4,5-dihydro-3h-pyrrolo[2,3-c]quinolin-4-one derivatives and uses thereof

Abstract

The application belongs to the technical field of medicine, and relates to a 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative and application thereof in ATX enzyme inhibition and in preparation of a drug for treating and / or preventing a disease caused by an abnormal ATX-LPA function axis, in particular, in preparation of a drug for treating and / or preventing a fibrosis disease and cancer. The derivative is a compound as shown in a general formula (I) and a pharmaceutically acceptable salt thereof. In vitro activity screening shows that the compound has outstanding ATX enzyme inhibition activity and certain anti-tumor cell proliferation activity, and shows better anti-fibrosis activity in a bleomycin-induced pulmonary fibrosis model, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative and its application as an ATX enzyme inhibitor and its application in the preparation of a drug for treating and / or preventing diseases caused by abnormality of the ATX-LPA functional axis, in particular, in the preparation of a drug for treating and / or preventing fibrotic diseases and cancer. BACKGROUND

[0002] Autotaxin (ATX) is an enzyme with lysophospholipase D activity, and the process of hydrolyzing lysophosphatidylcholine (LPC) to generate lysophosphatidate (LPA) is the main source of LPA in the human body in pathological conditions. In particular, in fibrotic and tumor lesion tissues, ATX is highly expressed, producing high concentrations of LPA, which, by binding to its receptors (LPAR 1～6 ), activates Rho / Rock, TGF-β / Smads, MAPK, VEGF, and other signaling pathways, thereby accelerating the occurrence and development of fibrosis, inflammation, cancer, and other diseases. Therefore, inhibiting the activity of ATX and blocking the generation of LPA from the source are effective ways to treat serious diseases such as fibrosis and tumors.

[0003] With the continuous deepening of research on the ATX target, great progress has been made in the development of new inhibitors, especially in the field of fibrotic diseases and cancer. Currently, 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-imidazol[4,5-b]pyridine drug IOA-289 (CN107428752) developed by iOnctura and the long alkyl chain-containing substrate analogue 2-carba-Cpa (US2011086820) developed by Ochanomizu University are in the clinical I / II phase research stage, and are suitable for fibrosis and solid tumors, etc. In addition, BBT-877 (phase II) developed by Boehringer Ingelheim and Bridge Biotherapeutics, and FTP-198 (phase I) developed by Hytharrx are also in the clinical research stage, but the chemical structures of the two have not been disclosed.

[0004] In recent years, there are very few patent reports on ATX inhibitors, especially non-competitive allosteric inhibitors. Among them, patent WO 2024 / 180520 reports a class of 2-indolone compounds, patent WO 2024 / 201308 reports a class of 1,3-dihydro-2H-benzo[d]imidazol-2-one compounds, and the unit reports a class of N-arylindole compounds in patent CN116396205. SUMMARY

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

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is:

[0007] A 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative, the derivative is a compound as shown in general formula (I) and its pharmaceutically acceptable salt:

[0008]

[0009] Among them,

[0010] L is selected from wherein y is selected from an integer from 0 to 3;

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

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

[0013] R 2 selected from 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring containing 1-3 N atoms, said aromatic ring and heteroaromatic ring can be optionally substituted with 1-3 same or different groups of 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 3selected from the group consisting of halogen, cyano, hydroxy, thiol, carboxy, phosphono, 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;

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

[0017] Preferably, the derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts 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 is selected from the group consisting of hydrogen, (C1-C5)alkyl;

[0021] R 2 is selected from the group consisting of an unsubstituted or optionally substituted 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, and the like, and the substituents are selected from the group consisting of halogen, nitro, (C1-C6)alkyl, (C3-C6)cycloalkylmethyl, (C1-C6)alkoxy;

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

[0023] R 3 is selected from the group consisting of halogen, cyano, hydroxy, thiol, carboxy, phosphono, 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 an integer selected from 1, 2, 3 or 4, and when x is greater than 1, R 3 may be the same or different.

[0025] Further preferably, the derivatives are compounds of the general formula (I) and pharmaceutically acceptable salts thereof; wherein

[0026] L is selected from

[0027] n is selected from 0 or 1;

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

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

[0030] Ring A is phenyl ring, pyrrole ring, pyridine ring, pyrimidine ring;

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

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

[0033] Still more preferably, the derivatives are compounds according to general formula (I) and pharmaceutically acceptable salts 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 selected from phenyl ring or pyrazole ring, which are substituted with 1-2 identical or different groups selected from halogen, nitro, (C1-C4)alkyl, (C3-C6)cycloalkylmethyl, (C1-C3)alkoxy;

[0038] Ring A is phenyl ring or pyridine ring;

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

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

[0041] Still more preferably, the derivatives are compounds according to general formula (I) and pharmaceutically acceptable salts thereof;

[0042] L is selected from

[0043] n is selected from 0 or 1 ;

[0044] R 1 is selected from methyl, ethyl, isopropyl;

[0045] R 2 is selected from a phenyl ring or a pyrazole ring substituted with halogen, nitro, methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, methoxy, ethoxy;

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

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

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

[0049] Most preferably, the derivatives are the following compounds, and pharmaceutically acceptable salts thereof,

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

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

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

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

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

[0059] 3-{5-isopropyl-4-oxo-3-(l-propyl-lH-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quin- olin-l-carboxamido}benzoic acid;

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

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

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

[0063] 4-{3-{5-methyl-4-oxo-3-(l-propyl-lH-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quin- ol-l-yl}ureido}benzoic acid;

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

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

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

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

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

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

[0070] Furthermore, the 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivatives of general formula (I) according to the present application can form pharmaceutically acceptable salts with bases according to some general methods in the field of the present application. The pharmaceutically acceptable addition salts include inorganic and organic base addition salts, and the salts formed with the following bases are particularly preferred: triethylamine, sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide.

[0071] In the present application "halogen" means fluorine, chlorine, bromine or iodine; "alkyl" means straight or branched chain alkyl groups.

[0072] A pharmaceutical composition comprising the compound of general formula (I) and pharmaceutically acceptable salts thereof.

[0073] The examples and preparations provided hereinafter further illustrate and exemplify the compounds of the present application and methods for their preparation. It is to be understood that the scope of the application is not to be in any way limited by the following examples and preparations.

