Oxaporthiochromenyl compounds containing different substituents on the sulfonamide nitrogen atom, their preparation and use

Abstract

The application provides a kind of oxo-bridged bicyclo-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituent groups and its preparation method and application, in the application, dienophile compound containing different sulfonamide nitrogen atom substituent groups and 3,4-diphenol furan / 3,4-diphenol furan containing halogen substitution are used as raw materials, oxo-bridged bicyclo-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituent groups are prepared by solvent-free reaction at 90 DEG C in one step;Such compounds show certain inhibitory activity and protein degradation activity on wild-type breast cancer cells MCF-7 and three drug-resistant mutant breast cancer cells MCF-7Y537S, MCF-7D538G, MCF-7EGFR;And oxo-bridged bicyclo-[2.2.1]-heptene compounds containing fluorine atom or chlorine atom substitution on benzene ring improve the affinity for estrogen receptor, and interfere with estrogen receptor dimerization interface, which is a new mechanism of estrogen receptor inhibitor for anti-breast cancer drug-resistant mutation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents, their preparation methods, and applications. Background Technology

[0002] In recent years, breast cancer has become one of the most common cancers among women, and overexpression of the estrogen receptor can lead to breast cancer. Therefore, anti-estrogenic drugs have been continuously developed and applied. However, studies have shown that long-term use of anti-estrogenic drugs can cause severe side effects and lead to drug-resistant breast cancer. Therefore, there is a need to develop anti-breast cancer drugs with novel mechanisms that target the estrogen receptor. Summary of the Invention

[0003] The purpose of this invention is to provide an oxygen-bridged bicyclic-[2.2.1]-heptene compound containing different sulfonamide nitrogen atom substituents, which can at least solve some of the defects existing in the prior art.

[0004] To achieve the above objectives, the present invention adopts the following technical solution:

[0005] Oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents have the structures shown in the following general formula:

[0006]

[0007] Where X is selected from -H, -F, or -Cl;

[0008] R2 is selected from

[0009] R1 is selected from

[0010] Preferably, the oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents are selected from any one of the following compounds:

[0011] 5,6-Bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-propyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0012] 5,6-Bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-(3,3,3-trifluoropropyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0013] 5,6-Bis(4-hydroxyphenyl)-N-isobutyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0014] 5,6-Bis(4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0015] N-Allyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0016] N-(2-hydroxyethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0017] N-(2-fluoro-2-methylpropyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0018] N-(cyclopropylmethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0019] N-(cyclobutylmethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0020] N-Cyclohexyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0021] 5,6-Bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0022] N-Benzyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0023] 4,4'-(5-(indoline-1-ylsulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl)diphenol;

[0024] 4,4'-(5-((6-methoxy-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl)diphenol;

[0025] 4,4'-(5-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl)diphenol;

[0026] 5,6-Bis(3-fluoro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0027] N-(cyclopropylmethyl)-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0028] N-(cyclobutylmethyl)-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0029] N-Cyclohexyl-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0030] 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0031] 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-(cyclopropylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0032] 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-(cyclobutylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0033] 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-cyclohexyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0034] 5,6-Bis(2-fluoro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0035] O-(cyclopropylmethyl)-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0036] N-(cyclobutylmethyl)-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0037] N-Cyclohexyl-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0038] 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0039] 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-(cyclopropylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0040] 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-(cyclobutylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide;

[0041] 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-cyclohexyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide.

[0042] In addition, the present invention also provides a method for preparing the above-mentioned oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents, comprising the following steps:

[0043] S1. Synthesize 3,4-di(4-hydroxyphenyl)-furan, or synthesize 3,4-di(4-hydroxyphenyl)-furan containing different halogen substitutions;

[0044] S2, Synthesizing vinylsulfonamide derivatives;

[0045] S3. The 3,4-di(4-hydroxyphenyl)-furan or 3,4-di(4-hydroxyphenyl)-furan containing different halogen substitutions synthesized in step S1 is subjected to a diene synthesis reaction with the ethylene sulfonamide derivative synthesized in step S2 to obtain oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents.

[0046] Specifically, in step S1, the synthetic route for 3,4-bis(4-hydroxyphenyl)-furan is as follows:

[0047]

[0048] 1) Synthesis of p-methoxybromoacetophenone

[0049] Weigh p-methoxyacetophenone, p-toluenesulfonic acid, and N-bromosuccinimide into a reaction vessel, add dichloromethane to dissolve them, and react the well-mixed reactants at room temperature. Monitor the completeness of the reaction using TLC thin-layer chromatography. After the reaction is complete, remove the solvent under reduced pressure, add ethyl acetate to dissolve, and wash successively with 2N dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. Dry the organic layer with anhydrous NaSO4, filter and evaporate to dryness to obtain the crude product. After purification by column chromatography, obtain white solid compound 2, namely p-methoxybromoacetophenone.

[0050] 2) Synthesis of 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester

[0051] Weigh p-methoxybromoacetophenone and p-methoxyphenylacetic acid into a reaction vessel, dissolve them in anhydrous acetonitrile, slowly add anhydrous triethylamine, and continue the reaction at room temperature. Monitor the completeness of the reaction using TLC thin-layer chromatography. After the reaction is complete, remove the acetonitrile and triethylamine by evaporation, dissolve them in ethyl acetate, and wash them successively with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. Dry the organic layer with anhydrous sodium sulfate, filter and evaporate to dryness to obtain the crude product. After purification by column chromatography, obtain yellow solid compound 4, namely 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester.

[0052] 3) Synthesis of 3,4-bis(4-methoxy-phenyl)furan-2-one

[0053] Under anhydrous and oxygen-free conditions, 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester was weighed into a reaction vessel under argon atmosphere and dissolved in anhydrous dimethyl sulfoxide. 80% NaH was slowly added dropwise, and the reaction was carried out at 25°C. The reaction was monitored for completeness using TLC thin-layer chromatography. After complete reaction, 2N dilute hydrochloric acid was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous NaSO4. The crude product was obtained by desolvation under reduced pressure and then purified by silica gel column chromatography to obtain compound 5, namely 3,4-di(4-methoxy-phenyl)furan-2-one.

[0054] 4) Synthesis of 3,4-di(4-hydroxy-phenyl)furan-2-one

[0055] Under anhydrous and oxygen-free conditions, 3,4-di(4-methoxy-phenyl)furan-2-one was weighed into a reaction vessel under argon atmosphere, dissolved in dichloromethane, and reacted with BBr3 at -20°C for 12 h. The reaction was then quenched with water, the reaction solution was extracted with ethyl acetate and washed with saturated NaHCO3 solution, the organic layer was dried over anhydrous NaSO4, and the crude product was obtained by desolvation under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain compound 6, namely 3,4-di(4-hydroxy-phenyl)furan-2-one.

[0056] 5) Synthesis of 3,4-bis(4-hydroxy-phenyl)furan

[0057] Under anhydrous and oxygen-free conditions, 3,4-bis(4-hydroxy-phenyl)furan-2-one was weighed into a reaction vessel under argon atmosphere. After hydrogenation with diisobutyl at -78°C for 12 h, the reaction was quenched with 4% H2SO4. The reaction solution was extracted with ethyl acetate and washed with saturated NaCl solution. The organic layer was dried with anhydrous NaSO4 and dissolved under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain compound 7, namely 3,4-bis(4-hydroxy-phenyl)furan.

[0058] Specifically, in step S1, the synthetic routes for 3,4-bis(4-hydroxyphenyl)-furan containing different halogen substitutions are as follows:

[0059]

[0060] 1) Synthesis of 3,4-dibromofuran

[0061] Weigh (E)-3,4-dibromohex-3-en-1,6-diol, add potassium dichromate and concentrated sulfuric acid, and then perform steam distillation to obtain compound 9, namely 3,4-dibromofuran.

[0062] 2) Synthesis of halogen-substituted 3,4-bis(4-methoxyphenyl)-furan

[0063] 3,4-Dibromofuran and the corresponding halogen-substituted p-methoxyphenylboronic acid were weighed into a reaction vessel, palladium catalyst and anhydrous tetrahydrofuran were added, and the mixture was heated to reflux. The reaction was monitored by TLC thin-layer chromatography to check whether the reaction was complete. After the reaction was complete, the tetrahydrofuran was evaporated, and the mixture was dissolved in ethyl acetate. The mixture was washed successively with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain the crude product. After purification by column chromatography, the corresponding compounds 11a-11d were obtained, namely halogen-substituted 3,4-di(4-methoxyphenyl)-furan.

[0064] 3) Synthesis of halogen-substituted 3,4-bis(4-hydroxyphenyl)-furan:

[0065] Under anhydrous and oxygen-free conditions, halogen-substituted 3,4-bis(4-methoxyphenyl)-furan was weighed into a reaction vessel under argon atmosphere, dissolved in dichloromethane, and reacted with BBr3 at -20°C for 12 h. The reaction was then quenched with water, and the reaction solution was extracted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was dried over anhydrous NaSO4, and the crude product was obtained by desolvation under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain compounds 12a-12d, i.e., halogen-substituted 3,4-bis(4-hydroxyphenyl)-furan.

[0066] Specifically, in step S2, the synthetic route for the ethylene sulfonamide derivative is as follows:

[0067]

[0068] 1) Synthesis of N-phenylacetamide compounds 15a-15c

[0069] p-Methoxyaniline and acid anhydride compounds 14a-14c were weighed into a single-necked flask, dissolved in dichloromethane, and then pyridine was slowly added. The reaction was continued at room temperature. The reaction was monitored by TLC thin-layer chromatography to check whether the reaction was complete. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain N-phenylacetamide compounds 15a-15c.

