Xanthone and derivatives and preparation method and use thereof

Abstract

A xanthone and derivatives, as well as preparation methods and uses thereof, belong to the field of medical technology. The invention relates to a xanthone represented by structural formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof. It also relates to a xanthone derivative represented by structural formula (IV) or (V) formed using the xanthone represented by structural formula (I) or (II) as a parent nucleus, and provides a method for preparing the above-mentioned xanthone and xanthone derivatives. It also relates to the use of xanthone and xanthone derivatives in the preparation of drugs for treating and / or preventing diabetes, cancer, and neurodegenerative diseases. In structural formulas (I), (II), (IV), and (V), R1, R2, R3, E3, and L are as described in the specification and claims.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to xanthone and derivatives, their preparation methods, and uses. Specifically, it relates to a xanthone-based derivative, which is a novel compound and derivative with anti-diabetic activity, or pharmaceutically acceptable salts and solvates thereof, as well as pharmaceutical compositions containing the compound. It also relates to a preparation method for the compound and its use in preparing a drug for treating and / or preventing diabetes. Background Art

[0002] Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia, resulting from impaired insulin secretion and / or utilization caused by multiple etiologies. DM is a common and frequently occurring disease, a global public health issue that poses a serious threat to human health. DM is a clinical syndrome caused by a combination of genetic and environmental factors, but its etiology and pathogenesis remain largely undefined.

[0003] Dual substrate-specific tyrosine phosphorylation-regulated kinase A (DYRK1A), a member of the CMGC family, is located in a critical region on chromosome 21 and is considered a key target for Down syndrome, as well as neurodegenerative diseases, Alzheimer's disease, and pancreatic cancer. Wang P et al. discovered that inhibiting DYRK1A promotes pancreatic beta cell proliferation, a finding that links DYRK1A targets to diabetes. DYRK1A affects the proliferation of pancreatic β cells by regulating important signaling pathways. Upregulation of DYRK1A leads to phosphorylation of NFAT in the nucleus, which is further phosphorylated by GSK3β and casein kinase and translocated to the cytoplasm; phosphorylation of p27kip and DREAM complex LIN52 leads to cell cycle arrest; interaction with insulin receptor substrate 2 (IRS-2) promotes phosphorylation of insulin receptor substrate, leading to proteasome degradation of IRS-2 and promoting β cell apoptosis; upregulation of IRS-1 protein expression, stabilization of IRS-1 by reducing IRS-1 ubiquitination; inhibition of SMAD signaling, thereby reducing CDKN2B expression, leading to a decrease in β cell number. Although it has been found that inhibition of DYRK1A through Ca 2+While the NFAT and TNFβ pathways synergistically promote β-cell proliferation, relatively few small-molecule inhibitors specifically targeting DYRK1A are known to promote pancreatic β-cell proliferation. Currently, only harmine, Leucetamine B, GNF4877, CC-401, and OST167 have been reported to promote β-cell proliferation by inhibiting DYRK1A. However, research on these small-molecule inhibitors remains largely preclinical and has yet to enter Phase I clinical trials. Most lead compounds for DYRK1A inhibition are based on harmine as a core structure for subsequent structural optimization. However, the toxic side effects of the harmine core and its nonspecific selectivity for kinases remain a challenge, limiting their potential applications.

[0004] Proteolysis targeting chimeras (PROTACs) are bifunctional small molecules in which the target protein ligand and the E3 ubiquitin ligase ligand are linked together by a linker to form a triplet compound. As a potential therapeutic approach, proteolysis targeting chimeras (PROTACs) can target specific proteins for degradation. Proteolysis targeting chimeras are specific biological functional molecules, usually consisting of a compound molecule that binds to the protein target, a ligand that recruits the E3 ubiquitin ligase, and a linker. PROTAC-induced selective polyubiquitination of the target protein and subsequent degradation on the proteasome. Compared with traditional small molecule inhibitors, PROTACs have multiple advantages, including the ability to exert their effects without binding to the active site of the target protein, the ability to degrade difficult-to-drug targets, and their event-driven and catalytic nature. They can act at lower doses, and therefore have great potential, particularly in the development of anti-cancer drugs. Summary of the Invention

[0005] The present invention provides a xanthone and derivatives, as well as preparation methods and uses thereof. The compounds are based on PROTAC technology and can target and degrade the DYRK1A enzyme, or pharmaceutically acceptable salts, hydrates or prodrugs thereof, as well as preparation methods and uses thereof.

[0006] The primary purpose of the present invention is to provide a xanthone that is a compound that can directly inhibit DYRK1A or induce DYRK1A protein degradation, and also relates to a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug of the xanthone.

[0007] At the same time, a xanthone derivative formed with xanthone as a parent core is provided.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned xanthone and xanthone derivatives.

[0009] Another object of the present invention is to provide the use of the above-mentioned xanthone and xanthone derivatives in the preparation of drugs for treating and / or preventing diabetes, cancer and neurodegenerative diseases.

[0010] The purpose of the present invention is achieved through the following technical solutions:

[0011] A xanthone of the present invention has a structural formula as shown in (I) or (II):

[0012]

[0013] The present invention provides a xanthone represented by structural formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof:

[0014] Wherein: R1 and R2 independently represent hydrogen, deuterium, hydroxyl, alkoxy, benzoyloxy, benzyloxy, p-toluenesulfonyloxy, methanesulfonyloxy, acetoxy, propynyloxy or one of the following structural formula (III):

[0015]

[0016] In the structural formula (III), T is selected from one of phenyl, piperazinyl, piperidinyl, heterocyclic group and hydrocarbon group;

[0017] B is selected from one of O, S, C, and H;

[0018] Y is selected from one of -alkyl, -cycloalkyl, -Cl, -F, -H, and -Br;

[0019] R1 is more preferably:

[0020]

[0021] R3 is selected from one of H and D.

[0022] When R1 or R2 is a formyloxy group or a benzoyloxy group, it becomes a xanthone with an ester group; when R1 or R2 is a sulfonyloxy group or a p-toluenesulfonyloxy group, it becomes a sulfonate ester, and the xanthone with a sulfonic acid group is formed. The xanthone with an ester group and the xanthone with a sulfonic acid group form a prodrug of xanthone, and the ester group or sulfonic acid group can be hydrolyzed into a hydroxyl group in the body.

[0023] A xanthone derivative of the present invention, or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, has a structural formula as shown in (IV) or (V):

[0024]

[0025] wherein R1, R2, and R3 are determined according to the xanthone forming the xanthone derivative;

[0026] E3 is one of the E3 ligase ligands CRBN, VHL, MDM2, CIAP, UBR7, RNF114, CBLB, and KEAP1. When E3 is a ligand for CRBN ligase, it is selected from thalidomide and its derivatives, lenalidomide and its derivatives, and pomalidomide and its derivatives;

[0027] More preferably, the E3 structure is any one of the structures shown in the following structural formula (VI):

[0028]

[0029] Wherein: In structural formula (VI), W is selected from one of CH2, C=O, SO2, NH, and N-alkyl;

[0030] X is selected from one of O and S;

[0031] Z is selected from one of -alkyl, -cycloalkyl, -Cl, -F, and -H;

[0032] G, G' are independently selected from one of -H, alkyl, -OH, and -CH2-heterocycle;

[0033] R 1 One selected from -H, -D, -F, -Cl, -Br, -I, -NO2, -CN, -NH2, -OH, -CH3, -CH2F, -CHF2, -CF3, -CH2D, -CHD2, -CD3, -CH2CH3;

[0034] Q is selected from one of CH2, C=O, -NH-C=O, -NH2, and -NHBoc;

[0035] M is selected from one of amide, ester, carboxyl and acyl chloride;

[0036] A is selected from a piperazinyl group, a piperidinyl group, a heterocyclic group or a linking group represented by the following structural formula (VII);

[0037] Wherein: the heterocyclic group is one of piperazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0038] The structural formula (VII) is as follows, wherein n is an integer from 0 to 3:

[0039]

[0040] L is a linker arm selected from a fatty chain, an aromatic chain, an ether chain, and an amide chain; the xanthone and E3 are connected by a covalent bond to form a multifunctional molecular compound; more preferably, the structure of L is any one of the structures shown in structural formula (VIII):

[0041]

[0042]

[0043] Among them, 1≤m≤10, more preferably 1≤m≤5.

[0044] The xanthone derivative of the present invention is preferably a xanthone derivative represented by the following structural formula (IX) or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof:

[0045]

[0046] Where: R 1 One selected from -H, -D, -F, -Cl, -Br, -I, -NO2, -CN, -NH2, -OH, -CH3, -CH2F, -CHF2, -CF3, -CH2D, -CHD2, -CD3, -CH2CH3; R 1 More preferably H;

[0047] A is selected from piperazinyl, piperidinyl, heterocyclic group or one of the linking groups represented by the structural formula (VII), more preferably piperazinyl;

[0048] Q is selected from one of CH2, C=O, -NH-C=O, -NH2, -NHBoc; more preferably, Q is -NH2 or -NHBoc;

[0049] M is selected from one of an amide group, an ester group, a carboxyl group, and an acyl chloride group, more preferably an ester group or an amide group, and the ester group is more specifically -COOCH3;

[0050] L is any one of the structural formulas (VIII);

[0051] The xanthone and xanthone derivatives of the present invention are further preferably xanthone derivatives represented by the structural formula (X) or pharmaceutically acceptable salts, hydrates, stereoisomers or prodrugs thereof:

[0052]

[0053] The xanthone or xanthone derivative may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. The present invention includes all stereoisomeric forms, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemates, which are included within the scope of the present invention.

[0054] Pharmaceutically acceptable salts of the xanthone or xanthone derivative include addition salts formed with the following acids: one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, pyruvic acid, and succinic acid.

[0055] The xanthone prodrugs of the present invention are derivatives of the structural formula (IX), which may have weak activity or even no activity themselves, but after administration, they are converted into corresponding biologically active forms under physiological conditions (such as through metabolism, solvent decomposition or other means).

[0056]

[0057] A pharmaceutical composition comprising at least one of the following substances: the xanthone, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its prodrug, the xanthone derivative, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its prodrug; and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or a combination thereof.

[0058] Wherein, the dosage form of the pharmaceutical composition is any one of injection, tablet or capsule.

[0059] A method for preparing xanthone or a xanthone derivative comprises the following steps:

[0060] Step 1: Dissolve 2,4-dihydroxybenzoic acid in Eaton's reagent, add phloroglucinol, and react at 80°C for two hours to obtain compound 1; the structural formula is:

[0061] Step 2: Compound 1 is dissolved in a certain amount of acetone, potassium carbonate or sodium hydride is added as a base, and the mixture is reacted at room temperature or heated to 60°C for 6 hours to overnight to perform hydroxyl etherification protection to obtain compound 2; the structural formula is:

[0062] Compound 1 was dissolved in tetrahydrofuran, triethylamine was added as a base, and various halides were added under ice bath to obtain compounds with different R1 and R2 groups.

