O-glucoside derivative as well as preparation method and application thereof

Abstract

The invention discloses an O-glucoside derivative as well as a preparation method and application thereof. The O-glucoside derivative disclosed by the invention has the advantages of obvious myocardial cell protection effect, feasible and reasonable preparation route, lower cost, less use of toxic and harmful reagents, no pollution to the environment and suitability for large-scale industrial production. According to the O-glucoside derivative with heart protection activity and the preparation method of the O-glucoside derivative, the basis can be effectively provided for developing new treatment of heart failure, the economic benefit in the future is huge, the wide social benefit can be generated, and the application prospect is wide.

Description

Technical Field

[0001] The present invention relates to an O-glucoside derivative and a preparation method thereof and application thereof in preparing a medicine for protecting myocardial cells and preventing myocardial cell damage. The present invention belongs to the field of pharmaceutical chemistry. Background Art

[0002] Heart failure is a progressive disease characterized by persistent or episodic worsening of symptoms, leading to worsening of functional capacity and requiring intensive treatment. According to the 2019 my country Heart Failure Blue Book Report, it is estimated that there are 6.5 million to 8.75 million heart failure patients. The prevalence of heart failure increases with age. The prevalence of heart failure in people over 70 years old is >10%. The 5-year mortality rate of heart failure patients is 50%, and the 1-year mortality rate of patients with severe heart failure can reach 50%. According to the left ventricular ejection fraction, heart failure can be divided into three categories: heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and heart failure with an intermediate ejection fraction. At present, there are few drug treatment options for patients with heart failure and mildly reduced or preserved left ventricular ejection fraction.

[0003] The natural product phlorizin is a naturally occurring O-glycoside found in many plants and the bark of apple trees and has been successfully used to lower serum glucose levels. Phlorizin derivatives were originally developed as hypoglycemic drugs for the treatment of type 2 diabetes, but the latest studies have shown that phlorizin derivatives (such as empagliflozin, dapagliflozin, sogliflozin and other gliflozin drugs) can reduce the risk of death and other adverse outcomes in patients with chronic heart failure and reduced ejection fraction (i.e., left ventricular ejection fraction ≤ 40%) and chronic kidney disease, regardless of whether they have type 2 diabetes. The low bioavailability and selectivity of the natural product phlorizin limit the clinical application of phlorizin.

[0004] The invention obtains novel O-glucoside derivatives by structurally modifying the natural product phlorizin, and finds that the O-glucoside derivatives have the effect of protecting myocardial cells, so the invention is proposed. Summary of the invention

[0005] The purpose of the present invention is to provide an O-glucoside derivative and a preparation method thereof and an application thereof in protecting myocardial cells and preventing myocardial cell damage.

[0006] Specifically, the present invention is realized through the following technical solutions:

[0007] The present invention provides an O-glucoside derivative or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or hydrate thereof, wherein the structure of the O-glucoside derivative is shown in general formula D, general formula E or general formula F:

[0008]

[0009] Wherein, R1, R2 and R3 are selected from any one of a benzene ring, a heteroaryl group, a five-membered ring or a six-membered ring; X1 and X2 represent substituents located at any substitutable position on the R1 or R2 group;

[0010] R4 is selected from hydrogen or a straight or branched chain alkyl group containing 1 to 3 carbons;

[0011] X1 is selected from any one of hydrogen, straight or branched alkyl containing 1 to 3 carbon atoms, carboxyl, cyano, ester, nitro, amino, halogen or haloalkyl containing 1 to 3 carbon atoms;

[0012] X2, X3 and X4 are each independently selected from any one of hydrogen, a straight or branched chain alkyl group containing 1 to 3 carbon atoms, a carboxyl group, a hydroxyl group, a cyano group, an ester group, a nitro group or an amino group.

[0013] Preferably, the straight-chain or branched alkyl group containing 1 to 3 carbon atoms includes methyl, ethyl, propyl and isopropyl; and the halogenated alkyl group includes monochloromethyl and trifluoromethyl.

[0014] Among them, preferably, the heteroaryl group is pyridine.

[0015] Wherein, preferably, the derivative is selected from any one of the following compounds:

[0016]

[0017]

[0018]

[0019] Furthermore, the present invention also provides a method for preparing the O-glucoside derivative represented by general formula D, the preparation method comprising the following steps:

[0020]

[0021] (1) 4-methoxyphenethylamine (Compound I) and Compound II (X1 is selected from any one of methyl, ethyl, trifluoromethyl or halogen, R1 is selected from any one of benzene ring, five-membered ring or six-membered ring) are reacted under alkaline conditions (potassium carbonate, pyridine, triethylamine can all be used as alkaline reagents, among which triethylamine is preferably an alkaline reagent), in the presence of 4-dimethylaminopyridine (DMAP) and 0°C, with dichloromethane (DCM) as a solvent, and the molar equivalent ratio of Compound I, Compound II, triethylamine and DMAP is 1.2:1:1:0.5, to obtain Compound III-1-III-11.

[0022]

[0023]

[0024]

[0025] (2) Compound III is dissolved in anhydrous DCM, and BBr3 is slowly added under argon at 0°C for 1-2 hours. The molar equivalent ratio of compound III to BBr is 1:4 to obtain compounds IV1-IV-11.

[0026]

[0027]

[0028]

[0029] (3) Compound IV and acetyl bromide-α-D-glucose are reacted under alkaline conditions (potassium carbonate, sodium hydroxide, and sodium carbonate can all be used as alkaline reagents, among which sodium hydroxide is preferably an alkaline reagent). The catalyst can be benzyltriethylammonium chloride, benzyltributylammonium chloride, or tetrabutylammonium bromide, among which tetrabutylammonium bromide is preferably used as the catalyst and DCM is used as the solvent. The reaction is performed for 12-28 hours, and the molar equivalent ratio of compound IV, compound V, tetrabutylammonium bromide, and sodium hydroxide is 1:2:1:5 to obtain compounds V-1-V-11.

[0030]

[0031]

[0032] (4) Compound V is dissolved in anhydrous MeOH, and lithium hydroxide is added at room temperature to react for 1-2 hours, wherein the molar equivalent ratio of compound V:lithium hydroxide is 1:4, to obtain compounds D1-D11.

[0033]

[0034] Furthermore, the present invention also provides a method for preparing the O-glucoside derivative represented by general formula E, the preparation method comprising the following steps:

[0035]

[0036] (1) Compound VII (X3 is selected from any one of methyl, ethyl or isopropyl) and compound VIII (X2 is selected from any one of methyl, ethyl, isopropyl, nitro or amino, R3 is selected from a benzene ring or any one of a heterocyclic ring containing O, N or S, and R4 is selected from hydrogen or methyl) are reacted under alkaline conditions (potassium carbonate, sodium hydride, and sodium carbonate can all be used as alkaline reagents, among which potassium carbonate is preferably an alkaline reagent), the reaction temperature is 0 to 80°C, ethanol or acetonitrile is used as a solvent, and the molar equivalent ratio of compound VII, compound VIII, and potassium carbonate is 1:1:4, and after the reaction, compounds IX-1 to IX-10 are obtained.

[0037]

[0038]

[0039] (2) Compound IX and 4-hydroxyphenylboronic acid are reacted under alkaline conditions (potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate can be used as alkaline reagents, wherein sodium carbonate is preferably used as alkaline reagent), the catalyst can be selected from bis(triphenylphosphine)palladium dichloride, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride, tetrakistriphenylphosphine palladium or 1,1'-bis(diphenylphosphino)ferrocene nickel dichloride, wherein tetrakistriphenylphosphine palladium is preferably used as the catalyst, the solvent can be selected from toluene:ethanol:water=3:1:3 or 1,4-dioxane:water=4:1, preferably 1,4-dioxane:water=4:1, the reaction is carried out for 12-20 hours, and the molar equivalent ratio of compound IX, 4-hydroxyphenylboronic acid, tetrakistriphenylphosphine palladium and sodium carbonate is 1:1.1:0.05:3, to obtain compound X-1-X-10.

[0040]

[0041]

[0042] (4) Compound X and acetyl bromide-α-D-glucose are reacted under alkaline conditions (potassium carbonate, sodium hydroxide, and sodium carbonate can all be used as alkaline reagents, wherein sodium hydroxide is preferably an alkaline reagent), the catalyst can be benzyltriethylammonium chloride, benzyltributylammonium chloride, and tetrabutylammonium bromide, wherein tetrabutylammonium bromide is preferably used as the catalyst, and DCM is used as the solvent. The reaction is carried out for 12-28 hours, and the molar equivalent ratio of compound X, acetyl bromide-α-D-glucose, tetrabutylammonium bromide, and sodium hydroxide is 1:2:1:5. After the reaction, compounds XI-1-XI-11 are obtained.

[0043]

[0044]

[0045] (4) Compound XI is dissolved in anhydrous MeOH, and lithium hydroxide is added at room temperature for reaction for 1-2 hours, wherein the molar equivalent ratio of compound XI to lithium hydroxide is 1:4, to obtain compounds E1-E10.

[0046]

[0047] Furthermore, the present invention also provides a pharmaceutical composition, which comprises the O-glucoside derivative of general formula D, general formula E or general formula F or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or hydrate thereof.

[0048] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.

[0049] Furthermore, the present invention also provides the O-glucoside derivative or its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or hydrate or the pharmaceutical composition for use in the preparation of a drug for protecting myocardial cells or preventing myocardial cell damage.

[0050] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0051] In the present invention, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by the same number of the same or different halogen atoms. Thus, "haloalkyl" encompasses the above definition of alkyl.

[0052] In the present invention, the term "heteroaryl" refers to one or more carbon atoms in the aromatic group replaced by heteroatoms (such as O, S or N). Preferably, heteroaryl refers to a 5- or 6-membered aromatic monocyclic ring, in which 1, 2 or 3 carbon atoms are replaced by the same or different O, N or S heteroatoms. Alternatively, preferably, it refers to an aromatic bicyclic or tricyclic ring system, in which 1, 2, 3, 4 or 5 carbon atoms are replaced by the same or different O, N or S heteroatoms. For example, furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 1H-indolyl, benzimidazolyl, benzoxazolyl, indoloxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzo pyridinyl, pyrrolidino, pyrrolidinyl, pyrrolopyrrolyl, pyrrolothiazyl, pyrrolidino, pyrrolopyrrolyl, pyrrolopyrrolyl, pyrrolothiazinyl, pyrrolidin ...

[0053] Compared with the prior art, the present invention has the following beneficial effects:

[0054] The present invention synthesizes a series of O-glucoside derivatives, and cell experiments prove that the obtained O-glucoside derivatives have good cardiomyocyte protective activity, and the cardiomyocyte protective activity of some derivatives is better than that of the natural product phlorizin, and they have the potential to become anti-heart failure drugs, providing an effective technical means for protecting cardiomyocytes and treating heart failure. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0056] Figure 1 It represents the in vitro cell survival rate of neonatal rat primary cardiomyocytes after starvation treatment with sugar-free DMEM medium for 3 hours when the compound represented by general formula D, general formula E or general formula F of the present invention is 100 μmol / L.