[0070] 2) Synthesis of N-alkylaniline compounds 16a-16d

[0071] Under argon protection, N-phenylacetamide compounds 15a-15c were weighed into a double-necked flask, dissolved in anhydrous tetrahydrofuran, and borane-tetrahydrofuran was slowly added dropwise at 0°C. After slowly raising the temperature to 60°C, the reaction was carried out for 24 hours. The reaction was quenched with methanol, and the crude product was obtained after desolvation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a white oily substance, namely N-alkylaniline compounds 16a-16d.

[0072] 3) Synthesis of sulfonamide dienophile compounds 17a-17d

[0073] The corresponding N-alkylaniline compounds 16a-16d were weighed and dissolved in dichloromethane. 2-chloroethanesulfonyl chloride was slowly added at 0°C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain sulfonamide dienophile compounds 17a-17d.

[0074] 4) Synthesis of sulfonamide dienophile compound 18

[0075] p-Methoxyaniline was weighed and dissolved in dichloromethane. 2-Chloroethanesulfonyl chloride was slowly added at 0°C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain sulfonamide dienophile compound 18.

[0076] 5) Synthesis of sulfonamide dienophile compounds 20a-20i

[0077] Sulfonamide dienophile compound 18 was weighed and dissolved in N,N-dimethylformamide. Potassium carbonate was added, followed by the slow addition of the corresponding bromoalkanes 19a-19i. After reacting at 60°C for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain sulfonamide dienophile compounds 20a-20i.

[0078] 6) Synthesis of sulfonamide dienophile compounds 22a-22c

[0079] The corresponding amine compounds 21a-21c were weighed and dissolved in dichloromethane. 2-chloroethanesulfonyl chloride was slowly added at 0°C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain sulfonamide dienophile compounds 22a-22c.

[0080] Specifically, in step S3, the synthetic route for oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents is as follows:

[0081]

[0082] Where R1 is

[0083] The synthesized 3,4-bis(4-hydroxy-phenyl)furan and any one of the ethylene sulfonamide derivatives 17a-17c, 20a-20i, and 22a-22c were dissolved in tetrahydrofuran and reacted at 90°C in one step to prepare oxygen-bridged bicyclic-[2.2.1]-heptene compounds 23a-23o with different sulfonamide nitrogen atom substituents.

[0084] Specifically, in step S3, the synthetic route for oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents is as follows:

[0085]

[0086] The synthesized 3,4-bis(4-hydroxyphenyl)-furan containing different halogen substitutions and any one of the ethylene sulfonamide derivatives 17c, 20e, 20f, and 20g were dissolved in tetrahydrofuran and reacted at 90°C in one step to prepare oxygen-bridged bicyclic-[2.2.1]-heptene compounds 24a to 24p containing different sulfonamide nitrogen atom substituents.

[0087] In addition, the present invention also provides the application of the above-mentioned oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents and their pharmaceutically acceptable salts in the preparation of anti-breast cancer drugs.

[0088] Furthermore, the anti-breast cancer drug includes one or more pharmaceutically acceptable carriers or excipients of the oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents.

[0089] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0090] This invention uses 3,4-di(4-hydroxyphenyl)-furan or 3,4-di(4-hydroxyphenyl)-furan with different halogen substitutions and diephilic compounds with different sulfonamide nitrogen atom substituents as raw materials to prepare oxygen-bridged bicyclic-[2.2.1]-heptene compounds with different sulfonamide nitrogen atom substituents in a one-step reaction. These compounds have shown certain inhibitory activity and protein degradation activity against wild-type breast cancer cells MCF-7, three drug-resistant mutant breast cancer cells MCF-7Y537S, MCF-7D538G, and MCF-7EGFR. Moreover, oxygen-bridged bicyclic-[2.2.1]-heptene compounds with fluorine or chlorine atoms substituent on the benzene ring further enhance the affinity for estrogen receptors and interfere with the estrogen receptor dimerization interface, which is a novel mechanism for estrogen receptor inhibitors against drug-resistant mutations in breast cancer. Detailed Implementation

[0091] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0092] I. Synthesis of 3,4-bis(4-hydroxyphenyl)-furan compound 7:

[0093]

[0094] a. Synthesis of p-methoxybromoacetophenone compound 2

[0095] Weigh 1.0 eq. p-methoxyacetophenone 1, 0.2 eq. p-toluenesulfonic acid and 1.2 eq. N-bromosuccinimide (NBS) into a 50 mL round-bottom flask, add 20 mL of CH2Cl2, and react at room temperature for 9 h. After the reaction is complete, monitor the reaction by TLC thin-layer chromatography. Remove the solvent under reduced pressure, add 50 mL of ethyl acetate to dissolve, and wash with 3.0 eq. 2N HCl, 2 × 30 mL of saturated NaHCO3 solution and 30 mL of saturated NaCl. Dry the organic layer with anhydrous NaSO4, filter and evaporate to dryness to obtain the crude product, which is purified by column chromatography to obtain a white solid compound 2.

[0096] b. Synthesis of compound 4, 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester

[0097] Weigh 1.0 eq. of compound 2 and 1.0 eq. of p-methoxyphenylacetic acid 3 into a 50 mL round-bottom flask, add 25 mL of anhydrous acetonitrile, and slowly add 1.0 eq. of anhydrous triethylamine (TEA). Continue the reaction at room temperature for 2 h. Monitor the reaction for completeness by TLC. After the reaction is complete, remove the acetonitrile and triethylamine by evaporation, dissolve in ethyl acetate, and wash successively with 5.0 eq. of 2N dilute hydrochloric acid, 2 × 30 mL of saturated sodium bicarbonate, and 30 mL of saturated sodium chloride. Dry the organic layer with anhydrous sodium sulfate, filter and evaporate to dryness to obtain the crude product. After purification by column chromatography, obtain the yellow solid compound 4.

[0098] c. Synthesis of 3,4-bis(4-methoxy-phenyl)furan-2-one compound 5

[0099] After baking a 25 mL two-necked flask and a magnetic separator at 105 °C for 15 min, the apparatus was heated and operated under anhydrous and oxygen-free conditions. 1.0 eq. of compound 4 was weighed under Ar purging, and 10 mL of anhydrous dimethyl sulfoxide (DMSO) was added. 2.0 eq. of 80% NaH was slowly added dropwise, and the reaction was carried out at 25 °C for 2 h. The reaction was monitored by TLC to ensure complete reaction. 5 mL of 4.0 eq. of 2N HCl was added to quench the reaction. The mixture was extracted with 3 × 25 mL of ethyl acetate, and the organic layer was dried over anhydrous NaSO4. The crude product was obtained by desolvation under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain compound 5.

[0100] d. Synthesis of 3,4-bis(4-hydroxy-phenyl)furan-2-one compound 6

[0101] After baking a 100 mL single-necked flask and magnetic flask at 105 °C for 15 min, the apparatus was heated and operated under anhydrous and oxygen-free conditions. 1.0 eq. of compound 5 was weighed under Ar purging. 25 mL of dichloromethane (DCM) was added, and 6.0 eq. of BBr3 was added at -20 °C. After reacting for 12 h, 10 mL of water was added to quench the reaction. The mixture was extracted with 3 × 20 mL of ethyl acetate, washed with 15 mL of saturated NaHCO3 solution, dried over anhydrous NaSO4, and dissolved under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:3) to obtain compound 6.

[0102] e. Synthesis of 3,4-bis(4-hydroxy-phenyl)furan compound 7

[0103] After baking a 50 mL single-necked flask and a magnetic flask at 105 °C for 15 min, the apparatus was heated and operated under anhydrous and oxygen-free conditions. 1.0 eq. of compound 6 was weighed under Ar purging. 4.0 eq. of diisobutylaluminum hydride (DIBAL-H) ​​was added at -78 °C and reacted for 12 h. The reaction was quenched with 4% H2SO4. The mixture was extracted with 3 × 25 mL ethyl acetate, washed with 30 mL saturated NaCl solution, dried over anhydrous NaSO4, and dissolved under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:4) to obtain compound 7.

[0104] II. Synthesis of 3,4-bis(4-hydroxyphenyl)-furan compounds containing different halogen substitutions

[0105]

[0106] Synthesis of α,3,4-dibromofuran 9:

[0107] Weigh (E)-3,4-dibromohex-3-ene-1,6-diol, add potassium dichromate and concentrated sulfuric acid, and then perform steam distillation to obtain 3,4-dibromofuran.

[0108] b. Synthesis of halogen-substituted 3,4-bis(4-methoxyphenyl)-furan compounds 11a-11d:

[0109] Weigh 1.0 eq. of 3,4-dibromofuran and 4.0 eq. of the corresponding halogen-substituted p-methoxyphenylboronic acid into a 50 mL round-bottom flask, add 0.02 eq. of palladium catalyst (Pd(dppf)2Cl2), add 10 mL of anhydrous tetrahydrofuran (THF), heat to reflux, monitor the reaction for completeness by TLC, after the reaction is complete, remove THF by evaporation, dissolve in ethyl acetate, wash successively with 5.0 eq. of 2N dilute hydrochloric acid, 2 × 30 mL saturated sodium bicarbonate and 30 mL saturated sodium chloride, dry the organic layer with anhydrous sodium sulfate, filter and evaporate to dryness to obtain crude product, and purify by column chromatography to obtain the corresponding compounds 11a-11d.

