Dibenzoquinoline compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a dibenzoquinoline compound as well as a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown as a formula (I), the compound has good AhR agonist activity, a new treatment strategy is provided for pharmacological targeting of AhR, and the compound can be used for various immune and inflammatory diseases (such as asthma, inflammatory bowel disease, rheumatoid arthritis and psoriasis), cardiovascular diseases and neurodegenerative diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a dibenzoquinoline compound and a preparation method, a pharmaceutical composition and use thereof, and in particular to a dibenzoquinoline compound having aromatic hydrocarbon receptor agonist activity and a preparation method, a pharmaceutical composition and use thereof. Background Art

[0002] Inflammation is a common pathological process. Traumatic infections on the body surface and most common and frequently-occurring diseases of various organs (such as furuncle, carbuncle, pneumonia, hepatitis, nephritis, etc.) are all inflammatory diseases. Currently, the main means of clinical treatment for inflammatory diseases are topical or systemic hormone drugs, which have obvious side effects.

[0003] Aryl hydrocarbon receptor (AhR) is a ligand-dependent and highly conserved nuclear receptor that belongs to the basic helix-loop-helix (bHLH)-Per-ARNT-SIM (PAS) class of transcription factors. It mainly regulates the expression of cytochrome P-450 enzyme family 1 (CYP1) and some phase II metabolic enzymes. It also has many endogenous functions, including regulating cell cycle, immune response and cell differentiation. AhR agonists can relieve inflammatory responses by upregulating anti-inflammatory factors such as IL-10 and inhibiting the release of pro-inflammatory factors such as IL-6, IL17A and TNF-α. They can also induce M2 macrophage polarization, affect T cell differentiation and control autoimmune diseases. Therefore, activation of AhR can play an important role in the occurrence and development of immune inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.

[0004] At present, AhR agonists include exogenous AhR agonists, endogenous AhR agonists, and AhR agonists from other sources. Among them, the exogenous AhR ligand tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent AhR agonists, but its long-term intake can cause toxic reactions, lead to tissue damage, and is highly carcinogenic. Endogenous AhR agonists include 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) obtained by oxidation of tryptophan, but it has problems such as poor activation effect, complex synthesis, and low bioavailability. Therefore, it is necessary to explore more advantageous AhR agonists. Summary of the invention

[0005] Purpose of the invention: The first purpose of the present invention is to provide a dibenzoquinoline compound having aromatic hydrocarbon receptor agonist activity, the second purpose is to provide a method for preparing the compound, the third purpose is to provide a pharmaceutical composition with the compound as an active ingredient, and the fourth purpose is to provide a pharmaceutical use of the compound and its pharmaceutical composition.

[0006] Technical solution: The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R 1 , R 2 , R 3 , R 4 are each independently selected from halogen, substituted C 1-3 Alkyl, substituted C 1-3 Alkoxy or hydroxy, wherein the substituent is selected from halogen or C 3-6 Cycloalkyl;

[0010] R 5 Select from H or C 1-3 alkyl.

[0011] Preferably, in the structure:

[0012] R 1 , R 2 , R 3 , R 4 Each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, difluoromethoxy, cyclopropylmethoxy or hydroxy;

[0013] R 5 Selected from H or methyl.

[0014] Preferably, in the structure:

[0015] R 1 , R 2 , R 3 , R 4 Each independently selected from fluoro, methoxy, hydroxy, difluoromethoxy or cyclopropylmethoxy;

[0016] R 5 For H.

[0017] Preferably, the compound is selected from any one of the following compounds:

[0018]

[0019]

[0020] Preferably, the pharmaceutically acceptable salt is a potassium salt, sodium salt, ammonium salt, hydrochloride, sulfate, phosphate, carbonate, hydrobromide, maleate, fumarate, citrate, malate, methanesulfonate, p-toluenesulfonate, tartrate, acetate or ferulate of the compound of formula (I).

[0021] When R 4 is hydroxyl group, R 5When is H, the compound of the present invention is obtained by cyclization and deprotection reaction of compound VI;

[0022]

[0023] Among them, R 1 , R 2 , R 3 The definition of is as mentioned above;

[0024] The compound I prepared by the above method is salified with a pharmaceutically acceptable acid to obtain the pharmaceutically acceptable salt.

