Benzofuran compound, preparation method and application thereof, and VEGFR2 / FLT3 / PDGFR alpha kinase inhibitor

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a benzofuran compound, a preparation method and application thereof and a VEGFR2 / FLT3 / PDGFR alpha kinase inhibitor. The structural formula of the benzofuran compound is shown in the specification, R1 is selected from any one of substituted or unsubstituted benzo fused ring, substituted or unsubstituted pyrazole and substituted phenyl, and R2 is selected from any one of substituted or unsubstituted pyridine and substituted phenyl. The benzofuran compound provided by the embodiment of the invention can simultaneously act on VEGFR2, FLT3 and PDGFR alpha, can be used as a multi-target inhibitor, improves the drug resistance, toxic and side effects and the like of a single-target inhibitor, and has a good treatment effect on cancers such as gastric cancer.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to benzofuran compounds, preparation methods and applications thereof, and VEGFR2 / FLT3 / PDGFRα kinase inhibitors. Background Art

[0002] Vascular endothelial growth factor and its receptor (VEGFR) are important growth factors that regulate endothelial cell angiogenesis, cell migration and permeability. Among them, VEGFR-2 plays a key role in the VEGFR family. Specifically, VEGF mainly regulates tumor angiogenesis by directly generating vascular signals with the help of VEGFR-2. As a key mediator of angiogenesis, VEGFR-2 is closely related to a variety of cancers, such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cell carcinoma, breast cancer, gastric cancer, glioma, etc. Therefore, VEGFR-2 is an important target for the treatment of various cancers. More and more VEGFR inhibitors have been found to be useful for the treatment of cancer and have achieved great success in clinical practice. However, the resistance mutations of single-target VEGFR inhibitors have greatly hindered the clinical application of VEGFR2 inhibitors.

[0003] Tyrosine kinase 3 (FLT3), a member of the type III receptor tyrosine kinase (RTKIII) family, plays an important role in the proliferation, differentiation, and apoptosis of hematopoietic cells. FLT3 ligand (FLT3L) is primarily secreted and expressed by various cell types, including bone marrow stromal cells, and exerts its biological function of inhibiting cell proliferation by forming a synergistic regulatory network with various hematopoietic growth factors. Studies have found that FLT3 is overexpressed in a variety of human cancers. For example, FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). Therefore, FLT3 inhibitors are crucial in the treatment of AML patients with FLT3 mutations.

[0004] Platelet-derived growth factor receptor α (PDGFRα) plays an important role in the tumor microenvironment, participating in tumor cell proliferation, migration, and matrix remodeling. Overactivation of PDGFRα is closely associated with the occurrence and progression of various solid tumors, and inhibiting its activity can effectively inhibit tumor growth.

[0005] Multi-target inhibitors can overcome the drug resistance problem of single-target drugs and improve therapeutic efficacy by acting on multiple signaling pathways simultaneously. However, the design of highly effective and low-toxic multi-target inhibitors faces huge challenges and requires balancing the selectivity, activity and safety of the drugs. Currently, there have been many studies on single-target inhibitors for VEGFR2, FLT3 and PDGFRα, but these drugs are often limited in clinical application due to drug resistance or toxic side effects. The development of multi-target inhibitors that simultaneously target VEGFR2, FLT3 and PDGFRα is expected to provide a better solution for tumor treatment.

[0006] In view of this, the present invention is proposed. Summary of the Invention

[0007] The present invention aims to provide benzofuran compounds, preparation methods, and uses thereof, as well as VEGFR2 / FLT3 / PDGFRα kinase inhibitors. The benzofuran compounds provided in the embodiments of the present invention can act simultaneously on VEGFR2, FLT3, and PDGFRα, and can be used as multi-target inhibitors, improving the drug resistance and toxic side effects of single-target inhibitors. They also have a good therapeutic effect on cancers such as gastric cancer.

[0008] The present invention is achieved in that:

[0009] In a first aspect, the present invention provides a benzofuran compound selected from the compounds represented by the following structural formula:

[0010] Wherein, R1 is selected from any one of substituted or unsubstituted benzo-fused ring, substituted or unsubstituted pyrazole and substituted phenyl, and R2 is selected from any one of substituted or unsubstituted pyridine and substituted phenyl.

[0011] In a second aspect, the present invention provides a method for preparing the benzofuran compound described in the aforementioned embodiment, which is synthesized according to the following synthesis route:

[0012]

[0013] Preferably, step a comprises: mixing the M1 compound and a strong base to perform a degreasing reaction;

[0014] Step b comprises: subjecting the M2 compound to an amide condensation reaction with the corresponding amine;

[0015] Step c comprises: mixing the M3 compound with a reducing agent to perform a reduction reaction;

[0016] Step d comprises: mixing the M4 compound and the aromatic aldehyde in a molar ratio of 1:(1.5-3) to react.

[0017] In a third aspect, the present invention provides a VEGFR2 / FLT3 / PDGFRα kinase inhibitor, which includes the benzofuran compound described in the aforementioned embodiment.

[0018] In a fourth aspect, the present invention provides any one of the following applications of the benzofuran compound described in the aforementioned embodiment:

[0019] (1) Preparation of VEGFR2 / FLT3 / PDGFRα kinase inhibitors;

[0020] (2) Application in drugs for treating tumors;

[0021] Preferably, the tumor comprises gastric cancer.

[0022] The present invention has the following beneficial effects: the benzofuran compounds provided in the embodiments of the present invention can simultaneously have a good inhibitory effect on VEGFR2, FLT3 and PDGFRα kinases, can be used as multi-target inhibition, and have a good therapeutic effect on tumors such as gastric cancer, and can be used in the treatment of tumors. DETAILED DESCRIPTION

[0023] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0024] In a first aspect, an embodiment of the present invention provides a benzofuran compound selected from the compounds represented by the following structural formula:

[0025] Wherein, R1 is selected from any one of substituted or unsubstituted benzo-fused ring, substituted or unsubstituted pyrazole and substituted phenyl, and R2 is selected from any one of substituted or unsubstituted pyridine and substituted phenyl.

[0026] Specifically, the benzo-fused ring described by R1 includes a benzoheteroaryl group or a benzocycloalkyl group, wherein the benzoheteroaryl group may be a benzo five-membered heteroaryl group, such as benzopyrrole. The benzocycloalkyl group includes a benzo C5-C8 cycloalkyl group, such as benzocyclopentyl. The substituent in the substituted benzo-fused ring is selected from a C1-C3 alkyl group, and the substituent is located on the fused ring in the benzo-fused ring.

