PROTAC Chimeras and Their Preparation and Use in the Preparation of Drugs for Targeted Degradation of RIPK3

Abstract

The present invention belongs to the field of pharmaceuticals, and particularly relates to a PROTAC chimera, which is a compound having the structure of Formula 1 (). The present invention also includes the preparation and application of the said compound. The present invention provides a novel compound, which has an excellent effect of targeting and degrading RIPK3.

Description

Technical Field:

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to the field of drug small molecule development. Background Art:

[0002] Programmed necrosis, also known as necroptosis, is different from apoptosis and is a caspase-independent programmed cell death mode. The characteristics of programmed necrosis lie in the phosphorylation of the mixed lineage kinase domain-like (MLKL) mediated by receptor interacting protein kinase 3 (RIPK3). Ripk3 is a key protein for cell necroptosis, and the signal pathway mediated by it is closely related to the body's inflammatory response. It may induce the activation of inflammasomes and promote the expression of inflammatory cytokines and amplify the inflammatory response by promoting cell necrosis and releasing DAMPs. Therefore, targeting the degradation of RIPK3 can effectively inhibit cell necroptosis and provide candidate drugs for the treatment of inflammation-related diseases.

[0003] Proteolysis-Targeting Chimeras (PROTAC) is a heterobifunctional molecule. This technology was first proposed by Sakamoto et al. in 2001, and a peptide-based degrader was reported. Subsequently, researchers developed a variety of small molecule PROTACs that target the degradation of different proteins on this basis and showed more excellent properties. Such compounds are composed of an E3 ubiquitin ligase ligand, a linker, and a target protein ligand. When PROTAC exerts its function, it will form a ternary complex with the E3 ubiquitin ligase and the target protein, and promote the ubiquitination of the target protein with the help of the ubiquitin-proteasome system, and then be degraded by the proteasome. After the process ends, PROTAC will be released again and reused. Due to the unique "event-driven mode" of PROTAC, its degradation of the target protein has some obvious advantages compared with traditional inhibitors, including overcoming drug resistance, high selectivity, being able to act on "undruggable proteins", high efficiency and low toxicity, etc. Using PROTAC technology for new drug molecule research and development has high advantages and feasibility, and PROTAC molecules may become the next generation of very promising new drugs. Summary of the Invention:

[0004] In view of this, the purpose of the present invention is to provide a PROTAC chimera that targets the degradation of RIPK3, and its preparation method and application.

[0005] A PROTAC chimera is a compound having the structure of Formula 1;

[0006]

[0007] In Formula 1, the described Y is a carbon chain or a heteroatom hybridized carbon chain, and the carbon chain has substituents.

[0008] The carbon number of the carbon chain is between 6 and 12, the heteroatom is O or N, and the substituents include at least one of H, C1-C6 alkyl, C1-C6 alkoxy, aryl, ester group, and amide group.

[0009] The present invention provides a PROTAC small molecule with a brand-new Formula 1 structure. The small molecule of Formula 1 can unexpectedly target and degrade the RIPK3 protein and can be used for the treatment of related diseases.

[0010] Preferably, the described Y is -(CH2)n-, where n is 8-12, more preferably 9-11; even more preferably 10.

[0011] For example, the preferred PROTAC chimera of the present invention is a compound having the structure of Formula 1-A.

[0012]

[0013] The research of the present invention shows that further optimizing and controlling the linking group of Y can unexpectedly further improve the intramolecular synergy of the compound and can further improve the ability of the compound to target and degrade the RIPK3 protein.

[0014] The present invention also provides a preparation method of the described PROTAC chimera, which is prepared by reacting a compound of Formula 2 and a compound of Formula 3;

[0015]

[0016] In Formula 2, the described Y is the same as in Formula 1, and in Formula 3, the described R is -OH, halogen, or alkoxy.

[0017] In the present invention, there are no special requirements for the conditions of the reaction of Formula 2:Formula 3, and it can be controlled according to the conventional amidation reaction method. For example, the molar ratio of the reaction of Formula 2:Formula 3 is 1-1.3:1.

