TW202104204A - Compounds for the treatment or prevention of liver disease - Google Patents

Abstract

A series of compounds for the treatment or prevention of liver disease is disclosed in the present invention. The compounds, stereoisomers or pharmaceutically acceptable salts are represented by Formula (I) or (II). The compounds, stereoisomers or pharmaceutically acceptable salts can be applied in preparation of pharmaceuticals for treating or preventing liver disease.

Description

Compound for treatment or prevention of liver disease

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of compounds with therapeutic or preventive effects on liver diseases.

With the continuous improvement of people's lifestyle and diet, long-term overnutrition can easily lead to the occurrence of Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD can be divided into non-alcoholic fatty liver (Non-Alcoholic Simple Fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH) and related liver cirrhosis and liver cancer according to its pathological process (Chinese Medical Association Liver Disease Division of Fatty Liver and Alcoholic Liver Disease Group, Guidelines for Diagnosis and Treatment of Non-alcoholic Fatty Liver Disease, Chinese Journal of Hepatology, 2006, 14:161-163). NASH refers to liver cell giant vesicle steatosis, cell swelling and degeneration, intralobular inflammation and other changes similar to alcoholic hepatitis, but the patient has no history of excessive drinking. At present, the prevalence of NAFLD in the general population is as high as 15%-20%, and the prevalence of NAFLD in obese patients is as high as 76%-90% (N. Belemets, N. Kobyliak, O. Virchenko, et al. Effects of polyphenol compounds melanin on NAFLD/NASH prevention. Biomedicine and Pharmacotherapy, 2017, 88: 267-276). It is estimated that the risk of NAFLD in the global population will significantly exceed hepatitis B and C in the future. At the same time, NAFLD is also the main cause of chronic liver disease, so there are many related serious health problems, such as liver cirrhosis, liver metastasis, liver cancer, and even death (N. Kobyliak, L. Abenavoli. The role of liver biopsy to assess non- alcoholic fatty liver disease. Reviews onRecent Clinical Trials. 2014, 9: 159-169; G. Musso, R. Gambino, M. Cassader, et al. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Annals of Medincine, 2011, 43: 617–649).

The etiology of NASH is closely related to metabolic syndromes such as obesity, hyperlipidemia and diabetes, but its pathogenesis is complex and has not been fully elucidated so far. The more classic is the "double hit" theory (C. P. Day, O. F. W. James. Steatohepatitis: A tale of two "hits". Gastroenterology, 1998, 114(4): 842-845). The "first blow" (development of liver steatosis) is believed to be mainly caused by insulin resistance (IR). Free Fatty Acid (FFA) comes from the decomposition of surrounding fat, ingested food or new lipid production; FFA is used during oxidation, phospholipid formation, and triglyceride (TG) synthesis. A dynamic balance is reached between production and utilization. However, when IR occurs, the physiological and biochemical reactions regulated by the insulin-mediated signaling pathway are disturbed, and its effect of inhibiting lipolysis of adipose tissue is blocked, causing excessive lipolysis of adipose tissue, thereby increasing the level of FFA in plasma, and increasing the level of TG. Formation greatly exceeds the rate of conversion and clearance, allowing TG to accumulate in the liver, so liver cells undergo giant vesicle steatosis (C. Postic, J. Girard. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. The Journal of Clinical Investigation, 2008, 118(3): 829-838). "Second blow" (fatty inflammation) is due to the excessive production of reactive oxygen species (ROS) and the reduction of antioxidant defense mechanisms, which leads to oxidative stress. A large number of FFA metabolism processes produce ROS, which undergo lipid peroxidation with the phospholipid bilayer of the cell membrane to generate active metabolites such as malonaldehyde and 4-hydroxynonenal, which cause damage to the structure and function of the cell membrane; at the same time, ROS can also cause mitochondria Body damage, the latter can lead to secondary mitochondrial fatty acid β oxidation pathway damage, further promote liver cell steatosis, forming a vicious circle; other secondary blow factors include the increase of endotoxin, iron overload and Kupffer cells’ priming overexpression, etc. (PZ Li, K. He, JZ Li, et al. The role of kupffer cells in hepatic diseases. Molecular Immunology, 2017, 85: 222-229).

At present, there is no therapeutic drug for NASH in the world. When the simple lifestyle adjustment is not enough, some insulin sensitizers, weight loss drugs, antioxidants, liver protection and lipid-lowering drugs are integrated into the treatment plan of NASH clinically. However, these drugs usually have potential safety risks and insufficient curative effects to meet the expected treatment expectations.

Some drugs that have entered the clinical phase of research, such as obeticholic acid developed by Intercept in the United States are in the phase III clinical research phase. It is a Farnesoid X Receptor (FXR) agonist, which reduces blood lipid levels through a variety of ways , Which reduces the accumulation of TG in the liver, and reduces the degree of oxidative stress and lipid peroxidation, but it has significant itching allergic reactions (The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in NASH Treatment Trial (FLINT). NCT01265498. 2015) , And high doses can cause serious liver injury and death risk (FDA Drug Safety Communication: FDA warns about serious liver injury with Ocaliva (obeticholic acid) for rare chronic liver disease. September 21, 2017). The drug was found in Phase III clinical trials, and 3% of patients had serious cardiovascular adverse events (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis (POISE). NCT01473524. 2017); Aramchol developed by Galmed Pharmaceuticals was A new type of fatty acid-cholic acid conjugate, used in the treatment of early NASH, but phase IIa clinical shows that its administration dose is higher, which needs to reach 300 mg/day to significantly reduce liver fat accumulation (R. Safadi, FM Konikoff , M. Mahamid, et al. The fatty acid–bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology, 2014 (12): 2085–2091); GS-4997 developed by Gilead is Highly selective small molecule Apoptosis Signal Regulating Kinase (ASK) inhibitor, which can be used to alleviate the liver fibrosis response to ROS, although its phase II clinical results show that 43% of subjects take the drug The degree of post-fibrosis has been improved, but the number of samples in the study is too small, and the data is not compared with placebo, so there is still a lot of uncertainty in follow-up studies (Safety, tolerability, and efficacy of GS-4997 alone or in combination with simtuzumab ( SIM) in adults with nonalcoholic steatohepatitis (NASH) and fibrosis stages F2-F3. NCT02466516. 2015); Elafibranor of French Genfit Company is a PPARα/δ dual agonist, which can improve insulin sensitivity and lipid metabolism disorders, and It can reduce inflammation, but in phase II clinical trials, the drug failed to reach the preset end point of the proportion of steatohepatitis without exacerbation of liver fibrosis. Only mild to moderate patients were evaluated to achieve the expected goal (Phase IIb study to evaluate the efficacy and safety of GFT505 v ersus placebo in patients eithnon-alcoholic steatohepatitis (NASH). NCT01694849. 2012). It can be seen that the various candidate drugs that are currently in the clinical research stage are not significant in terms of efficacy and all have certain toxic and side effects.

Silybin has anti-oxidant activity and has significant liver-protecting effects. By improving the function of mitochondria, scavenging oxygen free radicals, reducing the production of carbon monoxide, thereby reducing the level of lipid peroxidation, to achieve the effect of inhibiting liver cell steatosis (PF Surai. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives . Antioxidants (Basel), 2015(4): 204–247); at the same time, silibinin can also treat NASH disease comprehensively through multiple ways: it can inhibit the production of multiple inflammatory factors, such as NF-kB, IL1, and IL6 , TNFα, IFN-γ and GM-CSF (A. Federico, M. Dallio, C. Loguercio. Silymarin/silybin and chronic liver disease: a marriage of many years. Molecules, 2017(22): 2); also can pass Reduce the proliferation of stellate cells induced by platelet-derived growth factor (PDGF), and down-regulate the levels of type III procollagen, α-SMA and TGF-β, thereby alleviating or preventing the process of liver fibrosis (S Clichici, D. Olteanu, A. Filip, et al. Beneficial effects of silymarin after the discontinuation of CCl4-induced liver fibrosis. Journal of Medicinal Food, 2016(19): 789–797). NAFLD animal experiments have also confirmed that silibinin has a good liver-protecting effect. Silibinin can improve symptoms and liver biochemical functions of viral chronic hepatitis. It can be seen clinically that some patients have different degrees of improvement in liver histopathology, and it also has a certain effect on early liver cirrhosis.

At present, there have been clinical reports on the treatment of NASH with silybin alone or in combination with metformin and rosiglitazone (Liu Zhongxin. The efficacy of silybin combined with pioglitazone in the treatment of 76 cases of non-alcoholic fatty liver disease. Clinical digestive diseases Journal, 2012, 24(5): 288-290; Lu Sheling, Silybin combined with metformin in the treatment of non-alcoholic fatty liver, Journal of Medical Forum, 2016, 37(4): 153-154), but its preliminary efficacy limited. There are also clinical studies on silybin in the treatment of NAFLD. After 48 weeks of continuous administration, the lipidation level of patients was not significantly improved compared with placebo, but the degree of liver fibrosis was significantly reduced (WK Chan, N . Raihan. N. Mustapha, et al. A randomized trial of silymarin for the treatment of non-alcoholic steatohepatitis. Clinical Gastroenterology and Hepatology, 2017(15): 1940-1949). However, silybin also has problems such as poor solubility, poor oral absorption, and low bioavailability, which affect its clinical efficacy.

The treatment of NASH is a long-term clinical medication process, but the current clinical research phase of drugs has various problems such as unclear efficacy, large toxic side effects, and long-term use. Therefore, the NASH market urgently needs drugs with good efficacy and low toxicity.

The purpose of the present invention is to provide a class of compounds with potential therapeutic or preventive effects on liver diseases on the basis of the prior art.

Another object of the present invention is to provide a use of the above-mentioned compound in the treatment or prevention of diseases.

(I) (II) 其中： R¹ 或R² 分別獨立地選自氫、氘、羥基、鹵素、氰基、羧基、C_1-5 烷基、取代的C_1-5 烷基、C_1-5 烷氧基、取代的C_1-5 烷氧基、C_1-3 烷硫基或取代的C_1-3 烷硫基中的一個或多個； R³ 或R⁴ 分別獨立地選自氫、氘、羥基、氨基、取代氨基、硝基、鹵素、氰基、羧基、C_1-5 烷基、取代的C_1-5 烷基、C_1-3 烷氧基或取代的C_1-3 烷氧基，所述的取代基選自氘、羥基、氨基、硝基、鹵素、氰基、羧基、C_1-3 烷基或糖基中的一個或多個； R⁵ 選自氫、氘、羥基、鹵素、氰基、羧基、C_1-5 烷基、取代的C_1-5 烷基、C_1-3 烷氧基、取代的C_1-3 烷氧基、C_1-3 烷硫基或取代的C_1-3 烷硫基中的一個或多個； R⁶ 選自氫、氘、羥基、鹵素、氰基、氨基、取代氨基、羧基、C_1-5 烷基、取代的C_1-5 烷基、C_1-3 烷氧基或取代的C_1-3 烷氧基中的一個或多個，所述的取代基選自氘、羥基、氨基、硝基、鹵素、氰基、羧基或C_1-3 烷基中的一個或多個； R⁷ 或R⁸ 分別獨立地選自氫、氘、羥基、鹵素、氨基、取代氨基、硝基、氰基、C_1-3 烷基、取代的C_1-3 烷基、C_1-3 烷氧基或取代的C1-3烷氧基，所述的取代基選自氘、羥基、氨基、硝基、鹵素或氰基中的一個或多個； A選自氧、硫或CHR’，R’選自羥基、氨基、氰基、羧基或取代的C_1-5 烷基，所述的取代基選自氘、羥基、氨基、氰基或羧基中的一個或多個； A’或A”分別獨立地選自氧、硫、CO或CHR，R選自氫、氘、羥基、氨基、硝基、氰基、C_1-5 烷基或取代的C_1-5 烷基，所述的取代基選自氘、羥基、氨基、硝基、羧基、鹵素或氰基中的一個或多個； E或G分別獨立地選自C或CH，E和G之間為碳碳單鍵或碳碳雙鍵； X、Y、Z或Z’分別獨立地選自CH或N； m、n、p或q為0、1、2或3； R¹ 、R² 或R⁵ 中所述的取代基分別獨立地選自氘、羥基、氨基、硝基、鹵素、氰基、羧基或糖基中的一個或多個； 在式（II）所示的化合物中，A’和A”不同時選自氧。The object of the present invention can be achieved by the following measures: The present invention provides a class of compounds represented by general formula (I) or (II), optical isomers or pharmaceutically acceptable salts thereof,

(I) (II) Wherein: R ¹ or R ² are independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-5 alkoxy, substituted One or more of C _1-5 alkoxy, C _1-3 alkylthio or substituted C _1-3 ^{alkylthio; R 3} or R ⁴ are each independently selected from hydrogen, deuterium, hydroxyl, and amino , Substituted amino, nitro, halogen, cyano, carboxy, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the The substituent of is selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl, C _1-3 alkyl or sugar group; R ^{5 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano Group, carboxyl, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy, substituted C _1-3 alkoxy, C _1-3 alkylthio or substituted C _{1 -3} One or more of alkylthio; R ^{6 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, amino, substituted amino, carboxy, C _1-5 alkyl, substituted C _1-5 alkyl, a C _1-3 alkoxy group or a C _1-3 alkoxy group substituted with one or more of the substituents selected from deuterium, hydroxy, amino, nitro, halo, cyano, carboxy or C _{1- 3} One or more of alkyl groups; R ⁷ or R ⁸ are each independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, substituted amino, nitro, cyano, C _1-3 alkyl, substituted C _{1 -3} alkyl, C _1-3 alkoxy or substituted C 1-3 alkoxy, the substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, halogen or cyano; A Selected from oxygen, sulfur or CHR', R'is selected from hydroxyl, amino, cyano, carboxyl or substituted C _1-5 alkyl, and the substituent is selected from deuterium, hydroxyl, amino, cyano or carboxyl One or more; A'or A" are each independently selected from oxygen, sulfur, CO or CHR, R is selected from hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C _1-5 alkyl or substituted C _1-5 alkyl, the substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, carboxy, halogen or cyano; E or G is independently selected from C or CH, E and G Between is a carbon-carbon single bond or a carbon-carbon double bond; X, Y, Z or Z'are independently selected from CH or N; m, n, p or q are 0, ¹ , 2 or 3; R 1, R ^{The substituents in 2} or R ⁵ are each independently selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl or sugar group; in the compound represented by formula (II) , A'and A" are not simultaneously selected from oxygen.

In some embodiments, R ¹ or R ² are each independently selected from hydrogen, hydroxyl, halogen, cyano, carboxy, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy _{One or more of C 1-3} alkoxy, substituted C 1-3 alkoxy, C _1-3 alkylthio or substituted C _1-3 alkylthio, and the substituents are selected from deuterium, hydroxyl, amino, nitro One or more of group, halogen, cyano, carboxyl or sugar group.

In some other embodiments, R ¹ or R ^{2 are} preferably independently selected from hydroxyl, fluorine, chlorine, cyano, C _1-3 alkyl, substituted C _1-3 alkyl, and C _1-2 alkane. One or more of oxy or substituted C _1-2 alkoxy, and the substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, fluorine, chlorine, cyano or carboxyl.

When m, n, p or q in the present invention is greater than 2, it means that ^{there can be multiple defined corresponding groups (such as R 1} defined by m), and these multiple groups can be selected within a limited range (such as R ¹ The same groups within the limited range) can also be selected from different groups within the limited range.

In some embodiments, m or n is 0, 1, or 2.

In some other embodiments, m or n is 1 or 2.

R ¹ or R ² are each independently selected from hydroxy, halogen, cyano, C _1-3 alkyl, C 1-3 alkoxy or substituted C _1-2 alkoxy, and its substituent is selected from deuterium, hydroxy, Amino, fluoro or carboxy; m or n is 0, 1, or 2.

In some embodiments, R ³ or R ⁴ are each independently selected from hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C _1-3 alkyl, substituted C _1-5 alkyl, C _{1- 3} Alkoxy or substituted C _1-3 alkoxy, the substituents of which are selected from one or more of deuterium, hydroxyl, amino, nitro, cyano, carboxy or sugar.

In some other embodiments, R ³ or R ⁴ are each independently selected from hydrogen, deuterium, hydroxyl, amino, C _1-3 alkyl, or C _1-3 alkoxy.

In some other embodiments, R ³ or R ⁴ are each independently selected from hydrogen, hydroxyl, amino, C _1-3 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted The substituent of the C _1-3 alkoxy group is selected from deuterium, hydroxyl, amino, fluorine or carboxyl.

In some embodiments, R ^{5 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy, or substituted C _{1 -3} One or more of the alkoxy groups, the substituents of which are selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl or sugar group.

In some other embodiments, R ^{5 is} selected from one or more of hydrogen, deuterium, hydroxyl, halogen, cyano, or C _{1-2 alkoxy.}

In some other embodiments, R ^{5 is} selected from hydrogen, hydroxyl, halogen, cyano, C _1-2 alkoxy or substituted C _1-3 alkoxy, and its substituent is selected from deuterium, hydroxyl, fluorine. Or carboxyl.