[0025] The specific synthesis steps are as follows:

[0026] Step 1: Compound VI, a palladium catalyst and a suitable palladium catalyst ligand react under alkaline conditions in a solvent suitable for the reaction to prepare compound VII, wherein the palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, tris(bisbenzylideneacetone)dipalladium, 1,1-bis(diphenylphosphine)diferropalladium dichloride, preferably, the palladium catalyst is selected from palladium acetate; the palladium catalyst ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1′-ferrocenediyl-bis(diphenylphosphine), 2-(dicyclohexylphosphine)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, Preferably, the palladium ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from cesium carbonate; the suitable reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane or any combination thereof, preferably, the solvent suitable for the reaction is N,N-dimethylacetamide.

[0027] Step 2: Compound VII and 10% palladium on carbon are reacted in a suitable solvent under a hydrogen atmosphere to prepare compound I, wherein the suitable reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, methanol, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane or any combination thereof, preferably, the suitable solvent for the reaction is methanol.

[0028] Reaction Scheme II:

[0029]

[0030] Step 1: Compound II and benzyl bromide react under alkaline conditions in a solvent suitable for the reaction to prepare Compound III, wherein the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from potassium carbonate; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane or any combination thereof, preferably, the solvent suitable for the reaction is acetonitrile.

[0031] Step 2: Compound III and methoxymethyltriphenylphosphonium chloride (MeOCH2PPh3Cl) react under alkaline conditions in a suitable solvent to prepare compound IV, wherein the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from sodium tert-butoxide; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane or any combination thereof, preferably, the solvent suitable for the reaction is tetrahydrofuran.

[0032] Step 3: Compound IV and Compound V react under alkaline conditions in a solvent suitable for the reaction to prepare Compound VI, wherein the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from triethylamine; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane or any combination thereof, preferably, the solvent suitable for the reaction is acetonitrile.

[0033] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Citric acid, tartaric acid and methanesulfonic acid and similar acids; organic acid salts also include amino acids (such as arginine, etc.), glucuronic acid and other organic acid salts. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0034] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0035] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0036] The pharmaceutically acceptable carrier can be an adjuvant widely used in the field of drug production. The adjuvant is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical adjuvant can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical adjuvant can include one or more of the following adjuvants: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0037] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0038] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0039] The compound or pharmaceutically acceptable salt thereof of the present invention is used for preparing a drug for preventing and / or treating inflammatory diseases.

[0040] The pharmaceutical composition of the present invention is used to prepare drugs for preventing and / or treating inflammatory diseases.

[0041] Preferably, the drug is a drug for preventing and / or treating asthma, inflammatory bowel disease, rheumatoid arthritis, psoriasis, cardiovascular disease, or neurodegenerative disease.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0043] The compounds designed in the present invention can target the aryl hydrocarbon receptor (AhR) and have good agonist activity, providing a new strategy for the pharmacological targeted therapy of AhR, and can be used for various immune and inflammatory diseases (such as asthma, inflammatory bowel disease, rheumatoid arthritis and psoriasis), cardiovascular diseases and neurodegenerative diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The inhibitory effect of the compound on γδT17 cell activation. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is further described below in conjunction with embodiments.

[0046] Example 1: Synthesis of 1-fluoro-2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-9-ol (1-1)

[0047] Step 1: Synthesis of 5-benzyloxy-2-bromo-4-methoxybenzaldehyde (III-1)

[0048] 6-Bromoisovanillin II-1 (5 g, 21.64 mmol) and potassium carbonate (6 g, 43.28 mmol) were dissolved in acetonitrile (50 mL), followed by slow dropwise addition of benzyl bromide (5.55 g, 32.46 mmol), and refluxed for 2 h. TLC (thin layer chromatography analysis) (petroleum ether: ethyl acetate = 10:1) monitored the complete reaction of the raw materials and stopped the reaction. Most of the solvent was removed by concentration under reduced pressure, water (25 mL) was added to the residue, stirred at room temperature for 10 min and then filtered, the filter cake was washed with water (10 mL × 3), vacuum dried and recrystallized with petroleum ether, filtered, and 6.25 g of a white solid was obtained, with a yield of 90.3%.