[0063] Compound 1 was dissolved in tetrahydrofuran, and Ru catalyst, copper acetate, silver derivative, and deuterium oxide were added in sequence. The mixture was heated to 110-115°C and reacted for 24-36 hours to obtain compound 10. The structural formula is:

[0064] Step 3: Compound 2 and the azide-linked E3 ligand are dissolved in a solvent and linked by a Click reaction to obtain compounds of series 1-5, which are: one of compound X1-nP-Tha (n=1-5), compound X1-nCH2-VHL2 (n=1, 3, 5, 7), compound X1-nCH2-B4 (n=1, 3, 5, 7), compound X1-nP-B5 (n=1-5), and compound X1-nP-MDM2 (n=1-5);

[0065] Step 4: Deprotection of the compound of series 4 in ethyl acetate solution of HCl affords the compound of series 6; the compound of series 6, X1-nP-B5(T) (n=1-5), has the following structural formula:

[0066]

[0067] The solvent in the above preparation method is one or a combination of two of acetone, dichloromethane, THF, and water; the benzoic acid includes: 2,4,6-trihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5,6-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, and 2,3-trihydroxybenzoic acid.

[0068] The reaction pathway using 2,4,6-trihydroxybenzoic acid as the starting material is as follows:

[0069]

[0070] The present invention investigates the molecular mechanism by which DYRK1A protein and a series of synthetic compounds inhibit DYRK1A or induce DYRK1A protein degradation; studies the anti-diabetic activity and mechanism of action of the derivatives at the cellular and animal levels, as well as their improvement on pancreatic islet function and glycolipid metabolism in diabetic animals.

[0071] The present invention relates to the use of xanthone and its xanthone derivatives or their pharmaceutically acceptable salts, hydrates, stereoisomers or prodrugs, and pharmaceutical compositions thereof in the preparation of drugs for treating or preventing diabetes, cancer and neurodegenerative diseases.

[0072] The xanthone and derivatives of the present invention, as well as their preparation methods and uses, have the following beneficial effects:

[0073] The xanthone and xanthone derivatives of the present invention can promote pancreatic beta cell proliferation by inhibiting the DYRK1A enzyme. Using xanthone as the parent nucleus, xanthone derivatives are formed by linking an arm L with an E3 ligase ligand, capable of targeted degradation of the DYRK1A enzyme. Research has shown that these xanthone derivatives have broad application prospects in the preparation of drugs for treating and / or preventing diabetes, cancer, and neurodegenerative diseases. Compounds 1, 4, 7, 9, 10, and X1-CH2-V2 provided by the methods of the present invention can also effectively inhibit the DYRK1A enzyme and effectively promote pancreatic beta cell proliferation. These compounds can address the problem of diabetic drug resistance. The methods of the present invention provide a new therapeutic approach for the treatment of pancreatic beta cell-mediated diabetes, cancer, and neurodegenerative diseases.

[0074] Furthermore, the study found that xanthone derivatives have better inhibitory activity of DYRK1A enzyme (0.5±0.1 micromolar) to promote pancreatic beta cell proliferation, thereby providing useful value in the treatment and / or prevention of diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 Results of microthermophoresis analysis of the compounds and DYRK1A protein. In standard-treated capillaries, the affinity of compounds 1 (Panel a), X1-CH2-V2 (Panel b), 2 (Panel c), and 4 (Panel d) for DYRK1A protein was measured by MST. Kd values ​​were calculated based on the binding curves.

[0076] Figure 2 PROTAC mediates the degradation of DYRK1A protein in INS-1 cells;

[0077] Figure 3 The compound promoted INS-1 cell proliferation and regeneration; Figure: (a) Percentage of INS-1 cell proliferation in treatment groups with different concentrations. The proliferation rates at 37.5 and 75 μM of the compound were 22.94±20.62% and 31.46±14.38%, respectively, significantly higher than the control (-0.57±5.06%). (b) Insulin levels in the culture supernatant were significantly increased after treatment with the compound at concentrations of 9.375 to 300 μM. (c) Representative images of the effects of the compound (37.5 and 75 μM) on INS-1 cell proliferation, stained with EdU and DAPI (400× magnification). (d) Percentage of EdU+-INS-1 cells after compound treatment (n=3). (*P<0.05, **P<0.01, ***P<0.001, ##P≤0.01).

[0078] Figure 4Effects of compounds on the proliferation and regeneration of STZ-treated INS-1 cells. Figure: (a) Percentage of INS-1 cell proliferation in the different concentration-treated groups. (b) Representative images showing the effects of compounds (37.5 and 75 μM) on INS-1 cell proliferation, stained with EdU (green) and DAPI (blue) (400× magnification). (c) Percentage of EdU+-INS-1 cells after compound treatment (n = 3). (*P < 0.05, **P < 0.01, ***P < 0.001, ##P ≤ 0.01).

[0079] Figure 5 The compound regulates NFATc1 nuclear localization, stimulates INS-1 cell proliferation, and participates in the calcineurin / NFAT / DYRK1A signaling pathway. (a) Representative images (400×) showing the effect of compound (37.5 and 75 μM) treatment on NFATc1 nuclear localization in INS-1 cells. (b) Compared with the control group, the mRNA expression levels of cell proliferation-related factors (Ccnd1, Ccnd2, Ccnd3, and CDK4) after compound treatment were increased (*P < 0.05, **P < 0.01).

[0080] Figure 6 Effects of the compound on glycemic control in db / db mice; (a) Immunofluorescence double staining analysis of insulin and glucagon expression in pancreatic tissue. (b) Western blot analysis of FOXO1, PDX1, and insulin expression in pancreatic tissue. The compound induced PDX1 production and decreased FOXO1 expression. Protein levels were quantified using grayscale analysis using Image J software.

[0081] Figure 7 Effects of the compound on body weight, food intake, blood glucose levels, serum insulin levels, oral glucose tolerance test, and lipid profiles in diabetic mice. (a) Body weight increased steadily in all treatment groups, with no significant differences between groups. (b) Food intake was measured weekly for 6 consecutive weeks. (c) Blood glucose levels were measured weekly for 6 consecutive weeks. (d) Blood insulin levels were quantitatively measured. (n = 8) ## P < 0.01, compared with the normal group; *P < 0.05, **P < 0.01, compared with the diabetic group. Metformin (200 mg / kg) and harmine (200 mg / kg) served as positive controls. Low-dose (75 mg / kg) and high-dose (150 mg / kg) groups of the compound served as treatment groups. (e) Oral glucose tolerance test. (f) Glucose area under the curve (AUC). DETAILED DESCRIPTION

[0082] The following is a detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0083] Example 1 Preparation of Xanthone Compound 1

[0084]

[0085] 2,4,6-Trihydroxybenzoic acid (940 mg, 5 mmol) was dissolved in a solution of phosphorus pentoxide in methanesulfonic acid (12 mL of Eaton's reagent). Phloroglucinol (940 mg, 7.5 mmol) was added, and the mixture was refluxed at 80°C for 2 hours, resulting in a deep red solution. After cooling to room temperature, ice water was added and stirred for 2 hours, a thin slurry formed. The filtrate was filtered, and the filter cake was dried at 60°C, redissolved in methanol, and purified by open silica gel column chromatography (elution with dichloromethane:methanol = 50:1) to obtain xanthone compound 1 in a 30% yield.

[0086] 1 H NMR (400MHz, DMSO-d6) δ 11.91 (d, J = 5.2 Hz, 2H), 11.08 (s, 2H), 6.34 (dd, J = 7.7, 2.2 Hz, 2H), 6.18 (t, J = 2.7 Hz, 2H).

[0087] Example 2 Preparation of Xanthone Compound 2

[0088]

[0089] 1,3,6,8-Tetrahydroxyxanthone (Compound 1 104.8 mg, 0.4 mmol) was dissolved in acetone (6 mL), potassium carbonate K2CO3 (82.8 mg, 0.6 mmol) was added, and after stirring for 20 minutes, propargyl bromide (47.6 mg, 0.4 mmol) was added. The temperature was raised to 65 degrees and refluxed for 12 hours. After cooling to room temperature, the acetone was evaporated to dryness, and the mixture was redissolved in ethyl acetate (EA). The product was extracted with a saturated aqueous solution of HCl and purified by open silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white solid as xanthone compound 2 in a yield of 70%.

[0090] 1H NMR (400MHz, DMSO-d6) δ12.02(s,2H),11.84(s,1H),6.64(d,J=2.3Hz,1H),6.42(d,J=2.3Hz,1 H), 6.32 (d, J = 2.1Hz, 1H), 6.16 (d, J = 2.1Hz, 1H), 4.96 (d, J = 2.4Hz, 2H), 3.70 (t, J = 2.4Hz, 1H).

[0091] Example 3 Preparation of Xanthone Compound 3

[0092]

[0093] Specific operation and ratio refer to the preparation of xanthone compound 2

[0094] 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),11.85(s,1H),11.18(s,1H),7.50–7.32(m,5H),6.69(d ,J=2.3Hz,1H),6.52–6.45(m,1H),6.36(d,J=2.1Hz,1H),6.21(d,J=2.1Hz,1H),5.26(s,2H).

[0095] Example 4 Preparation of Xanthone Compound 4

[0096]

[0097] 1,3,6,8-Tetrahydroxyxanthone (compound 1 19 mg, 0.073 mmol) was dissolved in anhydrous tetrahydrofuran (THF 2 mL) and potassium carbonate triethylamine (TEA 7.4 mg, 0.073 mmol) was added. Acetyl chloride (5.7 mg, 0.073 mmol) was added dropwise with stirring in an ice bath. DMAP was added as a catalyst and the reaction was allowed to proceed for approximately 20 min (TLC monitoring). The tetrahydrofuran was evaporated to dryness and the product was redissolved in ethyl acetate (EA). The product was extracted with a saturated aqueous solution of HCl and purified by open silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain xanthone compound 4 as a white solid in a 70% yield.

[0098] 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),11.74(s,1H),11.29(s,1H),6.88(d,J=2.0Hz,1H), 6.64(d,J=2.0Hz,1H), 6.39(d,J=2.1Hz,1H), 6.24(d,J=2.1Hz,1H), 2.31(d,J=3.3Hz,3H).

[0099] Example 5 Preparation of Xanthone Compound 5

[0100]

[0101] Specific operation and ratio refer to the preparation of xanthone compound 4

[0102] 1 H NMR (600MHz, DMSO-d6) δ12.10(s,1H),11.92(s,1H),11.76(s,1H),8.18–8.13(m,2H),7.78(t,J=7.5Hz,1H),7. 64(t,J=7.8Hz,2H), 7.07(d,J=2.1Hz,1H), 6.83(d,J=2.1Hz,1H), 6.39(d,J=2.1Hz,1H), 6.24(d,J=2.1Hz,1H).

[0103] Example 6 Preparation of Xanthone Compound 6 and Xanthone Compound 7

[0104]

[0105] Specific operation and ratio refer to the preparation of xanthone compound 4. Open silica gel column chromatography purification of DCM

[0106] Xanthone compound 6: 1 H NMR (400MHz, DMSO-d6) δ11.92–11.81(m,2H),7.85(d,J=8.1Hz,4H),7.51(d,J=8.0Hz,4H),6.83(d,J=2.2Hz,2H),6.53(d,J=2.2Hz,2H),2.44(s,6H).

