CN114539279A

CN114539279A - Oxidobicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparation of anti-breast cancer drugs

Info

Publication number: CN114539279A
Application number: CN202210134213.8A
Authority: CN
Inventors: 周海兵; 董春娥; 辛丽兰; 李媛媛
Original assignee: Wuhan University WHU
Current assignee: Wuhan University WHU
Priority date: 2022-02-14
Filing date: 2022-02-14
Publication date: 2022-05-27
Anticipated expiration: 2042-02-14
Also published as: CN114539279B

Abstract

The invention discloses an oxo-bridged bicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparing anti-breast cancer drugs, belonging to the technical field of medicines. The compound can well inhibit MCF-7 cells, has certain degradation capability on estrogen receptors, can well inhibit aromatase, and has application prospect in the treatment of breast cancer.

Description

Oxidobicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparation of anti-breast cancer drugs

Technical Field

The invention belongs to the technical field of medicines, relates to a compound based on an oxido-bicyclo- [2.2.1] -heptene sulfonamide structure, and particularly relates to an oxido-bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle, a preparation method thereof and application thereof in preparing anti-breast cancer medicines.

Background

In recent years, breast cancer has jumped to become one of the most common cancers in women. Since overexpression of Estrogen Receptor (ER) leads to the generation of breast cancer, anti-estrogen drugs are being developed and used. Research shows that long-term use of anti-estrogen drugs such as tamoxifen can cause strong side effects and cause drug-resistant breast cancer. Therefore, there is a need to develop drugs with novel mechanisms of action against this target of estrogen receptors.

Disclosure of Invention

Selective estrogen receptor down-regulators (SERDs) directed to estrogen receptors have been the focus of research because of their novel mechanism of action. The selective estrogen receptor down-regulator can degrade ER alpha and shows good treatment effect on drug-resistant breast cancer in clinical tests. The invention designs and synthesizes a dual-functional selective estrogen receptor down-regulator by taking the oxido-bicyclo- [2.2.1] -heptene sulfonamide as a parent nucleus, and researches the biological activity of the dual-functional selective estrogen receptor down-regulator.

The invention designs and synthesizes a series of double-target conjugates which take oxido bridged bicyclic- [2.2.1] -heptene sulfonamide (OBHSA) as a mother nucleus and have aromatase inhibiting activity and estrogen receptor down-regulation activity. Subsequent biological activity tests show that the compounds have certain affinity and selectivity on ER alpha and have good inhibition effect on breast cancer cell proliferation, and in addition, the compounds can effectively inhibit the activity of aromatization enzyme and have certain degradation effect on ER alpha. More importantly, in the research field of ER ligands, by a molecular design concept, a bifunctional compound capable of inhibiting the activity of an aromatase and inducing the degradation of ER alpha is discovered, so that a new thought is provided for the development of a bifunctional ER ligand with structural diversity, and a new possibility is created for the development of drug-resistant breast cancer drugs.

The invention aims to provide an oxido-bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle, the compound is a compound with an oxido-bicyclo heptene sulfonamide structure and five-membered nitrogen heterocycle are combined to obtain an anti-tumor drug with a three-dimensional structure, and the synthesized target compound shows good anti-breast cancer cell activity in testing the biological activity of the target compound and has the capability of down-regulating the estrogen receptor level.

In addition, the invention provides application of the oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing the five-membered nitrogen heterocyclic structure in preparation of anti-breast cancer drugs.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, an oxo-bridged bicyclic- [2.2.1] -heptene sulfonamide (OBHSA) compound containing a five-membered nitrogen heterocycle is provided.

The OBHSA compound containing five-membered nitrogen heterocycle has a structure shown as a general formula I, II or III:

in the above formula, R₁Is selected from

R₂Is selected from CH₃、CH₂CH₃、CH₂CF₃，R₃Selected from H, OCH₃。

Preferably, the five-membered nitrogen heterocycle-containing OBHSA compound is selected from the following compounds:

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16a),

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16b),

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16c),

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16d),

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-phenyl-N- (2,2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16e),

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N- (2,2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16f),

(1R,4R) -6- (4- (1H-1,2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16g),

(1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16H),

(1R,4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16j),

(1R,4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-N- (2,2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16k),

(1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazolyl-4-yl) phenyl) -N- (2,2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16l),

(1R,4R) -6- (4- (1H-1,2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16N),

(1R,4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazol-cyclo [2.2.1] hept-5-ene-2-sulfonamide (18a),

(1R,4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18b),

(1R,4R) -6- (4- (1H-1,2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (18c),

(1R,4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 d).

In a second aspect, a method for preparing the oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide (OBHSA) compound containing the five-membered nitrogen heterocyclic structure is provided.

The preparation method of the OBHSA compound containing the five-membered nitrogen heterocycle, the structure of which is shown as the general formula I, comprises the following steps:

furan derivative 8a-c containing five-membered nitrogen heterocycle and R-containing compound₂And R₃The vinylsulfonamide derivative 24a-f of the group is prepared into the compound with the structure shown in the general formula I through Diels-Alder reaction.

The preparation method of the five-membered nitrogen heterocycle-containing OBHSA compound with the structure shown as the general formula II or III comprises the following steps:

bromo furan derivative 13 and compound containing R₃The vinylsulfonamide derivative 24c-d of the group is prepared into a compound shown by 15a-d through Diels-Alder reaction, and then is coupled with (1-methyl-1H-pyrazol-4-yl) boric acid to obtain a compound shown by a general formula II and a compound shown by a general formula III.

In a third aspect, there is provided a pharmaceutically acceptable salt of the above-mentioned oxo-bridged bicyclo- [2.2.1] -heptenesulfonamide (OBHSA) compound containing a five-membered nitrogen heterocyclic structure.

In a fourth aspect, the application of the oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide (OBHSA) compound containing the five-membered nitrogen heterocyclic structure or the pharmaceutically acceptable salt thereof in preparing the medicament is provided. The medicines comprise medicines for degrading estrogen receptors, medicines for resisting breast cancer, medicines for inhibiting aromatase activity and medicines for resisting breast cancer endocrine therapy.

A drug for degrading estrogen receptors, an anti-breast cancer drug, a drug for inhibiting the activity of aromatase or a drug resistant to endocrine therapy of breast cancer comprises the five-membered nitrogen heterocycle-containing oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound or pharmaceutically acceptable salts thereof, and also comprises one or more pharmaceutically acceptable carriers or excipients.

