Protein degradation agent compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a protein degradation agent compound as well as a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown in a formula I, the compound further comprises a deuterated compound, pharmaceutically acceptable salt or a mixture of the deuterated compound and the pharmaceutically acceptable salt, and the compound can effectively degrade MLKL protein on the nanomolar concentration level and achieve anti-necrotic activity on tumor cells and has application prospects as an anti-necrotic apoptosis active molecule. Meanwhile, the preparation method of the compound is convenient and suitable for various structure types.

Description

TECHNICAL FIELD

[0001] The present application relates to a protein degrader compound and its preparation method, pharmaceutical composition and application, in particular to a protein degrader compound with anti-necroptosis activity and its preparation method, pharmaceutical composition and application. BACKGROUND

[0002] Necroptosis, also known as necroptosis, is a newly emerging programmed cell death regulation mode. In recent years, more and more studies have shown that necroptosis plays an important role in the pathogenesis of various human diseases, such as ischemia-reperfusion injury, neurodegenerative diseases (such as amyotrophic lateral sclerosis, Alzheimer's disease), inflammatory diseases (such as colitis, pancreatitis, skin inflammation), viral infection, liver and kidney injury, tumor metastasis, etc. Therefore, the discovery of chemical molecules for treating necroptosis is important for necrosis-related diseases, and has a wide clinical application prospect.

[0003] Targeted protein degradation technology can utilize the cell's own protein clearance mechanism (such as lysosomal degradation, proteasomal degradation, autophagy, etc.) to degrade the target protein, and the subfield includes molecular glue, PROTAC, LYTAC, AUTAC, AbTAC, etc. Compared with traditional small molecule inhibitors, it expands the range of targetable protein targets, and can eliminate the function of the target protein in the cell until the protein is resynthesized. In addition, protein degraders can reduce potential drug resistance and improve drug safety. However, there are very few reported MLKL protein degraders, and there are problems of insufficient drug efficacy. SUMMARY

[0004] The first object of the present application is to provide a protein degrader compound, the second object is to provide a preparation method of the compound, the third object is to provide a pharmaceutical composition comprising the compound, and the fourth object is to provide a pharmaceutical application of the compound and its pharmaceutical composition.

[0005] Technical solution: The protein degrader compound of the present application has the structure of formula I, and also comprises its deuterated compound, pharmaceutically acceptable salt or mixture thereof,

[0006]

[0007] Among them:

[0008] L is selected from

[0009] R1 is selected from n is an integer selected from 2 to 8;

[0010] R2 is selected from (CH2)m m is selected from an integer from 1 to 12;

[0011] R3 is selected from a 5-6 membered heterocycloalkyl group containing 1-2 nitrogen atoms.

[0012] Preferably, the protein degrader compound according to the present application has a structure of formula I-1 to I-3:

[0013]

[0014] wherein:

[0015] R1 is selected from n is selected from an integer from 2 to 6;

[0016] R2 is selected from (CH2) m m is selected from an integer from 4 to 7;

[0017] R3 is selected from a 6 membered heterocycloalkyl group containing 1-2 nitrogen atoms.

[0018] Preferably, in the structure:

[0019] R1 is selected from

[0020] R2 is selected from R3 is selected from Preferably, the protein degrader compound according to the present application is selected from any one of the following compounds:

[0021]

[0022]

[0023]

[0024] The present application designs a series of MLKL protein degraders with high efficiency, which exhibit low nanomolar level of anti-programmed necrosis activity and MLKL degradation rate on human cells, and provides a new strategy for the development of MLKL degrader chemical drugs.

[0025] The pharmaceutically acceptable salt of the protein degrader compound according to the present application is a salt formed by the compound and an acid selected from any one of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.

[0026] "Pharmaceutically acceptable salt" refers to a salt of a compound, prepared from a compound having a particular substituent with a relatively non-toxic acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of the appropriate base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of the appropriate acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include mineral acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (yielding the carbonate or bicarbonate salt), phosphoric acid (yielding the phosphate, monohydrogenphosphate, dihydrogenphosphate, or salts of other inorganic acids such as sulfuric acid (yielding the sulfate or bisulfate), hydroiodic acid, phosphorous acid, and the like; and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; salts of amino acids (such as arginine, lysine, and the like), gluconic acid, and the like. When certain particular compounds contain both basic and acidic functionalities, they can be converted into either base or acid addition salts. Preferably, the salts are contacted with a base or acid in a conventional manner to isolate the free form of the compound, which is then regenerated. The free form of the compound differs from its various salt forms in certain physical properties such as solubility in water, solubility in organic solvents, and the like.

[0027] "Pharmaceutically acceptable salt" can be synthesized from a parent compound that contains a sufficiently basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared either by contacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both, to provide a solution of the desired salt. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, and the like, are preferred.