[0027] Furthermore, the substituted or unsubstituted benzo-fused ring includes any one of an unsubstituted benzo five-membered heteroaryl group, an unsubstituted benzo C5-C8 cycloalkyl group, and a C1-C3 alkyl-substituted benzo five-membered heteroaryl group; for example, any one of an unsubstituted benzopyrrole group, an unsubstituted benzocyclopentyl group, and a C1-C3 alkyl-substituted benzopyrrole group. In this case, the C1-C3 alkyl group is located on the pyrrole ring of the benzopyrrole, for example, connected to the nitrogen of the pyrrole of the benzopyrrole.

[0028] The substituent in the substituted pyrazole described by R1 is a C1-C3 alkyl group; and the substituent is located on the nitrogen of the pyrazole.

[0029] The substituent of the substituted phenyl group in R1 includes a cycloalkyl group; the cycloalkyl group is a substituted cycloalkyl group, specifically a cyano-substituted cycloalkyl group, for example, a cyano-substituted C5-C8 cycloalkyl group, and the substituted cycloalkyl group is located in the para position of the phenyl group.

[0030] In summary, R1 is selected from any one of unsubstituted benzo five-membered heteroaryl, unsubstituted benzo C5-C8 cycloalkyl, C1-C3 alkyl-substituted benzo five-membered heteroaryl, unsubstituted pyrazole, C1-C3 alkyl-substituted pyrazole, and cycloalkyl-substituted phenyl; preferably any one of unsubstituted benzopyrrole, unsubstituted benzocyclopentyl, C1-C3 alkyl-substituted benzopyrrole, unsubstituted pyrazole, C1-C3 alkyl-substituted pyrazole, and cyano-substituted C5-C8 cycloalkyl-substituted phenyl.

[0031] Furthermore, the substituent in the substituted pyridine is a halogen; the substituent is located at the ortho position of the N of the pyridine.

[0032] Furthermore, the number of substituents in the substituted phenyl group in R2 may be 1 or 2, and when the number of substituents is 1, the substituent may be located at the para position or the meta position of the phenyl group. When the number of substituents is 2, the two substituents are located at the para and meta positions, or at the para and ortho positions, of the phenyl group.

[0033] Furthermore, the substituent of the substituted phenyl group includes a tertiary amine group, the structural formula of which is R3 and R4 are each independently selected from C1-C3 alkyl.

[0034] The substituents of the substituted phenyl group also include substituted or unsubstituted six-membered heterocyclic groups, such as substituted or unsubstituted piperidine, specifically hydroxy-substituted piperidine, and in this case, the hydroxyl group is located at the para position of the piperidine N.

[0035] Substituents for the substituted phenyl group also include substituted or unsubstituted five-membered heterocyclic groups, such as substituted or unsubstituted tetrahydropyrrole.

[0036] The substituent of the substituted phenyl group also includes any one of a hydroxyl group, a C1-C3 alkoxy group and a halogen group.

[0037] It should be noted that the aforementioned C1-C3 alkyl groups include, but are not limited to, methyl, ethyl, and n-propyl groups. C1-C3 alkoxy groups include, but are not limited to, methoxy, ethoxy, and propoxy groups. Halogen groups include, but are not limited to, chlorine, bromine, and iodine.

[0038] Specifically, the benzofuran compound is selected from any one of the compounds represented by the following structural formulas:

[0039]

[0040] It should be noted that the numbers below the above structural formula correspond to the numbers of the compounds in the full text.

[0041] In a second aspect, the present invention provides a method for preparing the benzofuran compound described in the aforementioned embodiment, which is synthesized according to the following synthesis route:

[0042] in,

[0043] Step a comprises: mixing the M1 compound and a strong base to perform a degreasing reaction;

[0044] Step b comprises: subjecting the M2 compound to an amide condensation reaction with the corresponding amine;

[0045] Step c comprises: mixing the M3 compound with a reducing agent to perform a reduction reaction;

[0046] Step d comprises: mixing the M4 compound and the aromatic aldehyde in a molar ratio of 1:(1.5-3) to react.

[0047] The conditions of the above steps a, b, c and d refer to existing conditions and methods, and therefore, they will not be described in detail in the embodiment of the present invention.

[0048] For example, the overall reaction process is as follows: 5-nitrobenzofuran-2-carboxylic acid ethyl ester (M1) is hydrolyzed in the presence of NaOH to produce 5-nitrobenzofuran-2-carboxylic acid (M2). Subsequently, 5-nitrobenzofuran-2-carboxylic acid is dissolved in N,N-dimethylformamide (DMF), and O-benzotriazole-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU) and N,N-diisopropylethylamine (DIPEA) are added to react with the corresponding amine to form the corresponding amide (M3). The nitro group of compound (M3) is then reduced in the presence of zinc powder and ammonium chloride to form a compound (M4) with an amino group. Finally, compound (M4) reacts with an aromatic aldehyde in the presence of glacial acetic acid to yield the final product (M5).

[0049] After each step of the reaction, post-treatment is required to obtain a compound with higher purity. The post-treatment methods include pH adjustment, rotary evaporation, drying, and extraction, etc., which will not be described in detail in the embodiments of the present invention.

[0050] In a third aspect, the present invention provides a VEGFR2 / FLT3 / PDGFRα kinase inhibitor, which includes the benzofuran compound described in the aforementioned embodiment.

[0051] In a fourth aspect, the present invention provides any one of the following applications of the benzofuran compound described in the aforementioned embodiment:

[0052] (1) Preparation of VEGFR2 / FLT3 / PDGFRα kinase inhibitors;

[0053] (2) Application in drugs for treating tumors; preferably, the tumor includes gastric cancer.

[0054] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0055] Example 1

[0056] The present invention provides a method for synthesizing a benzofuran compound (denoted as A1), with reference to the following synthesis path:

[0057]

[0058] The specific steps are as follows:

[0059] Synthesis of M2 compound:

[0060] 25 g (8.5 mmol, 1 equivalent) of ethyl 5-nitrobenzofuran-2-carboxylate was dissolved in 400 ml of methanol, followed by the addition of approximately 8.5 mmol, 1.1 equivalents of NaOH, and the mixture was allowed to react in a 60°C oil bath. After approximately 3 hours, the reaction was complete. Water was added to the reaction flask, and the pH of the reaction solution was adjusted to a weakly acidic state with dilute hydrochloric acid. A large amount of white precipitate formed from the yellow transparent solution. This precipitate was then filtered to obtain the dry, milky white powder product M2 in a yield of approximately 95%.

[0061] Synthesis of M3 compound:

[0062] Dissolve 10 g of 5-nitrobenzofuran-2-carboxylic acid (M2) in 60 mL of DMF, then add 2 equivalents of TBTU, 2 equivalents of DIPEA, and 1.2 equivalents of substituted aniline to the reaction mixture. Stir at room temperature (e.g., 25°C). After approximately 6 hours, the solution gradually clears from turbidity, indicating completion of the reaction. Adding water to the reaction solution produces a precipitate, which is vacuum filtered and washed repeatedly with methanol in small amounts to obtain a powdered product (M3). The yield is approximately 70%.