Compared with the prior art, the invention has the advantages and beneficial effects that: the oxygen bridge bicyclo- [2.2.1] -heptene sulfonamide compound containing the five-membered nitrogen heterocyclic structure is prepared by reacting a furan derivative containing the five-membered nitrogen heterocyclic and a vinyl sulfonamide derivative at 90 ℃ for 12 hours in one step without using a solvent or a catalyst. In vitro experiments show that most of novel sulfonamide oxygen-bridged bicyclic- [2.2.1] -heptene compounds have stronger inhibitory activity on MCF-7 cells and certain degradation capability on estrogen receptors compared with the existing anti-breast cancer medicament tamoxifen, and in addition, have certain inhibitory action on aromatase.

Drawings

FIG. 1 shows the results of the determination of the degradation activity of compounds 16a-r and 18a-d on ER α, in which C is control (DMSO) and Ful is fulvestrant.

Detailed Description

The present invention is described in further detail below with reference to examples, which are provided only for illustration of the process of the present invention and are not intended to limit the remainder of the disclosure in any way.

Furan derivatives containing a five-membered nitrogen heterocycle, 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan 8a, 3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan 8b, 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan 8c, 4- (4-bromofuran-3-yl) phenol 13, vinylsulfonamide derivatives, and target compounds were synthesized by the reactions shown below. The specific operation steps can be as follows:

1. synthesis of furan derivative 8a-c containing five-membered azacyclo

^a Reagents and conditions:(a)NBS,p-TsOH,AlCl₃,CHCl₃,rt,12h；(b)2-(4-bromophenyl)acetic acid,Et₃N,CH3CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr₃,CH₂Cl₂,-20℃,12h；(e)DIBAL-H,THF,-78℃,8h；(f)For 8a:1H-imidazole,CuI,Cs₂CO₃,DMF,120℃,24h；For 8b:1,2,4H-triazole,CuI,Cs₂CO₃,DMF,120℃,24h；For 8c:1-methyl-1H-pyrazol-4-yl)boronic acid,Pd(dppf)Cl₂,K₃PO₄,H₂O,1,4-dioxane,80℃,16h.

a. Synthesis of p-methoxy bromoacetophenone compound 2

Weighing 1.0 eq.p-methoxyacetophenone 1, 0.2 eq.p-toluenesulfonic acid and 1.2 eq.N-bromosuccinimide in a 50mL round bottom flask, adding 20mL CH₃Cl, reaction at room temperature for 9h, TLC to monitor completion of the reaction, desolventizing under reduced pressure, dissolving in 50mL of ethyl acetate, dissolving in 3.0eq.2N HCl, 2X 30mL of saturated NaHCO₃The solution was washed with 30mL of saturated NaCl and the organic layer was washed with anhydrous NaSO₄Drying, filtering, spin-drying to obtain crude product, and purifying by column chromatography to obtain white solid compound 2.

b. Synthesis of 2- (4-methoxyphenyl) -2-oxyethyl 2- (4-bromophenyl) acetate Compound 4

Weighing 1.0eq.2 and 1.0eq.2- (4-bromophenyl) acetic acid 3 into a 50mL round-bottom flask, adding 25mL of anhydrous acetonitrile, slowly dropwise adding 1.0 eq.3 of anhydrous triethylamine, continuing to react for 2h at room temperature, monitoring the completion of the reaction by TLC, evaporating acetonitrile and triethylamine after the reaction is finished, adding ethyl acetate to dissolve, washing with 5.0 eq.2N diluted hydrochloric acid, 2 × 30mL of saturated sodium bicarbonate and 30mL of saturated sodium chloride, drying an organic layer with anhydrous sodium sulfate, filtering, spin-drying to obtain a crude product, and purifying by column chromatography to obtain a yellow solid compound 4.

c. Synthesis of 3- (4-bromophenyl) -4- (4-methoxyphenyl) furan-2- (5H) -one Compound 5

Baking 25mL of two-mouth bottle and magneton at 105 ℃ for 15min, putting the two-mouth bottle and magneton into a hot device, performing anhydrous and anaerobic operation, weighing 1.0eq compound 4 in the device under the condition of introducing Ar, adding 10mL of anhydrous DMSO, slowly dropwise adding 2.0 eq.80% NaH, reacting at 25 ℃ for 2h, monitoring the reaction by TLC, adding 5mL of 4.0eq 2N HCl to quench the reaction, extracting with 3 x 25mL of ethyl acetate, and obtaining an organic layer of anhydrous NaSO₄Drying and desolventizing under reduced pressure gave the crude product which was purified on silica gel (petroleum ether/ethyl acetate 9:1) to give compound 5.

d. Synthesis of 3- (4-bromophenyl) -4- (4-hydroxyphenyl) furan-2 (5H) -one Compound 6

Baking 100mL of single-mouth bottle and magneton at 105 ℃ for 15min, putting the bottle in a hot device, performing anhydrous and anaerobic operation, adding 1.0eq of compound 5 into the device under Ar introduction, adding 25mL of DCM, and adding 6.0eq.BBr at-20 ℃₃After 12h reaction, 10mL of water was added to quench the reaction, which was extracted with 3X 20mL of ethyl acetate and 15mL of saturated NaHCO₃Washing with the solution, and removing organic layer with anhydrous NaSO₄Drying and desolventizing under reduced pressure gave the crude product which was purified on silica gel (petroleum ether/ethyl acetate 7:3) to give compound 6.

e. Synthesis of 4- (4- (4-bromophenyl) furan-3-yl) phenol Compound 7

Baking 50mL of single-mouth bottle and magneton at 105 ℃ for 15min, putting the bottle and magneton into a hot device, performing anhydrous and anaerobic operation, weighing 1.0eq of compound 6 in the device under the action of Ar, adding 4.0eq of diisobutylaluminum hydride (DIBAL-H) at-78 ℃ for reaction for 12H, and adding 4% H₂SO₄The reaction was quenched, extracted with 3X 25mL ethyl acetate, washed with 30mL saturated NaCl solution, and the organic layer was anhydrous NaSO₄Drying and desolventizing under reduced pressure gave the crude product which was purified on silica gel (petroleum ether/ethyl acetate 6:4) to give compound 7.

f. Synthesis of 4- (4- (4- (1H-imidazol-1-yl) phenyl) furan-3-yl) phenol and 4- (4- (4- (1H-1,2, 4-triazol-1-yl) phenyl) furan-3-yl) phenol Compounds 8a-b