[0107] Xanthone compound 7: 1 H NMR(600MHz,DMSO-d6)δ12.07(s,1H),11.65(s,1H),11.32(s,1H),7.87–7.82(m,2H),7.53–7.49(m,2H) ,6.78(d,J=2.2Hz,1H),6.47(d,J=2.2Hz,1H),6.39(d,J=2.1Hz,1H),6.24(d,J=2.1Hz,1H),2.43(s,3H).

[0108] Example 7 Preparation of Xanthone Compounds 8 and 9

[0109]

[0110] Specific operation and ratio refer to the preparation of xanthone compound 4. Open silica gel column chromatography purification of DCM

[0111] Xanthone compound 8: 1 H NMR (400MHz, DMSO-d6) δ11.95 (s, 2H), 7.12 (d, J = 2.2Hz, 2H), 6.87 (d, J = 2.2Hz, 2H), 3.54 (s, 6H).

[0112] Xanthone compound 9: 1 H NMR (600MHz, DMSO-d6) δ12.14(s,1H),11.68(s,1H),11.36(s,1H),7.04(d,J=2.2Hz, 1H), 6.80 (d, J = 2.2Hz, 1H), 6.41 (d, J = 2.1Hz, 1H), 6.26 (d, J = 2.1Hz, 1H), 3.51 (s, 3H).

[0113] Example 8 Preparation of Xanthone Compound 10

[0114]

[0115] 1,3,6,8-Tetrahydroxyxanthone (compound 1 20 mg, 0.076 mmol) was dissolved in anhydrous tetrahydrofuran (THF 2 mL) and [RuCl2(p-cym)]2 (2.3 mg, 0.0038 mmol), Cu(OAc)2 (27.6 mg, 0.152 mmol), AgSbF6 (10.4 mg, 0.0304 mmol), and deuterium oxide (275 μL, 15.2 mmol) were added sequentially. The mixture was heated to 110°C for 24 h, diluted with ethyl acetate (EA), and filtered to remove impurities. The filtrate was extracted with a saturated aqueous solution of EA / HCl and purified by open silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain xanthone compound 10 as a pale yellow solid in a 90% yield.

[0116] 1 H NMR (600MHz, DMSO-d6) δ11.91 (d, J = 3.3Hz, 2H), 11.08 (s, 2H), 6.33 (d, J = 1.5Hz, 0.2H), 6.18 (d, J = 2.0Hz, 0.2H).

[0117] Example 9 Synthesis of Intermediate N3-nPEG-Tha (n=4)

[0118]

[0119] 58 mg of a thalidomide derivative (commercially available) was placed in an eggplant-shaped flask and added with 3 mL of DMF. 50 mg of azido-PEG4-amine (commercially available) and 47 μL of DIPEA were added sequentially with stirring. The mixture was reacted at 90°C for 3-4 hours, and extracted with 30 mL of water and 30 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by silica gel column chromatography with a gradient elution ratio of petroleum ether to ethyl acetate (1:2 to 1:4) to obtain a yellow oil in a 60% yield.

[0120] 1 H NMR(400MHz, CDCl3)δ8.81(br s,1H),7.48(dd,J=8.0,7.2Hz,1H),7.09(d,J=7.2Hz,1H),6.92(d,J=8.8Hz,1H),6.49(t,J=5.6Hz,1H),4.95–4.90(m,1H),3.7 13C NMR (100MHz, CDCl3) δ171.6,169.4,168.8,167.8,146.9,136.1,132.6,116.9,111.7,1 10.3,70.8,70.74,70.71,70.7,70.65,70.62,70.1,69.6,50.8,48.9,42.5,31.5,22.9.

[0121] The preparation process of the first series of intermediates is the same as that of Example 9

[0122]

[0123] 1 H NMR (600MHz, CDCl3) δ8.54(s,1H),7.49(dd,J=8.2,7.4Hz,1H),7.10(d,J=7.1Hz,1H),6.92(d,J=8.5Hz,1H),6.50(t,J=5.6Hz,1H),4.93(dd,J=12.4,5 .4Hz,1H),3.74(t,J=5.4Hz,2H),3.71–3.66(m,6H),3.48(q,J=5.5Hz,2H), 3.38(t,J=5.0Hz,2H),2.91–2.69(m,3H),2.11(ddd,J=9.8,5.2,2.3Hz,1H).

[0124]

[0125] 1 H NMR (600MHz, CDCl3) δ8.29(s,1H),7.49(dd,J=8.5,7.1Hz,1H),7.10(d,J=7.0Hz,1H),6.93(d,J=8.5Hz,1H),4.92(dd,J=12.4,5.3 Hz,1H),3.73(t,J=5.5Hz,2H),3.71–3.64(m,10H),3.48(t,J=5.5Hz,2H),3.42–3.32(m,2H),2.95–2.66(m,3H),2.17–2.06(m,1H).

[0126] Example 10 Preparation of xanthone derivative X1-P-Tha (series 1, n=1)

[0127]

[0128] Compound 2 (15 mg, 0.050 mmol) was dissolved in tetrahydrofuran solution (2 mL), and water (2 mL) was added. N3-nPEG-Tha (n=1) (21.4 mg, 0.055 mmol), VcNa (29.7 mg, 0.15 mmol), and CuSO4 (10 mg, 0.0625 mmol) were added respectively. The reaction system was turbid, but soon became clear. TLC monitoring showed that there was no starting material. Post-treatment was performed, extraction was performed with ethyl acetate / saturated HCl aqueous solution, and the organic layer was purified by silica gel column chromatography (elution with dichloromethane:methanol=30:1) to give a yellow solid in a yield of 50%. 1H NMR (400MHz, DMSO-d6) δ11.94(s,1H),11.82(s,1H),11.15(s,1H),11.10(s,1H),8.23(s,1H),7.54(t,J=7.8Hz,1H), 7.06(d,J=8.6Hz,1H),7.00(d,J=7.1Hz,1H),6.69(d,J=2.2Hz,1H),6.55(s,1H),6.45(d,J=2.2Hz,1H),6.35(d,J=2. 1Hz,1H),6.20(d,J=2.0Hz,1H),5.27(s,2H),5.04(dd,J=12.9,5.4Hz,1H),4.58(t,J=5.1Hz,2H),3.86(t,J=5.1Hz,2 H),3.60(t,J=5.4Hz,2H),3.40(q,J=5.9Hz,2H),2.88(ddd,J=18.1,13.8,5.4Hz,1H),2.63–2.55(m,2H),1.99(s,1H). 13 C NMR(101MHz,DMSO-d6)δ182.68,173.24,170.53,169.38,167.71,166.46,165.55,162.49,162.20,157.71,157.41,146.75,142.07,136.62,1 32.50,125.89,117.79,111.14,109.67,102.03,101.07,98.99,98.44, 94.79,94.17,69.31,69.10,62.34,60.23,49.93,49.02,31.44,22.60.

[0129] Example 11 Preparation of Xanthone Derivative X1-2P-Tha (Series 1, n=2)

[0130]

[0131] The preparation process and feeding ratio refer to Example 10

[0132] 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),11.82(s,1H),11.15(s,1H),11.09(s,1H),8.25(s,1H),7.51(dd,J=8.6,7.1Hz,1H),7 .05(d,J=8.6Hz,1H),6.97(d,J=7.0Hz,1H),6.68(d,J=2.2Hz,1H),6.54(t,J=5.8Hz,1H),6.44(d,J=2.2Hz,1H),6.34(d,J=2 .1Hz,1H),6.20(d,J=2.1Hz,1H),5.26(s,2H),5.04(dd,J=12.7,5.4Hz,1H),4.55(t,J=5.0Hz,2H),3.83(t,J=5.1Hz,2H),3. 59–3.52(m,6H),3.39(q,J=5.7Hz,2H),2.88(ddd,J=16.7,13.7,5.4Hz,1H),2.52(s,2H),2.03(ddt,J=13.5,6.2,3.1Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ182.67,173.23,170.53,169.42,167.68,166.47, 165.57,162.50,162.19,157.70,157.39,146.75,142.02,136.56,132.46, 125.82,117.73,111.06,109.67,102.01,101.07,99.01,98.41,94.78,94. 12,70.03,69.25,69.12,62.37,55.37,49.97,49.02,42.11,31.44,22.59.

[0133] Example 12 Preparation of Xanthone Derivative X1-3P-Tha (Series 1, n=3)

[0134]

[0135] The preparation process and feeding ratio refer to Example 10

[0136] 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),11.83(s,1H),11.15(s,1H),11.10(s,1H),8.25(s,1H),7.53(dd,J=8.6,7.1Hz,1H),7.07(d, J=8.6Hz,1H),6.99(d,J=7.0Hz,1H),6.71(d,J=2.3Hz,1H),6.55(t,J=5.8Hz,1H),6.47(d,J=2.2Hz,1H),6.35(d,J=2.1Hz,1H),6.2 1(d,J=2.1Hz,1H),5.28(s,2H),5.04(dd,J=12.7,5.4Hz,1H),4.55(t,J=5.1Hz,2H),3.81(t,J=5.1Hz,2H),3.59(t,J=5.4Hz,2H),3 .51(ddt,J=15.8,5.9,3.6Hz,8H),3.42(d,J=5.6Hz,2H),2.89(ddd,J=17.3,13.5,5.3Hz,1H),2.63–2.52(m,2H),2.07–2.01(m,1H). 13 C NMR(101MHz,DMSO-d6)δ182.68,173.28,170.54,169.37,167.71,166.46,16 5.59,162.50,162.19,157.71,157.41,146.76,141.98,136.58,132.48,125 .86,117.76,111.07,109.65,102.02,101.07,99.00,98.43,94.78,94.14,70.19,70.12,70.00,69.27,69.07,62.38,49.93,49.00,42.08,31.44,22.59.

[0137] Example 13 Preparation of Xanthone Derivative X1-4P-Tha (Series 1, n=4)

[0138]

[0139] The preparation process and feeding ratio refer to Example 10

[0140] 1H NMR (400MHz, DMSO-d6) δ11.94(s,1H),11.83(s,1H),11.38(s,1H),11.10(s,1H),8.25(s,1H),7.58–7.50(m,1H),7.09( d,J=8.6Hz,1H),7.01(d,J=7.1Hz,1H),6.71(d,J=2.2Hz,1H),6.56(t,J=5.8Hz,1H),6.47(d,J=2.2Hz,1H),6.35(d,J=2 .1Hz,1H),6.20(d,J=2.0Hz,1H),5.28(s,2H),5.05(dd,J=12.9,5.4Hz,1H),4.55(t,J=5.1Hz,2H),3.82(t,J=5.1Hz,2H ),3.60(t,J=5.4Hz,2H),3.55–3.39(m,16H),2.88(ddd,J=17.6,14.0,5.4Hz,1H),2.63–2.51(m,2H),2.06–1.97(m,1H).

[0141] 13 C NMR(101MHz,DMSO-d6)δ182.68,173.28,170.54,169.37,167.73,166.49,165 .60,162.50,162.20,157.71,157.42,146.79,141.98,136.60,132.50,125.87 ,117.80,111.09,109.67,102.02,101.06,99.01,98.44,94.78,94.14,70.26,70.20,70.05,69.99,69.30,69.09,62.37,49.94,49.01,42.11,31.44,22.60.

