Chimeric compounds for the recruitment of protein phosphatase pp5 to target dephosphorylation and pharmaceutical compositions and uses thereof

Abstract

The present application relates to the field of biological medicine and medicinal chemistry, and discloses a chimeric compound for targeting dephosphorylation of protein phosphatase PP5, a pharmaceutical composition and uses thereof. The chimeric compound is a bifunctional molecule formed by coupling a PP5 agonistic ligand, a small molecule montelukast derivative, and a target protein ligand through a chemical linker, and is used for inducing dephosphorylation of a disease-causing protein (including but not limited to AKT1, STAT5A, MEK1 / 2, CDC37, EGFR, BRD4, etc.). The compound and the pharmaceutical composition thereof are used in the preparation of a drug for treating or preventing a tumor disease, a neurodegenerative disease, an inflammatory disease or a metabolic disease.

Description

Technical Field

[0001] This invention relates to the fields of biomedicine and medicinal chemistry, specifically to a chimeric compound and pharmaceutical composition for recruiting protein phosphatase PP5 that targets dephosphorylation, and its uses. Background Technology

[0002] Protein phosphorylation and dephosphorylation are core mechanisms of cell signaling and functional regulation. Imbalances in phosphorylation (such as hyperphosphorylation) are frequently associated with disease development. For example, in various tumors, persistently high levels of phosphorylation of oncogene protein kinases lead to abnormal downstream signal activation and uncontrolled cell proliferation; in neurodegenerative diseases, hyperphosphorylation of Tau protein promotes the formation of toxic neurofibrillary tangles; and in inflammatory and metabolic diseases, abnormal phosphorylation of certain signaling molecules is also considered a pathogenic factor. For instance, persistent phosphorylation of AKT1 promotes cell survival and growth in various solid tumors; while hyperphosphorylation of STAT5A drives abnormal gene transcription and immune escape in leukemia and lymphoma. Furthermore, constitutive phosphorylation activation of MEK1 / 2 kinases can induce cell carcinogenesis, and excessive activation of the MEK pathway has been detected in diseases such as ovarian cancer and esophageal cancer. Phosphorylation of the kinase chaperone protein CDC37 at the Ser13 site enhances its interaction with HSP90, thereby stabilizing various oncogene kinases. The above examples demonstrate that abnormal phosphorylation states are important drivers of pathological mechanisms in different disease categories, thus restoring phosphorylation balance is of great significance in treating diseases.

[0003] Currently, the main strategy for intervening in abnormal phosphorylation is to inhibit upstream kinases. Numerous small-molecule kinase inhibitors are used clinically, blocking erroneous signal transduction by competing for ATP binding sites or through allosteric regulation to shut down the activity of abnormal kinases. This strategy has been successful in some cancer treatments but also faces significant limitations: first, long-term use of kinase inhibitors often leads to drug resistance, with cancer cells escaping inhibition through mutations or signal bypass pathways; second, many kinase inhibitors have broad spectrums but limited selectivity, potentially inhibiting non-target kinases and causing off-target toxicity. On the other hand, some studies have attempted to directly regulate phosphatases to correct phosphorylation imbalances, such as activating inhibited phosphatases or removing their inhibitory factors. However, phosphatases as drug targets are also challenging: many phosphatases have highly conserved and open catalytic sites, making it difficult to find highly selective inhibitors or activators; furthermore, typical serine / threonine protein phosphatases often function as complex holoenzyme complexes, making them difficult to precisely regulate with a single small molecule. Although new approaches such as allosteric regulators have emerged in recent years, overall, the development of drugs directly targeting phosphatases has progressed slowly.

[0004] Against this backdrop, the scientific community has begun exploring new strategies to restore protein phosphorylation balance. Inspired by PROTAC (Protein Degradation Chip Targeting) technology, researchers have proposed Phosphatase-Recruiting Chimeras (PHORCs). PHORC molecules have a bifunctional structure: one end binds to the target protein (usually a hyperphosphorylated pathogenic protein), and the other end binds to and recruits endogenous protein phosphatases. This molecule spatially brings the phosphatase and target protein close, utilizing the proximity effect to trigger dephosphorylation at a specific site. Unlike traditional methods that directly act on the phosphatase's active site, the PHORC strategy recruits endogenous phosphatases: the chimera itself does not need to inhibit the phosphatase but rather guides its natural catalytic activity to the lesion site. This method promises to be both highly efficient and selective because: firstly, PHORC, by simultaneously recognizing both the phosphatase and the target protein, only functions when both are bound, reducing the influence of irrelevant substrates; secondly, the phosphatase can repeatedly catalyze multiple target protein molecules under the guidance of a single PHORC molecule, achieving catalytic cascade amplification, thus producing significant effects even at low doses. In summary, PHORC technology provides an innovative approach for precisely regulating abnormal phosphorylation states and holds promise for breakthroughs in next-generation targeted therapy strategies. Summary of the Invention

[0005] Purpose of the Invention: The first purpose of this invention is to provide a chimeric compound for recruiting protein phosphatase PP5 that targets dephosphorylation; the second purpose is to provide a pharmaceutical composition with said compound as the active ingredient; and the third purpose is to provide a pharmaceutical use for said compound and the pharmaceutical composition thereof.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention provides a protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof, said compound having the structure of Formula I:

[0008] PLT

[0009] Formula I;

[0010] in:

[0011] P represents the binding ligand of protein phosphatase PP5, L represents the linker chain, and T represents the ligand of the target protein.