[0110] c. Synthesis of halogen-substituted 3,4-bis(4-hydroxyphenyl)-furan compounds 12a-12d:

[0111] After baking a 100 mL single-necked flask and magnetic flask at 105 °C for 15 min, the apparatus was heated and operated under anhydrous and oxygen-free conditions. 1.0 eq. of compounds 11a-11d were weighed under Ar purging. 25 mL of dichloromethane (DCM) was added, and 6.0 eq. of BBr3 was added at -20 °C and reacted for 12 h. The reaction was quenched with 10 mL of water, extracted with 3 × 20 mL of ethyl acetate, washed with 15 mL of saturated NaHCO3 solution, dried over anhydrous NaSO4, and dissolved under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:3) to obtain compounds 12a-12d.

[0112] III. Synthesis of Ethylenesulfonamide Derivatives

[0113]

[0114] a. Synthesis of N-phenylacetamide compounds 15a-15c:

[0115] 1 eq. of p-methoxyaniline 13 and 2 eq. of acid anhydride compounds 14a-14c were weighed into a 100 mL single-necked flask, dissolved in 40 mL of dichloromethane (DCM), and then 0.1 eq. of pyridine was slowly added. The reaction was continued at room temperature for 2 h. After the reaction was monitored by TLC thin-layer chromatography until it was complete, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to obtain acetamide compounds 15a-15c.

[0116] b. Synthesis of N-alkylaniline compounds 16a-16c:

[0117] Under Ar protection, 1 eq. of acetamide compounds 15a-15c was weighed into a 100 mL double-necked flask, dissolved in 20 mL of anhydrous tetrahydrofuran (THF), and 4 eq. of borane-tetrahydrofuran (BH3-THF) was slowly added dropwise at 0 °C. After slowly raising the temperature to 60 °C, the reaction was carried out for 24 h, and the reaction was quenched by adding 5 mL of methanol. After desolvation under reduced pressure, crude product was obtained, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12:1) to obtain white oily substances, namely N-alkylaniline compounds 16a-16c.

[0118] c. Synthesis of sulfonamide dienophile compounds 17a-17c:

[0119] The corresponding 1 eq. N-alkylaniline compounds 16a-16c were weighed and dissolved in 25 mL of dichloromethane (DCM). 1,2 eq. 2-chloroethanesulfonyl chloride was slowly added at 0 °C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1-3:2) to obtain sulfonamide dienophile compounds 17a-17c.

[0120] d. Synthesis of sulfonamide dienophile compound 18:

[0121] Similar to the synthesis of acetamide compounds 15a-15c described above, 1 eq. of p-methoxyaniline 13 was weighed and dissolved in 25 mL of dichloromethane. 1.2 eq. of 2-chloroethanesulfonyl chloride was slowly added at 0 °C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1-3:2) to obtain sulfonamide dienophile compound 18.

[0122] e. Synthesis of sulfonamide dienophile compounds 20a-20i:

[0123] Weigh out 1 eq. of the corresponding sulfonamide dienophile compound 18 and dissolve it in 25 mL of N,N-dimethylformamide (DMF). Add 1.2 eq. of potassium carbonate, and then slowly add the corresponding bromoalkanes 19a-19i. After reacting at 60 °C for 24 h, remove the solvent under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1-3:2) to obtain sulfonamide dienophile compounds 20a-20i.

[0124] f. Synthesis of sulfonamide dienophile compounds 22a-22c:

[0125] The corresponding 1 eq. amine compounds 21a-21c were weighed and dissolved in 25 mL of dichloromethane (DCM). 1,2 eq. 2-chloroethanesulfonyl chloride was slowly added at 0 °C. After reacting for 10 min, 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1-3:2) to obtain sulfonamide dienophile compounds 22a-22c.

[0126] Example 1:

[0127] This embodiment provides a 5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-propyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23a, the chemical structural formula of which is as follows:

[0128]

[0129] Weigh the synthesized 1 eq. 3,4-bis(4-hydroxyphenyl)-furan compound and 1 eq. N-(4-methoxyphenyl)-N-propylethylenesulfonamide compound into a 25 mL single-necked round-bottom flask, then slowly heat to 90 °C and react for 12 hours. After drying, directly separate and purify by column chromatography with a dichloromethane:methanol ratio of 60:1 to obtain a yellow solid with a yield of 59%. 1 H NMR(500MHz,acetone-d6)δ7.38–7.31(m,2H),7.25–7.15(m,4H),6.86(s,4H),6.82–6.77(m,2H),5.55(s,1H),5.35(d,J=1.0Hz, 1H),4.52(q,J=8.6Hz,2H),4.13–4.02(m,2H),3.79(s,3H),3.58(s,1H),2.26–2.17(m,1H),2.13–2.05(m,1H),1.25–1.17(m,3H). 13 C NMR (126MHz, acetone-d6) δ159.67,158.30,157.83,141.04,138.39,132.07,130.61,129.57,128.65,126.26,123.58,115.94,114.95,114. 51,84.55,82.88,68.19,61.80,55.10,30.69,30.32,29.65,29.50,29.35,29.19,29.04,28.88,28.73,20.17,13.84.ESI-HRMS(m / z):[M+Na] + calcd.for C 28 H 29 NO6NaS:530.1613; observed,530.1620.

[0130] Example 2:

[0131] This embodiment provides a 5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-(3,3,3-trifluoropropyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23b, the chemical structural formula of which is as follows:

[0132]

[0133] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan compound and 1eq. N-(4-methoxyphenyl)-N-(3,3,3-trifluoropropyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 62%. 1 HNMR(500MHz,acetone-d6)δ7.34(d,J=8.9Hz,2H),7.19(t,J=8.7Hz,4H),6.85(t,J=9.1Hz,4H),6.78(d,J=8.5Hz,2H),5.52(s,1 H),5.33(d,J=4.4Hz,1H),4.51(q,J=8.6Hz,2H),3.79(s,3H),3.55(dd,J=8.3,4.4Hz,1H),2.22–2.15(m,1H),2.10–2.05(m,3H). 13 CNMR(126MHz,acetone-d6)δ159.67,158.30,157.83,141.04,138.39,132.07,130.61,129.57,128.65,126.26,123.58,115.94,114.95,114. 51,84.55,82.88,68.19,61.80,55.10,30.69,30.32,29.65,29.50,29.35,29.19,29.04,28.88,28.73,20.17,13.84.ESI-HRMS(m / z):[M+Na] + calcd.for C 28 H 26 NO6NaSF3:584.1331; observed,584.1335.

[0134] Example 3:

[0135] This embodiment provides a 5,6-bis(4-hydroxyphenyl)-N-isobutyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23c, the chemical structural formula of which is as follows:

[0136]

[0137] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-isobutyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 55%. 1 H NMR (500MHz, CDCl3) δ7.24(d,J=8.9Hz,2H),7.13(t,J=8.4Hz,4H),6.81(d,J= 8.9Hz,2H),6.75(d,J=7.3Hz,4H),5.54(s,1H),5.47(d,J=2.5Hz,1H),3.79(s ,3H),3.55(d,J=7.3Hz,2H),3.41(dd,J=8.4,4.4Hz,1H),2.35–2.26(m,1H),2 .00–1.90(m,1H),1.57(dt,J=13.6,6.7Hz,1H),0.91(dd,J=10.5,6.7Hz,6H). 13 C NMR (126MHz, CDCl3) δ159.88,159.11,155.79,137.69,131.74,130.92,129.27,128.87,125.33,125.11,124.41,115.92,11 5.06,114.97,84.62,83.16,77.52,77.26,77.01,67.15,62.60,55.70,33.63,30.75,29.66,28.08.ESI-HRMS(m / z):[M+Na] + calcd.for C 29 H 31 NO6SNa:544.1770; observed,544.1763.

[0138] Example 4:

[0139] This embodiment provides a 5,6-bis(4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23d, the chemical structure of which is as follows:

[0140]

[0141] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-isopentyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 45%. 1H NMR(400MHz, Acetonitrile-d3)δ7.19–7.10(m,6H),6.84–6.72(m,6H),5.40(d,J=1.3Hz,1H),5.26(dd,J=4.4,1.3Hz,1H),3.77(s,3H),3.71–3.63(m,2H) ,3.36(dd,J=8.3,4.5Hz,1H),2.11(s,1H),2.01(dd,J=12.0,8.4Hz,1H),1.5 9(dd,J=13.4,6.7Hz,1H), 1.22(q,J=6.9Hz,2H), 0.83(dd,J=6.7,1.0Hz,6H). 13 C NMR(101MHz, Acetonitrile-d3)δ159.54,157.33,132.16,130.99,129.87,129.04,116.16,115. 93,114.64,85.00,83.25,61.27,55.69,50.15,37.76,30.87,25.44,22.13.HRMS(ESI)m / z[M+Na] + calcd for C 30 H 33 NO6S,535.2029; observed,558.1926.

[0142] Example 5:

[0143] This embodiment provides an N-allyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23e, the chemical structural formula of which is as follows:

[0144]

[0145] Following the preparation method of Example 1 above, using 1 eq. of 3,4-bis(4-hydroxyphenyl)-furan 1 eq. and N-allyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 21%. 1H NMR (400MHz, Acetonitrile-d3) δ7.18–7.12(m,6H),6.84–6.79(m,3H),6.79–6.72(m,3H),5.75(d,J=6.6Hz,1H),5.42(d,J=1.2Hz,1H),5.28(dd,J=4.3, 1.3Hz,1H),5.12–4.98(m,2H),4.27(dt,J=6.2,1.4Hz,2H),3.76(s,3H),3.4 0(dd,J=8.4,4.5Hz,1H),2.12(d,J=4.3Hz,1H),2.02(dd,J=12.0,8.4Hz,1H). 13 C NMR(101MHz, Acetonitrile-d3)δ159.57,157.51,138.05,134.59,131.22,129.83,129.08,11 8.37,116.15,115.94,114.58,84.98,83.28,61.84,55.68,54.79,30.87.HRMS(ESI)m / z[M+Na] + calcd for C 28 H 27 NO6S,505.1559; found,528.1451.