Baking 50mL of single-neck bottle and magneton at 105 deg.C for 15min, and weighing compound 7(1.0equiv.), 1H-imidazole or 1,2, 4-H-triazole (1.2equiv.), CuI (5% mmol), Cs₂CO₃(1.2equiv.), anhydrous and oxygen-free operation, dissolving with DMF, stirring at room temperature for half an hour, heating to 120 ℃, reacting for 24 hours, extracting with 3 × 25mL ethyl acetate, washing with 30mL saturated NaCl solution, and obtaining an organic layer of anhydrous NaSO₄Drying and desolventizing under reduced pressure to obtain a crude product, and purifying with a silica gel column (dichloromethane/methanol ratio 150:1 to 50: 1) to obtain the compounds 8 a-b.

g. Synthesis of 4- (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) furan-3-yl) phenol Compound 8c

A50 mL single-necked flask was charged with compound 7(1.0equiv.), 4- (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) furan-3-yl) phenol (1.2equiv.), Pd (dppf) Cl₂(5％mmol)、K₃PO₄(1.2equiv.) with 1,4-dioxane/H₂Dissolving O ═ 1: 1, reacting at 80 deg.C for 16h, extracting with 3X 25mL ethyl acetate, washing with 30mL saturated NaCl solution, and separating the organic layer with anhydrous NaSO₄Drying and desolventizing under reduced pressure to obtain a crude product, which is purified by silica gel column (dichloromethane/methanol ═ 150:1 to 50: 1) to obtain compound 8 c.

2. Synthesis of 4- (4-bromofuran-3-yl) phenol 13

^a Reagents and conditions:(a)NBS,p-TsOH,AlCl₃,CHCl₃,rt,12h；(b)2-(4-bromophenyl)acetic acid,Et₃N,CH3CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr₃,CH₂Cl₂,-20℃,12h；(e)DIBAL-H,THF,-78℃,8h.

Firstly, the compound 2 reacts with bromoacetic acid to obtain bromoacetate 9, and then the bromoacetate 9 reacts with PPh₃And Et₃N was refluxed at 100 ℃ to give the ring-closed product 10. Adding bromine to the compound 10 under the action of NBS to obtain bromofuranone 11, and performing BBr₃Demethylation and DIBAL-H reduction to yield bromofuran derivative 13.

3. Synthesis of ethenesulfonamide derivative 24a-f

a. Synthesis of N-phenylacetamide compound 20a-f

Weighing 1eq aromatic amine compound 19a-b and 2eq acetic anhydride or trifluoroacetic anhydride in a 100mL single-neck bottle, adding 40mL dichloromethane to dissolve, slowly adding 0.1 eq.4-Dimethylaminopyridine (DMAP), continuing to react for 2h at room temperature, after TLC monitoring reaction is completed, decompressing and removing the solvent to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 15:1) to obtain acetamide compound 20 a-f.

b. Synthesis of N-methyl-N-phenylacetamide Compound 21a-b

Under the protection of Ar, 1eq. acetamide compound 20a-b is weighed into a 150mL two-necked flask, 35mL of anhydrous tetrahydrofuran is added to dissolve the acetamide compound, sodium hydride (2eq.) is slowly added at 0 ℃, the reaction is continued for 4h at 0 ℃, 3mL of water is added to quench the reaction, the crude product is obtained after decompression and desolventization, and white N-methylacetamide compounds 21a-b are obtained after silica gel column purification (petroleum ether/ethyl acetate ═ 9: 1).

c. Synthesis of N-methylaniline compound 22a-b

1 eq.n-methylacetamide compounds 21a-b were weighed into a 100mL single vial, 20mL ethylene glycol and 10mL 10% diluted hydrochloric acid were added, heated under reflux for 4h, and desolventized under reduced pressure to give the crude product, which was purified by silica gel column (15: 1 petroleum ether/ethyl acetate) to give white oils 22 a-b.

d. Synthesis of N-alkylaniline compound 23c-f

Under the protection of Ar, weighing 1eq of acetamide compound 20c-f in a 100mL double-mouth bottle, adding 20mL of anhydrous tetrahydrofuran for dissolving, slowly dropwise adding 4eq of borane-dimethyl sulfide at 0 ℃, reacting for 24 hours after slowly raising the temperature to 60 ℃, and adding 5mL of methanol for quenching reaction; the crude product was obtained after desolventization under reduced pressure and purified by silica gel column (petroleum ether/ethyl acetate 12:1) to give white oils 23 c-f.

e. Synthesis of sulfonamide dienophiles 24a-f

Weighing corresponding 1 eq.N-methyl aromatic amide derivatives 22a-b or 23c-f, dissolving in 25mL of dichloromethane, slowly adding 1.2 eq.2-chloroethane sulfonyl chloride at 0 ℃, reacting for 10min, slowly dropwise adding 20% sodium hydroxide aqueous solution, reacting for 24h at room temperature, decompressing and removing the solvent to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 15: 1-3: 2) to obtain the N-methyl vinyl sulfonamide dienophile 24 a-f.

4. Synthesis of target Compounds 16a-r, 18a-d

(1) Taking a 25ml double-mouth bottle, baking magnetons at 105 ℃ for 15min, putting the bottle in a hot device, performing anhydrous and anaerobic operation, dissolving synthesized 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a, 3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan compound 8b, 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan compound 8c and ethylene sulfonamide derivative 24a-f in tetrahydrofuran under the condition of introducing Ar, reacting for 8 hours at 90 ℃ to prepare the oxabicycloheptene compound 16a-r containing five-membered nitrogen heterocycles in one step, the reaction formula is shown as follows:

(2) taking a 25ml double-mouth bottle, baking magnetons for 15min at 105 ℃, using a hot device, performing anhydrous and anaerobic operation, dissolving synthesized 4- (4-bromofuran-3-yl) phenol 13 and vinylsulfonamide derivative 24c-d in tetrahydrofuran under the condition of introducing Ar, reacting for 8 hours at 90 ℃ to prepare an oxa-bridged bicycloheptene compound 15a-d containing five-membered nitrogen heterocycle by one step, and obtaining 18a-d through suzuki reaction, wherein the reaction formula is shown as follows:

example 1 preparation of 6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 a):

