4, 5-dihydro-3H-pyrrolo [2, 3-c] quinoline-4-ketone derivative and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a 4, 5-dihydro-3H-pyrrolo [2, 3-c] quinoline-4-ketone derivative, an application of the 4, 5-dihydro-3H-pyrrolo [2, 3-c] quinoline-4-ketone derivative as an ATX enzyme inhibitor, and an application of the 4, 5-dihydro-3H-pyrrolo [2, 3-c] quinoline-4-ketone derivative in preparation of drugs for treating and / or preventing diseases caused by ATX-LPA functional axis abnormality. The invention particularly relates to application in preparation of drugs for treating and / or preventing fibrosis diseases and cancers. The derivative is a compound as shown in a general formula (I) and pharmaceutically acceptable salt thereof, and in-vitro activity screening shows that the compound has outstanding ATX enzyme inhibitory activity and certain anti-tumor cell proliferation activity, shows better anti-fibrosis activity in a bleomycin-induced pulmonary fibrosis model, and has a good application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a 4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-4-one derivative and its application as an ATX enzyme inhibitor and its application in preparing a drug for treating and / or preventing diseases caused by abnormal ATX-LPA functional axis, in particular, its application in preparing a drug for treating and / or preventing fibrotic diseases and cancer. Background Art

[0002] Autotaxin (ATX) is an enzyme with lysophospholipase D activity. Its process of hydrolyzing lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA) is the main source of LPA in the human body under pathological conditions. Especially in lesion tissues such as fibrosis and tumors, ATX is highly expressed and produces high concentrations of LPA, which binds to its receptor (LPAR 1～6 ) binds to activate Rho / Rock, TGF-β / Smads, MAPK, VEGF and other signaling pathways, thereby accelerating the occurrence and development of diseases such as fibrosis, inflammation, and cancer. Therefore, inhibiting the activity of ATX and blocking the generation of LPA from the source is an effective way to treat serious diseases such as fibrosis and tumors.

[0003] As the research on ATX targets continues to deepen, the development of its new inhibitors has also made great progress, especially in the fields of fibrotic diseases and cancer. At present, the indole drug PAT-409 (WO2015077503) developed by Blade Therapeutics is used for the treatment of idiopathic pulmonary fibrosis and has entered the clinical phase II research stage; the 3H-imidazole [4,5-b] pyridine drug IOA-289 (CN107428752) developed by iOnctura and the substrate analog containing a long alkyl chain 2-carba-Cpa (US2011086820) developed by Ochanomizu University are in the clinical phase I / II research stage, and the indications are fibrosis and solid tumors. In addition, BBT-877 (Phase II) jointly developed by Boehringer Ingelheim and Bridge Biotherapeutics and FTP-198 (Phase I) developed by Hisun are also in the clinical research stage, but their chemical structures have not yet been disclosed.

[0004] In recent years, patent reports on ATX inhibitors are very rare, especially non-competitive allosteric inhibitors. Among them, patent WO 2024 / 180520 reported a class of 2-indolone compounds, patent WO2024 / 201308 reported a class of 1,3-dihydro-2H-benzo[d]imidazol-2-one compounds, and our unit reported a class of N-aryl indole compounds in patent CN116396205. Summary of the invention

[0005] In view of the above technical problems, the present invention provides a 4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-4-one derivative with novel structure, excellent drug-like properties and outstanding activity, and its use as a non-competitive allosteric inhibitor of ATX enzyme and its use in the preparation of drugs for treating and / or preventing diseases caused by abnormal ATX-LPA functional axis, especially its use in the preparation of drugs for treating and / or preventing fibrotic diseases and cancer.

[0006] To achieve the above object, the technical solution adopted by the present invention is:

[0007] A 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative, wherein the derivative is a compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof:

[0008]

[0009] in,

[0010] L is selected from Wherein y is selected from an integer between 0 and 3;

[0011] n is an integer selected from 0 to 3;

[0012] R 1 Selected from hydrogen, (C1-C5) alkyl;

[0013] R 2 Selected from 6-10 membered aromatic rings or 5-10 membered heteroaromatic rings containing 1-3 N atoms, wherein the aromatic rings and heteroaromatic rings may be optionally substituted by 1-3 identical or different following groups: halogen, nitro, (C1-C6) alkyl, (C3-C6) cycloalkylmethyl, (C1-C6) alkoxy;

[0014] Ring A is a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1-3 N atoms;

[0015] R 3is selected from halogen, cyano, hydroxyl, thiol, carboxyl, phosphate, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C4) alkoxycarbonyl, (C1-C6) alkoxy, (C1-C6) acyl, amino substituted with 0-2 (C1-C6) alkyl, 5-6 membered heteroaryl or aliphatic heterocycle containing 1-3 atoms selected from N, O or S;

[0016] x is an integer selected from 1 to 4, and when x is greater than 1, R 3 Can be the same or different.

[0017] Preferably, the derivative is a compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof; wherein,

[0018] L is selected from wherein y is selected from 0, 1, 2 or 3;

[0019] n is selected from 0, 1, 2 or 3;

[0020] R 1 Selected from hydrogen, (C1-C5) alkyl;

[0021] R 2 Selected from benzene ring, naphthalene ring, pyrrole ring, pyrazole ring, imidazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, pyridine ring, pyrimidine ring, indole ring which are unsubstituted or optionally substituted by 1-3 identical or different following groups, wherein the following groups are halogen, nitro, (C1-C6) alkyl, (C3-C6) cycloalkylmethyl, (C1-C6) alkoxy;

[0022] Ring A is a benzene ring, a naphthalene ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, an indole ring or a quinoline ring;

[0023] R 3 is selected from halogen, cyano, hydroxyl, thiol, carboxyl, phosphate, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C4) alkoxycarbonyl, (C1-C6) alkoxy, (C1-C6) acyl, amino substituted with 0-2 (C1-C6) alkyl, 5-6 membered heteroaryl or aliphatic heterocycle containing 1-3 heteroatoms selected from N, O or S;

[0024] x is selected from 1, 2, 3 or 4, and when x is greater than 1, R 3 Can be the same or different.

[0025] Further preferably, the derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof;

[0026] L is selected from

[0027] n is selected from 0 or 1;

[0028] R1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl;

[0029] R 2 Selected from benzene ring, pyrrole ring, pyrazole ring, imidazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring which are unsubstituted or optionally substituted by 1-2 identical or different following groups, wherein the following groups are halogen, nitro, (C1-C4) alkyl, (C3-C6) cycloalkylmethyl, (C1-C3) alkoxy;

[0030] Ring A is a benzene ring, a pyrrole ring, a pyridine ring, or a pyrimidine ring;

[0031] R 3 is selected from halogen, cyano, hydroxy, carboxyl, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C3) alkoxycarbonyl, (C1-C3) alkoxy, (C1-C3) acyl, a 5-6 membered heteroaryl or aliphatic heterocycle containing 1-3 atoms selected from N, O or S;

[0032] When x is selected from 1 or 2 and x is greater than 1, R 3 Can be the same or different.

[0033] Still more preferably, the derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof;

[0034] L is selected from

[0035] n is selected from 0 or 1;

[0036] R 1 Selected from methyl, ethyl, isopropyl;

[0037] R 2 A benzene ring or a pyrazole ring substituted by 1-2 identical or different groups selected from the group consisting of halogen, nitro, (C1-C4) alkyl, (C3-C6) cycloalkylmethyl, (C1-C3) alkoxy;

[0038] Ring A is a benzene ring or a pyridine ring;

[0039] R 3 is selected from halogen, cyano, hydroxy, carboxyl, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C3) alkoxycarbonyl, (C1-C3) alkoxy, (C1-C3) acyl, 1,2,4-oxadiazol-3-yl;

[0040] When x is selected from 1 or 2 and x is greater than 1, R 3 Can be the same or different.

