Benzofuran compounds, methods of making and using the same, and pdgfr kinase inhibitors

Abstract

The present application relates to the technical field of targeting small molecules, in particular to a benzofuran compound, a preparation method and application thereof and a PDGFR kinase inhibitor. The benzofuran compound is selected from the compounds shown in the following structural formula: wherein R1 and R2 are respectively substituted or unsubstituted phenyl. The benzofuran compound can inhibit PDGFR kinase, and then has a good inhibitory effect on tumors such as breast cancer, lung adenocarcinoma and glioma, and can be used as an antitumor drug.

Description

Technical Field

[0001] This invention relates to the field of targeted small molecule technology, and more specifically, to benzofuran compounds, their preparation methods and applications, and PDGFR kinase inhibitors. Background Technology

[0002] Platelet-derived growth factor receptors (PDGFs) target malignant cells (such as glioblastoma, breast cancer, non-small cell carcinoma, acute leukemia, prostate cancer, etc.), vascular cells, and stromal cells to regulate tumor growth, metastasis, and the tumor microenvironment. PDGFR inhibitors can be divided into two categories based on their mechanism of action: one is ATP-competitive inhibitors, which target the ATP-binding site of PDGFR kinase and block phosphorylation; the other is PDGF antagonists, which are structurally similar to PDGF subtypes and inhibit the binding of PDGF to PDGFR. Most PDGFR inhibitors exhibit multi-target properties, leading to off-target effects in various cancers. However, the low activity of PDGFR inhibitors also hinders their clinical application.

[0003] In view of this, the present invention is proposed. Summary of the Invention

[0004] The purpose of this invention is to provide benzofuran compounds, their preparation methods, their applications, and PDGFR kinase inhibitors. This invention provides a benzofuran compound that can inhibit PDGFR kinase, thereby exhibiting good inhibitory effects on tumors such as breast cancer, lung adenocarcinoma, and glioma, and can be used as an anti-tumor drug.

[0005] This invention is implemented as follows:

[0006] In a first aspect, the present invention provides a benzofuran compound, which is selected from compounds shown in the following structural formulas:

[0007] R1 and R2 are substituted or unsubstituted phenyl groups, respectively.

[0008] In an optional embodiment, R1 is selected from substituted phenyl groups;

[0009] Preferably, the number of substituents in the substituted phenyl group of R1 is one, two, or three;

[0010] Preferably, when the number of substituents in the substituted phenyl group of R1 is one, the substituent is located at the meta or para position of the linking bond, wherein the linking bond is the position where the phenyl group is bonded to the benzofuran.

[0011] Preferably, when the number of substituents in the substituted phenyl group of R1 is two, the substituents are located at any two of the ortho, meta, and para positions of the linking bond, wherein the linking bond is the position where the phenyl group is bonded to the benzofuran.

[0012] In an optional embodiment, the substituent of the substituted phenyl group of R1 is selected from any one of hydroxyl, C1-C3 substituted or unsubstituted alkyl, C1-C3 alkoxy and carbonyl groups;

[0013] More preferably, the substituent of the substituted phenyl group in R1 is selected from any one of hydroxyl, unsubstituted C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, and methyl carbonyl.

[0014] Preferably, R1 is selected from any one of the groups shown in the following structural formulas:

[0015]

[0016] In an optional embodiment, R2 is selected from substituted phenyl groups;

[0017] Preferably, the number of substituents in the substituted phenyl group of R2 is one, two, or three;

[0018] Preferably, when the number of substituents in the substituted phenyl group of R2 is one, the substituent is located at the meta or para position of the linking bond, wherein the linking bond is the position where the phenyl group is bonded to the benzofuran.

[0019] Preferably, when the number of substituents in the substituted phenyl group of R2 is two, the substituents are located at the meta position of the linking bond, wherein the linking bond is the position where the phenyl group is bonded to the benzofuran.

[0020] In an optional embodiment, the substituent of the substituted phenyl group of R2 is selected from any one of nitro, cyano, C1-C3 alkoxy, C1-C3 unsubstituted alkyl and halogen;

[0021] Preferably, R2 is selected from any one of the groups shown in the following structural formulas:

[0022]

[0023] Secondly, the present invention provides a method for preparing the benzofuran compounds described in the foregoing embodiments, which is synthesized according to the following synthetic route:

[0024]

[0025] In an optional embodiment, step a includes: hydrolyzing ethyl 5-nitrobenzuran-2-carboxylate;

[0026] Preferably, step a includes: mixing the ethyl 5-nitrobenzuran-2-carboxylate and the alkaline substance in a molar ratio of 1:1.1-1.2 and then reacting them at 50-70°C;

[0027] Preferably, step b includes: mixing 5-nitrobenzofuran-2-carboxylic acid and the raw material containing R1 at a molar ratio of 1:1.1-1.2 and then reacting at 20-30°C;

[0028] Preferably, step c includes: mixing compound 3 and reducing agent to react, wherein the molar ratio of compound 3 to reducing agent is 1:3-5, and the reaction temperature is 45-75°C;

[0029] Preferably, step d includes: mixing compound 4 and benzyl bromoides to react, wherein the molar ratio of compound 4 to benzyl bromoides is 1:1.1-1.2, and the reaction temperature is 80-100℃.

[0030] Thirdly, the present invention provides a PDGFR kinase inhibitor comprising the benzofuran compounds described in the foregoing embodiments.

[0031] Fourthly, the present invention provides the application of the benzofuran compounds described in the foregoing embodiments in the preparation of antitumor drugs;

[0032] Preferably, the tumor includes breast cancer, lung adenocarcinoma, and glioma.

