A compound, a preparation method thereof, a pharmaceutical composition and application thereof

Abstract

This application discloses a compound, its preparation method, pharmaceutical composition, and application, belonging to the field of pharmaceutical synthesis and application technology. The compound is selected from formula (I) or formula (II). This compound can improve oral bioavailability, enabling oral administration and solving a series of problems associated with injecting fulvestrant in clinical practice. In vivo, it can be metabolized to produce fulvestrant and can inhibit / degrade estrogen receptor prodrug molecules, treating estrogen receptor-related diseases.

Description

Technical Field

[0001] This application relates to a compound and its preparation method, a pharmaceutical composition and its application, belonging to the field of pharmaceutical synthesis and application technology. Background Technology

[0002] Fulvestrant is a novel estrogen receptor (ER) blocker used to treat postmenopausal advanced breast cancer that is unresponsive to anti-estrogenic therapy and has a positive estrogen receptor. It is widely used clinically due to its effectiveness against both wild-type and mutant ER receptors.

[0003] However, due to the extremely low bioavailability of oral fulvestrant, it must be administered via intramuscular injection in the buttocks. Furthermore, the large volume and high viscosity of the single dose make the injection process time-consuming and can cause local reactions such as pain, redness, swelling, induration, and even nerve damage. Japanese MHLW and PMDA have issued black-box warnings for this. In addition, the injection requires professional medical personnel and often necessitates hospitalization, causing significant inconvenience.

[0004] Oral formulations completely avoid the physical pain and infection risks associated with intramuscular injections, significantly reducing the incidence of adverse reactions. Furthermore, they allow patients to self-medicate at home, reducing the time and effort required for hospital visits, making them particularly suitable for patients with advanced breast cancer requiring long-term treatment. Therefore, developing new, potent, orally administered drugs with high bioavailability and more ideal pharmacokinetic characteristics has immense clinical value.

[0005] Patents WO2023105303 and CN116836216 also disclose compounds containing fulvestrant prodrugs, but these compounds have low bioavailability, slow metabolic rates, and low metabolic conversion rates. The safety risks associated with prodrug introduction need to be considered, resulting in poor drug-likeness. Therefore, there is an urgent need for a compound structure that can improve bioavailability, mitigate safety risks, and achieve faster and more complete conversion. Summary of the Invention

[0006] To address the aforementioned issues, this paper presents a novel compound. After oral administration and absorption into the bloodstream, this compound is rapidly metabolized to fulvestrant with extremely low residual amounts of the original molecule. Furthermore, the conversion efficiency of the original molecule to the active product fulvestrant is high, significantly improving oral bioavailability. This enables oral administration of fulvestrant, effectively resolving many problems associated with injectable administration in clinical practice.

[0007] According to a first aspect of this application, a compound is provided, said compound being selected from formula (I) or formula (II):

[0008] Formula (I)

[0009] Equation (II) Wherein, R1 is selected from saturated or unsaturated hydrocarbon groups, aromatic groups, and combinations of hydrocarbon groups and aromatic groups with 1 to 20 carbon atoms; the hydrocarbon group can be a substituted or unsubstituted alkyl, cycloalkyl, oxocycloalkyl, azacycloalkyl, or thiocycloalkyl group; the substituent is selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -C≡C, -OCH3, -COCH3, -SO2CH3, -SO2NH2, -CF3, CF2Cl, -CHF2, -COOH; the aromatic group is selected from substituted or unsubstituted 5- or 6-membered aromatic heterocycles; when the aromatic group is substituted, the substituent is selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -C≡C, -OCH3, -COCH3, -SO2CH3, -SO2NH2, -CF3, -CHF2, -CF2Cl, -COOH; R2 is selected from hydrogen or... ; R3 is selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups, wherein the substituents are selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -C≡C, -OCH3, -COCH3, -SO2CH3, -SO2NH2, -CF3, CF2Cl, -COOH.

[0010] Optionally, R1 is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, styryl, propenyl, pyridine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, pyrrole, pyrazole, imidazole, oxazole, oxadiazole, 1, 2, 3 Triazole, 1,2,4-triazole, tetrazolium, pyridazine; or R1-COOH is at least one of lysine, arginine, histidine, glucuronic acid, gluconic acid, and betaine.

[0011] R3 is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The substituents of R1 or R3 are selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -OCH3, -SO2CH3, -SO2NH2, -CF3, -CHF2; Preferably, R1 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, styryl, 3-butyl-1,2-dithiacyclopentane, propenyl, 2-thiophene, 3-thiophene, 2-pyrazole, 3-pyrazole; R3 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the substituents of R1 or R3 are selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -OCH3, -SO2CH3, -SO2NH2, -CF3, -CHF2.

[0012] More preferably, R3 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0013] Optionally, R1 is selected from one of the following formulas: methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, styryl, 3-butyl-1,2-dithionecyclopentane.

[0014] Optionally, R1 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. , , , , , , , , At least one of them, * indicates a connection site.