[0146] Example 6:

[0147] This embodiment provides an N-(2-hydroxyethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23f, the chemical structure of which is as follows:

[0148]

[0149] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-(2-hydroxyethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 69%.

[0150] Example 7:

[0151] This embodiment provides 23g of N-(2-fluoro-2-methylpropyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide, the chemical structural formula of which is as follows:

[0152]

[0153] Following the preparation method of Example 1 above, using 1eq. 3,4-di(4-hydroxyphenyl)-furan and 1eq. N-(2-fluoro-2-methylpropyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 66%.

[0154] Example 8:

[0155] This embodiment provides an N-(cyclopropylmethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23h, the chemical structure of which is as follows:

[0156]

[0157] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-(cyclopropylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 32%. 1 H NMR(400MHz, Acetonitrile-d3)δ7.12–7.09(m,4H),7.05–7.01(m,2H),6.83–6.77(m,2H),6.75–6.68(m,4H),5.39(d,J=1 .2Hz,1H),5.27(dd,J=4.5,1.3Hz,1H),3.74(s,3H),3.30(dd,J=8.5,4.5Hz,1H),2.20(t,J=4.5Hz,1H),1.99–1.96(m,1H). 13 C NMR(101MHz, Acetonitrile-d3)δ159.64,149.85,132.84,131.54,129.88,129.04,116.16,115 .93,114.60,85.00,83.27,61.80,57.14,55.69,30.84,11.05,3.79,3.72.HRMS(ESI)m / z[M+Na] + calcd for C 29 H 29 NO6S,519.1716; observed,542.1612.

[0158] Example 9:

[0159] This embodiment provides an N-(cyclobutylmethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23i, the chemical structure of which is as follows:

[0160]

[0161] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-(cyclobutylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 48%. 1 H NMR(400MHz, Acetonitrile-d3)δ7.13(qd,J=6.4,2.1Hz,6H),6.89–6.66(m,6H),5.4 1(d,J=1.3Hz,1H),5.27(dd,J=4.4,1.3Hz,1H),3.77(s,3H),3.66(d,J=7.5Hz,2H),3. 36(dd,J=8.3,4.5Hz,1H),2.28–2.20(m,1H),2.12(d,J=4.4Hz,1H),2.01(dd,J=12.0, 8.4Hz,1H),1.90–1.82(m,2H),1.80–1.74(m,2H),1.63(ddd,J=11.0,6.9,2.8Hz,2H). 13 C NMR(151MHz, Acetonitrile-d3)δ159.02,156.75,141.02,137.51,130.50,128.46,115.60,115. 36,114.01,84.42,82.67,60.80,56.49,55.12,34.22,30.28,25.38,17.74.HRMS(ESI)m / z[M+Na] + calcd for C 30 H 31 NO6S,533.1872; observed,556.1765.

[0162] Example 10:

[0163] This embodiment provides an N-cyclohexyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23j, the chemical structural formula of which is as follows:

[0164]

[0165] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-cyclohexyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 45%.

[0166] Example 11:

[0167] This embodiment provides a 5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23k, the chemical structural formula of which is as follows:

[0168]

[0169] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-(4-methoxyphenyl)-N-phenylethanesulfonamide as raw materials, a yellow solid was obtained with a yield of 51%. 1 H NMR(400MHz, Acetonitrile-d3)δ7.43–7.38(m,2H),7.37–7.31(m,4H),7.29–7.24(m,1H),7.18–7.09(m,4H),6.90–6.84(m,2H),6.80–6.72( m,4H),5.46(d,J=1.3Hz,1H),5.29(dd,J=4.3,1.3Hz,1H),3.76(s,3H),3.64(dd,J=8.3,4.6Hz,1H),2.25–2.22(m,1H),2.10(d,J=2.6Hz,1H). 13 C NMR(101MHz, Acetonitrile-d3)δ157.53,157.39,142.75,137.90,134.61,131.18,129.97,129.80 ,129.10,128.83,127.92,115.94,115.09,85.25,83.29,63.23,55.75,31.18.HRMS(ESI)m / z[M+Na] + calcd for C 31 H 27 NO6S,541.1559; observed,564.1458.

[0170] Example 12:

[0171] This embodiment provides an N-benzyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 23l, the chemical structural formula of which is as follows:

[0172]

[0173] Following the preparation method of Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. N-benzyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 43%. 1 H NMR(400MHz, Acetonitrile-d3)δ7.26–7.21(m,4H),7.15(dd,J=8.8,3.2Hz,4H) ,7.10(d,J=8.7Hz,3H),6.81–6.77(m,2H),6.73(dd,J=10.6,7.9Hz,4H),5.47(d, J=1.3Hz,1H),5.31(d,J=4.3Hz,1H),4.86(d,J=3.3Hz,2H),3.71(s,3H),3.47(d d,J=8.3,4.5Hz,1H),2.20(dd,J=12.0,4.5Hz,1H),2.06(dd,J=12.1,8.4Hz,1H). 13 C NMR(151MHz, Acetonitrile-d3)δ163.36,157.25,130.51,130.01,129.80,129.31,128.51,128.38,12 8.35,127.54,115.62,115.38,113.91,80.51,78.95,56.24,55.13,55.05,26.77.HRMS(ESI)m / z[M+Na] + calcdfor C 32 H 29 NO6S,555.1716; observed,578.1635.

[0174] Example 13:

[0175] This embodiment provides a 4,4'-(5-(indoline-1-ylsulfonyl)-7-oxabicyclo[2.2.1]hept-2-en-2,3-diyl)diphenol 23m, the chemical structural formula of which is as follows:

[0176]

[0177] Following the preparation method described in Example 1 above, using 1eq. 3,4-bis(4-hydroxyphenyl)-furan and 1eq. 1-ethylenesulfonylindoline as raw materials, a yellow solid was obtained with a yield of 56%. 1 H NMR (400MHz, Acetone-d6) δ8.63(d,J=1.2Hz,2H),7.46(d,J=8.0Hz,1H),7.24(d,J=7 .4Hz,1H),7.20–7.13(m,3H),7.04–6.98(m,3H),6.81–6.70(m,4H),5.48(d,J=1.2Hz ,1H),5.31(dd,J=4.4,1.1Hz,1H),4.14–4.07(m,2H),3.67(dd,J=8.4,4.4Hz,1H),3. 12(td,J=8.2,5.0Hz,2H), 2.40(dt,J=11.9,4.5Hz,1H), 2.01(dd,J=11.9,8.4Hz,1H). 13 C NMR (101MHz, Acetone-d6) δ170.19,157.36,157.23,142.62,140.91,137.12,132.00,128.85,128.45,127.53,125.56,1 24.19,123.62,123.33,115.57,115.51,113.83,84.29,82.79,61.19,59.75,50.34,30.12,27.84,20.02,17.98,13.66.

[0178] Example 14:

[0179] This embodiment provides a 4,4'-(5-((6-methoxy-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-7-oxabicyclo[2.2.1]hept-2-en-2,3-diyl)diphenol 23n, the chemical structural formula of which is as follows:

[0180]

[0181] Following the preparation method of Example 1 above, using 1eq.3,4-bis(4-hydroxyphenyl)-furan and 1eq.6-methoxy-1-(vinylsulfonyl)-1,2,3,4-tetrahydroquinoline as raw materials, a yellow solid was obtained with a yield of 45%. 1H NMR(400MHz, Acetone-d6)δ8.67(d,J=16.8Hz,2H),7.64(d,J=9.0Hz,1H),7.20–7.12(m,2H), 7.06–6.97(m,2H),6.80–6.72(m,5H),6.69(d,J=3.0Hz,1H),5.34–5.24(m,2H),3.85–3.78(m, 1H),3.77(s,3H),3.76–3.68(m,1H),3.57(dd,J=8.4,4.5Hz,1H),2.71(dtd,J=23.3,16.8,6. 7Hz,2H),2.28(dt,J=11.8,4.4Hz,1H),2.03–1.97(m,1H),1.89(dtd,J=13.9,7.0,4.8Hz,2H). 13 C NMR (101MHz, Acetone-d6) δ157.31,157.30,156.57,140.97,137.27,131.59,130.42,128.78,128.63,124.35,1 24.28,123.62,115.58,115.47,114.03,112.24,84.55,82.55,61.94,54.78,54.73,46.50,30.38,26.80,22.45.

[0182] Example 15:

[0183] This embodiment provides a 4,4'-(5-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-7-oxabicyclo[2.2.1]hept-2-en-2,3-diyl)diphenol 23o, the chemical structural formula of which is as follows:

[0184]

[0185] Following the preparation method of Example 1 above, using 1eq.3,4-bis(4-hydroxyphenyl)-furan and 1eq.1-(vinylsulfonyl)-1,2,3,4-tetrahydroquinoline as raw materials, a yellow solid was obtained with a yield of 53%. 1H NMR(400MHz, Acetone-d6)δ8.61(s,1H),8.58(s,1H),7.64(d,J=8.3Hz,1H),7.19–7.13(m,2H),7.0 5–6.97(m,2H),6.94(dd,J=11.2,2.4Hz,2H),6.78(q,J=2.5Hz,2H),6.75(q,J=2.5Hz,2H),5.32(d, J=1.2Hz,1H),5.29(dd,J=4.4,1.1Hz,1H),3.86–3.70(m,2H),3.61(dd,J=8.3,4.5Hz,1H),2.81–2. 61(m,2H),2.31(dt,J=11.8,4.5Hz,1H),2.00(dd,J=11.9,8.4Hz,1H),1.89(pd,J=7.1,4.6Hz,2H). 13 C NMR (101MHz, Acetone-d6) δ157.30,157.27,141.00,137.27,134.97,133.51,130.16,129.55,129.51,128.71,128.68,1 27.12,124.27,123.63,122.33,115.56,115.50,84.49,82.60,61.97,59.75,46.66,30.31,26.71,22.55,19.87,13.67.