[0033] The present invention has the following beneficial effects: By setting amino and amide groups at specific positions in benzofuran and limiting the selection of groups R1 and R2, the compounds formed by the present invention can inhibit PDGFR kinase and have a good inhibitory effect on tumors such as breast cancer, lung adenocarcinoma and glioma. Attached Figure Description

[0034] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0035] Figure 1 The 1H NMR spectrum of the benzimidazole compound provided in Example 1 of this invention;

[0036] Figure 2 This is a mass spectrum of a benzimidazole compound provided in Example 1 of the present invention;

[0037] Figure 3The carbon NMR spectrum of the benzimidazole compound provided in Example 1 of this invention;

[0038] Figure 4 The 1H NMR spectrum of the benzimidazole compound provided in Example 4 of this invention;

[0039] Figure 5 This is the mass spectrum of the benzimidazole compound provided in Example 4 of the present invention;

[0040] Figure 6 The image shows the carbon NMR spectrum of the benzimidazole compound provided in Example 4 of this invention. Detailed Implementation

[0041] 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.

[0042] This invention provides a benzofuran compound, which is selected from compounds shown in the following structural formulas:

[0043] R1 and R2 are substituted or unsubstituted phenyl groups, respectively.

[0044] Wherein, R1 is selected from substituted phenyl groups; the number of substituents in the substituted phenyl group can be 1, 2, or 3; that is, one, 2, or 3 hydrogens on the phenyl group are replaced by substituents. Wherein, when there is 1 substituent, the substituent is located at the meta or para position of the linking bond; when there are 2 substituents, the substituent is located at any two of the ortho, meta, and para positions of the linking bond, which are the positions where the phenyl group and benzofuran are bonded.

[0045] Furthermore, the substituents of the substituted phenyl group of R1 are selected from any one of hydroxyl, C1-C3 substituted or unsubstituted alkyl, C1-C3 alkoxy and carbonyl; for example, including but not limited to any one of hydroxyl, methyl, ethyl, propyl, trifluoromethyl, monofluoromethyl, difluoromethyl, methoxy, ethoxy and methyl carbonyl.

[0046] Specifically, R1 is selected from any one of the groups shown in the following structural formulas:

[0047] The dashed lines in the above groups represent sites that are linked to benzofuran.

[0048] Furthermore, similarly, R2 is selected from substituted phenyl groups; the number of substituents in the substituted phenyl group can be 1, 2, or 3; that is, one, 2, or 3 hydrogens on the phenyl group are replaced by substituents. Among them, when the number of substituents is 1, the substituent is located at the meta or para position of the linking bond, and when the number of substituents is 2, the substituent is located at the meta position of the linking bond.

[0049] Furthermore, the substituent of the substituted phenyl group in R2 is selected from any one of nitro, cyano, C1-C3 alkoxy, C1-C3 unsubstituted alkyl, and halogen; for example, R2 is selected from any one of the groups shown in the following structural formulas:

[0050] The dashed lines in the above groups represent sites that are linked to benzofuran.

[0051] Furthermore, the benzofuran compound is selected from any one of the compounds shown in the following structural formulas:

[0052]

[0053] It should be noted that the numbering under the above structural formula corresponds to the numbering and structure of the compounds mentioned in the subsequent embodiments.

[0054] Secondly, embodiments of the present invention provide a method for preparing benzofuran compounds, which is synthesized according to the following synthetic route:

[0055]

[0056] Step a is performed as follows: Ethyl 5-nitrobenzofuran-2-carboxylate is hydrolyzed; the ethyl 5-nitrobenzofuran-2-carboxylate and the alkaline substance are mixed at a molar ratio of 1:1.1-1.2 and reacted at 50-70°C. Specifically, 1 equivalent of ethyl 5-nitrobenzofuran-2-carboxylate is dissolved in methanol, and then 1.1-1.2 equivalents of alkaline substances such as NaOH, sodium carbonate, or sodium hydride are added, and the mixture is placed in an oil bath at 50-70°C for reaction. After the reaction is complete, water is added to the reaction flask, and the pH of the reaction solution is adjusted to weakly acidic with dilute hydrochloric acid. At this point, a large amount of white precipitate precipitates from the yellow transparent solution. This precipitate is then filtered to obtain a dry, milky white powdery product.

[0057] Step b is performed as follows: 5-Nitrobenzofuran-2-carboxylic acid and the starting material containing R1 are mixed at a molar ratio of 1:1.1-1.2 and reacted at 20-30°C. Specifically, 1 equivalent of 5-nitrobenzofuran-2-carboxylic acid is dissolved in anhydrous acetonitrile. TCFH, NMI, and 1.1-1.2 equivalents of various substituted anilines are added sequentially to the reaction system, and the mixture is stirred at room temperature (approximately 20-30°C). The solution gradually becomes clear from turbid, indicating the reaction is complete. Upon addition of water to the reaction solution, a precipitate forms. The precipitate is filtered under vacuum and washed repeatedly with small amounts of methanol to obtain a powdered product.

[0058] Step c is performed as follows: Compound 3 and the reducing agent are mixed and reacted, wherein the molar ratio of compound 3 to the reducing agent is 1:3-5, and the reaction temperature is 45-75℃. Specifically, 1 equivalent of the compound (compound 3) synthesized in step b is weighed into a flask, and 3-5 equivalents of the reducing agent (e.g., zinc powder or other metal powder) and 3-5 equivalents of ammonium chloride are simultaneously weighed into the flask. The reactants are dissolved in a mixed solvent of methanol and water (methanol:water = 2:1), and nitrogen gas is repeatedly introduced for protection. After reacting on a heated stirring table at 45-75℃, water is added and a precipitate forms. The precipitate is filtered, and the filter cake is repeatedly washed with ethyl acetate. The combined washings are evaporated to dryness to obtain the solid product.