[0015] Optionally, the compound is selected from one of the following formulas: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; .

[0016] Preferably, the compound is selected from one of the following formulas:

[0017]

[0018]

[0019] According to a second aspect of this application, a pharmaceutical composition is provided comprising any of the compounds described above or their stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or eutectics, and pharmaceutically acceptable carriers or excipients.

[0020] Specifically, the pharmaceutical composition of this application can be in the form of a solid, semi-solid, liquid, or gaseous preparation, such as a powder, granules, pills, tablets, capsules, ointment, suppository, paste, decoction, mixture, syrup, injection, aerosol, or inhaler.

[0021] According to a third aspect of this application, an ADC, DAC, or other coupling molecule is provided, comprising any of the compounds described above or their stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or eutectics, and pharmaceutically acceptable carriers or excipients.

[0022] According to a fourth aspect of this application, a method for preparing the compound described in any of the preceding claims is provided, wherein when R2 is H, the method for preparing the compound with the structure of formula (I) includes the steps of: Fulvestrant and the first compound were added to a solvent and reacted at 0-5°C for 0.5-24 h in the presence of an acid-binding agent. The mixture was then washed, dried, filtered, and purified to obtain the final product. The method for preparing the compound with the structure of formula (II) includes the following steps: The fulvestrant and the second compound were added to a solvent and reacted at 0-5°C for the first time in the presence of an acid-binding agent, followed by a second time at 20-30°C. The mixture was then washed, dried, filtered, and purified to obtain the final product. R2 is The method for preparing the compound with the structure of formula (I) includes the following steps: Fulvestrant and the first compound were added to a solvent and reacted at 0-5°C for at least 2 hours in the presence of an acid-binding agent. After washing, drying, filtering, and purification, the first intermediate was obtained. The first intermediate and the first compound were then added to a solvent and reacted at 0-5°C for 0.5-24 hours in the presence of an acid-binding agent. After washing, drying, filtering, and purification, the final product was obtained. The method for preparing the compound with the structure of formula (II) includes the following steps: Fulvestrant and the second compound were added to a solvent and reacted at 0-5°C for a first time in the presence of an acid-binding agent, followed by a second time at 20-30°C. After washing, drying, filtering, and purification, the second intermediate was obtained. The first intermediate and the first compound were then added to a solvent and reacted at 0-5°C for 0.5-24 h in the presence of an acid-binding agent. After washing, drying, filtering, and purification, the final product was obtained. The first compound has a first reactive group and an R1 group, wherein the first reactive group is selected from acyl chloride and carboxyl groups; the structural formula of the second compound is: X is selected from halogens.

[0023] Optionally, the first time is 0.5-24h, and the second time is 0.5-24h.

[0024] According to a fifth aspect of this application, the use of any of the compounds described above, or the pharmaceutical compositions described above, or the ADCs, DACs, or other conjugates described above, in the preparation of medicaments for the prevention and / or treatment of estrogen receptor-mediated diseases is provided.

[0025] Preferably, the estrogen receptor-mediated diseases include tumors; Preferably, the estrogen receptor-mediated diseases include breast cancer, ovarian cancer, endometrial cancer, prostate cancer, colon cancer, lung cancer, and melanoma. More preferably, the estrogen receptor-mediated diseases include breast cancer, ovarian cancer, endometrial cancer, and cervical cancer.

[0026] According to the sixth aspect of this application, the use of any of the compounds described above, or the pharmaceutical compositions described above, or the ADCs, DACs, or other conjugates described above, in the preparation of medicaments for treating and inhibiting and / or degrading estrogen receptor-mediated diseases is provided.

[0027] The beneficial effects of this application include, but are not limited to: 1. The compounds of formula (I) or formula (II) of this application can improve the oral bioavailability of fulvestrant, which can be metabolized in vivo to produce fulvestrant and can inhibit / degrade estrogen receptor prodrug molecules for the treatment of estrogen receptor-related diseases.

[0028] 2. The compounds of formula (I) or formula (II) of this application, after being administered by gavage in animal experiments, can be rapidly metabolized into fulvestrant in mice, exhibiting high bioavailability and further enhancing the clinical application potential of fulvestrant for oral administration.

[0029] 3. According to the compounds of this application, compared with commercially available fulvestrant injection, the compounds of the present invention, when administered orally, will greatly reduce injection pain and inflammatory response, and increase patient compliance. Attached Figure Description

[0030] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings: Figure 1 The pharmacokinetic curves of compounds 3 and 6 of this application in mice after gavage administration.

[0031] Figure 2 The pharmacokinetic curves of compounds 7 and 8 of this application in mice after oral administration.

[0032] Figure 3 The pharmacokinetic curves of compounds 9 and 11 of this application in mice after gavage administration. Detailed Implementation

[0033] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0034] Unless otherwise specified, the raw materials used in the embodiments and comparative examples of this application were all purchased commercially.

[0035] Unless otherwise specified, the methods used in the embodiments and comparative examples of this application are conventional methods in the prior art.

