2-Indolone derivatives and their uses

Abstract

The present invention relates to a 2-indolinone derivative and a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a 2-indolinone derivative and a pharmaceutically acceptable salt thereof. The 2-indolinone derivative and the pharmaceutically acceptable salt thereof according to the present invention can be used for treating and preventing related diseases such as fibrosis, and can also be used for treating and preventing related diseases such as excessive or abnormal cell proliferation.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a 2-indolinone derivative, a pharmaceutical composition containing the compound, and their applications. Background Art

[0002] Nintedanib is an orally administered small molecule tyrosine kinase inhibitor developed by Boehringer-Ingelheim, which can competitively inhibit receptor tyrosine kinases such as fibroblast growth factor receptors (FGFR 1-3), vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFRα and β). Nintedanib is used for the treatment of idiopathic pulmonary fibrosis (IPF); for the treatment of systemic sclerosis-related interstitial lung disease (SSc-ILD); Nintedanib is used for the treatment of chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype, and can also be used for the treatment of cancer.

[0003] Currently, nintedanib still has suboptimal absorption, distribution, metabolism, and / or excretion (ADME) properties, which hinder its wider use or limit its application in specific indications. For example, due to the low oral bioavailability of the drug and / or the short elimination half-life in vivo, the drug exposure in the body is relatively small. The commonly adopted solution is to administer the drug frequently or at a high dose to obtain a sufficiently high drug exposure level. However, this introduces a large number of potential treatment problems, such as the compliance of patients with the dosing interval, and the side effects will be more severe with higher-dose administration, and the treatment cost is increased.

[0004] In order to obtain better ADME and / or pharmacological properties and achieve better therapeutic benefits, the structure of the drug or drug candidate can be modified. Due to the complexity of biological systems, the changes in the ADME and / or pharmacological properties of the drug or drug candidate caused by structure modification are usually unpredictable and empirical studies are required.

[0005] In addition, deuterium modification is also an alternative option. Compared with hydrogen, deuterium forms a stronger chemical bond with carbon. In selected cases, the increased bond strength conferred by deuterium can positively affect the ADME properties of the drug and has the potential to improve efficacy, safety, and / or tolerance. At the same time, since the size and shape of deuterium are similar to those of hydrogen, it is expected that replacing hydrogen with deuterium will not affect the biochemical efficacy and selectivity of the drug compared with the original chemical entity containing only hydrogen.

[0006] However, due to the complex metabolic processes in biological systems, the pharmacokinetic properties of drugs in the body are affected by multiple factors and also exhibit corresponding complexity. Compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetic properties of deuterated drugs show great contingency and unpredictability. For some compounds, deuteration slows down their metabolic clearance in the body and increases the half-life; for other compounds, deuteration does not cause metabolic changes; for still other compounds, deuteration accelerates metabolic clearance and shortens the half-life (Blake, MI et al, J Pharm Sci, 1975, 64: 367-91; Foster, AB, Adv Drug Res 1985, 14: 1-40; Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09; Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406).

[0007] In order to overcome the problems existing in nintedanib, the present invention obtains a class of drugs with good ADME performance; and / or good pharmacological activity; and / or reduced dosage or frequency; and / or reduced toxic and side effects by structurally modifying and / or deuterating nintedanib. Summary of the Invention

[0008] The object of the present invention is to provide 2-indolinone derivatives and their uses. The present invention first provides a compound represented by Formula I, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein:

[0011] R 1 and R 2 are each independently selected from H, deuterium (D), C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, a 3-6 membered saturated or unsaturated carbocyclic ring, a 3-6 membered saturated or unsaturated heterocyclic ring containing nitrogen (N) and / or oxygen (O) and / or sulfur (S), wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4The alkynyl group, a 3- to 6-membered saturated or unsaturated carbocyclic ring, or a 3- to 6-membered saturated or unsaturated heterocyclic ring containing nitrogen (N) and / or oxygen (O) and / or sulfur (S) is optionally substituted with zero or more substituents selected from deuterium, halogen, cyano, hydroxyl, and mercapto; or R 1 and R 2 , together with the atoms to which they are attached, form a ring;

[0012] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 and R 30 are each independently selected from hydrogen (H) or deuterium (D);

[0013] Provided that R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R28 , R 29 and R 30 are both hydrogen, at least one deuterium atom is contained in the R 1 or R 2 group.

[0014] Furthermore, the present invention provides any one of the following fourteen compounds (Compound ND801, Compound ND802, Compound ND803, Compound ND804, Compound ND805, Compound ND806, Compound ND807, Compound ND808, Compound ND809, Compound ND810, Compound ND811, Compound ND812, Compound ND813 or Compound ND814) or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs.

[0015]

[0016] Furthermore, the pharmaceutically acceptable salt is mesylate, esylate, benzenesulfonate, benzenesulfonate, phosphate, dextrorotatory camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, aspartate or glutamate of the compound, and preferably esylate.

[0017] The present invention also provides the use of the aforementioned compound or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of a drug for treating or preventing fibrotic diseases.

[0018] Furthermore, the fibrotic diseases are idiopathic pulmonary fibrosis, giant cell interstitial pneumonia, sarcoidosis, cystic fibrosis, respiratory distress syndrome, drug-induced pulmonary fibrosis, granulomatosis, scleroderma, interstitial lung disease, pneumoconiosis, silicosis, asbestosis, acute lung injury, cardiac fibrosis, liver cirrhosis, chronic kidney disease, myocardial infarction, heart failure, non-alcoholic fatty liver (NASH), lupus erythematosus.

[0019] The present invention also provides the use of the aforementioned compound or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of a drug for treating and preventing diseases related to excessive or abnormal cell proliferation.

[0020] Furthermore, the diseases related to excessive or abnormal cell proliferation include cancer, preferably the following diseases: acute myeloid leukemia, gastric tumor, neuroendocrine tumor, thyroid tumor, melanoma, squamous cell carcinoma, metastatic non-small cell lung cancer, soft tissue sarcoma, pterygium; neovascular eye diseases.

[0021] The present invention also provides the use of the aforementioned compound or its optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug in the preparation of a VEGFR receptor inhibitor, an FGFR receptor inhibitor or a PDGFR receptor inhibitor. The VEGFR receptor refers to the vascular endothelial growth factor receptor. The FGFR receptor refers to the fibroblast growth factor receptor. The PDGFR receptor refers to the platelet-derived growth factor receptor.

