Heteroanthrone compound as well as intermediate, preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a heteroanthrone compound as well as an intermediate, a preparation method, a pharmaceutical composition and application thereof. The heteroanthone compound is a heteroanthone compound as shown in a formula I which is described in the specification. The compounds can be used for preparing cccDNA inhibitors or hepatitis B drugs by inhibiting cccDNA and reducing the level of HBV-DNA, and have good market prospects. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a heteroanthrone compound and an intermediate thereof, a preparation method, a pharmaceutical composition and application. Background Art

[0002] Hepatitis B is a liver disease caused by hepatitis B virus (HBV) infection, with liver inflammation or liver cell necrosis as the main manifestation. If left untreated, it will lead to abnormal liver metabolism, liver fibrosis, liver cirrhosis and primary liver cancer. According to WHO statistics, as of 2015, there were about 257 million people infected with chronic hepatitis B worldwide. Among them, 1.34 million people died of viral hepatitis in 2015, with chronic hepatitis B accounting for 66% and hepatitis C accounting for 30% (Global Hepatitis Report, 2017). Hepatitis B has become a serious global public health problem.

[0003] HBV belongs to the Hepadnaviridae family and is a partially double-stranded relaxed circular DNA (rcDNA) consisting of a complete negative strand and an incomplete positive strand. HBV has three forms: large spherical particles, small spherical particles, and tubular particles. Among them, large spherical particles are infectious. First, after HBV enters the blood of a newly infected person, it spreads from the infected site to the whole body through the blood circulation and eventually accumulates in the liver. At this time, the large spherical particles of HBV enter the hepatocytes through adsorption, remove the viral envelope and enter the hepatocyte cytoplasm to become a nucleocapsid, then remove the capsid membrane, and the rcDNA enters the hepatocyte nucleus. At this time, the viral DNA has no replication function. Under the action of host enzymes, the negative strand DNA is used as a template to repair and obtain a highly stable covalently closed circular DNA (cccDNA). After that, the pregenome RNA (pgRNA) and three messenger RNAs are formed using cccDNA as a template. Using pgRNA as a template, under the action of HBV reverse transcriptase, progeny rcDNA is formed and assembled in the liver cytoplasm to form a complete HBV, which is released from the liver cells and enters the blood; the rcDNA in the liver cytoplasm can also enter the liver cell nucleus again and form cccDNA again, continuing the same replication process and eventually infecting all liver cells (Fabien Zoulin, Antiviral Res. 2012, 96(2), 256-259.).

[0004] At present, FDA-approved hepatitis B treatment drugs mainly include two categories: interferon (INF) and nucleoside (acid) analogs (NAs). Among them, interferon includes INFα-2b and pegylated INFα-2a. The advantages of interferon treatment are relatively short treatment courses, less prone to drug resistance, and sustained responses after discontinuation of the drug. However, the disadvantages of interferon treatment are that it requires subcutaneous and intramuscular injections, and has side effects such as fever, muscle and joint pain, and depression. In addition, the response rate of interferon treatment is not high. After 4 years of treatment with pegylated interferon, the hepatitis B surface antigen (HBsAg) clearance rate is less than 11% (Chen GF, et al. Liver Int. 2017, 37 (1), 59-66.). Nucleoside (acid) analogs mainly include nucleoside analogs: lamivudine (LAM), telbivudine (LdT), entecavir (ETV) and nucleotide analogs: adefovir dipivoxil (ADV), tenofovir disoproxil (TDF), tenofovir alafenamide (TAF). This type of drug mainly achieves its antiviral effect by inhibiting the replication of HBV DNA. Therefore, the advantage of nucleoside (acid) analog drugs is that they can strongly inhibit the replication of HBV, reduce HBV DNA to a low level in a short period of time, and almost terminate the replication. However, since it does not target the HBV replication template (cccDNA) in hepatocytes, it cannot completely eliminate HBV infection and is prone to relapse after discontinuation of the drug. In addition, this type of drug generally has varying degrees of hepatotoxicity and drug resistance during long-term use, which greatly limits the clinical use of nucleoside (acid) analog drugs (Lee M, et al. J Viral Hepat. 2014, 21 (12), 873-881.).

[0005] As human research on HBV infection deepens, a series of HBV infection mechanisms have been revealed, and drugs targeting various targets have been developed. Such as HBV adsorption and invasion inhibitors, cccDNA inhibitors, RNA inhibitors, HBsAg inhibitors, nucleocapsid Protein inhibitors, DNAPolymerase inhibitors, RNaseH inhibitors, virus maturation inhibitors and immunomodulators are being actively promoted (Shih C, et al. Trends Microbiol. 2016, 24 (9), 739-749.). Among them, cccDNA, as a template for HBV replication, exists in the nucleus of the infected liver cells. Existing drugs cannot directly inhibit or silence cccDNA for a long time. Once treatment is stopped, a small amount of cccDNA in the liver cells can replicate again and infect the entire liver cells, which makes hepatitis B difficult to cure and easy to relapse. For this reason, in 2017, the European Association for the Study of the Liver (EASL) updated its "Clinical Practice Guidelines for the Management of Chronic HBV Infection" and added cccDNA as a new biological marker, together with classic HBV biological markers such as HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb) and hepatitis B core antibody (HBcAb), as a key indicator for evaluating whether HBV is cured.

[0006] However, most drugs targeting cccDNA are still in the preclinical development stage. Several preclinical compounds that have been reported include CCC-0975, CCC-0346, MC2791, MC3119 (Bitton AM, et al. Liver Int. 2016 (6), 775-782.) and a class of compounds in WO2017202798. Therefore, the development of novel cccDNA inhibitors with good activity and safety is not only an urgent clinical need, but also a hopeful way to achieve a complete cure for hepatitis B. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the defects of the existing hepatitis B treatment drugs, such as inconvenient use, low response rate, easy recurrence and rebound of the disease after drug withdrawal, different degrees of liver and kidney toxicity and drug resistance, and provide heteroanthrone compounds and their intermediates, preparation methods, pharmaceutical compositions and applications. Such compounds can be used to prepare cccDNA inhibitors or hepatitis B drugs by inhibiting cccDNA and reducing the level of HBV-DNA. The heteroanthrone compounds have good market prospects.

[0008] The present invention mainly solves the above technical problems through the following technical solutions.

[0009] The present invention provides a heteroanthrone compound as shown in formula I, its cis-trans isomers or pharmaceutically acceptable salts thereof,

[0010]

[0011] Among them, R 1 H, hydroxyl, C 1-10 Alkyl or C 1-10 Alkoxy;

[0012] R 2 H, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen;

[0013] R 3 for The n is 0, 1, 2, 3, 4, 5 or 6, the m is 0 or 1, and the Y is C 1-10 Alkylene or C 3-10 Cycloalkylene;

[0014] R 4 Hydroxyl or Among them, R 4a C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-30 Aryl or substituted C 6-30 Aryl, the substituted C 6-30 The aryl substituent is C 1-10 Alkyl, C 1-10 alkoxy, halogen, nitro or cyano.

[0015] R 5 and R 6 Each independently is H, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen.

[0016] Q is O or methylene;

[0017] Z 1 and Z 2 are each independently O or S.

[0018] In the present invention, R 1 In the C 1-10 The alkyl group is preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl. 1-3 The alkyl group is preferably methyl, ethyl, propyl or isopropyl, more preferably methyl. 1-10 Alkoxy is preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy. 1-3The alkoxy group is preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, and more preferably a methoxy group.

[0019] The R 1 Preferred H, C 1-10 Alkyl or hydroxy, more preferably H.

[0020] The R 1 Preferred are H, methyl, methoxy or hydroxy, more preferred are H, methyl or hydroxy, and most preferred is H.

[0021] R 2 In the C 1-10 Alkyl and the halogen substituted C 1-10 C in the alkyl group 1-10 The alkyl groups are each independently preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl. 1-3 The alkyl group is preferably methyl, ethyl, propyl or isopropyl, more preferably methyl. 1-10 Alkoxy and the halogen substituted C 1-10 The alkoxy groups are each independently preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy. 1-3 The alkoxy group is preferably methoxy, ethoxy, propoxy or isopropoxybenzene, more preferably methoxy. 1-10 Alkyl and the halogen substituted C 1-10 The halogen in the alkoxy group is each independently preferably fluorine, chlorine, bromine or iodine, more preferably fluorine. The halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine or bromine.

[0022] R 2 wherein the halogen-substituted C 1-10 Alkyl and halogen substituted C 1-10 The number of halogen-substituted alkoxy groups is independently 1, 2 or 3, preferably 3. When the number of halogen-substituted alkoxy groups is plural, the types of halogen-substituted alkoxy groups may be the same or different, preferably the types of halogen-substituted alkoxy groups are the same.

[0023] The R 2 Preferably H, halogen substituted C 1-10 Alkoxy or halogen, more preferably H or halogen.

[0024] The R 2 Preferred are H, trifluoromethoxy, trifluoromethyl, chlorine or bromine, more preferred are H, chlorine or bromine, most preferred are H or bromine.

[0025] R 3 In, the Y, the C 1-10 The alkylene group is preferably C 1-6 Alkylene; more preferably C1-4 Alkylene. 1-4 The alkylene group is preferably a methylene group, an ethylene group, a n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group or a tert-butylene group, and more preferably an ethylene group, a propylene group or a butylene group.

[0026] The Y, the C 3-10 Cycloalkylene is preferably C 3-6 Cycloalkylene, more preferably C 4-6 Cycloalkylene. 4-6 Cycloalkylene More preferred

[0027] When m is 0, n may be 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3, 4 or 5.

[0028] When m is 1, n may be 1, 2, 3, 4 or 5, more preferably 2 or 3.

[0029] When m and n are both 0 or m is 0, the Y may be C 3-10 Cycloalkylene, preferably C 3-6 Cycloalkylene, more preferably C 4-6 Cycloalkylene. 4-6 Cycloalkylene is preferably

[0030] When n is 0, the Q is not O.

[0031] The R 3 In the embodiment, n is preferably 0, 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-6 More preferably, n is 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-6 Cycloalkylene; most preferably n is 1, 2, 3 or 4, Y is C 1-4 Alkylene or C 4-6 Cycloalkylene.

[0032] The R 3 Preferred are methylene, ethylene, propylene, butylene,

[0033] More preferably, ethylene, propylene, butylene,

[0034] Most preferably, ethylene, propylene, butylene,

[0035] More preferably, butylene,

[0036] R 4 In, R 4a Preferred C 1-10 Alkyl, more preferably C 1-6 Alkyl, most preferably C 1-3 Alkyl (eg methyl). 3-10 The cycloalkyl group is preferably C 3-6 Cycloalkyl. 3-6 The cycloalkyl group is preferably a cyclopropyl group. 6-30 Aryl and substituted C 6-30 C in aromatic groups 6-30 The aryl groups are each independently preferably C 6-14 Aryl, more preferably phenyl, naphthyl, anthracenyl or phenanthrenyl, most preferably phenyl.

[0037] R 4a wherein the substituted C 6-30 The substituents in the aryl group are preferably halogen or C 1-6 The halogen is preferably fluorine, chlorine, bromine or iodine. 6-30 C in aromatic groups 1-6 The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or an isomer thereof, an n-pentyl group or an isomer thereof, or an n-hexyl group or an isomer thereof, and more preferably a methyl group.

[0038] The R 4 Hydroxyl is preferred.

[0039] R 5 and R 6 In the C 1-10 Alkyl and the halogen substituted C 1-10 C in the alkyl group 1-10 The alkyl groups are each independently preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl. 1-3 The alkyl group is preferably methyl or isopropyl. 3-10 The cycloalkyl group is preferably the C 3-6 Cycloalkyl. 3-6 The cycloalkyl group is preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl. 1-10 Alkoxy and the halogen substituted C 1-10 C in alkoxy 1-10 The alkoxy groups are each independently preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy. 1-3 The alkoxy group is preferably a methoxy group. 1-3 The alkoxy group is preferably a trifluoromethoxy group.

[0040] The halogen-substituted C 1-10 The alkyl and halogen substituted C 1-10 The halogen in the alkoxy group is each independently preferably fluorine, chlorine, bromine or iodine, more preferably fluorine. The halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine or bromine.

[0041] R 5 and R 6 wherein the halogen-substituted C 1-10 The alkyl and halogen substituted C 1-10 The number of halogen-substituted alkoxy groups is independently 1, 2 or 3, preferably 3. When the number of halogen-substituted alkoxy groups is plural, the types of halogen-substituted alkoxy groups may be the same or different, preferably the types of halogen-substituted alkoxy groups are the same.

[0042] The R 5 Preferably H, halogen substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy or halogen; more preferably H, halogen substituted C 1-10 Alkyl or halogen.

[0043] The R 5 Preferred are H, methoxy, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl or bromo; more preferred are hydrogen, trifluoromethyl, trifluoromethoxy or bromo; most preferred are hydrogen, trifluoromethyl or bromo.

[0044] The R 6 Preferably H, halogen substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy, C 3-10 Cycloalkyl or halogen; more preferably halogen substituted C 1-10 Alkoxy or C 3-10 Cycloalkyl.

[0045] The R 6 Preferred are H, methoxy, trifluoromethyl, trifluoromethoxy, methyl, cyclopropyl, isopropyl, chlorine or bromine; more preferred are hydrogen, trifluoromethyl, trifluoromethoxy, cyclopropyl, isopropyl, chlorine or bromine; most preferred are trifluoromethoxy or cyclopropyl.

[0046] In one embodiment, the definitions of certain groups of the anthracene compound shown in Formula I are as follows, and the undefined groups are as described in the previous embodiment: 1 , R 2 , R 5 and R 6 is H;

[0047] Alternatively, the R 1 Hydroxyl, C 1-10 Alkyl or C1-10 Alkoxy; said R 2 , R 5 and R 6 is H;

[0048] Alternatively, the R 2 C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; said R 1 , R 5 and R 6 is H;

[0049] Alternatively, the R 5 C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; said R 1 , R 2 and R 6 For H.

[0050] Alternatively, the R 6 C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; said R 1 , R 2 and R 5 For H.

[0051] In one embodiment, some groups of the anthracene compound of formula I are defined as follows, and undefined groups are as described in any of the previous embodiments:

[0052] When the Z 1 and Z 2 When one is O and the other is S, or both are S, the R 1 , R 2 , R 5 and R 6 are each independently H; the R 3 for

[0053] In one embodiment, some groups of the anthracene compound of formula I are defined as follows, and undefined groups are as described in any of the previous embodiments:

[0054] When Q is a methylene group, R3 for

[0055] In one embodiment, some groups of the anthracene compound of formula I are defined as follows, and undefined groups are as described in any of the previous embodiments:

[0056] The R 1 Preferred H, C 1-10 Alkyl or hydroxyl;

[0057] The R 2 Preferably H, halogen substituted C 1-10 Alkoxy or halogen;

[0058] The R 3 wherein n is preferably 0, 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-6 Cycloalkylene;

[0059] The R 4 is hydroxyl group;

[0060] The R 5 H, halogen-substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy or halogen;

[0061] and the R 6 H, halogen-substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy, C 3-10 Cycloalkyl or halogen

[0062] In one embodiment, some groups of the anthracene compound of formula I are defined as follows, and undefined groups are as described in any of the previous embodiments:

[0063] The R 1 is H;

[0064] The R 2 is H or halogen;

[0065] The R 3 wherein n is 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-6 Cycloalkylene;

[0066] The R 5 H, halogen-substituted C 1-10 Alkyl or halogen;

[0067] and the R 6 Replace C with halogen 1-10 Alkoxy or C 3-10Cycloalkyl.

[0068] In one embodiment, the anthrone compound as shown in Formula I may be any of the following compounds:

[0069] 2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)acetic acid (I-1),

[0070] 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)propanoic acid (I-2),

[0071] 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)butanoic acid (I-3),

[0072] 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)-2,2-dimethylpropanoic acid (I-4),

[0073] 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)-2-methylpropanoic acid (I-5),

[0074] 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)butanoic acid (I-6),

[0075] 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)pentanoic acid (I-7),

[0076] (trans)-2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopropyl-1-carboxylic acid (I-8a),

[0077] (cis)-2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopropyl-1-carboxylic acid (I-8b),

[0078] (trans)-3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-9a),

[0079] (cis)-3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-9b),

[0080] 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopentyl-1-carboxylic acid (I-10),

[0081] 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclohexyl-1-carboxylic acid (I-11),

[0082] 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclohexyl-1-carboxylic acid (I-12),

[0083] (trans)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)cyclobutyl-1-carboxylic acid I-13a),

[0084] (cis)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)cyclobutyl-1-carboxylic acid (I-13b),

[0085] (trans)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)-N-(methylsulfonyl)cyclobutyl-1-carboxamide (I-14),

[0086] 3-(((5-chloro-9-oxo-9H-xanthene-3-)oxy)methyl)cyclobutyl-1-carboxylic acid (I-15),

[0087] 3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)propoxy)cyclobutyl-1-carboxylic acid (I-16),

[0088] (cis)-3-(2-((5,8-dichloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-17),

[0089] (cis)-3-(2-((5-chloro-2-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-18),

[0090] (cis)-3-(2-((2,5-dichloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-19),

[0091] (cis)-3-(2-((5-chloro-1-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-20),

[0092] (cis)-3-(2-((5-chloro-1-hydroxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-21),

[0093] (cis)-3-(2-((5-chloro-1-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-22), 3-(2-((5-chloro-6-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-23),

[0094] (trans)-3-(2-((5-chloro-6-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-24),

[0095] (cis)-3-(2-((5-chloro-8-trifluoromethyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-25),

[0096] (trans)-3-(2-((5-chloro-8-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-26),

[0097] (trans)-3-(2-((5-chloro-8-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-27), 3-(2-((5-chloro-6-trifluoromethyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-28), 3-(2-((5-chloro-6-cyclopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-29), 3-(2-((5-chloro-8-cyclopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1 -carboxylic acid (I-30), 3-(2-((5-chloro-8-trifluoromethoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-31), 3-(2-((5-chloro-6-trifluoromethoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-32), 3-(2-((5-chloro-8-isopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-33), 2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)acetic acid (I-34),

[0098] 3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)propanoic acid (I-35),

[0099] 4-((5-chloro-9-oxo-9H-xanthene-3-)oxy)butanoic acid (I-36),

[0100] 5-((5-chloro-9-oxo-9H-xanthene-3-)oxy)pentanoic acid (I-37),

[0101] 3-(2-((5-chloro-2-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-38),

[0102] (trans)-3-(2-((2-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-39), 3-(2-((2-trifluoromethyl-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-40), 3-(2-((2-trifluoromethoxy-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-41), 3-(2-((6-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-42),

[0103] 3-(2-((8-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-43),

[0104] 3-(2-((5-chloro-9-thioxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-44),

[0105] 3-(2-((5-chloro-9-oxo-9H-thioxanthen-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-45),

[0106] 3-(2-((5-chloro-9-thioxo-9H-thioxanthen-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-46),

[0107] 3-(3-(5-chloro-9-oxo-9H-xanthene-3-yl)propoxy)cyclobutyl-1-carboxylic acid (I-47),

[0108] 3-(3-((2-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)propoxy)cyclobutyl-1-carboxylic acid (I-48),

[0109] 3-(4-((5-chloro-9-oxo-9H-xanthene-3-)oxy)butoxy)cyclobutyl-1-carboxylic acid (I-49) and

[0110] 3-(5-((5-chloro-9-oxo-9H-xanthene-3-)oxy)pentyloxy)cyclobutyl-1-carboxylic acid (I-50);

[0111] Or its cis and trans isomers or a mixture of the two in any ratio.

