Compounds having benzamide structure, preparation method therefor, and use thereof

Abstract

Disclosed in the present application are compounds having a benzamide structure as shown in formula (I), a preparation method therefor, and the use thereof in preparing pharmaceutical formulations for preventing and / or treating diseases caused by CRBN abnormality. The compounds with the structure shown as formula (I) are small molecule compounds having activity of covalently binding to CRBN so as to inhibit same. The diseases caused by CRBN abnormality are tumors or autoimmune diseases, the tumors including mantle cell lymphoma, multiple myeloma, non-Hodgkin's lymphoma or solid tumors, and the autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis or psoriasis.

Description

A compound having a benzamide structure and its preparation method and application

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on March 6, 2024, with application number CN202410254850.8 and invention name “A compound having a benzamide structure, its preparation method and application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the field of small molecule drugs. Specifically, the present application provides a compound (i.e., a compound having a benzamide structure) that covalently binds to CRBN to inhibit its activity, as well as methods for synthesizing and using such a compound. Background Art

[0003] Cereblon (CRBN) is a conserved 442-amino acid protein located on the short arm of human chromosome 3, p26.3, with a molecular weight of 51 kDa. The CRBN gene has been identified as a candidate gene for autosomal recessive nonsyndromic mild mental retardation (ARNSMR). CRBN is widely expressed in the testes, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocytes, colon, brain, and retina, with expression significantly higher in brain (including the retina) and testis than in other tissues.

[0004] CRBN, as an important target for anti-tumor and immunomodulatory drugs, has been shown to be effective in treating various hematological malignancies such as multiple myeloma and chronic lymphocytic leukemia, skin diseases such as erythema nodosum leprosum, and autoimmune diseases such as systemic lupus erythematosus. However, amides are associated with significant side effects, particularly peripheral neuropathy. There is an urgent need to develop CRBN modulators with no teratogenic effects, reduced peripheral neuropathy, stronger immunomodulatory effects, and enhanced anti-tumor activity to improve clinical efficacy, reduce side effects, and facilitate long-term use in patients.

[0005] In recent years, the concept of targeted protein degradation (TPD) has made breakthrough progress, challenging the traditional new drug development strategy of protein inhibitors (Lai AC, et al, Nat Rev Drug Discov, 2017; 16(2): 101). Among them, the protein targeted degradation chimeric (PROTAC) constructed based on the ubiquitin-proteasome pathway has become a hot topic in drug research due to its outstanding performance in degrading proteins such as ER, AR, BTK, and EGFR. To date, more than 20 PROTACs have entered clinical research, and Arvinas's ER-targeted ARV-471 has entered Phase III clinical trials.

[0006] The mechanism of action of PROTAC is shown in Figure 1: one end of it is a ligand fragment connected to the target protein (Protein of Interest, POI), and the other end is a ligand fragment connected to the E3 ligase, and the two are connected by a linker. This allows the molecule to shorten the spatial distance between the E3 ligase and the POI through its amphiphilicity, constructing a ternary complex of E3 ligase-PROTAC-target protein, so that the POI is ubiquitinated and then degraded by the 26S-proteasome, releasing the PROTAC molecule to continue to function (Lu W. Innovation (Camb), 2023; 4(3): 100422.).

[0007] Currently, more than 600 E3 ligases are known to function in human cells, but the most commonly used ones are CRBN and VHL. Among them, CRBN is the most commonly used E3 ligase because its ligands (such as thalidomide, pomalidomide, lenalidomide and avadolamine) have a small molecular weight, reasonable drug lipophilicity and reduced HBD / nRotB number, which makes it easier to optimize drugability (Guedeney N et al. Drug Discov Today, 2023, 28(1): 103395). However, the use of CRBN ligand degraders will degrade the neo-substrate, resulting in some off-target toxicity, and may cause the degradation of lymphoid transcription factors such as IKZF1, IKZF3 and SALL4, which has the potential risk of teratogenicity (Steinebach C et al. J Med Chem, 2023; 66(21): 14513). Therefore, researchers have developed a series of new CRBN ligands, such as benzotriazine glutarimide, phenyl glutarimide, aniline glutarimide and phenyldihydrouracil. These CRBN ligands all retain high affinity with CRBN and show certain advantages in improving selectivity. However, since there are no Cys residues commonly used for covalent bonds near the binding pocket between CRBN and the ligand, the new CRBN ligands reported above are all reversible and non-covalent. The reversible CRBN ligands reported in the literature are shown in Figure 2. Traditional CRBN ligands are easily hydrolyzed or degraded by enzymes, which may cause degradation of lymphoid transcription factors and pose a potential risk of teratogenicity. The new CRBN ligand retains affinity with CRBN, improves physical and chemical properties, and has been successfully applied to PROTAC.

[0008] In 2022, Cruite et al. developed a covalent binder targeting the terminal histidine His353 residue of CRBN for the first time based on the SuFEx reaction. They found that the sulfonyl fluoride compound EM12-FS can not only efficiently covalently bind to CRBN but also maintain good stability in plasma and hepatocytes. They also found that this covalent binder has some regulatory functions that non-covalent binders do not have (Cruite JT, et al. RSC Chem Biol, 2022; 3(9): 1105).

[0009] However, since this type of covalent binder still retains the parent nuclear structure of the traditional CRBN ligand, it may still degrade the neo-substrate, causing some off-target toxicity, and may cause the degradation of lymphoid transcription factors such as IKZF1, IKZF3 and SALL4, thereby posing a teratogenic risk. Summary of the Invention

[0010] The present application addresses the deficiencies of the prior art by providing a compound having a benzamide structure and its pharmaceutically acceptable salt, a method for synthesizing the compound having a benzamide structure, and the use of the compound having a benzamide structure and its pharmaceutically acceptable salt in a medicament for inhibiting CRBN receptors. The compound provided herein does not degrade neosubstrate and does not cause teratogenicity by degrading lymphoid transcription factors such as IKZF1, IKZF3, and SALL4.

[0011] The purpose of this application is achieved through the following technical solution: a compound having a benzamide structure, having a structure as shown in formula (I):

[0012] Where R has any of the following structures:

[0013] X and Y are independently an alkyl group, an amino group, a substituted amino group, a hydroxyl group, a hydroxyalkyl group, a halogen atom or hydrogen.

[0014] Furthermore, the present application provides a compound having a benzamide structure having any of the following structures:

[0015] The compound having a benzamide structure described in the present application can be used alone or prepared into a pharmaceutically acceptable salt by conventional methods. The pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate, succinate, or a mixed salt of two or more of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate and succinate.

[0016] The present application also provides a method for preparing the hydrochloride of a compound having a benzamide structure, comprising the following steps:

[0017] The compound having a benzamide structure is dissolved in ethanol, HCl gas is slowly introduced into the ethanol at room temperature until saturation occurs, and the mixture is cooled in an ice bath to precipitate white crystals to obtain the hydrochloride salt of the compound having a benzamide structure;

[0018] The compound having a benzamide structure is the compound having a benzamide structure described in the above technical solution.

[0019] As a specific embodiment of the present invention, the compound having a benzamide structure is compound w-1;

[0020] The structural formula of the compound w-1 is

[0021] The present application also provides the pharmaceutical application of the compound having a benzamide structure and its pharmaceutically acceptable salt, and the specific application is: for preparing a pharmaceutical preparation for preventing or treating diseases caused by CRBN abnormalities; the disease is a tumor or an autoimmune disease, and the tumor includes mantle cell lymphoma, multiple myeloma, non-Hodgkin's lymphoma, and solid tumors; the autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and psoriasis; the compound having a benzamide structure and its pharmaceutically acceptable salt can also be used as a ligand for targeted protein degradation strategies.

[0022] The present application also provides a method for treating a disease caused by abnormal CRBN protein, comprising the following steps:

[0023] Diseases caused by abnormal CRBN protein are treated by taking the compound containing a benzamide structure described in the above technical solution or a pharmaceutically acceptable salt of the compound containing a benzamide structure described in the above technical solution.

[0024] The present application also provides a method for preparing a compound having a benzamide structure, including the first method or the second method; the reaction process of the first method is shown in Reaction Formula A, comprising the following steps:

[0025] As shown in Reaction Formula A, a 3-bromobenzoic acid methyl ester substituent (I) reacts with 3-aminopiperidine-2,6-dione in the presence of N,N-diisopropylethylamine (DIEA) to undergo a condensation reaction. The resulting intermediate (II) reacts with phenylmethylmercaptan for debromination, and the resulting intermediate (III) is treated with N-chlorosuccinimide (NCS) to obtain a sulfonyl chloride compound (IV), which is then replaced with potassium fluoride (KF) to obtain the target product sulfonyl fluoride compound (V); alternatively, the sulfonyl chloride compound (IV) is further reacted with a triazole compound to obtain the target sulfonyltriazole compound (VI); the triazole compound includes [1,2,4]-triazole or [1,2,3]-triazole;

[0026] The reaction process of the second method is shown in Reaction Formula B, which comprises the following steps: 3-hydroxybenzoic acid methyl ester substituent (VII) is protected by hydroxyl group (VIII), and then reacted with 3-aminopiperidine-2,6-dione in the presence of N,N-diisopropylethylamine (DIEA) to undergo condensation reaction and deprotection, and the resulting intermediate (IX) is reacted with (4-acetamidophenyl)(fluorosulfonyl)sulfamoyl fluoride to obtain the target fluorosulfonyl ester compound (X); or further reacted with a triazole compound to obtain the target triazole sulfonyl ester compound (XI); the triazole compound includes [1,2,4]-triazole or [1,2,3]-triazole;

[0027] Beneficial effects of this application:

[0028] The compounds with a benzamide structure provided in the present application can bind to CRBN in the form of a covalent bond and have better binding strength; at the same time, this type of compound eliminates the parent core structure of traditional CRBN ligands, will not degrade neosubstrate, and will not cause the degradation of lymphoid transcription factors such as IKZF1, IKZF3 and SALL4 to cause teratogenesis. Therefore, it can be widely used in the preparation of pharmaceutical preparations for preventing or treating diseases caused by CRBN abnormalities, and can also be used as ligands for targeted protein degradation. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 shows the mechanism of action of PROTAC technology;

[0030] Figure 2 shows reversible CRBN ligands reported in the literature. DETAILED DESCRIPTION

[0031] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions or according to the product specifications.

[0032] Example 1 Synthesis of Compound w-1

[0033] Step a: Synthesis of 3-bromo-N-(2,6-dioxypyridin-3-yl)benzamide

[0034] To a solution of methyl 3-bromobenzoate (4.90 mmol) and 3-aminopiperidine-2,6-dione (4.90 mmol) in dimethylformamide (30 mL) was added N,N-diisopropylethylamine (DIEA, 1.90 g, 14.69 mmol). The mixture was then stirred at 90°C for 5 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / methanol = 1 / 0 to 10 / 1) to afford the compound (500 mg) as a light yellow solid.

[0035] Step b: Synthesis of 3-(benzylthio)-N-(2,6-dioxypyridin-3-yl)benzamide

[0036] To a dioxane solution (12 mL) of the above-obtained 3-bromo-N-(2,6-dioxypyridin-3-yl)benzamide (2.48 mmol) and phenylmethanethiol (308 mg, 2.48 mmol) was added DIEA (640 mg, 4.95 mmol). After degassing, Pd(dba) (136 mg, 148.54 μmol) and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (172 mg, 297.08 μmol) were added. The mixture was degassed with N2 three times and then stirred at 120°C under N2 for 5 h. The reaction mixture was cooled to room temperature, filtered, and the collected solid was washed with H2O (50 mL) and EtOAc (50 mL). The filter cake was further dried under vacuum to yield the crude product (900 mg) as a gray solid, which was used directly in the next step without further purification.

[0037] Step c: Synthesis of 3-{[(2,6-dioxypyridin-3-yl)amino]carbonyl}benzenesulfonyl chloride

[0038] To a solution of the above-obtained 3-(benzylthio)-N-(2,6-dioxypyridin-3-yl)benzamide (100 mg) in H₂O (0.5 mL) and AcOH (4.5 mL) was added NCS (109 mg). The mixture was stirred at 20°C for 2 h, then diluted with H₂O (20 mL) and filtered. The filter cake was washed with water (20 mL) and dried under reduced pressure to afford a crude yellow solid, which was used directly in the next reaction without further purification.

[0039] Step d: Synthesis of 3-{[(2,6-dioxypyridin-3-yl)amino]carbonyl}benzenesulfonyl fluoride

[0040] To a solution of the above-obtained 3-{[(2,6-dioxyylidenehexahydropyridin-3-yl)amino]carbonyl}benzenesulfonyl chloride (90 mg) in acetone (5 mL) and H2O (5 mL) was added KF (229 mg, 3.94 mmol). The mixture was stirred at 20°C for 1 hour and then purified by prep-HPLC to obtain a white solid (43 mg). MS (M+H) + =314; 1H NMR(400MHz,dmso-d6)δ / ppm:2.01~2.13(m,2H),2.15~2.20(br,2H),4.50~4.58(m,1H),7.9 0(d,J=8.0Hz,1H),8.11(d,J=8.13Hz,1H),8.28(d,J=8.0Hz,1H),8.51(s,1H),11.07(s,1H).

[0041] Example 2 Synthesis of Compound w-2

[0042] A similar method as in Example 1 was used, but 3-amino-5-bromobenzoic acid methyl ester was used instead of 3-bromobenzoic acid methyl ester to synthesize compound w-2. MS (M+H) + =329; 1 H NMR (400MHz, dmso-d6) δ / ppm: 2.01~2.13(m,2H), 2.15~2.20(br,2H), 4.50~4.58(m,1H), 7.20(s,1H), 7.38(s,1H), 7.98(s,1H), 10.0(s,1H).

[0043] Example 3 Synthesis of Compound w-3

[0044] A similar method as in Example 1 was used, but 2-fluoro-3-amino-5-bromobenzoic acid methyl ester was used instead of 3-bromobenzoic acid methyl ester to synthesize compound w-3. MS (M+H) + =347; 1 H NMR(400MHz,dmso-d6)δ / ppm:10.03(s,1H),8.01(s,2H),7.96(s,1H),7.36(s,1H),4.53(m,1H ),4.0(br,s,2H),2.94-2.84(m,1H),2.67-2.54(m,1H),2.43-2.31(m,1H),2.08-1.97(m,1H).

[0045] Example 4 Synthesis of Compound w-4

[0046] The sulfonyl chloride compound was synthesized using the method of steps a to c in Example 1.

[0047] Step d: Synthesis of N-(2,6-dioxopiperidin-3-yl)-3([1,2,4]triazole-1-sulfonyl)benzamide

[0048] A solution of 3-{[(2,6-dioxyylidenehexahydropyridin-3-yl)amino]carbonyl}benzenesulfonyl chloride (0.2 g) in dichloromethane (DCM, 5 mL) was cooled to -2°C, and DIEA (151 mg, 1.17 mmol) and [1,2,4]-triazole (202 mg, 2.92 mmol) were added. The mixture was then stirred at 20°C for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (prep-HPLC) to obtain a white solid (5 mg). MS (M+H) + =363; 1 H NMR(400MHz,dmso-d6)δ / ppm:10.03(s,1H),8.31(s,2H),8.62(s,1H),8.18(d,1H),8.0(s,1H),7.90(d,2 H),7.72(m,1H),4.53(m,1H),2.93-2.83(m,1H),2.66-2.53(m,1H),2.43-2.30(m,1H),2.07-1.97(m,1H).

[0049] Example 5 Synthesis of Compound W-5

[0050] Compound w-5 was synthesized using a similar method as in Example 4, except that 3-amino-5-bromobenzoic acid methyl ester was used instead of 3-bromobenzoic acid methyl ester and [1,2,3]-triazole was used instead of [1,2,4]-triazole. MS (M+H) + =378; 1 H NMR(400MHz,dmso-d6)δ / ppm:10.03(s,1H),8.01(s,1H),7.98(s,1H),7.8(m,4H),7.38(s,1H),7.20(s,1H) ),4.53(m,1H),4.0(brs,2H),2.94-2.83(m,1H),2.65-2.52(m,1H),2.44-2.31(m,1H),2.09-1.98(m,1H).

[0051] Example 6 Synthesis of Compound W-6

[0052] Step a. Synthesis of methyl 3-acetoxybenzoate

[0053] To a solution of methyl 3-hydroxybenzoate (4.5 g) in THF (100 mL) was added triethylamine (8.2 g, 81.24 mmol), dimethylaminopyridine (331 mg, 2.71 mmol), and AcO (4.15 g, 40.62 mmol). The reaction was stirred at 20°C for 12 h. After quenching, the pH was adjusted to 1-3 with 6N HCl, followed by extraction with EtOAc (100 mL x 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to afford the crude title compound (6.2 g) as a pale yellow liquid, which did not require further purification.

[0054] Step b Synthesis of N-(3-hydroxy-benzoyl)-3-aminopiperidine-2,6-dione

[0055] To a solution of methyl 3-acetoxybenzoate (1.2 g, 4.90 mmol) and 3-aminopiperidine-2,6-dione (806 mg, 4.90 mmol) in dimethylformamide (30 mL) was added N,N-diisopropylethylamine (DIEA, 1.90 g, 14.69 mmol). The mixture was then stirred at 90°C for 5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate / methanol = 1 / 0 to 10 / 1) to obtain a light yellow solid (500 mg). Ms[M+H] + =248.

[0056] Step c.

[0057] To a THF solution (2 mL) of N-(3-hydroxybenzoyl)-3-aminopiperidine-2,6-dione (65 mg) were added (4-acetamidophenyl)(fluorosulfonyl)sulfamoyl fluoride (94 mg, 300 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 84 mg, 550 μmol). The reaction was stirred at 20°C for 10 min. H2O (5 mL) was then added to quench the reaction. The layers were separated and the aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography (prep-HPLC) to obtain a white solid (5 mg). MS [M+H] + =330. 1H NMR: (400MHz, DMSO-d6) δ / ppm: 10.04 (s, 1H), 8.5 (s, 1H), 7.58 (d, J = 2.2Hz, 1H), 7.42 (s, 1H), 7.31 (m, 1H), 6. 98(d,J=2.2Hz,1H),4.58(m,1H),2.97-2.85(m,1H),2.69-2.56(m,1H),2.45-2.31(m,1H),2.09-1.98(m,1H).

[0058] Example 7 Synthesis of Compound W-7

[0059] The sulfonyl fluoride compound was synthesized as in Example 6. Then, the target compound w-7 was synthesized as in step d of Example 4. MS [M+H] + =379. 1 H NMR: (400MHz, DMSO-d6) δ / ppm: 10.0 (s, 1H), 8.3 (s, 2H), 8.0 (s, 1H), 7.53 (d, J = 2.2Hz, 1H), 7.42 (s, 1H), 7.27 (m, 1H ),6.98(d,J=2.2Hz,1H),4.53(m,1H),2.92-2.82(m,1H),2.64-2.52(m,1H),2.41-2.31(m,1H),2.04-1.93(m,1H).

[0060] Example 8 Synthesis of Compound W-8

[0061] The sulfonyl fluoride compound was synthesized as in Example 6. Then, the target compound w-8 was synthesized as in step d of Example 4. MS [M+H] + =397. 1 H NMR: (400MHz, DMSO-d6) δ / ppm: 10.0 (s, 1H), 8.3 (s, 2H), 8.0 (s, 1H), 7.40 (s, 1H), 6.98 (d, J = 2.2Hz, 1H), 6.9 6(d,J=2.2Hz,1H),4.53(m,1H),2.92-2.82(m,1H),2.64-2.52(m,1H),2.41-2.31(m,1H),2.04-1.93(m,1H).

[0062] Example 9 Synthesis of Compound W-9

[0063] The sulfonyl fluoride compound was synthesized as in Example 6. Then, the target compound w-9 was synthesized as in step d of Example 4. MS [M+H] + =394. 1 H NMR: (400MHz, DMSO-d6)δ / ppm:10.0(s,1H),8.3(s,2H),8.0(s,1H),6.78(s,1H),6.71(s,1H),6.18(s,1H ),4.53(m,1H),4.0(brs,2H),2.94-2.83(m,1H),2.65-2.53(m,1H),2.44-2.32(m,1H),2.06-1.94(m,1H).

[0064] Example 10 Preparation of hydrochloride (taking the compound of Example 1 as an example)

[0065] Compound w-1 was dissolved in ethanol, and HCl gas was slowly introduced into the solution at room temperature until saturation. The solution was cooled in an ice bath to gradually precipitate white crystals, which were the hydrochloride salt of the compound.

[0066] Example 11 CRBN protein binding affinity experiment

[0067] The binding affinity of CRBN protein was detected by TR-FRET fluorescence method:

[0068] The Cullin4a / Rbx1 / DDB1 / CRBN E3Ligase Complex TR-FRET Kit rapidly and sensitively monitors the binding of ubiquitin proteins to the E3 complex in solution, resulting from enzymatic ubiquitination. This real-time TR-FRET assay measures the formation of ubiquitin chains with CRBN (or substrate). When no compound binds to CRBN, fluorescence at 665 nm is strong and at 620 nm is weak under excitation at 320 nm. When a compound binds to CRBN, fluorescence at 665 nm increases and at 620 nm decreases under excitation at 320 nm. The inhibition rate of CRBN binding is calculated by comparing the fluorescence intensities at λ = 665 nm and λ = 620 nm (refer to the kit instructions for calculation).

[0069] Experimental process:

[0070] Dilute 10X Reaction Buffer to 1X Reaction Buffer with dd H2O.

[0071] Preparation of 2.5X Mixture: Dispense 100 μL of UBA1, UBE2D1, Cul4a / Rbx1 Complex (neddyl.), DDB1 / CRBN, and TRF-Ubiquitin Mix into 3500 μL of 1X Reaction Buffer, place on ice until needed, and store any unused stock solution in aliquots at -80°C. Add 5 μL / well of the compound working solution dilution to the corresponding wells of the assay plate. Add 5 μL / well of 1X Reaction Buffer (5% DMSO) to the positive control wells and 5 μL / well of 1X Reaction Buffer to the blank control wells. Centrifuge at 1000 rpm for 1 min. Add 10 μL / well of 2.5X Mixture to the assay plate. Centrifuge at 1000 rpm for 1 min. Add 1 mL of 10X Mg-ATP to 1 mL of 1X Reaction Buffer. Prepare a 2.5X working solution in the buffer and dispense 10 μL / well of the working solution into the corresponding wells of the test plate; add 10 μL / well of 1X Reaction Buffer to the blank wells and incubate at room temperature for 20 minutes. After incubation, perform HTRF detection using Envision, with excitation at 320 nm and emission at 620 nm and 665 nm, and calculate the binding inhibition rate according to the method in the test kit instructions.

[0072] The results of the inhibition rate of different compounds binding to CRBN are as follows:

[0073] The synthesized target compound was subjected to TR-FRET fluorescence detection test, and EM12-FS and lenalidomide reported in the literature were used as positive drug controls. 50 The IC value is 1480nM, which is consistent with the IC value reported in the literature. 50 =1.5μM (Cruite JT, et al. RSC Chem Biol, 2022; 3(9): 1105), indicating that the accuracy and reliability of the TR-FRET fluorescence detection test in this experiment meet the requirements. The nine target compounds synthesized all have better inhibition rates on the binding of lenalidomide to CRBN and better than the positive control EM12-FS. Among them, w-9 has the best binding to CRBN, with IC 50The activity of the compound provided in the present application is 41nM, which is six times stronger than that of the positive drug EM12-FS. Therefore, the compound provided in the present application can bind to and inhibit CRBN well, and can be used as a ligand of the ubiquitin E3 ligase for targeted protein degradation strategy, or in the preparation of pharmaceutical preparations for preventing or treating diseases caused by abnormal CRBN. The disease is a tumor or an autoimmune disease, and the tumor includes mantle cell lymphoma, multiple myeloma, non-Hodgkin's lymphoma, solid tumors, and the autoimmune disease includes rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and psoriasis.

[0074] Although the above embodiment provides a detailed description of the present application, it is only a part of the embodiments of the present application, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present application.

Claims

1. A compound having a benzamide structure, characterized in that It has the structure shown in formula (I): Where R has any of the following structures: X and Y are independently alkyl, amino, hydroxy, hydroxyalkyl, halogen or hydrogen.

2. The compound having a benzamide structure according to claim 1, wherein Has any of the following structures:

3. The pharmaceutically acceptable salt of the compound having a benzamide structure according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate, succinate, or a mixed salt of two or more of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate and succinate.