[0022] The present invention also provides a therapeutic drug, which is a preparation made from the aforementioned compound or its optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug as the active ingredient, plus pharmaceutically acceptable excipients. The present invention also provides a combined drug, which is composed of the aforementioned compound or its optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug and other therapeutic drugs in any proportion.

[0023] As used herein, "deuterated" means that one or more hydrogens (H) in a compound are replaced by deuterium (D). In a preferred embodiment, the deuterium isotope content at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 40%, more preferably greater than 70%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%, more preferably greater than 99.5%.

[0024] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or a base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compound of the present invention with acids, including but not limited to: mesylate, ethanesulfonate, benzenesulfonate, benzenesulfonate, phosphate, d-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, aspartate or glutamate. Further, the pharmaceutically acceptable salt is ethanesulfonate.

[0025] The aforementioned pharmaceutically acceptable excipients have certain physiological activities, but the addition of this component will not change the dominant position of the above-mentioned drug in the treatment of diseases, but only play an auxiliary effect. These auxiliary effects are only the utilization of the known activities of this component and are common auxiliary treatment methods in the medical field. If the above-mentioned auxiliary components are used in combination with the drugs of the present invention, it still belongs to the scope of protection of the present invention.

[0026] The positive and progressive effects of the present invention are

[0027] (1) The compounds of the present invention have good pharmacokinetic properties, can reduce the dosage and / or reduce toxic metabolites, and have better drug-likeness.

[0028] (2) The compounds of the present invention have good effects in preventing and treating organ fibrosis, and can be effectively used for the treatment of diseases related to pulmonary fibrosis, liver fibrosis, cardiac fibrosis, renal fibrosis, and / or fibrosis of other organs.

[0029] (3) The compounds of the present invention have good effects in treating and preventing diseases related to excessive or abnormal cell proliferation, and can be effectively used for the treatment of acute myeloid leukemia, gastric tumors, neuroendocrine tumors, thyroid tumors, melanoma, squamous cell carcinoma, metastatic non-small cell lung cancer, soft tissue sarcoma, pterygium, and / or neovascular ophthalmopathy.

[0030] (4) The compounds of the present invention have good inhibitory effects on VEGFR, FGFR, and / or PDGFR, and can be effectively used for diseases related to VEGFR, FGFR, and / or PDGFR. Description of the Drawings

[0031] Figure 1 It is a schematic diagram comparing the hydroxyproline (HYP) content in the right lung of mice. Among them, a: control group, b: model group, c: nintedanib group, d: compound group of the example, and the vertical axis represents the HYP content.

[0032] Figure 2 It is a schematic diagram of the FVC measurement results of mice. Among them, a: control group, b: model group, c: nintedanib group, d: compound group of the example, and the vertical axis represents the FVC value.

[0033] Figure 3 It is a schematic diagram of the Cdyn measurement results of mice. Among them, a: control group, b: model group, c: nintedanib group, d: compound group of the example, and the vertical axis represents the Cdyn value.

[0034] Figure 4 It is a schematic diagram of the Re measurement results of mice. Among them, a: control group, b: model group, c: nintedanib group, d: compound group of the example, and the vertical axis represents the Re measurement value.

[0035] Figure 5 It is a schematic diagram of the Ri measurement results of mice. Among them, a: control group, b: model group, c: nintedanib group, d: compound group of the example, and the vertical axis represents the Ri measurement value.

[0036] Figure 6 It is a HE staining map of mouse pulmonary fibrosis. Among them, a: control group, b: model group, c: nintedanib group, d: compound group of the example.

[0037] Figure 7 Schematic diagram for the determination of the pulmonary fibrosis area in mice, where b: model group, c: nintedanib group, d: example compound group, and the vertical axis represents the percentage of fibrosis area.

[0038] Specific implementation method

[0039] The present invention will be further described below in conjunction with specific embodiments. These embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0040] The raw materials and instruments used in the present invention can be obtained through market purchase.

[0041] Taking the compound ND803 as an example, a preferred preparation process is as follows:

[0042]

[0043] Its specific synthesis method is described in Example 1.

[0044] Taking the compound ND801 as an example, another preferred preparation process is as follows:

[0045]

[0046] Its specific synthesis method is described in Example 2 and Example 3.

[0047] Example 1: Synthesis of compound ND803

[0048] Step 1: Synthesize compound ND203

[0049]

[0050] To 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (380 mg, 1 mmol) was added 3 mL of ultra-dry N,N-dimethylformamide (DMF) and stirred. A 2 mL ultra-dry DMF solution of compound ND201 (202 mg, 1 mmol) and DIEA (661 μL, 4 mmol) were then added at 0°C. The mixture was stirred for 10 minutes, followed by the addition of trideuteromethylamine hydrochloride (compound ND202) (2 mmol). The ice bath was removed and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the product was transferred to a separatory funnel, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (3 × 20 mL) and then saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography using a mixed solvent of dichloromethane and methanol as eluent and concentrated under reduced pressure to obtain compound ND203.

[0051] Step 2: Synthesis of compound ND205

[0052]

[0053] In anhydrous N,N-dimethyl sulfoxide (DMSO) (30 mL), potassium carbonate (40 mmol) and dimethyl malonate (compound ND204) (22 mmol) were added in sequence, and the mixture was stirred at room temperature for 2 min. Compound ND203 (20 mmol) was added in batches and the mixture was reacted at 40°C for 3 h. Ethyl acetate (60 mL) was added, and 1 mol·L -1 The product was washed with hydrochloric acid (60 mL) and saturated brine (2×60 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from ethyl acetate and dried to obtain compound ND205.

[0054] Step 3: Synthesis of compound ND206

[0055]

[0056] Compound ND205 (7.5 mmol), 5% Pd / C (0.23 g), ammonium formate (75 mmol), and glacial acetic acid (15 mL) were added sequentially to a reaction flask under nitrogen atmosphere at 100°C for 3 h. The Pd / C was removed by hot filtration, and the filtrate was evaporated under reduced pressure. Saturated sodium bicarbonate solution was slowly added dropwise to the residual solution until no bubbles escaped. Stirring was continued for 1 h, filtered, and the solid was rinsed with water (15 mL) and dried to obtain compound ND206.