[0059] Step d involves mixing compound 4 with a benzyl bromoidene compound and reacting them, wherein the molar ratio of compound 4 to the benzyl bromoidene compound is 1:1.1-1.2, and the reaction temperature is 80-100℃. Specifically, one equivalent of the series of compounds (compound 4) synthesized in step c is weighed into a reaction flask, and 1.1-1.2 equivalents of the corresponding benzyl bromoidene compound are added. Then, N,N-diisopropylethylamine is added, followed by the addition of anhydrous N,N-dimethylformamide to dissolve the raw material, and the reaction is stirred at 80-100℃. After the reaction is complete, water is added, and the mixture is extracted three times with ethyl acetate, then back-extracted with saturated brine, and dehydrated with anhydrous sodium sulfate. The filtrate is then added to silica gel and separated by silica gel column chromatography.

[0060] Thirdly, the present invention provides a PDGFR kinase inhibitor comprising the benzofuran compounds described in the foregoing embodiments.

[0061] Fourthly, the present invention provides the application of the benzofuran compounds described in the foregoing embodiments in the preparation of antitumor drugs; wherein the tumors include breast cancer, lung adenocarcinoma, and glioma.

[0062] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0063] Example 1

[0064] This invention provides a method for preparing a benzofuran compound (compound A4), which is synthesized according to the following synthetic route:

[0065]

[0066] The specific steps are as follows:

[0067] Step a: Dissolve 5 g (approximately 14.5 mmol, 1 equivalent) of ethyl 5-nitrobenzofuran-2-carboxylate in 200 ml of methanol, then add 2.55 g (approximately 63.7 mmol, 1.1 equivalent) of NaOH, and react in an oil bath at 60°C. After approximately 3 hours, the reaction is complete. Add water to the reaction flask and adjust the pH of the reaction solution to weakly acidic using dilute hydrochloric acid. At this point, a large amount of white precipitate precipitates from the yellow transparent solution. Filter the precipitate to obtain a dry, milky white powder product with a yield of approximately 95%.

[0068] Step b: Dissolve 2 g of 5-nitrobenzofuran-2-carboxylic acid (approximately 8.3 mmol, 1 equivalent) in 20 mL of anhydrous acetonitrile. Add TCFH (approximately 9.13 mmol, 1.1 equivalent), NMI (29.05 mmol, 3.5 equivalent), and 1.2 equivalent of p-anisidine sequentially to the reaction system and stir at room temperature. After approximately 6 hours, the solution gradually becomes clear, indicating the reaction is complete. Upon addition of water, a precipitate forms. The precipitate is filtered under vacuum and washed repeatedly with small amounts of methanol to obtain a powdered product. The yield is 70%.

[0069] Step c: Weigh 1 equivalent of the compound synthesized in step b into a 50 mL flask, and simultaneously weigh 5 equivalents of zinc powder and 4 equivalents of ammonium chloride into the flask. Dissolve the reactants in 30 mL of a mixed solvent of methanol and water (methanol:water = 2:1), and purge with nitrogen gas several times for protection. Then, place the flask on a heated and stirred table at 60 °C and react for 6 hours. After stopping the reaction, water is added, and a precipitate forms. Filter the precipitate, and wash the filter cake repeatedly with ethyl acetate. Combine the washings and evaporate to dryness to obtain the solid product. The yield is approximately 65%.

[0070] Step d: Weigh 1 equivalent of the compound synthesized in step c into a reaction flask, add 1.2 equivalents of m-methylbenzyl bromide, followed by 2 equivalents of N,N-diisopropylethylamine, and dissolve the starting material in 10 mL of anhydrous N,N-dimethylformamide. Stir the reaction mixture at 90 °C. After approximately 6 hours, the reaction is complete. Extract three times with ethyl acetate using water and ice, then perform reverse extraction with saturated brine. Remove water by adding anhydrous sodium sulfate, filter the mixture, and add silica gel for separation by silica gel column chromatography. The yield is approximately 75%.

[0071] Compound A4 obtained in this embodiment was characterized, and the characterization results are shown in [reference needed]. Figure 1 , Figure 2 and Figure 3 The specific data is represented as follows: 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),7.69(d,J=8.9Hz,2H),7.45(d,J=10.1Hz,1H),7.22(t,J=7.5Hz, 2H),7.14-7.02(m,4H),6.98-6.85(m,3H),4.69(s,3H),3.75(s,2H),2.28(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 12 N2O3:387.1708; found:387.1701.

[0072] 13 C NMR(151MHz,DMSO-d6)δ156.92,156.22,148.36,146.09,139.42,138.07,128.89,128 .47,127.79,124.31,122.49,114.98,114.26,112.40,110.70,104.35,55.47,21.58.

[0073] Examples 2-27

[0074] Examples 2-27 each provide a method for preparing benzofuran compounds. This method is the same as in Example 1, except that the corresponding raw materials are changed. The characterization data of the obtained benzofuran compounds are as follows:

[0075] Example 2—A1: N-(4-methoxyphenyl)-5-((3-nitrobenzyl)amino)benzofuran-2-carboxamide

[0076] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.29-8.15(m,3H),7.71-7.65(m,1H),7.59(d,J=8.8H z,3H),7.55-7.37(m,2H),6.99-6.84(m,3H),4.94(s,3H),3.74(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 23 H 19N3O5:418.1403; found:418.1396.

