Oxygen-bridged bicyclo-[2.2. 1] heptene estrogen receptor macrocyclic compound with different linkers as well as preparation method and application thereof

Abstract

The invention discloses an oxygen-bridged bicyclo-[2.2. 1] heptene estrogen receptor macrocyclic compound with different linkers as well as a preparation method and application of the oxygen-bridged bicyclo-[2.2. 1] heptene estrogen receptor macrocyclic compound. Diol compounds containing p-toluenesulfonyl protecting groups with different functions and oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different functional side chain structures are used as raw materials, only potassium carbonate and a small amount of DMF are used as solvents, and the oxygen-bridged bicyclo-[2.2. 1]-heptene estrogen receptor macrocyclic compounds containing benzyl protecting groups can be obtained through reaction. In-vitro experiments show that compared with the existing endocrine therapeutic drug tamoxifen, the novel oxygen-bridged bicyclo-[2.2. 1]-heptene estrogen receptor compound provided by the invention has stronger inhibitory activity on MCF-7 cells, and also has better anti-proliferative activity on endocrine drug-resistant MCF-7 mutant strain cells, so that the novel oxygen-bridged bicyclo-[2.2. 1]-heptene estrogen receptor compound can be used for preparing a medicine for treating endocrine. Good application prospects are realized in the aspect of treating the drug-resistant breast cancer.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and particularly relates to an oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers, and its preparation method and application. Background Art

[0002] Breast cancer is one of the most common cancers in women, and estrogen receptor (ER) is an important target for breast cancer treatment. ER belongs to the nuclear receptor superfamily and is divided into two subtypes, ERα and ERβ, encoded by different genes.

[0003] Existing anti-estrogen drugs, such as selective estrogen receptor modulators (SERMs), target the C-terminal ligand-binding domain (LBD) of ERα, but are prone to drug resistance. Selective estrogen receptor degraders (SERDs) and ER proteolysis-targeting chimeras (PROTACs) developed to overcome drug resistance. The former causes the protein spatial structure to be unstable after binding to ER, and the latter connects ER and E3 protease, and finally both degrade ER through the ubiquitin-proteasome pathway. Although both strategies effectively overcome the drug resistance of anti-estrogen drugs, their poor oral bioavailability greatly limits their clinical applications.

[0004] Macrocyclic compounds refer to covalent non-bridged cyclic molecular structures with 12 or more atoms, including small molecule compounds and cyclic peptides. The macrocyclization conformational restriction strategy has been widely used in drug design. The cyclization strategy refers to using a linker to connect the two ends of a linear molecule that is U-shaped or C-shaped in the bioactive conformation. The resulting macrocyclic compound has significantly improved affinity, selectivity, brain permeability, and pharmacokinetic properties for the target.

[0005] Therefore, the present invention develops a macrocyclic compound targeting ERα that can overcome drug resistance, has brain permeability and good oral bioavailability, providing a potential targeted treatment strategy for inhibiting breast cancer cells in the field of breast cancer treatment. Summary of the Invention

[0006] The present invention provides an oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers, which can inhibit the growth of breast cancer cells.

[0007] The second object of the present invention is to provide a preparation method of the above-mentioned oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound, with mild reaction conditions and low preparation cost.

[0008] The third object of the present invention is to provide an application of an oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers in the preparation of anti-breast cancer drugs.

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] In the first aspect, the present invention provides an oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers, and its structural general formula is as follows:

[0011]

[0012] Among them, Linker is a methylene group with 2 to 6 carbon atoms, -(CH2)2-O-(CH2)2-, -CH2-C=C-CH2-, -(CH2)2-C=C-(CH2)2-, One of them;

[0013] X1 is O or N; among them, when X1 is O, there is no R substituent; when X1 is N, R is One of them;

[0014] X2 is O;

[0015] X3 is one of O or NH-C=O.

[0016] As an optimization and improvement of the above macrocyclic compound structure, it can also be the following structural formula:

[0017]

[0018] Among them, Linker is one of a methylene group with 2 to 6 carbon atoms and a C2-O-C2 group.

[0019] In the second aspect, the present invention also provides a preparation method of the oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers, including the following steps:

[0020] S1. Synthesis of 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol;

[0021] S2. Synthesis of vinylsulfonamide derivatives;

[0022] Proceed according to the following reaction process:

[0023]

[0024]

[0025] S3. Synthesis of oxabicyclo-[2.2.1]-heptene compounds 9a - 9f with different functional side chain structures;

[0026] It is carried out according to the following reaction process:

[0027]

[0028] S4. Synthesis of diol compounds 11a - 11f with different functionalities and p-toluenesulfonyl protecting groups;

[0029] It is carried out according to the following reaction process:

[0030]

[0031] S5. Synthesis of bicyclo-[2.2.1]heptene macrocyclic compounds with different functional linkers; It is carried out according to the following reaction process:

[0032]

[0033]

[0034] As a preference of the technical solution of the present invention, the preparation of step S1 includes: Weigh 3,4-bis(4-hydroxyphenyl)furan, benzyl bromide, and potassium carbonate, add them to a round-bottom flask, then add DMF, react at room temperature, perform extraction after monitoring the completion of the reaction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and obtain 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol, denoted as compound 3, after purification by silica gel column.

[0035] As a preference of the technical solution of the present invention, the preparation of step S2 includes:

[0036] S21. Synthesis of N-phenylacetamide compounds 5a - 5e;

[0037] Weigh one of p-methoxyaniline 4a, 3-methoxyaniline 4b, or tert-butyl (4-aminophenyl)carbamate 4c and pyridine, add them to a single-neck flask, then add dichloromethane;

[0038] Mix trifluoroacetic anhydride, acetic anhydride, or isobutyric anhydride with dichloromethane and place it in a constant-pressure dropping funnel, slowly add it dropwise to the single-neck flask at low temperature, and react at room temperature; perform extraction after monitoring the completion of the reaction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain N-phenylacetamide compounds, denoted as 5a - 5e respectively;

[0039] S22. Synthesis of N-alkyl aniline compounds 6a - 6e, 6f;

[0040] Weigh N-phenylacetamide compounds 5a-5e, add them to a single-necked flask, then add anhydrous tetrahydrofuran to dissolve. Slowly add borane dimethyl sulfide complex dropwise at low temperature, slowly raise the temperature and carry out the reaction. After monitoring the completion of the reaction, add water to quench the reaction, then carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure, and finally purify by silica gel column to obtain a white oil, namely N-alkyl aniline compounds, denoted as 6a-6d, 6f respectively;

[0041] S23. Synthesis of sulfonamide dienophile compounds 6d, 7a-7e;

[0042] Weigh one of the compounds of N-alkyl aniline compounds 6a-6d, 6f or p-methoxyaniline 4a, add it to a single-necked flask containing dichloromethane, slowly add 2-chloroethanesulfonyl chloride at low temperature, slowly add pyridine dropwise after the reaction, then carry out the reaction. After monitoring the completion of the reaction, carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify by silica gel column to obtain sulfonamide dienophile compounds, denoted as 7a-7d, 7g, 6e respectively;

[0043] Weigh sulfonamide dienophile compound 6e and potassium carbonate, add them to a single-necked flask, then add DMF, and then add bromomethylcyclopropane or bromocyclohexane, react at room temperature. After monitoring the completion of the reaction, carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify by silica gel column to obtain sulfonamide dienophile compounds, denoted as 7e-7f;

[0044] S24. Synthesis of sulfonamide dienophile compounds 8a-8g;

[0045] Weigh one of the sulfonamide dienophile compounds 7a-7g and dissolve it in dichloromethane. Keep the condition of anhydrous and anaerobic, introduce N2, add BBr3 at low temperature, then carry out the reaction. After monitoring the completion of the reaction, add water to quench the reaction, then carry out extraction and washing, and dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify by silica gel column to obtain sulfonamide dienophile compounds, denoted as 8a-8g respectively;

[0046] S25. Synthesis of sulfonyl ester dienophile compound 8h;

[0047] Weigh 4-methoxyphenol and dissolve it in dichloromethane. Slowly add 2-chloroethanesulfonyl chloride at low temperature, slowly add pyridine dropwise after the reaction, then carry out the reaction; after monitoring the completion of the reaction, carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify by silica gel column to obtain sulfonyl ester dienophile compound, denoted as 8h.