[0186] Example 16:

[0187] This embodiment provides a 5,6-bis(3-fluoro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24a, the chemical structural formula of which is as follows:

[0188]

[0189] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-fluorophenol) and 1eq. N-isopentyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 43%. 1H NMR(500MHz,Chloroform-d)δ7.25(dd,J=7.9,1.9Hz,1H),7.13(dd,J=8.2,2.2Hz,3H),7.05(ddd,J=10.2,7.5,2 .2Hz,2H),6.90–6.80(m,4H),6.50(s,2H),5.36(td,J=4.2,1.1Hz,1H),4.89(dd,J=6.7,1.0Hz,1H),3.79(s,3H) ,3.77(dt,J=13.2,9.2Hz,1H),3.57(dt,J=13.3,9.3Hz,1H),3.45(td,J=8.0,6.7Hz,1H),2.55(ddd,J=12.2,7.9 ,4.2Hz,1H),2.43(ddd,J=12.4,8.0,4.2Hz,1H),1.78–1.53(m,3H),0.92(d,J=6.7Hz,3H),0.87(d,J=6.7Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ153.71,151.24,151.20,149.22,149.18,146.23,146.20,146.07 ,146.05,141.83,141.81,138.38,138.35,135.04,128.24,128.18,126.80,126.73,124.76,123 .21,123.19,123.11,123.08,116.46,116.44,116.40,116.37,115.85,115.56,115.40,115.12, 114.96,87.15,84.28,63.18,55.32,53.02,37.48,31.92,27.45,22.81.ESI-HRMS(m / z):[M+Na] + calcd.for C 30 H 31 F2NO6S:594.1840; observed,594.1335.

[0190] Example 17:

[0191] This embodiment provides an N-(cyclopropylmethyl)-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24b, the chemical structural formula of which is as follows:

[0192]

[0193] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-fluorophenol) and 1eq. N-(cyclopropylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 33%. 1 H NMR(500MHz,Chloroform-d)δ9.95(s,2H),7.39–7.31(m,4H),7.30(dd,J=5.6,2.0Hz,2H),6.92(dd,J=7.5,1.7Hz,4H),5.13(d,J=1.1Hz,1H),4. 64(d,J=0.9Hz,1H),4.58(s,1H),3.92(s,2H),3.80(s,3H),2.82(s,1H) ,2.77(s,1H),1.94(s,1H),1.35(d,J=4.9Hz,2H),1.22(d,J=5.1Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ153.70,151.24,151.20,149.22,149.18,146.23,146.20,146. 07,146.05,141.83,141.81,138.38,138.35,135.01,128.24,128.18,126.80,126.73,124.85 ,123.21,123.19,123.11,123.08,116.46,116.44,116.40,116.37,115.84,115.56,115.40,1 15.12,114.96,87.15,84.28,63.22,56.61,55.32,31.92,9.27,5.48.ESI-HRMS(m / z):[M+Na] + calcd.for C 29 H 27 F2NO6SN:578.1527; observed,578.1335.

[0194] Example 18:

[0195] This embodiment provides an N-(cyclobutylmethyl)-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24c, the chemical structural formula of which is as follows:

[0196]

[0197] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-fluorophenol) and 1eq. N-(cyclobutylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 38%. 1 H NMR(500MHz,Chloroform-d)δ7.25(dd,J=7.9,1.9Hz,1H),7.16–7.09(m,3H),7.05(ddd,J=10.2,7.5,2.2Hz, 2H),6.90–6.80(m,4H),6.50(s,2H),5.36(td,J=4.2,1.1Hz,1H),4.89(dd,J=6.7,1.0Hz,1H),3.79(s,2H),3. 75(dd,J=12.5,5.4Hz,1H),3.53(dd,J=12.5,5.3Hz,1H),3.46(td,J=7.9,6.7Hz,1H),2.55(ddd,J=12.2,7.9 ,4.2Hz,1H),2.43(ddd,J=12.4,8.0,4.2Hz,1H),2.23(p,J=5.4Hz,1H),1.86–1.70(m,4H),1.69–1.56(m,2H). 13 C NMR(125MHz,Chloroform-d)δ153.70,151.24,151.20,149.22,149.18,146.23,146.20,146.07 ,146.05,141.83,141.81,138.38,138.35,135.09,128.24,128.18,126.80,126.73,124.85,123 .21,123.19,123.11,123.08,116.46,116.44,116.40,116.37,115.84,115.56,115.40,115.12, 114.96,87.15,84.28,63.22,55.32,55.30,32.76,31.92,29.96,20.19.ESI-HRMS(m / z):[M+Na] + calcd.for C 30 H 29 F2NO6S:592.1684; observed,592.1335.

[0198] Example 19:

[0199] This embodiment provides an N-cyclohexyl-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24d, the chemical structural formula of which is as follows:

[0200]

[0201] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-fluorophenol) and 1eq. N-cyclohexyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 45%. 1 H NMR(500MHz,Chloroform-d)δ7.25(dd,J=7.9,1.9Hz,1H),7.16–7.01(m,5H),6.86(dd,J =10.1,5.0Hz,2H),6.83–6.79(m,2H),6.50(s,2H),5.36(td,J=4.2,1.1Hz,1H),4.92(dd ,J=6.9,1.1Hz,1H),3.86(p,J=7.1Hz,1H),3.79(s,3H),3.46(td,J=7.7,6.9Hz,1H),2.5 5(ddd,J=12.1,7.7,4.2Hz,1H),2.49–2.40(m,1H),1.95–1.81(m,4H),1.62–1.34(m,6H). 13 CNMR(125MHz,Chloroform-d)δ153.64,151.24,151.20,149.22,149.18,146.23,146.20,146.07 ,146.05,141.83,141.81,138.38,138.36,133.90,128.24,128.18,126.80,126.73,124.29,123 .21,123.19,123.11,123.08,116.46,116.44,116.40,116.37,115.56,115.48,115.40,115.12, 114.96,87.18,84.28,64.16,62.27,55.32,31.94,31.28,26.26,24.47.ESI-HRMS(m / z):[M+Na] + calcd.for C 31 H 31 F2NO6S:603.1840; observed,603.1335.

[0202] Example 20:

[0203] This embodiment provides a 5,6-bis(3-chloro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24e, the chemical structural formula of which is as follows:

[0204]

[0205] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-chlorophenol) and 1eq. N-isopentyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 63%. 1 H NMR(500MHz,Chloroform-d)δ7.51(d,J=1.9Hz,1H),7.41(d,J=2.2Hz,1H),7.18(ddd,J=9.0,3.0,2.0Hz,2H),7.16–7.1 1(m,2H),6.89(d,J=9.0Hz,2H),6.86–6.80(m,2H),6.48(s,2H),5.36(td,J=4.2,1.1Hz,1H),4.88(dd,J=6.7,1.0Hz,1H ),3.79(s,3H),3.77(dt,J=13.3,9.3Hz,1H),3.57(dt,J=13.3,9.3Hz,1H),3.45(td,J=8.0,6.7Hz,1H),2.55(ddd,J=12 .2,7.9,4.2Hz,1H),2.43(ddd,J=12.4,8.0,4.2Hz,1H),1.78–1.53(m,3H),0.92(d,J=6.7Hz,3H),0.87(d,J=6.7Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ155.08,155.02,153.71,140.73,137.42,135.04,129.07,128.78,127.54,126.17,126.11,124.76,120.3 8,120.35,116.50,116.47,115.85,86.87,83.97,63.17,55.32,53.02,37.48,31.92,27.45,22.81.ESI-HRMS(m / z):[M+Na]+calcd.for C 30 H 31 Cl2NO6S:626.1249; observed,626.1233.

[0206] Example 21:

[0207] This embodiment provides a 5,6-bis(3-chloro-4-hydroxyphenyl)-N-(cyclopropylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24f, the chemical structural formula of which is as follows:

[0208]

[0209] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-chlorophenol) and 1eq. N-(cyclopropylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 43%. 1 H NMR(500MHz,Chloroform-d)δ7.51(d,J=1.9Hz,1H),7.41(d,J=2.2Hz,1H),7.18(ddd,J=9.0,3.0,2.0Hz,2H) ,7.12(s,1H),7.15–7.09(m,0H),6.89(d,J=9.0Hz,2H),6.86–6.80(m,2H),6.48(s,2H),5.36(td,J=4.2,1.1H z,1H),4.88(dd,J=6.7,1.0Hz,1H),3.79(s,2H),3.63(dd,J=12.3,5.5Hz,1H),3.51–3.41(m,2H),2.55(ddd, J=12.2,7.9,4.2Hz,1H),2.43(ddd,J=12.4,8.0,4.2Hz,1H),1.35(dq,J=11.6,5.8Hz,1H),0.45–0.35(m,4H). 13 CNMR(125MHz,Chloroform-d)δ155.08,155.02,153.70,140.73,137.42,135.01,129.07,128.78,127.54,126.17,126.11,12 4.85,120.38,120.35,116.50,116.47,115.84,86.87,83.97,63.22,56.61,55.32,31.92,9.27,5.48.ESI-HRMS(m / z):[M+Na] + calcd.forC 29 H 27 Cl2NO6S:610.0936; observed,610.0436.