[0028] Preferably, the stereoisomer is the isomer introduced by the chiral C, N in R 1 , R 2 , R 3 .

[0029] Preferably, the tautomer is the isomer formed by the conjugated tautomerism of the double bond in the ring, including carbon-carbon double bond tautomerism, carbon-heteroatom double bond tautomerism, such as the double bond tautomerism in imidazole ring system, pyrazole ring.

[0030] Preferably, the prodrug is an ester, amide prodrug introduced by carboxyl, hydroxyl, amino, more preferably C1-C4 alkyl ester, C1-C4 carboxylic acid ester, C1-C4 alkyl amide.

[0031] Preferably, the solvate is a small molecule combination of the compound with a solvent molecule, more preferably a hydrate, alcoholate; the solvate can be further salified with the corresponding acid to obtain the salt of the solvate.

[0032] Preferably, the isotopic compound is a compound in which the hydrogen in the compound is replaced by deuterium.

[0033] Preferably, the crystal is a specific crystal structure formed by the compound in the crystallization process, including different crystal forms possessed by the compound itself, and also including different crystal forms of the salt, solvate, salt of solvate thereof.

[0034] The preparation method of the protein degradation agent compound according to the present application is selected from any one of the following methods:

[0035] Method one:

[0036]

[0037] Step (1) reaction reagent and condition: DIPEA, DMF, 80℃; Step (2) reaction reagent and condition: 1,7-dimethyl-8-(methylsulfonyl)-3-(propan-2-ine-1-yl)-3,7-dihydro-1H-purine-2,6-dione, sodium ascorbate, CuSO4, t-BuOH:H2O=1:1, r.t.;

[0038] Method two:

[0039]

[0040] Step (1) reaction reagent and condition: DIPEA, DMF, 90℃; Step (2) reaction reagent and condition: (a) LiOH, MeOH:THF:H2O=4:4:1, r.t., (b) 3-iodoaniline, EDCI, HOBT, DIPEA, DCM, r.t.; Step (3) reaction reagent and condition: 1,7-dimethyl-8-(methylsulfonyl)-3-(propan-2-ine-1-yl)-3,7-dihydro-1H-purine-2,6-dione, Pd(PPh3)4, CuI, Et3N, DMF, 50℃;

[0041] Method three:

[0042]

[0043] Step (1) Reaction reagents and conditions: DIPEA, DMF, 90 °C; Step (2) Reaction reagents and conditions: (a) LiOH, MeOH:THF:H2O = 4:4:1, r.t.; (b) 3-iodoaniline, EDCI, HOBT, DIPEA, DCM, r.t.; Step (3) Reaction reagents and conditions: 1,7-dimethyl-8-(methylsulfonyl)-3-(propan-2-ine-1-yl)-3,7-dihydro-1H-purine-2,6-dione, Pd(PPh3)4, CuI, Et3N, DMF, 50 °C;

[0044] wherein R1, R2, R3 are as defined above;

[0045] The corresponding acid is salted with the compound I-1 to I-3 prepared by the above method to obtain the pharmaceutically acceptable salt of the protein degrading agent compound.

[0046] The pharmaceutical composition of the present application comprises the protein degrading agent compound of the present application and a pharmaceutically acceptable carrier.

[0047] Preferably, the preparation form is selected from tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powder injections, injections.

[0048] The "pharmaceutically acceptable carrier" can be an excipient widely used in the field of pharmaceutical production. The excipient is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for the subject to receive the active ingredient to be dissolved at the desired rate after administration, or to promote the active ingredient to be effectively absorbed after the subject receives the composition administration. The pharmaceutical excipient can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipient can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeteners.

[0049] The pharmaceutical composition of the present application can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, micronizing, encapsulating, entrapping or lyophilizing processes.

[0050] The pharmaceutical composition described in the present application can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present application can also be a controlled or sustained release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, injection solutions, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspensions and injection emulsions. Examples of other suitable preparations of the pharmaceutical composition described include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.

[0051] The protein degrading agent compound described in the present application or a pharmaceutical composition thereof is applied in the preparation of a drug for resisting necrotic apoptosis.

[0052] Preferably, the drug is an MLKL protein degrading agent drug, further preferably an anti-tumor drug, more preferably an anti-colorectal cancer drug.

[0053] Beneficial effects: Compared with the prior art, the present application has the following remarkable advantages:

[0054] The compound designed in the present application can effectively degrade MLKL protein at the level of nanomolar concentration, and the degradation rate can reach more than 95%; and it can also effectively realize the anti-necrotic activity on tumor cells at the level of nanomolar concentration, and has application prospects as an active molecule for resisting necrotic apoptosis. At the same time, the preparation method of the compound is convenient and suitable for various structural types. DETAILED DESCRIPTION

[0055] The technical solutions of the present application are further described below in combination with examples.