[0057] Figure 2 It represents the in vitro cell survival rate of neonatal rat primary cardiomyocytes after starvation treatment with sugar-free DMEM medium for 8 hours when the compound represented by general formula D, general formula E or general formula F of the present invention is 100 μmol / L.

[0058] Figure 3 The graphs show the effects of the compounds D4 and E9 of the present invention on ATP (A) and SOD (B) in primary cardiomyocytes of neonatal rats starved for 8 h with sugar-free DMEM medium. DETAILED DESCRIPTION

[0059] The embodiments of the present invention are described in detail below. The embodiments are given to better illustrate the contents of the present invention and are only used to explain the present invention, but should not be understood as limiting the present invention.

[0060] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0061] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0062] Example 1: The synthesis method of compound V-1, the operation steps are as follows:

[0063] Weigh 69.82 mg (0.572 mmol) of DMAP and place it in a 50 mL dry single-mouth round-bottom flask, add 6 mL of dichloromethane, 204 uL (1.371 mmol) of 4-methoxyphenylethylamine, and 160 uL (1.143 mmol) of triethylamine, dissolve p-chloromethylbenzoyl chloride in 6 mL of dichloromethane, and slowly drop it into the reaction system. Start timing after the addition is completed, the temperature is 0°C, and the reaction time is 30 min-60 min. After the reaction is completed, 15 mL of distilled water is added to quench, and the reaction is extracted with dichloromethane. The organic layer is collected, anhydrous sodium sulfate is added to dry, and the filtrate is collected and concentrated under reduced pressure. Purification is performed by silica gel column chromatography, and the eluent V (dichloromethane): V (methanol) = 60:1. The separated product is concentrated and spin-dried to obtain a white solid III-1 with a yield of 92.52%. Weigh 200 mg (0.66 mmol) of white solid compound III-1 and dissolve it in 8 mL of dichloromethane. Under argon conditions at 0°C, slowly add 250 uL (2.64 mmol) of boron tribromide. Start timing after the addition is completed. The reaction time is 1-2 h. After the reaction is completed, slowly add saturated NaHCO3 aqueous solution to the reaction system to adjust it to weak alkalinity, filter it with suction, collect the filtrate, extract it with dichloromethane and distilled water, collect the organic layer, add anhydrous sodium sulfate to dry it, filter it with suction, and concentrate it under reduced pressure to obtain a white solid IV-1. Weigh 200 mg (1.388 mmol) of white solid IV-1, 224.72 mg (1.388 mmol) of tetrabutylammonium bromide, 576.74 mg (2.776 mmol) of acetyl bromide-α-D-glucose, and dissolve them in 12 mL of dichloromethane. Add 1.39 mL (6.94 mmol) of 5M NaOH. The reaction is carried out at room temperature for 12 hours. After the reaction is completed, 12 mL of distilled water is added to quench the reaction. The mixture is extracted with dichloromethane, and the organic layer is collected. Anhydrous sodium sulfate is added to dry the mixture, and the filtrate is collected and concentrated under reduced pressure. The mixture is purified by silica gel column chromatography, and the eluent V (petroleum ether): V (ethyl acetate) = 5:1-1:2. The separated product is concentrated and dried to obtain 223.06 mg of white solid V-1, and the yield is 26.01%.

[0064] 1H NMR (600MHz, DMSO-d6)) δ8.60 (s, 1H), 7.80 (t, J = 11.4Hz, 2H), 7.51 (d, J = 5.3Hz, 2H), 7.1 9(d,J=8.0Hz,2H),6.92(d,J=6.6Hz,2H),5.51(d,J=6.5Hz,1H),5.40(t,J=10.6Hz,1H),5 .01(dt,J=30.0,12.0Hz,2H),4.77(d,J=39.7Hz,2H),4.22(t,J=18.0Hz,2H),4.05(d,J= 12.0Hz,1H),3.45(s,2H),2.82(d,J=30.5Hz,2H),2.01(s,6H),1.99(s,3H),1.97(s,3H).

[0065] 13 C NMR (151MHz, DMSO-d6)) δ170.38,170.01,169.74,169.53,166.05,155.26,140.91,134.80,134.42,130.19,130.00,129.57,129. 10,127.89,127.86,122.03,116.72,97.62,72.29,71.10,68.41,62.00,45.84,41.37,34.53,33.95,20.85,20.78,20.73,20.68.

[0068] Example 2: The synthesis method of compound D1, the operation steps are as follows:

[0069] Weigh 90.20 mg (0.146 mmol) of white solid V-1 and 14.2 mg (0.581 mg) of LiOH into a 50 mL dry single-mouth round-bottom flask, add 8 mL of methanol, and react at room temperature for 2 h. After the reaction, spin dry the reaction solution, dissolve it with V (dichloromethane): V (methanol) = 8:1, and purify it by silica gel column chromatography, eluent V (dichloromethane): V (methanol) = 30:1-5:1. The separated product is concentrated and spin dried to obtain white solid D1, with a yield of 90.2%.

[0070] 1H NMR (600MHz, DMSO-d6)) δ8.58(dt,J=25.7,5.6Hz,1H),7.81(t,J=8.2Hz,2H),7.45(dd,J=78.1,8.1Hz,2H),7.14(d, J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),5.31(d,J=5.2Hz,1H),5.11(d,J=4.8Hz,1H),5.05(d,J=5.3Hz,1H),4.81(t,J=6 .0Hz,2H),4.58(t,J=5.8Hz,1H),4.46(s,1H),3.67(dd,J=11.9,5.3Hz,1H),3.46(t,J=6.0Hz,2H),3.42(q,J=6.0Hz, 1H)3.25(td,J=8.8,4.9Hz,1H),3.20(td,J=9.0,8.4,5.1Hz,1H),3.14(td,J=9.1,5.3Hz,1H),2.78(t,J=7.4Hz,2H).

[0071] 13 C NMR(151MHz,DMSO-d6))δ165.74,155.96,141.53,140.59,134.51,133.71,132.79,129.59,128.81,12 7.57,127.16,116.18,100.49,77.04,76.66,73.29,73.12,69.72,60.71,57.76,45.54,41.19,34.30.

[0073] MS ESI( + ):m / z:calculated for C 22 H 26 ClNO7 + ([M+H]+)452.35; found452.14.

[0074] Example 3: The synthesis method of compound V-2, the operation steps are as follows:

[0075] The preparation method is the same as that of Example 1 to obtain white solid V-2 with a yield of 23.96%.

[0076] 1H NMR (600MHz, DMSO-d6) δ8.63(t,J=5.6Hz,1H),7.83(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),7 .18(d,J=8.4Hz,2H),6.91(d,J=8.6Hz,2H),5.49(d,J=8.0Hz,1H),5.39(t,J=9.6Hz,1H),5.0 3(t,J=8.1Hz,1H),4.98(t,J=9.6Hz,1H),4.20(q,J=2.3Hz,2H),4.05(d,J=10.0Hz,1H),3.44 (q,J=6.8Hz,3H),2.79(t,J=7.3Hz,2H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.96(s,3H).

[0077] 13 C NMR(151MHz,DMSO-d6)δ170.02,169.65,169.38,169.18,165.13,154.93,136.44,134.03,133.32,129.82,129.82,129.08,,1 29.08,127.82,127.82,116.39,116.39,97.31,71.97,70.78,70.75,68.09,61.66,41.04,34.13,20.49,20.42,20.37,20.32.

[0078] Example 4: The synthesis method of compound D2, the operation steps are as follows:

[0079] The preparation method was the same as that of Example 2 to obtain white solid D2 with a yield of 77.4%.

[0080] 1H NMR (600MHz, DMSO-d6) δ8.63(t,J=5.6Hz,1H),7.83(d,J=8.3Hz,2H),7.53(d,J=8.2Hz,2H),7.14(d,J=8.2Hz,2H),6 .95(d,J=8.4Hz,2H),5.28(d,J=5.1Hz,1H),5.07(d,J=4.8Hz,1H),5.01(d,J=5.3Hz,1H),4.80(d,J=7.6Hz,1H),4.5 5(t,J=5.8Hz,1H),3.68(dd,J=10.7,4.8Hz,1H),3.45(q,J=6.1Hz,2H),3.42(d,J=6.3Hz,1H),3.35(dd,J=15.3,9.5 Hz,1H),3.24(dd,J=8.7,4.9Hz,1H),3.21(dd,J=7.8,5.1Hz,1H),3.16(dd,J=9.4,4.4Hz,1H),2.78(t,J=7.4Hz,2H).

[0081] 13 C NMR (151MHz, DMSO-d6) δ165.15, 155.96, 135.95, 133.36, 132.73, 129.55, 129.55, 129.10, 129. 10, 128.42, 128.42, 116.20, 116.20, 100.53, 77.03, 76.66, 73.28, 69.75, 60.74, 41.86, 34.21.

[0082] MS ESI( + ):m / z:calculated for C 21 H 24 ClNO7 + ([M]+)437.23; found 437.12.

[0083] Example 5: The synthesis method of compound V-3, the operation steps are as follows:

[0084] The preparation method is the same as that of Example 1 to obtain white solid V-3 with a yield of 25.76%.

[0085] 1H NMR (600MHz, DMSO-d6) δ8.48(t,J=5.6Hz,1H),7.72(d,J=7.9Hz,2H),7.25(d,J=7.9Hz,2H),7.18(d,J=8.2 Hz,2H),6.91(d,J=8.2Hz,2H),5.50(d,J=8.0Hz,1H),5.40(t,J=9.6Hz,1H),5.03(dd,J=9.8,8.0Hz,1H),4. 98(t,J=9.6Hz,1H),4.22(dd,J=13.8,5.8Hz,1H),4.18(t,J=6.0Hz,1H),4.05(dd,J=12.2,2.1Hz,1H),3.4 2(q,J=6.9Hz,2H),2.78(t,J=7.4Hz,2H),2.34(s,3H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.96(s,3H).

[0086] 13 C NMR (151MHz, DMSO-d6) δ170.09,169.72,169.44,169.24,166.05,154.93,140.99,131.82,129.87,129.87,128.86,,128.86,127. 20,127.20,116.39,116.39,97.29,71.97,70.78,70.75,68.08,61.68,,61.68,41.01,34.30,21.00,20.55,20.49,20.43,20.38.

[0087] Example 6: The synthesis method of compound D3, the operation steps are as follows:

[0088] The preparation method was the same as that of Example 2 to obtain white solid D3 with a yield of 84.19%.

