Benzofurans, their synthesis methods and applications

Abstract

This invention relates to the field of pharmaceutical synthesis technology, and more specifically, to benzofuran compounds, their synthetic methods, and their applications. The benzofuran compounds are selected from compounds with the following structural formulas: wherein R1 is selected from any one of the functional groups composed of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkyl groups, and R2 is selected from any one of the functional groups composed of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl groups. They can effectively inhibit mutant proteins of EGFR kinase, thereby showing good therapeutic effects on tumors such as lung cancer and glioma.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and more specifically, to benzofuran compounds, their synthesis methods, and their applications. Background Technology

[0002] Epidermal growth factor receptor (EGFR) is an important member of the ErbB family of receptor protein tyrosine kinases (RPTKs), playing a crucial role in the regulation of epithelial cells. Because EGFR mutations and / or overexpression frequently occur in various types of human cancers, EGFR holds significant importance for clinical cancer treatment and new drug development.

[0003] EGFR inhibitors, as typical small-molecule anticancer drugs, have been widely used in the treatment of malignant tumors in recent years. However, multiple drug resistance mutations in the EGFR tyrosine kinase domain have greatly hindered the clinical application of EGFR inhibitors. To overcome this difficulty, EGFR-TKIs have now been developed up to the fourth generation.

[0004] Benzofuran structures are important components of the structures of many complex small-molecule drugs, such as morphine and rifamycin. Currently, various benzofuran derivatives have been applied in various clinical treatment areas, such as mental illness, central nervous system-related diseases, inflammation, diabetes, hormonal imbalances, kidney disease, and cardiovascular disease, exhibiting antipyretic, anticoagulant, analgesic, antiviral, anti-HIV / HCV, antibacterial, anti-tuberculosis, and antifungal properties. However, there are few reports of benzofuran derivatives acting as EGFR inhibitors.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The purpose of this invention is to provide benzofuran compounds, their synthesis methods, and their applications. This invention provides a novel benzofuran compound that can effectively inhibit mutant proteins of EGFR kinase, thereby exhibiting good therapeutic effects against tumors such as lung cancer and glioma.

[0007] This invention is implemented as follows:

[0008] In a first aspect, the present invention provides a benzofuran compound selected from compounds shown in the following structural formulas:

[0009] Wherein, R1 is selected from any one of the functional groups composed of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkyl, and R2 is selected from any one of the functional groups composed of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

[0010] Secondly, the present invention provides a method for synthesizing the benzofuran compounds described in the foregoing embodiments, comprising: synthesizing according to the following synthetic route:

[0011]

[0012] Thirdly, the present invention provides the use of the benzofuran compounds described in the foregoing embodiments in the preparation of EGFR kinase inhibitors.

[0013] Fourthly, the present invention provides the use of the benzofuran compounds described in the foregoing embodiments in the preparation of medicaments for treating antitumor diseases;

[0014] Preferably, the tumor includes lung cancer and glioma.

[0015] The present invention has the following beneficial effects: The embodiments of the present invention provide a novel benzofuran compound that has a good inhibitory effect on mutant proteins of EGFR kinase and also has a good therapeutic effect on tumors such as lung cancer and glioma, and can be applied to the treatment of tumors. Detailed Implementation

[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0017] This invention provides a benzofuran compound selected from compounds with the following structural formulas:

[0018] Wherein, R1 is selected from any one of the functional groups composed of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkyl, and R2 is selected from any one of the functional groups composed of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

[0019] Specifically, the substituted or unsubstituted aryl group in R1 includes substituted or unsubstituted phenyl groups; the substituted phenyl group can be any one of C1-C3 alkyl substituted phenyl, halogen substituted phenyl and biphenyl; for example, methyl substituted phenyl, ethyl substituted phenyl, chloro substituted phenyl, bromo substituted phenyl and biphenyl, etc.

[0020] It should be noted that substitution can be monosubstituted, for example, meta-methyl substituted phenyl, para-methyl substituted phenyl, ortho-methyl substituted phenyl, ethyl substituted phenyl, n-propyl substituted phenyl, and halogen substituted phenyl can also be monosubstituted as described above. Substitution can also be disubstituted, trisubstituted, or polysubstituted, for example, 2,3-2-methyl substituted phenyl, 2,4-2-methyl substituted phenyl, 3,4-2-ethyl substituted phenyl, 3-methyl-4-ethyl substituted phenyl, 4-methyl-6-n-propyl substituted phenyl, 1-methyl-3-chloro substituted phenyl, 2,5-dichloro substituted phenyl, 2,chloro-6-bromo substituted phenyl, etc.

[0021] Further, the heteroatom of the substituted or unsubstituted heteroaryl group in R1 is selected from at least one of O, S, and N; the substituted or unsubstituted heteroaryl group in R1 includes substituted or unsubstituted C4-C6 heteroaryl groups; for example, the substituted or unsubstituted heteroaryl group in R1 includes any one of substituted or unsubstituted furan, substituted or unsubstituted pyridine, substituted or unsubstituted thiophene, substituted or unsubstituted piperidine, and substituted or unsubstituted pyrazole; specifically, the substituted or unsubstituted heteroaryl group in R1 includes any one of furan, C1-C3 alkyl-substituted furan, halogen-substituted furan, nitro-substituted furan, pyridine, C1-C3 alkyl-substituted pyridine, halogen-substituted pyridine, nitro-substituted pyridine, thiophene, C1-C3 alkyl-substituted thiophene, halogen-substituted thiophene, nitro-substituted thiophene, piperidine, C1-C3 alkyl-substituted piperidine, halogen-substituted piperidine, nitro-substituted piperidine, pyrazole, C1-C3 alkyl-substituted pyrazole, halogen-substituted pyrazole, and nitro-substituted pyrazole.