[0057] Step 4: Synthesis of compound ND208

[0058]

[0059] In a reaction flask, successively add compound ND206 (6 mmol), toluene (6 mL) and acetic anhydride (3 mL). While stirring, dropwise add triethyl orthobenzoate (compound ND207) (18 mmol). After the addition is complete, reflux the reaction mixture at 110 °C for 2 h. Cool to room temperature, concentrate, add 23 mL of saturated sodium bicarbonate solution, stir for 30 min, extract with ethyl acetate (2 × 30 mL), combine the extracts, wash successively with saturated sodium bicarbonate solution (2 × 45 mL) and saturated brine (45 mL), dry over anhydrous magnesium sulfate, concentrate, and recrystallize the residue from petroleum ether and dry to obtain compound ND208.

[0060] Step Five: Synthesis of compound ND103

[0061]

[0062] In ethyl acetate (60 mL), successively add compound N101 (50 mmol) and potassium carbonate (40 mmol), stir at room temperature, and dropwise add compound ND102 (chloroacetyl chloride) (5.62 mL, 75 mmol) dissolved in ethyl acetate (20 mL). React at room temperature for 1 h. Add water (3 × 60 mL) for washing, separate the layers, dry the organic layer over anhydrous magnesium sulfate, filter, concentrate the filtrate, recrystallize the obtained solid from ice-cold ethanol and dry to obtain compound ND103.

[0063] Step Six: Synthesis of compound ND105

[0064]

[0065] In acetonitrile (30 mL), successively add compound ND103 (30 mmol) and trimethylpiperazine-d3 (compound ND104) (33 mmol), stir and react at 35 °C for 3 h. Filter, concentrate the filtrate, add ethyl acetate (45 mL) to the residue, wash successively with saturated brine (3 × 45 mL) and dry over anhydrous magnesium sulfate, and concentrate to obtain compound ND105.

[0066] Step Seven: Synthesis of compound ND106

[0067]

[0068] In methanol (90 mL), successively add compound ND105 (25 mmol) and 10% Pd / C (0.75 g), pass hydrogen gas, stir at room temperature for 24 h, filter off the Pd / C, distill under reduced pressure to obtain an oily substance, add ether to precipitate a solid, filter, and dry the filter cake to obtain compound ND106.

[0069] Step Eight: Synthesis of compound ND803

[0070]

[0071] In methanol (12 mL), compound ND208 (3 mmol) and sodium methoxide (6 mmol) were successively added, and the mixture was stirred at room temperature for 2 h. Compound ND106 (3.6 mmol) and dimethyl sulfoxide (6 mL) were added, and the temperature was raised to 80 °C and reacted for 1 h. Methanol was removed by distillation under reduced pressure, ethyl acetate (30 mL) was added, and it was washed successively with water (3×30 mL), dried over anhydrous magnesium sulfate, concentrated, recrystallized from anhydrous methanol, and dried to obtain compound ND803. The 1H NMR spectrum of compound ND803 was as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (8H).

[0072] Example 2: Synthesis of compound MM01

[0073]

[0074] Step Nine: Synthesis of compound MM01

[0075] Nintedanib (1.62 g, 3 mmol) was added to 15 mL of tetrahydrofuran, and then sodium hydroxide solution (1 mol / L, 6 mL) was slowly added. The mixture was heated to 50 °C and stirred for reaction. The reaction process was monitored by TLC. After reacting for 8 h, it was concentrated under reduced pressure, 10 mL of water was added, and the pH value was adjusted to 2 - 3 by dropping hydrochloric acid solution (1 mol / L). A large amount of yellow solid precipitated out, and it was filtered under reduced pressure. The filter cake was washed with 20 mL of ethanol. The crude product was purified by Flash column chromatography (methylene chloride:methanol = 10:1), and concentrated under reduced pressure to obtain compound MM01.

[0076] Example 3: Synthesis method 2 of compound ND801

[0077]

[0078] Step Ten: Synthesis of compound ND801

[0079] To 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (380 mg, 1 mmol), add 3 mL of ultra-dry N,N-dimethylformamide (DMF), stir, and sequentially add 2 mL of an ultra-dry DMF solution of MM01 (526 mg, 1 mmol) and DIEA (661 μL, 4 mmol) to the suspension at 0 °C. After stirring the mixture for 10 min, add deuterated methylamine hydrochloride (Compound ND202) (2 mmol), remove the ice bath, and stir the reaction at room temperature for 24 h. After the reaction is completed, transfer the product to a separatory funnel, add 30 mL of water, and extract with ethyl acetate (3 × 10 mL). Combine the organic layers and wash successively with water (3 × 20 mL) and saturated brine (20 mL). Add anhydrous sodium sulfate for drying, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by Flash column chromatography (methylene chloride:methanol = 7:1), concentrate under reduced pressure to obtain Compound ND801. The 1H-NMR spectrum of Compound ND801 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (11H).

[0080] Example 4: Synthesis of Compound ND302

[0081]

[0082] Step 11: Synthesis of Compound ND302

[0083] To 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (380 mg, 1 mmol), add 3 mL of ultra-dry N,N-dimethylformamide (DMF), stir, and sequentially add 2 mL of an ultra-dry DMF solution of Compound ND201 (202 mg, 1 mmol) and DIEA (661 μL, 4 mmol) to the suspension at 0 °C. After stirring the mixture for 10 min, add methylamine hydrochloride (Compound ND301) (2 mmol), remove the ice bath, and stir the reaction at room temperature for 24 h. After the reaction is completed, transfer the product to a separatory funnel, add 30 mL of water, and extract with ethyl acetate (3 × 10 mL). Combine the organic layers and wash successively with water (3 × 20 mL) and saturated brine (20 mL). Add anhydrous sodium sulfate for drying, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by Flash column chromatography, elute with a mixed solvent of methylene chloride and methanol, concentrate under reduced pressure to obtain Compound ND302.

[0084] Example 5: Synthesis of Compound ND304

[0085]

[0086] Replace compound ND301 with compound ND303, and carry out the reaction according to the method of "Example 4: Synthesis of Compound ND302"

[0087] to obtain compound ND304.

[0088] Example 6: Synthesis of Compound ND306

[0089]

[0090] Replace compound ND301 with compound ND305, and carry out the reaction according to the method of "Example 4: Synthesis of Compound ND302"

[0091] to obtain compound ND306.

