TWI816842B - 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

Compounds for the 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 dietary structure, 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) according to its pathological process, as well as related cirrhosis and liver cancer (Chinese Medical Association Liver Disease Fatty Liver and Alcoholic Liver Disease Group of the Branch, Diagnosis and Treatment Guidelines for Non-Alcoholic Fatty Liver Disease, Chinese Journal of Hepatology, 2006, 14:161-163). NASH refers to changes similar to alcoholic hepatitis, such as macrovesicular steatosis, cell swelling and degeneration, and intralobular inflammation in hepatocytes, but the patient has no history of excessive drinking. Currently, the prevalence of NAFLD in the general population is as high as 15%-20%, while 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 for the global population will significantly exceed that of hepatitis B and C in the future. At the same time, NAFLD is also the main cause of chronic liver disease, resulting in many related serious health problems, such as 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 cause of NASH is closely related to obesity, hyperlipidemia, diabetes and other metabolic syndromes, but its pathogenesis is complex and has not yet been fully elucidated. The more classic one 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 hit” (development of hepatic steatosis) is thought to be primarily caused by insulin resistance (IR). Free Fatty Acid (FFA) comes from the decomposition of surrounding fat, ingested food or new lipid formation; FFA is used during oxidation, phospholipid formation and triglyceride (TG) synthesis, and its content in the body A dynamic balance is achieved between production and utilization. However, when IR occurs, the physiological and biochemical reactions regulated by the insulin-mediated signaling pathway are disordered, and its inhibitory effect on lipolysis of adipose tissue is blocked, resulting in excessive lipolysis of adipose tissue, thereby increasing the level of FFA in plasma and the level of TG. The formation rate greatly exceeds its conversion and clearance rate, causing TG to accumulate in the liver, so liver cells undergo macrovesicular 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 hit" (fatty inflammation) is due to the overproduction of reactive oxygen species (ROS) and the reduction of antioxidant defense mechanisms, resulting in oxidative stress effects. A large amount of FFA metabolism produces ROS, which reacts with the phospholipid bilayer of the cell membrane to produce lipid peroxidation, generating active metabolites such as malondialdehyde and 4-hydroxynonenal, which cause structural and functional damage to the cell membrane; at the same time, ROS can also cause mitochondrial damage. The latter can lead to damage to the secondary mitochondrial fatty acid β-oxidation pathway, further promote hepatocellular steatosis, and form a vicious cycle; other secondary hit factors include increased endotoxin, iron ion overload, and Overexpression of Kupffer cells (P. Z. Li, K. He, J. Z. Li, et al. The role of kupffer cells in hepatic diseases. Molecular Immunology, 2017, 85: 222-229).

Currently, there are no therapeutic drugs for NASH on the market globally. When simple lifestyle adjustments are not effective, some insulin sensitizers, weight loss drugs, antioxidants, hepatoprotective and lipid-lowering drugs are clinically integrated into the treatment plan for NASH. However, these drugs usually have potential drug safety risks, insufficient efficacy, and failure to meet treatment expectations.

Some drugs that have entered the clinical stage of research, such as obeticholic acid developed by Intercept in the United States, are in the phase III clinical research stage. It is a Farnesoid X Receptor (FXR) agonist and can reduce blood lipid levels through multiple ways. , reducing the accumulation of TG in the liver and alleviating the degree of oxidative stress and lipid peroxidation, but there is an allergic reaction with significant itching (The Farnesoid , and can cause serious liver injury and risk of death at excessive doses (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 that 3% of patients experienced serious adverse cardiovascular events (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis (POISE). NCT01473524. 2017); Aramchol developed by Galmed Pharmaceuticals is A new type of fatty acid-cholic acid conjugates are used for the treatment of early NASH, but phase IIa clinical trials show that its dosage is relatively high, requiring 300 mg/day, to significantly reduce liver fat accumulation (R. Safadi, F. M. 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 A highly selective small molecule inhibitor of Apoptosis Signal Regulating Kinase (ASK) can be used to reduce the pro-liver fibrosis response to ROS, although its phase II clinical results show that 43% of subjects took the drug The degree of fibrosis was improved after treatment, but the number of samples in the study was too small, and the data was not compared with placebo, so there is still a lot of uncertainty in subsequent 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); French Genfit's Elafibranor is a PPARα/δ dual agonist that can improve insulin sensitivity and lipid metabolism disorders, and It can reduce the inflammatory response, but in the Phase II clinical trial, the drug failed to reach the preset endpoint of the proportion of steatohepatitis disappearance without worsening of liver fibrosis, and only achieved the expected goal in mild to moderate patients (Phase IIb study to evaluate the Efficacy and safety of GFT505 versus placebo in patients with non-alcoholic steatohepatitis (NASH). NCT01694849. 2012). It can be seen that various candidate drugs currently in the clinical research stage are not significant in efficacy, and all have certain toxic and side effects.

Silybin has antioxidant activity and significant hepatoprotective effects. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives by improving mitochondrial function, scavenging oxygen free radicals, and reducing carbon monoxide production, thereby reducing lipid peroxidation levels and inhibiting hepatocyte steatosis (P. F. Surai. . Antioxidants (Basel), 2015(4): 204–247); at the same time, silibinin can also comprehensively treat NASH disease through multiple pathways: it can inhibit the production of multiple inflammatory factors, such as NF-kB, IL1, IL6 , TNFα, IFN-γ and GM-CSF (A. Federico, M. Dallio, C. Luguercio. Silymarin/silybin and chronic liver disease: a marriage of many years. Molecules, 2017(22): 2); can also pass Reduce stellate cell proliferation 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 good liver-protective effects. Silybin can improve symptoms and liver biochemical functions of viral chronic hepatitis. Clinically, it can be seen that the liver histopathology of some patients has been improved to varying degrees. It also has certain effects on early cirrhosis.

There have been clinical reports on silibinin alone or in combination with metformin and rosiglitazone in the treatment of NASH (Liu Zhongxin. Observation on the efficacy of silibinin 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 disease, Journal of Medical Forum, 2016, 37(4): 153-154), but its preliminary efficacy limited. There is also a clinical study on silibinin in the treatment of NAFLD. After 48 weeks of continuous administration, although the patient's lipidation level did not improve significantly compared with placebo, the degree of liver fibrosis was significantly reduced (W. K. 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, silibinin 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 drugs currently in the clinical research stage have various problems such as unclear efficacy, high toxic and side effects, and cannot be used for a long time. Therefore, the NASH market is in urgent need of 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 based on the existing technology.