[0077] 13 C NMR(151MHz,DMSO-d6)δ156.84,156.24,149.78,147.87,147.03,145.02,131.84 ,128.43,124.17,122.51,114.25,112.71,110.61,104.97,55.44(d,J=53.3Hz).

[0078] Example 3—A2: N-(4-methoxyphenyl)-5-((4-nitrobenzyl)amino)benzofuran-2-carboxamide

[0079] 1 H NMR (400MHz, DMSO-d6) δ10.28(d,J=14.0Hz,1H),8.28-8.22(m,1H),8.13(p,J=2.3Hz,2H),7.79(t,J=8.1Hz,2H),7.72-7.5 7(m,3H),7.53-7.40(m,2H),7.06-6.98(m,1H),6.95-6.89(m,2H),4.94(s,3H),3.74(d,J=1.1Hz,3H).HRMS(ESI)m / z:(M+H) + calcdfor C 23 H 19 N3O5:418.1403; found:418.1399.

[0080] 13 C NMR(151MHz,DMSO-d6)δ156.86,156.41,149.35,148.18,146.68,142.08,132.90(d,J=5.6Hz),130.3 9–128.62(m),128.39,122.50,116.71–115.14(m),114.28,112.94,110.68(d,J=5.9Hz),103.82,55.

[0081] Example 4—A3: 5-((4-aminobenzyl)amino)-N-(4-methoxyphenyl)benzofuran-2-carboxamide

[0082] See the characterization spectrum. Figures 4-6 . 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.80-7.59(m,2H),7.59-7.30(m,2H),7.01-6.89 (m,4H),6.57-6.39(m,4H),5.05(s,3H),4.55(s,2H),3.74(s,3H).HRMS(ESI)m / z:(M+H) + calcd forC 23 H 21 N3O3:388.1661; found:388.1663.

[0083] 13 C NMR(151MHz,DMSO-d6)δ156.96,156.21,149.35,148.18,146.38,140.08,131.90(d,J=5.6Hz),130.3 9–128.62(m),128.39,122.50,116.51–115.14(m),114.28,112.94,110.68(d,J=5.9Hz),103.82,55.

[0084] Example 5—A5: 5-((3,5-dimethoxybenzyl)amino)-N-(4-methoxyphenyl)benzofuran-2-carboxamide

[0085] 1 H NMR (400MHz, DMSO-d6) δ10.27(d,J=11.0Hz,1H),7.82-7.61(m,2H),7.48(d,J=3.0Hz,1H),6.93(d,J=8.9Hz ,4H),6.46(d,J=2.2Hz,3H),6.37(q,J=2.7Hz,2H),4.63(s,3H),3.69(d,J=1.0Hz,9H).HRMS(ESI)m / z:(M+H) + calcd for C 25 H 24 N2O5:433.1763; found:433.1756.

[0086] 13C NMR (151MHz, DMSO-d6) δ161.17, 156.55 (d, J = 103.0Hz), 149.44 (d, J = 51.1Hz), 148.43, 146.04, 142.13,131.95,128.39,122.48,115.09,114.27,112.39,110.73,105.28,98.66,55.64,55.52.

[0087] Example 6—A6: 5-((4-fluorobenzyl)amino)-N-(4-methoxyphenyl)benzofuran-2-carboxamide

[0088] 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.73-7.65(m,2H),7.50-7.44(m,2H),7.36-7.28(m,4H),7.20- 7.12(m,4H),6.98-6.93(m,3H),6.92(d,J=2.2Hz,1H),4.69(s,4H),3.75(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 23 H 19 FN2O3:391.1458; found:391.1455.

[0089] 13 C NMR (151MHz, DMSO-d6) δ162.46, 160.85, 156.56 (d, J = 99.3Hz), 149.67, 148.56, 145.71, 135.39 (d, J = 3.4Hz) ,131.93,129.23(d,J=8.3Hz),122.49,115.58(d,J=14.9Hz),114.27,112.49,110.66,105.17,55.63,54.77.

[0090] Example 7—A7: N-(3-methyl-4-(trifluoromethyl)phenyl)-5-((3-nitrobenzyl)amino)benzofuran-2-carboxamide

[0091] 1H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.21(d,J=2.3Hz,1H),8.02-7.85(m,1H),7.68-7.34(m,3H),7.02-6.81(m,2H),6.72(d,J=2.4Hz,1H ),6.61-6.47(m,2H),6.43(dd,J=7.8,1.4Hz,1H),6.17(t,J=5.8Hz,1H),4.14(d,J=5.8Hz,2H),2.41(d,J=2.2Hz,3H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 18 F3N3O4:470.1327; found:470.1327.

[0092] 13 C NMR(151MHz,DMSO-d6)δ162.83,145.70,143.49,137.36,134.45,132.93,130.2 5,128.27,124.16,122.11(d,J=7.2Hz),116.43,111.40,102.17,55.00,46.68.

[0093] Example 8—A8: N-(3-methyl-4-(trifluoromethyl)phenyl)-5-((4-nitrobenzyl)amino)benzofuran-2-carboxamide

[0094] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.23(s,1H),8.01-7.92(m,1H),7.73-7.61(m,4H),7.50(d,J=0.9Hz,1H),7.44(t,J=9.3Hz,2 H),6.92-6.86(m,1H),6.72(d,J=2.4Hz,1H),6.52(t,J=6.2Hz,1H),4.10(q,J=5.3Hz,2H),2.52-2.24(m,3H).HRMS(ESI)m / z:(M+H) + calcd forC 24 H 18 F3N3O4:470.1327; found:470.1324.