[0018] When R in Formula 3 is a hydroxyl group, a hydroxyl activating agent is preferably added during the reaction process.

[0019] Preferably, an acid-binding agent is also allowed to be added during the reaction of Formula 2 and Formula 3.

[0020] There are no special requirements for the temperature of the reaction process. For example, it can be at room temperature. The reaction time can be adjusted as needed. For example, it can be controlled by conventional in-process control reaction means.

[0021] In the present invention, the compound of Formula 2 is prepared by the reaction of Formula 4 and Formula 5 followed by deprotection:

[0022]

[0023] In Formula 5, Y is the same as in Formula 1, and R1 is a protecting group, further an alkoxycarbonyl group (for example, it can be -COOR a group, and R a is an alkyl group with 1 to 6 carbon atoms).

[0024] The reaction of Formula 4 and Formula 5 can be achieved by conventional substitution reaction means. For example, the molar ratio of Formula 4 to Formula 5 is 1:1 to 1.3. A base scavenger is preferably added during the reaction process. The temperature of the reaction process can be, for example, 50 to 100 °C.

[0025] In the present invention, Formula 3 is Formula 3-A, which is a compound of Formula 3 with R being -OH, and it is obtained by the reaction of a compound of Formula 6 and a compound of Formula 7 followed by an ester hydrolysis reaction.

[0026]

[0027] In Formula 7, R2 is an alkyl group with 1 to 6 carbon atoms, and X is a halogen, further Br.

[0028] In the reaction process of Formula 6 and Formula 7 in the present invention, the molar ratio of Formula 6 to Formula 7 is, for example, 1:1 to 1.3. A base scavenger is added during the reaction process, and the temperature of the reaction process can be, for example, room temperature.

[0029] When Formula 3 is Formula 3-B, which is a compound of Formula 3 with R being -halogen, it can be prepared from Formula 3-A and a halogenating reagent based on a conventional acylation reaction.

[0030] When Formula 3 is Formula 3-C, which is a compound of Formula 3 with R being -ester group, it can be prepared from Formula 3-A and an alcohol based on a conventional esterification reaction.

[0031] In the present invention, Formula 6 is obtained by the Suzuki coupling reaction of compounds of Formula 8 and Formula 9:

[0032]

[0033] In Formula 8, X is a halogen;

[0034] In Formula 9, R3 is a borate group, and R4 is a conventional amino protecting group (for example, it can be -COOR a group, and R a is an alkyl group with 1 to 6 carbon atoms).

[0035] In the present invention, the compounds of Formula 8 and Formula 9 can be prepared by conventional Suzuki coupling reaction.

[0036] The present invention also provides an application of the PROTAC chimeras in the preparation of drugs for targeted degradation of RIPK3.

[0037] In the application of the present invention, the drug for targeted degradation of RIPK3 is an anti-inflammatory drug, and further can be diseases such as abdominal aortic aneurysm or heat stroke, etc., which achieve pharmacological effects by degrading RIPK3.

[0038] In the application of the present invention, the PROTAC chimeras are combined with pharmaceutically acceptable excipients to prepare pharmaceutically acceptable preparations.

[0039] The present invention also provides a drug for targeted degradation of RIPK3, which contains a pharmaceutically effective amount of the PROTAC chimeras.

[0040] The drug for targeted degradation of RIPK3 according to the present invention further contains pharmaceutically acceptable excipients;

[0041] The drug for targeted degradation of RIPK3 according to the present invention also has a pharmaceutically acceptable dosage form.

[0042] Beneficial effects

[0043] The present invention provides a novel PROTAC small molecule with the structure of Formula 1. The small molecule of Formula 1 can unexpectedly target and degrade RIPK3 protein, and can be used for the treatment of related diseases. Description of the drawings:

[0044] Figure 1 It is a schematic protein band diagram and statistical chart of the effect of compound XC-1 on the intracellular RIPK3 protein content at different doses;

[0045] Figure 2 It is a schematic protein band diagram and statistical chart of the effect of compound XC-1 and positive control (GSK872) on the intracellular RIPK3 protein content at different doses;

[0046] Figure 3 It is a schematic protein band diagram and statistical chart of the effect of 20 μM dose of compound XC-1 on the cell RIPK3 protein content after different pretreatments;

[0047] Figure 4 It is a result diagram of the binding study between different molecules in Example 4 and RIPK3 protein; Detailed implementation manners:

[0048] The following is a detailed description of the specific implementation manners of the present invention with reference to the examples.

