Estrogen receptor degraders, methods of making and using the same

Abstract

The application discloses a kind of compounds or its pharmaceutically acceptable salt as estrogen receptor degrader and purposes thereof.The compound can be used for treating diseases related to estrogen receptor, especially can be used for treating breast cancer, and can effectively inhibit the proliferation of breast cancer cells.

Description

Technical Field

[0001] This invention relates to a class of compounds that act as estrogen receptor degraders or pharmaceutically acceptable salts thereof, and their use as selective estrogen receptor degraders (SERDs) in the prevention or treatment of related diseases. Background Technology

[0002] Breast cancer, often called the "pink killer," is the leading cause of cancer death among women. Globally, 2.26 million new cases of breast cancer are diagnosed each year, accounting for approximately 11.7% of all newly diagnosed cancers and 24.5% of newly diagnosed cancers in women. Meanwhile, more than 680,000 women die from breast cancer, representing about 6.9% of all cancer deaths and 15.5% of all cancer deaths among women worldwide, making it the leading cause of cancer death among women globally.

[0003] Estrogen (E2) and estrogen α receptor (ERα) are important drivers of breast cancer development and progression. More than two-thirds of breast cancer patients express the estrogen receptor (ER) transcription factor, and ER remains a key driver in most ER-positive patients, even in tumors that have progressed after early endocrine therapy. Therefore, ER is a major target for breast cancer treatment (Pharmacology & Therapeutics 186(2018)1-24). Endocrine therapy plays a crucial role in the treatment of estrogen receptor-positive breast cancer patients. Endocrine therapy is mainly divided into three categories. The first category is aromatase inhibitors (AIs), which inhibit the conversion of androgens into estrogens, thus lowering estrogen levels in the body. The second category is selective estrogen receptor modulators (SERMs), which antagonize the activity of estrogen receptors. The third category is selective estrogen receptor degraders (SERDs), which are small molecules that bind to estrogen receptors and cause their degradation; they not only antagonize estrogen receptor activity but also promote receptor degradation. Although endocrine therapy is the first-line treatment for estrogen receptor-positive breast cancer, approximately 30% of patients receiving adjuvant therapy experience recurrence, and almost all patients with metastatic breast cancer develop resistance and progress.

[0004] Studies have shown that SERDs are particularly effective in treating cancers resistant to tamoxifen and / or aromatase inhibitors (McDonnell et al., J. Med. Chem. 2015, 58:4883-4887). Currently, fulvestrant is the only approved SERD drug for the treatment of estrogen receptor-positive breast cancer. However, fulvestrant has poor drug properties and is metabolized too quickly in vivo. Although it can completely degrade estrogen receptors in in vitro studies, it cannot fully exert its estrogen receptor-degrading effect in vivo. Furthermore, fulvestrant has low oral bioavailability, making clinical use inconvenient. Therefore, it is crucial to develop a SERD drug with good efficacy, high bioavailability, few side effects, and convenient oral administration for the treatment of breast cancer and other estrogen receptor-related diseases. Summary of the Invention

[0005] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0006]

[0007] in,

[0008] X is independently selected from -O-, -SO-, or -SO2-;

[0009] m and n are independently selected from 0, 1, 2, 3 or 4;

[0010] R1 is independently selected from hydrogen, halogen, or -CH2OH;

[0011] R2 and R3 may be the same or different, and each is independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0012] R4 is independently selected from hydrogen, halogen, substituted or unsubstituted C. 1-10 Alkyl groups, whether straight-chain or branched.

[0013] In one embodiment of the compound of formula (I), R1 is selected from halogen or -CH2OH; preferably, R1 is F or -CH2OH.

[0014] In one embodiment of the compound of formula (I), R2 and R3 are each independently selected from halogens or C. 1-4 Alkyl group; preferably, R2 and R3 are each independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, butyl, isobutyl or sec-butyl; more preferably, R2 and R3 are both F.

[0015] In one embodiment of the compound of formula (I), R4 is independently selected from C4 substituted with a halogen. 1-10 Straight-chain or branched alkyl group; preferably, R4 is independently selected from C4 substituted with halogen. 1-6A straight-chain or branched alkyl group. Further, R4 is selected from -CF2CF3, -CF2CHF2, -CF2CH2F, -CF2CH3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CHFCH3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CCl2CCl3, -CBr2CBr3 or -CI2CI3; more preferably, R4 is -CF2CF3.

[0016] In one embodiment of the compound of formula (I), m and n are each independently selected from 2 or 3.

[0017] In one embodiment of the compound of formula (I), X is selected from -SO- or -SO2-; preferably -SO2-.