[0095] 13C NMR(151MHz,DMSO-d6)δ157.35,149.14,148.80,147.83,147.03,145.07,137.08,133.05,131.89–129. 33(m),128.43,124.13–122.68(m),117.83(d,J=6.1Hz),115.40,112.78,111.39,105.01,55.27,18.64.

[0096] Example 9—A9: 5-((4-aminobenzyl)amino)-N-(3-methyl-4-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0097] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.21(d,J=2.3Hz,1H),8.04-7.89(m,1H),7.81(d,J=8.1Hz,2H),7.59(d,J=8.0Hz,2H),7.52-7.37(m,3H), 6.90(dd,J=9.0,2.4Hz,1H),6.72(d,J=2.4Hz,1H),6.46(t,J=6.2Hz,1H),4.43(d,J=6.1Hz,2H),4.10(s,2H),2.41(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 20 F3N3O2:440.1586; found:440.1583.

[0098] 13 C NMR (151MHz, DMSO-d6) δ 157.48 (d, J = 17.1Hz), 149.62-147.87 (m), 146.37-142.02 (m), 137.31 (d, J = 7.1Hz), 132.76 (d, J = 8.2Hz), 130.58-127. 33(m),124.21,119.42(d,J=14.0Hz),117.87,116.37,113.51-112.11( m), 111.44 (d, J = 11.1Hz), 110.17 (d, J = 53.3Hz), 102.08, 55.39, 18.68.

[0099] Example 10—A10: 5-((4-aminobenzyl)amino)-N-(3-methyl-4-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0100] 1 H NMR(400MHz,DMSO-d6)δ10.76(d,J=18.3Hz,1H),8.23(s,1H),8.06-7.97(m,1H),7.80(dd,J=8.0,5.8Hz,4H),7 .63-7.54(m,2H),7.49(d,J=7.9Hz,2H),7.41(d,J=7.5Hz,2H),4.86(s,2H),2.40(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 25 H 18 F3N3O2:450.1429; found:450.1424.

[0101] 13 C NMR (151MHz, DMSO-d6) δ157.57,149.19(d,J=30.2Hz),148.43(d,J=22.5Hz),146.45,141.08,137.13,133.10,129.31,128.55-126.93(m ), 124.09 (d, J = 37.4Hz), 117.85 (d, J = 6.1Hz), 116.43, 115.80-114.18 (m), 113.04 (d, J = 16.9Hz), 112.30, 111.39, 101.75, 47.92, 18.67.

[0102] Example 11—A11: 5-(benzylamino)-N-(3-methyl-4-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0103] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.21(d,J=2.3Hz,1H),7.99-7.84(m,1H),7.53(d,J=0.9Hz,1H),7.44(dt,J=17.6,9. 4Hz,2H),7.38-7.29(m,7H),7.29-7.21(m,1H),6.99-6.95(m,2H),4.74(s,3H),2.41(d,J=2.1Hz,3H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 19 F3N2O2:425.1477; found:425.1474.

[0104] 13 C NMR(151MHz,DMSO-d6)δ157.41,148.78(d,J=71.4Hz),139.36,137.22,133.02,131.42,128.9 7,128.37,127.24(d,J=4.1Hz),124.12,115.54,111.96(d,J=152.5Hz),104.67,55.49,18.66.

[0105] Example 12—A12: 5-((4-fluorobenzyl)amino)-N-(3-methyl-4-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0106] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.21(d,J=2.3Hz,1H),8.03-7.89(m,1H),7.54(d,J=1.0Hz,1H),7.40-7.29 (m,3H),7.23-7.06(m,4H),6.99(dt,J=4.1,2.1Hz,2H),4.70(s,4H),2.41(d,J=2.1Hz,3H).HRMS(ESI)m / z:(M+H) + calcd for C 22 H 19 N3O2:443.1382; found:443.1372.

[0107] 13 C NMR(151MHz,DMSO-d6)δ158.41,148.78(d,J=71.4Hz),140.36,137.22,136.02,133.42,128.9 7,128.37,127.24(d,J=4.1Hz),126.12,115.54,111.96(d,J=152.5Hz),104.67,55.49,18.66.

[0108] Example 13—A13: N-(3,5-dimethoxyphenyl)-5-((3-nitrobenzyl)amino)benzofuran-2-carboxamide

[0109] 1H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 7.81 (d, J = 1.8Hz, 2H), 7.58-7.39 (m, 5H), 7.10 (d, J = 2. 3Hz,2H),6.92(d,J=2.5Hz,1H),6.28(s,1H),4.86(s,3H),3.73(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 21 N3O6:448.1508; found:448.1501.

[0110] 13 C NMR (151MHz, DMSO-d6) δ160.86, 157.17, 149.06 (d, J = 116.7Hz), 145.39 (d, J = 77.6Hz), 140.56, 132.96 ,128.37(d,J=38.8Hz),119.37,115.18,112.71,111.09,110.09,104.84,99.11,96.43,55.60,55.37.