[0112] The above compounds (I-1) to (I-50) are the compounds of Examples 1 to 50 of the present invention.

[0113] The present invention also provides a method for preparing anthraquinone compounds as shown in formula I, cis-trans isomers or pharmaceutically acceptable salts thereof, which is any one of method 1, method 2 and method 3:

[0114] When R' is C 1-4 Alkyl; R 1 , R 2 , R 3 , R 5 , R 6 , Q, Z 1 and Z 2 The definitions of are as described above, and the preparation method of the anthracene compound or its cis-trans isomers as shown in formula I is method 1.

[0115] Method 1 comprises the following steps: in a solvent, under the action of a base, subjecting compound V or its cis-trans isomers to a hydrolysis reaction as shown below to obtain R 4 The heteroanthrone compound of formula I or its cis-trans isomers thereof is hydroxyl group, that is:

[0116]

[0117] Where R' is C 1-4 Alkyl; R 4 is hydroxyl group; R 1 , R 2 , R 3 , R 5 , R 6 , Q, Z 1 and Z 2 The definitions are as mentioned above.

[0118] The hydrolysis reaction may be a conventional reaction of this type in the art.

[0119] The type of solvent is not specifically limited, as long as it can dissolve the substrate and does not affect the reaction. Alcohol and ether solvents are preferred. The alcohol solvent can be methanol and / or ethanol, preferably methanol. The ether solvent can be tetrahydrofuran.

[0120] The base is not particularly limited as long as it does not affect the reaction. An alkali metal inorganic base is preferred, sodium hydroxide or lithium hydroxide is more preferred, and lithium hydroxide is most preferred.

[0121] The volume mass ratio of the solvent to compound V or its cis-trans isomers may be 150 to 10 ml / g, preferably 100 to 10 ml / g.

[0122] The molar ratio of the base to the compound V or its cis-trans isomers may be 2-10.

[0123] The temperature of the hydrolysis reaction may be 25-50°C.

[0124] The hydrolysis reaction time is preferably 12 to 16 hours, until no further reaction occurs or the reaction of compound V or its cis- and trans-isomers is completely detected (eg, by LC-MS or TLC).

[0125] After the hydrolysis reaction is completed, the following post-treatment steps are also included: adjusting the pH to weak acidity, concentrating, filtering, washing with water, and drying. The acid used for adjusting the pH can be a conventional acid in the art, preferably hydrochloric acid, more preferably 2N hydrochloric acid. The conditions and operations for concentrating can be conventional conditions and operations in the art, preferably reduced pressure concentration. The conditions and operations for washing can be conventional conditions and operations in the art. The conditions and operations for drying can be conventional conditions and operations in the art, preferably vacuum drying.

[0126] When R 4 for R 1 , R 2 , R 3 , R 5 , R 6 , Q, Z 1 and Z 2 The definitions are as described above. The carboxylic acid of the anthracene compound of formula I obtained in method 1 can be further reacted with sulfonamide to obtain the sulfonamide of the anthracene compound of formula I or its cis-trans isomers, and the preparation method thereof is method 2.

[0127] Method 2 comprises the following steps: in an organic solvent, subjecting the carboxylic acid of the anthrone compound of formula I obtained in method 1 or its cis-trans isomers to a condensation reaction with compound U as shown below to obtain R 4 for The heteroanthrone compound as shown in formula I or its cis-trans isomers, that is:

[0128]

[0129] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , Q, Z 1 and Z 2 The definitions of are as mentioned above; R 4 for R 4a The definition of is as mentioned above.

[0130] The conditions of the condensation reaction can be conventional conditions for such reactions in the art, and the following conditions are preferred in the present invention:

[0131] The organic solvent may be a chlorinated alkane or an amide. The chlorinated alkane solvent is preferably dichloromethane. The amide solvent is preferably N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA).

[0132] The amount of the organic solvent used is not specifically limited, as long as it can dissolve the substrate and does not affect the reaction.

[0133] The molar ratio of the compound U to the carboxylic acid or the cis-trans isomers thereof of the anthrone compound of formula I may be 1.0 to 2.0, for example, 1.5.

[0134] The condensation reaction may be carried out in the presence of a catalyst (eg, carbonyldiimidazole (CDI) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), the molar ratio of the CDI to the DBU may be 1.0 to 2, such as 1.0).

[0135] The progress of the condensation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LC-MS). Generally, the reaction endpoint is when the carboxylic acid or cis-trans isomers of the anthrone compound shown in Formula I no longer reacts. The reaction time can be 4 to 16 hours, for example 16 hours.

[0136] After the reaction is completed, the following post-processing steps are further included: concentration, filtration and beating. The conditions and operation of the concentration can be conventional conditions and operations in the art, preferably reduced pressure concentration. The conditions and operation of the filtration can be conventional conditions and operations in the art, preferably reduced pressure filtration. After the filtration, the filter cake is further rinsed. The solvent used for the beating can be an ester solvent, preferably ethyl acetate.

[0137] When Z 1a O; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q, Z 1 and Z 2 The definitions are as described above. The carboxylic acid of the heteroanthraquinone compound as shown in formula I obtained by method 1 can be further reacted with a sulfiding agent to obtain a sulfide of the heteroanthraquinone compound as shown in formula I or its cis-trans isomers. The preparation method thereof is method 3:

[0138] Method 3 comprises the following steps: subjecting the carboxylic acid of the anthracene compound of formula I obtained in method 1 or its cis-trans isomers to a sulfurization reaction in an organic solvent as shown below in the presence of a sulfurizing agent to obtain Z 1 A sulfur-containing heteroanthrone compound as shown in formula I or its cis-trans isomers, that is:

[0139]

[0140] Among them, Z 1a O; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q, Z 1 and Z 2 The definitions are as mentioned above.

[0141] The vulcanization reaction can be a conventional reaction of this type in the art. The present invention preferably uses the following conditions:

[0142] The sulfurizing agent can be a conventional sulfurizing agent for this type of reaction in the art. The sulfurizing agent is preferably phosphorus pentasulfide (P2S5) or Lawesson reagent, such as Lawesson reagent.

[0143] The organic solvent may be one or more of chlorinated alkanes, benzene solvents and ether solvents. Benzene solvents are preferred. The chlorinated hydrocarbon solvent is preferably dichloromethane. The benzene solvent is preferably toluene. The ether solvent is preferably tetrahydrofuran (THF).

[0144] The amount of the organic solvent used is not specifically limited, as long as it can dissolve the substrate and does not affect the reaction.

[0145] The molar ratio of the sulfur atom in the sulfurizing agent to the carboxylic acid or the cis-trans isomers thereof of the anthracene compound as shown in Formula I may be 1.0 to 3.0, for example 1.2.

[0146] The reaction temperature may be 30-80°C, for example 60°C.

[0147] The progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC or LC-MS). Generally, the reaction endpoint is when the carboxylic acid of the anthrone compound shown in Formula I no longer reacts. The reaction time can be 4 to 16 hours, for example 16 hours.

[0148] The reaction further comprises post-treatment steps, concentration and chromatographic separation. The conditions and operation of the concentration may be conventional conditions and operations in the art, preferably reduced pressure concentration. The chromatographic separation may be a conventional chromatographic separation method in the art. Preferably, column chromatography separation, preparative TLC separation or preparative high performance liquid separation, for example, preparative high performance liquid separation.

[0149] The preparation method of the compound I further includes a preparation method of the compound V or its cis-trans isomers, and the preparation method of the compound V or its cis-trans isomers is any one of method A, method B and method C:

[0150] Method A comprises the following steps: in the presence of a base, compound II and compound III or its cis-trans isomers are reacted in an organic solvent as shown below to obtain compound V or its cis-trans isomers.

[0151]

[0152] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R', Z 1 and Z 2 The definitions of are as mentioned above, and Q is O.

[0153] The base may be an alkali metal inorganic base, preferably potassium carbonate.

[0154] The organic solvent may be a polar organic solvent; preferably one or more of a nitrile solvent, an amide solvent, and a sulfoxide solvent; more preferably an amide solvent. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA). The sulfoxide solvent is preferably dimethyl sulfoxide (DMSO).

[0155] The amount of the organic solvent used is not specifically limited, as long as it can dissolve the substrate and does not affect the reaction.

[0156] The molar ratio of the base to compound II may be 1.0 to 3.0, for example 1.2.

[0157] The molar ratio of the compound III or its cis-trans isomers to the compound II may be 1.0 to 1.5, for example 1.1.

[0158] The reaction temperature may be 80-100°C, for example 80°C.

[0159] The hydrolysis reaction time is preferably 12 to 18 hours, until the reaction stops or the reaction of compound II is complete as detected by LC-MS or TLC.

[0160] After the reaction is completed, the following post-treatment steps are further included: extraction and column chromatography. The conditions and operation of the extraction can be conventional conditions and operations in the art. The organic solvent for the extraction can be an ester solvent, preferably ethyl acetate. The conditions and operation of the column chromatography can be conventional conditions and operations in the art.

[0161] Method B comprises the following steps: Compound II and Compound IV or its cis-trans isomers are subjected to the following mitsunobu reaction in an organic solvent to obtain Compound V or its cis-trans isomers.

[0162]

[0163] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R', Z 1 and Z 2 The definitions of are as mentioned above, and Q is O.

[0164] The conditions of the Mitsunobu reaction can be conventional conditions for such reactions in the art, and the following conditions are preferred in the present invention:

[0165] The organic solvent may be a chlorinated alkane or an ether. The chlorinated alkane solvent is preferably dichloromethane. The ether solvent is preferably tetrahydrofuran.

[0166] The molar ratio of the compound IV or its cis-trans isomers to the compound II may be 1.0 to 2.0, preferably 1.5 to 2.0.

[0167] The Mitsunobu reaction can be carried out in the presence of a catalyst (eg, triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD), wherein the molar ratio of the PPh3 to the DIAD can be 1.0 to 2, eg, 1.0).

[0168] The progress of the Mitsunobu reaction can be monitored by conventional monitoring methods in the art (eg, TLC or LC-MS). The reaction endpoint is generally when compound II no longer reacts. The reaction time can be 4 to 16 hours, for example, 4 hours.

[0169] After the reaction is completed, the following post-treatment steps are further included: extraction and column chromatography. The conditions and operation of the extraction can be conventional conditions and operations in the art. The organic solvent for the extraction can be an ester solvent, preferably ethyl acetate. The conditions and operation of the column chromatography can be conventional conditions and operations in the art.

[0170] Method C comprises the following steps: in the presence of a base, compound II and compound M or its cis-trans isomers are reacted in an organic solvent as shown below to obtain compound V or its cis-trans isomers.

[0171]

[0172] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R', and Z 2 The definitions of Z are as mentioned above; 1 is O; X is halogen; Q is O.

[0173] The halogen may be fluorine, chlorine, bromine or iodine, preferably bromine.

[0174] The base may be an alkali metal inorganic base, preferably potassium carbonate.

[0175] The organic solvent may be a polar organic solvent; preferably one or more of a nitrile solvent, an amide solvent, and a sulfoxide solvent; more preferably an amide solvent. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA). The sulfoxide solvent is preferably dimethyl sulfoxide (DMSO).

[0176] The amount of the organic solvent used is not specifically limited, as long as it can dissolve the substrate and does not affect the reaction.

[0177] The molar ratio of the base to compound II may be 1.0 to 3.0, for example 2.0.

[0178] The molar ratio of the compound M or its cis-trans isomers to the compound II may be 1.0 to 2.0, for example 1.5.

[0179] The reaction temperature may be 80-100°C, for example 80°C.

[0180] The hydrolysis reaction time is until there is no further reaction or the reaction of compound II is complete as detected by LC-MS or TLC, for example, 16 h.

[0181] After the reaction is completed, the following post-treatment steps are also included: adding water after the reaction solution is cooled, filtering, washing, beating and drying. The conditions and operation of the filtration can be conventional conditions and operations in the art. The conditions and operation of the washing can be conventional conditions and operations in the art. The conditions and operation of the beating can be conventional conditions and operations in the art. The organic solvent for the beating can be an alcohol solvent, preferably ethanol. The conditions and operation of the drying can be conventional conditions and operations in the art, preferably vacuum drying.

[0182] The present invention also provides a compound as shown in Formula V or its cis-trans isomers:

[0183]

[0184] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R', Z 1 , Z 2 The definitions of and Q are as described above.

[0185] The compound V or its cis-trans isomers is preferably any of the following compounds:

[0186]

[0187]

[0188]

[0189] Among them, cis refers to two identical atoms or groups on the same side of the aliphatic ring, that is, cis isomers; trans refers to two identical atoms or groups on opposite sides of the aliphatic ring, that is, trans isomers.

[0190] The present invention also provides a compound as shown in Formula II:

[0191]

[0192] Among them, R 1 , R 2 , R 5 , R 6 and Z are defined as above.

[0193] The intermediate II is preferably any of the following compounds:

[0194]

[0195] The present invention also provides a use of an anthracene compound as shown in Formula I, its cis-trans isomers or a pharmaceutically acceptable salt thereof in the preparation of a cccDNA inhibitor.

[0196] The present invention also provides a use of an anthrone compound as shown in formula I, its cis-trans isomers or a pharmaceutically acceptable salt thereof in the preparation of a hepatitis B drug.

[0197] The present invention also provides a pharmaceutical composition, which comprises an effective dose of the above-mentioned anthraquinone compound as shown in Formula I, its cis-trans isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0198] Preferably, the pharmaceutical composition may further include other drugs for preventing and / or treating hepatitis B. The other drugs for preventing and / or treating hepatitis B may be one or more of HBV-DNA polymerase inhibitors, interferons, HBV adsorption invasion inhibitors, RNA inhibitors, HBsAg production and secretion inhibitors, nucleocapsid protein inhibitors, HBV preventive and therapeutic vaccines, HBV antibodies, RNaseH inhibitors, virus maturation inhibitors and immunomodulators.

[0199] The present invention also provides a scheme for treating a heteroanthrone compound as shown in formula I, a cis-trans isomer thereof or a pharmaceutically acceptable salt thereof in combination with one or more other drugs for preventing and / or treating hepatitis B. The other drugs for preventing and / or treating hepatitis B may be one or more of HBV-DNA polymerase inhibitors, interferons, HBV adsorption and invasion inhibitors, RNA inhibitors, HBsAg production and secretion inhibitors, nucleocapsid protein inhibitors, HBV preventive and therapeutic vaccines, HBV antibodies, RNaseH inhibitors, virus maturation inhibitors and immunomodulators.

[0200] In the present invention, compounds obtained by replacing one or more atoms in the anthracene compound shown in Formula I with their isotopes also belong to the content of the present invention.

[0201] In the isotope substitution, in the anthracene compound as shown in Formula I, preferably, the hydrogen atom is replaced by a deuterium atom. The number of hydrogen atoms replaced may be one or more. The change in the properties of the anthracene compound obtained by isotope substitution includes an improvement in metabolic stability, an extension of the in vivo half-life, a reduction in the dosage or a reduction in the frequency of administration.

[0202] In the present invention, the pharmaceutically acceptable carrier may be a conventional carrier in the art, including one or more of a lubricant, a binder, a filler and a disintegrant. The lubricant is selected from one or more of magnesium stearate, micropowdered silica gel, silicon dioxide and talc; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch and cross-linked polyvinylpyrrolidone; the binder is selected from one or more of hydroxypropyl cellulose, polyvinyl pyrrolidone and methyl cellulose; the filler is selected from one or more of lactose, pregelatinized starch and microcrystalline cellulose.

[0203] In the present invention, there is no particular limitation on the amount of the pharmaceutically acceptable carrier, as long as it can meet the requirements of conventional preparations in the art.

[0204] In the present invention, the pharmaceutical composition can be prepared into various dosage forms, such as tablets, capsules, pills, powders, emulsions, granules, suppositories and injections.

[0205] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C 1-10 , C 1-6 , C 1-4 ) is a straight or branched alkyl group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. 1-6

[0206] The term "alkoxy" refers to a group R X -O-, where R X is an alkyl group as defined above.

[0207] The term "cycloalkyl" refers to a cycloalkyl radical having a specified number of carbon atoms (e.g. 3-10 , C 3-6 ) is a saturated monocyclic ring group consisting of only carbon atoms. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0208] The term "aryl" refers to a radical having a specified number of carbon atoms (e.g. 6-30 , C 6-14 , C 6-10 ) and a cyclic group consisting only of carbon atoms, which is monocyclic or polycyclic, and at least one ring is aromatic or all are aromatic (in accordance with Huckel's rule). The aryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. The aryl group includes but is not limited to phenyl, naphthyl, etc.

[0209] The term "isomers" refers to isomerism with the same molecular formula but different structural formulas, which includes structural isomerism and stereoisomerism. Stereoisomerism refers to the isomerism in which the order of atoms or atomic groups connected to each other is the same, but the arrangement in space is different. Cis-trans isomerism refers to different spatial conformations.

[0210] The term "cis-trans isomerism" is a type of stereoisomerism. "Cis-trans isomerism" is generally caused by functional groups in the structure of organic compounds that cannot rotate freely, such as C=C double bond, C≡C triple bond, C=N double bond, N=N double bond or alicyclic ring. Organic compounds containing "cis-trans isomerism" are called cis-trans isomers, which have obvious differences in physical, chemical and biological properties. They can be named according to the "cis-trans isomer nomenclature" and the "ZE nomenclature".

[0211] Nomenclature of cis- and trans-isomers: Two identical atoms or groups on the same side of a double bond or alicyclic ring are cis-isomers, also represented by cis-. Two identical atoms or groups on opposite sides of a double bond or alicyclic ring are trans-isomers, also represented by trans-.

[0212] The room temperature described in the present invention refers to the ambient temperature, which is 10° C.-35° C. Overnight refers to 8-16 hours.

[0213] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0214] The reagents and raw materials used in the present invention are commercially available.