[0074] The following synthetic routes outline and describe the preparation of the 4,5-dihydro-3H- pyrrolo[2,3-c]quinolin-4-one derivatives of formula (I) according to the present application, all starting materials being prepared by the means described in the routes, by methods well known to those of ordinary skill in the art of organic chemistry or being commercially available. All derivatives of the present application are prepared by the means described in the routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors used in these routes are defined hereinafter.

[0075] Route 1

[0076]

[0077] The L of the general formula (I) of the present application is an amide bond, n is 0, R 3 is halogen, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, nitro, aminosulfonyl, carbamoyl, 1,2,4-oxadiazol-3-yl, methoxy, ethoxy, acetyl, etc., the corresponding target compound can be synthesized according to Route 1: first, N-alkylation and O-alkylation reactions are respectively carried out on 4-iodopyrazole or iodo-phenol to obtain the corresponding intermediate M 2a or M 2b ; then, 2,3-indole dione successively undergoes N-alkylation reaction, Wittig reaction, regioselective ring expansion reaction, coupling reaction, hydrolysis reaction, amide condensation reaction or acylation reaction to obtain the target compound I1. Among them, R 1 , R 2 , x and ring A are as defined above.

[0078] Route 2

[0079]

[0080] The L of the general formula (I) of the present application is an amide bond, n is 1, R 3 is halogen, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, nitro, aminosulfonyl, carbamoyl, 1,2,4-oxadiazol-3-yl, methoxy, ethoxy, acetyl, etc., the corresponding target compound can be synthesized according to Route 2: intermediate M6 successively undergoes N-alkylation reaction, hydrolysis reaction, amide condensation reaction or acylation reaction to obtain the target compound I2. Among them, R 1 , R 2 , x and ring A are as defined above.

[0081] Route 3

[0082]

[0083] The L of the general formula (I) of the present application is R 3 is halogen, cyano, hydroxyl, methoxycarbonyl, ethoxycarbonyl, nitro, aminosulfonyl, carbamoyl, 1,2,4-oxadiazol-3-yl, methoxy, ethoxy, acetyl, etc., the corresponding target compound can be synthesized according to Route 3: intermediate M8 or M 10 undergoes Curtius rearrangement reaction to obtain the target compounds I3 and I4. Among them, R 1 , R 2 , n, x, y and ring A are as defined above.

[0084] Route 4

[0085]

[0086] R of the general formula (I) of the present application 3 When R is a carboxyl group, the corresponding target compound can be synthesized according to Route 4: the corresponding carboxylate compound obtained by Route 1, Route 2 and Route 3 is subjected to a hydrolysis reaction under alkaline conditions to obtain the corresponding carboxyl-containing target compound I5. Among them, R 1 , R 2 , L, n and ring A are as defined above.

[0087] Use of the 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one derivative, use 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 the general formula (I) and the pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of an antitumor or antifibrosis drug.

[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 compounds of the present application have strong ATX enzyme inhibitory activity in vitro, and therefore, they can be used for the preparation of drugs for treating and / or preventing tumors and fibrosis diseases related to abnormalities in the ATX-LPA signal axis, such as tumors mainly including breast cancer, pancreatic cancer or glioma, and fibrosis diseases mainly including pulmonary fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, etc.

[0091] Preliminary in vivo experiments show that the preferred compounds in the present application have a good inhibitory effect on the pathological process of bleomycin-induced pulmonary fibrosis, showing the possibility of the compounds in this series as potential pulmonary fibrosis treatment drugs.

[0092] The active compounds of the present application or their pharmaceutically acceptable salts can be used alone as the only antitumor or antifibrosis drug, or can be used in combination with the currently marketed antitumor / antifibrosis drugs (such as paclitaxel, pirfenidone, nintedanib, etc.). The combination therapy is achieved by simultaneous, sequential or separate administration of each therapeutic component.

[0093] The present application has the following advantages:

[0094] The application provides a kind of 4, 5-dihydro-3H-pyrrolo [2, 3-c] quinolin-4-ketone compound with novel structure, which is the creative application of this skeleton structure type in the field.Compared with the currently reported ATX inhibitors, the compound has excellent drug-like parameters in physicochemical properties and the like; compared with the larger cLogP value (7.6) of PAT-409, the cLogP value of the molecule described in the application is reduced to a suitable range (1.5-4.5). In terms of biological activity, the compound has good inhibitory activity on ATX enzyme; in the pharmacodynamics experiment of mouse pulmonary fibrosis model, the compound provided by the application shows good anti-fibrosis effect. In summary, in view of the current clinical anti-fibrosis drug shortage dilemma, the molecule described in the application has good clinical application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0095] Figure 1 Improvement effect of compound 8 on bleomycin-induced mouse pulmonary fibrosis tissue (Masson staining results);

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

[0097] The examples are intended to illustrate but not limit the scope of the application. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-400 / 600, and the mass spectrum is measured by Agilent 1100 LC / MSD; the reagents used are analytical pure or chemically pure.

[0098]

[0099]

[0100]

[0101] Preparation of compound:

[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] Synthesis of 4-iodo-1-methyl-1H-pyrazole (M 2a -1)

[0104] NaH (1.86 g, 77.33 mmol) was slowly added to a solution of 4-iodopyrazole (10.00 g, 51.55 mmol) in DMF (80 mL) at 0°C. The mixture was allowed to react at 0°C for 15 min. CH3I (10.98 g, 77.33 mmol) was then added and the reaction continued at 0°C for 0.5 h. After the starting material was consumed as monitored by TLC, saturated ammonium chloride solution (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined and washed three times with 5% LiCl solution, 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 solution of indole-2,3-dione (10.00 g, 67.97 mmol) in DMF (80 mL) at 0°C. The mixture was allowed to react for 15 min at 0°C. CHI (11.58 g, 81.56 mmol) was then added and the mixture was allowed to react at room temperature for another 0.5 h. After the starting material was consumed as monitored by TLC, saturated ammonium chloride solution (200 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed three times with 5% LiCl solution. The solvent was then removed by distillation under reduced pressure to afford intermediate M4-1 as a red solid (8.97 g, 81.9% yield).

