Isoindolinone compounds, methods of making the same, and uses thereof

Abstract

This invention relates to the field of pharmaceutical synthesis technology, specifically to isoindolinone compounds, their preparation methods, and their applications. The structural formula of the isoindolinone compounds is as follows: where L is -NH- or a linking bond; X is -CM- or -N-; M represents H or a halogen; R1, R2, and R3 are independently selected from any one of hydrogen atoms, halogens, and alkoxy groups; Ar is any one of substituted or unsubstituted aromatic groups or substituted aromatic groups and substituted or unsubstituted heteroaryl groups. This compound can effectively act on the fibroblast growth factor receptor (FGFR) and has partial blood-brain barrier permeability, exhibiting good inhibitory effects against glioblastoma. Its in vitro kinase inhibitory activity, anti-tumor cell proliferation activity, and blood-brain barrier permeability were tested, and the results showed that this isoindolinone compound has good anti-tumor growth activity and can inhibit fibrosis and prevent liver fibrosis.

Description

Technical Field

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

[0002] Fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase family, which consists of four members (FGFR1-4). Over the past few decades, research on FGFR has deepened, and the role of FGFR abnormalities in tumorigenesis and development has been gradually revealed. The main causes of abnormal activation of the FGFR signaling axis are oncogenic fusions, activating mutations, and amplification of its genes. The regulatory role of the FGFR pathway in physiological functions exists in almost all organs, and abnormal activation of FGFR has been detected in various tumors. Therefore, inhibitors targeting FGFR have broad applications in the field of anti-tumor therapy.

[0003] The development and progression of glioblastoma are strongly linked to FGFR signaling, but the unique characteristics of the blood-brain barrier prevent most FGFR-targeting agents from reaching glioblastoma. Currently, the development of FGFR inhibitors mainly focuses on improving target selectivity, particularly FGFR4-selective inhibitors and dual-target FGFR inhibitors. No drugs specifically targeting the blood-brain barrier have been reported in the literature.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] The purpose of this invention is to provide isoindolinone compounds, their preparation methods, and their applications. This overcomes the problem in existing technologies of lacking fibroblast growth factor receptor inhibitor drugs, which is detrimental to anti-tumor therapy.

[0006] This invention is implemented as follows:

[0007] In a first aspect, the present invention provides an isoindolinone compound having the following structural formula:

[0008] Where L is -NH- or a linking bond;

[0009] X is -CM- or -N-, and M represents H or halogen;

[0010] R1, R2, and R3 are each independently selected from any one of hydrogen atoms, halogen atoms, and alkoxy groups;

[0011] Ar is any one of substituted or unsubstituted aromatic groups or substituted aromatic groups and substituted or unsubstituted heteroaryl groups.

[0012] Secondly, the present invention provides a method for synthesizing the isoindolinone compounds described in the foregoing embodiments, wherein the synthesis is carried out according to the following synthetic route:

[0013]

[0014] Thirdly, the present invention provides the application of the isoindolinone compounds described in the foregoing embodiments in the preparation of FGFR inhibitors.

[0015] Fourthly, the present invention provides the use of the isoindolinone compounds described in the foregoing embodiments in the preparation of antitumor drugs.

[0016] Fifthly, embodiments of the present invention provide the application of the isoindolinone compounds described in the foregoing embodiments in the preparation of drugs for treating organ fibrosis;

[0017] Preferably, the organ includes the liver;

[0018] Preferably, the use of the isoindolinone compound in the preparation of a drug for treating liver fibrosis;

[0019] Preferably, the isoindoline ketone compound is used in the preparation of a medicament for treating diseases caused by liver fibrosis.

[0020] The present invention has the following beneficial effects: The isoindolinone compounds of the present invention adopt an isoindolinone core structure, with one or more alkoxy groups attached to the benzene ring group on the left and an aromatic ring structure attached to the right of the isoindolinone core. This allows them to effectively act on the fibroblast growth factor receptor (FGFR) and exhibit partial blood-brain barrier permeability, demonstrating a good inhibitory effect on glioblastoma. Their in vitro kinase inhibitory activity, anti-tumor cell proliferation activity, and blood-brain barrier penetration ability were tested, and the results show that the isoindolinone compounds of the present invention have good anti-tumor growth activity and have the potential to be developed as anti-tumor drugs. Simultaneously, these isoindolinone compounds can inhibit cell fibrosis, thereby reducing liver fibrosis. Attached Figure Description

[0021] 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.

[0022] Figure 1 The detection results are provided for Experimental Example 4 of this invention. Detailed Implementation

[0023] 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.

[0024] This invention provides an isoindolinone compound having the following structural formula:

[0025] Where L is -NH- or a linking bond;

[0026] X is -CM- or -N-, M represents H or halogen; R1, R2 and R3 are each independently selected from any one of hydrogen atom, halogen atom and alkoxy group; preferably, the halogen atom includes fluorine atom and chlorine atom, and at least one of R1, R2 and R3 is alkoxy group; Ar is any one of substituted or unsubstituted aromatic group or substituted aromatic group and substituted or unsubstituted heteroaryl group.

[0027] Furthermore, the isoindolinone compounds are selected from compounds shown in the following structural formulas:

[0028] Wherein, X is -CM- or -N-, M represents H or halogen; R1 and R2 are each independently selected from H and alkoxy groups; preferably, at least one of R1 and R2 is an alkoxy group; Ar is any one of substituted or unsubstituted aromatic groups and substituted or unsubstituted heteroaryl groups.

[0029] Isoindolineone compounds are selected from compounds shown in the following structural formulas:

[0030] Where X is -CM- or -N-, M represents H or halogen; R2 and R3 are each independently selected from either hydrogen or halogen atoms; halogen atoms are selected from either fluorine or chlorine; Ar is any one of substituted or unsubstituted aromatic groups and substituted or unsubstituted heteroaryl groups.

[0031] Furthermore, in the above-mentioned isoindolinone compounds, X is any one of -CH-, -CF-, -CCl-, and -CBr-.

[0032] Furthermore, Ar can be any one of substituted or unsubstituted aromatic groups and substituted or unsubstituted heteroaryl groups. For example, the aromatic group can be phenyl, and the heteroaryl group can be pyrazole, pyridine, thiazole, and thiophene, etc.

[0033] For example, Ar is any one of substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazolyl and substituted or unsubstituted pyrimidine;

[0034] Wherein, the substituents of substituted phenyl, substituted pyridyl, substituted pyrimidine, substituted pyrazolyl, and substituted pyrimidine are selected from any one of halogen, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic alkyl, and substituted or unsubstituted cycloalkyl, and the heteroatom in the heterocyclic alkyl can be O, N, or S; for example, the substituents of substituted phenyl, substituted pyridyl, substituted pyrimidine, substituted pyrazolyl, and substituted pyrimidine are selected from halogen; C1-C10 alkoxy; unsubstituted amino; C1-C5 alkyl-substituted amino; unsubstituted C3-C6 oxygen Heterocyclic alkyl groups; unsubstituted C3-C6 nitrogen-containing heterocyclic alkyl groups; C3-C6 oxocyclic alkyl groups substituted with any one of alkyl, halogen, hydroxyl, carbonyl, or amino groups (C1-C10); C3-C6 monoazacyclic alkyl groups substituted with any one of alkyl, halogen, hydroxyl, or amino groups (C1-C10); C4-C6 diazacyclic alkyl groups substituted with C1-C3 alkyl and C3-C5 cycloalkyl groups (C1-C3 alkyl and C3-C5 cycloalkyl groups); C4-C6 diazaspirocyclic alkyl groups substituted with C1-C3 alkyl and C3-C5 cycloalkyl groups (C1-C8 cycloalkyl and C1-C10 alkyl groups). The substituted phenyl group may be any one of the following C3-C8 cycloalkyl groups: halogen, hydroxyl, and amino groups; specifically, the substituent for the substituted phenyl group may be any one of halogen, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic alkyl, and substituted or unsubstituted cycloalkyl; for example, substituents including the substituted phenyl group may include halogen; C1-C10 alkoxy; unsubstituted amino; C1-C5 alkyl-substituted amino; unsubstituted C3-C6 oxocyclic alkyl; unsubstituted C3-C6 azircyclic alkyl; C1-C10 alkyl, halogen C3-C6 oxocyclic alkyl groups substituted with any one of alkyl, halogen, or amino groups; C3-C6 monoazacyclic alkyl groups substituted with any one of alkyl, halogen, hydroxyl, or amino groups (C1-C10); C4-C6 diazacyclic alkyl groups substituted with C1-C3 alkyl and C3-C5 cycloalkyl groups; C4-C6 diazaspirocyclic alkyl groups substituted with C1-C3 alkyl and C3-C5 cycloalkyl groups; unsubstituted C3-C8 cycloalkyl groups and any one of C3-C8 cycloalkyl groups substituted with any one of alkyl, halogen, hydroxyl, or amino groups;

[0035] Furthermore, in the aforementioned isoindolinone compounds, R1, R2, and R3 are selected from alkoxy groups and the alkoxy groups mentioned in Ar above. The alkoxy groups can be C1-C10 alkoxy groups, preferably C1-C8 alkoxy groups, more preferably C1-C5 alkoxy groups, even more preferably C1-C3 alkoxy groups, and most preferably methoxy and ethoxy groups. In addition to methoxy and ethoxy groups, alkoxy groups such as n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and isohexoxy can also be selected.