[0089] 1H NMR (600MHz, DMSO-d6) δ8.46(t,J=5.6Hz,1H),7.72(d,J=7.9Hz,2H),7.25(d,J=7.8Hz,2H),7.14(d,J=8.2Hz,2H),6.95 (d,J=8.3Hz,2H),5.28(d,J=5.0Hz,1H),5.07(d,J=4.8Hz,1H),5.01(d,J=5.3Hz,1H),4.80(d,J=7.5Hz,1H),4.56(t,J=5 .8Hz,1H),3.68(dd,J=10.8,4.7Hz,1H),3.46(t,J=6.1Hz,1H),3.42(q,J=6.7Hz,2H),3.29(dd,J=14.9,10.8Hz,1H),3.2 4(dd,J=8.8,4.8Hz,1H),3.20(dd,J=13.0,7.7Hz,1H),3.17(dd,J=10.2,5.1Hz,1H),2.77(t,J=7.4Hz,2H),2.34(s,3H).

[0090] 13 C NMR(151MHz,DMSO-d6)δ166.06,155.93,140.93,132.85,131.85,129.53,129.53,128.83,128.83, 127.17,127.17,116.20,116.20,100.54,77.02,76.65,73.29,69.75,60.73,41.55,34.75,20.97.

[0091] MS ESI( + ):m / z:calculated for C 22 H 27 NO7 + ([M+H]+)418.92; found418.18.

[0092] Example 7: The synthesis method of compound V-4, the operation steps are as follows:

[0093] The preparation method is the same as that of Example 1 to obtain white solid V-4 with a yield of 25.87%.

[0094] 1H NMR (600MHz, DMSO-d6) δ8.57(t,J=5.6Hz,1H),7.88(dd,J=8.7,5.7Hz,2H),7.28(t,J=8.9Hz,2H ),7.19(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),5.49(d,J=8.0Hz,1H),5.39(t,J=9.6Hz,1H),5. 03(t,J=9.7Hz,1H)4.98(t,J=9.6Hz,1H),4.20(q,J=4.4Hz,2H),4.05(dd,J=11.9,1.9Hz,1H),3 .44(q,J=6.6Hz,2H),2.79(t,J=7.4Hz,2H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.96(s,3H).

[0095] 13 C NMR(151MHz,DMSO-d6)δ170.03,169.65,169.38,169.17,165.13,163.01,154.92,134.07,131.07,129.82,129.82,129.79,1 29.72,116.40,116.40,115.28,115.14,97.33,71.98,70.79,70.76,68.10,61.66,41.04,34.19,20.48,20.41,20.37,20.31.

[0096] Example 8: The synthesis method of compound D4, the operation steps are as follows:

[0097] The preparation method was the same as that of Example 2 to obtain white solid D4 with a yield of 70.31%.

[0098] 1H NMR (600MHz, DMSO-d6) δ8.57(t,J=5.6Hz,1H),7.88(d,J=14.0Hz,2H),7.28(d,J=17.4Hz,2H),7.14(d, J=8.4Hz,2H),6.95(d,J=8.2Hz,2H),5.29(d,J=4.9Hz,1H),5.08(d,J=4.6Hz,1H),5.02(d,J=5.2Hz,1H ),4.81(d,J=7.5Hz,1H),4.56(t,J=5.8Hz,1H),3.68(dd,J=11.4,6.0Hz,1H),3.47(t,J=6.0Hz,2H),3. 41(q,J=6.1Hz,1H),3.30(dd,J=15.6,9.8Hz,1H),3.25(dd,J=8.8,4.8Hz,1H),3.208(dd,J=13.0,7.9Hz 1H), 3.14 (dd, J=11.3, 5.2Hz, 1H), 2.78 (t, J=7.4Hz, 2H).

[0099] 13 C NMR(151MHz,DMSO-d6)δ165.14,163.01,155.95,132.77,131.11,129.80,129.74,129.54, 129.54,116.20,115.30,115.15,100.53,77.02,76.65,73.28,69.75,60.73,41.15,34.26.

[0100] MS ESI( + ):m / z:calculated for C 21 H 24 FNO7 + ([M]+)421.30; found 421.15.

[0101] Example 9: The synthesis method of compound V-5, the operation steps are as follows:

[0102] The preparation method is the same as that of Example 1 to obtain white solid V-5 with a yield of 26.67%.

[0103] 1H NMR(600MHz,Chloroform-d)δ7.60(d,J=7.5Hz,1H),7.36(t,J=4.71Hz,1H),7.33(d,J=7.8Hz,1H),7.30(t,J=7 .7Hz,1H),7.18(d,J=8.2Hz,2H),6.94(d,J=8.1Hz,2H),5.29(t,J=9.2Hz,1H),5.25(t,J=8.4Hz,1H),5.16(t,J =9.4Hz,1H),5.05(d,J=7.4Hz,1H),4.28(dd,J=12.3,5.3Hz,1H),4.16(dd,J=12.3,2.5Hz,1H),3.85(dd,J=4.8 ,2.5Hz,1H),3.70(q,J=6.7Hz,2H),2.91(t,J=7.0Hz,2H),2.06(s,3H),2.05(s,3H),2.04(s,3H),2.03(s,3H).

[0104] 13 C NMR (151MHz, CDCl3) δ170.73,170.40,169.56,169.46,166.62,155.75,135.17,133.84,131.44,130.68,130.68,130.35,13 0.22,130.07,127.23,117.39,117.39,99.36,72.84,72.15,71.28,68.40,62.10,41.47,34.82,20.83,20.77,20.77,20.73.

[0105] Example 10: The synthesis method of compound D5, the operation steps are as follows:

[0106] The preparation method was the same as that of Example 2 to obtain white solid D5 with a yield of 78.63%.

[0107] 1H NMR (600MHz, DMSO-d6) δ8.49(t,J=5.7Hz,1H),7.47(d,J=7.9Hz,1H),7.42(t,J=6.8Hz,1H),7.37(t,J=7.4Hz,1H),7.33(d,J=6. 0Hz,1H),7.17(d,J=8.1Hz,2H),6.96(d,J=8.2Hz,2H),5.29(d,J=5.1Hz,1H),5.07(d,J=4.9Hz,1H),5.01(d,J=5.3Hz,1H),4.81( d,J=7.6Hz,1H),4.56(t,J=5.8Hz,1H),3.68(dd,J=10.5,5.5Hz,1H),3.46(t,J=5.8Hz,1H),3.42(q,J=6.8Hz,2H),3.30(dd,J=9 .4,4.7Hz,1H),3.25(dd,J=8.7,4.8Hz,1H),3.21(dd,J=13.9,5.3Hz,1H),3.16(dd,J=14.5Hz,9.2Hz,1H),2.77(t,J=7.4Hz,2H).

[0108] 13 C NMR (151MHz, DMSO-d6δ166.30,156.00,137.15,132.62,130.69,129.90,129.62,129.62,129. 62,128.81,127.10,116.20,116.20,100.58,77.03,76.67,73.30,69.76,60.75,40.81,34.11.

[0109] MS ESI( + ):m / z:calculated for C 21 H 24 ClNO7 + ([M]+)437.34; found 437.12.

[0110] Example 11: A method for synthesizing compound V-6, the steps of which are as follows:

[0111] The preparation method is the same as that of Example 1 to obtain white solid V-6 with a yield of 22.78%.

[0112] 1H NMR(600MHz,Chloroform-d)δ7.28(d,J=9.0Hz,1H),7.24(t,J=14.8Hz,1H),7.18(d,J=7.6Hz,1H),7.15(t,J=8. 3Hz,1H),7.15(t,J=8.3Hz,2H),6.93(d,J=8.5Hz,2H),5.75(d,J=11.9Hz,1H),5.28(t,J=9.4Hz,1H),5.24(t,J=7 .3Hz,1H),5.15(t,J=9.4Hz,1H),5.04(d,J=7.4Hz,1H),4.27(dd,J=12.3,5.3Hz,1H),4.15(dd,J=12.4,2.5Hz,1H ),3.66(q,J=6.7Hz,2H),2.88(t,J=6.9Hz,2H),2.38(s,3H),2.05(s,3H),2.04(s,3H),2.03(s,3H),2.02(s,3H).

[0113] 13 C NMR (151MHz, CDCl3) δ170.72,170.39,170.21,169.55,169.45,155.73,136.55,136.16,133.91,131.15,130.01,130.01,12 6.69,125.85,117.38,117.38,99.35,72.83,72.15,71.28,68.39,62.08,41.02,35.06,20.82,20.77,20.74,20.72,19.84.

[0114] Example 12: The synthesis method of compound D6, the operation steps are as follows:

[0115] The preparation method was the same as that in Example 2 to obtain white solid D6 with a yield of 95.18%.

[0116] 1H NMR (600MHz, DMSO-d6) δ8.27(t,J=5.6Hz,1H),7.29(d,J=6,3Hz,1H),7.29(t,J=7,2Hz,1H),7.23(d,J=7.2Hz,1H),7.21(d,J=7.7Hz ,2H),7.16(d,J=8.2Hz,2H),6.96(d,J=8.1Hz,2H),5.29(d,J=5.1Hz,1H),5.07(d,J=4.8Hz,1H),5.01(d,J=5.4Hz,1H),4.80(d,J=7. 6Hz,1H),4.56(t,J=5.8Hz,1H),3.68(dd,J=11.4,5.8Hz,1H),3.46(q,J=5.6Hz,1H),3.42(t,J=7.0Hz,2H),3.30(dd,J=9.5,6.0Hz,1 H), 3.25 (dd, J = 8.7, 4.8Hz, 1H), 3.21 (dd, J = 13.6Hz, 5.9Hz, 1H), 3.16 (dd, J = 14.5Hz, 9.1Hz, 1H), 2.77 (t, J = 7.3Hz, 2H), 2.26 (s, 3H).

[0117] 13 C NMR(151MHz,DMSO-d6)δ169.06,155.97,137.39,135.14,132.77,130.39,129.59,129.59,129.16, 126.95,125.48,116.20,116.20,100.61,77.03,76.67,73.30,69.76,60.75,40.60,34.22,19.36.

[0118] MS ESI( + ):m / z:calculated for C 22 H 27 NO7 + ([M+H]+)418.82; found418.18.

[0119] Example 13: The synthesis method of compound V-7, the operation steps are as follows:

[0120] The preparation method is the same as that of Example 1 to obtain white solid V-7 with a yield of 27.39%.

[0121] 1H NMR(600MHz,Chloroform-d)δ7.10(d,J=8.1Hz,2H),6.93(d,J=8.1Hz,2H),5.44(t,J=5.7Hz,1H), 5.29(t,J=9.3Hz,1H)5.25(t,J=8.4Hz,1H),5.16(t,J=9.4Hz,1H),5.05(d,J=7.4Hz,1H),4.28(dd, J=12.4,5.4Hz,1H),4.17(dd,J=12.2,2.4Hz,1H),3.46(q,J=7.0Hz,2H),2.75(t,J=6.9Hz,2H),2.0 7(s,3H),2.06(s,3H),2.04(s,3H),2.03(s,3H),1.77(t,J=16.2Hz,5H),1.38(m,2H),1.21(m,4H).

[0122] 13 C NMR (151MHz, CDCl3) δ176.61,171.25,170.39,169.55,169.45,155.64,134.16,130.00,130.00,117.29,117.29,99.36, 72.83,72.15,71.29,68.40,62.08,45.66,40.59,35.07,29.80,29.80,25.83,25.83,25.83,20.83,20.77,20.74,20.72.