In some embodiments, R ^{6 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted One or more of the C _1-3 alkoxy groups, the substituents of which are selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano or carboxyl.

In some other embodiments, R ^{6 is} selected from hydrogen, deuterium, hydroxyl, amino, C _1-3 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy, or substituted C _{1- 3} Alkoxy, its substituent is selected from one or more of deuterium, hydroxyl, amino, fluorine, carboxyl or cyano.

In some embodiments, p is 0, 1, 2, or 3.

In some other embodiments, p is 0 or 1.

In some embodiments, q is 0, 1, or 2.

In some other embodiments, q is 0 or 1.

In some other embodiments, R ^{6 is} selected from hydrogen, deuterium, hydroxyl, cyano, amino, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy or substituted One or more of the C _1-3 alkoxy groups, the substituents of which are selected from deuterium, hydroxyl, amino, fluorine or carboxyl.

In some embodiments, R ⁷ or R ⁸ are each independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, cyano, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-3 Alkoxy or substituted C _1-3 alkoxy, the substituent is selected from one or more of deuterium, hydroxyl, amino or halogen.

In some other embodiments, R ⁷ or R ⁸ are each independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, and the substituents are selected from One or more of deuterium, hydroxyl, amino, or halogen.

In some other embodiments, R ⁷ or R ⁸ are each independently selected from hydrogen, hydroxyl, cyano, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy or Substituted C _1-3 alkoxy, and the substituent is selected from one or more of deuterium, hydroxyl, amino or fluorine.

In some embodiments, A is selected from oxygen, sulfur or CHR', R'is selected from hydroxyl, amino, cyano, carboxy or substituted C _1-3 alkyl, and the substituent is selected from hydroxyl, amino, One or more of cyano or carboxyl groups.

In some other embodiments, A is selected from oxygen, sulfur or CHR', and R'is selected from hydroxy, amino, cyano, hydroxy-substituted C _1-3 alkyl or amino-substituted C _1-3 alkyl.

In some embodiments, A is selected from oxygen or sulfur.

In some other embodiments, A is selected from oxygen.

In some embodiments, A'or A" are each independently selected from oxygen, sulfur, CO, or CHR.

In some other embodiments, A'or A" are each independently selected from oxygen, sulfur or CO.

In some embodiments, R is selected from hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C _1-3 alkyl or substituted C _1-3 alkyl, and its substituent is selected from hydroxyl, amino, carboxyl Or one or more of cyano groups.

In some other embodiments, R is selected from hydroxyl, amino, or substituted C _1-3 alkyl, and its substituent is selected from deuterium, hydroxyl, or amino.

In the present invention, "E or G are independently selected from C or CH" means that E or G is C respectively, or E or G is CH respectively. When E or G are respectively C, there is a carbon-carbon double bond between E and G, and when E or G are respectively CH, there is a carbon-carbon single bond between E and G. In some embodiments, E or G are each independently selected from CH, and there is a carbon-carbon single bond between E and G.

In some embodiments, X or Y are independently selected from CH or N, respectively.

In some other embodiments, X and Y are not selected from N at the same time.

In some embodiments, Z or Z'is selected from -CH.

The substituent groups in the present invention, such as substituted alkyl groups, substituted alkoxy groups, substituted alkylthio groups, substituted amino groups, etc., when not specifically defined, the substituent groups are selected from deuterium, hydroxyl, amino, nitro, One or more of halogen, cyano, carboxy, C _1-3 alkyl, C _1-3 alkoxy, or sugar group.

When there are multiple substituents in each group of the present invention (such as R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^8, etc.), the same substituents can be selected for these substituents Group, different substituent groups can also be selected.

In some embodiments, the compound of the present invention is selected from the following compounds: 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3 -Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol ( 4 ); (2R,3S)-2-{( 2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6 -Base}chroman-3,4,5,7-tetraol ( 5 ); (2R,3S)-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl) -2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,5,7-triol ( 6 ); 2- {8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6 -Base}chroman-3,5,7-triol ( 7 ); 2-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1, 4] Dioxirane-6-yl}chroman-3,4,5,7-tetraol ( 22 ); 2-{3-(5-methoxypyridin-2-yl)-2-methan Base-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol ( 38 ); 2-{3- (5-Hydroxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5 ,7-Tetraol ( 45 ); (2R,3S)-4-amino-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl- 2,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,5,7-triol ( 47 ); (2R,3S)-2-{ (2R,3R)-2-hydroxymethyl-3-[3-methoxy-4-(trideuteromethoxy)phenyl]-2,3-dihydrobenzo[b][1,4 ]Dioxirane-6-yl}-5,7-bis(trideuteromethoxy)chroman-3-ol ( 55 ); 2-{8-hydroxy-3-(4-hydroxy-3 -Methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-7-methoxy-chroman- 3,4,5-triol ( 66 ); 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[ b][1,4]Dioxirane-6-yl}-7-methoxychroman-3,5-diol ( 67 ); 7-{(3-hydroxy-5,7dimethoxycolor (Man-2-yl)-2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-2,3 dihydrobenzo[b][1,4]dioxirane} -5-alcohol ( 78 ); 2 -{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane- 6-yl}-5-methoxychroman-3,7-diol ( 85 ); 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl -2,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}-5,7-dimethoxychroman-3,4-diol ( 92 ); 7- Fluoro-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]diepoxy Ethane-6-yl}chroman-3,4,5-triol ( 101 ); 7-ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl) -2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,5-diol ( 105 ); 5-ethoxy 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]diepoxy Ethane-6-yl}chroman-3,7-diol ( 109 ); 2-{8-bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2 ,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol ( 117 ); 2-{8-bromo-3 -(4-Hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman- 3,5,7-triol ( 118 ); 2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-(3,5,7-trihydroxychroman-2- Group)-2,3-dihydrobenzo[b][1,4]dioxirane-5-carbonitrile ( 119 ); (2R,3S)-2-{2-aminomethyl- (2R ,3R)-3-(4-hydroxy-3-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3 ,5,7-triol ( 126 ); 2-{8hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b] [1,4]Dioxirane-6-yl}chroman-3,4,6,7-tetraol ( 136 ); 2-{8-hydroxy-3-(4-hydroxy-3-methoxy Phenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,6,7-triol ( 137 ); 2-{3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6 -Base} Seman-3,6,7-triol ( 140 ).

The present invention also provides a pharmaceutical composition, which uses the compounds, optical isomers or pharmaceutically acceptable salts thereof of the present invention as active ingredients or main active ingredients, supplemented with pharmaceutically acceptable excipients. That is, in the pharmaceutical composition of the present application, in addition to the compound of the present invention, optical isomers or pharmaceutically acceptable salts thereof as active ingredients, other types of active ingredients can be further added to achieve combination medication and synergistic effects. Or reduce side effects and other purposes.

The compounds, optical isomers, or pharmaceutically acceptable salts thereof involved in the present invention can be used in the preparation of drugs for the treatment or prevention of liver diseases, especially in the preparation of drugs for the treatment or prevention of fatty liver, liver fibrosis and liver cirrhosis. Drugs. On the other hand, the compounds of the present invention, optical isomers or pharmaceutically acceptable salts thereof can be used in the treatment or prevention of liver diseases, especially in the treatment or prevention of fatty liver, liver fibrosis and cirrhosis.

Unless otherwise specified, the following terms used in the claims and specification have the following meanings: "Hydrogen" refers to protium (1H), which is the main stable isotope of hydrogen. "Deuterium" refers to a stable isotope of hydrogen, also known as heavy hydrogen, and its element symbol is D. "Halogen" means fluorine atom, chlorine atom, bromine atom or iodine atom. "Hydroxy" refers to the -OH group. "Amino" refers to the -NH2 group. "Cyano" refers to the -CN group. "Nitro" refers to the -NO2 group. "Carboxy" refers to the -COOH group. "Alkyl" refers to a saturated aliphatic hydrocarbon group of 1-10 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as "1-10", refers to the group , In this case, it is an alkyl group, which can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). An alkyl group containing 1 to 4 carbon atoms is called a lower alkyl group. When a lower alkyl group has no substituents, it is called an unsubstituted lower alkyl group. The alkyl group can be C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, C _1-3 alkyl, C _1-2 alkyl, C _2-3 alkyl, C _2-4 Alkyl and so on. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl and the like. Alkyl groups can be substituted or unsubstituted. "Alkoxy" means -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl) groups, which further means -O- (unsubstituted alkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, and the like. "Alkylthio" means -S- (unsubstituted alkyl) and -S- (unsubstituted cycloalkyl) groups, which further means -S- (unsubstituted alkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, cyclopropylthio, and the like. "CO" refers to the -C(=O)- group. "E or G are independently selected from C or CH" means that when E and G are carbon-carbon single bonds, E or G is independently selected from CH, and when E and G are carbon-carbon double bonds, E Or G is each independently selected from C. "Glycosyl" means a monosaccharide residue or a polysaccharide residue. The monosaccharides used herein are 3-C monosaccharides to 8-C monosaccharides, preferably 6-carbon monosaccharides having the chemical formula C6H12O6 (ie, hexose). The hexose can be in D configuration, L configuration, or a combination thereof. Hexoses are generally classified according to functional groups. For example, aldhexose has an aldehyde at position 1, for example, allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; while ketohexose is at position 2 has ketones such as psicose, fructose, sorbose and tagatose. Hexose sugars also contain 6 hydroxyl groups. The aldehyde or ketone functional groups in the hexose can react with adjacent hydroxyl functional groups to form intramolecular hemiacetals or hemiketals, respectively. If the resulting cyclic sugar is a 5-membered ring, it is furanose. If the resulting cyclic sugar is a 6-membered ring, it is a pyranose. The ring opens and closes spontaneously, allowing the bond between the carbonyl group and the adjacent carbon atom to rotate, resulting in two different configurations (α and β). The hexose can be in the S configuration or the R configuration. "Pharmaceutically acceptable salt" is a salt comprising a compound of general formula (I) or (II) and an organic acid or inorganic acid, and represents those salts that retain the biological effectiveness and properties of the parent compound. Such salts include: (1) Formation of salts with acids, obtained by the reaction of free radicals of the parent compound with inorganic or organic acids, such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid , Sulfuric acid, sulfurous acid and perchloric acid, etc., organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, Citric acid, lactic acid, mandelic acid, succinic acid or malonic acid, etc. (2) The acidic protons present in the parent compound are replaced by metal ions or the salts formed by coordination with organic ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions, and organic ions such as ethanolamine, diethanolamine, Triethanolamine, tromethamine, N-methylglucamine, etc. "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts and prodrugs and other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. "Prodrug" refers to a compound that has a pharmacological effect after being transformed in an organism. The prodrug itself has no biological activity or very low activity, and becomes an active substance after being metabolized in the body. The purpose of this process is to increase the bioavailability of the drug, strengthen targeting, and reduce the toxicity and side effects of the drug.

The present invention further claims a pharmaceutical composition comprising any of the above-mentioned compounds, its pharmaceutically acceptable salt or its easily hydrolyzable prodrug amide and other pharmaceutically active ingredients.

The present invention also includes any of the above-mentioned compounds, their pharmaceutically acceptable salts, their easily hydrolyzed prodrug amides or isomers thereof, which can be formulated into clinically or pharmaceutically acceptable compounds in a manner known in the art. Any dosage form. When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, and syrups.

In the case of formulation, it is manufactured using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are commonly used. The solid preparation for oral administration can be prepared by mixing the compound with more than one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration may include water as a simple diluent and various excipients other than liquid paraffin, such as wetting agents, sweeteners, fragrances, preservatives, and the like. In preparations for non-oral administration, as non-aqueous solvents and suspensions, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable esters such as ethyl oleate can be used. As the base of the adjuvant, witepsol, polyethylene glycol, Tween 61, cocoa butter, glyceryl laurate, glycerin gelatin, etc. can be used.

The dosage of the compound used as the active ingredient of the pharmaceutical composition according to the present invention can be determined according to the age, sex, weight, and disease of the patient, and the specific dosage can be determined according to the route of administration, the degree of the disease, sex, and weight. , Age, etc. Therefore, the dosage does not limit the scope of the present invention in any form. The pharmaceutical composition can be administered to mammals such as mice, mice, livestock, humans and the like in various ways. All modes of administration are expected, for example, it can be administered by oral, rectal or intravenous, intramuscular, subcutaneous, inhalation intrabronchial, intrauterine, dural or intracerebrovascular injection.

Compared with the existing drugs of this kind (especially silibinin), the solubility of the compound of the present invention in different solutions has been greatly improved, which can more effectively increase the absorption efficiency of the drug by the human body, and greatly enhance the related therapeutic effect. The compounds represented by formula (I) or (II), optical isomers or pharmaceutically acceptable salts thereof provided by the present invention have good curative effects and low toxicity effects on liver diseases, especially fatty liver. Experiments show that the present invention Some of the compounds involved in the invention have a significant therapeutic effect on zebrafish non-alcoholic fatty liver, and can also significantly improve and treat non-alcoholic fatty liver disease in mice. Therefore, they are used in the treatment or prevention of liver diseases, especially fatty liver and liver disease. Fibrosis and liver cirrhosis drugs have good application prospects.

The scope of the present invention is not limited by any specific embodiment described herein. The following embodiments are presented as examples only.

Example 1: 2-{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]二Synthesis of oxirane-6-yl}chroman-3,4,5,7-tetraol (4).

Step A: Add 4-hydroxy-3-methoxybenzaldehyde (2.0 g, 13.1 mmol), ethoxymethylmethylene triphenylphosphine (5.04 g, 14.5 mmol) and dichloromethane (40 mL ) The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:20 ~ 1: 10 elution) to obtain 3-(4-hydroxy-3-methoxy) Phenyl) ethyl acrylate ( 1 ) (2.5 g). The yield was 85.9%.

Step B: At -50°C, to a solution of compound 1 (2.48 g, 11.2 mmol) in THF (25 mL) was added dropwise 1.5 M diisobutylaluminum hydride in THF (25 mL). After the addition, the temperature was raised to room temperature and stirring was continued for 0.5 hours. Pour the reaction solution slowly into ice water (40 mL), and adjust the pH value to 5 ~ 6 with 2 M citric acid solution. It was extracted with ethyl acetate (50 mL×3), and the combined organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 5: 1 ~ 2: 1 elution) to obtain 4-(3-hydroxyprop-1-ene- 1-yl)-2-methoxyphenol ( 2 ) (1.62 g). The yield was 80.3%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.99 (s, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.81-6.78 (m, 1H), 6.72-6.70 (m, 1H), 6.44 -6.40 (m, 1H), 6.21-6.14 (m, 1H), 4.77-4.74 (m, 1H), 4.09-4.06 (m, 2H), 3.81 (s, 3H).

Step C: Add 3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one (622 mg, 1.94 mmol), compound 2 (350 mg, 1.94 mmol) ), a mixture of acetone (10 mL) and benzene (20 mL) was stirred at 50°C for 10 minutes, and then silver carbonate (536 mg, 1.94 mmol) was added. After the addition, the resulting mixture was stirred at this temperature overnight. Cool to room temperature, add THF (15 mL), and filter to remove insoluble materials. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, methanol: methylene chloride = 1:100 ~ 1:60 elution) to obtain 3,5,7-trihydroxy-2-{8 -Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl } Chroman-4-one ( 3 ) (200mg). The yield was 20.7%. ¹ H NMR (DMSO-d6, 400 MHz) δ 11.88 (s, 1H), 10.84 (s, 1H), 9.21 (s, 1H), 9.15 (s, 1H), 7.00 (d, J = 1.6 Hz, 1H ), 6.86-6.77 (m, 2H), 6.58-6.53 (m, 2H), 5.91-5.79 (m, 3H), 4.99-4.96 (m, 1H), 4.87-4.83 (m, 2H), 4.53-4.48 (m, 1H), 4.11 (s, 1H), 3.78 (s, 3H), 3.51-3.48 (m, 2H). MS (EI, m/z): 497.4 [MH] ^- .

Step D: The mixture containing compound 3 (170 mg, 0.341 mmol), methanol (6 mL) and sodium borohydride (32 mg, 0.846 mmol) was stirred at room temperature for 2 hours, and then sodium borohydride (32 mg, 0.846 mmol), and the resulting mixture was stirred overnight at room temperature. Add water (15 mL) and adjust the pH to 5 ~ 6 with 2 M citric acid solution. It was extracted with ethyl acetate/THF (3V/1V, 15 mL×3), and the combined organic phase was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, dichloromethane: ethyl acetate: THF = 5: 1:1~2: 1:1 elution) to obtain 2-{8- Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl} Seman-3,4,5,7-tetraol ( 4 ). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.20 (bs, 4H), 6.98 (d, J = 2.0 Hz, 1H), 6.86-6.79 (m, 2H), 6.48 (s, 1H), 6.39 (d , J = 1.6 Hz, 1H), 5.85 (d, J = 2.4 Hz, 1H), 5.68-5.67 (m, 1H), 5.18-5.16 (m, 1H), 4.85-4.83 (m, 2H), 4.69- 4.68 (m, 1H), 4.51-4.48 (m, 1H), 4.08 (bs, 1H), 3.78 (s, 3H), 3.67-3.60 (m, 2H), 3.50-3.40 (m, 2H). MS (EI, m/z): 499.2 [MH] ^- .