3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a,1eq.) and N-methyl-N-phenyl ethenesulfonamide (24a,1eq.) were weighed, dissolved in 2-3mL THF, placed in a 25mL single-neck round-bottomed bottle, slowly warmed to 90 ℃ for reaction for 12 hours, spun dry, and directly purified by column chromatography separation, with an eluent ratio of dichloromethane to methanol of 60:1, to give a yellow solid in 61% yield. Light yellow solid, mp 127-.¹H NMR(400MHz,DMSO-d₆)δ9.79(d,J＝15.0Hz,1H),8.33(s,1H),7.81(s,1H),7.65(dd,J＝17.9,8.4Hz,2H),7.42(d,J＝6.1Hz,2H),7.36(dd,J＝15.2,8.3Hz,5H),7.28(t,J＝6.8Hz,1H),7.18–7.13(m,2H),6.75(dd,J＝14.8,8.5Hz,2H),5.50(d,J＝9.9Hz,1H),5.44–5.38(m,1H),3.74–3.52(m,1H),3.31(d,J＝4.7Hz,3H),2.00(dd,J＝20.4,11.8Hz,1H),1.92(d,J＝5.2Hz,1H).¹³C NMR(101MHz,DMSO-d₆)δ158.24,144.00,142.00,140.50,139.87,136.13,131.79,131.34,129.52,129.44,129.20,128.78,127.46,127.00,123.11,122.51,120.68,116.25,84.27,82.46,60.19,55.38,30.71.HRMS(ESI)calcd for C₂₈H₂₅N₃O₄S[M+H]⁺,501.1639；found 501.1638.

Example 2 preparation of (1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 b):

3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a,1eq.) and N- (4-methoxyphenyl) -N-methyl chlorosulfonamide (24b,1eq.) were dissolved in 2-3mL of THF, placed in a 25mL single-neck flask, slowly heated to 90 ℃ and reacted for 12 hours, then dried by spinning, and directly purified by column chromatography, with the ratio of dichloromethane to methanol being 60:1, the product being a pale yellow solid, and the yield being 75%.¹H NMR(400MHz,DMSO-d₆)δ9.75(s,1H),7.80(s,1H),7.68(d,J＝8.7Hz,2H),7.40(d,J＝8.6Hz,2H),7.31(d,J＝9.0Hz,2H),7.17(d,J＝8.6Hz,2H),7.12(s,1H),6.88(d,J＝9.0Hz,2H),6.73(d,J＝8.6Hz,2H),5.51(s,1H),5.40(s,1H),3.73(s,3H),3.63(dd,J＝12.0,5.7Hz,2H),3.17(d,J＝5.2Hz,3H),2.00(s,4H).¹³C NMR(101MHz,DMSO)δ158.54,158.17,144.63,140.66,140.07,136.54,136.17,135.89,134.57,131.85,131.40,130.44,129.61,129.18,128.70,123.59,122.08,120.85,120.67,118.23,116.27,116.08,115.04,114.55,84.17,82.30,59.97,59.63,55.71,49.08.HRMS(ESI)calcd for C₂₉H₂₇N₃O₅S[M+H]⁺,529.1671；found.

Example 3 preparation of (1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 c):

3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a,1eq.) and N-ethyl-N-phenyl ethenesulfonamide (24c,1eq.) are weighed, dissolved in 2-3mL THF, placed in a 25mL single-mouth round-bottom bottle, slowly heated to 90 ℃, reacted for 12 hours, then dried, and directly separated and purified by column chromatography, wherein the eluent ratio is dichloromethane to methanol (60: 1), the product is a light yellow solid, the yield is 58%, and the mp 132 ion 133 ℃.¹H NMR(400MHz,DMSO-d₆)δ9.75(s,1H),8.33(s,1H),7.84(s,1H),7.66(t,J＝11.2Hz,2H),7.53(s,1H),7.40(d,J＝6.3Hz,2H),7.33(d,J＝14.2Hz,5H),7.17(d,J＝3.4Hz,2H),6.73(d,J＝7.2Hz,2H),5.53(s,1H),5.41(s,1H),3.76(d,J＝6.7Hz,2H),3.60(s,1H),1.99(s,2H),0.96(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ158.14,143.96,139.17,136.20,131.32,129.56,129.49,129.20,129.15,128.15,123.17,120.88,116.06,84.16,82.67,61.22,46.13,30.40,14.72.HRMS(ESI)calcd for C₂₉H₂₇N₃O₄S[M+H]⁺,514.1795；found514.1798.

Example 4 preparation of (1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 d):

3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a,1eq.) and N-ethyl-N- (4-methoxyphenyl) vinylamide (24d,1eq.) were dissolved in 2-3mL of THF, placed in a 25mL single-neck round-bottomed bottle, slowly heated to 90 ℃ to react for 12 hours, and then dried by spinning, and directly separated and purified by column chromatography, wherein the eluent ratio is dichloromethane to methanol 60:1, the product is a yellow solid, the yield is 68%, and m.p.137-138 ℃.¹H NMR(400MHz,DMSO-d₆)δ9.80(s,1H),8.31(s,1H),7.80(s,1H),7.67(dd,J＝14.1,8.6Hz,2H),7.44(dd,J＝16.4,8.2Hz,4H),7.34(dd,J＝15.0,7.3Hz,2H),7.28(d,J＝7.7Hz,1H),7.22(dd,J＝12.9,8.6Hz,2H),7.13(s,1H),6.77(dd,J＝10.7,8.7Hz,2H),5.79(d,J＝14.2Hz,1H),5.54(d,J＝12.2Hz,1H),3.92(ddd,J＝19.5,10.6,5.6Hz,1H),2.27(dd,J＝12.0,4.6Hz,1H),2.19(dd,J＝12.1,8.3Hz,1H).¹³C NMR(101MHz,DMSO-d₆)δ158.27,149.33,144.33,140.18,136.63,135.83,131.66,131.00,130.57,129.88,129.20,128.77,122.75,120.79,116.25,84.00,82.69,60.78,30.54.HRMS(ESI)calcd for C₂₇H₂₂N₂O₅S[M+H]⁺,487.1322；found 487.1323.

