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

Abstract

The present invention discloses a cyclobutenedione quinoline compound and its preparation method, pharmaceutical composition and application. The compound has a structure as shown in formula (I) and also includes a pharmaceutically acceptable salt thereof, which can effectively inhibit P2Y 14 receptors, 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 it has strong versatility for the target chemical structure.

Description

Technical Field

[0001] The present invention relates to a cyclobutenedione quinoline compound and a preparation method, a pharmaceutical composition and application, in particular to a cyclobutenedione quinoline compound having 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 receptors. 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 microglia and the motility 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 The activation of P2YR is closely related to the intracellular cAMP content, and cAMP can prevent 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 R-induced ERK activation 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. Summary of the invention

[0006] 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 14The use of receptor inhibitor drugs.

[0007] Technical solution: The cyclobutenedione quinoline compound of the present invention has a structure of formula (I), and also includes a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] 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.

[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, 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.

[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 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 hydrogen, methyl, ethyl, methoxy.

[0015] Preferably, in the structure:

[0016] The substituent on the benzene ring is in the para-position or meta-position with respect 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]

[0019]

[0020] Cyclobutenedione quinoline is an important pharmacophore in modern drug discovery. It has low toxicity, high bioavailability, good biocompatibility and efficacy, and has therefore been widely used in many fields such as chemistry, medicine, biology and materials science. By using the principle of activity superposition, the activity of small molecule drugs is significantly improved after the introduction of cyclobutenedione quinoline groups into them.

[0021] The compound of the present invention is designed with the aim 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.

[0022] 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.

[0023] The method for preparing the cyclobutenedione quinoline compound of the present invention comprises the following steps:

[0024] Condensation reaction of compound (II) and compound (III) to obtain compound (I);

[0025]

[0026] A more specific method is as follows:

[0027]

[0028] Wherein, R is defined as above;

[0029] 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.

[0030] The cyclobutenedione quinoline compounds and pharmaceutically acceptable carriers of the present invention constitute the pharmaceutical composition of the present invention, which can be prepared into common pharmaceutical preparations such as tablets, capsules, syrups, suspensions or injections by adding common pharmaceutical excipients such as flavorings, sweeteners, liquid / solid fillers, diluents, etc.

[0031] The cyclobutenedione quinoline compound or the pharmaceutical composition thereof of the present invention is applied to P2Y 14 Preparation of receptor inhibitor drugs, specifically drugs for treating liver fibrosis, drug-induced liver injury, and ulcerative colitis.

[0032] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0033] This class of compounds can effectively inhibit P2Y 14 Receptor (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

[0034] Figure 1 Compound HDB-18 for P2Y 14 The inhibitory IC of R 50 value;

[0035] Figure 2 This is the result of ALT and AST levels in serum of mice 14 days after common bile duct ligation;

[0036] Figure 3 HE staining of mouse liver tissue 14 days after common bile duct ligation;

[0037] Figure 4 This is a Masson staining image of mouse liver tissue 14 days after common bile duct ligation.

[0038] Figure 5 This is the result of ALT and AST levels in mouse serum 24 hours after intraperitoneal injection of acetaminophen;

[0039] Figure 6 HE staining of mouse liver tissue 24 hours after intraperitoneal injection of acetaminophen;

[0040] Figure 7 This is the result diagram of the effect of HDB-18 intervention on the disease activity index of DSS-induced ulcerative colitis mice;

[0041] Figure 8 This is the result of HDB-18 intervention on the colon length of DSS-induced ulcerative colitis mice;

[0042] Fig. 9 Representative images of the effect of HDB-18 intervention on colon length in mice with DSS-induced ulcerative colitis;

[0043] Fig.10 This figure shows the effect of HDB-18 intervention on colon histopathology in mice with DSS-induced ulcerative colitis. DETAILED DESCRIPTION

[0044] The technical solution of the present invention is further described below in conjunction with embodiments.