[0049] Step 2: Synthesis of 1-benzyloxy-4-bromo-2-methoxy-5-(2-methoxyvinyl)benzene (IV-1)

[0050] Compound III-1 (6.25 g, 19.53 mmol), methoxymethyl triphenylphosphonium chloride (10 g, 29.30 mmol) and sodium tert-butoxide (2.82 g, 29.30 mmol) were added to a three-necked flask. Under ice bath conditions, dichloromethane (55 mL) was added under nitrogen protection. After addition, the mixture was transferred to room temperature and reacted for about 10 min. TLC (petroleum ether: ethyl acetate = 10:1) monitored that the raw material reaction was complete and the reaction was stopped. Immediately quenched with water (20 mL), the organic layer was separated, the aqueous layer was extracted with dichloromethane (10 mL × 3), the organic layers were combined and dried over anhydrous sodium sulfate. Filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 6 g of white solid with a yield of 88.3%.

[0051] Step 3: Synthesis of 1-(5-benzyloxy-2-bromopropane-4-methoxybenzyl)-7-fluoro-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylic acid benzyl ester (VI-1)

[0052] After trifluoroacetic acid (333 mg, 2.92 mmol) and acetonitrile (15 mL) were mixed, compound IV-1 (765 mg, 2.20 mmol) was added, and the mixture was stirred at room temperature for about 3 h. Then, benzyl (4-fluoro-3-methoxyphenethyl) carbamate (V-1, 733 mg, 2.42 mmol) was added, nitrogen was replaced, and the mixture was stirred at room temperature for about 5 d. TLC (petroleum ether: ethyl acetate = 3:1) monitored that the reaction of the raw material was complete and the reaction was stopped. The filter cake was washed with acetonitrile (8 mL × 3) and vacuum dried to obtain 864 mg of a white solid with a yield of 63.3%. MS-ESI: [M+H] + 621.5.

[0053] Step 4: Synthesis of benzyl 9-(benzyloxy)-1-fluoro-2,10-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzoquinoline-6-dicarboxylic acid dibutyl ester (VII-1)

[0054] Compound VI-1 (800 mg, 1.29 mmol), palladium acetate (42.6 mg, 0.26 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (244 mg, 0.51 mmol) and cesium carbonate (632 mg, 1.94 mmol) were added to a three-necked flask, and N,N-dimethylacetamide (10 mL) was added under nitrogen protection. After the addition was completed, the temperature was raised to 130 ° C and reacted for about 3 hours. TLC (petroleum ether: ethyl acetate = 3:1) monitored the complete reaction of the raw materials and stopped the reaction. After the reaction solution was cooled to room temperature, dichloromethane (15 mL) and water (30 mL) were added in turn, the aqueous layer was extracted with dichloromethane (10 mL × 3), the organic layers were combined, washed with water (15 mL × 3) and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain 328 mg of a white solid with a yield of 47.2%. MS-ESI: [M+H] + 540.2.

[0055] Step 5: Synthesis of 1-fluoro-2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinolin-9-ol (1-1)

[0056] Compound VII-1 (315 mg, 0.58 mmol) was dissolved in methanol (3 mL), and then 10% palladium carbon (equivalent to 3.09 g, 2.9 mmol) was added to replace the hydrogen, and the reaction was carried out at room temperature for about 5 h. TLC (dichloromethane: methanol = 5: 1) monitored that the raw material reaction was complete and the reaction was stopped. Celite was used for suction filtration, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 30: 1), and recrystallized from ethyl acetate to obtain 115 mg of a brown solid with a yield of 62.5%. MS-ESI: [M+H] + 315.1.

[0057] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.40(s,1H),7.42(s,1H),6.82-6.72(m,2H),3.82(s, 3H), 3.77 (s, 3H), 3.60 (m, 1H), 3.16 (q, J = 5.1Hz, 1H), 2.90-2.55 (m, 5H), 2.43 (m, 1H).