[0018] In one embodiment of the compound of formula (I),

[0019] X is independently selected from -O-, -SO-, or -SO2-;

[0020] m and n are each independently selected from 0, 1, 2, 3 or 4;

[0021] R1 is independently selected from halogens or -CH2OH; R2 and R3 may be the same or different, and are each independently selected from halogens.

[0022] R4 is independently selected from C4 substituted with halogen. 1-10 Straight-chain or branched alkyl groups;

[0023] The preferred halogen is F.

[0024] In one embodiment of the compound of formula (I),

[0025] X is independently selected from -SO- or -SO2-;

[0026] m and n are each independently selected from 2 or 3;

[0027] R1 is independently selected from hydrogen, halogen, or -CH2OH;

[0028] R2 and R3 may be the same or different, and each is independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0029] R4 is independently selected from hydrogen, halogen, substituted or unsubstituted C. 1-10 Alkyl groups, whether straight-chain or branched.

[0030] In one embodiment of the compound of formula (I),

[0031] X is independently selected from -SO- or -SO2-;

[0032] m and n are each independently selected from 2 or 3;

[0033] R1 is independently selected from halogens or -CH2OH; R2 and R3 may be the same or different, and are each independently selected from halogens.

[0034] R4 is independently selected from C4 substituted with halogen. 1-10 Straight-chain or branched alkyl groups;

[0035] The preferred halogen is F.

[0036] In one embodiment of the compound of formula (I),

[0037] X is independently selected from -O-, -SO-, or -SO2-;

[0038] m and n are each independently selected from 2 or 3;

[0039] R1 is independently selected from F, Cl, Br, I or -CH2OH;

[0040] R2 is independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, butyl, isobutyl or sec-butyl;

[0041] R3 is independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, butyl, isobutyl or sec-butyl;

[0042] R4 is independently selected from -CF2CF3, -CF2CHF2, -CF2CH2F, -CF2CH3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CHFCH3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CCl2CCl3, -CBr2CBr3, -CI2CI3.

[0043] In one embodiment of the compound of formula (I),

[0044] X is independently selected from -O-, -SO-, or -SO2-; m and n are each independently selected from 0, 1, 2, 3, or 4;

[0045] R1 can be independently selected as a halogen or -CH2OH, preferably F or -CH2OH;

[0046] R2 and R3 are both F; R4 is -CF2CF3.

[0047] In one embodiment of the compound of formula (I),

[0048] X is independently selected from -SO- or -SO2-; m and n are each independently selected from 2 or 3;

[0049] R1 is independently selected as a halogen or -CH2OH, preferably F or -CH2OH; R2 and R3 are both F;

[0050] R4 is independently selected from halogen-substituted methyl, ethyl, or propyl groups, preferably CF2CF3.

[0051] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0052]

[0053] In one aspect, the present invention provides a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The carrier includes excipients conventional in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents.

[0054] The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, nasal sprays, transdermal patches, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally, via mucosal routes, rectally, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal routes). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type.

[0055] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The appropriate daily dose for human or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0056] In one aspect, the present invention provides the use of any of the above-described compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to estrogen receptors.

[0057] Furthermore, the present invention provides the use of any of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of tumor diseases; wherein the tumor is preferably breast cancer.

[0058] Furthermore, the present invention provides any of the above-mentioned compounds or their pharmaceutically acceptable salts, or their pharmaceutical compositions, as selective estrogen receptor degraders with good degradation activity against ERα, and can effectively inhibit the proliferation of breast cancer cells.

[0059] Definitions and Explanations

[0060] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0061] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0062] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, having specific substituents. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or acid addition salt.

[0063] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0064] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0065] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0066] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0067] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient, including but not limited to: adhesives, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0068] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0069] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of an additional unlabeled reagent.

[0070] The terms "optional" or "optionally" refer to events or conditions described subsequently that may occur but are not required, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur. For example, "optionally substituted with one or more deuterium atoms" means that the group may be unsubstituted with deuterium atoms or substituted with one or more deuterium atoms, i.e., it includes cases where the group is unsubstituted, partially substituted, and / or fully substituted with deuterium.

[0071] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups.

[0072] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C6 indicates 1 to 6 carbons, C 1-10 Selected from C1, C2, C3, C4, C5, and C6.

[0073] Unless otherwise specified, the term "halogen" itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl straight-chain or branched alkyl groups. For example, the term "halo(C1-C6)alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, etc. Unless otherwise specified, examples of haloalkyl groups include, but are not limited to, 5,5,5-trifluoropentyl and 4,4-difluoro-5,5,5-trifluoropentyl.