[0036] To accomplish the objectives of this invention, compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Maclean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfasa (China) Chemical Co., Ltd., Bid Pharmaceutical, Shanghai Haohong Biomedical Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0037] The compounds used in the reactions described in this application are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are those obtained from legitimate commercial sources, including companies such as Titan Technology, Anaiji Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, Bid Pharmaceutical, and Bailingwei Technology. TLC: Thin-layer chromatography; Et3N: Triethylamine; DCM: Dichloromethane; MeOH: Methanol; DCC: N,N'-Dicyclohexylcarbodiimide; DMAP: 4-Dimethylaminopyridine.

[0038] Example 1 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0039] To a 10 ml single-necked flask, fulvestrant (606.7 mg, 1 mmol, 1.0 eq), Et3N (303.0 mg, 3 mmol, 3 eq), and DCM (5 ml) were added and stirred until dissolved. At 0-5 °C, a solution of acetyl chloride (78.5 mg, 1.0 mmol, 1.0 eq) in DCM (3 ml) was added dropwise. The reaction was carried out at 0-5 °C for 4 h, monitored by TLC. Once the reaction was complete, the reaction solution was washed successively with 20 ml of water and 40 ml of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (DCM: MeOH, 100:1, v / v) to obtain 263.3 mg of compound 1, with a yield of 40.6%.

[0040] ESI-MS: 649.3 [M+H] + .

[0041] 1 H NMR (600 MHz, CDCl3) δ 7.28 (d, J = 8.5 Hz, 1H), 6.86-6.83 (m, 1H), 6.78 (d,J = 2.2 Hz, 1H), 3.75 (t, J =8.5 Hz, 1H), 2.92-2.88 (m, 1H), 2.77-2.68(m, 4H), 2.67-2.61 (m, 1H), 2.37-2.32 (m, 1H), 2.28 (s, 3H), 2.27-2.06 (m,5H), 1.93-1.90 (m, 1H), 1.79-1.74 (m, 3H), 1.65-1.58 (m, 2H), 1.52-1.25 (m,18H), 1.05-0.98 (m, 1H), 0.77 (s, 3H).

[0042] Example 2 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0043] In a 10 ml single-necked flask, fulvestrant (606.7 mg, 1 mmol, 1.0 eq), potassium carbonate (414.0 mg, 3 mmol, 3.0 eq), and acetonitrile (5 ml) were added and suspended. At 0–5 °C, a solution of 2,2-dimethylpropionate iodomethyl ester (290.4 mg, 1.2 mmol, 1.2 eq) in acetonitrile (1 ml) was added. The reaction was carried out at 0–5 °C for 1 h, then at 25 °C for 8 h. TLC monitoring indicated the reaction was complete. The reaction solution was washed sequentially with 20 ml of water and 20 ml of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (DCM: MeOH, 120:1, v / v) to obtain 342.1 mg of compound 2, with a yield of 47.5%.

[0044] ESI-MS: 743.3 [M+H] + .

[0045] 1 H NMR (600 MHz, DMSO- d 6) δ 7.24 (d, J = 8.7 Hz, 1H), 6.79 (dd, J = 8.6, 2.7 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 5.73-5.69 (m, 2H), 4.50 (d, J= 4.8 Hz,1H), 3.56-3.52 (m, 1H), 2.87-2.79(m, 2H), 2.76-2.62 (m, 4H), 2.43-2.20 (m, 4H), 1.94-1.87 (m, 3H), 1.80-1.78 (m, 1H), 1.69-1.67 (m, 1H), 1.62-1.47 (m, 4H), 1.39-1.31 (m, 4H), 1.30-1.21(m,11H), 1.12(s, 9H), 0.89-0.85(m, 1H), 0.67 (s, 3H).

[0046] Example 3 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0047] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with nicotinic acid chloride, while the rest is the same as in Example 1, and compound 3 is prepared.

[0048] ESI-MS: 712.4 [M+H] + .

[0049] 1 H NMR (600 MHz, DMSO- d 6) δ 9.24 (d, J = 2.2 Hz, 1H), 8.90 (dd, J = 4.8,1.7 Hz, 1H), 8.46-8.43 (m, 1H), 7.67-7.64 (m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.4, 2.5 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 4.54 (d, J = 4.8 Hz, 1H),3.58-3.54 (m, 1H), 2.89-2.81 (m, 2H), 2.77-2.69 (m, 3H), 2.67-2.61 (m, 1H),2.44-2.29 (m, 4H), 1.92-1.87 (m, 3H), 1.83-1.79 (m, 1H), 1.73 (d, J= 11.1 Hz,1H), 1.62-1.58 (m, 3H), 1.52-1.48 (m, 1H), 1.41-1.31 (m, 8H), 1.28-1.21 (m,10H), 0.95-0.89 (m, 1H), 0.69 (s, 3H).

[0050] Example 4 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0051] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with pivaloyl chloride, while the rest is the same as in Example 1, and compound 4 is prepared.