[0036] It should be noted that the halogens mentioned above can be selected from fluorine and chlorine, the alkyl groups can be selected from C1-C10 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, and n-butyl, the cycloalkyl groups can be C3-C8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the heterocyclic alkyl groups can be selected from at least one of O and N. Even if the heteroatom is only O or N, the number of heteroatoms can be 2, 3, or 4, etc., of heterocyclic alkyl groups. For example, heterocyclic alkyl groups can be selected from morpholine, piperidine, piperazine, oxonitrile-heptanyl, azironitrile-heptanyl, azironitrile-octyl, norransine, decahydroquinolinyl, and thiomorpholinyl, etc.

[0037] Specifically, Ar is selected from phenyl,

[0038] Any one of them.

[0039] Secondly, embodiments of the present invention provide a method for synthesizing the above-mentioned isoindolinone compounds, which is carried out according to the following synthetic route:

[0040]

[0041] Further, the synthesis is performed according to the following synthesis path:

[0042]

[0043] It should be noted that the operating conditions and material selection in steps (a)-(e) above are merely examples of embodiments of the present invention and are not limited to the material selection and reaction conditions described above. Any method can be used as long as the desired material is obtained.

[0044] For example, the reagents and conditions for each reaction step are as follows: (a) KI, MeI, DMF, 80℃, 4h; (b) NBS, AIBN, DCM, reflux; (c) DIPEA, aniline ArNH2, MeOH, reflux; (d) PdCl2(DPPF)2, Cs2CO3, BINAP, DMSO, 3,5-dimethoxyphenylboronic acid pinacol ester, 110℃; (e) PdCl2(DPPF)2, Cs2CO3, BINAP, DMSO, 3,5-dimethoxyaniline, 110℃.

[0045] Thirdly, the present invention provides the application of the isoindolinone compounds described in the foregoing embodiments in the preparation of FGFR inhibitors.

[0046] Fourthly, the present invention provides the use of the isoindolinone compounds described in the foregoing embodiments in the preparation of antitumor drugs.

[0047] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0048] Example 1

[0049] This invention provides a method for synthesizing an isoindolineone compound (denoted as AF1), and the specific synthesis steps are as follows:

[0050] S1. Reaction a: 20 g of 4-bromo-2-methylbenzoic acid (approximately 92.6 mmol, 1 equivalent) was dissolved in 60 mL of DMF (N,N-dimethylformamide), along with 77 g of potassium iodide (5 equivalents) and 5.85 mL of iodomethane (1 equivalent). The mixture was stirred at 80 °C for 4 h. After the reaction was complete, the reaction solution was cooled and poured into ice water, resulting in the precipitation of a large amount of white precipitate. Vacuum filtration yielded the product (methyl 4-bromo-2-methylbenzoate), with a yield of approximately 90%.

[0051] S2. Reaction b: Dissolve 5 g of methyl 4-bromo-2-methylbenzoate (21.7 mmol, 1 equivalent) in 5 mL of dichloromethane. Mix 3.5 g of N-bromosuccinimide (NBS, 0.9 equivalent) and 0.36 g of azobisisobutyronitrile (AIBN, 0.1 equivalent) and dissolve in 10 mL of dichloromethane, then add the mixture dropwise to the reaction system in three batches. Reflux for approximately 10 h, stopping the reaction when a large amount of precipitate forms in the reaction solution. The precipitate is the debrominated succinimide salt, which can be removed by dissolving in water. Extraction yields the product (methyl 4-bromo-2-bromomethylbenzoate), which has similar polarity to the unbrominated starting material and is difficult to separate. Therefore, the mixture is evaporated to dryness for use in the next reaction step.

[0052] S3. Reaction c: 5 g of methyl 4-bromo-2-bromomethylbenzoate (16.2 mmol, 1 equivalent) was added to 20 mL of methanol, along with 1.2 equivalents of 4-(4-methylpiperazine)aniline and 3.4 mL of DIPEA (N-ethyldiisopropylamine, 1.2 equivalents). The mixture was refluxed for 48 h. Initially, the reaction solution was clear. The reaction was stopped when a large amount of precipitate appeared. The product was obtained by vacuum filtration, with a yield of approximately 80%.

[0053] S4. Reaction d: 2 g of 5-bromo-2-aniline isoindoline-1-one compound (1 equivalent) was dissolved in anhydrous DMSO. 0.05 equivalents of DPPF palladium dichloride catalyst {i.e., [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride(II)}, 2.4 equivalents of cesium carbonate, and 1.2 equivalents of pinacol 3,5-dimethoxyphenylborate were added. The reaction was carried out at 110 °C for 4 h under anhydrous and oxygen-free conditions. The mixture was separated by silica gel column chromatography to obtain compound AF1. The yield was approximately 70%.

[0054]

[0055] The compound AF1 was obtained and characterized by nuclear magnetic resonance (NMR). The NMR test results are as follows.

[0056] 1 H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.87–7.79(m,2H),7.76–7.69(m,2H),7.08–6.99(m,2H),6.88(d,J=2.2Hz,2H),6.5 7(t,J=2.3Hz,1H),5.01(s,2H),3.84(s,6H),3.15(t,J=5.0Hz,4H),2.47(d,J=5.1Hz,4H),2.24(s,3H).HRMS(ESI):calcd forC 27 H 29 N3O3:443.2209; found:443.2216. 13 C NMR(101MHz,Chloroform-d)δ161.23,148.43,145.01,142.61,140.81,132.62,131.86,127.66,1 24.24,121.31,121.02,116.58,105.78,99.93,55.53,55.49,55.09,51.08,49.31,46.19,46.16.

[0057] Example 2

[0058] This embodiment provides a method for synthesizing an isoindolinone compound (denoted as BF1), and the specific synthesis steps are as follows:

[0059] S1. Reaction a: 20 g of 5-bromo-3-methyl-2-carboxypyridine (approximately 92.6 mmol, 1 equivalent) was dissolved in 60 mL of DMF (N,N-dimethylformamide), along with 77 g of potassium iodide (5 equivalents) and 5.85 mL of iodomethane (1 equivalent). The mixture was stirred at 80 °C for 4 h. After the reaction was complete, the reaction solution was cooled and poured into ice water, resulting in the precipitation of a large amount of white precipitate. Vacuum filtration yielded the product (methyl 5-bromo-3-methylpyridine-2-carboxylic acid), with a yield of approximately 90%.

[0060] S2. Reaction b: Dissolve 5 g of methyl 5-bromo-3-methylpyridine-2-carboxylate (21.7 mmol, 1 equivalent) in 5 mL of dichloromethane. Mix 3.5 g of N-bromosuccinimide (NBS, 0.9 equivalent) and 0.36 g of azobisisobutyronitrile (AIBN, 0.1 equivalent) and dissolve in 10 mL of dichloromethane, then add the mixture dropwise to the reaction system in three batches. Reflux for approximately 10 h, stopping the reaction when a large amount of precipitate forms in the reaction solution. The precipitate is the debrominated succinimide salt, which can be removed by dissolving in water. Extraction yields the product (methyl 5-bromo-3-bromomethylpyridine-2-carboxylate), which has similar polarity to the unbrominated starting material and is difficult to separate. Therefore, the mixture is evaporated to dryness for use in the next reaction step.

[0061] S3. Reaction c: 5 g of methyl 5-bromo-3-bromomethylpyridine-2-carboxylic acid (16.2 mmol, 1 equivalent) was added to 20 mL of methanol, along with 1.2 equivalents of aniline and 3.4 mL of DIPEA (N-ethyldiisopropylamine, 1.2 equivalents). The mixture was refluxed for 48 h. Initially, the reaction solution was clear. The reaction was stopped when a large amount of precipitate appeared. The product was obtained by vacuum filtration, with a yield of approximately 80%.

[0062] S4. Reaction e: 2 g of 5-bromo-2-aniline isoindoline-1-one compound (1 equivalent) was dissolved in anhydrous DMSO. 0.05 equivalents of DPPF palladium dichloride catalyst {i.e., [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride(II)}, 2.4 equivalents of cesium carbonate, 0.15 equivalents of BINAP (2,2'-bisdiphenylphosphine-1,1'-binaphthyl) ligand, and 1.2 equivalents of 3,5-dimethoxyaniline were added. The reaction was carried out at 110 °C for 4 h under anhydrous and oxygen-free conditions. The mixture was separated by silica gel column chromatography to obtain compound BF1. The yield was approximately 70%.

