CN113024460A - Tetrahydroisoquinoline compounds as estrogen receptor and histone deacetylase double-target compounds, and synthesis method and application thereof - Google Patents

Abstract

The invention discloses a tetrahydroisoquinoline compound serving as an estrogen receptor and histone deacetylase double-target compound, a synthesis method and application. The invention can simultaneously target Estrogen Receptor (ER) and Histone Deacetylase (HDAC), plays the dual roles of degrading ER and inhibiting HDAC, and can be used forCan be used for preparing medicine for treating human breast cancer.

Description

Tetrahydroisoquinoline compounds as estrogen receptor and histone deacetylase double-target compounds, and synthesis method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a tetrahydroisoquinoline compound capable of targeted degradation of estrogen receptor alpha (ER alpha) and inhibition of Histone Deacetylase (HDAC), a synthesis method and application thereof.

Background

Estrogen Receptors (ERs) are one of 48 members of the Nuclear Receptor (NR) superfamily, and exert a hormonal action by combining with Estrogen ligands such as Estradiol (E2), and when an Estrogen signaling pathway is abnormal, various diseases such as endometrial cancer, ovarian cancer, osteoporosis, arteriosclerosis, alzheimer disease and the like are often caused, and especially, the breast cancer is closely related to the ER. At present, hormone replacement therapy is mainly adopted for clinically treating breast cancer. For example, first line drugs Selective Estrogen Receptor Modulators (SERMs) Tamoxifen (Tamoxifen), Raloxifene (Raloxifene), and selective estrogen receptor down-regulators (SERDs) such as Fulvestrant (Fulvestrant), and the like. However, these drugs often have side effects, such as tamoxifen, which may cause drug resistance and increase the risk of endometrial cancer after long-term use.

Histone and non-histone acetylation levels play important roles, among others, in gene translation, cell cycle and structural function of microtubules. Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs) regulate the balance of cellular acetylation levels. It was found that dysbalance between HATs and HDACs could lead to tumorigenesis. The HDACs family contains 18 kinds of deacetylases, and is different in structure, substrate specificity, enzyme activity mechanism, subcellular localization, and tissue specificity, and can be divided into 4 different families, i.e., I, II, III, and IV, according to their homology to yeast cell deacetylase sequences. Histone deacetylase 6(HDAC6) belongs to the IIb family, shuttles in the cytoplasm and nucleus, is mainly localized to the cytoplasm, and is the only isozyme in HDACs with two functionally homologous catalytic domains and a C-terminal ubiquitin-binding zinc finger domain. Thus, HDAC6 may regulate a range of cellular processes by deacetylating or ubiquitinating substrate proteins, affecting human diseases. In recent years, it has been found that HDACs can regulate the level of acetylation at several sites on the estrogen signaling pathway, and can affect gene transcription in the ER. Therefore, HDACs are also considered as a new target for treating breast cancer, and histone deacetylase inhibitors (HDACi) can inhibit the activity of HDACs in breast cancer cells, so that the acetylation degree of histone in breast cancer cells is increased, thereby inhibiting the proliferation of breast cancer cells. Tamoxifen-resistant breast cancer cell line T47D cells expressed higher HDAC6 than non-resistant T47D cells, and treatment with the specific small molecule inhibitor of HDAC6, tulcin, was effective in inhibiting the in vivo tumorigenic capacity of tamoxifen-resistant T47D cells. At present, some ER-HDACI double-target conjugates have been reported, which have good inhibitory effect on breast cancer cells and have the potential of overcoming drug resistance.

Disclosure of Invention

The purpose of the invention is as follows: the invention provides a tetrahydroisoquinoline compound serving as an estrogen receptor and histone deacetylase double-target compound, which can simultaneously target ER alpha and HDAC6 and play double roles of degrading ER alpha and inhibiting HDAC.

Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a pharmaceutical composition.

The last object of the invention is to provide the application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing hormone receptor positive breast cancer and triple negative breast cancer.