[0012] P is any one of the compounds shown in Formula II-1, Formula II-2, and Formula II-3:

[0013]

[0014] Formula II-1;

[0015]

[0016] Formula II-2;

[0017]

[0018] Formula II-3;

[0019] Wherein: Formula II-1 is Prenstar and its series of derivatives targeting CysLT1;

[0020] In Formula II-1, A is selected from H, NH2, COOH, OH or halogens;

[0021] B is selected from one of H, D, halogen, nitro, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and deuterated C1-C4 alkyl;

[0022] C is selected from C, N, or O;

[0023] D 1 Selected from C, N, or O;

[0024] E 1 Selected from C, N, or O;

[0025] F is selected from one of H, D, halogen, nitro, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and deuterated C1-C4 alkyl;

[0026] G is selected from one of H, D, halogen, nitro, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and deuterated C1-C4 alkyl;

[0027] In Formula II-2, Xaa1 represents one of threonine, alanine, and glycine, or it may not be present.

[0028] Xaa2 represents one of serine, methionine, and tryptophan, or its absence;

[0029] Xaa3 indicates one of arginine, histidine, and proline, or that it is not present.

[0030] M represents methionine;

[0031] E represents glutamic acid;

[0032] V represents valine;

[0033] D represents aspartic acid;

[0034] In Formula II-3, n represents any natural number between 1 and 10; Formula II-3 is covalently bound to the Halo Tag protein tag and covalently bound to PP5 expressing HaloTag protein in live cells or cell lysates.

[0035] Preferably, the prenlast and its derivatives are used to bind to and stimulate protein phosphatase PP5, further regulating protein phosphatase PP5-related biological signaling pathways.

[0036] Preferably, the prenlast and its derivatives serve as ligands for the protein phosphatase PP5 binding; the structural formula of the protein phosphatase PP5 binding ligand is selected from one of the following structures:

[0037]

[0038] .

[0039] Preferably, the prenlast derivative is a derivative obtained by modifying the prenlast core structure and introducing functional groups coupled to the linker chain L at appropriate sites; the functional groups are selected from amino, hydroxyl, carboxyl, azide, alkynyl, halogroup, maleimide, isocyanate, and sulfonyl chloride; the prenlast derivative after introducing the functional group coupled to the linker chain L has the following structure:

[0040]

[0041] Where n represents any independent natural number between 0 and 3.

[0042] Preferably, L is the structural formula shown in Formula III, and can be any one of the following structures, or may not exist:

[0043]

[0044]

[0045] in:

[0046] n represents any independent natural number between 1 and 10;

[0047] m represents any independent natural number between 1 and 10.

[0048] Preferably, T is a target protein-binding polypeptide or a target protein-binding small molecule drug derivative; the target protein-binding small molecule drug derivative is selected from the following structures:

[0049] .

[0050] Preferably, the compound shown in Formula I has one of the structural formulas of any one of Formulas 1-42:

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057] .

[0058] Preferably, the pharmaceutically acceptable salt is an inorganic acid salt, an organic acid salt, an inorganic base salt, or an organic base salt.

[0059] Preferably, the inorganic acid is selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

[0060] Preferably, the organic acid is selected from at least one of methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, and benzoic acid.

[0061] Preferably, the inorganic base is selected from at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0062] Preferably, the organic base is selected from at least one of methylamine, ethylamine, n-propylamine, isopropylamine, dimethylamine, diethylamine, triethylamine, diisopropylethylamine, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, benzylamine, morpholine, piperidine, piperazine, N-methylpiperazine, choline, arginine, lysine, histidine, and N-methylglucosamine.

[0063] The present invention also provides a pharmaceutical composition comprising any of the above-described protein phosphatase PP5 recruitment chimeric compounds or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, carriers or diluents.

[0064] The present invention also provides the use of a protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition in the preparation of a medicament for treating or preventing tumor diseases, neurodegenerative diseases, inflammatory diseases or metabolic diseases.

[0065] Preferably, the tumor disease is one or more of the following: gastric cancer, colon cancer, breast cancer, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, acute myeloid leukemia, or multiple myeloma.

[0066] Preferably, the neurodegenerative disease is one or more of Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0067] Preferably, the inflammatory disease is one or more of rheumatoid arthritis or asthma.

[0068] Preferably, the metabolic disease is one or more of type 2 diabetes, obesity, or fatty liver.

[0069] Beneficial effects: Compared with the prior art, the present invention has the following beneficial effects:

[0070] This invention provides a class of bifunctional molecules that use a prolansta derivative as a ligand recruiter for the protein phosphatase PP5 and are coupled to a target protein ligand via a linker strand. These molecules recruit PP5 and induce dephosphorylation of the target protein, thus providing a novel technical approach for the intervention of diseases related to abnormal phosphorylation. Compared to existing methods that primarily reduce substrate protein phosphorylation levels by inhibiting upstream kinase activity, this invention directly targets the abnormal phosphorylation state itself, exhibiting a mechanism of action distinct from existing kinase inhibition strategies.

[0071] The PP5 recruiting end used in this invention has a good functional basis. Experimental results show that prenstar can bind to PP5 and activate its enzyme activity, indicating that it can serve as an effective recruiting ligand in PP5 recruiting chimeric compounds, providing a feasible ligand basis for constructing PP5-based targeted dephosphorylation molecules.

[0072] The representative compounds of this invention can form ternary complexes and induce dephosphorylation of target proteins. Experimental results show that the representative compound A1PB can induce the formation of a PP5-compound-target protein ternary complex; AKPB (AP10C) can induce AKT1 dephosphorylation in a concentration-dependent manner; and YJP (MP6C) can induce MEK1 dephosphorylation in a concentration-dependent manner. These results indicate that the PP5 recruitment chimeric compounds of this invention possess a clear mechanism of action and good dephosphorylation activity.

[0073] Furthermore, this invention adopts a modular design approach of PP5 ligand module - linker chain module - target protein ligand module, which allows for rapid construction and optimization of compounds by changing the target protein ligand or adjusting the linker chain structure. It has good versatility and scalability, which is beneficial for structural iteration and functional optimization for different abnormal phosphorylation targets, thereby improving R&D efficiency and application potential.