[0063]

[0064] The compound BF1 was obtained and characterized by nuclear magnetic resonance (NMR). The NMR test results are as follows.

[0065] 1H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.44(d,J=2.5Hz,1H),7.72(d,J=14.4Hz,1H),7.89(d,J=8.2Hz,2H),7.44(t,J=7.7Hz,2 H),7.17(t,J=7.5Hz,1H),6.39(d,J=2.6Hz,2H),6.21(d,J=2.7Hz,1H),4.93(s,2H),3.75(d,J=0.9Hz,6H).HRMS(ESI):calcd for C 21 H 19 N3O3:361.1410; found:361.1417. 13 CNMR(101MHz,DMSO-d6)δ165.46,161.74,143.25,143.14,141.19,140.53,140.26,137 .69,129.45,124.38,119.25,114.50,97.67,94.75,55.68,55.65,55.61,55.57,48.36.

[0066] Example 3

[0067]

[0068] Following the synthetic route of Example 1 above, compound AF2 was synthesized, with the only difference being that in reaction d of S4, "3,5-dimethoxyphenylboronic acid pinacol ester" was replaced with "2,5-dimethoxyphenylboronic acid pinacol ester". The synthesized compound was AF2, which was characterized by nuclear magnetic resonance (NMR). The NMR test results are as follows. 1 H NMR (400MHz, DMSO-d6) δ7.80–7.71(m,4H),7.63(dd,J=7.9,1.5Hz,1H),7.10(d,J=8.9Hz,1H),7.06–6.99(m,2H),6..97(dd,J=8.9,3.1Hz,1H),6.93(d ,J=3.1Hz,1H),4.99(s,2H),3.75(d,J=15.0Hz,6H),3.14(d,J=5.1Hz,4H), 2.48(t,J=4.9Hz,4H),2.24(s,3H),1.24(d,J=3.5Hz,0H).HRMS(ESI):calcd for C 27 H 29 N3O3:443.2209; found:443.2217. 13C NMR(101MHz,Chloroform-d)δ153.84,150.71,148.37,142.27,140.04,132.12,132.00,130.75,129.8 3,123.64,123.56,121.02,116.81,116.60,113.85,112.73,56.29,55.88,55.09,51.11,49.34,46.19.

[0069] Example 4

[0070]

[0071] Following the synthetic route described in Example 1 above, compound AF3 was synthesized. The only difference was that in reaction c of S3, 4-(4-methylpiperazine)aniline was replaced with aniline. The synthesized compound AF3 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0072] 1 H NMR(400MHz, DMSO-d6)δ9.10(d,J=2.1Hz,1H),8.42(d,J=2.0Hz,1H)),7.99–7.92(m,2H),7.53–7.45(m,2H),7 .24(t,J=7.4Hz,1H),6.97(d,J=2.2Hz,2H),6.62(t,J=2.2Hz,1H),5.09(s,2H),3.85(s,6H).HRMS(ESI):calcd for C 21 H 18 N2O3:346..1317; found:346.1327. 13 C NMR(101MHz,DMSO-d6)δ161.61,149.87,149.55,139.88,139.02,138.23,136 .33,130.30,129.55,125.10,1119.84,105.94,101.22,55.96,55.92,48.61.

[0073] The intermediates and their characteristics are as follows:

[0074] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=2.2Hz,1H),8.15(d,J=2.2Hz,1H),3.87(s,3H),2.46(s,3H).

[0075] 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.2Hz,1H),8.41(d,J=2.2Hz,1H),4.91(s,2H),3.91(s,4H). 1 H NMR (400MHz, DMSO-d6) δ8.91(d,J=2.1Hz,1H),8.48(d,J=2.1Hz,1H),7.96–7.89(m,2H),7.53–7.44(m,2H),7.24(t,J=7.4Hz,1H),5.05(s,2H).

[0076] Example 5

[0077]

[0078] Following the synthetic route of Example 1 above, compound AF4 was synthesized, with the only difference being that in reaction S3c, 4-(4-methylpiperazine)aniline was replaced with aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound AF4 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0079] 1 H NMR (400MHz, DMSO-d6) δ8.88(d,J=1.9Hz,1H),8.24(d,J=1.9Hz,1H),8.00–7.93(m,2H),7.49(dd,J=8.6,7.3Hz,2H),7.24(t,J =7.4Hz,1H),7.19–7.12(m,1H),7.04(dt,J=5.0,2.8Hz,2H),5.09(s,2H),3.78(d,J=8.9Hz,6H),1.24(s,1H).HRMS(ESI):calcd for C 21 H 18 N2O3:346.1317; found:346.1318. 13 C NMR(101MHz,Chloroform-d)δ165.38,153.97,152.17,150.85,149.04,139.27,136.63,133.71,13 1.70,129.28,126.99,125.00,119.46,116.75,114.68,112.71,56.24,55.97,55.93,55.90,48.44.

[0080] Example 6

[0081]

[0082] Following the synthetic route of Example 1, compound AF5 was synthesized, with the only difference being that in reaction S3c, 4-(4-methylpiperazine)aniline was replaced with 3-amino-5-phenylpyrazole. The synthesized compound AF5 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0083] 1 H NMR (400MHz, DMSO-d6) δ13.08(s,1H),8.01(s,1H),7.85(s,2H),7.79(d,J=7.7Hz,3H),7.50(t,J=7.6Hz,3H),7.40(t,J=7 .3Hz,1H),7.23(d,J=2.2Hz,1H),6.90(d,J=2.2Hz,2H),6.58(t,J=2.3Hz,1H),5.05(s,2H),3.84(s,6H).HRMS(ESI):calcd forC 25 H 21 N3O3:411.1583; found:411.1582. 13 C NMR(101MHz,DMSO-d6)δ161.44,144.54,143.30,142.77,142.10,129.68,129.57,12 8.87,127.59,125.66,123.94,122.66,105.73,100.66,92.81,55.88,55.83,49.74.

[0084] Example 7

[0085]

[0086] Following the synthetic method of Example 1, compound AF6 was synthesized, with the only difference being that in reaction S3c, 4-(4-methylpiperazine)aniline was replaced with 4-methoxyaniline. The synthesized compound AF6 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0087] 1H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.87–7.74 (m, 4H), 7.09–6.99 (m, 2H), 6.87 (d, J = 3.0Hz, 2H),6.57(s,1H),5.03(s,2H),3.83(d,J=2.7Hz,6H),3.78(d,J=2.7Hz,3H).HRMS(ESI):calcd for C 23 H 21 NO4:375.1471; found:375.1463. 13 C NMR(101MHz,Chloroform-d)δ167.07,161.24,156.68,145.14,142.58,140.79,132.72,132. 49,127.71,124.32,121.42(d,J=16.2Hz),114.39,105.80,99.95,55.49(d,J=3.3Hz),51.21.

[0088] Example 8

[0089]

[0090] Following the synthetic route of Example 1, compound AF7 was synthesized, with the only difference being that in reaction S3c, 4-(4-methylpiperazine)aniline was replaced with 3,4-methylenedioxyaniline. The synthesized compound AF7 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0091] 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.88–7.78(m,2H),7.62(d,J=2.2Hz,1H),7.27(dd,J=8.5,2.2Hz,1H),7.00(d, J=8.5Hz,1H),6.88(d,J=2.2Hz,2H),6.57(t,J=2.2Hz,1H),6.05(s,2H),5.02(s,2H),3.83(s,6H).HRMS(ESI):calcd for C 23 H 19 NO5:388.1263; found:389.1265. 13C NMR(101MHz,Chloroform-d)δ161.24,145.29,142.52,140.66,133.89,132.33,127.76,12 4.38,121.30,112.90,108.21,105.80,102.63,101.40,99.97,55.54,55.50,55.47,51.52.

[0092] Example 9

[0093]

[0094] Following the synthetic route of Example 1, compound AF8 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-amino-N,N-dimethylaniline. The synthesized compound AF8 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0095] 1 H NMR (400MHz, DMSO-d6) δ7.94 (s, 1H), 7.87–7.76 (m, 2H), 7.70 (d, J = 9.1Hz, 2H), 6.88 (d, J = 2.2Hz, 2H), 6.82(d,J=9.1Hz,2H),6.57(t,J=2.2Hz,1H),4.99(s,2H),3.84(s,6H),2.91(s,6H).HRMS(ESI):calcd for C 24 H 24 N2O3:388.1796; found:388.1796. 13 C NMR(101MHz,Chloroform-d)δ166.92,161.22,148.20,144.84,142.70,140.91,132.78 ,129.23,127.60,124.18,121.67,121.29,113.07,105.78,99.93,55.50,51.37,40.84.