[0142] Example 14 Preparation of Xanthone Derivative X1-5P-Tha (Series 1, n=5)

[0143]

[0144] The preparation process and feeding ratio refer to Example 10

[0145] 1H NMR (400MHz, DMSO-d6) δ11.94(s,1H),11.84(s,1H),11.16(s,1H),11.10(s,1H),8.25(s,1H),7.55(dd,J=8.5,7.1Hz,1H) ,7.11(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.72(d,J=2.3Hz,1H),6.58(t,J=5.8Hz,1H),6.48(d,J=2.2Hz,1H),6.36(d, J=2.1Hz,1H),6.21(d,J=2.1Hz,1H),5.29(s,2H),5.05(dd,J=12.9,5.4Hz,1H),4.55(t,J=5.1Hz,2H),3.82(t,J=5.1Hz,2 H),3.60(t,J=5.4Hz,2H),3.57–3.49(m,6H),3.49–3.43(m,12H),2.95–2.82(m,1H),2.63–2.51(m,2H),2.06–1.99(m,1H). 13 C NMR(101MHz,DMSO-d6)δ182.70,173.28,170.54,169.38,167.74,166.47,165 .61,162.51,162.21,157.73,157.43,146.82,141.98,136.63,132.52,125.88 ,117.84,111.10,109.67,102.03,101.09,99.01,98.45,94.79,94.16,70.27,70.21,70.04,69.98,69.31,69.09,62.37,49.93,49.01,42.13,31.44,22.60.

[0146] Example 15 Preparation of Intermediate N3-CH2-VHL2 (n=1)

[0147]

[0148] To a 50.3 mg azido-CH2-carboxylic acid flask was added 5 mL of DCM. With stirring in an ice bath, 159 mg of EDCI, 112 mg of HoBt, 289 μL of DIPEA, and 200 mg of compound VHL2 hydrochloride were added sequentially. The mixture was then extracted with 30 mL of water and 30 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The organic layer was then purified by silica gel column chromatography (elution with dichloromethane:methanol = 25:1) to give a yellow solid in a 60% yield.

[0149] 1 H NMR (400MHz, CDCl3) δ8.70(s,1H),7.38(q,J=8.5Hz,4H),7.02(d,J=8.6Hz,1H),5.14–5.03(m,1H),4.73(t,J=7.8Hz,1H),4.57(d ,J=8.7Hz,2H),3.63(dd,J=11.3,3.7Hz,1H),2.60–2.50(m,4H),2.08(dd,J=19.9,6.3Hz,1H),1.48(d,J=6.9Hz,3H),1.06(s,8H).

[0150] The preparation process of the second series of intermediates is the same as that of Example 15

[0151]

[0152] 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 7.46–7.33 (m, 5H), 6.59 (d, J = 8.9Hz, 1H), 5.15–5.04 ( m,1H),4.68(t,J=7.9Hz,1H),4.60(d,J=8.9Hz,1H),4.51(s,1H),4.02(d,J=11.3Hz,1H) ,3.65(dd,J=11.2,3.8Hz,1H),3.40–3.25(m,3H),2.52(s,3H),2.47–2.21(m,4H),2.06( dd,J=9.0,2.6Hz,1H),1.89(dt,J=12.6,6.7Hz,3H),1.48(d,J=6.9Hz,3H),1.04(s,9H).

[0153]

[0154] 1H NMR (400MHz, CDCl3) δ8.68(s,1H),7.36(q,J=8.3Hz,4H),6.11(d,J=8.8Hz,1H),4.72(t,J= 8.0Hz,1H),4.64–4.47(m,3H),4.33(dd,J=14.9,5.1Hz,1H),3.60(dd,J=11.4,3.5Hz,1H),3 .26(t,J=6.8Hz,2H),2.61–2.54(m,1H),2.53(d,J=6.5Hz,3H),2.22(t,J=7.5Hz,2H),2.14( d,J=8.2Hz,1H),1.60(ddd,J=22.1,15.0,7.4Hz,4H),1.44–1.33(m,2H),0.97–0.88(m,9H).

[0155] Example 16 Preparation of xanthone derivatives X1-CH2-VHL2 (series 2, n=1)

[0156]

[0157] The preparation process and feeding ratio refer to Example 10

[0158] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.20(s,1H),8.99(s,1H),8.54(d,J=9.1Hz,1H),8.45(d,J=7. 8Hz,1H),8.25(s,1H),7.48–7.33(m,4H),6.74(d,J=2.3Hz,1H),6.49(d,J=2.3Hz,1H),6.37(d,J=2.1Hz,1H),6.21( d,J=2.1Hz,1H),5.35–5.23(m,4H),5.13(s,1H),4.94(p,J=7.1Hz,1H),4.55–4.41(m,1H),4.28(s,1H),3.66–3.51( m,3H),2.46(s,3H),2.05(d,J=10.3Hz,1H),1.79(ddd,J=12.9,8.7,4.5Hz,1H),1.39(d,J=7.0Hz,3H),0.97(s,9H). 13C NMR(101MHz,DMSO-d6)δ182.71,171.00,169.36,166.50,165.64,162.52,16 2.23,157.74,157.45,151.95,148.22,145.10,141.81,131.58,130.17,129 .30,127.19,126.85,102.05,101.08,99.02,98.45,94.80,94.16,69.24,62.29,59.11,57.43,56.92,51.84,48.19,38.18,35.99,26.81,22.90,16.45.

[0159] Example 17 Preparation of xanthone derivatives X1-3CH2-VHL2 (series 2, n=3)

[0160]

[0161] The preparation process and feeding ratio refer to Example 10

[0162] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),8.99(s,1H),8.39(d,J=7.8Hz,1H),8.30(s,1H),7.97(d,J=9.2Hz,1H),7.47 –7.35(m,4H),6.73(d,J=2.3Hz,1H),6.49(d,J=2.2Hz,1H),6.37(d,J=2.1Hz,1H),6.21(d,J=2.0Hz,1H),5.29(s,2H),5.13(s,1H ),4.92(p,J=6.8Hz,1H),4.52(d,J=9.3Hz,1H),4.43–4.35(m,3H),4.29(s,1H),3.62(d,J=3.3Hz,2H),2.46(s,3H),2.24(dh,J=2 9.3,7.6Hz,2H),2.11–2.00(m,3H),1.80(ddd,J=12.9,8.5,4.6Hz,1H),1.38(d,J=7.0Hz,3H),1.23(d,J=4.8Hz,1H),0.94(s,9H). 13C NMR(101MHz,DMSO-d6)δ182.71,171.49,171.08,169.97,166.51,165.62,162.5 2,162.21,157.74,157.46,151.95,148.22,145.11,142.13,130.15,129.28,12 6.84,125.38,102.07,101.09,99.03,98.46,94.80,94.15,69.24,62.43,59.02,57.04,56.75,49.57,48.16,38.18,35.64,32.08,26.90,26.60,22.89,16.44.

[0163] Example 18 Preparation of xanthone derivatives X1-5CH2-VHL2 (series 2, n=5)

[0164]

[0165] The preparation process and feeding ratio refer to Example 10

[0166] 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),11.85(s,1H),11.19(s,1H),8.98(s ,1H),8.38(d,J=7.8Hz,1H),8.29(s,1H),7.83(d,J=9.3Hz,1H),7.45–7.3 6(m,4H),6.73(d,J=2.3Hz,1H),6.48(d,J=2.3Hz,1H),6.37(d,J=2.1Hz,1 H),6.21(d,J=2.1Hz,1H),5.28(s,2H),5.12(s,1H),4.92(p,J=7.2Hz,1H) ,4.52(d,J=9.4Hz,1H),4.42(t,J=8.1Hz,1H),4.37(t,J=7.1Hz,2H),4.28 (s,1H),3.61(d,J=3.4Hz,2H),2.51(p,J=1.8Hz,3H),2.25(dt,J=14.6,7. 5Hz,1H),2.14(h,J=7.4Hz,1H),2.06–2.00(m,1H),1.87–1.79(m,3H),1.5 2(tt,J=14.0,6.8Hz,3H),1.37(d,J=7.0Hz,3H),1.23(s,1H),0.92(s,9H). 13C NMR(101MHz,DMSO-d6)δ182.72,172.33,171.08,170.05,166.50,165.63,162.52,1 62.21,157.74,157.45,151.94,148.21,145.11,142.04,130.15,129.28,126.84,1 25.30,102.05,101.09,99.02,98.46,94.79,94.16,69.23,62.43,59.01,56.82,56.74,49.81,48.15,38.20,35.64,35.07,29.90,26.90,25.96,25.24,22.89,16.44.

[0167] Example 19 Preparation of xanthone derivatives X1-7CH2-VHL2 (series 2, n=7)

[0168]

[0169] The preparation process and feeding ratio refer to Example 10

[0170] 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),11.85(s,1H),11.18(s,1H),8.99(s,1H),8.38(d,J=7.8Hz,1H),8.29(s,1H),7.79(d,J=9.3Hz,1H),7.47–7 .30(m,4H),6.73(d,J=2.2Hz,1H),6.48(d,J=2.2Hz,1H),6.37(d,J=2.1H z,1H),6.21(d,J=2.1Hz,1H),5.28(s,2H),5.11(d,J=3.5Hz,1H),4.98–4 .86(m,1H),4.52(d,J=9.3Hz,1H),4.45–4.34(m,3H),4.28(s,1H),3.61( d,J=3.5Hz,2H),2.45(s,3H),2.24(dt,J=14.7,7.6Hz,1H),2.16–2.07(m ,1H),2.09–1.97(m,1H),1.79(qd,J=8.4,7.8,4.9Hz,2H),1.46(dh,J=13 .9,7.2Hz,2H),1.37(d,J=7.0Hz,3H),1.22(d,J=8.7Hz,7H),0.93(s,9H). 13C NMR(101MHz,DMSO-d6)δ182.72,172.50,171.09,170.07,166.48,165.62,162.5 2,162.21,157.74,157.45,151.99,145.11,130.16,129.28,125.33,102.05,101 .10,99.03,98.48,94.80,94.18,69.22,62.43,59.00,56.80,56.72,49.88,48.16,38.19,35.65,35.27,30.13,28.91,28.54,26.90,26.20,25.75,22.88,16.44.

[0171] Example 20 Preparation of Intermediate N3-5CH2-B4 (n=5)

[0172]

[0173] 56.3 mg of azido-5CH2-carboxylic acid was placed in an eggplant-shaped flask, and 5 mL of DCM was added. 214 mg of EDCI, 150.7 mg of HoBt, 309 μL of TEA, and 200 mg of compound B4 hydrochloride were added sequentially with stirring in an ice bath. 30 mL of water and 30 mL of dichloromethane were added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography. The organic layer was then eluted with open silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain an oil in a 70% yield.