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

[0108] 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 thoroughly mixed and transferred to an 80°C oil bath. Morpholine (5.33 g, 61.22 mmol) was then added and the reaction continued for 2 min. After the starting material was consumed as monitored by TLC, the reaction solution was cooled to room temperature and recrystallized from ethanol to obtain Intermediate M5-1 as a red solid, 8.54 g, in a 66.4% yield. 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] Intermediate M5-1 (8.54 g, 36.93 mmol), p-tolylsulfonylmethyl isonitrile (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 starting material was consumed by TLC monitoring, the solvent was removed by distillation under reduced pressure, and the obtained residue was slurried with methanol to obtain intermediate M6-1 as a pink solid, 5.70 g, in a yield of 60.2%. Test data: ESI-MS [M+H] + (m / z): 271.2.

[0111] Step E 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 ethyl ester (M7-1)

[0112] After 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 sufficiently dried, they were added to dry toluene (15 mL), and then intermediate M 1a -1 (4.62 g, 22.20 mmol) and N,N'-dimethylethylenediamine (652 mg, 7.40 mmol) were added, and then the mixture was placed at 100°C and reacted under a nitrogen atmosphere for 24 h. After the starting material was consumed by TLC monitoring, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to obtain intermediate M7-1 as a pink solid, 1.87 g, in a yield of 72.1%. Test 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] Intermediate M7-1 (1.87 g, 5.34 mmol) was dissolved in a mixture of NaOH (1 mol / L) in H2O (10 mL) and 1,4-dioxane (10 mL), and reacted at room temperature for 0.5 h. After the starting material was consumed by TLC monitoring, 1,4-dioxane was removed by distillation under reduced pressure, the pH of the reaction solution was adjusted to 4 to 5 with dilute hydrochloric acid, and the product was precipitated, and the filter cake was collected by suction filtration under reduced pressure to obtain intermediate M8-1 as a white powder, 1.57 g, in a yield of 91.6%. Test data: ESI-MS [M-H] - (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] Intermediate M8-1 (200 mg, 0.62 mmol) was added to SOCl2(5 mL), a drop of DMF was added, refluxed for 1 h, SOCl2was removed by distillation under reduced pressure, the residue was redissolved in dry dichloromethane, triethylamine (188 mg, 1.86 mmol) and ethyl 3- aminobenzoate (103 mg, 0.62 mmol) were added, refluxed for 1 h, the solvent was removed by distillation under reduced pressure to give crude intermediate I1-1 which was used directly in the next step without purification.

[0117] Step H Synthesis of compound 1

[0118] The crude intermediate I1-1 from the previous step was added to a mixture of NaOH (1 mol / L) in H2O (5 mL) and 1,4-dioxane (5 mL), and the reaction was allowed to proceed at room temperature for 0.5 h. After the starting material was consumed as monitored by TLC, 1,4-dioxane was removed by distillation under reduced pressure, the pH of the reaction solution was adjusted to 3-4 with dilute hydrochloric acid, and the product was precipitated. The filter cake was collected by suction filtration under reduced pressure to give compound 1 as a white powder, 52 mg, in a total yield of 67.8% over two steps. Test data: ESI-MS [M-H] - (m / z): 440.1. 1 H NMR (600 MHz, DMSO-d6) δ 13.04 (s, 1H), 10.67 (s, 1H), 8.89 (dd, J = 8.1, 1.5 Hz, 1H), 8.50 (t, J = 1.9 Hz, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.07 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.76 (s, 1H), 7.69 (dt, J = 7.7, 1.4 Hz, 1H), 7.60 - 7.46 (m, 3H), 7.30 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H). 13 C NMR (150 MHz, DMSO-d6) δ 167.73, 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-(l -propyl- lH-pyrazol-4-yl)- 4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide (Compound 2)

[0120] Following the procedure of Example 1, Step A, using 4-iodopyrazole and 1- bromopropane as starting materials, 4-iodo-l-propyl-lH-pyrazole (M 2a -2) was prepared in 80.1% yield; analytical data: ESI-MS [M-H]

[0121] Following the procedure of Example 1, Steps E-F, using intermediate M 2a -2 and intermediate M6-1 as starting materials, 5-methyl-3-(l -propyl- lH-pyrazol-4-yl)- 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-2) was prepared in 58.7% yield; analytical data: ESI-MS [M-H] - (m / z): 349.0.

[0122] Following the procedure of Example 1, Step G, using intermediate M8-2 and 3- aminobenzamide as starting materials, Compound 2 was prepared in 73.6% yield. Analytical data: ESI-MS [M+H] + (m / z): 469.3. 1 H NMR (600 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.89 (dd, J = 8.1, 1.6 Hz, 1H), 8.29 (t, J = 2.0 Hz, 1H), 8.15 (d, J = 12.0 Hz, 2H), 7.98 (s, 1H), 7.95 - 7.91 (m, 1H), 7.76 (s, 1H), 7.61 (dt, J = 7.8, 1.4 Hz, 1H), 7.58 (dd, J = 8.6, 1.2 Hz, 1H), 7.53 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.29 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.13 (t, J = 6.9 Hz, 2H), 3.69 (s, 3H), 1.85 (h, J = 7.2 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 167.83, 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-(l-propyl-lH-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 into DMF and reacted at room temperature for 2 hours. Water was added into the reaction solution, and the product was precipitated. The filter cake was collected by suction filtration under reduced pressure, and the compound 3 was obtained by column chromatography separation and purification as a white solid, 181 mg, yield 71.8%. Test data: ESI-MS [M-H] - (m / z): 440.3. 1 H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.42 (s, 1H), 8.80 (dd, J = 8.1, 1.5 Hz, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.75 (s, 1H), 7.57 (dd, J = 8.6, 1.2 Hz, 1H), 7.52 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.28 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.18 - 7.09 (m, 2H), 6.51 (dt, J = 6.4, 2.5 Hz, 1H), 4.13 (t, J = 6.9 Hz, 2H), 3.68 (s, 3H), 1.85 (h, J = 7.2 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 163.08, 157.62, 153.92, 140.39, 136.90, 135.13, 134.52, 129.33, 127.90, 126.86, 126.11, 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-(l-propyl-lH-pyrazol-4-yl)-4,5- dihydro-3H-pyrrolo[2,3-c]quinoline-l-carboxamide (Compound 4)

