Stress particle targeted degradation agent as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, and discloses a stress particle targeted degradation agent as well as a preparation method and application thereof. The compound provided by the invention comprises a ternary complex composed of a stress particle protein, a linking group and an E3 ubiquitin ligase ligand or a ternary complex composed of a stress particle protein, a linking group and a ribonuclease L ligand, the compounds connected with different ligands have good targeting and degradation effects on the stress particles, can be used as a stress particle targeting degradation agent to be applied to preparation of anti-tumor drugs and anti-neurodegenerative disease drugs, and have good application prospects in treatment of stress particle induced tumor drug resistance and neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a stress granule targeted degradation agent and a preparation method and application thereof. Background Art

[0002] Stress granules (SGs) are dense, membrane-free granular structures in the cytoplasm formed by eukaryotic cells in the face of environmental stress (such as oxidative stress, hypoxic stress, heat shock, etc.). They are mainly composed of untranslated mRNA, translation initiation factors, small ribosomal subunits, and a variety of RNA-binding proteins (such as TIA1, G3BP, etc.). These RNA-binding proteins promote the formation of stress granules through self-polymerization and interaction with mRNA. Stress granules regulate the overall translation level of cells and related signaling pathways through their dynamic formation and disaggregation, and quickly respond to changes in the intracellular environment.

[0003] Under normal physiological conditions, stress granules minimize the damage caused by stress to cells by inhibiting the overall translation level of cells, optimizing resource allocation, and inhibiting apoptosis-related signaling pathways, thereby protecting cells from apoptosis. However, pathological mutations of proteins can lead to abnormal formation of stress granules and inhibit their disintegration, leading to the accumulation of toxic pathological stress granules. Studies have shown that the formation of abnormal toxic pathological stress granules is closely related to chemotherapeutic drug resistance and the occurrence and development of neurodegenerative diseases.

[0004] Many anti-tumor drugs (such as 5-fluorouracil, sorafenib, bortezomib, etc.) can induce the formation of stress granules through various mechanisms such as oxidative stress and endoplasmic reticulum stress. In this process, stress granules, as a cell adaptive protection mechanism, help protect tumor cells from apoptosis, thereby leading to the development of chemotherapy drug resistance. In the pathological process of neurodegenerative diseases, mutant RNA binding proteins, such as FUS, hnRNPA1 and TDP-43, are continuously recruited to stress granules, leading to abnormal pathology of stress granules, further promoting the accumulation of these proteins in the cytoplasm, and being retained in the cytoplasm to form fibrotic aggregates, thereby causing persistent lesions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

[0005] Therefore, stress granules are considered to be an important potential drug target in disease treatment. The development of drugs targeting stress granules has great significance and broad application prospects in treating neurodegenerative diseases and overcoming tumor resistance. Summary of the invention

[0006] The present invention aims to solve at least one of the above-mentioned technical problems existing in the prior art. To this end, one of the purposes of the present invention is to provide a compound; the second purpose of the present invention is to provide a method for preparing the compound; the third purpose of the present invention is to provide a stress granule targeted degradation agent; the fourth purpose of the present invention is to provide the application of the stress granule targeted degradation agent.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides a compound, whose structural formula is shown in formula (A), formula (B) or formula (C):

[0009]

[0010] Among them, in formula (A) to formula (C),

[0011] The A - are independently selected from methylated anions, iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methylsulfate or trifluoromethanesulfonate;

[0012] The R1 is a connecting group; the R2 is a ligand structural group, and the ligands are independently selected from E3 ubiquitin ligase ligands or ribonuclease L ligands.

[0013] In some embodiments of the present invention, in the formula (A) to the formula (C), the linking group R1 is independently selected from any one of the following groups:

[0014]

[0015] wherein n is independently selected from 1, 3 or 5.

[0016] In some embodiments of the present invention, in the formula (A) to the formula (C), the ligand structural group R2 is independently selected from the CRBN protein ligand structural group VHL protein ligand structural group or RNase L ligand structural group In some embodiments of the present invention, the compound is as shown in Formula 1-Formula 6:

[0017]

[0018] The second aspect of the present invention provides a method for preparing the compound described in the first aspect of the present invention. When the compound is represented by formula (A), the preparation method comprises the following steps:

[0019] The compound of formula (a) is reacted with a ligand to obtain a compound as shown in formula (A), wherein the structure of the compound of formula (a) is as follows:

[0020]

[0021] When the compound is as shown in formula (B), the preparation method thereof includes any one of the following two methods:

[0022] Method 1: reacting a compound of formula (b) with a ligand to obtain a compound of formula (B), wherein the structure of the compound of formula (b) is as follows:

[0023]

[0024] Method 2: The compound of formula (c), the ligand, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) are reacted to obtain a compound as shown in formula (B). The structure of the compound of formula (c) is as follows:

[0025]

[0026] When the compound is as shown in formula (C), the preparation method thereof comprises the following steps:

[0027] The compound of formula (d) is reacted with a ligand to obtain a compound of formula (C), wherein the structure of the compound of formula (d) is as follows:

[0028]

[0029] In some embodiments of the present invention, in the preparation of the compound shown in formula (A), the compound of formula (a) is prepared by a preparation method comprising the following steps:

[0030] 1) Reaction with propargyl bromide (1-2eq) and potassium carbonate (3-4eq) to obtain

[0031] 2) Heat with iodomethane (5-6eq) at 65-75°C to obtain

[0032] 3) and (1-1.5eq) is reacted under pyridine catalysis to obtain the compound of formula (a).

[0033] In some embodiments of the present invention, the molar ratio of the compound of formula (a) to the ligand is 1:(1-2).

[0034] In some embodiments of the present invention, in the preparation of the compound of formula (B), the compound of formula (b) or formula (c) is prepared by a preparation method comprising the following steps:

[0035] 1) Reaction with bromopropyne or bromoalkanoic acid (1.5-2eq) to obtain

[0036] 2) and (1-1.2 eq) is reacted under pyridine catalysis conditions to obtain the compound of formula (b) or formula (c).