[0210] Example 22:

[0211] This embodiment provides 24g of 5,6-bis(3-chloro-4-hydroxyphenyl)-N-(cyclobutylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide, the chemical structural formula of which is as follows:

[0212]

[0213] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-chlorophenol) and 1eq. N-(cyclobutylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 36%. 1 H NMR(500MHz,Chloroform-d)δ7.51(d,J=1.9Hz,1H),7.41(d,J=2.2Hz,1H),7.18(ddd,J=9.0,3.0,2.0Hz,2H),7.12(s, 1H),7.15–7.09(m,0H),6.91–6.80(m,3H),6.48(s,2H),5.36(td,J=4.2,1.1Hz,1H),4.88(dd,J=6.7,1.0Hz,1H),3.79 (s,2H),3.75(dd,J=12.5,5.4Hz,1H),3.53(dd,J=12.5,5.3Hz,1H),3.46(td,J=7.9,6.7Hz,1H),2.55(ddd,J=12.2,7. 9,4.2Hz,1H),2.43(ddd,J=12.4,8.0,4.2Hz,1H),2.23(dt,J=10.7,5.4Hz,1H),1.86–1.70(m,4H),1.69–1.56(m,2H). 13 C NMR(125MHz,Chloroform-d)δ155.08,155.02,153.70,140.73,137.42,135.09,129.07,128.78,127.54,126.17,126.11,124.85,120.3 8,120.35,116.50,116.47,115.84,86.87,83.97,63.22,55.32,55.30,32.76,31.92,29.96,20.19.ESI-HRMS(m / z):[M+Na]+calcd.for C 30 H 29 Cl2NO6S:624.1093; observed,624.1066.

[0214] Example 23:

[0215] This embodiment provides a 5,6-bis(3-chloro-4-hydroxyphenyl)-N-cyclohexyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24h, the chemical structural formula of which is as follows:

[0216]

[0217] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(2-chlorophenol) and 1eq. N-cyclohexyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 35%. 1 H NMR(500MHz,Chloroform-d)δ7.51(d,J=1.9Hz,1H),7.41(d,J=2.2Hz,1H),7.18(ddd,J=9.0,3.0,2 .0Hz,2H),7.13–7.07(m,2H),6.89(d,J=9.0Hz,2H),6.85–6.79(m,2H),6.48(s,2H),5.36(td,J=4.2 ,1.1Hz,1H),4.92(dd,J=6.9,0.9Hz,1H),3.86(p,J=7.1Hz,1H),3.79(s,2H),3.46(td,J=7.7,6.9H z,1H),2.55(ddd,J=12.0,7.7,4.3Hz,1H),2.49–2.40(m,1H),1.95–1.81(m,4H),1.62–1.34(m,6H). 13 C NMR(125MHz,Chloroform-d)δ155.08,155.02,153.64,140.73,137.42,133.90,129.07,128.78,127.54,126.17,126.11,124.29, 120.38,120.35,116.50,116.47,115.48,86.90,83.97,64.17,62.27,55.32,31.94,31.28,26.26,24.47.ESI-HRMS(m / z):[M+Na] + calcd.for C 31 H 31 Cl2NO6S:638.1249; observed,638.1149.

[0218] Example 24:

[0219] This embodiment provides a 5,6-bis(2-fluoro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24i, the chemical structural formula of which is as follows:

[0220]

[0221] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-fluorophenol) and 1eq. N-isopentyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 54%. 1 H NMR(500MHz,Chloroform-d)δ9.32(s,2H),7.24(ddd,J=12.0,8.7,5.0Hz,2H),7.17–7.11(m,2H),6.86–6.8 0(m,2H),6.65–6.57(m,4H),5.00(dd,J=6.7,1.0Hz,1H),4.71(td,J=4.1,1.0Hz,1H),3.79(s,3H),3.77(dt ,J=13.3,9.3Hz,1H),3.57(dt,J=13.3,9.3Hz,1H),3.47(td,J=8.0,6.7Hz,1H),2.59(ddd,J=12.1,7.9,4.1 Hz,1H),2.46(ddd,J=12.3,8.0,4.2Hz,1H),1.78–1.53(m,3H),0.92(d,J=6.7Hz,3H),0.87(d,J=6.7Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ162.23,162.06,160.21,160.04,159.45,159.42,159.39,159.35,153.71,13 9.22,139.20,139.16,139.13,136.96,136.93,136.90,136.87,135.04,129.88,129.81,129.76,129.70,12 4.76,115.85,114.39,114.23,111.69,111.68,111.66,111.65,110.95,110.79,104.59,104.56,104.43,10 4.40,85.19,85.16,82.52,82.49,63.20,55.32,53.02,37.48,32.03,27.45,22.81.ESI-HRMS(m / z):[M+Na]+ calcd.forC 30 H 31 F2NO6S:594.1840; observed,594.1436.

[0222] Example 25:

[0223] This embodiment provides an N-(cyclopropylmethyl)-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24j, the chemical structural formula of which is as follows:

[0224]

[0225] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-fluorophenol) and 1eq. N-(cyclopropylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 52%. 1 H NMR(500MHz,Chloroform-d)δ9.32(s,2H),7.24(ddd,J=12.0,8.7,5.0Hz,2H),7.15–7.09(m, 2H),6.86–6.80(m,2H),6.65–6.57(m,4H),5.00(dd,J=6.7,1.0Hz,1H),4.71(td,J=4.1,1.0Hz ,1H),3.79(s,2H),3.63(dd,J=12.3,5.5Hz,1H),3.52–3.41(m,2H),2.59(ddd,J=12.1,7.9,4. 1Hz, 1H), 2.46 (ddd, J=12.3, 8.0, 4.2Hz, 1H), 1.35 (dq, J=11.6, 5.8Hz, 1H), 0.45–0.35 (m, 4H). 13C NMR(125MHz,Chloroform-d)δ162.23,162.06,160.21,160.04,159.45,159.42,159.39,159.35,153.70, 139.22,139.20,139.16,139.13,136.96,136.93,136.89,136.87,135.01,129.88,129.81,129.76,129.7 0,124.85,115.84,114.39,114.23,111.69,111.68,111.66,111.65,110.95,110.79,104.59,104.56,104 .43,104.40,85.19,85.16,82.52,82.49,63.24,56.61,55.32,32.03,9.27,5.48.ESI-HRMS(m / z):[M+Na] + calcd.for C 29 H 27 F2NO6S:578.1527; observed,578.1335.

[0226] Example 26:

[0227] This embodiment provides an N-(cyclobutylmethyl)-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24k, the chemical structural formula of which is as follows:

[0228]

[0229] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-fluorophenol) and 1eq. N-(cyclobutylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ9.32(s,2H),7.24(ddd,J=12.0,8.7,5.0Hz,2H),7.15–7.09(m,2H) ,6.86–6.80(m,2H),6.65–6.57(m,4H),5.00(dd,J=6.7,1.0Hz,1H),4.71(td,J=4.1,1.0Hz,1H), 3.79(s,2H),3.75(dd,J=12.5,5.4Hz,1H),3.56–3.43(m,2H),2.59(ddd,J=12.1,7.9,4.1Hz,1H) ,2.46(ddd,J=12.3,8.0,4.2Hz,1H),2.23(p,J=5.4Hz,1H),1.86–1.70(m,4H),1.69–1.56(m,2H). 13 C NMR(125MHz,Chloroform-d)δ162.23,162.06,160.21,160.04,159.45,159.42,159.39,159.35,153.70,13 9.22,139.20,139.16,139.13,136.96,136.93,136.89,136.87,135.09,129.88,129.81,129.76,129.70,12 4.85,115.84,114.39,114.23,111.69,111.68,111.66,111.65,110.95,110.79,104.59,104.56,104.43,10 4.40,85.19,85.16,82.52,82.49,63.24,55.32,55.30,32.76,32.03,29.96,20.19.ESI-HRMS(m / z):[M+Na] + calcd.for C 30 H 29 F2NO6S:592.1684; observed,592.1436.

[0230] Example 27:

[0231] This embodiment provides an N-cyclohexyl-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24l, the chemical structural formula of which is as follows:

[0232]

[0233] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-fluorophenol) and 1eq. N-cyclohexyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 46%. 1 H NMR (500MHz, Chloroform-d) δ9.32 (s, 2H), 7.24 (ddd, J = 12.0, 8.7, 5.1Hz, 2H), 7.13–7. 07(m,2H),6.85–6.79(m,2H),6.65–6.57(m,4H),5.03(dd,J=6.9,1.1Hz,1H),4.71(td,J =4.1,1.0Hz,1H),3.86(p,J=7.1Hz,1H),3.79(s,2H),3.47(td,J=7.7,6.9Hz,1H),2.58 (ddd,J=12.1,7.7,4.2Hz,1H),2.52–2.43(m,1H),1.95–1.81(m,4H),1.62–1.34(m,5H). 13 C NMR(125MHz,Chloroform-d)δ162.23,162.06,160.21,160.04,159.45,159.42,159.39,159.35,153.64,13 9.22,139.20,139.16,139.13,136.96,136.93,136.90,136.87,133.92,129.88,129.81,129.76,129.70,12 4.29,115.48,114.39,114.23,111.69,111.68,111.66,111.65,110.95,110.79,104.59,104.56,104.43,10 4.40,85.26,85.23,82.52,82.49,64.22,62.27,55.32,32.05,31.28,26.26,24.47.ESI-HRMS(m / z):[M+Na] + calcd.forC 31 H 31 F2NO6S:606.1840; observed,606.1335.