[0096] Example 10

[0097]

[0098] Following the synthetic route of Example 2, compound BF2 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-methoxyaniline. The synthesized compound BF2 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0099] 1H NMR (400MHz, DMSO-d6) δ8.76(s,1H),7.77(s,1H),7.79–7.73(m,1H),7.26(s,1H),7.59(d,J=8.4Hz,1H),7.17–7.09(m,1H),6.99(d,J=8. 9Hz,2H),6.35(dd,J=2.3,0.9Hz,2H),6.14(d,J=2.4Hz,1H),4.87(s,2H),3.77(d,J=0.9Hz,3H),3.74(d,J=0.9Hz,6H).HRMS(ESI):calcd for C 23 H 22 N2O4:390.1580; found:390.1587. 13 C NMR (101MHz, DMSO-d6) δ166.84,161.64,156.01,147.84,144.11,143.54,133.64,124. 86,123.88,121.10,116.93,114.54,109.03,97.41,93.98,55.73,55.57,55.53,50.94.

[0100] Example 11

[0101]

[0102] Following the synthetic route of Example 2, compound BF3 was synthesized, with the only difference being that in reaction c of S3, aniline was replaced with 3,4-methylenedioxyaniline. The synthesized compound BF3 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0103] 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),7.63–7.55(m,2H),7.24(s,1H),7.20(dd,J=8.5,2.2Hz,1H),7.13(d,J=8.4Hz,1H),6.96(d,J=8 .8Hz,1H),6.35(d,J=2.2Hz,2H),6.15(t,J=2.3Hz,1H),6.03(d,J=0.9Hz,2H),4.86(s,2H),3.74(d,J=0.9Hz,6H).HRMS(ESI):calcd for C 23 H 20 N2O5:404.1372; found:404.1367. 13C NMR (101MHz, DMSO-d6) δ166.97,161.59,148.06,147.86,144.10,143.74,143.43,134.86,124.87,123. 54,116.89,112.53,108.85,108.59,101.91,101.59,97.46,93.94,55.61,55.57,55.53,55.50,51.27.

[0104] Example 12

[0105]

[0106] Following the synthetic route of Example 2, compound BF4 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-methylpiperazine)aniline. The synthesized compound BF4 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0107] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),7.69(d,J=8.9Hz,2H),7.57(d,J=8.3Hz,1H),7.25(s,1H),7.19–7.07(m,1H),6.99(d,J=9.0Hz,2H),6.34(d,J= 2.2Hz,2H),6.15(d,J=2.4Hz,1H),4.85(s,2H),3.74(d,J=1.0Hz,6H),3.41(d,J=16.0Hz,4H),3.12(d,J=5.9Hz,4H),2.25(s,3H).HRMS(ESI):calcd for C 27 H 30 N4O3:458.2318; found:458.2326. 13 C NMR(101MHz,DMSO-d6)δ166.74,161.62,147.89,147.76,144.19,143.47,132.35,124.72,124.00 ,120.60,116.90,116.22,109.08,97.34,93.88,55.60,55.56,55.52,55.02,50.84,48.84,46.17.

[0108] Example 13

[0109]

[0110] Following the synthetic route of Example 2, compound BF5 was synthesized, with the only difference being that in reaction c of S3, aniline was replaced with 3,4-methylenedioxyaniline. The synthesized compound BF6 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0111] 1 H NMR(400MHz, DMSO-d6)δ8.80(s,1H),7.57(d,J=8.3Hz,1H),7.45(d,J=2.6Hz,1H),7.30–7.22(m,2H),7.16–7.09(m,1H),6.89(d, J=8.8Hz,1H),6.35(d,J=2.2Hz,2H),6.15(d,J=2.2Hz,1H),4.84(s,2H),4.25(d,J=5.8Hz,4H),3.73(s,6H).HRMS(ESI):calcdfor C 24 H 22 N2O5:418.1529; found:418.1530. 13 C NMR (101MHz, DMSO-d6) δ161.59,147.99,144.12,143.63,143.44,140.15,134.14,124.83,123. 67,117.38,116.89,112.64,108.90,108.73,97.44,93.92,64.72,64.48,55.57,55.53,50.90.

[0112] Example 14

[0113]

[0114] Following the synthetic route of Example 2, compound BF6 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 1-methyl-1H-pyrazole-4-amine (CAS: 127107-23-7). The synthesized compound BF6 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0115] 1H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.06(s,1H),7.67(s,1H),7.57(d,J=8.3Hz,1H),7.24(s,1H),7.16–7.08(m,1H),6 .34(d,J=2.2Hz,2H),6.14(t,J=2.3Hz,1H),4.72(s,2H),3.86(s,3H),3.76–3.71(m,6H),0.43(s,5H).HRMS(ESI):calcd forC 20 H 20 N4O3:364.1535; found:364.1537. 13 C NMR(101MHz,DMSO-d6)δ165.57,161.64,147.67,144.12,143.93,128.99,124.61,1 23.55,123.27,120.51,116.77,109.44,97.34,93.98,55.56,55.52,50.37,39.27.

[0116] Example 15

[0117]

[0118] Following the synthetic route of Example 2, compound BF7 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-ethyl-1-piperazinyl)aniline. The synthesized compound BF7 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0119] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),7.69(d,J=8.7Hz,2H),7.57(d,J=8.3Hz,1H),7.25(s,1H),7.12(d,J=8.0Hz,1H),6.99(d,J=9.1Hz, 3H),6.34(d,J=2.2Hz,2H),6.14(s,1H),4.85(s,2H),3.74(s,6H),3.12(s,5H),2.55(s,4H),2.40(s,3H),1.06(s,3H).HRMS(ESI):calcd for C 28 H 32 N4O3:472.2474; found:472.2479. 13C NMR(101MHz,DMSO-d6)δ161.64,147.99,147.72,144.15,143.50,124.75,124.08,120.62 ,116.93,116.16,109.08,97.35,93.94,55.57,55.53,52.82,52.12,50.84,49.04,12.49.

[0120] Example 16

[0121]

[0122] Following the synthetic route of Example 2, compound BF8 was synthesized, with the only difference being that aniline was replaced with 4-morpholinoaniline in reaction c of S3. The synthesized compound BF2 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0123] 1 H NMR(400MHz, DMSO-d6)δ8.73(s,1H),7.71(d,J=9.1Hz,2H),7.58(d,J=8.4Hz,1H),7.25(s,1H),7.16–7.09(m,1H),7.00(d,J=9.0Hz,2H),6.34 (d,J=2.2Hz,2H),6.14(t,J=2.2Hz,1H),4.86(s,2H),3.75(t,J=4.7Hz,4H),3.74(s,6H),3.09(t,J=4.8Hz,4H),0.43(s,7H).HRMS(ESI):calcd for C 26 H 27 N3O4:445.2002; found:445.2007. 13 C NMR(101MHz,DMSO-d6)δ166.76,161.64,147.94,147.75,144.14,143.50,132.67,124.78, 124.04,120.59,116.94,116.00,109.08,97.36,93.94,66.57,55.56,55.51,50.83,49.29.

[0124] Example 17

[0125]

[0126] Following the synthetic route of Example 2, compound BF9 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 3,4-methylenedioxyaniline. The synthesized compound BF9 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0127] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.61–7.52(m,2H),7.18(dd,J=8.5,2.2Hz,1H),6.95(d,J=8.4Hz,1H),6.89(t,J=8 .0Hz,1H),6.83(d,J=8.4Hz,1H),6.76(s,1H),6.03(d,J=1.0Hz,2H),4.82(s,2H),3.92–3.88(m,6H).HRMS(ESI):calcd forC 23 H 18 F2N2O5:440.1184; found:440.1192. 13 C NMR(101MHz,DMSO-d6)δ167.01,149.13,147.85,144.30,144.20,144.16,143.75,143.29,142.34,142.31,139.96,13 9.93,134.85,124.71,123.27,119.21,115.05,112.58,108.57,107.37,101.95,101.58,96.66,57.19,57.15,51.16.

[0128] Example 18

[0129]

[0130] Following the synthetic route of Example 2, compound BF10 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-methyl-1-piperazinyl)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF10 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0131] 1H NMR (400MHz, DMSO-d6) δ8.51(s,,1H),7.70–7.63(m,2H),7.54(d,J=8.3Hz,1H),6.98(d,J=9.1Hz,2H),6.88(t,J=8.0Hz,1H),6.83(d ,J=8.4Hz,1H),6.77(s,1H),4.811(s,2H),3.90(s,6H),3.12(t,J=5.0Hz,4H),2.38(q,J=7.0Hz,4H),1.04(s,3H).HRMS(ESI):callcd for C 27 H 28 F2N4O3:494.2129; found:494.2134. 13 C NMR(101MHz,Chloroform-d)δ167.27,148.06,147.01,144.04,143.98,

[0132] The structural formula and corresponding characterization data of the intermediate forming BF10 are as follows:

[0133] Characterization data: 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=2.1Hz,1H),7.80(d,J=8.3Hz,1H),7.68(dd,J=8.4,2.1Hz,1H),4.99(s,2H),3.87(s,3H).