Example 2: (2R,3S)-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[ b][1,4]Dioxirane-6-yl}chroman-3,4,5,7-tetraol (5) synthesis.

To (2R,3R)-3,5,7-trihydroxy-2-((2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3 -Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-4-one (purchased from Shanghai Dibai Biotechnology Co., Ltd., production batch number EE09) as raw material to synthesize the compound The experimental operation of 5 was in accordance with the preparation method of step D in Example 1 ¹ H NMR (DMSO-d6, 400 MHz) δ 9.28-9.14 (s, 3H), 7.02-6.79 (m, 6H), 5.88-5.87 (m, 1H), 5.70-5.69 (m, 1H), 5.58 (s, 1H), 5.20 (s, 1H), 4.95-4.88 (m, 2H), 4.72 (s, 1H), 4.64-4.60 (m, 1H) , 4.14 (s, 1H), 3.80-3.75 (m, 4H), 3.54 (s, 1H), 3.36-3.28 (m, 1H). MS (EI, m/z): 483.2 [MH] ^- .

Example 3: (2R,3S)-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[ b] [1,4] Dioxirane-6-yl}chroman-3,5,7-triol (6) synthesis.

To a solution of compound 5 (103 mg, 0.213 mmol) in acetic acid (3 mL) was added sodium cyanoborohydride (50 mg, 0.796 mmol) in portions. After the addition, the resulting mixture was stirred at room temperature for 0.5 hours. Add water (10 mL), extract with ethyl acetate (15 mL×3), wash the combined organic phase with saturated sodium bicarbonate solution (10 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 5:1 elution) to obtain (2R,3S)-2-{(2R,3R)-3 -(4-Hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman- 3,5,7-triol ( 6 ). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.20 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H), 6.99-6.78 (m, 6H), 5.89 (d, J = 2.0 Hz , 1H), 5.70 (s, 1H), 4.96-4.86 (m, 3H), 4.59-4.56 (m, 1H), 4.13 (s, 1H), 3.89-3.87 (m, 1H), 3.77 (s, 3H) ), 3.54-3.51 (m, 1H), 3.35-3.27 (m, 1H), 2.68-2.65 (m, 1H), 2.40-2.34 (m, 1H). MS (EI, m/z): 467.2 [MH] ^- .

Example 4: 2-{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]二Synthesis of oxirane-6-yl}chroman-3,5,7-triol (7).

Using compound 4 as a raw material, the experimental operation of synthesizing compound 7 was in accordance with the preparation method of Example 3. ¹ H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 9.12 (s, 1H), 9.07 (s, 1H), 8.93 (s, 1H), 6.98-6.97 (m, 1H), 6.85 -6.76 (m, 2H), 6.42 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 5.88 (d, J = 2.0 Hz, 1H), 5.69 (d, J = 2.0 Hz, 1H), 4.92-4.90 (m, 1H), 4.84-4.79 (m, 2H), 4.51-4.49 (m, 1H), 4.09-4.05 (m, 1H), 3.85-3.80 (m, 1H) , 3.77 (s, 3H), 3.49-3.45 (m, 1H), 3.40-3.38 (m, 1H), 2.64-2.60 (m, 1H), 2.38-2.32 (m, 1H). MS (EI, m/z): 483.2 [MH] ^- .

Example 5: 3,5,7-trihydroxy-2-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]diepoxy Ethane-6-yl}chroman-4-one (21) and 2-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4 ]Dioxirane-6-yl}chroman-3,4,5,7-tetraol (22) synthesis.

Step A: Add 2,4,6-trihydroxyacetophenone (5.0 g, 29.7 mmol), chloromethyl methyl ether (9.7 g, 120.5 mmol), potassium carbonate (37.1 g, 269 mmol) and acetone (100 mL) was stirred under reflux for 2 hours. The solvent was evaporated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, methyl tert-butyl ether: petroleum ether = 1:15 ~ 1:8 elution) to obtain 1-[2-hydroxy-4, 6-Bis(methoxymethoxy)]acetophenone (8) (5.1 g). The yield was 67.0%. ¹ H NMR (DMSO-d6, 400 MHz) δ 13.34 (s, 1H), 6.23 (d, J = 2.4 Hz, 1H), 6.19 (d, J = 2.4 Hz, 1H), 5.30 (s, 2H), 5.23 (s, 2H), 3.44 (s, 3H), 3.38 (s, 3H), 2.60 (s, 3H).

Step B: Under ice water bath, add chloromethyl methyl ether (2.52 g, 31.3 mmol) dropwise to compound 8 (4.0 g, 15.6 mmol), sodium hydroxide (1.84 g, 46 mmol), water (4 mL ), tetrabutylammonium bromide (252 mg, 0.782 mmol) and dichloromethane (60 mL). After the addition, the resulting mixture was stirred at room temperature for 1 hour. Add water (40 mL), extract with dichloromethane (60 mL×2), wash the combined organic phase with saturated brine (30 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2,4,6-tris(methoxymethoxy)acetophenone (9) (4.6 g). The yield was 98.2%.

Step C: To a mixture containing methyl 3,4-dihydroxybenzoate (25.0 g, 149 mmol), potassium carbonate (20.5 g, 149 mmol) and acetonitrile (500 mL) was added dropwise benzyl bromide (25.4 g, 149 mmol), after the addition, the resulting mixture was stirred overnight under reflux. Evaporate most of the solvent under reduced pressure, add water (400 mL), extract with ethyl acetate (200 mL×3), wash the combined organic phase with saturated brine (100 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether: methylene chloride = 1:50:1 ~ 1:50:2 elution) to obtain 3-benzyloxy Methyl 4-hydroxybenzoate (10) (4.7 g) and methyl 4-benzyloxy-3-hydroxybenzoate (11) (11.3 g). The yields were 12.2% and 29.4%, respectively.

Step D: Dissolve 5-acetyl-2-methoxypyridine (2.54 g, 16.8 mmol) in acetic acid (40 mL), add 47% aqueous hydrobromic acid (5.79 g, 33.6 mmol), and add bromine dropwise (2.95 g, 18.5 mmol) in acetic acid (5 mL). After the addition, the temperature was raised to 40°C, and after stirring for about 3 hours, bromine (600 mg, 3.75 mmol) was added, and then stirring was continued for 5 hours. Add water (150 mL), extract with methyl tert-butyl ether (60 mL×4), wash the combined organic phase with saturated brine (40 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:100 ~ 1:10 elution) to obtain 2-bromo-1-(6-methoxy Pyridin-3-yl)ethanone (12) (1.91 g). The yield was 49.4%.

Step E: A mixture containing compound 10 (1.84 g, 7.12 mmol), compound 12 (1.64 g, 7.13 mmol), cesium carbonate (2.90 g, 8.90 mmol) and acetonitrile (25 mL) was stirred at 30°C for 2 hours. Add water (120 mL), extract with ethyl acetate (60 mL×3), and wash the combined organic phase with water (40 mL) and saturated brine (40 mL) successively, and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 3-benzyloxy-4-[2-(6-methoxypyridin-3-yl)-2-oxoethoxy]benzoate (13) (2.83 g). The yield was 97.4%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.90 (d, J = 2.4 Hz, 1H), 8.23 (dd, J = 2.4, 8.8 Hz, 1H), 7.62-7.48 (m, 4H), 7.42-7.29 (m, 3H), 7.06 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.68 (s, 2H), 5.20 (s, 2H), 3.97 (s, 3H) , 3.81 (s, 3H).

Step F: To a solution of compound 13 (2.83 g, 6.95 mmol) in methanol (40 mL) was added sodium borohydride (526 mg, 13.9 mmol) in portions. After the addition, the resulting mixture was stirred at room temperature for 4 hours. Add water (120 mL), extract with ethyl acetate (60 mL×3), and wash the combined organic phase with water (40 mL) and saturated brine (40 mL) successively, and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 3-benzyloxy-4-[2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy]benzoate (14) (2.61 g). The yield was 91.7%.

Step G: To a solution of compound 14 (2.6 g, 6.35 mmol) in THF (40 mL) was added 5% palladium on carbon (260 mg), and the resulting mixture was stirred in hydrogen at 30°C under normal pressure for 3 hours. Filter through celite and evaporate the solvent under reduced pressure to obtain 3-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-5,7-bis(methoxymethoxy)chroman-4 -Ketone (15) (1.96 g). The yield was 96.7%.

Step H: To a solution of compound 15 (1.94 g, 6.08 mmol) and triphenylphosphine (2.15 g, 8.20 mmol) in THF (35 mL) was added diisopropyl azodiacetate (1.66 g, 8.21 mmol), After the addition, the resulting mixture was stirred under reflux for 3.5 hours under nitrogen. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:dichloromethane=1:1-10:1 elution) to obtain 3-(6-methoxypyridine-3) -Yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-carboxylic acid methyl ester (16) (1.75 g). The yield was 95.5%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 2.4, 8.8 Hz, 1H), 7.53-7.49 (m, 2H), 7.06 (d , J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.33-5.30 (m, 1H), 4.53-4.50 (m, 1H), 4.32-4.27 (m, 1H), 3.87 ( s, 3H), 3.81 (s, 3H). MS (EI, m/z): 302.1 [M+H] ⁺ .

Step I: In an ice-water bath, to a mixture containing lithium aluminum hydride (441 mg, 11.6 mmol) and THF (15 mL) was added dropwise a solution of compound 16 (1.75 g, 5.81 mmol) in THF (7 mL). After the addition, continue to stir for 5 minutes, then warm to room temperature and continue stirring for 30 minutes. After the reaction is over, cool to 0 ~ 5℃, and slowly add water (0.5 mL), 10% sodium hydroxide solution (1.0 mL) and water (1.5 mL) to the reaction mixture. After the addition is complete, warm to room temperature to continue Stir for 5 minutes. Filter through celite to remove insoluble materials. Add ethyl acetate (60 mL) to the filtrate, wash with saturated brine (15 mL×2), dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 3-(6- Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-methanol (17) (1.52 g). The yield was 95.7%.

Step J: The mixture containing compound 17 (1.50 g, 5.49 mmol), manganese dioxide (2.39 g, 27.5 mmol) and chloroform (15 mL) was stirred at 43°C overnight. Filter through diatomaceous earth to remove the insoluble matter, evaporate the solvent under reduced pressure, and purify the product by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether=1:25~ 1:12 elution) to obtain 3-( 6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-carbaldehyde (18) (1.26 g). The yield was 84.6%.

Step K: At room temperature, add compound 18 (300 mg, 1.11 mmol) and compound 9 (332 mg, 1.11 mmol) to potassium hydroxide (186 mg, 3.32 mol) in ethanol (10 mL), add After completion, the resulting mixture was stirred at 30°C overnight. Evaporate most of the solvent under reduced pressure, add water (70 mL), extract with ethyl acetate (70 mL×3), wash the combined organic phase with saturated brine (40 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:20 ~ 1:2 elution) to obtain 3-{3-(6-methoxypyridine -3-yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-1-[2,4,6-tris(methoxymethoxy )Phenyl]prop-2-en-1-one (19) (510 mg). The yield was 83.0%.

Step L: Dissolve sodium hydroxide (360 mg, 9.0 mmol) in water (1.5 mL) and methanol (15 mL), then add compound 19 (500 mg, 0.903 mmol) and 30% hydrogen peroxide (1.03 g, 9.09 mmol) in sequence ), the resulting mixture was stirred at 25°C overnight. Add saturated brine (40 mL), extract with ethyl acetate (40 mL×3), wash the combined organic phase with saturated brine (20 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain {3-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6- Yl}oxiran-2-yl}[2,4,6-tris(methoxymethoxy)phenyl]methanone (20) (500 mg). The yield was 97.2%.

Step M: To a solution of compound 20 (490 mg, 0.860 mmol) in methanol (9 mL) and THF (3 mL) was added dropwise concentrated hydrochloric acid (1.2 mL). After the addition, the resulting mixture was stirred at 65°C for 2 hours. Evaporate most of the solvent under reduced pressure, add water (20 mL), extract with ethyl acetate (25 mL×3), wash the combined organic phase with saturated brine (15 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether: dichloromethane = 1:15:1 ~ 1:4:1 elution) to obtain 3,5, 7-Trihydroxy-2-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl} color Man-4-one (21). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.89 (s, 1H), 10.85 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.85-7.82 (m, 1H), 7.14-7.13 (m, 1H), 7.05-7.02 (m, 1H), 6.98-6.96 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.92-5.91 (m, 1H), 5.88-5.87 (m , 1H), 5.83-5.82 (m, 1H), 5.29-5.27 (m, 1H), 5.11-5.08 (m, 1H), 4.64-4.59 (m, 1H), 4.46-4.43 (m, 1H), 4.24 -4.17 (m, 1H), 3.87 (s, 3H). MS (EI, m/z): 436.1 [MH] ^- .

Step N: Compound 21 is reduced with sodium borohydride to obtain 2-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[1,4]dioxirane-6 -Base}chroman-3,4,5,7-tetraol (22), the specific experimental operation was in accordance with the preparation method of step D in Example 1. MS (EI, m/z): 438.1 [MH] ^- .

Example 6: 3,5,7-trihydroxy-2-{3-(6-methoxypyridin-3-yl)-2-methyl-2,3-dihydrobenzo[b][1, 4] Dioxirane-6-yl}chroman-4-one (37) and 2-{3-(5-methoxypyridin-2-yl)-2-methyl-2,3-di Synthesis of hydrogen benzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol (38).

Step A: Under an ice water bath, add acetyl chloride (3.22 g, 41.0 mmol) dropwise to compound 11 (5.3 g, 20.5 mmol) and triethylamine (3.11 g, 30.7 mmol) in dichloromethane (25 mL) In solution. After the addition was complete, the resulting mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, extracted with dichloromethane (80 mL×3), the combined organic phase was washed with water (40 mL) and saturated brine (40 mL) successively, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was recrystallized from dichloromethane/petroleum ether to obtain methyl 3-acetoxy-4-benzyloxybenzoate ( 23 ) (5.5 g). The yield was 89.3%.

Step B: To a solution of compound 23 (8.6 g, 28.6 mmol) in THF (120 mL) was added 5% palladium on carbon (800 mg), and the resulting mixture was stirred in hydrogen at 25° C. and normal pressure overnight. It was filtered through Celite, the solvent was evaporated under reduced pressure, and the product was recrystallized from petroleum ether to obtain methyl 3-acetoxy-4-hydroxybenzoate ( 24 ) (5.7g). The yield was 94.8%.

Step C: Add benzyl alcohol (7.68 g, 71.0 mmol) dropwise to a suspension of 60% sodium hydride (2.84 g, 71.0 mmol) in DMF (60 mL) at 0 ~ 5°C. After the addition is complete, continue stirring for 10 minutes, and then add 5-bromo-2-cyanopyridine (10.0 g, 54.6 mmol) in portions. The resulting mixture was continuously stirred at this temperature for 15 minutes. Add water (180 mL), filter, rinse the filter cake with water (100 mL), and then recrystallize with ethyl acetate/petroleum ether to give 5-benzyloxy-2-cyanopyridine ( 25 ) (9.2 g). The yield was 80.2%.

Step D: At -5 ~ 0°C, 2 M ethylmagnesium bromide THF solution (26.5 mL, 53 mmol) was added dropwise to the compound 25 (8.6 g, 40.9 mmol) in THF (30 mL) solution. After the addition was complete, the resulting mixture was continuously stirred at this temperature for 1 hour. Slowly add water (90 mL), adjust the pH to 3 ~ 4 with 2 M hydrochloric acid, extract with ethyl acetate (100 mL×3), and combine the organic phases with water (50 mL) and saturated brine (50 mL) successively Wash and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 1-(5-benzyloxypyridin-2-yl)propan-1-one ( 26 ) (9.74g). The yield was 98.7%.

The experimental operations of steps E and F were performed in accordance with the preparation methods of steps D and E in Example 5 to obtain 3-acetoxy-4-{[1-(5-benzyloxypyridin-2-yl)-1-oxygen Propan-2-yl]oxy}benzoic acid methyl ester ( 28 ). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.54 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.75-7.67 (m, 3H), 7.52-7.50 (m , 2H), 7.45-7.36 (m, 3H), 6.91 (d, J = 8.4 Hz, 1H), 6.28 (q, J = 6.8 Hz, 1H), 5.34 (s, 2H), 3.81 (s, 3H) , 2.30 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H).