[0234] Example 28:

[0235] This embodiment provides a 5,6-bis(2-chloro-4-hydroxyphenyl)-N-isopentyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24m, the chemical structural formula of which is as follows:

[0236]

[0237] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-chlorophenol) and 1eq. N-isopentyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 59%. 1 H NMR(500MHz,Chloroform-d)δ7.82(s,2H),7.20(d,J=9.3Hz,1H),7.16(d,J=9.2Hz,1H),7.17–7.11(m,2H),6.99(d,J= 2.3Hz,2H),6.86–6.80(m,2H),6.65(dd,J=9.3,2.2Hz,2H),5.00(dd,J=6.7,1.0Hz,1H),4.65(td,J=4.2,0.9Hz,1H),3 .79(s,3H),3.77(dt,J=13.3,9.3Hz,1H),3.57(dt,J=13.3,9.3Hz,1H),3.47(td,J=8.0,6.7Hz,1H),2.59(ddd,J=12.2 ,7.9,4.2Hz,1H),2.46(ddd,J=12.3,8.0,4.2Hz,1H),1.78–1.53(m,3H),0.92(d,J=6.7Hz,3H),0.87(d,J=6.7Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ157.61,157.59,153.71,139.98,138.01,135.04,133.35,133.34,128.80,128.64,128.56,127.25,124.7 6,116.95,116.94,115.85,115.10,85.06,82.42,63.20,55.32,53.02,37.48,31.92,27.45,22.81.ESI-HRMS(m / z):[M+Na]+calcd.for C 30 H 31 Cl2NO6S:626.1249; observed,626.1049.

[0238] Example 29:

[0239] This embodiment provides a 5,6-bis(2-chloro-4-hydroxyphenyl)-N-(cyclopropylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24n, the chemical structural formula of which is as follows:

[0240]

[0241] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-chlorophenol) and 1eq. N-(cyclopropylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 38%. 1 H NMR(500MHz,Chloroform-d)δ7.82(s,2H),7.22–7.09(m,4H),6.99(d,J=2.3Hz,2H),6.86–6 .80(m,2H),6.65(dd,J=9.3,2.2Hz,2H),5.00(dd,J=6.7,1.0Hz,1H),4.65(td,J=4.2,0.9Hz ,1H),3.79(s,2H),3.63(dd,J=12.3,5.5Hz,1H),3.52–3.41(m,2H),2.59(ddd,J=12.2,7.9, 4.2Hz, 1H), 2.46 (ddd, J=12.3, 8.0, 4.2Hz, 1H), 1.35 (hept, J=5.8Hz, 1H), 0.45–0.35 (m, 4H). 13 C NMR(125MHz,Chloroform-d)δ157.61,157.59,153.70,139.98,138.01,135.01,133.35,133.34,128.80,128.64,128.56,127.25,1 24.85,116.95,116.94,115.84,115.10,85.06,82.42,63.24,56.61,55.32,31.92,9.27,5.48.ESI-HRMS(m / z):[M+Na]+calcd.for C 29 H 27 Cl2NO6S:610.0936; observed,610.0436.

[0242] Example 30:

[0243] This embodiment provides a 5,6-bis(2-chloro-4-hydroxyphenyl)-N-(cyclobutylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24o, the chemical structural formula of which is as follows:

[0244]

[0245] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-chlorophenol) and 1eq. N-(cyclobutylmethyl)-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 42%. 1 H NMR(500MHz,Chloroform-d)δ7.82(s,2H),7.18(dd,J=17.3,9.3Hz,2H),7.14–7.09(m,2H),6.99(d,J= 2.3Hz,2H),6.86–6.80(m,2H),6.65(dd,J=9.3,2.2Hz,2H),5.00(dd,J=6.7,1.0Hz,1H),4.65(td,J=4.2 ,0.9Hz,1H),3.79(s,2H),3.75(dd,J=12.5,5.4Hz,1H),3.56–3.43(m,2H),2.59(ddd,J=12.2,7.9,4.2H z,1H),2.46(ddd,J=12.3,8.0,4.2Hz,1H),2.23(p,J=5.4Hz,1H),1.86–1.70(m,4H),1.69–1.56(m,2H). 13 C NMR(125MHz,Chloroform-d)δ157.61,157.59,153.70,139.98,138.01,135.09,133.35,133.34,128.80,128.64,128.56,127.25,124.8 5,116.95,116.94,115.84,115.10,85.06,82.42,63.24,55.32,55.30,32.76,31.92,29.96,20.19.ESI-HRMS(m / z):[M+Na]+calcd.forC 30 H 29 Cl2NO6S:624.1093; observed,624.1436.

[0246] Example 31:

[0247] This embodiment provides a 5,6-bis(2-chloro-4-hydroxyphenyl)-N-cyclohexyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide 24p, the chemical structural formula of which is as follows:

[0248]

[0249] Following the preparation method of Example 1 above, using 1eq. 4,4'-(furan-3,4-diyl)bis(3-chlorophenol) and 1eq. N-cyclohexyl-N-(4-methoxyphenyl)ethylenesulfonamide as raw materials, a yellow solid was obtained with a yield of 51%. 1 H NMR(500MHz,Chloroform-d)δ7.82(s,2H),7.18(dd,J=17.3,9.2Hz,2H),7.13–7.07(m,2H),6.99 (d,J=2.3Hz,2H),6.85–6.79(m,2H),6.65(dd,J=9.3,2.2Hz,2H),4.97(dd,J=6.9,1.1Hz,1H),4.6 5(td,J=4.2,0.9Hz,1H),3.86(p,J=7.1Hz,1H),3.79(s,2H),3.47(td,J=7.7,6.9Hz,1H),2.58(dd d,J=12.1,7.7,4.2Hz,1H),2.52–2.43(m,1H),1.95–1.81(m,4H),1.62–1.34(m,5H),1.44(s,0H). 13 C NMR(125MHz,Chloroform-d)δ157.61,157.59,153.64,139.98,138.01,133.92,133.35,133.34,128.80,128.64,128.56,127.25,124.2 9,116.95,116.94,115.48,115.10,85.10,82.42,64.25,62.27,55.32,32.06,31.28,26.26,24.47.ESI-HRMS(m / z):[M+Na]+calcd.for C 31 H 31 Cl2NO6S:638.1249; observed,638.1436.

[0250] Example 32:

[0251] This embodiment investigated the anti-drug-resistant mutant breast cancer activity of oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents prepared in Examples 1-31. The relative binding affinity (RBA) of the target compounds prepared in the above embodiments to ER and their inhibitory activity (IC50, unit mM) against wild-type MCF-7 and three drug-resistant mutant breast cancer cells MCF-7Y537S, MCF-7D538G were measured, and the results are shown in Table 1.

[0252] Table 1:

[0253] compound RBA MCF-7WT MCF-7Y537S MCF-7D538G MCF-7EGFR 23a 2.4 13.2 16.8 12.6 14.3 23b 3.2 9.2 12.3 10.0 10.4 23c 2.1 8.6 13.6 7.8 11.9 23d 1.4 16.2 19.1 15.2 18.3 23e 1.8 8.1 6.9 12.0 12.2 23f 3.1 7.9 8.2 8.6 13.3 23g 2.6 9.3 10.8 13.5 15.2 23h 1.5 16.8 25.4 15.2 17.0 23i 4.1 18.9 22.4 13.6 28.9 23j 3.9 31.1 36.8 23.5 34.3 23k 2.1 30.5 29.3 21.4 35.2 23l 3.5 79.4 69.6 61.5 75.9 23m 0.9 74.2 76.9 64.1 83.2 23n 1.1 39.2 47.3 33.4 37.6 23o 1.3 48.1 63.4 60.3 46.9 24a 6.3 7.2 6.8 6.6 8.3 24b 8.2 5.2 6.3 10.0 10.4 24c 9.1 4.6 5.6 7.8 8.9 24d 9.4 6.2 9.1 10.2 9.3 24e 5.8 8.1 6.9 11.2 10.2 24f 9.1 6.9 7.2 8.9 10.3 24g 12.6 5.3 6.8 9.5 10.2 24h 8.5 7.8 7.4 9.2 11.0 24i 7.1 5.9 5.4 7.6 8.9 24j 13.9 7.1 6.8 9.5 9.3 24k 12.1 4.5 4.3 8.4 9.2 24l 13.5 5.4 5.6 8.5 8.9 24m 10.9 6.2 6.9 9.1 8.2 24n 9.1 11.2 9.3 10.4 9.6 24o 8.3 4.1 6.4 10.3 9.9 24p 8.4 10.2 11.8 12.6 13.0

[0254] As shown in Table 1, the oxygen-bridged bicyclic-[2.2.1]-heptene compounds with different sulfonamide nitrogen atom substituents prepared in this invention all showed certain inhibitory activities against wild-type breast cancer cells MCF-7 and three drug-resistant mutant breast cancer cells MCF-7Y537S, MCF-7D538G, and MCF-7EGFR. Furthermore, the oxygen-bridged bicyclic-[2.2.1]-heptene compounds with fluorine or chlorine atoms substituting on the benzene ring further enhanced their affinity for estrogen receptors and interfered with the estrogen receptor dimerization interface.

[0255] The above examples are merely illustrative of the present invention and do not constitute a limitation on the scope of protection of the present invention. All designs that are the same as or similar to the present invention are within the scope of protection of the present invention.

Claims

1. An oxygen-bridged bicyclic-[2.2.1]-heptene compound containing different sulfonamide nitrogen atom substituents, characterized in that, It has the structure shown in the following general formula: ； Where X is selected from -H, -F, or -Cl; R2 is selected from , , or ; R1 is selected from , , , , , or .