[0134] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.70(d,J=8.1Hz,1H),7.64–7.53(m,4H),6.96–6.87( m,2H),4..72(s,2H),3.19–3.12(m,,4H),2.54(dd,J=6.1,3.9Hz,4H),2.30(s,3H).

[0135] Example 19

[0136]

[0137] Following the synthetic route of Example 2, compound BF11 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 3,4-ethylenedioxyaniline (CAS: 22013-33-8); and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF11 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0138] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),7.54(d,J=8.4Hz,1H),,7.43(d,J=2.7Hz,1H),7.25(dd,J=8.8,2.6Hz,1H),6.89(t,J=7. 9Hz,2H),6.83(d,J=8.4Hz,1H),6.75(s,1H),4.80((s,2H),4.25(q,J=5.2Hz,5H),3.90(s,6H),0.39(s,3H).HRMS(ESI):calcd for C 24 H 20 F2N2O5:454.1340; found:454.1337. 13 C NMR(101MHz,DMSO-d6)δ166.97,149.18,144.28,144.19,144.15,143.60,143.29,140.14,134.1 2,124.64,123.27,117.37,114.98,112.71,108.78,107.35,96.72,64.71,57.23,57.18,50.81.

[0139] Example 20

[0140]

[0141] Following the synthetic route of Example 2, compound BF12 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-ethyl-1-piperazinyl)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF12 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0142] 1H NMR (400MHz, DMSO-d6) δ8.51(s,1H),7.70–7.62(m,2H),7.54(d,J=8.4Hz,1H),7.01–6.94(m,2H),6.88(t,J=8.0Hz,1H),6.83(d,J=8 .4Hz,1H),3.90(s,6H),6.77(s,1H),4.80(s,2H),3.20–3.08(m,5H),2.37(q,J=7.3Hz,2H),1.04(t,J=7.2Hz,3H).HRMS(ESI):calcd for C 28 H 30 F2N4O3:508.2286; found:508.2295. 13 C NMR(101MHz,DMSO-d6)δ166.80,148.89,147.99,144.30,144.16,143.31,142.34,139.96,132.31,124.52, 123.64,120.67,119.30,116.16,114.98,107.52,96.58,57.19,57.16,52.79,52.11,50.76,49.03,12.45.

[0143] Example 21

[0144]

[0145] Following the synthetic route of Example 2, compound BF13 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-morpholinoaniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF13 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0146] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),7.69(d,J=8.7Hz,2H),7.54(d,J=8.4Hz,1H),6.99(d,J=8.9Hz,2H),6.89(t,J=8.0Hz,1H), 6.83(d,J=8.5Hz,1H),6.77(s,1H),4.81(s,2H),3.92–3.88(m,6H),3.80–3.72(m,4H),3.09(t,J=4.9Hz,4H).HRMS(ESI):calcd for C 26 H 25F2N4O3:481.1813; found:481.1820. 13 C NMR(101MHz,DMSO-d6)δ166.84,148.92,147.95,144.26,144.16,143.33,142.34,139.96,132.67, 124.55,123.61,120.66,116.00,114.99,107.51,96.59,66.56,57.19,57.15,57.12,50.74,49.30.

[0147] Example 22

[0148]

[0149] Following the synthetic route of Example 2, compound BF14 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-methylpiperazine)aniline (CAS No. 16153-81-4); and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-dichloro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF14 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0150] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.67(d,J=8.6Hz,2H),7.50(d,J=8.3Hz,1H),6.99(d,J=8.6Hz,2H),6.91(s,1H),6.6 7(d,J=8.5Hz,1H),6.59(s,1H),3.97(s,5H),4.78(s,2H),3.74(d,J=5.3Hz,4H),3.08(d,J=5.4Hz,4H).HRMS(ESI):calcd forC 27 H 28 Cl2N4O3:526.1538; found:526.1541. 13 C NMR (101MHz, DMSO-d6) δ166.90,155.25,149.35,147.89,143.31,136.89,132.40,124.54,123. 04,120.70,116.23,114.39,112.85,106.94,96.61,57.21,57.16,55.04,50.74,48.92,46.23.

[0151] Example 23

[0152]

[0153] Following the synthetic route of Example 2, compound BF15 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-ethylpiperazine)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-dichloro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF15 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0154] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.65(d,J=8.5Hz,2H),6.97(d,J=8.7Hz,2H),7.50(d,J=8.3Hz,1H),6.91(s,1H),6.67(d,J=8.4 Hz,1H),6.59(s,1H),4.77(s,2H),3.97(s,6H),3.11(s,4H),2.38(s,4H),1.37–1.27(m,2H),1.04(t,J=7.2Hz,3H).HRMS(ESI):calcd for C 27 H 28 Cl2N4O3:540.1695; found:540.1689. 13 C NMR(101MHz,DMSO-d6)δ155.25,149.36,147.96,143.32,136.89,132.37,124.54, 120.73,116.19,112.85,106.93,57.22,57.17,52.79,52.10,50.76,49.05,12.45.

[0155] Example 24

[0156]

[0157] Following the synthetic route of Example 2, compound BF16 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-morpholinoaniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-dichloro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF16 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0158] 1H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.67(d,J=8.6Hz,2H),7.50(d,J=8.3Hz,1H),6.99(d,J=8.6Hz,2H),6.92(s ,1H),6.67(d,J=8.5Hz,1H),6.59(s,1H),4.78(s,2H),3.97(s,5H),3.75(s,4H),3.08(s,4H).HRMS(ESI):calcd for C 26 H 25 Cl2N4O3:513.1222; found:513.1229. 13 C NMR(101MHz,DMSO-d6)δ166.90,155.25,149.33,147.92,143.33,136.88,132.75,124.58,1 23.07,120.68,116.02,114.41,112.83,106.94,96.57,66.57,57.18,57.14,50.72,49.34.

[0159] Example 25

[0160]

[0161] Following the synthetic route of Example 2, compound BF17 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-piperidineaniline (CAS No. 2359-60-6); and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF17 was characterized by nuclear magnetic resonance (NMR), and the NMR results are as follows.

[0162] 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),7.71(d,J=8.6Hz,2H),7.59(d,J=8.3Hz,1H),7.03(d,J=8.7Hz,2H),6.94(t,J=8.0Hz,1H),6.8 9(d,J=8.5Hz,1H),6.82(s,1H),4.86(s,2H),3.96(s,6H),3.17(t,J=5.3Hz,4H),1.69(s,4H),1.62–1.56(m,2H).HRMS(ESI):calcd for C 27 H 27 F2N3O3:479.2020; found:479.2027. 13C NMR(101MHz,Chloroform-d)δ166.24,145.94,143.06,141.17,138.72,124.66,12 3.93,119.73,118.50,115.21,107.30,94.70,56.16,56.12,49.83,24.63,23.07.

[0163] Example 26

[0164]

[0165] Following the synthetic route of Example 2, compound BF18 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-methylpiperazine)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF18 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0166] 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.29(s,1H),7.71–7.63(m,2H),7.09(s,1H),7.03–6.96(m,2H),6.91(t,J=8.0Hz,1H) ,4.82(s,2H),3.91(d,J=1.4Hz,6H),3.13(t,J=4.9Hz,4H),2.46(t,J=5.0Hz,4H),2.23(d,J=1.5Hz,3H).HRMS(ESI):calcd forC 26 H 27 F2N5O3:495.2082; found:495.2090. 13 C NMR(101MHz,Chloroform-d)δ167.27,148.06,147.01,144.04,143.98,142.20,142.16,140.40,132. 29,120.81,119.53,116.65,116.19,108.31,95.71,57.18,57.14,55.08,50.83,49.38,46.15,46.12.

[0167] Example 27

[0168]

[0169] Following the synthetic route of Example 2, compound BF19 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 3-chloro-4-(4-methylpiperazine)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF19 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0170] 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.05(t,J=2.1Hz,1H),7.71–7.64(m,1H),7.56(dd,J=8.3,1.6Hz,1H),7.22(d,J=8.7Hz,1H),6.89(t ,J=8.1Hz,1H),6.84(d,J=8.4Hz,1H),6.77(s,1H),4.85(s,2H),3.90(d,J=1.6Hz,6H),3.00(s,8H),2.34–2.29(m,3H).HRMS(ESI):calcd for C 27 H 27 F2N4O3:528.1740; found:528.1747. 13 C NMR(101MHz,Chloroform-d)δ167.25,148.01,147.04,143.97,142.23,142.19,139.78,131.27,124.57, 124.91,121.80,116.72,116.14,108.19,95.61,57.25,57.37,57.16,55.01,50.84,49.37,46.16,46.14.