[0048] As a preference of the technical solution of the present invention, the preparation of step S3 includes:

[0049] One of the obtained compound 3 and sulfonamide dienophile compounds 8a - 8g or sulfonyl ester dienophile compound 8h was added to anhydrous tetrahydrofuran, and then the reaction was carried out; after monitoring the completion of the reaction, extraction was carried out, the obtained organic layer was dried, the solvent was removed under reduced pressure to obtain a crude product, and then it was purified by silica gel column to obtain oxabicyclo-[2.2.1]-heptene compounds containing different functional side chain structures, denoted as 9a - 9h respectively.

[0050] Preferably, the preparation of step S4 includes:

[0051] Weigh one of the diol compounds 10a - 10i, add it to a reactor containing dichloromethane, then add p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine, and carry out the reaction at room temperature under light-shielded conditions. After monitoring the completion of the reaction, extraction was carried out, the obtained organic layer was dried, the solvent was removed under reduced pressure to obtain a crude product, and then it was purified by silica gel column to obtain diol compounds with p-toluenesulfonyl protecting groups, denoted as 11a - 11i respectively.

[0052] Preferably, the preparation of step S5 includes:

[0053] S51: Synthesis of oxabicyclo-[2.2.1]-heptene derivatives 9i - 9j containing an olefin side chain structure;

[0054] Weigh compound 9a, potassium hydroxide and tetrabutylammonium hydrogensulfate, add them to a single-necked flask, then add allyl bromide or 4-bromo-1-butene, DCM, and then carry out the reaction; after monitoring the completion of the reaction, extraction was carried out, the obtained organic layer was dried, the solvent was removed under reduced pressure to obtain a crude product, and then it was purified by silica gel column to obtain oxabicyclo-[2.2.1]-heptene derivatives containing an olefin side chain structure, denoted as 9i - 9j respectively;

[0055] S52: Synthesis of oxabicyclo-[2.2.1]-heptene derivatives 9k - 9m containing a hydroxypropionamide side chain structure;

[0056] Weigh compound 9g, one of trihydroxypropionic acid and its derivatives 11j - 11l, and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, add them to a single-necked flask, then add DMF, and then slowly dropwise add N,N-diisopropylethylamine, and carry out the reaction at room temperature; after monitoring the completion of the reaction, extraction was carried out, the obtained organic layer was dried, the solvent was removed under reduced pressure to obtain a crude product, and then it was purified by silica gel column to obtain oxabicyclo-[2.2.1]-heptene derivatives containing a hydroxypropionamide side chain structure, denoted as 9k - 9m respectively;

[0057] S53. Synthesis of Oxabicyclo-[2.2.1]heptene Macrolides 12a - 12s, 13a - 13f with Alkyl or Alkyl Ether Linkers Containing Benzyl Protecting Groups;

[0058] Weigh one of the compounds 9a - 9h and one of the compounds 11a - 11i, add them to a single - necked flask, then add potassium carbonate and DMF, and then carry out the reaction; after monitoring the completion of the reaction, carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography to obtain compounds 12a - 12s and 13a - 13f;

[0059] S54. Synthesis of Oxabicyclo-[2.2.1]heptene Macrolides 12t - 12u with Benzyl Protecting Groups and Olefin Linkers;

[0060] Weigh one of the compounds 9i - 9j, add it to a two - necked flask, then add benzylidene·[1,3 - bis(trimethylphenyl)-2 - imidazolinylidene]·dichloride·(tricyclohexylphosphine)ruthenium, then add DCM, keep the anhydrous and anaerobic condition and pass N2 to start the reaction; after the reaction is completed, carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography to obtain oxabicyclo-[2.2.1]heptene macrolides with benzyl protecting groups and olefin linkers, denoted as 12t - 12u respectively;

[0061] S55. Synthesis of Oxabicyclo-[2.2.1]heptene Macrolides 12v - 12x with Benzyl Protecting Groups and Propionamide Linkers;

[0062] Weigh one of the compounds 9k - 9m, add it to a single - necked flask, then add triphenylphosphine, diethyl azodicarboxylate and THF, and carry out the reaction at room temperature; after the reaction is completed, carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography to obtain oxabicyclo-[2.2.1]heptene macrolides with benzyl protecting groups and propionamide linkers, denoted as 12v - 12x respectively;

[0063] S56. Synthesis of Oxabicyclo-[2.2.1]heptene Macrolides 14a - 14x, 15a - 15f with Different Functional Linkers;

[0064] Weigh one of the compounds 12a - 12x or 13a - 13f, add it to a two - necked flask, then add dichloromethane, and then add BCl3 at ultra - low temperature, and then carry out the reaction; after monitoring that the reaction is complete, add water to quench the reaction, then carry out extraction, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column to obtain compounds 14a - 14x and 15a - 15f.

[0065] In a third aspect, the present invention also provides an anti - breast cancer drug composition, comprising the above - mentioned bridged - bicyclo[2.2.1]heptene - type estrogen receptor macrocyclic compounds with different linkers or their corresponding pharmaceutically acceptable salts, and pharmaceutically acceptable adjuvants.

[0066] In a fourth aspect, the present invention also provides the use of the above - mentioned bridged - bicyclo[2.2.1]heptene - type estrogen receptor macrocyclic compounds with different linkers, or the above - mentioned anti - breast cancer drug composition in the preparation of anti - breast cancer drugs.

[0067] In a fifth aspect, the present invention also provides a drug composition for degrading estrogen receptor, comprising the above - mentioned bridged - bicyclo[2.2.1] - heptene - type estrogen receptor macrocyclic compounds containing different functional side - chain structures and one or more pharmaceutically acceptable adjuvants.

[0068] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0069] The preparation method of the macrocyclic compound provided by the present invention, through the alkylation reaction of alcohol, uses different functional diol compounds containing p - toluenesulfonyl protecting groups and bridged - bicyclo[2.2.1] - heptene - type compounds containing different functional side - chain structures as raw materials, and only requires potassium carbonate and a small amount of DMF as a solvent, and the reaction can obtain a bridged - bicyclo[2.2.1] - heptene - type macrocyclic compound containing a benzyl protecting group.

[0070] For the macrocyclic compound provided by the present invention, in vitro experiments show that most of the novel bridged - bicyclo[2.2.1] - heptene (containing sulfonyl, sulfonamide) compounds have stronger inhibitory activity against MCF - 7 cells compared with the existing endocrine therapy drug tamoxifen, and also have good anti - proliferative activity against endocrine - resistant MCF - 7 mutant cells, and have good application prospects in the treatment of drug - resistant breast cancer. Detailed Embodiments

[0071] The features and advantages of the present invention can be further understood through the following detailed description. The following examples provided are only illustrative of the methods of the present invention and do not limit the rest of the content disclosed by the present invention in any way.

