Molecular chaperone HSP70 mediated EML4-ALK targeted degradation agent as well as preparation method and application of molecular chaperone HSP70 mediated EML4-ALK targeted degradation agent

Abstract

The invention discloses an EML4-ALK targeted degradation agent based on molecular chaperone HSP70 mediation as well as a preparation method and application thereof, and belongs to the technical field of medicines, the degradation agent does not depend on von Hippel-Lindeau E3 ligase and Cerebron E3 ligase ligands, and depends on a specific HSP70 molecular chaperone degradation pathway in cancers. Compared with the existing EML4-ALK degradation agent, the HSP70 molecular chaperone EML4-ALK degradation agent disclosed by the invention has the advantages that the anti-tumor activity is obviously improved, and the target spot selectivity is improved by more than 7 times. The degradation agent is simple in synthetic route and mild in reaction condition, can be used for being developed into a new generation of EML4-ALK targeted drugs, and has great clinical application value and considerable market potential.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical drugs, and particularly relates to an EML4-ALK targeted degrader based on the HSP70 molecular chaperone, and provides a preparation method of such degrader and the application of the degrader in anti-tumor treatment. Background Art

[0002] The EML4-ALK fusion gene was first reported by Soda et al. They amplified a 3926 bp DNA fragment from the tumor tissue of lung adenocarcinoma patients, and this fragment encoded a protein composed of 1059 amino acids, namely the fusion protein EML4-ALK. Soda et al. found in subsequent experiments that implanting the EML4-ALK gene into normal lung cells could induce carcinogenesis, suggesting that EML4-ALK has carcinogenic effects. Later, it was found that EML4-ALK was also highly expressed in lymphoma.

[0003] Non-small cell lung cancer (NSCLC) is a malignant tumor with relatively high morbidity and mortality, threatening human health. With the in-depth study of molecular targeting, a breakthrough has been made in the molecular mechanism of lung cancer. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is one of the most important pathogenic driver genes of NSCLC discovered so far. Therefore, EML4-ALK has become a research hotspot in NSCLC. Currently, four generations of targeted drugs against EML4-ALK have been developed, and patients have benefited significantly from these drugs. However, with the prolongation of the medication time, secondary mutations of EML4-ALK will occur, resulting in drug resistance in patients.

[0004] In view of the fact that long-term inhibition of the function of EML4-ALK often increases the probability of secondary mutations, targeted protein degradation may help to solve the problem of secondary mutations. Currently, several PROTAC degraders have also been reported for this target. For example, Gao et al. discovered the orally available PROTAC CPD-1224, which avoided the side effect of hemolysis, and degraded the difficult-to-treat mutants L1196M / G1202R in vivo, and correspondingly slowed down tumor growth, which was significantly superior to the third-generation ALK inhibitor drug lorlatinib. These results also verified that the degrader helps to solve the binding site resistance mutations in cancer.

[0005] However, multiple PROTAC degrading agents reported currently, such as CPD-1224, etc., are all developed based on von Hippel-Lindau E3 ligase and Cereblon E3 ligase ligands. Since the expression specificity of von Hippel-Lindau E3 ligase and Cereblon E3 ligase ligands in cancer is not high, the specificity of the existing EML4-ALK PROTAC designed based on this is not high and it is prone to off-target effects. In addition, the CRBN ligand in PROTAC is released in the blood, increasing the toxic and side effects. To solve this technical problem, the existing technical solution is to explore new degrading methods to improve the degrading activity and tumor tissue selectivity of EML4-ALK PROTAC.

[0006] Based on this, the present invention provides another technical solution, which is to research and develop an EML4-ALK degrading agent that is not an E3 ligase ligand. HSP70 is a highly conserved molecular chaperone that widely exists in eukaryotes and prokaryotes. It plays a key role in many important biological processes within cells, especially in protein folding, repair, transportation, and degradation. HSP70 not only helps newly synthesized polypeptide chains fold correctly but also participates in maintaining protein stability under stress conditions. In recent years, it has been found that HSP70 also plays an important role in the process of protein degradation, especially by interacting with the ubiquitin-proteasome pathway, lysosome pathway, and autophagy pathway to mediate the degradation of specific proteins. The abnormal expression or dysfunction of HSP70 is related to various diseases, including neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), cancer, and cardiovascular diseases, etc. In these diseases, HSP70 may affect the pathological process by regulating the protein degradation pathway. For example, it inhibits the accumulation of abnormal proteins or promotes the survival and drug resistance of cancer cells.

