,128.43,127.93,127.03,124.88,124.28,123.43,122.73,117.90,115.13,106.70,78.19,48.16,44.65,34.32.HRMS(EI):calcd for C ₂₀H ₁₆F ₃NO ₃S[M] ⁺m/z 407.0803； found,407.0801. The synthesis method refers to 15a to obtain 15.10 mg of white solid with a yield of 11.5%. Melting point: 323.9-325.0°C. ¹ H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.6Hz,1H), 8.18(d,J=7.9Hz,1H), 8.08(s,1H),7.84-7.79(m,2H ), 7.75-7.64 (m, 2H), 5.23 (d, J = 9.1 Hz, 1H), 3.35 (s, 3H), 3.21 (dd, J = 10.5, 5.2 Hz, 1H), 3.00 (dd, J = 16.5, 10.3 Hz, 1H), 1.80 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.54,153.81,149.66,146.86,132.33,128.82,128.43,127.93,127.03,124.88,124.28,123.43,122.73 ,117.90,115.13,106.70,78.19,48.16,44.65,34.32. HRMS(EI): calcd for C ₂₀ H ₁₆ F ₃ NO ₃ S[M] ⁺ m/z 407.0803; found, 407.0801.

trans-2-(2,4,5-三氟苯基)-6-甲酸甲酯基-3,4-二氢-2H-苯并[h]色满-3-胺(15e)trans-2-(2,4,5-trifluorophenyl)-6-methylcarboxylate-3,4-dihydro-2H-benzo[h]chroman-3-amine (15e)

合成方法参照15a，得白色固体55.15mg，收率15.0％。熔点：377.1-378.5℃。 ¹H NMR(400MHz,DMSO-d6)δ8.92(d,J＝8.6Hz,1H),8.21-8.03(m,2H),7.83-7.62(m,3H),7.56(t,J＝7.6Hz,1H),5.18(d,J＝9.1Hz,1H),3.96(s,3H),3.45-3.43(m,1H),3.16(dd,J＝16.4,5.1Hz,1H),2.95(dd,J＝16.4,10.4Hz,1H),1.27(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ168.47,157.32,155.65,151.65,151.36,149.71,147.63,146.04,133.34(s),131.74,128.35,126.60,126.19,124.54,121.83,120.72,120.47,118.09,112.13(s),107.53,72.95,56.48,46.55.HRMS(EI):calcd for C ₂₁H ₁₆F ₃NO ₃[M] ⁺m/z 387.1082；found,387.1080. The synthesis method refers to 15a to obtain 55.15 mg of white solid with a yield of 15.0%. Melting point: 377.1-378.5°C. ¹ H NMR(400MHz,DMSO-d6)δ8.92(d,J=8.6Hz,1H),8.21-8.03(m,2H),7.83-7.62(m,3H),7.56(t,J=7.6Hz ,1H), 5.18(d,J=9.1Hz,1H),3.96(s,3H),3.45-3.43(m,1H),3.16(dd,J=16.4,5.1Hz,1H), 2.95(dd, J = 16.4, 10.4 Hz, 1H), 1.27 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ168.47,157.32,155.65,151.65,151.36,149.71,147.63,146.04,133.34(s),131.74, 128.35,126.60,126.19,124.54,121.83,120.72,120.47,118.09,112.13(s),107.53,72.95,56.48,46.55.HRMS(EI):calcd for C ₂₁ H ₁₆ F ₃ NO ₃ [M] ⁺ m/ z 387.1082; found,387.1080.

trans-2-(2,4,5-三氟苯基)-6-甲磺酰胺基-3,4-二氢-2H-苯并[h]色满-3-胺(15f)trans-2-(2,4,5-trifluorophenyl)-6-methanesulfonamido-3,4-dihydro-2H-benzo[h]chroman-3-amine (15f)

合成方法参照15a，得白色固体44.55mg，收率12.0％。熔点：376.6-378.1℃。 ¹H NMR(400MHz,DMSO-d6)δ8.16(d,J＝8.3Hz,1H),7.96(d,J＝8.1Hz,1H),7.77-7.59(m,2H),7.51(dt,J＝14.9,7.0Hz,2H),7.27(s,2H),6.70(s,1H),5.05(d,J＝9.1Hz,1H),3.08(dd,J＝16.6,5.1Hz,1H),3.00(s,3H),2.89(dd,J＝16.4,10.3Hz,1H),1.77(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.50,149.52,147.96,146.86,130.46,126.87,126.61,126.27,125.82,124.95,124.05,123.92,121.62,117.73,115.80,106.66,77.59,48.53,34.78,22.97.HRMS(EI):calcd for C ₂₀H ₁₇F ₃N ₂O ₃S[M] ⁺m/z 422.0912；found,422.0911. For the synthesis method, refer to 15a to obtain 44.55 mg of white solid, with a yield of 12.0%. Melting point: 376.6-378.1°C. ¹ H NMR (400MHz, DMSO-d6) δ 8.16 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.77-7.59 (m, 2H), 7.51 (dt, J =14.9,7.0Hz,2H),7.27(s,2H),6.70(s,1H),5.05(d,J＝9.1Hz,1H),3.08(dd,J＝16.6,5.1Hz,1H),3.00 (s, 3H), 2.89 (dd, J = 16.4, 10.3 Hz, 1H), 1.77 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.50,149.52,147.96,146.86,130.46,126.87,126.61 ,126.27,125.82,124.95,124.05,123.92,121.62,117.73,115.80,106.66,77.59,48.53,34.78,22.97.HRMS(EI):calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₃ S[M] ⁺ m /z 422.0912; found,422.0911.

trans-2-(2,4,5-三氟苯基)-6-(1,1,1-三氟甲基)磺酰胺基-3,4-二氢-2H-苯并[h] 色满-3-胺(15g)trans-2-(2,4,5-trifluorophenyl)-6-(1,1,1-trifluoromethyl)sulfonamido-3,4-dihydro-2H-benzo[h] color Man-3-amine (15g)

合成方法参照15a，得白色固体55.50mg，收率15.0％。熔点：380.8-381.9℃。 ¹H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.40-8.28(m,1H),7.91(dd,J＝6.5,3.0Hz,1H),7.79-7.66(m,1H),7.56-7.47(m,1H),7.42(dd,J＝6.4,3.3Hz,2H),6.97(s,1H),5.50(d,J＝7.2Hz,1H),4.13(dd,J＝13.1,7.0Hz,1H),3.13(dd,J＝17.0,5.4Hz,1H),3.03(dd,J＝16.9,7.3Hz,1H). ¹³C NMR(151MHz,DMSO-d6)δ156.14,150.21,146.78,141.78,132.00,130.73,129.14,125.86,125.24,125.04,124.78,123.74,121.32,120.72,118.28,117.62,112.53,107.40,71.85,47.12,28.77.HRMS(EI):calcd for C ₂₀H ₁₄F ₆N ₂O ₃S[M] ⁺m/z 476.0629；found,476.0628. The synthesis method refers to 15a to obtain 55.50 mg of white solid with a yield of 15.0%. Melting point: 380.8-381.9°C. ¹ H NMR (400MHz, DMSO-d6) δ 10.12 (s, 1H), 8.40-8.28 (m, 1H), 7.91 (dd, J = 6.5, 3.0 Hz, 1H), 7.79-7.66 (m, 1H) ,7.56-7.47(m,1H),7.42(dd,J=6.4,3.3Hz,2H), 6.97(s,1H), 5.50(d,J=7.2Hz,1H), 4.13(dd,J=13.1 ,7.0Hz,1H),3.13(dd,J=17.0,5.4Hz,1H),3.03(dd,J=16.9,7.3Hz,1H). ¹³ C NMR(151MHz,DMSO-d6)δ156.14,150.21,146.78 ,141.78,132.00,130.73,129.14,125.86,125.24,125.04,124.78,123.74,121.32,120.72,118.28,117.62,112.53,107.40,71.85,47.12,28.77.HRMS(EI):calcd for C ₂₀ H ₁₄ F ₆ N ₂ O ₃ S[M] ⁺ m/z 476.0629; found, 476.0628.

trans-2-(2,4,5-三氟苯基)-6-(四氢-2H-吡喃-4-基)-3,4-二氢-2H-苯并[h]色满-3-胺(15h)trans-2-(2,4,5-trifluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[h]chroman- 3-amine (15h)

合成方法参照15a，得白色固体60.10mg，收率15.1％。熔点：402.9-403.6℃。 ¹H NMR(400MHz,DMSO-d6)δ8.12(d,J＝8.5Hz,1H),7.98(d,J＝8.1Hz,1H),7.64(dt,J＝17.2,11.2Hz,2H),7.49(dd,J＝15.6,8.1Hz,1H),7.46-7.39(m,1H),7.15(s,1H),4.99(d,J＝9.1Hz,1H),4.02(dd,J＝21.1,9.0Hz,2H),3.62(dd,J＝15.7,9.1Hz,2H),3.56-3.45(m,1H),3.05(dd,J＝16.5,5.1Hz,1H),2.86(dd,J＝16.3,10.3Hz,1H),1.85-1.70(m,5H). ¹³C NMR(151MHz,DMSO-d6)δ156.48,149.44,147.31,146.85,134.33,130.75,126.24,125.51,124.77,124.62,124.29,123.42,122.12,117.73,115.50,106.63,77.41,68.08,48.76,35.74,35.08,34.16. HRMS(EI):calcd for C ₂₄H ₂₂F ₃NO ₂[M] ⁺m/z 413.1603；found,413.1602. For the synthesis method, refer to 15a to obtain 60.10 mg of white solid with a yield of 15.1%. Melting point: 402.9-403.6°C. ¹ H NMR(400MHz,DMSO-d6)δ8.12(d,J=8.5Hz,1H),7.98(d,J=8.1Hz,1H), 7.64(dt,J=17.2,11.2Hz,2H), 7.49(dd,J=15.6,8.1Hz,1H),7.46-7.39(m,1H),7.15(s,1H),4.99(d,J=9.1Hz,1H),4.02(dd,J=21.1, 9.0Hz,2H),3.62(dd,J=15.7,9.1Hz,2H),3.56-3.45(m,1H),3.05(dd,J=16.5,5.1Hz,1H), 2.86(dd,J=16.3 , 10.3 Hz, 1H), 1.85-1.70 (m, 5H). ¹³ C NMR (151MHz, DMSO-d6) δ156.48,149.44,147.31,146.85,134.33,130.75,126.24,125.51,124.77,124.62,124.29,123.42, 122.12,117.73,115.50,106.63,77.41,68.08,48.76,35.74,35.08,34.16. HRMS(EI): calcd for C ₂₄ H ₂₂ F ₃ NO ₂ [M] ⁺ m/z 413.1603; found, 413.1602.

trans-2-(2,4,5-三氟苯基)-6-吗啉基-3,4-二氢-2H-苯并[h]色满-3-胺(15i)trans-2-(2,4,5-trifluorophenyl)-6-morpholino-3,4-dihydro-2H-benzo[h]chroman-3-amine (15i)

合成方法参照15a，得白色固体25.10mg，收率23.5％。熔点：431.9-433.2℃。 ¹H NMR(400MHz,DMSO-d6)δ8.12(d,J＝7.9Hz,1H),7.93(d,J＝8.0Hz,1H),7.77-7.56(m,2H),7.54-7.38(m,2H),6.92(s,1H),4.97(d,J＝9.1Hz,1H),3.95-3.72(m,4H),3.34-3.30(m,1H),3.02(dt,J＝12.0,6.0Hz,1H),2.98-2.90(m,4H),2.84(dd,J＝16.5,10.2Hz,1H),1.61(s,2H). ¹³C NMR(101MHz,DMSO-d6)δ150.70,148.10,145.26,142.86,139.89,128.29,126.00,125.87,125.39,124.26,123.55,121.89,117.62,117.01,115.57,106.59,77.36,67.15,53.88,48.80,35.16.HRMS(EI):calcd for C ₂₃H ₂₁F ₃N ₂O ₂[M] ⁺m/z 414.1555；found,414.1554. The synthesis method refers to 15a, and a white solid of 25.10 mg is obtained with a yield of 23.5%. Melting point: 431.9-433.2°C. ¹ H NMR(400MHz,DMSO-d6)δ8.12(d,J=7.9Hz,1H),7.93(d,J=8.0Hz,1H),7.77-7.56(m,2H),7.54-7.38(m ,2H),6.92(s,1H),4.97(d,J=9.1Hz,1H),3.95-3.72(m,4H),3.34-3.30(m,1H),3.02(dt,J=12.0,6.0 Hz, 1H), 2.98-2.90 (m, 4H), 2.84 (dd, J = 16.5, 10.2 Hz, 1H), 1.61 (s, 2H). ¹³ C NMR (101MHz, DMSO-d6) δ 150.70, 148.10, 145.26 ,142.86,139.89,128.29,126.00,125.87,125.39,124.26,123.55,121.89,117.62,117.01,115.57,106.59,77.36,67.15,53.88,48.80,35.16.HRMS(EI):calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ [M] ⁺ m/z 414.1555; found,414.1554.

trans-2-(2,4,5-三氟苯基)-6-羧基-3,4-二氢-2H-苯并[h]色满-3-胺(15j)trans-2-(2,4,5-trifluorophenyl)-6-carboxy-3,4-dihydro-2H-benzo[h]chroman-3-amine (15j)