[0037] In some embodiments of the present invention, the molar ratio of the compound of formula (b) to the ligand is 1:(1-2).

[0038] In some embodiments of the present invention, the molar ratio of the compound of formula (c), the ligand, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine is 1:(1-2):(1-2):(3-4).

[0039] In some embodiments of the present invention, in the preparation of the compound of formula (C), the compound of formula (d) is prepared by a preparation method comprising the following steps:

[0040] 1) N-Boc piperazine (1.5-2 eq), cesium carbonate (3-4 eq), tris(dibenzylideneacetone)dipalladium (0.01-0.1 eq) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.01-0.1 eq) were heated at 90-100°C to obtain

[0041] 2) Reaction with iodomethane (5-6eq) to obtain

[0042] 3) and (1-1.5 eq) is reacted under pyridine catalysis to obtain the compound of formula (d).

[0043] In some embodiments of the present invention, the molar ratio of the compound of formula (d) to the ligand is 1:(1-2).

[0044] In some embodiments of the present invention, in the preparation of compounds represented by formula (A) to formula (C), the ligands are independently selected from any one of the following:

[0045] (n=1, 3 or 5), (n=1 or 2),

[0046] (n=1, 3 or 5),

[0047] (n=1, 3 or 5), (n=1, 3 or 5), (n=1 or 2), (n=1 or 2),

[0048] (n=1 or 2),

[0049] (n=1 or 3),

[0050] (n=1 or 2).

[0051] In some embodiments of the invention, the ligand (n=1, 3 or 5) or (n=1 or 2) is prepared by a preparation method comprising the following steps:

[0052] 1) Reaction with dibromoalkane (1-1.5eq) or dibromopolyethylene glycol chain (1-1.2eq) and potassium carbonate (3-4eq) to obtain

[0053] 2) Reaction with sodium azide (3-5eq) to obtain the ligand (n=1, 3 or 5) or (n=1 or 2).

[0054] In some embodiments of the invention, the ligand (n=1 or 3) or ligand (n=1, 2 or 3) is prepared by a preparation method comprising the following steps:

[0055] 1) and (1-1.5eq), palladium acetate (0.01-0.1eq) and potassium acetate (3-4eq) are reacted to obtain Remove Boc;

[0056] 2) The product after Boc removal in 1) is mixed with (1-1.5 eq), 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (1-1.5 eq) and N,N-diisopropylethylamine (3-4 eq) were reacted to obtain Remove Boc;

[0057] 3) The product after Boc removal in 2) is mixed with (1-2eq), 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (1-1.5eq) and N,N-diisopropylethylamine (3-4eq) were reacted to obtain Remove Boc;

[0058] 4) The product after Boc removal in 3) is mixed with (1-2eq) or (n=1, 2 or 3) (1-2eq) are mixed to obtain the ligand (n=1 or 3) or the ligand (n=1 or 2).

[0059] In some embodiments of the invention, the ligand (n=1, 3 or 5), (n=1 or 2) is prepared by a preparation method comprising the following steps:

[0060] 1) Reaction with dibromoalkane (1-1.2 eq) or dibromopolyethylene glycol chain (1-1.2 eq) and potassium carbonate (3-4 eq) to obtain

[0061] 2) Mix with sodium azide (3-5eq) to obtain

[0062] 3) and (1-1.2eq) reaction to obtain the ligand (n=1, 3 or 5) or (n=1 or 2).

[0063] In some embodiments of the invention, the ligand (n=1, 3 or 5), (n=1 or 2) is prepared by a preparation method comprising the following steps:

[0064] Will Mix with tert-butyl bromoalkanoate (1-1.2 eq) or tert-butyl bromide (1-1.2 eq) and potassium carbonate (3-4 eq) to obtain After removing Boc, the ligand is obtained (n=1, 3 or 5) or (n=1 or 2).

[0065] In some embodiments of the present invention, in the preparation of the compound as shown in formula (A), the ligand is selected from any one of the following:

[0066] (n=1, 3 or 5), (n=1 or 2), (n=1, 3 or 5),

[0067] (n=1 or 2),

[0068] (n=1 or 3),

[0069] (n=1 or 2).

[0070] In some embodiments of the present invention, in the preparation of the compound as shown in formula (B), the ligand is selected from any one of the following:

[0071] (n=1, 3 or 5), (n=1, 3 or 5), (n=1 or 2), (n=1 or 2).

[0072] In some embodiments of the present invention, in the preparation of the compound as shown in formula (C), the ligand is selected from any one of the following:

[0073] (n=1, 3 or 5), (n=1, 3 or 5),

[0074] (n=1 or 2),

[0075] (n=1 or 2).

[0076] The third aspect of the present invention provides a stress granule targeted degradation agent, comprising the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0077] The fourth aspect of the present invention provides use of the stress granule targeted degrader described in the third aspect of the present invention in the preparation of anti-tumor drugs and / or anti-neurodegenerative disease drugs.

[0078] In some embodiments of the present invention, the tumor comprises pancreatic cancer, colorectal cancer, osteosarcoma, glioma, cervical cancer, breast cancer, prostate cancer, liver cancer, non-small cell lung cancer or melanoma.

[0079] In some embodiments of the invention, the neurodegenerative disease comprises Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) or Parkinson's disease (PD).