[0056] Example 1: Preparation of 3-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,7- dimethyl-8-(methylsulfonyl)-3,7-dihydro-1H-purine-2,6-dione (MP1): 2-(2,6- dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (300.0 mg, 1.09 mmol) was dissolved in DMF (15 mL) followed by the addition of 2-[2-(2-azidoethoxy)ethoxy]ethanamine (227.1 mg, 1.30 mmol) and DIPEA (280.74 mg, 2.17 mmol). The reaction was stirred at 80 °C for 6 h. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure and purified by flash column chromatography (DCM:EtOH = 30:1) to obtain intermediate 1a as a yellow oil. Intermediate 1a (60.0 mg, 155.29 mmol) was dissolved in a solution of t-BuOH / H2O (v / v = 1:1), followed by the addition of 1,7-dimethyl-8-(methylsulfonyl)-3-(propan-2-ine-1-yl)-3,7-dihydro-1H-purine-2,6-dione (46.0 mg, 155.29 mmol), sodium ascorbate (6.15 mg, 31.06 mmol) and copper sulfate (1.98 mg, 12.42 mmol) and stirred at room temperature for 2 h. After completion of the reaction, water (10 mL) was added and extracted with dichloromethane (3 x 20 mL), the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by flash column chromatography (DCM:EtOH = 1:1) to obtain the final product MP1 as a yellow solid in 44% yield. 1H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.01 (s, 1H), 7.55 (dd, J = 8.6, 7.0 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.58 (t, J = 5.9 Hz, 1H), 5.20 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.46 (t, J = 5.2 Hz, 2H), 4.18 (s, 3H), 3.78 (t, J = 5.2 Hz, 2H), 3.56 (t, J = 5.4 Hz, 2H), 3.52 (s, 3H), 3.51 (s, 4H), 3.42 (q, J = 5.6 Hz, 2H), 3.23 (s, 3H), 2.87 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.58 (dt, J = 17.2, 3.3 Hz, 1H), 2.52 (d, J = 1.5 Hz, 1H), 2.02 (dtd, J = 13.2, 5.4, 2.4 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 172.81, 170.09, 168.95, 167.28, 154.93, 150.27, 146.37, 145.29, 145.01, 141.82, 136.20, 132.06, 124.18, 117.41, 110.66, 109.46, 109.22, 69.58, 69.54, 68.84, 68.69, 54.92, 49.41, 48.55, 43.07, 41.64, 33.98, 30.98, 27.92, 22.12. HRMS (ESI) calcd for C 30 H 34 N 10 O 10 S[M+Na] + : 749.2072; found: 749.2067. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 11.34 min, purity = 99.72%.

[0057] Example 2: Preparation of 3-((1-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,7- dimethyl-8-(methylsulfonyl)-3,7-dihydro-1H-purine-2,6-dione (MP2): The amine in Example 1 was replaced with 11-azido-3,6,9-trioxaundecan-1-amine as the linking reagent, and the remaining procedure steps were the same as MP1 to give a yellow solid in 40% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.00 (s, 1H), 7.53 (dd, J = 8.5, 7.1 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 6.56 (t, J = 5.8 Hz, 1H), 5.19 (s, 2H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.44 (t, J = 5.2 Hz, 2H), 4.17 (s, 3H), 3.74 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 3.51 (d, J = 3.4 Hz, 5H), 3.49 - 3.44 (m, 4H), 3.45 - 3.40 (m, 4H), 3.22 (s, 3H), 2.86 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.57 (dt, J = 17.2, 3.2 Hz, 1H), 2.50 (t, J = 3.6 Hz, 1H), 2.01 (ddt, J = 10.5, 5.5, 2.7 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 172.83, 170.09, 168.93, 167.28, 154.93, 150.25, 146.37, 145.30, 144.99, 141.81, 136.18, 132.05, 124.21, 117.41, 110.63, 109.45, 109.19, 69.72, 69.66, 69.52, 68.85, 68.61, 49.37, 48.56, 43.08, 41.67, 38.28, 33.98, 30.98, 27.93, 22.13. HRMS (ESI) calcd for C 32 H 38 N 10 O 11 S[M+Na] +: 793.2334; found: 793.2329. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): tR= 11.40 min, purity = 97.46%. R = 11.40 min, purity = 97.46%.