[0126] Compound 4 was prepared according to the procedure of Example 1, Step G, using intermediate M8-2 and 3-aminobenzonitrile as starting materials in 75.2% yield. Test data: ESI-MS [M+Na] + (m / z): 473.2. 1 H NMR (600 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.87 (dd, J = 8.1, 1.5 Hz, 1H), 8.36 (t, J = 1.9 Hz, 1H), 8.19 - 8.14 (m, 2H), 8.08 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.73 (dt, J = 7.6, 1.4 Hz, 1H), 7.58 (dd, J = 8.6, 1.3 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.30 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 4.14 (t, J = 6.9 Hz, 2H), 3.69 (s, 3H), 2.60 (s, 3H), 1.85 (h, J = 7.2 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ 163.08, 157.62, 153.92, 140.39, 136.90, 135.13, 134.52, 129.33, 127.90, 126.86, 126.11, 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.

[0127] Example 5: N-(3-thiocarbamoylphenyl)-5-methyl-4-oxo-3-(1 -propyl- 1 H-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, then (NH2)2S (14 mg, 0.22 mmol) was added, and the reaction was carried out at 45 °C for 3 hours. Water was added to the reaction solution, and the product was precipitated, filtered under reduced pressure, and dried to obtain Compound 5 as a white solid, 92 mg, yield 85.5%. Test data: ESI-MS [M+H] + (m / z): 485.1. 1 H NMR (600 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.90 (s, 1H), 9.53 (s, 1H), 8.88 (dd, J = 8.1, 1.6 Hz, 1H), 8.32 (t, J = 2.0 Hz, 1H), 8.15 (d, J = 16.5 Hz, 2H), 7.95 (dd, J = 8.0, 2.2 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.55-7.48 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.34-7.24 (m, 1H), 4.13 (t, J = 6.9 Hz, 2H), 3.68 (s, 3H), 1.85 (h, J = 7.2 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ 200.90, 163.70, 154.36, 141.07, 139.45, 137.37, 135.61, 135.43, 128.71, 128.43, 127.36, 126.77, 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- 1 H-pyrazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1 -carboxamide (Compound 6)

[0130] Compound 6 was prepared according to the procedure of Example 1, Step G, using intermediate M8-2 and 3-(1,2,4-oxadiazol-3-yl)-aniline as starting materials in 70.5% yield. Assay data: ESI-MS [M+H] + (m / z): 494.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.74 (s, 1H), 8.89 (dd, J = 8.2, 1.5 Hz, 1H), 8.61 (t, J = 1.9 Hz, 1H), 8.18 (d, J = 5.5 Hz, 2H), 8.06 - 7.99 (m, 1H), 7.80 (dt, J = 7.8, 1.3 Hz, 1H), 7.77 (s, 1H), 7.61 - 7.56 (m, 2H), 7.53 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.31 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 4.14 (t, J = 6.9 Hz, 2H), 3.69 (s, 3H), 1.86 (h, J = 7.2 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.96, 167.34, 163.83, 154.37, 140.69, 137.40, 135.61, 135.55, 130.27, 128.45, 127.37, 126.82, 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- aminosulf onylphenyl)-4, 5-dihydro-3H-pyrrolo [2,3-c] quinoline-1 -carboxamide (Compound 7)

[0132] According to the procedure of Example 1, Step A, using 4-iodopyrazole and 2-bromopropane as starting materials, 4-iodo-1-isopropyl-1H-pyrazole (M 2a -3) was prepared in 68.4% yield;

[0133] According to the procedure of Example 1, Steps E-F, using intermediate M1a-3 and intermediate M6-1 as starting materials, 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 in 64.2% yield; ESI-MS [M-H]- (m / z): 349.1.

[0134] Following the procedure of Example 1, Step G, compound 7 was prepared in 65.6% yield using intermediate M8-3 and 3-aminobenzenesulfonamide as starting materials. Test data: ESI-MS [M+H] + (m / z): 505.2. 1 H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J = 14.6 Hz, 2H), 7.92 (q, J = 5.3, 4.0 Hz, 1H), 7.76 (s, 1H), 7.63 - 7.50 (m, 4H), 7.42 (s, 2H), 7.30 (t, J = 7.5 Hz, 1H), 4.57 (p, J = 6.6 Hz, 1H), 3.69 (s, 3H), 1.49 (d, J = 6.7 Hz, 6H). 13 C NMR (150 MHz, DMSO-d6) δ 163.80, 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- 1 H-pyrazol-4-yl)-4,5-dihydro-3H- pyrrolo[2,3-c]quinoline-1 -carboxamide} picolinic acid (Compound 8)

[0136] Following the procedure of Example 1, Steps B-D, 5-ethyl-4-oxo-4,5-dihydro-3H- pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester (M6-2) was prepared in 35.8% yield using indole-2,3-dione and iodoethane as starting materials;

[0137] Following the procedure of Example 1, Steps E-F, 5-ethyl-3-(1 -propyl- 1 H-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-4) was prepared in 65.4% yield using intermediate M 2a -2 and intermediate M6-2 as starting materials; test data: ESI-MS [M-H] - (m / z): 363.2.

[0138] Following the procedures of Example 1, Steps G-H, compound 8 was prepared in 59.4% yield from intermediate M8-4 and 6-amino-2-pyridinecarboxylic acid; analytical data: ESI-MS [M-H] - (m / z): 483.2; 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 11.03 (s, 1H), 8.93 (dd, J = 8.1, 1.5 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 8.04 (t, J = 7.9 Hz, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.77 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.53 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 4.14 (t, J = 6.9 Hz, 2H), 1.86 (h, J = 7.2 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.38, 164.47, 153.97, 152.67, 147.51, 139.79, 136.77, 136.12, 135.51, 128.56, 127.29, 127.19, 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-(l-cyclopropylmethyl-lH-pyrazol-4-yl)-5-methyl-4-oxo-4,5-dihydro- 3H-pyrrolo[2,3-c]quinoline-l-carboxamide} benzoic acid (Compound 9)

[0140] Following the procedures of Example 1, Step A, 4-iodo-l-cyclopropylmethyl-lH- pyrazole (M 2a -4) was prepared in 71.2% yield from 4-iodopyrazole and bromomethylcyclopropane;

[0141] Following the procedures of Example 1, Steps E-F, compound 9 was prepared in 59.4% yield from intermediate M 2a-4 and intermediate M6-1 as starting materials to give 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) in 57.6% yield; ESI-MS [M-H] - (m / z): 361.1.