[0022] It should be noted that the above substitutions can be monosubstituted, disubstituted, trisubstituted, or other multiple substituted substances, and the C1-C3 alkyl group can be methyl, ethyl, n-propyl, or isopropyl, and the halogen can be chlorine or bromine.

[0023] The substituted or unsubstituted alkyl group in R1 includes substituted or unsubstituted C1-C10 alkyl groups; preferably substituted or unsubstituted C1-C6 alkyl groups; the substituents of the substituted alkyl group in R1 include any one of substituted or unsubstituted phenyl, amino, halogen, and nitro groups. For example, the alkyl group can be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-(iso)propyl, and substituted or unsubstituted n-(iso, tert-)butyl, etc.

[0024] Further, R2 is a substituted or unsubstituted aryl substituted or unsubstituted phenyl group; R2 is selected from any one of substituted or unsubstituted aryl groups including phenyl, C1-C3 alkyl substituted phenyl, halogen substituted phenyl and biphenyl; R2 is selected from any one of substituted or unsubstituted aryl groups including phenyl, methyl substituted phenyl, ethyl substituted phenyl, chloro substituted phenyl, bromo substituted phenyl and biphenyl.

[0025] It should be noted that substitution can be monosubstituted, for example, meta-methyl substituted phenyl, para-methyl substituted phenyl, ortho-methyl substituted phenyl, ethyl substituted phenyl, n-propyl substituted phenyl, and halogen substituted phenyl can also be monosubstituted as described above. Substitution can also be disubstituted, trisubstituted, or polysubstituted, for example, 2,3-2-methyl substituted phenyl, 2,4-2-methyl substituted phenyl, 3,4-2-ethyl substituted phenyl, 3-methyl-4-ethyl substituted phenyl, 4-methyl-6-n-propyl substituted phenyl, 1-methyl-3-chloro substituted phenyl, 2,5-dichloro substituted phenyl, 2,chloro-6-bromo substituted phenyl, etc.

[0026] The heteroatom of the substituted or unsubstituted heteroaryl group in R2 is selected from at least one of O, S and N; the substituted or unsubstituted heteroaryl group in R2 includes substituted or unsubstituted C4-C6 heteroaryl groups; for example, the substituted or unsubstituted heteroaryl group in R2 includes any one of substituted or unsubstituted pyridine and substituted or unsubstituted thiophene; specifically, the following groups can be selected: any one of pyridine, C1-C3 alkyl-substituted pyridine, halogen-substituted pyridine, nitro-substituted pyridine, thiophene, C1-C3 alkyl-substituted thiophene, halogen-substituted thiophene and nitro-substituted thiophene in R2.

[0027] It should be noted that the above substitutions can be monosubstituted, disubstituted, trisubstituted, or other multiple substituted substances, and the C1-C3 alkyl group can be methyl, ethyl, n-propyl, or isopropyl, and the halogen can be chlorine or bromine.

[0028] The substituted or unsubstituted cycloalkyl group in R2 includes substituted or unsubstituted C3-C10 cycloalkyl groups; preferably substituted or unsubstituted C3-C6 cycloalkyl groups; the substituents in the substituted cycloalkyl group in R2 include any one of substituted or unsubstituted phenyl, amino, halogen and nitro groups; specifically, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl and other cycloalkyl groups can be selected.

[0029] The heteroatom in the substituted or unsubstituted heterocyclic alkyl group of R2 is selected from at least one of O, S, and N; the substituted or unsubstituted heterocyclic alkyl group of R2 includes substituted or unsubstituted C2-C6 heterocyclic alkyl groups; wherein the substituent in the substituted heterocyclic alkyl group of R2 includes any one of substituted or unsubstituted phenyl, C1-C5 alkyl, amino, halogen, and nitro groups. For example, tetrahydrofuran, morpholine, hexahydropiperidine, azircyclic octyl, oxazircyclic heptyl, and azircyclic heptyl can be selected.

[0030] Benzofuran compounds are selected from any one of the compounds shown in the following structural formulas:

[0031]

[0032] It should be noted that the symbols listed below the compounds in the above structural formulas are the corresponding compound labels.

[0033] Secondly, embodiments of the present invention provide a method for synthesizing the above-mentioned benzofuran compounds, comprising: synthesizing according to the following synthetic route:

[0034]

[0035] Specifically, step i includes: performing a deesterification reaction by mixing compound M-1 with a strong base;

[0036] Step ii involves mixing compound M-2 with an acyl chloride reagent to carry out an acylation reaction;

[0037] Step iii involves mixing compound M-3 and compound M-4 in a molar ratio of 1:0.8-1 and reacting them.

[0038] Step iv involves mixing compound M-5 with a reducing agent to carry out a reduction reaction;

[0039] Step v involves: mixing compound M-7 with a strong base to carry out a hydrogenation reaction;

[0040] Step vi involves reacting compound M-8 with a chlorine-containing reagent to undergo a chlorine substitution reaction;

[0041] Step vii involves mixing M-6 and M-9 in a molar ratio of 1:2.5-3.5 and reacting them.

[0042] The overall reaction process is as follows: Ethyl 5-nitrobenzofuran-2-carboxylate (M-1) is hydrolyzed under the action of a strong base (e.g., NaOH) to obtain the corresponding carboxylic acid (M-2). Subsequently, compound M-2 reacts with an acyl chloride reagent (thionyl chloride (SOCl2)) under the catalysis of N,N-dimethylformamide (DMF) to generate the corresponding acyl chloride (M-3). Due to its reactive nature, M-3 immediately undergoes condensation with the corresponding amine (M-4) under the neutralization of triethylamine (Et3N) to obtain the corresponding amide (M-5). The nitro group of compound M-5 is reduced to an amino group under the action of zinc powder and ammonium chloride to obtain compound M-6. For the final condensation reaction, the corresponding aldehyde compound (M-7) needs to be reduced with sodium borohydride to obtain the corresponding hydroxyl compound (M-8), and then M-8 undergoes a substitution reaction under the catalysis of DMF and SOCl2 to obtain the corresponding chloride (M-9). Finally, M-6 and M-9 reacted via the Buchwald reaction to yield the final products A1-24.