[0074] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0075] The present invention will be further illustrated below with reference to specific embodiments and test examples, but this does not limit the scope of the invention in any way.

[0076] Example 1: Synthesis of Compound A

[0077]

[0078] Step 1: Synthesis of Compound 2

[0079]

[0080] Compound 1 (6.0 g, 28.47 mmol, 1.0 eq), 5,5-difluoro-1,3,2-dioxoethyl 2,2-dioxide (4.9 g, 28.47 mmol, 1.0 eq), and K₂CO₃ (7.8 g, 56.94 mmol, 2.0 eq) were stirred in ACN (100 mL) at 80 °C for 6 h. The mixture was cooled to room temperature and filtered. TsOH (9.8 g, 56.94 mmol, 2.0 eq) and water (100 mL) were added to the filtrate. The mixture was stirred overnight at 80 °C. After cooling to room temperature, the pH was adjusted to ~9 with Na₂CO₃ solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and concentrated to give intermediate 2 (7.7 g, yellow oil).

[0081] Step 2: Synthesis of Compound 3

[0082]

[0083] Intermediate 2 (3.8 g, 14.16 mmol, 1.0 eq) was mixed with 4-bromo-2,6-difluorobenzaldehyde (2.5 g, 14.16 mmol, 1.0 eq) in toluene (50 mL) and AcOH (6 mL) and stirred at 90 °C for 4 h. The mixture was concentrated, and the residue was purified by column chromatography (EA / PE = 0-20%) to give intermediate 3 (4.5 g, yellow solid) in 67% yield. 1 H NMR (400MHz, DMSO) δ10.60(s,1H),7.41(d,J=8.6Hz,3H),7.19(d,J=8.0Hz,1H),7.04-6.93(m,2H),5.30(t,J=6.1Hz,1H),5.21(s,1H),3.69-3.55( m,1H),3.50-3.36(m,2H),3.17(q,J=15.3Hz,1H),2.89(dd,J=4.2,15.3Hz ,1H),2.66-2.56(m,2H),1.08(d,J=6.6Hz,3H); MSm / z(ESI): 471.1[M+1].

[0084] Step 3: Synthesis of Compound 4

[0085]

[0086] Intermediate 3 (5.0 g, 10.61 mmol, 1.0 eq), 1-tert-butoxycarbonyl-3-aminocyclobutane (2.2 g, 12.73 mmol, 1.2 eq), Cs₂CO₃ (10.3 g, 31.83 mmol, 3.0 eq), Pd₂(dba)₃ (972 mg, 1.06 mmol, 0.1 eq), and Xantphos (1.2 g, 2.12 mmol, 0.2 eq) were dissolved in dioxane (50 mL) and stirred at 110 °C under N₂ protection for 2 h. The mixture was concentrated and purified by column chromatography (EA / PE = 0–25%) to give intermediate 4 (5.4 g, yellow solid) in 90% yield.

[0087] Step 4: Synthesis of Compound 5

[0088]

[0089] To a 60 mL solution of dioxane containing intermediate 4 (5.4 g, 19.59 mmol, 1.0 eq), 9.3 g (95.9 mmol, 10 eq) of H₂SO₄ at 0 °C was added, and the mixture was stirred at room temperature for 1 h. An aqueous solution of NaHCO₃ (1.0 M) was added to the mixture to bring the pH to approximately 9. The mixture was extracted with ethyl acetate, washed with brine, dried over Na₂SO₄, and concentrated to give intermediate 5 (4.4 g, yellow solid).

[0090] Step 5: Synthesis of Compound 6

[0091]

[0092] A mixture of intermediate 5 (3.0 g, 6.49 mmol, 1.0 eq), (2-bromoethyl-4,4,5,5,5-pentafluoropentyl) sulfone (1.9 g, 6.49 mmol, 1.0 eq), and K₂CO₃ (1.8 g, 12.98 mmol, 2.0 eq) in ACN (40 mL) was stirred overnight at room temperature. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid column chromatography (EA / PE = 0–9%) to give intermediate 6 (1.1 g, yellow solid) in 25% yield.

[0093] Step 6: Synthesis of Compound 7

[0094]

[0095] To a THF (20 mL) solution of intermediate 6 (900 mg, 1.32 mmol, 1.0 eq) and imidazole (269 mg, 3.96 mmol, 3.0 eq), TBSCl (398 mg, 2.64 mmol, 2.0 eq) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by column chromatography (EA / PE = 0–50%) to give intermediate 7 (600 mg, yellow solid) in 57% yield.