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

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) Where: 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 independently selected from hydrogen, deuterium, hydroxyl, amino , substituted amino, nitro, halogen, cyano, carboxyl, C _1-5 alkyl, substituted C _1-5 alkyl, C _1-3 alkoxy or substituted C _1-3 alkoxy, the The substituent 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, cyanide 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 One or more of _-3 alkylthio groups; R ⁶ is selected from hydrogen, deuterium, hydroxyl, halogen, cyano, amino, substituted amino, carboxyl, C _1-5 alkyl, substituted C _1-5 alkyl, One or more of C _1-3 alkoxy or substituted C _1-3 alkoxy, the substituent is selected from deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl or C _1- One or more of ₃ alkyl groups; R ⁷ or R ⁸ are 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 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, carboxyl, halogen or cyano; E or G are independently selected from C or CH, E and G There are carbon-carbon single bonds or carbon-carbon double bonds; 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 described in ² or R ⁵ are independently selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl or sugar; 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 independently selected from hydrogen, hydroxyl, halogen, cyano, carboxyl, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-3 alkoxy group, one or more of substituted C _1-3 alkoxy group, C _1-3 alkylthio group or substituted C _1-3 alkylthio group, the substituent is selected from deuterium, hydroxyl, amino, nitro One or more of halogen, cyano, carboxyl or sugar groups.

In some additional embodiments, R ¹ or R ² is preferably independently selected from hydroxyl, fluorine, chlorine, cyano, C _1-3 alkyl, substituted C _1-3 alkyl, C _1-2 alkyl One or more of the oxygen groups or substituted C _1-2 alkoxy groups, and the substituents are 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 choose the defined range (such as R ¹ The same group within the limited range), or different groups within the limited range can be selected.

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

In some additional implementations, m or n is 1 or 2.

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, and its substituent is selected from deuterium, hydroxyl, Amino, fluorine or carboxyl; m or n is 0, 1 or 2.

In some embodiments, R ³ or R ⁴ are 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 substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, cyano, carboxyl or sugar.

In some additional 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 additional 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 C _1-3 alkoxy group, its substituent is selected from deuterium, hydroxyl, amino, fluorine or carboxyl.

In some embodiments, ^R5 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 alkoxy groups, the substituents of which are selected from one or more deuterium, hydroxyl, amino, nitro, halogen, cyano, carboxyl or sugar groups.

In some additional embodiments, ^R5 is selected from one or more of hydrogen, deuterium, hydroxyl, halogen, cyano, or C _1-2 alkoxy.

In some additional embodiments, ^R5 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, ^R6 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, and its substituent is selected from one or more of deuterium, hydroxyl, amino, nitro, halogen, cyano or carboxyl.

In some additional 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 group, its substituent is selected from one or more of deuterium, hydroxyl, amino, fluorine, carboxyl or cyano.

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

In some additional implementations, p is 0 or 1.

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

In some other implementations, q is 0 or 1.

In some additional 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 C _1-3 alkoxy groups, whose substituents are selected from deuterium, hydroxyl, amino, fluorine or carboxyl.

In some embodiments, R ⁷ or R ⁸ are 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 additional 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 substituent is selected from One or more of deuterium, hydroxyl, amino or halogen.

In some additional embodiments, R ⁷ or R ⁸ are 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 group, 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, carboxyl or substituted C _1-3 alkyl, and the substituent is selected from hydroxyl, amino, One or more of cyano or carboxyl.

In some additional 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 additional embodiments, A is selected from oxygen.

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

In some additional 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 the cyano groups.

In some additional 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 are respectively C, or E or G are respectively CH. 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 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.

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

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

Substituent groups in the present invention, such as substituted alkyl, substituted alkoxy, substituted alkylthio, substituted amino, etc., when not specifically limited, the substituents are selected from deuterium, hydroxyl, amino, nitro, One or more of halogen, cyano group, carboxyl group, C _1-3 alkyl group, C _1-3 alkoxy group 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.), these substituents can be the same substituents. group, you can also choose different substituent groups.

In some embodiments, the compounds of the present invention are 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 -yl}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 -yl}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-methyl 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-(trideuteratedmethoxy)phenyl]-2,3-dihydrobenzo[b][1,4 ]Dioxirane-6-yl}-5,7-bis(trideuteratedmethoxy)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-5,7dimethoxychroman) Man-2-yl)-2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-2,3dihydrobenzo[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-methoxy) Phenyl)-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]Dioxirane-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-di Alcohol ( 105 ); 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 ); 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]diepoxide Alk-6-yl}chroman-3,5,7-triol ( 118 ); 2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-(3,5, 7-Trihydroxychroman-2-yl)-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-tetrol ( 136 ); 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 ); 2-{3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3-dihydrobenzo[b][1, 4]Dioxirane-6-yl}chroman-3,6,7-triol ( 140 ).

The present invention also provides a pharmaceutical composition, which uses the compounds of the present invention, optical isomers or pharmaceutically acceptable salts thereof as active ingredients or main active ingredients, supplemented by pharmaceutically acceptable excipients. That is, in the pharmaceutical composition of the present application, in addition to using the compound of the present invention, optical isomers or pharmaceutically acceptable salts thereof as active ingredients, other types of active ingredients can also be further added to achieve combined use and synergy. 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 medicines for the treatment or prevention of liver diseases, especially in the preparation of medicines for the treatment or prevention of fatty liver, liver fibrosis and liver cirrhosis. Drugs. On the other hand, the compounds, optical isomers or pharmaceutically acceptable salts thereof of the present invention 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 stated, the following terms used in the claims and description have the following meanings: "Hydrogen" refers to protium (1H), which is the main stable isotope of the hydrogen element. "Deuterium" refers to a stable isotope of hydrogen, also known as heavy hydrogen, and its element symbol is D. "Halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an 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 this group , this time it is an alkyl group, which can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). Alkyl groups containing 1-4 carbon atoms are called lower alkyl groups. When the lower alkyl group has no substituent, it is called 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 etc. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc. Alkyl groups may 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 are independently selected from CH, and when there is a carbon-carbon double bond between E and G, E or G are each independently selected from C. "Glycosyl" means a monosaccharide residue or a polysaccharide residue. Monosaccharides used herein are 3-C monosaccharides to 8-C monosaccharides, preferably 6-carbon monosaccharides with the chemical formula C6H12O6 (ie, hexose). The hexose sugar may be in D configuration, L configuration or a combination thereof. Hexose sugars are usually classified based on functional groups. For example, aldohexoses have aldehydes at position 1, such as allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; whereas ketohexoses have aldehydes at position 1 2 has ketones such as psicose, fructose, sorbose and tagatose. Hexose also contains 6 hydroxyl groups. The aldehyde or ketone functional group in the hexose sugar can react with the adjacent hydroxyl functional group to form an intramolecular hemiacetal or hemiketal respectively. If the resulting cyclic sugar has a 5-membered ring, it is a furanose. If the resulting cyclic sugar has a 6-membered ring, it is a pyranose. The ring opens and closes spontaneously, allowing the bonds between the carbonyl group and adjacent carbon atoms to rotate, producing two different configurations (α and β). Hexose sugars can be in the S configuration or the R configuration. "Pharmaceutically acceptable salts" are salts containing compounds of general formula (I) or (II) formed with organic or inorganic acids, meaning those salts which retain the biological effectiveness and properties of the parent compound. Such salts include: (1) Salt formation with acids, obtained through the reaction of the free anhydride of the parent compound with inorganic acid or organic acid. Inorganic 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) Salts in which the acidic protons present in the parent compound are replaced by metal ions or coordinated with organic alkaloids, such as alkali metal ions, alkaline earth metal ions or aluminum ions, and organic alkaloids 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, with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate the administration of compounds to an organism. "Prodrugs" refer to compounds that have pharmacological effects after being transformed in vivo. Prodrugs themselves have no biological activity or very low activity, and become active substances after metabolism in the body. The purpose of this process is to increase the bioavailability of the drug, enhance 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, pharmaceutically acceptable salts thereof or easily hydrolyzable prodramides thereof and other pharmaceutically active ingredients.