[0215] The positive and progressive effects of the present invention are that the heteroanthrone compound as shown in Formula I of the present invention, its cis-trans isomers or pharmaceutically acceptable salts thereof are used to prepare drugs or cccDNA inhibitors for treating and / or preventing hepatitis B, which have the advantages of high activity. In addition, the preparation operation of the compound is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0216] Figure 1 The results of Southern blot detection of compound I-2 in HepDES19 cells, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0217] Figure 2 The results of Southern blot detection of compound I-6 in HepDES19 cells, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0218] Figure 3 The results of Southern blot detection of compound I-9a in HepDES19 cells are shown in Figure 1, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0219] Figure 4 The results of Southern blot detection of compound I-9b in HepDES19 cells are shown in Figure 3, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0220] Figure 5The results of Southern blot detection of compound I-10 in HepDES19 cells, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0221] Figure 6 The results of Southern blot detection of compound I-15 in HepDES19 cells, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0222] Figure 7 The results of Southern blot detection of compound I-17 in HepDES19 cells, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0223] Figure 8 The results of Southern blot detection of compound I-18 in HepDES19 cells, where 3.2 kb represents 3200 base pairs, 2.0 kb represents 2000 base pairs, and 1.3 kb represents 1300 base pairs.

[0224] Fig. 9 The results of cccDNA hybridization (Southern blot) detection of the compound 5-chloro-9-oxo-9H-xanthene-3-pyrrolidine-3-carboxylic acid obtained in Example 2 of reference document WO2017202798 A1 in HepDES19 cells, wherein 3.2kb represents 3200 base pairs, 2.0kb represents 2000 base pairs, and 1.3kb represents 1300 base pairs. DETAILED DESCRIPTION

[0225] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0226] Example 1 Preparation of 5-chloro-3-hydroxy-9H-anthracen-9-one (Intermediate A)

[0227]

[0228] Synthesis of intermediate A-1

[0229] 3-Chloro-2-fluorobenzoic acid (6.80 g, 38.96 mmol) and 1,3-dimethoxybenzene (5.65 g, 40.90 mmol) were added to 100 mL Eaton Reagent, heated to 80°C, reacted for 1 h, and the conversion was complete when detected by LCMS. The reaction solution was cooled, slowly poured into ice water to quench, extracted with ethyl acetate, evaporated the solvent, and the residue was purified by silica gel column chromatography to obtain a white solid, intermediate A-1 (9.00 g, yield: 78%). LCMS: M+1=295.

[0230] Synthesis of intermediate A-2

[0231] Dissolve intermediate A-1 (7.00 g, 23.75 mmol) in 70 mL of ultra-dry dichloromethane, add boron tribromide (17.85 g, 71.26 mmol) dropwise at 0°C, heat to 30-40°C, react overnight, and LCMS detects no raw material. Pour the reaction solution into ice water for quenching, extract with dichloromethane, evaporate the solvent, and purify the residue by silica gel column chromatography to obtain a yellow solid, intermediate A-2 (5.00 g, yield: 79%). LCMS: M+1=267.

[0232] Synthesis of Intermediate A

[0233] Intermediate A-2 (5.00 g, 18.75 mmol) was dissolved in 150 mL of acetonitrile, potassium carbonate (2.59 g, 18.75 mmol) was added, the temperature was raised to 80°C, the reaction was allowed to proceed overnight, and the reaction was complete when detected by LCMS. The reaction solution was cooled to room temperature, slurried with water, filtered, and the filter cake was washed with water and acetonitrile to obtain yellow solid intermediate A (4.00 g, yield: 86%). LCMS: M+1=247. 1 H-NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.10(dd,J=7.9,1.4Hz,1H),8.04(d,J=8.7Hz,1H),7.98 (dd, J = 7.9, 1.4 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 6.95 (dd, J = 8.7, 2.2 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H).

[0234] Example 2 Preparation of methyl 3-(2-(toluenesulfonyloxy)ethoxy)cyclobutanecarboxylate (Intermediate B-cis and Intermediate B-trans)

[0235]

[0236] Synthesis of intermediate B-1

[0237] Dissolve ethylene glycol monobenzyl ether (10.00 g, 65 mmol) in 150 ml of dichloromethane, add triethylamine (9.97 g, 98 mmol), cool to 0°C, slowly drop trimethylsilyl chloride (7.85 g, 72 mmol), and react at room temperature for 2 hours. TLC detection shows that the raw material has reacted. Filter, wash the filter cake with dichloromethane, concentrate, add 100 mL of methyl tert-butyl ether to the crude product, wash with water, dry and concentrate to obtain intermediate B-1 (14.50 g, yield: 98%).

[0238] Synthesis of intermediate B-2

[0239] Dissolve the intermediate B-1 (13.50 g, 60 mmol) in 150 ml of dry dichloromethane, add methyl 3-oxocyclobutanecarboxylate (8.48 g, 66 mmol), cool to -78 ° C, slowly drop trimethylsilyl trifluoromethanesulfonate (8.02 g, 36 mmol), stir at -60 ° C for 1 h, drop triethylsilane (8.40 g, 72 mmol), keep at -60 ° C for 2 h, naturally warm to room temperature, stir and react overnight, TLC detection raw material reaction is complete. Pour the reaction solution into ice water, extract with dichloromethane, wash with water and saturated sodium chloride solution respectively, dry and concentrate, concentrate, pass through a silica gel column to obtain intermediate B-2 (13.20 g, yield: 83%). LCMS: M+1=265.

[0240] Synthesis of intermediate B-3

[0241] Dissolve intermediate B-2 (12.20 g, 46 mmol) in 100 ml methanol, add palladium carbon (1.22 g, 10% w / w), add hydrogen at 2-3 atm, stir at 40 ° C overnight, and TLC detects that the reaction of the raw material is complete. Filter and concentrate to obtain intermediate B-3 (7.20 g, yield: 90%).

[0242] Synthesis of intermediate B

[0243] Under nitrogen protection, the intermediate B-3 (7.20 g, 41 mmol) was dissolved in 200 ml of dichloromethane, triethylamine (6.30 g, 62 mmol) and 4-dimethylaminopyridine (5.00 g, 41 mmol) were added, cooled to 0°C, 4-methylbenzenesulfonyl chloride (7.90 g, 41 mmol) was added in batches, stirred at 20°C overnight, the reaction solution was poured into ice water, extracted with dichloromethane, washed with water and saturated sodium chloride solution, dried, and purified by silica gel column chromatography to obtain intermediate B (10.2 g, yield: 75%) LCMS: M+1 = 329. According to the nuclear magnetic hydrogen spectrum, the ratio of cis-trans isomers was cis: trans = 40%: 60%. Take 2 g of intermediate B, and after further separation, intermediate B-cis (500 mg) and intermediate B-trans (700 mg) were obtained respectively. Intermediate In the cis-trans isomers, the chemical environments of H on the C-H bonds on the C1 and C2 atoms on the four-membered ring are different, which is reflected in the chemical shift in the H NMR spectrum. The H on the C-H bonds on the C1 and C2 atoms on the four-membered ring in the trans configuration is shifted toward the low field direction compared to the H on the C-H bonds in the cis configuration (reference documents WO2009071509 A1 pages 126 and 127, and CN102924458 A pages 300-302).

[0244] Intermediate B-cis NMR: 1 H-NMR (400MHz, CDCl3) δ7.80(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,2H),4.17–4.08(m,2H),3.90–3.78(m,1H ),3.68(s,3H),3.59–3.51(m,2H),2.65–2.54(m,1H),2.50–2.39(m,2H),2.45(s,3H),2.18–2.07(m,2H).

[0245] Intermediate B-trans NMR: 1 H-NMR (400MHz, CDCl3) δ7.80(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),4.15–4.09(m,3H),3.69(s ,3H),3.55–3.49(m,2H),3.04–2.89(m,1H),2.48–2.40(m,2H),2.45(s,3H),2.22–2.10(m,2H).

[0246] Example 3 Preparation of 2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)acetic acid (I-1)

[0247]

[0248] Synthesis of intermediate V1-1

[0249] At room temperature, add 60% sodium hydrogen (3.40g, 84.00mmol) to a 250ml three-necked flask, add anhydrous tetrahydrofuran (80ml) under ice bath, slowly add ethylene glycol monobenzyl ether (10.64g, 70.00mmol), keep the temperature below 5°C. After addition, react for 30min under ice bath. Add methyl bromoacetate (12.85g, 84.00mmol) dropwise, keep the temperature below 5°C, after addition, react at room temperature for 20h. TLC detection shows no raw material. Pour the reaction solution into water, extract with ethyl acetate (50ml*3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography to obtain intermediate V1-1 (5.82g, yield: 37%). LCMS: M+1=225.

[0250] Synthesis of intermediate V1-2

[0251] At room temperature, intermediate V1-1 (5.82 g, 25.99 mmol) was added to 100 ml of methanol, and 10% palladium carbon (1.16 g, 20% w / w) was added. The mixture was reacted at 40°C under hydrogen balloon pressure for 20 h. TLC detected that no raw material remained. The mixture was filtered and the filtrate was concentrated to obtain a crude oil intermediate V-2 (2.20 g, yield: 63%).

[0252] Synthesis of intermediate V1-3

[0253] At room temperature, add intermediate V1-2 (1.20 g, 8.95 mmol) to 30 ml of dichloromethane, add triethylamine (0.90 g, 8.95 mmol) and 4-dimethylaminopyridine (1.09 g, 8.95 mmol), add p-toluenesulfonyl chloride (2.56 g, 13.43 mmol) in batches under ice bath, keep the temperature below 10°C, and react overnight at room temperature. TLC detection shows no raw material (iodine display), the reaction solution is poured into water, 4N hydrochloric acid is adjusted to pH = 5, extracted with dichloromethane, dried, and purified by silica gel column chromatography to obtain colorless oil intermediate V1-3 (1.50 g, yield: 58%). LCMS: M+1 = 289.

[0254] Synthesis of intermediate V1-4

[0255] Intermediate A (200 mg, 0.81 mmol), intermediate 1-3 (257 mg, 0.89 mmol) and potassium carbonate (134 mg, 0.97 mmol) were added to 5 ml of dimethylformamide in sequence, and the reaction was carried out at an external temperature of 80°C overnight. LCMS detected that the conversion was complete. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The crude product was purified by silica gel column chromatography to obtain intermediate V1-4 (150 mg, yield: 51%). LCMS: M+1=363.

[0256] Add intermediate V1-4 (150 mg, 0.41 mmol) to 4 ml methanol, add 2N lithium hydroxide solution (1 ml, 2 mmol), react at 30°C for 16 h, LCMS detected no starting material. Adjust pH to 3-5 with 4N hydrochloric acid, concentrate, filter, wash with water, and dry to obtain a white solid, compound I-1 (100 mg, yield: 69%). LCMS: M+1=349. 1 H-NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.12(dd,J=7.9,1.6Hz,1H),8.10(d,J=8.9Hz,1H),8.02(dd,J=7.9,1.6Hz,1H),7. 46(t,J=7.9Hz,1H),7.22(d,J=2.4Hz,1H),7.10(dd,J=8.9,2.4Hz,1H),4.36–4.34(m,2H),4.12(s,2H),3.95–3.83(m,2H).

[0257] Example 4 Preparation of 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)propanoic acid (I-2)

[0258]

[0259] Synthesis of intermediate V2-1

[0260] At room temperature, add anhydrous THF (30 ml) to a 100 ml three-necked flask, add ethylene glycol monobenzyl ether (3.00 g, 19.74 mmol), add 60% NaH (0.04 g, 0.99 mmol) under ice bath, keep the temperature below 5 ° C. After addition, react for 5 min under ice bath. Add methyl acrylate (2.04 g, 23.68 mmol) dropwise, after addition, react at room temperature for 2 h, TLC detection shows no raw material. Pour the reaction solution into water, extract with ethyl acetate (30 ml * 3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography to obtain intermediate V2-1 (3.60 g, yield: 76%). LCMS: M+1 = 239.

[0261] The synthesis of intermediate V2-2 to Example 4 was carried out according to the synthesis method of intermediate V1-2 to Example 3 to obtain compound I-2. LCMS: M+1=363. 1H-NMR (400MHz, DMSO-d6) δ12.20(s,1H),8.12(dd,J=7.9,1.6Hz,1H),8.08(d,J=8.9Hz,1H),8.01(dd,J=7.9,1.6Hz,1H),7.45(t,J=7.9Hz, 1H), 7.20 (d, J = 2.3Hz, 1H), 7.09 (dd, J = 8.9, 2.3Hz, 1H), 4.35–4.27 (m, 2H), 3.83–3.75 (m, 2H), 3.70 (t, J = 6.3Hz, 2H), 2.49 (t, J = 6.3Hz, 2H).

[0262] Example 5 Preparation of 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)butyric acid (I-3)

[0263]

[0264] Synthesis of intermediate V3-1

[0265] Dissolve the intermediate B-1 (2.00 g, 8.91 mmol) in 40 ml of dry dichloromethane, add ethyl acetoacetate (1.28 g, 9.81 mmol), cool to -78 ° C, slowly drop trimethylsilyl trifluoromethanesulfonate (0.99 g, 4.46 mmol), stir at -60 ° C for 1 h, drop triethylsilane (1.24 g, 10.70 mmol), keep at -60 ° C for 2 h, naturally warm to room temperature, stir and react overnight, TLC detection raw material reaction is complete. Pour the reaction solution into ice water, extract with dichloromethane, wash with water and saturated sodium chloride solution, dry and concentrate, concentrate, and pass through Silica gel column to obtain intermediate V3-1 (1.52 g, yield: 64%). LCMS: M+1= 267。

[0266] Synthesis of Intermediate V3-2 to Example 5: According to the synthesis method of Intermediate V1-2 to Example 3, Example 5 was obtained. LCMS: M+1=377. 1H-NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.12(dd,J=7.9,1.5Hz,1H),8.09(d,J =8.9Hz,1H),8.01(dd,J=7.9,1.5Hz,1H),7.45(t,J=7.9Hz,1H),7.19(d,J=2.3H z,1H),7.08(dd,J=8.9,2.3Hz,1H),4.28(t,J=4.5Hz,2H),3.94–3.72(m,3H),2. 47(dd,J=15.3,5.9Hz,1H), 2.34(dd,J=15.3,5.9Hz,1H), 1.17(d,J=6.2Hz,3H).

[0267] Example 6 Preparation of 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)-2,2-dimethylpropanoic acid (I-4)

[0268]

[0269] Synthesis of intermediate V4-1

[0270]

[0271] Add 200ml of dry dichloromethane to a 500ml three-necked flask, cool to -78°C, add oxalyl chloride (12.60g, 99mmol), slowly drop dimethyl sulfoxide (12.27g, 198mmol) and keep the temperature not higher than -60°C. After addition, react at about -70°C for 15min, drop ethylene glycol monomethyl ether (10.00g, 66mmol), after addition, react at -60°C for 30min. Slowly drop triethylamine (33.33g, 330mmol), after addition, naturally rise to room temperature from -60°C, and react overnight. TLC detection shows that the raw material is completely converted. Add 100ml of water to the reaction solution, separate the liquids, extract with dichloromethane, concentrate the organic phase, and purify the crude product by silica gel column chromatography to obtain an oily product (7.5g, yield: 76%).

[0272] Synthesis of intermediate V4-2

[0273]

[0274] Add 3-hydroxy-2,2-dimethylpropionic acid methyl ester (3.62g, 27.4mmol) to a 250ml three-necked flask, add 100ml dry dichloromethane. Add triethylamine (4.15g, 41.1mmol), cool to 0℃, add trimethylsilyl chloride (3.57g, 32.9mmol) dropwise, keep the temperature not higher than 5℃, and react at room temperature overnight. TLC (iodine display) detected no raw materials, poured the reaction solution into water, extracted with dichloromethane, dried and concentrated the organic phase, added methyl tert-butyl ether, washed with water to remove residual triethylamine, dried and concentrated to obtain a brown oil (5.16g, yield: 92%).

[0275] Synthesis of intermediate V4-3

[0276] Add intermediate V4-1 (2.50 g, 16.90 mmol) and intermediate V4-2 (5.16 g, 25.30 mmol) to a 100 ml three-necked flask, and add 30 ml of dry dichloromethane. Cool to -70 °C, add trimethylsilyl trifluoromethanesulfonate (1.88 g, 8.45 mmol) dropwise, and keep the internal temperature at -60 °C. After the addition is complete, react at -60 °C for 1 h. Add triethylsilane (2.16 g, 18.59 mmol) dropwise, then naturally warm to room temperature and react overnight. TLC detected that the raw material was completely converted, and 30 ml of water was added to the reaction solution, separated, extracted with dichloromethane, and after the organic phase was concentrated, the crude product was purified by silica gel column chromatography to obtain a colorless oil, intermediate V4-3 (2.50 g, yield: 56%). LCMS: M+1=267.

[0277] The synthesis of intermediate V4-4 to Example 6 was carried out according to the synthesis method of intermediate V1-2 to Example 3 to obtain compound I-4. LCMS: M+1=391. 1 H-NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.12(dd,J=7.9,1.5Hz,1H),8.09(d,J=8.9Hz,1H),8.01(dd,J=7.9,1.5Hz,1H),7.46(t, J=7.9Hz,1H),7.21(d,J=2.3Hz,1H),7.09(dd,J=8.9,2.3Hz,1H),4.37–4.24(m,2H),3.85–3.74(m,2H),3.49(s,2H),1.09(s,6H).

[0278] Example 7 Preparation of 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)-2-methylpropanoic acid (I-5)

[0279]

[0280] According to the synthesis method of Example 6, 3-hydroxy-2-methylpropionic acid methyl ester was used instead of 3-hydroxy-2,2-dimethylpropionic acid methyl ester to obtain compound I-5. LCMS: M+1=377. 1 H-NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.04(d,J=7.6Hz,1H),8.00(d,J=8.7Hz,1H),7.92(d,J=7.6Hz,1H),7.39(t,J=7.6Hz,1H),7.06 (s,1H),7.00(d,J=8.7Hz,1H),4.26(s,2H),3.79(s,2H),3.72–3.60(m,1H),3.59–3.48(m,1H),2.66–2.61(m,1H),1.08(d,J=6.6Hz,3H).

[0281] Example 8 Preparation of 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)butyric acid (I-6)

[0282]

[0283] According to the synthesis method of Example 6, methyl 4-hydroxybutyrate was used instead of methyl 3-hydroxy-2,2-dimethylpropionate to obtain compound I-6. LCMS: M+1=377. 1 H-NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.11(d,J=7.9Hz,1H),8.07(d,J=8.9Hz,1H),7.99(d,J=7.9Hz,1H),7.45(t,J=7.9Hz,1H), 7.19(s,1H),7.08(dd,J=8.9,1.4Hz,1H),4.32(s,2H),3.76(s,2H),3.49(t,J=6.3Hz,2H),2.27(t,J=7.3Hz,2H),1.84–1.62(m,2H).

[0284] Example 9 Preparation of 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)pentanoic acid (I-7)

[0285]

[0286] According to the synthesis method of Example 5, methyl levulinate was used instead of ethyl acetoacetate to obtain compound I-7. LCMS: M+1=391. 1 H-NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.13(dd,J=7.9,1.5Hz,1H),8.10 (d, J = 8.9 Hz, 1H), 8.01(dd,J=7.9,1.5Hz,1H),7.46(t,J=7.9Hz,1H),7.21(d,J=2.3Hz,1H),7.10(dd,J=8.9,2.3Hz,1H),4.30(t,J=4.3Hz,2H ),3.91–3.76(m,1H),3.72–3.67(m,1H),3.59–3.45(m,1H),2.33–2.23(m,2H),1.75–1.59(m,2H),1.11(d,J=6.1Hz,3H).