[0142] Following the procedures of Example 1, Steps G-H, compound 9 was prepared from intermediate M8-5 and ethyl 3-aminobenzoate as starting materials in 63.5% yield. Test data: HRMS (ESI): m / z calcd. for C 27 H 22 N5O4[M-H] - 480.1677, found 480.1666. 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 10.66 (s, 1H), 8.92 (dd, J = 8.1, 1.4 Hz, 1H), 8.50 (t, J = 1.9 Hz, 1H), 8.25 (d, J = 7.8 Hz, 2H), 8.12 - 8.04 (m, 1H), 7.79 (s, 1H), 7.69 (dt, J = 7.7, 1.3 Hz, 1H), 7.63 - 7.44 (m, 3H), 7.30 (td, J = 7.5, 6.9, 1.3 Hz, 1H), 4.05 (d, J = 7.1 Hz, 2H), 3.69 (s, 3H), 1.30 (ddt, J = 12.3, 7.7, 4.7 Hz, 1H), 0.66 - 0.53 (m, 2H), 0.49 - 0.35 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.72, 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] Following the procedures of Example 1, Step B-D, ethyl 5-isopropyl-4-oxo-4,5-dihydro- 3H-pyrrolo[2,3-c]quinoline-1-carboxylate (M6-3) was prepared in 38.6% yield from indole-2,3-dione and 2-iodopropane;

[0145] Following the procedures of Example 1, Step E-F, intermediate M 2a -2 and intermediate M6-3 to give compound 10 in 67.5% yield. Test data: ESI-MS [M+H] - (m / z): 377.1.

[0146] Following the procedures of Example 1, Step G-H, compound 10 was prepared in 67.5% yield from intermediate M8-6 and ethyl 3-aminobenzoate. Test data: ESI-MS [M+H] - (m / z): 496.3. 1 H NMR (600 MHz, DMSO-d6) δ 12.97 (s, 1H), 10.50 (s, 1H), 8.83 (dd, J = 8.1, 1.6 Hz, 1H), 8.45 (t, J = 2.0 Hz, 1H), 8.15 (d, J = 18.3 Hz, 2H), 8.07 - 8.01 (m, 1H), 7.80 - 7.71 (m, 2H), 7.69 (dt, J = 7.7, 1.4 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.25 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 5.48 (s, 1H), 4.14 (t, J = 6.9 Hz, 2H), 1.85 (h, J = 7.2 Hz, 2H), 1.58 (d, J = 7.0 Hz, 6H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ 167.27, 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-l-carboxamide} benzoic acid (Compound 11)

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

[0149] To a solution of intermediate M6-1 (1.00 g, 3.70 mmol) in DMF was added 4- methoxybenzyl bromide (893 mg, 4.44 mmol) and potassium carbonate (1.02 g, 7.40 mmol) and the reaction mixture was stirred at 40 °C for 3 h. After the starting material was consumed by TLC monitoring, water (100 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous Na2S04and the solvent was removed under reduced pressure to give the crude intermediate M9-1, which was used directly in the next step without further purification.

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

[0151] To a solution of intermediate M9-1 (0.99 g, 3.20 mmol) in H20 (5 mL) and 1,4- dioxane (5 mL) was added 10 mL of NaOH (1 mol / L) and the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed by TLC monitoring, 1,4-dioxane was removed under reduced pressure. The pH of the reaction mixture was adjusted to 4-5 with dilute hydrochloric acid and the product was precipitated. The precipitate was collected by filtration under reduced pressure to give intermediate M 10 -1 as a white powder, 0.99 g, 69.4% overall yield for two steps. Test data: ESI-MS [M-H] - (m / z): 361.2.

[0152] Following the procedures of Steps G-H in Example 1, Compound 11 was prepared in 65.8% yield using intermediate M10-1 and ethyl 3-aminobenzoate as starting materials. Test data: ESI-MS [M+H] - (m / z): 480.2. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.95 (dd, J = 8.1, 1.5 Hz, 1H), 8.44 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.92 (ddd, J = 8.0, 2.3, 1.2 Hz, 1H), 7.66 (dt, J = 7.6, 1.4 Hz, 1H), 7.54 (dd, J = 8.7, 1.3 Hz, 1H), 7.48 (ddd, J = 8.5, 6.9, 1.6 Hz, 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 (100 MHz, DMSO-d6) δ

[0153] 170.70, 163.75, 159.15, 155.32, 139.18, 137.16, 134.51, 130.97, 129.58 (2C), 127.99, 127.72, 126.94, 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.

[0154] Example 12: 3-{3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3- c]quinoline-l-carboxamide}benzoic acid (Compound 12)

[0155] Following the procedures of Example 11, Steps I-J, using intermediate M6-1 and 4-fluorobenzyl bromide as the starting materials, 3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5- dihydro-3H-pyrrolo[2,3-c]quinoline-l-carboxylic acid (M 10 -2) was prepared in 73.5% yield; analytical data: ESI-MS [M-H] - (m / z): 349.4.

[0156] Following the procedures of Example 1, Steps G-H, using intermediate M 10 -2 and ethyl 3-aminobenzoate as the starting materials, Compound 12 was prepared in 66.7% yield. Analytical data: ESI-MS [M+H] - (m / z): 468.3. 1H NMR (600 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.49 (s, 1H), 8.82 (d, J = 8.1 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 - 7.46 (m, 3H), 7.46 - 7.25 (m, 3H), 7.18 (t, J = 8.6 Hz, 2H), 5.87 (s, 2H), 3.72 (s, 3H). 13 C NMR (150 MHz, DMSO-d6) δ 171.40, 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.

[0157] 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)

[0158] Following the procedures of Example 1, Step E-F, intermediate M6-1 and 4-nitrobenzeneboronic acid were used as starting materials to prepare 5-methyl-3-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (M8-7) in 58.9% yield; analytical data: ESI-MS [M-H] - (m / z): 362.2.