[0074] Therefore, the protein phosphatase PP5 recruitment chimeric compound provided by this invention can not only achieve targeted regulation of the abnormal phosphorylation state of the target protein, but also provide a new molecular type and research basis for drug development of abnormal phosphorylation-related diseases such as tumors, neurodegenerative diseases, inflammatory diseases and metabolic diseases. Attached Figure Description

[0075] Figure 1 Figure of cell thermal drift experiment of Pranlukast and PP5;

[0076] Figure 2 Isothermal titration calorimetry diagram of Pranlukast and PP5 protein and their domains;

[0077] Figure 3 Experimental diagram of A1PB-induced dephosphorylation of AKT1 and MEK1;

[0078] Figure 4 Experimental diagram of A1PB-induced ternary complex formation;

[0079] Figure 5 Experimental diagram of AKPB (AP10C)-induced AKT1 dephosphorylation;

[0080] Figure 6 Experimental diagram of YJP(MP6C)-induced MEK1 dephosphorylation;

[0081] Figure 7 This is the synthesis route diagram for Example 1;

[0082] Figure 8 This is the synthesis route diagram for Example 3. Detailed Implementation

[0083] Unless otherwise specified, the raw materials may be obtained commercially, or prepared by methods known in the art, or according to the methods described herein. The structure of the compounds was determined by nuclear magnetic resonance (NMR). 1 The NMR was determined by 1H-NMR and / or mass spectrometry (MS). NMR measurements were performed using a Varian INOVA (300 MHz) or Bruker Advance (400 MHz) NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and TMS as the internal standard. MS measurements were performed using a Waters Q-Tof miniature mass spectrometer. Column chromatography was performed using 200-300 mesh silica gel from Qingdao Marine Chemical Plant.

[0084] Example 1

[0085] The preparation of (S)-4-amino-N-(1-(4-chlorophenyl)-3-(4-(10-oxo-10-((4-(3-(4-((4-oxo-2-(2H-tetrazol-5-yl)-4H-chromen-8-yl)carbamoyl)phenoxy)propoxy)phenyl)amino)decanoyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AP10C) is shown in the following synthetic route. Figure 7 As shown.

[0086] (1) Preparation of (S)-10-(4-(3-(4-((tert-butoxycarbonyl)amino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-carboxamido)-3-(4-chlorophenyl)propyl)piperazin-1-yl)-10-oxodecanoic acid (AP10C-2)

[0087] Add 22 mg (0.1 mmol) of monomethyl sebacate, 16 mg (0.12 mmol) of 1-hydroxybenzotriazole, and 38 mg (0.2 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbamate hydrochloride to a 50 mL round-bottom flask in sequence, followed by the addition of dichloromethane to dissolve the reactants. After stirring at room temperature for 1 hour, add 60 mg (0.1 mmol) of tert-butyl(S)-(4-((1-(4-chlorophenyl)-3-(piperazin-1-yl)propyl)amide)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)carbamate (AKTligand). Detect by TLC; stop the reaction when starting material 1 has completely reacted. Dry the reaction mixture to obtain the crude product. The crude product was purified using a preparative thin-layer chromatography plate (eluent: dichloromethane: methanol = 20:1) to obtain 30 mg (0.037 mmol) of white solid AP10C-1, with a yield of 37%. Then, 30 mg (0.037 mmol) of AP10C-1, 3 mL of methanol, and 1 mL of 4 M sodium hydroxide aqueous solution were added sequentially to a 50 mL flask, and the mixture was stirred at room temperature for 3 hours. TLC analysis showed that the reactant AP10C-1 had reacted completely, and the reaction was terminated. 1.1 mL of ethyl acetate hydrochloride solution was added to the reaction mixture, and after thorough stirring, the reaction mixture was evaporated to dryness. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and evaporated to dryness to obtain 28.5 mg (0.036 mmol) of white solid AP10C-2, with a yield of 98%. 1H NMR (300 MHz, DMSO-d6)δ 11.67 (s, 1H), 8.30 (d, J= 7.7 Hz, 1H), 8.12 (s, 1H), 7.32 (s, 4H), 7.17 (s, 2H), 6.59 (d, J = 3.1 Hz,1H), 4.88 (q, J = 6.9 Hz, 1H), 4.20 (d, J = 13.0 Hz, 2H), 3.61 (s, 2H), 3.57(s, 3H), 3.47 (s, 4H), 2.33 – 2.21 (m, 10H), 1.97 (s, 4H), 1.86 (s, 2H), 1.55– 1.47 (m, 4H), 1.42 (s, 9H), 1.24 (s, 8H).

[0088] (2) Title compound (S)-4-amino-N-(1-(4-chlorophenyl)-3-(4-(10-oxo-10-((4-(3-(4-((4-oxo-2-(2H-tetrazol-5-yl)-4H-chromen-8-yl)carbamoyl)phenoxy)propoxy)phenyl)amino)decanoyl)piperazin-1-yl)propyl)-1-(7H-

[0089] Preparation of pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AP10C)