[0043] Each reaction step requires post-processing to obtain compounds with higher purity. Post-processing methods include pH adjustment, rotary evaporation, drying, and extraction, which will not be described in detail in the embodiments of this invention.

[0044] The benzofuran compounds provided in this invention have a good inhibitory effect on mutant proteins of EGFR kinase. Therefore, these benzofuran compounds can be used to prepare EGFR kinase inhibitors.

[0045] Furthermore, the benzofuran compounds provided in the embodiments of the present invention have good therapeutic effects on tumors such as lung cancer and glioma, and therefore, they can be used to prepare drugs for treating anti-tumor diseases.

[0046] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0047] Example 1

[0048] This invention provides a method for synthesizing a benzofuran compound (denoted as A1), following the synthetic route described below:

[0049]

[0050] The specific steps are as follows:

[0051] Synthesis of compound M-2:

[0052] Add 2 g (8.5 mmol) of the synthetic starting material M-1 (a type A compound) to a 25 mL round-bottom flask, followed by 1.02 g (25.5 mmol) of NaOH. Dissolve the mixture in 10 mL of methanol and stir in an oil bath at 60 °C. TLC monitoring can be used during stirring, with a petroleum ether (PE) : ethyl acetate (EA) ratio of 3:1 as the developing solvent. The reaction is complete after approximately 12 hours. The reaction flask is then removed and placed in a rotary evaporator to remove most of the methanol from the reaction solution through vacuum distillation. Next, 20 mL of ultrapure water is added to the reaction flask, and the pH of the solution is adjusted to a weakly acidic level with dilute hydrochloric acid. The product precipitates from the water, and after multiple filtrations, a moist product is obtained. The product is then freeze-dried for 12 hours to obtain a dry, yellow powder, M-2, which is then stored at 4 °C for later use.

[0053] The characterization data of the obtained intermediate M-2 are: purity > 95%. 1 H NMR(400MHz, DMSO-d6)δ12.49(s,1H),8.48(d,J=1.5Hz,1H),8.29–8.02(m,2H),7.83(d,J=1.6Hz,1H).HRMS(ESI)m / z:(M+H)+calcd for C9H5NO5:207.0168; found:207.0169.

[0054] Synthesis of M-3 compounds:

[0055] 1 g of intermediate M-2 was placed in a 25 mL round-bottom flask, and 10 mL of thionyl chloride (SOCl2) was added to dissolve M-2. Then, 3 drops of DMF were added as a catalyst. The reaction was carried out at 30 °C. During the reaction, the turbid solution clearly became clear. After 1 hour, the reaction was monitored by TLC. The specific monitoring method was to add one drop of the reaction solution to each of the EP tubes containing anhydrous dichloromethane and methanol, respectively. Two distinct spots were observed on the silica gel plate after development (PE:EA = 3:1), indicating that the reaction was complete. Subsequently, the reaction solution was evaporated to dryness using a rotary evaporator, and anhydrous dichloromethane was added repeatedly to the round-bottom flask and evaporated to dryness to remove excess thionyl chloride from the product. A pale yellow solid, intermediate M-3, was then obtained and immediately used in the next reaction step.

[0056] Synthesis of M-5 compounds:

[0057] 440 μL (4.03 mmol) of M-4a was measured into a 25 mL round-bottom flask, and 5 mL of anhydrous dichloromethane was added and mixed thoroughly. The flask was then placed in an ice-water bath. 1.09 g (4.83 mmol) of M-3 obtained in the previous step was dissolved in 3 mL of anhydrous DCM and gradually added dropwise to the round-bottom flask in the ice-water bath, stirring constantly. Then, 2.24 mL (16.11 mmol) of triethylamine was slowly added dropwise to the round-bottom flask in the ice-water bath. When the reaction mixture no longer produced strong fumes while stirring, the reaction was transferred to an oil bath at 30°C to continue the reaction. The reaction was monitored by TLC (evolving solvent: PE:EA = 3:1). The reaction was complete after approximately 6 hours. The dichloromethane in the reaction solution was then evaporated to dryness using a rotary evaporator. 10 ml of ultrapure water was added to the flask, and the flask was ultrasonically cleaned for 10 min. The mixture was then filtered, and the precipitate was washed several times with ultrapure water. The precipitate was collected and freeze-dried to obtain the white solid product M-5, which was stored at 4°C for later use.

[0058] The characterization data of the obtained intermediate M-5 are: purity > 95%. 1 H NMR(400MHz, DMSO-d6)δ8.56(d,J=1.7Hz,1H),8.35(d,J=7.9Hz,1H),8.18–7.97(m,3H),7.57 (dd,J=6.9,2.1Hz,1H),6.35–6.20(m,2H),4.50(d,J=7.7Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 14 H 10 N2O5:268.0592; found:268.0590.

[0059] Synthesis of intermediate M-6:

[0060] Weigh 1 g (3.38 mmol) of M-5a into a 25 mL round-bottom flask, and simultaneously weigh 2.21 g (33.8 mmol) of zinc powder and 1.81 g (33.8 mmol) of ammonium chloride into the flask. Dissolve the reactants in 15 mL of methanol. The reaction was carried out in an oil bath at 40 °C, and the reaction process could be monitored by TLC (developing solvent: PE:EA = 1:1). After the reaction was complete, the reaction solution was filtered, and the precipitate was washed several times with methanol. Then, the filtrate was evaporated to dryness using a rotary evaporator to obtain the orange solid product M-6, which was stored in a refrigerator at 4 °C for later use.