[0052] ESI-MS: 691.3 [M+H] + .

[0053] 1 H NMR (600 MHz, DMSO- d 6) δ 7.31 (d, J = 8.5 Hz, 1H), 6.81 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 4.53 (d, J = 4.7 Hz, 1H), 3.56-3.52 (m,1H), 2.87-2.81(m, 2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.43-2.25 (m,4H), 1.93-1.87 (m, 3H), 1.82-1.79 (m, 1H), 1.70-1.68 (m, 1H), 1.62-1.55 (m,3H), 1.50-1.46 (m, 1H), 1.42-1.30 (m, 7H), 1.28 (s, 9H), 1.26-1.16 (m, 11H),0.91-0.85 (m, 1H), 0.68 (s, 3H).

[0054] Example 5 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0055] To a 10 ml single-necked flask, fulvestrant (100 mg, 0.16 mmol, 1.0 eq), lipoic acid (34.2 mg, 0.16 mmol, 1.0 eq), DMAP (4.0 mg, 0.03 mmol, 0.2 eq), and DCM (1 ml) were dissolved. At 0-5 °C, a solution of DCC (34.2 mg, 0.16 mmol, 1.0 eq) in DCM (1 ml) was added dropwise. The reaction was carried out at 0-5 °C for 1 h, then increased to room temperature for 8 h. The reaction was monitored by TLC until completion. The reaction solution was washed sequentially with 10 ml of water and 10 ml of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (DCM: MeOH, 100:1, v / v) to obtain 81.3 mg of compound 5, with a yield of 62.0%.

[0056] ESI-MS: 794.9 [M+H] + .

[0057] 1 H NMR (600 MHz, DMSO- d 6) δ 7.30 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.6, 2.4 Hz, 1H), 6.78 (d, J = 2.6 Hz, 1H), 4.52 (d, J = 4.8 Hz, 1H), 3.68-3.63 (m,1H), 3.57-3.52 (m, 1H), 3.22-3.18 (m, 1H), 3.15-3.10 (m, 1H), 2.87-2.81 (m,2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.55 (t, J = 7.2 Hz, 2H), 2.44-2.25(m, 4H), 2.00-1.86 (m, 4H), 1.82-1.78 (m, 1H), 1.72-1.70 (m, 3H), 1.66-1.54(m, 6H), 1.49-1.44 (m, 3H), 1.37-1.29 (m, 6H), 1.32-1.18 (m, 11H), 1.07-0.99(m, 1H), 0.89-0.84 (m, 1H), 0.67 (s, 3H).

[0058] Example 6 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0059] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with isobutyryl chloride, while the rest is the same as in Example 1, and compound 6 is prepared.

[0060] ESI-MS: 677.3 [M+H] + .

[0061] 1 H NMR (600 MHz, DMSO- d 6) δ 7.30 (d, J = 8.6 Hz, 1H), 6.84-6.81 (m, 1H), 6.77 (d, J = 2.3 Hz, 1H), 4.52 (d, J = 4.9 Hz, 1H), 3.57-3.53 (m, 1H), 2.87-2.81(m, 2H), 2.80-2.69 (m, 4H), 2.67-2.61 (m, 1H), 2.45-2.25 (m, 4H), 1.93-1.86(m, 3H), 1.82-1.79 (m, 1H), 1.72-1.69 (m, 1H), 1.63-1.55 (m, 3H), 1.52-1.46(m, 1H), 1.40-1.23 (m, 15H), 1.21 (d, J = 1.6 Hz, 3H), 1.20 (d, J = 1.6 Hz, 3H), 1.19-1.16 (m, 3H), 0.92-0.84 (m, 1H), 0.68 (s, 3H).

[0062] Example 7 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0063] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with cyclopropylformyl chloride, while the rest is the same as in Example 1, and compound 7 is prepared.

[0064] ESI-MS: 675.3 [M+H] + .

[0065] 1 H NMR (600 MHz, DMSO-d 6) δ 7.29 (d, J = 8.6 Hz, 1H), 6.85-6.82 (m, 1H), 6.79 (d, J = 2.3Hz, 1H), 4.51(d, J = 4.8 Hz, 1H), 3.57-3.52 (m, 1H), 2.87-2.80(m, 2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.43-2.25 (m, 4H), 2.02-1.96(m, 1H), 1.93-1.79 (m, 5H), 1.70 (d, J = 9.4 Hz, 1H), 1.63-1.54 (m, 3H), 1.51-1.44 (m, 1H), 1.40-1.16 (m, 17H), 1.04-1.01 (m, 2H), 0.99-0.96 (m, 2H), 0.90-0.85 (m, 1H), 0.67 (s, 3H).

[0066] Example 8 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0067] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with cyclobutylformyl chloride, while the rest is the same as in Example 1, and compound 8 is prepared.

[0068] ESI-MS: 689.3 [M+H] + .