[0090] 84 mg (0.1075 mmol) of AP10C-2 was added to a 50 mL flask, followed by 60 mg (0.161 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate and 28 mg (0.215 mmol) of N,N-diisopropylethylamine. After stirring at room temperature for 1 hour, 57 mg (0.1075 mmol) of PLST was added. The reaction was continued for 5 hours. The reaction was stopped when no significant change in the concentration of the reactants was observed by TLC. The reaction solution was evaporated to dryness to obtain the crude product. The crude product was then purified using preparative thin-layer chromatography (eluent: dichloromethane: methanol: triethylamine = 10:1:0.1) to obtain 7.5 mg (0.0059 mmol) of white solid AP10C-3, with a yield of 5.52%. Add 2 mg (0.0016 mmol) of AP10C-3 and 2 mL of 1M ethyl hydrochloride solution to a 50 mL orb-shaped flask, and stir at room temperature for 3 hours. TLC analysis showed that the AP10C-3 reaction was complete, and the reaction was terminated. The reaction mixture was evaporated to dryness at 45°C, and the hydrochloride was extracted using a saturated sodium bicarbonate / ethyl acetate system. The organic layer was collected and evaporated to dryness to obtain 1.7 mg (0.00152) of AP10C, with a yield of 95%.1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, -1H), 9.97 (s, 1H), 9.62 (s, 1H), 8.76 (s, 2H), 8.18 (s, 1H),8.06 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.25 (s, 4H), 7.20 (s,1H), 6.96 (t, J = 4.4 Hz, 3H), 6.75 (d, J = 7.6 Hz, 2H), 6.71 (s, 1H), 4.77(s, 1H), 4.13 – 4.05 (m, 4H), 3.94 (t, J = 6.0 Hz, 4H), 2.88 (s, 4H), 2.11(s, 12H), 1.80 (d, J = 10.0 Hz, 2H), 1.74 (s, 4H), 1.29 (s, 4H), 1.09 (s,8H). HRMS (ESI): found 1161.52352 (C61H69ClN14O8 [M+H]+, requires1161.51841).

[0091] Example 2

[0092] Preparation of N1-(2-fluoro-3-((4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-chromen-3-yl)methyl)phenyl)-N6-(4-(3-(4-((4-oxo-2-(2H-tetrazol-5-yl)-4H-chromen-8-yl)carbamoyl)phenoxy)propoxy)phenyl)hexadiamide (MP6C)

[0093] Synthesis route:

[0094]

[0095] (1) Preparation of methyl 6-((2-fluoro-3-((4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-chromen-3-yl)methyl)phenyl)amino)hexanoate (MP6C-1)

[0096] Add 95 mg (0.25 mmol) of 3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-benzopyran-2-one (MEK1 ligand) and 64 mg (0.625 mmol) of triethylamine to a 50 mL three-necked flask, and dissolve the reactants in a suitable amount of dichloromethane. Then, dissolve 54 mg of methyl fatty acyl chloride in a suitable amount of dichloromethane and add it dropwise to the three-necked flask using a constant-pressure dropping funnel, completing the addition over 30 minutes. Continue stirring the reaction at room temperature for approximately 2 hours. Detect the reaction by TLC; stop the reaction when the reactant 1 has completely reacted. Dry the reaction mixture to obtain the crude product. Purify the crude product using a preparative thin-layer chromatography plate (eluent: dichloromethane: methanol = 20:1) to obtain 110 mg (0.212 mmol) of colorless crystals MP6C-1, with a yield of 84.7%. 1HNMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.68 (d, J = 4.8 Hz, 2H), 7.91 (d, J =8.8 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.26 (dd, J =8.8, 2.4 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 7.1 Hz, 1H), 4.01(s, 2H), 3.59 (s, 3H), 2.48 (s, 3H), 2.41 – 2.31 (m, 4H), 1.64 – 1.53 (m,4H).

[0097] (2) Preparation of the title compound N1-(2-fluoro-3-((4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-chromen-3-yl)methyl)phenyl)-N6-(4-(3-(4-((4-oxo-2-(2H-tetrazol-5-yl)-4H-chromen-8-yl)carbamoyl)phenoxy)propoxy)phenyl)hexadiamide (MP6C)

[0098] To a 50 mL flask, add 110 mg (0.212 mmol) of MP6C-1, 2 mL of methanol, 2 mL of tetrahydrofuran, and 1 mL of 4 M sodium hydroxide aqueous solution sequentially. Stir at room temperature for 3 hours. TLC analysis showed that the reactant MP6C-1 had reacted completely, and the reaction was terminated. Add 1.1 mL of 4 M ethyl hydrochloride solution to the reaction mixture, stir well, and evaporate to dryness to obtain a white solid. Dissolve the solid in methanol and dichloromethane, filter to remove sodium chloride, and collect the filtrate. Evaporate to dryness to obtain 97.5 mg (0.193 mmol) of white solid MP6C-2, with a yield of 91%. Add 36 mg (0.0712 mmol) of MP6C-2 to a 50 mL three-necked flask, and dissolve the reactants in dichloromethane. Separately, dilute 12.7 mg of thionyl chloride with dichloromethane and add it dropwise to the three-necked flask using a constant-pressure dropping funnel over 30 minutes. Continue the reaction for 2 hours. Once the reaction of MP6C-2 is complete, monitor by TLC and stop the reaction. Dry the reaction solution to obtain MP6C-3, and store it under nitrogen protection.

[0099] Add 38 mg (0.0712 mmol) of PLST, 20 mg (0.213 mmol) of anhydrous triethylamine, and a suitable amount of dichloromethane to a 50 mL Mitsui flask. Then dissolve 37 mg (0.0712 mmol) of MP6C-3 in the dichloromethane and add it dropwise to the three-necked flask using a constant-pressure dropping funnel, completing the addition over 30 minutes. Continue the reaction for 5 hours. TLC analysis showed that the PLST reaction was complete, and the reaction was terminated. The reaction mixture was evaporated to dryness to obtain crude MP6C. The crude product was purified using preparative thin-layer chromatography (eluent: dichloromethane: methanol: formic acid = 20:1:0.1) to obtain 8.2 mg (0.0083 mmol) of pale yellow MP6C powder, with a yield of 11.7%. 1H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.77 (s, 1H), 9.66(s, 1H), 8.68 (d, J = 4.8 Hz, 2H), 8.13 – 8.05 (m, 3H), 7.90 (d, J = 8.5 Hz,2H), 7.73 (s, 1H), 7.51 (d, J = 8.2 Hz, 3H), 7.39 – 7.24 (m, 3H), 7.15 (d, J= 8.5 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 4H), 4.26 (d, J= 7.1 HRMS (ESI): found 1008.30854(C53H44FN9O10 [M+Na]+, requires 1008.30874).