[0061] The characterization data for intermediate M-6 are: purity > 95%. 1H NMR(400MHz, DMSO-d6)δ8.42(t,J=7.9Hz,1H),7.87(d,J=1.5Hz,1H),7.62–7.52(m,3H),6.86(dd,J= 7.5,1.4Hz,1H),6.36–6.26(m,2H),5.15(s,2H),4.62(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcd forC 14 H 12 N2O3:256.0851; found:256.0848.

[0062] Synthesis of intermediate M-8:

[0063] 1 g of M-7f (9.4 mmol) and 367 mg of sodium borohydride were weighed into a 25 mL round-bottom flask. The two were then dissolved in 10 mL of ethanol, and the reaction was stirred at room temperature. The reaction was monitored by TLC (PE:EA = 1:1 as the developing solvent). After approximately 6 hours, the reaction mixture was evaporated to dryness, and the product was extracted multiple times with water and dichloromethane. The collected dichloromethane layer was washed with saturated brine, and the collected dichloromethane solution was then evaporated to dryness, yielding a colorless oily product, M-8f, which was stored at 4 °C for later use.

[0064] The characterization data for intermediate M-8 are: purity > 95%. 1 H NMR(400MHz, DMSO-d6)δ7.33(dt,J=17.3,3.4Hz,5H),4.70(d,J=6.3Hz,2H),3.91(t,J=6.4Hz,1H).HRMS(ESI)m / z:(M+H)+calcd for C7H8O:108.0575; found:108.0575.

[0065] Synthesis of intermediate M-9:

[0066] 500 μL (4.8 mmol) of M-8f was measured into a 10 mL round-bottom flask, and 3 mL of thionyl chloride was used as the solvent for this reaction. Two drops of DMF were added as a catalyst, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC (PE:EA = 1:1 as the developing solvent), and the reaction was completed after about 3 hours. After the reaction was completed, the reaction solution was evaporated to dryness using a rotary evaporator, and excess thionyl chloride was evaporated several times using anhydrous dichloromethane to obtain a pale yellow powder product, M-9f, which was stored in a refrigerator at 4 °C for later use.

[0067] The characterization data for intermediate M-9 are: purity > 95%. ¹H NMR (400 MHz, DMSO-d6) δ 7.46–7.36 (m, 5H), 4.62 (s, 2H). HRMS (ESI) m / z: (M+H)+calcd for C7H7Cl: 120.0238; found: 120.0236.

[0068] Synthesis of final product A1:

[0069] 200 mg (0.75 mmol) of M-6a and 285 mg (2.25 mmol) of M-9 were weighed into a 10 mL round-bottom flask. Then, 518 mg (3.76 mmol) of potassium carbonate was weighed into the flask, followed by the addition of 3.5 mL of DMF to dissolve the reactants. The flask was then placed in an oil bath at 100 °C for the reaction. The reaction was monitored by TLC (PE:EA = 1:1 as the developing solvent), and the reaction was completed after approximately 7 hours. After the reaction, the reaction solution was extracted with water and dichloromethane, and the collected dichloromethane solution was washed with saturated saline solution. After drying with anhydrous sodium sulfate, the collected dichloromethane solution was evaporated to dryness. The reactants were then transferred to a 4 g silica gel column using a dry loading method, and column chromatography was performed using an automated column chromatography system with a PE:EA = 1:1 ratio. The reaction product spots were detected by TLC comparison, and the collected product was then evaporated to obtain the gray powdery final product A1, which was then stored in a refrigerator at -20°C for later use.

[0070] Examples 2-28

[0071] The benzofuran compounds (correspondingly labeled A2-A28) corresponding to Examples 2-28 were synthesized using the same synthesis method as in Example 1. The synthesis methods are basically the same, except that the reactants and reaction conditions are modified accordingly. The reaction conditions are also within the scope of the embodiments of this invention and will not be described in detail here.

[0072] The specific structures of the benzofuran compounds prepared in Examples 1-28 are as follows:

[0073]

[0074] The above A1-A28 were characterized, and the characterization data are as follows:

[0075] A1: 5-(benzylamino)-N-(furan-2-ylmethyl)benzofuran-2-carboxamide

[0076] Purity > 95%. 1H-NMR (400MHz, DMSO-d6) δ8.38(t,,J=7.9Hz,1H),7.66(d,J=3.7Hz,2H),7.48(d,J=7.5Hz,1H),7.42–7.17(m,6H),6.48 (dd,J=7.6,1.4Hz,1H),6.37–6.23(m,3H),4.46(d,J=7.9Hz,2H),4.37(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcdfor C 21 H 18 N2O3:346.1317; found:346.1322.

[0077] A2: 5-(benzylamino)-N-(pyridin-2-ylmethyl)benzofuran-2-carboxamide

[0078] Purity > 95%. 1 H-NMR(400MHz,DMSO-d6)δ8.71–8.27(m,2H),7.73(td,J=7.5,1.5Hz,1H),7.6 7(s,1H),7.61(d,J=1.4Hz,1H),7.53–7.44(m,2H),7.38(s,1H),7.36(s,1H),7 .30(s,1H),7.30–7.18(m,1H),6.48(dd,J=7.4,1.6Hz,1H),6.34(t,J=8.0Hz, 1H),4.55(d,J=8.9Hz,2H),4.37(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcd forC 22 H 19 N3O2:357.1477; found:357.1484.

[0079] A3: 5-(benzylamino)-N-(thien-2-ylmethyl)benzofuran-2-carboxamide

[0080] Purity > 95%. 1H-NMR (400MHz, DMSO-d6) δ8.64(t,J=7.9Hz,1H),7.66(d,J=7.4Hz,2H),7.48(d,J=7.5Hz,1H),7.40–7.23(m,6H),7.05–6.91(m,2 H),6.48(dd,J=7.5,1.6Hz,1H),6.30(t,J=8.0Hz,1H),4.61(d,J=7.9Hz,2H),4.36(d,J=8.0Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 18 N2O2S:362.1089; found:362.1090.