The technical scheme is as follows: the present invention provides a compound having the general formula (I) capable of targeted degradation of ER α and effective inhibition of HDAC:

wherein:

x is H or F;

y is selected from the following structures:

in particular, the compound capable of targeted degradation of ER α and effective inhibition of HDAC is selected from the compounds of table 1:

TABLE 1

The second aspect of the present invention provides a method for synthesizing the above compound, the method comprising the steps of:

(1) heating and refluxing compound IA with hydrobromic acid to demethylate compound IB, preferably 48% hydrobromic acid;

(2) condensing the compound IB with a compound IC under the action of a condensing agent HATU to obtain a compound ID;

(3) reducing the compound ID under the action of sodium borohydride and iodine elementary substance to obtain a compound IE;

(4) cyclizing the compound IE and the compound IF under an alkaline condition to obtain a compound IG;

(5) the compound IG is subjected to ester hydrolysis by using lithium hydroxide or hydroxamation by using hydroxylamine hydrochloride to obtain the compound of the formula I, and the specific reaction formula is as follows:

IF is

R is

In a third aspect, the present invention provides the use of the above compound, an isomer or a pharmaceutically acceptable salt thereof for the preparation of an estrogen receptor down-regulator.

The fourth aspect of the present invention provides the use of the above-mentioned compound, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a histone deacetylase inhibitor.

The fifth aspect of the invention provides the use of the compound, the isomer thereof or the pharmaceutically acceptable salt thereof in the preparation of medicaments for treating or preventing hormone receptor positive breast cancer and triple negative breast cancer. The sixth aspect of the present invention provides a composition, which includes the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.

Has the advantages that:

compared with the prior art, the compound provided by the invention has better SERD activity, and also has histone deacetylase inhibitory activity, and has the potential of overcoming drug resistance.

Drawings

FIG. 1 is a graph showing the results of an experiment in which the compounds of the present invention have ER α degradation.

Detailed Description

The NMR data of the final product and the intermediate in the examples are DMSO-d6 or CDCl₃-d3 as solvent and TMS as internal standard, measured by Bruker's 300MHz or 400MHz NMR spectrometer; high Resolution Mass Spectrometry (HRMS) was determined by an Agilent model Q-TOF 6520 mass spectrometer.

Reagents used in the synthesis, purification and isolation of the compounds are: (1) column chromatography silica gel: 200 or 300 mesh silica gel is purchased from Qingdao ocean chemical industry; (2) HSGF254 TLC plate: purchased from the tobacco desk chemical research institute; (3) the conventional solvents used in the column chromatography elution system, such as petroleum ether, dichloromethane, ethyl acetate, methanol and the like, and chemical reagents required by the reaction are all commercially available chemical pure products or analytically pure products except for special instructions.

Example 1: (E) synthesis of (I-1) -3- (4- (2- (2-fluoro-2-methylpropyl) -6-hydroxy-1, 2, 3, 4-tetrahydroisoquinolin-1-yl) phenyl) acrylic acid

Synthesis route:

step 1:

compound IA (3g, 19.7mmol) was dissolved in 20ml of 48% hydrobromic acid and heated at reflux for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature, distilled under reduced pressure, and the solvent was dried by rotary drying to obtain red brown solid IA (2.7g, 99.2%).¹H NMR(300MHz，Methanol-d₄)δ7.23-7.13(m，1H)，6.79-6.69(m，3H)，3.17(t，J＝7.7Hz，2H)，2.91(t，J＝7.6Hz，2H).

Step 2:

compound IB (2.2g, 10mmol) was dissolved in 20ml of N, N-Dimethylformamide (DMF), and N, N-diisopropylethylamine (DIPEA, 5ml,3mmol) and IC-1(1.17g, 11mmol), stirring at room temperature for 10min under nitrogen protection, adding 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 2.85g, 15mmol) under ice bath, and reacting at room temperature for 2 h. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried, and then the solvent was distilled off under reduced pressure, and purified by column chromatography to obtain the objective product ID-1(1.1g, 48%)¹H NMR(300MHz，DMSO-d6)δ9.28(s，1H)，8.08(q，J＝5.1Hz，1H)，7.12-6.99(m，1H)，6.58(dt，J＝4.0，2.5Hz，3H)，3.30-3.19(m，2H)，2.64(dd，J＝8.3，6.6Hz，2H)，1.45(s，3H)，1.38(s，3H).