[0080] Compared with the prior art, the present invention has the following beneficial effects:

[0081] The compound provided by the present invention consists of three parts: stress granule protein, a linking group and an E3 ubiquitin ligase ligand or a ribonuclease L ligand. In the ternary complex consisting of the stress granule protein, the linking group and the E3 ubiquitin ligase ligand, the stress granule protein is labeled with a ubiquitination tag through the linking group, and then the ubiquitinated stress granule protein is recognized and degraded by the proteasome 26S. In the ternary complex consisting of the stress granule protein, the linking group and the ribonuclease L ligand, the ribonuclease L ligand is recruited into the stress granule through the linking group, the ribonuclease L ligand is activated and the selective cutting of the stress granule RNA is induced, thereby exerting a degradation effect on the stress granule. The compounds connected with different ligands all have good targeting and degradation effects on the stress granules, and are used as stress granule targeted degraders in the preparation of anti-tumor drugs and anti-neurodegenerative disease drugs, and have good application prospects in the treatment of tumor resistance induced by stress granules and neurodegenerative diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 This is an experimental diagram of the targeting effect of the compound of formula (II) prepared in Example 2 on stress granules;

[0083] Figure 2 This is a graph showing the experimental results of the targeting of the compound of formula (II) prepared in Example 2 to stress granules;

[0084] Figure 3 This is an experimental diagram of the targeting of the compound of formula (III) prepared in Example 3 to stress granules;

[0085] Figure 4 This is a graph showing the experimental results of the targeting of the compound of formula (III) prepared in Example 3 to stress granules;

[0086] Figure 5 This is an experimental diagram of the degradation effect of the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 on stress granules;

[0087] Figure 6 The results of the degradation experiments on stress granules by the compounds of formula (II) and formula (III) prepared in Examples 2 and 3;

[0088] Figure 7 This is an experimental diagram of the degradation mechanism of stress granules by the compound of formula (II) prepared in Example 2;

[0089] Figure 8 This is an experimental diagram of the degradation mechanism of stress granules by the compound of formula (III) prepared in Example 3. DETAILED DESCRIPTION

[0090] The present invention is further described in detail below by specific examples. The raw materials, reagents or devices used in the examples can be obtained from conventional commercial sources or by prior art methods unless otherwise specified. Unless otherwise specified, the experiments or test methods are conventional methods in the art.

[0091] Example 1

[0092] This example prepares a compound, the structural formula of which is shown in formula (I):

[0093] Among them, A is Br.

[0094] The preparation method is as follows:

[0095] (1) Synthesis of CRBN protein ligand:

[0096] 2-(2,6-Dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (300 mg, 1.09 mmol) and 1,3-dibromopropane (231 mg, 1.15 mmol) were dissolved in 3.0 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (453 mg, 3.28 mmol) was added under stirring. The reaction was carried out at room temperature for 6 h, and water was added to quench the reaction. The reaction was extracted with ethyl acetate three times. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and purified by silica gel column with petroleum ether / ethyl acetate (5:1, v / v) as eluent to obtain a white solid with a yield of 57%.

[0097] 4-(3-Bromopropoxy)-2-(2,6-bipyridone-3-yl)isoindoline-1,3-dione (200 mg, 506 mmol) was added to sodium azide (97 mg, 1.50 mmol), and the mixture was stirred at room temperature for 24 h to obtain a light yellow clear solution. The solution was quenched with water and extracted with ethyl acetate. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a white solid, recorded as SL3-N3, with a yield of 91%.

[0098] (2) Synthesis of the compound of formula (b):

[0099] 2-Methylbenzothiazole (3.90 g, 26.1 mmol) and propargyl bromide (6.30 g, 52.9 mmol) were dissolved in acetonitrile, stirred and refluxed at 80°C for 24 h, cooled to room temperature, and a large amount of light yellow precipitate was precipitated. The precipitate was filtered off under reduced pressure, washed with cold anhydrous ethanol, and dried in a vacuum drying oven to obtain a light yellow solid with a yield of 43%.

[0100] 2-Methyl-3-(prop-2-ynyl-1-yl)benzothiazole iodide (300 mg, 1.1 mmol) and julolidine aldehyde (270 mg, 1.3 mmol) were dissolved in 3.0 mL of ethanol, refluxed with stirring at 75°C for 6 h, cooled to room temperature, and a large amount of purple solid precipitated. The mixture was filtered off under reduced pressure, washed with cold anhydrous ethanol, and dried in vacuo to obtain a purple solid compound of formula (b), recorded as TASG-8-C, with a yield of 71%.

[0101] (3) Synthesis of the compound of formula (I):

[0102] TASG-8-C (25 mg, 67.29 μmol) and SL3-N3 (29 mg, 81 μmol) were dissolved in 4.0 mL of dichloromethane / methanol (1:10, v / v) solution, and then copper sulfate (10 mg, 62.66 μmol) and sodium ascorbate (22.20 mg, 112.07 μmol) were dissolved in 0.3 mL of water, respectively, and added to the above reaction solution under stirring conditions. The mixture was stirred at room temperature for 24 h, and the solvent was removed under reduced pressure. The mixture was re-dissolved in dichloromethane / methanol (10:1, v / v) and purified using a preparative chromatography plate. The developing solvent was dichloromethane / methanol (50:1, v / v) to obtain the compound of formula (Ⅰ) as a purple solid with a yield of 36%.

[0103] The compound of formula (I) in Example 1 was subjected to nuclear magnetic resonance. 1 HNMR and 13 The results of C NMR analysis are:

[0104] 1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),8.47(s,1H),8.21(d,J=8.0H z,1H),8.10(d,J=8.5Hz,1H),7.89(d,J=14.8Hz,1H),7.76(t,J=7.9Hz,1H),7.70–7.64(m,2H),7.5 7(t,J=7.6Hz,1H),7.48(s,2H),7.44(d,J=7.2Hz,1H),7.41(d,J=8.6Hz,1H),6.09(s,2H),5.08(dd ,J=12.8,5.5Hz,1H),4.58(t,J=7.0Hz,2H),4.15(t,J=6.1Hz,2H),3.35(s,4H),2.91–2.84(m,1H), 2.69(t,J=6.2Hz,4H),2.61–2.53(m,2H),2.32–2.26(m,2H),2.04–1.99(m,1H),1.90–1.84(m,4H).;

[0105] 13 C NMR(126MHz,DMSO-d6)δ172.82,170.48,169.97,166.80,165.39,155.48, 150.84,148.15,140.98,140.14,137.12,133.16,130.83,128.65,126.92 ,126.36,124.60,123.78,121.29,120.73,119.80,116.42,115.59,103.9 3,65.67,49.74,48.78,46.47,42.50,30.96,29.19,26.92,22.05,20.54..