[0287] Example 10 Preparation of 2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopropyl-1-carboxylic acid (I-8a, I-8b)

[0288]

[0289] Synthesis of intermediate V8-1

[0290] Add intermediate A (0.50 g, 2.0 mmol) to tetrahydrofuran, add ethylene glycol monovinyl ether (0.23 g, 2.6 mmol) and triphenylphosphine (3.20 g, 14 mmol), cool to 0 ° C, slowly add diisopropyl azodicarboxylate (2.80 g, 14 mmol), after addition, warm to room temperature, stir for 15 hours, LC-MS detects that the raw material has reacted. Pour the reaction solution into water, extract twice with ethyl acetate, wash the organic phase with water and saturated brine in turn, dry and concentrate. Purify by silica gel column chromatography to obtain intermediate V8-1 (0.49 g, yield: 85%). LCMS: M+1=317.

[0291] Synthesis of intermediate V8-2

[0292] Under nitrogen protection, the intermediate 8-1 (0.49 g, 1.7 mmol) was dissolved in dichloromethane, and dimerized rhodium acetate (0.12 g, 2.6 mmol) was added. The dichloromethane solution of ethyl diazoacetate (0.50 g, 4.3 mmol) was slowly added dropwise at 40°C, and the reaction was refluxed for 15 h. LC-MS detected that the raw material had reacted completely. Filter, concentrate, and purify the crude product by silica gel column chromatography to obtain cis-trans isomers. Intermediate V8-2a (0.21 g, yield: 31%), intermediate 8-2b (0.10 g, yield 15%). LCMS: M+1=403.

[0293] Synthesis of I-8a

[0294] Dissolve the intermediate V8-2a (0.21 g, 0.52 mmol) in 5 ml methanol, add 2N lithium hydroxide aqueous solution (1 mL), heat to 40°C, and react for 14 h. LC-MS detected that the raw material had reacted completely. The reaction solution was adjusted to pH = 5 with 2N hydrochloric acid, the methanol was concentrated, the residue was added with water, filtered, and dried to obtain compound I-8a (0.13 g, yield: 64%). LCMS: M+1 = 389. 1 H-NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.13(d,J=7.9Hz,1H),8.10(d,J=8.9Hz,1H),8.02(d,J=7.9Hz,1H),7.46(t,J=7.9Hz,1H),7.22(d,J=1.4Hz ,1H),7.10(dd,J=8.9,1.4Hz,1H),4.34(s,2H),3.94–3.84(m,2H),3.67(s ,1H),1.73–1.63(m,1H),1.28–1.17(m,1H),1.11(dd,J=11.9,6.1Hz,1H).

[0295] Synthesis of I-8b

[0296] Dissolve the intermediate V8-2b (0.10 g, 0.25 mmol) in 5 ml methanol, add 2N lithium hydroxide aqueous solution (1 mL), heat to 40°C, and react for 14 h. LC-MS detected that the raw material had reacted completely. The reaction solution was adjusted to pH = 5 with 2N hydrochloric acid, the methanol was concentrated, the residue was added with water, filtered, and dried to obtain compound I-8b (0.062 g, yield: 66%). LCMS: M+1 = 389. 1 H-NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 8.12 (dd, J = 7.9, 1.4Hz, 1H), 8.09 (d ,J=8.9Hz,1H),8.01(dd,J=7.9,1.4Hz,1H),7.46(t,J=7.9Hz,1H),7.20(d,J= 2.2Hz,1H),7.09(dd,J=8.9,2.2Hz,1H),4.36–4.23(m,2H),3.91–3.81(m,1H) ,3.80–3.69(m,2H),1.69–1.64(m,1H),1.30–1.27(m,1H),1.06–1.01(m,1H).

[0297] Example 11a Preparation of (trans)-3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-9a)

[0298]

[0299] Synthesis of intermediate V9-1a

[0300] Intermediate A (150 mg, 0.61 mmol), intermediate B-trans (220 mg, 0.67 mmol) and potassium carbonate (101 mg, 0.73 mmol) were added to 5 ml of dimethylformamide and reacted at an external temperature of 80°C for 16 h. LCMS detected that intermediate A was completely converted. The reaction solution was added with 20 ml of water, extracted with ethyl acetate (20 ml*3), washed with water, washed with saturated brine, dried, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain intermediate V9-1a (130 mg, yield: 53%). LCMS: M+1=403.

[0301] The intermediate V9-1a (130 mg, 0.32 mmol) was added to 5 ml of methanol, and 1 ml of 2N lithium hydroxide solution was added, and the mixture was reacted at 30°C for 16 h. The hydrolysis was complete after LCMS detection. The reaction solution was adjusted to pH 3-5 with 4N hydrochloric acid, concentrated, filtered, washed with water, and dried to obtain compound I-9a (100 mg, yield: 80%). LCMS: M+1=389.

[0302] 1 H-NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.13(dd,J=8.0,1.6Hz,1H),8.10(d ,J=8.9Hz,1H),8.02(dd,J=8.0,1.6Hz,1H),7.46(t,J=8.0Hz,1H),7.22(d,J= 2.4Hz,1H),7.11(dd,J=8.9,2.4Hz,1H),4.36–4.27(m,2H),4.23–4.13(m,1H) ,3.74–3.64(m,2H),2.95–2.89(m,1H),2.43–2.37(m,2H),2.22–2.10(m,2H).

[0303] Example 11b Preparation of (cis)-3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-9b)

[0304]

[0305] According to the synthesis method of Example 11a, intermediate B-cis was used instead of intermediate B-trans to obtain compound I-9b. LCMS: M+1=389. 1H-NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.13(dd,J=7.9,1.6Hz,1H),8.10(d ,J=8.9Hz,1H),8.02(dd,J=7.9,1.6Hz,1H),7.47(t,J=7.9Hz,1H),7.22(d,J= 2.4Hz,1H),7.12(dd,J=8.9,2.4Hz,1H),4.35–4.26(m,2H),4.03–3.91(m,1H) ,3.75–3.66(m,2H),2.66–2.54(m,1H),2.49–2.39(m,2H),2.08–1.93(m,2H).

[0306] Example 12 Preparation of 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopentyl-1-carboxylic acid (I-10)

[0307]

[0308] According to the synthesis method of Example 5, 3-oxocyclopentyl-1-carboxylic acid methyl ester was used instead of ethyl acetoacetate to obtain compound I-10 (compound I-10 was a mixture of cis and trans). LCMS: M+1=403. 1 H-NMR (400MHz, DMSO-d6) δ12.07(s,1H),8.13(dd,J=7.9,1.5Hz,1H),8.09(d,J=8.9Hz,1 H),8.02(dd,J=7.9,1.5Hz,1H),7.46(t,J=7.9Hz,1H),7.22(d,J=2.3Hz,1H),7.10(dd,J= 8.9,2.3Hz,1H),4.37–4.25(m,2H),4.08–4.04(m,0.8H),4.01–3.97(m,0.2H),3.73–3.75 (m,2H),2.86–2.75(m,0.8H),2.72–2.64(m,0.2H),1.98–1.76(m,4H),1.73–1.64(m,2H).

[0309] Example 13 Preparation of 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclohexyl-1-carboxylic acid (I-11)

[0310]

[0311] According to the synthesis method of Example 5, 3-oxocyclohexyl-1-carboxylic acid methyl ester was used instead of ethyl acetoacetate to obtain compound I-11 (compound I-11 was a mixture of cis and trans). LCMS: M+1=417. 1 H-NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.13(dd,J=7.9,1.5Hz,1H),8.09(d,J=8.9Hz,1H),8.01(dd,J=7.9,1.5Hz,1H),7 .46(t,J=7.9Hz,1H),7.24(d,J=2.3Hz,0.29H),7.22(d,J=2.3Hz,0.71H),7.10(dd,J=8.9,2.3Hz,1H),4.34(t,J=4.4Hz,0. 58H),4.31(t,J=4.4Hz,1.42H),3.86–3.80(m,1.42H),3.80–3.75(m,0.58H),3.68(s,0.29H),3.39–3.36(m,0.71H),2.32– 2.17(m,1.42H),2.00–1.96(m,0.71H),1.90–1.87(m,0.29H),1.84–1.66(m,2H),1.65–1.51(m,0.58H),1.33–1.01(m,4H).

[0312] Example 14 Preparation of 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclohexyl-1-carboxylic acid (I-12)

[0313]

[0314] According to the synthesis method of Example 5, 4-oxocyclohexyl-1-carboxylic acid methyl ester was used instead of ethyl acetoacetate to obtain compound I-12 (compound I-12 is a mixture of cis and trans). LCMS: M+1=417. 1H-NMR (400MHz, DMSO-d6) δ12.07 (s, 1H), δ8.13 (dd, J = 7.9, 1.4Hz, 1H), 8.10 (d, J=8.9Hz,1H),8.02(dd,J=7.9,1.4Hz,1H),7.47(t,J=7.9Hz,1H),7.25(d,J=2. 3Hz, 0.25H), 7.23 (d, J=2.3Hz, 0.75H), 7.10 (dd, J=8.9, 2.3Hz, 1H), 4.36–4.27 (m,2H),3.84–3.79(m,1.5H),3.78–3.73(m,0.5H),3.54(s,0.25H),3.33(s,in H2O),2.33–2.26(m,0.25H),2.21–2.10(m,0.75H),2.02–1.99(m,1H),1.92–1.88( m,1H),1.76–1.66(m,1H),1.56–1.53(m,1H),1.41–1.31(m,2H),1.23–1.16(m,2H).

[0315] Example 15 Preparation of 3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)cyclobutyl-1-carboxylic acid (I-13a and I-13b are cis-trans isomers)

[0316]

[0317] Synthesis of intermediate V13-1

[0318] At room temperature, add methyl 3-oxocyclobutanecarboxylate (10.00g, 78.00mmol) to a 250ml three-necked flask, add 100ml tetrahydrofuran and 20ml methanol, add sodium borohydride (2.97g, 78.00mmol) in batches under stirring, and keep the temperature not higher than 10℃. After addition, react at room temperature for 2h. TLC detects the end point of the reaction (iodine display), adds 100ml water to the reaction solution under ice bath, stirs for 30min, extracts with ethyl acetate (50ml*3), combines the organic phases, washes with saturated brine, dries, and concentrates to obtain a crude product. By comparing with the literature by NMR, the cis configuration: trans configuration = 9:1 (8.50g, yield: 84%).

[0319] Synthesis of intermediate V13-2

[0320] Add intermediate A (1.00 g, 4.05 mmol), intermediate 13-1 (0.63 g, 4.87 mmol) and triphenylphosphine (2.13 g, 8.11 mmol) to 40 ml of dry tetrahydrofuran. Add diisopropyl azodicarboxylate (1.64 g, 8.11 mmol) dropwise under ice bath, and react at room temperature for 4 h. TLC detection shows that intermediate A is completely converted. Pour the reaction solution into 30 ml of water, extract with ethyl acetate (30 ml*3), dry and concentrate the organic phase, and purify the crude product by silica gel column chromatography to obtain a mixture of cis and trans isomers, intermediate V13-2 (1.10 g, yield: 76%). LCMS: M+1=359.

[0321] Add intermediate V13-2 (1.10 g, 3.07 mmol) to 10 ml methanol, add 2N lithium hydroxide solution 3 ml, and keep at 30°C overnight. LCMS detected that the hydrolysis was complete. Adjust pH to 3-5 with 4N hydrochloric acid, concentrate, add water to make pulp, filter, wash with water, and dry. The crude product was separated by preparative separation to obtain the trans-configuration product I-13a (500 mg, yield: 47%). LCMS: M+1=345. 1 H-NMR (400MHz, DMSO-d6) δ12.45(s,1H),8.14–8.07(m,2H),8.01(dd,J=7.9,1.5Hz,1H),7.46(t,J=7.9Hz,1H),7.04(dd, J=8.9, 2.3Hz, 1H), 6.98 (d, J= 2.3Hz, 1H), 5.07 (p, J= 6.2Hz, 1H), 3.15–3.08 (m, 1H), 2.78–2.72 (m, 2H), 2.43–2.36 (m, 2H).

[0322] Cis-configuration product I-13b (30 mg, yield: 2.8%). LCMS: M+1=345. 1 H-NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.15–8.08(m,2H),8.02(dd,J=7.9,1.6Hz,1H),7.46 (t,J=7.9Hz,1H),7.08–7.04(m,2H),4.99–4.86(m,1H),2.76–2.72(m,3H),2.27–2.21(m,2H).

[0323] Example 16 Preparation of (trans)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)-N-(methylsulfonyl)cyclobutyl-1-carboxamide (I-14)

[0324]

[0325] I-13a (100 mg, 0.29 mmol) and carbonyldiimidazole (140 mg, 0.87 mmol) were added to 30 ml of dry dichloromethane and reacted at 5 °C for 2 h under nitrogen. Methanesulfonamide (41 mg, 0.44 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 30 mg, 0.87 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. LCMS detected that the raw material was completely converted, the reaction solution was concentrated, stirred with water, filtered, the filter cake was rinsed with ethanol, and slurried with ethyl acetate to obtain compound I-14 (35 mg, yield: 29%). LCMS: M+1=422. 1 H-NMR (400MHz, DMSO-d6) δ11.80(s,1H),8.13(dd,J=7.9,1.6Hz,1H),8.12(d,J=8.9Hz,1H),8.03(dd,J=7.9,1.6Hz,1H),7.47(t,J=7.9Hz,1H) ,7.06(dd,J=8.9,2.3Hz,1H),7.01(d,J=2.3Hz,1H),5.10–5.00(m,1H) ,3.30(s,3H),3.29–3.23(m,1H),2.85–2.73(m,2H),2.44–2.36(m,2H).

[0326] Example 17 Preparation of 3-(((5-chloro-9-oxo-9H-xanthene-3-)oxy)methyl)cyclobutyl-1-carboxylic acid (I-15)

[0327]

[0328] Synthesis of intermediate V15-1

[0329] 3-Methylenecyclobutanenitrile (2.00 g, 20 mmol) and potassium hydroxide (4.25 g, 60 mmol, 85% content) were added to 20 ml of ethanol and 10 ml of water, and the mixture was reacted under reflux for 4 h. The ethanol was evaporated, the pH was adjusted to 3-5 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate, dried, and concentrated to obtain a colorless oil (2.24 g, yield: 100%).

[0330] Synthesis of intermediate V15-2

[0331] Intermediate V15-1 (2.24 g, 20 mmol), potassium carbonate (5.52 g, 40 mmol) and dimethyl sulfate (3.02 g, 24 mmol) were added to 40 ml of acetone in sequence and refluxed overnight. The mixture was filtered, the filter cake was washed with dichloromethane, the filtrate was combined, dried and concentrated to obtain a crude oil (1.85 g, yield: 73%).

[0332] Synthesis of intermediate V15-3

[0333] Add intermediate V15-2 (0.50 g, 4.0 mmol) to a three-necked flask, add ultra-dry THF under nitrogen, cool to -10°C, add borane tetrahydrofuran (1N, 9.0 ml, 9.0 mmol) dropwise, and react at -10°C for 3 h. Add 4 ml of 3N sodium hydroxide solution dropwise, keep the temperature below -5°C, then add 2 ml of hydrogen peroxide dropwise, and react at 0°C for 1 h. Add saturated sodium thiosulfate solution under stirring until the starch potassium iodide test paper does not change color, extract with dichloromethane, dry, and concentrate to obtain a crude product (220 mg, yield: 38%).

[0334] Synthesis of intermediate V15-4

[0335] Add intermediate V15-4 (220 mg, 1.54 mmol), intermediate A (190 mg, 0.77 mmol) and triphenylphosphine (606 mg, 2.31 mmol) to 20 ml of dry tetrahydrofuran. Add diisopropyl azodicarboxylate (467 mg, 2.31 mmol) dropwise under ice bath, and react at room temperature for 4 h. TLC detection shows that intermediate A is completely converted. Pour the reaction solution into 30 ml of water, extract with ethyl acetate (30 ml*3), dry and concentrate the organic phase, and purify the crude product by silica gel column chromatography to obtain a mixture of cis and trans isomers, intermediate 15-4 (180 mg, yield: 63%). LCMS: M+1=373.

[0336] Add intermediate V15-4 (180 mg, 0.48 mmol) to 4 ml methanol, add 2N lithium hydroxide solution (1 ml, 2 mmol), react at 30°C for 16 h, and LCMS shows no raw material. Adjust pH to 3-5 with 4N hydrochloric acid, concentrate, filter, wash with water, and dry to obtain a white solid, compound I-15 (100 mg, yield: 58%, cis configuration: trans configuration = 2:1). LCMS: M+1 = 359. Nuclear magnetic resonance determines that I-15 is a mixture of cis and trans isomers, cis configuration: trans configuration = 2:1. 1H-NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.20–8.14(m,2H),8.09–8.06(m,1H),7. 54–7.50(m,2H),7.28(d,J=2.3Hz,0.33H),7.25(d,J=2.3Hz,0.66H),7.17–7.12( m,1H),4.32(d,J=6.5Hz,0.66H),4.21(d,J=6.5Hz,1.32H),3.27-3.20(m,0.33H) ,3.14-3.05(m,0.66H),2.84–2.71(m,1H),2.45–2.32(m,2H),2.20–2.06(m,2H).

[0337] Example 18 Preparation of 3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)propoxy)cyclobutyl-1-carboxylic acid (I-16)

[0338]

[0339] The synthesis of intermediate V16-4 was carried out according to the synthesis method of intermediate B, except that propylene glycol monobenzyl ether was used to replace the starting material ethylene glycol monobenzyl ether to obtain intermediate V16-4. LCMS: M+1=343.

[0340] According to the synthesis method of Example 3, Example 18 was prepared from Intermediate A and Intermediate V16-4 by hydrolysis of Intermediate V16-5. LCMS: M+1=403. 1 H-NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.12(d,J=7.8Hz,1H),8.09(d,J=8.9Hz,1H),8.0 1(d,J=7.8Hz,1H),7.46(t,J=7.8Hz,1H),7.20(s,1H),7.08(d,J=8.9Hz,1H),4.26–4.22( m,2H),4.10(p,J=6.4Hz,0.6H),3.87(p,J=7.4Hz,0.4H),3.46(t,J=6.1Hz,2H),2.94–2.8 7(m,0.6H),2.63–2.54(m,0.4H),2.46–2.34(m,2H),2.18–2.09(m,1H),2.04–1.93(m,3H).

[0341] Example 19 Preparation of (cis)-3-(2-((5,8-dichloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-17)

[0342]

[0343] The synthesis of intermediate V17-3 was carried out according to the synthesis method of intermediate A, except that 3,6-dichloro-2-fluorobenzoic acid was used to replace the starting material 3-chloro-2-fluorobenzoic acid to obtain intermediate V17-3. LCMS: M+1=281.

