Compound with NF-kappa B signal inhibition activity and application

Abstract

The invention discloses a compound. The structural formula of the compound is shown in the specification. R is selected from-C (O) NR1R2,-N (R1) C (O) R2 and-C (O) R3; r1, R2 and R3 are respectively and independently selected from C1-C3 alkyl groups, 4-8-membered aryl groups, 4-8-membered heteroaryl groups and 4-10-membered heterocyclic groups, and the aryl groups can be further substituted by methyl and halogen. Cell experiments prove that the small molecule compound disclosed by the invention has a remarkable inhibition effect on TNF-alpha induced NF-kappa B signal activation, and has no obvious cytotoxicity. Animal experiments prove that the preferable compound has a remarkable improvement effect on the level of inflammatory factors in peripheral blood of a lipopolysaccharide-induced mouse sepsis model and the survival rate of mice. These compounds and pharmaceutical compositions are envisaged to be useful in the prevention or treatment of inflammatory diseases, such as sepsis, acute and chronic bronchitis, and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic drugs, and particularly relates to a compound with NF-κB signal inhibition activity and its application. Background Art

[0002] It has been more than 40 years since the discovery of the NF-κB signal. Initially, Ranjan Sen and David Baltimore determined the binding of a nuclear factor in B lymphocytes to the kappa enhancer of the gene encoding the immunoglobulin κ light chain through electrophoretic mobility analysis of end-labeled DNA fragments, and named it the nuclear factor binding factor near the κ light chain. The NF-κB signal is a strictly controlled signal transduction pathway, which is mainly manifested by the activation of the NF-κB transcription factor protein family, including Rel (c-Rel), RELB, RelA / p65, NFκB1 p50 / p105, and NFκB2 p52 / p100. These proteins act as dimerized transcription factors, which can regulate gene expression and affect various different biological processes. When sepsis occurs, a large number of inflammatory cells are activated, and the levels of inflammatory factors such as TNF-α, IL-1β, and IL-6 in the patient's body are abnormally increased. The inflammatory mediators released by these inflammatory cells induce the activation of NF-κB, phosphorylate NF-κB p65 and enter the nucleus to promote the expression of downstream genes, causing a cascade amplification of inflammation, and ultimately inducing the production of a cytokine storm, leading to the death of the patient. Chronic bronchitis is one of the common diseases. Pathogenic substances such as bacteria, viruses, and chlamydia in various respiratory tracts will activate alveolar macrophages and induce the activation of the NF-κB signaling pathway, thereby promoting the expression and secretion of various inflammatory factors. These inflammatory factors further recruit more inflammatory cells, such as macrophages and neutrophils, to infiltrate the lungs, aggravating lung inflammation. These previous studies have all shown that the NF-κB signal plays a key role in inflammatory diseases such as sepsis and pneumonia. Therefore, new anti-inflammatory therapeutic drugs targeting the NF-κB signal have always been a hot spot in drug research and development. Summary of the Invention

[0003] The purpose of the embodiment of the present application is to provide a small molecule compound with NF-κB signal inhibition activity for the above deficiencies in the prior art.

[0004] To achieve the above purpose, the technical solution adopted by the present invention to solve its technical problems is:

[0005] A compound, characterized in that the structural formula of the compound is:

[0006]

[0007] Wherein R is different substituents.

[0008] R is selected from -C(O)NR1R2, -N(R1)C(O)R2, -C(O)R3; R1, R2, and R3 are each independently selected from C1-C3 alkyl, 4-8 membered aryl, 4-8 membered heteroaryl, 4-10 membered heterocyclic group, and the aryl may be further substituted by methyl or halogen.

[0009] Preferably, R1, R2, and R3 are each independently selected from methyl, phenyl, thiazolyl, pyridyl, and pyrrolidinylbenzene, and the benzene ring may be further substituted by halogen.

[0010] Preferably, R1 is selected from methyl; R2 is selected from phenyl, chlorophenyl, thiazolyl, pyridyl; R3 is selected from pyrrolidinylbenzene.

[0011] Preferably, the R substituent is one of the following structures:

[0012]

[0013] More specifically, the compound is selected from the following structures:

[0014]

[0015]

[0016] A small molecule that can effectively inhibit the activity of NF-κB signal, including the above compound and its pharmaceutically acceptable salts or cocrystals, deuterated compounds, solvates, and enantiomers.

[0017] A composition comprising the compound described in any one of the above technical solutions.

[0018] Use of the compound or composition described in any one of the above technical solutions in the preparation of a drug for treating inflammatory diseases that benefit from the inhibition of NF-κB signal activation.

[0019] Furthermore, the NF-κB signal is TNF-α-induced NF-κB signal activation.

[0020] Furthermore, the disease is an inflammatory disease selected from one or more of sepsis, acute and chronic bronchitis, and pneumonia.

[0021] A method for preparing the above compound, comprising: reacting a carboxylic acid compound represented by formula (I) with an organic amine compound represented by formula (II) in the presence of HOBt, EDCI, and DIPEA through an amidation reaction;

[0022]

[0023] R is defined as described above.

[0024] The beneficial effects of the present invention are as follows:

[0025] The bioactive small molecule compounds in the present invention can effectively inhibit the NF-κB signal. It has been confirmed by cell experiments that they have a significant inhibitory effect on the activation of the NF-κB signal induced by TNF-α and have almost no physiological toxicity. Further, preferably, compound M3 has a significant improvement effect on both the survival rate of septic mice induced by lipopolysaccharide (LPS) and the levels of inflammatory factors in peripheral blood serum. Such compounds or combinations are expected to have a significant therapeutic effect on improving various inflammatory diseases caused by overactivation of the NF-κB signal, such as sepsis and chronic bronchitis.

[0026] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit this application. Description of the Drawings

[0027] The drawings herein are incorporated into the specification and form a part of the specification, showing embodiments consistent with this application, and are used together with the specification to explain the principles of this application.

[0028] Figure 1 Effect of the preferred compound M3 on the levels of inflammatory factors in peripheral blood serum of a mouse sepsis model induced by LPS.

[0029] Figure 2 Improvement of the survival rate of a mouse sepsis model induced by LPS by the preferred compound M3. Detailed Embodiments

[0030] The present invention will be further described below in conjunction with embodiments and the drawings. The following embodiments are only illustrative of the present invention and do not limit the present invention in any way.

[0031] Example 1 N 4 -Methyl-N 1 -((S)-4-(neopentylamino)-1,4-dioxo-1-(((S)-1-oxo-4-phenyl-1-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)butan-2-yl)amino)butan-2-yl)-N 4 -(thiazol-2-yl)piperidine-1,4-dicarboxamide (M1)

[0032]

[0033] Dissolve Boc-L-aspartic acid 1-benzyl ester (3.23 g, 10.0 mmol) in dichloromethane (40.0 mL). Add HOBt (1.49 g, 11.0 mmol) and EDCI (3.17 g, 16.5 mmol) at 0 °C and stir at room temperature for half an hour. Then add pivalamine hydrochloride (1.24 g, 10.0 mmol) and DIPEA (5.6 mL, 30.0 mmol) to the reaction system and stir for another 3 hours. After the reaction is completed, extract the reaction system with saturated aqueous NaHCO3 solution (30.0 mL) and saturated aqueous NaCl solution (30.0 mL). After drying the organic layer with anhydrous sodium sulfate, rotary evaporate the solvent. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain white solid 2. ESI-MS: m / z = 393.2385 [M+H] + .

[0034] Dissolve compound 2 (1.96 g, 5.0 mmol) in 20.0 mL of dichloromethane, slowly add 10.0 mL of trifluoroacetic acid, react at room temperature for 1 h. After the reaction is completed, rotary evaporate the solvent to obtain colorless oil 3, which is directly used for the next step reaction. ESI-MS: m / z = 293.1861 [M+H] + .

[0035] Dissolve compound 4 (1.14 g, 10.0 mmol) in 10 mL of DMF, add HATU (5.40 g, 15.0 mmol) and DIPEA (3.50 mL, 20.0 mmol), then add compound 5 (2.51 g, 11.0 mmol) and stir for another 3 hours. After the reaction is completed, extract the reaction system with saturated aqueous NaHCO3 solution (30.0 mL) and saturated aqueous NaCl solution (30.0 mL). After drying the organic layer with anhydrous sodium sulfate, rotary evaporate the solvent. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 3:1). Then dissolve the purified compound in 20.0 mL of dichloromethane, slowly add 10.0 mL of trifluoroacetic acid, react at room temperature for 1 h. After the reaction is completed, rotary evaporate the solvent to obtain compound 6, which is directly used for the next step reaction. ESI-MS: m / z = 226.0932 [M+H] + .

[0036] The N 4-Neopentyl-L-asparagine benzyl ester 3 (0.98 g, 2.5 mmol) was dissolved in dichloromethane (10.0 mL), and saturated aqueous NaHCO3 solution (10.0 mL) was added thereto. The temperature of the reaction system was lowered to 0 °C, and then triphosgene (0.30 g, 1.0 mmol) was added and stirred for 15 minutes. Then the organic layer of the reaction system was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. It was used directly in the next step without purification. The prepared isocyanate was dissolved in dichloromethane and mixed with compound 6 (0.77 g, 2.5 mmol), and DIPEA (1.5 mL, 7.5 mmol) was added thereto. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction system was extracted with saturated aqueous NaHCO3 solution (20.0 mL), saturated aqueous NH4Cl solution (20.0 mL), and saturated aqueous NaCl solution (20.0 mL), and dried over anhydrous sodium sulfate. The organic solution was collected, the solvent was evaporated under reduced pressure, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 30:1) to obtain 0.71 g of white solid 7. ESI-MS: m / z = 544.2590 [M+H] + .

[0037] Compound 7 (1.96 g, 5.0 mmol) was dissolved in methanol (10.0 mL), and 10% Pb / C (0.20 g) was added thereto. The mixture was stirred under a hydrogen atmosphere for 2 - 3 h. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and evaporated under reduced pressure to obtain white solid 8, which was used directly in the next step without purification. ESI-MS: m / z = 454.2115 [M+H] + .

[0038] Compound 9 (2.79 g, 10.0 mmol) was dissolved in 10 mL of DMF, and HATU (5.40 g, 15.0 mmol) and DIPEA (3.50 mL, 20.0 mmol) were added. Subsequently, compound 10 (1.61 g, 11.0 mmol) was added, and the mixture was stirred again for 3 hours. After the reaction was completed, the reaction system was extracted with saturated aqueous NaHCO3 solution (30.0 mL) and saturated aqueous NaCl solution (30.0 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1). The purified compound was then dissolved in 20.0 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid was slowly added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain compound 11, which was used directly in the next step. ESI-MS: m / z = 309.1960 [M+H] + .

[0039] Compound 8 (1.50 g, 5.0 mmol) was dissolved in dichloromethane (20.0 mL). At 0 °C, HOBt (0.74 g, 5.5 mmol) and EDCI (1.59 g, 8.3 mmol) were added. The mixture was stirred at room temperature for half an hour. Then DIPEA (2.8 mL, 15.0 mmol) was added to the reaction system. Finally, compound 11 (1.54 g, 5.0 mmol) was added and the mixture was stirred for another 3 hours. After the reaction was completed, the reaction system was extracted with saturated aqueous NaHCO3 solution (30.0 mL) and saturated aqueous NaCl solution (30.0 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane:ethyl acetate = 3:1) to obtain 1.6 g of white solid M1.

[0040]

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 3.2 Hz, 1H, NH), 7.30 - 7.23 (m, 2H), 7.21 - 7.14 (m, 4H), 7.13 - 7.08 (m, 4H), 7.06 - 7.01 (m, 2H), 6.90 (d, J = 4.8 Hz, 1H, NH), 6.19 (t, J = 6.4 Hz, 1H, NH), 5.22 - 5.12 (m, 1H, CH), 4.47 - 4.37 (m, 2H, CH), 3.87 (d, J = 13.6 Hz, 1H), 3.81 - 3.67 (m, 4H), 3.04 (dd, J = 13.6, 6.8 Hz, 1H), 2.94 - 2.81 (m, 3H), 2.81 - 2.61 (m, 7H), 2.40 - 2.29 (m, 1H), 2.04 - 1.95 (m, 2H), 1.83 - 1.70 (m, 7H), 0.86 (s, 9H, CH3). 13 C NMR (100 MHz, CDCl3) δ 171.94, 171.44, 170.37, 157.40, 140.90, 137.76, 136.84, 128.96, 128.63, 128.55, 128.48, 126.90, 126.18, 126.05, 53.37, 53.01, 50.66, 47.43, 43.13, 42.91, 39.73, 36.83, 33.50, 32.06, 31.87, 30.06, 29.33, 27.84, 27.79, 27.13, 20.02; ESI-MS: m / z = 744.4 [M + H] + .

[0042] Example 2 (S)-2-(4-(N-methylnicotinamido)piperidine-1-carboxamido)-N 4 -neopentyl-N 1 -((S)-1-oxo-4-phenyl-1-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)butan-2-yl)succinimide M2

[0043] According to the preparation method of Similar Example 1, replace N-methyl-2-thiazolamine with 2-aminopyridine

[0044]

[0045] 1 H NMR(500MHz,DMSO-d6)δ8.69-8.62(m,1H,pyridine-H),8.59(s,1H,pyridine-H),8.30(d,J=8.5Hz,1H,pyridine-H),8.04-7.95(m,1H,NH),7.83-7.80(m,1H,NH),7.78-7.72(m,1H,NH),7.51-7.44(m,1H,pyridine-H),7.29-7.25(m,2H,Ar-H),7.20-7.16(m,3H,Ar-H),7.15-7.10(m,3H,Ar-H),7.08-7.05(m,1H,Ar-H),6.84-6.71(m,1H,NH),5.00-4.91(m,1H,CH),4.43-4.33(m,1H,CH),4.25-4.18(m,1H,CH),4.11-3.87(m,2H),2.87-2.76(m,4H),2.74-2.65(m,5H),2.64-2.57(m,3H),2.57-2.52(m,2H),2.08-2.00(m,1H),1.91-1.81(m,3H),1.73-1.54(m,6H),0.80(s,9H,CH3). 13 C NMR(100MHz,CDCl3)δ171.46,170.30,168.99,157.11,150.71,140.83,137.73,136.68,132.47,129.04,128.56,128.41,127.05,126.24,126.06,60.41,53.24,52.96,50.65,47.48,36.69,33.75,31.89,30.06,29.30,27.13,20.03,14.21;ESI-MS:m / z=738.4[M+H] + .

[0046] Example 3 N4-(3-chlorophenyl)-N4-methyl-N1-((S)-4-(neopentylamino)-1,4-dioxo-1-(((S)-1-oxo-4-phenyl-1-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)butan-2-yl)amino)butan-2-yl)piperidine-1,4-dicarboxamide (M3)

[0047] According to the preparation method of Example 1, replace N-methyl-2-thiazolamine with 3-chloro-N-methylaniline

[0048]

[0049] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.4 Hz, 1H, NH), 8.00 (d, J = 8.0 Hz, 1H, NH), 7.72 (t, J = 5.6 Hz, 1H, NH), 7.60 - 7.38 (m, 3H, Ar-H), 7.38 - 7.23 (m, 3H, Ar-H), 7.20 - 7.02 (m, 7H, Ar-H), 6.62 (d, J = 6.8 Hz, 1H, NH), 5.00 - 4.89 (m, 1H, CH), 4.41 - 4.29 (m, 1H, CH), 4.23 - 4.12 (m, 1H, CH), 3.87 - 3.72 (m, 2H), 3.14 (s, 3H, CH3), 2.87 - 2.67 (m, 4H), 2.65 - 2.51 (m, 3H), 2.47 - 2.12 (m, 3H), 2.11 - 1.97 (m, 1H), 1.92 - 1.77 (m, 3H), 1.72 - 1.61 (m, 2H), 1.55 - 1.37 (m, 4H), 0.78 (s, 9H, CH3). 13 C NMR (100 MHz, DMSO) δ 172.17, 170.71, 169.91, 156.79, 141.47, 137.22, 137.02, 131.12, 128.56, 128.45, 128.36, 128.25, 128.07, 126.91, 126.54, 125.86, 125.75, 125.67, 52.31, 52.06, 49.60, 46.49, 42.75, 42.49, 38.46, 37.40, 33.77, 31.80, 31.29, 29.69, 28.78, 27.96, 27.91, 27.13, 26.32, 20.00; ESI-MS: m / z = 771.4 [M + H] + .

[0050] Example 4 (S)-2-(4-(Indoline-1-carbonyl)piperidine-1-carboxamido)-N4-neopentyl-N1-((S)-1-oxo-4-phenyl-1-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)butan-2-yl)-1,4-succinamide M4

[0051] According to the preparation method of Example 1, replace N-methyl-2-thiazolamine with indoline

[0052]

[0053] 1 H NMR(500MHz,CDCl3)δ8.21(d,J=7.5Hz,1H),7.29-7.13(m,10H),7.11-7.07(m,2H),7.06-6.99(m,2H),6.94-6.77(m,1H),6.58-6.29(m,1H),5.18-5.07(m,1H),4.54-4.36(m,2H),4.14-4.03(m,2H),3.96-3.84(m,1H),3.83-3.72(m,1H),3.25-3.16(m,2H),3.06-2.97(m,1H),2.94-2.86(m,1H),2.76-2.55(m,9H),2.37-2.25(m,1H),2.07-1.93(m,2H),1.90-1.84(m,1H),1.82-1.70(m,6H),0.84(s,9H,CH3). 13 C NMR(125MHz,CDCl3)δ178.10,172.53,170.77,157.51,148.17,142.93,140.88,137.72,131.15,128.98,128.55,128.49,127.61,126.98,126.17,126.08,124.58,123.94,117.38,53.59,50.72,47.88,47.60,43.29,43.08,37.13,33.51,32.07,31.87,29.99,29.28,28.07,27.76,27.69,27.12,20.00;ESI-MS:m / z=749.4[M+H] + .

[0054] Example 5 (Activity evaluation) Evaluate the cytotoxicity of M1-M4 and their inhibitory effects on TNF-α-induced NF-κB signal activation detection

[0055] The specific experiments are as follows:

[0056] Determination 1: Detect the cytotoxicity of a series of compounds using the CCK-8 method

[0057] Seed HEK293T cells into a 96-well plate at a density of 5×10 3 cells / well. There are a total of 9 groups in each plate, including 1 control group (only adding the drug solvent dimethyl sulfoxide) and 8 drug-added groups (adding a series of compounds M1-M4 at 1, 5, 10, 50, 100, 500, 1000, and 5000 nM respectively). Each group has 5 replicates, and the culture medium is complete medium (DMEM + 10% FBS + 1% double antibody), and they are cultured for 24, 48, and 72 hours respectively. At the corresponding time points, add 10 μl of CCK-8 reagent to each well, take it out after incubating in the cell culture incubator for 1 hour under dark conditions, shake it well on the microplate reader and measure the absorbance value at 450 nm (the more active cells, the higher the absorbance). The IC 50 of the cytotoxicity of each compound to HEK293T cells is as follows (Table 1).

[0058] Determination 2: Detect the inhibitory effect of a series of compounds on TNF-α-induced NF-κB signal activation using the dual-luciferase assay

[0059] To quickly and conveniently detect the NF-κB signal inhibitory activity of the target compound, HEK293T cells stably expressing NF-kB-Luciferase Reporter (NF-kB-Luc-293T cells) are selected as tools for activity detection. Seed NF-kB-Luc-293T cells into a 24-well plate at a density of 5×10 5 cells / well. After the cells adhere, starve them for 8 hours using serum-free medium. Add gradient concentrations of candidate compounds, and the final doses are 6 drug doses that do not cause cytotoxicity according to Test 1, such as: 5, 10, 50, 100, 500, 1000 nM. After acting for 30 min, add 20 ng / ml of TNF-α to stimulate for 10 min and then collect the cells, and measure the firefly luciferase activity of each group according to the instructions of the commercially available luciferase kit (such as the TM040 kit from Promage Company).

[0060]

[0061] To determine the IC 50 , fit the S-shaped curve to a curve of % inhibition against the Log 10 compound concentration, and calculate the IC 50 of the inhibition of the compound on the NF-kB signal (Table 1).