[0041] Still more preferably, the derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof;

[0042] L is selected from

[0043] n is selected from 0 or 1;

[0044] R 1 Selected from methyl, ethyl, isopropyl;

[0045] R 2 A benzene ring or a pyrazole ring substituted by the following groups: halogen, nitro, methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, methoxy, ethoxy;

[0046] Ring A is a benzene ring or a pyridine ring;

[0047] R 3 is selected from halogen, cyano, hydroxy, carboxyl, sulfamoyl, carbamoyl, thiocarbamoyl, methoxycarbonyl, methoxy, acetyl, 1,2,4-oxadiazol-3-yl;

[0048] When x is selected from 1 or 2 and x is greater than 1, R 3 Can be the same or different.

[0049] Most preferably, the derivative is specifically the following compound and its pharmaceutically acceptable salt,

[0050] 3-{5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid;

[0051] N-(3-Carbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide;

[0052] N-(3-Hydroxyphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide;

[0053] N-(3-cyanophenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide;

[0054] N-(3-thiocarbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide;

[0055] N-[3-(1,2,4-oxadiazol-3-yl)phenyl]-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide;

[0056] 3-(1-isopropyl-1H-pyrazol-4-yl)-5-methyl-4-oxo-N-(3-aminomethanesulfonylphenyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide;

[0057] 6-{5-ethyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}picolinic acid;

[0058] 3-{3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid;

[0059] 3-{5-isopropyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid;

[0060] 3-{3-(4-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid;

[0061] 3-{3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid;

[0062] 3-{5-methyl-3-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid;

[0063] 4-{3-{5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoic acid;

[0064] 1-(3-acetylphenyl)-3-{5-ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl}urea;

[0065] 3-{3-{3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-5-ethyl-4-oxo-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoic acid;

[0066] 4-{3-{3-(4-ethoxyphenyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl}ureido}benzoic acid;

[0067] 5-Methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-3,5-dichlorobenzyl ester;

[0068] 5-Methyl-3-(1-isopropyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-3-acetylphenyl ester

[0069] 5-Ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-2-methoxyphenyl ester.

[0070] Moreover, according to some common methods in the field to which the present invention belongs, the 4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-4-one derivative of the general formula (I) of the present invention can form a pharmaceutically acceptable salt with a base. Pharmaceutically acceptable addition salts include inorganic base and organic base addition salts, and salts formed with the following bases are particularly preferred: triethylamine, sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide.

[0071] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight-chain or branched alkyl.

[0072] A pharmaceutical composition comprising the compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof.

[0073] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0074] The following synthetic routes summarize and describe the preparation of 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivatives of formula (I) of the present invention, all of which are prepared by the methods described in the route, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All derivatives of the present invention are prepared by the methods described in the route or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these routes are as defined below or as defined in the claims.

[0075] Route 1

[0076]

[0077] In the general formula (I) of the present invention, L is an amide bond, n is 0, and R 3 When the halogen, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, nitro, aminosulfonyl, carbamoyl, 1,2,4-oxadiazol-3-yl, methoxy, ethoxy, acetyl and the like are present, the corresponding target compound can be synthesized according to route 1: First, 4-iodopyrazole or iodophenol is subjected to N-alkylation reaction and O-alkylation reaction to obtain the corresponding intermediate M 2a or M 2b ; Then, the 2,3-indoledione undergoes N-alkylation reaction, Wittig reaction, regioselective ring expansion reaction, coupling reaction, hydrolysis reaction, amide condensation reaction or acylation reaction in sequence to obtain the target compound I1. 1 , R 2 , x and ring A are as defined in the claims.

[0078] Route 2

[0079]

[0080] In the general formula (I) of the present invention, L is an amide bond, n is 1, and R 3 When it is a halogen, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, nitro, sulfamoyl, carbamoyl, 1,2,4-oxadiazole-3-yl, methoxy, ethoxy, acetyl or the like, the corresponding target compound can be synthesized according to route 2: the intermediate M6 undergoes N-alkylation reaction, hydrolysis reaction, amide condensation reaction or acylation reaction in sequence to obtain the target compound I2. 1 , R 2 , x and ring A are as defined in the claims.

[0081] Route 3

[0082]

[0083] L in the general formula (I) of the present invention is R 3 When the intermediate M8 or M 10 The target compounds I3 and I4 were obtained by Curtius rearrangement reaction. 1 , R 2 , n, x, y and ring A are as defined in the claims.

[0084] Route 4

[0085]

[0086] R of the general formula (I) of the present invention 3 When R is a carboxyl group, the corresponding target compound can be synthesized according to route 4: the corresponding carboxylate compounds obtained by routes 1, 2 and 3 are hydrolyzed under alkaline conditions to obtain the corresponding carboxyl group-containing target compound I5. 1 , R 2 , L, n and ring A are as defined in the claims.

[0087] An application of the 4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-4-one derivative, and an application of the compound represented by the general formula (I) and the pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of an ATX inhibitor.

[0088] Use of the compound represented by general formula (I) and its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 7 in the preparation of anti-tumor or anti-fibrosis drugs.

[0089] The tumor is pancreatic cancer, breast cancer or glioma, and the fibrosis is pulmonary fibrosis, liver fibrosis, myocardial fibrosis or renal fibrosis.

[0090] We have found that the compound of the present invention has strong ATX enzyme inhibitory activity in vitro, therefore, it can be used to prepare drugs for treating and / or preventing tumors and fibrotic diseases associated with abnormal ATX-LPA signaling axis, such as tumors mainly including breast cancer, pancreatic cancer or glioma, etc., and fibrotic diseases mainly including pulmonary fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, etc.

[0091] In vivo experiments preliminarily show that the preferred compounds of the present invention have a good inhibitory effect on the pathological process of bleomycin-induced pulmonary fibrosis, indicating the possibility of this series of compounds as potential therapeutic drugs for pulmonary fibrosis.

[0092] The active compound of the present invention or its pharmaceutically acceptable salt can be used alone as the only anti-tumor or anti-fibrosis drug, or can be used in combination with the currently marketed anti-tumor / anti-fibrosis drugs (such as paclitaxel, pirfenidone, nintedanib, etc.). Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

[0093] The advantages of the present invention are:

[0094] The present invention provides a class of novel 4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-4-one compounds, which is a creative application of this skeleton structure type in this field. Compared with the ATX inhibitors reported so far, this class of compounds performs extremely well in terms of drug-like parameters such as physical and chemical properties. Compared with the larger cLogP value (7.6) of PAT-409, the cLogP value of the molecule described in the present invention is reduced to a suitable range (1.5 to 4.5). In terms of biological activity, this class of compounds has good inhibitory activity against the ATX enzyme; in the pharmacodynamic experiment of the mouse pulmonary fibrosis model, the compounds provided by the present invention showed good anti-fibrotic effects. In summary, in view of the current plight of the scarcity of anti-fibrotic drugs in clinical practice, the molecules described in the present invention have good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 Compound 8 improves bleomycin-induced pulmonary fibrosis in mice (Masson staining results);

[0096] Among them, Ctrl is normal lung tissue, BLM is bleomycin-induced pulmonary fibrosis tissue, BLM+PAT-409 is bleomycin-induced pulmonary fibrosis tissue treated with positive drug PAT-409, and BLM+8 is bleomycin-induced pulmonary fibrosis tissue treated with compound 8. DETAILED DESCRIPTION

[0097] The examples are intended to illustrate rather than limit the scope of the present invention. The H NMR spectra of the compounds were measured using Bruker ARX-400 / 600, and the mass spectra were measured using Agilent 1100 LC / MSD; all reagents used were analytically pure or chemically pure.