[0096] Step 7: Synthesis of Compound 8

[0097]

[0098] H₂O₂ (255 mg, 7.55 mmol, 10.0 eq) was added to an EA / AcOH (5 mL / 1 mL) solution of intermediate 7 (600 mg, 0.75 mmol, 1.0 eq). The mixture was stirred at room temperature for 7 h. NaHCO₃ aqueous solution was added, followed by EA (50 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (MeOH / DCM = 0-5%) to give intermediate 8 (270 mg, yellow solid) in 44% yield.

[0099] Step 8: Synthesis of Compound A

[0100]

[0101] TBAF (173 mg, 0.66 mmol, 2.0 eq) was added to a THF (10 mL) solution of intermediate 8 (270 mg, 0.33 mmol, 1.0 eq). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with NH4Cl / NaCl (1 / 1, 30 mL × 3). The organic layer was dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (MeOH / DCM = 0-5%) to give compound A (160 mg, yellow solid) in a yield of 69%. 1H NMR (400MHz, DMSO-d6): δ10.51(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H), 7.00-6.91(m,2H),6.71(d,J=6.8Hz,1H),6.10(d,J=12.4Hz,2H),5.25-5.22(m,1H),5 .05(s,1H),3.97-3.95(m,1H),3.67-3.63(m,3H),3.45-3.35(m,2H),3.14-3.06(m,1H ),2.89-2.60(m,11H),2.49-2.32(m,2H),1.95-1.87(m,2H),1.06(d,J=6.4Hz,3H).MS m / z(ESI): 699.1[M+1].

[0102] Example 2: Synthesis of Compound B

[0103]

[0104] Compound B was prepared in a manner similar to that used in Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),7.38(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H ),7.01-6.92(m,2H),6.73(d,J=6.8Hz,1H),6.11(d,J=12.4Hz,2H),5.11(s,1H),3 .97-3.94(m,1H),3.68-3.65(m,2H),3.44-3.37(m,2H),3.95-2.55(m,11H),2.49 -2.32(m,2H),1.95-1.89(m,2H),1.11(d,J=6.4Hz,3H).MSm / z(ESI): 687.2[M+1].

[0105] Example 3: Synthesis of Compound C

[0106]

[0107] Compound C was prepared in a manner similar to that in Example 1. 1H NMR:(400MHz,DMSO-d6)δ10.57(br s,1H),7.38(d,J=7.6Hz,1H),7.19(d,J=7.9Hz,1H),7.04-6.92(m,2H),6.77-6.68(m ,1H),6.18-6.07(m,2H),5.11(s,1H),4.00-3.89(m,1H),3.69-3.61(m,2H),3.50-3. 38(m,3H),3.00-2.71(m,8H),2.69-2.64(m,1H),2.59-2.54(m,1H),2.46-2.42(m,1H ),2.43-2.25(m,1H),1.97-1.85(m,2H),1.72-1.59(m,2H),1.11(d,J=6.6Hz,3H).MS m / z(ESI): 701.2[M+1].

[0108] Example 4: Synthesis of Compound D

[0109]

[0110] Step 1: Synthesis of Compound 10

[0111]

[0112] TEA (17.0 g, 168 mmol, 23.4 mL, 1.5 eq) was added to a DCM (200 mL) solution of compound 9 (20.0 g, 112 mmol, 1.0 eq). TosCl (25.6 g, 134 mmol, 1.2 eq) was added. The mixture was stirred at 25 °C for 12 h. TLC showed that compound 9 reacted completely. The reaction mixture was quenched with H2O (200 mL) and then extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with aqueous solution. The organic phase was washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give intermediate 10 (31.0 g, colorless oil).

[0113] Step 2: Synthesis of Compound 11

[0114]

[0115] Potassium thioacetate (10.5 g, 92.5 mmol, 2.12 eq) was added to an acetone (150 mL) solution of compound 10 (14.5 g, 43.6 mmol, 1.0 eq). The mixture was stirred at 60 °C for 10 h. TLC (petroleum ether: ethyl acetate = 20:1) showed that compound 10 was completely consumed. The reaction mixture was quenched with H₂O (150 mL) and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with aqueous solution and then with saturated brine (100 mL). The mixture was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give intermediate 11 (4.20 g, yellow oil).

[0116] Step 3: Synthesis of Compound 12

[0117]

[0118] NaOMe (1.44 g, 26.6 mmol, 1.5 eq) was added to a mixture of 1-bromo-3-chloropropane (4.20 g, 26.6 mmol, 2.62 mL, 1.5 eq) and MeOH (8.00 mL) under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for 30 min. Compound 11 (4.20 g, 17.7 mmol, 1.0 eq) was added under nitrogen. The mixture was stirred at 20 °C for 2 h. TLC (petroleum ether: ethyl acetate = 20:1) showed that compound 11 was completely consumed. The reaction mixture was quenched with H2O (10 mL) and then extracted with DCM (10 mL x 3). The combined organic layers were washed with aqueous solution, then the organic phase was washed with saturated brine (100 mL), dried with Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give compound 12 (1.50 g, yellow oil).