[0049] A typical PROTAC chimera of the present invention, taking Formula 1-A as an example, its synthesis method is, for example:

[0050]

[0051] The present invention also discloses a preparation method of a PROTAC chimera targeting the degradation of RIPK3 protein, and the preparation method includes the following steps:

[0052] The compounds shown in Formulas II and III are co-dissolved in ethanol at a molar ratio of 1:1.2, an appropriate amount of 10M hydrochloric acid is added, and the mixture is refluxed at 82 °C for 2.5 h. After filtration and drying, the hydrochloride form of the compound shown in Formula IV is obtained;

[0053]

[0054] The compounds shown in Formulas IV and V are co-dissolved in a mixed solvent (dioxane: water = 4:1) at a molar ratio of 1:1.2, 3 equivalents of CsCO3 and 0.05 equivalent of Pd(dppf)Cl2 are added, and the reaction is carried out at 95 °C for 12 h under N2 protection. After the reaction is completed, it is purified by column chromatography to obtain the compound shown in Formula VI. It is dissolved in dichloromethane, and an appropriate amount of 10M hydrochloric acid solution is added to obtain the hydrochloride form of the compound shown in Formula VII.

[0055]

[0056] The compounds shown in Formulas VII and VIII are co-dissolved in DMF at a molar ratio of 1:1.2, 3 equivalents of K2CO3 are added, and the reaction is carried out at room temperature of 25 - 30 °C for 6 h. After the reaction is completed, it is purified by column chromatography to obtain the compound shown in Formula IX. It is dissolved in dichloromethane, and an appropriate amount of 10M hydrochloric acid solution is added to obtain the hydrochloride form of the compound shown in Formula X.

[0057]

[0058] The compounds shown in Formulas XI and XII are co-dissolved in DMF at a molar ratio of 1:1.2, 2 equivalents of DIPEA are added, and the reaction is carried out at 80 °C for 6 h. After the reaction is completed, it is purified by column chromatography to obtain the compound shown in Formula XIII. It is dissolved in dichloromethane, and an appropriate amount of 10M hydrochloric acid solution is added to obtain the hydrochloride form of the compound shown in Formula XIV.

[0059]

[0060]

[0061] The compounds shown in Formulas X and XIV were co-dissolved in DMF at a molar ratio of 1:1.2, and then 1.2 equivalents of HOBT, 1.2 equivalents of EDCI, and 2 equivalents of TEA were added. The reaction was carried out at room temperature of 25 - 30 °C for 12 h to obtain Compound I, namely XC-1;

[0062]

[0063] The present invention also discloses the preparation of the PROTAC chimera XC-1 targeting RIPK3 and its application in degrading RIPK3 protein in cells.

[0064] The beneficial effects of the present invention are as follows: Based on the reported RIPK3 inhibitor (GSK872) in the literature, the present invention has developed a novel-structured PROTAC chimera targeting RIPK3. Through relevant experiments, it is confirmed that the protein-targeting degradation chimera of the present invention can bind to RIPK3 protein and cause effective degradation, thereby leading to the application of inhibiting the proliferation ability of tumor cells. Therefore, it has excellent prevention and treatment effects on diseases related to high expression of RIPK3.

[0065] Example 1: Synthesis of the PROTAC chimera targeting RIPK3

[0066] The PROTAC chimera targeting RIPK3 was synthesized by the following synthetic route:

[0067] Synthesis of Compound IV:

[0068] Compound II and III were co-dissolved in an appropriate amount of ethanol solution at a molar ratio of 1:1.2, and an appropriate amount of 10 M hydrochloric acid was added. The reaction was refluxed at 82 °C for 2.5 h. The reaction solution was filtered, and the solid collection was retained. After drying, the hydrochloride form of Compound IV was obtained.