称取3-氨基-2-(2,4,5-三氟苯基)-3,4-二氢-2H-苯并[h]色烯-6-羧酸甲酯(20.00mg，0.05mmol)，加入2mL甲醇溶解,加入氢氧化钠水溶液(6.00mg，0.15mmol)，50℃回流，反应结束后，稀盐酸调节PH至中性，乙酸乙酯(10mL)萃取三次，无水Na ₂SO ₄干燥，硅胶柱层析纯化(PE:EA＝1:2)，得白色固体10.10mg，收率50.0％。熔点：484.5-485.6℃。 ¹H NMR(400MHz,DMSO-d6)δ9.01(d,J＝8.5Hz,1H),8.03(d,J＝6.7Hz,2H),7.78-7.62(m,2H),7.59(t,J＝7.1Hz,1H),7.49(t,J＝7.2Hz,1H),5.14(d,J＝9.0Hz,1H),3.12(dd,J＝16.4,5.1Hz,2H),2.92(dd,J＝16.3,10.3Hz,2H),1.91(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ172.00,156.35,154.12,149.45,143.19,132.78,129.92,129.24,128.36,128.09,127.35,126.15, 123.75,122.63,117.90,116.93,106.64,77.07,48.31,34.45.HRMS(EI):calcd for C ₂₀H ₁₄F ₃NO ₃[M] ⁺m/z 373.0926；found,373.0925. Weigh 3-amino-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-benzo[h]chromene-6-carboxylic acid methyl ester (20.00mg, 0.05mmol ), add 2mL methanol to dissolve, add sodium hydroxide aqueous solution (6.00mg, 0.15mmol), reflux at 50℃, after the reaction, adjust the pH to neutral with dilute hydrochloric acid, extract three times with ethyl acetate (10mL), anhydrous Na ₂ SO ₄ Dry and purify by silica gel column chromatography (PE:EA=1:2) to obtain 10.10 mg of white solid, with a yield of 50.0%. Melting point: 484.5-485.6°C. ¹ H NMR(400MHz,DMSO-d6)δ9.01(d,J=8.5Hz,1H), 8.03(d,J=6.7Hz,2H), 7.78-7.62(m,2H), 7.59(t,J ＝7.1Hz,1H),7.49(t,J＝7.2Hz,1H), 5.14(d,J＝9.0Hz,1H), 3.12(dd,J＝16.4,5.1Hz,2H), 2.92(dd,J = 16.3, 10.3 Hz, 2H), 1.91 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ172.00,156.35,154.12,149.45,143.19,132.78,129.92,129.24,128.36,128.09,127.35,126.15, 123.75,122.63,117.90,116.93,106.64,77.07,48.31,34.45. HRMS(EI): calcd for C ₂₀ H ₁₄ F ₃ NO ₃ [M] ⁺ m/z 373.0926; found, 373.0925.

trans-2-(2,4,5-三氟苯基)-6-(3-(甲基磺酰)苯基)-3,4-二氢-2H-苯并[h]色满-3-胺(15k)trans-2-(2,4,5-trifluorophenyl)-6-(3-(methylsulfonyl)phenyl)-3,4-dihydro-2H-benzo[h]chroman-3 -Amine (15k)

合成方法参照15a，得白色固体10.50mg，收率10.1％。熔点：430.5-431.6℃。 ¹H NMR(400MHz,DMSO-d6)δ8.19-8.08(m,1H),8.08-8.00(m,2H),7.95-7.82(m,2H),7.81-7.64(m,3H),7.60-7.48(m,2H),7.36(s,1H),5.14(d,J＝9.1Hz,1H),3.36(s,3H),3.18(dd,J＝16.6,5.2Hz,1H),2.98(dd,J＝16.5,10.2Hz,1H),1.73(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.49,149.59,149.03,148.75,146.88,141.66,141.49,135.45,130.60,130.50,130.09,129.70,128.32,127.08,126.17,126.04,125.09,124.60,124.02,122.04,117.74,115.92,106.67,77.73,48.60,43.97,34.75.HRMS(EI):calcd for C ₂₆H ₂₀F ₃NO ₃S[M] ⁺m/z 483.1116；found,483.1115. The synthesis method refers to 15a to obtain 10.50 mg of white solid with a yield of 10.1%. Melting point: 430.5-431.6°C. ¹ H NMR (400MHz, DMSO-d6) δ 8.19-8.08 (m, 1H), 8.08-8.00 (m, 2H), 7.95-7.82 (m, 2H), 7.81-7.64 (m, 3H), 7.60- 7.48 (m, 2H), 7.36 (s, 1H), 5.14 (d, J = 9.1Hz, 1H), 3.36 (s, 3H), 3.18 (dd, J = 16.6, 5.2 Hz, 1H), 2.98 (dd , J = 16.5, 10.2 Hz, 1H), 1.73 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.49,149.59,149.03,148.75,146.88,141.66,141.49,135.45,130.60,130.50,130.09, 129.70,128.32,127.08,126.17,126.04,125.09,124.60,124.02,122.04,117.74,115.92,106.67,77.73,48.60,43.97,34.75.HRMS(EI):calcd for C ₂₆ H ₂₀ F ₃ NO ₃ S[M ] ⁺ m/z 483.1116; found,483.1115.

(13)trans-2-(2,4,5-三氟苯基)-2,3,4,7-四氢吡喃并[2,3-e]吲哚3-胺的合成(20)(13) Synthesis of trans-2-(2,4,5-trifluorophenyl)-2,3,4,7-tetrahydropyrano[2,3-e]indole 3-amine (20)

合成方法参照15a，得白色固体125.00mg,收率为33.0％。熔点：310.1-313.5℃。 ¹H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.68-7.55(m,2H),7.22-7.13(m,1H),6.96(d,J＝8.4Hz,1H),6.81(d,J＝8.2Hz,1H),6.27(d,J＝2.0Hz,1H),4.93(d,J＝8.9Hz,1H),3.31(dd,J＝8.7,4.9Hz,1H),2.96(dd,J＝15.7,5.2Hz,1H),2.77(dd,J＝15.6,10.1Hz,1H),1.59(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.28,149.32,146.82,146.72,136.60,124.56,124.28,123.26,118.17, 117.77,109.45,106.58,105.32,98.26,77.12,49.02,34.63.HRMS(EI):calcd for C ₂₀H ₁₄F ₃NO ₃[M] ⁺m/z 318.0980；found,318.0982. The synthesis method refers to 15a, 125.00 mg of white solid is obtained, and the yield is 33.0%. Melting point: 310.1-313.5°C. ¹ H NMR(400MHz,DMSO-d6)δ11.01(s,1H), 7.68-7.55(m,2H), 7.22-7.13(m,1H), 6.96(d,J=8.4Hz,1H), 6.81 (d,J=8.2Hz,1H), 6.27(d,J=2.0Hz,1H), 4.93(d,J=8.9Hz,1H),3.31(dd,J=8.7,4.9Hz,1H),2.96 (dd,J=15.7,5.2Hz,1H),2.77(dd,J=15.6,10.1Hz,1H),1.59(s,2H). ¹³ C NMR(151MHz,DMSO-d6)δ156.28,149.32,146.82, 146.72,136.60,124.56,124.28,123.26,118.17, 117.77,109.45,106.58,105.32,98.26,77.12,49.02,34.63.HRMS(EI):calcd for C ₂₀ H ₁₄ F ₃ NO ₃ [M] ⁺ m/z 318.0980; found,318.0982.

(14)1,1,1-三氟-N-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)甲磺酰胺的合成(25e)(14) 1,1,1-Trifluoro-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ) Synthesis of Methanesulfonamide (25e)

取3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(1.00g，4.76mmol)，三乙胺(0.92g，9.14mmol),二氯甲烷(10mL)于100mL反应瓶中，-78℃下加如三氟甲磺酸酐(1.29g，4.76mmol)，滴加完毕后移至室温继续搅拌，TLC监测反应。待原料转化完全后，向反应瓶加入水淬灭，二氯甲烷(20mL)萃取三次，有机相用卤水洗涤，无水Na ₂SO ₄干燥，柱层析分离纯化(PE:EA＝5:1)，得产品1.20g，产率为68.2％。 ¹H NMR(400MHz,CDCl ₃)δ7.65(d,J＝7.1Hz,1H),7.54(d,J＝1.9Hz,1H),7.40-7.26(m,3H),1.30-1.15(m,12H).LC-MS(ESI)m/z 350.09[M-H] ^-. Take 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (1.00g, 4.76mmol), triethylamine (0.92g, 9.14mmol ), dichloromethane (10mL) in a 100mL reaction flask, add trifluoromethanesulfonic anhydride (1.29g, 4.76mmol) at -78°C. After the addition is complete, move to room temperature and continue stirring. TLC monitors the reaction. After the conversion of the raw materials is complete, add water to the reaction flask to quench, extract with dichloromethane (20 mL) three times, wash the organic phase with brine, dry with anhydrous Na ₂ SO ₄ , and separate and purify by column chromatography (PE:EA=5:1 ), the product is 1.20 g, and the yield is 68.2%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.65 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.40-7.26 (m, 3H), 1.30-1.15 (m, 12H).LC-MS(ESI)m/z 350.09[MH] ^- .

4-羟基-(1,1'-联苯)-3-甲醛衍生物(26a-j)的合成Synthesis of 4-hydroxy-(1,1'-biphenyl)-3-carboxaldehyde derivative (26a-j)

4-羟基-(1,1'-联苯)-3-甲醛(26a)4-hydroxy-(1,1'-biphenyl)-3-carbaldehyde (26a)

将5-溴-2-羟基苯甲醛(1.00g，5.00mmol)，苯硼酸(1.22g，10.00mmol)，碳酸铯(4.88g，15.00mmol)，PdCl ₂(dppf) ₂(183.10mg，0.25mmol)加入到反应瓶中，甲苯30mL,水5mL溶解，氮气保护，100℃加热回流，TLC监测。反应结束后，过滤，滤液用乙酸乙酯(10mL)萃取三次，再用无水Na ₂SO ₄干燥，将溶液旋干，硅胶柱层析分离(PE:EA＝10:1)，得产品0.80g，产率为80.1％。 ¹H NMR(400MHz,CDCl ₃)δ11.01(s,1H),9.96(s,1H),7.79-7.72(m,2H),7.54(d,J＝7.3Hz,2H),7.45(t,J＝7.7Hz,2H),7.35(t,J＝7.3Hz,1H),7.07(d,J＝8.5Hz,1H).LC-MS(ESI)m/z 197.01[M-H] ^-. Combine 5-bromo-2-hydroxybenzaldehyde (1.00g, 5.00mmol), phenylboronic acid (1.22g, 10.00mmol), cesium carbonate (4.88g, 15.00mmol), PdCl ₂ (dppf) ₂ (183.10mg, 0.25mmol) ) Was added to the reaction flask, dissolved in 30 mL of toluene and 5 mL of water, protected by nitrogen, heated to reflux at 100°C, and monitored by TLC. After the reaction, it was filtered, the filtrate was extracted three times with ethyl acetate (10 mL), and then dried over anhydrous Na ₂ SO ₄ , the solution was spin-dried and separated by silica gel column chromatography (PE:EA=10:1) to obtain the product 0.80 g, the yield is 80.1%. ¹ H NMR(400MHz,CDCl ₃ )δ11.01(s,1H),9.96(s,1H),7.79-7.72(m,2H),7.54(d,J=7.3Hz,2H),7.45(t, J=7.7Hz,2H),7.35(t,J=7.3Hz,1H),7.07(d,J=8.5Hz,1H).LC-MS(ESI)m/z 197.01[MH] ^- .

4-羟基-3'-(甲基磺酰基)-[1,1'-联苯]-3-甲醛(26b)4-Hydroxy-3'-(methylsulfonyl)-[1,1'-biphenyl]-3-carbaldehyde(26b)

合成方法参照26a，得产物1.22g，产率90.1％。 ¹H NMR(400MHz,CDCl ₃)δ11.10(s,1H),10.02(s,1H),8.15(s,1H),7.93(t,J＝8.8Hz,1H),7.90-7.79(m,3H),7.74-7.65(m,1H),7.14(d,J＝8.6Hz,1H),3.13(s,3H).LC-MS(ESI)m/z 275.10[M-H] ^-. The synthesis method refers to 26a, and 1.22 g of the product is obtained with a yield of 90.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ 11.10 (s, 1H), 10.02 (s, 1H), 8.15 (s, 1H), 7.93 (t, J = 8.8 Hz, 1H), 7.90-7.79 (m, 3H),7.74-7.65(m,1H),7.14(d,J=8.6Hz,1H),3.13(s,3H).LC-MS(ESI)m/z 275.10[MH] ^- .

3'-甲酰基-4'-羟基-[1,1'-联苯基]-3-羧酸甲酯(26c)3'-Formyl-4'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid methyl ester (26c)

合成方法参照26a，得产物1.10g，产率为85.9％。 ¹H NMR(400MHz,CDCl ₃)δ11.05(s,1H),10.00(s,1H),8.24(t,J＝1.6Hz,1H),8.05-8.00(m,1H),7.84-7.78(m,2H),7.75(dd,J＝3.9,2.7Hz,1H),7.53(t,J＝7.8Hz,1H),7.10(d,J＝9.3Hz,1H),3.96(s,3H).LC-MS(ESI)m/z 255.10[M-H] ^-. The synthesis method refers to 26a, and the product is 1.10g, and the yield is 85.9%. ¹ H NMR (400MHz, CDCl ₃ ) δ 11.05 (s, 1H), 10.00 (s, 1H), 8.24 (t, J = 1.6 Hz, 1H), 8.05-8.00 (m, 1H), 7.84-7.78 ( m, 2H), 7.75 (dd, J = 3.9, 2.7 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 3.96 (s, 3H). LC-MS(ESI)m/z 255.10[MH] ^- .

N-(3'-甲酰基-4'-羟基-[1,1'-联苯]-3-基)甲磺酰胺(26d)N-(3'-formyl-4'-hydroxy-[1,1'-biphenyl]-3-yl)methanesulfonamide (26d)

合成方法参照26a，得产物1.02g，产率91.1％。 ¹H NMR(400MHz,CDCl ₃)δ11.05(s,1H),9.97(s,1H),7.83-7.70(m,2H),7.48(s,1H),7.45(t,J＝7.8Hz,1H),7.38(d,J＝7.8Hz,1H),7.32(s,1H),7.29-7.24(m,1H),7.09(t,J＝12.1Hz,1H),3.10(s,3H).LC-MS(ESI)m/z 290.01[M-H] ^-. The synthesis method refers to 26a, and 1.02 g of the product is obtained with a yield of 91.1%. ¹ H NMR(400MHz,CDCl ₃ )δ11.05(s,1H),9.97(s,1H),7.83-7.70(m,2H),7.48(s,1H),7.45(t,J=7.8Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.32 (s, 1H), 7.29-7.24 (m, 1H), 7.09 (t, J = 12.1Hz, 1H), 3.10 (s, 3H). LC-MS(ESI)m/z 290.01[MH] ^- .

1,1,1-三氟-N-(3'-甲酰基-4'-羟基-[1,1'-联苯]-3-基)甲磺酰胺(26e)1,1,1-Trifluoro-N-(3'-formyl-4'-hydroxy-[1,1'-biphenyl]-3-yl)methanesulfonamide (26e)

合成方法参照26a，得产物1.50g，产率89.1％。 ¹H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.94(s,1H),10.34(s,1H),7.89(d,J＝2.5Hz,1H),7.81(dd,J＝8.6,2.5Hz,1H),7.55(t,J＝6.1Hz,1H),7.54-7.46(m,2H),7.25(dd,J＝7.9,1.0Hz,1H),7.14(d,J＝8.6Hz,1H).LC-MS(ESI)m/z 255.10[M-H] ^-. The synthesis method refers to 26a, and the product is 1.50g, and the yield is 89.1%. ¹ H NMR(400MHz,DMSO-d6)δ11.97(s,1H), 10.94(s,1H), 10.34(s,1H), 7.89(d,J=2.5Hz,1H), 7.81(dd,J ＝8.6,2.5Hz,1H),7.55(t,J＝6.1Hz,1H),7.54-7.46(m,2H),7.25(dd,J＝7.9,1.0Hz,1H),7.14(d,J＝ 8.6Hz,1H).LC-MS(ESI)m/z 255.10[MH] ^- .