[0098]

[0099]

[0100]

[0101] Preparation of compounds:

[0102] Example 1: 3-{5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid (Compound 1)

[0103] Step A4-Iodo-1-methyl-1H-pyrazole (M 2a -1) Synthesis

[0104] NaH (1.86 g, 77.33 mmol) was slowly added to a DMF (80 mL) solution of 4-iodopyrazole (10.00 g, 51.55 mmol) at 0°C, and the mixture was reacted at 0°C for 15 min. CH3I (10.98 g, 77.33 mmol) was then added, and the reaction was continued at 0°C for 0.5 h. After the raw material was exhausted as monitored by TLC, a saturated ammonium chloride solution (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined and washed with 5% LiCl solution for 3 times, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain intermediate M. 2a -1, colorless oily liquid, 8.91 g, yield 83.1%.

[0105] Step B1 - Synthesis of methyl 2,3-indoledione (M4-1)

[0106] NaH (1.96 g, 81.56 mmol) was slowly added to a DMF (80 mL) solution of indole-2,3-dione (10.00 g, 67.97 mmol) at 0°C, and the mixture was reacted at 0°C for 15 min. CH3I (11.58 g, 81.56 mmol) was then added, and the mixture was moved to room temperature and the reaction was continued for 0.5 h. After the raw material was exhausted as monitored by TLC, a saturated ammonium chloride solution (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with 5% LiCl solution for 3 times, and the solvent was removed by distillation under reduced pressure to obtain intermediate M4-1 as a red solid, 8.97 g, with a yield of 81.9%.

[0107] Step C Synthesis of ethyl 2-(1-methyl-2-oxoindoline-3-methylidene)acetate (M5-1)

[0108] The intermediate M4-1 (8.97 g, 55.66 mmol), PPh3 (16.06 g, 61.22 mmol) and ethyl bromoacetate (10.22 g, 61.22 mmol) were fully mixed and moved to an 80°C oil bath, and then morpholine (5.33 g, 61.22 mmol) was added and the reaction was continued for 2 min. After the raw materials were exhausted by TLC monitoring, the reaction solution was cooled to room temperature and recrystallized from ethanol to obtain the intermediate M5-1, a red solid, 8.54 g, with a yield of 66.4%. Detection data: ESI-MS [M+H] + (m / z):232.4.

[0109] Step D Synthesis of 5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester (M6-1)

[0110] The intermediate M5-1 (8.54 g, 36.93 mmol), p-methylbenzenesulfonylmethyl isocyanide (7.25 g, 36.93 mmol) and K2CO3 (10.21 g, 73.86 mmol) were dissolved in ethanol (50 mL) and refluxed for 3 h. After the raw materials were exhausted by TLC monitoring, the reaction solution was distilled under reduced pressure to remove the solvent, and the resulting residue was beaten with methanol to obtain the intermediate M6-1, a pink solid, 5.70 g, with a yield of 60.2%. Detection data: ESI-MS [M+H] + (m / z):271.2.

[0111] Step E Synthesis of ethyl 5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylate (M7-1)

[0112] After the intermediate M6-1 (2.00 g, 7.40 mmol), K3PO4 (2.36 g, 11.10 mmol) and CuI (0.70 g, 3.70 mmol) were fully dried, they were added to dry toluene (15 mL), and then the intermediate M 1a -1 (4.62g, 22.20mmol) and N,N'-dimethylethylenediamine (652mg, 7.40mmol), then placed at 100°C, reacted under nitrogen atmosphere for 24h. After TLC monitoring, the reaction solution was decompressed and the solvent was removed by distillation, and the residue was purified by column chromatography to obtain intermediate M7-1, pink solid, 1.87g, yield 72.1%. Detection data: ESI-MS [M+H] + (m / z):351.2.

[0113] Step F Synthesis of 5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-1)

[0114] The intermediate M7-1 (1.87 g, 5.34 mmol) was dissolved in a mixed solution of 20 mL NaOH (1 mol / L) H2O (10 mL) and 1,4-dioxane (10 mL) and reacted at room temperature for 0.5 h. After the raw material was exhausted by TLC monitoring, 1,4-dioxane was removed by vacuum distillation, and the pH of the reaction solution was adjusted to 4-5 with dilute hydrochloric acid to precipitate the product. The product was filtered under reduced pressure and the filter cake was collected to obtain the intermediate M8-1, a white powder, 1.57 g, with a yield of 91.6%. Detection data: ESI-MS [MH] - (m / z):321.1.

[0115] Step G Synthesis of ethyl 3-{5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoate (I1-1)

[0116] The intermediate M8-1 (200 mg, 0.62 mmol) was added to SOCl2 (5 mL), and a drop of DMF was added. The mixture was refluxed for 1 h, and SOCl2 was removed by distillation under reduced pressure. The residue was redissolved with dry dichloromethane, and triethylamine (188 mg, 1.86 mmol) and ethyl 3-aminobenzoate (103 mg, 0.62 mmol) were added. The mixture was refluxed for 1 h, and the solvent was removed by distillation under reduced pressure to obtain the crude intermediate I1-1, which was directly used in the next step without purification.

[0117] Step H Synthesis of Compound 1

[0118] The crude intermediate I1-1 obtained in the previous step was added to a mixed solution of 10 mL NaOH (1 mol / L) in H2O (5 mL) and 1,4-dioxane (5 mL) and reacted at room temperature for 0.5 h. After the raw materials were exhausted by TLC monitoring, 1,4-dioxane was removed by vacuum distillation, and the pH of the reaction solution was adjusted to 3-4 with dilute hydrochloric acid to precipitate the product. The product was filtered under reduced pressure and the filter cake was collected to obtain compound 1, a white powder, 52 mg, and a total yield of 67.8% in two steps. Detection data: ESI-MS [MH] - (m / z):440.1. 1 H NMR (600MHz, DMSO-d6) δ13.04(s,1H),10.67(s,1H),8.89(dd,J=8.1,1.5Hz,1H),8.50(t,J=1.9Hz,1H),8.21(s,1H),8.16(s,1H),8.07(ddd,J= 8.2, 2.3, 1.1Hz, 1H), 7.76 (s, 1H), 7.69 (dt, J=7.7, 1.4Hz, 1H), 7.60-7. 46(m,3H),7.30(ddd,J=8.2,7.0,1.2Hz,1H),3.93(s,3H),3.69(s,3H). 13 C NMR(150MHz,DMSO-d6)δ167.73,163.78,154.36,140.16,137.35,135.74(2C),135.68,131.73,129.37,128. 44,128.11,126.79,125.97,124.74,124.56,122.32,122.13,121.16,117.42,115.76,115.60,40.51,29.42.

[0119] Example 2: N-(3-carbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 2)

[0120] According to the method of step A in Example 1, 4-iodopyrazole and 1-bromopropane were used as raw materials to prepare 4-iodo-1-propyl-1H-pyrazole (M 2a -2), yield 80.1%;

[0121] According to the method of steps EF in Example 1, intermediate M 2a -2 and intermediate M6-1 were used as raw materials to prepare 5-methyl-3-(1-propyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-2) with a yield of 58.7%; detection data: ESI-MS [MH] - (m / z):349.0.