2. The oxygen-bridged bicyclic-[2.2.1]-heptene compound containing different sulfonamide nitrogen atom substituents as described in claim 1, characterized in that, Selected from any one of the following compounds: N-Allyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-(2-hydroxyethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-(cyclopropylmethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-(cyclobutylmethyl)-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-Cyclohexyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-Benzyl-5,6-bis(4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 4,4'-(5-(indoline-1-ylsulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl)diphenol; 4,4'-(5-((6-methoxy-3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl)diphenol; 4,4'-(5-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene-2,3-diyl)diphenol; N-(cyclopropylmethyl)-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-(cyclobutylmethyl)-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-Cyclohexyl-5,6-bis(3-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-(cyclopropylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-(cyclobutylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(3-chloro-4-hydroxyphenyl)-N-cyclohexyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-(cyclopropylmethyl)-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-(cyclobutylmethyl)-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; N-Cyclohexyl-5,6-bis(2-fluoro-4-hydroxyphenyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-(cyclopropylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-(cyclobutylmethyl)-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide; 5,6-Bis(2-chloro-4-hydroxyphenyl)-N-cyclohexyl-N-(4-methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide.

3. The method for preparing oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents as described in claim 1 or 2, characterized in that, Includes the following steps: S1. Synthesize 3,4-di(4-hydroxyphenyl)-furan, or synthesize 3,4-di(4-hydroxyphenyl)-furan containing different halogen substitutions; the structural formula of 3,4-di(4-hydroxyphenyl)-furan containing different halogen substitutions is as follows: Where X is selected from -F or -Cl; S2, Synthesizing vinylsulfonamide derivatives; S3. The 3,4-di(4-hydroxyphenyl)-furan or 3,4-di(4-hydroxyphenyl)-furan containing different halogen substitutions synthesized in step S1 is subjected to a diene synthesis reaction with the ethylene sulfonamide derivative synthesized in step S2 to obtain oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents.

4. The preparation method according to claim 3, characterized in that, In step S1, the synthetic route for 3,4-bis(4-hydroxyphenyl)-furan is as follows: ； 1) Synthesis of p-methoxybromoacetophenone Weigh p-methoxyacetophenone, p-toluenesulfonic acid, and N-bromosuccinimide into a reaction vessel, add dichloromethane to dissolve them, and react the well-mixed reactants at room temperature. Monitor the completeness of the reaction using TLC thin-layer chromatography. After the reaction is complete, remove the solvent under reduced pressure, add ethyl acetate to dissolve, and wash successively with 2N dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. Dry the organic layer with anhydrous NaSO4, filter and evaporate to dryness to obtain the crude product. After purification by column chromatography, obtain white solid compound 2, namely p-methoxybromoacetophenone. 2) Synthesis of 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester Weigh p-methoxybromoacetophenone and p-methoxyphenylacetic acid into a reaction vessel, dissolve them in anhydrous acetonitrile, slowly add anhydrous triethylamine, and continue the reaction at room temperature. Monitor the completeness of the reaction using TLC thin-layer chromatography. After the reaction is complete, remove the acetonitrile and triethylamine by evaporation, dissolve them in ethyl acetate, and wash them successively with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. Dry the organic layer with anhydrous sodium sulfate, filter and evaporate to dryness to obtain the crude product. After purification by column chromatography, obtain yellow solid compound 4, namely 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester. 3) Synthesis of 3,4-bis(4-methoxy-phenyl)furan-2-one Under anhydrous and oxygen-free conditions, 2-(4-methoxyphenyl)-2-carbonylethyl-2-(4-methoxyphenyl)acetic acid ester was weighed into a reaction vessel under argon atmosphere and dissolved in anhydrous dimethyl sulfoxide. 80% NaH was slowly added dropwise, and the reaction was carried out at 25 °C. The reaction was monitored for completeness using TLC thin-layer chromatography. After complete reaction, 2N dilute hydrochloric acid was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous NaSO4. The crude product was obtained by desolvation under reduced pressure and then purified by silica gel column chromatography to obtain compound 5, namely 3,4-di(4-methoxy-phenyl)furan-2-one. 4) Synthesis of 3,4-di(4-hydroxy-phenyl)furan-2-one Under anhydrous and oxygen-free conditions, 3,4-di(4-methoxy-phenyl)furan-2-one was weighed into a reaction vessel under argon atmosphere, dissolved in dichloromethane, and reacted with BBr3 at -20°C for 12 h. The reaction was then quenched with water, the reaction solution was extracted with ethyl acetate and washed with saturated NaHCO3 solution, the organic layer was dried over anhydrous NaSO4, and the crude product was obtained by desolvation under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain compound 6, namely 3,4-di(4-hydroxy-phenyl)furan-2-one. 5) Synthesis of 3,4-bis(4-hydroxy-phenyl)furan Under anhydrous and oxygen-free conditions, 3,4-bis(4-hydroxy-phenyl)furan-2-one was weighed into a reaction vessel under argon atmosphere. Diisobutylaluminum hydride was added at -78°C and reacted for 12 h. The reaction was then quenched with 4% H2SO4. The reaction solution was extracted with ethyl acetate and washed with saturated NaCl solution. The organic layer was dried with anhydrous NaSO4 and dissolved under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain compound 7, namely 3,4-bis(4-hydroxy-phenyl)furan.

5. The preparation method according to claim 3, characterized in that, In step S1, the synthetic routes for 3,4-bis(4-hydroxyphenyl)-furan with different halogen substitutions are as follows: ； 1) Synthesis of 3,4-dibromofuran Weigh (E)-3,4-dibromohex-3-en-1,6-diol, add potassium dichromate and concentrated sulfuric acid, and then perform steam distillation to obtain compound 9, namely 3,4-dibromofuran. 2) Synthesis of halogen-substituted 3,4-bis(4-methoxyphenyl)-furan 3,4-Dibromofuran and the corresponding halogen-substituted p-methoxyphenylboronic acid were weighed into a reaction vessel, and palladium catalyst Pd(dppf)2Cl2 and anhydrous tetrahydrofuran were added. The mixture was heated to reflux, and the reaction was monitored by TLC thin-layer chromatography to check whether the reaction was complete. After the reaction was complete, the tetrahydrofuran was evaporated, and the mixture was dissolved in ethyl acetate. The mixture was washed successively with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain the crude product. After purification by column chromatography, the corresponding compounds 11a-11d were obtained, namely halogen-substituted 3,4-di(4-methoxyphenyl)-furan. 3) Synthesis of halogen-substituted 3,4-bis(4-hydroxyphenyl)-furan: Under anhydrous and oxygen-free conditions, halogen-substituted 3,4-bis(4-methoxyphenyl)-furan was weighed into a reaction vessel under argon atmosphere, dissolved in dichloromethane, and reacted with BBr3 at -20°C for 12 h. The reaction was then quenched with water, and the reaction solution was extracted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was dried over anhydrous NaSO4, and the crude product was obtained by desolvation under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain compounds 12a–12d, i.e., halogen-substituted 3,4-bis(4-hydroxyphenyl)-furan.

6. The preparation method according to claim 3, characterized in that, In step S2, the synthetic route for the vinyl sulfonamide derivative is as follows: ； 1) Synthesis of sulfonamide dienophile compound 18 p-Methoxyaniline was weighed and dissolved in dichloromethane. 2-Chloroethanesulfonyl chloride was slowly added at 0 °C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain sulfonamide dienophile compound 18. 2) Synthesis of sulfonamide dienophile compounds 20b, 20c, 20e-20i Sulfonamide dienophile compound 18 was weighed and dissolved in N,N-dimethylformamide. Potassium carbonate was added, followed by the slow addition of one of the corresponding bromoalkanes 19b, 19c, 19e-19i. After reacting at 60 °C for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the corresponding sulfonamide dienophile compounds 20b, 20c, 20e-20i. 3) Synthesis of sulfonamide dienophile compounds 22a-22c One of the corresponding amine compounds 21a to 21c was weighed and dissolved in dichloromethane. 2-Chloroethanesulfonyl chloride was slowly added at 0 °C. After reacting for 10 min, a 20% sodium hydroxide aqueous solution was slowly added dropwise. After reacting at room temperature for 24 h, the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain the corresponding sulfonamide dienophile compounds 22a to 22c.

7. The preparation method according to claim 6, characterized in that, In step S3, the synthetic route for oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents is as follows: ； Where R1 is , , , , , or R2 is , or ; One of the synthesized ethylene sulfonamide derivatives 20b, 20c, 20e-20i, and 22a-22c was dissolved in tetrahydrofuran with 3,4-bis(4-hydroxy-phenyl)furan and reacted at 90°C in one step to prepare the corresponding oxygen-bridged bicyclic-[2.2.1]-heptene compounds 23b, 23c, 23e-23i, and 23m-23o with different sulfonamide nitrogen atom substituents.

8. The preparation method according to claim 6, characterized in that, In step S3, the synthetic route for oxygen-bridged bicyclic-[2.2.1]-heptene compounds containing different sulfonamide nitrogen atom substituents is as follows: ； The synthesized 3,4-bis(4-hydroxyphenyl)-furan with different halogen substitutions and any one of the ethylene sulfonamide derivatives 20e, 20f, and 20g were dissolved in tetrahydrofuran and reacted at 90 °C in one step to prepare the corresponding oxygen-bridged bicyclic-[2.2.1]-heptene compounds 24b~24d, 24f~24h, 24j~24l, and 24n~24p with different sulfonamide nitrogen atom substituents.

9. The use of oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents as described in claim 1 or 2, and their pharmaceutically acceptable salts, in the preparation of anti-breast cancer drugs.

10. The application as described in claim 9, characterized in that, The anti-breast cancer drug includes one or more pharmaceutically acceptable carriers or excipients of the oxygen-bridged bicyclic-[2.2.1]-hepten compounds containing different sulfonamide nitrogen atom substituents.

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