Example 5 preparation of (1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-phenyl-N- (2,2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 e):

weighing 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a,1eq.) and N-phenyl-N- (2,2, 2-trifluoroethyl) vinylamide (24e,1eq.) and dissolving with 2-3mL THF, placing in a 25mL single-mouth round bottom bottle, slowly heating to 90 ℃, reacting for 12 hours, spin-drying, directly separating and purifying by column chromatography, wherein the eluent ratio is dichloromethane: methanol: 60:1, the product is yellow solid, the yield is 78%,¹H NMR(400MHz,Acetone-d₆)δ8.13(s,5H),7.86(d,J＝1.8Hz,4H),7.72(d,J＝1.7Hz,4H),7.64–7.56(m,13H),7.42(d,J＝8.6Hz,6H),7.15–7.11(m,12H),6.84(d,J＝8.5Hz,7H),5.64(d,J＝4.3Hz,1H),5.47–5.38(m,1H),4.61(qd,J＝8.7,8.2,4.1Hz,2H),3.76(dd,J＝8.3,4.4Hz,1H),3.63(dd,J＝8.0,4.8Hz,1H),2.21(q,J＝4.5Hz,1H),2.19–2.08(m,2H).¹³C NMR(101MHz,Acetone)δ159.15,156.95,141.17,140.69,136.26,135.34,131.26,130.08,129.79,129.61,129.33,129.07,128.87,128.45,128.32,125.64,124.81,122.82,120.81,120.65,120.60,117.75,117.62,115.87,115.66,115.41,82.84,81.42,71.39,71.06,42.95,23.43.

example 6 preparation of (1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N- (2,2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 f):

weighing 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a,1eq.) and N- (4-methoxyphenyl) -N- (2,2, 2-trifluoroethyl) vinylamide (24f,1eq.) and dissolving the mixture in 2-3mL THF, placing the solution in a 25mL single-neck round-bottom bottle, slowly heating the solution to 90 ℃, reacting the solution for 12 hours, spin-drying the solution, and directly carrying out column chromatography separation and purification, wherein the eluent ratio is dichloromethane to methanol 60:1, the product is a yellow solid, the yield is 54%, and the mp 129-ion 131 ℃.¹H NMR(400MHz,Acetone-d₆)δ8.94(s,1H),8.22(s,1H),7.73(s,1H),7.65(d,J＝8.5Hz,2H),7.49(d,J＝8.5Hz,2H),7.41(d,J＝8.9Hz,2H),7.23(d,J＝8.6Hz,3H),6.90(d,J＝9.0Hz,2H),6.83(d,J＝8.6Hz,2H),5.64(s,1H),5.43(d,J＝4.2Hz,1H),4.54(q,J＝8.6Hz,2H),3.79(d,J＝7.1Hz,3H),3.73(dd,J＝8.2,4.4Hz,1H),2.21(dt,J＝12.0,4.4Hz,1H),2.12(d,J＝9.2Hz,1H).¹³C NMR(101MHz,Acetone-d₆)δ159.49,144.31,136.19,131.90,131.46,130.34,129.64,129.14,128.84,128.19,125.80,123.45,120.81,115.59,114.32,113.08,84.24,82.85,61.89,59.67,54.89,54.08,19.94.HRMS(ESI)calcd for C₃₀H₂₆F₃N₃O₅S[M+H]⁺,598.1618；found 598.1615.

Example 7 preparation of (1R,4R) -5- (4-hydroxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 g):

3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan (8b,1eq.) and N-methyl-N-phenyl ethenesulfonamide (24a,1eq.) are weighed, dissolved in 2-3mL of THF, placed in a 25mL single-mouth round-bottomed bottle, slowly heated to 90 ℃, reacted for 12 hours, then dried by spinning, separated and purified by direct column chromatography, the eluent ratio is dichloromethane to methanol is 60:1, the product is light yellow solid, the yield is 59%,¹³C NMR(101MHz,Acetone-d₆)δ157.62,142.80,142.26,140.81,139.31,137.22,136.02,132.73,130.31,129.19,128.92,127.79,127.55,127.30,126.45,125.29,125.15,123.96,123.35,122.18,115.55,84.27,82.83,60.82,38.27,30.46.

EXAMPLE 8 preparation of (1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16H):

weighing 3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan (8b,1eq.) and N- (4-methoxyphenyl) -N-methyl chlorosulfonamide (24b,1eq.) and dissolving with 2-3mL THF, placing in a 25mL single-mouth bottle, slowly heating to 90 ℃, reacting for 12 hours, spin-drying, directly separating and purifying by column chromatography, wherein the eluent ratio is dichloromethane to methanol (60: 1), the product is yellow solid, the yield is 70%,¹H NMR(400MHz,Methanol-d₄)δ7.92(d,J＝12.6Hz,1H),7.81(d,J＝11.7Hz,1H),7.50–7.39(m,1H),7.37–7.21(m,3H),7.15(dd,J＝8.6,6.8Hz,2H),6.85(dd,J＝31.3,9.0Hz,2H),6.74(dd,J＝17.1,8.6Hz,2H),5.47(d,J＝8.1Hz,1H),5.32(t,J＝4.8Hz,1H),3.91(d,J＝5.0Hz,3H),3.75(d,J＝12.3Hz,2H),3.54(d,J＝4.0Hz,0H),3.33(d,J＝3.3Hz,2H),2.46–2.15(m,0H),1.99(d,J＝8.4Hz,0H).

example 9 preparation of (1R,4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 j):

weighing 3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan (8b,1eq.) and N-ethyl-N- (4-methoxyphenyl) vinyl amide (24d,1eq.) and dissolving the mixture in 2-3mL THF, placing the solution in a 25mL single-mouth bottle with round bottom, slowly heating the solution to 90 ℃, reacting for 12 hours, spin-drying, directly separating and purifying by column chromatography, wherein the eluent ratio of dichloromethane to methanol is 60:1, the product is yellow solid, the yield is 78%,¹H NMR(400MHz,Methanol-d₄)δ7.88(d,J＝49.7Hz,1H),7.46(s,1H),7.37–7.13(m,4H),6.88(d,J＝52.9Hz,4H),5.50(d,J＝9.4Hz,1H),5.35(s,1H),3.92(d,J＝7.1Hz,2H),3.78(s,2H),2.74–2.18(m,1H),2.04(s,1H),1.34–1.21(m,8H).