[0072] In the present invention, the English names, abbreviations or purchase information of some chemical substances are as follows:

[0073] Pyridine, Pyridine;

[0074] Dichloromethane, DCM;

[0075] Trifluoroacetic anhydride, Trifluoroacetic anhydride;

[0076] Acetic anhydride, Acetic anhydride;

[0077] Borane dimethyl sulfide complex, BH3·SMe3;

[0078] 2-Chloroethanesulfonyl chloride, 2-chloroethanesulfonyl chloride;

[0079] (Bromomethyl)cyclopropane, (bromomethyl)cyclopropane;

[0080] 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HATU, CAS No. 148893-10-1;

[0081] N,N-Diisopropylethylamine, DIPEA;

[0082] Benzylidene·[1,3-bis(trimethylphenyl)-2-imidazolinylidene]·dichloro·(tricyclohexylphosphine)ruthenium, the second-generation Grubbs catalyst, purchased from Bide Co., item number BD165627;

[0083] Triphenylphosphine, PPh3;

[0084] N,N-Dimethylformamide, DMF.

[0085] Unless otherwise specified, all chemical substances in the present invention are purchased through market channels. Among them, 3,4-bis(4-hydroxyphenyl)furan (i.e., compound 1) is prepared by the method disclosed in patent application CN109942595A, which is prior art.

[0086] In the present invention, an oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers as described above is provided, and its structural general formula is as follows:

[0087]

[0088] Among them, Linker is a methylene group with 2 to 6 carbon atoms, -(CH2)2-O-(CH2)2-, -CH2-C=C-CH2-, -(CH2)2-C=C-(CH2)2-, One of them;

[0089] X1 is O or N; wherein, when X1 is O, there is no R substituent; when X1 is N, R is one of the following;

[0090] X2 is O;

[0091] X3 is one of O or NH-C=O.

[0092] As an optimization and improvement of the above macromolecular compound structure, in some embodiments, it may also be a chemical substance with the following structural formula:

[0093]

[0094] Among them, Linker is one of a methylene group with 2 to 6 carbon atoms or a C2-O-C2 group.

[0095] As an example of the above structural formula, the macromolecular compound provided by the present invention may be:

[0096] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,9-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclononane-2 2 -ene-3,3-dioxide (No. 14a, named with the labels appearing below, the same hereinafter);

[0097] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,10-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane-2 2 -ene-3,3-dioxide (14b);

[0098] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,11-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocycloundecane-2 2 -ene-3,3-dioxide (14c);

[0099] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7,6,12 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocyclododecane - 2 2 - ene - 3,3 - dioxide (14d);

[0100] 2 3 -(4 - hydroxyphenyl)-4-(2,2,2 - trifluoroethyl)-2 7 ,6,9,12 - Tetraoxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1(1,4),5(1,3) - dibenzocyclododecane - 2 2 - ene - 3,3 - dioxide (14e);

[0101] 2 3 -(4 - hydroxyphenyl)-4-(2,2,2 - trifluoroethyl)-2 7 ,6,13 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocyclotridecane - 2 2 - ene - 3,3 - dioxide (14f);

[0102] 4 - ethyl - 2 3 -(4 - hydroxyphenyl)-2 7 ,6,11 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocycloundecane - 2 2 - ene - 3,3 - dioxide (14g);

[0103] 4 - ethyl - 2 3 -(4 - hydroxyphenyl)-2 7 ,6,13 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocyclotridecane - 2 2 - ene - 3,3 - dioxide (14h);

[0104] 2 3 -(4 - hydroxyphenyl)-4 - isobutyl - 2 7 ,6,11 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocycloundecane - 2 2 - ene - 3,3 - dioxide (14i);

[0105] 2 3 -(4 - hydroxyphenyl)-4 - isobutyl - 2 7,6,13 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocyclotridecane - 2 2 - ene - 3,3 - dioxide (14j);

[0106] 4 - (Cyclopropylmethyl) - 2 3 - (4 - hydroxyphenyl) - 2 7 ,6,11 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocycloundecane - 2 2 - ene - 3,3 - dioxide (14k);

[0107] 4 - (Cyclopropylmethyl) - 2 3 - (4 - hydroxyphenyl) - 2 7 ,6,13 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocyclotridecane - 2 2 - ene - 3,3 - dioxide (14l);

[0108] 4 - Cyclohexyl - 2 3 - (4 - hydroxyphenyl) - 2 7 ,6,11 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocycloundecane - 2 2 - ene - 3,3 - dioxide (14m);

[0109] 4 - (Cyclopropylmethyl) - 2 3 - (4 - hydroxyphenyl) - 2 7 ,6,11 - Trioxa - 3 - thia - 4 - aza - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocycloundecane - 2 2 - ene - 3,3 - dioxide (14n);

[0110] 2 3 - (4 - hydroxyphenyl) - 2 7 ,4,6,11 - Tetraoxa - 3 - thia - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocycloundecane - 2 2 - ene - 3,3 - dioxide (14o);

[0111] 2 3 - (4 - hydroxyphenyl) - 2 7 ,4,6,13 - Tetraoxa - 3 - thia - 2(2,6) - bicyclo[2.2.1]heptane - 1,5(1,4) - dibenzocyclotridecane - 22 -ene-3,3-dioxide (14p);

[0112] 2 3 -(4-hydroxyphenyl)-8,8-dimethyl-4-(2,2,2-trifluoroethyl)-2 7 ,6,10-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane-2 2 -ene-3,3-dioxide (14q);

[0113] 8,8-difluoro-23-(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-27,6,10-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane-2 2 -ene-3,3-dioxide (14r);

[0114] 3'-(4-hydroxyphenyl)-4'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,8'-2 7 ,6,10-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane]-2'-ene-3',3'-dioxide (14s);

[0115] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,11-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocycloundecane-2 2 ,8-diene-3,3-dioxide (14t);

[0116] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,13-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclotridecane-2 2 ,9-diene-3,3-dioxide (14u);

[0117] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,10-dioxa-3-thia-4,6-diaza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane-2 2-ene-7-one-3,3-dioxide (14v);

[0118] 2 3 -(4-hydroxyphenyl)-8,8-dimethyl-4-(2,2,2-trifluoroethyl)-2 7 ,10-dioxa-3-thia-4,6-diaza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane-2 2 -ene-7-one-3,3-dioxide (14w);

[0119] 3'-(4-hydroxyphenyl)-4'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,8'-2,10-dioxa-3-thia-4,6-diaza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane]-2'-ene-7'-one-3',3'-dioxide (14x);

[0120] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,9-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzononacyclane-2 2 -ene-3,3-dioxide (15a);

[0121] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,10-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzodecacyclane-2 2 -ene-3,3-dioxide (15b);

[0122] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,11-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzocycloundecane-2 2 -ene-3,3-dioxide (15c);

[0123] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,12-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzododecacyclane-22 -ene-3,3-dioxide (15d);

[0124] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,9,12-tetraoxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzacyclododecene-2 2 -ene-3,3-dioxide (15e);

[0125] 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,13-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzatridecene-2 2 -ene-3,3-dioxide (15f).