[0069] Synthesis of Compound VII:

[0070] Compound IV and V were co-dissolved in a mixed solvent (dioxane: water = 4:1) at a molar ratio of 1:1.2, and 3 equivalents of CsCO3 and 0.05 equivalents of Pd(dppf)Cl2 were added. The reaction was carried out at 95 °C under N2 protection for 12 h. After the reaction was completed, it was diluted with ethyl acetate and then washed 3 times each with water and saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate and filtering, the filtrate was rotary evaporated to dryness. The obtained concentrate was separated by silica gel column chromatography (the eluent was petroleum ether / ethyl acetate with a volume ratio of 1:1). After obtaining the collection, it was dissolved in a small amount of dichloromethane solution, and an appropriate amount of hydrochloric acid ethyl acetate solution was added. The reaction was carried out at room temperature of 25 - 30 °C for 0.5 h. After filtration and drying, the hydrochloride form of the corresponding Compound VII was obtained.

[0071] Synthesis of Compound X:

[0072] Compound VII and VIII were co-dissolved in DMF in a molar ratio of 1:1.2, 3 equivalents of K2CO3 were added, and the reaction was carried out at room temperature of 25 - 30 °C for 6 h. After the reaction was completed, it was diluted with ethyl acetate and washed 3 times each with water and saturated sodium chloride aqueous solution successively, then dried over anhydrous sodium sulfate and filtered. The filtrate was rotary evaporated to dryness, and the obtained concentrate was separated by silica gel column chromatography (the eluent was petroleum ether / ethyl acetate with a volume ratio of 1:1), and after obtaining the collected product, it was dissolved in a small amount of dichloromethane solution, an appropriate amount of hydrochloric acid ethyl acetate solution was added, and the reaction was carried out at room temperature of 25 - 30 °C for 0.5 h. After filtration and drying, the hydrochloride form of the corresponding compound X was obtained.

[0073] Synthesis of compound XIV:

[0074] Compound XI and XII were co-dissolved in DMF in a molar ratio of 1:1.2, 2 equivalents of DIPEA were added, and the reaction was carried out at 80 °C for 6 h. After the reaction was completed, it was diluted with ethyl acetate and washed 3 times each with water and saturated sodium chloride aqueous solution successively, then dried over anhydrous sodium sulfate and filtered. The filtrate was rotary evaporated to dryness, and the obtained concentrate was separated by silica gel column chromatography (the eluent was petroleum ether / ethyl acetate with a volume ratio of 2:1), and after obtaining the collected product, it was dissolved in a small amount of dichloromethane solution, an appropriate amount of hydrochloric acid ethyl acetate solution was added, and the reaction was carried out at room temperature of 25 - 30 °C for 0.5 h. After filtration and drying, the hydrochloride form of the corresponding compound XIV was obtained.

[0075] Synthesis of compound I:

[0076] Compound X and XIV were co-dissolved in DMF in a molar ratio of 1:1.2, 1.2 equivalents of HOBT, 1.2 equivalents of EDCI and 2 equivalents of TEA were added, and the reaction was carried out at room temperature of 25 - 30 °C for 12 h. After the reaction was completed, it was diluted with ethyl acetate and washed 3 times each with water and saturated sodium chloride aqueous solution successively, then dried over anhydrous sodium sulfate and filtered. The filtrate was rotary evaporated to dryness, and the obtained concentrate was separated by silica gel column chromatography (the eluent was dichloromethane / methanol with a volume ratio of 20:1), and compound I was obtained.

[0077] The partial structure characterization results of the synthesized compounds are as follows:

[0078] N-(6-bromoquinolin-4-yl)benzo[d]thiazol-5-amine. (IV)

[0079] Yellow solid, yield: 85%.