[0063] Synthesis of M4 compound:

[0064] Weigh 1 equivalent of M3 into a 50 mL eggplant-shaped flask, along with 5 equivalents of zinc powder and 5 equivalents of ammonium chloride. Add 30 mL of a methanol-water mixture (methanol:water = 2:1) and repeatedly purge with nitrogen for protection. The mixture is then placed on a heated stirring platform at 60°C for 6 hours before being stopped. Add water to produce a precipitate, which is filtered and the filter cake is repeatedly washed with ethyl acetate. The combined washings are then spin-dried to yield the solid product (M4). The yield is approximately 80%.

[0065] Synthesis of final product A1:

[0066] Weigh 1 equivalent of M4 and dissolve it in methanol. Add 1.5 equivalents of an aromatic aldehyde, then add 1 equivalent of glacial acetic acid to catalyze the reaction. Stir the reaction at room temperature. A large amount of precipitate will form, monitored by TLC. After approximately 4 hours of complete reaction, the resulting solid is collected by filtration and recrystallized from methanol. The collected product is then dried to obtain the final product, A1, as a red powder. Store it in a refrigerator at -20°C until ready for use.

[0067] The characterization data of compound A1 are as follows:

[0068] Purity>95%. Red solid, 150 mg, yield 40%. 1 H NMR(400MHz,DMSO-d6)δ11.17(d,J=19.8Hz,1H),10.40-9.54(m,1H),8.52 (s,1H),7.83-7.77(m,2H),7.71(dd,J=11.5,8.7Hz,1H),7.63-7.54(m,1H) ,7.43-7.33(m,3H),7.28(t,J=8.7Hz,1H),7.10(q,J=8.0Hz,1H),6.87-6.7 6(m,3H),6.58(d,J=9.5Hz,1H)3.04(d,J=8.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 26 H 22 N4O:423.1816; found:423.1813.

[0069] Example 2-Example 43

[0070] The benzofuran compounds of Examples 2 to 43 (labeled A2 to A43) were synthesized according to the synthesis method of Example 1, with the only difference being the changes in the corresponding reaction raw materials and reaction conditions. The reaction conditions are also within the scope of the present invention and are not described in detail here. The following provides characterization data for the benzofuran compounds prepared in Examples 2 to 43. Specifically:

[0071] Example 2: Compound A2

[0072] Purity>95%. Yellow solid, 447 mg, yield 62%. 1H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 10.26 (s, 1H), 8.78 (d, J = 2.3Hz, 1H), 8.55 (s,1H),7.83(s,1H),7.80-7.71(m,2H),7.67(d,J=8.6Hz,2H),7.29(dd,J=13.5, 5.6Hz,3H),7.15-7.02(m,1H),6.57(d,J=19.5Hz,1H),6.22(d,J=11.7Hz,1H),6. 11(s,1H),3.41(d,J=7.0Hz,4H),1.16(s,3H),1.14(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 28 H 26 N4O3:467.2078; found:467.2084.

[0073] Example 3: Compound A3

[0074] Purity>95%. Yellow solid, 175 mg, yield 54%. 1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),10.27(s,1H),8.48(s,1H),7.81(s,1H),7.75(d ,J=8.8Hz,2H),7.71(d,J=8.8Hz,1H),7.59(d,J=1.9Hz,1H),7.40-7.37(m,1H),7.37-7 .33(m,2H),7.28(s,1H),7.11(t,J=7.8Hz,1H),6.77(d,J=8.7Hz,2H),6.59(s,1H),3. 46(d,J=7.1Hz,2H),3.42(d,J=7.2Hz,2H),1.14(d,J=6.9Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 28 H 26 N4O2:451.2129; found: 451.2133.

[0075] Example 4: Compound A4

[0076] Purity>95%. Orange solid, 58 mg, yield 29%. 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.50(s,1H),8.04(d,J=2.0Hz,1H),7.78(d,J=8.7 Hz,2H),7.72(d,J=6.2Hz,1H),7.69(s,1H),7.59(d,J=2.2Hz,1H),7.52(dd,J=8.7,1.9H z,1H),7.43(d,J=8.8Hz,1H),7.38(dd,J=8.7,2.3Hz,1H),7.33(d,J=3.0Hz,1H),6.82(s ,1H),6.80(s,1H),6.43(d,J=3.1Hz,1H),3.80(s,3H),3.03(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 27 H 24 N4O2:437.1972; found:437.1978.

[0077] Example 5: Compound A5

[0078] Purity>95%. Yellow solid, 47 mg, yield 31%. 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.36(s,1H),8.77(s,1H),8.04(s,1H),7.74(s,3H),7.63(s,2H),7.36-7.31(m, 3H),6.43(d,J=3.0Hz,1H),6.41(d,J=3.1Hz,1H),6.10(s,1H),3.79(d,J=7.0Hz,7H),1.16(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 28 N4O3:481.2234; found: 481.2236.

[0079] Example 6: Compound A6

[0080] Purity>95%. Brown solid, 47 mg, yield 34%. 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.45(s,1H),7.81(s,1H),7.73(d,J=8.7Hz,3H),7.67(s,2H),7.54(s ,1H),7.44-7.32(m,2H),6.77(s,4H),3.80(s,1H),3.72(s,3H),1.14(t,J=7.0Hz,9H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 28 N4O2:465.2285; found: 465.2293.

[0081] Example 7: Compound A7

[0082] Purity>95%. Yellow solid, 125 mg, yield 49%. 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.50(s,1H),7.78(d,J=8.8Hz,2H),7.7 5-7.70(m,2H),7.69(s,1H),7.59(d,J=2.2Hz,1H),7.52(d,J=8.1Hz,1H),7.38 (dd,J=8.8,2.2Hz,1H),7.21(d,J=8.2Hz,1H),6.81(d,J=8.8Hz,2H),3.03(s, 6H),2.86(dt,J=14.8,7.3Hz,4H),2.04(p,J=7.5Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 27 H 25 N3O2:424.202; found:424.2020.

[0083] Example 8: Compound A8

[0084] Purity>95%. Dark yellow solid, 119 mg, yield 52%. 1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),10.51-10.34(m,1H),8.76(s,1H),7.83-7.69(m,2H) ,7.70-7.61(m,1H),7.60-7.43(m,1H),7.36(d,J=8.9Hz,1H),7.24(dd,J=22.0,8.7Hz,2H), 7.13(d,J=9.0Hz,1H),6.41-6.27(m,1H),6.18-6.02(m,1H),3.40(s,4H),2.87-2.81(m,4H ),2.04-1.97(m,2H),1.16(d,J=3.9Hz,2H),1.13(s,2H),1.12(s,2H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 29 N3O3:468.2242; found: 468.2247.