Step G: Stir a mixture containing compound 28 (5.0 g, 11.1 mmol), potassium carbonate (3.08 g, 22.3 mmol) and methanol (120 mL) at 5 ~ 10°C for 15 minutes, then add sodium borohydride (1.26 g, 33.3 mmol), and the resulting mixture was stirred at room temperature for 0.5 hours. Add saturated brine (360 mL) and adjust the pH to 7 ~ 8 with 2 M citric acid solution. It was extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and then filtered through a short silica gel pad. The solvent was evaporated under reduced pressure to obtain methyl 4-{[1-(5-benzyloxypyridin-2-yl)-1-hydroxyprop-2-yl]oxy}-3-hydroxybenzoate ( 29 ) ( 4.49 g). The yield was 98.8%. ¹ H NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.52-7.50 (m, 1H), 7.42-7.34 (m, 7H), 6.96 (d , J = 8.4 Hz, 1H), 5.12 (s, 2H), 4.85-4.84 (m, 1H), 4.58-4.56 (m, 1H), 3.87 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H).

Step H: To a solution of compound 29 (4.49 g, 11.0 mmol) and triphenylphosphine (3.88 g, 14.8 mmol) in THF (20 mL) was added diisopropyl azodiacetate (2.99 g, 14.8 mmol), After the addition, the resulting mixture was stirred under reflux for 2.5 hours under nitrogen. After cooling to room temperature, the solvent was evaporated under reduced pressure. The product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:30 ~ 1:10 elution) to obtain 3-(5-benzyloxy) Pyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-methyl carboxylate ( 30 ) (3.87 g). The yield was 89.9%.

Step I: To a solution of compound 30 (2.78 g, 7.10 mmol) in DMF (30 mL) was added 5% palladium on carbon (280 mg), and the resulting mixture was stirred in hydrogen at 40° C. and normal pressure for 4 hours. Filter through celite, add water (120 mL), extract with ethyl acetate (60 mL×3), and wash the combined organic phase with water (30 mL×2) and saturated brine (30 mL), anhydrous sodium sulfate dry. The solvent was evaporated under reduced pressure to obtain 3-(5-hydroxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-carboxylic acid Methyl ester ( 31 ) (1.80 g). The yield was 84.1%.

Step J: The mixture containing compound 31 (575 mg, 1.91 mmol), potassium carbonate (343 mg, 2.49 mmol), methyl iodide (406 mg, 2.86 mmol) and DMF (10 mL) was stirred at 30°C overnight. Water (40 mL) was added, extracted with ethyl acetate (20 mL×3), the combined organic phase was washed with water (15 mL×2) and saturated brine (15 mL) successively, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-(5-methoxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6 -Methyl formate ( 32 ) (617 mg). The yield is 100%.

The experimental operations of steps K and L were performed according to the preparation methods of steps G and H in Example 6, to obtain 3-(5-methoxymethoxypyridin-2-yl)-2-methyl-2,3-dihydro Benzo[b][1,4]dioxirane-6-carbaldehyde ( 34 ). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.83 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.53-7.46 (m, 4H), 7.13 (d, J = 8.4 Hz, 1H ), 4.96 (d, J = 7.2 Hz, 1H), 4.62-4.58 (m, 1H), 3.86 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H).

The experimental operations of steps M, N and O were performed according to the preparation methods of steps I, J and K in Example 6, to obtain 3,5,7-trihydroxy-2-{3-(5-methoxypyridin-2-yl )-2-Methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-4-one ( 37 ). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.90 (s, 1H), 10.87 (s, 1H), 8.34 (s, 1H), 7.50 (s, 2H), 7.11-6.96 (m, 3H), 5.92 -5.84 (m, 3H), 5.10-5.08 (m, 1H), 4.88-4.86 (m, 1H), 4.61 (s, 1H), 4.45 (s, 1H), 3.87 (s, 3H), 1.15 (s , 3H). MS (EI, m/z): 450.1 [MH] ^- .

Step P: Compound 37 is reduced with sodium borohydride to obtain 2-{3-(5-methoxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4 ]Dioxirane-6-yl}chroman-3,4,5,7-tetraol ( 38 ), the specific experimental operation was in accordance with the preparation method of Example 1 step D. MS (EI, m/z): 452.1 [MH] ^- .

Example 7: 3,5,7-trihydroxy-2-{3-(6-hydroxypyridin-3-yl)-2-methyl-2,3-dihydrobenzo[b][1,4] Dioxirane-6-yl}chroman-4-one (44) and 2-{3-(5-hydroxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[ b] [1,4] Dioxirane-6-yl}chroman-3,4,5,7-tetraol (45) synthesis.

Using compound 30 as a raw material, the experimental operations of steps A, B, C, D and E follow the preparation methods of steps I, J, K, L and M in Example 5 to obtain 2-{3-(5-benzyloxy (Pyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-3,5,7-trihydroxychroman- 4-ketone ( 43 ). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.90 (s, 1H), 10.86 (s, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.56-7.36 (m, 7H), 7.11-6.94 (m, 3H), 5.92-5.82 (m, 3H), 5.22 (s, 2H), 5.10-5.07 (m, 1H), 4.87-4.86 (m, 1H), 4.63-4.58 (m, 1H), 4.47 -4.42 (m, 1H), 1.14 (d, J = 6.0 Hz, 3H).

Step F: To a DMF (10 mL) solution of compound 43 (780 mg, 1.57 mmol) was added 5% palladium on carbon (80 mg), and the resulting mixture was stirred in hydrogen at 40° C. and normal pressure overnight. After filtering through diatomaceous earth, add water (40 mL), filter, and dissolve the filter block with ethyl acetate (20 mL×3), then wash with saturated brine (20 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained product was recrystallized with ethyl acetate/petroleum ether to obtain 3,5,7-trihydroxy-2-{3-(5-hydroxypyridin-2-yl)-2-methyl-2 ,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-4-one (44). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.90 (s, 1H), 10.87 (s, 1H), 10.16 (s, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.39-7.37 (m , 1H), 7.26-7.23 (m, 1H), 7.10 (s, 1H), 7.03-7.01 (m, 1H), 6.96-6.94 (m, 1H), 5.92-5.82 (m, 3H), 5.10-5.07 (m, 1H), 4.80-4.78 (m, 1H), 4.63-4.59 (m, 1H), 4.43-4.39 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H). MS (EI, m/z): 436.1 [MH] ^- .

Step G: Compound 44 is reduced with sodium borohydride to obtain 2-{3-(5-hydroxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]bis Ethylene oxide-6-yl}chroman-3,4,5,7-tetraol (45), the specific experimental operation was in accordance with the preparation method of step D in Example 1. MS (EI, m/z): 438.1 [MH] ^- .

Example 8: (2R,3S)-3,5,7-trihydroxy-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl- 2,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-4-one oxime (46) and (2R,3S)-4-amino-2-{ (2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane- Synthesis of 6-yl}chroman-3,5,7-triol (47).

Step A: Add (2R,3R)-3,5,7-trihydroxy-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl -2,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-4-one (500 mg, 1.04 mmol), hydroxylamine hydrochloride (94 mg, 1.35 mmol) The mixture of pyridine and pyridine (5 mL) was stirred at 70°C overnight. After the reaction, the product was purified by column chromatography (200 ~ 300 mesh silica gel, dichloromethane: methanol = 1:100 ~ 1:40 elution) to obtain (2R,3S)-3,5,7-trihydroxy- 2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]diepoxy Ethane-6-yl}chroman-4-one oxime (46) (481 mg). The yield was 93.0%. ¹ H NMR (DMSO-d6, 400 MHz) δ 11.34-11.32 (m, 1H), 11.09-10.80 (m, 1H), 9.85 (s, 1H), 9.15-9.14 (m, 1H), 7.08-6.72 ( m, 5H), 6.56-6.46 (m, 1H), 5.93-5.85 (m, 2H), 5.36-5.32 (m, 1H), 4.96-4.90 (m, 3H), 4.17-4.14 (m, 1H), 3.79-3.75 (m, 3H), 3.62-3.60 (m, 3H). MS (EI, m/z): 496.1 [MH] ^- .

Step B: The mixture containing compound 46 (100 mg, 0.207 mmol), Raney nickel (10 mg) and methanol (15 mL) was stirred under reflux under hydrogen overnight. Cool to room temperature, filter, and rinse the filter block with a small amount of ethyl acetate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, methanol: methylene chloride = 1:50 ~ 1:20 elution) to obtain (2R,3S)-4-amino-2-{ (2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane- 6-yl}chroman-3,5,7-triol (47). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.27-9.02 (m, 3H), 7.03-6.81 (m, 7H), 5.78-5.64 (m, 3H), 5.18-5.14 (m, 1H), 4.96 4.90 (m, 3H), 4.61-4.59 (m, 1H), 4.18-4.13 (m, 1H), 3.80-3.63 (m, 3H), 3.61-3.53 (m, 3H). MS (EI, m/z): 482.2 [MH] ^- .

Example 9: (2R,3S)-2-{(2R,3R)-2-hydroxymethyl-3-[3-methoxy-4-(trideuteromethoxy)phenyl]-2, Synthesis of 3-dihydrobenzo[b][1,4]dioxirane-6-yl}-5,7-bis(trideuteromethoxy)chroman-3-ol (55).

A mixture containing compound 6 (110 mg, 0.235 mmol), potassium carbonate (195 mg, 1.41 mmol), deuterated methyl iodide (136 mg, 0.938 mmol) and DMF (5 mL) was stirred at room temperature overnight. Add water (20 mL), extract with ethyl acetate (20 mL×3), wash the combined organic phase with saturated brine (10 mL×2), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: THF: methylene chloride = 1:1:40 ~ 1:1:20 elution) to obtain (2R, 3S) -2-{(2R,3R)-2-hydroxymethyl-3-[3-methoxy-4-(trideuteromethoxy)phenyl]-2,3-dihydrobenzo[b] [1,4] Dioxirane-6-yl}-5,7-bis(trideuteromethoxy)chroman-3-ol (55). ¹ H NMR (DMSO-d6, 400 MHz) δ 7.03-6.86 (m, 6H), 6.11 (d, J = 2.4 Hz, 1H), 6.03 (d, J = 2.4 Hz, 1H), 5.05 (d, J = 5.2 Hz, 1H), 4.97-4.92 (m, 2H), 4.69-4.66 (m, 1H), 4.19-4.15 (m, 1H), 3.97-3.92 (m, 1H), 3.82-3.74 (m, 4H) ), 3.55-3.51 (m, 1H), 2.69-2.65 (m, 1H), 2.46-2.40 (m, 1H). MS (ESI, m/z): 518.3 [MH] ^- .

Example 10: 2-{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]二Synthesis of oxirane-6-yl}-7-methoxy-chroman-3,4,5-triol (66).

Step A: Dissolve methyl gallate (30.0 g, 163 mmol) and N,N-diisopropylethylamine (126 g, 977 mmol) in dichloromethane (120 mL), and then add dropwise under ice water bath Chloromethyl methyl ether (52.5 g, 652 mmol), after the addition, warm to room temperature and continue stirring for 1.5 hours, add water (240 mL), separate the layers, and extract the aqueous layer with dichloromethane (50 mL×2) , The combined organic phase was washed with water (50 mL×2) and saturated brine (50 mL) successively, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether = 1:1:10 ~ 1:1:6) to obtain 3, 4, 5-tris-methoxymethoxy-benzoic acid methyl ester (56) (47.9g), the yield was 93.0%.

Step B: Suspend lithium tetrahydroaluminum (2.88 g, 75.9 mmol) in THF, slowly add a THF solution of compound 56 (20.0 g, 63.2 mmol) in an ice-salt bath. After the addition is complete, continue to heat and stir for 40 minutes . Water (3 mL), 10% sodium hydroxide solution (6 mL) and water (9 mL) were added dropwise to the reaction solution successively, stirred for 10 minutes, filtered through Celite, and dried over anhydrous sodium sulfate. Divide the solvent under reduced pressure to obtain (3,4,5-trimethoxymethoxyphenyl)methanol (57) (18.1 g), with a yield of 99.5%.

Step C: The mixture containing compound 57 (18.0 g, 62.4 mmol), chloroform (150 mL) and manganese dioxide (27.3 g, 312 mmol) was stirred overnight at 43°C, and the reaction solution was filtered through Celite. The filter residue was eluted with dichloromethane, and the solvent was evaporated under reduced pressure to obtain 3,4,5-tris-methoxymethoxy-benzaldehyde (58) (17.9 g) with a yield of 100%.

Step D: Add 2,4,6-trihydroxyacetophenone (25.6 g, 149 mmol), potassium carbonate (20.6 g, 149 mmol), dimethyl sulfate (28.1 g, 223 mmol) and acetone (250 mL) The mixture was stirred under reflux for 2 hours. The reaction solution was cooled to room temperature, filtered to remove insoluble matter, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:dichloromethane:petroleum ether = 1:1:40 ~ 1: 1:6) After elution, 1-(2,6-dihydroxy-4-methoxy-phenyl)ethanone (59) (8.51 g) was obtained. The yield was 31.4%.

Step E: Dissolve compound 59 (8.50 g, 46.7 mmol) and N,N-diisopropylethylamine (15.1 g, 117 mmol) in dichloromethane (50 ml), and then add methyl chloride dropwise under an ice water bath Methyl ether (5.63 g, 70.0 mmol), after the addition, warm to room temperature and continue stirring for 1 hour. Water (50 mL) was added, the layers were separated, the aqueous layer was washed with dichloromethane (30 mL), the combined organic phase was washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:40 ~ 1:20 elution) to obtain 1-(2-hydroxy-4-methoxy) -6-Methoxymethoxy-phenyl)ethanone (60) (8.31 g), the yield was 78.6%.

Using compound 60 as a raw material, the experimental operation of synthesizing compound 64 was performed in accordance with the preparation method of steps B, K, L, and M in Example 5 to obtain 3,5-dihydroxy-7-methoxy-2-(3,4,5 -Trihydroxy-phenyl)chroman-4-one (64) (1.70 g). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.86 (s, 1H), 8.96 (s, 2H), 8.24 (s, 1H), 6.45 (s, 2H), 6.10 (d, J = 2.4 Hz, 1H ), 6.07 (d, J = 2.4 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 4.49-4.45 (m, 1H), 3.78 (s , 3H).

Using compound 64 as a raw material, the experimental operation of synthesizing compound 65 was carried out according to the preparation method of step C in Example 1 to obtain 3,5-dihydroxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxybenzene) Yl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-7-methoxychroman-4-one (65) ¹ H NMR (DMSO-d6, 400 MHz) δ 11.85 (s, 1H), 9.23 (s, 1H), 9.16 (s, 1H), 7.00 (s, 1H), 6.86-6.77 (m, 2H), 6.11 ( s, 1H), 6.09 (d, J = 2.0 Hz, 1H), 5.87 (d, J = 2.4 Hz, 1H), 5.04 (d, J = 11.2 Hz, 1H), 4.87-4.85 (m, 2H), 4.60-4.56 (m, 1H), 4.14-4.10 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.51-3.44 (m, 3H).

Using compound 65 as a raw material, the experimental operation of synthesizing compound 66 was performed according to the preparation method of step D in Example 1 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl Group-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-7-methoxy-chroman-3,4,5-triol (66). MS (ESI, m/z): 515.2 [M+H] ⁺ .

Example 11: 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bis Synthesis of oxirane-6-yl}-7-methoxychroman-3,5-diol (67).

Using compound 66 as a raw material, the experimental procedure for synthesizing compound 67 was obtained according to the preparation method of the procedure in Example 3 (67). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.39 (s, 1H), 9.13-9.09 (m, 2H), 6.98 (s, 1H), 6.85-6.76 (m, 2H), 5.98 (d, J = 2.4 Hz, 1H), 5.89 (d, J = 2.4 Hz, 1H), 4.98 (d, J = 5.2 Hz, 1H), 4.84-4.80 (m, 2H), 4.58-4.56 (m, 1H), 4.10- 4.07 (m, 1H), 3.90-3.85 (m, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 3.49-3.45 (m, 1H), 3.41-3.38 (m, 1H), 2.66 2.61 (m, 1H), 2.43-2.37 (m, 1H). MS (ESI, m/z): 499.2 [M+H] ⁺ .

Example 12: 7-{(3-hydroxy-5,7dimethoxychroman-2-yl)-2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-2, Synthesis of 3-dihydrobenzo[b][1,4]dioxirane}-5-ol (78).

Step A: Stir a mixture containing methyl gallate (20.0 g, 109 mmol), potassium carbonate (90.1 g, 652 mmol), DMF (120 mL), and benzyl bromide (74.3 g, 434 mmol) at 40°C overnight , Add water (240 mL), extract with dichloromethane (120 mL×2), and wash the combined organic phase with water (50 mL×2) and saturated brine (50 mL) successively, and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3,4,5-tris-benzyloxy-benzoic acid methyl ester (68) (46.5 g) with a yield of 94.2%.

Using compound 68 as a raw material, the experimental operation of synthesizing compound 70 was performed in accordance with the preparation methods of steps B and C in Example 10 to obtain 3,4,5-tris-benzyloxy-benzaldehyde (70).