The present invention also includes any of the above compounds, pharmaceutically acceptable salts thereof, easily hydrolyzable prodrugamides 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, syrups, etc.

In the case of formulation, it is produced using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration can be prepared by mixing the compound with one or more excipients, 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 various excipients other than water and liquid paraffin that are commonly used as simple diluents, such as wetting agents, sweeteners, aromatics, preservatives, etc. In preparations for parenteral administration, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate can be used as non-aqueous solvents and suspensions. As the base of the adjuvant, witepsol, polyethylene glycol, Tween 61, cocoa butter, laurin, glycerin gelatin, etc. can be used.

The usage amount of the compound as the active ingredient of the pharmaceutical composition according to the present invention can be determined according to the age, gender, weight, and disease of the patient. It can be determined according to the route of administration, degree of disease, gender, and weight. , age, etc. increase or decrease. Therefore, the dosage described does not limit the scope of the invention in any way. The pharmaceutical composition can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration are contemplated, for example, administration may be by oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine, dural or intracerebrovascular injection.

Compared with existing drugs of this type (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 improve the related therapeutic effects. The compounds represented by formula (I) or (II), optical isomers or pharmaceutically acceptable salts thereof provided by the present invention have good curative effect and low toxicity on liver diseases, especially fatty liver. Experiments show that the compound Some of the compounds involved in the invention have significant therapeutic effects on non-alcoholic fatty liver disease in zebrafish, and can also significantly improve and treat non-alcoholic steatohepatitis in mice. Therefore, they can be used to treat or prevent liver diseases, especially fatty liver and liver disease. In terms of drugs for fibrosis and liver cirrhosis, it has good application prospects.

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

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

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

Step B: To a solution of compound 1 (2.48 g, 11.2 mmol) in THF (25 mL), a 1.5 M solution of diisobutylaluminum hydride in THF (25 mL) was added dropwise at -50°C. After the addition is complete, the temperature is raised to room temperature and stirring is continued for 0.5 hours. Slowly pour the reaction solution into ice water (40 mL), and adjust the pH value to 5 ~ 6 with 2 M citric acid solution. Extract with ethyl acetate (50 mL×3), wash the combined organic phases with saturated brine (30 mL), and dry 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) 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: Combine 3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one (622 mg, 1.94 mmol) and compound 2 (350 mg, 1.94 mmol). ), acetone (10 mL) and benzene (20 mL) were stirred at 50°C for 10 minutes, and then silver carbonate (536 mg, 1.94 mmol) was added. After the addition was completed, the resulting mixture was stirred at this temperature overnight. Cool to room temperature, add THF (15 mL), and filter to remove insoluble matter. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, methanol: dichloromethane = 1:100 ~ 1:60) 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 is 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: Stir a mixture containing compound 3 (170 mg, 0.341 mmol), methanol (6 mL) and sodium borohydride (32 mg, 0.846 mmol) at room temperature for 2 hours, then add sodium borohydride (32 mg, 0.846 mmol) and the resulting mixture was stirred at room temperature overnight. Add water (15 mL) and adjust the pH to 5 ~ 6 with 2 M citric acid solution. Extract with ethyl acetate/THF (3V/1V, 15 mL×3), wash the combined organic phases with saturated brine (10 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 ~ 300 mesh silica gel, methylene chloride: ethyl acetate: THF = 5: 1:1 ~ 2: 1:1) to obtain 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 ). 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] Synthesis of [1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol (5).

With (2R,3R)-3,5,7-trihydroxy-2-{(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3 -Dihydrobenzo[b][1,4]diethylene oxide-6-yl}chroman-4-one (purchased from Shanghai Dibai Biotechnology Co., Ltd., production batch number is EE09) is used as raw material to synthesize the compound The experimental operation of 5 was carried out according to 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] Synthesis of [1,4]dioxirane-6-yl}chroman-3,5,7-triol (6).

To a solution of compound 5 (103 mg, 0.213 mmol) in acetic acid (3 mL) was added portionwise sodium cyanoborohydride (50 mg, 0.796 mmol). After the addition was complete, the resulting mixture was stirred at room temperature for 0.5 h. Add water (10 mL), extract with ethyl acetate (15 mL×3), wash the combined organic phases with saturated sodium bicarbonate solution (10 mL), and dry 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) 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]di Synthesis of ethylene oxide-6-yl}chroman-3,5,7-triol (7).

Compound 4 was used as raw material, and the experimental operation for synthesizing compound 7 was according to 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 Ethan-6-yl}chroman-4-one (21) and 2-{3-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4 ]Synthesis of diexirane-6-yl}chroman-3,4,5,7-tetraol (22).

Step A: Combine 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) mixture was stirred at reflux for 2 h. The solvent was evaporated under reduced pressure, water (50 mL) was added, and extracted with ethyl acetate (40 mL×3). The combined organic phases were 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) to obtain 1-[2-hydroxy-4, 6-Bis(methoxymethoxy)]acetophenone (8) (5.1 g). The yield is 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 an ice-water bath, add chloromethyl methyl ether (2.52 g, 31.3 mmol) dropwise to a solution containing compound 8 (4.0 g, 15.6 mmol), sodium hydroxide (1.84 g, 46 mmol), and water (4 mL ), tetrabutylammonium bromide (252 mg, 0.782 mmol) and dichloromethane (60 mL). After 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 phases with saturated brine (30 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2,4,6-tris(methoxymethoxy)acetophenone (9) (4.6 g). The yield is 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), benzyl bromide (25.4 g, 149 mmol), and after the addition was complete, the resulting mixture was stirred under reflux overnight. Most of the solvent was evaporated under reduced pressure, water (400 mL) was added, and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (100 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: dichloromethane = 1:50:1 ~ 1:50:2) to obtain 3-benzyloxy Methyl 4-benzyloxy-3-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% hydrobromic acid aqueous solution (5.79 g, 33.6 mmol), and then add bromine dropwise. (2.95 g, 18.5 mmol) in acetic acid (5 mL), after adding, raise the temperature to 40°C, stir for about 3 hours, then add bromine (600 mg, 3.75 mmol), and continue stirring for 5 hours. Add water (150 mL), extract with methyl tert-butyl ether (60 mL×4), wash the combined organic phases with saturated brine (40 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:100 to 1:10) to obtain 2-bromo-1-(6-methoxy) Pyridin-3-yl)ethanone (12) (1.91 g). The yield is 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), wash the combined organic phase with water (40 mL) and saturated brine (40 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-benzyloxy-4-[2-(6-methoxypyridin-3-yl)-2-oxyethoxy]benzoic acid methyl ester (13) (2.83g). The yield is 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), sodium borohydride (526 mg, 13.9 mmol) was added in portions. After the addition was completed, the resulting mixture was stirred at room temperature for 4 hours. Add water (120 mL), extract with ethyl acetate (60 mL×3), wash the combined organic phase with water (40 mL) and saturated brine (40 mL), and dry over 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 is 91.7%.