4. The method for preparing the compound having a benzamide structure according to claim 1 or 2, wherein: Including the first method and the second method; The reaction process of the first method is shown in Reaction Formula A, which comprises the following steps: A 3-bromobenzoic acid methyl ester substituted compound having the structure shown in I is subjected to a condensation reaction with 3-aminopiperidine-2,6-dione in the presence of N,N-diisopropylethylamine to obtain an intermediate having the structure shown in II; Debromination of the intermediate having the structure shown in II is reacted with phenylmethyl mercaptan to obtain an intermediate having the structure shown in III; Treating the intermediate shown in III with N-chlorosuccinimide to obtain a sulfonyl chloride compound having a structure shown in IV; Replacing the sulfonyl chloride compound having the structure shown in IV with potassium fluoride to obtain a sulfonyl fluoride compound having the structure shown in V; or reacting the sulfonyl chloride compound having the structure shown in IV with a triazole compound to obtain a sulfonyltriazole compound having the structure shown in VI, wherein the triazole compound includes [1,2,4]-triazole or [1,2,3]-triazole; The reaction process of the second method is shown in Reaction Formula B, comprising the following steps: The 3-hydroxybenzoic acid methyl ester substituent having the structure shown in VII is subjected to hydroxyl protection to obtain an intermediate having the structure shown in VIII; The intermediate having the structure shown in VIII is subjected to a condensation reaction with 3-aminopiperidine-2,6-dione in the presence of N,N-diisopropylethylamine and then deprotected to obtain an intermediate having the structure shown in IX; Reacting the intermediate having the structure shown in IX with (4-acetylaminophenyl)(fluorosulfonyl)sulfamoyl fluoride to obtain the target fluorosulfonyl ester compound having the structure shown in X; reacting the target fluorosulfonyl ester compound having the structure shown in X with a triazole compound to obtain a target triazole sulfonyl ester compound having the structure shown in XI, wherein the triazole compound includes [1,2,4]-triazole or [1,2,3]-triazole; 5. The preparation method according to claim 4, characterized in that: After the condensation reaction, the step further comprises: concentrating the reaction mixture to dryness under reduced pressure, and purifying the residue by column chromatography to obtain an intermediate having a structure shown in II; After the intermediate having the structure shown in II is reacted with phenylmethyl mercaptan for debromination, the debromination reaction system is filtered, the solid is collected and washed with H2O and EtOA, and the filter cake is dried under vacuum conditions; After treating the intermediate shown in III with N-chlorosuccinimide, the method further comprises: diluting the treated system with H2O and filtering, washing the filter cake with water, and drying under reduced pressure to obtain a sulfonyl chloride compound with the structure shown in IV.

6. The preparation method according to claim 4, characterized in that: After the hydroxyl protection, the following steps are further performed: adjusting the pH to 1 to 3 with HCl, extracting with EtOAc, combining the organic layers, drying with Na2SO4, filtering, and concentrating under reduced pressure to obtain an intermediate having the structure shown in VIII; After reacting the intermediate having the structure shown in IX with (4-acetamidophenyl)(fluorosulfonyl)sulfamoyl fluoride, the following steps further include: adding H2O to quench the reaction, then separating the layers, and extracting the aqueous layer with EtOAc; washing the combined organic layers with brine, drying over Na2SO4, filtering, and concentrating under reduced pressure to obtain a residue; and purifying the residue by high performance liquid chromatography to obtain the target fluorosulfonyl ester compound having the structure shown in X.

7. A method for preparing the hydrochloride of a compound having a benzamide structure, characterized in that: The following steps are involved: The compound having a benzamide structure is dissolved in ethanol, HCl gas is slowly introduced into the ethanol at room temperature until saturation occurs, and the mixture is cooled in an ice bath to precipitate white crystals to obtain the hydrochloride salt of the compound having a benzamide structure; The compound having a benzamide structure is the compound having a benzamide structure according to claim 1 or 2.

8. The preparation method according to claim 7, characterized in that The compound having a benzamide structure is compound w-1; The structural formula of the compound w-1 is 9. Use of the compound containing a benzamide structure according to claim 1 or 2, or a pharmaceutically acceptable salt of the compound containing a benzamide structure according to claim 3, in the preparation of a pharmaceutical preparation for preventing and / or treating diseases caused by abnormal CRBN protein.

10. The use according to claim 9, characterized in that The disease caused by abnormal CRBN protein is a tumor or an autoimmune disease.

11. The use according to claim 10, characterized in that The tumor is mantle cell lymphoma, multiple myeloma, non-Hodgkin's lymphoma or solid tumor; The autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis or psoriasis.

12. Use of the compound containing a benzamide structure according to claim 1 or 2 or a pharmaceutically acceptable salt of the compound containing a benzamide structure according to claim 3 as a ligand of ubiquitin E3 ligase in a targeted protein degradation strategy.

13. A method for treating a disease caused by abnormal CRBN protein, characterized in that: The following steps are involved: Diseases caused by abnormal CRBN protein are treated by taking the compound containing a benzamide structure according to claim 1 or 2 or a pharmaceutically acceptable salt of the compound containing a benzamide structure according to claim 3.

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