[0344] Synthesis of intermediate V17-4

[0345] Intermediate V17-3 (150 mg, 0.53 mmol), intermediate B-cis (192 mg, 0.59 mmol) and potassium carbonate (89 mg, 0.64 mmol) were added to 5 ml of dimethylformamide and reacted at an external temperature of 80°C for 16 h. LCMS detected that intermediate 17-3 was completely converted. The reaction solution was added with 20 ml of water, extracted with ethyl acetate (20 ml*3), washed with water, washed with saturated brine, dried, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain intermediate V17-4 (100 mg, yield: 43%). LCMS: M+1=437.

[0346] Add intermediate V17-4 (100 mg, 0.23 mmol) to 5 ml methanol, add 1 ml of 2N lithium hydroxide solution, react at 30°C for 16 h, and LCMS shows that hydrolysis is complete. The reaction solution is adjusted to pH 3-5 with 4N hydrochloric acid, concentrated, filtered, washed with water, and dried to obtain compound I-17 (60 mg, yield: 62%). LCMS: M+1=423. 1 H-NMR (400MHz, DMSO-d6) δ12.21(s,1H),8.04(d,J=8.9Hz,1H),7.95(d,J=8.6Hz,1H),7.48(d,J=8.6Hz,1H),7.16(d,J=2.2Hz,1H),7.10(d d,J=8.9,2.2Hz,1H),4.35–4.26(m,2H),3.96(p,J=7.3Hz,1H),3.75–3.66(m,2H),2.63–2.54(m,2H),2.49–2.37(m,2H),2.06–1.94(m,2H).

[0347] Example 20 Preparation of (cis)-3-(2-((5-chloro-2-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-18)

[0348]

[0349] The synthesis of intermediate 18-3 was carried out according to the synthesis method of intermediate A, except that 2,4-dimethoxytoluene was used to replace the starting material 1,3-dimethoxybenzene to obtain intermediate 18-3. LCMS: M+1=261.

[0350] According to the synthesis method of Example 19, intermediate 18-3 and intermediate B-cis were hydrolyzed via intermediate V18-4 to obtain compound I-18. LCMS: M+1=403. 1 H-NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.14(dd,J=7.9,1.5Hz,1H),8.01(dd,J=7.9,1.5Hz,1H),7.96(s,1H),7.46(t,J=7.9Hz,1H),7. 21(s,1H),4.35–4.29(m,2H),4.04–3.94(m,1H),3.77–3.70(m,2H),2.65–2.54(m,1H),2.49–2.41(m,2H),2.28(s,3H)2.06–1.95(m,2H).

[0351] Example 21 Preparation of (cis)-3-(2-((2,5-dichloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-19)

[0352]

[0353] According to the synthesis method of Example 20, 2,4-dimethoxychlorobenzene was used instead of the starting material 2,4-dimethoxytoluene to obtain compound I-19. LCMS: M+1=423. 1 H-NMR (400MHz, DMSO-d6) δ8.13(dd,J=7.9,1.6Hz,1H),8.13(s,1H),8.05(dd,J=7.9,1.6Hz,1H),7.49(t,J=7.9Hz,1H),7.46( s,1H),4.46–4.37(m,2H),4.01(p,J=7.7Hz,1H),3.78–3.69(m,2H),2.65–2.53(m,1H),2.48–2.36(m,2H),2.07–1.95(m,2H).

[0354] Example 22 Preparation of (cis)-3-(2-((5-chloro-1-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-20)

[0355]

[0356] According to the synthesis method of Example 20, 3,5-dimethoxytoluene was used to replace the starting material 2,4-dimethoxytoluene to obtain compound I-20. LCMS: M+1=403. 1 H-NMR (400MHz, DMSO-d6) δ12.20(s,2H),8.08(dd,J=7.9,1.6Hz,1H),7.97(dd,J=7.9,1.6Hz,1H),7.43(t,J=7.9Hz,1H),7.04(d,J=2.4Hz,1H),6.9 1(d,J=2.6Hz,1H),4.31–4.24(m,2H),3.99–3.91(m,1H),3.72–3.65(m,2 H),2.79(s,3H),2.61–2.55(m,1H),2.47–2.37(m,2H),2.05–1.95(m,2H).

[0357] Example 23 Preparation of (cis)-3-(2-((5-chloro-1-hydroxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-21)

[0358]

[0359] Synthesis of intermediate V21-1

[0360] 3-Chloro-2-hydroxybenzoic acid (1.00 g, 5.79 mmol) and phloroglucinol (0.73 g, 5.73 mmol) were added to 20 mL of Eaton's reagent, heated to 80°C, stirred for 1 h, and the reaction was complete after LCMS detection. The reaction solution was cooled to room temperature, slowly poured into ice water for quenching, filtered, and the filter cake was dried to obtain a yellow solid intermediate 21-1 (0.80 g, yield: 52%). LCMS: M+1=263.

[0361] Synthesis of intermediate V21-2

[0362] Intermediate V21-1 (0.40 g, 1.52 mmol), potassium carbonate (0.32 g, 2.28 mmol) and intermediate B-cis (0.55 g, 1.68 mmol) were added to 5 ml of anhydrous dimethylformamide. After the addition was completed, the mixture was stirred at 80°C overnight under nitrogen protection. TLC detected that there was no starting material. The reaction solution was poured into water, extracted with ethyl acetate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain a white solid intermediate V21-2 (0.3 g, yield: 47%). LCMS: M+1=419.

[0363] The intermediate V21-2 (0.30 g, 0.71 mmol) was dissolved in 3 mL of methanol, 1 mL of 2N lithium hydroxide was added, and the mixture was stirred at 30°C overnight. LCMS detected that there was no starting material. The reaction solution was adjusted to pH 4-5 with 4N hydrochloric acid, and water was added after the methanol was concentrated. The mixture was stirred and filtered, and the filter cake was dried to obtain compound I-21 (0.10 g, yield: 35%). LCMS: M+1=405. 1 H-NMR (400MHz, DMSO-d6) δ12.59(s,1H),12.17(s,1H),8.12(dd,J=7.9,1.6Hz,1H),8.05(dd,J=7.9,1.6Hz,1H),7.49(t,J=7.9Hz,1H),6.73(d,J=2.2 Hz,1H),6.48(d,J=2.2Hz,1H),4.31–4.23(m,2H),3.96(p,J=7.7Hz,1H),3 .71–3.64(m,2H),2.64–2.53(m,1H),2.48–2.41(m,2H),2.05–1.93(m,2H).

[0364] Example 24 Preparation of (cis)-3-(2-((5-chloro-1-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-22)

[0365]

[0366] Synthesis of intermediate V22-1

[0367] The intermediate V21-2 (100 mg, 0.24 mmol) of Example 21, potassium carbonate (66 mg, 0.48 mmol) and iodomethane (51 mg, 0.36 mmol) were added to 5 ml of dimethylformamide and reacted at 80°C overnight under a sealed tube. The conversion of the raw materials was complete when detected by LCMS. 20 ml of water was added to the reaction solution, extracted with ethyl acetate, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography to obtain the intermediate V22-1 (80 mg, yield: 77%). LCMS: M+1=433.

[0368] The intermediate V22-1 (80 mg, 0.18 mmol) was dissolved in 3 mL of methanol, 1 mL of 2N lithium hydroxide was added, and the mixture was stirred at 30°C overnight. LCMS detected that there was no starting material. The reaction solution was adjusted to pH 4-5 with 4N hydrochloric acid, and water was added after the methanol was concentrated. The mixture was stirred and filtered, and the filter cake was dried to obtain compound I-22 (40 mg, yield: 52%). LCMS: M+1=419. 1H-NMR (400MHz, DMSO-d6) δ12.21(s,1H),8.02(d,J=7.9Hz,1H),7.94(d,J=7.9Hz,1H),7.40(t,J=7.9Hz,1H),6.75(s,1H),6.5 9(s,1H),4.29(s,2H),4.00–3.92(m,1H),3.90(s,3H),3.68(s,2H),2.62–2.55(m,1H),2.48–2.39(m,2H),2.06–1.94(m,2H).

[0369] Example 25 Preparation of 3-(2-((5-chloro-6-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-23)

[0370]

[0371] Synthesis of intermediate V23-1

[0372] 2-Fluoro-4-nitrobenzoic acid (10.00 g, 50.02 mmol) was dissolved in 100 mL of methanol, 10 mL of concentrated sulfuric acid was added dropwise, the temperature was raised to reflux and stirred overnight, the methanol was evaporated after the reaction, and the mixture was poured into ice water to quench, extracted with ethyl acetate, and the solvent was evaporated to obtain a white solid intermediate V23-1 (10.00 g, yield: 92%). LCMS: M+1=200.

[0373] Synthesis of intermediate V23-2

[0374] Dissolve methyl 2-fluoro-4-nitrobenzoate (intermediate 23-1, 0.60 g, 3.01 mmol) and 2-chloro-3-methoxyphenol (0.48 g, 3.01 mmol) in 10 mL of acetonitrile, add potassium carbonate (0.50 g, 3.62 mmol), heat to reflux overnight, cool after the reaction, add water, extract with ethyl acetate, evaporate the solvent, and purify the residue by silica gel column chromatography to obtain white solid intermediate V23-2 (0.90 g, yield: 88%). LCMS: M+1=338.

[0375] Synthesis of intermediate V23-3

[0376] Add intermediate V23-2 (0.90 g, 2.66 mmol) to 10 ml methanol, add 3 ml of 2N LiOH solution, react overnight at 30°C, and the reaction is complete when detected by LCMS. The reaction solution is concentrated to remove methanol, 20 ml of water is added, 4N hydrochloric acid is used to adjust pH to 3-5, and DCM is used for extraction. The organic phase is concentrated to obtain a crude product, which is directly used for the next step. Intermediate V23-3 (0.86 g, yield = 100%). LCMS: M+1 = 324.

[0377] Synthesis of intermediate V23-4

[0378] Intermediate 23-3 (0.86 g, 2.66 mmol) was added to 10 mL Eaton's reagent, heated to 80°C, and reacted for 1 h. LCMS detected that the raw material was completely converted. The reaction solution was cooled to room temperature, poured into ice water for quenching, filtered, the filter cake was washed with water, rinsed with ethanol, and dried to obtain a yellow solid, intermediate 23-4 (0.60 g, yield: 73%). LCMS: M+1=306.

[0379] Synthesis of intermediate V23-5

[0380] The intermediate V23-4 (0.60 g, 1.96 mmol) was dissolved in 6 mL of ethanol and 3 mL of water, and reduced iron powder (0.55 g, 9.81 mmol) and ammonium chloride (0.10 g, 1.96 mmol) were added, and stirred at 80°C for 3 h. The conversion was complete after LCMS detection. The reaction solution was filtered while hot, water was added, and dichloromethane was extracted. The solvent was evaporated to dryness to obtain a reddish brown solid, intermediate 23-5 (crude product 0.40 g, yield: 74%). LCMS: M+1=276.

[0381] Synthesis of intermediate V23-6

[0382] The intermediate V23-5 (0.40 g, 1.45 mmol) was dissolved in 6 mL of 50% sulfuric acid, and 1 ml of an aqueous solution of sodium nitrite (0.30 g, 4.35 mmol) was added at zero degrees, stirred at 0-5°C for 2 h, and 20 ml of water was added, and the temperature was raised to 100°C, and stirring was continued for 0.5 h. After the reaction was completed, the mixture was cooled in an ice bath, filtered, and the filter cake was dried to obtain a yellow solid, the intermediate V23-6 (0.20 g, yield: 50%). LCMS: M+1=277.

[0383] Synthesis of intermediate V23-7

[0384] Intermediate V23-6 (150 mg, 0.54 mmol) and methyl 3-(2-(toluenesulfonyloxy)ethoxy)cyclobutanecarboxylate (Intermediate B, 180 mg, 0.54 mmol) were dissolved in 6 mL of ultra-dry dimethylformamide, potassium carbonate (75 mg, 0.54 mmol) was added, the temperature was raised to 80°C, and stirred for 2 h. LCMS detected that intermediate 23-6 was completely converted. The reaction solution was poured into ice water, extracted with ethyl acetate, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain white solid intermediate V23-7 (120 mg, yield: 51%). LCMS: M+1=433.

[0385] The intermediate V23-7 (120 mg, 0.28 mmol) was dissolved in 3 mL of methanol, 1 mL of 2N lithium hydroxide was added, and the mixture was stirred at 30°C overnight. The hydrolysis was complete after LCMS detection. The pH was adjusted to 3-5 with 4N hydrochloric acid, and the methanol was concentrated and water was added. After stirring, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound I-23 (50 mg, yield: 43%). LCMS: M+1=419. 1 H-NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.14(d,J=9.0Hz,1H),8.08(d,J=8.8H z,1H),7.35(d,J=9.0Hz,1H),7.19(d,J=2.1Hz,1H),7.09(d,J=8.8Hz,1H),4.3 5–4.25(m,2H),4.23–4.15(m,0.67H),4.04(s,3H),3.99–3.94(m,0.33H),3.73 –3.65(m,2H),2.97–2.87(m,0.67H),2.43–2.36(m,2.33H),2.19–2.13(m,2H).

[0386] Example 26 Preparation of (trans)-3-(2-((5-chloro-6-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-24)

[0387]

[0388] According to the synthesis method of Example 25, 2-chloro-3-methylphenol was used instead of 2-chloro-3-methoxyphenol to obtain compound I-24 (during the synthesis, intermediate B-trans was used as the side chain). LCMS: M+1=403. 1H-NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 8.09 (d, J=8.9Hz, 1 H),8.02(d,J=8.1Hz,1H),7.46(d,J=8.1Hz,1H),7.21(d,J=2.3Hz,1H),7.10( dd,J=8.9,2.3Hz,1H),4.36–4.26(m,2H),4.19(p,J=6.4Hz,1H),3.74–3.65( m,2H),2.96–2.89(m,1H),2.54(s,3H),2.44–2.37(m,2H),2.24–2.11(m,2H).

[0389] Example 27 Preparation of (cis)-3-(2-((5-chloro-8-trifluoromethyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-25)

[0390]

[0391] According to the synthesis method of Example 3, 2-chloro-5-trifluoromethylphenol was used to replace 2-chloro-3-methoxyphenol to obtain compound I-25 (during the synthesis, intermediate B-cis was used as the side chain). LCMS: M+1=457. 1 H-NMR (400MHz, DMSO-d6) δ8.19(d,J=8.4Hz,1H),8.09(d,J=8.9Hz,1H),7.86(d,J=8.4Hz,1H),7.23(d,J=2.3Hz,1H),7.14(dd,J=8. 9,2.3Hz,1H),4.38–4.28(m,2H),3.96(p,J=7.4Hz,1H),3.77–3.67(m,2H),2.64–2.54(m,1H),2.48–2.39(m,2H),2.05–1.95(m,2H).

[0392] Example 28 Preparation of (trans)-3-(2-((5-chloro-8-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-26)

[0393]

[0394] According to the synthesis method of Example 25, 2-chloro-5-methoxyphenol was used to replace 2-chloro-3-methoxyphenol to obtain compound I-26 (during the synthesis, intermediate B-trans was used as the side chain). LCMS: M+1=419. 1 H-NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.00(d,J=8.8Hz,1H),7.89(d,J=9.1Hz,1H),7.12(d,J=2.1Hz,1H),7.05(d,J=8.8Hz,1H),7.02(d,J =9.1Hz,1H),4.32–4.25(m,2H),4.22–4.13(m,1H),3.91(s,3H),3.73– 3.64(m,2H),2.98–2.87(m,1H),2.44–2.35(m,2H),2.19–2.13(m,2H).

[0395] Example 29 Preparation of (trans)-3-(2-((5-chloro-8-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-27)

[0396]

[0397] According to the synthesis method of Example 25, 2-chloro-5-methylphenol was used to replace 2-chloro-3-methoxyphenol to obtain compound I-27 (during the synthesis, intermediate B-trans was used as the side chain). LCMS: M+1=403. 1 H-NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.06(d,J=8.9Hz,1H),7.85(d,J=8.1Hz,1H),7.23(d,J=8.1Hz,1H),7.15(d,J=2.1Hz,1H),7.07(dd,J= 8.9,2.1Hz,1H),4.35–4.27(m,2H),4.25–4.14(m,1H),3.75–3.66(m,2H ),2.96–2.89(m,1H),2.82(s,3H),2.45–2.36(m,2H),2.22–2.12(m,2H).

[0398] Example 30 Preparation of 3-(2-((5-chloro-6-trifluoromethyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-28)

[0399]

[0400] According to the synthesis method of Example 25, 2-chloro-3-trifluoromethylphenol was used instead of 2-chloro-3-methoxyphenol to obtain the real compound I-28. LCMS: M+1=457. 1 H-NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.27(d,J=8.3Hz,1H),8.10(d,J=8.9Hz, 1H),7.88(d,J=8.3Hz,1H),7.26(d,J=1.6Hz,1H),7.13(d,J=8.9Hz,1H),4.32(s,2 H),4.24–4.14(m,0.7H),4.03–3.89(m,0.3H),3.70(s,2H),2.97–2.86(m,0.7H),2 .65–2.55(m,0.3H),2.45–2.35(m,2H),2.21–2.12(m,1.4H),2.04–1.95(m,0.6H).

[0401] Example 31 Preparation of 3-(2-((5-chloro-6-cyclopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-29)

[0402]

[0403] The synthesis of intermediate V29-6 was carried out according to the synthesis method of the corresponding intermediate described in Example 23, and 2-chloro-3-bromophenol was used to replace 2-chloro-3-methoxyphenol to obtain intermediate V29-6. LCMS: M+1=481.

[0404] Synthesis of intermediate V29-7

[0405] Dissolve the intermediate V29-6 (0.1 g, 0.21 mmol) in 10 mL of toluene / water (10 / 1), add cyclopropylboric acid (0.037 g, 0.43 mmol), potassium phosphate (0.086, 0.32 mmol), tricyclohexylphosphine (0.009 g, 0.03 mmol) and palladium acetate (0.0036 g, 0.016 mmol), and bubble nitrogen for 5 min. React at 80 ° C overnight under a sealed tube. LC-MS detects that the raw material has reacted. Pour the reaction solution into water, extract with ethyl acetate, wash with water and saturated brine in turn, dry, concentrate, and pass the residue through a column to obtain the intermediate V29-7 (80 mg, yield: 86%). LCMS: M+1=443.