3'-甲酰基-4'-羟基-[1,1'-联苯基]-3-羧酸(26f)3'-formyl-4'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (26f)

合成方法参照26a，得产物1.51g，产率90.2％。 ¹H NMR(400MHz,DMSO-d6)δ13.03(s,1H),10.78(d,J＝174.9Hz,1H),10.34(s,1H),8.16(s,1H),7.98(d,J＝2.2Hz,1H),7.95-7.87(m,3H),7.59(t,J＝7.7Hz,1H),7.14(d,J＝8.6Hz,1H).LC-MS(ESI)m/z 241.10[M-H] ^-. The synthesis method refers to 26a, and the product is 1.51 g, and the yield is 90.2%. ¹ H NMR (400MHz, DMSO-d6) δ 13.03 (s, 1H), 10.78 (d, J = 174.9 Hz, 1H), 10.34 (s, 1H), 8.16 (s, 1H), 7.98 (d, J =2.2Hz,1H),7.95-7.87(m,3H),7.59(t,J=7.7Hz,1H),7.14(d,J=8.6Hz,1H).LC-MS(ESI)m/z 241.10 [MH] ^- .

4-羟基-3'-(1H-四唑-5-基)-[1,1'-联苯]-3-甲醛(26g)4-Hydroxy-3'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-carbaldehyde (26g)

合成方法参照26a，得产物0.51g，产率31.2％。 ¹H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.45-10.33(m,1H),8.32(t,J＝1.5Hz,1H),8.06(d,J＝2.5Hz,1H),8.04(dd,J＝11.3,4.6Hz,1H),7.96(dd,J＝8.6,2.5Hz,1H),7.88-7.82(m,1H),7.67(t,J＝7.8Hz,1H),7.18(d,J＝4.0Hz,1H).LC-MS(ESI)m/z 241.10[M-H] ^-. The synthesis method refers to 26a, and the product is 0.51 g, and the yield is 31.2%. ¹ H NMR(600MHz,DMSO-d6)δ11.00(s,1H), 10.45-10.33(m,1H), 8.32(t,J=1.5Hz,1H), 8.06(d,J=2.5Hz,1H ), 8.04 (dd, J = 11.3, 4.6 Hz, 1H), 7.96 (dd, J = 8.6, 2.5 Hz, 1H), 7.88-7.82 (m, 1H), 7.67 (t, J = 7.8 Hz, 1H) ,7.18(d,J=4.0Hz,1H).LC-MS(ESI)m/z 241.10[MH] ^- .

3'-甲酰基-4'-羟基-[1,1'-联苯]-3-甲腈(26h)3'-formyl-4'-hydroxy-[1,1'-biphenyl]-3-carbonitrile (26h)

合成方法参照26a，得产物1.40g，产率85.4％。 ¹H NMR(400MHz,CDCl ₃)δ11.09(s,1H),10.00(s,1H),7.85-7.83(m,1H),7.82-7.78(m,1H),7.78-7.71(m,2H),7.67-7.63(m,1H),7.58(t,J＝7.7Hz,1H),7.13(d,J＝8.4Hz,1H).LC-MS(ESI)m/z 222.10[M-H] ^-. The synthesis method refers to 26a, and the product is 1.40g, and the yield is 85.4%. ¹ H NMR (400MHz, CDCl ₃ ) δ 11.09 (s, 1H), 10.00 (s, 1H), 7.85-7.83 (m, 1H), 7.82-7.78 (m, 1H), 7.78-7.71 (m, 2H) ),7.67-7.63(m,1H),7.58(t,J=7.7Hz,1H),7.13(d,J=8.4Hz,1H).LC-MS(ESI)m/z 222.10[MH] ^- .

2',4'-二氟-4-羟基-[1,1'-联苯]-3-甲醛(26i)2',4'-Difluoro-4-hydroxy-[1,1'-biphenyl]-3-carbaldehyde (26i)

合成方法参照26a，得产物1.10g，产率89.2％。 ¹H NMR(400MHz,CDCl ₃)δ11.06(s,1H),9.95(s,1H),7.76-7.60(m,2H),7.39(td,J＝8.7,6.6Hz,1H),7.08(d,J＝8.6Hz,1H),7.03-6.88(m,2H).LC-MS(ESI)m/z 233.10[M-H] ^-. The synthesis method is referred to 26a, and the product is 1.10g with a yield of 89.2%. ¹ H NMR(400MHz, CDCl ₃ )δ11.06(s,1H),9.95(s,1H),7.76-7.60(m,2H),7.39(td,J=8.7,6.6Hz,1H), 7.08( d,J=8.6Hz,1H),7.03-6.88(m,2H).LC-MS(ESI)m/z 233.10[MH] ^- .

4-羟基-3',4'-二甲氧基-[1,1'-联苯]-3-甲醛(26j)4-hydroxy-3',4'-dimethoxy-[1,1'-biphenyl]-3-carbaldehyde (26j)

合成方法参照26a，得产物1.20g，产率82.2％。 ¹H NMR(400MHz,CDCl ₃)δ10.88(s,1H),9.87(s,1H),7.63(dd,J＝8.5,2.3Hz,1H),7.61(d,J＝2.2Hz,1H),7.02-6.98(m,1H),6.96(dd,J＝5.3,3.1Hz,2H),6.87-6.84(m,1H),3.87(s,3H),3.83(s,3H).LC-MS(ESI)m/z 257.01[M-H] ^-. The synthesis method refers to 26a, and the product is 1.20 g, and the yield is 82.2%. ¹ H NMR(400MHz, CDCl ₃ )δ10.88(s,1H), 9.87(s,1H), 7.63(dd,J=8.5,2.3Hz,1H), 7.61(d,J=2.2Hz,1H) ,7.02-6.98(m,1H),6.96(dd,J=5.3,3.1Hz,2H),6.87-6.84(m,1H),3.87(s,3H),3.83(s,3H).LC-MS (ESI)m/z 257.01[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-溴-2H-色满的合成(22)Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-6-bromo-2H-chroman (22)

5-溴-2-羟基苯甲醛(1.00g，5.00mmol)，20mL甲苯，2,4,5-三氟苯硝基乙烯(1.12g，5.50mmol)，L-哌啶加酸(0.65g，5.00mmol)，加入到100mL反应瓶中氮气保护，120℃过夜搅拌。冷却至室温，二氯甲烷萃取三次，无水Na ₂SO ₄干燥，减压蒸发，硅胶柱层析纯化(PE:EA＝15:1)，得橙红色目标产物1.50g，收率为78.1％。 ¹H NMR(400MHz,CDCl ₃)δ7.93(s,1H),7.39(d,J＝2.2Hz,1H),7.32(dt,J＝11.9,5.9Hz,1H),6.98-6.84(m,2H),6.73(s,1H),6.66(t,J＝10.2Hz,1H). 5-bromo-2-hydroxybenzaldehyde (1.00g, 5.00mmol), 20mL toluene, 2,4,5-trifluorophenylnitroethylene (1.12g, 5.50mmol), L-piperidine plus acid (0.65g, 5.00mmol), added to a 100mL reaction flask under nitrogen protection, and stirred overnight at 120°C. Cool to room temperature, extract with dichloromethane three times, dry with anhydrous Na ₂ SO ₄ , evaporate under reduced pressure, and purify by silica gel column chromatography (PE:EA=15:1) to obtain 1.50 g of orange-red target product, with a yield of 78.1% . ¹ H NMR (400MHz, CDCl ₃ ) δ7.93 (s, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.32 (dt, J = 11.9, 5.9 Hz, 1H), 6.98-6.84 (m, 2H), 6.73 (s, 1H), 6.66 (t, J = 10.2 Hz, 1H).

2-(2,4,5-三氟苯基)-3-硝基-6-苯基-2H-色满衍生物(27a-j)的合成Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-6-phenyl-2H-chroman derivative (27a-j)

2-(2,4,5-三氟苯基)-3-硝基-6-苯基-2H-色满(27a)2-(2,4,5-trifluorophenyl)-3-nitro-6-phenyl-2H-chroman(27a)

合成方法参照22，得产物1.01g，产率88.4％。 ¹H NMR(400MHz,CDCl ₃)δ8.14(s,1H),7.56(dd,J＝8.4,2.1Hz,1H),7.54-7.51(m,2H),7.50(s,1H),7.43(t,J＝7.6Hz,2H),7.35(t,J＝7.3Hz,1H),7.09-6.94(m,2H),6.90(d,J＝8.4Hz,1H),6.84(s,1H). Refer to 22 for the synthesis method to obtain 1.01 g of the product with a yield of 88.4%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.56 (dd, J = 8.4, 2.1 Hz, 1H), 7.54-7.51 (m, 2H), 7.50 (s, 1H), 7.43 ( t,J=7.6Hz,2H), 7.35(t,J=7.3Hz,1H), 7.09-6.94(m,2H), 6.90(d,J=8.4Hz,1H), 6.84(s,1H).

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(甲基磺酰基)苯基)-2H-色满(27b)2-(2,4,5-trifluorophenyl)-3-nitro-6-(3-(methylsulfonyl)phenyl)-2H-chroman(27b)

合成方法参照22，得产物1.31g，产率90.4％。 ¹H NMR(400MHz,CDCl ₃)δ8.21(s,1H),8.13(t,J＝1.6Hz,1H),7.94(t,J＝9.3Hz,1H),7.89-7.80(m,1H),7.69(t,J＝7.8Hz,1H),7.66-7.60(m,2H),7.12-7.01(m,2H),6.99(d,J＝8.0Hz, 1H),6.90(s,1H),3.13(s,3H). For the synthesis method referring to 22, 1.31 g of the product was obtained, and the yield was 90.4%. ¹ H NMR(400MHz,CDCl ₃ )δ8.21(s,1H), 8.13(t,J=1.6Hz,1H),7.94(t,J=9.3Hz,1H),7.89-7.80(m,1H) ,7.69(t,J=7.8Hz,1H),7.66-7.60(m,2H),7.12-7.01(m,2H),6.99(d,J=8.0Hz, 1H),6.90(s,1H), 3.13(s,3H).

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(甲酸甲酯基)苯基)-2H-色满(27c)2-(2,4,5-Trifluorophenyl)-3-nitro-6-(3-(methyl formate)phenyl)-2H-chroman(27c)

合成方法参照22，得产物1.21g，产率86.4％。 ¹H NMR(400MHz,CDCl ₃)δ8.22(s,1H),8.18(s,1H),8.03(d,J＝7.8Hz,1H),7.72(d,J＝7.8Hz,1H),7.62-7.60(m,1H),7.60(s,1H),7.52(t,J＝7.8Hz,1H),7.10-6.98(m,2H),6.94(d,J＝9.2Hz,1H),6.87(s,1H),3.95(s,3H). For the synthesis method, refer to 22 to obtain 1.21 g of the product with a yield of 86.4%. ¹ H NMR(400MHz, CDCl ₃ )δ8.22(s,1H), 8.18(s,1H), 8.03(d,J=7.8Hz,1H), 7.72(d,J=7.8Hz,1H), 7.62 -7.60(m,1H),7.60(s,1H), 7.52(t,J=7.8Hz,1H), 7.10-6.98(m,2H), 6.94(d,J=9.2Hz,1H), 6.87( s,1H), 3.95(s,3H).

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(甲磺酰胺基)苯基)-2H-色满(27d)2-(2,4,5-trifluorophenyl)-3-nitro-6-(3-(methanesulfonamido)phenyl)-2H-chroman(27d)

合成方法参照22，得产物1.11g，产率89.0％。 ¹H NMR(400MHz,CDCl ₃)δ8.20(s,1H),7.61-7.56(m,2H),7.51-7.42(m,2H),7.38(d,J＝7.8Hz,1H),7.23(d,J＝7.6Hz,1H),7.13-7.00(m,2H),6.95(d,J＝9.1Hz,1H),6.89(s,1H),6.85(s,1H),3.09(s,3H).LC-MS(ESI)m/z 475.10[M-H] ^-. Refer to 22 for the synthesis method to obtain 1.11 g of the product with a yield of 89.0%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.61-7.56 (m, 2H), 7.51-7.42 (m, 2H), 7.38 (d, J = 7.8Hz, 1H), 7.23 ( d,J=7.6Hz,1H),7.13-7.00(m,2H),6.95(d,J=9.1Hz,1H),6.89(s,1H),6.85(s,1H),3.09(s,3H) ).LC-MS(ESI)m/z 475.10[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-(3-((1,1,1-三氟甲基)甲磺酰胺基)苯基)-2H-色满(27e)2-(2,4,5-trifluorophenyl)-3-nitro-6-(3-((1,1,1-trifluoromethyl)methanesulfonamido)phenyl)-2H-color Full (27e)

合成方法参照22，得产物1.20g，产率87.0％。 ¹H NMR(400MHz,CDCl ₃)δ8.10(s,1H),7.53-7.44(m,2H),7.41-7.33(m,4H),7.18(dd,J＝7.1,3.7Hz,1H),7.02-6.90(m,2H),6.86(d,J＝9.1Hz,1H),6.79(s,1H).LC-MS(ESI)m/z 529.01[M-H] ^-. Refer to 22 for the synthesis method to obtain 1.20 g of the product with a yield of 87.0%. ¹ H NMR(400MHz,CDCl ₃ )δ8.10(s,1H),7.53-7.44(m,2H),7.41-7.33(m,4H),7.18(dd,J=7.1,3.7Hz,1H), 7.02-6.90(m,2H),6.86(d,J=9.1Hz,1H),6.79(s,1H).LC-MS(ESI)m/z 529.01[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(羧基)苯基)-2H-色满(27f)2-(2,4,5-trifluorophenyl)-3-nitro-6-(3-(carboxy)phenyl)-2H-chroman(27f)

合成方法参照22，得产物1.10g，产率89.0％。 ¹H NMR(400MHz,DMSO)δ10.29(s,1H),8.48(s,1H),8.17(s,1H),7.99(d,J＝1.8Hz,1H),7.92(d,J＝7.7Hz,1H),7.87(d,J＝7.8Hz,1H),7.72(dd,J＝8.5,1.9Hz,1H),7.67-7.54(m,2H),7.48(dd,J＝17.1,8.8Hz,1H),6.97(d,J＝8.5Hz,1H),6.88(s,1H).LC-MS(ESI)m/z 426.01[M-H] ^-. For the synthesis method referring to 22, 1.10 g of the product was obtained with a yield of 89.0%. ¹ H NMR (400MHz, DMSO) δ 10.29 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.72 (dd, J = 8.5, 1.9 Hz, 1H), 7.67-7.54 (m, 2H), 7.48 (dd, J = 17.1, 8.8 Hz ,1H),6.97(d,J=8.5Hz,1H),6.88(s,1H).LC-MS(ESI)m/z 426.01[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(四唑基)苯基)-2H-色满(27g)2-(2,4,5-trifluorophenyl)-3-nitro-6-(3-(tetrazolyl)phenyl)-2H-chroman (27g)

合成方法参照22，得产物0.20g，产率23.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.00(s,1H),7.90-7.75(m,2H),7.72-7.62(m,2H),7.57(t,J＝6.9Hz,1H),7.51-7.43(m,2H),6.94-6.90(m,2H),6.63(s,2H).LC-MS(ESI)m/z 450.01[M-H] ^-. Refer to 22 for the synthesis method to obtain 0.20 g of the product with a yield of 23.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.00 (s, 1H), 7.90-7.75 (m, 2H), 7.72-7.62 (m, 2H), 7.57 (t, J = 6.9Hz, 1H), 7.51 7.43(m,2H),6.94-6.90(m,2H),6.63(s,2H).LC-MS(ESI)m/z 450.01[MH] ^- .