EXAMPLE 10 preparation of (1R,4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-N- (2,2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 k):

weighing 3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan (8b,1eq.) and N-phenyl-N- (2,2, 2-trifluoroethyl) vinylamide (24e,1eq.) and dissolving the mixture in 2-3mL THF, placing the solution in a 25mL single-neck round-bottomed bottle, slowly heating the solution to 90 ℃, reacting the solution for 12 hours, spin-drying the solution, and directly separating and purifying the solution by column chromatography, wherein the eluent ratio is dichloromethane to methanol (60: 1) to obtain 125mg yellow solid, the yield is 76%, and the m.p. is 145-146 ℃.¹H NMR(400MHz,Methanol-d₄)δ7.94(d,J＝13.8Hz,1H),7.82(d,J＝12.4Hz,1H),7.47(dd,J＝16.0,8.1Hz,2H),7.32(d,J＝5.8Hz,2H),7.29–7.24(m,1H),7.17(d,J＝8.6Hz,1H),6.78(d,J＝8.6Hz,1H),6.73(d,J＝8.8Hz,1H),5.49(d,J＝4.9Hz,1H),5.34(t,J＝4.2Hz,1H),3.92(d,J＝5.0Hz,3H),3.86–3.78(m,1H),3.49(ddd,J＝34.1,8.3,4.4Hz,1H),2.22(ddd,J＝18.6,8.2,4.3Hz,0H),2.04(dd,J＝37.5,8.4Hz,0H),1.09–1.03(m,2H).HRMS(ESI)calcd for C₂₈H₂₄N₂O₅S[M+H]⁺,；found.

EXAMPLE 11 preparation of (1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazolyl-4-yl) phenyl) -N- (2,2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 l):

weighing 3- (4-hydroxyphenyl) -4- ((1H-1,2, 4-triazol-1-yl) phenyl) furan (8b,1eq.) and N- (4-methoxyphenyl) -N- (2,2, 2-trifluoroethyl) vinylamide (24f,1eq.) to dissolve with 2-3mL THF, placing in a 25mL single-neck round-bottomed bottle, slowly heating to 90 ℃, reacting for 12 hours, spin-drying, and directly performing column chromatography for separation and purification, wherein the eluent ratio is dichloromethane to methanol is 60:1, the product is a yellow solid, the yield is 42% yield, and the mp 136 ion 137 ℃.¹H NMR(400MHz,DMSO-d₆)δ9.74(s,1H),8.16(s,1H),7.87(s,1H),7.50(d,J＝8.2Hz,2H),7.26(dd,J＝11.4,8.7Hz,4H),7.18(d,J＝8.4Hz,2H),6.85(d,J＝8.8Hz,2H),6.77(d,J＝8.5Hz,2H),5.56(d,J＝8.9Hz,1H),5.41(s,1H),4.58–4.46(m,2H),3.85(s,3H),3.78–3.69(m,3H),3.51(t,J＝6.1Hz,1H),2.00(d,J＝6.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ159.22,158.18,140.77,139.27,136.56,132.55,131.84,130.65,129.81,128.38,127.68,125.41,122.69,121.88,116.16,114.77,84.16,82.40,61.17,55.74,52.17,30.79,26.81.HRMS(ESI)calcd for C₃₁H₂₈F₃N₃O₅S[M+Na]⁺,634.1594；found 634.1588.

Example 12 preparation of (1R,4R) -6- (4- (1H-1,2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16N):

weighing 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan (8c,1eq.) and N- (4-methoxyphenyl) -N-methyl chlorosulfonamide (24b,1eq.) and dissolving the mixture in 2-3mL of THF, placing the solution in a 25mL single-mouth round bottom bottle, slowly heating the solution to 90 ℃, reacting the solution for 12 hours, then spin-drying the solution, directly separating and purifying by column chromatography, wherein the eluent ratio of dichloromethane to methanol is 60:1, the product is a yellow solid, the yield is 65%,¹H NMR(400MHz,Acetone-d₆)δ9.07(d,J＝9.5Hz,2H),8.81(d,J＝19.8Hz,2H),8.12(d,J＝5.4Hz,3H),7.85(d,J＝8.9Hz,1H),7.47(dd,J＝16.8,8.7Hz,7H),7.35(q,J＝6.6Hz,6H),7.28(d,J＝8.2Hz,4H),7.21(d,J＝11.8Hz,2H),6.87–6.79(m,5H),5.54(s,2H),5.41–5.37(m,4H),3.67(ddd,J＝49.1,8.4,5.1Hz,3H),3.41(s,5H),2.96(s,22H),2.23–2.14(m,2H),2.13–1.98(m,3H).

EXAMPLE 13 preparation of (1R,4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 a):

weighing (1S, 4R) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15a, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol) and barium hydroxide (1.0eq.), using 1,4-dioxane/H₂Dissolving O (10:1), placing the solution in a 25mL round-bottomed single-necked flask, slowly heating the solution to 100 ℃, reacting the solution for 24 hours, extracting and spin-drying the solution, and directly separating and purifying the solution by column chromatography, wherein the eluent ratio is dichloromethane to methanol (60: 1), the product is a light yellow solid, the yield is 31%, and the mp 114-.¹H NMR(400MHz,Acetone-d₆)δ8.76(s,1H),7.74(s,1H),7.49(s,1H),7.44(d,J＝7.5Hz,2H),7.39(t,J＝7.5Hz,2H),7.33(d,J＝7.1Hz,1H),7.29(d,J＝8.6Hz,2H),6.82(dd,J＝25.4,8.6Hz,2H),5.49(s,1H),5.24(d,J＝4.0Hz,1H),3.89(s,3H),3.88–3.81(m,2H),3.38(dd,J＝8.2,4.5Hz,1H),2.25–2.17(m,1H),2.12(dd,J＝23.9,6.9Hz,1H),1.02(dt,J＝25.5,7.0Hz,4H).¹³C NMR(101MHz,Acetone-d₆)δ157.25,139.86,139.47,137.35,129.77,129.17,128.98,128.72,128.06,127.49,124.93,115.50,113.06,84.01,82.57,61.68,46.13,38.23,31.11,13.99.HRMS(ESI)calcd for C₂₄H₂₅N₃O₄S[M+H]⁺,452.1639；found 452.1638.