Using compound 70 as a raw material, the experimental operation of synthesizing compound 73 was carried out according to the preparation method of steps K, L, and M in Example 5 to obtain 3,5,7-trihydroxy-2-(3,4,5-tris-benzyloxy) -Phenyl)chroman-4one (73). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.92 (s, 1H), 10.90 (s, 1H), 7.50-7.26 (m, 15H), 7.06 (s, 2H), 5.94 (d, J = 2.0 Hz , 1H), 5.17-5.09 (m, 6H), 4.95 (s, 2H), 4.76-4.72 (m, 1H).

Using compound 73 as a raw material, the experimental operation of synthesizing compound 74 was performed in accordance with the preparation method of step D in Example 1 to obtain 2-(3,4,5-tribenzyloxy-phenyl)chroman-3,4,5,7 -Tetraol (74).

Using compound 74 as a raw material, the experimental operation of synthesizing compound 75 was performed according to the preparation method of Example 3 to obtain 2-(3,4,5-tribenzyloxy-phenyl)chroman-3,5,7-triol (75 ).

Step I: A mixture of compound 75 (1.10 g, 1.91 mmol), potassium carbonate (792 mg, 5.72 mmol), methyl iodide (682 mg, 4.77 mmol) and DMF (25 mL) was stirred at room temperature overnight. Water (50 ml) was added, extracted with ethyl acetate (25 ml×2), the combined organic phase was washed with water (50 mL×2) and saturated brine (50 mL) successively, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether = 1: 1: 20 ~ 1: 1: 8 elution) to obtain 5,7- Di-methoxy-2-(3,4,5-tris-benzyloxyphenyl)chroman-3-ol (76) (1.00 g), the yield was 86.7%.

Using compound 76 as a raw material, the experimental operation of synthesizing compound 77 was performed in accordance with the preparation method of step G in Example 5 to obtain 5-(3-hydroxy-5,7-di-methoxy-chroman-2 yl)-benzene-1, The yield of 2,3-triol (77) (500 mg) was 91.4%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.79 (s, 2H), 8.03 (s, 1H), 6.25 (s, 2H), 6.10 (d, J = 2.4 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 5.95 (d, J = 4.8 Hz, 1H), 4.53 (d, J = 6.8 Hz, 1H), 3.87-3.81 (m, 1H), 3.73 (s, 3H), 3.69 (s , 3H), 2.65-2.59 (m, 1H), 2.44-2.38 (m, 1H).

Using compound 77 as a raw material, the experimental operation of synthesizing compound 78 was performed according to the preparation method of step C in Example 1 to obtain 7-(3-hydroxy-5,7-dimethoxy-chroman-2-yl)-2-(4 -Hydroxy-3-methoxy-phenyl)-3 hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-5-ol (78). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.17-9.15 (m, 2H), 6.97 (s, 1H), 6.84-6.78 (m, 2H), 6.42 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 6.15 (d, J = 2.0 Hz, 1H), 6.03 (d, J = 2.0 Hz, 1H), 5.05 (d, J = 4.8 Hz, 1H), 4.87-4.81 (m, 2H), 4.61 (d, J = 6.8 Hz, 1H), 4.10-4.06 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 3.57- 3.51 (m, 2H), 2.64-2.58 (m, 1H), 2.45-2.39 (m, 1H). MS (ESI, m/z): 513.2 [M+H] ⁺ .

Example 13: 2-{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]二Synthesis of oxirane-6-yl}-5-methoxychroman-3, 7-diol (85).

Step A: Dissolve compound 73 (2.0 g, 3.39 mmol) and N,N-diisopropylethylamine (569 mg, 4.40 mmol) in dichloromethane (20 mL), and then add methyl chloride dropwise under an ice water bath After the addition, warm up to room temperature and continue stirring for 1 hour. Add water (20 mL), separate the layers, extract the aqueous layer with dichloromethane (10 mL×2), and use saturated brine to extract the combined organic phase. (20 mL) Wash and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:10 ~ 1:4 elution) to obtain 3,5-dihydroxy-7-methoxy Methoxy-2-(3,4,5-tribenzyloxy-phenyl)chroman 4-one (79) (1.82 g), the yield was 84.7%.

Using compound 79 as a raw material, the experimental operation of synthesizing compound 80 was performed in accordance with the preparation method of step D in Example 1 to obtain 7-methoxymethoxy-2-(3,4,5-tribenzyloxy-phenyl) color. Full -3,4,5-triol (80).

Using compound 80 as a raw material, the experimental operation of synthesizing compound 81 was performed according to the preparation method of Example 3 to obtain 7-methoxymethoxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3 , 5-diol (81).

Step D: A mixture of compound 81 (1.00 g, 1.61 mmol), potassium carbonate (267 mg, 1.93 mmol), methyl iodide (343 mg, 2.42 mmol) and DMF (10 mL) was stirred at room temperature for 5 hours. Add water (20 mL), extract with ethyl acetate (20 mL×2), wash the combined organic phase with saturated brine (20 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:15 ~ 1:6 elution) to obtain 5-methoxy-7-methoxymethyl Oxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3-ol (82) (610 mg), the yield is 59.7%. ¹ H NMR (DMSO-d6, 400 MHz) δ 7.44-7.27 (m, 15H), 6.83 (s, 2H), 6.24 (d, J = 2.4 Hz, 1H), 6.16 (d, J = 2.4 Hz, 1H ), 5.15-5.09 (m, 1H), 4.92 (s, 2H), 4.66 (d, J = 7.6 Hz, 1H), 4.05-4.00 (m, 1H), 3.75 (s, 3H), 3.65-3.57 ( m, 1H), 3.36 (s, 3H), 2.73-2.67 (m, 1H), 2.47-2.40 (m, 1H).

Step E: Stir a mixture of compound 82 (580 mg, 0.914 mmol), methanol (6 mL), tetrahydrofuran (2 mL), and concentrated hydrochloric acid (2 mL) at 40°C for 30 minutes, add water (20 mL), and acetic acid Extract with ethyl ester (20 mL×2), and wash the combined organic phase with saturated brine (20 mL) and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-methoxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3,7-diol (83) (510 mg). The yield was 98.1%.

Using compound 83 as a raw material, the experimental operation of synthesizing compound 84 was carried out according to the preparation method of step G in Example 5 to obtain 5-(3,7-dihydroxy-5-methoxychroman-2-yl)benzene-1,2, 3-Triol (84).

Using compound 84 as a raw material, the experimental operation of synthesizing compound 85 was performed according to the preparation method of step C in Example 1 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl Base-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-5-methoxychroman-3,7-diol (85). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.23 (s, 1H), 9.15 (s, 1H), 9.12 (s, 1H), 6.97 (s, 1H), 6.84-6.75 (m, 2H), 6.41 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 5.97 (d, J = 2.4 Hz, 1H), 5.85 (d, J = 2.4 Hz, 1H), 4.98 (d , J = 4.8 Hz, 1H), 4.83-4.10 (m, 2H), 4.55 (d, J = 6.8 Hz, 1H), 4.09-4.05 (m, 1H), 3.88-3.84 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.68-3.66 (m, 1H), 3.50-3.48 (m, 1H), 2.632.55 (m, 1H), 2.40-2.34 (m, 1H). MS (ESI, m/z): 497.2 [MH] ^- .

Example 14: 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bis Synthesis of oxirane-6-yl}-5,7-dimethoxychroman-3,4-diol (92).

Step A: Add 2,4,6-trihydroxyacetophenone (25.0 g, 149 mmol), potassium carbonate (20.6 g, 149 mmol), dimethyl sulfate (28.1 g, 223 mmol) and acetone (250 mL ) The mixture was stirred under reflux for 2 hours. Cool to room temperature, filter to remove insoluble materials, evaporate the solvent under reduced pressure, and purify the product by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether = 1:1:40 ~ 1:1: 6) After elution, 1-(4-hydroxy-2,6-methoxy-phenyl)ethanone (86) (16.0 g) was obtained. The yield was 54.9%.

Using compound 86 as a raw material, the experimental operation of synthesizing compound 91 was performed in accordance with the preparation method of step D in Example 1 to obtain 3-hydroxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)- 2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-5,7-dimethoxychroman-4-one (91). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.19 (s, 1H), 9.15 (s, 1H), 7.00 (s, 1H), 6.86-6.76 (m, 2H), 6.56 (d, J = 2.4 Hz , 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.36 (d, J = 4.8 Hz, 1H ), 4.97-4.85 (m, 2H), 4.29-4.26 (m, 1H), 4.11-4.09 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.51-3.49 (m, 1H), 3.47-3.46 (m, 1H). MS (ESI, m/z): 549.2 [M+Na] ⁺ .

Using compound 91 as a raw material, the experimental operation of synthesizing compound 92 was performed according to the preparation method of step D in Example 1 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl Base-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-5,7-dimethoxychroman-3,4-diol (92). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.15 (s, 1H), 9.10 (s, 1H), 6.99 (s, 1H), 6.85-6.75 (m, 2H), 6.46 (d, J = 2.0 Hz , 1H), 6.36 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H ), 5.18 (d, J = 5.6 Hz, 1H ), 4.90-4.81 (m, 2H), 4.60-4.58 (m, 2H), 4.50 (d, J = 4.4 Hz, 1H), 4.09-4.06 (m, 1H), 3.77 (s, 3H), 3.75 ( s, 3H), 3.70 (s, 3H), 3.46 to 3.43 (m, 3H). MS (ESI, m/z): 551.2 [M+Na] ⁺ .

Example 15: 7-fluoro-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1 ,4]Dioxirane-6-yl}chroman-3,4,5-triol (101) synthesis.

Step A: The compound 1,3-dimethoxy-5-fluorobenzene (6.50 g, 41.6 mmol) was dissolved in dichloromethane (65 ml), and boron tribromide (24.0 g, 24.0 g, 95.7 mmol), after the addition, warm to room temperature and continue stirring overnight. The reaction solution was added dropwise to ice water, the pH value was adjusted to 7 ~ 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine (100 mL), anhydrous Dry with sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:20 ~ 1:10 elution) to obtain 5-fluorobenzene-1,3-diol ( 93) (4.82 g), the yield was 90.4%.

Step B: A mixture of compound 93 (4.80 g, 37.5 mmol), aluminum trichloride (15.0 g, 112 mmol), and chlorobenzene (50 ml) was stirred at 45°C for 10 minutes. Acetyl chloride (4.12 g, 52.5 mmol) was slowly added dropwise to the reaction system and stirred overnight at 75°C. Add the reaction system dropwise to ice water, adjust the pH to 3~4 with 2 mol/L hydrochloric acid, add ethyl acetate (60 ml×2) for extraction, and wash the combined organic phase with saturated brine (60 mL), anhydrous sulfuric acid Sodium is dry. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:40 ~ 1:20 elution) to obtain 1-(4-fluoro-2,6-di Hydroxy-phenyl)ethanone (94) (2.48 g), the yield was 38.9%.

Using compound 94 as a raw material, the experimental operation of synthesizing compound 101 was performed according to the preparation method of steps E, F, G, H, I, J, and K in Example 10 to obtain 7-fluoro-2-{8-hydroxy-3-(4 -Hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4 ,5-Triol (101). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.91 (br, 1H), 9.21 (br, 2H), 6.98 (s, 1H), 6.94-6.76 (m, 2H), 6.48 (d, J = 1.2 Hz , 1H), 6.39 (d, J = 1.2 Hz, 1H), 6.22-6.19 (m, 1H), 6.14-6.11 (m, 1H), 5.32-5.31 (d, J = 6.0 Hz, 1H), 4.83 ( d, J = 8.0 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.64 (d, J = 8.8 Hz, 1H), 4.10-4.07 (m, 1H), 3.77 (s, 3H), 3.74-3.65 (m, 2H), 3.54-3.52 (m, 1H). MS (ESI, m/z): 501.2 [MH] ^- .

Example 16: 7-ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b] [1,4] Dioxirane-6-yl} Chroman-3, 5-diol (105) synthesis.

Step A: The mixture containing compound 81 (750 mg, 1.21 mmol), potassium carbonate (217 mg, 1.57 mmol), benzyl bromide (310 mg, 1.81 mmol) and DMF (10 mL) was stirred at room temperature overnight. Add water (20 mL), extract with ethyl acetate (20 mL×2), wash the combined organic phase with saturated brine (20 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:10 ~ 1:5 elution) to obtain 5-benzyloxy-7-methoxymethyl Oxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3-ol (102) (640 mg), the yield was 74.5%.

Using compound 102 as a raw material, the experimental operation of synthesizing compound 105 was performed according to the preparation methods of steps E, F, and G in Example 12 to obtain 7-ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methyl) Oxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,5-diol (105) . ¹ H NMR (DMSO-d6, 400 MHz) δ 9.35 (s, 1H), 9.12 (s, 1H), 9.08 (s, 1H), 6.98 (s, 1H), 6.84-6.75 (m, 2H), 6.42 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 5.96 (d, J = 2.4 Hz, 1H), 5.86 (d, J = 2.4 Hz, 1H), 4.96 (d , J = 5.2 Hz, 1H), 4.83-4.80 (m, 2H), 4.56 (d, J = 7.2 Hz, 1H), 4.09-4.04 (m, 1H), 3.90-3.78 (m, 3H), 3.77 ( s, 3H), 3.35-3.38 (m, 2H), 2.67-2.59 (m, 1H), 2.42-2.37 (m, 1H). MS (ESI, m/z): 511.3 [MH] ^- .

Example 17: 5-Ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b] [1,4] Dioxirane-6-yl} Chroman-3, 7-diol (109) synthesis.

Step A: The mixture containing compound 81 (630 mg, 1.01 mmol), potassium carbonate (182 mg, 1.32 mmol), benzyl bromide (260 mg, 1.52 mmol) and DMF (10 mL) was stirred at room temperature overnight. Add water (20 mL), extract with ethyl acetate (20 mL×2), wash the combined organic phase with saturated brine (20 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:10 ~ 1:5 elution) to obtain 5-ethoxy-7-methoxymethyl Oxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3-ol (106) (620 mg), the yield was 94.2%.

Using compound 106 as a raw material, the experimental operation of synthesizing compound 109 was performed according to the preparation method of steps E, F, and G in Example 12 to obtain 5-ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methyl) (Oxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,7-diol (109) . ¹ H NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.23 (s, 1H), 9.05 (s, 1H), 7.21 (s, 1H), 7.08-7.07 (t, 1H), 6.97 (s, 1H), 6.94-6.85 (m, 2H), 5.97 (d, J = 2.4 Hz, 1H), 5.77 (d, J = 2.4 Hz, 1H), 5.08 (d, J = 5.6 Hz, 1H) , 5.08-5.01 (m, 2H), 4.61 (d, J = 7.6 Hz, 1H), 4.35-4.30 (m, 1H), 3.94-3.88 (m, 1H), 3.83 (s, 3H), 3.69-3.67 (m, 1H), 3.65-3.43 (m, 1H), 2.79-2.74 (m, 1H), 2.45-2.39 (m, 1H). MS (ESI, m/z): 511.3 [MH]-.

Example 18: 2-{8-Bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bis Synthesis of oxirane-6-yl}chroman-3,4,5,7-tetraol (117).

Step A: Dissolve 3-methoxy-4-hydroxy (5 g, 32.9 mmol) and sodium acetate (3.23 g, 39.4 mmol) in acetic acid (25 ml), add bromine (5.78 g, 36.1 mmol) in acetic acid (5 mL). After dripping, the temperature was raised to room temperature and stirring was continued for 1.5 hours. Add a saturated solution of sodium sulfite (5 ml) and water (50 mL) to the reaction solution, and filter to obtain 3-bromo-4-hydroxy-5-methoxybenzaldehyde (110) (6.98 g) with a yield of 92.0% .

Step B: The mixture containing compound 110 (6.95 g, 30.1 mmol), aluminum trichloride (4.41 g, 33.1 mmol), pyridine (10.7 g, 135.4 mmol) and dichloromethane (50 mL) was stirred overnight under reflux. Evaporate the solvent under reduced pressure, add water (50 mL), adjust the pH to 3 ~ 4 with 2 M hydrochloric acid solution, extract with ethyl acetate (50 ml×2), and combine the organic phase with saturated brine (50 mL) Wash and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-bromo-4,5-dihydroxybenzaldehyde (111) (6.50 g) with a yield of 99.5%.

Step C: Dissolve compound 111 (6.40 g, 30.1 mmol) and N,N-diisopropylethylamine (11.4 g, 88.5 mmol) in anhydrous dichloromethane (50 mL), and add methyl chloride dropwise under an ice water bath Methyl ether (5.93 g, 73.7 mmol). After the addition, the temperature was raised to room temperature and stirring was continued for 1 hour. Water (50 mL) was added, the layers were separated, the aqueous layer was extracted with dichloromethane (50 mL), the combined organic layer was washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:50 ~ 1:20 elution) to obtain 3-bromo-4,5-dimethoxy Methoxybenzaldehyde (9.00 g) (112), the yield was 93.1%.