And step 3:

sodium borohydride (1g, 3mmol) and ID-1(2g, 10mmol) were dissolved in 25ml of anhydrous tetrahydrofuran and a solution of iodine in anhydrous tetrahydrofuran (25ml) was added dropwise slowly at room temperature under nitrogen. After the dropwise addition, nitrogen gas is refluxed and reacted for 6 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline, dried, subjected to reduced pressure distillation to spin-dry the solvent, and purified by column chromatography to obtain the target product IE-1(1.2g, 64%).¹H NMR(400MHz，DMSO-d₆)δ9.30(brs，1H)，7.08(td，J＝7.6，0.9Hz，1H)，6.67-6.55(m，3H)，2.89-2.78(m，4H)，2.69(dd，J＝9.1，6.3Hz，2H)，1.36(s，3H)，1.31(s，3H).

And 4, step 4:

activated molecular sieves were added to a reaction flask, IE-1(0.1g, 0.47mmol) and IF-1(0.19g, 0.95mmol) were dissolved in dry toluene (2ml), followed by triethylamine (0.3ml, 2mmol) and reaction at 90 ℃ for 2h under nitrogen. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline solution, dried, subjected to reduced pressure distillation to spin-dry the solvent, and purified by column chromatography to obtain the target product IG-1(30mg, 16.0%).¹H NMR(300MHz，Chloroform-d)δ7.71(d，J＝16.0Hz，1H)，7.49(d，J＝8.0Hz，2H)，7.34(s，1H)，6.66(d，J＝2.4Hz，1H)，6.62-6.52(m，2H)，6.45(dd，J＝16.0，4.0Hz，1H)，4.60(s，1H)，4.31(q，J＝7.1Hz，2H)，3.53-3.40(m，1H)，3.12-2.99(m，1H)，2.82(d，J＝16.8Hz，1H)，2.68(s，1H)，2.62(d，J＝14.9Hz，1H)，2.50(t，J＝14.5Hz，1H)，1.30(t，J＝10.9Hz，6H)，0.97-0.85(m，3H).

And 5:

compound IG-l (30mg, 0.25mmol) was dissolved in a mixed solvent of tetrahydrofuran (1ml) and water (1ml), and lithium hydroxide (10mg, 0.42mmol) was added. The reaction was carried out overnight at room temperature, and after completion of the reaction, the solvent was distilled off under reduced pressure and purified by column chromatography to give the objective product I-1(15mg, 53.8%).¹H NMR(300MHz，Methanol-d₄)δ7.75-7.63(m，1H)，7.56(dd，J＝8.3，2.0Hz，2H)，7.34(dd，J＝8.1，1.6Hz，2H)，6.62-6.58(m，1H)，6.54-6.44(m，3H)，4.61(s，1H)，3.44(dd，J＝11.6，5.4Hz，1H)，3.03(ddd，J＝14.9，9.1，5.2Hz，1H)，2.80(dt，J＝15.8，4.6Hz，1H)，2.72-2.56(m，2H)，2.51(d，J＝14.4Hz，1H)，1.31-1.24(m，3H)，1.21(d，J＝11.7Hz，3H).

Examples 2 to 20

The synthetic route is as follows:

step 1:

compound IA (3g, 19.7mmol) was dissolved in 20ml of 48% hydrobromic acid and heated at reflux for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature, distilled under reduced pressure, and the solvent was dried by rotary drying to obtain red brown solid IA (2.7g, 99.2%).¹H NMR(300MHz，Methanol-d₄)δ7.23-7.13(m，1H)，6.79-6.69(m，3H)，3.17(t，J＝7.7Hz，2H)，2.91(t，J＝7.6Hz，2H).

Step 2:

dissolving compound IB (2.2g, 10mmol) in 20ml of N, N-Dimethylformamide (DMF), adding N, N-diisopropylethylamine (DIPEA, 5ml, 3mmol) and IC-1(1.17g, 11mmol) under stirring, stirring at room temperature for 10min under the protection of nitrogen, adding 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 2.85g, 15mmol) under ice bath, and reacting at room temperature for 2 h. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate, and saturated with foodWashing with saline, drying, distilling under reduced pressure to remove solvent, and purifying by column chromatography to obtain target product ID-1(1.1g, 48.0%)¹HNMR(300MHz，DMSO-d6)δ9.28(s，1H)，8.08(q，J＝5.1Hz，1H)，7.12-6.99(m，1H)，6.58(dt，J＝4.0，2.5Hz，3H)，3.30-3.19(m，2H)，2.64(dd，J＝8.3，6.6Hz，2H)，1.45(s，3H)，1.38(s，3H).