[0085] Example 9: Compound A9

[0086] Purity>95%. Light yellow solid, 171 mg, yield 58%. 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.46(s,1H),7.80-7.67(m,5H),7.58( d,J=2.2Hz,1H),7.52(d,J=8.2Hz,1H),7.36(dd,J=8.9,2.2Hz,1H),7.21(d, J=8.2Hz,1H),6.76(d,J=8.8Hz,2H),4.11(q,J=5.3Hz,4H),2.86(dt,J=14.8 ,7.4Hz,4H),2.13-1.88(m,2H),1.14(t,J=7.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 29 N3O2:452.2333; found: 452.2333.

[0087] Example 10: Compound A10

[0088] Purity>95%. Orange solid, 69 mg, yield 38%. 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.38(s,1H),9.67(s,1H),8.10(d,J=7.6Hz,1H),7.73-7.65(m,3H),7.62(d,J=8.7Hz,1H),7.50(d,J=8.4Hz ,1H),7.32(dt,J=5.5,2.4Hz,3H),7.15-7.09(m,1H),6.80(d,J=8.7Hz,2 H),6.40(d,J=2.6Hz,1H),3.18(s,1H),3.05(s,5H).HRMS(ESI)m / z:(M+H) + calcd for C 26 H 22 N4O2:423.1816; found:423.1817.

[0089] Example 11: Compound A11

[0090] Purity>95%. Yellow solid, 101 mg, yield 43%. 1 H NMR(400MHz,DMSO-d6)δ13.58(s,1H),11.11(s,1H),10.44(s,1H),8.77(s,1H ),8.11(d,J=1.8Hz,1H),7.77(s,1H),7.76(s,1H),7.74(d,J=2.9Hz,1H),7.5 5-7.45(m,2H),7.39-7.30(m,3H),6.40(s,1H),6.38-6.32(m,1H),6.11(d,J= 2.4Hz,1H),3.41(q,J=7.1Hz,4H),1.14(t,J=7.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 28 H 26 N4O3:467.2078; found: 467.2081.

[0091] Example 12: Compound A12

[0092] Purity>95%. Dark brown solid, 73 mg, yield%. 1H NMR (400MHz, DMSO-d6) δ11.11(d,J=10.3Hz,1H),10.42(d,J=56.3Hz,1H),9.63(s,1H),8.13-7.98 (m,1H),7.88(d,J=13.5Hz,1H),7.72-7.64(m,2H),7.54(dd,J=32.7,8.9Hz,2H),7.37-7.27(m,2H) ,7.23(s,1H),7.11-6.97(m,1H),6.77(d,J=8.9Hz,2H),6.40(s,1H),3.58(d,J=7.1Hz,1H),3.45(q ,J=7.0Hz,3H),1.20(t,J=7.0Hz,2H),1.15(s,1H),1.13(s,2H),1.11(s,1H).HRMS(ESI)m / z:(M+H) + calcd for C 28 H 26 N4O2:451.2129; found: 451.2126.

[0093] Example 13: Compound A13

[0094] Purity>95%. Yellow solid, 48 mg, yield 36%. 1 H NMR (400MHz, DMSO-d6) δ11.20(d,J=9.2Hz,1H),10.24(d,J=66.6Hz,1H),9.68(s,1H),7.9 3(d,J=8.7Hz,1H),7.90-7.80(m,1H),7.73-7.64(m,2H),7.60-7.51(m,1H),7.35(dq,J=6 .6,3.0Hz,2H),7.29(t,J=8.1Hz,1H),7.17-7.06(m,2H),7.05-6.96(m,2H),6.62-6.53(m ,1H),3.49(s,2H),3.45-3.41(m,2H),1.60(dd,J=15.7,9.4Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 26 N4O2:463.2129; found: 463.2130.

[0095] Example 14: Compound A14

[0096] Purity>95%. Light yellow solid, 20 mg, yield 21%. 1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.51(s,1H),7.79(s,1H),7.76(s,1H),7.74( s,1H),7.72(s,1H),7.70(s,1H),7.60(d,J=2.1Hz,1H),7.52(d,J=8.2Hz,1H),7.38( dd,J=8.8,2.3Hz,1H),7.21(d,J=8.1Hz,1H),7.03(d,J=8.6Hz,2H),3.17(s,2H),2. 86(dt,J=14.9,7.6Hz,4H),2.04(t,J=7.4Hz,2H),1.61(s,8H).HRMS(ESI)m / z:(M+H) + calcd for C 30 H 29 N3O2:464.2333; found: 464.2331.

[0097] Example 15: Compound A15

[0098] Purity>95%. Orange solid, 101 mg, yield 48%. 1 H NMR(400MHz,DMSO-d6)δ11.13(d,J=7.2Hz,1H),10.43(s,1H),8.51(s,1H),8.27-7.99(m,1 H),7.80-7.75(m,3H),7.72(d,J=8.8Hz,1H),7.61(d,J=2.2Hz,1H),7.51(d,J=8.5Hz,1H), 7.40(d,J=2.2Hz,1H),7.37(dd,J=6.2,2.1Hz,1H),7.33(dt,J=5.5,2.3Hz,1H),7.02(d,J= 9.0Hz,2H),6.41(d,J=2.7Hz,1H),3.34(d,J=6.2Hz,4H),1.60(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 26 N4O2:463.2129; found: 481.2236.

[0099] Example 16: Compound A16

[0100] Purity>95%. Yellow solid, 65 mg, yield 38%. 1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),10.27(s,1H),8.50(s,1H),7.84-7.7 6(m,3H),7.71(d,J=8.8Hz,1H),7.60(d,J=2.2Hz,1H),7.44-7.34(m,3H),7. 29(d,J=8.1Hz,1H),7.11(t,J=7.8Hz,1H),6.68-6.56(m,4H),4.11(q,J=5. 4Hz,1H),3.18(d,J=5.2Hz,2H),2.00(t,J=4.8Hz,4H).HRMS(ESI)m / z:(M+H) + calcd for C 28 H 24 N4O2:449.1972; found:449.1976.

[0101] Example 17: Compound A17

[0102] Purity>95%. Yellow solid, 34 mg, yield 29%. 1 H NMR (400MHz, DMSO-d6) δ10.39 (d, J = 5.1Hz, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7. 77(d,J=8.3Hz,2H),7.74-7.67(m,1H),7.59(s,1H),7.52(d,J=9.3Hz,1H),7. 43(d,J=8.7Hz,1H),7.40-7.32(m,2H),6.65(d,J=8.5Hz,3H),6.43(d,J=3.1H z,1H),3.80(s,3H),3.17(d,J=5.1Hz,2H),2.00(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 26 N4O2:463.2129; found: 463.2133.