[0081] A4: 5-(benzylamino)-N-(pyridin-3-ylmethyl)benzofuran-2-carboxamide

[0082] Purity > 95%. 1 H-NMR(400MHz,DMSO-d6)δ8.62(t,J=9.8Hz,1H),8.57–8.53(m,1H),8.46(dd,J=7 .6,1.6Hz,1H),7.72(d,J=7.5Hz,1H),7.67(s,1H),7.62(d,J=1.7Hz,1H),7.48(d ,J=7.5Hz,1H),7.42–7.21(m,6H),6.48(dd,J=7.5,1.6Hz,1H),6.34(t,J=8.0Hz, 1H),4.52(d,J=9.8Hz,2H),4.37(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcdfor C 22 H 19 N3O2:357.1477; found:357.1480.

[0083] A5: 5-(benzylamino)-N-((1-methylpiperidin-4-yl)methyl)benzofuran-2-carboxamide

[0084] Purity > 95%. 1H-NMR(400MHz,DMSO-d6)δ9.13(t,J=7.5Hz,1H),8.08–7.78(m,2H),7.63(d, J=7.5Hz,1H),7.51–7.06(m,5H),6.48(dd,J=7.5,1.6Hz,1H),6.33(t,J=8.1 Hz,1H),4.37(d,J=8.1Hz,2H),3.32(t,J=7.3Hz,2H),3.04–2.79(m,2H),2.7 1–2.46(m,2H),2.28(s,3H),1.89–1.55(m,5H).HRMS(ESI)m / z:(M+H)+calcd for C 23 H 27 N3O2:377.4880; found:377.4883.

[0085] A6: 5-(benzylamino)-N-((1-methyl-1H-pyrazol-3-yl)methyl)benzofuran-2-carboxamide

[0086] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ8.73(t,J=8.7Hz,1H),7.78–7.41(m,4H),7.40–7.13(m,6H),6.48–6.42(m,1H),6.40(d,J=2.7 Hz,1H),6.39(d,J=2.4Hz,1H),4.52(d,J=8.7Hz,2H),4.47(d,J=8.0Hz,2H),3.95(s,3H).HRMS(ESI)m / z:(M+H)+calcdfor C 21 H 20 N4O2:360.1580; found:360.1505.

[0087] A7: 5-(benzylamino)-N-(2-(isopropylamino)ethyl)benzofuran-2-carboxamide

[0088] Purity > 95%. 1H-NMR(400MHz,DMSO-d6)δ8.62(t,J=7.7Hz,1H),7.63(dd,J=23.7,6.7Hz,3H),7.3 2(ddd,J=25.0,17.7,7.1Hz,5H),7.13(dd,J=7.4,1.5Hz,1H),6.65–6.24(m,1H),4 .37(d,J=7.9Hz,2H),3.41(q,J=7.2Hz,2H),3.31–3.14(m,1H),3.08–2.94(m,1H), 2.82(q,J=7.2Hz,2H),1.22(dd,J=6.9,2.5Hz,6H).HRMS(ESI)m / z:(M+H)+calcdfor C 21 H 25 N3O2:351.1974; found:351.5670.

[0089] A8: 5-(benzylamino)-N-pentylbenzofuran-2-carboxamide

[0090] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ8.12(t,J=6.8Hz,1H),7.65(dd,J=11.0,1.7Hz,2H),7.62–7.07(m,6H),6.87(dd,J=7.5,1.5Hz,1H),6.42–6.22(m,1H ),4.46(d,J=8.0Hz,2H),3.66–3.44(m,2H),1.88–1.63(m,3H),1.67–1.34(m,J=4.1Hz,4H),1.08(t,J=7.7Hz,3H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 24 N2O2:336.1838; found:336.4450.

[0091] A9: N-Benzyl-5-((pyridin-2-ylmethyl)amino)benzofuran-2-carboxamide

[0092] Purity > 95%. 1H-NMR (400MHz, DMSO-d6) δ8.68–8.46(m,1H),8.43(dd,J=7.6,1.6Hz,1H),7.92–7.70(m,1H),7.74–7.57(m,2H),7.60–7.45(m,2H),7.42 –6.95(m,6H),6.41(dd,J=7.5,1.4Hz,1H),6.31–6.19(m,1H),4.72(d,J=8.1Hz,2H),4.45(d,J=8.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 22 H 19 N3O2:357.1477; found:357.1482.

[0093] A10: N-(pyridin-2-ylmethyl)-5-((pyridin-2-methyl)amino)benzofuran-2-carboxamide

[0094] Purity > 95%. 1 H-NMR(400MHz,DMSO-d6)δ8.79(t,J=9.0Hz,1H),8.65(dd,J=7.4,1.6Hz,1H),8.5 1(dd,J=7.6,1.5Hz,1H),7.98–7.72(m,2H),7.66(d,J=1.9Hz,1H),7.60–7.47(m, 2H),7.34(ddd,J=19.8,7.5,1.5Hz,2H),6.49(d,J=1.4Hz,0H),6.33(t,J=8.1Hz, 1H),4.81(d,J=8.1Hz,2H),4.75(d,J=8.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcdfor C 21 H 18 N4O2:358.1430; found:358.1436.

[0095] A11: 5-((pyridin-2-ylmethyl)amino)-N-(thiophen-2-ylmethyl ester)benzofuran-2-carboxamide

[0096] Purity > 95%. 1H-NMR(400MHz,DMSO-d6)δ8.64(t,J=7.9Hz,1H),8.39(dd,J=7.4,1.7Hz,1H), 7.83–7.55(m,3H),7.51(td,J=7.7,6.9,2.3Hz,2H),7.35(ddd,J=17.0,7.3,1 .7Hz,2H),7.13–6.81(m,2H),6.48(dd,J=7.5,1.6Hz,1H),6.31(t,J=8.0Hz,1 H),4.78(d,J=8.1Hz,2H),4.71(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 20 H 17 N3O2S:363.1041; found:363.1044.