[0069] 1 H NMR (600 MHz, DMSO- d 6) δ 7.30 (d, J = 8.5 Hz, 1H), 6.85-6.82 (m, 1H), 6.79 (d, J = 2.2 Hz, 1H), 4.51 (s, 1H), 3.55 (t, J= 8.5Hz, 1H), 3.43-3.36 (m,1H), 2.87-2.81 (m, 2H), 2.77-2.69 (m, 3H), 2.67-2.61 (m, 1H) 2.40-2.21 (m,8H), 2.03-1.96 (m, 2H),1.94-1.85 (m, 4H),1.81-1.79 (m, 1H), 1.70 (d, J = 9.4Hz, 1H), 1.65-1.55 (m, 3H), 1.50-1.43 (m, 1H), 1.37-1.20 (m, 17H), 0.91-0.84(m, 1H), 0.67 (s, 3H).

[0070] Example 9 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0071] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with cyclopentylformyl chloride, while the rest is the same as in Example 1, and compound 9 is prepared.

[0072] ESI-MS: 703.3 [M+H] + .

[0073] 1 H NMR (600 MHz, DMSO- d 6) δ 7.30 (d, J = 8.5 Hz,1H), 6.84-6.81 (m,1H),6.78 (d, J = 2.2 Hz, 1H), 4.51 (s, 1H), 3.55 (t, J = 8.5Hz, 1H), 3.02-2.96 (m,1H), 2.87-2.80 (m, 1H), 2.76-2.60 (m, 5H), 2.43-2.25 (m, 4H), 1.97-1.87 (m,3H), 1.86-1.76 (m, 3H), 1.70-1.64 (m, 4H), 1.60-1.54 (m, 5H), 1.52-1.45 (m,2H), 1.38-1.19 (m, 17H), 0.91-0.84 (m, 1H), 0.67 (s, 1H).

[0074] Example 10 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0075] The difference between this embodiment and Example 1 is that acetyl chloride is replaced with cyclohexylformyl chloride, while the rest is the same as in Example 1, to prepare compound 10.

[0076] ESI-MS: 717.3 [M+H] + .

[0077] 1 H NMR (600 MHz, DMSO- d 6) δ 7.30 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.0Hz,1H), 6.76 (s, 1H), 4.50 (s, 1H), 3.54 (s, 1H), 2.84-2.81 (m, 2H), 2.73-2.70(m, 3H), 2.66-2.55 (m, 2H), 2.40-2.27 (m, 4H), 1.94-1.89 (m, 5H), 1.82-1.80 (m, 1H), 1.70 (s, 1H), 1.60-1.44 (m, 7H), 1.35-1.17 (m, 21H), 0.96-0.88 (m, 1H), 0.67 (s, 1H).

[0078] Example 11 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0079] The difference between this embodiment and Example 5 is that lipoic acid is replaced with cinnamic acid, while the rest is the same as in Example 5, to prepare compound 11.

[0080] ESI-MS: 737.3 [M+H] + .

[0081] 1 H NMR (600 MHz, DMSO- d6 ) δ 7.84-7.79 (m, 3H), 7.47-7.45 (m, 3H),7.34(d, J= 8.5Hz, 3H), 6.94-6.92 (m, 1H), 6.88-6.84 (m, 2H), 4.51-4.49(m, 1H), 3.58-3.53 (m,1H), 2.87-2.81 (m, 2H), 2.77-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.42-2.28 (m, 4H), 1.93-1.87 (m, 3H), 1.82 (m, 1H), 1.75-1.72 (m, 1H), 1.61-1.49 (m, 5H), 1.39-1.18 (m, 17H), 0.93-0.90 (m, 1H), 0.68 (s, 3H).

[0082] Example 12 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0083] The difference between this embodiment and Example 1 is that fulvestrant is replaced with compound 3 of Example 3, while the rest is the same as in Example 1, to prepare compound 12.

[0084] ESI-MS: 754.3 [M+H] + .

[0085] 1 H NMR (600 MHz, DMSO- d6 ) δ 9.23 (d, J = 2.1 Hz, 1H), 8.90-8.88 (m,1H), 8.45-8.42 (m, 1H),7.66-7.63 (m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.06-7.04(m, 1H), 7.01 (d, J= 2.1 Hz, 1H), 2.92-2.87 (m, 1H), 2.87-2.81 (m, 1H), 2.78-2.69 (m, 3H), 2.66-2.62 (m, 1H), 2.45-2.36 (m, 4H), 2.16-2.09 (m, 1H), 2.01(s, 3H), 1.93-1.87 (m, 2H), 1.76-1.73 (m, 1H), 1.68-1.57 (m, 4H), 1.54-1.45(m, 2H), 1.42-1.36 (m, 8H), 1.25-1.20 (m, 10H), 0.96-0.92 (m, 1H), 0.81 (s, 3H).

[0086] Example 13 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0087] The difference between this embodiment and Example 1 is that fulvestrant is replaced with compound 6 from Example 6, while the rest is the same as in Example 1, to prepare compound 13.