[0123] Example 14: The synthesis method of compound D7, the operation steps are as follows:

[0124] The preparation method was the same as that in Example 2 to obtain white solid D7 with a yield of 89.19%.

[0125] 1H NMR (600MHz, DMSO-d6) δ7.71(t,J=5.6Hz,1H),7.08(d,J=8.6Hz,2H),6.93(d,J=8.5Hz,2H),5.28(d,J=5.1Hz,1H),5.07(d,J=4.8 Hz,1H),5.01(d,J=5.3Hz,1H),4.79(d,J=7.6Hz,1H),4.55(t,J=5.5Hz,1H),3.68(dd,J=9.7,5.3Hz,1H),3.45(t,J=6.0Hz,1H),3. 28(dd,J=5.7,2.1Hz,1H),3.24(dd,J=8.8,4.9Hz,1H),3.20(dd,J=12.7Hz,7.3Hz,3H),3.15(dd,J=9.2Hz,3.8Hz,1H),2.62(t,J= 7.3Hz,2H),2.03(tt,J=11.6,3.4Hz,1H),1.68(m,2H),1.61(dd,J=16.4,12.9Hz,3H),1.29(m,2H),1.17(dd,J=25.2,12.3Hz,3H).

[0126] 13 C NMR(151MHz,DMSO-d6)δ175.12,155.89,132.85,129.52,129.52,116.13,116.13,100.56,7 7.02,76.65,73.28,69.75,60.73,44.03,40.21,34.37,29.25,25.51,25.51,25.32,25.32.

[0127] MS ESI( + ):m / z:calculated for C 21 H 31 NO7 + ([M]+)409.28; found 409.21.

[0128] Example 15: The synthesis method of compound V-8, the operation steps are as follows:

[0129] The preparation method is the same as that of Example 1 to obtain white solid V-8 with a yield of 22.60%.

[0130] 1H NMR (600MHz, DMSO-d6) δ7.79(t,J=5.7Hz,1H),7.15(d,J=8.7Hz,2H),6.92(d,J=8.6Hz,2H),5.50(d, J=8.0Hz,1H),5.42(t,J=9.6Hz,1H),5.06(t,J=7.98Hz,1H),5.00(t,J=9.6Hz,1H),4.23(dd,J=21.12 Hz,7.74Hz,2H),4.08(dd,J=12.0,2.1Hz,1H),3.23(q,J=7.2Hz,2H),2.66(t,J=7.3Hz,2H),2.49(d,J =7.4Hz,1H),2.03(s,6H),2.02(s,3H),1.98(s,3H),1.69(t,J=9.5Hz,2H),1.59(m,4H),1.49(m,2H).

[0131] 13 C NMR(151MHz,DMSO-d6)δ175.08,169.97,169.59,169.32,169.10,154.86,134.11,129.75,129.75,116.29,116.29,97 .34,71.95,70.77,70.72,68.08,61.65,44.30,40.24,34.32,29.93,29.93,25.56,25.56,20.46,20.37,20.32,20.28.

[0132] Example 16: The synthesis method of compound D8, the operation steps are as follows:

[0133] The preparation method was the same as that in Example 2 to obtain white solid D8 with a yield of 84.08%.

[0134] 1H NMR (600MHz, DMSO-d6) δ7.82(t,J=5.6Hz,1H),7.09(d,J=8.1Hz,2H),6.93(d,J=8.1Hz,2H),5.29(d,J=5.0Hz,1H), 5.10(d,J=4.8Hz,1H),5.04(d,J=5.2Hz,1H),4.79(d,J=7.6Hz,1H),4.57(t,J=5.8Hz,1H),3.67(dd,J=13.0,4.3Hz, 1H),3.45(dd,J=11.8,6.0Hz,2H),3.29(dd,J=9.5,5.6Hz,1H),3.25(dd,J=8.8,4.7Hz,1H),3.21(dd,J=11.2,5.9Hz ,3H),3.16(dd,J=9.1,5.2Hz,1H),2.63(t,J=7.4Hz,2H),1.68(t,J=9.4Hz,2H),1.58(m,4H),1.47(t,J=9.4Hz,2H).

[0135] 13 C NMR(151MHz,DMSO-d6)δ175.21,155.91,132.87,132.87,129.52,129.52,116.16,100.5 7,77.02,76.66,73.29,69.75,60.73,44.35,40.44,34.40,30.01,25.64,30.01,25.64.

[0136] MS ESI( + ):m / z:calculated for C 20 H 29 NO7 + ([M+H]+)396.83; found 396.19.

[0137] Example 17: The synthesis method of compound V-9, the operation steps are as follows:

[0138] The preparation method is the same as that of Example 1 to obtain white solid V-9 with a yield of 28.48%.

[0139] 1H NMR(600MHz,DMSO-d6)δ8.66(t,J=5.6Hz,1H),7.85(s,1H),7.78(d,J=7.8Hz,1H),7.59(d,J=5.8Hz,1H), 7.49(t,J=7.8Hz,1H),7.19(d,J=8.2Hz,2H),6.92(d,J=8.2Hz,2H),5.50(d,J=7.9Hz,1H),5.40(t,J=9.6 Hz,1H),5.04(t,J=7.9Hz,1H),4.99(t,J=9.6Hz,1H),4.21(dd,J=17.2Hz,7.7Hz,2H),4.06(dd,J=12.1,2 .1Hz,1H),3.45(q,J=6.8Hz,2H),2.80(t,J=7.2Hz,2H),2.01(d,J=3.0Hz,6H),1.99(s,3H),1.96(s,3H).

[0140] 13 C NMR(151MHz,DMSO-d6)δ169.96,169.59,169.33,169.11,164.70,154.91,136.55,133.97,133.15,130.94,130.31,129.78,1 29.78,126.94,125.88,116.37,116.37,97.31,71.95,70.77,70.73,68.09,61.64,41.03,34.04,20.44,20.37,20.33,20.28.

[0141] Example 18: The synthesis method of compound D9, the operation steps are as follows:

[0142] The preparation method was the same as that in Example 2 to obtain white solid D9 with a yield of 84.57%.

[0143] 1H NMR (600MHz, DMSO-d6) δ8.67(t,J=5.6Hz,1H),7.85(s,1H),7.78(d,J=7.8Hz,1H),7.59(d,J=6.1Hz,1H),7.49(t,J=7.9Hz,1H ),7.15(d,J=8.2Hz,2H),6.95(d,J=8.0Hz,2H),5.26(d,J=5.1Hz,1H),5.05(d,J=4.8Hz,1H),4.99(d,J=5.3Hz,1H),4.81(d,J =7.6Hz,1H),4.53(t,J=5.9Hz,1H),3.68(dd,J=12.0,5.7Hz,1H),3.47(dd,J=11.6,6.0Hz,1H),3.44(t,J=6.4Hz,2H),3.30(t ,J=5.0Hz,1H),3.25(dd,J=8.7,4.6Hz,1H),3.21(dd,J=13.0,4.9Hz,1H),3.16(dd,J=14.3,9.0Hz,1H),2.78(t,J=7.5Hz,2H).

[0144] 13 C NMR(151MHz,DMSO-d6)δ164.71,155.95,136.59,133.16,132.67,130.93,130.33,129.50,129. 50,126.96,125.90,116.19,116.19,100.53,77.00,76.64,73.26,69.72,60.70,41.16,34.13.

[0145] MS ESI( + ):m / z:calculated for C 21 H 24 ClNO7 + ([M]+)437.36; found 437.12.

[0146] Example 19: The synthesis method of compound V-10, the operation steps are as follows:

[0147] The preparation method is the same as that of Example 1 to obtain white solid V-10 with a yield of 25.87%.

[0148] 1H NMR (600MHz, DMSO-d6) δ8.47(t,J=5.2Hz,1H),7.63(s,1H),7.60(d,J=6.1Hz,1H),7.35(t,J=6.4Hz,1H),7 .32(d,J=5.0Hz,1H),7.19(d,J=8.1Hz,2H),6.92(d,J=8.1Hz,2H),5.50(d,J=8.1Hz,1H),5.40(t,J=9.6Hz ,1H),5.04(t,J=8.9Hz,1H),4.99(t,J=9.6Hz,1H),4.20(dd,J=20.8,8.8Hz,2H),4.06(d,J=11.9Hz,1H),3 .44(q,J=7.0Hz,2H),2.80(t,J=7.5Hz,2H),2.35(s,3H),2.01(d,J=3.5Hz,6H),1.99(s,3H),1.96(s,3H).

[0149] 13 C NMR (151MHz, DMSO-d6) δ169.96,169.58,169.32,169.11,166.24,154.88,137.47,134.61,134.10,131.59,129.76,129.76,128. 12,127.68,124.22,116.37,116.37,97.32,71.95,70.76,70.72,68.08,61.63,40.91,34.20,20.93,20.43,20.37,20.32,20.27.

[0150] Example 20: A method for synthesizing compound D10, wherein the steps are as follows:

[0151] The preparation method was the same as that of Example 2 to obtain white solid D10 with a yield of 67.17%.

[0152] 1H NMR (600MHz, DMSO-d6) δ8.47(t,J=5.6Hz,1H),7.63(s,1H),7.60(d,J=6.3Hz,1H),7.32(d,J=6.1Hz,2H),7.14(d,J=8.1Hz ,2H),6.95(d,J=8.1Hz,2H),5.26(d,J=5.1Hz,1H),5.05(d,J=4.7Hz,1H),4.99(d,J=5.2Hz,1H),4.81(d,J=7.5Hz,1H),4. 54(t,J=5.8Hz,1H),3.68(dd,J=11.2,4.6Hz,1H),3.47(dd,J=12.1,6.0Hz,1H),3.42(s,2H),3.30(dd,J=9.4,5.9Hz,1H), 3.25(dd,J=8.7,4.8Hz,1H), 3.22(dd,J=7.8,5.1Hz,1H), 3.16(dd,J=9.8,5.3Hz,1H), 2.78(t,J=7.4Hz,2H), 2.35(s,3H).

[0153] 13 C NMR(151MHz,DMSO-d6)δ166.25,155.91,137.48,134.65,132.80,131.59,129.48,129.48,128.14, 127.69,124.24,116.17,116.17,100.53,76.99,76.63,73.26,69.72,60.70,41.04,34.27,20.95.

[0154] MS ESI( + ):m / z:calculated for C 22 H 27 NO7 + ([M+H]+)418.87; found418.18.

[0155] Example 21: A method for synthesizing compound V-10, wherein the steps are as follows:

[0156] The preparation method is the same as that of Example 1 to obtain white solid V-11 with a yield of 24.94%.