[0097] A12: N-(furan-2-ylmethyl)-5-(pyridin-2-ylmethylamino)benzofuran-2-carboxamide

[0098] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ8.70(dd,J=7.4,1.6Hz,1H),8.49(t,J=7.9Hz,1H),7.74–7.62(m,3H),7.48(td,J=7.5,1.5Hz,1H),7.38(t,J=7.7Hz,3H ),6.48(dd,J=7.5,1.5Hz,1H),6.38(t,J=7.5Hz,1H),6.35–6.16(m,2H),4.82(d,J=8.1Hz,2H),4.70(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 20 H 17 N3O3:347.1270; found:347.1277.

[0099] A13: 5-((pyridin-2-ylmethyl)amino)-N-(pyridin-3-ylmethyl)benzofuran-2-carboxamide

[0100] Purity > 95%. 1H-NMR(400MHz,DMSO-d6)δ8.95–8.81(m,1H),8.61–8.45(m,3H),7.81–7.68(m,4H),7.55–7.37(m,4H),6.6 2(dd,J=7.5,1.4Hz,1H),6.37(t,J=8.0Hz,1H),4.79(dd,J=19.2,8.8Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 18 N4O2:358.1430; found:358.1434.

[0101] A14: N-Benzyl-5-((thien-2-ylmethyl)amino)benzofuran-2-carboxamide

[0102] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.39–9.17(m,1H),7.98(d,J=10.1Hz,2H),7.52(t,J=5.4Hz,2H),7.28(ddd,J=18.3,6.5,3.8Hz, 5H),7.11–6.90(m,2H),6.56(dd,J=7.5,1.5Hz,1H),6.28–6.15(m,1H),4.84(t,J=8.4Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 18 N2O2S:362.1089; found:362.1089.

[0103] A15: N-(pyridin-3-ylmethyl)-5-(thiophen-2-ylmethyl)amino)benzofuran-2-carboxamide

[0104] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.29–9.17(m,1H),8.68(dd,J=7.8,1.4Hz,2H),8.05–7.76(m,3H),7.70–7.46(m,3H),7.18–6.91(m, 2H),6.48(dd,J=7.5,1.6Hz,1H),6.38–6.23(m,1H),4.81(d,J=6.8Hz,2H),4.65(d,J=9.7Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 20 H 17N3O2S:363.1041; found:363.1045.

[0105] A16: N-(thien-2-ylmethyl)-5-((thien-2-methyl)amino)benzofuran-2-carboxamide

[0106] Purity > 95%. 1 H-NMR(400MHz,DMSO-d6)δ9.38(t,J=8.0Hz,1H),8.15–7.94(m,3H),7.70–7.52(m,2H),7.2 2–6.91(m,4H),6.67–6.35(m,2H),4.73(dd,J=9.2,7.5Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 19 H 16 N2O2S2:368.0653; found:368.0651.

[0107] A17: N-(furan-2-ylmethyl)-5-(thiophen-2-ylmethylamino)benzofuran-2-carboxamide

[0108] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.19(t,J=7.9Hz,1H),8.30–8.11(m,2H),7.83–7.60(m,3H),7.23–7.12(m,2H),7.08(dd,J=7.5,1. 5Hz,1H),6.68(t,J=7.0Hz,1H),6.45–6.27(m,2H),5.02(d,J=7.0Hz,2H),4.95(d,J=7.9Hz,2H).HRMS(ESI)m / z:(M+H)+calcd for C 19 H 16 N2O3S:352.0882; found:352.0883.

[0109] A18: N-Benzyl-5-((cyclohexylmethyl)amino)benzofuran-2-carboxamide

[0110] Purity > 95%. 1H-NMR (400MHz, DMSO-d6) δ9.27(t,J=9.0Hz,1H),7.76–7.16(m,9H),6.78–6.55(m,1H),6.38(t,J= 6.4Hz,1H),4.54(d,J=8.9Hz,2H),3.46(t,J=6.7Hz,2H),1.79(d,9H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 22 N2O3:362.2002; found:362.2004.

[0111] A19: 5-((cyclohexylmethyl)amino)-N-(thien-2-ylmethyl)benzofuran-2-carboxamide

[0112] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.27(t,J=8.0Hz,1H),7.76–7.38(m,4H),7.14–6.84(m,3H),6.19(t,J=6 .4Hz,1H),4.65(d,J=8.1Hz,2H),3.69(t,J=6.8Hz,2H),1.54(d,12H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 22 N2O3:368.1567; found:368.1565.

[0113] A20: N-Benzyl-5-(((tetrahydrofuran-2-yl)methyl)amino)benzofuran-2-carboxamide

[0114] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.22(t,J=8.9Hz,1H),7.79(d,J=6.3Hz,2H),7.68–7.47(m,4H),7.33(dt,J=12.3,7.7Hz,2H),6.9 9–6.68(m,2H),4.78–4.41(m,2H),4.32–3.96(m,3H),3.86(t,J=6.8Hz,2H),2.13–1.80(m,4H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 22 N2O3:350.1630; found:350.1638.

[0115] A21: N-(furan-2-ylmethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)benzofuran-2-carboxamide

[0116] Purity > 95%. 1 H-NMR(400MHz,DMSO-d6)δ9.10(t,J=7.9Hz,1H),7.73(d,J=1.6Hz,1H),7.6 7–7.47(m,3H),6.84(t,J=6.7Hz,1H),6.59–6.26(m,4H),4.50(d,J=7.9Hz,2 H),4.40–4.18(m,1H),3.92(tt,J=7.0,4.4Hz,2H),3.75–3.47(m,2H),1.95 (pq,J=6.7,3.2,2.4Hz,3H),1.88–1.68(m,1H).HRMS(ESI)m / z:(M+H)+calcd for C 19 H 20 N2O4:340.1423; found:340.1414.