[0007] In view of this, the present invention utilizes the high specific expression of HSP70 in cancer and the characteristics of multi-pathway protein degradation of HSP70 to develop a chimera for targeted degradation of EML4-ALK mediated by the molecular chaperone HSP70. Summary of the Invention

[0008] Aiming at the problems existing in the prior art, the first aspect of the design of the present invention is to provide an EML4-ALK targeted degrading agent mediated by the molecular chaperone HSP70, and this targeted degrading agent is a compound represented by the structural general formula (Ⅰ) or a pharmaceutically acceptable salt.

[0009]

[0010] The second aspect of the present invention is to provide a preparation method of an EML4-ALK targeted degrading agent mediated by the molecular chaperone HSP70, including the following steps:

[0011] Step 1: Synthesis of the compound 1,2-bis(4-methoxyphenyl)ethane-1,2-dione shown in formula (II):

[0012] Oxalyl chloride (3 mL, 35.2 mmol) was slowly added to a mixture of anisole (11.4 g, 106 mmol) and anhydrous aluminum trichloride (21.3 g, 250 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, it was cooled to room temperature and poured into ice water. It was extracted with dichloromethane, and the organic phase was collected, washed with 2N HCl, then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 5.97 g (62%) of the purified product as a yellow solid.

[0013] Step 2: Synthesis of the compound 4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazol-1-yl)methyl)benzoic acid (Apoptozole-COOH) shown in formula (III):

[0014] 4-(Aminomethyl)benzoic acid (2 g, 13.2 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (3.27 mL, 19.8 mmol), 4,4-dimethoxybenzil (5.36 g, 19.8 mmol), and ammonium acetate (6.17 g, 79.4 mmol) were dissolved in acetic acid and stirred at 100 °C for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, and washed with water, saturated NaHCO3, and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash column chromatography (DCM:MeOH = 15:1) to obtain 1.6 g (52%) of the purified product as a white solid.

[0015] Step 3: Synthesis of the carboxylic acid intermediate Apoptozole-Linker shown in formula (V):

[0016] The Apoptozole-COOH intermediate prepared in the previous step and amino-substituted tert-butyl ester derivatives of different lengths were reacted under the action of EDCI / HOBT to form the amide intermediate shown in formula (IV); then it was dissolved in a solution of DCM:TFA (1:1), stirred at room temperature for 4 hours, the excess solvent was evaporated, and the residue was purified by silica gel column chromatography to obtain the corresponding carboxylic acid intermediate.

[0017] Step 4: Synthesis of the final targeted degrader shown in formula (VI)

[0018] Dissolve the Apoptozole-Linker carboxylic acid intermediate prepared above in DMF, add HATU, DIPEA and commercially available Ceritinib, stir at room temperature for 12 hours for reaction, dilute with water after the reaction, extract with ethyl acetate and wash with saturated brine, filter and concentrate after drying, and purify by column chromatography to obtain the final product.

[0019] The synthetic route is as follows:

[0020]

[0021] The above synthetic method has high selectivity and mild reaction conditions, and can effectively synthesize target compounds containing multiple aromatic rings and complex structures. Through reasonable reaction steps and synthetic routes of intermediates, not only the synthesis efficiency is improved, but also complex post-treatment steps are avoided, ensuring the purity and yield of the product. In addition, the method of the present invention can be applied to large-scale production, and provides a new synthetic route for the development of new drug molecules or functional materials.

[0022] The third aspect of the present invention lies in providing a pharmaceutical composition, which comprises the above compound for targeted degradation of EML4-ALK based on HSP70 molecular chaperone or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0023] The fourth aspect of the present invention lies in providing the application of the above targeted degrader and the above pharmaceutical composition in the preparation of drugs for treating EML4-ALK-related diseases.