[0159] Following the procedures of Example 1, Step G-H, intermediate M8-7 and ethyl 3- aminobenzoate were used as starting materials to prepare Compound 13 in 67.3% yield; analytical data: ESI-MS [M-H] - (m / z): 481.3. 1 H NMR (600 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.91 (dd, J = 8.0, 1.6 Hz, 1H), 8.42 - 8.32 (m, 4H), 7.95 (s, 1H), 7.88 - 7.82 (m, 2H), 7.71 - 7.55 (m, 3H), 7.40 (t, J = 7.7 Hz, 1H), 7.37 - 7.31 (m, 1H), 3.70 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 162.93, 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.

[0160] Example 14: 4-{3-{5-methyl-4-oxo-3-(l-propyl-lH-pyrazol-4-yl)-4,5-dihydro-3H- pyrazolo[2,3-c]quinolin-l-yl}ureido}benzoic acid (Compound 14)

[0161] Step K Synthesis of ethyl 4-{3-{5-methyl-4-oxo-3-(l-propyl-lH-pyrazol-4-yl)-4,5- dihydro-3H-pyrazolo[2,3-c]quinolin-l-yl}ureido}benzoate (I3-1)

[0162] To a solution of M8-2 (200 mg, 0.57 mmol) in dry toluene was added triethylamine (173 mg, 1.71 mmol) and diphenyl phosphorazide (236 mg, 0.86 mmol) and reacted at 50 °C for 0.5 h, then ethyl 4-aminobenzoate (141 mg, 0.86 mmol) was added and the reaction was heated to 80 °C for 2 h. The solvent was removed by distillation under reduced pressure, the residue was slurried with water and the filter cake was collected to give compound I3-1 as a light brown powder, 124 mg, 42.4% yield. Test data: ESI-MS [M+H] + (m / z): 513.2.

[0163] Step L Synthesis of Compound 14

[0164] Compound I3-1 (124 mg, 0.26 mmol) was dissolved in a mixture 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 starting material was consumed as monitored by TLC, the MeOH and THF were removed by distillation under reduced pressure, the reaction mixture was adjusted to pH = 4-5 with dilute hydrochloric acid and the product was precipitated, which was collected by suction filtration under reduced pressure to give compound 14 as a white powder, 65 mg, 55.5% yield. Test data: ESI-MS [M-H] - (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.

[0165] 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)

[0166] 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%;

[0167] 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.

[0168] 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 (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.40-8.23 (m, 2H), 8.12 (d, J = 14.2 Hz, 2H), 7.81-7.67 (m, 2H), 7.67-7.54 (m, 3H), 7.46 (dt, J = 26.5, 7.7 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 4.19 (q, J = 7.3 Hz, 2H), 2.55 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H), 1.27-1.20 (m, 3H).

[0169] Example 16: 3-{3-{3-(l-cyclopropylmethyl-lH-pyrazol-4-yl)-5-ethyl-4-oxo-4,5- dihydro-3H-pyrrolo[2,3-c]quinolin-l-yl}ureido}benzoic acid (Compound 16)

[0170] Following the procedures of Example 1, Step E-F, intermediate M6-2 and intermediate M4 were used as starting materials to give 5-ethyl-3-(l-cyclopropylmethyl-lH-pyrazol-4-yl)-4-oxo-4,5- dihydro-3H-pyrrolo[2,3-c]quinoline-l-carboxylic acid (M8-9) in 63.4% yield; assay data: ESI-MS [M-H] 2a -4 and intermediate M6-2 as starting materials to give 5-ethyl-3-(l-cyclopropylmethyl-lH-pyrazol-4-yl)-4-oxo-4,5- dihydro-3H-pyrrolo[2,3-c]quinoline-l-carboxylic acid (M8-9) in 63.4% yield; assay data: ESI-MS [M-H] - (m / z): 375.4.

[0171] Following the procedures of Example 14, Step K-L, intermediate M8-9 and ethyl 3- aminobenzoate were used as starting materials to give Compound 16 in 40.1% yield. Assay data: ESI-MS [M+H] - (m / z): 509.2.

[0172] Example 17: 4-{3-{3-(4-ethoxyphenyl)-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3- c]quinolin-l-yl}ureido}benzoic acid (Compound 17)

[0173] Following the procedures of Example 1, Step E-F, intermediate M6-1 and 4-iodophenetole were used as starting materials to give 5-methyl-3-(4-ethoxyphenyl)-4-oxo-4,5- dihydro-3H-pyrrolo[2,3-c]quinoline-l-carboxylic acid (M8-10) in 56.4% yield; assay data: ESI-MS [M-H] - (m / z): 361.2.

[0174] Compound 17 was prepared according to the procedures of Steps K-L in Example 14 using intermediate M8-10 and ethyl 4-aminobenzoate as starting materials in 44.0% yield. Test data: ESI-MS [M+H] - (m / z): 495.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.37 (s, 1H), 8.41 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.69 - 7.59 (m, 3H), 7.59 - 7.45 (m, 2H), 7.34 (dd, J = 11.3, 7.8 Hz, 3H), 7.00 (d, J = 8.7 Hz, 2H), 4.10 (q, J = 6.9 Hz, 2H), 3.64 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H).

[0175] Example 18: 5-methyl-4-oxo-3-(l-propyl-lH-pyrazol-4-yl)-4,5-dihydro-3H- pyrrolo[2,3-c]quinolin-l-yl-carbamic acid-3,5-dichlorobenzyl ester (Compound 18)

[0176] Compound 18 was prepared according to the procedure of Step K in Example 14 using intermediate M8-2 and 3,5-dichlorobenzyl alcohol as starting materials in 71.1% yield. Test data: ESI-MS [M+H] + (m / z): 524.1.

[0177] Example 19: 5-methyl-3-(l-isopropyl-lH-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H- pyrrolo[2,3-c]quinolin-l-yl-carbamic acid-3-acetylphenyl ester (Compound 19)

[0178] Compound 19 was prepared according to the procedure of Step K in Example 14 using intermediate M8-3 and methyl 3-hydroxybenzoate as starting materials in 66.2% yield. Test data: ESI-MS [M+H] + (m / z): 500.2.