[0058] Example 3: Preparation of 3-((1-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)-1H-1,2,3-triazol-4-yl)methyl)-1,7-dimethyl-8-(methylsulfonyl)-3,7-dihydro-1H-purine-2,6-dione (MP3): The amine in Example 1 was replaced by O-(2-aminoethyl)-O'-(2-azidoethyl)triethylene glycol as the linking reagent, and the remaining procedure was the same as MP1 to give a yellow solid in 51% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.00 (s, 1H), 7.54 (dd, J = 8.6, 7.1 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.57 (t, J = 5.8 Hz, 1H), 5.20 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.45 (t, J = 5.3 Hz, 2H), 4.18 (s, 3H), 3.75 (t, J = 5.3 Hz, 2H), 3.60 (t, J = 5.5 Hz, 2H), 3.54 (dd, J = 6.3, 3.8 Hz, 2H), 3.51 (s, 3H), 3.50 (q, J = 4.2, 3.7 Hz, 4H), 3.46 (dq, J = 5.8, 1.9, 1.2 Hz, 4H), 3.42 (dd, J = 6.0, 3.4 Hz, 4H), 3.23 (s, 3H), 2.87 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.57 (dt, J = 17.2, 3.1 Hz, 1H), 2.52 - 2.49 (m, 1H), 2.02 (dtd, J = 13.0, 5.4, 2.2 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 172.82, 170.08, 168.93, 167.29, 154.93, 150.25, 146.37, 145.30, 145.00, 141.82, 136.19, 132.06, 124.18, 117.40, 110.64, 109.45, 109.20, 69.79, 69.76, 69.72, 69.58, 69.50, 68.85, 68.62, 49.37, 48.56, 43.06, 41.67, 38.29, 33.97, 30.98, 27.93, 22.13. HRMS (ESI) calcd for C 34 H 42 N 10 O 12 S[M+Na] + : 837.2597; found: 837.2599. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 11.49 min, purity = 97.80%.

[0059] Example 4: Preparation of 3-((1-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxahexadecyl)-1H-1,2,3-triazol-4-yl)methyl)-1,7-dimethyl-8-(methylsulfonyl)-3,7-dihydro-1H-purine-2,6-dione (MP4): The amine in Example 1 was replaced by 17-azido-3,6,9,12,15-pentaoxahexadecan-1-amine as the linking reagent, and the remaining procedure was the same as MP1 to give a yellow solid in 46% yield. 1H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.01 (s, 1H), 7.56 (dd, J = 8.6, 7.0 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 5.9 Hz, 1H), 5.21 (s, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.46 (t, J = 5.2 Hz, 2H), 4.19 (s, 3H), 3.77 (t, J = 5.2 Hz, 2H), 3.61 (t, J = 5.5 Hz, 2H), 3.55 (dd, J = 6.1, 3.6 Hz, 2H), 3.53 (s, 3H), 3.51 (s, 2H), 3.49-3.47 (m, 2H), 3.46-3.44 (m, 8H), 3.43 (q, J = 2.6 Hz, 4H), 3.24 (s, 3H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.59 (dt, J = 17.0, 3.1 Hz, 1H), 2.54-2.51 (m, 1H), 2.03 (dtd, J = 13.0, 5.4, 2.3 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 172.81, 170.07, 168.92, 167.28, 154.93, 150.25, 146.38, 145.30, 145.00, 141.85, 136.19, 132.06, 124.19, 117.41, 110.64, 109.45, 109.20, 69.81, 69.76, 69.71, 69.58, 69.49, 68.85, 68.63, 49.37, 48.55, 43.05, 41.67, 38.30, 33.97, 30.98, 27.93, 22.13. HRMS (ESI) calcd for C 36 H 46 N 10 O 13 S[M+Na] + : 881.2859; found: 881.2853. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 11.53 min, purity = 97.96%.

[0060] Example 5: Preparation of 3-((1-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15,18-hexaoxaeicosyl)-1H-1,2,3-triazol-4-yl)methyl)-1,7-dimethyl-8-(methylsulfonyl)-3,7-dihydro-1H-purine-2,6-dione (MP5): The amine in Example 1 was replaced with 20-azido-3,6,9,12,15,18-hexaoxaicosan-1-amine as the linking reagent, and the remaining procedure steps were the same as MP1 to give a yellow solid in 41% yield. 1 HNMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.02 (s, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 5.9 Hz, 1H), 5.21 (s, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.46 (t, J = 5.2 Hz, 2H), 4.19 (s, 3H), 3.77 (t, J = 5.2 Hz, 2H), 3.61 (t, J = 5.5 Hz, 2H), 3.55 (dd, J = 6.2, 3.6 Hz, 2H), 3.53 (s, 3H), 3.52 (d, J = 5.1 Hz, 2H), 3.49 (dd, J = 6.3, 3.6 Hz, 4H), 3.46 (m, 5H), 3.45 (d, J = 3.0 Hz, 4H), 3.44 - 3.42 (m, 4H), 3.24 (s, 3H), 2.88 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.59 (dt, J = 17.1, 3.2 Hz, 1H), 2.55 - 2.51 (m, 1H), 2.07 - 1.99 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 172.82, 170.07, 168.93, 167.29, 154.94, 150.26, 146.39, 145.32, 145.01, 141.82, 136.21, 132.07, 124.17, 117.44, 110.65, 109.46, 109.21, 69.78, 69.76, 69.74, 69.74, 69.70, 69.59, 69.50, 68.87, 68.63, 49.37, 48.56, 43.07, 41.69, 38.31, 33.99, 30.98, 27.94, 22.14. HRMS (ESI) calcd for C 38 H 50 N10 O 14 S[M+Na] + : 925.3121 ; found: 925.3114. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 11.73 min, purity = 98.82%.