EXAMPLE 14 preparation of (1R,4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 b):

weighing (1S, 4R) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolylcyclo [ 2.2.1%]Hept-5-ene-2-sulfonamide (15b, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol) and barium hydroxide (1.0eq.), using 1,4-dioxane/H₂Dissolving O (10:1), placing the solution in a 25mL round-bottomed single-necked flask, slowly heating to 100 ℃, reacting for 24 hours, extracting, spin-drying, and directly performing column chromatography separation and purification to obtain a product which is a light yellow solid with the eluent ratio of dichloromethane to methanol of 60:1, wherein the yield is 41%, and mp 115-.¹H NMR(400MHz,Acetone-d₆)δ8.73(s,1H),7.76(s,1H),7.50(s,1H),7.31(dd,J＝14.4,8.7Hz,4H),6.92(d,J＝8.9Hz,2H),6.86(d,J＝8.5Hz,2H),5.48(s,1H),5.24(d,J＝4.2Hz,1H),3.89(s,3H),3.84–3.73(m,5H),3.35(d,J＝12.7Hz,1H),2.21(d,J＝12.0Hz,1H),2.11(s,1H),1.04(t,J＝7.1Hz,3H).¹³C NMR(101MHz,Acetone-d₆)δ160.79,158.96,141.54,139.16,133.57,132.39,131.66,130.47,129.83,126.82,117.26,115.82,114.85,85.80,84.35,63.21,56.63,48.13,40.01,32.93,15.78.HRMS(ESI)calcd for C₂₅H₂₇N₃O₅S[M+H]⁺,482.1744；found 482.1743.

Example 15 preparation of (1R,4R) -6- (4- (1H-1,2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (18 c):

weighing (1R, 4S) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15c, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol) and barium hydroxide (1.0eq.), using 1,4-dioxane/H₂Dissolving O (10:1), placing the solution in a 25mL round-bottomed single-necked flask, slowly heating the solution to 100 ℃, reacting the solution for 24 hours, extracting and spin-drying the solution, and directly performing column chromatography separation and purification, wherein the eluent ratio is dichloromethane to methanol (60: 1), the product is a light yellow solid, the yield is 35%, and mp 116-.¹H NMR(400MHz,Acetone-d₆)δ8.82(s,1H),7.79(s,1H),7.53(s,1H),7.44–7.31(m,5H),7.28(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),5.38(d,J＝12.8Hz,1H),5.35(d,J＝4.3Hz,1H),3.90–3.82(m,5H),3.52(dd,J＝8.3,4.4Hz,1H),2.15–2.09(m,1H),1.90(dd,J＝11.9,8.4Hz,1H),1.05(t,J＝7.1Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ157.64,139.20,137.48,135.70,133.08,129.52,129.49,129.42,128.69,128.08,123.76,116.11,113.62,84.06,82.21,61.73,55.40,46.00,30.57,14.71.HRMS(ESI)calcd for C₂₄H₂₅N₃O₄S[M+H]⁺,452.1639；found 452.1634.

EXAMPLE 16 preparation of (1R,4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 d):

weighing (1R, 4S) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15d, 1.0eq.), (1-methyl-)-1H-pyrazol-4-yl) boronic acid (1.0eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol) and barium hydroxide (1.0eq.), using 1,4-dioxane/H₂Dissolving O (10:1), placing the solution in a 25mL round-bottomed single-necked flask, slowly heating the solution to 100 ℃, reacting the solution for 24 hours, extracting and spin-drying the solution, and directly performing column chromatography separation and purification, wherein the eluent ratio is dichloromethane to methanol (60: 1), the product is a light yellow solid, the yield is 40%, and the mp 112 ion 113 ℃.¹H NMR(400MHz,Acetone-d₆)δ8.75(s,1H),7.79(s,1H),7.53(s,1H),7.29(d,J＝8.7Hz,4H),6.89(d,J＝8.1Hz,4H),5.39(s,1H),5.35(d,J＝4.3Hz,1H),3.87(s,3H),3.81(s,3H),3.80–3.75(m,2H),3.49(dd,J＝8.3,4.4Hz,1H),2.13(d,J＝11.8Hz,1H),1.91(dd,J＝11.8,8.4Hz,1H),1.04(t,J＝7.1Hz,3H).¹³C NMR(101MHz,Acetone-d₆)δ158.99,157.31,137.16,136.02,133.25,131.78,130.56,128.54,124.38,115.66,114.04,113.82,84.22,82.28,61.92,54.84,46.31,38.16,30.23,13.99.HRMS(ESI)calcd for C₂₅H₂₇N₃O₅S[M+H]⁺,482.1744；found 482.1744.

[ example 17 ] anti-tumor Activity test of Oxybicyclo- [2.2.1] -heptene sulfonamides having different five-membered aza-ring structures

MCF-7 human breast cancer cell line and MCF-10A normal breast cells were obtained from ATCC. Cells were cultured in DMEM containing phenol red with 10% FBS and 1% double antibody. Test compounds were dissolved in DMSO at a drug concentration of 100 mol/L. Cells were seeded in 96-well plates (Nest Biotech Co, china) and incubated in an incubator for 24 h. Different concentrations of test compound were added to 96-well plates, 3 wells in parallel per concentration, and vehicle DMSO was used as a negative control, 4-hydroxy tamoxifen as a positive control. After 72H, 10. mu.L of 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonated benzene) -2H-tetrazole monosodium salt (CCK-8) solution was added to each well and incubated for an additional 2H. Absorbance (OD) was read at 490nm on a WellscanMK-2 microplate reader. Determination of IC by the Logit method₅₀(concentration to induce apoptosis of 50%). All compounds were tested in at least 3 replicates and the results are shown in table 1.

TABLE 1 OBHSA family of compounds of different five-membered azacyclic structures for MCF-7 inhibitory Activity test (IC)₅₀,μM)

^aIC₅₀Is the mean ± standard deviation of at least three independent experiments.

This example tested the inhibitory activity of these 23 compounds against MCF-7 and the inhibitory activity of LCC2 in drug resistant breast cancer cells, and the results are listed in table 1. As can be seen from the above table, most compounds have certain inhibitory activity on MCF-7 cells and have no substantial toxicity on MCF-10A. Wherein the inhibition activity of the

compounds

16f, 16h and 16q on MCF-7 is better than that of 4-hydroxy tamoxifen, and the inhibition activity of the compound 16a on MCF-7 is equivalent to that of 4-hydroxy tamoxifen. The inhibitory activity of the compound on LCC 2-resistant strain cells is tested next, and the inhibitory activity of 16b and 16e on LCC 2-resistant strain cells is found to be better than that of 4-hydroxy tamoxifen, and the inhibitory activity of 16b and 16r on LCC 2-resistant strain cells is equivalent to that of 4-hydroxy tamoxifen.

[ example 18 ] assay of aromatization enzyme inhibitory Activity of Compounds

Aromatase (CYP19A) inhibitor screening kit (fluorescence) kit selected from Biovision corporation, recombinant human aromatase stock (2X) was prepared by reconstitution with 1mL of aromatase assay buffer. The contents were mixed thoroughly by vortexing to obtain a homogeneous solution (the solution would have a slightly opaque milky appearance) and the solution was transferred to a 15mL conical tube. The volume was increased to 2450. mu.L using an Aromatase Assay Buffer, and 50. mu.L of NADPH-producing system (10X) was added to make a final total volume of 2.5 mL.