[0092] Example 7: Synthesis of Compound ND203

[0093]

[0094] Replace compound ND301 with compound ND202, and carry out the reaction according to the method of "Example 4: Synthesis of Compound ND302"

[0095] to obtain compound ND203.

[0096] Example 8: Synthesis 1 of Compound ND401

[0097]

[0098] Step Twelve: Synthesize Compound ND401

[0099] Add 4-nitroiodobenzene (compound ND402) (10 mmol), trimethylamine hydrochloride (compound ND202) (50 mmol), 5.3 mL of 9.5 mol / L sodium hydroxide (50 mmol) aqueous solution and copper powder (5 mol%) into a 30 mL sealed tube, stir magnetically, react in an oil bath at 100 °C for 12 hours, then cool to room temperature, and extract three times with ethyl acetate (3 × 20 mL). Combine the ethyl acetate extracts, add anhydrous sodium sulfate for drying, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by silica gel column chromatography, elute with a mixed solvent of petroleum ether and ethyl acetate to obtain compound ND401. The 1H NMR spectrum of compound ND401 is as follows: 1 1H-NMR (DMSO-d6) δ (ppm) 7.3 (1H), 6.7 (2H), 8.0 (2H).

[0100] Example 9: Synthesis of Compound ND401 2

[0101]

[0102] Replace compound ND402 with compound ND404, and carry out the reaction according to the method of "Example 8: Synthesis of Compound ND401 1" to obtain compound ND401. The 1H-NMR spectrum of compound ND401 is as follows: 1 1H-NMR(DMSO-d6) δ(ppm) 7.3(1H), 6.7(2H), 8.0(2H).

[0103] Example 10: Synthesis of Compound ND401 3

[0104]

[0105] Replace compound ND402 with compound ND405, and carry out the reaction according to the method of "Example 8: Synthesis of Compound ND401

[0106] " to obtain compound ND401. The 1H-NMR spectrum of compound ND401 is as follows: 1 1H-NMR(DMSO-d6) δ(ppm) 7.3(1H), 6.7(2H), 8.0(2H).

[0107] Example 11: Synthesis of Compound ND401 4

[0108]

[0109] Step Thirteen: Synthesis of Compound ND401

[0110] p-Nitroaniline (compound ND406) (25 mmol) and tri-deuterated iodomethane (compound ND407) (10 mmol) are refluxed (65 °C) in tetra-deuterated methanol (25 mL) for 10 hours. The reaction solution is cooled to room temperature, adjusted to alkaline with 20% (w / v) potassium hydroxide, and an aqueous solution (1.5 ml) of zinc chloride (1.5 g, 11 mmol) is added. The reaction mixture is cooled to 5 °C, stirred and then filtered by suction. The thick paste is extracted three times (3 × 30 mL) with petroleum ether (bp 60 - 80 °C). The combined organic extracts are washed with water (3 × 30 mL) and 25% aqueous ammonia solution (30 mL) respectively. The organic layer is dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure and recrystallized from methanol to obtain compound ND401. The 1H-NMR spectrum of compound ND401 is: 1H-NMR(DMSO-d6) δ(ppm) 7.3(1H), 6.7(2H), 8.0(2H).

[0111] Example 12: Synthesis of Compound ND801

[0112]

[0113] Replace compound ND104 with compound ND501, and carry out the reaction according to the method of "Example 1: Synthesis of compound ND803" to obtain compound ND801. The 1H NMR spectrum of compound ND801 is as follows: 1 1H-NMR(DMSO-d6) δ 12.1(1H), 11.0(1H), 8.2(1H), 7.4 - 7.6(5H), 7.3(1H), 6.8 - 7.2(5H), 5.8(1H), 3.1(3H), 2.7(2H), 1.9 - 2.3(11H).

[0114] Example 13: Synthesis of compound ND802

[0115]

[0116] Replace compound ND101 with compound ND401, and carry out the reaction according to the method of "Example 12: Synthesis of compound ND801" to obtain compound ND802. The 1H NMR spectrum of compound ND802 is as follows: 1 1H-NMR(DMSO-d6) δ 12.1(1H), 11.0(1H), 8.2(1H), 7.4 - 7.6(5H), 7.3(1H), 6.8 - 7.2(5H), 5.8(1H), 2.7(2H), 1.9 - 2.3(11H).

[0117] Example 14: Synthesis of compound ND804

[0118]

[0119] Replace compound ND501 with compound ND104, and carry out the reaction according to the method of "Example 13: Synthesis of compound ND802" to obtain compound ND804. The 1H NMR spectrum of compound ND804 is as follows: 1 1H-NMR(DMSO-d6) δ 12.1(1H), 11.0(1H), 8.2(1H), 7.4 - 7.6(5H), 7.3(1H), 6.8 - 7.2(5H), 5.8(1H), 2.7(2H), 1.9 - 2.3(8H).

[0120] Example 15: Synthesis of compound ND805

[0121]

[0122] Replace methanamine hydrochloride-d3 (Compound ND202) with dimethylamine hydrochloride (Compound ND305), and carry out the reaction according to the method of "Example 1: Synthesis of Compound ND803" to obtain Compound ND805. The 1H NMR spectrum of Compound ND805 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 - 2.8 (8H), 1.9 - 2.3 (8H).

[0123] Example 16: Synthesis of Compound ND806

[0124]

[0125] Replace methanamine hydrochloride-d3 (Compound ND202) with methanamine hydrochloride (Compound ND301), and carry out the reaction according to the method of "Example 13: Synthesis of Compound ND802" to obtain Compound ND806. The 1H NMR spectrum of Compound ND806 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 2.7 - 2.8 (5H), 1.9 - 2.3 (11H).

[0126] Example 17: Synthesis of Compound ND807

[0127]

[0128] Replace methanamine hydrochloride-d3 (Compound ND202) with methanamine hydrochloride (Compound ND301), and carry out the reaction according to the method of "Example 1: Synthesis of Compound ND803" to obtain Compound ND807. The 1H NMR spectrum of Compound ND807 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 - 2.8 (5H), 1.9 - 2.3 (8H).

[0129] Example 18: Synthesis of Compound ND808

[0130]

[0131] Replace trimethylamine hydrochloride (Compound ND202) with methylamine hydrochloride (Compound ND301), and conduct the reaction according to the method of "Example 14: Synthesis of Compound ND804" to obtain Compound ND808. The 1H-NMR spectrum of Compound ND808 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 2.7 - 2.8 (5H), 1.9 - 2.3 (8H).