2-(2,4,5-三氟苯基)-3-硝基-6-(3-(氰基)苯基)-2H-色满(27h)2-(2,4,5-Trifluorophenyl)-3-nitro-6-(3-(cyano)phenyl)-2H-chroman (27h)

合成方法参照22，得产物1.11g，产率87.0％。 ¹H NMR(400MHz,CDCl ₃)δ8.10(s,1H),7.74(d,J＝1.4Hz,1H),7.71-7.67(m,1H),7.62-7.54(m,1H),7.52-7.46(m,3H),7.02-6.92(m,2H),6.92-6.86(m,1H),6.80(s,1H). Refer to 22 for the synthesis method to obtain 1.11 g of the product with a yield of 87.0%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.71-7.67 (m, 1H), 7.62-7.54 (m, 1H), 7.52 7.46(m,3H),7.02-6.92(m,2H),6.92-6.86(m,1H), 6.80(s,1H).

2-(2,4,5-三氟苯基)-3-硝基-6-(2,4-二氟苯基)-2H-色满(27i)2-(2,4,5-trifluorophenyl)-3-nitro-6-(2,4-difluorophenyl)-2H-chroman(27i)

合成方法参照22，得产物1.33g，产率93.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.16(s,1H),7.54-7.46(m,2H),7.40-7.31(m,1H),7.11-7.08(m,2H),7.01-6.90(m,3H),6.87(s,1H),2.04(s,1H). Refer to 22 for the synthesis method to obtain 1.33 g of the product with a yield of 93.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.54-7.46 (m, 2H), 7.40-7.31 (m, 1H), 7.11-7.08 (m, 2H), 7.01-6.90 (m ,3H), 6.87(s,1H), 2.04(s,1H).

2-(2,4,5-三氟苯基)-3-硝基-6-(3,4-二甲氧基苯基)-2H-色满(27j)2-(2,4,5-trifluorophenyl)-3-nitro-6-(3,4-dimethoxyphenyl)-2H-chroman(27j)

合成方法参照22，得产物1.43g，产率90.1％。 ¹H NMR(400MHz,CDCl ₃)δ8.07(s,1H),7.47-7.41(m,2H),6.99(dd,J＝8.2,2.1Hz,1H),6.97-6.92(m,2H),6.91(dd,J＝7.3,4.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.81(d,J＝8.4Hz,1H),6.76(s,1H),3.86(s,3H),3.83(s,3H). Refer to 22 for the synthesis method to obtain 1.43 g of the product with a yield of 90.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (s, 1H), 7.47-7.41 (m, 2H), 6.99 (dd, J = 8.2, 2.1Hz, 1H), 6.97-6.92 (m, 2H), 6.91 (dd, J = 7.3, 4.1 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 3.86 (s, 3H) ), 3.83(s, 3H).

2-(2,4,5-三氟苯基)-3-硝基-6-溴-3,4-二氢-2H-色满的合成(23)Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-6-bromo-3,4-dihydro-2H-chroman (23)

将化合物2-(2,4,5-三氟苯基)-3-硝基-6-溴-2H-色满(500.00mg,1.30mmol)加入到25mL反应瓶中，加入THF 5mL和CH ₃OH 0.5mL溶解，冰浴下搅拌，然后缓慢加入NaBH ₄固体(266.00mg，7.00mmol)，TLC监测反应进度，反应结束后，加入饱和NH ₄Cl溶液，再用乙酸乙酯和水萃取，有机相用无水Na ₂SO ₄干燥，减压蒸发除去溶剂。乙醇5mL将上述粗品溶解，加入DIPEA 0.25mL,常温搅拌，TLC监测。反应结束后，然后用乙酸乙酯和水萃取三次，有机相用卤水洗涤，无水Na ₂SO ₄干燥，减压蒸发除去溶剂，得反式消旋体产品，用于下一步反应的原料。 Add the compound 2-(2,4,5-trifluorophenyl)-3-nitro-6-bromo-2H-chroman (500.00mg, 1.30mmol) into a 25mL reaction flask, add THF 5mL and CH ₃ Dissolve 0.5 mL of OH, stir under ice bath, then slowly add NaBH ₄ solid (266.00 mg, 7.00 mmol), TLC monitor the progress of the reaction, after the reaction is over, add saturated NH ₄ Cl solution, and then extract with ethyl acetate and water, organic The phase was dried with anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to remove the solvent. Dissolve the above crude product in 5 mL of ethanol, add DIPEA 0.25 mL, stir at room temperature, and monitor by TLC. After the reaction, it was extracted three times with ethyl acetate and water, the organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure to remove the solvent to obtain the trans racemate product, which was used as the raw material for the next reaction.

2-(2,4,5-三氟苯基)-3-硝基-6-苯基-3,4-二氢-2H-色满衍生物的合成(28a-j)Synthesis of 2-(2,4,5-trifluorophenyl)-3-nitro-6-phenyl-3,4-dihydro-2H-chroman derivatives (28a-j)

2-(2,4,5-三氟苯基)-3-硝基-6-苯基-3,4-二氢-2H-色满(28a)2-(2,4,5-trifluorophenyl)-3-nitro-6-phenyl-3,4-dihydro-2H-chroman(28a)

28a-j合成方法参照化合物23，粗品直接投下一步反应。The synthesis method of 28a-j refers to compound 23, and the crude product is directly thrown into the next reaction.

trans-2-(2,4,5-三氟苯基)-6-溴-3,4-二氢-2H-色满-3-胺的合成(24)Synthesis of trans-2-(2,4,5-trifluorophenyl)-6-bromo-3,4-dihydro-2H-chroman-3-amine (24)

称取化合物trans-2-(2,4,5-三氟苯基)-3-硝基-6-溴-3,4-二氢-2H-色满(500.00mg,1.30mmol),锌粉(845.00mg,13.00mmol),乙醇5mL,6N盐酸4mL加入到25mL三口反应瓶中，常温下搅拌，TLC监测，反应结束后，加入饱和NaHCO ₃溶液调节PH至7-8，减压抽滤，滤液用乙酸乙酯和水洗涤，有机用相卤水洗涤，无水Na ₂SO ₄干燥，硅胶柱层析纯化(PE:EA＝1:1)，得白色固体100.05mg，产率为21.6％。熔点：282.1-283.2℃。 ¹H NMR(400MHz,DMSO-d6)δ7.66-7.54(m,2H),7.34(d,J＝2.3Hz,1H),7.24(dd,J＝8.7,2.4Hz,1H),6.77(d,J＝8.7Hz,1H),4.86(d,J＝9.1Hz,1H),3.24(td,J＝9.7,5.2Hz,1H),2.97(dd,J＝16.6,5.1Hz,1H),2.73(dd,J＝16.5,10.6Hz,1H),1.58(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.36,153.63,149.45,146.78,132.32,130.32,125.07,123.71,118.51,117.79,112.43,106.52,77.25,48.02,34.42.HRMS(EI):calcd for C ₁₅H ₁₁BrF ₃NO[M] ⁺m/z 356.9976；found,356.9975. Weigh the compound trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-bromo-3,4-dihydro-2H-chroman (500.00mg, 1.30mmol), zinc powder (845.00mg, 13.00mmol), 5mL of ethanol, 4mL of 6N hydrochloric acid were added to a 25mL three-necked reaction flask, stirred at room temperature, TLC monitoring, after the completion of the reaction, add saturated NaHCO ₃ solution to adjust the pH to 7-8, vacuum filtration, The filtrate was washed with ethyl acetate and water, the organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , and purified by silica gel column chromatography (PE:EA=1:1) to obtain 100.05 mg of white solid with a yield of 21.6%. Melting point: 282.1-283.2°C. ¹ H NMR(400MHz,DMSO-d6)δ7.66-7.54(m,2H), 7.34(d,J=2.3Hz,1H), 7.24(dd,J=8.7,2.4Hz,1H), 6.77(d ,J=8.7Hz,1H), 4.86(d,J=9.1Hz,1H), 3.24(td,J=9.7,5.2Hz,1H), 2.97(dd,J=16.6,5.1Hz,1H), 2.73 (dd, J=16.5, 10.6 Hz, 1H), 1.58 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.36,153.63,149.45,146.78,132.32,130.32,125.07,123.71,118.51,117.79, 112.43,106.52,77.25,48.02,34.42.HRMS(EI):calcd for C ₁₅ H ₁₁ BrF ₃ NO[M] ⁺ m/z 356.9976; found,356.9975.

trans-2-(2,4,5-三氟苯基)-6-苯基-3,4-二氢-2H-色满-3-胺衍生物的合成(29a-j)Synthesis of trans-2-(2,4,5-trifluorophenyl)-6-phenyl-3,4-dihydro-2H-chroman-3-amine derivatives (29a-j)

trans-2-(2,4,5-三氟苯基)-6-苯基-3,4-二氢-2H-色满-3-胺(29a)trans-2-(2,4,5-trifluorophenyl)-6-phenyl-3,4-dihydro-2H-chroman-3-amine (29a)

合成方法参照化合物24，得产物15.05mg，产率为78.5％。熔点：316.4-318.4℃。 ¹H NMR(400MHz,DMSO-d6)δ7.64-7.60(m,3H),7.47-7.43(m,2H),7.42-7.38(m 2H),7.35-7.27(m,1H),6.89(d,J＝8.4Hz,1H),4.90(d,J＝9.1Hz,1H),3.30(d,J＝4.4Hz,1H),3.05(dd,J＝16.4,5.1Hz,1H),2.80(dd,J＝16.2,10.6Hz,1H),1.24(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.43,154.00,149.51,146.77,140.36,133.25,129.30,128.31,127.19,126.66,126.06,123.99,122.65,117.78,116.79,106.53,77.29,48.44,34.86.HRMS(EI):calcd for C ₂₁H ₁₆F ₃NO[M] ⁺m/z 355.1184；found,355.1183. The synthesis method refers to compound 24, and the product is 15.05 mg, and the yield is 78.5%. Melting point: 316.4-318.4°C. ¹ H NMR (400MHz, DMSO-d6) δ7.64-7.60 (m, 3H), 7.47-7.43 (m, 2H), 7.42-7.38 (m 2H), 7.35-7.27 (m, 1H), 6.89 (d ,J=8.4Hz,1H), 4.90(d,J=9.1Hz,1H), 3.30(d,J=4.4Hz,1H),3.05(dd,J=16.4,5.1Hz,1H), 2.80(dd , J = 16.2, 10.6 Hz, 1H), 1.24 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.43,154.00,149.51,146.77,140.36,133.25,129.30,128.31,127.19,126.66,126.06, 123.99,122.65,117.78,116.79,106.53,77.29,48.44,34.86.HRMS(EI):calcd for C ₂₁ H ₁₆ F ₃ NO[M] ⁺ m/z 355.1184; found,355.1183.

trans-2-(2,4,5-三氟苯基)-6-(3-(甲磺酰基)苯基)-3,4-二氢-2H-色满-3-胺(29b)trans-2-(2,4,5-trifluorophenyl)-6-(3-(methylsulfonyl)phenyl)-3,4-dihydro-2H-chroman-3-amine (29b)

合成方法参照化合物24，得产物60.10mg，产率为70.0％。熔点：340.2-340.7℃。 ¹H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.98(d,J＝7.2Hz,1H),7.86(d,J＝7.1Hz,1H),7.70(t,J＝7.5Hz,1H),7.67-7.55(m,3H),7.52(d,J＝7.9Hz,1H),6.94(d,J＝8.2Hz,1H),4.93(d,J＝8.7Hz,1H),3.35-3.27(m,4H),3.07(d,J＝12.5Hz,1H),2.91-2.75(m,1H),1.63(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.38,154.70,149.50,146.81,142.02,141.52,131.60,131.39,130.43,128.71,126.45,125.40,124.81,123.89,122.99,117.81,117.03,106.59,77.40,48.38,43.95,34.75.HRMS(EI):calcd for C ₂₂H ₁₈F ₃NO ₃S[M] ⁺m/z 433.0959；found,433.0959. For the synthesis method referring to compound 24, 60.10 mg of the product was obtained, and the yield was 70.0%. Melting point: 340.2-340.7°C. ¹ H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.98(d,J=7.2Hz,1H), 7.86(d,J=7.1Hz,1H), 7.70(t,J=7.5 Hz, 1H), 7.67-7.55 (m, 3H), 7.52 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.93 (d, J = 8.7 Hz, 1H), 3.35-3.27(m,4H),3.07(d,J=12.5Hz,1H),2.91-2.75(m,1H),1.63(s,2H). ¹³ C NMR(151MHz,DMSO-d6)δ156.38,154.70 ,149.50,146.81,142.02,141.52,131.60,131.39,130.43,128.71,126.45,125.40,124.81,123.89,122.99,117.81,117.03,106.59,77.40,48.38,43.95,34.75.HRMS(EI):calcd for C ₂₂ H ₁₈ F ₃ NO ₃ S[M] ⁺ m/z 433.0959; found, 433.0959.

trans-2-(2,4,5-三氟苯基)-6-(3-(甲酸甲酯基)苯基)-3,4-二氢-2H-色满-3-胺(29c)trans-2-(2,4,5-trifluorophenyl)-6-(3-(methylformate)phenyl)-3,4-dihydro-2H-chroman-3-amine (29c)