[0045] Example 1: Synthesis of 3-(quinoline-6-amino)-4-(p-toluylamino)cyclobut-3-ene-1,2-dione

[0046]

[0047] 1.34 g of quinoline-6-amine was dissolved in methanol, 1.42 g of 3,4-dimethoxycyclobutane-3-ene-1,2-dione was added, and the mixture was stirred at room temperature for 24 h. When the reaction was complete, the crude product was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried under reduced pressure. The product was purified by silica gel column chromatography, eluted with dichloromethane: methanol (50: 1) to give 3-(quinoline-6-ylamino)-4-methoxycyclobutane-3-ene-1,2-dione.

[0048] 0.642 g of p-toluidine was dissolved in methanol, 0.642 g of 3-(quinoline-6-ylamino)-4-methoxycyclobut-3-ene-1,2-dione, 4.28 g of 1-hydroxybenzotriazole were added, and the mixture was stirred at 65°C for 24 hours. When the reaction was complete, the crude product was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried under reduced pressure. The product was purified by silica gel column chromatography, eluting with dichloromethane: methanol (100: 1) to give 3-(quinoline-6-amino)-4-(p-toluylamino)cyclobut-3-ene-1,2-dione.

[0049] The NMR data are as follows:

[0050] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0051] 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.

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

[0053]

[0054] Take m-methylaniline as raw material, and refer to Example 1 for the synthesis method.

[0055] The NMR data are as follows:

[0056] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0057] 13 C NMR (101 MHz, DMSO-d 6 )δ166.61,165.80,149.42,144.74,139.23,138.83,137.21,136.01,130.5 4,129.69,128.98,124.68,123.18,122.60,119.65,116.31,114.62,21.62.

[0058] Example 3: Synthesis of 3-((4-methoxyphenyl)amino)-4-(quinoline-6-amino)cyclobut-3-ene-1,2-dione

[0059]

[0060] Use p-methoxyaniline as raw material, and refer to Example 1 for the synthesis method.

[0061] The NMR data are as follows:

[0062] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0063] 13 C NMR (101 MHz, DMSO-d 6)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.

[0064] Example 4: Synthesis of 3-(3-methoxyphenyl)amino)-4-(quinoline-6-amino)cyclobut-3-ene-1,2-one

[0065]

[0066] Using m-methoxyaniline as raw material, the synthesis method is shown in Example 1.

[0067] The NMR data are as follows:

[0068] 1 H NMR (400 MHz, DMSO-d 6 )δ10.15(s,1H),9.96(s,1H),8.25(s,1H),8.01(s,1H),7.92(d,J=26.4H z,2H),7.49(s,1H),7.25(s,2H),6.98(s,1H),6.65(s,1H),3.77(s,3H).

[0069] 13 C NMR (101 MHz, DMSO-d 6 )δ182.12,166.41,165.88,160.61,149.57,145.03,140.10,137.02,135.67,13 0.74,130.67,128.89,122.97,122.54,114.61,111.13,109.57,104.74,55.56.

[0070] Example 5: Synthesis of 3-(quinoline-6-amino)-4-(p-toluylamino)cyclobut-3-ene-1,2-dione

[0071]

[0072] Take o-ethylaniline as raw material, and refer to Example 1 for the synthesis method.

[0073] The NMR data are as follows:

[0074] 1 H NMR (400 MHz, DMSO-d 6)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),7.97-7.8 8(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).

[0075] 13 C NMR (101 MHz, DMSO-d 6 )δ182.57,166.55,165.54,149.30,144.61,139.53,137.24,136.55,1 36.02,130.44,129.01,123.16,122.56,119.25,114.51,27.95,16.08.

[0076] Example 6: Synthesis of 3-(quinoline-6-amino)-4-(m-ethylphenylamino)cyclobut-3-ene-1,2-dione

[0077]

[0078] Take m-ethylaniline as raw material, and refer to Example 1 for the synthesis method.

[0079] The NMR data are as follows:

[0080] 1 H NMR (400 MHz, DMSO-d 6 )δ10.16(s,1H),9.95(s,1H),8.78(s,1H),8.26(d,J=8.1Hz,1H),8.04-7.86(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).