[0174] 1 H NMR (400MHz, CDCl3) δ7.39 (d, J=8.6Hz, 1H), 7.27 (dd, J=8.1, 6.1Hz, 2H), 7.21 (t, J=7.6Hz, 3H), 6.56(d,J=8.1Hz,1H),4.57(td,J=8.9,5.0Hz,1H),4.29–4.13(m,2H),3.72(s,2H),3.28(t,J=6 .8Hz,1H),3.22(t,J=6.9Hz,2H),3.11(dd,J=13.8,5.8Hz,1H),2.96(dd,J=13.8,9.9Hz,1H),2. 35(t,J=7.4Hz,1H),2.12–2.01(m,2H),1.71–1.39(m,9H),1.31–1.21(m,3H),0.97–0.87(m,6H).

[0175] Example 21 Preparation of xanthone derivatives X1-CH2-B4 (series 3, n=1)

[0176]

[0177] The preparation process and feeding ratio refer to Example 10

[0178] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.26(d,J=8.9Hz,1H),8.06(s,1H),7.87(d,J=8.5Hz,1H),7 .32–7.17(m,5H),6.75(d,J=2.3Hz,1H),6.50(d,J=2.3Hz,1H),6.40–6.30(m,2H),6.20(dd,J=10.8,2.1Hz,1H),5.29(s,2H),5. 12(d,J=16.3Hz,1H),4.99(d,J=16.2Hz,1H),4.41–4.31(m,1H),4.24–4.18(m,1H),3.91(dd,J=5.8,2.5Hz,1H),3.61(d,J=2.3H z,3H),2.86(dd,J=13.3,7.4Hz,1H),2.66(dd,J=13.3,7.4Hz,1H),2.00(q,J=7.4Hz,1H),1.76–1.54(m,2H),0.91–0.80(m,6H). 13 C NMR (101MHz, DMSO-d6) δ182.74,173.16,172.15,166.50,165.65,165.13,162.53,162.23,157.76,157.47,141.84,138.87,129.64,128. 76,126.78,126.71,102.07,101.10,99.03,98.47,94.80,94.18,71.01,62.29,54.19,52.40,51.98,50.12,37.31,24.62,23.25,21.63.

[0179] Example 22 Preparation of xanthone derivatives X1-3CH2-B4 (series 3, n=3)

[0180]

[0181] The preparation process and feeding ratio refer to Example 10

[0182] 1H NMR (400MHz, DMSO-d6) δ11.92(d,J=59.5Hz,2H),8.23(s,1H),7.85(d,J=8.4Hz,1H),7.65(d,J=8.8Hz,1H),7. 32–7.12(m,6H),6.73(d,J=2.2Hz,1H),6.48(d,J=2.3Hz,1H),6.35(d,J=2.1Hz,1H),6.19(d,J=2.1Hz,2H),5. 28(s,2H),4.39–4.31(m,1H),4.24(dt,J=10.6,6.7Hz,3H),3.87(s,1H),3.60(s,3H),2.82(dd,J=13.4,6.9Hz ,1H),2.66(dd,J=13.3,8.0Hz,1H),2.02(s,4H),1.53–1.32(m,2H),1.24(d,J=7.4Hz,1H),0.86–0.72(m,6H). 13 C NMR(101MHz,DMSO-d6)δ182.67,173.18,172.42,171.05,165.61,162.52,162.22,157.77,157.47,142.07,139.25,129.67,128.61,126.54,12 5.37,102.07,101.02,99.09,98.46,94.85,94.17,71.66,70.25,62.40 ,53.62,52.37,50.04,49.41,37.36,32.37,26.45,24.48,23.24,21.58.

[0183] Example 23 Preparation of xanthone derivatives X1-5CH2-B4 (series 3, n=5)

[0184]

[0185] The preparation process and feeding ratio refer to Example 10

[0186] 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),11.84(s,1H),11.20(s,1H),8.28(s,1H),7.84(d,J=8.5Hz,1H),7.52(dd,J=8.8,3 .4Hz,1H),7.32–7.14(m,5H),6.71(d,J=2.3Hz,1H),6.46(d,J=2.2Hz,1H),6.36(d,J=2.1Hz,1H),6.27–6.18(m,2H),5.26 (s,2H),4.35(q,J=8.6,6.9Hz,3H),4.18(qd,J=7.6,2.5Hz,1H),3.85(s,1H),3.61(s,3H),2.85–2.76(m,1H),2.64(dd,J= 13.3,7.7Hz,1H),2.11–1.89(m,2H),1.77(p,J=7.3Hz,2H),1.59–1.38(m,5H),1.23(s,2H),0.81(dd,J=20.2,6.2Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ182.71,173.20,172.47,172.04,166.51,165.61,162. 52,162.21,157.73,157.44,142.05,139.25,129.65,128.62,126.54,125.27,1 02.04,101.07,99.02,98.44,94.79,94.13,71.61,62.41,53.64,52.38,50.07 (d,J=10.2Hz),49.76,37.30,35.34,29.96,25.85,25.04,24.48,23.29,21.63.

[0187] Example 24 Preparation of xanthone derivatives X1-7CH2-B4 (series 3, n=7)

[0188]

[0189] The preparation process and feeding ratio refer to Example 10

[0190] 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),11.84(s,1H),11.19(s,1H),8.29(s,1H),7.85(d,J=8.5Hz,1H),7.48(d,J=8.9Hz,1H),7.30 –7.13(m,5H),6.71(d,J=2.2Hz,1H),6.47(d,J=2.3Hz,1H),6.36(d,J=2.1Hz,1H),6.21(d,J=2.1Hz,2H),5.28(s,2H),4.35(q,J=1 0.1,8.4Hz,3H),4.18(qd,J=7.7,2.4Hz,1H),3.86(d,J=2.7Hz,1H),3.61(s,3H),2.81(dd,J=13.3,7.1Hz,1H),2.66(dd,J=13.3,7 .7Hz,1H),1.99(qt,J=14.5,7.6Hz,2H),1.79(p,J=7.2Hz,2H),1.69–1.26(m,7H),1.23–1.16(m,4H),0.82(dd,J=21.6,6.3Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ182.68,173.20,172.48,172.21,166.58,165.60,162. 51,162.20,157.73,157.43,142.06,139.24,129.63,128.59,126.51,125.29,1 02.03,101.04,99.04,98.46,94.80,94.15,71.69,62.42,53.63,52.37,50.03,49.88,37.28,35.59,30.15,28.88,28.67,26.19,25.54,24.49,23.29,21.65.

[0191] Example 25 Preparation of Intermediate N3-2P-B5 (n=2)

[0192]

[0193] Compound B5 was placed in an eggplant-shaped flask and added with 5 mL of DCM. 188 mg of EDCI, 132 mg of HoBt, 272 μL of TEA, and 94 μL of azido-2PEG-NH2 were added sequentially with stirring in an ice bath. The mixture was then extracted with 30 mL of water and 30 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The organic layer was then purified by open silica gel column chromatography (elution with dichloromethane:methanol = 50:1) to obtain an oil in a 70% yield.

[0194] 1 H NMR (400MHz, CDCl3) δ7.33–7.27(m,2H),7.23(d,J=7.5Hz,3H),6.57(s,1H),5.01(d,J=8.0Hz,1H),4.45(d,J=4.7Hz,1H),4.13(s,1H),3.98(s,1H ),3.67–3.60(m,2H),3.59–3.52(m,2H),3.37(dd,J=21.2,16.4Hz,3H),3 .18(d,J=13.9Hz,1H),3.03(s,1H),1.43–1.33(m,8H),0.95–0.86(m,6H).

[0195] The feeding and operation of other intermediates are the same as above

[0196]

[0197] 1 H NMR (400MHz, CDCl3) δ7.32–7.27(m,2H),7.25–7.19(m,3H),6.67(s,1H),5.58(s,1H),5.04 (d,J=8.2Hz,1H),4.45(dd,J=11.6,6.5Hz,1H),4.09(dd,J=26.7,24.2Hz,2H),3.71–3.58( m,7H),3.55(dd,J=9.4,5.0Hz,2H),3.51–3.43(m,2H),3.39(dd,J=11.6,6.6Hz,3H),3.07( d,J=40.9Hz,2H),1.62(dt,J=15.9,10.2Hz,3H),1.38(s,9H),0.91(dd,J=12.5,6.1Hz,6H).

[0198]

[0199] 1H NMR (400MHz, CDCl3) δ7.31–7.26 (m, 2H), 7.22 (dd, J = 8.6, 4.5Hz, 3H), 6.88 (s,1H),5.04(s,1H),4.48(s,1H),4.13(s,2H),3.70–3.50(m,16H),3.40(d d,J=18.6,13.7Hz,4H),3.02(d,J=16.1Hz,2H),1.71(dd,J=11.1,6.4Hz,2H ),1.64–1.51(m,2H),1.38(d,J=11.6Hz,8H),0.92(dd,J=11.3,6.2Hz,6H).

[0200] Example 26 Preparation of xanthone derivative X1-P-B5 (series 4, n=1)

[0201]

[0202] The preparation process and feeding ratio refer to Example 10

[0203] 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),11.84(s,1H),11.18(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.61(d,J=9.0Hz,1H),7.21(ddt,J=18 .3,14.1,7.2Hz,5H),6.71(d,J=2.3Hz,1H),6.47(d,J=2.2Hz,1H),6.36(d,J=2.2Hz,1H),6.23–6.15(m,2H),5.99(s,1H),5.28(s,2H),4. 55(t,J=5.1Hz,2H),4.34(td,J=9.2,5.2Hz,1H),3.96(ddt,J=12.4,8.5,4.3Hz,1H),3.81(q,J=5.2,4.4Hz,3H),3.42(t,J=5.9Hz,2H),3. 18(q,J=5.8Hz,2H),2.78(s,1H),2.67(dd,J=13.3,7.7Hz,1H),1.60–1.49(m,2H),1.28(s,9H),1.22(s,1H),0.83(dd,J=16.0,6.4Hz,6H). 13C NMR(101MHz,DMSO-d6)δ182.69,172.32,172.02,166.52,165.61,162.51,162 .21,157.72,157.43,155.33,142.05,139.18,129.68,128.58,126.46,125.8 6,102.02,101.05,99.02,98.42,94.79,94.13,78.03,71.88,69.11,68.89,62.34,54.93,50.75,49.88,42.06,38.83,38.04,28.56,24.43,23.59,22.14.

[0204] Example 27 Preparation of xanthone derivative X1-2P-B5 (series 4, n=2)

[0205]

[0206] The preparation process and feeding ratio refer to Example 10

[0207] 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H),11.84(s,1H),11.17(s,1H),8.25( s,1H),8.14–8.03(m,1H),7.60(d,J=9.0Hz,1H),7.31–7.13(m,5H),6.72( d,J=2.3Hz,1H),6.48(d,J=2.3Hz,1H),6.36(d,J=2.1Hz,1H),6.23–6.14( m,2H),5.98(d,J=6.1Hz,1H),5.29(s,2H),4.55(t,J=5.2Hz,2H),4.35(td ,J=9.0,5.1Hz,1H),4.00–3.85(m,1H),3.83(q,J=6.8,5.1Hz,3H),3.51( dd,J=6.1,3.5Hz,2H),3.45(dd,J=6.1,3.6Hz,2H),3.36(s,2H),3.18(q,J =5.9Hz,2H),2.78(dd,J=13.3,7.2Hz,1H),2.66(dd,J=13.3,7.7Hz,1H),1 .58–1.49(m,2H),1.28(s,9H),1.15(s,1H),0.83(dd,J=15.2,6.4Hz,6H). 13C NMR(101MHz,DMSO-d6)δ182.71,172.28,171.96,166.50,165.62,162.51,162.21 ,157.73,157.43,155.33,142.01,139.18,129.68,128.59,126.47,125.86,102. 03,101.07,99.01,98.45,94.79,94.15,78.03,71.86,69.91,69.85,69.30,69.11,62.36,54.94,50.74,49.92,42.13,38.99,38.03,28.57,24.42,23.59,22.16.