Step G: Add 5% palladium on carbon (260 mg) to a solution of compound 14 (2.6 g, 6.35 mmol) in THF (40 mL), 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 is 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 was complete, the resulting mixture was stirred at reflux under nitrogen for 3.5 hours. 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) 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 is 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: A solution of compound 16 (1.75 g, 5.81 mmol) in THF (7 mL) was added dropwise to a mixture containing lithium aluminum hydride (441 mg, 11.6 mmol) and THF (15 mL) under an ice-water bath. After the addition is complete, continue stirring for 5 minutes, then raise the temperature to room temperature and continue stirring for 30 minutes. After the reaction is completed, cool to 0 ~ 5°C, slowly add water (0.5 mL), 10% sodium hydroxide solution (1.0 mL) and water (1.5 mL) to the reaction mixture in sequence. After the addition is completed, warm to room temperature and continue. Stir for 5 minutes. Filter through celite to remove insoluble matter, add ethyl acetate (60 mL) to the filtrate, wash with saturated brine (15 mL×2), dry over 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 is 95.7%.

Step J: A 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. Insoluble matter was removed by celite filtration, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:25 to 1:12) 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: Add compound 18 (300 mg, 1.11 mmol) and compound 9 (332 mg, 1.11 mmol) to a solution of potassium hydroxide (186 mg, 3.32 mol) in ethanol (10 mL) at room temperature, and add After completion, the resulting mixture was stirred at 30°C overnight. Most of the solvent was evaporated under reduced pressure, water (70 mL) was added, and extracted with ethyl acetate (70 mL × 3). The combined organic phases were washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:20 to 1:2) 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 ), and 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 phases with saturated brine (20 mL), and dry over 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- ethyl}oxirane-2-yl}[2,4,6-tris(methoxymethoxy)phenyl]methanone (20) (500 mg). The yield is 97.2%.

Step M: To a solution of compound 20 (490 mg, 0.860 mmol) in methanol (9 mL) and THF (3 mL), concentrated hydrochloric acid (1.2 mL) was added dropwise. After the addition was completed, the resulting mixture was stirred at 65 °C for 2 hours. Most of the solvent was evaporated under reduced pressure, water (20 mL) was added, and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine (15 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: dichloromethane = 1:15:1 ~ 1:4:1) 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 -Based}chroman-3,4,5,7-tetraol (22), the specific experimental operation was according to 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 hydrobenzo[b][1,4]dioxirane-6-yl}chroman-3,4,5,7-tetrol (38).

Step A: 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) under an ice-water bath. in solution. After the addition was complete, the resulting mixture was stirred at room temperature for 2 hours. Add water (50 mL), extract with dichloromethane (80 mL×3), wash the combined organic phase with water (40 mL) and saturated brine (40 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was recrystallized with dichloromethane/petroleum ether to obtain 3-acetyloxy-4-benzyloxybenzoic acid methyl ester ( 23 ) (5.5 g). The yield was 89.3%.

Step B: Add 5% palladium on carbon (800 mg) to a solution of compound 23 (8.6 g, 28.6 mmol) in THF (120 mL), and the resulting mixture was stirred in hydrogen at 25°C under normal pressure overnight. Filter through celite, evaporate the solvent under reduced pressure, and recrystallize the product with petroleum ether to obtain 3-acetyloxy-4-hydroxybenzoic acid methyl ester ( 24 ) (5.7g). The yield is 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, stirring is continued for 10 minutes, and then 5-bromo-2-cyanopyridine (10.0 g, 54.6 mmol) is added in portions. The resulting mixture was stirred at this temperature for a further 15 minutes. Add water (180 mL), filter, rinse the filter block with water (100 mL), and then recrystallize with ethyl acetate/petroleum ether to obtain 5-benzyloxy-2-cyanopyridine ( 25 ) (9.2 g). The yield was 80.2%.

Step D: Add 2 M ethylmagnesium bromide THF solution (26.5 mL, 53 mmol) dropwise to a solution of compound 25 (8.6 g, 40.9 mmol) in THF (30 mL) at -5 ~ 0°C. After the addition was complete, the resulting mixture was stirred at this temperature for an additional hour. Slowly add water (90 mL), adjust the pH value to 3 ~ 4 with 2 M hydrochloric acid, extract with ethyl acetate (100 mL × 3), and add water (50 mL) and saturated saline (50 mL) to the combined organic phase. Wash and dry over 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 is 98.7%.

The experimental operations of steps E and F were carried out according to the preparation methods of steps D and E in Example 5 to obtain 3-acetyloxy-4-{[1-(5-benzyloxypyridin-2-yl)-1-oxo Prop-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 the 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 h. Add saturated saline (360 mL) and adjust the pH to 7 ~ 8 with 2 M citric acid solution. Extract with ethyl acetate (100 mL×3), wash the combined organic phases with saturated brine (50 mL×2), dry over anhydrous sodium sulfate, and then filter through a short silica gel pad. The solvent was evaporated under reduced pressure to obtain 4-{[1-(5-benzyloxypyridin-2-yl)-1-hydroxyprop-2-yl]oxy}-3-hydroxybenzoic acid methyl ester ( 29 ) ( 4.49 g). The yield is 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 was complete, the resulting mixture was stirred at reflux under nitrogen for 2.5 hours. Cool to room temperature, evaporate the solvent under reduced pressure, and purify the product by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: petroleum ether = 1:30 ~ 1:10) to obtain 3-(5-benzyloxy (pyridin-2-yl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-carboxylic acid methyl ester ( 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 diatomaceous earth, add water (120 mL), extract with ethyl acetate (60 mL×3), wash the combined organic phase with water (30 mL×2) and saturated brine (30 mL), and wash with 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: A 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. Add water (40 mL), extract with ethyl acetate (20 mL×3), wash the combined organic phase with water (15 mL×2) and saturated brine (15 mL), and dry over 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 carried out according to the preparation methods of steps G and H in Example 6 to obtain 3-(5-methoxymethoxypyridin-2-yl)-2-methyl-2,3-dihydrogen. 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 carried out 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 according to the preparation method of step D in Example 1. 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] Synthesis of [1,4]dioxirane-6-yl}chroman-3,4,5,7-tetraol (45).