[0100] Example 3

[0101] The preparation of 4-(3-(4-(6-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazacyclohept-6-yl)acetamyl)hexamido)phenoxy)propoxy)-N-(4-oxo-2-(2H-tetrazol-5-yl)-4H-benzopyran-8-yl)benzamide (BP6C) is described by the following synthetic route. Figure 8 As shown.

[0102] (1) Preparation of 6-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thiopheno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazacyclohept-6-yl)acetamyl)hexanoic acid (BP6C-2)

[0103] Add 50 mg (0.125 mmol) of 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetic acid (BRD4 ligand), 32 mg (0.25 mmol) of N,N-diisopropylethylamine, and 71 mg (0.187 mmol) of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate to a 50 mL round-bottom flask, followed by dissolving the reactants in dichloromethane. After stirring at room temperature for 1 hour, add 22.5 mg (0.125 mmol) of methyl 6-aminohexanoate. The reaction was stopped by TLC after the starting material BRD4 ligand had completely reacted. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was purified using a preparative thin-layer chromatography plate (eluent: dichloromethane: methanol = 15:1) to obtain 44 mg (0.084 mmol) of pale yellow solid BP6C-1, with a yield of 67%. Then, 44 mg (0.084 mmol) of BP6C-1, 3 mL of methanol, and 1 mL of 4 M sodium hydroxide aqueous solution were added sequentially to a 50 mL flask, and the mixture was stirred at room temperature for 3 hours. TLC analysis showed that the reactant BP6C-1 had reacted completely, and the reaction was terminated. 1.1 mL of 4 M ethyl hydrochloride solution was added to the reaction mixture, and after thorough stirring, the reaction mixture was evaporated to dryness. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and evaporated to dryness to obtain 41 mg (0.08 mmol) of pale yellow solid BP6C-2, with a yield of 95%. 1H NMR (300 MHz, DMSO-d6) δ 8.19 (d, J =6.3 Hz, 1H), 7.53 – 7.40 (m, 4H), 4.55 – 4.48 (m, 1H), 3.25 – 3.18 (m, 2H), 3.08 (dt, J = 12.4, 6.7 Hz, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 2.19 (t, J = 7.5Hz, 2H), 1.62 (s, 3H), 1.46 (dq, J = 21.2, 7.1 Hz, 4H), 1.30 (d, J = 6.8 Hz,2H).

[0104] (2) Preparation of the title compound 4-(3-(4-(6-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazacyclohept-6-yl)acetamyl)hexamido)phenoxy)propoxy)-N-(4-oxo-2-(2H-tetrazol-5-yl)-4H-benzopyran-8-yl)benzamide (BP6C)

[0105] Add 41 mg (0.08 mmol) of BP6C-2 to a 50 mL three-necked flask. Separately, dilute 14 mg of thionyl chloride with dichloromethane and slowly add it dropwise to the three-necked flask using a constant-pressure dropping funnel, completing the addition within 30 minutes. Continue stirring at room temperature for 1 hour. Stop the reaction after TLC monitoring shows complete reaction of BP6C-2. Reduce the reaction solution to dryness to obtain a brown solid, AP10C-3, which can be used directly without purification and stored under nitrogen protection. Next, add 20 mg (0.08 mmol) of PLST and 24 mg (0.24 mmol) of anhydrous triethylamine to a 50 mL three-necked flask, and then dissolve the reactants in dichloromethane. Dilute 41 mg (0.08 mmol) of BP6C-3 with dichloromethane and slowly add it dropwise to the three-necked flask using a constant-pressure dropping funnel, completing the addition within 30 minutes. Continue the reaction at room temperature for 5 hours. TLC analysis showed that the BP6C-3 reaction was complete, and the reaction was terminated. The reaction solution was evaporated to dryness to obtain crude BP6C, which was then purified using a preparative thin-layer chromatography plate (eluent: dichloromethane: methanol: triethylamine = 10:1:0.1) to obtain 12 mg (0.012 mmol) of pale yellow solid BP6C, with a yield of 15%. 1H NMR (300 MHz, DMSO-d6) δ 11.05(s, -1H), 10.11 (s, 1H), 8.41 (s, 1H), 8.09 (d, J = 8.2 Hz, 3H), 7.89 (d, J =7.8 Hz, 1H), 7.50 (dd, J = 8.5, 5.3 Hz, 5H), 7.46 – 7.18 (m, 3H), 7.15 (d, J= 8.4 Hz, 2H), 6.92 (s, 1H), 6.89 (d, J = 3.2 Hz, 2H), 4.28 (d, J = 6.4 Hz, 2H), 4.11 (d, J = 6.7 Hz, 2H), 2.99 (q, J = 7.3 Hz, 52H), 2.59 (s, 3H), 2.41(s, 3H), 2.26 (d, J = 7.7 Hz, 2H), 2.21 (s, 2H), 1.62 (s, 3H), 1.35 (s, 2H),1.17 (t, J = 7.2 Hz, 75H). HRMS (ESI): found 992.30731 (C51H48ClN11O7S [MH]-, requires 992.30746).