[0126] Of course, the present invention also provides a method for preparing the above-mentioned oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compounds with different linkers, including the following steps:

[0127] S1. Synthesis of 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol;

[0128] Carried out according to the following reaction process:

[0129]

[0130] S2. Synthesis of vinylsulfonamide derivatives;

[0131] Carried out according to the following reaction process:

[0132]

[0133] S3. Synthesis of oxygen-bridged bicyclo-[2.2.1]-heptene compounds 9a - 9f with different functional side chain structures;

[0134] Carried out according to the following reaction process:

[0135]

[0136] S4. Synthesis of different functional diol compounds 11a - 11f with p-toluenesulfonyl protecting groups; carried out according to the following reaction process:

[0137]

[0138] S5. Synthesis of bicyclo-[2.2.1]heptene macrocyclic compounds containing different functional linkers;

[0139] The process is carried out as follows:

[0140]

[0141]

[0142]

[0143] In the above preparation process, first, a synthesis method of bicyclo-[2.2.1]heptene macrocyclic compounds containing different functional linkers is provided. The precursors of such target compounds are obtained from the following two substrates: furan derivatives and vinyl sulfonyl esters or vinyl sulfonamide derivatives. They are used to prepare oxo-bridged bicycloheptene compounds, that is, the precursors of macrocyclic compounds, through the Diels - Alder reaction. This Diels - Alder reaction requires no solvent and no precious metal catalysis, and the reaction conditions are mild. Secondly, based on the above preparation method, the present invention also provides the synthesis steps for obtaining oxo-bridged bicycloheptene macrocyclic compounds from the above oxo-bridged bicycloheptene compounds through the alkylation reaction of alcohols, olefin metathesis reaction or Mitsunobu reaction. This step has low cost and mild reaction conditions. That is to say, the synthesis method of the macrocyclic compounds provided by the present invention mainly includes: 1) synthesizing the macrocyclic precursor; 2) converting the macrocyclic precursor into a macrocyclic compound through specific chemical reactions, and optimizing the structure of the macrocyclic compound to improve its stability and bioavailability.

[0144] In some embodiments, the preparation method of the oxo-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compounds with different linkers provided by the present invention includes the following steps (specifically defining key parameters such as reaction conditions and dosages):

[0145] S1. Synthesis of 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol: Weigh 1.0 eq. of 3,4-bis(4-hydroxyphenyl)furan (refer to patent document CN109942595A), 1.2 eq. of benzyl bromide, and 1.5 eq. of potassium carbonate, add them to a 500 mL round-bottom flask, then add 10 mL of DMF, and react at room temperature for 16 h. After monitoring the reaction to completion by TLC, perform extraction (using 3×25 mL of ethyl acetate and 3×25 mL of saturated ammonium chloride aqueous solution). Dry the obtained organic layer with Na2SO4, remove the solvent under reduced pressure to obtain a crude product, and purify it by silica gel column (petroleum ether / ethyl acetate = 4:1) to obtain 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol, denoted as compound 3.

[0146] S2. Synthesis of vinyl sulfonamide derivatives:

[0147] S21. Synthesis of N-phenylacetamide compounds 5a - 5e;

[0148] Weigh 1 eq. of one of p-methoxyaniline 4a, 3-methoxyaniline 4b, or tert-butyl (4-aminophenyl) carbamate 4c and 0.1 eq. of pyridine, add them to a 100 mL single-necked flask, and then add 40 mL of dichloromethane;

[0149] Mix 5 eq. of trifluoroacetic acid, acetic anhydride, or isobutyric anhydride with 10 mL of dichloromethane and place it in a constant-pressure dropping funnel. Slowly add it dropwise to the single-necked flask at 0 °C and react at room temperature for 10 h. After monitoring the reaction to completion by TLC, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water). Dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain N-phenylacetamide compounds, denoted as 5a - 5e respectively;

[0150] S22. Synthesis of N-alkyl aniline compounds 6a - 6d, 6f;

[0151] Weigh 1 eq. of N-phenylacetamide compounds 5a - 5e, add them to a 100 mL single-necked flask, then add 20 mL of anhydrous tetrahydrofuran to dissolve. Slowly add borane dimethyl sulfide complex dropwise at 0 °C, slowly warm up to 60 °C and react for 2 h. After monitoring the reaction to completion by TLC, add 5 mL of water to quench the reaction, then perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water). Dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure, and finally purify it by silica gel column (petroleum ether / ethyl acetate = 8:1) to obtain a white oil, namely N-alkyl aniline compounds, denoted as 6a - 6d, 6f respectively;

[0152] S23. Synthesis of sulfonamide dienophile compounds 6e, 7a - 7g;

[0153] Weigh 1 eq. of one of the compounds of N-alkyl aniline compounds 6a - 6d, 6f or p-methoxyaniline 4a, add it to a single-necked flask containing 30 mL of dichloromethane, slowly add 3 eq. of 2-chloroethanesulfonyl chloride at 0 °C, react for 20 min, then slowly add 0.5 eq. of pyridine dropwise, and then continue the reaction (room temperature, 24 h). After monitoring the reaction to completion by TLC, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water). Dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 5:1) to obtain sulfonamide dienophile compounds, denoted as 7a - 7d, 7g, 6e respectively;

[0154] Weigh 1 eq. of sulfonamide dienophile compound 6d and 3 eq. of potassium carbonate, add them to a single-necked flask, then add 5 mL of DMF, and subsequently add 1.5 eq. of bromomethylcyclopropane or bromocyclohexane. React at room temperature for 12 h. After monitoring the reaction to completion by TLC, perform extraction (3×25 mL of ethyl acetate and 3×25 mL of saturated ammonium chloride aqueous solution). Dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 4:1) to obtain the sulfonamide dienophile compound, denoted as 7e - 7f;

[0155] S24. Synthesis of sulfonamide dienophile compounds 8a - 8g;

[0156] Weigh one of 1 eq. of sulfonamide dienophile compounds 7a - 7g and dissolve it in 20 mL of dichloromethane. Keep the anhydrous and anaerobic condition and introduce N2. Add 3.0 eq. of BBr3 at -20 °C, and then react for 12 h. After monitoring the reaction to completion by TLC, add 10 mL of water to quench the reaction, then perform extraction with 3×20 mL of ethyl acetate and wash with saturated NaHCO3 solution. Dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 3:1) to obtain the sulfonamide dienophile compounds, denoted as 8a - 8g respectively;

[0157] S25. Synthesis of sulfonyl ester dienophile compound 8h;

[0158] Weigh 1 eq. of 4 - methoxyphenol and dissolve it in 30 mL of dichloromethane. Slowly add 3 eq. of 2 - chloroethanesulfonyl chloride at 0 °C. After reacting for 20 min, slowly dropwise add 0.5 eq. of pyridine, and then react at room temperature for 24 h; After monitoring the reaction to completion by TLC, perform extraction (3×25 mL of ethyl acetate and 3×25 mL of saturated ammonium chloride aqueous solution). Dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 4:1) to obtain the sulfonyl ester dienophile compound, denoted as 8f.

[0159] The reaction equations are as follows:

[0160]

[0161]

[0162] S3. Synthesis of oxabicyclo-[2.2.1]-heptene compounds 9a - 9h with different functional side chain structures: Add 1.1 eq. of the obtained compound 3 and 1 eq. of one of the sulfonamide dienophile compounds 8a - 8g or the sulfonyl ester dienophile compound 8h to 3 mL of anhydrous tetrahydrofuran, and then react at 90 °C for 12 h; after monitoring the reaction to completion by TLC, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and purify it by silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain oxabicyclo-[2.2.1]-heptene compounds with different functional side chain structures, denoted as 9a - 9h respectively.