Using compound 30 as raw material, the experimental operations of steps A, B, C, D and E were carried out according to 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]dioxiran-6-yl}-3,5,7-trihydroxychroman- 4-keto ( 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 solution of compound 43 (780 mg, 1.57 mmol) in DMF (10 mL) was added 5% palladium on carbon (80 mg), and the resulting mixture was stirred in hydrogen at 40°C under normal pressure overnight. After filtering through diatomaceous earth, add water (40 mL) and filter. Dissolve the filter block with ethyl acetate (20 mL×3), then wash with saturated brine (20 mL), and dry over 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 For oxirane-6-yl}chroman-3,4,5,7-tetraol (45), the specific experimental operation was according to 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 a compound containing (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 with 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) 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 Ethan-6-yl}chroman-4-one oxime (46) (481 mg). The yield is 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: A mixture containing compound 46 (100 mg, 0.207 mmol), Raney nickel (10 mg), and methanol (15 mL) was stirred at 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: dichloromethane = 1:50 ~ 1:20) 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-(trideuteratedmethoxy)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 iodomethane (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 phases with saturated brine (10 mL×2), and dry 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:THF: dichloromethane = 1:1:40 ~ 1:1:20) to obtain (2R, 3S) -2-{(2R,3R)-2-hydroxymethyl-3-[3-methoxy-4-(trideuteratedmethoxy)phenyl]-2,3-dihydrobenzo[b] [1,4]Dioxiran-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]di Synthesis of ethylene oxide-6-yl}-7-methoxy-chroman-3,4,5-triol (66).

Step A: Dissolve gallic acid methyl ester (30.0 g, 163 mmol) and N,N-diisopropylethylamine (126 g, 977 mmol) in dichloromethane (120 mL), and then add dropwise in an ice-water bath After adding chloromethyl methyl ether (52.5 g, 652 mmol), warm to room temperature and continue stirring for 1.5 hours. Add water (240 mL), separate the layers, and extract the water layer with dichloromethane (50 mL×2) , the combined organic phase was washed with water (50 mL×2) and saturated brine (50 mL) in sequence, 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 = 1:1:10 ~ 1:1:6) and dissolved to obtain 3,4, 5-Tris-methoxymethoxy-benzoic acid methyl ester (56) (47.9g), yield 93.0%.

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

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

Step D: Combine 2,4,6-trihydroxyacetophenone (25.6 g, 149 mmol), potassium carbonate (20.6 g, 149mmol), dimethyl sulfate (28.1 g, 223 mmol) and acetone (250 mL). The mixture was stirred at 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) was dissolved to obtain 1-(2,6-dihydroxy-4-methoxy-phenyl)ethanone (59) (8.51 g), with a yield of 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 in an ice-water bath. Methyl ether (5.63 g, 70.0 mmol), after addition, warm to room temperature and continue stirring for 1 hour. Add water (50 mL), separate the layers, wash the aqueous layer with dichloromethane (30 mL), wash the combined organic phase with saturated brine (50 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:40 to 1:20) to obtain 1-(2-hydroxy-4-methoxy) -6-Methoxymethoxy-phenyl)ethanone (60) (8.31 g), yield 78.6%.

Using compound 60 as raw material, the experimental operation for synthesizing compound 64 was carried out according to 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 raw material, the experimental operation for 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 base)-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 raw material, the experimental operation for synthesizing compound 66 was carried out according to the preparation method of step D in Example 1 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl. yl-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]di Synthesis of ethylene oxide-6-yl}-7-methoxychroman-3,5-diol (67).

Using compound 66 as raw material, the experimental operation for synthesizing compound 67 was carried out according to the preparation method of the operating steps in Example 3 to obtain (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 the 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), wash the combined organic phase with water (50 mL×2) and saturated brine (50 mL), and dry over 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 raw material, the experimental operation for synthesizing compound 70 was carried out according to the preparation method of steps B and C in Example 10 to obtain 3,4,5-tris-benzyloxy-benzaldehyde (70).

Using compound 70 as raw material, the experimental operation for 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-tri-benzyloxy -phenyl)chroman-4-one (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 raw material, the experimental operation for synthesizing compound 74 was carried out according to 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 raw material, the experimental operation for synthesizing compound 75 was carried out 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. Add water (50 ml), extract with ethyl acetate (25 ml × 2), wash the combined organic phase with water (50 mL × 2) and saturated brine (50 mL), and dry 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: 20 ~ 1: 1: 8) to obtain 5,7- Di-methoxy-2-(3,4,5-tri-benzyloxyphenyl)chroman-3-ol (76) (1.00 g), yield 86.7%.

Using compound 76 as raw material, the experimental operation for synthesizing compound 77 was carried out according to the preparation method of step G of Example 5 to obtain 5-(3-hydroxy-5,7-di-methoxy-chroman-2yl)-benzene-1, 2,3-triol (77) (500 mg), yield 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 raw material, the experimental operation for synthesizing compound 78 was carried out according to the preparation method of step C of Example 1 to obtain 7-(3-hydroxy-5,7-dimethoxy-chroman-2-yl)-2-(4 -Hydroxy-3-methoxy-phenyl)-3hydroxymethyl-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]di Synthesis of ethylene oxide-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), then add methyl chloride dropwise in an ice-water bath. After adding methyl ether, raise the temperature 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 combine the organic phases. (20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:10 to 1:4) to obtain 3,5-dihydroxy-7-methoxy. Methoxy-2-(3,4,5-tribenzyloxy-phenyl)chroman 4-one (79) (1.82 g), yield 84.7%.

Using compound 79 as raw material, the experimental operation for synthesizing compound 80 was carried out according to the preparation method of step D in Example 1 to obtain 7-methoxymethoxy-2-(3,4,5-tribenzyloxy-phenyl) color Man-3,4,5-triol (80).

Using compound 80 as raw material, the experimental operation for synthesizing compound 81 was carried out 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 phases with saturated brine (20 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:15 to 1:6) to obtain 5-methoxy-7-methoxymethyl. Oxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3-ol (82) (610 mg), yield 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), wash the combined organic phases with saturated brine (20 mL), and dry over 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 raw material, the experimental operation for 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 raw material, the experimental operation for synthesizing compound 85 was carried out according to the preparation method of step C in Example 1 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl. yl-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), 2.63-2.55 (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]di Synthesis of ethylene oxide-6-yl}-5,7-dimethoxychroman-3,4-diol (92).

Step A: Combine 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 ) and the mixture was stirred at reflux for 2 hours. Cool to room temperature, filter to remove insoluble matter, and evaporate the solvent under reduced pressure. The product is purified by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether = 1:1:40 ~ 1:1: 6) Dissolve to obtain 1-(4-hydroxy-2,6-methoxy-phenyl)ethanone (86) (16.0 g) with a yield of 54.9%.

Using compound 86 as raw material, the experimental operation for synthesizing compound 91 was carried out according to 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 raw material, the experimental operation for synthesizing compound 92 was carried out according to the preparation method of step D in Example 1 to obtain 2-{8-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl. yl-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), 3.46-3.43 (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]Synthesis of diexirane-6-yl}chroman-3,4,5-triol (101).