[0061] Example 6: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo- 1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1 -yl)phenyl)-5-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide (MP7): 2-(2,6-dioxopiperidin- 3-yl)-4-fluoroisoindoline-1,3-dione (400.0 mg, 1.45 mmol) was dissolved in DMF (18 mL) followed by addition of 4-aminoglutaramide (203.57 mg, 1.74 mmol) and DIPEA (374.33 mg, 2.90 mmol). The reaction was stirred at 80 °C for 8 h. After monitoring the reaction completion by TLC, it was concentrated under reduced pressure and purified by flash column (DCM:EtOH = 40:1 ) to get the intermediate 2a as yellow oil. 2a (400 mg, 1.07 mmol) was dissolved in THF / methanol / H2O (v / v / v = 4:4:1 ) solution and lithium hydroxide (256.55 mg, 10.71 mmol) was added. After completion of the reaction, it was concentrated under reduced pressure and pH was adjusted to 4-5 using 2 mol / L HCI solution. The resulting filter cake was used for further reaction without purification. The dried filter cake (300.0 mg, 0.83 mmol) was dissolved in DCM (18 mL) and EDCI (240.07 mg, 1.25 mmol), HOBt (169.22 mg, 1.25 mmol) and DIPEA (323.71 mg, 2.50 mmol) were added. The reaction was initiated by addition of 3-iodoaniline (182.86 mg, 0.83 mmol) and stirred at room temperature overnight. After completion of the reaction, it was concentrated under reduced pressure and purified by flash column (DCM:EtOH = 20:1 ) to get 3a. 3a (100.0 mg, 0.18 mmol) was dissolved in dry DMF (9 mL) and 1,7-dimethyl-8- (methylsulfonyl)-3-(prop-2-yn-1 -yl)-3,7-dihydro-1 H-purine-2,6-dione (50.37 mg, 0.18 mmol) along with Pd(PPh3)4(8.25 mg, 7.14 mmol), copper iodide (0.68 mg, 3.57 mmol) and triethylamine (374.33 mg, 2.90 mmol) were added. The reaction was stirred at 60 °C for 6 h under nitrogen atmosphere. After completion of the reaction, it was concentrated under reduced pressure and purified by flash column (DCM:EtOH = 30:1 ) to get yellow solid in 73% yield. 1H NMR (600 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.97 (s, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.6, 7.1 Hz, 1H), 7.47 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.06 (dt, J = 7.6, 1.3 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.5 Hz, 1H), 5.00 (s, 2H), 4.20 (s, 3H), 3.54 (s, 3H), 3.28 (s, 3H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.59 (dt, J = 17.0, 3.0 Hz, 1H), 2.56 - 2.52 (m, 1H), 2.50 (d, J = 2.7 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.06 - 2.00 (m, 1H), 1.70 - 1.63 (m, 2H), 1.63 - 1.56 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 172.83, 171.35, 170.11, 168.91, 167.31, 154.88, 150.03, 146.36, 145.30, 144.42, 139.42, 136.24, 132.23, 129.16, 126.05, 121.81, 121.75, 119.51, 117.17, 110.38, 109.68, 109.06, 83.86, 82.65, 54.92, 48.54, 43.25, 41.54, 36.03, 34.09, 33.17, 30.99, 28.25, 28.02, 22.38, 22.16. HRMS (ESI) calcd for C 35 H 34 N8O9S [M + Na] + : 765.2062; found: 765.2065. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 15.94 min, purity = 98.30%.