Using compound 112 as a raw material, the experimental operation of synthesizing compound 115 was performed according to the preparation method of steps K, L, and M in Example 5 to obtain 2-(3-bromo-4,5-dihydroxyphenyl)-3, 5,7- Trihydroxychroman-4-one (115) (2.6 g). The total yield of steps D, E, and F is 23.0%.

Using compound 115 as a raw material, the experimental operation of synthesizing compound 116 was performed according to the preparation method of step C in Example 1 to obtain 2-{8-bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl Group-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}-3,5,7-trihydroxychroman-4-one (116). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.94 (s, 1H), 10.94 (br, 1H), 9.26 (s, 1H), 7.40 (s, 1H), 7.19 (s, 1H), 7.09 (s , 1H), 6.95-6.86 (m, 2H), 5.97 (d, J = 2.4 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.16 (d, J =11.6 Hz, 1H), 5.05 (d, J = 7.2 Hz, 1H), 4.74-4.68 (m, 1H), 4.40-4.36 (m, 1H), 3.84 (s, 3H), 3.71-3.66 (m, 1H), 3.55-3.52 (m , 1H). MS (ESI, m/z): 583.0 [M+Na] ⁺ .

Using compound 116 as a raw material, the experimental operation of synthesizing compound 117 was performed according to the preparation method of step D in Example 1 to obtain 2-{8-bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl Group-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol. MS (ESI, m/z): 585.1 [M+Na] ⁺ .

Example 19: 2-{8-Bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bis Synthesis of oxirane-6-yl}chroman-3,5,7-triol (118).

Using compound 117 as a raw material, the experimental operation of synthesizing compound 118 was in accordance with the preparation method in Example 3 to obtain 2-{8-bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl -2,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol (118). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.23 (s, 1H), 9.05 (s, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 7.06 (s , 1H), 6.98-6.85 (m, 2H), 5.97 (d, J = 2.4 Hz, 1H), 5.77 (d, J = 2.4 Hz, 1H), 5.08 (d, J = 5.6 Hz, 1H), 5.03 -5.01 (m, 2H), 4.61 (d, J = 7.6 Hz, 1H), 4.35-4.30 (m, 1H), 3.94-3.88 (m, 1H), 3.83 (s, 1H), 3.69-3.65 (m , 1H), 2.79-2.74 (m, 1H), 2.45-2.39 (m, 1H). MS (ESI, m/z): 548.2 [M+Na] ⁺ .

Example 20: 2-(4-Hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-(3,5,7-trihydroxychroman-2-yl)-2,3-di Synthesis of hydrogen benzo[b][1,4]dioxirane-5-carbonitrile (119).

The mixture containing compound 118 (218 mg, 39.8 μmol), cuprous cyanide (39.2 mg, 43.8 μmol) and N-methylpyrrolidone (5 mL) was stirred at 150°C for 2 hours. Cool to room temperature, add water (15 mL), extract with ethyl acetate (15 mL×2), wash the combined organic phase with saturated brine (20 mL), and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, methanol: ethyl acetate: dichloromethane = 1:100:100 ~ 1:50:50 elution) to obtain 2-(4- Hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-(3,5,7-trihydroxychroman-2-yl)-2,3-dihydrobenzo[b][1, 4] Dioxirane-5-carbonitrile (119). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 7.12 (s, 1H), 7.00 (s, 1H), 6.88-6.79 (m, 3H), 6.04 (d, J = 2.0 Hz, 1H), 5.02-4.95 (m, 4H), 4.60-4.56 (m, 1H), 4.28-4.21 (m, 1H), 3.86-3.81 (m , 1H), 3.78 (s, 3H), 3.65-3.60 (m, 1H), 3.83 (s, 1H), 2.68-2.57 (m, 1H), 2.37-2.33 (m, 1H). MS (ESI, m/z): 494.1 [M+H] ⁺ .

Example 21: (2R,3S)-2-{2-aminomethyl-(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2,3-dihydrobenzo[ b] [1,4] Dioxirane-6-yl}chroman-3,5,7-triol (126) synthesis.

Step A: Combine compound 6 (1.50 g, 3.20 mmol), 4,4'-bismethoxytrityl chloride (DMTCl) (1.41 g, 4.16 mmol), DMAP (78.2 mg, 0.64 mmol), Et3N ( A mixture of 389 mg, 38.4 mmol) and pyridine (10 mL) was stirred at 100°C overnight. Evaporate most of the pyridine under reduced pressure, add ethyl acetate (20 mL×2) and water (20 mL) for extraction, and wash the combined organic phase with saturated brine (20 mL) and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: methylene chloride = 1:10 ~ 1:5 elution) to obtain (2R,3S)-2-{2- [Bis-(4-methoxyphenyl)phenyl-methoxymethyl]- (2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro Benzo[b][1,4]dioxirane-6-yl}chroman-3,5,7-triol (6) (1.15 g), the yield was 46.6%.

Step B: A mixture of compound 120 (1.13 g, 1.47 mmol), acetic anhydride (2.99 g, 29.3 mmol), and pyridine (5 mL) was stirred at room temperature overnight. Add ethyl acetate (20 mL×2) and water (20 mL) for extraction, and the combined organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether = 1:10:10 ~ 1:5:5 elution) to obtain 3,5- Diacetoxy-(2R,3S)-2-{(2R,3R)-3-(4-acetoxy-3-methoxyphenyl)-2-[bis-(4-methoxy Phenyl)phenyl-methoxymethyl]-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-7-yl acetate ( 121) (1.38 g). The compound was used directly in the next step without purification.

Step C: Dissolve compound 121 (1.38 g, 1.47 mmol) in dichloromethane (10 mL), add 10% formic acid in dichloromethane (10 mL), stir at room temperature for 1 hour, add water (20 mL) for extraction , The aqueous phase was washed with dichloromethane (10 mL), the combined organic phase was washed with saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:10 ~ 1:5 elution) to obtain 3,5-diacetoxy-( 2R,3S)-2-{(2R,3R)-3- (4-acetoxy-3-methoxyphenyl)-2-hydroxymethyl]-2,3-dihydrobenzo[b ][1,4]Dioxirane-6-yl}chroman-7-yl acetate (122) (855 mg), the yield was 91.4%.

Step D: Dissolve compound 122 (850 mg, 1.34 mmol) and Et3N (176 mg, 1.74 mmol) in dichloromethane (10 mL), and add methylsulfonate chloride (184 mg, 1.60 mmol) dropwise under ice bath. Dichloromethane solution (2 mL), stirring at room temperature for 1 hour, adding water (20 mL) for extraction, washing the aqueous phase with dichloromethane (10 mL), washing the combined organic phase with saturated brine, and drying with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:10 ~ 1:6 elution) to obtain 3,5-diacetoxy-( 2R,3S)-2-((2R,3R)-3- (4-acetoxy-3-methoxyphenyl)-2-methanesulfonyloxymethyl-2,3-dihydrobenzene And [b][1,4]dioxirane-6-yl}chroman-7-yl acetate (123) (905 mg), the yield was 94.9%.

Step E: Stir a mixture of compound 123 (300 mg, 420 μmol), NaN3 (81.9 mg, 1.26 mmol), and DMF (5 mL) at 70°C overnight, and add ethyl acetate (15 mL×2) and water ( 15 mL) extraction, the combined organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:10 ~ 1:5 elution) to obtain 3,5-diacetoxy-( 2R,3S)-2-{(2R,3R)-3- (4-acetoxy-3-methoxyphenyl)-2-azidomethyl-2,3-dihydrobenzo[ b] [1,4] Dioxirane-6-yl}chroman-7-yl acetate (124) (125 mg), the yield was 45.0%.

Step F: Stir a mixture of compound 124 (120 mg, 181 μmol), concentrated hydrochloric acid (1 mL), and EtOH (4 mL) at 50°C for 0.5 hours. Add ethyl acetate (10 mL×2) and water (10 mL). mL) extraction, the combined organic phase was washed with saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:5 ~ 1:3 elution) to obtain (2R,3S)-2-{2- Azidomethyl-(2R,3R)-3-(4-acetoxy-3-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]diepoxy Ethane-6-yl}chroman-3,5,7-triol (125) (55.0 mg), the yield was 61.5%.

Step G: A mixture of compound 125 (50 mg, 101 μmol), Pd/C (5 mg), and methanol (3 mL) was stirred overnight at room temperature. Filtered on a pad of Celite, the filtrate was evaporated under reduced pressure to remove the solvent, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:3 ~ 2:1 elution) to obtain (2R, 3S) )-2-{2-Aminomethyl- (2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]二Ethylene oxide-6-yl}chroman-3,5,7-triol (126). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 9.07 (s, 1H), 8.93 (s, 1H), 7.01 (s, 1H), 6.94-6.80 (m, 2H), 5.90 (d, J = 2.0 Hz, 1H), 5.70 (d, J = 2.0 Hz, 1H), 4.94 (br, 1H), 4.87 (d, J = 8.0 Hz, 1H), 4.58 (d, J = 5.6 Hz , 1H), 4.18-4.15 (m, 1H), 3.89-3.86 (m, 1H), 3.79 (s, 3H), 3.76-3.74 (m, 1H), 2.74 (br, 2H), 2.69-2.65 (m , 1H), 2.41-2.35 (m, 1H). MS (ESI, m/z): 466.2 [MH] ^- .

Example 22: 2-{8hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bicyclo Synthesis of oxyethane-6-yl}chroman-3,4,6,7-tetraol (136).

Step A: Dissolve 2,4,5-trimethoxybenzaldehyde (6.00 g, 30.6 mmol) in anhydrous THF (50 mL), and add methylmagnesium bromide in THF (3.0M, 13.3 mL, 39.8mmol), after the addition, continue to stir for 2 hours under an ice-salt bath. It was quenched with water (100 mL), and ethyl acetate (50 mL×2) was added for extraction. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:20 ~ 1:6 elution) to obtain 1-(2,4,5-trimethoxy) Phenyl)ethanol (127) (4.66 g), the yield was 71.8%.

Step B: A mixture of compound 127 (4.65 g, 21.9 mmol), MnO2 (9.52 g, 110 mmol), and dichloromethane (35 mL) was refluxed overnight. The reaction solution was filtered through Celite, the filtrate was evaporated under reduced pressure to remove the solvent, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:15 ~ 1:10 elution) to obtain 1-( 2,4,5-Trimethoxyphenyl)ethanone (128) (2.33 g), the yield was 50.5%.

Step C: Dissolve compound 128 in dichloromethane (20 mL), protect with N2, add BBr3 dropwise under ice bath, and stir overnight at room temperature after addition. Pour the reaction solution into crushed ice, adjust the pH value to 4~5 with 2N NaOH solution, add ethyl acetate (50 mL×2) for extraction, wash the combined organic phase with saturated brine, and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:5 ~ 1:1 elution) to obtain 1-(2,4,5-trihydroxy) Phenyl) ethanone (129) (1.41 g), the yield was 76.6%.

Using compound 129 as a raw material, the experimental operation of synthesizing compound 131 was carried out according to the preparation methods of steps A and B in Example 5 to obtain 1-(2,4,5-trimethoxymethoxyphenyl)ethanone (131) (1.82) g).

Using compound 131 as a raw material, the experimental operation of synthesizing compound 135 was carried out according to the preparation method of steps G, H, I, and J in Example 10 to obtain 3,6,7-trihydroxy-2-{3-(4-hydroxy-3- Methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-4-one(135)(150 mg).

Using compound 135 as a raw material, the experimental operation of synthesizing compound 136 was performed according to the preparation method of step D in Example 1 to obtain 2-{8hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl -2,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,6,7-tetraol (136). MS (ESI, m/z): 499.1 [MH] ^- .

Example 23: 2-{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bis Synthesis of oxirane-6-yl}chroman-3,6,7-triol (137).

Using compound 136 as a raw material, the experimental operation of synthesizing compound 137 was performed according to the preparation method in Example 3 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2 ,3-Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,6,7-triol (137). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.12 (s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 7.01 (s, 1H), 7.00-6.79 (m, 2H), 6.46-6.38 (t, 2H), 6.24 (s, 1H), 4.93 (d, J = 5.6 Hz, 1H), 4.92-4.83 (m, 2H), 4.50 (d, J = 7.2 Hz, 1H), 4.12-4.09 (m, 1H), 3.89-3.88 (m, 1H), 3.87 (s, 3H), 3.50-3.48 (m, 1H), 3.44-3.43 (m, 1H), 2.75 2.71 (m, 1H), 2.62-2.58 (m, 1H). MS (ESI, m/z): 483.2 [MH] ^- .

Example 24: 2-{3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane Synthesis of -6-yl}chroman-3,6,7-triol (140).

Step A: A mixture of compound 122 (130 mg, 204 μmol), Et3N (31.0 mg, 306 μmol), MsCl (30.4 mg, 265 μmol), and dichloromethane (3 mL) was stirred at room temperature for 1.5 hours. Dichloromethane (10 mL×2) and water were added for extraction, and the combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3,7-diethyloxy-(2R,3S)-2-{(2R,3R)-3-(4-acetoxy-3-methoxyphenyl) -2-Methanesulfonyloxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-5-yl acetate (138) ( 143 mg), used directly in the next step without purification.

Step B: Stir a mixture of compound 138 (140 mg, 196 μmol), TMSCN (311 mg, 314 mmol), TBAF (666 mg, 255 mmol), THF (3 mL), and acetonitrile (3 mL) at 80°C overnight. Cooled to room temperature, added ethyl acetate (10 mL×2) and water (10 mL) for extraction, the combined organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether = 1:1:15 ~ 1:1:5 elution) to obtain 3,7- Diacetoxy-(2R,3S)-2-{(2R,3R)-3-(4-acetoxy-3-methoxyphenyl)-2-cyanomethyl-2,3 -Dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-5-yl acetate (139) (120 mg).

Step C: The mixture of compound 139 (110 mg, 170 μmol) and 4M NaOH aqueous solution (mL) was stirred overnight at 80°C. Adjust the pH to 3~4 with 2 N hydrochloric acid, add ethyl acetate (10 mL×2) and water (10 mL) for extraction, wash the combined organic phase with saturated brine, and dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with ethyl acetate) to obtain {(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)- 6-(3,5,7-Trihydroxychroman-2-yl)-2,3-dihydrobenzo[b][1,4]dioxiran-2-yl}acetic acid (140). MS (ESI, m/z): 495.1 [MH] ^- .

Example 25: Determination of compound solubility

1. Test materials

The test compounds were 7, 67 and 85, respectively; the control compound was silibinin, purchased from Shanghai Dibai Biotechnology Co., Ltd., and the batch number was HH06. Both the test compound and the control compound were prepared as 10 mM stock solutions using DMSO. Phosphate buffered saline (PBS), with pH values of 4.0 and 7.4, was used to test the solubility of the test compound.

2. Test method

Treatment of test compound and control compound: Add 30 μL of test compound or control compound stock solution (10 mM) per well in a special solubility sample plate, and then add 970 μL of PBS with different pH values to each well. Respectively 4.0 and 7.4), the test set up repeated holes. Add a stir bar to each hole and cover with a Teflon or silicone plug. Stir at 1100 rpm for 2 hours at 25°C. Take 10 μL of sample from each well, then add 990 μL of water and acetonitrile mixture (including internal standard substance) to mix well, and then filter with a filter plate.

Standard treatment: 10 mM stock solution is diluted with DMSO to 300 μM, and then 10 μL of compound diluent is taken, and 990 μL of water and acetonitrile mixture (including internal standard substance) are added to mix well, and the final concentration is 3 μM. Standard solution.

The solubility sample plate is placed in the autosampler, and the LC-MS/MS method is used for analysis. The concentration of the test compound is calculated from the response value of the test compound and standard, and the concentration of the standard.

3. Test results

As shown in Table 1, in the PBS buffer solution at pH 4.0 and 7.4, the solubility of test compounds 7, 67 and 85 in the PBS buffer solution was significantly higher than that of silibinin. Table 1. Solubility of compounds in different pH buffer solutions Compound Solubility (μM) pH = 4.0 pH = 7.4 7 209.07 213.74 67 148.15 146.17 85 159.84 150.47 Silybin 1.08 15.00

The poor solubility of silybin has caused the problem of low bioavailability. The solubility of compounds 7, 67 and 85 has been significantly improved, which may increase the absorption of these compounds in the body, thereby increasing the bioavailability of the compounds Degree, thereby improving the pharmacological activity of the compound.

Example 26: Test of the fat reduction or elimination effect of the compound on zebrafish non-alcoholic fatty liver

1. Test materials

1. Test compound

Test compounds 4, 5, 6, 7, 46, 67, 78, 85, 92, and 101 were prepared with DMSO to prepare 40 mM mother liquors for later use, and stored in a refrigerator at -20 ℃. The positive control compound S-adenosylmethionine (hereinafter referred to as SAM) was purchased from Aladdin Reagent (Shanghai) Co., Ltd., the batch number is F1523051, and it was prepared into a 50 mM mother liquor with DMSO for use. The reference compound silibinin was purchased from Shanghai Dibo Biotechnology Co., Ltd., the batch number is EE09, and it was prepared into a 40 mM mother liquor with DMSO for use. Thioacetamide was purchased from Sigma-Aldrich, the batch number is BCBV3031, and it was prepared into a 1 M mother liquor with DMSO for later use. Oil Red O was purchased from Sigma-Aldrich, the batch number is SLBP5248V. 4% paraformaldehyde was purchased from Dingguo Biotechnology Co., Ltd., batch number 773001800. Propylene glycol was purchased from Sinopharm Chemical Reagent Co., Ltd., batch number 20170615.