[0088] ESI-MS: 719.3 [M+H] + .

[0089] 1 H NMR (600 MHz, DMSO- d 6) δ 7.30 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.3, 2.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 3.43-3.38 (m, 1H), 2.87-2.81 (s, 2H), 2.75-2.69 (m, 3H), 2.67-2.71 (m, 1H), 2.35-2.24 (m, 5H), 2.15-2.08 (m, 1H),2.02 (s, 3H), 1.93-1.86 (m, 3H), 1.74-1.72 (m, 2H), 1.64-1.57 (m, 3H), 1.52-1.47 (m, 1H), 1.36-1.18 (m, 22H), 0.90-0.86 (m, 1H), 0.79 (s, 3H).

[0090] Example 14 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0091] The difference between this embodiment and Example 1 is that fulvestrant is replaced with compound 7 from Example 7, while the rest is the same as in Example 1, to prepare compound 14.

[0092] ESI-MS: 717.3 [M+H] + .

[0093] 1 H NMR (600 MHz, DMSO- d 6) δ 7.29 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 2.87-2.81 (m, 2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.46-2.30 (m, 4H), 2.15-2.08(m, 1H), 2.00 (s, 3H), 1.93-1.88 (m, 3H), 1.87-1.82 (m, 1H), 1.73-1.71 (m, 2H), 1.63-1.57 (m, 3H), 1.51-1.46 (m, 2H), 1.39-1.30 (m, 7H), 1.25-1.18 (m, 9H), 1.04-1.01 (m, 2H), 0.99-0.96 (m, 2H), 0.91-0.84 (m, 1H), 0.79 (s, 3H).

[0094] Example 15 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0095] The difference between this embodiment and Example 1 is that fulvestrant is replaced with compound 8 from Example 8, while the rest is the same as in Example 1, to prepare compound 15.

[0096] ESI-MS: 731.3 [M+H] + .

[0097] 1 H NMR (600 MHz, DMSO- d6) δ 7.30 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.4, 2.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 3.42-3.37 (m, 1H), 2.87-2.81 (m, 2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.43-2.21 (m, 8H), 2.15-2.08 (m, 0.92-0.84 (m, 1H), 0.79 (s, 3H).

[0098] Example 16 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0099] The difference between this embodiment and Example 1 is that fulvestrant is replaced with compound 9 of Example 9, while the rest is the same as in Example 1, to prepare compound 16.

[0100] ESI-MS: 745.3 [M+H] + .

[0101] 1 H NMR (600 MHz, DMSO- d 6) δ 7.29 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H), 6.79 (d, J= 2.5 Hz, 1H), 3.01-2.96 (m, 1H), 2.87-2.81 (m, 2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2.43-2.30 (m, 4H), 2.15-2.08 (m, 1H),2.00 (s, 3H), 1.98-1.86 (m, 4H), 1.86-1.79 (m, 2H), 1.74 -1.70 (m, 2H), 1.69-1.56 (m, 8H), 1.52-1.45 (m, 2H), 1.40-1.18 (m, 17H), 0.92-0.84 (m, 1H), 0.79 (s, 3H).

[0102] Example 17 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0103] The difference between this embodiment and Example 5 is that lipoic acid is replaced with propionic acid, while the rest is the same as in Example 5, and compound 17 is prepared.

[0104] ESI-MS: 663.3 [M+H] + .

[0105] 1 H NMR (600 MHz, DMSO- d 6) δ 7.29 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 4.49 (d, J = 4.4 Hz, 1H), 3.57-3.53 (m,1H), 2.87-2.81 (m, 2H), 2.76-2.69 (m, 3H), 2.67-2.62 (m, 1H), 2,58-2.53 (m,2H), 2.45-2.26 (m, 4H), 1.94-1.86 (m, 3H), 1.83-1.80 (m, 1H), 1.71-1.69 (m,1H), 1.64-1.55 (m, 3H), 1.50-1.46 (m, 1H), 1.38-1.23 (m, 18H), 1.11 (t, J= 7.5Hz, 3H), 0.92-0.82 (m, 1H), 0.67 (s, 3H).

[0106] Example 18 This embodiment relates to the synthesis of a compound, and the specific reaction formula and steps are as follows:

[0107] The difference between this embodiment and Example 5 is that lipoic acid is replaced with butyric acid, while the rest is the same as in Example 5, to prepare compound 18.

[0108] ESI-MS: 676.3 [M+H] + .

[0109] 1 H NMR (600 MHz, DMSO- d 6) δ 7.29 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 4.49 (d, J = 4.4 Hz, 1H), 3.57-3.53 (m,1H), 2.87-2.81 (m, 2H), 2.76-2.69 (m, 3H), 2.67-2.61 (m, 1H), 2.53-2.50 (m,2H), 2.45-2.26 (m, 4H), 1.94-1.86 (m, 3H), 1.82-1.80 (m, 1H), 1.71-1.79 (m,1H), 1.69-1.55 (m, 5H), 1.52-1.46 (m, 1H), 1.38-1.30 (m, 6H), 1.29-1.17 (m,12H), 0.96 (t, J = 7.4 Hz, 3H), 0.92-0.84 (m, 1H), 0.68 (s, 3H).