[0080] 11H NMR (400 MHz, DMSO-d6) δ 11.34–11.24 (m, 1H), 9.54 (s, 1H), 9.21 (dt, J = 7.0, 2.3 Hz, 1H), 8.54 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.22 (t, J = 2.5 Hz, 1H), 8.08 (dd, J = 9.1, 2.8 Hz, 1H), 7.62 (dd, J = 8.6, 2.0 Hz, 1H), 6.92 (d, J = 7.0 Hz, 1H).

[0081] 13 13C NMR (101 MHz, DMSO-d6) δ 158.91, 154.87, 154.41, 143.55, 137.68, 137.18, 135.92, 133.19, 126.69, 124.46, 123.55, 122.89, 120.44, 120.09, 119.10, 101.07.

[0082] TOF MS ES+: 355.9860 [M+H] + , (calcd for C 16 H 10 N3BrS, 355.9857).

[0083] 2-(4-(3-(4-(benzo[d]thiazol-5-ylamino)quinolin-6-yl)phenyl)piperazin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide. (XC-1)

[0084] Yellow oil,yield:25%.

[0085] 11H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.32 (s, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 8.7, 2.0 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.77 (t, J = 6.0 Hz, 1H), 7.63–7.49 (m, 3H), 7.43–7.37 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 22.6 Hz, 1H), 7.03 (d, J = 5.4 Hz, 2H), 7.02–6.99 (m, 1H), 6.48 (q, J = 6.7, 5.9 Hz, 1H), 4.62–4.41 (m, 1H), 3.48 (s, 2H), 3.34–3.30 (m, 4H), 3.28–3.20 (m, 2H), 3.11 (q, J = 6.7 Hz, 2H), 2.99 (s, 2H), 2.63 (t, J = 4.8 Hz, 4H), 2.33–2.27 (m, 2H), 1.55 (p, J = 7.1 Hz, 2H), 1.43 (p, J = 6.9 Hz, 2H), 1.33–1.24 (m, 12H).

[0086] 13 13C NMR (101 MHz, DMSO-d6) δ 173.02, 170.47, 169.29, 157.80, 154.65, 152.06, 151.12, 148.74, 148.46, 146.66, 141.10, 139.74, 137.64, 136.30, 133.05, 130.01, 129.19, 129.01, 123.55, 121.94, 120.28, 120.09, 118.49, 117.03, 116.59, 115.15, 114.65, 110.52, 102.23, 61.77, 53.30, 52.04, 51.68, 48.70, 38.64, 30.97, 29.41, 26.82, 24.07.

[0087] TOF MS ES+: 906.4120 [M+H] + , (calcd for C 51 H 55 O5N9S, 906.4125).

[0088] Example 2: Verification of the RIPK3 Degradation Function of Compound XC-1

[0089] 1. Cell Culture and Seeding

[0090] The experiment used the L929 cell line in passages 10 - 20 with good condition. The cells were seeded into six - well plates at a density of 1×10 5 cells / mL (2×10 4 cells / cm 2 ²). Each well served as a drug - intervention group. When the cells grew to 70% confluence, the medium in the drug - treated groups was replaced with DMEM medium containing different concentrations of Compound I; the control group was added with DMEM medium containing an equal amount of DMSO.

[0091] 2. Cell protein extraction

[0092] After adding the drug and incubating in a 37°C, 5% CO₂ cell incubator for 48 h, cell protein extraction was performed. All operations were carried out on an ice box and specifically included the following steps:

[0093] ① Preparation of protein lysis buffer: Mix Western and IP cell lysis buffer (Beyotime, P0013) + 1% PMSF (Beyotime, ST505);

[0094] ② Remove the medium and rinse the cells in the six - well plates once with 1 mL of PBS;

[0095] ③ Add 120 μL of protein lysis buffer to each well and incubate in a 4°C refrigerator for 30 min;

[0096] ④ Use a cell scraper to scrape off the adherent cells and transfer the cells + lysis buffer to a pre - cooled 1.5 mL EP tube at the bottom;

[0097] ⑤ Centrifuge the EP tube containing the cells at 4°C, 13300 r / min for 15 min;

[0098] ⑥ After centrifugation, transfer the supernatant to another pre - cooled 1.5 mL EP tube at the bottom.