[0122] According to the method of step G in Example 1, intermediate M8-2 and 3-aminobenzamide were used as raw materials to prepare compound 2 with a yield of 73.6%. Detection data: ESI-MS [M+H] + (m / z):469.3. 1 H NMR (600MHz, DMSO-d6) δ10.43(s,1H),8.89(dd,J=8.1,1.6Hz,1H),8.29(t,J=2.0Hz,1H),8.15(d,J= 12.0Hz,2H),7.98(s,1H),7.95-7.91(m,1H),7.76(s,1H),7.61(dt,J=7.8,1.4Hz,1H),7.58(dd,J=8 .6,1.2Hz,1H),7.53(ddd,J=8.5,7.0,1.6Hz,1H),7.44(t,J=7.9Hz,1H),7.38(s,1H),7.29(ddd,J=8 .1,6.9,1.2Hz,1H),4.13(t,J=6.9Hz,2H),3.69(s,3H),1.85(h,J=7.2Hz,2H),0.91(t,J=7.4Hz,3H). 13C NMR(150MHz,DMSO-d6)δ167.83,163.07,153.79,139.29,136.80,135.03,134.97,134.82,128.41,127.85,126.79, 126.22,125.36,122.54,122.12,121.81,121.72,121.30,119.50,116.86,115.19(2C),53.27,28.85,23.12,10.82.

[0123] Example 3: N-(3-hydroxyphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 3)

[0124] M8-2 (200 mg, 0.57 mmol), 3-aminophenol (62 mg, 0.57 mmol), EDCI (131 mg, 0.68 mmol) and HOBt (93 mg, 0.68 mmol) were added to DMF and reacted at room temperature for 2 hours. Water was added to the reaction solution to precipitate the product, which was filtered under reduced pressure and the filter cake was collected and purified by column chromatography to obtain compound 3 as a white solid, 181 mg, with a yield of 71.8%. Detection data: ESI-MS [MH] - (m / z):440.3. 1 H NMR (600MHz, DMSO-d6) δ10.22(s,1H),9.42(s,1H),8.80(dd,J=8.1,1.5Hz,1H),8.15(s,1H ),8.06(s,1H),7.75(s,1H),7.57(dd,J=8.6,1.2Hz,1H),7.52(ddd,J=8.5,7.0,1.6Hz,1H), 7.44-7.39(m,1H),7.28(ddd,J=8.1,7.0,1.2Hz,1H),7.18-7.09(m,2H),6.51(dt,J=6.4,2 .5Hz,1H),4.13(t,J=6.9Hz,2H),3.68(s,3H),1.85(h,J=7.2Hz,2H),0.91(t,J=7.4Hz,3H). 13C NMR (150MHz, DMSO-d6) δ163.08,157.62,153.92,140.39,136.90,135.13,134.52,129.33,127.90,126.86,126.1 1,125.34,121.79,121.73,121.43,116.99,115.67,115.31,110.70,110.66,107.06,53.38,28.95,23.23,10.93.

[0125] Example 4: N-(3-cyanophenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 4)

[0126] According to the method of step G in Example 1, intermediate M8-2 and 3-aminobenzonitrile were used as raw materials to prepare compound 4 with a yield of 75.2%. Detection data: ESI-MS [M+Na] + (m / z):473.2. 1 HNMR (600MHz, DMSO-d6) δ10.50(s,1H),8.87(dd,J=8.1,1.5Hz,1H),8.36(t,J=1.9Hz,1H),8. 19-8.14(m,2H),8.08(ddd,J=8.1,2.2,1.0Hz,1H),7.76(d,J=0.8Hz,1H),7.73(dt,J=7.6,1. 4Hz,1H),7.58(dd,J=8.6,1.3Hz,1H),7.56-7.49(m,2H),7.30(ddd,J=8.1,6.9,1.3Hz,1H),4 .14(t,J=6.9Hz,2H),3.69(s,3H),2.60(s,3H),1.85(h,J=7.2Hz,2H),0.91(t,J=7.4Hz,3H). 13 C NMR (150MHz, DMSO-d6) δ197.74,163.32,153.88,139.76,137.33,136.91,135.15,135.02,129.16,127.98,126.91,126.2 9,125.46,124.41,123.61,121.97,121.84,121.37,119.07,116.93,115.30,115.20,53.37,28.95,26.80,23.22,10.93.

[0127] Example 5: N-(3-thiocarbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 5)

[0128] Compound 4 (100 mg, 0.22 mmol) was dissolved in DMF and (NH2)2S (14 mg, 0.22 mmol) was added and reacted at 45°C for 3 hours. Water was added to the reaction solution to precipitate the product, which was filtered under reduced pressure and the filter cake was collected and dried to obtain compound 5 as a white solid, 92 mg, with a yield of 85.5%. Detection data: ESI-MS [M+H] + (m / z):485.1. 1 H NMR (600MHz, DMSO-d6) δ10.47(s,1H),9.90(s,1H),9.53(s,1H),8.88(dd,J=8.1,1.6H z,1H),8.32(t,J=2.0Hz,1H),8.15(d,J=16.5Hz,2H),7.95(dd,J=8.0,2.2Hz,1H),7.76 (s,1H),7.58(d,J=8.5Hz,1H),7.55-7.48(m,2H),7.41(t,J=7.9Hz,1H),7.34-7.24(m ,1H),4.13(t,J=6.9Hz,2H),3.68(s,3H),1.85(h,J=7.2Hz,2H),0.91(t,J=7.4Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ200.90,163.70,154.36,141.07,139.45,137.37,135.61,135.43,128.71,128.43,127.36,12 6.77,125.92,122.95,122.38,122.29,121.86,121.63,120.58,117.43,115.76,115.71,53.84,29.42,23.69,11.40.

[0129] Example 6: N-[3-(1,2,4-oxadiazol-3-yl)phenyl]-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 6)

[0130] According to the method of step G in Example 1, intermediate M8-2 and 3-(1,2,4-oxadiazole-3-yl)-aniline were used as raw materials to prepare compound 6 with a yield of 70.5%. Detection data: ESI-MS [M+H] + (m / z):494.3. 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.74(s,1H),8.89(dd,J=8.2,1.5Hz,1H),8.61(t, J=1.9Hz,1H),8.18(d,J=5.5Hz,2H),8.06-7.99(m,1H),7.80(dt,J=7.8,1.3Hz,1H),7.77 (s,1H),7.61-7.56(m,2H),7.53(ddd,J=8.5,6.8,1.5Hz,1H),7.31(ddd,J=8.2,6.8,1.4 Hz,1H),4.14(t,J=6.9Hz,2H),3.69(s,3H),1.86(h,J=7.2Hz,2H),0.91(t,J=7.4Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ167.96,167.34,163.83,154.37,140.69,137.40,135.61,135.55,130.27,128.45,127.37,126.8 2,126.76,125.96,123.21,122.58,122.46,122.31,121.86,118.78,117.41,115.75,115.66,53.85,29.43,23.68,11.39.

[0131] Example 7: 3-(1-isopropyl-1H-pyrazol-4-yl)-5-methyl-4-oxo-N-(3-aminomethanesulfonylphenyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 7)

[0132] According to the method of step A in Example 1, 4-iodopyrazole and 2-bromopropane were used as raw materials to prepare 4-iodo-1-isopropyl-1H-pyrazole (M 2a -3), yield 68.4%;

[0133] According to the method of steps EF in Example 1, 5-methyl-3-(1-isopropyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-3) was prepared using intermediate M1a-3 and intermediate M6-1 as raw materials. The yield was 64.2%; ESI-MS [MH]- (m / z):349.1.