[0062] Example 7: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo- 1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1 -yl)phenyl)-6-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide (MP8): Replace the ester in Example 6 with 6-aminohexanoic acid methyl ester as the linking reagent, and the rest of the procedure is the same as MP7 to give a yellow solid in 70% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.94 (s, 1H), 7.76 (t, J = 2.0 Hz, 1H), 7.59-7.54 (m, 1H), 7.49-7.44 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 6.9 Hz, 1H), 6.57-6.52 (m, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 5.00 (s, 2H), 4.21 (s, 3H), 3.54 (s, 3H), 3.28 (s, 3H), 2.88 (ddd, J = 16.8, 13.9, 5.4 Hz, 1H), 2.63-2.56 (m, 1H), 2.50 (s, 1H), 2.30 (t, J = 7.4 Hz, 2H), 2.07-1.97 (m, 1H), 1.61 (dt, J = 15.0, 7.6 Hz, 4H), 1.38 (dd, J = 15.6, 8.0 Hz, 2H), 1.24 (d, J = 5.7 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 172.81, 171.43, 170.10, 168.93, 167.30, 154.88, 150.02, 146.40, 145.30, 144.41, 139.45, 136.26, 132.19, 121.79, 117.27, 117.13, 110.31, 109.67, 109.00, 83.83, 82.64, 54.91, 48.52, 43.24, 41.71, 36.32, 34.08, 33.16, 30.97, 28.51, 28.01, 25.94, 24.76, 22.14. HRMS (ESI) calcd for C 36 H 36 N8O9S [M + Na] +: 779.2218; found: 779.2219. HPLC analysis (MeCN / H20 = 35 / 65 to 70 / 30): tR= 17.68 min, purity = 97.33%. R = 17.68 min, purity = 97.33%.

[0063] Example 8: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)- 2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1 -yl)phenyl)-7-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamide (MP9): The ester in Example 6 was replaced by methyl 7-aminoheptanoate as the linking reagent and the remaining procedure was the same as MP7 to give a yellow solid in 61% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.94 (s, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.47 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.11 - 7.04 (m, 2H), 7.01 (d, J = 7.0 Hz, 1H), 6.52 (t, J = 5.9 Hz, 1H), 5.04 (dd, J = 12.9, 5.5 Hz, 1H), 5.00 (s, 2H), 4.20 (s, 3H), 3.54 (s, 3H), 3.28 (s, 3H), 2.88 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.55 - 2.51 (m, 2H), 2.29 (t, J = 7.4 Hz, 2H), 2.02 (ddd, J = 10.5, 5.4, 2.7 Hz, 1H), 1.58 (td, J = 8.1, 7.6, 3.7 Hz, 6H), 1.41 - 1.28 (m, 4H). 13CNMR (151 MHz, DMSO-d6) δ 172.83, 171.51, 170.12, 168.95, 167.31, 154.88, 150.02, 146.42, 145.30, 144.42, 139.47, 136.28, 132.20, 129.15, 126.00, 121.80, 121.73, 119.49, 117.17, 110.37, 109.68, 109.01, 83.84, 82.66, 48.54, 43.25, 41.80, 36.34, 34.09, 33.17, 30.99, 28.56, 28.35, 28.02, 26.11, 24.95, 22.16. HRMS (ESI) calcd for C 37 H 38 N8O9S[M+Na] + : 793.2375; found: 793.2379. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 14.82 min, purity = 96.81%.

[0064] Example 9: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7- tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenyl)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)octanamide (MP10): The ester in Example 6 was replaced by 8- aminooctanoic acid methyl ester as the linking reagent, and the remaining steps were the same as MP7 to give a yellow solid in 65% yield. 1H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.93 (s, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.47 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.11 - 7.03 (m, 2H), 7.01 (d, J = 7.0 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.5 Hz, 1H), 5.00 (s, 2H), 4.20 (s, 3H), 3.54 (s, 3H), 3.28 (s, 3H), 2.96 - 2.82 (m, 1H), 2.58 (ddd, J = 17.1, 4.6, 2.5 Hz, 1H), 2.54 - 2.50 (m, 2H), 2.28 (t, J = 7.4 Hz, 2H), 2.07 - 1.97 (m, 1H), 1.56 (q, J = 7.4 Hz, 6H), 1.39 - 1.22 (m, 8H). 13 C NMR (151 MHz, DMSO-d6) δ 172.83, 171.54, 170.12, 168.95, 167.31, 154.88, 150.02, 146.42, 145.30, 144.42, 139.48, 136.27, 132.20, 129.15, 125.99, 121.80, 121.72, 119.49, 117.17, 110.36, 109.67, 109.00, 83.84, 82.66, 48.54, 43.25, 41.80, 36.37, 34.08, 33.17, 30.98, 28.65, 28.57, 28.50, 28.02, 26.19, 24.95, 22.15. HRMS (ESI) calcd for C 38 H 40 N8O9S [M + Na] + : 807.2531 ; found: 807.2527. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 16.86 min, purity = 96.37%.