[0208] Example 28 Preparation of xanthone derivatives X1-3P-B5 (series 4, n=3)

[0209]

[0210] The preparation process and feeding ratio refer to Example 10

[0211] 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H),11.84(s,1H),11.18(s,1H),8.26(s, 1H),8.15–8.04(m,1H),7.60(d,J=9.0Hz,1H),7.31–7.14(m,5H),6.71(d,J =2.3Hz,1H),6.47(d,J=2.2Hz,1H),6.36(d,J=2.1Hz,1H),6.23–6.14(m,2H ),5.99(s,1H),5.29(s,2H),4.56(t,J=5.2Hz,2H),4.35(td,J=9.1,5.2Hz, 1H),3.95(dtd,J=10.0,7.5,2.5Hz,1H),3.86–3.79(m,3H),3.52(dd,J=6.1 ,3.5Hz,2H),3.46(d,J=6.7Hz,4H),3.37(t,J=5.9Hz,4H),3.18(q,J=6.0Hz ,2H),2.79(dd,J=13.2,7.2Hz,1H),2.67(dd,J=13.3,7.7Hz,1H),1.59–1.4 6(m,2H),1.28(s,9H),1.15(d,J=3.3Hz,1H),0.83(dd,J=15.2,6.4Hz,6H). 13CNMR(101MHz,DMSO-d6)δ182.69,172.28,171.95,166.52,165.60,162.51,162.21,15 7.72,157.42,155.33,142.00,139.18,129.76(d,J=16.5Hz),128.59,126.47,125.85 ,102.02,101.05,99.02,98.44,94.79,94.13,78.03,71.85,70.23–69.86(m),69.30, 69.11,62.36,54.94,50.73,49.93,42.17,39.01,38.03,28.57,24.42,23.59,22.18.

[0212] Example 29 Preparation of xanthone derivatives X1-4P-B5 (series 4, n=4)

[0213]

[0214] The preparation process and feeding ratio refer to Example 10

[0215] 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),11.84(s,1H),11.17(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.60(d,J=9.0Hz,1H),7.28–7.17(m,5H) ,6.73(d,J=2.2Hz,1H),6.48(d,J=2.3Hz,1H),6.36(d,J=2.1Hz,1H),6.24–6.15(m,2H),5.98(s,1H),5.29(s,2H),4.56(t,J=5.1Hz,2H),4.3 4(td,J=9.1,5.2Hz,1H),4.00–3.90(m,1H),3.86–3.79(m,3H),3.52(dd,J=6.0,3.4Hz,2H),3.46(s,6H),3.41–3.33(m,6H),3.18(d,J=4.9Hz ,2H),2.78(dd,J=13.3,7.2Hz,1H),2.66(dd,J=13.3,7.7Hz,1H),1.57–1.46(m,2H),1.28(s,9H),1.15(s,1H),0.83(dd,J=15.4,6.4Hz,6H). 13C NMR(101MHz,DMSO-d6)δ182.71,172.27,171.94,166.50,165.61,162.52,162.22 ,157.73,157.44,155.33,141.99,139.19,129.68,128.59,126.47,125.87,102.0 4,101.08,99.02,98.46,94.79,94.16,78.03,71.85,70.23–69.97(m),69.30,69. 10,62.37,54.93,50.73,49.93,42.19,39.01,38.03,28.57,24.43,23.59,22.19.

[0216] Example 30 Preparation of xanthone derivatives X1-5P-B5 (series 4, n=5)

[0217]

[0218] The preparation process and feeding ratio refer to Example 10

[0219] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.19(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.60(d,J=9.0Hz,1H),7.33–7.16(m,5H),6.7 3(d,J=2.3Hz,1H),6.48(d,J=2.2Hz,1H),6.37(d,J=2.1Hz,1H),6.24–6. 15(m,2H),5.99(s,1H),5.29(s,2H),4.56(t,J=5.1Hz,2H),4.34(td,J=9 .0,5.3Hz,1H),4.00–3.93(m,1H),3.83(p,J=4.9,3.9Hz,3H),3.52(dd,J =6.1,3.5Hz,2H),3.48(s,6H),3.37(dd,J=11.3,5.2Hz,8H),3.18(d,J=5 .8Hz,4H),2.78(dd,J=13.3,7.2Hz,1H),2.66(dd,J=13.3,7.7Hz,1H),1.56–1.44(m,2H),1.28(s,9H),1.15(s,1H),0.83(dd,J=15.7,6.4Hz,6H). 13C NMR(101MHz,DMSO-d6)δ182.71,172.27,171.94,166.53,165.62,162.52,162.22,157 .74,157.45,155.33,141.99,139.19,129.68,128.59,126.47,125.87,102.04,101.0 7,99.03,98.47,94.80,94.17,78.03,71.85,70.18(d,J=4.3Hz),70.05,70.00,69.30 ,69.10,62.38,54.94,50.73,49.93,42.20,39.02,38.03,28.58,24.43,23.60,22.20.

[0220] Example 31 Preparation of Intermediate N3-2P-MDM2 (n=2)

[0221]

[0222] Compound MDM2 (200 mg) was placed in an eggplant-shaped flask, and 5 mL of DCM was added. 118.9 mg of EDCI, 83.8 mg of HoBt, 216 μL of DIPEA, and 59.2 mg of azido-2PEG-NH2 were added sequentially with stirring in an ice bath. The mixture was then extracted with 30 mL of water and 30 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The organic layer was then purified by silica gel column chromatography (elution with dichloromethane:methanol = 25:1) to give a white solid in a 70% yield.

[0223] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=8.5Hz,1H),7.03(d,J=7.6Hz,4H),6.86(dd,J=11.8,8.4Hz,4H),6.51( dd,J=8.5,2.2Hz,1H),6.45(d,J=2.1Hz,1H),6.27(t,J=5.4Hz,1H),5.59(d,J=9.9Hz,1H),5.45(d,J=9. 9Hz,1H),4.59(dt,J=12.0,6.0Hz,1H),3.94–3.78(m,5H),3.75–3.68(m,2H),3.68–3.59(m,2H),3.57– 3.39(m,6H),3.38–3.32(m,2H),3.31–3.22(m,1H),3.10(t,J=5.2Hz,2H),1.37(dd,J=16.5,6.0Hz,6H).

[0224] The other intermediates are fed as above

[0225]

[0226] 1 H NMR(400MHz, CDCl3) δ7.59(d,J=8.5Hz,1H),7.06(dd,J=20.9,8.5Hz,4H),6.91(dd,J=26.3,8.4 Hz,4H),6.55(dd,J=8.5,2.2Hz,1H),6.51–6.40(m,2H),5.57(d,J=9.7Hz,1H),5.48(d,J=9.7Hz, 1H),4.62(dt,J=12.1,6.0Hz,1H),3.97–3.79(m,5H),3.78–3.57(m,9H),3.57–3.46(m,3H),3.41 (dt,J=10.1,4.4Hz,4H),3.32–3.19(m,1H),3.11(t,J=5.2Hz,2H),1.36(dd,J=14.8,6.0Hz,6H).

[0227]

[0228] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=8.5Hz,1H),7.10(d,J=8.5Hz,2H),7.04(d,J=8.6Hz,2H),6.95(d,J=8.4 Hz,2H),6.88(d,J=8.4Hz,2H),6.56(dd,J=8.5,2.2Hz,1H),6.48(d,J=2.1Hz,1H),5.61(s,2H),4.69–4. 52(m,1H),3.94(d,J=15.7Hz,1H),3.86(s,3H),3.85–3.75(m,2H),3.68–3.57(m,16H),3.51(dd,J=12.7 ,7.7Hz,5H),3.43–3.34(m,4H),3.29(dd,J=13.1,6.2Hz,1H),3.13(s,2H),1.37(dd,J=16.9,6.0Hz,6H).

[0229] Example 32 Preparation of xanthone derivative X1-P-MDM2 (series 5, n=1)

[0230]

[0231] The preparation process and feeding ratio refer to Example 10

[0232] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.25(s,1H),7.93(t,J=5.8Hz,1H),7.55(s,1H) ,7.13(dd,J=13.5,7.9Hz,4H),7.04(s,2H),6.97(d,J=8.0Hz,2H),6.73(s,1H),6.60(d,J=7.3Hz,2H),6.49(d,J=2. 1Hz,1H),6.37(d,J=2.1Hz,1H),6.22(d,J=2.1Hz,1H),5.66(s,1H),5.29(s,1H),4.76–4.68(m,1H),4.54(t,J=5.2 Hz,2H),3.90–3.50(m,11H),3.40(t,J=5.7Hz,3H),3.17(q,J=6.1Hz,3H),2.99(d,J=5.7Hz,2H),1.29–1.15(m,6H). 13 C NMR(101MHz,DMSO-d6)δ182.73,167.81,166.49,165.63,164.84,162.88,1 62.53,162.23,157.76,157.46,131.76,131.61,130.10,129.21,127.92,10 5.48,102.07,101.11,99.79,99.03,98.46,94.80,94.17,70.34,69.09,68.84,62.38,55.90,49.88,49.45,49.02,46.94,42.48,38.77,22.19,22.11.

[0233] Example 33 Preparation of xanthone derivative X1-2P-MDM2 (series 5, n=2)

[0234]

[0235] The preparation process and feeding ratio refer to Example 10

[0236] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.25(s,1H),7.94(t,J=5.6Hz,1H),7.54(s,1H),7. 13(dd,J=14.5,8.1Hz,4H),7.05(s,2H),6.97(d,J=8.1Hz,2H),6.73(d,J=2.2Hz,1H),6.60(d,J=6.9Hz,2H),6.49(d,J =2.2Hz,1H),6.37(d,J=2.1Hz,1H),6.22(d,J=2.1Hz,1H),5.65(s,1H),5.29(s,1H),4.75–4.68(m,1H),4.55(t,J=5.1 Hz,2H),3.88–3.55(m,11H),3.48(ddd,J=25.3,6.6,4.0Hz,6H),3.16(q,J=6.0Hz,4H),2.99(s,2H),1.29–1.13(m,6H).

[0237] 13 C NMR(101MHz,DMSO-d6)δ182.74,167.79,166.49,165.63,164.81,162.85,162.53,162.2 2,157.76,157.46,156.94,136.85,131.73,131.59,130.12,129.19,127.92(d,J=3.2Hz) ,125.93,105.47,102.06,101.11,99.78,99.03,98.48,94.80,94.19,70.32,69.92,69.85,69.36,69.10,62.38,55.90,49.95,49.47,48.97,46.92,42.47,38.96,22.19,22.11.