[0106] Example 2

[0107] This example prepares a compound, the structural formula of which is shown in formula (II):

[0108] Among them, A is CF3COO.

[0109] The preparation method is as follows:

[0110] (1) Synthesis of CRBN protein ligand:

[0111] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (300 mg, 1.09 mmol) and tert-butyl 6-bromohexanoate (224 mg, 1.15 mmol) were dissolved in 3.0 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (453 mg, 3.28 mmol) was added under stirring. The reaction was carried out at room temperature for 6 h, and water was added to quench the reaction. The reaction was extracted with ethyl acetate three times. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and purified by silica gel column with petroleum ether / ethyl acetate (5:1, v / v) as eluent to obtain a white solid with a yield of 33%.

[0112] Tert-butyl 2-((2-(2,6-bipyridone-3-yl)-1,3-dioxindolin-4-yl)oxy)acetate (100 mg, 257 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2:1, v / v) and stirred at room temperature for 2 h. After TLC detection, the reaction was completed and concentrated by rotary evaporation to obtain a white solid, recorded as SL2-COOH.

[0113] (2) Synthesis of the compound of formula (d):

[0114] 6-Bromo-2-methylbenzothiazole (2g, 8.77mmol), N-methylpiperazine (2.45g, 13.15mmol), cesium carbonate (8.57g, 26.30mmol), tris(dibenzylideneacetone)dipalladium (402mg, 0.44mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (173mg, 0.44mmol) were dissolved in 20mL of anhydrous 1,4-dioxane, replaced with nitrogen three times, and heated at 95°C for 24h. The reaction solution was filtered through diatomaceous earth, extracted with dichloromethane and water, the organic phase was washed with saturated brine, concentrated by rotary evaporation, mixed with silica gel, and purified by silica gel column with dichloromethane / methanol (200:1, v / v) to obtain a light yellow solid with a yield of 65%.

[0115] 6-(4-tert-Butyloxycarbonylpiperazine-1-yl)-2-methylbenzothiazole (1 g, 3 mmol) was added to 12 mL of acetonitrile, and iodomethane (1.28 g, 9 mmol) was added dropwise. The mixture was stirred and refluxed at 70°C in a pressure tube for 12 h. The mixture was cooled to room temperature to precipitate a large amount of white solid. The solid was filtered off under reduced pressure, washed with isopropanol, and dried in a vacuum oven to obtain a white solid with a yield of 68%.

[0116] 6-(4-tert-Butyloxycarbonylpiperazine-1-yl)-2,3-dimethylbenzothiazole iodide (800 mg, 1.68 mmol) and julolidine aldehyde (321 mg, 1.60 mmol) were dissolved in 5.0 mL of anhydrous ethanol and refluxed at 80 ° C in a pressure tube with stirring for 6 h. The solution turned purple and was cooled to room temperature to precipitate a large amount of purple solid. The solution was filtered under reduced pressure, washed with cold anhydrous ethanol, and dried in a vacuum drying oven to obtain a purple solid with a yield of 48%.

[0117] (E)-6-(4-tert-Butyloxycarbonylpiperazin-1-yl)-3-methyl-2-(2-(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)vinyl)benzothiazole iodide (300 mg, 564 μmol) was dissolved in dichloromethane / trifluoroacetic acid (2:1, v / v) and stirred at room temperature for 2 h. After TLC detection, the reaction was completed and concentrated by rotary evaporation to obtain the compound of formula (d) as a purple solid, recorded as TASG-8-D.

[0118] (3) Synthesis of the compound of formula (II):

[0119] TASG-8-D (25 mg, 57.92 μmol), SL2-COOH (27 mg, 81.26 μmol), 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (33 mg, 86.88 μmol) and N,N-diisopropylethylamine (22.5 mg, 173.76 μmol) were dissolved in 4.0 mL of N,N-dimethylformamide, stirred at room temperature for 12 h, extracted with dichloromethane and water, the organic phase was washed three times with saturated brine, concentrated by rotary evaporation, and purified by preparative chromatography with a developing solvent of dichloromethane / methanol (30:1, v / v) containing 0.1% triethylamine to obtain a purple solid compound of formula (II) with a yield of 26%.

[0120] The compound of formula (II) in Example 2 was subjected to nuclear magnetic resonance. 1 H NMR and 13 The results of C NMR analysis are:

[0121] 1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),7.88(d,J=9.3Hz,1H),7.77–7.72(m,2H),7.65–7.6 0(m,1H),7.44(s,2H),7.40(d,J=15.2Hz,1H),7.14(d,J=8.6Hz,1H),7.09(d,J=7.3Hz,2H ),5.11–5.05(m,1H),4.28(d,J=4.1Hz,2H),4.12(s,3H),3.70(s,4H),3.35(d,J=4.9Hz,6 H),2.72(t,J=5.9Hz,4H),2.64–2.52(m,4H),1.92–1.86(m,4H),1.21(d,J=13.9Hz,2H).;

[0122] 13 C NMR (126MHz, DMSO-d6) δ174.86,173.33,170.57,169.30,167.82,167.48,167.13,150.37,147.56,145.94,136.69,135.09,132 .48,130.28,121.46,117.93,116.54,111.38,110.05,108.07,50.00,49.06,46.05,35.67,31.46,27.45,22.62,21.14,9.01.

[0123] Example 3

[0124] This example prepares a compound, the structural formula of which is shown in formula (III):

[0125] Among them, A is CF3COO.

[0126] The preparation method is as follows:

[0127] (1) Synthesis of RNase L ligand:

[0128] 3,4-Dihydroxybenzaldehyde (300 mg, 2.17 mmol), tert-butyl bromoacetate (444 mg, 2.28 mmol) and potassium carbonate (900 mg, 6.52 mmol) were dissolved in 3.0 mL of N,N-dimethylformamide, and the reaction was stirred at room temperature for 12 h. Ethyl acetate and water were added for extraction. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and eluted with petroleum ether / ethyl acetate (10:1, v / v) and purified by silica gel column to obtain a white solid with a yield of 52%.