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

Step B: Stir a mixture of compound 93 (4.80 g, 37.5 mmol), aluminum trichloride (15.0 g, 112 mmol), and chlorobenzene (50 ml) at 45°C for 10 minutes, and add acetyl chloride (4.12 g, 52.5 mmol) was slowly added dropwise to the reaction system, and stirred at 75°C overnight. 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 drying. 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) to obtain 1-(4-fluoro-2,6-di Hydroxy-phenyl)ethanone (94) (2.48 g), yield 38.9%.

Using compound 94 as raw material, the experimental operation for synthesizing compound 101 was carried out according to the preparation method of steps E, F, G, H, I, J, 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] Synthesis of [1,4]dioxirane-6-yl}chroman-3,5-diol (105).

Step A: A 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 phases with saturated brine (20 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:10 to 1:5) to obtain 5-benzyloxy-7-methoxymethyl. Oxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3-ol (102) (640 mg), yield 74.5%.

Using compound 102 as raw material, the experimental operation for synthesizing compound 105 was carried out according to the preparation method 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] Synthesis of [1,4]dioxirane-6-yl}chroman-3,7-diol (109).

Step A: A 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 phases with saturated brine (20 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate:petroleum ether = 1:10 to 1:5) to obtain 5-ethoxy-7-methoxymethyl. Oxy-2-(3,4,5-tribenzyloxy-phenyl)chroman-3-ol (106) (620 mg), yield 94.2%.

Using compound 106 as raw material, the experimental operation for synthesizing compound 109 was carried out 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]di Synthesis of ethylene oxide-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), and add bromine (5.78 g, 36.1) dropwise at room temperature. mmol) in acetic acid (5 mL). After the dripping is completed, the temperature is raised to room temperature and stirring is continued for 1.5 hours. Add saturated sodium sulfite solution (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: A 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 under reflux overnight. The solvent was evaporated under reduced pressure, water (50 mL) was added, the pH value was adjusted to 3 ~ 4 with 2 M hydrochloric acid solution, extracted with ethyl acetate (50 ml × 2), and the combined organic phase was treated with saturated brine (50 mL). Wash and dry over 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 in an ice-water bath. Methyl ether (5.93 g, 73.7 mmol). After the addition is complete, warm to room temperature and continue stirring for 1 hour. Add water (50 mL), separate the layers, extract the aqueous layer with dichloromethane (50 mL), wash the combined organic layers with saturated brine (50 mL), and dry 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) to obtain 3-bromo-4,5-dimethoxy Methoxybenzaldehyde (9.00 g) (112), yield 93.1%.

Using compound 112 as raw material, the experimental operation for synthesizing compound 115 was carried out 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 was 23.0%.

Using compound 115 as raw material, the experimental operation for synthesizing compound 116 was carried out according to the preparation method of step C in Example 1 to obtain 2-{8-bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl. Base-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 raw material, the experimental operation for synthesizing compound 117 was carried out according to the preparation method of step D in Example 1 to obtain 2-{8-bromo-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl. Base-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]di Synthesis of ethylene oxide-6-yl}chroman-3,5,7-triol (118).

Using compound 117 as raw material, the experimental operation for synthesizing compound 118 was according to 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 hydrobenzo[b][1,4]dioxirane-5-carbonitrile (119).

A 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 h. Cool to room temperature, add water (15 mL), extract with ethyl acetate (15 mL×2), wash the combined organic phases with saturated brine (20 mL), and dry over 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) 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] Synthesis of [1,4]dioxirane-6-yl}chroman-3,5,7-triol (126).

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, 0.64mmol), Et3N ( A mixture of pyridine (389 mg, 38.4 mmol) and pyridine (10 mL) was stirred at 100 °C overnight. Most of the pyridine was evaporated under reduced pressure, and extracted with ethyl acetate (20 mL × 2) and water (20 mL). The combined organic phases were 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 = 1:10 ~ 1:5) 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), yield 46.6%.

Step B: Stir a mixture of compound 120 (1.13 g, 1.47 mmol), acetic anhydride (2.99 g, 29.3 mmol) and pyridine (5 mL) at room temperature overnight. Add ethyl acetate (20 mL × 2) and water (20 mL) for extraction. The combined organic phases were 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) to obtain 3,5- Diethyloxy-(2R,3S)-2-{(2R,3R)-3-(4-ethyloxy-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). This 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 phases were 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) to obtain 3,5-diethyloxy-( 2R,3S)-2-{(2R,3R)-3-(4-acetyloxy-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 methylsulfonyl chloride (184 mg, 1.60 mmol) dropwise in an ice bath. Dichloromethane solution (2 mL), stirred at room temperature for 1 hour, added water (20 mL) for extraction, washed the aqueous phase with dichloromethane (10 mL), washed the combined organic phase 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 ~ 1:6) to obtain 3,5-diethyloxy-( 2R,3S)-2-{(2R,3R)-3-(4-acetyloxy-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), the combined organic phases were 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) to obtain 3,5-diethyloxy-( 2R,3S)-2-{(2R,3R)-3-(4-acetyloxy-3-methoxyphenyl)-2-azidomethyl-2,3-dihydrobenzo[ b][1,4]Dioxirane-6-yl}chroman-7-yl acetate (124) (125 mg), yield 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, and add ethyl acetate (10 mL×2) and water (10 mL), the combined organic phases were 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) to obtain (2R,3S)-2-{2- Azidomethyl-(2R,3R)-3-(4-acetyloxy-3-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]diepoxy Ethane-6-yl}chroman-3,5,7-triol (125) (55.0 mg), yield 61.5%.

Step G: Stir a mixture of compound 125 (50 mg, 101 μmol), Pd/C (5 mg), and methanol (3 mL) at room temperature overnight. Filter through diatomaceous earth pad, evaporate the solvent from the filtrate under reduced pressure, and purify the product by column chromatography (200 ~ 300 mesh silica gel, ethyl acetate: dichloromethane = 1:3 ~ 2:1) to obtain (2R, 3S )-2-{2-Aminomethyl- (2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]di Oxirane-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 THF solution (3.0M, 13.3 mL, 39.8mmol), after addition, continue stirring in an ice-salt bath for 2 hours. Add water (100 mL) to quench, add ethyl acetate (50 mL×2) for extraction, wash the combined organic phases with saturated brine, and dry 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) to obtain 1-(2,4,5-trimethoxy Phenyl)ethanol (127) (4.66 g), yield 71.8%.

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

Step C: Dissolve compound 128 in dichloromethane (20 mL), protect it with N2, add BBr3 dropwise in an ice bath, and stir at room temperature overnight after the addition. Pour the reaction solution into crushed ice, adjust the pH to 4~5 with 2N NaOH solution, add ethyl acetate (50 mL×2) for extraction, wash the combined organic phases with saturated brine, and dry 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 ~ 1:1) to obtain 1-(2,4,5-trihydroxy Phenyl)ethanone (129) (1.41 g), yield 76.6%.

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

Using compound 131 as raw material, the experimental operation for 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 raw material, the experimental operation for synthesizing compound 136 was carried out 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]di Synthesis of ethylene oxide-6-yl}chroman-3,6,7-triol (137).