合成方法参照化合物24，得产物50.10mg，产率为63.0％。熔点：393.8-394.6℃。 ¹H NMR(400MHz,DMSO-d6)δ8.15(t,J＝1.6Hz,1H),7.91(dd,J＝7.8,1.3Hz,2H),7.5-7.68(m,3H),7.50(d,J＝2.1Hz,1H),7.45(dd,J＝8.5,2.2Hz,1H),6.91(d,J＝8.4Hz,1H),4.91(d,J＝9.1Hz,1H),3.89(s,3H),3.29(dd,J＝9.7,5.1Hz,1H),3.07(dd,J＝16.4,5.1Hz,1H),2.81(dd,J＝16.3,10.7Hz,1H),1.59(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ166.72,156.37,154.41,149.45,146.78,140.86,132.06,131.49,130.72,129.87,128.47,127.85,127.04,126.20,123.94,122.92,117.82,116.98,106.58,77.37,52.70,48.40,34.77.HRMS(EI):calcd for C ₂₃H ₁₈F ₃NO ₃[M] ⁺m/z 413.1239；found,413.1238. The synthesis method refers to compound 24, and the product is 50.10 mg, and the yield is 63.0%. Melting point: 393.8-394.6°C. ¹ H NMR (400MHz, DMSO-d6) δ 8.15 (t, J = 1.6 Hz, 1H), 7.91 (dd, J = 7.8, 1.3 Hz, 2H), 7.5-7.68 (m, 3H), 7.50 (d ,J=2.1Hz,1H),7.45(dd,J=8.5,2.2Hz,1H), 6.91(d,J=8.4Hz,1H), 4.91(d,J=9.1Hz,1H), 3.89(s ,3H), 3.29 (dd, J = 9.7, 5.1 Hz, 1H), 3.07 (dd, J = 16.4, 5.1 Hz, 1H), 2.81 (dd, J = 16.3, 10.7 Hz, 1H), 1.59 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ 166.72,156.37,154.41,149.45,146.78,140.86,132.06,131.49,130.72,129.87,128.47,127.85,127.04,126.20,123.94,122.92,117.82,116.98,106.58 ,77.37,52.70,48.40,34.77.HRMS(EI):calcd for C ₂₃ H ₁₈ F ₃ NO ₃ [M] ⁺ m/z 413.1239; found,413.1238.

trans-2-(2,4,5-三氟苯基)-6-(3-(甲磺酰胺基)苯基)-3,4-二氢-2H-色满-3-胺(29d)trans-2-(2,4,5-trifluorophenyl)-6-(3-(methanesulfonamido)phenyl)-3,4-dihydro-2H-chroman-3-amine (29d)

合成方法参照化合物24，得产物40.50mg，产率为85.0％。熔点：392.8-393.5℃。 ¹H NMR(400MHz,DMSO-d6)δ7.68-7.56(m,2H),7.43(d,J＝1.7Hz,1H),7.42-7.38(m,2H),7.38-7.33(m,2H),7.20-7.14(m,1H),6.93(d,J＝8.4Hz,1H),5.02(d,J＝8.9Hz,1H),3.46(m,1H),3.10(dd,J＝16.5,5.1Hz,1H),3.10(s,3H),2.94-2.82(m,1H),1.99(s,1H). ¹³C NMR(151MHz,DMSO-d6)δ172.51,170.84,156.29,152.78,150.38,146.81,140.42,134.53,129.56,128.39,126.88,122.97,122.19,121.48,120.68,119.23,118.10,117.28,107.38,72.09,46.87,28.95.HRMS(EI):calcd for C ₂₂H ₁₉F ₃N ₂O ₃S[M] ⁺m/z 448.1068；found,448.1071. The synthesis method refers to compound 24, and the product is 40.50 mg with a yield of 85.0%. Melting point: 392.8-393.5°C. ¹ H NMR (400MHz, DMSO-d6) δ 7.68-7.56 (m, 2H), 7.43 (d, J = 1.7 Hz, 1H), 7.42-7.38 (m, 2H), 7.38-7.33 (m, 2H) ,7.20-7.14(m,1H),6.93(d,J=8.4Hz,1H),5.02(d,J=8.9Hz,1H),3.46(m,1H),3.10(dd,J=16.5,5.1 Hz, 1H), 3.10 (s, 3H), 2.94-2.82 (m, 1H), 1.99 (s, 1H). ¹³ C NMR (151MHz, DMSO-d6) δ172.51,170.84,156.29,152.78,150.38,146.81, 140.42,134.53,129.56,128.39,126.88,122.97,122.19,121.48,120.68,119.23,118.10,117.28,107.38,72.09,46.87,28.95.HRMS(EI):calcd for C ₂₂ H ₁₉ F ₃ N ₂ O ₃ S [M] ⁺ m/z 448.1068; found,448.1071.

trans-2-(2,4,5-三氟苯基)-6-(3-((1,1,1-三氟甲基)甲磺酰胺基)苯基)-3,4-二氢-2H-色满-3-胺(29e)trans-2-(2,4,5-trifluorophenyl)-6-(3-((1,1,1-trifluoromethyl)methanesulfonamido)phenyl)-3,4-dihydro -2H-Chroman-3-amine (29e)

合成方法参照化合物24，得产物50.50mg，产率为89.0％。熔点：397.0-397.9℃。 ¹H NMR(400MHz,DMSO)δ8.49-7.97(s,1H),7.72(dd,J＝17.0,10.1Hz,1H),7.63(dd,J＝17.0,8.6Hz,1H),7.50-7.37(m,2H),7.33-7.23(m,2H),7.19(d,J＝7.6Hz,1H),7.09-6.95(m,2H),5.38(d,J＝8.0Hz,1H),4.14-4.02(m,1H),3.26-3.17(m,1H),3.08(dd,J＝16.3,8.7Hz,1H). ¹³C NMR(151MHz,DMSO)δ156.37,153.94,149.72,146.80,141.48,139.38,133.07,130.28,128.36,126.30,123.23,122.37,122.01,118.66,118.07,117.82,116.99,106.80,76.38,60.23,48.13,33.48.HRMS(EI):calcd for C ₂₂H ₁₆F ₆N ₂O ₃S[M] ⁺m/z 502.0786；found,502.0781. The synthesis method refers to compound 24, and the product is 50.50 mg, and the yield is 89.0%. Melting point: 397.0-397.9°C. ¹ H NMR (400MHz, DMSO) δ 8.49-7.97 (s, 1H), 7.72 (dd, J = 17.0, 10.1 Hz, 1H), 7.63 (dd, J = 17.0, 8.6 Hz, 1H), 7.50-7.37 (m, 2H), 7.33-7.23 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.09-6.95 (m, 2H), 5.38 (d, J = 8.0 Hz, 1H), 4.14 4.02 (m, 1H), 3.26-3.17 (m, 1H), 3.08 (dd, J = 16.3, 8.7 Hz, 1H). ¹³ C NMR (151MHz, DMSO) δ156.37,153.94,149.72,146.80,141.48,139.38, 133.07,130.28,128.36,126.30,123.23,122.37,122.01,118.66,118.07,117.82,116.99,106.80,76.38,60.23,48.13,33.48.HRMS(EI):calcd for C ₂₂ H ₁₆ F ₆ N ₂ O ₃ S [M] ⁺ m/z 502.0786; found,502.0781.

trans-2-(2,4,5-三氟苯基)-6-(3-(羧基)苯基)-3,4-二氢-2H-色满-3-胺(29f)trans-2-(2,4,5-trifluorophenyl)-6-(3-(carboxy)phenyl)-3,4-dihydro-2H-chroman-3-amine(29f)

合成方法参照化合物24，得产物20.50mg，产率为70.0％。熔点：500.8-501.6℃。 ¹H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.89(d,J＝7.4Hz,1H),7.78(d,J＝7.7Hz,1H),7.70-7.56(m,2H),7.55-7.46(m,2H),7.44(d,J＝8.5Hz,1H),6.91(d,J＝8.4Hz,1H),4.95(d,J＝9.1Hz,1H),3.40-3.31(m,1H),3.09(dd,J＝16.4,5.0Hz,1H),2.84(dd,J＝16.3,10.6Hz,1H). ¹³C NMR(151MHz,DMSO-d6)δ168.47,157.32,155.65,151.65(s),151.36,149.71,147.63,146.04,133.34,131.74,128.35,126.60,126.19,124.54,121.83,120.72,120.47,118.09,112.13,107.53,72.95,56.48,46.55.HRMS(EI):calcd for C ₂₂H ₁₆F ₃NO3[M] ⁺m/z 399.1082；found,399.1080. The synthesis method refers to compound 24, and the product is 20.50 mg, and the yield is 70.0%. Melting point: 500.8-501.6°C. ¹ H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.89(d,J=7.4Hz,1H),7.78(d,J=7.7Hz,1H),7.70-7.56(m,2H ),7.55-7.46(m,2H),7.44(d,J=8.5Hz,1H), 6.91(d,J=8.4Hz,1H), 4.95(d,J=9.1Hz,1H), 3.40-3.31 (m, 1H), 3.09 (dd, J = 16.4, 5.0 Hz, 1H), 2.84 (dd, J = 16.3, 10.6 Hz, 1H). ¹³ C NMR (151MHz, DMSO-d6) δ168.47,157.32,155.65, 151.65(s),151.36,149.71,147.63,146.04,133.34,131.74,128.35,126.60,126.19,124.54,121.83,120.72,120.47,118.09,112.13,107.53,72.95,56.48,46.55.HRMS(EI):calcd for C ₂₂ H ₁₆ F ₃ NO3[M] ⁺ m/z 399.1082; found,399.1080.

trans-2-(2,4,5-三氟苯基)-6-(3-(四唑基)苯基)-3,4-二氢-2H-色满-3-胺(29g)trans-2-(2,4,5-trifluorophenyl)-6-(3-(tetrazolyl)phenyl)-3,4-dihydro-2H-chroman-3-amine (29g)

合成方法参照化合物24，得产物10.50mg，产率为10.5％。熔点：761.6-762.8℃。 ¹H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.10(s,1H),7.92(d,J＝7.5Hz,1H),7.72-7.57(m,2H),7.48(dt,J＝27.8,7.6Hz,4H),6.91(d,J＝8.4Hz,1H),4.93(d,J＝9.0Hz,1H),3.10(dd,J＝16.4,5.0Hz,1H),2.85(dd,J＝15.8,10.5Hz,1H),1.89(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ156.42,153.90,149.58,146.81,140.35,133.54,133.25,130.12,129.42,128.26,126.09,125.45,124.81,124.09,123.76,122.42,117.82,116.87,106.65,76.94,48.33,34.36.HRMS(EI):calcd for C ₂₂H ₁₆F ₃N ₅O[M] ⁺m/z 423.1307；found,423.1306. The synthesis method refers to compound 24, and the product is 10.50 mg, and the yield is 10.5%. Melting point: 761.6-762.8°C. ¹ H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.10(s,1H),7.92(d,J=7.5Hz,1H),7.72-7.57(m,2H),7.48(dt ,J=27.8,7.6Hz,4H), 6.91(d,J=8.4Hz,1H), 4.93(d,J=9.0Hz,1H), 3.10(dd,J=16.4,5.0Hz,1H), 2.85 (dd, J=15.8, 10.5 Hz, 1H), 1.89 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ156.42,153.90,149.58,146.81,140.35,133.54,133.25,130.12,129.42,128.26, 126.09,125.45,124.81,124.09,123.76,122.42,117.82,116.87,106.65,76.94,48.33,34.36.HRMS(EI):calcd for C ₂₂ H ₁₆ F ₃ N ₅ O[M] ⁺ m/z 423.1307; found , 423.1306.

trans-2-(2,4,5-三氟苯基)-6-(3-(氰基)苯基)-3,4-二氢-2H-色满-3-胺(29h)trans-2-(2,4,5-trifluorophenyl)-6-(3-(cyano)phenyl)-3,4-dihydro-2H-chroman-3-amine (29h)

合成方法参照化合物24，得产物45.05mg，产率为79.5％。熔点：405.2-406.2℃。 ¹H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.94(d,J＝8.1Hz,1H),7.72(d,J＝7.7Hz,1H),7.66-7.53(m,4H),7.50(dd,J＝8.5,2.0Hz,1H),6.95(d,J＝8.5Hz,1H),5.16(d,J＝8.6Hz,1H),3.59(td,J＝9.1,5.5Hz,1H),3.28-3.11(m,1H),2.97(dd,J＝16.5,9.8Hz,1H). ¹³C NMR(151MHz,DMSO-d6)δ156.35,154.21,149.91,146.75,141.23,131.29,130.73,130.45,130.04,128.75,126.59,122.46,121.58,119.31,117.89,117.13,112.47,106.90,75.65,47.96,32.23.HRMS(EI):calcd for C ₂₂H ₁₅F ₃N ₂O[M] ⁺m/z 380.1136；found,380.1131. The synthesis method refers to compound 24 to obtain 45.05 mg of the product with a yield of 79.5%. Melting point: 405.2-406.2°C. ¹ H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.94(d,J=8.1Hz,1H),7.72(d,J=7.7Hz,1H),7.66-7.53(m,4H ), 7.50 (dd, J = 8.5, 2.0 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 5.16 (d, J = 8.6 Hz, 1H), 3.59 (td, J = 9.1, 5.5 Hz , 1H), 3.28-3.11 (m, 1H), 2.97 (dd, J = 16.5, 9.8 Hz, 1H). ¹³ C NMR (151MHz, DMSO-d6) δ156.35, 154.21, 149.91, 146.75, 141.23, 131.29, 130.73 ,130.45,130.04,128.75,126.59,122.46,121.58,119.31,117.89,117.13,112.47,106.90,75.65,47.96,32.23.HRMS(EI):calcd for C ₂₂ H ₁₅ F ₃ N ₂ O[M] ⁺ m /z 380.1136; found,380.1131.

trans-2-(2,4,5-三氟苯基)-6-(2,4-二氟苯基)-3,4-二氢-2H-色满-3-胺(29i)trans-2-(2,4,5-trifluorophenyl)-6-(2,4-difluorophenyl)-3,4-dihydro-2H-chroman-3-amine (29i)