[0065] Example 10: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo- 1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1 -yl)phenyl)-2-(4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1 -yl)acetamide (MP11): 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (400.0 mg, 1.45 mmol) was dissolved in DMF (18 mL) followed by the addition of tert-butyl 2-(piperazin-1 -yl)acetate (348.48 mg, 1.74 mmol) and DIPEA (374.33 mg, 2.90 mmol). The reaction was stirred at 70 °C for 6 h. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure and purified by flash chromatography column (PE:EtOAc = 2:1 ) to give intermediate 4a as a yellow oil. 4a (400 mg, 0.88 mmol) was dissolved in dioxane (5 mL) and hydrogen chloride (319.46 mg, 8.8 mmol) was added. After completion of the reaction, the reaction was concentrated under reduced pressure to give intermediate 5a, which was used for further reaction without purification. The subsequent reaction was carried out under the same conditions as for the preparation of MP7. A yellow solid was obtained in 35% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1 H), 9.87 (s, 1 H), 7.79 (t, J = 1.9 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.62 (d, J = 1.7 Hz, 1 H), 7.36 (d, J = 2.3 Hz, 1 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.26 (dd, J = 8.7, 2.3 Hz, 1 H), 7.1 1 (dt, J = 7.6, 1.3 Hz, 1 H), 5.08 (dd, J = 12.8, 5.4 Hz, 1 H), 5.00 (s, 2H), 4.20 (s, 3H), 3.54 (s, 3H), 3.52 (d, J = 7.0 Hz, 4H), 3.28 (s, 3H), 3.20 (s, 2H), 2.88 (ddd, J = 16.7, 13.6, 5.4 Hz, 1 H), 2.65 (s, 4H), 2.61 - 2.56 (m, 1 H), 2.57-2.52 (m, 1 H), 2.05-2.00 (m, 1 H). 13C NMR (126 MHz, DMSO-d6) δ 172.82, 170.10, 167.56, 166.98, 154.87, 150.02, 145.30, 144.42, 138.77, 133.88, 129.16, 126.49, 124.92, 122.28, 121.82, 120.05, 117.84, 109.67, 107.99, 83.98, 82.55, 52.14, 48.78, 46.78, 43.25, 34.09, 33.16, 30.98, 28.02, 22.18. HRMS (ESI) calcd for C 36 H 35 N9O9S[M+Na] + : 792.2171 ; found: 792.2176. HPLC analysis (MeCN / H20 = 35 / 65 to 70 / 30): t R = 14.15 min, purity = 99.14%.

[0066] Example 11: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)- 2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1 -yl)phenyl)-1 -(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide (MP12): replace the ester in Example 10 with piperidine-4-carboxylic acid tert-butyl ester as the linking reagent, and follow the remaining procedure steps as MP11 to give a yellow solid in 31% yield. 1 HNMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.02 (s, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.08 (dt, J = 7.7, 1.3 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 5.00 (s, 2H), 4.20 (s, 3H), 3.54 (s, 3H), 3.28 (s, 3H), 3.04 (td, J = 13.0, 2.7 Hz, 2H), 2.88 (ddd, J = 16.6, 13.6, 5.2 Hz, 1H), 2.72 - 2.53 (m, 4H), 2.07 - 1.97 (m, 1H), 1.94 - 1.81 (m, 2H), 1.67 (qd, J = 12.5, 3.9 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 173.19, 172.78, 170.07, 167.58, 166.95, 154.85, 150.00, 145.30, 144.40, 139.40, 134.02, 129.14, 126.11, 124.98, 121.95, 121.80, 119.66, 117.78, 109.66, 107.96, 83.86, 82.60, 48.74, 46.76, 43.23, 42.42, 34.06, 33.14, 30.96, 27.99, 27.40, 26.32, 22.17. HRMS (ESI) calcd for C 36 H 34 N8O9S[M+Na] + : 777.2062; found: 777.2057. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 13.59 min, purity = 99.42%.

[0067] Example 12: Preparation of N-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)- 2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1 -yl)phenyl)-2-(1 -(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetamide (MP13): The ester in Example 10 was replaced by tert-butyl 2-(piperidin-4-yl)acetate as the linking reagent and the remaining procedure was the same as MP11 to give a yellow solid in 39% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.97 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.8, 2.4 Hz, 1H), 7.07 (dt, J = 7.7, 1.3 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 5.00 (s, 2H), 4.21 (s, 3H), 4.03 (d, J = 13.5 Hz, 2H), 3.55 (s, 3H), 3.28 (s, 3H), 3.04 - 2.93 (m, 2H), 2.88 (ddd, J = 16.8, 13.8, 5.4 Hz, 1H), 2.57 (td, J = 15.2, 14.4, 3.9 Hz, 2H), 2.25 (d, J = 7.1 Hz, 2H), 2.03 (dtt, J = 20.0, 7.4, 4.2 Hz, 2H), 1.80 - 1.71 (m, 2H), 1.32 - 1.18 (m, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 172.76, 170.30, 170.07, 167.60, 166.93, 154.88, 154.83, 149.98, 145.30, 144.38, 139.27, 134.02, 129.12, 126.09, 124.95, 121.80, 119.54, 117.61, 117.42, 109.64, 107.75, 83.84, 82.61, 48.73, 47.27, 43.22, 43.07, 34.04, 33.13, 32.86, 30.97, 30.67, 27.97, 26.32, 24.75, 22.17. HRMS (ESI) calcd for C 37 H 36 N8O9S [M + Na] + : 791.2218; found: 791.2220. HPLC analysis (MeCN / H2O = 35 / 65 to 70 / 30): t R = 14.10 min, purity = 98.60%.