[0171] Example 28

[0172]

[0173] Following the synthetic route of Example 2, compound BF20 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-cyclohexylaniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF20 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0174] 1H NMR (400MHz, DMSO-d6)7.79–7.66(m,2H), δ8.59(s,1H),7.55(d,J=8.3Hz,1H),7.24(d,J=8.2Hz,2H),6.89(t,J=7.9Hz,1H),6.84(d,J=8.5Hz,1H),6. 78(s,1H),4.84(s,3H),3.90(d,J=1.3Hz,6H),2.50(s,1H),1.79(d,J=10.3Hz,4H),1.68(t,J=17.4Hz,2H),1.32(d,J=64.5Hz,4H).HRMS(ESI):calcd for C 28 H 28 F2N2O3:478.2068; found:478.2071. 13 C NMR(101MHz,DMSO-d6)δ167.13,149.23,143.41,143.27,138.24,127.45,124.70, 123.31,119.42,114.99,107.39,57.23,57.19,50.58,43.65,34.51,26.84,26.07.

[0175] Example 29

[0176]

[0177] Following the synthetic route of Example 2, compound BF21 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 3-fluoro-4-(4-methylpiperazine)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF21 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0178] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=2.8Hz,1H),7.55(d,J=8.5Hz,1H),7.83(d,J=15.5Hz,1H),7.45(d,J=8.8Hz,1H),7.08(t,J=9.5Hz,1H),6 .90(t,J=8.0Hz,1H),6.84(d,J=8.4Hz,1H),6.78(s,1H),4.83(s,2H),3.90(s,6H),3.01(s,4H),2.26(s,4H),1.24(s,3H).HRMS(ESI):calcd for C 27H 27 F3N4O3:512.2035; found:512.2028. 13 C NMR(101MHz,Chloroform-d)δ167.28,148.06,147.05,143.97,142.20,142.17,139.78,132.27,125.57, 124.91,120.80,116.63,116.16,108.29,95.70,57.21,57.17,57.13,55.09,50.83,49.38,46.16,46.13.

[0179] Example 30

[0180]

[0181] Following the synthetic route of Example 2, compound BF22 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-(4-methylpiperazine)aniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF22 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0182] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.60(d,J=8.3Hz,1H),7.52(d,J=2.4Hz,1H),7.33(d,J=8.0Hz,1H),7.27(t,J=8.1Hz,1H),6.95(t,J=8.0Hz,1H), 6.90(d,J=8.5Hz,1H),6.83(s,1H),6.77(d,J=8.1Hz,1H),4.92(s,2H),3.9 5(d,J=1.7Hz,6H),3.24(s,4H),2.60(s,5H),2.34(s,3H).HRMS(ESI):calcd for C 27 H 28 F2N4O3:494.2129; found:494.2123. 13C NMR(101MHz,DMSO-d6)δ167.30,152.03,149.19,144.26,144.17,143.40,142.31,141.19,139.97,129.68,124 .71,123.44,115.03,111.24,110.12,107.35,106.63,96.66,57.21,57.15,55.04,50.74,48.57,46.20,46.17.

[0183] Example 31

[0184]

[0185] Following the synthetic route of Example 2, compound BF23 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-piperidineaniline; and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-dichloro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF23 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0186] 1 H NMR(400MHz, DMSO-d6)δ8.49(s,1H),7.66–7.59(m,2H),7.50(d,J=8.3Hz,1H),6.99–6.89(m,3H),6.67(dd,J=8.3,2.0Hz,1H),6.5 9(d,J=1.9Hz,1H),4.77(s,2H),3.97(s,5H),3.10(t,J=5.4Hz,4H),1.63(h,J=5.4Hz,5H),1.53(d,J=5.4Hz,2H).HRMS(ESI):calcd for C 27 H 27 Cl2N3O3:511.1429; found:511.1437. 13 C NMR(101MHz,DMSO-d6)δ155.25,149.28,143.32,136.90,124.54,123.14, 120.74,116.74,112.84,96.57,57.19,57.14,50.74,50.48,25.73,24.36.

[0187] Example 32

[0188]

[0189] Following the synthetic route of Example 2, compound BF24 was synthesized, with the only difference being that in reaction S3c, aniline was replaced with 4-amino-N,N-dimethylaniline (CAS No.: 99-98-9); and in reaction S4d, 3,5-dimethoxyphenylboronic acid pinacol ester was replaced with 2,6-difluoro-3,5-dimethoxyphenylboronic acid pinacol ester. The synthesized compound BF24 was characterized by nuclear magnetic resonance (NMR), and the NMR test results are as follows.

[0190] 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.65–7.56(m,2H),7.53(d,J=8.3Hz,1H),6.84(dt,J=2 1.6,8.1Hz,2H),6.81–6.74(m,3H),4.78(s,2H),3.89(s,6H),2.88(s,6H).HRMS(ESI):calcd for C 24 H 23 F2N3O3:439.1707; found:439.1716. 13 C NMR(101MHz,DMSO-d6)δ166.68,148.77,147.80,144.30,144.26,144.16,143.31,142.30,139.96,1 30.19,124.42,123.79,121.19,114.95,113.21,107.55,96.54,57.19,57.15,50.91,40.92,40.89.

[0191] Example 33

[0192]

[0193] Following the synthetic route of Example 2, compound BF25 was synthesized. The only differences in the synthesis process were: in S3, aniline was replaced with 4-amino-N,N-diethylaniline (CAS: 93-05-0); in S4, 3,5-dimethoxyaniline was replaced with 2,6-difluoro-3,5-dimethoxyaniline (CAS: 651734-54-2). Compound BF25 was synthesized and characterized by nuclear magnetic resonance. Its structural characterization data are as follows.

[0194] 1H NMR (400MHz, DMSO-d6) δ8.48(s,1H),7.56(d,J=8.9Hz,2H),7.52(d,J=8.4Hz,1H),6.88(t,J=7.9Hz,1H),6.83(d,J=8.4Hz ,1H),6.76(s,1H),6.70(d,J=8.9Hz,2H),4.77(s,2H),3.90(s,6H),3.34(s,4H),1.09(t,J=6.9Hz,7H).HRMS(ESI):calcd forC 26 H 27 F2N3O3:467.2030; found:467.2030. 13 C NMR(101MHz,DMSO-d6)δ166.60,148.70,144.79,144.29,144.19,143.31,142.33,129.04,1 24.37,123.85,121.79,114.93,112.41,107.56,96.53,57.19,57.15,50.98,44.24,12.87.

[0195] Example 34

[0196]

[0197] Following the synthetic route of Example 2, compound BF26 was synthesized. The only difference in the synthesis process was that aniline used in S3 was replaced with 4-(4-methylpiperazine)aniline (CAS: 16153-81-4); and in S4, 3,5-dimethoxyaniline was replaced with 2,6-difluoro-3,5-dimethoxyaniline. Compound BF26 was synthesized and characterized by nuclear magnetic resonance. Its structural characterization data are as follows.

[0198] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.80(d,J=7.9Hz,2H),7.57(d,J=8.1Hz,1H),7.31(d,J=8.3Hz,2H),6.89(t,J=7.9Hz,1H),6.84(d ,J=8.5Hz,1H),6.78(s,1H),4.86(s,2H),3.90(d,J=1.9Hz,6H),3.43(s,2H),2.34(s,4H),2.17(s,4H),1.24(s,3H).HRMS(ESI):calcd for C 28 H 30F2N4O3:508.2286; found:508.2285. 13 C NMR (101MHz, DMSO-d6) δ167.26,149.35,144.29,143.41,142.37,139.43,130.00,124. 78,123.17,119.17,119.00,115.00,107.37,96.77,61.52,57.24,57.19,54.16,50.54.

[0199] Example 35

[0200]

[0201] Following the synthetic route of Example 2, compound BF27 was synthesized. The only differences in the synthesis process were: in S3, aniline was replaced with 4-(4-ethylpiperazine)aniline (CAS: 115619-01-7); in S4, 3,5-dimethoxyaniline was replaced with 2,6-difluoro-3,5-dimethoxyaniline. Compound BF27 was synthesized and characterized using nuclear magnetic resonance (NMR). Its structural characterization data are as follows.

[0202] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.80(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,1H),7.31(d,J=8.3Hz,2H),6.89(t,J=8.1Hz,1H),6.84(d ,J=8.4Hz,1H),6.78(s,1H),4.87(s,2H),3.90(s,6H),3.43(s,2H),2.35(s,8H),1.24(s,2H),0.98(t,J=7.1Hz,3H).HRMS(ESI):calcd for C 29 H 32 F2N4O3:522.2442; found:522.2444. 13 C NMR (101MHz, DMSO-d6) δ167.25,149.33,144.29,143.41,142.39,139.98,139.37,129. 93,124.78,123.19,118.99,115.00,107.38,96.76,61.69,57.24,57.19,51.73,50.54.