[0238] Example 34 Preparation of xanthone derivative X1-3P-MDM2 (series 5, n=3)

[0239]

[0240] The preparation process and feeding ratio refer to Example 10

[0241] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.26(s,1H),7.96(t,J=5.6Hz,1H),7.55(s,1 H),7.14(dd,J=13.7,7.9Hz,4H),7.08–7.02(m,2H),6.97(d,J=8.1Hz,2H),6.73(s,1H),6.62(s,2H),6.48(s,1H) ,6.37(s,1H),6.24–6.17(m,1H),5.68(s,1H),5.29(s,1H),4.73(p,J=6.0Hz,1H),4.56(t,J=5.1Hz,2H),3.91–3 .50(m,14H),3.35(s,8H),3.24–3.15(m,3H),3.00(d,J=5.5Hz,2H),1.27(d,J=5.8Hz,3H),1.22(d,J=5.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ182.72,170.81,167.79,166.49,165.62,164.78,162.93,162.53, 162.22,157.74,157.45,156.96,136.78,132.37,131.79,131.65,130.12,129.22,127.93, 105.51,102.06,101.10,99.81,99.02,98.47,94.80,94.17,70.37,70.13,70.05,69.99,69.38,69.10,62.41,60.22,55.90,49.95,49.46,48.96,46.89,42.47,38.98,22.18,22.11.

[0242] Example 35 Preparation of Xanthone Derivative X1-4P-MDM2 (Series 5, n=4)

[0243]

[0244] The preparation process and feeding ratio refer to Example 10

[0245] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.18(s,1H),8.27(s,1H),7.96(t,J=5.5Hz,1H),7.56(s,1H) ,7.14(dd,J=13.2,7.8Hz,4H),7.04(s,2H),6.97(d,J=8.1Hz,2H),6.73(s,1H),6.62(d,J=8.9Hz,2H),6.49(s,1H) ,6.37(s,1H),6.22(s,1H),5.69(s,1H),5.29(s,1H),4.80–4.69(m,1H),4.56(t,J=5.1Hz,2H),3.92–3.49(m,18H) ,3.36(d,J=4.5Hz,8H),3.18(q,J=6.0Hz,3H),3.00(d,J=5.9Hz,2H),1.28(d,J=5.7Hz,3H),1.23(d,J=5.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ182.72,170.81,167.78,166.48,165.62,164.77,162.96,162.5 2,162.22,157.74,157.45,156.93,136.73,131.82,131.67,130.10,129.23,127.93,10 5.53,102.05,101.09,99.82,99.02,98.47,94.79,94.17,70.40,70.23–69.95(m),69.3 8,69.09,62.44,60.22,55.91,49.96,49.46,48.97,46.89,42.48,38.99,22.18,22.11.

[0246] Example 36 Preparation of xanthone derivative X1-5P-MDM2 (series 5, n=5)

[0247]

[0248] The preparation process and feeding ratio refer to Example 10

[0249] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.85(s,1H),11.18(s,1H),8.27(s,1H),7.96(t,J=5.5Hz,1H),7.57(s ,1H),7.15(dd,J=13.4,7.6Hz,4H),7.04(s,2H),6.97(d,J=8.1Hz,2H),6.73(s,1H),6.64(s,2H),6.49(s,1H), 6.37(s,1H),6.22(s,1H),5.71(s,1H),5.29(s,1H),4.75(d,J=9.6Hz,1H),4.56(t,J=5.1Hz,2H),3.92–3.47(m ,22H),3.36(d,J=6.2Hz,8H),3.18(q,J=5.8Hz,3H),2.99(s,2H),1.29(d,J=5.6Hz,3H),1.23(d,J=5.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ182.72,167.78,166.49,165.62,164.76,162.98,162.52,162.22 ,157.74,157.45,156.91,131.84,131.68,130.09,129.23,127.94,105.55,102.05,101. 09,99.84,99.02,98.47,94.79,94.17,70.42,70.16(d,J=5.4Hz),70.02(d,J=5.1Hz),69 .38,69.08,62.46,60.22,55.92,49.97,49.45,48.97,46.88,42.48,38.99,22.18,22.11.

[0250] Example 37 Preparation of xanthone derivative X1-P-B5(T) (series 6, n=1)

[0251]

[0252] Compound X1-P-B5 was dissolved in ethyl acetate solution, and an excess of HCl in ethyl acetate solution was added. The reaction was monitored by thin layer chromatography. When the reaction was complete, the product was evaporated to dryness.

[0253] 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),11.84(s,1H),11.30(s,1H),8.27(s,1H),8.19(t,J=5.7Hz,1H),8.03(s,1H),7.30(ddd,J=18 .7,11.4,7.1Hz,5H),6.72(dd,J=12.8,4.0Hz,2H),6.48(d,J=2.2Hz,1H),6.42(d,J=2.1Hz,1H),6.25(d,J=2.1Hz,1H),5.28(s,2H), 4.53(t,J=5.1Hz,2H),4.26(td,J=8.3,5.8Hz,1H),4.01(q,J=4.0,3.5Hz,1H),3.78(t,J=5.1Hz,2H),3.55(s,1H),3.41(d,J=5.9Hz ,4H),3.24–3.09(m,2H),2.90(qd,J=13.8,7.1Hz,2H),1.57(dt,J=13.6,7.5Hz,1H),1.51–1.43(m,2H),0.86(dd,J=9.2,4.9Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ182.72,172.24,171.04,166.62,165.61,162.49,162.22,157.72,157.47,142.04,136.76,129.89,129.09,127.38,12 5.89,102.06,101.07,99.07,98.45,94.84,94.17,69.05,68.88,68.72 ,62.36,54.70,51.72,49.87,41.44,38.86,35.13,24.68,23.29,22.42.

[0254] Example 38 Preparation of xanthone derivative X1-2P-B5(T) (series 6, n=2)

[0255]

[0256] The specific operation is the same as Example 37

[0257] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.84(s,1H),11.34(s,1H),8.27(s,1H),8.19(t,J=5.5Hz,1H),8.00(s,1H),7.30(h,J=7.1, 6.6Hz,5H),6.73(s,2H),6.47(s,1H),6.42(d,J=1.9Hz,1H),6.25(d,J=1.9Hz,1H),5.29(s,2H),4.55(t,J=5.1Hz,2H),4.26(q,J=7 .7Hz,1H),4.00(q,J=4.3,3.7Hz,1H),3.81(t,J=5.0Hz,2H),3.60–3.46(m,4H),3.45–3.41(m,2H),3.33(d,J=5.7Hz,3H),3.15(dt, J=12.5,5.9Hz,2H),2.92(dq,J=15.1,7.8Hz,2H),1.57(dd,J=13.1,6.7Hz,1H),1.48(tt,J=13.5,5.9Hz,2H),0.85(t,J=7.0Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ182.70,172.20,170.99,166.65,165.59,162.46,1 62.20,157.69,157.45,142.00,136.81,129.90,129.07,127.36,125.88,1 02.04,101.03,99.08,98.46,94.84,94.16,69.92,69.84,69.26,69.11,68.70,62.36,54.71,51.72,49.93,41.49,39.01,35.10,24.65,23.29,22.45.

[0258] Example 39 Preparation of Xanthone Derivative X1-3P-B5(T) (Series 6, n=3)

[0259]

[0260] The specific operation is the same as Example 37

[0261] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.83(s,1H),11.34(s,1H),8.27(s,1H),8.19(t,J=5.6Hz,1H),8.00(s,1H),7.39–7.20(m,5H),6.72( t,J=4.4Hz,2H),6.47(d,J=2.2Hz,1H),6.42(d,J=2.1Hz,1H),6.25(d,J=2.1Hz,1H),5.29(s,2H),4.56(t,J=5.1Hz,2H),4.26(td,J=8.3,5.9 Hz,1H),4.01(q,J=3.6Hz,1H),3.82(t,J=5.1Hz,2H),3.55(s,1H),3.51(dd,J=6.1,3.5Hz,2H),3.47–3.44(m,2H),3.41–3.32(m,8H),3.17(t t,J=13.4,6.5Hz,2H),2.91(qd,J=13.7,7.1Hz,2H),1.59(dt,J=13.5,7.0Hz,1H),1.48(ddd,J=13.4,9.8,5.5Hz,2H),0.86(t,J=6.9Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ182.69,172.20,170.98,166.65,165.58,162.47,16 2.20,157.69,157.45,142.00,136.81,129.91,129.08,127.36,125.86,102. 04,101.03,99.07,98.45,94.84,94.15,70.13,70.05,69.98,69.27,69.12,68.68,62.36,54.71,51.70,49.94,41.51,39.03,35.11,24.65,23.29,22.46.

[0262] Example 40 Preparation of Xanthone Derivative X1-4P-B5(T) (Series 6, n=4)

[0263]

[0264] The specific operation is the same as Example 37

[0265] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.84(s,1H),11.33(s,1H),8.27(s,1H),8.20(t,J=5.7Hz,1H),8.00(s,1H),7.30(tq,J=13.8 ,7.2Hz,5H),6.72(dd,J=12.1,4.0Hz,2H),6.48(d,J=2.2Hz,1H),6.42(d,J=2.0Hz,1H),6.25(d,J=2.1Hz,1H),5.29(s,2H),4.56(t, J=5.1Hz,2H),4.27(td,J=8.3,5.9Hz,1H),4.08–3.98(m,1H),3.83(t,J=5.0Hz,2H),3.52(dd,J=6.1,3.4Hz,5H),3.37(s,12H),3.17 (dtt,J=19.6,13.5,6.2Hz,2H),2.91(qd,J=13.8,7.1Hz,2H),1.59(dt,J=13.4,6.9Hz,1H),1.53–1.43(m,2H),0.86(t,J=7.0Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ182.71,172.19,170.98,166.64,165.60,162.48,16 2.21,157.70,157.46,141.99,136.79,129.91,129.08,127.37,125.88,102. 05,101.04,99.08,98.46,94.84,94.17,70.19,70.06,70.00,69.28,69.11,68.69,62.37,54.72,51.70,49.94,41.53,39.03,35.12,24.66,23.29,22.46.

[0266] Example 41 Preparation of Xanthone Derivative X1-5P-B5(T) (Series 6, n=5)

[0267]

[0268] 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),11.84(s,1H),11.33(s,1H),8.27(s,1H),8.20(t,J=5.6Hz,1H),8.00(s,1H),7.31(ddd,J=18.9,11. 5,7.0Hz,5H),6.72(dd,J=15.8,4.0Hz,2H),6.48(d,J=2.2Hz,1H),6.42(d,J=2.1Hz,1H),6.25(d,J=2.1Hz,1H),5.29(s,2H),4.56(t,J=5.1 Hz,2H),4.27(td,J=8.3,6.1Hz,1H),4.00(dd,J=5.8,3.3Hz,1H),3.83(t,J=5.0Hz,2H),3.52(dd,J=6.1,3.5Hz,5H),3.46(d,J=3.3Hz,16H) ,3.17(dtq,J=19.4,12.3,5.9Hz,2H),2.91(qd,J=13.7,7.1Hz,2H),1.59(dt,J=13.6,7.0Hz,1H),1.52–1.43(m,2H),0.87(t,J=7.1Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ182.71,172.20,170.97,166.64,165.61,162.48,16 2.22,157.71,157.46,141.99,136.79,129.91,129.09,127.37,125.88,102. 05,101.05,99.08,98.47,94.84,94.18,70.18,70.06,70.00,69.28,69.10,68.69,62.38,54.72,51.70,49.94,41.53,39.04,35.12,24.66,23.29,22.46.