[0081] 13 C NMR (101 MHz, DMSO-d 6 )δ182.47,182.15,166.58,165.75,149.55,145.52,145.02,138.85,137.10,135.66,1 30.74,129.69,128.91,123.48,122.97,122.54,118.43,116.49,114.55,28.60,15.74.

[0082] Example 7: Synthesis of 3-(quinoline-6-amino)-4-(cyclobutylamino)cyclobut-3-ene-1,2-one

[0083]

[0084] Using cyclobutaneamine as raw material, the synthesis method is shown in Example 1.

[0085] The NMR data are as follows:

[0086] 1 H NMR (400 MHz, DMSO-d 6 )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),7.92-7.79(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).

[0087] 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.

[0088] Example 8: Synthesis of 3-(quinoline-6-amino)-4-(cyclopentylamino)cyclobut-3-ene-1,2-one

[0089]

[0090] Using cyclopentaneamine as raw material, the synthesis method is shown in Example 1.

[0091] The NMR data are as follows:

[0092] 1H 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).

[0093] 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.

[0094] Example 9: Synthesis of 3-(cyclopropylamino)-4-(quinoline-6-amino)cyclobut-3-ene-1,2-one

[0095]

[0096] Using cyclopropaneamine as raw material, the synthesis method is shown in Example 1.

[0097] The NMR data are as follows:

[0098] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0099] 13C 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.

[0100] Example 10: Synthesis of 3-(bicyclo[1.1.1]pentan-1-ylamino)-4-(quinolin-6-ylamino)cyclobut-3-ene-1,2-dione

[0101]

[0102] Using bicyclo[1.1.1]pentane-1-amine as raw material, the synthesis method is shown in Example 1.

[0103] The NMR data are as follows:

[0104] 1 H NMR (400 MHz, DMSO-d 6 )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=7.5Hz,1H),7.3 8(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).

[0105] 13 C 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.

[0106] Example 11: Synthesis of 3-(cyclohexylamino)-4-(quinoline-6-amino)cyclobut-3-ene-1,2-one

[0107]

[0108] Using cyclopentaneamine as raw material, the synthesis method is shown in Example 1.

[0109] The NMR data are as follows:

[0110] 1 H NMR (400 MHz, DMSO-d 6 )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=9.3,4.4H z, 2H), 1.55 (d, J = 11.9Hz, 1H), 1.33 (p, J = 12.1Hz, 4H), 1.19 (d, J = 9.6Hz, 1H).

[0111] 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.

[0112] Example 12: Compounds for P2Y 14 Evaluation of inhibitory activity of receptors

[0113] Stable expression of P2Y 14 HEK293 cell lines (purchased from Keygen Biotech) were cultured in DMEM high-glucose medium (containing 10% fetal bovine serum) and inoculated into 384-well culture plates about 24 h before the experiment at a seeding density of 1×10 4 The cells were cultured at 37°C and 95% O 2 , 5% CO 2 Culture under humidity conditions. 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. AC agonist Forskolin (10 μM) was used to stimulate the production of cell 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 14Receptor agonist UDPG, after 30 minutes, 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 .

[0114] Table 1 Compounds for P2Y 14 Inhibitory activity of receptors

[0115]

[0116]

[0117] ND:Not Detected

[0118] The results showed that the inhibition rate of compound (3) (hereinafter referred to as HDB-18) was 120.90%, IC 50 The value is 2.304nM.