[0157] 1H NMR (600MHz, DMSO-d6) δ8.81(t,J=5.6Hz,1H),8.15(s,1H),8.12(d,J=8.0Hz,1H),7.89(d,J=7.8Hz ,1H),7.71(t,J=7.8Hz,1H),7.20(d,J=8.1Hz,2H),6.92(d,J=8.1Hz,2H),5.49(d,J=8.0Hz,1H),5. 40(t,J=9.6Hz,1H),5.04(t,J=8.9Hz,1H),4.99(t,J=9.6Hz,1H),4.20(t,J=12.2Hz,2H),4.06(d,J =11.9Hz,1H),3.48(q,J=7.0Hz,2H),2.82(t,J=7.5Hz,2H),2.01(s,6H),1.99(s,3H),1.96(s,3H).

[0158] 13 C NMR(151MHz,DMSO-d6)δ169.94,169.58,169.32,169.10,164.65,154.92,135.41,133.94,131.24,129.78,129.78,129.63,129.2 2,129.00,127.70,123.72,116.38,116.38,97.31,71.94,70.76,70.73,68.08,61.63,41.08,34.05,20.41,20.37,20.30,20.27.

[0159] Example 22: A method for synthesizing compound D11, wherein the steps are as follows:

[0160] The preparation method was the same as that of Example 2 to obtain white solid D11 with a yield of 95.28%.

[0161] 1H NMR (600MHz, DMSO-d6) δ8.82(t,J=5.6Hz,1H),8.16(s,1H),8.12(d,J=7.8Hz,1H),7.89(d,J=7.8Hz,1H),7.72(t,J=7.8Hz,1H ),7.16(d,J=8.6Hz,2H),6.96(d,J=8.5Hz,2H),5.26(d,J=5.1Hz,1H),5.05(d,J=4.8Hz,1H),4.99(d,J=5.3Hz,1H),4.81(d,J= 7.5Hz,1H),4.53(t,J=5.8Hz,1H),3.68(dd,J=9.7,3.2Hz,1H),3.48(dd,J=7.9,6.0Hz,2H),3.45(t,J=5.7Hz,1H),3.30(dd,J =8.7,4.6Hz,1H),3.25(dd,J=8.8,4.7Hz,1H),3.22(dd,J=7.7,5.0Hz,1H),3.16(dd,J=8.8,5.2Hz,1H),2.80(t,J=7.4Hz,2H).

[0162] 13 C NMR(151MHz,DMSO-d6)δ164.66,155.97,135.44,132.65,131.26,129.65,129.51,129.51,129.22, 129.01,127.69,123.74,116.20,116.20,100.54,77.00,76.63,73.25,69.71,60.70,41.22,34.14.

[0163] MS ESI( + ):m / z:calculated for C 22 H 24 F3NO7 + ([M+H]+)472.36; found 472.15.

[0164] Example 23: The synthesis method of compound XI-1, the operation steps are as follows:

[0165] Weigh 200 mg (1.36 mmol) of 3-bromopyrazole and 751.84 mg (5.44 mmol) of anhydrous potassium carbonate, place in a 50 mL dry single-mouth round-bottom flask, add 10 mL of anhydrous ethanol and 161.63 uL (1.36 mmol) of benzyl bromide, reflux, and stir to react for 2-3 hours. After the reaction is completed, add 10 mL of distilled water to quench, extract with ethyl acetate, collect the organic layer, add anhydrous sodium sulfate to dry, filter, collect the filtrate, and concentrate under reduced pressure to obtain a crude product, which is a light yellow oil IX-1. Weigh 200 mg (0.796 mmol) of the light yellow oily intermediate IX-1, 120.83 mg (0.876 mmol) of 4-hydroxyphenylboronic acid, 253.10 mg (2.388 mmol) of anhydrous sodium carbonate, and 45.99 mg (0.039 mmol) of tetrakistriphenylphosphine palladium, place in a 38 mL explosion-proof tube, add 10 mL of 1,4-dioxane, 2.5 mL of water, stir the reaction at 80 ° C under argon conditions for 12 hours, spin dry the reaction solution after the reaction, extract with ethyl acetate and distilled water, collect the organic layer, add anhydrous sodium sulfate to dry, filter, collect the filtrate, and spin dry under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography, eluent V (petroleum ether): V (ethyl acetate) = 30:1-4:1. The separated product is concentrated and spin dried to obtain a light yellow oily substance X-1 with a yield of 81.75%.

[0166] Weigh the light yellow oily intermediate X-1200mg (0.757mmol), tetrabutylammonium bromide 244.03mg (0.757mmol), acetyl bromide-α-D-glucose 622.23mg (1.513mmol) and dissolve in 12mL dichloromethane, add 5M NaOH 757uL (3.785mmol), react at room temperature, reaction time 12h, add 12mL distilled water quench after the reaction, extract with dichloromethane, collect the organic layer, add anhydrous sodium sulfate to dry, filter, collect the filtrate, concentrate under reduced pressure, purify by silica gel column chromatography, eluent V (petroleum ether): V (ethyl acetate) = 15:1-1:1. The separated product is concentrated and dried to obtain a light yellow oily substance XI-1127.20mg, with a yield of 27.82%.

[0167] 1H NMR (600MHz, DMSO-d6) δ7.86(d,J=2.3Hz,1H),7.74(d,J=8.7Hz,2H),7.35(t,J=7.5Hz,2H),7.29(d,J=7 .3Hz,1H),7.26(t,J=7.1Hz,2H),7.01(d,J=7.0Hz,2H),6.69(d,J=2.4Hz,1H),5.59(d,J=7.6Hz,1H),5. 42(t,J=9.6Hz,1H),5.36(s,2H),5.06(t,J=7.8Hz,1H),5.00(t,J=9.7Hz,1H),4.26(dd,J=12.1,5.5Hz, 1H), 4.21 (d, J = 12.2Hz, 1H), 4.07 (d, J = 10.0Hz, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H).

[0168] 13 C NMR(151MHz,DMSO-d6)δ170.03,169.63,169.36,169.16,155.82,149.94,137.67,132.03,128.56,128.56,128.41,127.61,127.5 0,127.50,126.40,126.40,116.62,116.62,102.60,97.17,71.94,70.82,70.76,68.06,61.65,54.86,20.51,20.41,20.37,20.31.

[0169] Example 24: The synthesis method of compound E1, the operation steps are as follows:

[0170] Weigh 100 mg (0.168 mmol) of the light yellow oily intermediate XI-1 and 16.11 mg (0.763 mmol) of LiOH into a 50 mL dry single-mouth round-bottom flask, add 12 mL of methanol, and react at room temperature for 2 h. After the reaction, spin dry the reaction solution, dissolve it with V (dichloromethane): V (methanol) = 8:1, and purify it by silica gel column chromatography, eluent V (dichloromethane): V (methanol) = 30:1-10:1. The separated product is concentrated and spin dried to obtain white solid E-1, with a yield of 92.06%.

[0171] 1H NMR (600MHz, DMSO-d6) δ7.85(d,J=2.3Hz,1H),7.69(d,J=8.8Hz,2H),7.35(t,J=7.5Hz,2H),7.29(t,J=7.2Hz,1H),7.2 7(d,J=6.8Hz,2H),7.03(d,J=8.8Hz,2H),6.67(d,J=2.3Hz,1H),5.35(s,2H),5.33(d,J=5.1Hz,1H),5.11(d,J=4.8Hz,1 H),5.04(d,J=5.3Hz,1H),4.87(d,J=7.6Hz,1H),4.58(t,J=5.8Hz,1H),3.69(dd,J=9.8,5.4Hz,1H),3.47(q,J=5.9Hz, 1H), 3.32 (dd, J=5.9, 3.9Hz, 1H), 3.27 (dd, J=8.7, 4.8Hz, 1H), 3.24 (dd, J=7.5, 5.1Hz, 1H), 3.17 (dd, J=7.3, 2.1Hz, 1H).

[0172] 13 C NMR(151MHz,DMSO-d6)δ156.91,150.21,137.71,131.94,128.56,128.56,127.60,127.55,127.55,1 27.28,126.19,126.19,116.36,116.36,102.40,100.38,77.08,76.63,73.28,69.71,60.69,54.85.

[0173] MS ESI( + ):m / z:calculated for C 22 H 24 N2O6 + ([M+H]+)413.33; found 413.16.

[0174] Example 25: The synthesis method of compound XI-1, the operation steps are as follows:

[0175] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-1 with a yield of 27.80%.

[0176] 1H NMR (600MHz, DMSO-d6) δ7.82(d,J=1.8Hz,1H),7.73(d,J=6.0Hz,2H),7.17(d,J=6.9Hz,2H),7.14(d ,J=7.0Hz,2H),7.00(d,J=6.7Hz,2H),6.67(d,J=2.0Hz,1H),5.58(d,J=7.9Hz,1H),5.42(t,J=12.3H ,1H),5.29(s,2H),5.07(t,J=7.8Hz,1H),5.00(t,J=7.2Hz,1H),4.26(t,J=7.5Hz,1H),4.21(d,J=11 .7Hz,1H),4.07(d,J=12.1Hz,1H),2.27(s,3H),2.02(s,3H),2.01(s,3H),2.00(s,3H),1.97(s,3H).

[0177] 13 C NMR(151MHz,DMSO-d6)δ170.05,169.65,169.39,169.18,155.81,149.83,136.85,134.61,131.85,129.10,129.10,128.45,127.61,1 27.61,126.38,126.38,116.61,116.61,102.55,97.17,71.94,70.82,70.77,68.06,61.66,54.69,20.71,20.53,20.43,20.39,20.33.

[0178] Example 26: The synthesis method of compound E2, the operation steps are as follows:

[0179] The preparation method was the same as that of Example 23 to obtain white solid E2 with a yield of 92.06%.

[0180] 1H NMR (600MHz, DMSO-d6) δ7.81(d,J=2.2Hz,1H),7.69(d,J=8.3Hz,2H),7.18(d,J=8.0Hz,2H),7.15(d,J=8.0Hz,2H),7 .03(d,J=8.4Hz,2H),6.65(d,J=2.3Hz,1H),5.34(d,J=5.1Hz,1H),5.28(s,2H),5.11(t,J=4.9Hz,1H),5.04(t,J=5. 4Hz, 1H), 4.88 (d, J = 7.5Hz, 1H), 4.59 (t, J = 5.8Hz, 1H), 4.12 (t, J = 5.3Hz, 1H), 3.69 (q, J = 5.4Hz, 1H), 3.47 (dd, J = 12. 0,6.1Hz,1H),3.33(dd,J=11.9,6.00Hz,1H),3.27(dd,J=8.8,4.9Hz,1H),3.24(dd,J=7.8,5.4Hz,1H),2.27(s,3H).

[0181] 13 C NMR (151MHz, DMSO-d6) δ156.90,150.12,136.84,134.66,131.75,129.10,129.10,127.65,127.65,127. 33,126.18,126.18,116.36,116.36,102.36,100.39,77.09,76.65,73.30,69.72,60.69,54.68,20.72.

[0182] MS ESI( + ):m / z:calculated for C 23 H 26 N2O6 + ([M+H]+)427.07; found 427.18.

[0183] Example 27: The synthesis method of compound XI-3, the operation steps are as follows:

[0184] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-3 with a yield of 22.35%.