[0134] According to the method of step G in Example 1, intermediate M8-3 and 3-aminobenzenesulfonamide were used as raw materials to prepare compound 7 with a yield of 65.6%. Detection data: ESI-MS [M+H] + (m / z):505.2. 1 H NMR (600MHz, DMSO-d6) δ10.57(s,1H),8.89(d,J=8.0Hz,1H),8.42(s,1H),8.20(d,J=14.6Hz,2H),7.92(q,J=5.3,4.0Hz,1H), 7.76(s,1H),7.63-7.50(m,4H),7.42(s,2H),7.30(t,J=7.5Hz,1H),4.57(p,J=6.6Hz,1H),3.69(s,3H),1.49(d,J=6.7Hz,6H). 13 C NMR (150MHz, DMSO-d6) δ163.80,154.34,145.12,140.20,137.39,135.68,135.24,129.89,128.49,126.75,125. 97,125.09,123.22,122.42,122.31,121.78,121.05,117.39,117.30,115.80,115.46,53.99,29.45,23.11(2C).

[0135] Example 8: 6-{5-ethyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}picolinic acid (Compound 8)

[0136] According to the method of step BD in Example 1, indole-2,3-dione and iodoethane were used as raw materials to prepare 5-ethyl-4-oxo-4,5-dihydro-3H-pyrrole[2,3-c]quinoline-1-carboxylic acid ethyl ester (M6-2) with a yield of 35.8%;

[0137] According to the method of steps EF in Example 1, intermediate M 2a -2 and intermediate M6-2 were used as raw materials to prepare 5-ethyl-3-(1-propyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-4) with a yield of 65.4%; detection data: ESI-MS [MH] - (m / z):363.2.

[0138] According to the method of steps GH in Example 1, intermediate M8-4 and 6-amino-2-pyridinecarboxylic acid were used as raw materials to prepare compound 8 with a yield of 59.4%; detection data: ESI-MS [MH] - (m / z): 483.2; 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),11.03(s,1H),8.93(dd,J=8.1,1.5Hz,1H),8.46(d,J=8.3 Hz,1H),8.24(s,1H),8.16(s,1H),8.04(t,J=7.9Hz,1H),7.82(d,J=7.4Hz,1H),7.77(s,1H),7. 62(d,J=8.7Hz,1H),7.53(ddd,J=8.5,6.9,1.6Hz,1H),7.27(t,J=7.6Hz,1H),4.37(q,J=7.0Hz, 2H), 4.14 (t, J = 6.9Hz, 2H), 1.86 (h, J = 7.2Hz, 2H), 1.24 (t, J = 7.0Hz, 3H), 0.91 (t, J = 7.4Hz, 3H). 13 C NMR(100MHz,DMSO-d6)δ166.38,164.47,153.97,152.67,147.51,139.79,136.77,136.12,135.51,128.56,127.29,1 27.19,126.29,122.29,122.07,121.91,120.95,118.54,117.69,115.52,114.50,53.83,36.71,23.68,13.34,11.41.

[0139] Example 9: 3-{3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid (Compound 9)

[0140] According to the method of step A in Example 1, 4-iodopyrazole and bromomethylcyclopropane were used as raw materials to prepare 4-iodo-1-cyclopropylmethyl-1H-pyrazole (M 2a -4), yield 71.2%;

[0141] According to the method of steps EF in Example 1, intermediate M 2a-4 and intermediate M6-1 were used as raw materials to prepare 5-methyl-3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-5) with a yield of 57.6%; ESI-MS [MH] - (m / z):361.1.

[0142] According to the method of steps GH in Example 1, intermediate M8-5 and ethyl 3-aminobenzoate were used as raw materials to prepare compound 9 with a yield of 63.5%. Detection data: HRMS (ESI): m / z calcd.for C 27 H 22 N5O4[MH] - 480.1677, found 480.1666. 1 H NMR (400MHz, DMSO-d6) δ12.9 (s, 1H), 10.66 (s, 1H), 8.92 (dd, J = 8.1, 1.4Hz, 1H), 8.50 (t ,J=1.9Hz,1H),8.25(d,J=7.8Hz,2H),8.12-8.04(m,1H),7.79(s,1H),7.69(dt,J=7.7, 1.3Hz,1H),7.63-7.44(m,3H),7.30(td,J=7.5,6.9,1.3Hz,1H),4.05(d,J=7.1Hz,2H), 3.69(s,3H),1.30(ddt,J=12.3,7.7,4.7Hz,1H),0.66-0.53(m,2H),0.49-0.35(m,2H). 13 C NMR(100MHz,DMSO-d6)δ167.72,163.76,154.37,140.18,137.36,135.78,135.58,131.73,129.36,128.43,126.84( 2C),126.02,124.72,124.56,122.30(2C),122.07,121.16,117.45,115.75,115.56,56.62,29.45,11.93,4.09(2C).

[0143] Example 10: 3-{5-isopropyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid (Compound 10)

[0144] According to the method of step BD in Example 1, indole-2,3-dione and 2-iodopropane were used as raw materials to prepare 5-isopropyl-4-oxo-4,5-dihydro-3H-pyrrole[2,3-c]quinoline-1-carboxylic acid ethyl ester (M6-3) with a yield of 38.6%;

[0145] According to the method of steps EF in Example 1, intermediate M 2a -2 and intermediate M6-3 were used as raw materials to prepare 5-isopropyl-3-(1-propyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-6) with a yield of 65.4%; detection data: ESI-MS [MH] - (m / z):377.1.

[0146] According to the method of steps GH in Example 1, intermediate M8-6 and ethyl 3-aminobenzoate were used as raw materials to prepare compound 10 with a yield of 67.5%. Detection data: ESI-MS [M+H] - (m / z):496.3. 1 H NMR(600MHz,DMSO-d6)δ12.97(s,1H),10.50(s,1H),8.83(dd,J=8.1,1.6Hz,1H),8.45( t,J=2.0Hz,1H),8.15(d,J=18.3Hz,2H),8.07-8.01(m,1H),7.80-7.71(m,2H),7.69(dt, J=7.7,1.4Hz,1H),7.54-7.44(m,2H),7.25(ddd,J=8.0,7.0,1.0Hz,1H),5.48(s,1H),4. 14(t,J=6.9Hz,2H), 1.85(h,J=7.2Hz,2H), 1.58(d,J=7.0Hz,6H), 0.91(t,J=7.4Hz,3H). 13 CNMR(150MHz,DMSO-d6)δ167.27,163.33,154.47,139.65,135.23(2C),135.13,131.28,128.97,127.45,126.87,126.61 ,125.37,124.28,124.00,122.35,121.54,121.51,120.64,117.70,114.90(2C),53.37,48.61,23.24,19.80(2C),10.94.

[0147] Example 11: 3-{3-(4-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid (Compound 11)

[0148] Step I Synthesis of ethyl 3-(4-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylate (M9-1)

[0149] 4-Methoxybenzyl bromide (893 mg, 4.44 mmol) and potassium carbonate (1.02 g, 7.40 mmol) were added to a DMF solution of intermediate M6-1 (1.00 g, 3.70 mmol) and reacted at 40°C for 3 h. After the raw material was exhausted as monitored by TLC, water (100 mL) was added to the reaction solution, and ethyl acetate was extracted (100 mL×3). The organic phases were combined, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain a crude intermediate M9-1, which was directly used in the next step without purification.

[0150] Step J 3-(4-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M 10 -1) Synthesis

[0151] The crude intermediate M9-1 obtained in the previous step was added to a mixed solution of 10 mL NaOH (1 mol / L) in H2O (5 mL) and 1,4-dioxane (5 mL) and reacted at room temperature for 0.5 h. After the raw material was exhausted as monitored by TLC, 1,4-dioxane was removed by vacuum distillation, and the pH of the reaction solution was adjusted to 4-5 with dilute hydrochloric acid to precipitate the product, which was then filtered under reduced pressure and the filter cake was collected to obtain the intermediate M 10 -1, white powder, 0.99 g, two-step total yield 69.4%. Detection data: ESI-MS [MH] - (m / z):361.2.