Solutions containing test compound and corresponding no-inhibitor control, background control solution (no fluorescent aromatase substrate) and 5 μ M letrozole solution (5 × positive inhibition control solution, 1 μ M final concentration) were prepared. An aliquot of aromatase assay buffer is prepared which contains an organic solvent for dissolving the test compound at a final concentration of 5 ×.

TABLE 2 solution formulation for each test well in aromatization enzyme test

	No inhibitor (mu L)	Test Compound (μ L)	Negative control (. mu.L)	Positive control (μ L)
					Aromatization enzyme stock solution (2X)	50	50	50	50
Test Compound solution (5X)	--	20	--	--
					5 μ M letrozole solution (5X)	--	--	--	20
Aromatization enzyme buffer(5×)	20	--	50	--

The Corning 384 well plates were incubated at 37 ℃ for at least 10 minutes to allow the test ligand to interact with the aromatase enzyme. Depending on the mechanism of action, the pre-incubation time can be optimized for other test ligands.

During incubation, aromatase substrate/NADP was prepared by adding 6. mu.L of reconstituted 1mM aromatase⁺Mixture (3X) substrate stock solution and 50. mu.L of reconstituted 10mM β -NADP⁺Stock (100X) to 1444. mu.L of aromatase assay buffer in a total volume of 1.5 mL.

Add 30. mu.l aromatase substrate/NADP to each well by using multichannel pipette⁺(3X) the mixture (except for background control) was started to react, resulting in a final reaction volume of 100. mu.L/well.

The fluorescence at Ex/Em-488/527 nm was measured immediately (over 1 min) in kinetic mode for 60 min. Δ F ═ F (RFU)₂–RFU₁)，ΔT＝(T₂–T₁)。R＝(ΔF-ΔF_BC)/ΔT。％Relative Inhibition＝(R_SC–R_TC)/R_SC×100％。

TABLE 3 OBHSA family of compounds with different five-membered nitrogen heterocyclic structures tested for their aromatase inhibiting activity (IC)₅₀,nM)

The 23 compounds tested in this example have certain inhibitory activity on aromatization enzymes, and it can be seen from the table that the compounds with imidazole substituent all have certain inhibitory activity on aromatization enzymes, and the compounds with N-methylpyrazole substituent have no inhibitory activity on aromatization enzymes.

[ example 19 ] determination of degradation Activity of Compounds 16a-r and 18a-d on ER α

Cells were incubated with DMSO or compound (5 μ M) for 24 hours. Whole proteins were extracted and analyzed for ER α protein levels by western blot. Proteins from cell lysates were separated using 8% SDS-PAGE gel electrophoresis. The gel was then electroblotted onto polyvinylidene fluoride (PVDF) membranes, blocked with 5% skim milk, incubated with rabbit anti-ER α antibody (1: 1000, CST) and mouse anti- β -actin antibody (1: 10000, ABClonal Technology) overnight at 4 ℃. The membrane was washed 3 times 5 minutes with TBS containing 0.1% Tween-20. The membrane was then incubated with goat anti-rabbit secondary antibody for 1 hour at room temperature, and the membrane was washed with 0.1% tween-20 in TBS for 3 times 10 minutes. Taking the film to a dark room and developing the film by an X-ray film. The developed film is shot by a camera, and the film is put into Quantity One software for analysis and quantification.

Since sulfonamide compounds were found to have the effect of degrading ER α, this example was conducted to measure ER α -degrading activity of sulfonamide compounds 16a-r and 18a-d, and the results are shown in FIG. 1. Protein immunoblot Western blot experiments were performed with 5 μ M selected for the drug concentration of all compounds, including the control drug fulvestrant, taking into account the cell antiproliferative activity of the compounds. The results show that the

compounds

16m, 16q, 16l and 16r have obvious protein degradation effect, the degradation effect of the compounds 16a-c has certain degradation effect, and other compounds have no degradation activity.

Claims

1. An oxygen bridge bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle, which is characterized in that: having a structure represented by formula I, II or III:

in the above formula, R₁Is selected from

2. The oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle according to claim 1, wherein: a compound selected from:

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-phenyl-N- (2,2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N- (2,2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -6- (4- (1H-1,2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-N- (2,2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazolyl-4-yl) phenyl) -N- (2,2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,

(1R,4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide.

3. The process for preparing oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle as claimed in claim 1, wherein:

the preparation method of the OBHSA compound containing the five-membered nitrogen heterocycle as shown in the general formula I comprises the following steps: furan derivative containing five-membered azacyclo and R-containing compound₂And R₃Preparing a compound with a structure shown in a general formula I by using a vinylsulfonamide derivative of a group through a Diels-Alder reaction;

the preparation method of the five-membered nitrogen heterocycle-containing OBHSA compound with the structure shown as the general formula II or III comprises the following steps: bromo-furan derivatives and compounds containing R₃The ethylene sulfonamide derivative of the group is prepared into an intermediate product through Diels-Alder reaction, and the intermediate product is coupled with (1-methyl-1H-pyrazol-4-yl) boric acid to obtain compounds shown in a general formula II and a general formula IIIThe compounds shown in (A) and (B);

the structural formula of the furan derivative containing five-membered nitrogen heterocycle is

The structural formula of the vinylsulfonamide derivative containing R2 and R3 groups is shown in the specification

The structural formula of the bromofuran derivative is shown in the specification

Vinylsulfonamide derivatives containing an R3 group

In each structural formula, R₁Is selected from

4. The five-membered nitrogen heterocycle-containing oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound as claimed in claim 1 or 2, which is a pharmaceutically acceptable salt.

5. The use of the oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle or the pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 for the preparation of a medicament, wherein: the medicines comprise medicines for degrading estrogen receptors, medicines for resisting breast cancer, medicines for inhibiting aromatase activity and medicines for resisting breast cancer endocrine therapy.

6. A drug that degrades estrogen receptor, an anti-breast cancer drug, a drug that inhibits aromatase activity, or a drug resistant to endocrine therapy of breast cancer, characterized in that: a bridged bicyclic- [2.2.1] -heptene sulfonamide compound containing a five-membered nitrogen heterocycle, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2.

7. The medicament of claim 6, wherein: comprising one or more pharmaceutically acceptable carriers or excipients.