[0185] 1H NMR (600MHz, DMSO-d6) δ7.84(d,J=3.4Hz,1H),7.73(d,J=8.3Hz,2H),7.21(d,J=8.1Hz,2H),7.19(d,J=8.3Hz,2H ),7.01(d,J=8.3Hz,2H),6.68(d,J=3.4Hz,1H),5.59(d,J=7.9Hz,1H),5.42(t,J=9.6Hz,1H),5.30(s,2H),5.06( t,J=8.9Hz,1H),5.00(t,J=9.7Hz,1H),4.26(d,J=15.8Hz,1H),4.21(dd,J=12.0,5.4Hz,1H),4.07(d,J=12.0Hz, 1H),2.84(dq,J=14.1,7.0Hz,1H),2.03(s,3H),2.02(s,3H),2.01(s,3H),1.97(s,3H),1.17(s,3H),1.16(s,3H).

[0186] 13 C NMR(151MHz,DMSO-d6)δ170.04,169.65,169.38,169.18,155.81,149.85,147.84,135.07,131.91,128.44,127.64,127.64,126.46,126.46, 126.38,126.38,116.61,116.61,102.55,97.17,71.94,70.82,70.77, 68.06,61.66,54.69,33.16,23.88,23.88,20.53,20.43,20.39,20.33.

[0187] Example 28: The synthesis method of compound E3, the operation steps are as follows:

[0188] The preparation method was the same as that of Example 24 to obtain white solid E3 with a yield of 50.06%.

[0189] 1H NMR (600MHz, DMSO-d6) δ7.83(d,J=3.4Hz,1H),7.69(d,J=8.2Hz,2H),7.21(d,J=8.1Hz,2H),7.03(d,J=8.2Hz,2H),6.65(d ,J=3.4Hz,1H),5.34(d,J=7.9Hz,1H),5.33(d,J=7.9Hz,1H),5.29(s,2H),5.12(d,J=4.8Hz,1H),5.05(d,J=5.3Hz,1H),4.8 8(d,J=7.5Hz,1H),4.59(t,J=5.9Hz,1H),3.70(t,J=9.3Hz,1H),3.52(q,J=6.0Hz,1H),3.46(dd,J=12.4,6.2Hz,1H),3.28 (dd,J=13.5,5.3Hz,1H),3.23(dd,J=12.6,2.6Hz,1H),3.17(dd,J=9.4,8.4Hz,1H),2.85(m,1H),1.17(s,3H),1.16(s,3H).

[0190] 13 C NMR(151MHz,DMSO-d6)δ156.89,150.13,147.82,135.11,131.82,127.68,127.68,127.30,127.30,126.46,126 .18,126.18,116.35,116.35,102.35,100.38,77.09,76.64,73.29,69.71,60.68,54.68,33.16,23.89,23.89.

[0191] MS ESI( + ):m / z:calculated forC 25 H 30 N2O6 + ([M]+)454.37; found454.21.

[0192] Example 29: The synthesis method of compound IX-4, the operation steps are as follows:

[0193] Weigh 200 mg (1.36 mmol) of 3-bromopyrazole and 1.29 g (5.10 mmol) of 3-bromomethylpyridine hydrobromide, place in a 50 mL dry single-mouth round-bottom flask, add 12 mL of anhydrous acetonitrile, slowly add 204 mg (5.103 mmol) of sodium hydride, start timing after the addition is complete, and stir to react for 12-16 hours. After the reaction is completed, spin dry the reaction solution, add 10 mL of distilled water to quench, extract with ethyl acetate, collect the organic layer, add anhydrous sodium sulfate to dry, filter, collect the filtrate, and concentrate under reduced pressure to obtain a crude product, the product is a light yellow oil IX-4.

[0194] Example 30: The synthesis method of compound XI-4, the operation steps are as follows:

[0195] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-4 with a yield of 38.56%.

[0196] 1 H NMR (600MHz, DMSO-d6) δ8.54(s,1H),8.50(d,J=9.5Hz,1H),7.89(d,J=12.6Hz,1H),7.73(d,J=8.0Hz,2H),7. 67(d,J=8.3Hz,1H),7.37(t,J=7.9Hz,1H),7.01(d,J=7.9Hz,2H),6.69(d,J=12.5Hz,1H),5.58(d,J=7.8Hz,1H ),5.41(s,2H),5.39(t,J=12.5Hz,1H),5.05(t,J=10.8Hz,1H),5.00(t,J=10.3Hz,1H),4.27(d,J=10.3Hz,1H ),4.18(dd,J=17.3,11.9Hz,1H),4.07(d,J=12.8Hz,1H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.97(s,3H).

[0197] 13 C NMR(151MHz,DMSO-d6)δ169.99,169.60,169.35,169.14,155.88,150.29,148.93,148.87,135.39,132.14,128.27,126.43,12 6.43,123.67,123.67,116.63,116.63,102.78,97.18,71.94,70.82,70.76,68.07,61.64,52.34,20.48,20.38,20.34,20.28.

[0198] Example 31: The synthesis method of compound E4, the operation steps are as follows:

[0199] The preparation method was the same as that of Example 24 to obtain white solid E4 with a yield of 49.49%.

[0200] 1 H NMR (600MHz, DMSO-d6) δ8.44(s,1H),8.21(d,J=2.2Hz,1H),7.69(d,J=8.4Hz,1H),7.57(d,J=2.1Hz,1H),7.34(d,J=9.0Hz ,2H),7.30(t,J=4.7Hz,1H),7.11(d,J=8.4Hz,2H),6.40(d,J=1.9Hz,1H),5.40(s,2H),5.33(d,J=7.9Hz,1H),5.09(d,J=8. 3Hz,1H),5.03(d,J=7.1Hz,1H),4.92(d,J=4.7Hz,1H),4.56(t,J=9.9Hz,1H),4.10(t,J=5.5Hz,1H),3.70(dd,J=10.1,4.0 Hz,1H),3.48(dd,J=6.3,3.4Hz,1H),3.33(dd,J=4.3,1.0Hz,1H),3.27(dd,J=1.8,1.1Hz,1H),3.24(dd,J=6.4,1.0Hz,1H).

[0201] 13 C NMR (151MHz, DMSO-d6) δ157.64,148.64,148.09,143.19,139.08,134.64,133.33,129.81,129. 81,123.62,123.44,116.52,116.52,106.37,100.23,77.09,76.58,73.22,69.67,60.68,50.20.

[0202] MS ESI( + ):m / z:calculated for C 21 H 23 N3O6 + ([M]+)413.44; found 413.16.

[0203] Example 32: The synthesis method of compound XI-5, the operation steps are as follows:

[0204] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-5 with a yield of 38.56%.

[0205] 1 H NMR (600MHz, DMSO-d6) δ7.59(d,J=1.8Hz,1H),7.29(d,J=4.7Hz,2H),7.27(t,J=4.6Hz,2H),7.22(t,J=3.72Hz,1 H),7.07(d,J=5.6Hz,2H),7.05(d,J=4.4Hz,2H),6.35(d,J=1.8Hz,1H),5.62(d,J=18.6Hz,1H),5.55(q,J=7.1Hz, 1H), 5.41 (t, J = 9.6Hz, 1H), 5.08 (t, J = 8.9Hz, 1H), 5.01 (t, J = 8.2Hz, 1H), 4.26 (d, J = 10.1Hz, 1H), 4.20 (dd, J = 14. 5,5.6Hz,1H),4.08(d,J=12.3Hz,1H),2.02(s,3H),2.01(s,3H),1.99(s,3H),1.97(s,3H),1.80(d,J=7.0Hz,3H).

[0206] 13 C NMR(151MHz,DMSO-d6)δ170.34,169.96,169.60,169.11,156.44,142.54,138.42,130.25,128.40,128.40,128.40,127.16,125.88,1 25.88,124.91,116.58,116.55,106.14,106.12,71.92,70.85,70.66,67.98,61.57,59.74,56.68,20.74,20.43,20.37,20.32,20.27.

[0207] Example 33: The synthesis method of compound E5, the operation steps are as follows:

[0208] The preparation method was the same as that of Example 24 to obtain white solid E5 with a yield of 50.06%.

[0209] 1H NMR (600MHz, DMSO-d6) δ7.57(d,J=1.8Hz,1H),7.28(d,J=7.4Hz,2H),7.24(t,J=3.1Hz,2H),7.21(t,J=7.3Hz,1H),7.10(d,J=6. 8Hz,2H),7.06(d,J=6.7Hz,2H),6.33(d,J=4.0Hz,1H),5.56(q,J=6.5Hz,1H),5.33(d,J=11.9Hz,1H),5.09(d,J=9.0Hz,1H),5.02 (d,J=7.1Hz,1H),4.92(d,J=11.4Hz,1H),4.56(t,J=12.7Hz,1H),4.10(t,J=5.3Hz,1H),3.70(dd,J=11.6,5.7Hz,1H),3.47(dd,J =11.4,5.7Hz,1H),3.28(dd,J=8.8,4.4Hz,1H),3.27(dd,J=4.0,2.7Hz,1H),3.24(dd,J=5.94,1.0Hz,1H),1.80(d,J=6.9Hz,3H).

[0210] 13 C NMR (151MHz, DMSO-d6) δ157.60,142.86,138.40,130.01,128.40,128.40,128.40,128.40,128.40127. 17,125.95,125.95,123.78,116.45,116.38,105.97,76.58,73.21,69.68,60.69,56.62,48.60,22.02.

[0211] MS ESI( + ):m / z:calculated for C 23 H 26 N2O6 + ([M+H]+)427.03; found 427.18.

[0212] Example 34: The synthesis method of compound XI-6, the operation steps are as follows:

[0213] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-6 with a yield of 39.7%.

[0214] 1H NMR (600MHz, DMSO-d6) δ7.98(s,1H),7.37(d,J=8.5Hz,2H),7.34(d,J=7.5Hz,2H),7.30(t,J=5.9Hz,2H ),7.27(d,J=2.6Hz,1H),7.01(d,J=8.6Hz,2H),5.56(d,J=8.1Hz,1H),5.42(t,J=9.6Hz,1H),5.36(s,1 H),5.24(s,1H),5.06(t,J=8.2Hz,1H),5.01(t,J=9.7Hz,1H),4.25(d,J=12.3Hz,1H),4.21(dd,J=12.0 ,5.4Hz,1H),4.07(d,J=11.8Hz,1H),2.26(s,3H),2.02(s,3H),2.01(s,3H),1.99(s,3H),1.97(s,3H).

[0215] 13 C NMR(151MHz,DMSO-d6)δ169.98,169.59,169.32,169.12,154.64,144.37,137.62,128.88,128.60,128.49,128.49,128.40,128.08,1 27.63,127.63,127.56,126.99,119.37,116.72,97.29,71.95,70.76,68.07,61.63,59.73,54.61,20.47,20.37,20.33,20.27,10.08.