[0203] Example 36

[0204]

[0205] Following the synthetic route of Example 2, compound BF28 was synthesized. The only differences in the synthesis process were: in S3, aniline was replaced with 4-(4-methylpiperazine)aniline; and in S4, 3,5-dimethoxyaniline was replaced with 2,6-difluoro-3,5-dimethoxyaniline. Compound BF28 was synthesized and characterized by nuclear magnetic resonance. Its structural characterization data are as follows.

[0206] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.46(d,J=2.8Hz,1H),8.03(dd,J=9.2,2.8Hz,1H),7.55(d,J=8.3Hz,1H),6.93–6.86(m,2H) ,6.84(d,J=9.8Hz,1H),6.77(s,1H),4.81(s,2H),3.89(s,6H),3.65–3.54(m,4H),2.43(s,4H),2.23(s,3H).HRMS(ESI):calcdfor C 26 H 27 F2N5O3:495.2082;

[0207] Found: 495.2091. 13 C NMR (101MHz, DMSO-d6) δ143.60,139.57,130.31,124.59,123.06,107.52,57.21,54.75,50.52,45.42.

[0208] Example 37

[0209]

[0210] Following the synthetic route of Example 2, compound BF29 was synthesized. The only differences in the synthesis process were: in S3, aniline was replaced with 4-(4-hydroxypiperidin-1-yl)aniline; and in S4, 3,5-dimethoxyaniline was replaced with 2,6-difluoro-3,5-dimethoxyaniline. Compound BF29 was synthesized and characterized by nuclear magnetic resonance (NMR). Its structural characterization data are as follows.

[0211] 1H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 7.68–7.60 (m, 2H), 7.53 (d, J = 8.3Hz, 1 H),6.88(t,J=8.0Hz,1H),6.97(d,J=9.1Hz,2H),6.83(d,J=8.4Hz,1H),6.7 7(s,1H),4.80(s,2H),4.67(d,J=4.2Hz,1H),3.90(s,6H),3.76–3.47(m,1H ),3.36(s,8H),1.82(d,J=12.5Hz,2H),1.60–1.40(m,2H).HRMS(ESI):calcd for C 27 H 27 F2N3O4:495.1970; found:495.1960. 13 C NMR(101MHz,DMSO-d6)δ166.76,148.87,147.96,144.29,144.16,143.31,139.97,131.93,124.51, 123.68,120.73,119.31,116.55,114.97,107.52,96.59,66.52,57.19,57.16,50.75,47.31,34.29.

[0212] Example 38

[0213]

[0214] Following the synthetic route of Example 2, compound BF30 was synthesized, with the only differences being: in S3, aniline was replaced with 4-(4-aminophenyl)morpholin-3-one; and in S4, 3,5-dimethoxyaniline was replaced with 2,6-difluoro-3,5-dimethoxyaniline. Compound BF30 was synthesized and characterized using nuclear magnetic resonance (NMR). Its structural characterization data are as follows.

[0215] 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.92–7.84(m,2H),7.58(d,J=8..4Hz,1H),7.47–7.38(m,2H),6.94–6.82(m,2H),6.79 (s,1H),4.89(s,2H),4.21(s,2H),3.99(dd,J=6.1,4.1Hz,2H),3.90(s,6H),3.74(dd,J=5.9,4.2Hz,2H).HRMS(ESI):calcd forC 26 H23 F2N3O5:495.1606; found::495.1606. 13 C NMR (101MHz, DMSO-d6) δ167.28,166.45,149.34,144.27,144.21,143.47,142.33,138.59,137.36,126. 44,124.89,123.13,119.43,119.16,115.10,107.40,96.74,68.23,63.98,57.21,57.17,50..57,49.52.

[0216] Example 39

[0217]

[0218] Following the synthetic route in Example 2, compound BF31 was synthesized. Characterization data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 1H), 7.73–7.65 (m, 2H), 6.95 (d, J = 9.1Hz, 2H), 6.78 (t, J = 8.0Hz, 1H), 6.85 (d, J = 8.4Hz, 1H),6.73(s,1H),4.82(s,2H),3.91(s,6H),3.10(t,J=5.0Hz,4H),2.39(q,J=7.0Hz,4H),1.02(s,3H).HRMS(ESI):calcd for C 27 H 27 F3N4O3:512.2035; found:512.2035. 13 C NMR(101MHz,DMSO-d6)δ167.27,1148.03,147.04,143.96,142.10,142.27,139.78,132.17,125.47,12 4.61,120.81,116.63,116.33,108.19,95.71,57.22,57.13,57.14,55.09,50.83,49.38,46.13,46.14.

[0219] Example 40

[0220]

[0221] Following the synthetic route in Example 2, compound BF3 was synthesized. Characterization data: 1H NMR (400MHz, DMSO--d6) δ8.54(s,1H),7.65(m,2H),7.54(d,J=8.3Hz,1H),6.98(d,J=9.1Hz,2H),6.80(t,J=8.0Hz,1H),6.83(d,J=8.4Hz,1H), 6.77(s,1H),4.81(s,2H),3.90(s,6H),3.21(d,J=5.0Hz,4H),2.36(q,J=5.0Hz,2H),,1.02(s,3H),0.98(d,J=5.0Hz,6H)HRMS(ESI):calcdfor C 29 H 32 F2N4O3:522.2242; found:522.2242. 13 C NMR(101MHz,DMSO-d6)δ167.25,148.05,147.05,144.01,143.96,142.27,142.18,132.20,125.61,1124.92,12 0.83,119.51,116.65,116.19,108.37,95.71,63.41,63.44,55.05,50.83,49.30,46.17,46.12,16.71,16.73.

[0222] Example 41

[0223]

[0224] Following the synthetic route in Example 2, compound BF33 was synthesized. Its characterization is as follows: 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.80(m,2H),7.54(d,J=8.3Hz,1H),6.98(d,J=9.1Hz,2H),6.88(t,J=8.0Hz,1H),6.83 (d,J=8.4Hz,1H),6.74(s,1H),4.85(s,2H),3.92(s,6H),3.59(s,4H),3.22(s,4H),0.98(d,J=5.0Hz,3H).HRMS(ESI):calcd for C 28 H 28 F2N4O3:506.2129; found:506.2129. 13C NMR(101MHz,Chloroform-d)δ1167.26,148.04,147.51,142.04,141.98,141.20,143.16,133.21,126.12,124 .64,121.81,120.53,116.65,115.19,107.32,96.73,65.18,65.14,63.08,65.83,49.38,46.15,46.12,44.16.

[0225] Example 42

[0226]

[0227] Following the synthetic route in Example 2, compound BF34 was synthesized. Details are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.60(m,2H),7.34(d,J=8.3Hz,1H),6.78(d,J=9.1Hz,2H),6.68(t,J=8.0Hz,1H),6.81(d,J=8.4Hz,1H),6.7 1(s,1H),4.90(s,2H),3.83(s,6H),3.44(t,J=5.1Hz,4H),2.57(t,J=5.1Hz,4H),2.25(m,J=5.0Hz,1H),0.82(d,J=5.0Hz,4H).HRMS(ESI):calcd for C 29 H 30 F2N4O3:520.2286; found:520.2286. 13 C NMR(101MHz,DMSO-d6)δ167.23,148.01,147.08,143.02,142.97,142.21,142.15,132.26,125.62,124.93 ,120.81,119.53,117.64,117.13,109.33,94.73,58.12,58.14,55.07,50.84,49.38,39.51,16.32,16.31.

[0228] The series of compounds synthesized in Examples 1-42 above are summarized in Tables 1 and 2.

[0229] Table 1. Structures of AF series compounds

[0230]

[0231] Table 2. Structures of BF series compounds

[0232]

[0233]

[0234] By implementing the synthetic route, 38 previously unreported isoindolinone compounds were synthesized and analyzed by high-resolution mass spectrometry (HRMS) and proton nuclear magnetic resonance (NMR) spectroscopy. 1 The structure of the compounds was confirmed by 1H NMR. Based on whether the Markush structure core is linked by -NH-, the obtained compounds can be divided into two series, and the specific structures are shown in Table 1 and Table 2 above.

[0235] Experimental Example 1

[0236] The isoindoline ketone compounds synthesized in Examples 1-38 above were analyzed for FGFR inhibition rate using the radioisotope-labeled ATP method. The results are shown in Tables 3-5.

[0237] Table 3. Inhibition rate (%) of AF series compounds against FGFR at 1 μM.