[0132] Example 19: Synthesis of Compound ND809

[0133]

[0134] Replace trimethylamine hydrochloride (Compound ND202) with hexadeuterodimethylamine hydrochloride (Compound ND303), and conduct the reaction according to the method of "Example 12: Synthesis of Compound ND801" to obtain Compound ND809. The 1H-NMR spectrum of Compound ND809 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (11H).

[0135] Example 20: Synthesis of Compound ND810

[0136]

[0137] Replace trimethylamine hydrochloride (Compound ND202) with hexadeuterodimethylamine hydrochloride (Compound ND303), and conduct the reaction according to the method of "Example 13: Synthesis of Compound ND802" to obtain Compound ND810. The 1H-NMR spectrum of Compound ND810 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 2.7 (2H), 1.9 - 2.3 (11H).

[0138] Example 21: Synthesis of Compound ND811

[0139]

[0140] Replace trimethylamine hydrochloride (Compound ND202) with hexadeuterated dimethylamine hydrochloride (Compound ND303), and carry out the reaction according to the method of "Example 1: Synthesis of Compound ND803" to obtain Compound ND811. The proton nuclear magnetic resonance spectrum of Compound ND811 is as follows: 1 H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (8H).

[0141] Example 22: Synthesis of Compound ND812

[0142]

[0143] Replace trimethylamine hydrochloride (Compound ND202) with hexadeuterated dimethylamine hydrochloride (Compound ND303), and carry out the reaction according to the method of "Example 14: Synthesis of Compound ND804" to obtain Compound ND812. The proton nuclear magnetic resonance spectrum of Compound ND812 is as follows: 1 H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 2.7 (2H), 1.9 - 2.3 (8H).

[0144] Example 23: Synthesis of Compound ND813

[0145]

[0146] Replace trimethylamine hydrochloride (Compound ND202) with dimethylamine hydrochloride (Compound ND305), and carry out the reaction according to the method of "Example 14: Synthesis of Compound ND804" to obtain Compound ND813. The proton nuclear magnetic resonance spectrum of Compound ND813 is as follows: 1 H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 2.7 - 2.8 (8H), 1.9 - 2.3 (8H).

[0147] Example 24: Synthesis of Compound ND814

[0148]

[0149] Replace methanamine hydrochloride-d3 (Compound ND202) with dimethylamine hydrochloride (Compound ND305), and carry out the reaction according to the method of "Example 13: Synthesis of Compound ND802" to obtain Compound ND814. The 1H-NMR spectrum of Compound ND814 is as follows: 1 1H-NMR(DMSO-d6) δ 12.1(1H), 11.0(1H), 7.4 - 7.6(5H), 7.3(1H), 6.8 - 7.2(5H), 5.8(1H), 2.7 - 2.8(8H), 1.9 - 2.3(11H).

[0150] Example 25: Method 2 for the Synthesis of Compound ND809

[0151]

[0152] Replace methanamine hydrochloride-d3 (Compound ND202) with methanamine hydrochloride-d6 (Compound ND303), and carry out the reaction according to the method of "Example 3: Method 2 for the Synthesis of Compound ND801" to obtain Compound ND809. The 1H-NMR spectrum of Compound ND809 is as follows: 1 1H-NMR(DMSO-d6) δ 12.1(1H), 11.0(1H), 7.4 - 7.6(5H), 7.3(1H), 6.8 - 7.2(5H), 5.8(1H), 3.1(3H), 2.7(2H), 1.9 - 2.3(11H).

[0153] Example 26: Synthesis of Compound ND322

[0154]

[0155] Replace Compound ND301 with Compound ND321, and carry out the reaction according to the method of "Example 4: Synthesis of Compound ND302" to obtain Compound ND322.

[0156] Example 27: Synthesis of Compound ND324

[0157]

[0158] Replace Compound ND301 with Compound ND323, and carry out the reaction according to the method of "Example 4: Synthesis of Compound ND302" to obtain Compound ND324.

[0159] Example 28: Synthesis of Compound ND815

[0160]

[0161] Replace trimethylamine hydrochloride (Compound ND202) with ethyl-d5-amine hydrochloride (Compound ND321), and carry out the reaction according to the method of "Example 12: Synthesis of Compound ND801" to obtain Compound ND815. The 1H-NMR spectrum of Compound ND815 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (11H).

[0162] Example 29: Synthesis of Compound ND815 2

[0163]

[0164] Replace trimethylamine hydrochloride (Compound ND202) with ethyl-d5-amine hydrochloride (Compound ND321), and carry out the reaction according to the method of "Example 3: Synthesis Method 2 of Compound ND801" to obtain Compound ND815. The 1H-NMR spectrum of Compound ND815 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (11H).

[0165] Example 30: Synthesis of Compound ND816

[0166]

[0167] Replace trimethylamine hydrochloride (Compound ND202) with n-butyl-d9-amine (Compound ND323), and carry out the reaction according to the method of "Example 1: Synthesis of Compound ND803" to obtain Compound ND816. The 1H-NMR spectrum of Compound ND816 is as follows: 1 1H-NMR (DMSO-d6) δ 12.1 (1H), 11.0 (1H), 8.2 (1H), 7.4 - 7.6 (5H), 7.3 (1H), 6.8 - 7.2 (5H), 5.8 (1H), 3.1 (3H), 2.7 (2H), 1.9 - 2.3 (8H).

[0168] Example 31: In Vitro Kinase Inhibition Assay

[0169] The pathogenesis of fibrosis is not yet clear. The current view is that blocking the intracellular signal transduction pathways of VEGFR, FGFR, and / or PDGFR can inhibit the proliferation, migration, and transformation of fibroblasts into myofibroblasts, thereby reducing the degree of fibrosis. Therefore, it is considered that the inhibition of kinases FGFR, VEGFR, and / or PDGFR can improve pulmonary fibrosis. In this example, the inhibitory activities of the compounds of the present invention against kinases FGFR-1, VEGFR2, and PDGFRα were determined.

[0170] Using the Mobility Shift Assay method, the inhibitory activities of the compounds against kinases FGFR-1, VEGFR2, and PDGFRα were detected under the condition of KmATP (KmATP represents the ATP concentration corresponding to half of the maximum reaction rate of the kinase with ATP).