[0117] A22: N-Benzyl-5-((pyridin-3-ylmethyl)amino)benzofuran-2-carboxamide

[0118] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.13(t,J=9.0Hz,1H),8.85(d,J=1.4Hz,1H),8.31(dd,J=7.4,1.4Hz,1H),7.99–7.66(m,4H),7.56–7.44( m,2H),7.41–7.24(m,2H),6.52(dd,J=7.5,1.5Hz,1H),6.50–6.34(m,1H),4.66(dd,J=32.2,8.9Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 22 H 19 N3O2:357.1477; found:357.1470.

[0119] A23: 5-(pyridin-3-ylmethyl)amino)-N-(thiophen-2-ylmethyl)benzofuran-2-carboxamide

[0120] Purity > 95%. 1H-NMR (400MHz, DMSO-d6) δ9.30(t,J=8.0Hz,1H),9.17(d,J=1.5Hz,1H),8.46(dd,J=7.5,1.7Hz,1H),8.05–7.74(m,3H ),7.63–7.31(m,3H),7.26–7.01(m,2H),6.80–6.60(m,2H),4.73(dd,J=53.6,8.4Hz,4H).HRMS(ESI)m / z:(M+H)+calcd forC 20 H 17 N3O2S:363.1041; found:363.1043.

[0121] A24: N-(furan-2-ylmethyl)-5-(pyridin-3-ylmethyl)amino)benzofuran-2-carboxamide

[0122] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.55(t,J=7.9Hz,1H),9.35(td,J=3.6,1.4Hz,2H),8.09(dd,J=21.5,7.0Hz ,3H),7.80–7.44(m,3H),6.51–6.23(m,4H),4.69(dd,J=54.6,8.3Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 20 H 17 N3O3:347.1270; found:347.1272.

[0123] A25: N-(pyridin-3-ylmethyl)-5-((pyridin-3-methyl)amino)benzofuran-2-carboxamide

[0124] Purity > 95%. 1 H-NMR(400MHz,DMSO-d6)δ9.67(t,J=9.8Hz,1H),8.82(dd,J=12.8,1.5Hz,2H),8.73–8.61(m,2H),7.96–7.75 (m,3H),7.65–7.44(m,5H),6.42(t,J=8.7Hz,1H),4.77(dd,J=32.2,9.3Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 18 N4O2:358.1430; found:358.1433.

[0125] A26: N-Benzyl-5-((thien-3-ylmethyl)amino)benzofuran-2-carboxamide

[0126] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.17(t,J=8.9Hz,1H),8.07(dd,J=31.7,7.5Hz,3H),7.63–7.55(m,1H),7.45–7.23(m,5H),7.02( d,J=5.1Hz,2H),6.72–6.56(m,1H),6.40(dd,J=7.5,1.5Hz,1H),4.61(dd,J=11.2,8.4Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 21 H 18 N2O2S:362.1089; found:362.1093.

[0127] A27: N-(thien-2-ylmethyl)-5-((thien-3-ylmethyl)amino)benzofuran-2-carboxamide

[0128] Purity > 95%. 1 H-NMR (400MHz, DMSO-d6) δ9.32(t,J=8.0Hz,1H),7.59(s,1H),7.54–7.38(m,3H),7.20–7.04(m,3H),7.03(s,0H ),6.65(dd,J=7.5,1.4Hz,1H),6.35(t,J=8.0Hz,1H),4.51(dd,J=8.0,4.3Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 19 H 16 N2O2S2:368.0653; found:368.0653.

[0129] A28: N-(furan-2-ylmethyl)-5-(thiophen-3-ylmethyl)amino)benzofuran-2-carboxamide

[0130] Purity > 95%. 1H-NMR(400MHz, DMSO-d6)δ8.98(t,J=7.8Hz,1H),7.63–7.47(m,2H),7.47–7.31(m,3H),7.30–7.11(m,3H), 6.60(t,J=8.0Hz,1H),6.38–6.25(m,2H),4.41(dd,J=25.0,8.0Hz,4H).HRMS(ESI)m / z:(M+H)+calcd for C 19 H 16 N2O3S:352.0882; found:352.0890.

[0131] Experimental Example 1

[0132] The in vitro antitumor activity of the benzofuran compounds (A1-A28) provided in the embodiments of the present invention was detected using the Cell Counting Kit 8 (CCK8) method.

[0133] The cells used were as follows: PC-9 (human non-small cell lung cancer cells, EGFR). del19 / T790M / C797S Mutant cell line), NCI-H1975 (human non-small cell lung cancer cell line, EGFR del19 / T790M Mutant cell lines) and U251 (human glioma cells, EGFR positive).

[0134] Specifically, as follows: according to 1.5 × 10 5 cells·mL -1 The cell culture solution was seeded at a concentration of 100 μL per well in 96-well plates. No seeding was performed around the edge of the plate, and 100 μL of PBS buffer was added to the wells at the edge to prevent edge effects from affecting the experiment. After seeding, the 96-well plates were transferred to an incubator and cultured for 24 hours before administering the drug.

[0135] Five concentrations of benzofuran compounds and positive control drugs were set up: 10 μM, 3.33 μM, 1.11 μM, 0.123 μM, and 0.041 μM. 10 μL of the corresponding compound was added to each well of the cell plate (three wells per compound). 10 μL of the corresponding complete culture medium was added to three wells of the blank control group (three replicates). A blank control group was also included. The administered compounds were then incubated for 48 h.