[0099] 3. Sample preparation and Western Blot

[0100] The entire process of sample preparation and Western Blot specifically included the following steps:

[0101] ① Determination of total protein concentration: The total protein concentration was determined using the BCA colorimetric method. 2 μL of the protein extract was added to a 96-well plate, diluted to 20 μL with PBS, 200 μL of BCA working solution was prepared and added, and the absorbance value at 562 nm was measured after incubation at 37 °C for 30 min. Each sample well was replicated three times. The protein standard provided in the BCA kit (Thermo, 23225) was used to draw a standard curve, and the average total protein concentration of each sample was calculated based on the obtained absorbance value, and the loading volume of each sample was calculated by unifying the total protein loading amount.

[0102] ② Sample preparation: 5x Loading Buffer (Thermo, NP0008) was added to the protein sample and mixed with the cell extract at a volume ratio of 1:4, and heated in a metal bath at 100 °C for 10 min.

[0103] ③ Electrophoresis: 14.4 g of glycine, 3.03 g of TRIS base, 1 g of SDS were used, and the volume was made up to 1 L with pure water to prepare the electrophoresis solution. Protein samples or 2 μL of protein marker were added to each well in sequence, the pre-prepared electrophoresis solution was filled into the electrophoresis tank, electrophoresed at 80 V for 30 min, and then electrophoresed at 120 V for 50 min.

[0104] ④ Transfer: 14.4 g of glycine, 3.03 g of TRIS base were used, and the volume was made up to 1 L with pure water to prepare the transfer solution. A sandwich system was formed in the Transfer Buffer (Tris-Glycine-SDS-ethanol) and transferred to the transfer tank, which was filled with the pre-prepared transfer solution, and transferred on ice at 270 mA for 95 min to transfer the protein blot on the gel to the PVDF membrane.

[0105] ⑤ Blocking and membrane cutting: The PVDF membrane after transfer was immediately placed face down into an incubation box containing 5% skim milk powder and shaken at room temperature for 1 h, then washed three times with TBST solution, and then the bands were cut out at the corresponding positions according to the molecular weights of eEF2K and GAPDH.

[0106] ⑥ Primary antibody incubation: The primary antibody against RIPK3 was anti-RIPK3 (CST, 3493S, 1:1000) diluted 1:1000, and the primary antibody against GAPDH was GAPDH (Servicebio, GB11002) diluted 1:2000. Incubate at 4 °C for 15 - 18 h. After primary antibody incubation, rinse three times with TBST to remove the residual unbound antibody on the membrane.

[0107] ⑦ Secondary antibody incubation: The secondary antibody was a rabbit secondary antibody diluted 1:5000 and incubated at room temperature for 2 h. After secondary antibody incubation, rinse three times with TBST to remove the residual unbound antibody on the membrane.

[0108] ⑧Strip exposure: Prepare 2 mL of luminescent solution (New Cellmax, P10300), evenly drop it on the surface of the PVDF membrane, and perform imaging in the automatic exposure mode to obtain the corresponding protein bands.

[0109] 4. Band analysis and statistics

[0110] The processing of images and the analysis of band abundance were performed using Image Lab software, and the data aggregation and statistics were performed using GraphPad software. Each group of results was subjected to two to three independent repeated experiments.

[0111] The specific results are as Figure 1 shown. At different concentration doses, compound XC-1 has a concentration-dependent and time-dependent degradation effect on RIPK3 protein in L929 cells. And at different concentrations, the degradation effect of XC-1 on RIPK3 is far better than that of the positive control group (GSK872) ( Figure 2 ). After pre-treating L929 cells with the NEDD8-activating enzyme inhibitor MLN4924, the proteasome inhibitor MG132, the RIPK3 ligand (GSK872), or the CRBN E3 ubiquitin ligase ligand Thalidomide for 4 h, and then incubating with 20 μM concentration of XC-1 for 36 h, the degradation effect of XC-1 on RIPK3 protein was significantly restored compared with the non-intervention group ( Figure 3 ).