[0171] Corning 3674 white 384-well assay plates, kinase VEGFR2 (Invitrogen), kinase FGFR-1 (Invitrogen), kinase PDGFRα (Invitrogen), and ATP (Sigma) were used. The buffer included 50 mM HEPES (pH 7.5), 0.015% (v / v) Brij-35, 10 mM MgCl2, and 2 mM DTT. The termination solution included 100 mM HEPES (pH 7.5), 0.015% (v / v) Brij-35, 0.2% (v / v) Coating Reagent #3, and 50 mM EDTA. The enzyme solution was obtained by taking a kinase with a concentration (in the unit of kinase titer) 2.5 times and adding it to 1 volume of the buffer. The substrate solution was obtained by taking a substrate "FAM-labeled polypeptide and ATP" with a concentration corresponding to a kinase with a concentration (in the unit of kinase titer) 2.5 times and adding it to 1 volume of the buffer.

[0172] The compounds of this example were diluted with DMSO to a solution with a concentration of 500 μM, and then serially diluted three-fold with DMSO to the lowest concentration of 250 nM, with a total of 10 concentrations. 10 μL of each of these 10 concentrations of the compounds was taken and added to 90 μL of the buffer to obtain 10 concentrations of the compounds to be tested. 5 μL of each of the 10 concentrations of the compounds to be tested was taken and added to 10 μL of the enzyme solution, and incubated at room temperature for 10 minutes; then 10 μL of the substrate solution was added and incubated at 28 °C for an appropriate time (the time was adjusted according to different kinases); then 25 μL of the termination solution was added to terminate the reaction. The values were read.

[0173] The inhibition percentage was calculated according to the following formula:

[0174] Inhibition % = [1 - (A 化合物 - A min ) / (Amax -A min )]×100

[0175] Where A 化合物 is the reading at the concentration of the compound to be tested in this example, A min is the reading without adding kinase, and A max is the reading without adding the compound of this example. The IC 50 values of each compound are shown in Table 1 below.

[0176] Table 1: IC 50 values (unit: nM) of the compounds in this example against kinases VEGFR2, FGFR-1 and PDGFRα

[0177] Compound VEGFR2 FGFR-1 PDGFRα Example Compound W1 W1 W2

[0178] Labeling (grade): W1 is 10 - 3000; W2 is 50 - 3000.

[0179] As can be seen from the results, the IC 50 values of the compounds in this example against VEGFR2 and FGFR-1 are both within 10 - 3000 nM; the IC 50 values against PDGFRα are both within 50 - 3000 nM, indicating that the compounds in this example have inhibition on kinases VEGFR2, FGFR-1 and PDGFRα and have the potential to improve pulmonary fibrosis.

[0180] Example 32: Pharmacokinetics in Rats

[0181] Forty-two male Sprague-Dawley rats, 6 - 9 weeks old, weighing about 220 g, were divided into 7 groups (Compound ND801 group, Compound ND802 group, Compound ND803 group, Compound ND805 group, Compound ND807 group, Compound ND815 group and Nintedanib group), with 6 rats in each group. According to the grouping, a single oral gavage was given with a dose of 30 mg / kg of Compound ND801, Compound ND802, Compound ND803, Compound ND805, Compound ND807, Compound ND815 or Nintedanib, and their pharmacokinetic differences were compared. The rats were fasted 12 hours before dosing. The dosing solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na). Blood was collected from the orbital cavity at the time points of 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after dosing. After separating the plasma from the blood samples, the plasma was stored in a -80°C refrigerator for later use. An LC-MS / MS analytical method was established to determine the plasma samples.

[0182] It can be seen from the experimental results that, compared with nintedanib, the relative bioavailability and / or elimination half-life T of compound ND801, compound ND802, compound ND803, compound ND805, compound ND807 or compound ND815 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max is increased by more than 100%.

[0183] It can be seen from this result that, compared with nintedanib, the compounds ND801, ND802, ND803, ND805, ND807 and / or ND815 of the present invention have better pharmacokinetic properties in rats, indicating better pharmacodynamic and therapeutic effects.

[0184] Example 33: Pharmacokinetics in Rats

[0185] Forty-two male Sprague-Dawley rats, 6-9 weeks old, weighing about 220 g, were divided into 7 groups (compound ND809 group, compound ND810 group, compound ND812 group, compound ND813 group, compound ND814 group, compound ND816 group and nintedanib group), with 6 rats in each group. The rats in each group were given a single intragastric administration of a dose of 30 mg / kg of compound ND809, compound ND810, compound ND812, compound ND813, compound ND814, compound ND816 or nintedanib, and their pharmacokinetic differences were compared. The rats were fasted for 12 hours before dosing. The dosing solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na). Blood was collected from the orbital cavity at the time points of 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after dosing. After separating the plasma from the blood samples, the plasma was stored in a -80 °C refrigerator for later use. An LC-MS / MS analytical method was established to determine the plasma samples.

[0186] It can be seen from the experimental results that, compared with nintedanib, the relative bioavailability and / or elimination half-life T of compound ND809, compound ND810, compound ND812, compound ND813, compound ND814 or compound ND816 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max is increased by more than 100%.

[0187] It can be seen from this result that, compared with nintedanib, the compounds ND809, ND810, ND812, ND813, ND814 and / or ND816 of the present invention have better pharmacokinetic properties in rats, indicating better pharmacodynamic and therapeutic effects.

[0188] Example 34: Inhibiting Bleomycin-Induced Pulmonary Fibrosis in Mice

[0189] The bleomycin (BLM) model is a classic animal model of pulmonary fibrosis. Due to its conformity to many characteristics of pulmonary fibrosis and other fibrotic interstitial lung diseases (ILDs), as well as good reproducibility and inducibility, it has become the most widely used animal model of pulmonary fibrosis. Currently, the evaluation indexes of animal models of pulmonary fibrosis (PF) mainly include observation of the general state of animals; fibrosis-related factors, such as hydroxyproline (HYP); pulmonary function indexes, such as forced vital capacity (FVC), respiratory dynamic compliance (Cdyn), inspiratory airway resistance (Ri), and expiratory airway resistance (Re); and pathological examination of lung tissues, such as the fibrotic area.