[0152] According to the method of steps GH in Example 1, intermediate M10-1 and ethyl 3-aminobenzoate were used as raw materials to prepare compound 11 with a yield of 65.8%. Detection data: ESI-MS [M+H] - (m / z):480.2. 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.95(dd,J=8.1,1.5Hz,1H),8.44(s,1H),8 .35(t,J=1.8Hz,1H),7.92(ddd,J=8.0,2.3,1.2Hz,1H),7.66(dt,J=7.6,1.4Hz,1 H),7.54(dd,J=8.7,1.3Hz,1H),7.48(ddd,J=8.5,6.9,1.6Hz,1H),7.39-7.32(m, 2H),7.31-7.21(m,2H),6.91-6.78(m,2H),5.82(s,2H),3.71(s,3H),3.69(s,3H). 13 C NMR(100MHz,DMSO-d6)δ170.70,163.75,159.15,155.32,139.18,137.16,134.51,130.97,129.58(2C),127.99,127.72,1 26.94,125.76,124.81,122.24(2C),121.90,121.53,121.20,117.97,115.69,115.30,114.34(2C),55.51,51.11,29.36.

[0153] Example 12: 3-{3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid (Compound 12)

[0154] According to the method of step IJ in Example 11, 3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5-hydrogen-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M6-1) was prepared using intermediate M6-1 and 4-fluorobenzyl bromide as raw materials. 10 -2), yield 73.5%; detection data: ESI-MS [MH] - (m / z):349.4.

[0155] According to the method of step GH in Example 1, intermediate M 10 -2 and 3-aminobenzoic acid ethyl ester were used as raw materials to prepare compound 12 with a yield of 66.7%. Detection data: ESI-MS [M+H] - (m / z):468.3. 1H NMR (600MHz, DMSO-d6) δ12.61(s,1H),10.49(s,1H),8.82(d,J=8.1Hz,1H),8.42(s,1H),8.25(s,1H),8.03(d,J=8.1H z,1H),7.69(d,J=7.7Hz,1H),7.62-7.46(m,3H),7.46-7.25(m,3H),7.18(t,J=8.6Hz,2H),5.87(s,2H),3.72(s,3H). 13 C NMR(150MHz,DMSO-d6)δ171.40,166.64,162.87,161.74,160.13,154.14,139.00,136.12,133.95,133.40,130.69,128.99,128 .94,128.31,127.11,125.52,124.64,123.59,123.39,121.28,120.57,120.07,116.62,114.77,114.63,113.99,47.96,28.28.

[0156] Example 13: 3-{5-methyl-3-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid (Compound 13)

[0157] According to the method of step EF in Example 1, 5-methyl-3-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-7) was prepared using intermediate M6-1 and 4-nitroiodide as raw materials. The yield was 58.9%; detection data: ESI-MS [MH] - (m / z):362.2.

[0158] According to the method of steps GH in Example 1, intermediate M8-7 and ethyl 3-aminobenzoate were used as raw materials to prepare compound 13 with a yield of 67.3%; detection data: ESI-MS [MH] - (m / z):481.3. 1 H NMR(600MHz,DMSO-d6)δ10.53(s,1H),8.91(dd,J=8.0,1.6Hz,1H),8.42-8.32(m,4H),7.95(s,1 H),7.88-7.82(m,2H),7.71-7.55(m,3H),7.40(t,J=7.7Hz,1H),7.37-7.31(m,1H),3.70(s,3H). 13C NMR(150MHz,DMSO-d6)δ162.93,153.79,146.41,144.00,137.03,134.54,129.66,128.37,128.21, 127.63(2C),127.61,126.74,126.46,123.65(2C),122.07,121.62,116.86,116.68,115.46,29.12.

[0159] Example 14: 4-{3-{5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoic acid (Compound 14)

[0160] Step K Synthesis of ethyl 4-{3-{5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoate (I3-1)

[0161] Triethylamine (173 mg, 1.71 mmol) and diphenylphosphoryl azide (236 mg, 0.86 mmol) were added to a dry toluene solution of M8-2 (200 mg, 0.57 mmol), and the mixture was reacted at 50°C for 0.5 h. Ethyl 4-aminobenzoate (141 mg, 0.86 mmol) was added, and the mixture was heated to 80°C for 2 h. The solvent was removed by distillation under reduced pressure, water was added to make a slurry, and the filter cake was collected by filtration to obtain compound I3-1, a light brown powder, 124 mg, with a yield of 42.4%. Detection data: ESI-MS [M+H] + (m / z):513.2.

[0162] Step L Synthesis of Compound 14

[0163] Compound I3-1 (124 mg, 0.26 mmol) was dissolved in a mixed solution of NaOH (1 mol / L) in H2O (2 mL), THF (2 mL) and MeOH (1 mL) and reacted at room temperature for 8 h. After the raw materials were exhausted by TLC monitoring, MeOH and THF were removed by vacuum distillation, and the pH of the reaction solution was adjusted to 4-5 with dilute hydrochloric acid to precipitate the product. The product was filtered under reduced pressure and the filter cake was collected to obtain compound 14, a white powder, 65 mg, and a yield of 55.5%. Detection data: ESI-MS [MH] - (m / z):483.2. 1H NMR (400MHz, DMSO-d6) δ10.31 (s, 1H), 8.93 (s, 1H), 8.44 (dd, J = 8.0, 1.4Hz, 1H), 8.12(s,1H),7.89-7.84(m,2H),7.70(s,1H),7.66-7.60(m,3H),7.55(dd,J=8.7, 1.2Hz,1H),7.49(ddd,J=8.5,7.0,1.4Hz,1H),7.30(td,J=7.5,7.0,1.2Hz,1H), 4.11(t,J=7.0Hz,2H),3.66(s,3H),1.85(h,J=7.3Hz,2H),0.90(t,J=7.3Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ167.56,154.36,154.24,145.02,136.90,135.39,131.00(2C),127.83,127.57,126.87,12 4.27,123.77,122.42,122.32,121.17,119.20,117.64,117.57,117.36(2C),115.67,53.78,29.32,23.66,11.41.

[0164] Example 15: 1-(3-acetylphenyl)-3-{5-ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl}urea (Compound 15)

[0165] According to the method of step A in Example 1, 4-iodopyrazole and iodoethane were used as raw materials to prepare 4-iodo-1-ethyl-1H-pyrazole (M 2a -5), yield 64.8%;

[0166] According to the method of steps EF in Example 1, intermediate M 2a -5 and intermediate M6-2 were used as raw materials to prepare 5-ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-8) with a yield of 62.9%; detection data: ESI-MS [MH] - (m / z):349.3.

[0167] According to the method of step K in Example 14, intermediate M8-8 and 3-aminoacetophenone were used as raw materials to prepare compound 15 with a yield of 54.2%. Detection data: ESI-MS [M+H] + (m / z):483.2.1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.40-8.23 (m, 2H), 8.12 (d, J = 14.2Hz, 2H), 7.81-7.67 (m, 2H), 7.67-7.54 (m, 3H), 7.46 (dt, J = 26.5 ,7.7Hz,2H),7.31(t,J=7.5Hz,1H),4.36(q,J=7.0Hz,2H),4.19(q,J=7.3Hz,2H),2.55(s,3H),1.44(t,J=7.3Hz,3H),1.27-1.20(m,3H).

[0168] Example 16: 3-{3-{3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-5-ethyl-4-oxo-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoic acid (Compound 16)

[0169] According to the method of steps EF in Example 1, intermediate M 2a -4 and intermediate M6-2 were used as raw materials to prepare 5-ethyl-3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-9) with a yield of 63.4%; detection data: ESI-MS [MH] - (m / z):375.4.

[0170] According to the method of step KL in Example 14, intermediate M8-9 and ethyl 3-aminobenzoate were used as raw materials to prepare compound 16 with a yield of 40.1%. Detection data: ESI-MS [M+H] - (m / z):509.2.