[0103] Example 18: Compound A18

[0104] Purity>95%. Yellow solid, 150 mg, yield 56%. 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.48(s,1H),7.80-7.66(m,5H),7.58(d,J=2.2Hz,1H),7.53(d,J=8.2Hz,1H),7.37(dd,J=8.8,2.2 Hz,1H),7.21(d,J=8.2Hz,1H),6.64(d,J=8.6Hz,2H),3.33(s,4H),2.86(dt,J=14.8,7.3Hz,4H),2.09-1.96(m,6H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 27 N3O2:450.2176; found: 450.2180.

[0105] Example 19: Compound A19

[0106] Purity>95%. Yellow solid, 65 mg, yield 48%. 1 H NMR(400MHz,DMSO-d6)δ11.24-11.04(m,1H),10.42(d,J=61.6Hz,1H),9.64(s,1H),8.8 5(s,1H),8.19-7.96(m,2H),7.84(d,J=10.5Hz,1H),7.75-7.61(m,2H),7.57-7.46(m,1H ),7.40-7.29(m,2H),7.19-6.99(m,1H),6.79(d,J=8.8Hz,1H),6.67-6.60(m,1H),6.40 (dt,J=5.2,2.4Hz,1H),3.44(d,J=24.3Hz,4H),2.22-1.76(m,4H).HRMS(ESI)m / z:(M+H) + calcd for C 28 H 24 N4O2:449.1972; found:449.1977.

[0107] Example 20: Compound A20

[0108] Purity>95%. Yellow solid, 80 mg, yield 47%. 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.50(s,1H),7.84(s,1H),7.81-7.75(m,2H),7.70-7.63(m,2H),7.57(d,J=2.1Hz,1H ),7.36(dd,J=8.8,2.2Hz,1H),6.81(d,J=8.9Hz,2H),6.58(d,J=2.3Hz,1H),3.81(s,3H),3.03(s,6H).HRMS(ESI)m / z:(M+H) + calcd for C 22 H 21 N5O2:388.1768; found:388.1764.

[0109] Example 21: Compound A21

[0110] Purity>95%. Yellow solid, 58 mg, yield 48%. 1 H NMR (400MHz, DMSO-d6) δ13.58(s,1H),11.06(s,1H),8.76(s,1H),7.87(s,1H),7. 70(d,J=9.6Hz,2H),7.64(s,1H),7.46(d,J=8.8Hz,1H),7.35(d,J=8.7Hz,1H),6. 64-6.54(m,1H),6.33(d,J=8.8Hz,1H),6.10(s,1H),3.81(s,3H),3.42(s,1H),3. 41(s,1H),3.39(s,1H),3.37(s,1H),1.13(t,J=7.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 25 N5O3:432.203; found: 432.2029.

[0111] Example 22: Compound A22

[0112] Purity>95%. Yellow solid, 64 mg, yield 41%. 1H NMR(400MHz,DMSO-d6)δ11.13(d,J=28.5Hz,1H),9.63(s,1H),8.20-8.08(m,1H),7.87( d,J=14.2Hz,1H),7.83-7.71(m,1H),7.69-7.62(m,3H),7.40-7.24(m,1H),7.08-6.97(m ,1H),6.76(d,J=8.8Hz,1H),6.58(dd,J=7.3,2.3Hz,1H),3.81(d,J=4.0Hz,3H),3.61(q, J=7.0Hz,2H),3.46(d,J=6.9Hz,2H),1.17(dt,J=30.5,7.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 25 N5O2:416.2081; found:416.2082.

[0113] Example 23: Compound A23

[0114] Purity>95%. Dark brown solid, 59 mg, yield 38%. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.69(s,1H),8.52(s,1H),8.05(d,J=1.9Hz,1H),7.78(d,J=8 .5Hz,2H),7.73(d,J=3.9Hz,1H),7.69(dd,J=8.9,2.5Hz,1H),7.56(dd,J=39.9,2.2Hz,1H),7.46-7. 36(m,2H),7.33(d,J=3.1Hz,1H),7.05(d,J=3.7Hz,2H),6.43(d,J=3.1Hz,1H),4.74(s,1H),3.80(s ,3H),3.73(d,J=6.0Hz,1H),3.20-3.01(m,4H),1.85(s,2H),1.54-1.32(m,2H).RMS(ESI)m / z:(M+H) + calcd for C 30 H 28 N4O3:493.2234; found: 493.2237.

[0115] Example 24: Compound A24

[0116] Purity>95%. Light yellow solid, 245 mg, yield 69%. 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.51(s,1H),7.82-7.68(m,5H),7.60(d,J=2.2Hz,1H),7.53(d, J=8.1Hz,1H),7.38(dd,J=8.7,2.2Hz,1H),7.21(d,J=8.2Hz,1H),7.04(d,J=8.7Hz,2H),4.74(d,J=4. 2Hz,1H),4.13(s,1H),3.72(dd,J=10.6,6.1Hz,3H),3.09-2.98(m,2H),2.89(d,J=7.3Hz,1H),2.87-2 .82(m,2H),2.04(p,J=7.4Hz,2H),1.83(d,J=13.0Hz,2H),1.45(q,J=9.2Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 30 H 29 N3O3:480.2282; found: 480.2282.

[0117] Example 25: Compound A25

[0118] Purity>95%. Light green solid, 116 mg, yield 56%. 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),10.27(s,1H),8.53(s,1H),7.83-7.77(m,3H),7.73(d ,J=8.9Hz,1H),7.62(d,J=2.0Hz,1H),7.45-7.34(m,3H),7.29(d,J=8.2Hz,1H),7.11(t,J=7. 9Hz,1H),7.04(d,J=8.6Hz,2H),6.59(s,1H),4.74(d,J=4.1Hz,1H),3.75(s,1H),3.18(d,J=5 .2Hz,2H),3.05(t,J=11.0Hz,2H),1.82(s,2H),1.45(d,J=11.6Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 26 N4O3:479.2078; found:479.2081.

[0119] Example 26: Compound A26

[0120] Purity>95%. Light yellow solid, 75 mg, yield 43%. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.43(s,1H),8.52(s,1H),8.11(d,J=1.6Hz,1H),7.81-7. 75(m,3H),7.72(d,J=8.8Hz,1H),7.61(d,J=2.2Hz,1H),7.51(d,J=8.5Hz,1H),7.43-7.28(m,3H), 7.04(d,J=8.8Hz,2H),6.40(s,1H),4.74(d,J=4.2Hz,1H),3.72(dd,J=10.3,5.7Hz,3H),3.18(d, J=5.2Hz,1H),3.12-3.00(m,2H),1.83(d,J=12.8Hz,2H),1.51-1.40(m,1H).HRMS(ESI)m / z:(M+H) + calcd for C 29 H 26 N4O3:479.2078; found:479.2083.