[0111] Example 14—A14: N-(3,5-dimethoxyphenyl)-5-((4-nitrobenzyl)amino)benzofuran-2-carboxamide

[0112] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.22(dd,J=8.7,4.0Hz,2H),7.66(d,J=8.6Hz,2H),7.51-7.37(m,2H),7.11(d,J=2.3Hz,2H),7.01-6.8 4(m,1H),6.71(d,J=2.3Hz,1H),6.51(t,J=6.2Hz,1H),6.28(t,J=2.3Hz,1H),4.53-4.34(m,2H),3.73(d,J=2.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 21 N3O6:448.1508; found:448.1498.

[0113] 13C NMR(151MHz,DMSO-d6)δ160.86,157.29,151.12–147.00(m),146.90,145.67,141.21. 140.57,128.64,123.99,116.22,112.70,111.02,102.16,99.12,96.38,55.59,46.98.

[0114] Example 15—A15: 5-((4-cyanobenzyl)amino)-N-(3,5-dimethoxyphenyl)benzofuran-2-carboxamide

[0115] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.82(d,J=1.8Hz,2H),7.50(s,2H),7.49(d,J=2.6Hz,4H),7.10 (d,J=2.3Hz,2H),6.92(d,J=2.5Hz,1H),6.28(s,1H),4.86(s,4H),3.73(s,6H).HRMS(ESI)m / z:(M+H) + calcdfor C 25 H 21 N3O4:428.1610; found:428.1606.

[0116] 13 C NMR (151MHz, DMSO-d6) δ160.86, 157.17, 149.06 (d, J = 116.7Hz), 145.39 (d, J = 77.6Hz), 142.56, 135.96 ,128.37(d,J=38.8Hz),119.37,115.18,112.71,111.09,110.09,104.84,99.11,96.43,55.60,55.37.

[0117] Example 16—A16: 5-((3-aminobenzyl)amino)-N-(3,5-dimethoxyphenyl)benzofuran-2-carboxamide

[0118] 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),7.50(s,1H),7.12(t,J=3.1Hz,2H),7.00(d,J=2.9Hz,1H),6.97(d,J=7.8Hz,1H),6.89(s,1H ),6.52(d,J=2.0Hz,2H),6.45(d,J=2.4Hz,2H),6.27(t,J=2.3Hz,1H),5.13(s,4H),4.56(s,3H),3.73(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 23 N3O4:418.1767; found:418.1706.

[0119] 13 C NMR(151MHz,DMSO-d6)δ160.82,157.30,149.65–145.42(m),143.77,140.41(d,J=81.8Hz),129.30(d,J =83.5Hz), 115.55 (d, J = 69.5Hz), 113.54 (d, J = 3.6Hz), 103.93, 99.13, 96.36, 63.53, 55.62 (d, J = 3.5Hz).

[0120] Example 17—A17: 5-((3,5-dimethoxybenzyl)amino)-N-(3,5-dimethoxyphenyl)benzofuran-2-carboxamide

[0121] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.53(s,1H),7.11(d,J=2.3Hz,2H),6.95(d,J=2.5Hz,1H),6.46(d,J =2.2Hz,4H),6.38(t,J=2.3Hz,2H),6.28(t,J=2.3Hz,1H),4.64(s,4H),3.69(s,12H).HRMS(ESI)m / z:(M+H) + calcd for C 26 H 26 N2O6:463.1869; found:463.1872.

[0122] 13C NMR (151MHz, DMSO-d6) δ160.84,157.34,149.51,148.47,146.03,142.11,140.95,128. 35,115.25,112.42,111.06,105.27,104.53,99.21,98.63,96.31,55.85,55.57,55.51.

[0123] Example 18—A18: N-(2-hydroxy-4-methylphenyl)-5-((3-methylbenzyl)amino)benzofuran-2-carboxamide

[0124] 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 7.83 (d, J = 8.1Hz, 1H), 7.45 (s, 1H), 7.38-7.26 (m, 2H), 7.22 (t, J = 7.5Hz, 1H), 7.16-7. 03(m,6H),7.01-6.87(m,1H),6.82(d,J=8.1Hz,1H),4.37(d,J=5.1Hz,2H),2.31(s,2H),2.28(s,4H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 22 N2O3:387.1708; found:387.1697.

[0125] 13 C NMR (151MHz, DMSO-d6) δ160.84, 157.30, 148.79 (d, J = 122.3Hz), 148.07, 142.27-138.43 (m), 132.08-126. 33 (m), 124.29, 116.21, 111.82 (d, J = 184.3Hz), 104.35, 97.77 (d, J = 419.1Hz), 55.53 (d, J = 16.8Hz), 22.57.

[0126] Example 19—A19: N-(2-hydroxy-4-methylphenyl)-5-((4-methylbenzyl)amino)benzofuran-2-carboxamide

[0127] 1H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 7.63-7.45 (m, 1H), 7.22 (t, J = 7.5Hz, 2H), 7.11 (s, 4H), 7.07-7.0 2(m,3H),6.94(d,J=7.7Hz,2H),6.27(t,J=2.3Hz,1H),4.69(s,4H),2.27(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 22 N2O3:387.1708; found:387.1698.

[0128] 13 C NMR (151MHz, DMSO-d6) δ160.84, 157.30, 148.79 (d, J = 122.3Hz), 146.07, 141.27-137.43 (m), 130.08-127. 33 (m), 124.29, 115.21, 111.82 (d, J = 184.3Hz), 104.35, 97.77 (d, J = 419.1Hz), 55.53 (d, J = 16.8Hz), 21.57.