[0024] This application has great clinical application value for targeted treatment or prevention of diseases mediated by abnormal expression or activation of EML4-ALK, and has considerable market potential.

[0025] Furthermore, the EML4-ALK-related diseases include lung cancer and lymphoma.

[0026] Furthermore, both the lung cancer and lymphoma are caused by high expression or abnormal activation of EML4-ALK, including non-small cell lung cancer, T cell lymphoma cells and anaplastic large cell lymphoma.

[0027] Compared with the prior art, the HSP70 chaperone-based EML4-ALK degrader provided by the present invention has strong degradation activity, high selectivity, and good safety. The cytotoxic effect on the human T-cell lymphoma cell line Karpas-299 was measured at the cellular level, and the results showed that the EML4-ALK degrader of the present invention had more than 4-fold tumor suppression activity compared with similar compounds. The degradation and selectivity of the EML4-ALK protein were measured at the molecular level, and the results showed that the EML4-ALK degrader of the present invention had more than 19-fold selectivity compared with similar compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 1H NMR spectrum of compound GDAz-15;

[0029] Figure 2 13C NMR spectrum of compound GDAz-15;

[0030] Figure 3 1H NMR spectrum of compound GDAz-16;

[0031] Figure 4 13C NMR spectrum of compound GDAz-16;

[0032] Figure 5 1H NMR spectrum of compound GDAz-17;

[0033] Figure 6 13C NMR spectrum of compound GDAz-17;

[0034] Figure 7 IC50 of compounds GDAz-15 to 17 against Karpas-299 cell line;

[0035] Figure 8 Degradation of EML4-ALK protein in Karpas-299 cell line by compounds GDAz-15 and GDAz-17. DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention will be further described below in conjunction with specific embodiments for better understanding of the technical solution.

[0037] Example 1: The synthesis routes of EML4-ALK degraders GDAz-15 to 17 are as follows:

[0038]

[0039] Preparation method: Preparation of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione shown in formula (II): Oxalyl chloride (3 ml, 35.2 mmol) was slowly added to a mixture of anisole (11.4 g, 106 mmol) and anhydrous aluminum chloride (21.3 g, 250 mmol) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 6 hours. After cooling, it was poured into ice water, extracted with dichloromethane, and the collected organic phase was washed with 2N HCl and then with anhydrous Na 2 SO 4 dried, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol. The obtained precipitate was heated, washed several times with ethanol, and dried to obtain 5.97 g (62%) of pure product as a yellow solid.

[0040] Synthesis of the compound shown in formula (III), 4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazol-1-yl)methyl)benzoic acid (Apoptozole-COOH): 4-(Aminomethyl)benzoic acid (2 g, 13.2 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (3.27 mL, 19.8 mmol), 4,4-dimethoxybenzil (5.36 g, 19.8 mmol), and ammonium acetate (6.17 g, 79.4 mmol) were dissolved in acetic acid and stirred at 100 °C for 12 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM:MeOH = 15:1) and dried to obtain 1.6 g (52%) of pure product in the form of a white solid.

[0041] Preparation of the intermediate shown in formula (IV):

[0042] EDCI (1.2 equivalents), HOBT (1.2 equivalents), and an ammonia derivative containing a tert-butyl ester (1.2 equivalents) were added to a DMF solution of the carboxylic acid intermediate shown in formula (III) prepared above (1.2 equivalents). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction system was diluted with water, extracted 3 times with ethyl acetate, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by column chromatography to obtain the intermediate shown in formula (IV).

[0043] Preparation of the intermediate shown in formula (V):

[0044] Dissolve the above-prepared intermediate (IV) in a mixed solution of DCM:TFA = 1:1 and stir at room temperature for 4 hours. Subsequently, remove the excess solvent by rotary evaporation under reduced pressure, and continue to purify the obtained residue by silica gel column chromatography to obtain the carboxylic acid derivative shown in formula (V) with a yield of 90%.