[0238]

[0239] Table 4. Inhibition rate of BF series compounds against FGFR at 1 μM

[0240]

[0241]

[0242] Table 5 shows the IC50 of some isoyindolone compounds on FGFR1. 50 value

[0243]

[0244] Experimental Example 2

[0245] The in vitro antitumor proliferation activity of isoindolinone compounds was investigated as follows:

[0246] U87, U251, and HepG2 cells were removed from a -80°C cryopreservation incubator or liquid nitrogen tank and revived. They were then cultured at 37°C with 5% CO2, passaged twice, and seeded into 96-well plates at densities depending on the cell species: 3000 cells / well for HepG2, 1500 cells / well for U87, and 2000 cells / well for U251. A preferred compound was prepared as a 10mM stock solution and diluted with complete culture medium to five concentrations: 10μM, 5μM, 2.5μM, 1.25μM, and 0.625μM. These concentrations were then added to the 96-well plates containing the seeded cells and incubated for 72 hours. Cell viability was assessed using the CCK8 assay.

[0247] Cell viability is calculated using the following formula:

[0248]

[0249] OD experiment The absorbance value of the experimental group is OD. control The absorbance value of the control group is OD. blank The absorbance values ​​are for the blank group; the results are shown in Table 6.

[0250] Table 6. In vitro antitumor cell proliferation activity of isoyindolone compounds.

[0251]

[0252] In vitro anti-tumor cell proliferation experiments showed that isoindolinone compounds exhibited good anti-tumor cell proliferation activity against glioma cells U251 and U87, as well as liver cancer cells HepG2. Among them, isoindolinone compound BF21 showed the best activity, with an IC50 concentration of [missing information - likely a specific value] against U251, U87, and HepG2 cells. 50 The effective molecular weights (MnM), molecular weights (MnM), and molecular weights (MnM) were 585 nM, 1.21 μM, and 3.48 μM, respectively, which were stronger than those of AZD4547 (MnM), 2.217 μM, and 5.38 μM, respectively.

[0253] Experimental Example 3

[0254] To better investigate the practical application effects of the aforementioned isoindolinone compounds, an in vitro model was used to evaluate their blood-brain barrier permeability. The Parallel Artificial Membrane Assay for Blood-Brain Barrier (PAMPA-BBB) is a high-throughput in vitro model for evaluating the blood-brain barrier permeability of compounds. PAMPA was initially established by Kansy in 1998 to simulate the passive absorption of drugs in the gastrointestinal tract during oral administration. This model consists of a "sandwich" structure composed of a lipophilic 96-well filter plate coated with phospholipids and a PTFE receiving plate. The drug molecule diffuses through the filter plate and passes through the phospholipid-coated membrane into the receiving plate; therefore, by measuring the concentrations of the supply and receiving solutions, the effective permeability coefficient (Pe) can be calculated using a formula. The PAMPA model is characterized by high throughput, low cost, convenient detection, and high flexibility. PAMPA constructed using brain-specific lipids has also been widely used to evaluate blood-brain barrier permeability. The results are shown in Table 7.

[0255] Table 7 PAMPA Test Results

[0256]

[0257] The effective penetration rates (LogPe) of isoindolinone compounds BF10, BF21, and BF29 were -4.41, -3.99, and -4.53, respectively, all higher than that of AZD4547 (-4.77), indicating better blood-brain barrier permeability. The isoindolinone compounds provided in this invention, using isoindolinone as the parent nucleus, have been used to design a series of novel FGFR inhibitors with superior blood-brain barrier permeability. In vitro kinase inhibitory activity, anti-tumor cell proliferation activity, and blood-brain barrier penetration tests demonstrate that the compounds of this invention have significant drug development potential.

[0258] In summary, among the isoindolinone compounds synthesized in the embodiments of this invention, 15 exhibited good FGFR inhibitory efficacy, with inhibition of FGFR1 exceeding 90% at a concentration of 1 μM. The most active compounds, BF10, BF12, and BF28, showed IC50 values ​​of 4 nM, 4 nM, and 5 nM against FGFR1, respectively, close to the 1 nM value of the positive control compound AZD4547. Several compounds also demonstrated good anti-tumor cell proliferation activity in vitro, with anti-proliferative activities against glioma cells U251 and U87, and hepatocellular carcinoma cells HepG2, all approaching or exceeding those of AZD4547. The most active compound, BF21, showed an IC50 of 581 nM against U251, significantly better than the 2.217 μM value of AZD4547. Furthermore, the IC50 values ​​of BF10, BF12, BF22, BF27, BF28, and BF29 were all below 1 μM.

[0259] According to parallel artificial membrane permeability experiments, the permeability coefficients LogPe of BF10, BF21, and BF29 were -4.41, -3.99, and -4.53, respectively, all higher than that of AZD4547 (-4.77). This indicates that the FGFR inhibitor of this invention has higher permeability than AZD4547, and theoretically, has better blood-brain barrier permeability.

[0260] Therefore, the isoindolinone compounds of the present invention are excellent FGFR inhibitors and can be used as lead compounds for the development of glioma treatment drugs.

[0261] Experiment Example 4

[0262] Liver fibrosis is a common outcome of chronic liver injury, characterized by hepatocyte damage, recruitment and activation of inflammatory cells, and excessive deposition of extracellular matrix proteins (including type I, III, and IV collagen, fibronectin, and laminin). Hepatic stellate cells (HSCs) are the main cellular source of myofibroblasts in fibrotic liver tissue. In a normal liver, HSCs are in a quiescent state, but in chronic liver diseases, such as chronic hepatitis caused by HBV and non-alcoholic steatohepatitis (NASH), the liver is in a state of chronic injury and inflammation. Factors such as TGF-β activate HSCs, which then secrete fibrous extracellular collagen, such as college I and college III, accompanied by an imbalance of matrix metalloproteinases / tissue metalloproteinase inhibitors (MMPs / TIMPs), leading to liver fibrosis and subsequently various liver diseases. Therefore, preventing and treating liver fibrosis is of great significance for the prevention of various liver diseases.

[0263] Therefore, this experimental example explores the therapeutic effect of the compound provided in the embodiments of the present invention on TGF-β-induced LX-2 cell fibrosis. The specific experimental procedure is as follows:

[0264] (1) Cell starvation treatment

[0265] LX-2 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / ml penicillin, and 100 mg / ml streptoxin at 37°C in a 5% CO2 incubator. After stable passage, cells were seeded into six-well plates. Once cells adhered, dead cells and serum-containing medium were washed away with PBS, and then the complete medium was replaced with serum-free medium, followed by starvation for 24 hours.

[0266] (2) Establishment of an in vitro fibrosis model

[0267] After overnight starvation, cells were induced for 24 hours with a final concentration of 5 ng / ml of TGF-β.

[0268] (3) Detecting the effects of compounds on fibrotic cell models

[0269] After induction with TGF-β, the experimental group was treated with a final concentration of 5 μM, while the control group was treated with an equal amount of DMSO. After 24 hours of reaction, cells were collected, cellular RNA was extracted, and the expression of COL1A1, MMP2, TGF-β, and α-SMA was detected by qPCR.

[0270] See results Figure 1 ,according to Figure 1 It is known that TGF-β1 protein can induce the expression of MMP2 gene in LX-2, and the tested compound can reduce the expression of MMP2, indicating that it inhibits the increase of TGF-β-induced liver fibrosis-related genes and has the effect of preventing and treating organ fibrosis.

[0271] 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. An isoindolineone compound, characterized in that, It is selected from any one of the compounds shown in the following structural formulas: Equation 2, where X is CH; R2 and R3 are each independently selected from either hydrogen atoms or halogen atoms; Ar represents a substituted phenyl group, and the substituent of the substituted phenyl group is selected from any one of the following: C1-C5 alkyl-substituted amino groups; unsubstituted C3-C6 azircyclic alkyl groups; C1-C10 alkyl-substituted C3-C6 monoazircyclic alkyl groups; and C1-C3 alkyl-substituted C4-C6 diazircyclic alkyl groups.

2. An isoindolineone compound, characterized in that, It is selected from any one of the compounds shown in the following structural formulas: Equation 2, where X is CH; R2 and R3 are each independently selected from either hydrogen atoms or halogen atoms; Ar selected , , , , , , , , , , , and Any one of them.

3. A method for synthesizing the isoindolinone compound according to claim 1, characterized in that, Synthesize according to the following synthesis path: The conditions for steps (a), (b), (c), and (e) are as follows: (a) KI, MeI, DMF, 80℃, 4h; (b) NBS, AIBN, DCM, reflux; (c) DIPEA, ArNH2, MeOH, reflux; (e) PdCl2(DPPF)2, Cs2CO3, BINAP, DMSO. , 110℃.

4. The use of the isoindolinone compound of claim 1 in the preparation of FGFR inhibitors.

5. The use of the isoindolinone compound of claim 1 in the preparation of a drug for treating liver fibrosis.

6. The application according to claim 5, characterized in that, The use of the isoindoline ketone compounds in the preparation of drugs for treating diseases caused by liver fibrosis.

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