[0121] Example 27: Compound A27

[0122] Purity>95%. Light yellow solid, 58 mg, yield 41%. 1 H NMR(400MHz,DMSO-d6)δ11.32-10.70(m,1H),9.64(s,1H),7.94-7.86(m,1H) ,7.71-7.60(m,4H),7.40(d,J=8.8Hz,1H),6.92(d,J=2.2Hz,1H),6.86(dd,J =8.8,2.3Hz,1H),6.64(d,J=8.5Hz,2H),6.55(d,J=2.2Hz,1H),3.80(d,J=6. 6Hz,4H),2.55(s,1H),1.98(td,J=7.6,6.7,4.3Hz,5H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 23 N5O2:414.1925; found:414.1927.

[0123] Example 28: Compound A28

[0124] Purity>95%. Brown solid, 69 mg, yield 38%. 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.33(d,J=9.7Hz,1H),10.14(s,1H),9.70(s ,1H),9.57(s,1H),7.87(s,1H),7.81(dd,J=11.7,8.7Hz,1H),7.74(d,J=2.2Hz,1H) ,7.42(dd,J=8.8,2.3Hz,1H),7.39-7.33(m,2H),7.33-7.23(m,3H),7.10(t,J=7.8H z,1H),6.93(dd,J=8.2,5.7Hz,1H),6.58(q,J=3.8,2.5Hz,1H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 17 N3O4:412.1292; found: 412.1291.

[0125] Example 29: Compound A29

[0126] Purity>95%. Yellow solid, 58 mg, yield 34%. 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.30(s,3H),8.74(s,1H),7.82(s,1H),7.79-7.70(m,2H),7.46(dd,J=8.8,2.3Hz,1H),7.39-7.33(m,2H), 7.29(dd,J=8.5,1.7Hz,2H),7.11(t,J=7.8Hz,1H),6.59(t,J=2.1Hz,1H),6.23(dd,J=8.5,2.2Hz,1H),6.08(d,J=2.2Hz,1H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 17 N3O4:412.1291; found: 412.1289.

[0127] Example 30: Compound A30

[0128] Purity>95%. Yellow solid, 46 mg, yield 31%. 1H NMR (400MHz, DMSO-d6) δ13.25(s,1H),11.20(s,1H),10.34(s,1H),9.06(s,1H),7.93-7.86(m,2H),7.83(d,J=8.8Hz,1H),7.61(dd,J=8.8,2.2Hz,1H ),7.40-7.34(m,2H),7.29(td,J=5.8,2.9Hz,2H),7.20-7.08(m,2H),6.95 (t,J=7.9Hz,1H),6.60(d,J=2.8Hz,1H),3.85(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 25 H 19 N3O4:426.1448; found: 426.1449.

[0129] Example 31: Compound A31

[0130] Purity>95%. Yellow solid, 48 mg, yield 30%. 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),10.29(s,2H),8.60(s,1H),7.95(s,1H),7.83(s,1H),7.77(t,J=9.4Hz,2H),7.66(s,1 H),7.43(d,J=8.8Hz,1H),7.39-7.33(m,2H),7.29(d,J=8.1Hz,1H),7.11(t,J=7.6Hz,2H),6.59(s,1H).HRMS(ESI)m / z:(M+H) + calcd for C 24 H 16 ClN3O3:430.0953; found: 430.0958.

[0131] Example 32: Compound A32

[0132] Purity>95%. Yellow solid, 52 mg, yield 34%. 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),10.34(s,1H),10.10(d,J=26.5Hz,1H),9.03(s,1H),7.94-7.86(m,3H),7.83(d,J=8.9Hz,1H),7.64-7. 50(m,2H),7.43-7.34(m,2H),7.30(d,J=8.1Hz,1H),7.11(t,J=7.9Hz,1H),6.98(d,J=8.8Hz,1H),6.60(t,J=2.6Hz,1H).HRMS(ESI)m / z:(M+H) + calcdfor C 24 H 16 BrN3O3:474.0448; found: 474.0449.

[0133] Example 33: Compound A33

[0134] Purity>95%. Yellow solid, 317 mg, yield 75%. 1 H NMR (400MHz, DMSO-d6) δ11.06(d,J=14.1Hz,2H),10.28(d,J=65.7Hz,1H),8.65(s,1H),7.76(s,1H),7.72-7.58(m,3H),7. 42-7.27(m,2H),6.62-6.52(m,1H),6.27-6.19(m,1H),6.12(d,J=2.3Hz,1H),3.80(d,J=8.4Hz,3H).HRMS(ESI)m / z:(M+H) + calcd for C 20 H 16 N4O4:377.1244; found:377.1244.

[0135] Example 34: Compound A34

[0136] Purity>95%. Orange solid, 53 mg, yield 36%. 1H NMR (400MHz, DMSO-d6) δ13.24(s,1H),11.11(s,1H),9.05(s,1H),7.94-7. 85(m,2H),7.78(d,J=8.8Hz,1H),7.65(s,1H),7.58(dd,J=8.8,2.3Hz,1H), 7.27(dd,J=7.9,1.5Hz,1H),7.15(dd,J=8.1,1.4Hz,1H),6.94(t,J=7.9Hz, 1H),6.59(d,J=2.1Hz,1H),3.84(s,3H),3.81(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 21 H 18 N4O4:391.1401; found:391.1402.

[0137] Example 35: Compound A35

[0138] Purity>95%. Brown solid, 20 mg, yield 21%. 1 H NMR(400MHz,DMSO-d6)δ11.27-10.60(m,1H),9.80(s,1H),8.58(s,1H),8.06-7.84(m,2H),7.84-7.56(m,3H),7.46-7.31 (m,1H),7.13(dd,J=12.3,8.4Hz,1H),6.85-6.71(m,1H),6.65-6.53(m,1H),3.80(d,J=6.5Hz,3H).HRMS(ESI)m / z:(M+Na) + calcd for C 20 H 15 ClN4O3:417.0725; found: 417.0728.

[0139] Example 36: Compound A36

[0140] Purity>95%. Orange solid, 51 mg, yield 37%. 1H NMR (400MHz, DMSO-d6) δ13.06(s,1H),11.11(s,1H),9.03(s,1H),7.94-7.88(m,2H),7.86(d,J=2.1Hz,1H),7.79(d,J=8.8Hz,1H ),7.74-7.61(m,1H),7.58(dt,J=8.7,2.8Hz,2H),6.98(d,J=8.8Hz,1H),6.63-6.53(m,1H),3.81(s,3H).HRMS(ESI)m / z:(M+Na) + calcd for C 20 H 15 BrN4O3:461.022; found: 461.0219.