[0129] Tert-butyl 2-(4-formaldehyde-2-hydroxyphenoxy) acetate (200 mg, 634.50 μmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrothiophene-3-carboxylate (171 mg, 650.86 μmol) were dissolved in 4.0 mL of ethanol, and a drop of piperidine was added as a catalyst. After stirring and refluxing at 80° C. in a pressure tube for 12 h, the solution was cooled to room temperature to precipitate a large amount of light yellow solid. The solution was filtered under reduced pressure, washed with cold anhydrous ethanol, and dried in a vacuum drying oven to obtain a light yellow solid with a yield of 63%.

[0130] Ethyl (Z)-5-(4-(2-(tert-butoxy)-2-oxoethoxy)-3-hydroxybenzylidene)-4-oxo-2-(phenylamino)-4,5-dihydrothiophene-3-carboxylate (100 mg, 200 μmol) was dissolved in dichloromethane / trifluoroacetic acid (2:1, v / v) and stirred at room temperature for 2 h. After TLC detection, the reaction was completed and concentrated by rotary evaporation to obtain a white solid, recorded as R2-COOH.

[0131] (2) Synthesis of the compound of formula (III):

[0132] TASG-8-D (25 mg, 57.92 μmol, the compound of formula (d) prepared in Example 2), R2-COOH (36 mg, 81.26 μmol), 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (33 mg, 86.88 μmol) and N,N-diisopropylethylamine (22.5 mg, 173.76 μmol) were dissolved in 4.0 mL of N,N-dimethylformamide, stirred at room temperature for 12 h, extracted with dichloromethane and water, the organic phase was washed three times with saturated brine, concentrated by rotary evaporation, and purified by preparative chromatography using a developing solvent of dichloromethane / methanol (30:1, v / v) containing 0.1% triethylamine to obtain a purple solid compound of formula (III) with a yield of 16%.

[0133] The compound of formula (III) in Example 3 was subjected to nuclear magnetic resonance. 1 H NMR and 13 The results of C NMR analysis are:

[0134] 1H NMR (500MHz, DMSO-d6) δ11.25(s,1H),9.67(d,J=25.5Hz,1H),7.86(d,J=9.3Hz,1H),7.72(d,J=14. 3Hz,1H),7.69(s,1H),7.53(dd,J=13.4,6.0Hz,4H),7.48(s,1H),7.46–7.41(m,4H),7.37(d,J=15. 3Hz,1H),6.97(d,J=6.9Hz,3H),4.94(s,2H),4.27(q,J=7.0Hz,2H),4.11(s,3H),3.63(s,4H),3.33 (d,J=5.7Hz,6H),2.71(t,J=5.9Hz,4H),1.89(d,J=4.9Hz,4H),1.29(t,J=7.1Hz,3H),1.22(s,2H).

[0135] 13 C NMR (126MHz, DMSO) δ167.42,166.66,165.30,150.33,148.67,147.75,147.55,135.04,130.19,128.75,127.57,126.05,125.5 8,121.45,121.07,117.84,116.57(d,J=16.3Hz),115.34,107.98,105.25,97.34,59.99,49.99,35.64,27.45,21.13,14.88.

[0136] Example 4

[0137] This example prepares a compound, the structural formula of which is shown in formula (IV):

[0138] Among them, A is I.

[0139] The preparation method is as follows:

[0140] (1) Synthesis of RNase L ligand:

[0141] 3,4-Dihydroxybenzaldehyde (300 mg, 2.17 mmol), 1,7-dibromoheptane (588 mg, 2.28 mmol) and potassium carbonate (900 mg, 6.52 mmol) were dissolved in 3.0 mL of N,N-dimethylformamide, and the reaction was stirred at room temperature for 12 h. Ethyl acetate and water were added for extraction. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and eluted with petroleum ether / ethyl acetate (10:1, v / v) and purified by silica gel column to obtain a white solid with a yield of 37%.

[0142] 4-(7-Bromoheptyloxy)-3-hydroxybenzaldehyde (200 mg, 634.50 μmol) was dissolved in 5.0 mL of N,N-dimethylformamide, sodium azide (123 mg, 1.90 mmol) was added, and the mixture was stirred at room temperature. After reacting for 24 h, a light yellow clear solution was obtained. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a white solid with a yield of 83%.

[0143] 4-(7-azidoheptyloxy)-3-hydroxybenzaldehyde (190 mg, 685.12 μmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrothiophene-3-carboxylate (171 mg, 650.86 μmol) were dissolved in 4.0 mL of ethanol, and a drop of piperidine was added as a catalyst. After stirring and refluxed at 80° C. in a pressure tube for 12 h, the solution was cooled to room temperature to precipitate a large amount of light yellow solid. The solution was filtered under reduced pressure, washed with cold anhydrous ethanol, and dried in a vacuum drying oven to obtain a light yellow solid, recorded as RIBO7-N3, with a yield of 78%.

[0144] (2) Synthesis of the compound of formula (a):

[0145] 2-Methyl-6-hydroxybenzothiazole (1 g, 6.05 mmol), 3-bromopropyne (792 mg, 6.66 mmol) and potassium carbonate (1.25 g, 9.08 mmol) were added to 8 mL of N,N-dimethylformamide, and the reaction was stirred at room temperature for 8 h. The mixture was quenched with water and extracted with dichloromethane. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, mixed with silica gel, and purified by silica gel column with petroleum ether / ethyl acetate (5:1, v / v) to obtain a white solid with a yield of 72%.

[0146] 2-Methyl-6-(2-propynyloxy)benzothiazole (700 mg, 3.44 mmol) was added to 5 mL of acetonitrile, and iodomethane (977 mg, 6.89 mmol) was added dropwise. The mixture was stirred and refluxed at 70°C in a pressure tube for 12 h. The mixture was cooled to room temperature to precipitate a large amount of white solid. The mixture was filtered off under reduced pressure, washed with isopropanol, and dried in a vacuum oven to obtain a white solid with a yield of 93%.