[0110] Pharmacokinetics of test cases in CD-1 mice Test method: Body weight 20 Six 26 g female CD-1 mice (SPF grade, purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd.) were randomly assigned to each compound from each example.

[0111] Intravenous administration group: Fulvestrant was prepared as a clear solution with a concentration of 2.0 mg / ml, with the prescription being 5% DMSO + 5% Tween 80 + 90% normal saline.

[0112] Blood samples were collected from the orbital venous plexus at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug administration and placed into centrifuge tubes pre-added with EDTA-K2. Plasma was separated by centrifugation, and the sample concentration was subsequently determined using a non-standard method developed in the laboratory. In the gavage administration group, the test compound was administered at an equimolar dose (equivalent to 25 mg / kg of fulvestrant, calculated as compound dose = 25 * MW). cpd / MW 氟维司群 Mice were administered the following medication by gavage: 6.5% DMSO + 20% Polyoxyl 15 Hydroxystearate + 73.5% physiological saline. Blood samples were collected from the orbital venous plexus at 0.167, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, under ice-water bath conditions, and transferred to centrifuge tubes pre-added with PMSF (esterase inhibitor) and EDTA-K2. Plasma was rapidly separated by centrifugation and pre-treatment (the centrifugation and pre-treatment times were controlled within the pre-defined whole blood / plasma stability time range). Subsequently, the sample concentration was determined according to a non-standard method developed in the laboratory.

[0113] Bioavailability calculation: F%* = AUC cpd / AUC 氟维司群 / 2.5×100% Among them: AUC cpd The AUC values ​​for the release of fulvestrant from the compounds of this invention are shown in Table 1. AUC 氟维司群 AUC corresponding to 10 mpk IV 10 mpk of fulvestrant; The calculation method marked with * refers to the invention patent "Flavivestram Derivatives and Their Preparation Methods and Pharmaceutical Uses", patent number CN 116836216 A.

[0114] Reference compound A is compound Ia disclosed in WO2023105303, with the following structural formula:

[0115] Reference compound A The control compound B is compound 1 disclosed in CN116836216, with the following structure:

[0116] Reference compound B The pharmacokinetic parameters of the compounds in this application and control compounds A and B are detailed in Table 1.

[0117] Table 1. Pharmacokinetic parameters of the compounds

[0118] Table 2 details the test results of the pharmacokinetic parameters of the compounds in this application and control compounds A and B converted to fulvestrant.

[0119] Table 2. Pharmacokinetic parameters of the compound converted to fulvestrant

[0120] Note: 1. The formula for calculating F (marked with *) is F% = AUCcpd / AUC fulvestrant / 2.5 × 100% AUCcpd is the AUC of the fulvestrant released by the compound of the present invention, corresponding to the AUC values ​​in Table 1; AUC for fulvestrant is the AUC corresponding to 10 mpk of fulvestrant administered intravenously (IV 10 mpk). 2. The above pharmacokinetic data are derived from mean plasma concentration. Time data were calculated using Phoenix WinNonlin 8.1 (non-room model). N / A indicates not applicable, and NT indicates not measured.

[0121] Figure 1 A comparison of the parent drug and its metabolite fulvestrant after oral administration of compounds 3 and 6. Figure 2 A comparison of the parent drug and its metabolite fulvestrant after oral administration of compounds 7 and 8. Figure 3 A comparison of the parent drug and the metabolite fulvestrant after gavage administration of compounds 9 and 11.

[0122] Based on the above test results, the compounds in this application, after prodrug modification, achieve relatively ideal oral bioavailability. In terms of Tmax, Cmax, and AUC of conversion to fulvestrant, the compounds synthesized in this application can be rapidly and relatively completely converted to fulvestrant (the Tmax of compounds 1 / 3 / 5 / 6 / 7 / 8 / 15 / 17 / 18 converted to fulvestrant is 0.5-1h, and the exposure of the original drug of the above compounds is less than 5% of the sum of the exposure of the original drug and the exposure of the converted fulvestrant).

[0123] The above description is merely an embodiment of this application, and the scope of protection of this application is not limited to these specific embodiments, but is determined by the claims of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the technical concept and principles of this application should be included within the scope of protection of this application.