[0163] The reaction equation is as follows:

[0164]

[0165] S4. Synthesis of diol compounds 11a - 11i with different functionalities and p-toluenesulfonyl protecting groups: Weigh 1.0 eq. of one of the diol compounds 10a - 10i, add it to a reactor containing 20 mL of dichloromethane, then add 4 eq. of p-toluenesulfonyl chloride, 10 eq. of triethylamine, and 0.2 eq. of 4-dimethylaminopyridine, and react at room temperature for 12 h under light-free conditions. After monitoring the reaction to completion by TLC, perform extraction, dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 3:1) to obtain diol compounds with p-toluenesulfonyl protecting groups, denoted as 11a - 11i respectively.

[0166] The reaction equation is as follows:

[0167]

[0168] S5. Synthesis of bicyclo-[2.2.1]heptene macrocyclic compounds with different functional linkers:

[0169] S51. Synthesis of oxabicyclo-[2.2.1]-heptene derivatives 9i - 9j with olefin side chain structures;

[0170] Weigh 1 eq. of compound 9a, 4 eq. of potassium hydroxide, and 0.1 eq. of tetrabutylammonium hydrogen sulfate, add them to a single-necked flask, then add 10 mL of allyl bromide or 4-bromo-1-butene and 1 mL of DCM, and then react at room temperature for 12 h; after monitoring the reaction to completion by TLC, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain oxygen-bridged bicyclo-[2.2.1]-heptene derivatives containing an olefin side chain structure, denoted as 9i - 9j respectively;

[0171] S52. Synthesis of oxygen-bridged bicyclo-[2.2.1]-heptene derivatives 9k - 9m containing a hydroxypropionamide side chain structure;

[0172] Weigh 1 eq. of compound 9g, one of 1.1 eq. of trihydroxypropionic acid and its derivatives 11j - 11l, and 1.1 eq. of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, add them to a single-necked flask, then add 2 mL of DMF, and then slowly dropwise add 3.5 eq. of N,N-diisopropylethylamine, and react at room temperature for 12 h; after monitoring the reaction to completion by TLC, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of saturated ammonium chloride aqueous solution), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 5:1:1) to obtain oxygen-bridged bicyclo-[2.2.1]-heptene derivatives containing a hydroxypropionamide side chain structure, denoted as 9k - 9m respectively;

[0173] S53. Synthesis of oxygen-bridged bicyclo-[2.2.1]heptene macrocycles 12a - 12l, 13a - 13f containing a benzyl-protected alkyl or alkyl ether linker;

[0174] Weigh one of 1 eq. of compounds 9a - 9f and one of 1.1 eq. of 11a - 11f, add them to a single-necked flask, then add 3 eq. of potassium carbonate and 2 mL of DMF, and then react at 95 °C for 4 h; after monitoring the reaction to completion by TLC, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of saturated ammonium chloride aqueous solution), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compounds 12a - 12s and 13a - 13f;

[0175] S54. Synthesis of oxygen-bridged bicyclo-[2.2.1]heptene macrocycles 12t - 12u containing a benzyl-protected group and an olefin linker;

[0176] Weigh one of the compounds 1.0 eq. of 9i - 9j, add it to a two-necked flask, then add 0.1 eq. of the second-generation Grubbs catalyst benzylidene·[1,3-bis(trimethylphenyl)-2-imidazolinylidene]·dichloride·(tricyclohexylphosphine)ruthenium, then add 2 mL of DCM, keep the anhydrous and anaerobic condition and introduce N2, react at 45 °C for 3 h; after the reaction is completed, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 4:1) to obtain the oxabicyclo-[2.2.1]heptene macrocyclic compounds containing benzyl protecting group and olefin linker, denoted as 12t - 12u respectively;

[0177] S55: Synthesis of oxabicyclo-[2.2.1]heptene macrocyclic compounds 12v - 12x containing benzyl protecting group and propionamide linker;

[0178] Weigh one of the compounds 1.0 eq. of 9k - 9m, add it to a single-necked flask, then add 1.5 eq. of triphenylphosphine, 1.5 eq. of diethyl azodicarboxylate and 2 mL of THF, react at room temperature for 5 h; after the reaction is completed, perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain the oxabicyclo-[2.2.1]heptene macrocyclic compounds containing benzyl protecting group and propionamide linker, denoted as 12v - 12x respectively;

[0179] S56: Synthesis of oxabicyclo-[2.2.1]heptene macrocyclic compounds 14a - 14x, 15a - 15f with different functional linkers;

[0180] Weigh one of the compounds 1.0 eq. of 12a - 12x or 13a - 13f, add it to a two-necked flask, then add 1 mL of DCM, add 2.0 eq of BCl3 at -78 °C, and then react for 15 min; when the reaction is monitored to be complete by TLC, add 10 mL of water to quench the reaction, then perform extraction (3 × 25 mL of ethyl acetate and 3 × 25 mL of water), dry the obtained organic layer with anhydrous Na2SO4, remove the solvent under reduced pressure to obtain the crude product, and then purify it by silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain compounds 14a - 14x and 15a - 15f.

[0181] The reaction equations are as follows:

[0182]

[0183]

[0184] It is understandable that, based on the above-prepared macrocyclic compound, the present invention can also react it with an acid to form a pharmaceutically acceptable salt. The acid can include inorganic acids or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0185] Certainly, the present invention also provides an anti-breast cancer drug composition, comprising the above-mentioned oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compounds with different linkers or their corresponding pharmaceutically acceptable salts, and pharmaceutically acceptable adjuvants. That is to say, the drug composition provided by the present invention can be a drug obtained by mixing the compound itself with pharmaceutically acceptable diluents, adjuvants and / or carriers, or can be a drug obtained by mixing a composition containing the compound of the present invention or its pharmaceutically acceptable salt, solvate, optical isomer or polymorph as one of the active ingredients with pharmaceutically acceptable diluents, adjuvants and / or carriers.

[0186] Certainly, it is understandable that in the preparation process of the above drug, the added excipients can be prepared according to general processes, and the obtained drug dosage forms include but are not limited to: tablets, capsules, oral liquid preparations, injections, granules or various sustained-release and controlled-release preparations, etc. The above-mentioned carriers are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents or matrices, etc.

[0187] Certainly, the present invention also provides an application of the above-mentioned oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compounds with different linkers, or the above anti-breast cancer drug composition in the preparation of anti-breast cancer drugs.

[0188] Certainly, the present invention also provides a drug composition for degrading estrogen receptor, comprising the above-mentioned oxygen-bridged bicyclo-[2.2.1]-heptene estrogen receptor macrocyclic compounds containing different functional side chain structures and one or more pharmaceutically acceptable adjuvants.

[0189] It should be particularly emphasized that the compounds prepared in the subsequent examples of the present invention are all prepared under the above specific process conditions. Of course, it is understandable that this does not constitute a limitation on the preparation process and protection scope of the present invention.

[0190] The following specific examples are used to further demonstrate the technical concept of the present invention.

[0191] Example 1

[0192] In this example, 2 3-(4-Hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,9-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclononane-2 2 -ene-3,3-dioxide (14a), whose structural formula is as follows:

[0193]

[0194] Prepared by the aforementioned method, namely compound 14a, with a yield of 23%.