And step 3:

sodium borohydride (1g, 3mmol) and ID-1(2g, 10mmol) were dissolved in 25ml of anhydrous tetrahydrofuran and a solution of iodine in anhydrous tetrahydrofuran (25ml) was added dropwise slowly at room temperature under nitrogen. After the dropwise addition, nitrogen gas is refluxed and reacted for 6 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline solution, dried, subjected to reduced pressure distillation to spin-dry the solvent, and purified by column chromatography to obtain the target product IE-1(1.2g, 64.0%).¹H NMR(400MHz，DMSO-d₆)δ9.30(brs，1H)，7.08(td，J＝7.6，0.9Hz，1H)，6.67-6.55(m，3H)，2.89-2.78(m，4H)，2.69(dd，J＝9.1，6.3Hz，2H)，1.36(s，3H)，1.31(s，3H).

And 4, step 4:

activated molecular sieves were charged into a reaction flask, IE-1(0.1g, 0.47mmol) and IF-16(0.11g, 0.47mmol) were dissolved in dry toluene (2ml), followed by triethylamine (0.3ml, 2mmol) and reaction at 90 ℃ for 2h under nitrogen. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline, dried, subjected to reduced pressure distillation to spin-dry the solvent, and purified by column chromatography to obtain the target product IG-16(50mg, 24.6%).¹H NMR(300MHz，Chloroform-d)δ7.75(d，J＝8.0Hz，2H)，7.38(d，J＝8.1Hz，2H)，6.82(t，J＝5.1Hz，1H)，6.66(d，J＝2.2Hz，1H)，6.52(d，J＝2.5Hz，1H)，4.59(s，1H)，4.27(d，J＝3.5Hz，2H)，4.25(s，2H)，3.43(dt，J＝11.2，4.9Hz，1H)，3.14-2.97(m，1H)，2.82(d，J＝14.6Hz，1H)，2.76-2.61(m，2H)，2.58-2.34(m，1H)，1.40-1.29(m，6H)，1.27(s，1H)，1.24(s，1H)，1.20(s，1H).

Step 5

Hydroxylamine hydrochloride (4.67g, 67mmo1) was dissolved in methanol (24m1), and potassium hydroxide (5.61g, 100 mmol) was added dropwise in an ice bath) Then reacted at 0 ℃ for 30 min. And after the reaction is finished, carrying out suction filtration on the reaction liquid, and collecting filtrate, namely the methanol solution of hydroxylamine. Adding the compound IG-16(50mg, 0.12mmol) into a newly prepared hydroxylamine methanol solution, reacting at room temperature for 2h, after the reaction is completed, distilling the solvent under reduced pressure, and purifying by column chromatography to obtain the target product I-16(15mg, 53.8%).¹H NMR(400MHz，Methanol-d4)δ7.80(dd，J＝23.9，7.9Hz，2H)，7.39(d，J＝7.8Hz，2H)，6.59(s，1H)，6.46(d，J＝1.4Hz，2H)，4.60(s，1H)，4.03(s，2H)，3.43(d，J＝17.0Hz，1H)，3.26-2.82(m，2H)，2.72(s，2H)，2.63-2.11(m，1H)，1.30(s，6H).

The following other compounds of the present invention were prepared using procedures analogous to those described above.

TABLE 2 exemplary derivatives of Compounds I-16

Example 21: activity assay

Table 3 is a source of reagents used in the following activity tests.

TABLE 3 sources of reagents

Table 4 is the source of the instruments used for the following activity tests.

TABLE 4 Instrument sources

Pharmacological (antiproliferative) test of Compounds

Since MCF-7 cell antiproliferative assays can be used to initially evaluate the inhibition of ER-positive breast cancer by compounds in vitro, some of the compounds synthesized herein were subjected to in vitro MCF-7 antiproliferative assays.