[0147] 2,3-Dimethyl-6-(2-propynyloxy)benzothiazole iodide (350 mg, 1.60 mmol) and julolidine aldehyde (306 mg, 1.52 mmol) were dissolved in 3.0 mL of anhydrous ethanol and refluxed at 80° C. in a pressure tube with stirring for 6 h. The solution turned purple and was cooled to room temperature to precipitate a large amount of purple solid. The solution was filtered under reduced pressure, washed with cold anhydrous ethanol, and dried in vacuo to obtain a purple solid of the compound of formula (a), recorded as TASG-8-A, with a yield of 59%.

[0148] (3) Synthesis of the compound of formula (IV):

[0149] TASG-8-A (30 mg, 74.71 μmol) and RIBO7-N3 (42.79 mg, 82.18 μmol) were dissolved in 4.0 mL of dichloromethane / methanol (1:10, v / v) solution, and then copper sulfate (10 mg, 62.66 μmol) and sodium ascorbate (22.20 mg, 112.07 μmol) were dissolved in 0.3 mL of water, respectively, and added to the above reaction solution under stirring conditions. The mixture was stirred at room temperature for 24 h, and the solvent was removed under reduced pressure. The mixture was re-dissolved in dichloromethane / methanol (10:1, v / v) and purified using a preparative chromatography plate. The developing solvent was dichloromethane / methanol (30:1, v / v) to obtain the compound of formula (IV) as a purple solid with a yield of 17%.

[0150] The compound of formula (IV) in Example 4 was subjected to nuclear magnetic resonance. 1 HNMR and 13 The results of C NMR analysis are:

[0151] 1 H NMR (400MHz, DMSO-d6) δ11.29–11.17(m,1H),9.38–9.30(m,1H),8.30(s,1H),7.94(d,J=2.4Hz,1H),7.91(s, 1H),7.73(s,1H),7.53(s,1H),7.52(s,1H),7.50(s,2H),7.48(s,1H),7.43(s,4H),7.39(s,1H),7.37–7.34(m ,1H),6.95(d,J=8.0Hz,2H),5.25(s,2H),4.37(s,2H),4.26(d,J=7.1Hz,2H),4.12(s,3H),3.92(s,2H),2.70( t,J=5.9Hz,4H),1.92–1.86(m,4H),1.73(d,J=72.4Hz,6H),1.33(s,2H),1.29(t,J=7.1Hz,6H),1.23(s,3H).;

[0152] 13C NMR(126MHz,DMSO-d6)δ181.37,169.05,165.34,157.59,149.42,147.83,147.41,14 2.32,136.68,130.46,130.10,128.52,126.46,125.92,125.25,124.90,123.58,121. 47,121.02,117.93,116.92,116.27,113.78,108.40,104.97,97.30,68.55,62.38,59.97,50.03,49.86,35.75,29.97,28.84,28.42,27.42,26.12,25.64,21.08,14.87.

[0153] Performance Testing

[0154] 1. Explore the targeting effects of the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 on stress granules:

[0155] Hela cells in the logarithmic growth phase were inoculated in 96-well laser confocal culture plates (MatTek) at 3500 cells per well and cultured in a 37°C incubator containing 5% CO2 for 48 hours. Sodium arsenite was prepared into a working concentration of 500 μmol / L using a culture medium containing 10% fetal bovine serum. The culture medium of the 96-well plate was discarded, and 100 μL of a culture medium containing 500 μmol / L sodium arsenite was added to each well for stress for 1 hour. The culture medium was discarded, and 50 μL of 4% paraformaldehyde was added to each well and incubated at room temperature for 20 minutes for cell fixation. The paraformaldehyde was discarded, and the cells were washed three times with 1×PBS buffer. 50 μL of 0.5% PBST was added to each well and incubated at 37°C for 30 minutes for cell permeabilization. The PBST was discarded, and the cells were washed three times with 1×PBS buffer. 50 μL of 5% BSA / PBS was added to each well and incubated at 37°C for 30 minutes for blocking. Discard BSA, add 25 μL of a solution containing G3BP antibody (prepared with 1% BSA / PBS, dilution factor of 1:1000) to each well, and incubate overnight in a 4°C refrigerator. Discard the primary antibody, wash three times with 1×PBS, add 30 μL of a solution containing a fluorescent secondary antibody (prepared with 1% BSA / PBS) to each well, and incubate in a 37°C incubator for 1 h. Take the compounds of formula (II) and formula (III) prepared in Examples 2 and 3, respectively, and prepare them with 1×PBS to a working concentration of 1 μmol / L, discard the secondary antibody, add 100 μL of the above compounds to each well, incubate at room temperature in the dark for 2 h, and then use a FV3000 laser confocal microscope (Olympus) for cell imaging.

[0156] 2. Investigate the degradation effects of the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 on stress granules:

[0157] Take 3500 HeLa cells in the logarithmic growth phase and inoculate them in a 96-well laser confocal culture plate (MatTek) at each well, and place them in a 37°C incubator containing 5% CO2 for 48 hours. Take sodium arsenite and prepare it to a working concentration of 500 μmol / L with a culture medium containing 10% fetal bovine serum. Discard the culture medium of the 96-well plate, and add 100 μL of a culture medium containing 500 μmol / L sodium arsenite to each well for stress for 1 hour. Take sodium arsenite and prepare it to a working concentration of 50 μmol / L with a culture medium containing 10% fetal bovine serum. Take the compounds of formula (II) and formula (III) prepared in Examples 2 and 3, respectively, and prepare them to working concentrations of 5 μmol / L and 20 μmol / L with the above 50 μmol / L sodium arsenite culture medium, respectively. The culture medium was discarded, and 100 μL of the culture medium containing sodium arsenite and compounds was added to each well, and 100 μL of 50 μmol / L sodium arsenite culture medium without compounds was added to each well. After incubation for 6 hours, the culture medium was discarded, and 50 μL of 4% paraformaldehyde was added to each well and incubated at room temperature for 20 minutes for cell fixation. The paraformaldehyde was discarded, and the cells were washed three times with 1× PBS buffer. 50 μL of 0.5% PBST was added to each well and incubated in a 37°C incubator for 30 minutes for cell permeabilization. PBST was discarded, and the cells were washed three times with 1× PBS buffer. 50 μL of 5% BSA was added to each well and incubated in a 37°C incubator for 30 minutes for blocking. BSA was discarded, and 25 μL of a solution containing G3BP antibody (prepared with 1% BSA / PBS, with a dilution factor of 1:1000) was added to each well, and incubated overnight in a 4°C refrigerator. The primary antibody was discarded, the cells were washed three times with 1× PBS, and 30 μL of a solution containing a fluorescent secondary antibody (prepared with 1% BSA / PBS) was added to each well and incubated at 37°C for 1 hour. The secondary antibody was discarded, and 0.5 mg / L 4',6-diamidino-2-phenylindole solution was added to each well and incubated at room temperature for 30 minutes. Cell imaging was then performed using a FV3000 laser confocal microscope (Olympus) and analyzed using Fiji / ImageJ (statistical analysis of the ratio of stress granule area to cell nucleus area).

[0158] 3. Investigate the degradation mechanism of the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 on stress granules:

[0159] HeLa cells in the logarithmic growth phase were inoculated into 6-well plates at 200,000 / well and cultured in a cell culture incubator containing 5% CO2 and 37°C for 48h. Sodium arsenite was prepared into a working concentration of 500μmol / L using a culture medium containing 10% fetal bovine serum. The culture medium of the 6-well plate was discarded, and 2mL of a culture medium containing 500μmol / L sodium arsenite was added to each well for stress for 1h. Sodium arsenite was prepared into a working concentration of 50μmol / L using a culture medium containing 10% fetal bovine serum, and the compound of formula (II) prepared in Example 2 was prepared into 20μmol / L using the above 50μmol / L sodium arsenite culture medium. The culture medium was discarded, and 2mL of the above culture medium containing sodium arsenite and compound was added to each well, and the control group was 2mL of 50μmol / L sodium arsenite culture medium without compound. After discarding the culture medium, the cells were washed 3 times with 1×PBS, and the cells were collected in EP tubes by scraping on ice with a cell scraper. After centrifugation at 3000rpm for 5min, discard 1×PBS and collect the cell pellet. Add an appropriate amount of RIPA lysis buffer and lyse on ice for 3min. Centrifuge at 4℃, 12000rpm for 15min, and take the supernatant as the total protein sample. After determining the concentration of the protein sample by the BCA method, add protein loading buffer to the protein sample, heat at 95℃ for 10min for denaturation, cool to room temperature and store at -20℃. Electrophoresis separation: Load 10-20μg of protein sample on SDS-PAGE gel for electrophoresis, 80V 30min, 120V 1h. Transfer: Activate the polyvinylidene fluoride membrane with anhydrous methanol and soak it in transfer buffer for use. Then, under ice bath conditions, use Bio-Red wet transfer membrane transfer instrument to transfer the protein in SDS-PAGE to the polyvinylidene fluoride membrane, 400mA, 42min. Blocking: Place the polyvinylidene fluoride membrane in 5% BSA (prepared in TBST) blocking solution and block at room temperature for 1.5 hours. Incubate the primary antibody: Dilute the G3BP primary antibody and Actin primary antibody with antibody diluent at a ratio of 1:1000, incubate the polyvinylidene fluoride membrane, and shake overnight at 4°C. Wash the membrane: Wash the polyvinylidene fluoride membrane 3 times with 1×TBST, 5 minutes each time. Incubate the secondary antibody: Dilute the secondary antibody with antibody diluent at a ratio of 1:5000, incubate with the polyvinylidene fluoride membrane, and incubate at room temperature for 1 hour with slow shaking. Wash the membrane: Wash the polyvinylidene fluoride membrane 3 times with 1×TBST, 5 minutes each time. Develop: Place the polyvinylidene fluoride membrane in a dark room, add chemiluminescent solution to the membrane, take pictures with Tanon-4200SF chemiluminescence instrument, and analyze the experimental results with ImageJ software.

[0160] HeLa cells in the logarithmic growth phase were inoculated into 6-well plates at 200,000 / well and cultured in a cell culture incubator containing 5% CO2 and 37°C for 48 hours. Sodium arsenite was prepared into a working concentration of 500 μmol / L using a culture medium containing 10% fetal bovine serum. The culture medium of the 6-well plate was discarded, and 2 mL of a culture medium containing 500 μmol / L sodium arsenite was added to each well for stress for 1 hour. Sodium arsenite was prepared into a working concentration of 50 μmol / L using a culture medium containing 10% fetal bovine serum, and the compound of formula (III) prepared in Example 3 was prepared into 5 μmol / L using the above 50 μmol / L sodium arsenite culture medium. The culture medium was discarded, and 2 mL of the above culture medium containing sodium arsenite and compound was added to each well, and the control group was 2 mL of 50 μmol / L sodium arsenite culture medium without compound. After washing the cells with 1×PBS, total RNA was extracted using a total RNA rapid small extraction kit. The concentration of RNA was determined by ultra-micro UV spectrophotometer, and the samples were stored in a -80°C refrigerator. Take 1000ng of total RNA extract in an EP tube, add 1μL of gDNAClean Reagent, 2μL of 5×gDNA Clean Buffer, and finally make up to 10μL with RNase-free water. Mix well and place in a PCR instrument at 42°C×2min, then cool to 4°C. Add 1μL of EvoMMLVRTase Enzyme Mix, 1μL of RT Primer Mix and 4μL of 5×RTase Reaction Buffer Mix I to the 10μL reaction solution obtained in the above steps, and finally add 4μL of RNase-free water to make up the total volume to 20μL. Mix the above system well and place in a PCR instrument at 37°C for 15min, then at 85°C for 5s, and finally cool to 4°C. cDNA samples were stored in a 4°C refrigerator. 1μL cDNA, 0.4μL 10μmol / L Forward Primer, 0.4μL 10μμmol / L Reverse Primer, 8.2μL RNase freewater and 10μL 2×RealStar Green Fast Mixture. Then add the PCR system to the PCR plate, seal the film, and centrifuge it at 2000rpm for 1-2min. Finally, place the PCR plate in a real-time fluorescence quantitative PCR instrument and perform 40 cycles of amplification at 95℃×30s, 95℃×5s, 62℃×1min, 40℃×30s. After the end, place it at 4℃ and calculate the relative change of RNA level by Ct value.