[0406] Add intermediate V29-7 (80 mg, 0.18 mmol) to 5 ml methanol, add 2N lithium hydroxide solution (1 ml), react at 30°C overnight, LCMS detected complete hydrolysis. Concentrate the reaction solution to dryness, add 10 ml of water, adjust pH to 3-5 with 4N hydrochloric acid, solid precipitates, filter, wash the filter cake with water, and dry to obtain compound I-29 (60 mg, yield: 77%). LCMS: M+1=429. 1 H-NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.08(d,J=8.9Hz,1H),8.00(d,J=8.4Hz,1H),7.22(d,J =2.0Hz,1H),7.10(d,J=8.9Hz,1H),7.06(d,J=8.4Hz,1H),4.38–4.27(m,3H),4.22–4.14(m,0.6 7H),3.98–3.93(m,0.33H),3.73–3.67(m,2H),2.97–2.87(m,0.67H),2.63–2.57(m,0.33H),2.4 4–2.38(m,2H),2.19–2.14(m,1.4H),2.02–1.96(m,0.7H),1.21–1.17(m,2H),0.93–0.89(m,2H).

[0407] Example 32 Preparation of 3-(2-((5-chloro-8-cyclopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-30)

[0408]

[0409] According to the synthesis method of Example 31, 2-chloro-5-bromophenol was used instead of 2-chloro-3-methoxyphenol to obtain compound I-30. LCMS: M+1=429. 1H-NMR (400MHz, DMSO-d6) δ12.20(s,1H),8.07(d,J=8.9Hz,1H),7.81(d,J=8.4Hz,1H),7.13(s ,1H),7.07(d,J=8.9Hz,1H),6.99(d,J=8.4Hz,1H),4.29(s,2H),4.24–4.14(m,0.6H),4.02–3. 90(m,0.4H),3.69(s,2H),3.59–3.47(m,1H),2.99–2.87(m,0.6H),2.64–2.55(m,0.4H),2.45– 2.35(m,2H),2.21–2.12(m,1.2H),2.07–1.92(m,0.8H),1.12–1.01(m,2H),0.80–0.76(m,2H).

[0410] Example 33 Preparation of 3-(2-((5-chloro-8-trifluoromethoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-31)

[0411]

[0412] According to the synthesis method of Example 25, 2-chloro-5-trifluoromethoxyphenol was used instead of 2-chloro-3-methoxyphenol to obtain compound I-31. LCMS: M+1=473. 1 H-NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.10(d,J=8.6Hz,1H),8.07(d,J=8.9Hz,1 H),7.42(d,J=8.6Hz,1H),7.20(d,J=2.0Hz,1H),7.12(d,J=8.9Hz,1H),4.31(s,2H ),4.24–4.14(m,0.6H),4.01–3.92(m,0.4H),3.75–3.65(m,2H),2.95–2.89(m,0.6 H),2.62–2.55(m,0.4H),2.47–2.36(m,2H),2.21–2.12(m,1H),2.04–1.96(m,1H).

[0413] Synthesis of intermediate 2-chloro-5-trifluoromethoxyphenol:

[0414]

[0415] 2-Chloro-5-trifluoromethoxyphenylboronic acid (2.00 g, 8.32 mmol) was added to 20 ml of tetrahydrofuran, 1N sodium hydroxide (12.5 ml) was added under ice bath, 30% hydrogen peroxide (1.42 g, 12.5 mmol) was added dropwise under stirring, and the mixture was reacted under ice bath for 2 h. LCMS detected that the raw material was completely converted, the reaction solution was poured into saturated sodium bisulfite solution, stirred for 30 min, extracted with ethyl acetate, dried, and concentrated to obtain crude 2-chloro-5-trifluoromethoxyphenol (1.30 g, yield: 74%) LCMS: M-1=211.

[0416] Example 34 Preparation of 3-(2-((5-chloro-6-trifluoromethoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-32)

[0417]

[0418] According to the synthesis method of Example 25, 2-chloro-3-trifluoromethoxyphenol was used instead of 2-chloro-3-methoxyphenol to obtain compound I-32. LCMS: M+1=473. 1 H-NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.11(d,J=8.9Hz,1H),7.78(d,J=8.2Hz,1H),7. 49(d,J=8.2Hz,1H),7.26(d,J=2.3Hz,1H),7.14(d,J=8.9Hz,1H),4.34–4.29(m,2H),4.2 3–4.15(m,0.6H),3.98–3.95(m,0.4H),3.72–3.68(m,2H),2.95–2.90(m,0.6H),2.62–2. 56(m,0.4H),2.41–2.36(m,1H),2.31–2.25(m,1H),2.19–2.14(m,1H),2.03–1.98(m,1H).

[0419] Synthesis of intermediate 2-chloro-3-trifluoromethoxyphenol:

[0420]

[0421] Synthesis of intermediate V32-1

[0422] 3-Trifluoromethoxyphenol (1.00 g, 5.62 mmol) was added to 20 ml of dry tetrahydrofuran, the temperature was lowered to 0-5°C, potassium tert-butoxide (1.26 g, 11.24 mmol) was added in batches, and the mixture was stirred at 0°C for 10 min. 2-Methoxyethoxymethyl chloride (1.39 g, 11.24) was added dropwise, and the mixture was reacted at room temperature overnight. TLC detected that the raw material was completely converted, the reaction solution was poured into 30 ml of water, and extracted with ethyl acetate (20 ml*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography to obtain intermediate V32-1 (1.20 g, yield: 80%).

[0423] Synthesis of intermediate V32-2

[0424] Add intermediate V32-1 (1.00 g, 3.76 mmol) to 20 ml of dry tetrahydrofuran, cool to -78 ° C, add 1.3 M sec-butyl lithium cyclohexane solution (5.8 ml, 7.51 mmol) dropwise, and maintain -78 ° C for 2 h. At this temperature, add 1,1,2-trifluorotrichloroethane (1.41 g, 7.51 mmol) dropwise, and maintain -78 ° C for 1 h. LCMS detected that the raw material disappeared, and slowly added saturated ammonium chloride aqueous solution to the reaction solution at low temperature. After quenching, extract with ethyl acetate (20 ml * 3) at room temperature, dry the organic phase, and concentrate to obtain intermediate V32-2 (0.69 g, yield: 61%).

[0425] Synthesis of intermediate V32-3

[0426] Intermediate V32-2 (0.69 g, 2.29 mmol) was added to 20 ml of 4N hydrogen chloride ethanol and reacted at 40°C for 6 h. LCMS showed that the starting material disappeared. The reaction solution was concentrated and evaporated to dryness to obtain intermediate V32-3 (0.48 g, yield: 98%). LCMS: M-1=211. 1 H-NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.25(t,J=8.3Hz,1H),7.01(d,J=8.3Hz,1H),6.95(d,J=8.3Hz,1H).

[0427] Example 35 Preparation of 3-(2-((5-chloro-8-isopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-33)

[0428]

[0429] According to the synthesis method of Example 25, 2-chloro-5-isopropylphenol was used instead of 2-chloro-3-methoxyphenol to obtain compound I-33. LCMS: M+1=431. 1 H-NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.06(d,J=8.9Hz,1H),7.91(d,J=8.4Hz,1H),7.41(d,J= 8.4Hz,1H),7.14(d,J=1.9Hz,1H),7.07(d,J=8.9Hz,1H),4.72–4.65(hept,J=6.9Hz,1H),4.29(s, 2H),4.23–4.14(m,0.67H),4.01–3.92(m,0.33H),3.74–3.65(m,2H),2.98–2.87(m,0.67H),2.62 –2.55(m,0.33H),2.45–2.35(m,2H),2.20–2.12(m,1H),2.05–1.94(m,1H),1.25(d,J=6.8Hz,6H).

[0430] Synthesis of intermediate 2-chloro-5-isopropylphenol:

[0431]

[0432] Add 3-isopropylphenol (5g, 0.037mol) to 100ml chloroform, cool to 0-5℃, add tert-butyl hypochlorite (4.4g, 0.040mol) dropwise, and warm to room temperature to react for 2h. The raw material disappears on TLC. Pour the reaction solution into water, quench the reaction with sodium bisulfite solution, extract with dichloromethane, dry, and purify the crude product by silica gel column chromatography to remove 4-chloro-3-isopropylphenol (20%). 1 H-NMR (400MHz,CDCl3)δ7.18(d,J=8.6Hz,1H),6.77(d,J=3.0Hz,1H),6.60(dd,J=8.6,3.0Hz,1H),5.30(s,1H),3.34(hept,J=6.9Hz,1H),1.21(d,J=6.9Hz,6H). After preparative separation, a small amount of 2-chloro-3-isopropylphenol was removed to obtain 2-chloro-5-isopropylphenol (2.3g, yield 37%). 1 H-NMR (400MHz, CDCl3) δ7.17(d,J=8.2Hz,1H),6.85(d,J=2.0Hz,1H),6.69(dd,J=8.2,2.0Hz,1H),5.47(s,1H),2.86–2.74(m,1H),1.18(d,J=6.9Hz,6H).

[0433] Example 36 Preparation of 2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)acetic acid (I-34)

[0434]

[0435] Synthesis of intermediate V34-1

[0436] Intermediate A (100 mg, 0.40 mmol), methyl bromoacetate (93 mg, 0.61 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added to 5 ml of dimethylformamide and reacted at an external temperature of 80°C for 16 h. LCMS detected that intermediate A was completely converted. The reaction solution was added with 20 ml of water, filtered, washed with water, slurried with ethanol, and dried to obtain intermediate V34-1 (85 mg, yield: 66%). LCMS: M+1=319.

[0437] The intermediate V34-1 (85 mg, 0.27 mmol) was added to 5 ml of methanol, and 1 ml of 2N lithium hydroxide solution was added, and the mixture was reacted at 30°C for 16 h. The hydrolysis was complete after LCMS detection. The reaction solution was adjusted to pH 3-5 with 4N hydrochloric acid, concentrated, filtered, washed with water, and dried to obtain I-34 (50 mg, yield: 61%). LCMS: M+1=305. 1 H-NMR (400MHz, DMSO-d6) δ8.14(d,J=7.8Hz,1H),8.12(d,J=9.2Hz,1H),8.02(d,J= 7.8Hz, 1H), 7.47 (t, J = 7.8Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 9.2Hz, 1H), 4.95 (s, 2H).

[0438] Example 37 Preparation of 3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)propanoic acid (I-35)

[0439]

[0440] Synthesis of Intermediate 35-1

[0441] Intermediate A (300 mg, 1.22 mmol) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) were added to 10 ml of methyl acrylate, and the mixture was reacted at 100°C for 72 h under sealed conditions. The reaction solution was concentrated to remove methyl acrylate, ethyl acetate was added, the raw material was filtered out, the filtrate was washed with 1N hydrochloric acid, and the crude product was purified by silica gel column chromatography to obtain intermediate V35-1 (100 mg, yield: 25%). LCMS: M+1=333.

[0442] The intermediate V35-1 (100 mg, 0.30 mmol) was added to 10 ml of hydrochloric acid (6N), and the reaction was carried out at an external temperature of 100°C for 16 h. LCMS detected that 90% of the raw material was hydrolyzed. The reaction solution was cooled to room temperature, diluted with 10 ml of water, extracted with dichloromethane, and the organic phase was purified by silica gel plate preparation to obtain compound I-35 (60 mg, yield: 63%). LCMS: M+1=319. 1 H-NMR (400MHz, DMSO-d6) δ12.47(s,1H),8.12(dd,J=7.9,1.4Hz,1H),8.09(d,J=8.9Hz,1H),8.01(dd,J=7.9,1.4Hz,1H) ,7.46(t,J=7.9Hz,1H),7.22(d,J=2.2Hz,1H),7.08(dd,J=8.9,2.2Hz,1H),4.39(t,J=5.9Hz,2H),2.78(t,J=5.9Hz,2H).

[0443] Example 38 Preparation of 4-((5-chloro-9-oxo-9H-xanthene-3-)oxy)butyric acid (I-36)

[0444]

[0445] According to the synthesis method of Example 36, methyl 4-bromobutyrate was used instead of methyl 2-bromoacetate to obtain compound I-36. LCMS: M+1=333. 1 H-NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.12(d,J=7.8Hz,1H),8.10(d,J=8.9Hz,1H),8.01(d,J=7.8Hz,1H),7.46(t,J=7.8 Hz,1H),7.20(d,J=1.8Hz,1H),7.09(dd,J=8.9,1.8Hz,1H),4.22(t,J=6.4Hz,2H),2.43(t,J=7.2Hz,2H),2.07–1.95(m,2H).

[0446] Example 39 Preparation of 5-((5-chloro-9-oxo-9H-xanthene-3-)oxy)pentanoic acid (I-37)

[0447]

[0448] According to the synthesis method of Example 36, methyl 5-bromovalerate was used instead of methyl 2-bromoacetate to obtain compound I-37. LCMS: M+1=347. 1H-NMR (400MHz, DMSO-d6) δ12.04(s,1H),8.13(d,J=7.9Hz,1H),8.09(d,J=8.8Hz,1H),8.01(d,J=7.9Hz,1H),7.46(t,J=7.9Hz ,1H),7.19(s,1H),7.08(d,J=8.8Hz,1H),4.20(t,J=6.1Hz,2H),2.32(t,J=7.2Hz,2H),1.84–1.78(m,2H),1.72–1.65(m,2H).

[0449] Example 40 Preparation of 3-(2-((5-chloro-2-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-38)

[0450]

[0451] According to the synthesis method of Example 25, intermediate V38-1 was used to replace intermediate V23-1, and the starting material 2-chlorophenol was reacted in dimethylformamide at an external temperature of 150° C. for 8 h. The synthesis of intermediate 38-1 was reported in WO2008051547. Compound I-38 was obtained. LCMS: M+1=419. 1 H-NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.15(dd,J=7.9,1.5Hz,1H),8.01(dd,J=7.9,1.5Hz,1H),7.52(s,1H),7.47(t,J=7.9Hz,1H),7.30 (s,1H),4.35–4.30(m,2H),4.26–4.16(m,0.7H),4.02–3.94(m,0.3H),3.91(s,3H),3.75–3.69(m,2H),2.97–2.89(m,0.7H),2.62–2.56(m, 0.3H),2.45–2.37(m,2H),2.21–2.15(m, 1.4H), 2.03–1.97 (m, 0.6H).

[0452] Example 41 Preparation of (trans)-3-(2-((2-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-39)

[0453]

[0454]

[0455] According to the synthesis method of Example 20, 1-bromo-2,4-dimethoxybenzene was used instead of 2,4-dimethoxytoluene to obtain compound I-39. LCMS: M+1=467. 1 H-NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.25(s,1H),8.11(d,J=7.9Hz,1H),8.02(d,J=7.9Hz,1H),7.47(t,J=7.9Hz,1H) ,7.38(s,1H),4.39(s,2H),4.25(p,J=6.7Hz,1H),3.74(s,2H),2.98–2.88(m,1H),2.46–2.38(m,2H),2.24–2.13(m,2H).

[0456] Example 42 Preparation of 3-(2-((2-trifluoromethyl-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-40)

[0457]

[0458] According to the synthesis method of Example 20, 2,4-dimethoxytrifluorotoluene was used instead of 2,4-dimethoxytoluene to obtain compound I-40. LCMS: M+1=457.

[0459] Example 43 Preparation of 3-(2-((2-trifluoromethoxy-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-41)

[0460]

[0461] According to the synthesis method of Example 20, 2,4-dimethoxytrifluoromethoxybenzene was used instead of 2,4-dimethoxytoluene to obtain compound I-41. LCMS: M+1=473. 1 H-NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.12(dd,J=7.9,1.3Hz,1H),8.04(dd,J =7.9,1.3Hz,1H),8.01(s,1H),7.55(s,1H),7.49(t,J=7.9Hz,1H),4.43(s,2H), 4.26–4.14(m,0.6H),4.02–3.92(m,0.4H),3.72(s,2H),2.96–2.87(m,0.6H),2. 60–2.55(m,0.4H),2.47–2.34(m,2H),2.20–2.09(m,1.2H),2.04–1.94(m,0.8H).

[0462] Example 44 Preparation of 3-(2-((6-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-42)

[0463]

[0464] Intermediate V29-6 was hydrolyzed with lithium hydroxide and purified by post-treatment to obtain compound I-42. LCMS: M+1=467. 1 H-NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.08(d,J=8.9Hz,1H),8.02(d,J=8.6Hz,1 H),7.83(d,J=8.6Hz,1H),7.22(d,J=1.6Hz,1H),7.12(d,J=8.9Hz,1H),4.31(s,2H) ,4.19(p,J=5.5Hz,0.6H),4.01–3.91(m,0.4H),3.70(s,2H),2.97–2.88(m,0.6H), 2.64–2.55(m,0.4H),2.47–2.36(m,2H),2.22–2.11(m,1.2H),2.05–1.95(m,0.8H).

[0465] Example 45 Preparation of 3-(2-((8-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-43)

[0466]

[0467] The intermediate of Example 32 was hydrolyzed with lithium hydroxide and purified by post-treatment to obtain compound I-43. LCMS: M+1=467. 1 H-NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.05(d,J=8.9Hz,1H),7.86(d,J=8.5Hz,1H),7. 68(d,J=8.5Hz,1H),7.16(d,J=2.2Hz,1H),7.10(dd,J=8.9,2.2Hz,1H),4.32–4.27(m,2H ),4.19(p,J=6.8Hz,0.6H),3.96(p,J=7.5Hz,0.4H),3.72–3.67(m,2H),2.96–2.88(m,0. 6H),2.62–2.54(m,0.4H),2.47–2.36(m,2H),2.21–2.12(m,1.2H),2.04–1.95(m,0.8H).

[0468] Example 46 Preparation of 3-(2-((5-chloro-9-thioxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-44)

[0469]

[0470] The compound of Example I-9a (100 mg, 0.26 mmol) and Lawesson reagent (31 mg, 0.08 mmol) were added to 5 ml of dry toluene, and reacted at an external temperature of 60° C. for 16 h. The reaction solution was concentrated, and the crude product was separated by preparative liquid phase to obtain compound I-44 (30 mg, yield: 29%). LCMS: M+1=405. 1 H-NMR (400MHz, CDCl3) δ8.25–8.09(m,2H),7.78–7.68(m,1H),7.33–7.22(m,1H, in CDCl3),7.04–6.87(m,2H),4.28–4.13(m,3H),3.82–3.71(m,2H),3.18–2.96(m,1H),2.64–2.52(m,2H),2.37–2.20(m,2H).

[0471] Example 47 Preparation of 3-(2-((5-chloro-9-oxo-9H-thioxanthen-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-45)

[0472]

[0473] Synthesis of intermediate V45-1

[0474] Add methyl 4-chloro-2-fluorobenzoate (2.00 g, 10.61 mmol), potassium carbonate (1.76 g, 12.73 mmol) and 3-methoxythiophenol (1.56 g, 11.14 mmol) to 10 ml of dimethylformamide, heat to 80°C, react for 16 h, and complete conversion is detected by LCMS. The reaction solution is cooled, poured into 60 ml of water, extracted with ethyl acetate (20 ml*3), and the organic phase is dried and purified by silica gel column chromatography to obtain a yellow solid, intermediate V45-1 (2.60 g, yield: 79%). LCMS: M+1=309.