[0216] Example 35: The synthesis method of compound E6, the operation steps are as follows:

[0217] The preparation method was the same as that of Example 24 to obtain white solid E6 with a yield of 59.43%.

[0218] 1H NMR (600MHz, DMSO-d6) δ7.96(s,1H),7.34(d,J=3.9Hz,2H),7.33(d,J=2.1Hz,2H),7.29(t,J=1.7Hz,2H),7.27(d, J=2.4Hz,1H),7.04(d,J=8.8Hz,2H),5.35(s,1H),5.29(d,J=5.0Hz,1H),5.24(s,1H),5.07(d,J=4.7Hz,1H),5.00( d,J=5.3Hz,1H),4.85(d,J=7.5Hz,1H),4.55(t,J=5.8Hz,1H),4.08(t,J=5.2Hz,1H),3.70(t,J=6.3Hz,1H),3.47( q,J=6.0Hz,1H),3.27(dd,J=8.9,4.0Hz,1H),3.25(dd,J=7.6,2.5Hz,1H),3.22(dd,J=7.1,1.2Hz,1H)2.28(s,3H).

[0219] 13 C NMR(151MHz,DMSO-d6)δ155.75,144.31,137.68,128.72,128.61,128.50,128.50,128.16,127.85, 127.64,127.64,127.55,126.97,119.64,116.52,77.06,76.63,73.26,69.74,60.72,54.61,10.12.

[0220] MS ESI( + ):m / z:calculated for C 23 H 26 N2O6 + ([M+H]+)427.17; found 427.18.

[0221] Example 36: The synthesis method of compound XI-7, the operation steps are as follows:

[0222] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-7 with a yield of 39.7%.

[0223] 1H NMR (600MHz, DMSO-d6) δ7.94(s,1H),7.36(d,J=9.1Hz,2H),7.18(d,J=8.4Hz,2H),7.15(d,J=9.1H z,2H),7.00(d,J=8.9Hz,2H),5.55(d,J=7.9Hz,1H),5.41(t,J=9.6Hz,1H),5.30(s,1H),5.18(s,1 H),5.06(t,J=9.6Hz,1H),5.00(t,J=9.7Hz,1H),4.25(d,J=7.3Hz,1H),4.20(q,J=7.3Hz,1H),4.0 7(d,J=11.6Hz,1H),2.27(s,3H),2.25(s,3H),2.03(s,3H),2.02(s,3H),1.99(s,3H),1.97(s,3H).

[0224] 13 C NMR (151MHz, DMSO-d6) δ169.98,169.60,169.33,169.13,154.63,144.25,136.79,134.57,129.03,129.03,128.69,128.39,128.06,127. 71,127.71,127.01,119.32,116.78,116.72,97.30,71.96,70.77,68 .08,61.64,59.74,54.42,20.67,20.47,20.37,20.33,20.28,10.08.

[0225] Example 37: The synthesis method of compound E7, the operation steps are as follows:

[0226] The preparation method was the same as that of Example 24 to obtain white solid E7 with a yield of 59.43%.

[0227] 1H NMR (600MHz, DMSO-d6) δ7.92(s,1H),7.32(d,J=8.6Hz,2H),7.18(d,J=7.9Hz,2H),7.15(d,J=8.0Hz,2H) ,7.04(d,J=8.8Hz,2H),5.29(s,1H),5.29(s,1H),5.17(s,2H),5.07(d,J=4.7Hz,1H),5.00(d,J=5.3Hz,1 H),4.85(d,J=2.2Hz,1H),4.56(t,J=5.8Hz,1H),3.70(q,J=6.4Hz,1H),3.47(dd,J=12.1,6.1Hz,1H),3. 28(dd,J=8.9,4.8Hz,1H),3.25(dd,J=7.8,5.0Hz,1H),3.23(dd,J=6.8Hz,1H),2.27(s,3H),2.26(s,3H).

[0228] 13 C NMR(151MHz,DMSO-d6)δ155.74,144.19,136.79,134.63,129.04,129.04,128.53,128.15,127.83,127.73, 127.73,127.00,119.59,116.59,116.52,100.60,77.07,76.63,73.27,69.74,60.73,54.42,20.69,10.13.

[0229] MS ESI( + ):m / z:calculated for C 24 H 28 N2O6 + ([M+H]+)441.28; found 441.19.

[0230] Example 38: The synthesis method of compound XI-8, the operation steps are as follows:

[0231] The preparation method is the same as Example 23 to obtain a light yellow oily substance XI-8 with a yield of 29.76%.

[0232] 1H NMR (600MHz, DMSO-d6) δ7.96 (s, 1H), 7.37 (d, J = 8.4Hz, 2H), 7.22 (d, J = 1.14Hz, 2H), 7.20 (d, J = 3.84Hz, 1H), 7.1 1(d,J=7.8Hz,1H),7.01(d,J=8.6Hz,2H),5.55(d,J=8.1Hz,1H),5.41(t,J=9.5Hz,1H),5.30(s,1H),5.18(s,1H ),5.06(t,J=8.9Hz,1H),5.00(t,J=9.6Hz,1H),4.24(d,J=12.1Hz,1H),4.21(d,J=12.1Hz,1H),4.07(q,J=2.2H z,1H),2.86(m,1H),2.26(s,3H),2.03(s,3H),2.02(s,2H),2.01(s,3H),1.97(s,3H),1.17(s,3H),1.17(s,3H).

[0233] 13 C NMR(151MHz,DMSO-d6)δ170.33,169.98,169.59,169.32,154.62,147.78 ,144.25,135.02,128.74,128.39,128.30,128.05,127.75,127.75,127. 12,126.49,126.39,126.39,119.31,116.72,97.30,71.95,70.76,68.07 ,61.63,59.74,54.42,33.12,23.83,20.47,20.37,20.33,20.27,10.19.

[0234] Example 39: The synthesis method of compound E8, the operation steps are as follows:

[0235] The preparation method was the same as that of Example 24 to obtain white solid E8 with a yield of 68.68%.

[0236] 1H NMR (600MHz, DMSO-d6) δ7.95 (s, 1H), 7.33 (d, J = 8.4Hz, 2H), 7.21 (d, J = 1.1Hz, 2H), 7.20 (d, J = 3.8Hz, 1H), 7.11 (d, J = 7.8Hz, 1H),7.04(d,J=8.7Hz,2H),5.29(d,J=8.1Hz,1H),5.28(s,1H),5.18(s,1H),5.07(d,J=4.7Hz,1H),5.00(d,J=5.3Hz,1H),4. 85(d,J=7.5Hz,1H),4.56(t,J=5.8Hz,1H),3.70(t,J=5.3Hz,1H),3.46(q,J=6.0Hz,1H),3.28(dd,J=13.9,3.36Hz,1H),3.24 (dd,J=11.8,8.3Hz,1H),3.18(dd,J=14.6,5.5Hz,1H),3.16(dd,J=12.7,5.5Hz,1H),2.26(s,3H),1.18(s,3H),1.17(s,3H).

[0237] 13 C NMR(151MHz,DMSO-d6)δ155.73,147.78,144.19,135.07,128.58,128.15,127.83,127.76,127.76,127.11,126.50 ,126.40,126.40,119.58,116.51,100.59,77.06,76.63,73.26,69.73,60.72,54.42,33.13,23.85,23.85,10.15.

[0238] MS ESI( + ):m / z:calculated for C 26 H 32 N2O6 + ([M+H]+)469.13; found 469.23.

[0239] Example 40: The synthesis method of compound XI-9, the operation steps are as follows:

[0240] The preparation method is the same as that of Example 39 to obtain a light yellow oily substance XI-9. The product and the impurity have similar polarity and are difficult to separate. The yield is 55.9%.

[0241] Example 41: A method for synthesizing compound E9, wherein the steps are as follows:

[0242] The preparation method was the same as that of Example 24 to obtain white solid E9 with a yield of 41.07%.

[0243] 1 H NMR (600MHz, DMSO-d6) δ8.54(s,1H),8.48(d,J=22.3Hz,1H),7.69(d,J=35.5Hz,1H),7.59(d,J=39.1Hz,1H),7.37(d,J =4.2Hz,2H),7.32(s,1H),7.05(d,J=7.9Hz,2H),5.41(d,J=5.8Hz,1H),5.40(d,J=5.8Hz,1H),5.30(s,2H),5.08(d,J= 5.7Hz,1H),5.02(d,J=6.2Hz,1H),4.86(d,J=6.9Hz,1H),4.60(t,J=6.54Hz,1H),3.70(q,J=12.8Hz,1H),3.48(dd,J=1 2.1, 6.3Hz, 1H), 3.29 (dd, J = 7.9, 2.4Hz, 1H), 3.26 (dd, J = 8.1, 6.1Hz, 1H), 3.22 (dd, J = 29.22, 11.7Hz, 1H), 2.35 (s, 3H).

[0244] 13 C NMR(151MHz,DMSO-d6)δ155.89,148.99,148.77,148.54,137.40,135.07,128.23,127.92,123.74, 123.67,119.72,116.59,116.53,100.59,77.07,76.64,73.27,69.74,60.73,52.08,49.79,10.10.

[0245] MS ESI( + ):m / z:calculated for C 22 H 25 N3O6 + ([M+H]+)428.09; found 428.17.

[0246] Example 42: The synthesis method of compound XI-10, the operation steps are as follows:

[0247] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-10 with a yield of 55.9%.

[0248] 1H NMR (500MHz, DMSO-d6) δ7.64(s,1H),7.34(t,J=9.2Hz,2H),7.32(d,J=8.0Hz,2H),7.25(d,J=8.8Hz,1 H),7.22(d,J=7.8Hz,2H),7.01(d,J=7.4Hz,2H),5.65(q,J=7.3Hz,1H),5.56(d,J=7.9Hz,1H),5.41(t ,J=9.6Hz,1H),5.06(t,J=8.7Hz,1H),5.00(t,J=9.7Hz,1H),4.26(d,J=5.0Hz,1H),4.21(q,J=5.0Hz, 1H), 4.14 (t, J = 4.5Hz, 1H), 2.26 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H), 1.81 (d, J = 6.8Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δ170.00,169.61,169.33,169.13,154.73,142.85,136.69,134.37,128.57,128.57,128.54,128.54,128.41,127. 27,126.12,126.12,119.29,116.74,116.74,97.28,71.95,70.77,69.36,68.06,61.63,56.61,20.53,20.47,20.38,20.35,20.28,9.90.

[0250] Example 43: A method for synthesizing compound E10, wherein the steps are as follows:

[0251] The preparation method was the same as that of Example 24 to obtain white solid E10 with a yield of 41.07%.