Using compound 136 as raw material, the experimental operation for synthesizing compound 137 was carried out according to the preparation method in Example 3 to obtain 2-{8-hydroxy3-(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: Stir 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) at room temperature for 1.5 hours. Add dichloromethane (10 mL×2) and water for extraction. The combined organic phases were 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-ethyloxy-3-methoxyphenyl) -2-Methanesulfonyloxymethyl-2,3-dihydrobenzo[b][1,4]dioxirane-6-yl}chroman-5-yl acetate (138) ( 143 mg) and was 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. Stay overnight. Cool to room temperature, add ethyl acetate (10 mL×2) and water (10 mL) for extraction, wash the combined organic phases with saturated brine, and dry 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) to obtain 3,7- Diethyloxy-(2R,3S)-2-{(2R,3R)-3- (4-ethyloxy-3-methoxyphenyl)-2-cyanomethyl-2,3 -Dihydrobenzo[b][1,4]dioxyethane-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 at 80°C overnight. Adjust the pH value 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 over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 to 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]dioxirane-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., the batch number was HH06. Test compounds and control compounds were prepared as 10 mM stock solutions in DMSO. Phosphate buffer saline (PBS), with pH values of 4.0 and 7.4, was used to test the solubility of the test compounds.

2. Test methods

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

Standard treatment: dilute the 10 mM stock solution with DMSO to 300 μM, then take 10 μL of compound dilution, add 990 μL of water and acetonitrile mixture (including internal standard), mix evenly, and prepare a final concentration of 3 μM. Standard solution.

The solubility sample plate is placed in the autosampler and analyzed using the LC-MS/MS method. The concentration of the test compound is calculated based on the response values of the test compound and standard, as well as the concentration of the standard.

3. Test results

As shown in Table 1, in PBS buffer solutions of pH 4.0 and 7.4, the solubility of test compounds 7, 67 and 85 in PBS buffer solutions 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 silibinin 1.08 15.00

The extremely 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 improving the bioavailability of the compounds. degree, thereby improving the pharmacological activity of the compound.

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

1. Test materials

1. Test compound

Test compounds 4, 5, 6, 7, 46, 67, 78, 85, 92 and 101 were respectively prepared into 40 mM stock solutions with DMSO and stored in a -20°C refrigerator. 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 was prepared with DMSO into a 50 mM stock solution for later use. The control compound silibinin was purchased from Shanghai Dibai Biotechnology Co., Ltd., the batch number is EE09, and was prepared into a 40 mM stock solution with DMSO for later use. Thioacetamide was purchased from Sigma-Aldrich, the batch number is BCBV3031, and was prepared with DMSO to make a 1 M stock solution for later use. Oil Red O was purchased from Sigma-Aldrich, lot number SLBP5248V. 4% paraformaldehyde was purchased from Dingguo Biotechnology Co., Ltd., the batch number is 773001800. Propylene glycol was purchased from Sinopharm Chemical Reagent Co., Ltd., the batch number is 20170615.

2. Experimental animals

Melanin allele mutant translucent Albino strain zebrafish are reproduced through natural pair mating. The fish age was 3 days after fertilization, and there were 30 fish in each experimental group.

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

2. Test methods

1. Establishment of zebrafish non-alcoholic fatty liver model

The normal melanin allele mutant translucent Albino strain zebrafish 3 days after fertilization were randomly selected and placed in a six-well plate, with 30 fish in each well (i.e., each experimental group), and then treated with ethyl thiol at a final concentration of 7 mM. Treating zebrafish with amide for 72 hours establishes the zebrafish non-alcoholic fatty liver model.

2. Efficacy evaluation of test compounds

The zebrafish were transferred to a six-well plate, and 30 fish were randomly assigned to each well (i.e., each experimental group). Establishment of nonalcoholic fatty liver disease model in zebrafish induced by thioacetamide. Quantitatively transfer 40 mM test compounds 4, 5, 6, 7, 46, 67, 78, 85, 92 and 101 into a six-well plate and dilute to the corresponding concentration with water. Among them, the test compounds 4, 5, 6 and 7 were formulated with water into two concentration dosage groups with a final concentration of 100 µM and 200 µM respectively; the test compound 46 was formulated into a dosage group with a final concentration of 200 µM; the test compound 67, 78, 85, 92 and 101 were formulated into dosage groups with a final concentration of 100 µM; 50 mM positive control SAM was formulated with water into a dosage group with a final concentration of 50 μM; 40 mM positive control silibinin was formulated with water Prepare two concentration dose groups with final concentrations of 100 µM and 200 µM, and set up a normal control group (zebrafish treated with fish culture water) and a model control group at the same time. The total volume of liquid in each well is 3 mL. 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 from each experimental group were randomly selected and photographed under a dissecting microscope, and the images were analyzed with NIS -Elements D 3.10 advanced image processing software was used to analyze the image and collect data. The sum of optical density (S) of zebrafish liver fat was analyzed and counted. The inhibitory effect of each experimental group on zebrafish liver steatosis was evaluated using the following calculation formula. Inhibition rate of compounds on zebrafish liver steatosis %, statistical processing results are expressed as mean ± SE:

Hepatic steatosis inhibition rate (%) = [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 significant differences. The hepatic steatosis inhibition rate represents the extent to which the test compound reduces liver fat in zebrafish after modeling. The larger the value, the more obvious the test compound's effect on reducing or removing liver fat.

3. Test results

As shown in Tables 2 and 3, the average sum of optical density of zebrafish liver fat in the model control group was 22816, which was significantly greater than the average value of the normal control group (17734). Statistical analysis between the model control group and the normal control group showed , p value >0.001, indicating that the model is successfully established. Comparing the total optical density of zebrafish liver fat with the model control group, the positive control SAM (50 µM) inhibited zebrafish liver steatosis by 89% (p value > 0.001); silibinin at concentrations of 100 µM and 200 At µM, the inhibition rates of zebrafish liver steatosis were 49% and 69% respectively, and the related p values were >0.05 and >0.01 respectively. It shows that both the positive control substances SAM and silibinin have a protective effect on non-alcoholic fatty liver disease in zebrafish.