1. Experimental methods

Human breast cancer MCF-7 cells were taken for the biological activity assay in the logarithmic growth phase, the density of the digested cell mass was diluted to 5 × 104 cells/ml with complete medium and the cell suspension was inoculated into 96-well plates with a row gun. Each 96-well plate is provided with a group of blank negative control and a group of blank positive control, the negative control is replaced by complete culture medium with the same volume without adding drugs or cell suspension, the positive control is only added with cell suspension without adding drugs, and the drug is replaced by complete culture medium with the same volume and containing 0.1 percent of DMSO during drug administration. In addition, in order to prevent solvent evaporation of cell suspension in the central test area of the 96-well plate due to long-term placement in a cell culture chamber, 200. mu.l of PBS buffer solution was added to the peripheral 36 wells. After the cells are laid, the cells are placed into the cellsAnd incubating for 24 hours in the cell incubator. Then, the 96-well plate was taken out, and 100. mu.l of complete medium containing the sample was added to each well so that the final concentrations of the samples to be tested were 80. mu.M, 40. mu.M, 20. mu.M, 10. mu.M, and 1. mu.M in this order, and 3 duplicate wells were set for each concentration. After culturing in an incubator for 48 hours, 20. mu.l of 5mg/ml MTT solution was added to each well in the dark, and the mixture was incubated in the incubator for 4 hours. And (3) taking out the 96-well plate, carefully sucking out the culture medium, adding 150 mu l of DMSO solution into each well, placing the well into a shaking instrument, shaking for 10min to completely dissolve out the purple crystals at the bottom, and detecting the light absorption value (OD) of the crystals in an enzyme-linked immunosorbent assay (ELIAS) instrument, wherein the detection wavelength is set to 490 nm. The inhibition rate of each concentration is calculated according to the following formula, a concentration-inhibition rate curve is drawn by GraphPad Prism 7.0, and finally the IC of the compound is given₅₀Value (inhibition rate ═ OD assay-OD negative/OD positive-OD negative).

2. Results of the experiment

Table 5 shows the results of pharmacological (antiproliferative) experiments on the compounds.

Table 5 shows the results of pharmacological (antiproliferative) experiments on the compounds

The human breast cancer MCF-7 cell line is from Kyoho Kayki Biotechnology GmbH, and an estrogen receptor modulator tamoxifen and a histone deacetylase inhibitor SAHA are used as a control group.

Research results show that the compound of the invention has better inhibitory activity on MCF-7 cells.

Antiproliferative activity experiment of (II) triple-negative breast cancer cell line MDA-MB-231

1. Experimental methods

The procedure and dosing concentration settings were the same as MCF-7, and MDA-MB-231 cells were dosed 24h after plating and incubated 24h after dosing.

2. Results of the experiment

Table 6 shows the results of the anti-proliferative Activity test of triple negative breast cancer cell line MDA-MB-231

Table 6 shows the results of the anti-proliferative Activity test of triple negative breast cancer cell line MDA-MB-231

Compound	IC50(μM)	Compound	IC50(μM)
				I-1	-	I-2	-
I-3	-	I-4	-
				I-5	1.01	I-6	0.38
I-7	-	I-8	-
				I-9	-	I-10	＞80μM
I-11	-	I-12	-
				I-13	-	I-14	-
I-15	-	I-16	-
				I-17	-	I-18	-
I-19	-	I-20	-
				Tamoxifen	＞80μM	SAHA	15.44

Research results show that the compound of the invention has better inhibitory activity on MDA-MB-23. And the structure effect trend is consistent with MCF-7.

(III) measuring in vitro HDAC6 inhibitory activity by fluorescence analysis method

To demonstrate that the compounds of the invention have inhibitory effects on HDAC6, the inhibitory activity of HDAC6 of the compounds of the invention was determined using a fluorescence assay with the non-selective HDAC inhibitor SAHA as a positive control.

The results of the experiment (Table 7) show that the compounds of the present invention exhibit certain inhibitory activity against HDAC6 at both 1. mu.M and 0.1. mu.M.

(IV) detection of ER alpha level by Western Blot method

In order to prove that the compound has ER alpha degradation effect, the down-regulation effect of the compounds I-5, I-6, I-2, I-20 and I-10 on the level of ER alpha protein is respectively tested by using a Western Blot method and Fulvestrant as a positive control.