[0045] Synthesis of the final product shown in formula (VI)

[0046] Add HATU (1.2 equivalents), DIPEA (6 equivalents) and commercially available Ceritinib (1.2 equivalents) to a DMF solution of the above-prepared carboxylic acid intermediate (V) (1.2 equivalents). Stir the reaction mixture at room temperature for 12 hours. After the reaction is completed, dilute the reaction system with water, extract it 3 times with ethyl acetate, wash it with saturated brine, and dry it over Na 2 SO 4 dry, filter and concentrate. The obtained residue is purified by column chromatography to obtain the colorless final product GDAz-15-17 as a colorless solid. The following are the specific NMR characterization data of the final product:

[0047] 4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazol-1-yl)methyl)-N-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)benzamide, denoted as GDAz-15, and its 1H NMR spectrum is as Figure 1 shown, and its 13C NMR spectrum is as Figure 2 shown:

[0048] 1 H NMR (400 MHz, CDCl 3)δ9.45(s,1H),8.50(d,J=7.6Hz,1H),8.10–7.91(m,4H),7.86(dd,J=7.9,1.6Hz,1H),7.77–7.68(m,3H),7.52(d,J=7.8Hz,1H),7.45–7.40(m,2H),7.14–7.06(m,2H),7.02(d,J=5.3Hz,1H),6.89(d,J=8.0Hz,2H),6.84–6.78(m,2H),6.74–6.68(m,2H),6.59(s,1H),5.06(s,2H),4.70(dd,J=10.8,2.2Hz,1H),4.45(p,J=6.1Hz,1H),3.90(d,J=14.7Hz,1H),3.75(d,J=5.5Hz,4H),3.69(s,3H),3.58(s,8H),3.18(h,J=6.9Hz,1H),3.03(td,J=13.2,2.4Hz,1H),2.80(td,J=10.2,8.6,5.8Hz,1H),2.62–2.46(m,3H),2.09(s,3H),1.71(t,J=14.9Hz,2H),1.52–1.42(m,2H),1.32–1.21(m,13H). 13 C NMR(101MHz,CDCl 3 )δ168.10,165.66,159.13,157.58,156.31,154.31,154.13,143.69,143.11,139.22,137.88,137.39,135.51,133.62,133.06,131.82,131.20,131.07,130.74,130.26,129.42,127.49,126.92,126.81,125.88,125.49,124.67,123.85,123.33,122.61,122.15,120.96,119.72,113.62,112.68,109.75,104.82,70.63,69.34,68.96,66.13,54.43,54.26,54.16,47.14,45.44,41.55,38.88,37.20,32.44,32.28,31.13,21.22,17.93,14.33.HRMS(ESI)calcd for[C 68 H 71 ClF 6 N 8 O 9 S+H]+ 1325.4736, found 325.4711。

[0049] 4 - ((2 - (3,5 - bis(trifluoromethyl)phenyl)-4,5 - bis(4 - methoxyphenyl)-1H - imidazol - 1 - yl)methyl)-N-(2-(2-(2-(3-(4-(4 - ((5 - chloro - 4 - ((2 - (isopropylsulfonyl)phenyl)amino)pyrimidin - 2 - yl)amino)-5 - isopropoxy - 2 - methylphenyl)piperidin - 1 - yl)-3 - oxopropoxy)ethoxy)ethoxy)ethyl)benzamide, denoted as GDAz - 16, and its proton nuclear magnetic resonance spectrum is as Figure 3 shown, and its carbon nuclear magnetic resonance spectrum is as Figure 4 shown:

[0050] 1 H NMR(400MHz, CDCl 3 ) δ 9.48(s, 1H), 8.48(d, J = 8.5Hz, 1H), 8.03(d, J = 21.0Hz, 3H), 7.90(s, 1H), 7.85(d, J = 6.4Hz, 1H), 7.75(s, 2H), 7.66(s, 1H), 7.56–7.50(m, 1H), 7.46–7.40(m, 2H), 7.28(d, J = 5.3Hz, 1H), 7.12–7.06(m, 2H), 6.90(d, J = 8.2Hz, 2H), 6.83–6.78(m, 2H), 6.73–6.68(m, 2H), 6.60(s, 1H), 5.06(s, 2H), 4.68(d, J = 13.1Hz, 1H), 4.49–4.41(m, 1H), 3.86(d, J = 13.6Hz, 1H), 3.74(s, 3H), 3.68(s, 5H), 3.56(d, J = 6.2Hz, 12H), 3.17(q, J = 6.9Hz, 1H), 2.99(t, J = 13.1Hz, 1H), 2.83–2.73(m, 3H), 2.52–2.45(m, 1H), 2.08(s, 3H), 1.75–1.62(m, 2H), 1.46(ddd, J = 16.8, 8.5, 4.1Hz, 2H), 1.30–1.22(m, 12H). 13 C NMR(101MHz, CDCl 3)δ168.03,165.66,159.14,157.59,156.12,154.37,153.58,143.92,143.07,139.08,137.72,137.29,135.82,133.63,133.11,131.70,131.20,131.08,130.75,130.25,129.45,127.55,126.93,126.60,125.85,125.41,124.63,123.85,122.61,122.25,120.89,120.61,120.01,113.62,112.69,109.81,104.76,70.60,69.40,69.28,69.07,68.90,66.12,54.47,54.25,54.16,47.16,45.31,41.45,38.85,37.20,32.39,32.22,31.13,21.21,21.14,17.91,14.32.HRMS(ESI)calcd for[C 70 H 75 ClF 6 N 8 O 10 S+H] + 1369.4998,found 1369.4969。

[0051] 4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazol-1-yl)methyl)-N-(15-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)benzamide, denoted as GDAz-17, and its proton nuclear magnetic resonance spectrum is as Figure 5 shown, and its carbon nuclear magnetic resonance spectrum is as Figure 6 shown:

[0052] 1 H NMR(400MHz,CDCl 3)δ9.43(s,1H),8.49(d,J=7.3Hz,1H),8.06(s,1H),8.01(s,2H),7.94(s,1H),7.84(dd,J=7.9,1.6Hz,1H),7.75–7.72(m,2H),7.57–7.48(m,2H),7.45–7.40(m,2H),7.35–7.30(m,1H),7.12–7.07(m,2H),6.88(d,J=8.1Hz,2H),6.83–6.78(m,2H),6.74–6.69(m,2H),6.59(s,1H),5.07(s,2H),4.68(d,J=13.4Hz,1H),4.46(p,J=6.1Hz,1H),3.85(d,J=13.4Hz,1H),3.73(s,3H),3.69(s,4H),3.58–3.50(m,16H),3.34(s,1H),3.18(p,J=6.9Hz,1H),2.98(t,J=11.8Hz,1H),2.79(t,J=12.0Hz,1H),2.54(t,J=6.8Hz,3H),2.09(s,3H),1.70(t,J=9.1Hz,2H),1.51–1.38(m,2H),1.29–1.22(m,12H). 13 C NMR(101MHz,CDCl 3 )δ167.99,165.61,159.12,157.57,156.36,154.28,143.68,143.11,139.16,137.39,135.57,133.64,133.06,131.85,131.19,130.24,129.46,127.48,126.92,125.85,125.52,124.63,123.82,122.62,122.15,120.97,119.70,113.61,112.68,109.75,70.58,69.40,69.08,68.96,66.27,54.43,54.25,54.16,47.15,45.35,41.43,38.82,37.21,32.37,32.24,31.17,21.15,17.94,14.32.HRMS(ESI)calcd for[C 72 H 79 ClF 6 N 8 O 11 S+H] + 1413.5260,found 1413.5236。

[0053] Example 2: Inhibitory Activity of EML4-ALK Degrader GDAz-15-17 against Cancer Cell Lines

[0054] Anti-cell Proliferation Activity Assay: The cytotoxicity and IC of all target compounds in Karpas-299 cells (RPMI 1640 medium), a human T-cell lymphoma cell line with high ALK expression, were evaluated using the CCK-8 method 50 . The cells were seeded in 96-well plates at a cell density of 5×10 3 cells / well for 24 hours. Then, the cells were treated with different concentrations of the compound for 72 h. After discarding the original medium, 100 μL (1:10) of the medium solution containing CCK-8 was added to each well. After culturing for 1.5 h, the absorbance at 450 nm was measured using a microplate reader (TECAN). After converting the absorbance value to the inhibition rate, the IC 50 value was calculated using Graphpad Prism 5. The results are as Figure 7 shown. Compounds GDAz-15 and GDAz-17 showed prominent anti-cell proliferation activity, especially GDAz-17