[0195] The NMR data are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.51 (m, 2H), 7.35 (m, 4H), 6.87 (m, 2H), 6.83 (m, 2H), 6.77 (m, 2H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.54 (m, 2H), 4.26 (d, J = 9.0 Hz, 4H), 2.61 (s, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 160.53, 156.92, 156.56, 141.58, 136.73, 136.19, 133.29, 132.91, 131.40, 128.37, 124.88, 119.67, 118.61, 118.41, 117.35, 83.64, 81.96, 68.24, 62.05, 56.78, 36.58. HRMS (ESI) calcd for C 28 H 24 F3NO6S [M+Na]+, 582.1174; found 582.1174.

[0196] Example 2

[0197] In this example, 2 3 -(4-Hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,10-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclodecane-2 2 -ene-3,3-dioxide (14b), whose structural formula is as follows:

[0198]

[0199] Prepared by the aforementioned method, namely compound 14b, with a yield of 23%.

[0200] The NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.52(m,3H),7.35(m,5H),6.84(m,5H),6.77(m,3H),5.95(s,1H),5.14(d,J=1.1Hz,1H),4.94(d,J=0.9Hz,1H),4.67(s,1H),4.54(m,2H),4.18(d,J=3.1Hz,5H),2.61(s,1H),2.22(d,J=17.8Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ160.53,159.96,159.32,141.58,136.73,136.19,133.29,132.91,131.40,128.37,124.88,119.67,118.67,118.08,117.35,83.64,81.96,68.85,68.82,62.05,56.78,36.58,31.71.HRMS(ESI)calcd for C 29 H 26 F3NO6S[M+H]+,574.1511;found 574.1509。

[0201] Example 3

[0202] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,11-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocycloundecane-2 2 -ene-3,3-dioxide (14c) is provided, and its structural formula is as follows:

[0203]

[0204] Prepared by the aforementioned method, namely compound 14c, with a yield of 23%.

[0205] The NMR data are as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.52 (m, 2H), 7.35 (m, 4H), 6.84 (m, 4H), 6.77 (m, 2H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.54 (m, 2H), 4.07 (s, 3H), 2.61 (s, 1H), 2.28 (s, 1H), 1.93 (s, 2H). 13 13C NMR (125 MHz, Chloroform-d) δ 160.61, 160.53, 158.57, 141.58, 136.73, 136.19, 133.29, 132.91, 131.40, 128.37, 124.88, 119.67, 118.67, 117.94, 117.35, 83.64, 81.96, 73.40, 62.05, 56.78, 36.58, 27.18. HRMS (ESI) calcd for C 30 H 28 F3NO6S [M+Na]+, 610.1487; found 610.1487。

[0206] Example 4

[0207] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,12-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzocyclododecene-2 2 -ene 3,3-dioxide (14d) was provided, and its structural formula is as follows:

[0208]

[0209] It was prepared using the aforementioned method, namely compound 14d, with a yield of 17%.

[0210] The NMR data is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.52 (m, 2H), 7.35 (m, 4H), 6.84 (m, 4H), 6.77 (m, 2H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.54 (m, 2H), 4.07 (d, J = 4.8 Hz, 4H), 2.61 (s, 1H), 2.28 (s, 1H), 1.81 (d, J = 14.7 Hz, 2H), 1.76 (s, 1H). 13 13C NMR (125 MHz, Chloroform-d) δ 160.53, 160.46, 158.57, 141.58, 136.73, 136.19, 133.29, 132.91, 131.40, 128.37, 124.88, 119.67, 118.67, 117.94, 117.35, 83.64, 81.96, 70.59, 62.05, 56.78, 36.58, 28.03, 25.69. HRMS (ESI) calcd for C 31 H 20 F3NO6S [M+Na]+, 624.1644; found 624.1643.

[0211] Example 5

[0212] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,9,12-tetraoxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzoxacyclododec-2 2 -ene-3,3-dioxide (14e) was provided, and its structural formula is as follows:

[0213]

[0214] It was prepared by using the aforementioned method, that is, compound 14e, with a yield of 30%.

[0215] The NMR data are as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.51 (m, 2H), 7.35 (m, 4H), 6.86 (m, 4H), 6.77 (m, 2H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.54 (m, 2H), 4.16 (d, J = 2.0 Hz, 4H), 3.69 (d, J = 8.9 Hz, 4H), 2.61 (s, 1H). 13 13C NMR (125 MHz, Chloroform-d) δ 160.53, 158.58, 157.75, 141.58, 136.73, 136.19, 133.29, 132.91, 131.40, 128.37, 124.88, 119.67, 118.67, 118.40, 117.35, 83.64, 81.96, 70.36, 68.64, 68.54, 62.05, 56.78, 36.58. HRMS (ESI) calcd for C 30 H 28 F3NO7S [M+Na]+, 626.1436; found 626.1428。

[0216] Example 6

[0217] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,13-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzoxatridecane-2 2 -ene-3,3-dioxide (14f) was provided, and its structural formula is as follows:

[0218]

[0219] It was prepared using the aforementioned method, namely compound 14f, with a yield of 18%.

[0220] The NMR data is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.52 (m, 3H), 7.35 (m, 5H), 6.84 (m, 5H), 6.77 (m, 3H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.54 (m, 2H), 4.07 (d, J = 4.8 Hz, 5H), 2.61 (s, 1H), 2.28 (s, 1H), 1.84 (s, 2H), 1.78 (s, 2H), 1.65 (s, 2H). 13 13C NMR (125 MHz, Chloroform-d) δ 160.53, 160.46, 158.57, 141.58, 136.73, 136.19, 133.29, 132.91, 131.40, 128.37, 124.88, 119.67, 118.67, 117.94, 117.35, 83.64, 81.96, 70.75, 62.05, 56.78, 36.58, 28.25, 26.22. HRMS (ESI) calcd for C 32 H 32 F3NO6S [M+Na]+, 638.1800; found 638.1788。

[0221] Example 7

[0222] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,11-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1,5(1,4)-dibenzacycloundecane-2 2 ,8-diene-3,3-dioxide (14t) was provided, and its structural formula is as follows:

[0223]

[0224] It was prepared using the aforementioned method, namely compound 14m, with a yield of 18%.

[0225] The NMR data is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.51 (m, 2H), 7.35 (m, 4H), 6.95 (m, 2H), 6.87 (m, 2H), 6.77 (m, 2H), 5.95 (s, 1H), 5.90 (s, 2H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 1.0 Hz, 1H), 4.76 (dd, J = 14.5, 0.9 Hz, 4H), 4.67 (s, 1H), 4.54 (m, 2H), 2.61 (s, 1H). 13 13C NMR (125 MHz, Common NMR Solvents) δ 160.59, 160.53, 158.52, 141.58, 136.73, 136.19, 133.29, 132.91, 131.40, 128.37, 126.62, 124.88, 119.67, 118.95, 118.36, 117.35, 83.64, 81.96, 80.73, 79.66, 62.05, 56.78, 36.58. HRMS (ESI) calcd for C 32 H 32 F3NO6S [M+Na]+, 608.1331; found 608.1322.

[0226] Example 8

[0227] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-2 7 ,6,11-trioxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzacycloundec-2 2 -ene-3,3-dioxide (15c) was provided, and its structural formula is as follows:

[0228]

[0229] It was prepared using the aforementioned method, that is, compound 15c, with a yield of 20%.