2. Experimental animals

The melanin allele mutant translucent Albino strain of zebrafish is reproduced in natural paired mating. The fish age was 3 days after fertilization, and each experimental group had 30 fish.

The above zebrafish were raised in fish farming water at 28 ℃ (water quality: 200 mg instant sea salt is added to 1 L of reverse osmosis water, the conductivity is 480-510 μS/cm; the pH is 6.9-7.2; the hardness is 53.7-71.6 mg /L CaCO3), the experimental animal use license number is: SYXK (Zhejiang) 2012-0171. Feeding management meets the requirements of international AAALAC certification.

2. Test method

1. The establishment of non-alcoholic fatty liver model in zebrafish

Randomly select the normal melanin allele mutant translucent Albino strain zebrafish 3 days after fertilization and place them in a six-well plate with 30 fish per well (that is, each experimental group), and then use a final concentration of 7 mM thioacetate Zebrafish were treated with amide for 72 hours to establish a zebrafish non-alcoholic fatty liver model.

2. Evaluation of the efficacy of the test compound

The zebrafish were transferred to a six-well plate, with 30 fish per well (that is, each experimental group) at random. Using thioacetamide to induce zebrafish to establish a non-alcoholic fatty liver model. 40 mM test compounds 4, 5, 6, 7, 46, 67, 78, 85, 92, and 101 were quantitatively transferred to a six-well plate, and diluted with water to the corresponding concentration. Among them, test compounds 4, 5, 6 and 7 were formulated into two dose groups with a final concentration of 100 µM and 200 µM, respectively; test compound 46 was formulated into a dose group with a final concentration of 200 µM; test compound 67, 78, 85, 92 and 101 were formulated into a dose group with a final concentration of 100 µM; 50 mM positive control SAM was formulated with water to a final concentration of 50 μM, and a 40 mM positive control silybin was formulated with water Formulated into two concentration dose groups with final concentrations of 100 µM and 200 µM, and set up a normal control group (zebrafish treated with fish farming water) and a model control group, with a total liquid volume of 3 mL per well. Except for the normal control group, the other experimental groups were treated with thioacetamide for 72 hours and then stained with oil red O. After staining, 10 zebrafish were randomly selected from each experimental group and photographed under a dissecting microscope with NIS -Elements D 3.10 Advanced image processing software performs image analysis and collects data, analyzes and counts the total optical density of zebrafish liver fat (S). The inhibitory effect of each experimental group on zebrafish liver steatosis is evaluated by the following calculation formula. The compound's inhibition rate of zebrafish liver steatosis is %, and the statistical processing result is expressed as mean ± SE:

Inhibition rate of liver steatosis (%)=[S(model control group)-S(test compound group)]/[S(model control group)-S(normal control group)]×100%

Statistical analysis was performed using analysis of variance and Dunnett’s T-test, and p>0.05 indicated a significant difference. The inhibition rate of hepatic steatosis represents the degree of reduction of the zebrafish liver fat by the test compound after modeling. The larger the value, the more obvious the reduction or elimination effect of the test compound on liver fat.

3. Test results

As shown in Table 2 and Table 3, the average value of the total optical density of zebrafish liver fat in the model control group is 22816, which is significantly greater than the average value of the normal control group (17734). The statistical analysis between the model control group and the normal control group shows , P value>0.001, indicating that the model is established successfully. Compared with the model control group by the sum of zebrafish liver fat optical density, the positive control SAM (50 µM) inhibited zebrafish liver steatosis by 89% (p value> 0.001); silybin was at the concentration of 100 µM and 200 µM. At µM, the inhibition rates of zebrafish liver steatosis were 49% and 69%, and the relevant p values were >0.05 and >0.01, respectively. It shows that both the positive controls SAM and silibinin have protective effects on zebrafish non-alcoholic fatty liver.

The test results are shown in Table 2 and Figure 1. When the test compounds 4, 5, 6 and 7 have a concentration of 200 µM, the inhibition rates of hepatic steatosis in zebrafish after modeling are 99%, 86%, and 92%, respectively. And 93%, the lipid droplets (oil red O staining) in the liver of the test compound zebrafish in each group were significantly reduced, while at the same concentration, the positive control silybin inhibited only 69%. The test results show that at a concentration of 200 µM, the test compounds 4, 5, 6, 7 and 46 have a significant therapeutic effect on zebrafish non-alcoholic fatty liver, and have a fat reduction or elimination effect on zebrafish non-alcoholic fatty liver. Far better than silibinin. Table 2. The inhibitory effects of test compounds and silibinin on zebrafish liver steatosis at a concentration of 200 µM (SAM concentration is 50 µM, n=10) Group The total optical density of liver fat (picture element, mean ± SE ) Inhibition rate of liver steatosis % Normal control group 17734 ± 532 - Model control group 22816 ± 910 - 4 17802 ± 487 99*** 5 18452 ± 795 86** 6 18157 ± 572 92*** 7 18090 ± 437 93*** 46 19767 ± 814 60* S- adenosylmethionine 18301 ± 783*** 89*** Silybin 19300 ± 502** 69** Compared with the model control group, ^* p> 0.05, ^** p> 0.01, ^*** p> 0.001

The inhibitory rates of test compounds 4, 5, 7, 67, 85, 92 and 101 at the concentration of 100 µM on the fatty degeneration of the zebrafish liver after modeling were 83%, 84%, 98%,>100%,> 100, respectively. %, 98% and 93%, the lipid droplets (oil red O staining) in the liver of the test compound zebrafish in each group were significantly reduced, while the positive control silibinin inhibited only 49%, indicating that these compounds are effective against The fat reduction or elimination effect of zebrafish non-alcoholic fatty liver is far better than silibinin. At a concentration of 100 µM, the test compounds 4, 5, 6, 7, 67, 78, 85, 92 and 101 have significant therapeutic effects on zebrafish non-alcoholic fatty liver. The test results are shown in Table 3 and Figure 2. Table 3. The inhibitory effects of test compounds and silibinin on zebrafish liver steatosis at a concentration of 100 µM (SAM concentration is 50 µM, n=10) Group The total optical density of liver fat (picture element, mean ± SE ) Inhibition rate of liver steatosis % Normal control group 17734 ± 532 - Model control group 22816 ± 910 - 4 18598 ± 608 83** 5 18496 ± 862 85** 6 19868 ± 556 58* 7 17835 ± 351 98*** 67 16667 ± 469 >100*** 78 19665 ± 1330 62** 85 17378 ± 710 >100*** 92 17836 ± 639 98*** 101 18090 ± 837 93*** S- adenosylmethionine 18301 ± 783*** 89*** Silybin 20326 ± 924* 49* Compared with the model control group, ^* p> 0.05, ^** p> 0.01, ^*** p> 0.001

The test results show that some of the compounds 4, 5, 7, 67, 85, 92 and 101 involved in this patent have significantly higher inhibition rates of liver steatosis than silibinin, and show extremely excellent treatment for zebrafish non-alcoholic fatty liver. effect.

Example 27: Evaluation of the efficacy of the compound on non-alcoholic steatohepatitis (NASH) mice

1. Test materials

1. Test compound and solution preparation

The test compounds were 4 and 7 respectively; the positive control was silibinin, purchased from Shanghai Dibai Biotechnology Co., Ltd., and the batch number was HH06.

Low-dose group (35 mg/kg) solution preparation: accurately weigh a quantitative test compound, add a certain amount of physiological saline, and prepare the oral suspension solution with a concentration of 3.5 mg/mL. The administration volume is 10 mL/kg body weight.

High-dose group (70 mg/kg) solution preparation: accurately weigh a quantitative test compound, add a certain amount of physiological saline, and prepare the oral suspension solution with a concentration of 7.0 mg/mL. The administration volume is 10 mL/kg body weight.

2. Modeling feed

High-fat feed: basic feed ingredients are corn, flour, imported fish meal, soybean meal, secondary meal, yeast meal, soybean oil, etc. The high-fat feed is a 73.6% basic feed with 10% lard, 10% egg yolk powder, 5% sucrose, 1.2% cholesterol and 0.2% pig bile salt.

3. Experimental animals

Source, strain, strain: C57BL/6 mice, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Nanjing Branch (Experimental animal production license: SCXK (苏) 2016-0003); Laboratory animal use license: SYXK (Army) 2012-0049; Week age: 6-8 weeks at the start of dosing; Weight: 18-22 g; Gender: half male and half.

Four, test method

After 3 days of adaptive feeding of mice with normal feed, they were randomly assigned according to body weight: 8 mice were fed with normal feed and set as normal control group (NC); other mice were fed with high-fat feed until the end of the experiment. The mice were weighed and recorded every 3 days. The mice were fed with high-fat diet for 56 days (8 weeks) to make the model, and the mice were taken blood from the orbital vein to detect the blood biochemical indicators to identify whether the model was successful.

After successful modeling, the mice in the high-fat diet group were randomly divided into 6 groups, each with 8 animals, namely the model group, the compound 4 low-dose group, the compound 4 high-dose group, the compound 7 low-dose group, and the compound 7 high-dose group. The positive silibinin group and the high-dose silibinin group were administered intragastrically according to the animal’s body weight every day for 28 consecutive days (4 weeks). At the same time, during the administration period, the animals in each administration group and model group continued to be fed with high-fat feed until the end of the experiment. The normal control group was given a corresponding volume of saline.

On the last day of the experiment, the mice in each group were fasted for 8 hours, and blood was taken from the orbit, and the serum was separated. After the serum was separated, the mice were stored at -20°C. After blood collection, the mice were sacrificed, the liver was quickly separated, weighed, and stored in a refrigerator at -80°C. Serum samples and liver tissue samples were subjected to serum triglyceride (TG), serum total cholesterol (TC), serum high-density lipoprotein (HDL-C), serum low-density lipoprotein (LDL-C), serum alanine aminotransferase ( ALT), serum aspartate aminotransferase (AST), serum tumor necrosis factor α (TNFα), liver triglycerides (TG), liver total cholesterol (TC), liver malondialdehyde (MDA), liver superoxide dismutase (SOD) ) And other biochemical indicators; in addition, some mouse livers in the blank control group, model group, compound 7 low-dose group, and silibinin high-dose group were fixed in neutral formaldehyde fixative, and HE staining was performed on the liver. The tissue is analyzed for pathology.

3. Test results

As shown in Table 4, Table 5, Table 6, and Table 7, the high-fat diet was used to feed C57BL/6 mice. After 3 months of modeling, the liver coefficient of the model group was significantly higher than that of the blank control group (p >0.01), the serum indexes (TC, TG, LDL-C, ALT, AST and TNFα) and liver tissue indexes (TC, TG, MDA and SOD) of the model group are significantly different from those of the blank control group (p >0.01). Compared with the model group, the positive compound silibinin was administered continuously by intragastric administration at 70 mg/kg for 1 month, which can significantly reduce the blood levels of ALT, AST, LDL-C and TNFα, and at the same time significantly reduce the TC in liver tissues. The levels of TG and MDA increased the activity of SOD (all p>0.01), and the liver coefficient decreased significantly (p>0.05), indicating that the positive compound silibinin has a certain therapeutic effect on NASH mice.

± SD) 組別 給藥劑量 (mg/kg/day) 肝重 (g) 肝臟係數 正常組 - 1.12±0.07^** 4.20±0.30^** 模式組 - 1.84±0.09 5.57±0.84 化合物 4 低劑量組 35 1.39±0.03^** 4.43±0.31^* 化合物 4 高劑量組 70 1.43±0.03^** 4.54±0.33^* 化合物 7 低劑量組 35 1. 40±0.05^** 4.53±0.38^* 化合物 7 高劑量組 70 1.41±0.02^** 4.51±0.28^* 水飛薊賓 70 1.40±0.06^** 4.58±0.40^* 註：與模式組比較，^* p >0.05，^** p >0.01；肝臟係數(%)=肝臟重量/體重*100% 表5. 化合物對NASH小鼠血生化指標中TC、TG、HDL-C和LDL-C的影響 (

± SD) 組別 給藥劑量 (mg/kg/day) TC (mmol/L) TG (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) 正常組 - 2.50±0.12^* 1.09±0.20^** 0.99±0.52 0.61±0.33^** 模式組 - 3.66±1.23 1.69±0.40 0.68±0.21 2.86±0.51 化合物 4 低劑量組 35 2.59±0.32 1.18±0.02^* 0.95±0.33 2.55±0.50 化合物 4 高劑量組 70 2.58±0.30 1.24±0.16^* 0.97±0.37 2.13±0.54^* 化合物 7 低劑量組 35 2.59±0.38 1.13±0.06^* 0.83±0.35 1. 95±0.50^** 化合物 7 高劑量組 70 2.63±0.81 1.11±0.07^** 0.89±0.46 1.85±0.37^** 水飛薊賓 70 2.75±0.84 1.16±0.22^* 0.85±0.48 1.91±0.35^** 註：與模式組比較，^* p >0.05，^** p >0.01。 表6. 化合物對NASH小鼠血生化指標中ALT、AST和TNF-α的影響 (

± SD) 組別 給藥劑量 (mg/kg/day) ALT (U/L) AST (U/L) TNF-α (ng/L) 正常組 - 52.12±30.39^** 46.84±5.02^** 359.38±9.92^** 模式組 - 220.24±59.28 288.50±86.43 471.04±13.09 化合物4 低劑量組 35 89.08±18.93^** 140.13±13.93^** 414.20±13.46^* 化合物4 高劑量組 70 98.29±75.07^** 120.04±12.55^** 415.80±13.54^** 化合物7 低劑量組 35 63.03±30.59^** 115.16±13.42^** 414.26±11.57^** 化合物7 高劑量組 70 75.75±27.48^** 123.61±5.41^** 425.80±9.77^** 水飛薊賓 70 103.33±26.43^** 127.39±7.75^** 423.36±8.73^** 註：與模式組比較，^* p >0.05，^** p >0.01。 表7. 化合物對NASH小鼠肝臟組織生化指標的影響 (

± SD) 組別 給藥劑量 (mg/kg/day) TC (mmol/L) TG (mmol/L) MDA (nmol/mg) SOD (U/mg) 正常組 - 1.20±0.13^** 1.04±0.03^** 2.27±0.39^** 21.83±2.01^** 模式組 - 2.54±0.19 1.52±0.07 3.60±0.52 14.72±4.53 化合物4 低劑量組 35 1.51±0.06^** 1.21±0.05^** 2.91±0.42^** 18.08±3.90 化合物4 高劑量組 70 1.51±0.11^** 1.18±0.06^** 2.80±0.21^** 17.42±4.16 化合物7 低劑量組 35 1.53±0.06^** 1.22±0.06^** 2.84±0.24^** 18.54±4.41 化合物7 高劑量組 70 1.54±0.09^** 1.25±0.06^** 2.79±0.21^** 19.44±3.11^* 水飛薊賓組 70 1.55±0.08^** 1.24±0.05^** 2.69±0.22^** 24.89±6.09^** 註：與模式組比較，^* p >0.05，^** p >0.01。Compounds 4 and 7 were administered by intragastric administration at 35 or 70 mg/kg for 1 month, respectively. Compared with the model group, the ALT and AST levels in the blood were significantly reduced. At the same time, the TC, TG and MDA in the liver tissue were also affected. Significant improvement effect (all p values> 0.01), and can significantly reduce the expression level of inflammatory factor TNFα; compound 7 can also significantly reduce the level of TG and LDL-C in the blood, and its low-dose group can also significantly increase the activity of SOD ( p>0.05). Table 4. Effects of compounds on liver weight and liver coefficient in NASH mice with non-alcoholic steatohepatitis (

± SD) Group Dosage (mg/kg/day) Liver weight (g) Liver coefficient normal group - 1.12±0.07 ^** 4.20±0.30 ^** Pattern group - 1.84±0.09 5.57±0.84 Compound 4 low-dose group 35 1.39±0.03 ^** 4.43±0.31 ^* Compound 4 high-dose group 70 1.43±0.03 ^** 4.54±0.33 ^* Compound 7 low-dose group 35 1. 40±0.05 ^** 4.53±0.38 ^* Compound 7 high dose group 70 1.41±0.02 ^** 4.51±0.28 ^* Silybin 70 1.40±0.06 ^** 4.58±0.40 ^* Note: Compared with the model group, ^* p>0.05, ^** p>0.01; liver coefficient (%)=liver weight/body weight*100% Table 5. Compounds in the blood biochemical indicators of NASH mice TC, TG, HDL-C And the influence of LDL-C (