[0269] Example 43 Drug Screening Based on DYRK1A Enzyme Activity Inhibition

[0270] The DYRK1A enzyme activity and the inhibitory effect of a series of compounds were detected by measuring NADH consumption. 30 μL of enzyme reaction solution (containing 28.5 μL of 0.70 μM DYRK1A, 1.5 μL of the test compound with different gradient concentrations or 1.5 μL of 100% DMSO) was incubated at room temperature for 30 min and then added to a 96-well plate pre-filled with 70 μL of a mixture (containing 10 μL of 250 mM HEPES pH 7.5; 10 μL of 1.5 M NaCl; 1 μL of 0.5 M MgCl2; 4 μL of 50 mM ATP; 0.2 μL of 250 mM NADH; 5 μL of 100 mM potassium phosphoenolpyruvate; 4 μL of 12.5 mM RARPGTPALRE; 1.5 μL of 2.5 KU / mL lactate dehydrogenase; 1 μL of 5 KU / mL M2 pyruvate kinase; and 33.3 μL of water). The plate was immediately incubated using a BioTEK Synergy The H1 multifunctional microplate reader was used to monitor the UV absorption wavelength at 340 nm every 1 min for 20 min, and the changes in absorbance were recorded. IC was calculated using GraphPad Prism version 6 using standard dose-response curve fitting. 50 The experimental results are shown in Table 1.

[0271] Example 44 Microthermophoresis Experiment

[0272] Using Monolith NT TM DYRK1A protein was labeled using the Protein Labeling Kit RED (Cat#L001). Samples were diluted with 20 mM HEPES (pH 7.5) and 0.5 (v / v)% Tween-20. Test compound powder was dissolved in 10% DMSO and serially diluted 1:1. The protein and compound were then incubated at room temperature for 15 minutes at a 1:1 volume ratio. The complex was then loaded into a Monolith™ standard-treated capillary tube and thermophoresis was measured at 20°C on a Monolith NT.115 instrument (NanoTemper Technologies, Munich, Germany). The LED power was set to 100%. Dissociation constants (Kd) were fitted using NTAnalysis software (NanoTemper Technologies, Munich, Germany).

[0273] The experimental results show that ( Figure 1 ), the equilibrium dissociation constants Kd of compounds 1, X1-CH2-V2, 2 and 4 were 265.00±41.30μM, 14.80±1.56μM, 17.00±2.16μM and 6.26±0.65μM, respectively.

[0274] Example 45 PROTAC mediates degradation of DYRK1A protein in INS-1 cells

[0275] INS-1 cells in the logarithmic phase were prepared into a cell suspension with a concentration of 50,000 / mL using fresh culture medium, mixed and added to a 6-well plate, 2 mL per well; after the cells adhered, different concentrations of the test compound (containing 0.5% DMSO) were added, and after 24 hours of treatment, the cells were collected by centrifugation; the collected cells were subjected to Western Blot detection, and the degradation of DYRK1A protein was detected using DYRK1A antibody. The results showed that PROTAC (X1-PT, X1-3P-T, X1-4P-T, X1-5P-T, X1-2P-MDM2, X1-3P-MDM2, X1-5P-B(T), X1-CH2-B4, X1-CH2-V2, X1-7CH2-V2) was able to induce the degradation of DYRK1A protein in INS-1 cells at 1.25 μM. The experimental results are shown in Figure 2 .

[0276] Example 46 Determination of the effect of compound X1-CH2-V2 on promoting INS-1 cell proliferation

[0277] INS-1 cells are derived from a rat insulinoma cell line. Because they share many key features of pancreatic β cells, they are widely used as a model cell line for assessing β cell function. Therefore, we employed INS-1 cells to further investigate the effect of compound X1-CH2-V2 on β cell proliferation. CCK-8 assays revealed that compound X1-CH2-V2 exhibited a concentration-dependent effect on INS-1 cell proliferation. At 75 μM, the proliferation rate reached 31.46 ± 14.38% (**P < 0.01), significantly higher than the control (-0.57 ± 5.06%). Treatment with compound X1-CH2-V2 at concentrations of 9.375 μM or higher also increased insulin levels in the culture supernatant. This suggests that proliferating INS-1 cells possess insulin secretion and that compound X1-CH2-V2 effectively induces insulin secretion in INS-1 cells. Treatment with compound X1-CH2-V2 significantly increased the number of EdU-positive INS-1 cells. In addition, we also determined the effect of compound X1-CH2-V2 on the proliferation of STZ-injured INS-1 cells. The results showed that after 24 hours of treatment with compound X1-CH2-V2, the proliferation of STZ-injured INS-1 cells increased. Figure 3 and Figure 4 .

[0278] Example 46 Compound X1-CH2-V2 promotes β-cell proliferation through the NFAT pathway and upregulates cell proliferation-related proteins

[0279] Immunofluorescence was used to detect the distribution of NFATc1 protein in INS-1 cells after compound treatment; treatment with compound X1-CH2-V2 induced a dose-dependent increase in NFATc1 protein in INS-1 cells relative to cytoplasmic NFATc1 protein ( Figure 5 a). This suggests that compound X1-CH2-V2 may stimulate the translocation of NFATc1 protein from the cytoplasm to the nucleus.

[0280] Ccdns promotes cell proliferation by promoting the transition from the G1 to S phase of the cell cycle. Real-time PCR was used to detect the mRNA levels of Ccdns and CDK4. Gene expression analysis showed that the mRNA levels of Ccnd1, Ccnd2, and Ccnd3 in INS-1 cells were upregulated in a dose-dependent manner after treatment with compound X1-CH2-V2, while the mRNA level of CDK4 was not significantly affected ( Figure 5 b) The above results suggest that compound X1-CH2-V2 regulates the NFAT pathway by inhibiting DYRK1A, promoting NFATc1 nuclear localization, and upregulating the expression levels of cell proliferation-related proteins, thereby promoting INS-1 cell proliferation. Figure 5 .

[0281] Example 47 Compound X1-CH2-V2 can restore pancreatic islet function in db / db mice and its effect on the expression levels of FOXO1, PDX1, and Insulin proteins in their pancreatic islet tissue

[0282] Immunofluorescence double staining was used to analyze the expression levels of insulin (green) and glucagon (red) to evaluate the repair of damaged pancreatic islets induced by Compound X1-CH2-V2. The pancreatic islets of normal mice were intact, with clear boundaries and high insulin levels, but only a small amount of glucagon was present at the outer edges of the pancreas. The pancreatic islets of diabetic mice exhibited irregular morphology, decreased insulin levels, and a chaotic and scattered distribution of insulin and glucagon. Compared to the diabetic group, six weeks of treatment with high and low doses of Harmine and Compound X1-CH2-V2 restored the morphology of the pancreatic islet tissue in diabetic mice, and insulin and glucagon expression returned to normal. The improvement in pancreatic islet function was most pronounced in the high-dose Compound X1-CH2-V2 group, approaching the levels of normal controls. These results demonstrate that Compound X1-CH2-V2 can protect and repair pancreatic islets, improving their function. Furthermore, the protein expression levels of PDX1 and insulin in the pancreatic islet tissue of diabetic mice decreased. After 6 weeks of treatment with compound, Harmine, and metformin, the protein expression levels of PDX1 and insulin in the four groups of animals were significantly increased compared with the diabetic group. Among them, the expression level of compound X1-CH2-V2 high-dose group increased most significantly. The expression of FOXO1 protein in the pancreatic islet tissue of diabetic mice was significantly increased. After 6 weeks of treatment with compound, Harmine, and metformin, the expression level of FOXO1 protein in the pancreatic islet tissue of diabetic mice decreased compared with the diabetic group. Among them, the expression level of compound X1-CH2-V2 high-dose group decreased most significantly. The experimental results are shown in Figure 6 .

[0283] Example 48 Effects of Compound X1-CH2-V2 on Body Weight, Food Intake, Blood Glucose Level, Serum Insulin Level, Oral Glucose Tolerance Test, and Blood Lipid Levels in Diabetic Mice

[0284] After 6 weeks of administration, the 6-hour fasting blood glucose levels of db / db mice treated with compound, Harmine and metformin were all reduced compared with the control group. Compared with normal mice, the body weight and food intake of diabetic mice increased significantly, and no significant differences were observed in these parameters between the treatment groups. Among them, the blood glucose level in the Harmine treatment group decreased more slowly than that in the compound and metformin treatment groups. The compound can significantly reduce the fasting blood glucose level of diabetic mice in a dose-dependent manner. The fasting blood glucose level of diabetic mice remained at a high level throughout the administration period. An oral glucose tolerance test was performed 6 weeks after administration to assess the glucose homeostasis of mice. The results showed that diabetic mice had impaired oral glucose tolerance. The blood glucose levels of all drug-treated mice began to steadily decrease from 30 minutes after administration. This shows that the compound can significantly improve the oral glucose tolerance of diabetic mice. These experimental results show that compound treatment led to a significant increase in the mass of β cells in diabetic mice, which may explain the glucose control effect of the compound. The insulin content in the serum of mice in the administration group increased significantly. Experimental results are shown in Figure 7 .

[0285] Table 1 IC of compounds inhibiting DYRK1A enzyme activity 50 value

[0286]

[0287] From the above table, it can be seen that compounds 1, 4, 7, 9, 10 and X1-CH2-VHL2 have better inhibitory effects on DYRK1A enzyme activity.

Claims

1. A xanthone having the structural formula (I) or a pharmaceutically acceptable salt thereof: in: R1 independently represents propynyloxy, benzyloxy, acetoxy, benzoyloxy, p-toluenesulfonyloxy or methylsulfonyloxy; R2 independently represents hydroxyl, propynyloxy, benzyloxy, acetoxy, benzoyloxy, p-toluenesulfonyloxy or methylsulfonyloxy; R3 is selected from one of H and D.

2. A xanthone derivative or a pharmaceutically acceptable salt thereof, characterized in that: The xanthone derivative is selected from the following series 1-6: n＝1-5、7。 3. A pharmaceutical composition, characterized in that The invention comprises the xanthone or a pharmaceutically acceptable salt thereof according to claim 1 or the xanthone derivative or a pharmaceutically acceptable salt thereof according to claim 2, and further comprises a pharmaceutically acceptable carrier, diluent or a combination thereof.

4. A method for preparing the xanthone derivative according to claim 2, characterized in that: The following steps are involved: The reaction pathway using 2,4,6-trihydroxybenzoic acid as the starting material is as follows: n＝1-5、7。 5. Use of the xanthone or a pharmaceutically acceptable salt thereof according to claim 1, the xanthone derivative or a pharmaceutically acceptable salt thereof according to claim 2, or the pharmaceutical composition according to claim 3 in the preparation of a drug for treating or preventing diabetes.

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