[0141] Example 37: Compound A37

[0142] Purity>95%. White solid, 127 mg, yield 52%. 1 H NMR (400MHz, DMSO-d6) δ11.32-10.79(m,1H),8.92(d,J=2.3Hz,1H),8.83(s,1H),8.39(dd,J=8.3,2.4Hz,1H),7.90(d,J=7.7Hz,1H),7.79-7.7 3(m,2H),7.70(d,J=8.3Hz,1H),7.64(d,J=2.3Hz,1H),7.49(dd,J=8.7,2.2Hz,1H),6.59(d,J=2.3Hz,1H),3.81(s,3H).HRMS(ESI)m / z:(M+Na) + calcd for C 19 H 14 ClN5O2:402.07289; found: 402.0733.

[0143] Example 38: Compound A38

[0144] Purity>95%. Gray solid, 342 mg, yield 79%. 1H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 10.32 (s, 1H), 8.93 (d, J = 2.4Hz, 1H), 8. 85(s,1H),8.41(dd,J=8.3,2.4Hz,1H),7.87(s,1H),7.84-7.76(m,2H),7.70(d ,J=8.3Hz,1H),7.52(dd,J=8.8,2.2Hz,1H),7.36(t,J=5.3Hz,2H),7.30(d,J=8 .1Hz,1H),7.11(t,J=7.8Hz,1H),6.60(d,J=3.1Hz,1H).HRMS(ESI)m / z:(M+Na) + calcd for C 23 H 15 ClN4O2:437.0776; found: 437.0777.

[0145] Example 39: Compound A39

[0146] Purity>95%. Cyan solid, 301 mg, yield 76%. 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),10.33(s,1H),8.82(s,1H),8.81-8.73(m,2H),7.96-7.86(m,3H),7.82(dd,J=5.6,3.2Hz,2H),7.5 5(dd,J=8.8,2.1Hz,1H),7.37(t,J=5.3Hz,2H),7.30(d,J=8.1Hz,1H),7.11(t,J=7.8Hz,1H),6.60(d,J=3.1Hz,1H).HRMS(ESI)m / z:(M+H) + calcd for C 23 H 16 N4O2:381.1346; found: 381.1347.

[0147] Example 40: Compound A40

[0148] Purity>95%. White solid, 287 mg, yield 68%. 1H NMR (400MHz, DMSO-d6) δ10.67 (s, 1H), 8.93 (d, J = 2.3Hz, 1H), 8.83 (s, 1H), 8.4 0(dd,J=8.3,2.4Hz,1H),7.87(d,J=8.5Hz,2H),7.81(d,J=9.4Hz,1H),7.79-7. 76(m,2H),7.70(d,J=8.3Hz,1H),7.56-7.47(m,3H),2.49-2.36(m,2H),2.07(d d,J=12.9,7.8Hz,2H),1.89(ddd,J=7.0,5.2,3.0Hz,4H).HRMS(ESI)m / z:(M+H) + calcd for C 27 H 21 ClN4O2:469.1426; found: 469.1428.

[0149] Example 41: Compound A41

[0150] Purity>95%. Yellow solid, 102 mg, yield 57%. 1 H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.81(s,1H),8.80-8.77(m,2H),7.92-7 .87(m,3H),7.86(d,J=2.0Hz,1H),7.84(s,1H),7.83-7.79(m,2H),7.56(d,J= 2.1Hz,1H),7.53(d,J=4.3Hz,1H),7.51(d,J=2.1Hz,1H),2.41(dd,J=12.0,5. 9Hz,2H),2.16-2.03(m,2H),1.90(dq,J=7.1,3.3Hz,4H).HRMS(ESI)m / z:(M+H) + calcd for C 27 H 22 N4O2:435.1816; found: 435.1816.

[0151] Example 42: Compound A42

[0152] Purity>95%. Yellow solid, 332 mg, yield 80%. 1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.46(s,1H),7.90-7.82(m,2H),7.79-7.69( m,4H),7.59(d,J=2.2Hz,1H),7.53-7.46(m,2H),7.38(dd,J=8.8,2.2Hz,1H),6.80 -6.74(m,2H),3.43(q,J=7.0Hz,4H),2.47-2.35(m,2H),2.08(dd,J=12.8,7.8Hz,2 H),1.90(ddd,J=6.4,4.9,2.7Hz,4H),1.14(t,J=7.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 32 H 32 N4O2:505.2598; found:505.2601.

[0153] Example 43: Compound-

[0154] Purity>95%. Light yellow solid, 132 mg, yield 58%. 1 H NMR(400MHz,DMSO-d6)δ10.58(d,J=61.7Hz,1H),9.61(s,1H),8.78(s,1H),7.92-7.75(m,4H ),7.57(t,J=5.3Hz,1H),7.54-7.40(m,3H),7.05-6.87(m,1H),6.53-6.33(m,1H),6.09(dd,J =39.8,2.4Hz,1H),3.21(d,J=29.3Hz,4H),2.41(dt,J=12.4,4.0Hz,2H),2.08(dd,J=9.4,3.7 Hz,2H),1.90(dq,J=7.8,5.1,3.6Hz,4H),1.13(dt,J=14.2,7.0Hz,6H).HRMS(ESI)m / z:(M+H) + calcd for C 32 H 32 N4O3:521.2547; found:521.2547.

[0155] Experimental Example 1

[0156] Study on the inhibitory activity of benzofuran compounds provided in the embodiments of the present invention on VEGFR2, FLT3, and PDGFRα kinases

[0157] The specific process is as follows:

[0158] 1. Dilute the compound to 50× the final concentration in DMSO and transfer 100 μL of the stock solution to a 96-well plate.

[0159] 2. In the same 96-well plate, add 100 μL of DMSO as a no-compound control and a no-enzyme control, and mark the plate as the original plate;

[0160] 3. Prepare the intermediate plate: Transfer 10 μL of compound stock solution from the original plate to a new 96-well plate as the intermediate plate. Add 90 μL of 1× kinase buffer to each well of the intermediate plate and shake for 10 minutes.

[0161] 4. Prepare 2.5x enzyme solution: Add VEGFR2, FLT3, or PDGFRα kinase to 1x kinase buffer;

[0162] 5. Prepare a 2.5x peptide solution: Add FAM-labeled peptide and ATP to 1x kinase buffer;

[0163] 6. Add 5 μL of the test compound solution to each well of the 384-well assay plate, then add 10 μL of 2.5× enzyme solution to each well and incubate at room temperature for 10 minutes;

[0164] 7. Add 10 μL of 2.5× peptide solution to each well of the 384-well assay plate, incubate at 28°C for 1 hour, and then add 25 μL of stop solution to stop the reaction.

[0165] 8. Use Caliper to collect data. The inhibition rate of enzyme (% Inh) = (max-conversion) / (max-min)*100.

[0166] The results are shown in Table 1.

[0167] Table 1 Inhibitory effect of benzofuran compounds on VEGFR2, FLT3 and PDGFRα at a concentration of 10 μM

[0168]

[0169]

[0170] It can be seen that the benzofuran compounds provided in the embodiments of the present invention have inhibitory effects on VEGFR2, FLT3 and PDGFRα kinases at the same time.