合成方法参照化合物24，得产物70.50mg，产率为80.5％。熔点：342.6-343.8℃。 ¹H NMR(400MHz,DMSO-d6)δ7.67-7.54(m,2H),7.54-7.48(m,1H),7.34-7.27(m,2H),7.27-7.22(m,1H),7.20-7.08(m,1H),6.89(d,J＝8.4Hz,1H),4.92(d,J＝9.1Hz,1H),3.30(td,J＝9.8,5.1Hz,1H),3.02(dd,J＝16.4,5.1Hz,1H),2.79(dd,J＝16.2,10.6Hz,1H),1.57(s,2H). ¹³C NMR(151MHz,DMSO-d6)δ161.43,159.80,156.39,154.12,149.43,146.79,131.94,130.38,128.19,127.16,125.08,123.88,122.48,117.74,116.51,112.35,106.47,104.79,77.33,48.43,34.77.HRMS(EI):calcd for C ₂₁H ₁₄F ₅NO[M] ⁺m/z 391.0996；found,391.0995. The synthesis method refers to compound 24, and the product is 70.50 mg with a yield of 80.5%. Melting point: 342.6-343.8°C. ¹ H NMR(400MHz,DMSO-d6)δ7.67-7.54(m,2H),7.54-7.48(m,1H),7.34-7.27(m,2H),7.27-7.22(m,1H),7.20- 7.08 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.92 (d, J = 9.1 Hz, 1H), 3.30 (td, J = 9.8, 5.1 Hz, 1H), 3.02 (dd, J = 16.4, 5.1 Hz, 1H), 2.79 (dd, J = 16.2, 10.6 Hz, 1H), 1.57 (s, 2H). ¹³ C NMR (151MHz, DMSO-d6) δ161.43,159.80,156.39,154.12,149.43, 146.79,131.94,130.38,128.19,127.16,125.08,123.88,122.48,117.74,116.51,112.35,106.47,104.79,77.33,48.43,34.77.HRMS(EI):calcd for C ₂₁ H ₁₄ F ₅ NO[M] ⁺ m/z 391.0996; found, 391.0995.

trans-2-(2,4,5-三氟苯基)-6-(3,4-二甲氧基苯基)-3,4-二氢-2H-色满-3-胺(29j)trans-2-(2,4,5-trifluorophenyl)-6-(3,4-dimethoxyphenyl)-3,4-dihydro-2H-chroman-3-amine (29j)

合成方法参照化合物24，得产物60.50mg，产率为81.5％。熔点：408.4-409.5℃。 ¹H NMR(400MHz,DMSO-d6)δ7.70-7.53(m,2H),7.46-7.38(m,2H),7.17(d,J＝2.0Hz,1H),7.13(dd,J＝8.3,2.1Hz,1H),7.00(dd,J＝12.7,8.7Hz,1H),6.89(d,J＝8.4Hz,1H),5.09(d,J＝8.6Hz,1H),3.84(s,3H),3.78(s,3H),3.55(td,J＝9.1,5.3Hz,1H),3.13(dd,J＝16.5,5.1Hz,1H),2.92(dd,J＝16.4,9.8Hz,1H). ¹³C NMR(151MHz,DMSO-d6)δ156.34,153.05,149.83,149.49,148.52,146.82,133.65,133.10,127.98,126.11,122.82,121.27,118.76,117.90,116.78,112.64,110.56,106.90,75.69,60.23,56.02,32.60.HRMS(EI):calcd for C ₂₃H ₂₀F ₃NO ₃[M] ⁺m/z 415.1395；found,415.1397. The synthesis method refers to compound 24, and the product is 60.50 mg with a yield of 81.5%. Melting point: 408.4-409.5°C. ¹ H NMR(400MHz,DMSO-d6)δ7.70-7.53(m,2H),7.46-7.38(m,2H),7.17(d,J=2.0Hz,1H), 7.13(dd,J=8.3, 2.1Hz, 1H), 7.00 (dd, J = 12.7, 8.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.09 (d, J = 8.6 Hz, 1H), 3.84 (s, 3H) , 3.78 (s, 3H), 3.55 (td, J = 9.1, 5.3 Hz, 1H), 3.13 (dd, J = 16.5, 5.1 Hz, 1H), 2.92 (dd, J = 16.4, 9.8 Hz, 1H). ¹³ C NMR (151MHz, DMSO-d6) δ156.34,153.05,149.83,149.49,148.52,146.82,133.65,133.10,127.98,126.11,122.82,121.27,118.76,117.90,116.78,112.64,110.56,106.90,75.69,60.23, 56.02,32.60.HRMS(EI):calcd for C ₂₃ H ₂₀ F ₃ NO ₃ [M] ⁺ m/z 415.1395; found,415.1397.

trans-2-(2,4,5-三氟苯基)-3-硝基-6-羟基-7-氰基-3,4-二氢-2H-苯并[f]色满(5)的合成trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-hydroxy-7-cyano-3,4-dihydro-2H-benzo[f]chroman(5) Synthesis

称取trans-2-(2,4,5-三氟苯基)-3-硝基-6-甲氧基-7-氰基-3,4-二氢-2H-苯并[f]色满(1.00g，2.41mmol)于100mL三颈瓶中，加入10mL CH ₂Cl ₂溶解，-78℃下搅拌10min。加入BBr ₃(1.81g，7.23mmol)，装置转移至常温，继续搅拌，TLC监测反应进度。原料转化完全后，冰浴下逐滴滴加CH ₃OH。有机相用CH ₂Cl ₂(3×15mL)萃取，无水Na ₂SO ₄干燥，硅胶柱(200-300目)纯化(PE:EA＝5:1)，得到棕褐色产品0.75g，产率77.6％。 ¹H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.20(s,1H),8.02-7.95(m,1H),7.65(d,J＝8.9Hz,1H),7.61-7.50(m,1H),7.07(s,1H),6.98(d,J＝8.9Hz,1H),5.89(d,J＝11.0Hz,1H),5.86-5.79(m,1H),3.46(d,J＝6.0Hz,1H),3.10(dd,J＝14.5,4.6Hz,1H).LC-MS(ESI)m/z 399.21[M-H] ^-. Weigh trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-methoxy-7-cyano-3,4-dihydro-2H-benzo[f] Fill it up (1.00 g, 2.41 mmol) in a 100 mL three-necked flask, add 10 mL CH ₂ Cl _{2 to} dissolve, and stir at -78° C. for 10 min. BBr ₃ (1.81 g, 7.23 mmol) was added, the device was transferred to room temperature, and stirring was continued, and the progress of the reaction was monitored by TLC. After the conversion of the raw materials is complete, CH ₃ OH is added dropwise under an ice bath. The organic phase was extracted with CH ₂ Cl ₂ (3×15 mL), dried with anhydrous Na ₂ SO ₄ , and purified by silica gel column (200-300 mesh) (PE:EA=5:1) to obtain 0.75 g of a brown product with a yield 77.6%. ¹ H NMR (400MHz, DMSO-d6) δ 10.65 (s, 1H), 8.20 (s, 1H), 8.02-7.95 (m, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.61-7.50 (m, 1H), 7.07 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 5.89 (d, J = 11.0 Hz, 1H), 5.86-5.79 (m, 1H), 3.46 (d, J＝6.0Hz,1H),3.10(dd,J＝14.5,4.6Hz,1H).LC-MS(ESI)m/z 399.21[MH] ^- .

trans-2-(2,4,5-三氟苯基)-3-硝基-7-氰基-3,4-二氢-2H-苯并[f]色满-6-取代衍生物(6a和6d)的合成trans-2-(2,4,5-trifluorophenyl)-3-nitro-7-cyano-3,4-dihydro-2H-benzo[f]chroman-6-substituted derivative ( 6a and 6d) synthesis

trans-2-(2,4,5-三氟苯基)-3-硝基-6-(甲氧基-d3)-7-氰基-3,4-二氢-2H-苯并[f]色满(6a)trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-(methoxy-d3)-7-cyano-3,4-dihydro-2H-benzo[f ]Color full (6a)

称取trans-2-(2,4,5-三氟苯基)-3-硝基-6-羟基-7-氰基-3,4-二氢-2H-苯并[f]色满(1.00g,2.50mmol)，氘代碘甲烷(0.40g,2.75mmol)，碳酸钾(0.79g,7.50mmol)于100mL三颈烧瓶中，加入乙腈15mL溶解。升温至40℃，TLC监测反应。反应结束后，冷却至室温，加入水10mL，乙酸乙酯萃取三次，无水Na ₂SO ₄干燥，200-300目硅胶柱纯化(PE:EA＝8:1)。得到0.68g淡黄色产物，产率为65.4％。 ¹H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.7Hz,1H),7.81(d,J＝7.81Hz,2H),7.76-7.67(m,1H),7.61-7.50(m,1H),7.25(s,1H),7.16(d,J＝8.9Hz,1H),5.93(d,J＝7.8Hz,1H),5.82-5.77(m,1H),3.73-3.66(m,1H),3.60(m,1H).LC-MS(ESI)m/z 416.30[M-H] ^-. Weigh trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-hydroxy-7-cyano-3,4-dihydro-2H-benzo[f]chroman ( 1.00g, 2.50mmol), deuterated methyl iodide (0.40g, 2.75mmol), potassium carbonate (0.79g, 7.50mmol) in a 100mL three-necked flask, add 15mL of acetonitrile to dissolve. The temperature was raised to 40°C, and the reaction was monitored by TLC. After the reaction is completed, cool to room temperature, add 10 mL of water, extract three times with ethyl acetate, dry with anhydrous Na ₂ SO ₄ , and purify by 200-300 mesh silica gel column (PE:EA=8:1). 0.68 g of light yellow product was obtained, and the yield was 65.4%. ¹ H NMR (400MHz, DMSO-d6) δ8.41 (d, J = 2.7Hz, 1H), 7.81 (d, J = 7.81Hz, 2H), 7.76-7.67 (m, 1H), 7.61-7.50 (m ,1H),7.25(s,1H),7.16(d,J=8.9Hz,1H),5.93(d,J=7.8Hz,1H),5.82-5.77(m,1H),3.73-3.66(m, 1H),3.60(m,1H).LC-MS(ESI)m/z 416.30[MH] ^- .

trans-2-(2,4,5-三氟苯基)-3-硝基-6-乙氧基-7-氰基-3,4-二氢-2H-苯并[f]色满(6b)trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-ethoxy-7-cyano-3,4-dihydro-2H-benzo[f]chroman( 6b)

合成方法参照6a。得到淡黄色固体0.80g，收率66.0％。 ¹H NMR(400MHz,CDCl ₃)δ8.11(s,1H),7.69(d,J＝8.9Hz,1H),7.24-7.19(m,1H),7.07(d,J＝9.0Hz,1H),7.05-7.00(m,1H),6.99(s,1H),5.79(d,J＝7.6Hz,1H),5.34-5.29(m,1H),3.83(dd,J＝16.2,8.5Hz,1H),3.51(dd,J＝16.3,5.8Hz,1H).LC-MS(ESI)m/z 427.39[M-H] ^-. Refer to 6a for synthesis method. 0.80 g of light yellow solid was obtained with a yield of 66.0%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.11 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.24-7.19 (m, 1H), 7.07 (d, J = 9.0 Hz, 1H) ,7.05-7.00(m,1H),6.99(s,1H),5.79(d,J=7.6Hz,1H),5.34-5.29(m,1H),3.83(dd,J=16.2,8.5Hz,1H ),3.51(dd,J=16.3,5.8Hz,1H).LC-MS(ESI)m/z 427.39[MH] ^- .

trans-2-(2,4,5-三氟苯基)-7-氰基-3,4-二氢-2H-苯并[f]色满-3-胺-6-取代衍生物(7a和7d)的合成trans-2-(2,4,5-trifluorophenyl)-7-cyano-3,4-dihydro-2H-benzo[f]chroman-3-amine-6-substituted derivative (7a And 7d) synthesis

trans-2-(2,4,5-三氟苯基)-6-(甲氧基-d3)-7-氰基-3,4-二氢-2H-苯并[f]色满-3-胺(7a)trans-2-(2,4,5-trifluorophenyl)-6-(methoxy-d3)-7-cyano-3,4-dihydro-2H-benzo[f]chroman-3 -Amine (7a)

称取trans-2-(2,4,5-三氟苯基)-3-硝基-6-(甲氧基-d3)-7-氰基-3,4-二氢-2H-苯并[f]色满(0.50g,1.20mmol)，锌粉(0.78g,12.00mmol)，4mL 6N的盐酸于50mL两口反应瓶，再加入5mL CH ₃CH ₃OH溶解，常温下充分搅拌，TLC监测反应进度。原料转化完全后，加入饱和碳酸氢淬灭反应。有机相用乙酸乙酯(3×10mL)萃取三次，无水Na ₂SO ₄干燥，硅胶柱(200-300目)纯化(PE:EA＝1:1)。得到白色粉末0.25g，收率为54.3％。熔点：434.96-436.90℃。 ¹H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.80(d,J＝8.9Hz,1H),7.77-7.64(m,2H),7.29(s,1H),7.10(d,J＝8.9Hz,1H),5.02(d,J＝9.1Hz,1H),3.48(dd,J＝9.3,5.5Hz,1H),2.88(dd,J＝16.1,9.9Hz,1H),1.75(s,2H).HRMS(EI):calcd for C ₂₁H ₁₂D ₃F ₃N ₂O ₂[M] ⁺m/z 387.3765；found,387.3762. Weigh trans-2-(2,4,5-trifluorophenyl)-3-nitro-6-(methoxy-d3)-7-cyano-3,4-dihydro-2H-benzo [f] Seman (0.50g, 1.20mmol), zinc powder (0.78g, 12.00mmol), 4mL 6N hydrochloric acid in a 50mL two-necked reaction flask, then add 5mL CH ₃ CH ₃ OH to dissolve, stir well at room temperature, TLC monitoring Response progress. After the conversion of the raw materials was completed, saturated hydrogen carbonate was added to quench the reaction. The organic phase was extracted three times with ethyl acetate (3×10 mL), dried with anhydrous Na ₂ SO ₄ , and purified by silica gel column (200-300 mesh) (PE:EA=1:1). 0.25 g of white powder was obtained, and the yield was 54.3%. Melting point: 434.96-436.90°C. ¹ H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.80(d,J=8.9Hz,1H),7.77-7.64(m,2H),7.29(s,1H),7.10(d ,J=8.9Hz,1H),5.02(d,J=9.1Hz,1H), 3.48(dd,J=9.3,5.5Hz,1H), 2.88(dd,J=16.1,9.9Hz,1H),1.75 (s,2H).HRMS(EI):calcd for C ₂₁ H ₁₂ D ₃ F ₃ N ₂ O ₂ [M] ⁺ m/z 387.3765; found, 387.3762.

trans-2-(2,4,5-三氟苯基)-6-乙氧基-7-氰基-3,4-二氢-2H-苯并[f]色满-3-胺(7d)trans-2-(2,4,5-trifluorophenyl)-6-ethoxy-7-cyano-3,4-dihydro-2H-benzo[f]chroman-3-amine(7d )

合成方法参照7a。得到白色粉末0.50g，收率为55.0％。熔点：446.23-447.20℃。 ¹H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.80(d,J＝9.0Hz,1H),7.78-7.64(m,2H),7.29(s,1H),7.09(d,J＝8.9Hz,1H),5.02(d,J＝9.2Hz,1H),4.38-4.35(m,1H),3.47(d,J＝4.5Hz,1H),2.87(dd,J＝16.3,10.0Hz,1H),1.78(s,2H).HRMS(EI):calcd for C ₂₂H ₁₇F ₃N ₂O ₂[M] ⁺m/z 398.3852；found,398.3855. Refer to 7a for synthesis method. 0.50 g of white powder was obtained, and the yield was 55.0%. Melting point: 446.23-447.20°C. ¹ H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.80(d,J=9.0Hz,1H),7.78-7.64(m,2H),7.29(s,1H),7.09(d ,J=8.9Hz,1H),5.02(d,J=9.2Hz,1H), 4.38-4.35(m,1H), 3.47(d,J=4.5Hz,1H), 2.87(dd,J=16.3, 10.0Hz,1H),1.78(s,2H).HRMS(EI):calcd for C ₂₂ H ₁₇ F ₃ N ₂ O ₂ [M] ⁺ m/z 398.3852; found, 398.3855.