[0252] 1H NMR (500MHz, DMSO-d6) δ7.62(s,1H),7.33(t,J=8.7Hz,2H),7.29(d,J=6.5Hz,2H),7.25(d,J=6.1Hz,1H),7.22(d,J=7.8Hz, 2H),7.05(d,J=6.5Hz,2H),5.65(q,J=7.1Hz,1H),5.29(d,J=4.0Hz,1H),5.07(d,J=4.5Hz,1H),5.01(d,J=4.3Hz,1H),4.85 (d,J=7.5Hz,1H),4.56(d,J=5.4Hz,1H),4.09(t,J=5.4Hz,1H),3.69(q,J=11.9,5.4Hz,1H),3.47(dd,J=15.4,6.1Hz,1H),3 .29(dd,J=7.2,4.3Hz,1H),3.24(dd,J=16.0,5.8Hz,1H),3.22(dd,J=10.2,5.8Hz,1H),2.26(s,3H),1.81(d,J=6.9Hz,3H).

[0253] 13 C NMR (126MHz, DMSO) δ155.82,142.91,136.63,128.54,128.54,128.54,128.54,128.32,128.32,127.25,1 26.11,126.11,119.52,116.54,116.54,100.58,77.07,76.62,73.26,69.72,60.71,56.58,21.94,9.95.

[0254] MS ESI( + ):m / z:calculated for C 24 H 28 N2O6 + ([M+H]+)441.27; found 441.19.

[0255] Example 44: The synthesis method of compound XIII-10, the operation steps are as follows:

[0256] The preparation method is the same as that of Example 23 to obtain a light yellow oily substance XI-10 with a yield of 21.43%.

[0257] 1H NMR (600MHz, DMSO-d6) δ8.54(d,J=2.46Hz,1H),7.91(d,J=8.2Hz,2H),7.77(d,J=3.54Hz,2H),7.74(d ,J=3.96Hz,1H),7.70(d,J=8.3Hz,2H),7.10(d,J=8.2Hz,2H),6.55(t,J=2.1Hz,1H),5.63(d,J=8.0Hz ,1H),5.44(t,J=9.6Hz,1H),5.09(t,J=8.9Hz,1H),5.03(t,J=9.7Hz,1H),4.28(d,J=9.6Hz,1H),4.22 (dd,J=12.3,5.5Hz,1H),4.09(d,J=12.2Hz,1H),2.04(s,3H),2.04(s,3H),2.02(s,3H),1.98(s,3H).

[0258] 13 C NMR(151MHz,DMSO-d6)δ170.00,169.60,169.33,169.13,156.05,141.03,138.73,137.17,133.92,127.81,127.81,127.70,12 7.37,127.37,118.74,118.74,116.87,116.87,107.91,97.14,71.94,70.84,70.75,68.07,61.65,20.49,20.38,20.34,20.28.

[0259] Example 45: The synthesis method of compound F1, the operation steps are as follows:

[0260] The preparation method was the same as that of Example 24 to obtain white solid F1 with a yield of 66.26%.

[0261] 1H NMR (600MHz, DMSO-d6) δ8.53(d,J=2.46Hz,1H),7.90(d,J=8.1Hz,2H),7.76(d,J=3.54Hz,2H),7.75(d,J=4.0Hz,1H) ,7.66(d,J=8.2Hz,2H),7.14(d,J=8.3Hz,2H),6.56(t,J=2.1Hz,1H),5.33(d,J=4.8Hz,1H),5.09(d,J=4.5Hz,1H),5. 03(d,J=5.3Hz,1H),4.92(d,J=7.3Hz,1H),4.58(t,J=5.7Hz,1H),3.72(t,J=5.4Hz,1H),3.49(q,J=5.4Hz,1H),3.37( dd,J=7.92,5.64Hz,1H),3.31(dd,J=8.6,4.8Hz,1H),3.27(dd,J=12.18,5.64Hz,1H),3.20(dd,J=8.16,5.16Hz,1H).

[0262] 13 C NMR(151MHz,DMSO-d6)δ157.17,140.99,138.56,137.44,132.74,127.67,127.51,127.51,127.2 0,127.20,118.75,118.75,116.76,116.76,107.89,100.46,77.11,76.63,73.27,69.73,60.72.

[0263] MS ESI( + ):m / z:calculated for C 21 H 22 N2O6 + ([M+H]+)399.14; found 399.15.

[0264] Example 46: Cell viability test of the compounds of the present invention

[0265] 1. Experimental Materials

[0266] Experimental cells: primary neonatal rat cardiomyocytes

[0267] Test substances: compounds D1-D11, E1-E10 and F1 represented by general formula D, E or F of the present invention; control compounds: empagliflozin and phlorizin.

[0268] 3. Experimental methods

[0269] 3.1 Culture of primary neonatal rat cardiomyocytes, drug administration, and CCK-8 detection

[0270] The heart of the suckling mouse was squeezed out, and the heart was taken out with curved forceps. The blood vessels on the surface of the heart, the residual blood and the attached lung tissue were removed, and the heart was placed in another culture dish pre-filled with D-Hank' solution. The heart fragments were sucked into a 15ml centrifuge tube, the supernatant was discarded, and the trypsin digestion was terminated. The digestion was filtered through a filter and centrifuged for 5 minutes. The supernatant was discarded and the bottom cell pellet was kept. The DMEM culture medium containing 10% FBS was taken into a centrifuge tube, the cells were blown evenly and moved to a bottle, and cultured in an incubator at 37°C and 5% CO2 for 1.5-2 hours. The suspended cardiomyocytes were aspirated and re-plated on a 96-well plate. After continuing to culture for 48 hours, they were used for subsequent experiments in good condition. Sugar-free DMEM culture medium was used to induce cell damage for 8 hours to simulate cardiomyocyte damage. After the cells were rinsed with PBS buffer, D1-D11, E1-E10 and F1 compounds were added at a final concentration of 100μM, and 100μM phlorizin and empagliflozin were used as controls, and 3 replicates of each concentration were cultured for 24 hours. After 24 hours, dilute the CCK-8 solution with DMEM medium in a light-proof condition at a ratio of 1:10. Replace the medium. After incubation at 37°C for 1-4 hours, shake the solution in an ELISA reader for 10 seconds and record the absorbance at 450nm.

[0271] 4. Data processing and results

[0272] 4.1 Data processing

[0273] According to the calculation formula: cell survival rate % = (OD450 value of cells in the drug group - OD450 value of blank wells / OD450 value of cells in the control group - OD450 value of blank wells) * 100, the relative survival rate of different compounds 100 μM on primary cardiomyocyte injury induced by sugar-free DMEM medium in neonatal rats was calculated. The experimental data were expressed as mean ± standard error, and the OD450 values ​​of cells in each group were analyzed by One-way ANOVA. P < 0.05 indicated significant differences. The experimental results were statistically analyzed and plotted using Graphpad Prism 8.0.

[0274] 4.2 Experimental Results

[0275] When the D1-D11, E1-E10 and F1 compounds were 100 μmol / L, the in vitro cell survival rate of neonatal rat primary cardiomyocytes after starvation with sugar-free DMEM medium for 3 h and 8 h was as follows Figure 1 , Figure 2 Among them, compounds D4 and E9 had higher survival rates in primary cardiomyocytes of neonatal rats induced by sugar-free DMEM medium compared with the control drugs phlorizin and empagliflozin.

[0276] Example 47: Efficacy test of the compounds of the present invention

[0277] This example shows the protective effects of compounds D4 and E9 on primary cardiomyocyte injury induced by sugar-free DMEM medium in neonatal rats.

[0278] 1. Experimental Materials

[0279] Experimental cells: primary neonatal rat cardiomyocytes

[0280] Test compounds: D4 and E9 compounds, control compounds: empagliflozin and phlorizin

[0281] 2.1 Primary cardiomyocyte culture, drug administration and detection

[0282] The culture method was the same as above. Primary cardiomyocytes were cultured in 6-well plates. Sugar-free DMEM medium was used to induce cell injury for 8 hours to simulate cardiomyocyte injury. D4 and E9 compounds were then added at final concentrations of 50 and 100 μM, with 100 μM empagliflozin and phlorizin as controls, and 2 replicates were cultured for 24 hours at each concentration. The ATP content and SOD level in the cells were determined according to the instructions of the ATP and SOD detection kits. The experiment was repeated 3 times.

[0283] 3. Data processing and results

[0284] 3.1 Data processing

[0285] The experimental data were expressed as mean ± standard error, and One-way ANOVA was used to analyze the ATP content of each group of cells. P < 0.05 indicated a significant difference. Graphpad Prism 8.0 was used for statistics and graphing of the experimental results.

[0286] 3.2 Experimental Results

[0287] Compared with the model group, compound D4 (50, 100 μM) and compound E9 (50, 100 μM) were able to increase the ATP content in primary cardiomyocytes of neonatal rats, with the maximum increase of ATP content in cardiomyocytes being 50.25%, which was significantly better than the effects of empagliflozin and phlorizin at the same concentration. Figure 3 A.

[0288] Compared with the model group, compounds D4 (50, 100 μM) and E9 (50, 100 μM) were able to increase the SOD content in primary cardiomyocytes of neonatal rats, which was significantly better than the effects of empagliflozin and phlorizin at the same concentration. Figure 3 B.

[0289] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present invention.

Claims

1. An O-glucoside derivative or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or hydrate thereof, characterized in that: The structure of the O-glucoside derivative is shown in Formula D, Formula E or Formula F: Wherein, R1, R2 and R3 are selected from any one of a benzene ring, a heteroaryl group, a five-membered ring or a six-membered ring; X1 and X2 represent substituents located at any substitutable position on the R1 or R2 group; R4 is selected from hydrogen or a straight or branched chain alkyl group containing 1 to 3 carbons; X1 is selected from any one of hydrogen, straight or branched alkyl containing 1 to 3 carbon atoms, carboxyl, cyano, ester, nitro, amino, halogen or haloalkyl containing 1 to 3 carbon atoms; X2, X3 and X4 are each independently selected from any one of hydrogen, a straight or branched chain alkyl group containing 1 to 3 carbon atoms, a carboxyl group, a hydroxyl group, a cyano group, an ester group, a nitro group or an amino group.

2. The O-glucoside derivative according to claim 1 or a pharmaceutically acceptable salt, stereoisomerism, polymorph, solvate or hydrate thereof, characterized in that: The straight-chain or branched alkyl group containing 1 to 3 carbon atoms includes methyl, ethyl, propyl and isopropyl; the halogenated alkyl group includes monochloromethyl and trifluoromethyl.

3. The O-glucoside derivative according to claim 1 or a pharmaceutically acceptable salt, stereoisomerism, polymorph, solvate or hydrate thereof, characterized in that: The heteroaryl group is pyridine.

4. The O-glucoside derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomerism, polymorph, solvate or hydrate thereof, characterized in that: Any one selected from the following compounds: 。 5. A pharmaceutical composition, characterized in that The invention comprises the O-glucoside derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomerism, polymorph, solvate or hydrate thereof.

6. The pharmaceutical composition according to claim 5, characterized in that It is characterized in that Pharmaceutically acceptable carriers, diluents or excipients are also included.

7. Use of the O-glucoside derivative according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, stereoisomerism, polymorph, solvate or hydrate or the pharmaceutical composition according to claim 5 or 6 in the preparation of a drug for protecting myocardial cells or preventing myocardial cell damage.

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