[0190] In this example, a pulmonary fibrosis model was established in C57BL / 6 male mice by intratracheal injection of bleomycin. After modeling, compared with the control group of mice, the content of HYP in the lung tissues of the model group was significantly increased (P < 0.01); compared with the control group of mice, both FVC and Cdyn in the model group were significantly decreased (P < 0.01), Ri was significantly increased (P < 0.01), and Re was increased; the lungs of the mice were significantly fibrotic, and the fibrotic area was equal to or greater than 20%. In this example, a comparative study was conducted on the improvement of nintedanib (60 mg / kg) and the compound of the example (40 mg / kg) on pulmonary fibrosis in mice.

[0191] (1) Experimental Animals

[0192] Forty SPF-grade C57BL / 6 male mice, 8 - 10 weeks old, with a body weight of (25 ± 2 g), were allowed to freely eat, drink, and have maintenance feed, and were kept under a day-night alternating cycle at a temperature of 25 ± 2°C and a relative humidity of 50 ± 10%.

[0193] (2) Animal Grouping and Drug Administration

[0194] Forty male C57BL / 6 mice were divided into four groups of 10 mice each, namely the control group, the model group, the nintedanib group, and the example compound group. On the first day, the mice in the model group, the nintedanib group, and the example compound group were modeled with bleomycin (2 mg / kg). The operation was as follows: The mice were anesthetized by intraperitoneal injection of 5% chloral hydrate, and the trachea was isolated and exposed. A 1 mL syringe needle was used to aspirate the bleomycin solution, and the needle was inserted into the trachea of the mice between two tracheal rings, and then the bleomycin solution was injected. After the administration, the mice were held upright and rotated left and right to evenly distribute the bleomycin solution in the lungs. The control group mice were instilled with an equal volume of normal saline into the trachea under the same conditions. On the 8th - 14th days, the mice in the nintedanib group were given 60 mg / kg of nintedanib by gavage every day; the mice in the example compound group were given 40 mg / kg of the example compound by gavage; the control group and the model group were given an equal volume of normal saline respectively. The behaviors, activities, food intake, urine, feces and other symptoms of the animals were observed before and after drug administration every day, and the body weights were measured.

[0195] (3) Data processing

[0196] The experimental data were all expressed as mean ± standard deviation (±s), and analyzed using SPSS 22.0 statistical software. One-way ANOVA was used to compare the differences between groups. p < 0.05 indicated a statistically significant difference; p < 0.01 indicated a significant difference.

[0197] (4) Determination of the content of hydroxyproline (HYP) in lung tissue

[0198] After the mice were sacrificed on the 15th day, the right lungs of the mice in the control group, the model group, the nintedanib group, and the example compound group were minced and mixed evenly, then added with 9 times the volume of precooled normal saline and homogenized. The operation was carried out according to the instructions of the hydroxyproline detection kit, and the hydroxyproline content of the right lungs was calculated. The determination results of the hydroxyproline (HYP) content in the right lungs of the mice are as Figure 1 and Table 2 shows:

[0199] Table 2: Comparison of the hydroxyproline (HYP) content in the right lungs of mice

[0200]

[0201] Labeling (grade): A1 is 100 - 116; A2 is 127 - 148; A3 is 124 - 143; A4 is 108 - 123.

[0202] (5) Detection of mouse lung function

[0203] On the 15th day, mice were anesthetized with 5% chloral hydrate. The trachea was separated layer by layer, and tracheal intubation was performed. The other end of the trachea was connected to the mouse body anchor box, and the body anchor box was sealed. The animal lung function analysis system in the pulmonary function instrument was used to collect forced vital capacity (FVC), respiratory dynamic compliance (Cdyn), expiratory airway resistance (Re), and inspiratory airway resistance (Ri). The FVC measurement results of the mice are shown in Figure 2 and Table 3; the Cdyn measurement results of the mice are shown in Figure 3 and Table 4; the Re measurement results of the mice are shown in Figure 4 ; the Ri measurement results of the mice are shown in Figure 5 .

[0204] Table 3: FVC measurement results of mice

[0205] Group Control Group Model Group Nintedanib Group Example Compound Group Average FVC B1 B2 B3 B4

[0206] Annotation (grade): B1 is 0.78 - 0.92; B2 is 0.33 - 0.51; B3 is 0.52 - 0.62; B4 is 0.62 - 0.72.

[0207] Table 4: Cdyn measurement results of mice

[0208] Group Control Group Model Group Nintedanib Group Example Compound Group Average Cdyn C1 C2 C3 C4

[0209] Annotation (grade): C1 is 0.020 - 0.024; C2 is 0.009 - 0.015; C3 is 0.010 - 0.016; C4 is 0.016 - 0.020.

[0210] (6) Measurement of pulmonary fibrosis area

[0211] After sacrificing the mice on the 15th day, the lung tissues were dehydrated, embedded, sectioned, and stained with HE. The pathological conditions of the lung tissues were observed under a light microscope, and the Image Pro Plus software was used to statistically analyze the pulmonary fibrosis area and calculate the percentage of the pulmonary fibrosis area. The HE staining pictures are shown in Figure 6 ; the percentage of the pulmonary fibrosis area is shown in Figure 7 and Table 5.

[0212] Table 5: Percentage of pulmonary fibrosis area

[0213] Group Model Group Nintedanib Group Example Compound Group Average Area of Pulmonary Fibrosis % D1 D2 D3

[0214] Annotation (grade): D1 is 20 - 27; D2 is 13 - 19; D3 is 7 - 13.

[0215] As can be seen from the above figures and tables, the determination results of hydroxyproline (HYP) in lung tissues showed that the content of hydroxyproline in the lung tissues of the model group was significantly higher than that of the control group; compared with the model group, the content of HYP in the lung tissues of the nintedanib group decreased; compared with the model group, the content of HYP in the lung tissues of the compound group of the examples decreased; and the content of HYP in the lung tissues of the compound group of the examples was less than that of the nintedanib group.

[0216] The results of mouse lung function detection showed that both FVC and Cdyn of the model group were significantly lower than those of the control group; compared with the model group, FVC of the nintedanib group increased somewhat and Cdyn changed little; compared with the model group, both FVC and Cdyn of the compound group of the examples increased significantly; and both FVC and Cdyn of the compound group of the examples were significantly greater than those of the nintedanib group.