[0475] Synthesis of intermediate V45-2

[0476] Dissolve the intermediate V45-1 (2.60 g, 8.42 mmol) in 10 mL methanol and 10 ml tetrahydrofuran, add 2N lithium hydroxide aqueous solution (8.42 ml, 16.84 mmol) at room temperature, react overnight at room temperature, and LCMS shows that the hydrolysis is complete. The reaction solution is concentrated, 20 ml of water is added, and the pH is adjusted to 3-5 with 6N hydrochloric acid under ice bath. The precipitated solid is filtered and dried to obtain a yellow solid, intermediate 45-2 (2.00 g, yield: 81%). LCMS: M+1=295.

[0477] Synthesis of intermediate V45-3

[0478] Add intermediate V45-2 (2.00 g, 6.79 mmol) to 10 ml Eaton's reagent, heat to 80°C, the raw material gradually dissolves, react for 1 hour, and the reaction is complete by LCMS. The reaction solution is cooled to room temperature and slowly poured into ice water for quenching. The precipitated solid is filtered, the filter cake is washed with water, and filtered to obtain a yellow solid, intermediate V45-3 (1.50 g, yield: 80%). LCMS: M+1=277.

[0479] Synthesis of intermediate V45-4

[0480] The intermediate V45-3 (1.50 g, 5.42 mmol) was added to 20 ml of dry dichloromethane, and a dichloromethane solution of boron tribromide (1.36 g, 5.42 mmol) was added dropwise at room temperature. After the addition was completed, the mixture was reacted at 40°C overnight. LCMS detected that there was no starting material, and the reaction solution was poured into ice water to quench, the insoluble matter was filtered, and the filtrate was extracted with dichloromethane, concentrated, combined with the filter cake, and slurried with acetonitrile to obtain a yellow solid, intermediate V45-4 (1.00 g, yield: 70%). LCMS: M+1=263.

[0481] Synthesis of intermediate V45-5

[0482] Intermediate V45-4 (150 mg, 0.57 mmol) and methyl 3-(2-(toluenesulfonyloxy)ethoxy)cyclobutanecarboxylate (Intermediate B, 188 mg, 0.57 mmol) were dissolved in 6 mL of ultra-dry dimethylformamide, potassium carbonate (95 mg, 0.68 mmol) was added, the temperature was raised to 80°C, and stirred for 2 h. LCMS detected that intermediate V45-4 was completely converted. The reaction solution was poured into ice water, extracted with ethyl acetate, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain a light yellow solid, intermediate V45-5 (120 mg, yield: 50%). LCMS: M+1=419.

[0483] The intermediate V45-5 (120 mg, 0.29 mmol) was added to 3 mL of methanol and 3 mL of tetrahydrofuran, and 1 mL of 2N lithium hydroxide was added, and the mixture was stirred at 30°C overnight. The hydrolysis was complete after LCMS detection. After the methanol was concentrated, 10 mL of water was added, and 4N hydrochloric acid was used to adjust the pH to 3-5. After stirring, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound I-45 (80 mg, yield: 69%). LCMS: M+1=405. 1 H-NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.45(dd,J=8.0,1.2Hz,1H),8.38(d,J=9.0Hz,1H),7. 98(dd,J=8.0,1.2Hz,1H),7.61(t,J=8.0Hz,1H),7.52(d,J=2.4Hz,1H),7.22(dd,J=9.0,2.4Hz, 1H),4.30–4.26(m,2H),4.22–4.14(m,0.7H),4.00–3.91(m,0.3H),3.71–3.66(m,2H),2.96–2.8 8(m,0.7H),2.62–2.56(m,0.3H),2.45–2.36(m,2H),2.21–2.11(m,1.4H),2.04–1.98(m,0.6H).

[0484] Example 48 Preparation of 3-(2-((5-chloro-9-thioxo-9H-thioxanthen-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid (I-46)

[0485]

[0486] Compound I-45 (100 mg, 0.25 mmol) and Lawesson's reagent (30 mg, 0.07 mmol) were added to 5 ml of dry toluene, reacted at an external temperature of 60°C for 16 h, the reaction solution was concentrated, and the crude product was separated by preparative liquid phase to obtain compound I-46 (21 mg, yield: 20%). LCMS: M+1=421. 1 H-NMR(400MHz, CDCl3)δ8.50–8.37(m,2H),7.63–7.55(m,1H),7.39–7.30(m,1H),7.02–6.91(m,2H),4.18–4 .08(m,2H),3.99–3.88(m,1H),3.73–3.64(m,2H),3.06–2.90(m,1H),2.56–2.46(m,2H),2.27–2.16(m,2H).

[0487] Example 49 Preparation of 3-(3-(5-chloro-9-oxo-9H-xanthene-3-yl)propoxy)cyclobutyl-1-carboxylic acid (I-47)

[0488]

[0489] Synthesis of intermediate V47-1

[0490] Add tert-butyl 3-oxocyclobutanecarboxylate (5.00 g, 29.38 mmol) to 50 ml tetrahydrofuran, add 10 ml methanol, add sodium borohydride (1.22 g, 32.31 mmol) in batches under ice bath, react at room temperature for 2 h after addition, and complete conversion by TLC detection. Add saturated ammonium chloride solution to the reaction solution, stir for 30 min, extract with ethyl acetate (30 ml*3), dry the organic phase, and concentrate to obtain intermediate V47-1 (4.00 g, yield: 79%).

[0491] Synthesis of intermediate V47-2

[0492] Add intermediate V47-1 (2.00 g, 11.61 mmol) to 10 ml of dry dimethylformamide, add sodium hydride (0.56 g, 13.94 mmol, 60%) under ice bath, stir for 10 min after addition. Add allyl bromide (1.55 g, 12.77 mmol) dropwise under ice bath, react overnight at room temperature, and complete conversion by TLC detection. Add 50 ml of water to the reaction solution, extract with ethyl acetate (20 ml*3), dry and concentrate the organic phase, and purify by silica gel column chromatography to obtain intermediate V47-2 (1.00 g, yield: 40%). LCMS: M+1=213. 1 H-NMR(400MHz,DMSO-d6)δ5.95–5.85(m,1H),5.29–5.23(m,1H),5.18–5.14( m,1H),3.94–3.84(m,3H),2.55–2.41(m,3H),2.21–2.11(m,2H),1.43(s,9H).

[0493] Synthesis of intermediate V47-4

[0494] Intermediate V47-3 (the synthesis method of intermediate V47-3 refers to WO2017202798, 200 mg, 0.65 mmol), intermediate V47-2 (206 mg, 0.97 mmol) and cesium carbonate (421 mg, 1.29 mmol) were added to toluene, nitrogen was bubbled for 5 min, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (44 mg, 0.06 mmol) was added, and nitrogen was bubbled for 5 min. The reaction solution was reacted in a sealed tube at an external temperature of 100°C for 16 h, and LCMS detected no raw material. The crude product was purified by silica gel column chromatography to obtain intermediate V47-4 (96 mg, yield: 34%). LCMS: M+1=441.

[0495] Synthesis of intermediate V47-5

[0496] Intermediate V47-4 (96 mg, 0.22 mmol) was added to 10 mL methanol, and 20 mg of palladium carbon was added. The mixture was reacted at 40° C. under hydrogen for 16 h. No starting material was detected by LCMS. The reaction solution was filtered and concentrated to obtain intermediate 47-5 (96 mg, yield: 100%). LCMS: M+1=443.

[0497] The intermediate V47-5 (96 mg, 0.22 mmol) was added to 10 mL of methanol, and 1 mL of concentrated hydrochloric acid was added, and stirred at room temperature for 2 h. LCMS detected that there was no starting material. The reaction solution was concentrated, 10 ml of water was added, and extracted with dichloromethane. The crude product was purified by preparative purification to obtain I-47 (40 mg, yield: 48%). LCMS: M+1=387.

[0498] Example 50 Preparation of 3-(3-((2-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)propoxy)cyclobutyl-1-carboxylic acid (I-48)

[0499]

[0500] Synthesis of Intermediate 48-1

[0501] The intermediate of I-39 (100 mg, 0.31 mmol), potassium carbonate (51 mg, 0.37 mmol) and intermediate V16-4 (105 mg, 0.31 mmol) were dissolved in 6 mL of ultra-dry dimethylformamide, heated to 80 ° C, stirred for 2 h, and the conversion was complete after LCMS detection. The reaction solution was poured into ice water, extracted with ethyl acetate, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain a white solid intermediate V48-1 (80 mg, yield: 52%). LCMS: M+1=495.

[0502] The intermediate V48-1 (80 mg, 0.28 mmol) was added to 3 mL of methanol and 3 mL of tetrahydrofuran, and 1 mL of 2N lithium hydroxide was added, and the mixture was stirred at 30°C overnight. The hydrolysis was complete after LCMS detection. After the organic solvent was concentrated, 10 mL of water was added, and 4N hydrochloric acid was used to adjust the pH to 3-5. After stirring, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound I-48 (50 mg, yield: 64%). LCMS: M+1=481. 1 H-NMR (400MHz, DMSO-d6) δ12.15 (s, 1H), 8.28 (s, 1H), 8.13 (dd, J = 7.9, 1.4Hz, 1H), 8. 04(dd,J=7.9,1.4Hz,1H),7.48(t,J=7.9Hz,1H),7.42(s,1H),4.35(t,J=6.1Hz,2H), 4.15–4.05(m,0.7H),3.90–3.85(m,0.3H),3.51(t,J=6.1Hz,2H),2.94–2.87(m,0.7H ),2.61–2.53(m,0.3H),2.41–2.33(m,2H),2.17–2.10(m,1.4H),2.05–2.00(m,0.6H).

[0503] Example 51 Preparation of 3-(4-((5-chloro-9-oxo-9H-xanthene-3-)oxy)butoxy)cyclobutyl-1-carboxylic acid (I-49)

[0504]

[0505] Referring to the synthesis method of compound I-16, propylene glycol monobenzyl ether was replaced with butanediol monobenzyl ether to obtain compound I-49. LCMS: M+1=417. 1H-NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.12(dd,J=7.9,1.5Hz,1H),8.08(d,J=8.9Hz,1H),8.01(dd,J=7.9,1.5Hz,1H),7.45(t,J=7.9Hz, 1H),7.17(d,J=2.2Hz,1H),7.07(dd,J=8.9,2.2Hz,1H),4.20(t,J=6.4Hz,2H),4.12–4.03(m,0.66H),3.90–3.80(m,0.34H),3.36–3.33(in H2O,2H),2.95–2.86(m,0.66H),2.61–2.55(m,0.34H),2.46–2.33(m,2H),2.1 7–2.08(m,1.3H),2.01–1.92(m,0.7H),1.87–1.78(m,2H),1.70–1.61(m,2H).

[0506] Example 52 Preparation of 3-(5-((5-chloro-9-oxo-9H-xanthene-3-)oxy)pentyloxy)cyclobutyl-1-carboxylic acid (I-50)

[0507]

[0508] Referring to the synthesis method of compound I-16, propylene glycol monobenzyl ether was replaced with pentanediol monobenzyl ether to obtain compound I-50. LCMS: M+1=431. 1 H-NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.13(dd,J=7.9,1.5Hz,1H),8.09(d,J=8.9Hz,1H),8.02(dd,J=7.9,1.5Hz,1H),7.46(t,J=7. 9Hz,1H),7.19(d,J=2.2Hz,1H),7.08(dd,J=8.9,2.1Hz,1H),4.19(t,J=6.4Hz,2H),4.10–4.00(m,0.5H),3.87–3.78(m,0.5H),3.30(in H2O,2H),2.94–2.84(m,0.5H),2.61–2.56(m,0.5H),2.46–2.31(m,2H),2.15–2.07( m,1H),1.99–1.90(m,1H),1.84–1.74(m,2H),1.59–1.54(m,2H),1.51–1.43(m,2H).

[0509] Comparative Example 1 Preparation of 4-((5-chloro-9-oxo-9H-xanthene-3-)amino)butyric acid

[0510]

[0511] For the synthesis of intermediate Y, refer to the synthesis method of intermediate 1 (3-bromo-5-chloro-xanthen-9-one) in WO2017202798 A1.

[0512] Intermediate Y (100 mg, 0.32 mmol), 4-aminobutyric acid (50 mg, 0.48 mmol) and tripotassium phosphate (137 mg, 0.65 mmol) were added to N-methylpyrrolidone (5 mL). After addition, the mixture was reacted at 150° C. for 16 h under nitrogen protection. Water was added to the reaction solution, and 2N hydrochloric acid was used to adjust the pH to 4-5. The mixture was extracted with dichloromethane, dried and concentrated. The crude product was separated by preparative separation to obtain compound I-51 (30 mg, yield: 28%). LCMS: M+1=332. 1 H-NMR (400MHz, DMSO-d6) δ8.06(d,J=7.8Hz,1H),7.92(d,J=7.8Hz,1H),7.86(d,J=8.9Hz,1H),7.39(t,J=7.8Hz,1H) ,7.25(s,1H),6.75(dd,J=8.9,1.5Hz,1H),6.54(s,1H),3.25–3.19(m,2H),2.36(t,J=7.2Hz,2H),1.87–1.77(m,2H).

[0513] Effect Example 1 Detection of HBeAg in the supernatant of HepDES19 cells and cccDNA in cells

[0514] 1. Purpose of the experiment

[0515] The HBeAg content in the culture supernatant of HepDES19 cells was detected by enzyme-linked immunosorbent assay (ELISA), and the cccDNA content in the cells was detected by Southern blot to evaluate the inhibitory effect of the compounds on HBV.

[0516] 2. Experimental Materials

[0517] 2.1 Cell line: HepDES19 cells

[0518] 2.2. Main reagents:

[0519] Hepatitis B e antigen quantitative detection kit, phenol chloroform, RNase, positively charged nylon membrane, anti-digoxigenin antibody, digoxigenin washing and blocking buffer set, digoxigenin color development solution.

[0520] 2.2. Consumables and instruments:

[0521] 12-well cell culture plate, 96-well cell culture plate, CO2 incubator, microplate reader, hybridization oven (UVP-HL-200HybriLinker), chemiluminescence analyzer (GE-ImageQuantTM LAS400).

[0522] 3. Test methods:

[0523] 3.1 EC 50 Test method

[0524] 3.1.1 HepDES19 cell expansion

[0525] HepDES19 cells were cultured in DMEM / F12 medium (DMEM / F12, GVco Cat.11330057), 10% Fetal Bovine Serum (FBS, Clontech Cat.631101), 100 unis / ml 100 ug / ml Penicillin / streptomycin (Hyclone, Cat.SV30010), 2 mM GlutaMAX (GVco, Cat.35050061), 1% MEMNEAA (GVco, Cat.11140-050), 0.1 mM Geneticin (GVco, Cat.10131-027, 1 μg / ml Tetracycline hydrochloride (Sigma Cat.T7660), passaged and expanded at a ratio of 1:3, and then HepDES19 cells were cultured at 4×10 6 The cells were seeded into T150 culture flasks at a density of 1 × 10 7 cells / branch).

[0526] 3.1.2. Detection of HBeAg in the supernatant of HepDES19 cells

[0527] (1) Resuscitate HepDES19 cells and seed HepDES19 cells into 96-well plates (6×10 4 cells / well) and cultured overnight at 37°C, 5% CO2.

[0528] (2) On the second day, dilute the compound, 4-fold gradient dilution to a total of 8 concentrations. Add different concentrations of the compound to the culture wells, duplicate wells. The final concentration of DMSO in the culture medium is 1%.

[0529] (3) On the seventh day, the culture medium in the culture wells was collected and the content of hepatitis B virus e antigen was determined by ELISA. After the culture medium in the culture wells was aspirated, Celltiter-Glo reagent was added to each well of the 96-well plate, and the chemiluminescence value of each well was detected by an enzyme-labeled instrument to detect cell viability.

[0530] ELISA is used to determine the content of hepatitis B virus e antigen. The steps are briefly described as follows: take 50μl of sample and standard and add them to the reaction plate respectively, then add 50μl of enzyme conjugate to each well, shake and mix, incubate at 37℃ for 60 minutes, then wash the plate 6 times with washing solution, then add 50μl of luminescent substrate to each well, mix, react at room temperature in the dark for 10 minutes, and finally detect the chemiluminescence intensity with an enzyme reader.

[0531] 3.1.3 Data Analysis:

[0532] Calculate the inhibition percentage:

[0533] Inhibition percentage (Inh%) = (1-e antigen value in sample / e antigen value in DMSO control) x 100.

[0534] Calculation of EC 50 GraphPad Prism software was used to calculate the 50% inhibitory concentration (EC 50 ).

[0535] 3.1.4 EC 50 Test results

[0536]

[0537]

[0538] Reference document WO2017202798 A1 discloses heteroanthracene compounds and determines the inhibitory ability of such compounds on extracellular HBeAg levels. The IC value of the compound 5-chloro-9-oxo-9H-xanthene-3-pyrrolidine-3-carboxylic acid (1-(5-chloro-9-oxo-xanthen-3-yl)pyrrolidine-3-carboxylic acid) obtained in Example 2 on HBV is 50 It is 2.18μM.

[0539] 3.2 Detection of cccDNA content in HepDES19 cells

[0540] (1) HepDE19 cells were revived and seeded into 12-well plates (6×10 5 cells / well) and cultured overnight at 37°C, 5% CO2.

[0541] (2) On the second day, dilute the compound, 10-fold gradient dilution to a total of 5 concentrations. Add different concentrations of the compound to the culture wells, duplicate wells. The final concentration of DMSO in the culture medium is 1%.

[0542] (3) On the seventh day, cells were collected for cccDNA extraction and detected by Southern blot.

[0543] The improved Hirt extraction method was used to extract protein-free hepatitis B virus DNA (including cccDNA and dp-RCDNA). The method is briefly described as follows: SDS lysis buffer was added to HepDES19 cells to fully lyse the cells. After incubation at room temperature for 30 minutes, the cells were transferred to a 1.5 ml centrifuge tube, 5M NaCl solution was added, and incubated overnight. The supernatant was centrifuged and extracted three times with phenol chloroform and isoamyl alcohol, the DNA was precipitated with isopropanol, and then the DNA was dissolved with TE. cccDNA was detected by Western blotting (Southern blot)

[0544] The cccDNA samples were separated by 1.2% agarose gel electrophoresis and transferred to a positively charged nylon membrane. Then, the hepatitis B virus DNA on the nylon membrane was detected with a digoxigenin-labeled hepatitis B virus DNA probe. The method is briefly described as follows: the probe was added after prehybridization at 60°C for 1 hour, and hybridization was carried out at 60°C overnight. Wash twice with 2×SSC / 0.1% SDS solution at room temperature for 5 minutes each, and then wash twice with 0.2×SSC / 0.1% SDS solution at 60°C for 5 minutes each. Block the membrane with blocking solution for 30 minutes, and then incubate with antibody solution for 30 minutes. After equilibration of the membrane with detection buffer at room temperature for 5 minutes, the membrane was exposed after rinsing with colorimetric solution.