[0171] Example 17: 4-{3-{3-(4-ethoxyphenyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl}ureido}benzoic acid (Compound 17)

[0172] According to the method of step EF in Example 1, 5-methyl-3-(4-ethoxyphenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-10) was prepared using intermediate M6-1 and 4-iodophenethyl ether as raw materials with a yield of 56.4%. Detection data: ESI-MS [MH] - (m / z):361.2.

[0173] According to the method of step KL in Example 14, intermediate M8-10 and ethyl 4-aminobenzoate were used as raw materials to prepare compound 17 with a yield of 44.0%. Detection data: ESI-MS [M+H] - (m / z):495.2. 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),9.37(s,1H),8.41(s,1H),8.28(d,J=7.9Hz,1H),7.87(d,J=8.4Hz,2H),7.69-7.59(m,3H), 7.59-7.45(m,2H),7.34(dd,J=11.3,7.8Hz,3H),7.00(d,J=8.7Hz,2H),4.10(q,J=6.9Hz,2H),3.64(s,3H),1.38(t,J=7.0Hz,3H).

[0174] Example 18: 5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-3,5-dichlorobenzyl ester (Compound 18)

[0175] According to the method of step K in Example 14, intermediate M8-2 and 3,5-dichlorobenzyl alcohol were used as raw materials to prepare compound 18 with a yield of 71.1%. Detection data: ESI-MS [M+H] + (m / z):524.1.

[0176] Example 19: 5-Methyl-3-(1-isopropyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-3-acetylphenyl ester (Compound 19)

[0177] According to the method of step K in Example 14, intermediate M8-3 and methyl 3-hydroxybenzoate were used as raw materials to prepare compound 19 with a yield of 66.2%. Detection data: ESI-MS [M+H] + (m / z):500.2.

[0178] Example 20: 5-ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-2-methoxyphenyl ester (Compound 20)

[0179] According to the method of step K in Example 14, intermediate M8-8 and 2-methoxyphenol were used as raw materials to prepare compound 20 with a yield of 52.2%. ESI-MS [M+H] +(m / z):472.1.

[0180] The compounds prepared in the above examples were tested for in vitro and in vivo pharmacological activity:

[0181] 1. Study on inhibition of Autotaxin (ATX) enzyme activity

[0182] 1. Preparation of enzyme activity assay buffer: Add 1.51 g Tris, 238 mg MgCl2, 277 mg CaCl2 and 25 mg Triton X-100 to 230 mL double distilled water, stir thoroughly to dissolve the solids completely, adjust the pH to 7.4 with dilute hydrochloric acid, make up to volume with a 250 mL volumetric flask, and store at 4°C.

[0183] 2. Preparation of compound stock solutions: All compounds and positive drugs (PAT-409) were dissolved in DMSO to prepare 4 mM stock solutions and stored at -20°C.

[0184] 3. Enzyme Activity Inhibition Test

[0185] The test compound and the positive drug (PAT-409) stock solution obtained above were diluted into 8 gradient concentrations, and 10 μL was added to each well of the 96-well plate. Then, 20 μL of ATX (1 μg / mL) solution was added to each well and incubated at room temperature for 30 minutes. Then, 20 μL (1 μM) FS-3 solution was added to each well and incubated at 37°C for 1 hour. Then, the 96-well plate was placed on an ELISA reader to read the fluorescence value (λ ex / λ em =487 / 520nm); the experimental results were input into GraphPad Prism software, and the IC of each compound was obtained by fitting calculation. 50 The results are shown in Table 1.

[0186] Table 1 Results of the test compounds' inhibitory activity against ATX enzyme and anti-MCF-7 cell proliferation activity

[0187]

[0188] Note: A<10,10 <B<100,100≤C≤1000

[0189] The experimental results show that the compounds of the present invention have good inhibitory activity against ATX enzyme (IC 50 Values ​​less than 1000 nM are considered to have strong activity), IC 50 The values ​​were all less than 1000nM, and the IC 50 The values ​​were less than 10 nM, especially compound 7 (IC 50 =4.5nM), 8(IC 50=0.97nM), 9(IC 50 =2.4 nM), 11 (IC 50 =3.1 nM) and other inhibitory activities against ATX enzyme were better than the positive control PAT-409 (IC 50 =4.9nM).

[0190] 2. In vitro anti-tumor cell proliferation activity study

[0191] The example compounds of the present invention were screened for their in vitro anti-proliferation activity against MCF-7 breast cancer cells.

[0192] 1. Inoculate MCF-7 cells in the logarithmic growth phase into a 96-well plate and control the cell density to 10 4 Place the cells in an incubator overnight to allow them to adhere to the wall.

[0193] 2. The next day, the old culture medium was discarded, and 200 μL of culture medium (90% DMEM-H + 10% FBS) containing test samples (compounds prepared in the above examples) of different concentrations (30 μM, 10 μM, 1 μM, 333 nM, 111 nM, 37 nM, 12 nM, 4 nM) was added to each well. A blank control group (0.1% DMSO) and a positive drug group (PAT-409) were set up at the same time. Each group was set up with 3 replicate wells in parallel, and cultured in a conventional incubator for 72 h.

[0194] 3. After the cells were treated with drugs for 72 hours, MTT solution (5 mg / mL, 20 μL / well) was added to the 96-well plate, incubated in the incubator for 4 hours, the supernatant was discarded, and DMSO (150 μL / well) was added to dissolve the formazan crystals.

[0195] 4. Use an enzyme-labeled instrument to read the absorbance value of each well at a wavelength of 492 nm. Input the experimental results into GraphPadPrism software and obtain the IC value of each compound through fitting calculation. 50 The results are shown in Table 1.

[0196] As shown in Table 1, most of the compounds of the present invention showed moderate antiproliferative activity against breast cancer MCF-7 cells. Among them, compounds 1, 6, 7, 8, 9, 11, 12, 15 and 16 had the same IC values ​​of antiproliferative activity against MCF-7 cells in vitro as the positive control PAT-409. 50 The value was maintained between 10 nM and 100 nM.

[0197] 3. In vivo anti-pulmonary fibrosis experiment

[0198] 1. Modeling

[0199] C57BL / 6J mice were raised and adapted to the environment for one week under standard SPF laboratory conditions. The mice were weighed and randomly divided into 4 groups: Ctrl (control group), BLM (model group), positive drug group (BLM+PAT-409), and test group (BLM+8), with 8 mice in each group. All mice were fasted and had free access to water the night before modeling.

[0200] C57BL / 6J mice were anesthetized by intraperitoneal injection of 4% chloral hydrate (10mL / kg). After the righting reflex disappeared, the upper incisors of the mice were hung on a rubber band. The tongue and jaw of the mice were clamped with tweezers, the mouth was gently opened, and the bleomycin solution (4U / kg) was dripped into the mouse trachea with a pipette. After the dripping was completed, asthma-like breathing sounds could be heard in the mice. The mice were continued to be suspended on the rubber band for 10 to 15 minutes, and finally the mice were returned to the cage and waited for them to wake up.

[0201] 2. Drug administration

[0202] Preparation of drug solution: First, add the drug (compound prepared in the above example) or control drug to 1% DMSO and 50% PEG 400, respectively, and ultrasonicate for 5 minutes, then add 5% Tween 80 and 44% saline, and ultrasonicate for 5 minutes. The drug-containing preparation is finally clear and transparent.

[0203] Dosage: The test group (Compound 8) was intragastrically administered with 60 mg / kg, the positive drug group (PAT-409) was intragastrically administered with 60 mg / kg, and the control group and the model group were intragastrically administered with a blank preparation.