Claims

1. A compound, characterized in that, The compound is selected from formula (I) or formula (II): Formula (I) Equation (II) Wherein, R1 is selected from saturated or unsaturated hydrocarbon groups, aromatic groups, and combinations of hydrocarbon groups and aromatic groups with 1 to 20 carbon atoms; the hydrocarbon group can be a substituted or unsubstituted alkyl, cycloalkyl, oxetyl, azacycloalkyl, or thioheteroalkyl group; the substituent is selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -C≡C, -OCH3, -COCH3, -SO2CH3, -SO2NH2, -CF3, CF2Cl, -CHF2, -COOH; the aromatic group is selected from substituted or unsubstituted 5- or 6-membered aromatic heterocycles; when the aromatic group is substituted, the substituent is selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -C≡C, -OCH3, -COCH3, -SO2CH3, -SO2NH2, -CF3, -CHF2, -CF2Cl, -COOH; R2 is selected from hydrogen or... ; R3 is selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups, wherein the substituents are selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -C≡C, -OCH3, -COCH3, -SO2CH3, -SO2NH2, -CF3, CF2Cl, -COOH.

2. The compound according to claim 1, characterized in that, R1 is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, styryl, 3-butyl-1,2-dithiacyclopentane, propenyl, pyridine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, pyrrole, pyrazole, imidazole, oxazole, oxadiazole, 1,2,3 Triazole, 1,2,4-triazole, tetrazolium, pyridazine; or R1-COOH is at least one of lysine, arginine, histidine, glucuronic acid, gluconic acid, and betaine; R3 is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The substituents of R1 or R3 are selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -OCH3, -SO2CH3, -SO2NH2, -CF3, -CHF2; Preferably, R1 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, styryl, 3-butyl-1,2-dithiacyclopentane, propenyl, 2-thiophene, 3-thiophene, 2-pyrazole, 3-pyrazole; R3 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the substituents of R1 or R3 are selected from 0 to 4 halogens, -OH, -NH2, -NO2, -CONH2, -CN, -OCH3, -SO2CH3, -SO2NH2, -CF3, -CHF2.

3. The compound according to claim 1, characterized in that, R1 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. , , , , , , , , At least one of them, * indicates a connection site.

4. The compound according to claim 3, characterized in that, The compound is selected from one of the following formulas: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。 5. A pharmaceutical composition, characterized in that, It includes the compound or its stereoisomer, deuterated product, solvate, pharmaceutically acceptable salt or eutectic as described in any one of claims 1-4, and pharmaceutically acceptable carrier or excipient.

6. An ADC, DAC, or other coupling molecule, characterized in that, It includes the compound or its stereoisomer, deuterated product, solvate, pharmaceutically acceptable salt or eutectic as described in any one of claims 1-4, and pharmaceutically acceptable carrier or excipient.

7. A method for preparing the compound according to any one of claims 1-4, characterized in that, When R2 is H, the method for preparing the compound with the structure of formula (I) includes the following steps: Fulvestrant and the first compound were added to a solvent and reacted at 0-5°C for 0.5-24 h in the presence of an acid-binding agent. The mixture was then washed, dried, filtered, and purified to obtain the final product. The method for preparing the compound with the structure of formula (II) includes the following steps: The fulvestrant and the second compound were added to a solvent and reacted at 0-5°C for the first time in the presence of an acid-binding agent, followed by a second time at 20-30°C. The mixture was then washed, dried, filtered, and purified to obtain the final product. R2 is The method for preparing the compound with the structure of formula (I) includes the following steps: Fulvestrant and the first compound were added to a solvent and reacted at 0-5°C for at least 2 hours in the presence of an acid-binding agent. After washing, drying, filtering, and purification, the first intermediate was obtained. The first intermediate and the first compound were then added to a solvent and reacted at 0-5°C for 0.5-24 hours in the presence of an acid-binding agent. After washing, drying, filtering, and purification, the final product was obtained. The method for preparing the compound with the structure of formula (II) includes the following steps: Fulvestrant and the second compound were added to a solvent and reacted at 0-5°C for a first time in the presence of an acid-binding agent, followed by a second time at 20-30°C. After washing, drying, filtering, and purification, the second intermediate was obtained. The first intermediate and the first compound were then added to a solvent and reacted at 0-5°C for 0.5-24 h in the presence of an acid-binding agent. After washing, drying, filtering, and purification, the final product was obtained. The first compound has a first reactive group and an R1 group, wherein the first reactive group is selected from acyl chloride and carboxyl groups; the structural formula of the second compound is: X is selected from halogens.

8. The preparation method according to claim 7, characterized in that, The first time is 0.5-24h, and the second time is 0.5-24h.

9. The use of the compound of any one of claims 1-6, the pharmaceutical composition of claim 5, or the ADC, DAC, or other conjugate of claim 6 in the preparation of a medicament for the prevention and / or treatment of estrogen receptor-mediated diseases; Preferably, the estrogen receptor-mediated diseases include tumors; More preferably, the estrogen receptor-mediated diseases include breast cancer, ovarian cancer, endometrial cancer, prostate cancer, colon cancer, lung cancer, and melanoma. More preferably, the estrogen receptor-mediated diseases include breast cancer, ovarian cancer, endometrial cancer, and cervical cancer.

10. The use of the compound of any one of claims 1-6, the pharmaceutical composition of claim 5, or the ADC, DAC, or other conjugate of claim 6 in the preparation of a medicament for treating and inhibiting and / or degrading estrogen receptor-mediated diseases.

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