[0106] Example 4

[0107] Preparation of 4-(3-(4-(6-(4-(((6-chlorohexyl)oxy)phenoxy)hexamido)phenoxy)propoxy)-N-(4-oxo-2-(2H-tetrazol-5-yl)-4H-benzopyran-8-yl)benzamide (A1PB)

[0108] Synthesis route:

[0109]

[0110] (1) Preparation of 4-((6-chlorohexyl)oxy)phenol (A1T-1)

[0111] Add 1.65 g (15 mmol) of hydroquinone, 3.59 g (18 mmol) of 6-chloro-1-hexanol, 2.52 g (18 mmol) of potassium carbonate, and 30 mL of anhydrous acetone to a 50 mL three-necked flask. Reflux and stir at 60 °C for 24 hours, then stop the reaction. Filter the reaction mixture, wash the filter cake with an appropriate amount of DCM, collect the filtrate and evaporate to dryness to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain 2.12 g (9.3 mmol) of white crystals AlT-1, with a yield of 62%. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 6.81 – 6.65 (m, 4H), 3.87 (t, J = 6.4 Hz, 2H), 3.67 (t, J= 6.6 Hz, 2H), 1.73 (dt, J = 20.2, 7.1 Hz, 4H), 1.51 – 1.41 (m, 4H).

[0112] (2) Preparation of methyl 6-(4-(6-chlorohexyl)oxyphenoxy)hexanoate (A1T-2)

[0113] Add 1.15 g (5 mmol) of A1T-1, 1.25 g (6 mmol) of methyl 6-bromohexanoate, 0.83 g (6 mmol) of potassium carbonate, and 15 mL of anhydrous acetone to a 50 mL three-necked flask. Reflux and stir at 60 °C for 12 hours, then stop the reaction. Filter the reaction mixture, wash the filter cake with an appropriate amount of DCM, collect the filtrate and evaporate to dryness to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain 0.96 g (2.7 mmol) of white crystals of A1T-2, in a yield of 54%. 1H NMR (300 MHz, DMSO-d6) δ6.86 (s, 4H), 3.91 (t, J = 4.2 Hz, 4H), 3.67 (t, J = 6.5 Hz, 2H), 3.61 (s,3H), 2.36 (t, J = 7.3 Hz, 2H), 1.71 (s, 6H), 1.61 (t, J = 7.5 Hz, 2H), 1.45(s, 6H).

[0114] (3) Preparation of 6-(4-((6-chlorohexyl)oxy)phenoxy)hexanoyl chloride (AlT-3-Cl)

[0115] Add 600 mg (1.68 mmol) of A1T-2 to a 50 mL flask, followed by 2 mL of 4M sodium hydroxide aqueous solution, 2 mL of methanol, and 2 mL of tetrahydrofuran. Stir at 60 °C for 3 hours. Analyze by TLC. Stop the reaction when A1T-2 has completely reacted. After adjusting the pH to 3-4 with an appropriate amount of ethyl acetate hydrochloride solution, the reaction solution was evaporated to dryness to obtain the crude product. The crude product was dissolved with an appropriate amount of DCM, filtered, and the filter cake was washed with an appropriate amount of DCM. The filtrate was collected, and 1 ml of thionyl chloride was added to the filtrate. The reaction was carried out for 3 hours, and the solution was evaporated to dryness to obtain 559 mg (1.63 mmol) of brown solid AlT-3, with a yield of 97%. ¹H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 6.82 (s, 4H), 3.87 (td, J = 6.5, 2.8 Hz, 4H), 3.69–3.55 (m, 3H), 2.27 (dt, J = 29.7, 7.3 Hz, 2H), 1.79–1.34 (m, 15H).

[0116] Under a nitrogen atmosphere, 342 mg (1.0 mmol) of AlT-3 and 10 mL of anhydrous DCM were added sequentially to a 50 mL dry three-necked flask. A constant-pressure dropping funnel was connected, and 0.078 mL (1.1 mmol) of thionyl chloride was added to the funnel and dissolved in 10 mL of anhydrous DCM. The mixture was heated to reflux at 55 °C, and thionyl chloride was slowly added dropwise over 30 minutes. The reaction was continued at room temperature for 2 hours. TLC was used to monitor the reaction, and the reaction was stopped when AlT-3 had completely reacted. The reaction solution was evaporated to dryness to obtain AlT-3-Cl, which was then stored under nitrogen protection.

[0117] (4) Preparation of the title compound 4-(3-(4-(6-(4-(((6-chlorohexyl)oxy)phenoxy)hexamido)phenoxy)propoxy)-N-(4-oxo-2-(2H-tetrazol-5-yl)-4H-benzopyran-8-yl)benzamide (A1PB)

[0118] To a dry 50 mL three-necked flask, add 50 mg (0.1 mmol) of PLST, 30 mg (0.3 mmol) of anhydrous triethylamine, and 10 mL of anhydrous DCM sequentially. Connect a constant-pressure dropping funnel and add 34 mg (0.1 mmol) of AlT-3-Cl to the funnel, dissolving it in 10 mL of anhydrous DCM. Under ice bath conditions, slowly add AlT-3-Cl dropwise over 30 minutes, and continue the reaction at room temperature for 3 hours. Monitor the reaction by TLC; stop the reaction when PSLT is completely reacted. Reduce the reaction mixture to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent:DCM:MeOH:acetic acid = 20:1:0.1) to obtain A1PB. ¹H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.81 (s, 1H), 8.11 (dd, J = 7.7, 5.1 Hz, 3H), 7.93–7.88 (m, 1H), 7.51 (dd, J = 8.5, 6.5 Hz, 3H), 7.16 (d, J = 8.5 Hz, 2H), 6.94 (s, 1H), 6.91 (d, J = 2.5 Hz, 2H), 6.83 (s, 4H), 4.29 (t, J = 6.2 Hz, 2H), 4.14 (t, J = 4H). = 6.1 Hz, 2H), 3.89 (td, J = 6.4, 2.9 Hz, 4H), 3.65 (t, J =6.6 Hz, 2H), 2.33 – 2.28 (m, 2H), 2.22 (t, J = 6.4 Hz, 2H), 2.00 (s, 2H), 1.68 (q, J = 9.2 Hz, 8H), 1.45 – 1.41 (m, 4H), 1.36 (d, J = 4.6 Hz, 2H).