[0112] Example 3

[0113] Through docking simulation of structural formula A and formula VII with RIPK3 (PDB code: 7MX3) using Maestro 13.5 software, it was found that as Figure 4 shown in A, when structural formula A binds to RIPK3, its structure completely enters the active pocket of RIPK3, which hinders the design of PROTAC. Figure 4 In B, the sulfonic acid group in structural formula A was replaced with a benzene ring group substituted by m-piperazine, resulting in formula VII. Docking found that compared with structural formula A, formula VII can well expose the piperazine ring to the solvent area for the connection of the PROTAC linker. At the same time, formula VII can form interaction forces with more pocket amino acids. Figure 4 In C, the docking simulation scores also indicate that formula VII may have a better binding ability to RIPK3 than structural formula A. Therefore, VII was used as the RIPK3 recognition end of the subsequent PROTAC targeting RIPK3 degradation.

Claims

1. A PROTAC chimera, characterized in that, It is a compound with the structure of Formula 1; Formula 1 In Formula 1, Y is -(CH2)n-, where n is from 9 to 11.

2. The PROTAC chimera according to claim 1, wherein n is 10.

3. A method for preparing the PROTAC chimera according to claim 1 or 2, characterized in that, It is prepared by the reaction of a compound of Formula 2 and a compound of Formula 3; Formula 2 Formula 3 In Formula 2, Y is the same as that in Formula 1, and in Formula 3, R is -OH, halogen or alkoxy.

4. The method for preparing the PROTAC chimera according to claim 3, wherein The said Formula 2 is prepared by the reaction of Formula 4 and Formula 5, followed by deprotection: Formula 4 Formula 5 In Formula 5, Y is the same as that in Formula 1, and R1 is a protecting group, and the protecting group is alkoxycarbonyl.

5. The method for preparing the PROTAC chimera according to claim 3, characterized in that, The said Formula 3 is Formula 3-A, which is a compound of Formula 3 with R being -OH, and it is obtained by the reaction of a compound of Formula 6 and a compound of Formula 7, followed by ester hydrolysis reaction: Formula 6 Formula 7 In Formula 7, R2 is an alkyl group with 1 to 6 carbon atoms, and X is halogen.

6. The method for preparing the PROTAC chimera according to claim 3, characterized in that, The said Formula 3 is Formula 3-B, which is a compound of Formula 3 with R being -halogen, and it can be prepared by the acylation reaction of Formula 3-A and a halogenating reagent; Formula 3-A is a compound of Formula 3 with R being -OH.

7. The method for preparing the PROTAC chimera according to claim 3, wherein The said Formula 3 is Formula 3-C, which is a compound of Formula 3 with R being alkoxy, and it can be prepared by the esterification reaction of Formula 3-A and an alcohol; Formula 3-A is a compound of Formula 3 with R being -OH.

8. Use of the PROTAC chimera according to claim 1 or 2 in the preparation of a drug for targeted degradation of RIPK3.

9. Use of the PROTAC chimera according to claim 8, characterized in that, The said drug for targeted degradation of RIPK3 is an anti-inflammatory drug.

10. Use of the PROTAC chimera according to claim 8, characterized in that, The said drug for targeted degradation of RIPK3 is a drug for the treatment of abdominal aortic aneurysm and / or heat stroke.

11. Use of the PROTAC chimera according to any one of claims 8 to 10, characterized in that, The said PROTAC chimera is combined with pharmaceutically acceptable excipients to prepare a pharmaceutically acceptable preparation.

12. A drug for targeted degradation of RIPK3, characterized in that, It contains a pharmaceutically effective amount of the PROTAC chimera according to claim 1 or 2.

13. The targeted RIPK3-degrading drug according to claim 12, wherein It also contains pharmaceutically acceptable excipients.

14. The RIPK3-targeted degrading drug according to claim 12, wherein, It also has a pharmaceutically acceptable dosage form.

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