2-甲氧基-6-氰基-7-甲氧基-1-萘甲醛(31)2-Methoxy-6-cyano-7-methoxy-1-naphthaldehyde (31)

合成方法参照9a。得白色固体2.00g，产率为74.5％。 ¹H NMR(400MHz,DMSO-d ₆):δ10.71(s,1H),8.77(s,1H),8.50(s,1H),8.29(d,J＝8.4Hz,1H),7.55(d,J＝8.8Hz,1H),4.09(s,3H),3.98(s,3H).LC-MS(ESI)m/z 242.10[M+1] ⁺. Refer to 9a for synthesis method. 2.00 g of white solid was obtained, and the yield was 74.5%. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.71 (s, 1H), 8.77 (s, 1H), 8.50 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.55 (d ,J=8.8Hz,1H),4.09(s,3H),3.98(s,3H).LC-MS(ESI)m/z 242.10[M+1] ⁺ .

2-羟基-6-氰基-7-甲氧基-1-萘甲醛(32)2-hydroxy-6-cyano-7-methoxy-1-naphthaldehyde (32)

合成方法参照11a。得白色黄色固体1.50g，产率为70.0％。 ¹H NMR(400MHz,DMSO-d ₆):δ12.14(s,1H),10.68(s,1H),8.58(s,1H),8.35(s,1H),8.03(d,J＝9.2Hz,1H),7.11(d,J＝8.8Hz,1H),3.93(s,3H).LC-MS(ESI)m/z 296.10[M+1] ⁺,294.10[M-1] ^-. Refer to 11a for synthesis method. 1.50 g of white yellow solid was obtained, and the yield was 70.0%. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.14 (s, 1H), 10.68 (s, 1H), 8.58 (s, 1H), 8.35 (s, 1H), 8.03 (d, J = 9.2 Hz) ,1H),7.11(d,J=8.8Hz,1H),3.93(s,3H).LC-MS(ESI)m/z 296.10[M+1] ⁺ ,294.10[M-1] ^- .

2-(2,5-三氟苯基)-6-甲氧基-7-氰基-3-硝基-2H-苯并色满(33)2-(2,5-Trifluorophenyl)-6-methoxy-7-cyano-3-nitro-2H-benzochroman(33)

合成方法参照13a。得到橘黄色固体1.50g，收率40％。 ¹H NMR(400MHz, DMSO-d ₆)δ9.13(s,1H),8.44(s,1H),7.97(d,J＝9.1Hz,1H),7.88(s,1H),7.35(td,J＝9.4,4.5Hz,1H),7.24(dd,J＝23.1,8.5Hz,2H),7.04(d,J＝8.9Hz,1H),6.99(s,1H),4.09(s,3H).LC-MS(ESI)m/z 395.08[M+1] ⁺. Refer to 13a for synthesis method. 1.50 g of orange solid was obtained with a yield of 40%. ¹ H NMR(400MHz, DMSO-d ₆ )δ9.13(s,1H),8.44(s,1H),7.97(d,J=9.1Hz,1H),7.88(s,1H),7.35(td, J = 9.4, 4.5 Hz, 1H), 7.24 (dd, J = 23.1, 8.5 Hz, 2H), 7.04 (d, J = 8.9 Hz, 1H), 6.99 (s, 1H), 4.09 (s, 3H). LC-MS(ESI)m/z 395.08[M+1] ⁺ .

trans-2-(2,5-三氟苯基)-6-甲氧基-7-氰基-3-硝基-3,4-二氢-2H-苯并色满(34)trans-2-(2,5-trifluorophenyl)-6-methoxy-7-cyano-3-nitro-3,4-dihydro-2H-benzochroman(34)

合成方法参照6a，得到淡黄色固体1.10g，产率为23％。 ¹H NMR(400MHz,CDCl ₃)δ8.04(s,1H),7.63(d,J＝9.0Hz,1H),7.02(tt,J＝13.8,7.0Hz,4H),6.94(s,1H),5.86(d,J＝6.7Hz,1H),5.28(q,J＝6.5Hz,1H),3.97(s,3H),3.79(dd,J＝16.7,7.2Hz,1H),3.38(dd,J＝16.7,5.6Hz,1H).LC-MS(ESI)m/z 409.10[M-1] ^-. The synthesis method refers to 6a, and 1.10 g of light yellow solid is obtained, and the yield is 23%. ¹ H NMR(400MHz,CDCl ₃ )δ8.04(s,1H), 7.63(d,J=9.0Hz,1H), 7.02(tt,J=13.8,7.0Hz,4H), 6.94(s,1H) ,5.86(d,J=6.7Hz,1H), 5.28(q,J=6.5Hz,1H), 3.97(s,3H), 3.79(dd,J=16.7,7.2Hz,1H), 3.38(dd, J＝16.7,5.6Hz,1H).LC-MS(ESI)m/z 409.10[M-1] ^- .

trans-2-(2,5-二氟苯基)-6-甲氧基-7-氰基-3,4-二氢-2H-苯并色满-3-胺(7c)trans-2-(2,5-difluorophenyl)-6-methoxy-7-cyano-3,4-dihydro-2H-benzochroman-3-amine (7c)

合成参考7a。得白色固体1.00g，收率13％。熔点:233.7-235.1℃, ¹H NMR(400MHz,DMSO-d ₆)δ8.44(s,1H),7.79(d,J＝8.9Hz,1H),7.43-7.28(m,3H),7.25(s,1H),7.09(d,J＝8.9Hz,1H),5.17(d,J＝8.0Hz,1H),4.04(s,3H),3.64(d,J＝5.7Hz,1H),2.96(dd,J＝16.6,9.3Hz,1H). ¹³C NMR(101MHz,DMSO-d ₆)δ157.10,154.60,136.96,136.50,130.48,129.09,123.39,117.98,117.84,117.12,116.19,116.18,116.17,115.97,112.77,102.28,99.86,76.36,56.66,47.83,29.86.HRMS(ESI):calcd for C ₂₀H ₁₅F ₂NO ₃[M+H] ⁺367.1020,found 367.1259.Purity:98.44％(t _R14.12min). Synthesis reference 7a. 1.00 g of white solid was obtained, with a yield of 13%. Melting point: 233.7-235.1℃, ¹ H NMR(400MHz,DMSO-d ₆ )δ8.44(s,1H),7.79(d,J=8.9Hz,1H),7.43-7.28(m,3H),7.25( s, 1H), 7.09 (d, J = 8.9 Hz, 1H), 5.17 (d, J = 8.0 Hz, 1H), 4.04 (s, 3H), 3.64 (d, J = 5.7 Hz, 1H), 2.96 ( dd, J = 16.6, 9.3 Hz, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ157.10,154.60,136.96,136.50,130.48,129.09,123.39,117.98,117.84,117.12,116.19,116.18,116.17,115.97 ,112.77,102.28,99.86,76.36,56.66,47.83,29.86.HRMS(ESI):calcd for C ₂₀ H ₁₅ F ₂ NO ₃ [M+H] ⁺ 367.1020,found 367.1259.Purity:98.44%(t _R 14.12min ).

实施例2.生物活性测试Example 2. Biological Activity Test

实验原理：正常状态下，肝星状细胞处于非活化状态，但是在长期肝损伤状态下，肝星状细胞会被激活并转变为成肌纤维细胞，产生大量α-平滑肌动蛋白(α-SMA)和细胞外基质，促进肝纤维化。其中，TGF-β是一种重要的促纤维化细胞因子，能够直接导致肝星状细胞激活与表型改变1。因此，利用TGF-β诱导的肝星状细胞LX2表型变化，可以评价化合物是否具有抑制细胞活化的作用Experimental principle: Under normal conditions, hepatic stellate cells are in an inactive state, but under long-term liver damage, hepatic stellate cells will be activated and transformed into myofibroblasts, producing large amounts of α-smooth actin (α-SMA) And extracellular matrix, promote liver fibrosis. Among them, TGF-β is an important pro-fibrotic cytokine, which can directly cause hepatic stellate cell activation and phenotypic changes1. Therefore, the use of TGF-β-induced LX2 phenotypic changes in hepatic stellate cells can be used to evaluate whether the compound has the effect of inhibiting cell activation

实验步骤：Experimental steps:

1)培养LX2细胞，培养基为DMEM+2％FBS，按照1:2传代；1) Cultivate LX2 cells with DMEM+2% FBS as the culture medium, and pass through 1:2;

2)若LX2生长密度为80％～90％时收集细胞，加入胰酶1.5ml，3分钟，加入3ml MEM培养基终止，将细胞收集在15ml离心管中；2) If the growth density of LX2 is 80%～90%, collect the cells, add 1.5ml trypsin, 3 minutes, add 3ml MEM medium to stop, collect the cells in a 15ml centrifuge tube;

3)取20μl细胞液体和20μl台盼蓝按照1:1混匀，进行细胞计数，记录数据；将15ml离心管离心，300g，5分钟；3) Take 20μl of cell liquid and 20μl of trypan blue and mix 1:1, count the cells, and record the data; centrifuge the 15ml centrifuge tube at 300g for 5 minutes;

4)用DMEM将细胞重悬至15000cell/ml，混匀，500μl/well加入已铺好胶的#3524 24孔板中；4) Resuspend the cells to 15000cell/ml with DMEM, mix well, add 500μl/well to the #3524 24-well plate that has been coated with gel;

5)细胞贴壁后，换DMEM+0.5％FBS饥饿12h；5) After the cells adhere to the wall, change to DMEM+0.5% FBS and starve for 12 hours;

6)用DMEM培养基配制10ng/ml的TGF-β，用配置好的TGF-β溶液配制的化合物；6) Prepare 10ng/ml TGF-β with DMEM medium, and prepare the compound with the prepared TGF-β solution;

7)将配制的化合物加入24孔板，500μl/well，混匀，置于37℃培养箱，孵育24小时；7) Add the prepared compound to a 24-well plate, 500μl/well, mix well, place in a 37°C incubator, and incubate for 24 hours;

8)用PBS缓冲液洗细胞两遍，每孔加入100μl 1×的loading buffer，细胞收样于1.5mlEP管中；8) Wash the cells twice with PBS buffer, add 100μl 1× loading buffer to each well, and collect the cells in a 1.5ml EP tube;

9)100℃煮样品10分钟，离心后放入-20℃冰箱待用；9) Boil the sample at 100°C for 10 minutes, centrifuge and put it in the refrigerator at -20°C for later use;

10)细胞免疫印迹(western blot)；10) Western blot;

实验结果：Experimental results:

ND：未测ND: not tested

结论：in conclusion:

本发明的化合物均能够不同程度地以浓度依赖性的方式降低α-SMA表达，从而抑制LX2的活化。本发明的大多数化合物的抑制效果强于阳性对照。在本发明的化合物中，7c-1、7c-2、7j、7r、7y、15i、29i在1和10μM两个浓度时均表现出较强的抑制活性，有些化合物甚至明显强于阳性对照；有些化合物，例如化合物7、7a、7h、7i、7l、7o、7q、7s、7t、7u、7v、7w、7x、F1a、F2、F3、F4a、F5a、15a、15b、15c、15e、15h、15k、20、24、29a、29b、29c、29f、29h和29j在10μM浓度下的抑制效果显著强于阳性对照。The compounds of the present invention can reduce the expression of α-SMA in a concentration-dependent manner to varying degrees, thereby inhibiting the activation of LX2. The inhibitory effect of most of the compounds of the present invention is stronger than that of the positive control. Among the compounds of the present invention, 7c-1, 7c-2, 7j, 7r, 7y, 15i, 29i showed strong inhibitory activity at two concentrations of 1 and 10 μM, and some compounds were even significantly stronger than the positive control; Some compounds, such as compound 7, 7a, 7h, 7i, 7l, 7o, 7q, 7s, 7t, 7u, 7v, 7w, 7x, F1a, F2, F3, F4a, F5a, 15a, 15b, 15c, 15e, 15h The inhibitory effect of, 15k, 20, 24, 29a, 29b, 29c, 29f, 29h and 29j at a concentration of 10μM was significantly stronger than that of the positive control.