[0119] HRMS (ESI): found 821.30793 (C44H47ClN6O8 [MH]-, requires821.30711).

[0120] Example 5

[0121] Phosphatase activity assay (pNPP method)

[0122] The procedure for testing PP5 enzyme activity using the pNPP method is as follows: First, prepare 50 mL of buffer solution containing 100 mM Tris, 50 mM NaCl, and 0.5 mM MnCl2 (pH = 8.0). Dissolve the test compound (DMSO content less than 10%), PP5 protein, and pNPP substrate in this buffer solution. Use a 96-well clear plate with three replicates. Add 50 μL of PP5 protein solution (240 nM), 50 μL of compound solution (60 μM), and finally 50 μL of substrate solution (5 mg / mL) to each well. For the positive control wells, add 50 μL of PP5 protein solution, 50 μL of MEEVD positive control solution, and 50 μL of substrate solution. For the blank wells, add 50 μL of PP5 protein solution, 50 μL of buffer solution, and 50 μL of substrate solution. Incubate the 96-well plate at room temperature (25℃) for 10 min. Collect data using a microplate reader at a wavelength of 410 nm. Analyze the results using GraphPad software.

[0123] Table 1. Activating activity of compounds on PP5 enzyme.

[0124]

[0125] Note: The structure of the compound is as follows:

[0126]

[0127] As shown in Table 1, the commercially available compound Pranlukast exhibits activating activity against PP5. At a concentration of 20 μM, the compound showed a 15-fold increase in PP5 activation activity, superior to the positive control compound MEEVD. This indicates that the compounds in this patent embodiment retain strong PP5 enzyme activation activity.

[0128] Example 6

[0129] Cellular thermal shift assay (CETSA)

[0130] CETSA Procedure: HCT116 cells in logarithmic growth phase were cultured to approximately 80% density using standard methods. Pranlukast was then added to a final concentration of 20 μM, with an equal volume of DMSO as a negative control. Both were incubated at 37°C with 5% CO2 for 12 hours. The treated cells were collected, washed with pre-chilled PBS, and resuspended. The cell suspension was divided into several aliquots. Each aliquot was subjected to heat shock at a gradient of 37°C, 42°C, 47°C, 52°C, 55°C, 58°C, 61°C, 64°C, 67°C, and 70°C, incubating for 3 minutes at each temperature. Immediately after the shock, the aliquots were freeze-thawed in liquid nitrogen. The cooled aliquots were then sonicated and centrifuged at 12000 rpm for 15 minutes at 4°C. The supernatant was collected to obtain soluble proteins. Western blotting was then performed. The specific experimental procedures included polyacrylamide gel preparation, SDS-PAGE analysis, primary antibody incubation, secondary antibody incubation, and result scanning. In the experiment, the expression level of PP5 was tested.

[0131] The binding configuration of compound Pranlukast with PP5 is as follows:

[0132] like Figure 1 As shown, after gradient heat shock treatment, the intensity of the PP5 protein band in the DMSO control group decreased rapidly with increasing temperature, showing significant weakening at approximately 55°C and almost complete disappearance above 61°C. In contrast, the PP5 protein band remained clearly detectable at higher temperatures in the Pranlukast-treated group, with a significantly slower decay rate than the control group. This result indicates that Pranlukast enhances the thermal stability of PP5 after binding to it.

[0133] Example 7

[0134] ITC method for testing the binding activity of Pranlukast with PP5 protein and its domains

[0135] ITC Procedure: Recombinant full-length PP5 protein, TPR domain protein, and PP5 catalytic domain protein (PP5C) were prepared. After dialysis to remove salts, the protein concentration was uniformly adjusted to 20 μM. Pranlukast solution was prepared to a final concentration of 200 μM in the titration syringe. All samples used the same buffer system to reduce background interference. In an isothermal titration calorimeter, the protein solution was placed in the sample cell, and the Pranlukast solution was placed in the titration syringe. The experiment was conducted at 25°C using continuous titration mode: 2 μL of ligand solution was injected each time, with an interval of 120 seconds to ensure sufficient decay of the thermal signal. The original thermal signal was integrated using the instrument's software to obtain the enthalpy change (ΔH) corresponding to each drop. The binding constant (Kbinding constant) was calculated by nonlinear fitting combined with the isothermal titration curve. d ), combined with thermodynamic parameters such as enthalpy (ΔH) and stoichiometry (n).

[0136] like Figure 2 As shown, the ITC experimental results clearly demonstrate from a thermodynamic perspective that Pranlukast cannot bind to the PP5 catalytic domain protein (PP5C), but can directly bind to the full-length PP5 protein, and its binding site is located in the TPR domain.

[0137] Example 8

[0138] Western blot analysis was performed to assess the dephosphorylation activity of A1PB molecules on non-substrate proteins AKT1 and MEK1.

[0139] The procedure for Western blot testing is as follows:

[0140] Western blotting experiments were conducted according to standard procedures. The specific procedures included cell drug administration, cell lysis, total protein collection, preparation of polyacrylamide gels, SDS-PAGE analysis, primary antibody incubation, secondary antibody incubation, and result scanning. During the experiments, AKT1 and p-AKT1 were tested. T308 p-AKT1 S473 MEK1 and p-MEK1 S217 / 221 The amount of expression.

[0141] The dephosphorylation effect of compound A1PB on AKT1 and MEK1 in the embodiments of the present invention is as follows:

[0142] like Figure 3 As shown, the test results indicate that A1PB dephosphorylates AKT1 in a concentration-dependent manner and MEK1 in a time-dependent manner.