[0119] Example 13: Study on the Effect of Compounds on Alleviating Liver Fibrosis

[0120] Male C57BL / 6 mice, 6-8 weeks old, weighing 20-25g, were given free access to water and food, and were illuminated for 12h per day. The ambient temperature was 25±2℃. The mice were randomly divided into 5 groups: control group, model group, positive drug group (magnesium isoglycyrrhizinate 20mg / kg), HDB-18 low-dose group (HDB-18, 10mg / kg), and HDB-18 high-dose group (HDB-18, 20mg / kg), with 8 mice in each group. The common bile duct ligation was used to establish a mouse liver fibrosis model. The common bile duct was separated after laparotomy and ligated twice with 5-0 silk thread. Except that the sham operation group was not ligated, the other steps were the same as the model group. On the second day after bile duct ligation, the treatment group was intraperitoneally injected with drugs once a day, and the sham operation group was injected with the same dose of normal saline until the model was completed. After 14 days, the eyeballs were removed and blood was collected to determine the serum ALT and AST levels using ALT and AST kits. The mice were killed to obtain liver tissue fixation for HE staining and Masson staining.

[0121] The results are as follows Figure 2 As shown, 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. Figure 3 , 4 The results showed that HDB-18 treatment could significantly reduce the degree of liver cell necrosis and inflammatory cell infiltration in mice with liver fibrosis, and could significantly reduce the degree of liver fibrosis in mice with liver fibrosis (blue represents collagen fibers).

[0122] Example 14: Study on the Effect of Compounds on Alleviating Drug-Induced Liver Injury

[0123] Male C57BL / 6 mice, 6-8 weeks old, weighing 20-25g, free access to water and food, 12h lighting per day, and an ambient temperature of 25±2℃. The mice were randomly divided into 5 groups: control group, model group, positive drug group (magnesium isoglycyrrhizinate 20mg / kg), HDB-18 low-dose group (HDB-18, 10mg / kg), HDB-18 high-dose group (HDB-18, 20mg / kg), 8 mice in each group. After fasting for 16h, the mice were intraperitoneally injected with acetaminophen (350mg / kg) once to establish a drug-induced liver injury model, and the animal status was observed after injection. The treatment group was given the treatment drug 1h before the intraperitoneal injection of acetaminophen, and the normal control group was injected with the same dose of saline. 24h after the intraperitoneal injection of acetaminophen, the eyeballs were removed and blood was collected, and the serum ALT and AST levels were measured. The mice were killed to obtain liver tissue fixation for HE staining.

[0124] The results are as follows Figure 5 , 6 It was shown that HDB-18 treatment could 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 can significantly reduce the degree of hepatocyte necrosis and inflammatory cell infiltration in mice with drug-induced liver injury.

[0125] Example 15: Study on the Effect of Compounds on Alleviating DSS-Induced Ulcerative Colitis

[0126] Male C57BL / 6 mice, 6-8 weeks old, weighing 20-25g, were given free access to water and food, with 12h lighting per day and an ambient temperature of 25±2℃. The mice were randomly divided into 5 groups: control group, model group, positive drug group (mesalazine 50mg / kg), HDB-18 low-dose group (HDB-18, 50μM), and HDB-18 high-dose group (HDB-18, 100μM), with 8 mice in each group. Except for the control group mice that freely drank distilled water, the model group and each drug-treated group mice freely drank 3.5% DSS solution for 7 days, and the freshly prepared DSS solution was replaced every 2 days. During the modeling period, the positive control group was given oral administration, and the HDB-18 group was given rectal administration. The weight, stool hardness and rectal bleeding of each group of mice were recorded daily, and the disease activity index of each group of mice was scored. On the 8th day, the mice were killed to obtain the entire colon from the anus to the end of the cecum, the colon length was measured, and the distal colon tissue was collected and fixed for pathological examination.

[0127] The results are as follows Figure 7As shown, HDB-18 treatment can significantly reduce the disease activity index of mice. Figure 8 , 9 As shown, HDB-18 treatment significantly inhibited the shortening of colon length in mice. ## P<0.01, ### P < 0.001, compared with the control group; ** P<0.01, *** P<0.001, compared with the model group. Fig.10 As shown, the crypt structure of mouse colon tissue 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 a 3-6 membered cycloalkyl group, a benzene ring, a 4-6 membered heterocyclic group containing 1-2 N, O, S heteroatoms, or a 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, and 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. A cyclobutenedione quinoline compound, 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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