[0119] Step 4: Synthesis of Compound 13

[0120]

[0121] H₂O₂ (4.76 g, 41.9 mmol, 4.03 mL, 30.0% purity, 16.2 eq) was added dropwise to a mixture of compound 12 (700 mg, 2.59 mmol, 1.0 eq) and acetic acid (5 mL) at 50 °C. The reaction mixture was heated to 70 °C and stirred for 2 h. Then, the reaction mixture was heated to 90 °C and stirred for 1 h. TLC showed that compound 12 was completely consumed. The reaction mixture was quenched with H₂O (10 mL) and then extracted with DCM (10 mL x 3). The combined organic layers were washed with aqueous solution, washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The concentrate was washed with saturated Na₂S₂O₃ solution (5 mL). The residue was used directly in the next step without further purification.

[0122] Step 5: Synthesis of Compound D

[0123]

[0124] Cs₂CO₃ (281 mg, 864 μmol, 4.0 eq) and NaI (129 mg, 864 μmol, 406 μL, 4.0 eq) were added to a CH₃CN (5 mL) solution of intermediate 5 (0.1 g, 216 μmol, 1.0 eq). Compound 13 (106 mg, 350 μmol, 1.62 eq) was added. The mixture was stirred at 83 °C for 12 h. TLC was used to determine if intermediate 5 was completely reacted. The reaction was quenched with H₂O (10 mL) and then extracted with DCM (10 mL x 3). The combined organic layers were washed with aqueous solution, washed with saturated brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [Water(NH4HCO3)-ACN]; B%: 45%-75%, 8min) to give compound D (30.0 mg, white solid) in 18.3%. 1H NMR (400MHz, DMSO-d6) δ10.63-10.52(m,1H),7.43-7.35(m,1H),7.26-7.15(m,1H),7.03-6.90(m,2H),6.7 7-6.67(m,1H),6.20-6.04(m,2H),5.17-5.05(m,1H),4.32-4.00(m,1H),3.98-3.89(m,1H),3.72-3.58(m,2 H),3.50-3.37(m,2H),3.27-3.21(m,2H),3.17-3.08(m,2H),3.00-2.90(m,1H),2.85-2.71(m,3H),2.58(dd ,J=6.1,15.4Hz,1H),2.49-2.32(m,3H),2.01-1.88(m,2H),1.68(q,J=7.3Hz,2H),1.11(d,J=6.6Hz,3H).MS m / z(ESI): 717.2[M+1].

[0125] Example 5: Synthesis of Compound E

[0126]

[0127] Compound E was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=7.8Hz,1H),7.01-6.89(m,2H),6.69(br d,J=6.7Hz,1H),6.10(br d,J=12.0Hz,2H),5.29-5.17(m,1H),5.05(s,1H),3.97-3.88(m,1H),3.70-3.58(m,3H),3.47-3.36(m,2H),3.14-3.02(m,1H),2.89-2. 57(m,8H),2.41-2.27(m,2H),1.90(q,J=7.7Hz,2H),1.70-1.58(m,2H),1.54-1.47(m,1H),1.31-1.22(m,2H),1.06(d,J=6.6Hz,3H).MS m / z(ESI): 713.3[M+1].

[0128] Example 6: Synthesis of Compound F

[0129]

[0130] Compound F was prepared in a manner similar to that used in Example 4. 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.37(d,J=7.5Hz,1H),7.18(d,J=7.9Hz,1H),7.03-6.88(m,2H),6.70(br d,J=6.6Hz,1H),6.17-6.03(m,2H),5.25(br s,1H),5.11-5.01(m,1H),4.31-4.03(m,1H),3.99-3.88(m,1H),3.74-3.58(m,3H),3.47-3.36(m,2H),3.28-3.20(m,2H),3.16-2.99( m,3H),2.87-2.71(m,3H),2.68-2.53(m,2H),2.49-2.32(m,3H),1.94(qd,J=8.1,15.8Hz,2H),1.73-1.63(m,2H),1.12-1.01(m,3H).MS m / z(ESI): 729.2[M+1].