± SD) Group Dosage (mg/kg/day) TC (mmol/L) TG (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) normal group - 2.50±0.12 ^* 1.09±0.20 ^** 0.99±0.52 0.61±0.33 ^** Pattern group - 3.66±1.23 1.69±0.40 0.68±0.21 2.86±0.51 Compound 4 low-dose group 35 2.59±0.32 1.18±0.02 ^* 0.95±0.33 2.55±0.50 Compound 4 high-dose group 70 2.58±0.30 1.24±0.16 ^* 0.97±0.37 2.13±0.54 ^* Compound 7 low-dose group 35 2.59±0.38 1.13±0.06 ^* 0.83±0.35 1. 95±0.50 ^** Compound 7 high dose group 70 2.63±0.81 1.11±0.07 ^** 0.89±0.46 1.85±0.37 ^** Silybin 70 2.75±0.84 1.16±0.22 ^* 0.85±0.48 1.91±0.35 ^** Note: Compared with the model group, ^* p>0.05, ^** p>0.01. Table 6. Effects of compounds on ALT, AST and TNF-α in blood biochemical indexes of NASH mice (

± SD) Group Dosage (mg/kg/day) ALT (U/L) AST (U/L) TNF-α (ng/L) normal group - 52.12±30.39 ^** 46.84±5.02 ^** 359.38±9.92 ^** Pattern group - 220.24±59.28 288.50±86.43 471.04±13.09 Compound 4 low-dose group 35 89.08±18.93 ^** 140.13±13.93 ^** 414.20±13.46 ^* Compound 4 high-dose group 70 98.29±75.07 ^** 120.04±12.55 ^** 415.80±13.54 ^** Compound 7 low-dose group 35 63.03±30.59 ^** 115.16±13.42 ^** 414.26±11.57 ^** Compound 7 high dose group 70 75.75±27.48 ^** 123.61±5.41 ^** 425.80±9.77 ^** Silybin 70 103.33±26.43 ^** 127.39±7.75 ^** 423.36±8.73 ^** Note: Compared with the model group, ^* p>0.05, ^** p>0.01. Table 7. Effects of compounds on biochemical indicators of liver tissue in NASH mice (

± SD) Group Dosage (mg/kg/day) TC (mmol/L) TG (mmol/L) MDA (nmol/mg) SOD (U/mg) normal group - 1.20±0.13 ^** 1.04±0.03 ^** 2.27±0.39 ^** 21.83±2.01 ^** Pattern group - 2.54±0.19 1.52±0.07 3.60±0.52 14.72±4.53 Compound 4 low-dose group 35 1.51±0.06 ^** 1.21±0.05 ^** 2.91±0.42 ^** 18.08±3.90 Compound 4 high-dose group 70 1.51±0.11 ^** 1.18±0.06 ^** 2.80±0.21 ^** 17.42±4.16 Compound 7 low-dose group 35 1.53±0.06 ^** 1.22±0.06 ^** 2.84±0.24 ^** 18.54±4.41 Compound 7 high dose group 70 1.54±0.09 ^** 1.25±0.06 ^** 2.79±0.21 ^** 19.44±3.11 ^* Silybin group 70 1.55±0.08 ^** 1.24±0.05 ^** 2.69±0.22 ^** 24.89±6.09 ^** Note: Compared with the model group, ^* p>0.05, ^** p>0.01.

The histopathological results of the NASH mouse model group (Figure 3) showed that the liver cells of the model group had obvious steatosis and necrosis, and there were inflammatory cell foci, which indicated that the NASH model was successfully established. However, there were no lipid droplet vacuoles caused by steatosis in the mouse liver cells of the compound 7 low-dose group, and there were very few inflammatory cells in the liver tissues of individual mice. Therefore, it is shown that compound 7 can effectively improve the lipidation degree of liver tissue of NASH mice and reduce inflammation.

The test results show that some of the compounds 4 and 7 involved in this patent have significant therapeutic effects on non-alcoholic steatohepatitis in mice.

Example 28: Acute Toxicity Test of Compound Single Administration in Mice

1. Test materials

1. Test compound and solution preparation

The test compound was compound 7; the positive control was silibinin, purchased from Shanghai Dibai Biotechnology Co., Ltd., and the batch number was HH06. Immediately before use, the suspension was prepared with normal saline and ultrasound to prepare the corresponding concentration of the suspension.

Low-dose group (1.5 g/kg) solution preparation: accurately weigh a quantitative test compound 7 or positive control, add a certain amount of physiological saline, sonicate until the dispersion is uniform, and prepare an oral mixture with a concentration of 75 mg/mL Suspension. The administration volume is 20 mL/kg.

High-dose group (3.0 g/kg) solution preparation: accurately weigh a quantitative test compound 7 or positive control, add a certain amount of normal saline, sonicate until the dispersion is uniform, and prepare a concentration of 150 mg/mL for oral suspension liquid. The administration volume is 20 mL/kg.

2. Experimental animals and breeding conditions

ICR mice, SPF grade, weight: 16-18 g, 6-8 weeks old. Provided by Nantong University, laboratory animal production license number: SCXK (苏) 2014-0001); laboratory animal use license: SYXK (苏) 2017-0007.

2. Test method

16 ICR mice were randomly divided into compound 7 low-dose group, compound 7 high-dose group, silibinin low-dose group, and silibinin high-dose group. Each group has 4 mice, half male and half, fasted for 6 One hour later, the compound 7 suspension or silibinin suspension was given by single gavage at 20 mL/kg.

3. Test results

The dosage and mortality of each group of mice are shown in Table 8. No immediate toxicity was seen in each administration group after administration, and no delayed toxicity was seen during the observation period from 24 hours to 14 days. The animals were in good condition and all the mice survived. The maximum tolerated dose of compound 7 and silibinin in the acute toxicity test in mice was 3 g/kg. Table 8. Dosage and mortality of ICR mice Group Number of animals (only) Dosage ( g/kg ) Concentration ( mg/mL ) Dosing volume ( mL/kg ) mortality rate Compound 7 low-dose group 4 1.5 75 20 0/4 Compound 7 high dose group 4 3.0 150 20 0/4 Silibinin low-dose group 4 1.5 75 20 0/4 Silybin high-dose group 4 3.0 150 20 0/4

When combined with the accompanying drawings, the above and other objectives and features of the present invention will become apparent from the following description of the invention, in which: Figure 1 is a microscopic photograph of zebrafish oil red O staining after administration of each test compound. In the figure, the dotted area shows the liver, a is the normal control group, b is the model control group, c is the positive control S-adenosylmethionine group (50 µM), and d is the positive control Silybum marianum Bin group (200 µM), e is compound 4 group (200 µM), f is compound 6 group (200 µM), g is compound 7 group (200 µM); Figure 2 is a microscopic photograph of zebrafish oil red O staining after administration of each test compound. In the figure, the dotted area shows the liver, a is the normal control group, b is the model control group, c is the positive control S-adenosylmethionine group (50 µM), and d is the positive control Silybum marianum Bin group (100 µM), e is compound 4 group (100 µM), f is compound 6 group (100 µM), g is compound 7 group (100 µM), h is compound 67 group (100 µM), i is compound 85 group (100 µM), j is compound 92 group (100 µM); Figure 3 is a photo of histopathological staining (HE staining, 400×). In the figure, A is the blank control group; B is the model group; C is the compound 7 low-dose group (35 mg/kg).

Claims (10)

An optical isomer or a pharmaceutically acceptable salt thereof, represented by the general formula (I) or (II),

(I) (II) Wherein: R ¹ or R ² are independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, carboxyl, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-5 alkoxy, substituted One or more of C _1-5 alkoxy, C _1-3 alkylthio or substituted C _1-3 ^{alkylthio; R 3} or R ⁴ are each independently selected from hydrogen, deuterium, hydroxyl, and amino , Substituted amino, nitro, halogen, cyano, carboxy, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the The substituent of is selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl, C _1-3 alkyl or sugar group; R ^{5 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano Group, carboxyl, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy, substituted C _1-3 alkoxy, C _1-3 alkylthio or substituted C _{1 -3} One or more of alkylthio; R ^{6 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, amino, substituted amino, carboxy, C _1-5 alkyl, substituted C _1-5 alkyl, a C _1-3 alkoxy group or a C _1-3 alkoxy group substituted with one or more of the substituents selected from deuterium, hydroxy, amino, nitro, halo, cyano, carboxy or C _{1- 3} One or more of alkyl groups; R ⁷ or R ⁸ are each independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, substituted amino, nitro, cyano, C _1-3 alkyl, substituted C _{1 -3} alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, halogen or cyano; A is selected from oxygen, sulfur or CHR', R'is selected from hydroxyl, amino, cyano, carboxy or substituted C _1-5 alkyl, and the substituent is selected from deuterium, hydroxyl, amino, cyano or carboxy One or more of; A'or A" are independently selected from oxygen, sulfur, CO or CHR, and R is selected from hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C _1-5 alkyl or substituted C _1-5 alkyl, the substituents are selected from one or more of deuterium, hydroxyl, amino, nitro, carboxy, halogen or cyano; E or G are independently selected from C or CH, E and Between G is a carbon-carbon single bond or a carbon-carbon double bond; X, Y, Z or Z'are independently selected from CH or N; m, n, p or q are 0, ¹ , 2 or 3; R 1, The substituents described in R ² or R ⁵ are each independently selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl or sugar group; and in the formula (II) In the compound, A'and A" are not simultaneously selected from oxygen. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R ¹ or R ² are each independently selected from hydrogen, hydroxy, halogen, cyano, carboxy, and C _1-3 alkane Group, substituted C _1-3 alkyl group, C _1-3 alkoxy group, substituted C _1-3 alkoxy group, C _1-3 alkylthio group or substituted C _1-3 alkylthio group or Multiple, the substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl, or sugar group; R ¹ or R ^{2 are} preferably independently selected from hydroxyl, fluorine One or more of, chlorine, cyano, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-2 alkoxy or substituted C _1-2 alkoxy, said substituted The group is selected from one or more of deuterium, hydroxyl, amino, nitro, fluorine, chlorine, cyano or carboxy; m or n is 0, 1 or 2; and m or n is preferably 1 or 2. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R ³ or R ⁴ are each independently selected from hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C _{1 -3} alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the substituents of which are selected from deuterium, hydroxyl, amino, nitro, cyano, carboxyl Or one or more of the sugar groups; and R ³ or R ^{4 are} preferably independently selected from hydrogen, deuterium, hydroxyl, amino, C _1-3 alkyl or C _1-3 alkoxy. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R ^{5 is} selected from hydrogen, deuterium, hydroxyl, halogen, cyano, C _1-3 alkyl, substituted C _{1 -3} alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy one or more, the substituents of which are selected from deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxy or One or more of sugar groups; R ⁵ is preferably selected from one or more of hydrogen, deuterium, hydroxyl, halogen, cyano or C _1-2 alkoxy; R ^{6 is} selected from hydrogen, deuterium, hydroxyl, halogen One or more of, cyano, amino, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, and the substituents are selected From one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano or carboxy; R ⁶ is preferably selected from hydrogen, deuterium, hydroxyl, amino, C _1-3 alkyl, substituted C _1-5 alkane Group, C _1-3 alkoxy or substituted C _1-3 alkoxy, the substituents of which are selected from one or more of deuterium, hydroxyl, amino, fluorine, carboxyl or cyano; p is 0, 1, 2 or 3, q is 0, 1 or 2; and p is preferably 0 or 1, and q is preferably 0 or 1. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R ⁷ or R ⁸ are each independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, cyano, C _{1- 3} Alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the substituents are selected from one or more of deuterium, hydroxyl, amino or halogen And R ⁷ or R ^{8 are} preferably independently selected from hydrogen, deuterium, hydroxyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, and the substituents are selected from deuterium, hydroxyl, amino Or one or more of the halogens. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein: A is selected from oxygen, sulfur or CHR', and R'is selected from hydroxyl, amino, cyano, carboxy or substituted C _1-3 alkyl, the substituent is selected from one or more of hydroxy, amino, cyano or carboxy; A'or A" is independently selected from oxygen, sulfur, CO or CHR, and R is selected from hydrogen , Deuterium, hydroxy, amino, nitro, cyano, C _1-3 alkyl or substituted C _1-3 alkyl, the substituents of which are selected from one or more of hydroxy, amino, carboxy or cyano; E Or G is independently selected from CH, and E and G is a carbon-carbon single bond; X or Y is independently selected from CH or N; and Z or Z'is selected from CH. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R ¹ or R ² are each independently selected from hydroxyl, halogen, cyano, C _1-3 alkyl, C _{1 -3} Alkoxy or substituted C _1-2 alkoxy, the substituents of which are selected from deuterium, hydroxyl, amino, fluorine or carboxy; m or n are 0, 1 or 2; R ³ or R ⁴ are each independently selected From hydrogen, hydroxy, amino, C _1-3 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the substituent is selected from deuterium, hydroxyl, Amino, fluorine or carboxyl; R ^{5 is} selected from hydrogen, hydroxyl, halogen, cyano, C _1-2 alkoxy or substituted C _1-3 alkoxy, and its substituent is selected from deuterium, hydroxyl, fluorine or carboxy; R ^{6 is} selected from one of hydrogen, deuterium, hydroxyl, cyano, amino, C _1-3 alkyl, substituted C _1-3 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy or Multiple, the substituents of which are selected from deuterium, hydroxyl, amino, fluorine or carboxyl, p or q are each independently 0, 1 or 2; R ⁷ or R ⁸ are each independently selected from hydrogen, hydroxyl, cyano, C _{1 -3} alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, and the substituent is selected from one or more of deuterium, hydroxyl, amino or fluorine; A is selected from oxygen, sulfur or CHR', R'is selected from hydroxyl, amino, cyano, hydroxy-substituted C _1-3 alkyl or amino-substituted C _1-3 alkyl; A'or A" are each independently selected From oxygen, sulfur, CO or CHR, R is selected from hydroxyl, amino or substituted C1-3 alkyl, and its substituent is selected from deuterium, hydroxyl or amino; E or G is independently selected from CH, between E and G Is a carbon-carbon single bond; X or Y are each independently selected from CH or N; and Z or Z'is selected from CH. The compound, optical isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-base}chroman-3,4,5,7-tetraol; (2R,3S)-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1 ,4]Dioxirane-6-yl}chroman-3,4,5,7-tetraol; (2R,3S)-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1 ,4]Dioxirane-6-yl}chroman-3,5,7-triol; 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-base}chroman-3,5,7-triol; 2-{3-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4 ,5,7-tetraol; 2-{3-(5-methoxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl} color Full -3,4,5,7-tetraol; 2-{3-(5-hydroxypyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman- 3,4,5,7-tetraol; (2R,3S)-4-amino-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[ b][1,4]dioxirane-6-yl}chroman-3,5,7-triol; (2R,3S)-2-{(2R,3R)-2-hydroxymethyl-3-[3-methoxy-4-(tri-deuterated methoxy)phenyl]-2,3-dihydro Benzo[b][1,4]dioxirane-6-yl}-5,7-bis(trideuteromethoxy)chroman-3-ol; 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-yl}-7-methoxy-chroman-3,4,5-triol; 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-yl}-7-methoxychroman-3,5-diol; 7-{(3-hydroxy-5,7dimethoxychroman-2-yl)-2-(4-hydroxy-3-methoxyphenyl) -3-hydroxymethyl-2,3-dihydrobenzene And [b][1,4]dioxirane}-5-ol; 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-yl}-5-methoxychroman-3, 7-diol; 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-yl}-5,7-dimethoxychroman-3,4-diol; 7-Fluoro-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]bis Ethylene oxide-6-yl}chroman-3,4,5-triol; 7-ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4 ]Dioxirane-6-yl}chroman-3,5-diol; 5-ethoxy-2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4 ]Dioxirane-6-yl}chroman-3,7-diol; 2-{8-Bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-base}chroman-3,4,5,7-tetraol; 2-{8-Bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-base}chroman-3,5,7-triol; 2-(4-Hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-(3,5,7-trihydroxychroman-2-yl)-2,3-dihydrobenzo[ b][1,4]dioxirane-5-carbonitrile; (2R,3S)-2-{2-Aminomethyl- (2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2,3-dihydrobenzo[b][1 ,4]Dioxirane-6-yl}chroman-3,5,7-triol; 2-{8hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane- 6-base}chroman-3,4,6,7-tetraol; 2-{8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane -6-yl}chroman-3,6,7-triol; and 2-{3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl }Seman-3,6,7-triol. A pharmaceutical composition which uses the compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1 as the active ingredient or main active ingredient, supplemented with pharmaceutically acceptable excipients. A use of the compound, optical isomer or pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicine for the treatment or prevention of liver diseases, especially fatty liver, liver fibrosis and cirrhosis, or claim 1 The compounds, optical isomers or pharmaceutically acceptable salts thereof are used in the treatment or prevention of liver diseases, especially fatty liver, liver fibrosis and liver cirrhosis.

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