[0161] Figure 1 This is an experimental diagram of the targeting effect of the compound of formula (II) prepared in Example 2 on stress granules. Figure 1In the figure, from left to right are G3BP stress granule signal (G3BP), compound signal of formula (II) (Compound II), stress granule signal and compound signal of formula (II) (Merge), Figure 2 This is a graph showing the experimental results of the targeting of the compound of formula (II) prepared in Example 2 to stress granules; Figure 3 This is an experimental diagram of the targeting of the compound of formula (III) prepared in Example 3 to stress granules. Figure 3 In the figure, from left to right are G3BP stress granule signal (G3BP), compound signal of formula (III) (Compound III), stress granule signal and compound signal of formula (III) (Merge), Figure 4 The experimental results of the targeting of the compound of formula (III) prepared in Example 3 to stress granules are shown in FIG. Figure 1-Figure 4 It can be seen that the compounds of formula (II) and formula (III) can both recognize stress granules well and have good targeting properties to stress granules.

[0162] Figure 5 This is an experimental diagram of the degradation effect of the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 on stress granules, Figure 6 The results of the degradation experiments of the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 on stress granules are shown in FIG. Figure 5 and Figure 6 It can be seen that compared with the control group, when the concentration of the compound of formula (II) or formula (III) is 5 μmol / L, the fluorescent bright spots are reduced. As the concentration of the compounds of formula (II) and formula (III) increases to 20 μmol / L, the stress granules gradually decrease, indicating that the compounds of formula (II) and formula (III) prepared in Examples 2 and 3 have a good degradation effect on stress granules.

[0163] Figure 7 The experimental diagram of the degradation mechanism of stress granules by the compound of formula (II) prepared in Example 2 is shown in FIG. Figure 7 It can be seen that compared with the control group, when the concentration of the compound of formula (II) is 5 μmol / L, the GCBP content in the cells can be reduced. As the concentration increases, the reducing effect on G3BP becomes stronger, indicating that the compound of formula (II) can achieve the degradation of stress granules by degrading the stress granule skeleton protein G3BP.

[0164] Figure 8 The experimental diagram of the degradation mechanism of stress granules by the compound of formula (III) prepared in Example 3 is shown in FIG. Figure 8 It can be seen that the compound of formula (III) can achieve the degradation of stress granules by degrading the RNA constituting the stress granules.

Claims

1. A compound, characterized in that Its structural formula is shown in formula (A), formula (B) or formula (C): Among them, in formula (A) to formula (C), The A - are independently selected from methylated anions, iodide, bromide, p-toluenesulfonate, trifluoroacetate, perchlorate, tetrafluoroborate, methylsulfate or trifluoromethanesulfonate; The R1 is a connecting group; the R2 is a ligand structural group, and the ligands are independently selected from E3 ubiquitin ligase ligands or ribonuclease L ligands.

2. The compound according to claim 1, characterized in that In the formula (A) to the formula (C), the linking groups R1 are independently selected from any one of the following groups: wherein n is independently selected from 1, 3 or 5.

3. The compound according to claim 2, characterized in that In the formula (A) to the formula (C), the ligand structural group R2 is independently selected from the CRBN protein ligand structural group VHL protein ligand structural group or RNase L ligand structural group 4. The compound according to claim 3, characterized in that The compounds are shown in Formula 1 to Formula 6:

5. The method for preparing the compound according to any one of claims 1 to 4, characterized in that: When the compound is as shown in formula (A), the preparation method thereof comprises the following steps: The compound of formula (a) is reacted with a ligand to obtain a compound as shown in formula (A), wherein the structure of the compound of formula (a) is as follows: When the compound is as shown in formula (B), the preparation method thereof includes any one of the following two methods: Method 1: reacting a compound of formula (b) with a ligand to obtain a compound of formula (B), wherein the structure of the compound of formula (b) is as follows: Method 2: reacting the compound of formula (c), the ligand, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a compound of formula (B), wherein the structure of the compound of formula (c) is as follows: When the compound is as shown in formula (C), the preparation method thereof comprises the following steps: The compound of formula (d) is reacted with a ligand to obtain a compound of formula (C), wherein the structure of the compound of formula (d) is as follows:

6. The preparation method according to claim 5, characterized in that: The molar ratio of the compound of formula (a) to the ligand is 1:(1-2); and / or, the molar ratio of the compound of formula (b) to the ligand is 1:(1-2); and / or, the molar ratio of the compound of formula (c), the ligand, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine is 1:(1-2):(1-2):(3-4); And / or, the molar ratio of the compound of formula (d) to the ligand is 1:(1-2).

7. The preparation method according to claim 5, characterized in that: In the preparation of the compounds shown in formula (A) to formula (C), the ligands are independently selected from any one of the following:

8. A stress granule targeted degradation agent, characterized in that: The invention comprises a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

9. Use of the stress granule targeted degradation agent according to claim 8 in the preparation of anti-tumor drugs and / or anti-neurodegenerative disease drugs.

10. The use according to claim 9, characterized in that: The tumor includes pancreatic cancer, colorectal cancer, osteosarcoma, glioma, cervical cancer, breast cancer, prostate cancer, liver cancer, non-small cell lung cancer or melanoma; And / or, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease or Parkinson's disease.

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