[0129] Example 20—A20: 5-((4-fluorobenzyl)amino)-N-(2-hydroxy-4-methylphenyl)benzofuran-2-carboxamide

[0130] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),7.83(d,J=8.0Hz,1H),7.57(dd,J=6.0,2.6Hz,1H),7.45(s,1H),7.35-7.29(m,3H),7.25(dt,J=7. 6,2.3Hz,1H),7.19-7.12(m,4H),7.05(d,J=1.7Hz,1H),6.95(d,J=2.6Hz,1H),4.36(t,J=5.1Hz,2H),2.31(s,3H).HRMS(ESI)m / z:(M+H) + calcd forC 23 H 19 FN2O3:391.1458; found:391.1453.

[0131] 13C NMR(151MHz,DMSO-d6)δ163.49–160.35(m),150.09–147.85(m),145.95(d,J=46.0Hz),135.39(d,J=19.3Hz),133.67,130.41–12 7.98(m),124.65(d,J=13.0Hz),122.21(d,J=122.4Hz),115.80(d,J=3.7Hz),114.27,113.04–109.80(m),105.16,54.70,21.48.

[0132] Example 21—A21: 5-(benzylamino)-N-(2-hydroxy-4-methylphenyl)benzofuran-2-carboxamide

[0133] 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 7.58-7.37 (m, 1H), 7.21 (d, J = 7.5Hz, 1H), 7.18-6.98 (m, 5H), 6.9 4(d,J=7.7Hz,1H),6.27(t,J=2.3Hz,1H),4.69(s,2H),3.73(s,3H),2.27(s,3H).HRMS(ESI)m / z:(M+H) + calcdfor C 23 H 20 N2O3:373.1552; found:373.1545.

[0134] 13 C NMR (151MHz, DMSO-d6) δ166.14,162.88,156.70,152.72-141.36(m),132.96,128.23,125.94-115.67(m),110.07,55.34,21.47.

[0135] Example 22—A22: 5-((3-nitrobenzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0136] 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.26(s,1H),8.17-8.00(m,4H),7.78(d,J =7.6Hz,2H),7.69-7.42(m,4H),7.06(s,1H),4.95(s,3H).HRMS(ESI)m / z:(M+H) +calcdfor C 23 H 16 F3N3O4:456.1171; found:456.1158.

[0137] 13 C NMR(151MHz,DMSO-d6)δ157.50,151.21–148.12(m),145.18,140.88(d,J=345.2Hz),134.14,131.33–129.08(m ),128.49,126.07–123.23(m),123.23–119.48(m),118.97–114.88(m),112.25(d,J=184.1Hz),105.34,55.00.

[0138] Example 23—A23: 5-(benzylamino)-N-(3-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0139] 1 H NMR (400MHz, DMSO-d6) δ10.71(d,J=2.9Hz,1H),8.27(s,1H),8.08(d,J=8.3Hz,1H),7.59(d,J=9.3Hz,1H),7 .48(d,J=8.9Hz,2H),7.43-7.18(m,8H),6.98(t,J=5.1Hz,1H),4.74(d,J=2.7Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 23 H 17 F3N2O2:411.1320; found:411.1314.

[0140] 13 C NMR (151MHz, DMSO-d6) δ 157.58, 148.71 (d, J = 46.0Hz), 146.07, 139.39, 130.40, 129.00, 127.28, 124.35, 115.65, 112.51, 104.67, 55.50.

[0141] Example 24—A24: 5-((3-methylbenzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0142] 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),8.08(d,J=8.2Hz,1H),7.66-7.51(m,2H),7.52-7.43(m,1H),7.22(t,J =7.5Hz,2H),7.16-6.99(m,5H),6.96(dd,J=5.0,2.4Hz,1H),4.70(s,3H),2.28(s,4H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 19 F3N2O2:425.1477; found:425.1473.

[0143] 13 C NMR(151MHz,DMSO-d6)δ157.58,148.67(d,J=50.8Hz),146.14,141.02–135.68(m),130.18(d,J=52.4Hz),128.83–125.57 (m),125.82–122.73(m),121.48–119.48(m),116.95(d,J=3.8Hz),115.44,112.10(d,J=117.4Hz),104.37,55.46,21.55.

[0144] Example 25—A25: 5-((3-aminobenzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0145] 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.20(s,1H),8.01(d,J=8.2Hz,1H),7.62-7.47(m,2H),7.47- 7.30(m,1H),6.98-6.75(m,3H),6.54-6.27(m,5H),4.99(s,3H),4.49(s,3H).HRMS(ESI)m / z:(M+H) + calcd forC 23 H 18 F3N3O2:426.1429; found:426.1422.

[0146] 13C NMR(151MHz,DMSO-d6)δ157.63,149.88-147.37(m),146.48,139.90(d,J=42.4Hz),132.67-129.08(m),128.3 1,124.93(d,J=170.8Hz),123.80-119.96(m),117.56-116.27(m),114.60,113.33-111.25(m),103.87,55.60.

[0147] Example 26—A26: 5-((4-cyanobenzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0148] 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.27(s,1H),8.11-8.02(m,1H),7.86-7.75(m,3H),7.66 -7.54(m,2H),7.50(d,J=8.3Hz,5H),6.94(t,J=2.5Hz,1H),4.87(s,3H).HRMS(ESI)m / z:(M+H) + calcd forC 24 H 16 F3N3O2:436.1429; found:436.1269.

[0149] 13 C NMR(151MHz,DMSO-d6)δ160.90(d,J=8.6Hz),157.30,151.46–147.87(m),145.36(d,J=92.0Hz),1 28.51 (d, J = 30.4Hz), 123.95, 116.21, 111.86 (dd, J = 252.3, 9.7Hz), 102.15, 99.11, 96.36, 46.99.