[0204] Administration time: The drug was administered for 21 consecutive days starting from the first day of modeling. The drug was administered once a day, and the weight, hair gloss and autonomous activity of the mice were recorded.

[0205] 3. Masson staining of lung tissue

[0206] After continuous administration for 21 days, the mice were killed, and the lung tissues of the mice in each experimental group were taken for Masson staining to compare and observe their pathological changes.

[0207] The experimental results are as follows Figure 1 As shown in the results, in the BLM-induced pulmonary fibrosis model, the alveolar wall was significantly thickened and collagen tissue was seriously deposited. After treatment with compound 8, the collagen tissue was significantly reduced compared with the BLM group, and the alveolar wall also tended to normal thickness. The experimental results show that compound 8 can resist the bleomycin-induced changes in lung tissue morphology and inhibit the formation of lung collagen tissue, thereby playing an anti-fibrotic role.

Claims

1. A 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative, characterized in that: The derivatives are compounds represented by the general formula (I) and their pharmaceutically acceptable salts: in, L is selected from wherein y is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3; R 1 Selected from hydrogen, (C1-C5) alkyl; R 2 Selected from 6-10 membered aromatic rings or 5-10 membered heteroaromatic rings containing 1-3 N atoms, wherein the aromatic rings and heteroaromatic rings may be optionally substituted by 1-3 identical or different following groups: halogen, nitro, (C1-C6) alkyl, (C3-C6) cycloalkylmethyl, (C1-C6) alkoxy; Ring A is a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1-3 N atoms; R 3 is selected from halogen, cyano, hydroxyl, thiol, carboxyl, phosphate, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C4) alkoxycarbonyl, (C1-C6) alkoxy, (C1-C6) acyl, amino substituted with 0-2 (C1-C6) alkyl, 5-6 membered heteroaryl or aliphatic heterocycle containing 1-3 atoms selected from N, O or S; x is an integer selected from 1 to 4, and when x is greater than 1, R 3 Can be the same or different.

2. The 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 1, characterized in that: The derivatives are compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof; wherein, L is selected from wherein y is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3; R 1 Selected from hydrogen, (C1-C5) alkyl; R 2 Selected from benzene ring, naphthalene ring, pyrrole ring, pyrazole ring, imidazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, pyridine ring, pyrimidine ring, indole ring which are unsubstituted or optionally substituted by 1-3 identical or different following groups, wherein the following groups are halogen, nitro, (C1-C6) alkyl, (C3-C6) cycloalkylmethyl, (C1-C6) alkoxy; Ring A is a benzene ring, a naphthalene ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, an indole ring or a quinoline ring; R 3 is selected from halogen, cyano, hydroxyl, thiol, carboxyl, phosphate, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C4) alkoxycarbonyl, (C1-C6) alkoxy, (C1-C6) acyl, amino substituted with 0-2 (C1-C6) alkyl, 5-6 membered heteroaryl or aliphatic heterocycle containing 1-3 heteroatoms selected from N, O or S; x is selected from 1, 2, 3 or 4, and when x is greater than 1, R 3 Can be the same or different.

3. The 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 2, characterized in that: The derivatives are compounds represented by general formula (I) and pharmaceutically acceptable salts thereof; L is selected from n is selected from 0 or 1; R 1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl; R 2 Selected from benzene ring, pyrrole ring, pyrazole ring, imidazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring which are unsubstituted or optionally substituted by 1-2 identical or different following groups, wherein the following groups are halogen, nitro, (C1-C4) alkyl, (C3-C6) cycloalkylmethyl, (C1-C3) alkoxy; Ring A is a benzene ring, a pyrrole ring, a pyridine ring, or a pyrimidine ring; R 3 is selected from halogen, cyano, hydroxy, carboxyl, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C3) alkoxycarbonyl, (C1-C3) alkoxy, (C1-C3) acyl, a 5-6 membered heteroaryl or aliphatic heterocycle containing 1-3 atoms selected from N, O or S; When x is selected from 1 or 2 and x is greater than 1, R 3 Can be the same or different.

4. The 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 3, characterized in that: The derivatives are compounds represented by general formula (I) and pharmaceutically acceptable salts thereof; L is selected from n is selected from 0 or 1; R 1 Selected from methyl, ethyl, isopropyl; R 2 A benzene ring or a pyrazole ring substituted by 1-2 identical or different groups, wherein the following groups are halogen, nitro, (C1-C4) alkyl, (C3-C6) cycloalkylmethyl, (C1-C3) alkoxy; Ring A is a benzene ring or a pyridine ring; R 3 is selected from halogen, cyano, hydroxy, carboxyl, sulfamoyl, carbamoyl, thiocarbamoyl, (C1-C3) alkoxycarbonyl, (C1-C3) alkoxy, (C1-C3) acyl, 1,2,4-oxadiazol-3-yl; When x is selected from 1 or 2 and x is greater than 1, R 3 Can be the same or different.

5. The 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 4, characterized in that: The derivatives are compounds represented by general formula (I) and pharmaceutically acceptable salts thereof; L is selected from n is selected from 0 or 1; R 1 Selected from methyl, ethyl, isopropyl; R 2 A benzene ring or a pyrazole ring substituted by the following groups: halogen, nitro, methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, methoxy, ethoxy; Ring A is a benzene ring or a pyridine ring; R 3 is selected from halogen, cyano, hydroxy, carboxyl, sulfamoyl, carbamoyl, thiocarbamoyl, methoxycarbonyl, methoxy, acetyl, 1,2,4-oxadiazol-3-yl; When x is selected from 1 or 2 and x is greater than 1, R 3 Can be the same or different.

6. The 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 4, characterized in that: The derivatives are specifically the following compounds and pharmaceutically acceptable salts thereof, 3-{5-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid; N-(3-Carbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide; N-(3-Hydroxyphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide; N-(3-cyanophenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide; N-(3-thiocarbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide; N-[3-(1,2,4-oxadiazol-3-yl)phenyl]-5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide; 3-(1-isopropyl-1H-pyrazol-4-yl)-5-methyl-4-oxo-N-(3-aminomethanesulfonylphenyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide; 6-{5-ethyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}picolinic acid; 3-{3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid; 3-{5-isopropyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid; 3-{3-(4-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid; 3-{3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid; 3-{5-methyl-3-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide}benzoic acid; 4-{3-{5-methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoic acid; 1-(3-acetylphenyl)-3-{5-ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl}urea; 3-{3-{3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-5-ethyl-4-oxo-4,5-dihydro-3H-pyrazolo[2,3-c]quinolin-1-yl}ureido}benzoic acid; 4-{3-{3-(4-ethoxyphenyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl}ureido}benzoic acid; 5-Methyl-4-oxo-3-(1-propyl-1H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-3,5-dichlorobenzyl ester; 5-Methyl-3-(1-isopropyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-3-acetylphenyl ester 5-Ethyl-3-(1-ethyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-1-yl-carbamic acid-2-methoxyphenyl ester.

7. A pharmaceutical composition, characterized in that: Contains the compound represented by the general formula (I) as claimed in claim 1 and its pharmaceutically acceptable salt.

8. A use of the 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 1, characterized in that: Use of the compound represented by general formula (I) and the pharmaceutically acceptable salt or the pharmaceutical composition according to claim 7 in the preparation of ATX inhibitors.

9. The use of the 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 7, characterized in that: Use of the compound represented by general formula (I) and its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 7 in the preparation of anti-tumor or anti-fibrosis drugs.

10. The use of the 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative according to claim 8, characterized in that: The tumor is pancreatic cancer, breast cancer or glioma, and the fibrosis is pulmonary fibrosis, liver fibrosis, myocardial fibrosis or renal fibrosis.

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