[0131] Example 7: Synthesis of Compound G

[0132]

[0133] Step 1: Synthesis of Compound 14

[0134]

[0135] NaH (2.02 g, 50.5 mmol, 60.0%, 3.0 eq) was added dropwise to a THF solution (90 mL) of compound 9 (3.0 g, 16.8 mmol, 1.0 eq) at 0 °C. After addition, the mixture was stirred at this temperature, and then a THF solution (10 mL) of benzyl 2-bromoethyl ether (3.62 g, 16.8 mmol, 1.0 eq) of compound 1 was added dropwise at 0–5 °C for 12 h. The reaction was monitored by TLC until complete, and the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1–10 / 1) to give compound 14 (1.10 g, colorless oil).

[0136] Step 2: Synthesis of Compound 15

[0137]

[0138] Under argon protection at 25 °C, Pd(OH)₂ (100 mg, 142 μmol, 20.0% purity) was added to a THF (10 mL) solution of compound 14 (500 mg, 1.60 mmol, 1.0 eq). The suspension was degassed three times with H₂. The mixture was stirred at 50 °C and H₂ (50 psi) for 4 h. TLC showed complete consumption of the starting material. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give compound 15 (200 mg, yellow oil).

[0139] Step 3: Synthesis of Compound 16

[0140]

[0141] TEA (239 mg, 2.36 mmol, 1.5 eq) and TosCl (600 mg, 3.15 mmol, 2.0 eq) were added dropwise to a DCM (10 mL) solution of compound 15 (350 mg, 1.58 mmol, 1.0 eq) at 25 °C. The mixture was stirred at 40 °C for 12 h. TLC showed complete consumption of the starting material. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with aqueous solution. NaCl (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 16 (180 mg, yellow oil). 1 H NMR(400MHz,DMSO-d6)δ7.72(d,J=8.38Hz,2H)7.27(d,J=8.13Hz,2H)4.07-4.11(m,2H)3 .53-3.58(m,2H)3.39(t,J=5.94Hz,2H)2.37(s,3H)1.92-2.06(m,3H)1.66-1.75(m,2H).

[0142] Step 4: Synthesis of compound G

[0143]

[0144] K₂CO₃ (193 mg, 1.40 mmol, 3.0 eq) and intermediate 5 (215 mg, 465 μmol, 1.0 eq) were added to a 5 mL solution of ACN containing compound 16 (175 mg, 465 μmol, 1.0 eq) at 25 °C. The mixture was stirred at 40 °C for 15 h. LC-MS showed complete consumption of the starting material. The reaction mixture was diluted with 10 mL of H₂O and extracted with solvent (10 mL x 3). The combined organic layers were washed with aqueous solution. The organic phase was washed with saturated brine (10 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / DCM = 0–5%) to give compound G (82 mg, white solid) in a yield of 26.5%. 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H) 7.38 (d, J = 7.70Hz, 1H) 7.18 (d, J = 7.82Hz, 1H) 6.91-7.01 (m, 2H) 6.6 9(d,J=6.60Hz,1H)6.09(d,J=12.10Hz,2H)5.24(t,J=6.05Hz,1H)3.88-3.97(m,1H)5.05(s,1H)3.63(br t,J=6.60Hz,2H)3.43(br t,J=

[0145] 6.17Hz,4H)3.36(t,J=5.69Hz,3H)3.01-3.16(m,1H)2.77-2.86(m,3H)2.62(brd,J=14.55Hz,1H)2.55(br t,J=5.75Hz,3H)2.14-2.31(m,2H)1.68-1.77(m,2H)1.07(d,J=6.60Hz,3H).MS m / z(ESI): 667.2[M+1].

[0146] Experimental Example 1. Degradation of ERα protein by the compound

[0147] 1. Purpose of the experiment

[0148] The purpose of this experiment is to determine the degradation effect of the compounds of this invention on ERα protein, based on DC... 50 and maximum degradation efficiency E max Evaluate the in vitro degradation activity of the compounds.