[0058] Referring to the preparation method of compound I-1, the following compound was prepared:

[0059]

[0060]

[0061] Example 2: Inhibitory effect of compounds on γδT17 cell activation

[0062] 1. Experimental methods

[0063] Mouse spleen lymphocyte suspension was sorted out of γδT cells using TCRγ / δ+T Cell magnetic bead sorting kit, centrifuged at 300g for 10min, and the supernatant was discarded. RPMI1640 medium was added and inoculated into cell culture plates. IL-1β (10ng / mL) and IL-23 (10ng / mL), demethylisoboldine (3μM, 10μM), and compound (3μM) were added and stimulated for 72h. qPCR was used to detect the expression of IL-17A mRNA.

[0064] 2. Experimental results

[0065] like Figure 1 As shown, compounds I-2, I-5, I-6, and I-7 at a concentration of 3 μM can significantly downregulate the expression of IL-17A mRNA.

[0066] Example 3: Cytotoxic effects of compounds on EL-4 mouse lymphoma cells

[0067] 1. Experimental methods

[0068] EL-4 cells in the logarithmic growth phase were cultured at 2×10 5 Cells / ml were inoculated in a 96-well plate, and compounds (concentrations were A2 (20 μM, 30 μM, 40 μM, 50 μM, 60 μM); A1, A3, A4, A5, A7, A8 (5 μM, 10 μM, 20 μM, 30 μM, 40 μM)) were added. The 96-well plate was placed in a cell culture incubator for 72 h, 20 μL of MTT solution (5 mg / mL) was added to each well, and culture was continued for 4 h. 100 μL of the triple solution was added to each well, and culture was continued for 12 h at 37 ° C and 5% CO2 to fully dissolve the crystals, and the absorbance at 570 nm was measured by an ELISA reader.

[0069] 2. Experimental results

[0070] Table 1 Cytotoxic effects of compounds on EL-4 mouse lymphoma cells

[0071]

[0072]

[0073] As shown in Table 1, the compounds of the present invention have no significant cytotoxicity to EL-4 mouse lymphoma cells.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R 1 , R 2 , R 3 , R 4 are each independently selected from halogen, substituted C 1-3 Alkyl, substituted C 1-3 Alkoxy or hydroxy, wherein the substituent is selected from halogen or C 3-6 Cycloalkyl; R 5 Select from H or C 1-3 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: In the structure described: R 1 , R 2 , R 3 , R 4 Each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, difluoromethoxy, cyclopropylmethoxy or hydroxy; R 5 Selected from H or methyl.

3. The compound according to claim 1, characterized in that In the structure described: R 1 , R 2 , R 3 , R 4 Each independently selected from fluoro, methoxy, hydroxy, difluoromethoxy or cyclopropylmethoxy; R 5 For H.

4. The compound according to claim 1, characterized in that Any one of the following compounds: 1-Fluoro-2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinolin-9-ol; 2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinolin-9-ol; 1-(Difluoromethoxy)-2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinolin-9-ol; 1-(Cyclopropylmethoxy)-2,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinolin-9-ol; 1-Fluoro-2,9,10-trimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline; 1-(Difluoromethoxy)-2,9,10-trimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline; 1-(Cyclopropylmethoxy)-2,9,10-trimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is potassium salt, sodium salt, ammonium salt, hydrochloride, sulfate, phosphate, carbonate, hydrobromide, maleate, fumarate, citrate, malate, methanesulfonate, p-toluenesulfonate, tartrate, acetate or ferulate of the compound of formula (I).

6. A method for preparing the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: When R 4 is hydroxyl group, R 5 When is H, the compound is prepared by cyclization and deprotection reaction of compound VI to obtain compound I. Among them, R 1 , R 2 , R 3 The definition of is as in claim 1; The compound I prepared by the above method is salified with a pharmaceutically acceptable acid to obtain the pharmaceutically acceptable salt.

7. A pharmaceutical composition, characterized in that It comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating inflammatory diseases.

9. Use of the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating inflammatory diseases.

10. The use according to claim 8 or 9, characterized in that The medicine is a medicine for preventing and / or treating asthma, inflammatory bowel disease, rheumatoid arthritis, psoriasis, cardiovascular disease, and neurodegenerative disease.

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