[0136] Against a relatively dark background, add 10 μL of CCK8 solution to each well of the cell plate after 48 hours of culture (avoid adding air bubbles as much as possible to prevent them from affecting the experimental results). Then, place the cell plate in an incubator and culture for 2 hours. Finally, place the cell plate in a microplate reader to detect the OD value.

[0137] The formula for calculating cell viability is as follows:

[0138] Cell viability (%) = [OD 实验组 -OD 空白对照组 ] / [OD 阳性对照组 -OD 空白对照组 ]×100%

[0139] The results are shown in Table 1:

[0140] Table 1. Results of in vitro antiproliferative activity of benzofuran compounds.

[0141]

[0142]

[0143] Therefore, it can be seen that the benzofuran compounds provided in the embodiments of the present invention can inhibit lung cancer and glioma.

[0144] Experiment Example 2

[0145] EGFR kinase inhibitory activity study

[0146] The specific process is as follows:

[0147] 1. Dilute the compound with DMSO to 50× of the final reaction concentration, and transfer 100 μL of the mother liquor to a 96-well plate;

[0148] 2. In the same 96-well plate, add 100 μL of DMSO as a compound-free control and an enzyme-free control, and label the plate as the original plate;

[0149] 3. Preparation of intermediate plate: Transfer 10 μL of the compound stock solution from the original plate to a new 96-well plate as an intermediate plate. Add 90 μL of 1× kinase buffer to each well of the intermediate plate and shake for 10 minutes.

[0150] 4. Prepare a 2.5-fold enzyme solution: Add EGFR (T790M / C797S / L858R) kinase to 1× kinase buffer;

[0151] 5. Prepare a 2.5-fold peptide solution: Add the FAM-labeled peptide and ATP to a 1× kinase buffer;

[0152] 6. Add 5 μL of the test compound solution to each well of the 384-well detection plate, then add 10 μL of 2.5× enzyme solution to each well, and incubate at room temperature for 10 minutes;

[0153] 7. Add 10 μL of 2.5× peptide solution to each well of the 384-well detection plate, incubate at 28°C for 1 hour, then add 25 μL of stop solution to stop the reaction;

[0154] 8. Data was collected using Caliper. The inhibition rate of the enzyme (%Inh) = (max-conversion) / (max-min)*100.

[0155] The results are shown in Table 2:

[0156] Table 2. Effects of benzofuran compounds on EGFR at a concentration of 10 μM. L858R / T790M / C797S inhibition rate

[0157]

[0158] As shown in the table above, most benzofuran compounds are affected by EGFR. L858R / T790M / C797S It has a good inhibitory effect.

[0159] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The application of a benzofuran compound in the preparation of EGFR kinase inhibitors, characterized in that, The benzofuran compounds are selected from compounds shown in the following structural formulas: R1 is selected from any one of phenyl, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, biphenyl, furan, C1-C3 alkyl-substituted furan, halogen-substituted furan, nitro-substituted furan, pyridine, C1-C3 alkyl-substituted pyridine, halogen-substituted pyridine, nitro-substituted pyridine, thiophene, C1-C3 alkyl-substituted thiophene, halogen-substituted thiophene, nitro-substituted thiophene, piperidine, C1-C3 alkyl-substituted piperidine, halogen-substituted piperidine, nitro-substituted piperidine, pyrazole, C1-C3 alkyl-substituted pyrazole, halogen-substituted pyrazole, nitro-substituted pyrazole, substituted or unsubstituted C1-C10 alkyl groups; Wherein, the substituents in the C1-C10 alkyl groups are selected from any one of phenyl, amino, halogen and nitro groups; R2 is selected from any one of phenyl, C1-C3 alkyl-substituted phenyl, halogen-substituted phenyl, biphenyl, pyridine, C1-C3 alkyl-substituted pyridine, halogen-substituted pyridine, nitro-substituted pyridine, thiophene, C1-C3 alkyl-substituted thiophene, halogen-substituted thiophene, nitro-substituted thiophene, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl; Wherein, the substituents in the C3-C10 cycloalkyl groups are selected from any one of phenyl, amino, halogen and nitro groups; The substituents in the C2-C6 heterocyclic alkyl groups are selected from any one of phenyl, C1-C5 alkyl, amino, halogen, and nitro groups.

2. The application according to claim 1, characterized in that, R1 is selected from any one of phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, chloro-substituted phenyl, bromo-substituted phenyl, and biphenyl.

3. The application according to claim 1, characterized in that, R1 is selected from substituted or unsubstituted C1-C6 alkyl groups.

4. The application according to claim 1, characterized in that, R2 is selected from any one of phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, chloro-substituted phenyl, bromo-substituted phenyl, and biphenyl.

5. The application according to claim 1, characterized in that, R2 is selected from substituted or unsubstituted C3-C6 cycloalkyl groups.

6. The application according to claim 1, characterized in that, The heteroatom of the substituted or unsubstituted C2-C6 heterocyclic alkyl group in R2 is selected from at least one of O, S, and N.

7. The application according to any one of claims 1-6, characterized in that, The benzofuran compounds are selected from any one of the compounds shown in the following structural formulas: 。 8. The application according to claim 1, characterized in that, include: The benzofuran compounds were synthesized according to the following synthetic route: 。 9. The application according to claim 8, characterized in that, Step i involves: performing a deesterification reaction of compound M-1 in a mixture with a strong base; Step ii involves mixing compound M-2 with an acyl chloride reagent to carry out an acylation reaction; Step iii involves mixing compound M-3 and compound M-4 in a molar ratio of 1:0.8-1 and reacting them. Step iv involves mixing compound M-5 with a reducing agent to carry out a reduction reaction; Step v involves: mixing compound M-7 with a strong base to carry out a hydrogenation reaction; Step vi involves reacting compound M-8 with a chlorine-containing reagent to undergo a chlorine substitution reaction; Step vii involves mixing M-6 and M-9 in a molar ratio of 1:2.5-3.5 and reacting them.

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