[0179] Example 20: 5-ethyl-3-(l-ethyl-lH-pyrazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3- c]quinolin-l-yl-carbamic acid-2-methoxyphenyl ester (Compound 20)

[0180] Compound 20 was prepared according to the procedure of Step K in Example 14 using intermediate M8-8 and 2-methoxyphenol as starting materials in 52.2% yield. ESI-MS [M+H] +(m / z): 472.1.

[0181] The compounds prepared in the above examples were tested for pharmacological activity in vitro and in vivo:

[0182] I. Inhibition of Autotaxin (ATX) enzyme activity

[0183] 1. Preparation of enzyme activity assay buffer: 1.51 g of Tris, 238 mg of MgCl2, 277 mg of CaCl2 and 25 mg of Triton X-100 were added to 230 mL of double distilled water, and the solids were completely dissolved by stirring. The pH was adjusted to 7.4 with dilute hydrochloric acid, and the volume was made up to 250 mL with a volumetric flask, and the solution was stored at 4°C.

[0184] 2. Preparation of compound stock solutions: All compounds and the positive drug (PAT-409) were dissolved in DMSO to prepare a 4 mM stock solution, which was stored at -20°C.

[0185] 3. Enzyme activity inhibition test

[0186] The above-obtained stock solutions of the test compounds and the positive drug (PAT-409) were diluted to 8 concentrations, and 10 μL of each solution was added to each well of a 96-well plate. Then, 20 μL of an ATX (1 μg / mL) solution was added to each well, and the plate was incubated at room temperature for 30 minutes. Next, 20 μL of a 1 μM FS-3 solution was added to each well, and the plate was incubated at 37°C for 1 hour. Then, the 96-well plate was placed on a microplate reader to read the fluorescence value (λ ex / λ em = 487 / 520 nm). The results were input into GraphPad Prism software, and the IC 50 values of the compounds were calculated by fitting. The results are shown in Table 1.

[0187] Table 1. Results of the inhibition of ATX enzyme and the anti-MCF-7 cell proliferation activity of the test compounds

[0188]

[0189] Note: A < 10, 10 < B < 100, 100 ≤ C ≤ 1000

[0190] The experimental results show that the compounds of the present application have good inhibitory activity against ATX enzyme (IC 50 values less than 1000 nM are considered to have strong activity). The IC 50 values of the example compounds are all less than 1000 nM, and the IC 50 values of some of the compounds are less than 10 nM. In particular, the IC 50 = 4.5 nM) and 8 (IC 50= 0.97 nM), 9 (IC 50 = 2.4 nM), 11 (IC 50 = 3.1 nM) and the like have better inhibitory activity on ATX enzyme than the positive control PAT-409 (IC 50 = 4.9 nM).

[0191] II. In vitro anti-tumor cell proliferation activity study

[0192] The example compounds of the present application were screened for in vitro anti-MCF-7 breast cancer cell proliferation activity.

[0193] 1. MCF-7 cells in logarithmic growth phase were inoculated into 96-well plates to control the cell density at 10 4 cells / well, so that the cells were evenly distributed in the wells. The cells were incubated in an incubator overnight to adhere to the wall.

[0194] 2. The next day, the old culture medium was removed, and 200 μL of culture medium (90% DMEM-H + 10% FBS) containing different concentrations (30 μM, 10 μM, 1 μM, 333 nM, 111 nM, 37 nM, 12 nM, 4 nM) of the test sample (the compounds prepared in the above examples) was added to each well, while a blank control group (0.1% DMSO) and a positive drug group (PAT-409) were set up, and each group had 3 parallel wells. The cells were incubated in the incubator for 72 h.

[0195] 3. After the cells were treated with the drugs for 72 h, MTT solution (5 mg / mL, 20 μL / well) was added to the 96-well plate, and the plate was incubated in the incubator for 4 h. The supernatant was removed, and DMSO (150 μL / well) was added to dissolve the formazan crystals.

[0196] 4. The absorbance value of each well at 492 nm was read by an enzyme-labeled instrument. The experimental results were input into GraphPad Prism software, and the IC 50 values of the compounds were calculated by fitting. The results are shown in Table 1.

[0197] As can be seen from Table 1, most of the compounds of the present application showed moderate anti-proliferation activity on breast cancer MCF-7 cells. Among them, compounds 1, 6, 7, 8, 9, 11, 12, 15 and 16, like the positive control PAT-409, have an IC 50 value of 10 nM to 100 nM for in vitro anti-MCF-7 cell proliferation activity.

[0198] III. In vivo anti-pulmonary fibrosis experiment

[0199] 1. Modeling

[0200] C57BL / 6J mice were housed and acclimated to the environment for one week under standard SPF laboratory conditions. The mice were then weighed and randomly divided into four groups: Ctrl (control), BLM (model), positive drug group (BLM + PAT-409), and test group (BLM + 8), with eight mice in each group. All mice were fasted and had free access to water the night before modeling.

[0201] C57BL / 6J mice were anesthetized with an intraperitoneal injection of 4% chloral hydrate (10 mL / kg). After the righting reflex disappeared, the mouse's upper incisors were suspended from a rubber band. The mouse's tongue and jaw were grasped with forceps, the mouth was gently opened, and bleomycin solution (4 U / kg) was dripped into the mouse's trachea using a pipette. After the instillation was complete, asthmatic breathing could be heard. The mouse was suspended from the rubber band for 10-15 minutes. Finally, the mouse was returned to its cage and allowed to recover.

[0202] 2. Administer medication

[0203] Preparation of drug solution: First, the drug (compound prepared in the above example) or control drug was added to 1% DMSO and 50% PEG 400 and sonicated for 5 minutes. Then, 5% Tween 80 and 44% saline were added and sonicated for 5 minutes. The drug-containing preparation was finally clear and transparent.

[0204] Dosage: The test group (Compound 8) was administered 60 mg / kg via oral gavage, the positive drug group (PAT-409) was administered 60 mg / kg via oral gavage, and the control group and model group were administered blank preparation via oral gavage.

[0205] Dosage time: Starting from the first day of model establishment, the drug was administered for 21 consecutive days. The mice were given once a day, and their body weight, hair glossiness, and autonomous activity were recorded.