[0217] The results of mouse lung function detection showed that both Ri and Re of the compound group of the examples were improved compared with the model group; and the improvement effects of both Ri and Re of the compound group of the examples were significantly better than those of the nintedanib group. The determination results of the pulmonary fibrosis area showed that compared with the model group, the pulmonary fibrosis area (%) of the nintedanib group was significantly reduced; compared with the model group, the pulmonary fibrosis area (%) of the compound group of the examples was significantly reduced; and the pulmonary fibrosis area (%) of the compound group of the examples was significantly less than that of the nintedanib group.

[0218] The above results all showed that the compound of the example (40 mg / kg) had significantly better therapeutic effects on the mouse pulmonary fibrosis model induced by bleomycin than nintedanib (60 mg / kg).

[0219] Example 35: Inhibiting bleomycin-induced pulmonary fibrosis in mice

[0220] In this example, a pulmonary fibrosis model was established in C57BL / 6 male mice by intratracheal injection of bleomycin. A comparative study was conducted on the improvement effects of the compound of this example, compound ND901, and compound ND902 on the pulmonary fibrosis area (%). The structural formulas of compound ND901 and compound ND902 are shown as follows:

[0221]

[0222] After establishing a pulmonary fibrosis model in C57BL / 6 male mice by intratracheal injection of bleomycin, the lungs of the mice were significantly fibrotic, and the fibrosis area was equal to or greater than 20%. In this example, a comparative study was conducted on the improvement of the pulmonary fibrosis area (%) of the compound of the example (40 mg / kg), compound ND901 (40 mg / kg), and compound ND902 (40 mg / kg) in mice.

[0223] (1) Experimental animals

[0224] Twenty-five SPF-grade male C57BL / 6 mice, 8-10 weeks old, weighing (25±2 g), were allowed to eat and drink freely and were fed maintenance feed. They were kept under a day-night cycle at a temperature of 25±2 °C and a relative humidity of 50±10%.

[0225] (2) Animal grouping and administration

[0226] Twenty-five male C57BL / 6 mice were divided into five groups of 5 mice each, namely the control group, the model group, the example compound group, the compound ND901 group, and the compound ND902 group. On the first day, the mice in the model group, the example compound group, the compound ND901 group, and the compound ND902 group were modeled with bleomycin (2 mg / kg). The operation was as follows: The mice were anesthetized by intraperitoneal injection of 5% chloral hydrate, and the trachea was isolated and exposed. A 1 mL syringe needle was used to aspirate the bleomycin solution, which was then inserted into the trachea of the mice between the two tracheal rings, and the bleomycin solution was injected. After the administration, the mice were held upright and rotated left and right to evenly distribute the bleomycin solution in the lungs. The control group mice were instilled with an equal volume of normal saline into the trachea under the same conditions. On days 8-14, the example compound group was given 40 mg / kg of the example compound by gavage daily; the compound ND901 group was given 40 mg / kg of the compound ND901 by gavage; the compound ND902 group was given 40 mg / kg of the compound ND902 by gavage; the control group and the model group were given an equal volume of normal saline respectively. The behavior, activity, food intake, urine, feces and other symptoms of the animals were observed before and after administration every day, and the body weight was measured.

[0227] (3) Data processing

[0228] The experimental data were expressed as mean ± standard deviation (±s), and analyzed using SPSS 22.0 statistical software. One-way ANOVA was used to compare the differences between groups. p<0.05 indicated a statistically significant difference; p<0.01 indicated a significant difference.

[0229] (4) Determination of the pulmonary fibrosis area

[0230] After the mice were sacrificed on the 15th day, the lung tissues were dehydrated, embedded, sectioned, and stained with HE. The pathological changes of the lung tissues were observed under a light microscope, and the pulmonary fibrosis area was statistically analyzed using Image Pro Plus software to calculate the percentage of the pulmonary fibrosis area. The percentage of the pulmonary fibrosis area is shown in Table 6.

[0231] Table 6: Percentage of the pulmonary fibrosis area

[0232] Group Average Area of Pulmonary Fibrosis % Model Group E1 Example Compound E2 Compound ND901 E3 Compound ND902 E3

[0233] Labeling (grade): E1 is 20-28; E2 is 6-13; E3 is 14-20.

[0234] The measurement results of the pulmonary fibrosis area showed that, compared with the model group, the pulmonary fibrosis area (%) in the compound ND901 group and the compound ND902 group decreased; compared with the model group, the pulmonary fibrosis area (%) in the example compound group decreased significantly; and the pulmonary fibrosis area (%) in the example compound group was significantly smaller than that in the compound ND901 group and the compound ND902 group.

[0235] This result indicates that the therapeutic effect of the example compound (40 mg / kg) on the bleomycin-induced mouse pulmonary fibrosis model is significantly better than that of compound ND901 (40 mg / kg) and compound ND902 (40 mg / kg).

[0236] Finally, it is necessary to note that the above detailed description of the specific embodiments of the present invention is only for exemplification purposes, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is one of the compounds shown below:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is methanesulfonate, ethanesulfonate, benzenesulfonate, benzenesulfonate, phosphate, camsylate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, aspartate or glutamate of the compound.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is the ethanesulfonic acid salt of the compound.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The invention can be used for preparing medicines for treating or preventing fibrosis-related diseases.

5. The use according to claim 4, wherein, The compound or a pharmaceutically acceptable salt thereof is used in the preparation of a drug for treating or preventing idiopathic pulmonary fibrosis, giant cell interstitial pneumonia, sarcoidosis, cystic fibrosis, respiratory distress syndrome, drug-induced pulmonary fibrosis, granulomatosis, scleroderma, interstitial lung disease, pneumoconiosis, silicosis, asbestosis, acute lung injury, cardiac fibrosis, cirrhosis, chronic kidney disease, myocardial infarction, heart failure, non-alcoholic fatty liver disease (NASH), and lupus erythematosus.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The invention can be used for preparing medicines for treating and preventing diseases related to excessive or abnormal cell proliferation.

7. The use according to claim 6, wherein, The compound or a pharmaceutically acceptable salt thereof is used in preparing a drug for treating and preventing acute myeloid leukemia, gastric tumors, neuroendocrine tumors, thyroid tumors, melanoma, squamous cell carcinoma, metastatic non-small cell lung cancer, soft tissue sarcoma, pterygium or neovascular eye disease.

8. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a VEGFR receptor inhibitor, a FGFR receptor inhibitor or a PDGFR receptor inhibitor.

9. A drug, characterized in that: The preparation is prepared by taking the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable excipients.

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