[0171] Experimental Example 2

[0172] The compound represented by the following structural formula was tested according to the method of Experimental Example 1:

[0173]

[0174] See Table 2 for the results.

[0175] Table 2 Inhibition rate of VEGFR2 by compounds at a concentration of 10 μM

[0176]

[0177]

[0178] According to Tables 1 and 2, even though both are benzofuran nuclei with amide bonds, different group selections, such as different selections of R1, result in the inability of the formed benzofuran to simultaneously inhibit multiple kinases. In other words, the benzofuran compounds formed after changing the groups cannot serve as multi-target inhibitors.

[0179] Experimental Example 3

[0180] In vitro antitumor activity

[0181] The details are as follows: According to 1.5×10 5 cells·mL -1 A 96-well plate was inoculated with 100 μL of liquid per well. The edge of the plate was left uninoculated, and 100 μL of PBS buffer was added to the wells to prevent edge effects. After inoculation, the 96-well plate was transferred to an incubator and incubated for 24 hours before dosing.

[0182] Benzofuran compounds were dosed at five concentrations: 10 μM, 5.0 μM, 2.50 μM, 1.25 μM, and 0.625 μM. 10 μL of the corresponding compound was then added to each well of the cell plate (three wells per compound). In the blank control group, 10 μL of the corresponding complete medium was added to three wells, with three replicates. A blank control group was also set up. The administered compounds were then placed in an incubator and cultured for 48 hours.

[0183] Under a darker background, add 10 μL of CCK8 solution to each experimental well of the cell plate after 48 h of culture (avoid bubbles during the addition process to prevent them from affecting the experimental results). Then, place the cell plate in an incubator and culture for 2 h. Then, place the cell plate in a microplate reader to detect the OD value.

[0184] The calculation formula for cell viability is:

[0185] Cell viability (%) = [OD experimental group - OD blank control group] / [OD positive control group - OD blank control group] × 100%.

[0186] The cells used are as follows: HCT-116 (human colon cancer cells), HGC-27, MGC-823 (human gastric cancer cells), MCF-7 (human breast cancer cells), and MDB-MA-231 (human triple-negative breast cancer cells).

[0187] See Table 3 for the results.

[0188] Table 3 In vitro antiproliferative activity results of benzofuran compounds

[0189]

[0190]

[0191]

[0192] According to Table 3, the benzofuran compounds provided in the embodiments of the present invention have a therapeutic effect on gastric cancer.

[0193] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A benzofuran compound, characterized in that It is selected from the compounds represented by the following structural formula: Wherein, R1 is selected from any one of substituted or unsubstituted benzo-fused ring, substituted or unsubstituted pyrazole and substituted phenyl, and R2 is selected from any one of substituted or unsubstituted pyridine and substituted phenyl.

2. The benzofuran compound according to claim 1, wherein The benzo-fused ring includes a benzoheteroaryl group or a benzocycloalkyl group; Preferably, the benzo-fused ring comprises a benzo five-membered heteroaryl group or a benzo C5-C8 cycloalkyl group; Most preferably, the benzo-fused ring comprises benzopyrrole or benzocyclopentyl.

3. The benzofuran compound according to claim 1 or 2, characterized in that The substituents in the substituted benzo-fused ring are selected from C1-C3 alkyl groups; Preferably, the substituted or unsubstituted benzo-fused ring includes any one of an unsubstituted benzo five-membered heteroaryl group, an unsubstituted benzo C5-C8 cycloalkyl group, and a C1-C3 alkyl-substituted benzo five-membered heteroaryl group; Preferably, the substituted or unsubstituted benzo-fused ring includes any one of unsubstituted benzopyrrole, unsubstituted benzocyclopentyl and C1-C3 alkyl-substituted benzopyrrole.

4. The benzofuran compound according to claim 1, wherein The substituent in the substituted pyrazole is a C1-C3 alkyl group; Preferably, the substituents of the substituted phenyl group in R1 include cycloalkyl groups; Preferably, the substituents of the substituted phenyl group in R1 include cyano-substituted C5-C8 cycloalkyl groups.

5. The benzofuran compound according to claim 1, characterized in that R1 is selected from any one of unsubstituted benzo five-membered heteroaryl, unsubstituted benzo C5-C8 cycloalkyl, C1-C3 alkyl-substituted benzo five-membered heteroaryl, unsubstituted pyrazole, C1-C3 alkyl-substituted pyrazole, and cycloalkyl-substituted phenyl; Preferably, R1 is selected from any one of unsubstituted benzopyrrole, unsubstituted benzocyclopentyl, C1-C3 alkyl-substituted benzopyrrole, unsubstituted pyrazole, C1-C3 alkyl-substituted pyrazole, cyano-substituted C5-C8 cycloalkyl-substituted phenyl.

6. The benzofuran compound according to claim 1, characterized in that The substituent in the substituted pyridine is a halogen; Preferably, the substituent of the substituted phenyl group in R2 is any one of a tertiary amino group, a substituted or unsubstituted five-membered heterocyclic group, a substituted or unsubstituted six-membered heterocyclic group, a hydroxyl group, a C1-C3 alkoxy group and a halogen; Preferably, the substituent of the substituted phenyl group in R2 is Any one of substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydropyrrole, hydroxyl, C1-C3 alkoxy and halogen; wherein R3 and R4 are independently selected from C1-C3 alkyl; Preferably, R2 is selected from unsubstituted pyridine, halogen-substituted pyridine and substituted phenyl, wherein the substituent of the substituted phenyl is Any one of unsubstituted piperidine, hydroxy-substituted piperidine, unsubstituted tetrahydropyrrole, hydroxy, C1-C3 alkoxy and halogen; wherein R3 and R4 are independently selected from C1-C3 alkyl.

7. The benzofuran compound according to claim 1, characterized in that The benzofuran compound is selected from any one of the compounds represented by the following structural formulas:

8. A method for preparing a benzofuran compound according to claim 1, characterized in that: The synthesis was carried out according to the following synthesis route: Preferably, step a comprises: mixing the M1 compound and a strong base to perform a degreasing reaction; Step b comprises: subjecting the M2 compound to an amide condensation reaction with the corresponding amine; Step c comprises: mixing the M3 compound with a reducing agent to perform a reduction reaction; Step d comprises: mixing the M4 compound and the aromatic aldehyde in a molar ratio of 1:(1.5-3) to react.

9. A VEGFR2 / FLT3 / PDGFRα kinase inhibitor, characterized in that It comprises the benzofuran compound according to claim 1.

10. A benzofuran compound according to claim 1 for use in any one of the following applications: (1) Application in the preparation of VEGFR2 / FLT3 / PDGFRα kinase inhibitors; (2) Application in drugs for treating tumors; Preferably, the tumor comprises gastric cancer.

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