[0206] 3. Masson staining of lung tissue

[0207] After 21 days of continuous administration, 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.

[0208] The experimental results are as follows Figure 1 As shown, in the BLM-induced pulmonary fibrosis model, alveolar walls were significantly thickened and collagen deposition was severe. However, after treatment with Compound 8, collagen deposition was significantly reduced compared to the BLM group, and alveolar walls returned to normal thickness. These results demonstrate that Compound 8 can counteract bleomycin-induced changes in lung tissue morphology and inhibit the production of lung collagen, thereby exerting its anti-fibrotic effect.

Claims

1. A 4,5-dihydro-3 H -pyrrolo[2,3- c ] Quinolin-4-one derivatives, characterized in that: The derivatives are compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof: （I） 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 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 Selected from halogen, cyano, hydroxy, thiol, carboxyl, phosphate, sulfamoyl, carbamoyl, thiocarbamoyl, C1-C4 alkoxycarbonyl, C1-C6 alkoxy, C1-C6 acyl, amino substituted with 0-2 C1-C6 alkyl groups, 5-6 membered heteroaryl 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. 4,5-dihydro-3-(4-nitro-2-nitropropene)-2-nitro H -pyrrolo[2,3- c ] Quinolin-4-one derivatives, characterized in that: The derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof; Where, 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 C1-C5 alkyl; R 2 A benzene ring, a naphthalene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a pyridine ring, a pyrimidine ring, an indole ring, which are unsubstituted or optionally substituted with 1-3 identical or different 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, hydroxy, thiol, carboxyl, phosphate, sulfamoyl, carbamoyl, thiocarbamoyl, C1-C4 alkoxycarbonyl, C1-C6 alkoxy, C1-C6 acyl, amino substituted with 0-2 C1-C6 alkyl groups, and 5-6 membered heteroaryl 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. 4,5-dihydro-3-(4-nitro-2-nitropropene)-2-nitropropene according to claim 2 H -pyrrolo[2,3- c ] Quinolin-4-one derivatives, characterized in that: The derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof; L is selected from 、 、 、 ; n is selected from 0 or 1; R 1 Selected from methyl, ethyl, propyl, isopropyl, isobutyl; R 2 A benzene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, which are unsubstituted or optionally substituted with 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, 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, and a 5-6 membered heteroaryl group 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. 4,5-dihydro-3-nitropropane according to claim 3 H -pyrrolo[2,3- c ] Quinolin-4-one derivatives, characterized in that: The derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt 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 pyrazole ring substituted with 1-2 identical or different groups selected from the following groups: 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. 4,5-dihydro-3-(4-(2-nitro-1,4-dihydro-2-nitropropene)-1,2-dihydro-3-nitropropene ... H -pyrrolo[2,3- c ] Quinolin-4-one derivatives, characterized in that: The derivative is a compound represented by general formula (I) and a pharmaceutically acceptable salt 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 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. 4,5-dihydro-3-(4-nitro-2-nitro-3-nitropropene) H -pyrrolo[2,3- c ] Quinolin-4-one derivatives, characterized in that: The derivatives are specifically the following compounds and pharmaceutically acceptable salts thereof, 3-{5-methyl-3-(1-methyl-1 H -pyrazol-4-yl)-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}benzoic acid; N -(3-carbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinoline-1-carboxamide; N -(3-hydroxyphenyl)-5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinoline-1-carboxamide; N -(3-cyanophenyl)-5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinoline-1-carboxamide; N -(3-thiocarbamoylphenyl)-5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinoline-1-carboxamide; N -[3-(1,2,4-oxadiazol-3-yl)phenyl]-5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinoline-1-carboxamide; 3-(1-isopropyl-1 H -pyrazol-4-yl)-5-methyl-4-oxo- N -(3-aminomethanesulfonylphenyl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinoline-1-carboxamide; 6-{5-ethyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}picolinic acid; 3-{3-(1-cyclopropylmethyl-1 H -pyrazol-4-yl)-5-methyl-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}benzoic acid; 3-{5-isopropyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}benzoic acid; 3-{3-(4-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}benzoic acid; 3-{3-(4-fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}benzoic acid; 3-{5-methyl-3-(4-nitrophenyl)-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinoline-1-carboxamide}benzoic acid; 4-{3-{5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrazolo[2,3- c ]quinolin-1-yl}ureido}benzoic acid; 1-(3-acetylphenyl)-3-{5-ethyl-3-(1-ethyl-1 H -pyrazol-4-yl)-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinolin-1-yl}urea; 3-{3-{3-(1-cyclopropylmethyl-1 H -pyrazol-4-yl)-5-ethyl-4-oxo-4,5-dihydro-3 H -pyrazolo[2,3- c ]quinolin-1-yl}ureido}benzoic acid; 4-{3-{3-(4-ethoxyphenyl)-5-methyl-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]quinolin-1-yl}ureido}benzoic acid; 5-methyl-4-oxo-3-(1-propyl-1 H -pyrazol-4-yl)-4,5-dihydro-3 H -pyrrolo[2,3- c ] Quinolin-1-yl-carbamic acid-3,5-dichlorobenzyl ester; 5-methyl-3-(1-isopropyl-1 H -pyrazol-4-yl)-4-oxo-4,5-dihydro-3 H -pyrrolo[2,3- c ]Quinolin-1-yl-carbamic acid-3-acetylphenyl ester 5-ethyl-3-(1-ethyl-1 H -pyrazol-4-yl)-4-oxo-4,5-dihydro-3 H -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 4,5-dihydro-3- H -pyrrolo[2,3- c ] Use of a quinoline-4-one derivative or the pharmaceutical composition according to claim 7 in the preparation of an ATX inhibitor.

9. A 4,5-dihydro-3- H -pyrrolo[2,3- c ] Use of a quinoline-4-one derivative or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating and / or preventing tumors and fibrotic diseases associated with abnormal ATX-LPA signaling axis.

10. 4,5-dihydro-3-(2-nitro-1,2-dihydro-2-nitropropene)-2-nitropropene according to claim 9 H -pyrrolo[2,3- c ] The use of quinoline-4-one derivatives, 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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