[0143] Example 9

[0144] HaloTrap Pulldown test A1PB induces ternary complex formation

[0145] The steps for performing a HaloTrap Pulldown test are as follows:

[0146] The experiment followed standard experimental procedures. The specific experimental process included cell lysis, administration of lysis buffer, collection of total protein, magnetic bead incubation, preparation of polyacrylamide gel, SDS-PAGE analysis, primary antibody incubation, secondary antibody incubation, and result scanning. Western blotting was used to measure the expression levels of H-AKT1 and PP5.

[0147] like Figure 4 As shown, the test results indicate that A1PB can induce the formation of ternary complexes in a concentration-dependent manner.

[0148] Example 10

[0149] Western blot analysis of the dephosphorylation activity of AKPB (AP10C) molecules on non-substrate proteins.

[0150] The procedure for Western blot testing is as follows:

[0151] Western blotting experiments were conducted according to standard procedures. The specific procedures included cell drug administration, cell lysis, total protein collection, preparation of polyacrylamide gels, SDS-PAGE analysis, primary antibody incubation, secondary antibody incubation, and result scanning. During the experiments, AKT1 and p-AKT1 were tested. T308 and p-AKT1 S473 The amount of expression.

[0152] The dephosphorylation effect of compound AKPB (AP10C) on AKT1 in this embodiment of the invention is as follows:

[0153] like Figure 5 As shown, the test results indicate that AKPB (AP10C) dephosphorylates AKT1 in a concentration-dependent manner.

[0154] Example 11

[0155] Western blot analysis of the dephosphorylation activity of YJP(MP6C) molecules on non-substrate proteins.

[0156] The procedure for Western blot testing is as follows:

[0157] Western blotting experiments were conducted according to standard procedures. The specific procedures included cell drug administration, cell lysis, total protein collection, preparation of polyacrylamide gels, SDS-PAGE analysis, primary antibody incubation, secondary antibody incubation, and result scanning. MEK1 and p-MEK1 were tested in the experiments. S217 / 221 The amount of expression.

[0158] The dephosphorylation effect of compound YJP(MP6C) on MEK1 in this invention embodiment is as follows:

[0159] like Figure 6 As shown, the test results indicate that YJP(MP6C) dephosphorylates MEK1 in a concentration-dependent manner.

Claims

1. A protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound has the structure of Formula I: PLT Formula I; in: P represents the binding ligand of protein phosphatase PP5, L represents the linker chain, and T represents the ligand of the target protein. P is any one of the compounds shown in Formula II-1, Formula II-2, and Formula II-3: Formula II-1; Formula II-2; Formula II-3; Wherein: Formula II-1 is Prenstar and its series of derivatives targeting CysLT1; In Formula II-1, A is selected from H, NH2, COOH, OH or halogens; B is selected from one of H, D, halogen, nitro, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and deuterated C1-C4 alkyl; C is selected from C, N, or O; D 1 Selected from C, N, or O; E 1 Selected from C, N, or O; F is selected from one of H, D, halogen, nitro, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and deuterated C1-C4 alkyl; G is selected from one of H, D, halogen, nitro, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and deuterated C1-C4 alkyl; In Formula II-2, Xaa1 represents one of threonine, alanine, and glycine, or it may not be present. Xaa2 represents one of serine, methionine, and tryptophan, or its absence; Xaa3 indicates one of arginine, histidine, and proline, or that it is not present. M represents methionine; E represents glutamic acid; V represents valine; D represents aspartic acid; In Formula II-3, n represents any natural number between 1 and 10; Formula II-3 is covalently bound to the Halo Tag protein tag and covalently bound to PP5 expressing HaloTag protein in live cells or cell lysates.

2. The protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The prence and its derivatives are used to bind to and stimulate protein phosphatase PP5, further regulating protein phosphatase PP5-related biological signaling pathways.

3. The protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, The prenlast and its derivatives serve as ligands for the protein phosphatase PP5 binding agonist, and the structural formula of the PP5 binding ligand is selected from one of the following structures: 。 4. The protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that, The Prenstar derivative is a derivative obtained by modifying the Prenstar core structure and introducing functional groups coupled to the linker chain L at appropriate sites; the functional groups are selected from amino, hydroxy, carboxyl, azide, alkynyl, halogroup, maleimide, isocyanate, and sulfonyl chloride. The Prenst derivatives with the introduction of functional groups coupled to linker chain L include the following structures: Where n represents any independent natural number between 0 and 3.

5. The protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The L is the structural formula shown in Equation III, and can be any of the following structures, or it may not exist: in: n represents any independent natural number between 1 and 10; m represents any independent natural number between 1 and 10.

6. The protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The T represents a target protein-binding polypeptide or a target protein-binding small molecule drug derivative; the target protein-binding small molecule drug derivative is selected from the following structures: 。 7. The protein phosphatase PP5 recruitment chimeric compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound shown in Formula I has a structural formula that is one of any of the structures in Formulas 1-42: 。 8. A pharmaceutical composition, characterized in that, It comprises the protein phosphatase PP5 recruitment chimeric compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

9. Use of the protein phosphatase PP5 recruiting chimeric compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical combination of claim 8, in the preparation of a medicament for the treatment or prevention of oncological diseases, neurodegenerative diseases, inflammatory diseases, or metabolic diseases.

10. The use according to claim 9, characterized in that, The tumor disease is one or more of the following: gastric cancer, colon cancer, breast cancer, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, acute myeloid leukemia, or multiple myeloma; the neurodegenerative disease is one or more of the following: Alzheimer's disease, Parkinson's disease, or Huntington's disease; the inflammatory disease is one or more of the following: rheumatoid arthritis or asthma; and the metabolic disease is one or more of the following: type 2 diabetes, obesity, or fatty liver.

Images