[0055] Example 3: EML4-ALK Protein Degradation Activity of EML4-ALK Degraders GDAz-15 and GDAz-17 against Karpas-299 Cells of Human T-Cell Lymphoma Cell Line

[0056] Karpas-299 cells were cultured in vitro and then seeded at 1 million cells / well in 6-well plates with a total volume of 2 ml per well. After culturing for 24 hours, the medium was discarded, and 2 ml of the medium with different drug concentrations was added. At the same time, a solvent control group was set up. After the drug acted for 48 h, the total cell protein was collected by RIPA, and the protein levels of the target protein EML4-ALK and the internal reference protein GAPDH in the cells were detected by WB. The results are as Figure 8 shown. Compounds GDAz-15 and GDAz-17 could significantly degrade the EML4-ALK fusion protein at low concentrations

[0057] Example 4: Comparison of the Degradation Selectivity of GDAz-17 and CPD-1224 for ALK Fusion Protein

[0058] Construct 293T cells stably expressing CAD-ALK, ATIC-ALK, KLC1-ALK, EML4-ALK-GFP fusion proteins and RFP protein, as well as 293T cells stably expressing p113-GFP fusion protein and RFP protein. Seed each 293T cell expressing dual fluorescent proteins into a 96-well plate at a concentration of 10,000 cells / well, with a total volume of 200 μl per well. After culturing for 24 hours, discard the medium and add 200 μl of medium with different drug concentrations. At the same time, set up a solvent control group. After the drug acts for 48 hours, use an enzyme-linked immunosorbent assay (ELISA) reader to detect the GFP emission wavelength at 509 nm and the RFP emission wavelength at 588 nm. Calculate the relative fluorescence value of GFP / RFP per well. Calculate the DC of the compound promoting the degradation of the ALK fusion protein 50 , and the results are shown in the following table. By comparison, the EML4-ALK fusion protein target selectivity of GDAz-17 is about 7 times higher than that of CPD-1224 (124 nM / 17 nM = 7.29), and the results are shown in Table 1.

[0059] Table 1

[0060]

[0061]

Claims

1. A molecular chaperone HSP70-mediated EML4-ALK targeted degradation agent, characterized in that: The targeted degradation agent is a compound represented by the general structural formula (I) or a pharmacologically acceptable salt thereof.

2. The method for preparing a molecular chaperone HSP70-mediated EML4-ALK targeted degradation agent according to claim 1, characterized in that: The following steps are involved: 1) slowly adding oxalyl chloride into a mixture of anisole and anhydrous aluminum chloride to react to obtain a compound represented by formula (II); 2) reacting the compound represented by formula (II), 4-(aminomethyl)benzoic acid, 3,5-bis(trifluoromethyl)benzaldehyde and ammonium acetate in acetic acid to obtain the intermediate compound represented by formula (III) as the linker part with HSP70; 3) reacting the compound intermediate represented by formula (III) with tert-butyl ester derivatives substituted with amino groups of different lengths under the action of EDCI / HOBT to form an amide intermediate represented by formula (IV); 4) dissolving the amide intermediate represented by formula (IV) in a mixed solution of DMC and TFA to react to obtain a carboxylic acid intermediate represented by formula (V); 5) The carboxylic acid intermediate represented by formula (V) is dissolved in DMF, and the final product targeted degradation agent represented by formula (VI) is prepared under the conditions of HATU and DIPEA. The synthesis route is as follows:

3. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound or pharmacologically acceptable salt for targeting and degrading EML4-ALK based on the HSP70 molecular chaperone as described in claim 1, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

4. Use of the targeted degradation agent according to claim 1 and the pharmaceutical composition according to claim 3 in the preparation of drugs for treating EML4-ALK related diseases.

5. The use according to claim 4, characterized in that The EML4-ALK-related diseases include lung cancer and lymphoma.

6. The use according to claim 5, characterized in that The lung cancer and lymphoma are both caused by high expression or abnormal activation of EML4-ALK.

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