Claims

通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物在制备预防或治疗肝纤维化的药物中的用途：Use of a compound represented by the general formula I, or a pharmaceutically acceptable salt or prodrug, or an optically active isomer or solvate thereof in the preparation of a medicine for preventing or treating liver fibrosis:

式中：Where:

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

A是带有1-5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C _1-6烷基或被卤素、优选F，更优选1-5个F取代的C _1-6烷基、C1-6烷氧基或被卤素、优选F，更优选1-5个F取代的C _1-6烷氧基； A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl or substituted by halogen, preferably F, more preferably 1-5 F C _1-6 alkyl, C1-6 alkoxy or halogen, preferably F, and more preferably 1 to 5 F substituted C _1-6 alkoxy;

A环还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；Ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano, and boronic acid groups;

A杂环选自以下结构：A heterocycle is selected from the following structures:

环B、C不同时存在，Rings B and C do not exist at the same time,

环B选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，Ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

其取代基R独立选自H、卤素、氰基、羟基、C _1-6烷基或含1-5个F原子C _1-6烷基、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，n＝1-4， Which substituent group R is independently selected from H, halo, cyano, hydroxy, C _1-6 alkyl containing 1-5 F atoms or C _1-6 alkyl, C _1-6 alkoxy, or an 1-5 F atom C _1-6 alkoxy, n=1-4,

环C选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，Ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

其取代基R ₁独立选自H、卤素、任选取代的C _1-6烷基、氰基、任选取代的氨基、羰基、羟基、C _1-3羧基(优选COOH)、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，C _1-6氘代烷氧基或含1-5个F原子C _1-6氘代烷氧基，n＝1-4；或者 Its substituent R _{1 is} independently selected from H, halogen, optionally substituted C _1-6 alkyl, cyano, optionally substituted amino, carbonyl, hydroxyl, C _1-3 carboxy (preferably COOH), C _1-6 an alkoxy group having 1 to 5 F atoms or C _1-6 alkoxy, C _1-6 alkoxy or deuterated having 1-5 C _1-6 F atoms deuterated alkoxy group, n = 1- 4; or

环C不存在时，R ₁直接与化合物主体相连， When ring C does not exist, R _{1 is} directly connected to the main body of the compound,

此时，R ₁为H、羰基、卤素、任选取代的苯基、氰基、任选取代的氨基、任选取代的含1-2个选自N或O的杂原子的5-6元杂环基、羟基、C _1-3羧基(优选COOH)、C _1-3羧酸酯基(优选甲酸甲酯基)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，m＝1-2。 In this case, R ₁ is H, carbonyl, halogen, optionally substituted phenyl, cyano, optionally substituted amino, optionally substituted 5-6 member containing 1-2 heteroatoms selected from N or O Heterocyclic group, hydroxyl group, C _1-3 carboxyl group (preferably COOH), C _1-3 carboxylate group (preferably methyl formate group), optionally substituted C _1-6 alkyl, optionally substituted C _{1- 10} Alkoxy (preferably C _1-6 alkoxy), optionally substituted C _2-10 alkoxy containing ethylenic or acetylenic bond, optionally substituted benzyloxy, optionally substituted C _1-10 Alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _{1-6 alkoxyformyl, carbamoyl} Acyl, amino, optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _{3-5 alkyllactam} , optionally substituted C _1-6 alkylsulfonamido, optionally substituted C _3-5 alkyl lactam sulfonyl group, mercapto group, optionally substituted C _1-5 alkyl mercapto group, optionally substituted C _1-5 alkylsulfonyl group, optionally substituted C _3-5 cycloalkylsulfonyl group Acyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m = 1-2.
如权利要求1所述的用途，其特征在于，所述化合物是通式(II)所示化合物：The use according to claim 1, wherein the compound is a compound represented by the general formula (II):

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

A是带有1-5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C _1-6烷基或被卤素、优选F，更优选1-5个F取代的C _1-6烷基、C1-6烷氧基或被卤素、优选F，更优选1-5个F取代的C _1-6烷氧基； A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl or substituted by halogen, preferably F, more preferably 1-5 F C _1-6 alkyl, C1-6 alkoxy or halogen, preferably F, and more preferably 1 to 5 F substituted C _1-6 alkoxy;

R ₄独立选自H、羟基、F、氰基； R _{4 is} independently selected from H, hydroxyl, F, cyano;

R ₅为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，任选取代的苯基，q＝1-2。 R ₅ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted benzyloxy, optionally substituted C _1-10 alkylformyloxy, any Optional substituted C _1-3 alkoxy methoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _1-6 alkoxyformyl, carbamoyl, amino, NR ² R ³ , Optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _3-5 alkyl lactam, optionally substituted C _1-6 alkylsulfonamide, optionally substituted C _{3- 5} Alkyl lactamyl, mercapto, optionally substituted C _1-5 alkyl mercapto, optionally substituted C _1-5 alkylsulfonyl, optionally substituted C _3-5 cycloalkylsulfonyl, any Select substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q=1-2.
如权利要求1所述的用途，其特征在于，所述化合物是通式(III)所示化合物：The use according to claim 1, wherein the compound is a compound represented by the general formula (III):

其中，in,

X选自O、S、NH(优选O)；X is selected from O, S, NH (preferably O);

R ₆为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苯基(优选甲磺酰基取代的苯基)、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基(优选任选取代的***啉基)； R ₆ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted phenyl (preferably methanesulfonyl substituted phenyl), optionally substituted benzyloxy , Optionally substituted C _1-10 alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _{1 -6} alkoxyformyl, carbamoyl, amino, NR ² R ³ , optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _{3-5 alkyllactam} , optionally substituted C _1-6 alkyl sulfonamido group, optionally substituted C _3-5 alkyl lactam group, mercapto group, optionally substituted C _1-5 alkyl mercapto group, optionally substituted C _1-5 alkyl sulfonate Acyl, optionally substituted C _3-5 cycloalkylsulfonyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl (preferably any (Optionally substituted morpholinyl);

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基(优选F)。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano (preferably F).
如权利要求1所述的用途，其特征在于，所述化合物是通式(IV)所示化合物：The use according to claim 1, wherein the compound is a compound represented by the general formula (IV):

其中，in,

X选自O、S、NH(优选O)；X is selected from O, S, NH (preferably O);

R ₁₀为独立选自为氢、卤素(优选F)、氰基、羟基、疏基、C _1-3羧基(优选COOH)、C _1-3羧酸甲酯基(优选甲酸甲酯基)、C _1-6烷基磺酰基、C _1-6烷基磺酰胺基或被卤素、优选F，更优选1-5个F取代的烷基磺酰胺基、C _1-6烷氧基、四唑基，r＝1-5； R ₁₀ is independently selected from hydrogen, halogen (preferably F), cyano, hydroxy, mercapto, C _1-3 carboxyl (preferably COOH), C _1-3 carboxylate (preferably methyl formate), C _1-6 alkylsulfonyl, C _1-6 alkylsulfonamido or alkylsulfonamido substituted by halogen, preferably F, more preferably 1-5 F, C _1-6 alkoxy, tetrazole Base, r=1-5;

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基(优选F)。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano (preferably F).
如权利要求1所述的用途，其特征在于，所述化合物是通式(V)所示化合物：The use according to claim 1, wherein the compound is a compound represented by the general formula (V):

其中，in,

X选自O、S、NH(优选O)；X is selected from O, S, NH (preferably O);

R ₁₁独立选自为C _1-6氘代甲氧基、C _1-6烷氧基或被卤素、优选F，更优选1-5个F取代的烷氧基或任选取代的苯基；R ₁₂独立选自为H或氰基。 R _{11 is} independently selected from C _1-6 deuterated methoxy, C _1-6 alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1-5 F, or optionally substituted phenyl; R _{12 is} independently selected from H or cyano.

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano.
选自下组的化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物在制备预防或治疗肝纤维化的药物中的用途：Use of a compound selected from the following group or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof in the preparation of a medicine for preventing or treating liver fibrosis:
如权利要求6所述的用途，其特征在于，所述化合物是选自下组的化合物：The use according to claim 6, wherein the compound is a compound selected from the following group:
通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：The compound represented by the general formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

式中：Where:

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

A是带有1-5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C _1-6烷基或被卤素、优选F，更优选1-5个F取代的C _1-6烷基、C1-6烷氧基或被卤素、优选F，更优选1-5个F取代的C _1-6烷氧基； A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl or substituted by halogen, preferably F, more preferably 1-5 F C _1-6 alkyl, C1-6 alkoxy or halogen, preferably F, and more preferably 1 to 5 F substituted C _1-6 alkoxy;

A环还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；Ring A can also be selected from nitrogen-containing, sulfur-containing five-membered or six-membered saturated or unsaturated heterocyclic rings with 1-4 substituents, and each substituent is independently selected from halogen, cyano, and boronic acid groups;

A杂环选自以下结构：A heterocycle is selected from the following structures:

环B、C不同时存在，Rings B and C do not exist at the same time,

环B选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，Ring B is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

其取代基R独立选自H、卤素、氰基、羟基、C _1-6烷基或含1-5个F原子C _1-6烷基、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，n＝1-4， Which substituent group R is independently selected from H, halo, cyano, hydroxy, C _1-6 alkyl containing 1-5 F atoms or C _1-6 alkyl, C _1-6 alkoxy, or an 1-5 F atom C _1-6 alkoxy, n=1-4,

环C选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，Ring C is selected from aromatic benzene ring, aromatic heterocyclic ring, saturated or unsaturated five-membered six-membered ring, five-membered or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur,

其取代基R ₁独立选自H、卤素、氰基、羟基、C _1-6烷氧基或含1-5个F原子C _1-6烷氧基，n＝1-4；或者 Substituents R ₁ which is independently selected from H, halo, cyano, hydroxy, C _1-6 alkoxy group having 1 to 5 F atoms or C _1-6 alkoxy, n = 1-4; or

环C不存在时，R ₁直接与化合物主体相连， When ring C does not exist, R _{1 is} directly connected to the main body of the compound,

此时，R ₁为H、羰基、卤素、任选取代的苯基、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，m＝1-2。 At this time, R ₁ is H, carbonyl, halogen, optionally substituted phenyl, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _1-6 alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted benzyloxy, optionally substituted C _{1 -10} alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _1-6 alkoxyformyl, Carbamoyl, amino, optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _{3-5 alkyllactam} , optionally substituted C _1-6 alkylsulfonamido, optionally Substituted C _3-5 alkyl lactamyl, mercapto, optionally substituted C _1-5 alkyl mercapto, optionally substituted C _1-5 alkylsulfonyl, optionally substituted C _3-5 cycloalkane Group sulfonyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, m = 1-2.
如权利要求8所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(II)所示化合物：The compound of claim 8, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is a compound represented by the general formula (II):

X选自CH ₂、O、S、NH； X is selected from CH ₂ , O, S, NH;

A是带有1-5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C _1-6烷基或被卤素、优选F，更优选1-5个F取代的C _1-6烷基、C1-6烷氧基或被卤素、优选F，更优选1-5个F取代的C _1-6烷氧基； A is a benzene ring with 1-5 substituents, each substituent is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl or substituted by halogen, preferably F, more preferably 1-5 F C _1-6 alkyl, C1-6 alkoxy or halogen, preferably F, and more preferably 1 to 5 F substituted C _1-6 alkoxy;

R ₄独立选自H、羟基、F、氰基； R _{4 is} independently selected from H, hydroxyl, F, cyano;

R ₅为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基，任选取代的苯基，q＝1-2。 R ₅ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted benzyloxy, optionally substituted C _1-10 alkylformyloxy, any Optional substituted C _1-3 alkoxy methoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _1-6 alkoxyformyl, carbamoyl, amino, NR ² R ³ , Optionally substituted C _1-5 alkyl carboxamido, optionally substituted C _3-5 alkyl lactam, optionally substituted C _1-6 alkyl sulfonamide, optionally substituted C _{3- 5} Alkyl lactamyl, mercapto, optionally substituted C _1-5 alkyl mercapto, optionally substituted C _1-5 alkylsulfonyl, optionally substituted C _3-5 cycloalkylsulfonyl, any Optional substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl, optionally substituted phenyl, q=1-2.
如权利要求8所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(III)所示化合物：The compound according to claim 8, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is a compound represented by the general formula (III):

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₆为H、羰基、卤素、氰基、羟基、C _1-3羧基(优选COOH)、任选取代的C _1-6烷基、任选取代的C _1-10烷氧基(优选C _1-6烷氧基)、任选取代的C _2-10含烯键、炔键的烷氧基、任选取代的苯基(优选甲磺酰基取代的苯基)、任选取代的苄氧基、任选取代的C _1-10烷基甲酰氧基、任选取代的C _1-3烷氧基甲氧基、双取代基OCH ₂CH ₂O和OCH ₂O、任选取代的C _1-6烷氧甲酰基、氨基甲酰基、氨基、NR ²R ³、任选取代的C _1-5烷基甲酰胺基、任选取代的C _3-5烷基内酰胺基、任选取代的C _1-6烷基磺酰胺基、任选取代的C _3-5烷基内磺酰胺基、巯基、任选取代的C _1-5烷基巯基、任选取代的C _1-5烷基磺酰基、任选取代的C _3-5环烷基磺酰基、任选取代的C _1-5烷基亚磺酰基、任选取代的***啉基、任选取代的四氢吡喃基； R ₆ is H, carbonyl, halogen, cyano, hydroxyl, C _1-3 carboxy (preferably COOH), optionally substituted C _1-6 alkyl, optionally substituted C _1-10 alkoxy (preferably C _{1 -6} alkoxy), optionally substituted C _2-10 ethylenic or acetylene bond-containing alkoxy, optionally substituted phenyl (preferably methanesulfonyl substituted phenyl), optionally substituted benzyloxy , Optionally substituted C _1-10 alkylformyloxy, optionally substituted C _1-3 alkoxymethoxy, di-substituent OCH ₂ CH ₂ O and OCH ₂ O, optionally substituted C _{1 -6} alkoxyformyl, carbamoyl, amino, NR ² R ³ , optionally substituted C _1-5 alkylcarboxamido, optionally substituted C _3-5 alkyl lactam, optionally substituted C _1-6 alkylsulfonamide group, optionally substituted C _3-5 alkyl lactamyl sulfonamide group, mercapto group, optionally substituted C _1-5 alkyl mercapto group, optionally substituted C _1-5 alkylsulfonyl group Acyl, optionally substituted C _3-5 cycloalkylsulfonyl, optionally substituted C _1-5 alkylsulfinyl, optionally substituted morpholinyl, optionally substituted tetrahydropyranyl;

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano.
如权利要求8所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(IV)所示化合物：The compound of claim 8, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is a compound represented by the general formula (IV):

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₁₀为独立选自为氢、卤素、氰基、羟基、疏基、C _1-3羧基(优选COOH)、C _1-3羧酸甲酯基(优选甲酸甲酯基)、C _1-6烷基磺酰基、C _1-6烷基磺酰胺基或被卤素、优选F，更优选1-5个F取代的烷基磺酰胺基、C _1-6烷氧基、四唑基，r＝1-5； R ₁₀ is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, C _1-3 carboxyl (preferably COOH), C _1-3 methyl carboxylate (preferably methyl formate), C _1-6 Alkylsulfonyl, C _1-6 alkylsulfonamido or alkylsulfonamido substituted by halogen, preferably F, more preferably 1-5 F, C _1-6 alkoxy, tetrazolyl, r= 1-5;

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano.
如权利要求8所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(V)所示化合物：The compound of claim 8, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is a compound represented by the general formula (V):

其中，in,

X选自O、S、NH；X is selected from O, S, NH;

R ₁₀独立选自为C _1-6氘代甲氧基、C _1-6烷氧基或被卤素、优选F，更优选1-5个F取代的烷氧基；R ₁₂独立选自为氰基。 R _{10 is} independently selected from C _1-6 deuterated methoxy, C _1-6 alkoxy or alkoxy substituted by halogen, preferably F, more preferably 1-5 F; R _{12 is} independently selected from cyano base.

R ₇、R ₈、R ₉独立选自氢、Cl、F、氰基。 R ₇ , R ₈ , and R _{9 are} independently selected from hydrogen, Cl, F, and cyano.
选自下组的化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：A compound selected from the following group or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
如权利要求13所述的化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物选自下组：The compound of claim 13 or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is selected from the following group: