Cyclobutenedione-based quinoline compound, preparation method therefor, pharmaceutical composition thereof, and use thereof

Abstract

A cyclobutenedione-based quinoline compound, a preparation method therefor, a pharmaceutical composition thereof, and a use thereof. The structure of the compound is represented by formula (I). The compound further contains a pharmaceutically acceptable salt of the compound, and can effectively inhibit a P2Y14 receptor, thereby exerting the therapeutic effect on liver fibrosis, drug-induced liver injury, and ulcerative colitis. In-vivo and in-vitro activity is significant, and the application is wide; the preparation method is simple and easily implemented, and has strong universality on a target chemical structure.

Description

Cyclobutenedione quinoline compounds and preparation methods, pharmaceutical compositions and applications thereof Technical Field

[0001] The present invention relates to a cyclobutenedione quinoline compound, a preparation method, a pharmaceutical composition and an application thereof, in particular to a cyclobutenedione quinoline compound having a P2Y 14 Cyclobutenedione quinoline compounds with receptor inhibitory activity, preparation methods, pharmaceutical compositions and applications thereof. Background Art

[0002] P2Y 14 receptor (P2Y 14 P2Y receptors are members of the P2Y receptor family. After being specifically activated by uridine 5'-diphosphoglucose (UDPG) and other endogenous UDP-sugars, they can inhibit adenylate cyclase (AC) through Gi / o proteins, thereby reducing the production of 3',5'-cyclic adenosine monophosphate (cAMP) in cells. 14 R is widely expressed in tissues and organs such as the heart, placenta, adipose tissue, gastrointestinal tract, bone marrow, and thymus, and is particularly evident in the immune system.

[0003] When P2Y 14 When activated, P2Y can promote the release of mediators from mast cells and inflammation of renal intercalated cells, increase the hypersensitivity of microglial cells and the chemotaxis of neutrophils; and inhibit the release of metalloproteinases and tumor necrosis factor from astrocytes. 14 The high expression level of R suggests that it may play an important role in immune regulation.

[0004] P2Y 14 Activation of P2YR is closely related to the intracellular cAMP content, and cAMP can inhibit the activation of NLRP3 inflammasome. 14 R may regulate the inflammatory response through the NLRP3 inflammasome. In chronic liver disease, fibrosis is the main factor determining prognosis, but there is a lack of effective anti-fibrosis treatment. Studies have shown that P2Y 14 ERK activation induced by R is the main reason for the profibrotic effect of hepatic stellate cells.

[0005] Currently reported P2Y 14 The structure of R receptor inhibitors has disadvantages such as poor solubility and unsatisfactory metabolic stability, which limits their subsequent drugability research.

[0006] Summary of the Invention

[0007] Objectives of the invention: The first objective of the present invention is to provide a cyclobutenedione quinoline compound, the second objective is to provide a method for preparing the compound, the third objective is to provide a pharmaceutical composition comprising the compound, and the fourth objective is to provide a method for preparing P2Y 14 The use of receptor inhibitor drugs.

[0008] Technical solution: The cyclobutenedione quinoline compound of the present invention has a structure of formula (I), and further includes a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] R is selected from a 3-6 membered cycloalkyl group, a 5-8 membered bridged cycloalkyl group, a benzene ring, a 4-6 membered heterocyclic group containing 1-2 N, O, and S heteroatoms, and a 5-6 membered heteroaryl group containing 1-3 N, O, and S heteroatoms; the benzene ring is substituted by any substituent selected from the following: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, halogen, hydroxyl, nitro, cyano, amino, and thiol.

[0011] Preferably, in the structure:

[0012] R is selected from a 3-5 membered cycloalkyl group, a benzene ring, a 5-6 membered heterocyclic group containing 1-2 N, O heteroatoms, or a 5-6 membered heteroaryl group containing 1-2 N, O, or S heteroatoms; the benzene ring is substituted by any substituent selected from the following: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxyl, nitro, or cyano.

[0013] Preferably, in the structure:

[0014] R is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, thiazole ring, oxazole ring, furan ring, pyran ring, piperidine ring, piperazine ring, pyridine ring, pyrazine ring, benzene ring, more preferably selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene ring; the benzene ring is substituted by any substituent selected from the following: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, fluorine, chlorine, nitro, trifluoromethyl, trifluoromethoxy, more preferably selected from hydrogen, methyl, ethyl, methoxy.

[0015] Preferably, in the structure:

[0016] The substituent on the benzene ring is in the para or meta position relative to the imino group, and is more preferably selected from p-tolyl, m-tolyl, p-methoxyphenyl, m-methoxyphenyl, p-ethylphenyl, and m-ethylphenyl.

[0017] Specifically, the cyclobutenedione quinoline compound of the present invention is preferably selected from any of the following compounds:

[0018] Cyclobutenedione quinolines are important pharmacophores in modern drug discovery. Their low toxicity, high bioavailability, good biocompatibility, and therapeutic efficacy have led to their widespread application in numerous fields, including chemistry, medicine, biology, and materials science. By leveraging the principle of activity superposition, the activity of small molecule drugs can be significantly enhanced by introducing the cyclobutenedione quinoline group.

[0019] The compound of the present invention is designed with the goal of improving drugability. By introducing a new structure of cyclobutenedione quinoline, the activity of the inhibitor is further enhanced, and the solubility and metabolic stability of the compound are improved.

[0020] Furthermore, the pharmaceutically acceptable salt is a salt formed by the cyclobutenedione quinoline 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, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

[0021] The preparation method of the cyclobutenedione quinoline compound of the present invention comprises the following steps:

[0022] Condensation reaction of compound (II) and compound (III) to obtain compound (I);

[0023] A more specific method is as follows:

[0024] Wherein, R is defined as above;

[0025] The corresponding acid is reacted with the compound (I) prepared by the above method to form a salt to obtain a pharmaceutically acceptable salt of the compound.

[0026] The cyclobutenedione quinoline compounds and pharmaceutically acceptable carriers described herein constitute the pharmaceutical compositions described herein. Common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, or injections, are prepared by adding common pharmaceutical excipients, such as flavorings, sweeteners, liquid / solid fillers, and diluents.

[0027] The cyclobutenedione quinoline compound or its pharmaceutical composition of the present invention is applied to P2Y 14 Preparation of a receptor inhibitor drug, specifically a drug for treating liver fibrosis, drug-induced liver injury, and ulcerative colitis.

[0028] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0029] This class of compounds can effectively inhibit P2Y 14 Receptors (inhibitory IC 50 The value reaches the nanomolar concentration level, with the optimal value being less than 5nM), thereby exerting therapeutic effects on liver fibrosis, drug-induced liver injury, and ulcerative colitis; it has significant in vitro and in vivo activity and is widely used; the preparation method is simple and easy, and has strong versatility for the target chemical structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Compound HDB-18 for P2Y 14 The inhibitory IC of R 50 value;

[0031] FIG2 is a graph showing the serum ALT and AST levels in mice 14 days after common bile duct ligation;

[0032] FIG3 is HE staining of mouse liver tissue 14 days after common bile duct ligation;

[0033] FIG4 is a Masson staining image of mouse liver tissue 14 days after common bile duct ligation.

[0034] FIG5 is a graph showing the serum ALT and AST levels in mice 24 hours after intraperitoneal injection of acetaminophen;

[0035] FIG6 is a HE staining image of mouse liver tissue 24 hours after intraperitoneal injection of acetaminophen;

[0036] FIG7 shows the effect of HDB-18 intervention on the disease activity index of DSS-induced ulcerative colitis mice;

[0037] FIG8 shows the effect of HDB-18 intervention on colon length in mice with DSS-induced ulcerative colitis;

[0038] Figure 9 shows representative images of the effect of HDB-18 intervention on colon length in mice with DSS-induced ulcerative colitis;

[0039] FIG10 shows the results of the effect of HDB-18 intervention on colon histopathology in mice with DSS-induced ulcerative colitis. DETAILED DESCRIPTION

[0040] The technical solution of the present invention will be further described below in conjunction with embodiments.

[0041] Example 1: Synthesis of 3-(quinoline-6-amino)-4-(p-toluylamino)cyclobut-3-ene-1,2-dione

[0042] Dissolve 1.34 g of quinolin-6-amine in methanol, add 1.42 g of 3,4-dimethoxycyclobutane-3-ene-1,2-dione, and stir the mixture at room temperature for 24 hours. When the reaction is complete, extract the crude product with water and ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure. The product is purified by silica gel column chromatography, eluting with dichloromethane:methanol (50:1) to yield 3-(quinolin-6-ylamino)-4-methoxycyclobutane-3-ene-1,2-dione.

[0043] Dissolve 0.642 g of p-toluidine in methanol, add 0.642 g of 3-(quinolin-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione and 4.28 g of 1-hydroxybenzotriazole, and stir the mixture at 65°C for 24 hours. When the reaction is complete, extract the crude product with water and ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and dried under reduced pressure. The product is purified by silica gel column chromatography, eluting with dichloromethane:methanol (100:1) to yield 3-(quinolin-6-amino)-4-(p-tolylamino)cyclobut-3-ene-1,2-dione.

[0044] The NMR data are as follows:

[0045] 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.91(s,1H),8.81(s,1H),8.31(s,1H) ,7.97(t,J=19.0Hz,3H),7.53(s,1H),7.37(s,2H),7.18(s,2H),2.27(s,3H).

[0046] 13 C NMR (101MHz, DMSO-d6) δ166.63,149.26,144.46,137.33,136.41,136.28,133.18,130.24,129.03,123.33,122.63,119.25,114.57,20.83.

[0047] Example 2: Synthesis of 3-(quinoline-6-amino)-4-(m-toluylamino)cyclobut-3-ene-1,2-one

[0048] Using m-methylaniline as raw material, the synthesis method is shown in Example 1.

[0049] The NMR data are as follows:

[0050] 1H NMR (400MHz, DMSO-d6) δ10.14(s,1H),9.91(s,1H),8.79(s,1H),8.27(d,J=8.2Hz,1H),8.01(d,J=8 .6Hz,1H),7.98-7.86(m,2H),7.53-7.43(m,1H),7.26(d,J=16.3Hz,3H),6.90(s,1H),2.30(s,3H).

[0051] 13 C NMR(101MHz,DMSO-d6)δ166.61,165.80,149.42,144.74,139.23,138.83,137.21,136 .01,130.54,129.69,128.98,124.68,123.18,122.60,119.65,116.31,114.62,21.62.

[0052] Example 3: Synthesis of 3-((4-methoxyphenyl)amino)-4-(quinoline-6-amino)cyclobut-3-ene-1,2-dione

[0053] Use p-anisidine as raw material. See Example 1 for the synthesis method.

[0054] The NMR data are as follows:

[0055] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.86(s,1H),8.77(s,1H),8.25(s,1H),8.05-7.83(m,3H),7.43(d,J=59.7Hz,3H),6.93(s,2H),3.71(s,3H).

[0056] 13 C NMR(101MHz,DMSO-d6)δ181.67,166.49,165.24,156.24,149.37,137.25,135 .84,131.99,130.57,128.95,123.07,122.54,120.80,114.98,114.43,55.75.

[0057] Example 4: Synthesis of 3-(3-methoxyphenyl)amino)-4-(quinolin-6-amino)cyclobut-3-ene-1,2-one

[0058] Using m-anisidine as raw material, the synthesis method is shown in Example 1.

[0059] The NMR data are as follows:

[0060] 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.96(s,1H),8.25(s,1H),8.01(s,1H),7.92( d,J=26.4Hz,2H),7.49(s,1H),7.25(s,2H),6.98(s,1H),6.65(s,1H),3.77(s,3H).

[0061] 13 C NMR(101MHz,DMSO-d6)δ182.12,166.41,165.88,160.61,149.57,145.03,140.10,137.02, 135.67,130.74,130.67,128.89,122.97,122.54,114.61,111.13,109.57,104.74,55.56.

[0062] Example 5: Synthesis of 3-(quinoline-6-amino)-4-(p-toluylamino)cyclobut-3-ene-1,2-dione

[0063] Take o-ethylaniline as raw material, and the synthesis method is shown in Example 1.

[0064] The NMR data are as follows:

[0065] 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.94(s,1H),8.83-8.74(m,1H),8.28(d,J=8.3Hz,1H),8.02(d,J=9.0Hz,1H) ,7.97-7.88(m,2H),7.51(s,1H),7.39(d,J=7.8Hz,2H),7.20(d,J=7.9Hz,2H),2.56(d,J=7.6Hz,2H),1.15(s,3H).

[0066] 13 C NMR(101MHz,DMSO-d6)δ182.57,166.55,165.54,149.30,144.61,139.53,137.24 ,136.55,136.02,130.44,129.01,123.16,122.56,119.25,114.51,27.95,16.08.

[0067] Example 6: Synthesis of 3-(quinoline-6-amino)-4-(m-ethylphenylamino)cyclobut-3-ene-1,2-dione

[0068] Using m-ethylaniline as raw material, the synthesis method is shown in Example 1.

[0069] The NMR data are as follows:

[0070] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.95(s,1H),8.78(s,1H),8.26(d,J=8.1Hz,1H),8.0 4-7.86(m,3H),7.49(s,1H),7.32(d,J=31.8Hz,3H),6.94(s,1H),2.61(s,2H),1.20(s,3H).

[0071] 13 C NMR(101MHz,DMSO-d6)δ182.47,182.15,166.58,165.75,149.55,145.52,145.02,138.85,137.10 ,135.66,130.74,129.69,128.91,123.48,122.97,122.54,118.43,116.49,114.55,28.60,15.74.

[0072] Example 7: Synthesis of 3-(quinoline-6-amino)-4-(cyclobutylamino)cyclobut-3-ene-1,2-one

[0073] Using cyclobutaneamine as raw material, the synthesis method is shown in Example 1.

[0074] The NMR data are as follows:

[0075] 1 H NMR(400MHz, DMSO-d6)δ9.86(s,1H),8.75(dd,J=4.1,1.6Hz,1H),8.22(dd,J=8.4,1.6Hz,1H),7.99(s,1H),7.97(s,1H),7.92-7.7 9(m,2H),7.47(dd,J=8.3,4.1Hz,1H),4.56(q,J=8.4Hz,1H),2.32(d,J=8.9Hz,2H),2.07(pd,J=9.4,2.7Hz,2H),1.73-1.62(m,2H).

[0076] 13 C NMR(101MHz,DMSO-d6)δ184.47,180.82,168.81,163.58,149.25,144.80,13 7.47,135.52,130.70,129.02,122.77,122.48,113.73,49.25,32.08,14.43.

[0077] Example 8: Synthesis of 3-(quinoline-6-amino)-4-(cyclopentylamino)cyclobut-3-ene-1,2-one

[0078] Using cyclopentaneamine as raw material, the synthesis method is shown in Example 1.

[0079] The NMR data are as follows:

[0080] 1 H NMR (400MHz, DMSO-d6) δ9.80(s,1H),8.74(dd,J=4.2,1.7Hz,1H),8.20(d,J=7.6Hz,1H),7.96(d,J=9.0Hz,1H),7.88(s,1H),7.83(dd,J=9.0,2.5Hz ,1H),7.77(d,J=8.1Hz,1H),7.45(dd,J=8.3,4.1Hz,1H),4.41(p,J=6.6Hz ,1H),1.96(dt,J=12.2,6.7Hz,2H),1.73-1.66(m,2H),1.63-1.52(m,4H).

[0081] 13 C NMR (101MHz, DMSO-d6) δ180.59,169.31,163.67,149.23,144.76,137.54,135.51,130.71,129.04,122.73,122.50,113.64,56.06,34.18,23.62.

[0082] Example 9: Synthesis of 3-(cyclopropylamino)-4-(quinoline-6-amino)cyclobut-3-ene-1,2-one

[0083] Using cyclopropaneamine as raw material, the synthesis method is shown in Example 1.

[0084] The NMR data are as follows:

[0085] 1H NMR(400MHz, DMSO-d6)δ9.75(s,1H),8.75(dd,J=4.2,1.6Hz,1H),8.21(d,J=8.2Hz,1H),7.97(d,J=9.0Hz,1H),7.86(d,J=2.5Hz,1H),7 .82(dd,J=9.0,2.6Hz,1H),7.47(dd,J=8.3,4.1Hz,1H),3.13(tt,J=7.1,3.7Hz,1H),0.79(h,J=5.0Hz,2H),0.68(q,J=5.2,4.2Hz,2H).

[0086] 13 C NMR (101MHz, DMSO-d6) δ181.25,171.03,164.11,149.24,144.79,137.49,135.52,130.62,128.98,122.81,122.47,113.72,26.54,7.50.

[0087] Example 10: Synthesis of 3-(bicyclo[1.1.1]pentan-1-ylamino)-4-(quinolin-6-ylamino)cyclobut-3-ene-1,2-dione

[0088] Bicyclo[1.1.1]pentane-1-amine was used as the raw material. The synthesis method was as described in Example 1.

[0089] The NMR data are as follows:

[0090] 1 H NMR (400MHz, DMSO-d6) δ9.76(s,1H),8.85(dd,J=7.5,1.5Hz,1H),8.53(dd,J=7.6,1.4Hz,1H),8.22(dt,J=7.5,1.5Hz,1H),7.72(d,J=7.5H z,1H),7.38(t,J=7.5Hz,1H),6.93(t,J=1.5Hz,1H),2.46(hept,J=7.0Hz,1H),2.02(dd,J=13.0,7.0Hz,3H),1.89(dd,J=13.0,7.0Hz,3H).

[0091] 13C NMR(101MHz,DMSO-d6)δ184.59,183.43,150.12,149.48,147.77,142.16,13 4.72,133.40,129.84,128.17,124.24,121.24,116.21,61.95,52.59,26.34.

[0092] Example 11: Synthesis of 3-(cyclohexylamino)-4-(quinolin-6-amino)cyclobut-3-ene-1,2-one

[0093] Using cyclopentaneamine as raw material, the synthesis method is shown in Example 1.

[0094] The NMR data are as follows:

[0095] 1 H NMR(400MHz, DMSO-d6)δ9.85(s,1H),8.73(dd,J=4.1,1.7Hz,1H),8.19(d,J=8.2Hz ,1H),7.96(d,J=8.9Hz,1H),7.88(s,1H),7.84(d,J=8.7Hz,1H),7.75(d,J=8.0Hz, 1H),7.45(dd,J=8.3,4.2Hz,1H),3.86(s,1H),1.97-1.89(m,2H),1.70(dd,J=9.3, 4.4Hz, 2H), 1.55 (d, J = 11.9Hz, 1H), 1.33 (p, J = 12.1Hz, 4H), 1.19 (d, J = 9.6Hz, 1H).

[0096] 13 C NMR(101MHz,DMSO-d6)δ184.40,180.54,169.14,163.69,149.22,144.76,137.5 5,135.50,130.71,129.04,122.73,122.49,113.65,53.14,34.03,25.16,24.47.

[0097] Example 12: Compounds for P2Y 14 Evaluation of receptor inhibitory activity

[0098] Stable expression of P2Y 14 HEK293 cells (purchased from Keygen Biotech) were cultured in DMEM high-glucose medium (containing 10% fetal bovine serum) and seeded into 384-well culture plates approximately 24 h before the experiment at a seeding density of 1 × 10 4Cells were cultured at 37°C, 95% O2, and 5% CO2 humidity. Before the experiment, the culture medium was discarded and replaced with serum-free DMEM high-glucose culture medium. IBMX (500 μM) and Ro 20-1724 (100 μM) were added to inhibit PDEs activity to ensure that cAMP was at a high level. The AC agonist Forskolin (10 μM) was used to stimulate the production of cellular cAMP. Different concentrations of cyclobutenedione quinoline compounds (0.01, 0.1, 1, 10, 100 nM) were added in advance, and PPTN (CAS No.: 1160271-30-6) was used as a positive control. At the same time, 10 μM P2Y 14 After 30 min, the intracellular cAMP content was detected according to the instructions of the cAMP GloTM Assay Kit (PROMEGA Co. Ltd, USA). IC was calculated based on the cAMP content. 50 The results are shown in Table 1 and Figure 1.

[0099] Table 1 Compounds for P2Y 14 Receptor inhibitory activity

[0100] ND: Not Detected

[0101] The results showed that the inhibition rate of compound (3) (hereinafter named HDB-18) was 120.90%, IC 50 The value is 2.304nM.

[0102] Example 13: Study on the Effect of Compounds on Alleviating Liver Fibrosis

[0103] Male C57BL / 6 mice, 6-8 weeks old, weighing 20-25 g, were given free access to food and water, and maintained a 12-hour light schedule daily at an ambient temperature of 25 ± 2°C. The mice were randomly divided into five groups: control, model, positive drug group (20 mg / kg magnesium isoglycyrrhizinate), low-dose HDB-18 group (10 mg / kg HDB-18), and high-dose HDB-18 group (20 mg / kg HDB-18). A mouse liver fibrosis model was established by common bile duct ligation. After laparotomy, the common bile duct was isolated and ligated twice with 5-0 silk suture. The sham-operated group underwent the same procedures as the model group, except that no ligation was performed. On day 2 after bile duct ligation, the treatment group received intraperitoneal injection of the drug once daily, while the sham-operated group received the same dose of saline until the model was established. Fourteen days later, blood was collected from the eyeballs and serum ALT and AST levels were measured using ALT and AST assays. The mice were sacrificed and liver tissue was fixed for hematoxylin and eosin staining and Masson staining.

[0104] The results are shown in Figure 2 , which show that HDB-18 treatment can significantly improve the liver function of mice with liver fibrosis. ### P < 0.001, compared with the control group; *** P < 0.001, compared with the model group. As shown in Figures 3 and 4, HDB-18 treatment can significantly reduce the degree of liver cell necrosis and inflammatory cell infiltration in mice with liver fibrosis, and can significantly reduce the degree of liver fibrosis in mice with liver fibrosis (blue represents collagen fibers).

[0105] Example 14: Study on the Effect of Compounds on Alleviating Drug-Induced Liver Injury

[0106] Male C57BL / 6 mice, 6-8 weeks old, weighing 20-25g, were given free access to food and water, with 12 hours of light daily and an ambient temperature of 25±2°C. The mice were randomly divided into five groups: control, model, positive drug group (20 mg / kg magnesium isoglycyrrhizinate), low-dose HDB-18 group (10 mg / kg HDB-18), and high-dose HDB-18 group (20 mg / kg HDB-18), with eight mice per group. After a 16-hour fast, the mice were given a single intraperitoneal injection of acetaminophen (350 mg / kg) to establish a drug-induced liver injury model. The animals were observed after the injection. The treatment groups received the drug 1 hour before the intraperitoneal injection of acetaminophen, while the control group received the same dose of saline. 24 hours after the intraperitoneal injection of acetaminophen, blood was collected from the eyeballs for measurement of serum ALT and AST levels. The mice were sacrificed and liver tissue was fixed for HE staining.

[0107] The results shown in Figures 5 and 6 show that HDB-18 treatment can significantly improve the liver function of mice with drug-induced liver injury. ### P < 0.001, compared with the control group; ** P < 0.01, *** P < 0.001, compared with the model group. HDB-18 treatment significantly reduced the degree of hepatocyte necrosis and inflammatory cell infiltration in mice with drug-induced liver injury.