[0062] Table 1. IC of the cytotoxic effect of Compounds M1-M4 on HEK293T cells 50 and IC of the inhibition of TNF-α-induced NF-κB signaling activation 50

[0063]

[0064] Therapeutic effect of the preferred M3 compound in Example 6 on LPS-induced murine sepsis

[0065] (1) Establishment of LPS-induced septic mice and administration

[0066] Systemic bacterial infection can cause systemic inflammation, thus triggering the occurrence of sepsis. We established a murine sepsis model by intraperitoneal injection of lipopolysaccharide (LPS). A total of 80 adult C57 mice, half male and half female, were divided into a control group, an LPS group, an LPS + M3 1 mg / kg group, an LPS + 3 mg / kg group, and an LPS + 9 mg / kg group, with 16 mice in each group. After 24 hours of modeling, 6 mice from each group were taken to collect peripheral blood serum for determination of inflammatory factors, and the other 10 mice were used for survival rate observation for a total of 7 days. After random grouping of the mice, a sepsis model was made by intraperitoneal injection of 40 mg / kg of LPS, and the control group was only injected with the same volume of normal saline. 1 mg / kg, 3 mg / kg, and 9 mg / kg of Compound M3 were intraperitoneally injected 3 hours and 12 hours after modeling, and the control group and the model group were only injected with the same volume of solvent.

[0067] (2) Detection of inflammatory factors in peripheral blood serum

[0068] For the above mice, 6 mice from each group were bled from the orbital cavity 24 hours after administration, centrifuged, and the supernatant was taken. The contents of TNF-α, IL-6, and IL-1β were detected using an ELISA kit (the ELISA kit was from Linker Biotechnology). The experimental results showed that the levels of TNF-α, IL-6, and IL-1β in the peripheral blood serum of LPS-induced septic mice were significantly higher than those of the control group, and the test compound M3 could dose-dependently reduce the elevated levels of TNF-α, IL-6, and IL-1β induced by LPS, with significant improvement at the doses of 3 and 9 mg / kg.

[0069] Among them, Figure 1 Effect of the preferred M3 compound on the levels of inflammatory factors in the peripheral blood serum of LPS-induced murine sepsis model (n = 6, ##P < 0.01 vs Ctrl group; *P < 0.05, **P < 0.01 vs LPS)

[0070] (3) Observation of mouse survival rate

[0071] All mice were placed in an environment with a temperature of 20 - 25 °C, a relative humidity of 30 - 70%, and a 12:12 h light - dark illumination; their survival rate was observed under free access to food and water. The experimental results showed that: mice in the LPS - induced group began to die on the first day, and all 10 mice died within 3 days, while administration of Compound M3 could significantly extend the survival rate of mice. Among them, in the 9 mg / kg dose group, 5 mice (50%) were still alive on the 7th day. Figure 2 Improvement results of the survival rate of the LPS - induced mouse sepsis model by the preferred Compound M3 (n = 10, *P < 0.05, **P < 0.01).

Claims

1. A compound, characterized in that, The structural formula of the compound is as follows: R is selected from -C(O)NR1R2, -N(R1)C(O)R2, -C(O)R3; R1, R2, and R3 are each independently selected from C1-C3 alkyl, 4-8-membered aryl, 4-8-membered heteroaryl, 4-10-membered heterocyclic group, and the aryl may be further substituted by methyl or halogen.

2. The compound according to claim 1, wherein R1, R2, and R3 are each independently selected from methyl, phenyl, thiazolyl, pyridyl, benzotetrahydropyrrolyl, and the benzene ring may be further substituted by halogen.

3. The compound according to claim 1, wherein R1 is selected from methyl; R2 is selected from phenyl, chlorophenyl, thiazolyl, pyridyl; R3 is selected from benzotetrahydropyrrolyl.

4. The compound according to claim 1, wherein The R substituent is one of the following structures:

5. The compound according to claim 1, wherein The structural formula of the compound is as follows:

6. The compound according to claim 1, characterized in that, It includes the compound according to any one of claims 1 to 3 and its pharmaceutically acceptable salts or cocrystals, deuterated compounds, solvates, enantiomers.

7. A composition, characterized in that, It contains the compound according to any one of claims 1 to 6.

8. Use of the compound according to any one of claims 1 to 6 or the composition according to claim 7 in the preparation of a medicament for treating inflammatory diseases that benefit from the inhibition of NF-κB signal activation.

9. The application according to claim 8, wherein The NF-κB signal is TNF-α-induced NF-κB signal activation.

10. The application according to claim 8, wherein, The disease is selected from one or more of sepsis, acute and chronic bronchitis, and pneumonia.

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