[0545] Compounds I-2, I-6, I-9a, I-10, I-15, I-18, I-36, and I-37 were prepared into DMSO solutions of different concentrations. The content of cccDNA in HepDES19 cells was detected by Southern blot. Figure 1 It can be seen that compound I-2 exhibits an inhibitory effect on cccDNA at molar concentrations of 1 μM and 10 μM. Figure 2 It can be seen that compound I-6 exhibits an inhibitory effect on cccDNA at a molar concentration of 1 μM. Figure 3 It can be seen that compound I-9a exhibits an inhibitory effect on cccDNA at molar concentrations of 0.1 μM and 1 μM. Figure 4 It can be seen that compound I-10 exhibits an inhibitory effect on cccDNA at a molar concentration of 1 μM. Figure 5 It can be seen that compound I-15 exhibits an inhibitory effect on cccDNA at molar concentrations of 1 μM and 10 μM. Figure 6 It can be seen that compound I-18 exhibits an inhibitory effect on cccDNA at a molar concentration of 1 μM. Figure 7 It can be seen that compound I-36 exhibits an inhibitory effect on cccDNA at a molar concentration of 1 μM. Figure 8 It can be seen that compound I-37 exhibits an inhibitory effect on cccDNA at molar concentrations of 0.1 μM, 1 μM, and 10 μM. Fig. 9 It can be seen that the compound 5-chloro-9-oxo-9H-oxanthene-3-pyrrolidine-3-carboxylic acid obtained in Example 2 of reference document WO2017202798 A1 exhibits an inhibitory effect on cccDNA at molar concentrations of 0.1 μM, 1 μM and 10 μM.

[0546] Depend on Figures 1 to 8 It can be seen that as the concentration of the compound of the present invention increases, the cccDNA color band gradually weakens. The strength of the cccDNA color band reflects the inhibitory effect of the compound on cccDNA. The compound of the present invention exhibits a good inhibitory effect on cccDNA, and as the concentration increases, the inhibitory effect on intracellular cccDNA becomes stronger.

[0547] Effect Example 2 Pharmacokinetics test in mice

[0548] 1. Experimental animals: 7-9 week old C3H / HeN male mice, 3 mice in each group, one group was injected by tail vein and the other was gavage, and the mice were fasted for 16 hours before administration.

[0549] 2. Dosage concentration and dosage:

[0550] Tail vein injection, solvent 10% DMSO / 30% PEG400 / 10% kolliphor EL / 50% water, prepared concentration 0.2 mg / mL, dosage 1 mg / kg.

[0551] Oral gavage, solvent: 2% Klucel, 0.1% Tween 80, 0.1% Parabens in water, prepared concentration: 0.5 mg / mL, dosage: 5 mg / kg.

[0552] 3. Blood collection time:

[0553] 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after tail vein injection

[0554] 0.25, 0.5, 1, 2, 4, 8 and 24 hours after oral administration

[0555] 4. Sample collection and analysis: About 30uL of blood was collected from the saphenous vein at each time point and sent to LC / MS / MS for analysis after processing.

[0556] Test results:

[0557]

[0558]

[0559] It can be seen from the blood drug concentration in mice in the above table that: at the same dosage (1 mg / kg) of mice, the compounds I-16, I-31 and I-39 of the present invention show a longer half-life and a higher exposure than the compound 5-chloro-9-oxo-9H-xanthene-3-pyrrolidine-3-carboxylic acid obtained in Example 2 of reference document WO2017202798 A1. Therefore, compared with the compound 5-chloro-9-oxo-9H-xanthene-3-pyrrolidine-3-carboxylic acid obtained in Example 2 of reference document WO2017202798 A1, the heteroanthrone compound shown in formula I, its cis-trans isomers or pharmaceutically acceptable salts thereof, has obvious pharmacokinetic advantages in mice.

Claims

1. A heteroanthrone compound as shown in formula I, its cis-trans isomers or pharmaceutically acceptable salts thereof, in, R 1 H, hydroxyl, C 1-10 Alkyl or C 1-10 Alkoxy; R 2 H, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; R 3 for The n is 0, 1, 2, 3, 4, 5 or 6, the m is 0 or 1, and the Y is C 1-10 Alkylene or C 3-10 Cycloalkylene; R 4 Hydroxyl or Among them, R 4a C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-30 Aryl or substituted C 6-30 Aryl, the substituted C 6-30 The aryl substituent is C 1-10 Alkyl, C 1-10 alkoxy, halogen, nitro or cyano; R 5 and R 6 Each independently is H, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; Q is O or methylene; Z 1 and Z 2 are each independently O or S.

2. The anthraquinone compound of formula I as claimed in claim 1, its cis-trans isomers or pharmaceutically acceptable salts thereof, characterized in that: R 1 In the C 1-10 Alkyl is C 1-6 Alkyl, preferably C 1-3 Alkyl; further preferably methyl, ethyl, propyl or isopropyl, more preferably methyl; and / or, R 1 In the C 1-10 Alkoxy is preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy; further preferably methoxy, ethoxy, propoxy or isopropoxybenzene, more preferably methoxy; and / or, R 2 In the C 1-10 Alkyl and the halogen substituted C 1-10 C in the alkyl group 1-10 The alkyl groups are each independently C 1-6 Alkyl, preferably C 1-3 Alkyl; further preferably methyl, ethyl, propyl or isopropyl, more preferably methyl; and / or, R 2 In the C 1-10 Alkoxy and the halogen substituted C 1-10 The alkoxy groups are each independently C 1-6 Alkoxy, preferably C 1-3 Alkoxy; further preferably methoxy, ethoxy, propoxy or isopropoxybenzene, more preferably methoxy; and / or, R 2 wherein the halogen-substituted C 1-10 Alkyl and the halogen substituted C 1-10 The halogens in the alkoxy group are each independently fluorine, chlorine, bromine or iodine, preferably fluorine; when the number of halogen substitutions is multiple, the types of halogens substituted by the halogens may be the same or different, preferably the types of halogens substituted by the halogens are the same; and / or, R 2 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine; and / or, R 2 wherein the halogen-substituted C 1-10 Alkyl and halogen substituted C 1-10 The number of halogen-substituted alkoxy groups is independently 1, 2 or 3, preferably 3; and / or, R 3 In, the Y, the C 1-10 Alkylene is C 1-6 Alkylene; preferably C 1-4 Alkylene; further preferably methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene or tert-butylene, preferably ethylene, propylene or butylene; and / or, R 3 In, the Y, the C 3-10 Cycloalkylene is C 3-6 Cycloalkylene, preferably C 4-6 Cycloalkylene; further preferably More preferred and / or, R 4a In the C 1-10 Alkyl is C 1-6 Alkyl, preferably C 1-3 alkyl; and / or, R 4a In the C 3-10 Cycloalkyl is C 3-6 Cycloalkyl, further cyclopropyl; and / or, R 4a In the C 6-30 Aryl and substituted C 6-30 C in aromatic groups 6-30 The aryl groups are each independently C 6-14 Aryl, preferably phenyl, naphthyl, anthracenyl or phenanthryl, more preferably phenyl; and / or, R 4a wherein the substituted C 6-30 The substituents in the aryl group are halogen or C 1-6 Alkyl; wherein the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or its isomers, n-pentyl or its isomers, n-hexyl or its isomers, preferably methyl; and / or, R 5 and R 6 In the C 1-10 Alkyl and the halogen substituted C 1-10 C in the alkyl group 1-10 The alkyl groups are each independently C 1-6 Alkyl, preferably C 1-3 Alkyl; further preferably methyl or isopropyl; and / or, R 5 and R 6 In the C 3-10 The cycloalkyl group is preferably the C 3-6 Cycloalkyl; further preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl; and / or, R 5 and R 6 In the C 1-10 Alkoxy and the halogen substituted C 1-10 C in alkoxy 1-10 The alkoxy groups are each independently C 1-6 Alkoxy, preferably C 1-3 Alkoxy; C 1-3 Alkoxy is further preferably methoxy; halogen substituted C 1-3 Alkoxy is further preferably trifluoromethoxy; and / or, R 5 and R 6 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine; and / or, R 5 and R 6 wherein the halogen-substituted C 1-10 Alkyl and the halogen substituted C 1-10 The halogens in the alkoxy group are each independently fluorine, chlorine, bromine or iodine, preferably fluorine; when the number of halogen substitutions is multiple, the types of halogens substituted by the halogens may be the same or different, preferably the types of halogens substituted by the halogens are the same; and / or, R 5 and R 6 wherein the halogen-substituted C 1-10 Alkyl and the halogen substituted C 1-10 The number of halogen-substituted alkoxy groups is independently 1, 2 or 3, preferably 3; when the number of halogen-substituted alkoxy groups is multiple, the types of halogen-substituted alkoxy groups may be the same or different, preferably the types of halogen-substituted alkoxy groups are the same.

3. The anthraquinone compound of formula I as claimed in claim 1, its cis-trans isomers or pharmaceutically acceptable salts thereof, characterized in that: The R 1 H, C 1-10 Alkyl or hydroxyl, the R 1 Further H, methyl, methoxy or hydroxy, preferably H, methyl or hydroxy, more preferably H; and / or, the R 2 H, halogen substituted C 1-10 Alkoxy or halogen, preferably H or halogen; said R 2 Further H, trifluoromethoxy, trifluoromethyl, chlorine or bromine, preferably H, chlorine or bromine, more preferably hydrogen or bromine; and / or, R 3 In, when m is 0, n is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3, 4 or 5; and / or, R 3 When m is 1, n is 1, 2, 3, 4 or 5, preferably 2 or 3; and / or, R 3 When m and n are both 0 or m is 0, the Y is C 3-10 Cycloalkylene, preferably C 3-6 Cycloalkylene; more preferably C 4-6 Cycloalkylene; more preferably and / or, R 3 , when n is 0, the Q is not 0; and / or, the R 3 In the formula, n is 0, 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-6 Cycloalkylene; preferably n is 1, 2, 3 or 4, Y is C 1-6 Alkylene or C 3-6 Cycloalkylene; most preferably n is 1, 2, 3 or 4, Y is C 1-4 Alkylene or C 4-6 Cycloalkylene; Furthermore, the R 3 Preferred are methylene, ethylene, propylene, butylene, Preferred are ethylene, propylene, butylene, More preferably, ethylene, propylene, butylene More preferably, butylene, and / or, R 4 is hydroxyl group; and / or, the R 5 H, halogen-substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy or halogen; preferably H, halogen-substituted C 1-10 Alkyl or halogen; further H, methoxy, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl or bromine; preferably hydrogen, trifluoromethyl, trifluoromethoxy, or bromine; more preferably hydrogen, trifluoromethyl or bromine; and / or, the R 6 H, halogen-substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy, C 3-10 Cycloalkyl or halogen; preferably halogen substituted C 1-10 Alkoxy or C 3-10 Cycloalkyl; further H, methoxy, trifluoromethyl, trifluoromethoxy, methyl, cyclopropyl, isopropyl, chlorine or bromine; preferably H, trifluoromethyl, trifluoromethoxy, cyclopropyl, isopropyl, chlorine or bromine; more preferably trifluoromethoxy or cyclopropyl.

4. The anthraquinone compound of formula I as claimed in claim 1, its cis-trans isomers or pharmaceutically acceptable salts thereof, characterized in that: The R 1 , R 2 , R 5 and R 6 Each independently is H; Or, the R 1 Hydroxyl, C 1-10 Alkyl or C 1-10 Alkoxy; said R 2 , R 5 and R 6 Each independently is H; Or, the R 2 C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; said R 1 , R 5 and R 6 Each independently is H; Or, the R 5 C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; said R 1 , R 2 and R 6 Each independently is H; Or, the R 6 C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy or halogen; said R 1 , R 2 and R 5 Each independently is H; Or, when the Z 1 and Z 2 When one is O and the other is S, or both are S, the R 1 , R 2 , R 5 and R 6 are each independently H; the R 3 for Or, when the Q is a methylene group, the R 3 for Or, the R 1 H, C 1-10 Alkyl or hydroxyl; said R 2 Preferably H, halogen substituted C 1-10 Alkoxy or halogen; said R 3 wherein n is 0, 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-6 Cycloalkylene; said R 4 is a hydroxyl group; said R 5 H, halogen-substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy or halogen; and said R 6 H, halogen-substituted C 1-10 Alkyl, halogen substituted C 1-10 Alkoxy, C 3-10 Cycloalkyl or halogen; Or, the R 1 is H; said R 2 is H or halogen; said R 3 wherein n is 1, 2, 3 or 4, and Y is C 1-6 Alkylene or C 3-10 Cycloalkylene; said R 5 H, halogen-substituted C 1-10 Alkyl or halogen; and said R 6 Replace C with halogen 1-10 Alkoxy or C 3-10 Cycloalkyl.

5. The heteroanthrone compound of formula I as claimed in claim 1, its cis-trans isomers or pharmaceutically acceptable salts thereof, characterized in that: The heteroanthrone compound as shown in formula I is any of the following compounds: 2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)acetic acid, 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)propanoic acid, 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)butanoic acid, 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)-2,2-dimethylpropanoic acid, 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)-2-methylpropanoic acid, 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)butanoic acid, 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)pentanoic acid, (trans)-2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopropyl-1-carboxylic acid, (cis)-2-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopropyl-1-carboxylic acid, (trans)-3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclopentyl-1-carboxylic acid, 3-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclohexyl-1-carboxylic acid, 4-(2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclohexyl-1-carboxylic acid, (trans)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)cyclobutyl-1-carboxylic acid, (cis)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)cyclobutyl-1-carboxylic acid, (trans)-3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)-N-(methylsulfonyl)cyclobutyl-1-carboxamide, 3-(((5-chloro-9-oxo-9H-xanthene-3-)oxy)methyl)cyclobutyl-1-carboxylic acid, 3-(3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)propoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((5,8-dichloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((5-chloro-2-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((2,5-dichloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((5-chloro-1-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((5-chloro-1-hydroxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((5-chloro-1-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-6-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (trans)-3-(2-((5-chloro-6-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (cis)-3-(2-((5-chloro-8-trifluoromethyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (trans)-3-(2-((5-chloro-8-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (trans)-3-(2-((5-chloro-8-methyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-6-trifluoromethyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-6-cyclopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-8-cyclopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-8-trifluoromethoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-6-trifluoromethoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-8-isopropyl-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 2-((5-chloro-9-oxo-9H-xanthene-3-)oxy)acetic acid, 3-((5-chloro-9-oxo-9H-xanthene-3-)oxy)propanoic acid, 4-((5-chloro-9-oxo-9H-xanthene-3-)oxy)butanoic acid, 5-((5-chloro-9-oxo-9H-xanthene-3-)oxy)pentanoic acid, 3-(2-((5-chloro-2-methoxy-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, (trans)-3-(2-((2-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((2-trifluoromethyl-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((2-trifluoromethoxy-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((6-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((8-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-9-thioxo-9H-xanthene-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-9-oxo-9H-thioxanthen-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(2-((5-chloro-9-thioxo-9H-thioxanthen-3-)oxy)ethoxy)cyclobutyl-1-carboxylic acid, 3-(3-(5-chloro-9-oxo-9H-xanthene-3-yl)propoxy)cyclobutyl-1-carboxylic acid, 3-(3-((2-bromo-5-chloro-9-oxo-9H-xanthene-3-)oxy)propoxy)cyclobutyl-1-carboxylic acid, 3-(4-((5-chloro-9-oxo-9H-xanthene-3-)oxy)butoxy)cyclobutyl-1-carboxylic acid and 3-(5-((5-chloro-9-oxo-9H-xanthene-3-)oxy)pentyloxy)cyclobutyl-1-carboxylic acid; Or its cis-trans isomers or a mixture of the two in any ratio.

6. A method for preparing the anthrone compound of formula I as claimed in any one of claims 1 to 5, its cis-trans isomers or pharmaceutically acceptable salts, characterized in that: It is any one of method 1, method 2 and method 3: Method 1 comprises the following steps: in a solvent, under the action of a base, subjecting compound V or its cis-trans isomers to a hydrolysis reaction as shown below to obtain R 4 The heteroanthrone compound of formula I or its cis-trans isomers thereof is hydroxyl group, that is: Where R' is C 1-4 alkyl; Method 2 comprises the following steps: in an organic solvent, subjecting the carboxylic acid of the anthrone compound of formula I obtained in method 1 or its cis-trans isomers to a condensation reaction with compound U as shown below to obtain R 4 for The heteroanthrone compound as shown in formula I or its cis-trans isomers, that is: Method 3 comprises the following steps: subjecting the carboxylic acid of the anthracene compound of formula I obtained in method 1 or its cis-trans isomers to a sulfurization reaction in an organic solvent as shown below in the presence of a sulfurizing agent to obtain Z 1 A sulfur-containing heteroanthrone compound as shown in formula I or its cis-trans isomers, that is: Among them, Z 1a is O.

7. The method for preparing the anthrone compound or its cis-trans isomers as shown in formula I according to claim 6, characterized in that: It further includes a method for preparing compound V, wherein the method for preparing compound V is any one of method A, method B and method C: Method A comprises the following steps: in the presence of a base, compound II and compound III or its cis-trans isomers are reacted in an organic solvent as shown below to obtain compound V or its cis-trans isomers. Method B comprises the following steps: Compound II and Compound IV or its cis-trans isomers are subjected to the following mitsunobu reaction in an organic solvent to obtain Compound V or its cis-trans isomers. Method C comprises the following steps: in the presence of a base, compound II and compound M or its cis-trans isomers are reacted in an organic solvent as shown below to obtain compound V or its cis-trans isomers.

8. A compound of formula V or its cis-trans isomers, or a compound of formula II: in, R 1 , R 2 , R 3 , R 5 , R 6 , R', Z 1 , Z 2 and Q are as defined in any one of claims 1 to 5, and R' is as defined in claim 6.

9. The compound of formula V or its cis-trans isomers as claimed in claim 8, or the compound of formula II, characterized in that: The compound represented by formula V or its cis-trans isomers, or the compound represented by formula II is any of the following compounds: Among them, cis refers to two identical atoms or groups on the same side of the aliphatic ring, that is, cis isomers; trans refers to two identical atoms or groups on opposite sides of the aliphatic ring, that is, trans isomers.

10. Use of the anthracene compound of formula I as claimed in any one of claims 1 to 5, its cis-trans isomers or pharmaceutically acceptable salts thereof in the preparation of a cccDNA inhibitor or a hepatitis B drug.

11. A pharmaceutical composition comprising an effective dose of the anthraquinone compound of formula I as described in any one of claims 1 to 5, its cis-trans isomers or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A combination of a heteroanthrone compound of formula I as claimed in any one of claims 1 to 5, a cis-trans isomer or a pharmaceutically acceptable salt thereof and a hepatitis B drug; The hepatitis B drug is preferably one or more of HBV-DNA polymerase inhibitors, interferons, HBV adsorption and invasion inhibitors, RNA inhibitors, HBsAg production and secretion inhibitors, nucleocapsid protein inhibitors, HBV preventive and therapeutic vaccines, HBV antibodies, RNaseH inhibitors, virus maturation inhibitors and immunomodulators.

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