[0149] 2. Test methods

[0150] MCF-7 cells (ATCC, HTB-22) were cultured in 88% RPMI 1640 (Invitrogen, 22400-089) medium containing 10% FBS (ExCell Bio, FSP500), 1% P / S (Hyclone, SV30010), and 1% GlutaMax (Invitrogen, 25030-061). On the first day of the experiment, after centrifugation, digestion, and cell collection, the cell suspension concentration was adjusted to 8.75 × 10⁻⁶. 440 μL of the suspension was added to each well of a 384-well plate (Greiner, 781090) and incubated overnight at 37°C with 5% CO2. The next day, the compound was prepared as a 10 mM stock solution with 100% DMSO and diluted to 2.5 μM (5X) with 1640 complete medium, followed by a 4-fold serial dilution to a total of 10 concentration points. 1 μM fulvestrant was used as the low control (LC), and 0.5% DMSO as the high control (HC). 10 μL of the corresponding compound was added to each well of the 384-well plate and incubated for 24 hours at 37°C with 5% CO2. On the third day, 50 μL of 8% paraformaldehyde (EMSciences, 15710-S) was added to each well of the 384-well plate and fixed at room temperature for 40 minutes. 100 μL of PBS was added to each well for washing twice, followed by 50 μL of 0.1% Triton X-100 (Sigma, T9284) to each well, and incubation at room temperature for 15 minutes. The plate was washed five times with PBS, followed by 50 μL of blocking buffer containing 0.1% Tween 20 (Sigma, P1379) to each well, and incubation at room temperature for 1 hour. The original liquid in the plate was aspirated, and the primary antibody (Estrogen Receptorα(D8H8) Rabbit mAb, Cell Signal, 8644S) was diluted 1:1000, with 25 μL added to each well, and incubated overnight at 4°C. On the fourth day, the culture plate was washed five times. Then, the secondary antibody (IRDye 800CW Goatanti-Rabbit, Licor, 926-32211, 1:1000) and DRAQ5 (Cell Signal, 4084L, 1:2000) were diluted with blocking buffer, with 25 μL added to each well and incubated at room temperature for 1 hour. The plate was then washed five more times, and signal values ​​at 800 nm and 700 nm were read using an Odyssey imaging system. The inhibition rate was calculated using the ratio (800 nm / 700 nm), i.e., %Inhibition = (Assay well - Average_HC) / (Average_LC - Average_HC) * 100%. In Prism 5, the dose-response curve was fitted using "log(inhibitor) vs. response - Variable slope" to calculate the DC. 50 Maximum degradation rate of the compound E max The percentage of residual ERα levels in cells after 500 nM treatment compared to the percentage of ERα levels after 500 nM fulvestrant treatment.

[0151] 3. Test Results

[0152] The degradation activity of the disclosed compound against ERα was determined by In-Cell-Western assay, and the measured DC... 50 and E max See Table 1.

[0153] Table 1. Degradation effect of the compounds of this invention on ERα

[0154] compound <![CDATA[DC 50 (nM)]]> <![CDATA[E max Degradation (%) A 0.46 68.7 B 0.75 65.8 C 1.65 82.4 D 10.40 93.7 E 1.22 54.1 F 1.65 85.9 G 3.95 42.9

[0155] Conclusion: Compounds A, B, C, D, and F disclosed in this invention have good degradation activity against ERα.

[0156] Experimental Example 2. Inhibitory effect of the compound on the proliferation of MCF-7 cells

[0157] 1. Experimental Objective

[0158] The purpose of this experiment was to determine the inhibitory effect of the compound of this invention on the in vitro proliferation of MCF-7 cells, based on IC50. 50 Evaluate the activity of the compound.

[0159] 2. Experimental Methods

[0160] MCF-7 cells (ATCC, HTB-22) were cultured in 1640 medium (Gibco, 22400089) containing 10% fetal bovine serum (Hyclone, SV30087.03), 1% PS (penicillin-streptomycin antibiotic, Gibco, 15070063), and 1% Glutamax (Gibco, 35050061). On day 1, after centrifugation, digestion, and cell collection, the cell concentration was adjusted with complete medium and seeded at a density of 600 cells / well in 384-well plates (Greiner-781091), with 40 μL of cell suspension per well. The plates were incubated overnight at 37°C in a 5% CO2 incubator. On day 2, the compound was prepared as a 10 mM stock solution with 100% DMSO and further diluted to 5 μM (10X) with 1640 medium, followed by a 4-fold serial dilution to a total of 8 concentration points. 2 μM fulvestrant was used as the low control (LC), and 0.5% DMSO as the high control (HC). 10 μL of the corresponding compound was added to each well of a 384-well plate and incubated at 37°C with 5% CO2 for 6 days. On day 8, 25 μL of CellTiter-Glo (Promega, G7573) was added to each well of the plate, and the plates were incubated at 400 rpm for 10 minutes at room temperature. The luminescence signal was then read using an Envision (PerkinElmer) scanner. The inhibition rate was calculated using the following formula: %Inhibition = (Assay well - Average_HC) / (Average_LC - Average_HC) * 100%. The dose-response curve was fitted using Prism 5 "log(inhibitor) vs. response - Variable slope" to calculate the IC50. 50 .

[0161] 3. Measurement Results

[0162] The inhibitory effect of the disclosed compound on the proliferation of MCF-7 cells was determined by CellTiter-Glo assay of intracellular ATP content in live cells. The measured IC50 value was... 50 See Table 2.