The test results are shown in Table 2 and Figure 1. When the concentration of test compounds 4, 5, 6 and 7 was 200 µM, the inhibition rates of steatosis in the modeled zebrafish liver were 99%, 86% and 92% respectively. and 93%, the lipid droplets (oil red O staining) in the liver of zebrafish in each group were significantly reduced, while at the same concentration, the inhibition rate of the positive control silibinin was only 69%. The test results show that at a concentration of 200 µM, the test compounds 4, 5, 6, 7 and 46 have significant therapeutic effects on zebrafish non-alcoholic fatty liver disease, and have a fat reduction or elimination effect on zebrafish non-alcoholic fatty liver disease. Far superior to silibinin. Table 2. Inhibitory effects of test compounds and silibinin on steatosis in zebrafish liver at a concentration of 200 µM (SAM concentration is 50 µM, n=10) Group Sum of liver fat optical density (pixel, mean ± SE ) Liver steatosis inhibition rate % 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*** silibinin 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 a concentration of 100 µM for steatosis in the modeled zebrafish liver were 83%, 84%, 98%, > 100% and > 100 respectively. %, 98% and 93%, the lipid droplets (oil red O staining) in the liver of zebrafish in each group were significantly reduced, while the inhibition rate of the positive control silibinin was only 49%, indicating that these compounds The fat reduction or elimination effect of zebrafish non-alcoholic fatty liver disease is much better than silibinin. At a concentration of 100 µM, test compounds 4, 5, 6, 7, 67, 78, 85, 92 and 101 had significant therapeutic effects on zebrafish non-alcoholic fatty liver disease. The test results are shown in Table 3 and Figure 2. Table 3. Inhibitory effects of test compounds and silibinin on steatosis in zebrafish liver at a concentration of 100 µM (SAM concentration is 50 µM, n=10) Group Sum of liver fat optical density (pixel, mean ± SE ) Liver steatosis inhibition rate % 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*** silibinin 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 greater inhibition rates on liver steatosis than silibinin, and are extremely effective in treating non-alcoholic fatty liver disease in zebrafish. effect.

Example 27: Evaluation of the efficacy of compounds 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., the batch number was HH06.

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

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

2. Modeling feed

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

3. Experimental animals

Source, species, strain: C57BL/6 mice, provided by Nanjing Branch of Beijing Vitong Lever Experimental Animal Technology Co., Ltd. (Experimental Animal Production License: SCXK (Su) 2016-0003); Experimental Animal Use License: SYXK (Military) 2012-0049; age: 6-8 weeks at the start of administration; weight: 18-22 g; gender: half male and half female.

4. Test methods

After adaptively feeding the mice with normal feed for 3 days, they were randomly assigned according to body weight: 8 mice were fed normal feed and set as the normal control group (NC); the other mice were fed high-fat feed until the end of the experiment. Mice were weighed and recorded every 3 days. After feeding mice with high-fat feed for 56 days (8 weeks) to establish the model, blood was collected from the orbital vein of the mice to detect blood biochemical indicators to determine whether the model was successfully established.

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

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

3. Test results

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

Compounds 4 and 7 were administered continuously for 1 month at 35 or 70 mg/kg respectively. Compared with the model group, they could significantly reduce the levels of ALT and AST in the blood. They also had an effect on TC, TG and MDA in the liver tissue. Significant improvement (all p values>0.01), and can significantly reduce the expression level of the inflammatory factor TNFα; Compound 7 can also significantly reduce the levels of TG and LDL-C in the blood, and its low-dose group can also significantly increase SOD activity ( 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 ^* silibinin 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. Effects of compounds on TC, TG, and HDL-C in blood biochemical indicators of NASH mice and the impact 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 ^** silibinin 70 2.75±0.84 1.16±0.22 ^* 0.85±0.48 1.91±0.35 ^** Note: Compared with the pattern group, ^* p >0.05, ^** p >0.01. Table 6. Effects of compounds on ALT, AST and TNF-α in blood biochemical indicators 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 ^** silibinin 70 103.33±26.43 ^** 127.39±7.75 ^** 423.36±8.73 ^** Note: Compared with the pattern 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 pattern group, ^* p >0.05, ^** p >0.01.

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

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: Single-dose acute toxicity test study on mice of compounds

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., the batch number was HH06. Before use, a suspension of corresponding concentration was prepared by ultrasound with normal saline.

Solution preparation for the low-dose group (1.5 g/kg): Precisely weigh a quantitative amount of test compound 7 or positive control, add a certain amount of physiological saline, and sonicate until evenly dispersed, and prepare an oral mixture with a concentration of 75 mg/mL. suspension. The dosing volume is 20 mL/kg.

Preparation of solution for the high-dose group (3.0 g/kg): Precisely weigh a quantitative amount of test compound 7 or positive control, add a certain amount of normal saline, sonicate until evenly dispersed, and prepare an oral suspension with a concentration of 150 mg/mL. liquid. The dosing volume is 20 mL/kg.

2. Experimental animals and feeding conditions

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

2. Test methods

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, with 4 mice in each group, half male and half female, and fasted for 6 Hours later, compound 7 suspension or silibinin suspension was administered by intragastric administration in a single dose at 20 mL/kg.

3. Test results

The dosage and mortality rate of mice in each group are shown in Table 8. No immediate toxic reactions were seen in each administration group after administration, and no delayed toxic reactions were seen during the observation period from 24 hours to 14 days. The animals were in good condition and all mice survived. The maximum tolerated dose of compound 7 and silibinin in the mouse acute toxicity test was 3 g/kg. Table 8. Dosage and mortality rate 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 Silybin low dose group 4 1.5 75 20 0/4 Silybin high dose group 4 3.0 150 20 0/4

The above and other objects and features of the present invention will become apparent from the following description of the invention when taken in conjunction with the accompanying drawings, in which: Figure 1 is a photo of oil red O stained microscopic examination of zebrafish after administration of each test compound. In the figure, the dotted area shows the liver part, 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 milk thistle. 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 photo of oil red O stained microscopic examination of zebrafish after administration of each test compound. In the figure, the dotted area shows the liver part, 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 milk thistle. 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 Group 85 (100 µM), j is compound 92 group (100 µM); Figure 3 shows histopathological staining photos (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 (8)

A compound, optical isomer or pharmaceutically acceptable salt thereof, represented by general formula (I),

Where: R ¹ is selected from hydroxyl, halogen or C _1-5 alkyl; R ² is selected from hydroxyl; R ³ is selected from hydrogen or hydroxyl; R ⁴ is selected from hydroxyl; R ⁵ is selected from hydrogen or hydroxyl; R ⁶ is selected from substitution C _1-5 alkyl, wherein the substituent in the substituted C _1-5 alkyl in the R ⁶ optional group is selected from hydroxyl; R ⁷ is selected from C _1-3 alkoxy; R ⁸ is selected from hydroxyl; A is selected from oxygen; A' or A" are independently selected from oxygen; E or G are independently selected from C or CH, and there is a carbon-carbon single bond between E and G; X and Y are independently selected ground is selected from CH; Z, Z' are each independently selected from CH; n is 0, 1 or 2; q is 0, 1, 2 or 3; p is 1, 2 or 3; and r is 0 or 1. The compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1, wherein: n is 1; p is 1; q is 1; and r is 1. The compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1, wherein the halogen is fluorine. The compound, optical isomer or pharmaceutically acceptable salt thereof as described in 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-yl}chroman-3,4,5,7-tetrol; 2-{8 -Hydroxy-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-yl}-7-methoxychroman-3,5-diol; and 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. The compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1, wherein the compound is selected from any of the following compounds: (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; and (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. A pharmaceutical composition, in which the compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1 is the active ingredient or the main active ingredient, supplemented by pharmaceutically acceptable excipients. The use of a compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1 in the preparation of a medicament for treating or preventing liver disease. The use of a compound, optical isomer or pharmaceutically acceptable salt thereof as described in claim 1 in the preparation of a medicament for treating or preventing fatty liver, liver fibrosis and cirrhosis.