[0230] The NMR data is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.52 (m, 2H), 7.34 (m, 2H), 7.25 (t, J = 7.5, 7.5 Hz, 1H), 7.08 (dt, J = 7.5, 2.0, 2.0 Hz, 1H), 6.80 (m, 5H), 6.52 (t, J = 2.0, 2.0 Hz, 1H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.61 (m, 2H), 4.12 (d, J = 1.8 Hz, 2H), 4.07 (s, 2H), 2.61 (s, 1H), 2.28 (s, 1H), 1.93 (s, 2H). 13 13C NMR (125 MHz, Chloroform-d) δ 160.61, 160.53, 159.17, 141.60, 141.58, 136.19, 133.29, 132.91, 131.89, 131.40, 128.37, 124.86, 118.78, 117.94, 117.35, 116.01, 106.88, 83.64, 81.96, 73.48, 73.40, 62.63, 56.84, 36.58, 27.18. HRMS (ESI) calcd for C 30 H 28 F3NO6S [M+Na]+, 610.1487; found 610.1478.

[0231] Example 9

[0232] In this example, 2 3 -(4-hydroxyphenyl)-4-(2,2,2-trifluoroethyl)-27,6,9,12-tetraoxa-3-thia-4-aza-2(2,6)-bicyclo[2.2.1]heptane-1(1,4),5(1,3)-dibenzoxacyclododecene-22-ene-3,3-dioxide (15e) was provided, and the structural formula is as follows:

[0233]

[0234] It was prepared by using the aforementioned method, that is, compound 15e, with a yield of 25%.

[0235] The NMR data are as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.51 (m, 2H), 7.34 (m, 2H), 7.25 (t, J = 7.5, 7.5 Hz, 1H), 7.08 (dt, J = 7.5, 2.0, 2.0 Hz, 1H), 6.87 (m, 2H), 6.78 (m, 3H), 6.52 (t, J = 2.0, 2.0 Hz, 1H), 5.95 (s, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 4.67 (s, 1H), 4.61 (m, 2H), 4.17 (m, 4H), 3.69 (d, J = 8.8 Hz, 4H), 2.61 (s, 1H). 13 13C NMR (125 MHz, Chloroform-d) δ 160.53, 159.74, 158.58, 141.58, 136.19, 133.29, 132.91, 131.89, 131.40, 128.37, 124.86, 118.78, 118.40, 117.35, 116.73, 106.54, 83.64, 81.96, 70.36, 70.30, 69.16, 68.54, 62.63, 56.84, 36.58. HRMS (ESI) calcd for C 30 H 28 F3NO7S [M+Na]+, 626.1436; found 626.1440。

[0236] Application Example

[0237] The anti-wild type and drug-resistant mutant breast cancer activities of the oxy-bridged bicyclo-[2.2.1]-heptene estrogen receptor macrocyclic compounds containing different functional linkers prepared in the above Examples 1-9 were determined. The wild type cell line used was MCF-7 cells, and the three drug-resistant mutant breast cancer cell lines were MCF-7 Y537S ,MCF-7 D538G ,MCF-7 EGFR The inhibitory activities (IC50, unit μM) were measured.

[0238] MCF-7 cells were cultured in phenol red-containing MEM liquid medium supplemented with 10% fetal bovine serum. When the cell density reached 80%-90%, the cells were digested and the cell suspension was plated into a 96-well cell culture plate with phenol red-free DMEM medium supplemented with 10% fetal bovine serum. After the cells were completely adherent, the original culture medium was discarded, and 100 μl of fresh compound solution prepared with phenol red-free MEM medium supplemented with 10% fetal bovine serum was added to each well. The compound concentration gradient was: 1×10 -7 M, 1×10 -6M, 1×10 -5 M, 5×10 -5 M, 1×10 -4 M. After culturing with the drug for 3 to 5 days, take out the culture plate, discard the drug-containing culture medium, add 100 μL of CCK8 working solution to each well, and incubate in the dark at 37 °C and 5% CO2 incubator for 1.5 hours. Read the plate on an enzyme-linked immunosorbent assay (ELISA) reader, select the wavelength at 450 nm as the main wavelength, analyze the experimental results, and calculate the IC50 using GraphPad Prism 8.0.

[0239] Table 1 lists the results of the inhibitory activity of the MCF-7 cell proliferation of the representative target compounds 14a-14f, 14m, 15c, and 15e synthesized in the present invention. Among them, Fulvestrant is fulvestrant, and 4-Hydroxytamoxifen is 4-hydroxytamoxifen.

[0240] Table 1

[0241]

[0242]

[0243] As can be seen from the results in Table 1, the bridged bicyclo-[2.2.1]-heptene estrogen receptor macrocyclic compounds containing different sulfonamide nitrogen atom substituents prepared in the present invention show 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; and the antiproliferative effect of the para-linker is better than that of the meta-linker.

[0244] The above examples are only illustrative of the present invention and do not constitute a limitation on the protection scope of the present invention. Any design identical or similar to the present invention falls within the protection scope of the present invention.

Claims

1. An oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound having different linkers, characterized in that: The general structure is as follows: Among them, Linker is a methylene group having 2 to 6 carbon atoms, -(CH2)2-O-(CH2)2-, -CH2-C=C-CH2-, -(CH2)2-C=C-(CH2)2-, One of these; X1 is O or N; when X1 is O, there is no R substituent; when X1 is N, R is One of these; X2 is 0; X3 is one of O and NH-C=O.

2. An oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound having different linkers, characterized in that: The structural formula is as follows: Wherein, Linker is one of a methylene group having 2 to 6 carbon atoms and a C2-O-C2 group.

3. A method for preparing the oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers as claimed in claim 1 or 2, characterized in that: The steps include: S1. Synthesis of 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol; S2. Synthesis of vinylsulfonamide derivatives; S3, Synthesis of oxygen-bridged bicyclo-[2.2.1]-heptene compounds containing different functional side chain structures; S4. Synthesis of diol compounds containing p-toluenesulfonyl protecting groups with different functionalities; S5. Synthesis of bicyclo-[2.2.1]heptene macrocyclic compounds containing different functional linkers.

4. The preparation method according to claim 3, characterized in that: The preparation of step S1 includes: weighing 3,4-di(4-hydroxy-phenyl)furan, benzyl bromide, and potassium carbonate, adding them into a round-bottom flask, then adding DMF, reacting at room temperature, monitoring the reaction to be complete, extracting, drying the obtained organic layer, and removing the solvent under reduced pressure to obtain a crude product, which is purified by a silica gel column to obtain 4-[4-(4-benzyloxyphenyl)furan-3-yl]phenol, recorded as compound 3.