[0108] Example 15: Study on the Effect of Compounds on Alleviating DSS-Induced Ulcerative Colitis

[0109] Male C57BL / 6 mice, 6-8 weeks old, weighing 20-25 g, were given free access to food and water, with 12 hours of light per day and an ambient temperature of 25 ± 2°C. The mice were randomly divided into five groups: control, model, positive drug group (mesalazine 50 mg / kg), low-dose HDB-18 group (50 μM HDB-18), and high-dose HDB-18 group (100 μM HDB-18), with eight mice per group. Except for the control group, mice in the model and all drug groups had free access to distilled water for 7 days, with fresh DSS solution replaced every 2 days. During the modeling period, the positive control group received drug administration by gavage, while the HDB-18 group received drug administration by rectal administration. Body weight, stool consistency, and rectal bleeding were recorded daily, and a disease activity index score was calculated for each group. Mice were sacrificed on day 8, and the entire colon from the anus to the end of the cecum was obtained. Colon length was measured, and distal colon tissue was collected and fixed for pathological examination.

[0110] The results are shown in Figure 7. HDB-18 treatment significantly reduced the disease activity index of mice. As shown in Figures 8 and 9, HDB-18 treatment significantly inhibited the shortening of the colon length of mice. ## P < 0.01, ### P < 0.001, compared with the control group; ** P < 0.01, *** P < 0.001, compared with the model group. As shown in Figure 10, the crypt structure of the colon tissue of mice was relatively intact after HDB-18 treatment.

Claims

1. A cyclobutenedione quinoline compound, characterized in that: Having the structure of formula (I), and also including pharmaceutically acceptable salts thereof: in: R is selected from 3-6 membered cycloalkyl, 5-8 membered bridged cycloalkyl, benzene ring, 4-6 membered heterocyclic group containing 1-2 N, O, S heteroatoms, 5-6 membered heteroaryl group containing 1-3 N, O, S heteroatoms; the benzene ring is substituted by any substituent selected from the following: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, halogen, hydroxyl, nitro, cyano, amino, thiol.

2. The cyclobutenedione quinoline compound according to claim 1, characterized in that In the structure: R is selected from a 3-5 membered cycloalkyl group, a benzene ring, a 5-6 membered heterocyclic group containing 1-2 N, O heteroatoms, or a 5-6 membered heteroaryl group containing 1-2 N, O, S heteroatoms; the benzene ring is substituted by any substituent selected from the following: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxyl, nitro, and cyano.

3. The cyclobutenedione quinoline compound according to claim 1, characterized in that In the structure: R is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, thiazole ring, oxazole ring, furan ring, pyran ring, piperidine ring, piperazine ring, pyridine ring, pyrazine ring, and benzene ring; the benzene ring is substituted by any substituent selected from the following: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, fluorine, chlorine, nitro, trifluoromethyl, and trifluoromethoxy.

4. The cyclobutenedione quinoline compound according to claim 1, characterized in that: In the structure: The substituents on the benzene ring are in the para or meta position to the imino group.

5. The cyclobutenedione quinoline compound according to claim 1, characterized in that: Select any of the following compounds:

6. The cyclobutenedione quinoline 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, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

7. A method for preparing the cyclobutenedione quinoline compound according to claim 1, characterized in that: The following steps are involved: Condensation reaction of compound (II) and compound (III) to obtain compound (I); Wherein, R is defined as in claim 1; The corresponding acid is reacted with the compound (I) prepared by the above method to form a salt, thereby obtaining a pharmaceutically acceptable salt of the compound.

8. A pharmaceutical composition, characterized in that The invention comprises the cyclobutenedione quinoline compound according to claim 1 and a pharmaceutically acceptable carrier.

9. A cyclobutenedione quinoline compound according to claim 1 or a pharmaceutical composition according to claim 8 in the preparation of P2Y 14 The use of receptor inhibitor drugs.

10. The application according to claim 9, characterized in that: The medicine is a medicine for treating liver fibrosis, drug-induced liver injury and ulcerative colitis.

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