1. Experimental methods

After MCF-7 cells are treated by the compound, the culture medium is removed, PBS is used for washing for 2-3 times, protease inhibitor and RIPA lysate are sequentially added, the culture plate is repeatedly shaken to enable the cells to be in full contact with the culture plate, and then the cells are scraped by a scraper. Transferring the obtained cell suspension into a centrifuge tube, cracking on ice for 30min, repeatedly blowing with a pipette to promote cell lysis, and centrifuging (4 deg.C, 12,000g, 10min) to obtain supernatant as total protein solution. Protein concentration was determined using BCA protein quantitative assay kit according to the kit instructions, then 5 × protein loading buffer was added at a ratio of 4: 1 protein solution to protein loading buffer and boiled in boiling water bath for 15min in preparation for the next step of protein isolation. An equal amount of the above protein solution was added to the gel loading well and prepared for electrophoresis, wherein the voltage of the concentrated gel was 75V and the voltage of the separation gel was 120V. And (5) electrophoretic until bromophenol blue just runs out, and then carrying out mold conversion. Stripping off the band of the target protein, sticking a PVDF membrane, transferring the band to the PVDF membrane through electrophoresis, and then sealing the band for 1h on a decoloring shaking table by using 5% skimmed milk. Primary antibody was added and incubated overnight at 4 ℃ followed by three washes with TBST for 5min each. Secondary antibody was added and incubated at room temperature for 30min, followed by three washes with TBST for 5min each. Preparing ECL mixed solution in a dark room according to the proportion of ECLA to ECLB being 1: 1, then placing the processed PVDF film face upwards in an exposure box, adding the prepared ECL mixed solution to react for 1-2min, discarding the reaction solution, adjusting the exposure condition according to the luminous intensity of the developing reagent, and starting exposure. The resulting films were scanned, destained using Photoshop, and analyzed for optical density values using Alpha software.

2. Results of the experiment

The results are shown in fig. 1, and show that representative compounds selected from the present invention have a degradation effect on ER α protein at a concentration of 0.1 μ M compared to the positive drug fluvetrant, wherein I-6 efficacy is comparable to the positive drug.

Claims (7)

1. A tetrahydroisoquinoline compound used as a dual-target compound of an estrogen receptor and histone deacetylase, an isomer or a pharmaceutically acceptable salt thereof has a structural formula shown as a general formula (I):

wherein:

x is H or F;

y is selected from the following structures:

2. the tetrahydroisoquinoline compound as the dual-target compound of estrogen receptor and histone deacetylase, or the isomer or the pharmaceutically acceptable salt thereof according to claim 1, which is any one of the following compounds:

3. the use of the tetrahydroisoquinoline compounds, isomers or pharmaceutically acceptable salts thereof as estrogen receptor and histone deacetylase double-target compounds according to claim 1 in the preparation of estrogen receptor down-regulating agents.

4. The use of the tetrahydroisoquinoline compounds, isomers or pharmaceutically acceptable salts thereof as estrogen receptor and histone deacetylase double-target compounds according to claim 1 in the preparation of histone deacetylase inhibitors.

5. The use of the tetrahydroisoquinoline compounds, isomers or pharmaceutically acceptable salts thereof as estrogen receptor and histone deacetylase double-target compounds according to claim 1 in the preparation of medicaments for treating or preventing hormone receptor positive breast cancer and triple negative breast cancer.

6. A pharmaceutical composition, comprising the tetrahydroisoquinoline compound as the estrogen receptor and histone deacetylase double-target compound of claim 1, an isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant in a therapeutically effective amount.

7. The method for synthesizing the tetrahydroisoquinoline compounds, isomers or pharmaceutically acceptable salts thereof as the estrogen receptor and histone deacetylase double-target compounds according to claim 1, comprising the steps of:

(1) heating, refluxing and demethylating the compound IA by hydrobromic acid to prepare a compound IB;

(2) condensing the compound IB with a compound IC under the action of a condensing agent HATU to obtain a compound ID;

(3) reducing the compound ID under the action of sodium borohydride and iodine elementary substance to obtain a compound IE;

(4) cyclizing the compound IE and the compound IF under an alkaline condition to obtain a compound IG;

(5) compound IG is subjected to ester hydrolysis using lithium hydroxide or hydroxamation using hydroxylamine hydrochloride to give the compound of formula I, the reaction formula is shown below:

IF is

R is

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