5. The preparation method according to claim 4, characterized in that: The preparation of step S2 includes: S21, synthesis of N-phenylacetamide compounds 5a-5e; Weigh one of p-methoxyaniline 4a, 3-methoxyaniline 4b or tert-butyl (4-aminophenyl) carbamate 4c and pyridine, add them into a single-necked flask, and then add dichloromethane; Trifluoroacetic anhydride, acetic anhydride or isobutyric anhydride and dichloromethane are mixed and placed in a constant pressure dropping funnel, and slowly added dropwise to a single-necked flask at low temperature, and reacted at room temperature; after monitoring the completion of the reaction, extraction is performed, the obtained organic layer is dried, and the solvent is removed under reduced pressure to obtain N-phenylacetamide compounds, which are respectively recorded as 5a-5e; S22, synthesis of N-alkylaniline compounds 6a-6d, 6f; Weigh N-phenylacetamide compounds 5a-5e, add them into a single-necked flask, then add anhydrous tetrahydrofuran to dissolve, slowly dropwise add borane dimethyl sulfide complex at low temperature, slowly increase the temperature to react, monitor the reaction completion, add water to quench the reaction, then extract, dry the obtained organic layer, remove the solvent under reduced pressure, and finally purify with a silica gel column to obtain a white oil, i.e., N-alkylaniline compounds, which are respectively recorded as 6a-6d and 6f; S23, synthesis of sulfonamide dienophile compounds 6e, 7a-7g; Weigh one of the N-alkylaniline compounds 6a-6d, 6f or p-methoxyaniline 4a, add it into a single-necked flask filled with dichloromethane, slowly add 2-chloroethanesulfonyl chloride at low temperature, slowly add pyridine dropwise after the reaction, and then react. After monitoring the completion of the reaction, extract the obtained organic layer, dry it, remove the solvent under reduced pressure to obtain a crude product, and then purify it with a silica gel column to obtain sulfonamide dienophile compounds, which are respectively recorded as 7a-7d, 7g, and 6e; Weigh the sulfonamide dienophile compound 6e and potassium carbonate, add them into a single-necked flask, then add DMF, then add bromomethylcyclopropane or bromocyclohexane, react at room temperature, monitor the reaction completion, extract, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it on a silica gel column to obtain a sulfonamide dienophile compound, recorded as 7e-7f; S24, synthesis of sulfonamide dienophile compounds 8a-8g; Weigh one of the sulfonamide dienophile compounds 7a-7g and dissolve it in dichloromethane, introduce N2 under anhydrous and oxygen-free conditions, add BBr3 at low temperature, and then react. After monitoring the reaction completion, add water to quench the reaction, then extract and wash, and dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it through a silica gel column to obtain sulfonamide dienophile compounds, which are respectively recorded as 8a-8g; S25, synthesis of sulfonyl ester dienophile compound 8h; Weigh 4-methoxyphenol and dissolve it in dichloromethane. Slowly add 2-chloroethanesulfonyl chloride at low temperature. After the reaction, slowly add pyridine dropwise and then react. After monitoring the completion of the reaction, extract the obtained organic layer, dry the organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it on a silica gel column to obtain a sulfonyl ester dienophile compound, which is recorded as 8h.

6. The preparation method according to claim 5, characterized in that: The preparation of step S3 includes: The obtained compound 3 and one of the sulfonamide dienophile compounds 8a-8g or the sulfonyl ester dienophile compound 8h are added to anhydrous tetrahydrofuran, followed by a reaction; after monitoring the completion of the reaction, extraction is performed, the obtained organic layer is dried, and the solvent is removed under reduced pressure to obtain a crude product, which is purified by a silica gel column to obtain oxygen-bridged bicyclo-[2.2.1]-heptene compounds containing different functional side chain structures, which are respectively recorded as 9a-9h.

7. The preparation method according to claim 6, characterized in that: The preparation of step S4 includes: Weigh one of the diol compounds 10a-10i, add it to a reactor filled with dichloromethane, then add p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine, react at room temperature under light-proof conditions, monitor the reaction completion, extract, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it on a silica gel column to obtain a diol compound with a p-toluenesulfonyl protecting group, which are respectively denoted as 11a-11i; The reaction equation is as follows:

8. The preparation method according to claim 7, characterized in that: The preparation of step S5 comprises: S51, synthesis of oxygen-bridged bicyclo-[2.2.1]-heptene derivatives 9i-9j containing olefin side chain structures; Weigh compound 9a, potassium hydroxide and tetrabutylammonium hydrogen sulfate, add them into a single-necked flask, then add allyl bromide or 4-bromo-1-butene and dichloromethane, and then react; when the reaction is monitored to be complete, extract, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it with a silica gel column to obtain oxygen-bridged bicyclo-[2.2.1]-heptene derivative compounds containing olefin side chain structures, which are respectively recorded as 9i-9j; S52, synthesis of oxygen-bridged bicyclo-[2.2.1]-heptene derivatives 9k-9m containing hydroxypropionamide side chain structure; Weigh compound 9g, trihydroxypropionic acid and one of its derivatives 11j-111, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, add them into a single-necked flask, then add DMF, and then slowly drop N,N-diisopropylethylamine, and react at room temperature; when the reaction is monitored to be complete, extract the obtained organic layer, dry it, and remove the solvent under reduced pressure to obtain a crude product, which is then purified by a silica gel column to obtain oxygen-bridged bicyclo-[2.2.1]-heptene derivative compounds containing a hydroxypropionamide side chain structure, which are respectively denoted as 9k-9m; S53, synthesis of oxygen-bridged bicyclo-[2.2.1]heptene macrocyclic compounds 12a-12s, 13a-13f with alkyl or alkyl ether linkers containing benzyl protecting groups; Weigh one of the compounds 9a-9h and one of the compounds 11a-11i, add them to a single-necked flask, then add potassium carbonate and DMF, and then react; when the reaction is monitored to be complete, extract, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it on a silica gel column to obtain compounds 12a-12s and 13a-13f; S54, synthesis of oxygen-bridged bicyclo-[2.2.1]heptene macrocyclic compounds 12t-12u containing a benzyl protecting group and an olefin linker; Weigh one of the compounds 9i-9j, add it to a two-necked flask, then add benzylene [1,3-bis (trimethylphenyl) -2-imidazolinylidene] dichloro (tricyclohexylphosphine) ruthenium, then add DCM, maintain anhydrous and oxygen-free conditions, introduce N2, and start the reaction; after the reaction, extract, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it on a silica gel column to obtain oxygen-bridged bicyclo-[2.2.1] heptene macrocyclic compounds containing a benzyl protecting group and an olefin linker, which are respectively recorded as 12t-12u; S55, synthesis of oxygen-bridged bicyclo-[2.2.1]heptene macrocyclic compounds 12v-12x containing a benzyl protecting group and a propionamide linker; Weigh one of the compounds 9k-9m, add it to a single-necked flask, then add triphenylphosphine, diethyl azodicarboxylate and THF, and react at room temperature; after the reaction, extract, dry the obtained organic layer, remove the solvent under reduced pressure to obtain a crude product, and then purify it on a silica gel column to obtain an oxygen-bridged bicyclo-[2.2.1]heptene macrocyclic compound containing a benzyl protecting group and a propionamide linker, which are respectively recorded as 12v-12x; S56, synthesis of oxygen-bridged bicyclo-[2.2.1]heptene macrocyclic compounds 14a-14x, 15a-15f with different functional linkers; Weigh one of the compounds 12a-12x or 13a-13f, add it to a two-necked flask, then add DCM, and then add BCl3 at ultra-low temperature, and then react; when the reaction is monitored to be complete, add water to quench the reaction, followed by extraction, dry the obtained organic layer, and remove the solvent under reduced pressure to obtain a crude product, which is then purified by a silica gel column to obtain compounds 14a-14x and 15a-15f.

9. An anti-breast cancer pharmaceutical composition, characterized in that: The invention comprises the oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers as claimed in claim 1 or 2 or its corresponding pharmaceutically acceptable salt, and a pharmaceutically acceptable auxiliary agent.

10. Use of the oxygen-bridged bicyclo-[2.2.1]heptene estrogen receptor macrocyclic compound with different linkers as claimed in claim 1 or 2, or the anti-breast cancer drug composition as claimed in claim 9 in the preparation of anti-breast cancer drugs.

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