[0163] Table 2. Inhibitory effect of the compounds of this invention on the proliferation of MCF-7 cells.

[0164] compound <![CDATA[IC 50 (nM)]]> A 1.59 B 4.94 C 2.73 D 9.70 E 0.89 F 1.20 G 1.61

[0165] Conclusion: The compounds disclosed in this invention have a significant inhibitory effect on the proliferation of MCF-7 cells.

[0166] Experimental Example 3. Evaluation of the metabolic stability of the compound of the present invention in in vitro liver microsomes

[0167] 1. Experimental materials and reagents

[0168] Human liver microsomes, rat liver microsomes, NADPH, positive control compound fulvestrant, methanol, phosphate buffer, magnesium chloride solution, acetonitrile, and tolbutamide.

[0169] 2. Solution preparation

[0170] 1) Preparation of working solution for test sample: Dilute the test sample with methanol to 100 μM;

[0171] 2) Preparation of working solution for liver microsomes: Dilute liver microsomes with 100mM phosphate buffer to 0.56mg / ml;

[0172] 3) Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH and dilute it to 20 mM with phosphate buffer, then add an equal volume of 60 mM MgCl2 solution.

[0173] 4) Preparation of stop solution: Dilute toluenebutyrate to 20 ng / mL with acetonitrile to prepare the stop solution containing internal standard.

[0174] 3. Experimental Methods

[0175] 1) Prepare incubation anti-adsorption EP tubes, and label the species, test sample, control (testosterone, dextromethorphan), time points (0, 5, 10, 20, 30, 60 min), Blank60, NCF60, etc.

[0176] 2) Add 2 μL of the test sample or control working solution and 178 μL of liver microsome working solution to each tube. Add 2 μL of acetonitrile to the Blank tube instead of the test sample. Incubate in a 37°C water bath for about 10 min. Each sample is repeated in triplicate.

[0177] 3) After the pre-incubation, except for 0 min and NCF60, add 20 μL of NADPH working solution to each tube to start the reaction. Add 20 μL of phosphate buffer (containing 30 mM MgCl2) to the NCF60 tube. The final concentration of the test sample or control sample in the incubation system is 1 μM, the final concentration of liver microsomes is 0.5 mg / mL, the final concentration of NADPH is 1 mM, and the final concentration of MgCl2 is 3 mM.

[0178] 4) For the 0 min sample, first add 600 μL of stop solution and then add NADPH working solution. After each sample has been incubated for the corresponding time, add 600 μL of stop solution to terminate the reaction.

[0179] 5) After each sample is terminated, vortex for 30 seconds, then centrifuge at 13500 rpm for 10 min. Take 100 μL of supernatant into an EP tube, add 100 μL of Milli-Q water, vortex and mix well, and then analyze using LC-MS / MS.

[0180] 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0181] 4. Data Analysis

[0182] The percentage of the test sample remaining after 60 minutes of testing is shown in Table 3.

[0183] Table 3. Evaluation of the metabolic stability of the compounds of the present invention and control compounds in rat and human liver microsomes.

[0184]

[0185] Conclusion: The compound AG disclosed in this invention exhibits significantly better stability than fulvestrant in rat and human liver microsomes in vitro.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, ， in, X is independently selected from -SO- or -SO2-; m and n are each independently selected from 2 or 3; R1 is independently selected from hydrogen, F, or -CH2OH; R2 is selected from hydrogen, F, or C. 1-6 alkyl; R3 is F; R4is C substituted with F 1-10 linear or branched alkyl.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein, R1 is selected from F or -CH2OH.

3. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 or 2, wherein, R1 is F.

4. The compound or pharmaceutically acceptable salt thereof of claim 3, wherein, R2 is selected from F, methyl, ethyl, isopropyl, butyl, isobutyl or sec-butyl.

5. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 or 2, wherein, R4is C substituted with F 1-6 linear or branched alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from -CF2CF3, -CF2CHF2, -CF2CH2F, -CF2CH3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CHFCH3, -CH2CF3, -CH2CHF2 or -CH2CH2F.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, X is independently selected from -SO- or -SO2-; m and n are each independently selected from 2 or 3; R1 is selected from F or -CH2OH; R2 and R3 are both F; R4 is CF2CF3.

8. The following compounds or their pharmaceutically acceptable salts are selected from: 。 9. A pharmaceutical composition comprising the compound of any one of claims 1, 6-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The use of the compound of any one of claims 1, 6-8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for the prevention or treatment of estrogen receptor-related diseases.

11. Use according to claim 10, wherein, The disease in question is breast cancer.