[0068] Example 13: Evaluation of the anti-necrotic activity and the degradation activity of MLKL protein of the compounds of the application on human colorectal cancer cells

[0069] 1. Experimental method

[0070] Cells were stimulated with TNFα / Smac mimetic / zVAD for 24 h, and drugs were pre-incubated for one hour in advance. EC 50 Three replicate wells were set for each compound, and each experiment was repeated three times. The experimental results are expressed as mean ± SEM. Protein degradation experiments were performed using a fully automated Western immunoblotting system. Cells were lysed 24 hours after administration, and the lysate was loaded according to the system operation for analysis of protein content.

[0071] 2. Experimental results

[0072] Table 1. Anti-necrosis activity of compounds MP1 to MP5 on HT-29 cells and degradation activity of MLKL protein 1,2

[0073] Compound MLKLDC 50 (μM) MLKLD max (%)]] HT-29 EC 50 (μM) MP1 >20 10.94±1.59 16.51±0.81 MP2 >20 8.12±0.15 >20 MP3 >20 8.55±0.51 13.40±1.34 MP4 >20 N.D. >20 MP5 >20 N.D. >20

[0074] 1 After 24 h of treatment, cell viability was detected using the CCK-8 assay;

[0075] 2 The data are derived from the results of three independent parallel experiments.

[0076] Table 2. Anti-necrosis activity of compounds MP7 to MP13 on HT-29 cells and degradation activity of MLKL protein 1,2

[0077] Compound MLKLDC 50 (μM) MLKLD max (%)]] HT-29 EC 50 (μM) MP7 0.029±0.004 92.30±4.55 0.031±0.008 MP8 0.14±0.03 87.55±4.14 0.19±0.04 MP9 0.081±0.02 91.38±5.19 0.14±0.02 MP10 0.28±0.06 91.11±5.58 0.50±0.08 MP11 0.012±0.003 95.06±2.82 0.017±0.003 MP12 0.192±0.051 90.56±4.59 0.094±0.032 MP13 0.082±0.003 89.22±4.24 0.042±0.011

[0078] 1 After 24 h of treatment, cell viability was detected using the CCK-8 assay;

[0079] 2 The data are derived from the results of three independent parallel experiments.

[0080] As shown in Table 1 and Table 2, the compounds designed in the present invention can effectively degrade MLKL protein at the molecular level. 50 The value reaches micromolar and nanomolar concentration levels, with the optimal value being below 20nM; D max The results show that the anti-necrosis activity of the drug against tumor cells reaches micromolar and nanomolar concentrations, with the optimal concentration being less than 20 nM.

Claims

1. A protein degradation agent compound, characterized in that: Having the structure of formula I, also including deuterated compounds, pharmaceutically acceptable salts or mixtures thereof, in: L is selected from R1 is selected from n is an integer selected from 2 to 8; R2 is selected from (CH2) m , m is selected from an integer of 1 to 12; R3 is selected from 5-6 membered heterocycloalkyl groups containing 1-2 nitrogen atoms.

2. The protein degradation agent compound according to claim 1, characterized in that Having the structures of formula I-1 to I-3: in: R1 is selected from n is an integer selected from 2 to 6; R2 is selected from (CH2) m , m is selected from an integer of 4 to 7; R3 is selected from 6-membered heterocycloalkyl groups containing 1 to 2 nitrogen atoms.

3. The protein degradation agent compound according to claim 1, characterized in that In the structure: R1 is selected from R2 is selected from R3 is selected from 4. The protein degradation agent compound according to claim 1, characterized in that A compound selected from any of the following:

5. The protein degradation agent compound according to claim 1, characterized in that The pharmaceutically acceptable salt is a salt formed by the compound and any one of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

6. A method for preparing the protein degradation agent compound according to claim 1, characterized in that: Choose from any of the following methods: Method 1: Method 2: Method 3: Wherein, R1, R2, and R3 are defined as in claim 1; The corresponding acid is reacted with compounds I-1 to I-3 prepared by the above method to form salts to obtain pharmaceutically acceptable salts of the protein degradation agent compounds.

7. A pharmaceutical composition, characterized in that Comprising the protein degrader compound according to claim 1 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that The dosage form is selected from tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powder injections, and injections.

9. Use of the protein degrader compound according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of an anti-necroptosis drug.

10. The use according to claim 9, characterized in that The drug is an anti-tumor drug.

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