[0150] Example 27—A27: 5-((3,5-dimethoxybenzyl)amino)-N-(3-(trifluoromethyl)phenyl)benzofuran-2-carboxamide

[0151] 1H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.27(t,J=2.0Hz,1H),8.08(dd,J=8.2,2.1Hz,1H),7.71-7.34(m, 3H),6.96(d,J=7.3Hz,1H),6.42(dd,J=32.4,2.3Hz,4H),4.64(s,2H),3.69(s,7H).HRMS(ESI)m / z:(M+H) + calcd for C 25 H 21 F3N2O4:471.1531; found:471.1523.

[0152] 13 C NMR(151MHz,DMSO-d6)δ161.17,157.58,148.70(d,J=38.7Hz),146.11,142.07,139.74,131.92 –129.08(m),128.27,126.07–121.73(m),120.70(d,J=4.7Hz),116.96(q,J=3.9Hz),115.54,11.

[0153] Experimental Example 1

[0154] PDGFR in vitro activity assay

[0155] Cellular drug administration: This experiment included a blank control group, a positive control group, and a drug administration group. 1 μL of the prepared compound solution was added to an EP tube containing 999 μL of complete culture medium, mixed thoroughly, and labeled. The original culture medium in the 96-well plate was aspirated. 100 μL of the compound solution was added to each well of the positive control group and the drug administration group, while fresh complete culture medium was added to the blank control group. Each compound was administered in triplicate. After drug administration, the 96-well plate was placed in a cell culture incubator for further incubation.

[0156] Add CCK-8 reagent: After incubating the drug and cells together for 48 hours, remove the original culture medium, and then add 90 μL of complete culture medium and 10 μL of CCK-8 mixed solution to each well. Continue to incubate in the incubator for 2 hours, and then take it out to detect its absorbance.

[0157] Measurement of optical density (OD): The 96-well plate was placed in a microplate reader and the absorbance was measured at a wavelength of 450 nm. Cell viability was calculated as shown in formula (1).

[0158] Cell viability (%) = [OD experimental group - OD blank group] / [OD positive control group - OD blank group] × 100%

[0159] Preliminary cell viability screening: Following the procedures outlined in the cell viability testing section, the synthesized compounds were administered to four different cell types at a concentration of 10 μM and the results were measured. Compounds exhibiting an inhibition rate greater than 50% were administered at five concentrations: 10 μM, 5.0 μM, 2.50 μM, 1.25 μM, and 0.625 μM. These compounds were then administered to the corresponding cell types using the same method, and the results were measured in triplicate for each group. The results are shown in Table 1.

[0160] Table 1 In vitro antitumor IC50 50 value

[0161]

[0162]

[0163] Experimental Example 2

[0164] The kinase detection method used in this experiment was ADP-Glo. TM This method detects ADP formed during a kinase reaction, which is then converted into ATP, and finally, ATP is reacted with Ultra-Glo. TM Luciferase converts light signals into luminescent signals. The luminescence signal is directly proportional to the kinase activity. The specific method is as follows:

[0165] Prepare 2×ATP / substrate solution and 2×kinase solution using kinase reaction buffer.

[0166] Transfer 50 nL of the compound dilution to a 384 detection plate using an Echo 655; centrifuge and add 2.5 μL of 2× kinase solution to the 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0167] Add 2.5 μL of 2× substrate and ATP solution to a 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes (PDGFR).

[0168] Prepare 2×XL665 and antibody detection reagents using detection buffer.

[0169] Add 5 μL of kinase assay reagent to the test plate and incubate at 25°C. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 1 hour.

[0170] Fluorescence signals on the BMG were read at 620 nm (Cryptate) and 665 nm (XL665).

[0171] The test results are shown in Table 2.

[0172] Table 2 shows the inhibition rate of the compounds against PDGFR at a concentration of 10 μM.

[0173]

[0174] As shown in Table 2, A9 has an inhibition rate of 34.1% against PDGFRα, which needs further modification to improve.

[0175] 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. A benzofuran compound, characterized in that, It is selected from any one of the compounds shown in the following structural formulas: , , , , and .

2. A method for preparing the benzofuran compound according to claim 1, characterized in that, It is synthesized according to the following synthesis path: The selection of R1 and R2 is as described in claim 1.

3. The preparation method according to claim 2, characterized in that, Step a involves hydrolyzing ethyl 5-nitrobenzuran-2-carboxylate.

4. The preparation method according to claim 2, characterized in that, Step a includes: mixing the ethyl 5-nitrobenzofuran-2-carboxylate and the basic substance in a molar ratio of 1:1.1-1.2 and then reacting them at 50-70°C.

5. The preparation method according to claim 2, characterized in that, Step b involves mixing 5-nitrobenzofuran-2-carboxylic acid and the starting material containing R1 at a molar ratio of 1:1.1-1.2 and then reacting the mixture at 20-30°C.

6. The preparation method according to claim 2, characterized in that, Step c includes: mixing compound 3 and reducing agent to react, wherein the molar ratio of compound 3 to reducing agent is 1:3-5, and the reaction temperature is 45-75℃.

7. The preparation method according to claim 2, characterized in that, Step d includes: mixing compound 4 and benzyl bromoides and reacting them, wherein the molar ratio of compound 4 to benzyl bromoides is 1:1.1-1.2, and the reaction temperature is 80-100℃.

8. A PDGFR kinase inhibitor, characterized in that, It includes the benzofuran compounds as described in claim 1.

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