CN116813526A - Isoindolinone compound, preparation method and application thereof - Google Patents
Isoindolinone compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicine synthesis, in particular to an isoindolinone compound, a preparation method and application thereof. The structural formula of the isoindolinone compound is as follows:wherein L is-NH-or a bond; x is-CM-or-N-, M represents H or halogen; r1, R2 and R3 are each independently selected from any one of a hydrogen atom, a halogen and an alkoxy group; ar is a substituted or unsubstituted aromatic group or any one of a substituted aromatic group and a substituted or unsubstituted heteroaryl group. The compound can effectively act on fibroblast growth factor receptor FGFR, has partial blood brain barrier permeability, and has good inhibition effect on glioblastoma. The in vitro kinase inhibition activity, the anti-tumor cell proliferation activity and the blood brain barrier penetration capability of the isoindolinone compound are tested, and the result shows that the isoindolinone compound has good anti-tumor growth activity, can inhibit fibrosis and prevent liver fibrosis.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to an isoindolinone compound, a preparation method and application thereof.
Background
Fibroblast growth factor receptor (Fibroblast growth factor receptor, FGFR), belonging to the receptor tyrosine kinase family, which consists of four members (FGFR 1-4). Over the last few decades, studies on FGFR have been in progress, and the role of FGFR abnormalities in tumorigenesis and development has been revealed, leading to abnormal activation of FGFR signaling axes mainly due to oncogenic fusion, activating mutation, and amplification of their genes. The modulation of physiological function by FGFR pathway is present in almost all organs, and abnormal activation of FGFR is detected in various tumors. Therefore, the FGFR-targeted inhibitor has a wide application range in the field of anti-tumor.
The occurrence and development of glioblastoma and FGFR signals have a strong relation, and the specificity of the blood brain barrier determines that most FGFR targeting agents cannot reach the glioblastoma. Currently, the development of FGFR inhibitors is mainly focused on improving target selectivity, especially FGFR4 selective inhibitors and dual-target FGFR inhibitors, and drugs developed for the blood brain barrier have not been reported in the literature.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide isoindolinone compounds, a preparation method and application thereof. It overcomes the problems of lack of fibroblast growth factor receptor inhibitor drugs in the prior art and adverse effect on anti-tumor treatment.
The invention is realized in the following way:
in a first aspect, the invention provides an isoindolinone compound having the following structural formula:
wherein L is-NH-or a bond;
x is-CM-or-N-, M represents H or halogen;
r1, R2 and R3 are each independently selected from any one of a hydrogen atom, a halogen atom and an alkoxy group;
ar is a substituted or unsubstituted aromatic group or any one of a substituted aromatic group and a substituted or unsubstituted heteroaryl group.
In a second aspect, the present invention provides a method for synthesizing an isoindolinone according to the previous embodiment, wherein the synthesis is performed by referring to the following synthesis route:
in a third aspect, the present invention provides an application of the isoindolinone compound according to the previous embodiment in preparing FGFR inhibitors.
In a fourth aspect, the invention provides an application of the isoindolinone compound in preparation of antitumor drugs.
In a fifth aspect, the present embodiment provides an application of the isoindolinone compound according to the previous embodiment in preparing a medicament for resisting organ fibrosis;
preferably, the organ comprises a liver;
preferably, the isoindolinone compound is applied to the preparation of a medicament for treating liver fibrosis;
preferably, the isoindolinone compound is applied to the preparation of a medicament for treating diseases caused by liver fibrosis.
The invention has the following beneficial effects: the isoindolinone compound adopts an isoindolinone mother nucleus structure, more than one alkoxy is connected to a benzene ring group on the left side, and an aromatic ring structure is connected to the right side of the isoindolinone mother nucleus, so that the isoindolinone compound can effectively act on a fibroblast growth factor receptor FGFR, has partial blood brain barrier permeability, and has a good inhibition effect on glioblastoma. The in vitro kinase inhibition activity, the anti-tumor cell proliferation activity and the blood brain barrier penetration capability of the isoindolinone compound are tested, and the result shows that the isoindolinone compound has good anti-tumor growth activity and has potential for developing as an anti-tumor drug. Meanwhile, the isoindolinone compound can inhibit cell fibrosis, and then reduce liver fibrosis.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the results of the test provided in Experimental example 4 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention provides an isoindolinone compound, which has the following structural formula:
wherein L is-NH-or a bond;
x is-CM-or-N-, M represents H or halogen; r1, R2 and R3 are each independently selected from any one of a hydrogen atom, a halogen atom and an alkoxy group; preferably, the halogen atom includes a fluorine atom and a chlorine atom, and at least one of R1, R2 and R3 is an alkoxy group; ar is a substituted or unsubstituted aromatic group or any one of a substituted aromatic group and a substituted or unsubstituted heteroaryl group.
Further, the isoindolinone compound is selected from the compounds represented by the following structural formula:
wherein X is-CM-or-N-, M represents H or halogen; r1 and R2 are each independently selected from any one of H and alkoxy; preferably, at least one of R1 and R2 is alkoxy; ar is any one of a substituted or unsubstituted aromatic group and a substituted or unsubstituted heteroaryl group.
The isoindolinone compound is selected from compounds shown in the following structural formula:
wherein X is-CM-or-N-, M represents H or halogen; r2 and R3 are each independently selected from any one of a hydrogen atom and a halogen atom; the halogen atom is selected from fluorine or chlorine; ar is any one of a substituted or unsubstituted aromatic group and a substituted or unsubstituted heteroaryl group.
Further, X in the isoindolinone compound is any one of-CH-, -CF-, -CCl-and-CBr-.
Further, ar is any one of a substituted or unsubstituted aromatic group and a substituted or unsubstituted heteroaryl group, for example, an aromatic group may be selected from phenyl groups, and a heteroaryl group may be selected from pyrazole, pyridine, thiazole, thiophene, and the like.
For example, ar is any one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidine group, a substituted or unsubstituted pyrazolyl group, and a substituted or unsubstituted pyrimidinyl group;
wherein, the substituent groups of the substituted phenyl, the substituted pyridyl, the substituted pyrimidine, the substituted pyrazolyl and the substituted pyrimidine are respectively selected from any one of halogen, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted cycloalkyl, and the heteroatom in the heterocycloalkyl can be O, N, S; for example, substituted phenyl, substituted pyridinyl, substituted pyrimidine, substituted pyrazolyl, and substituted pyrimidine substituents are each selected from halogen; C1-C10 alkoxy; unsubstituted amine groups; C1-C5 alkyl substituted amino; unsubstituted C3-C6 oxacycloalkyl; unsubstituted C3-C6 azacycloalkyl; C1-C10 alkyl, halogen, hydroxy, carbonyl and amino substituted C3-C6 oxacycloalkyl; C1-C10 alkyl, halogen, hydroxy and any substituted C3-C6 monoazacycloalkyl of amino; C1-C3 alkyl and C3-C5 cycloalkyl substituted C4-C6 diazacycloalkyl; C1-C3 alkyl and C3-C5 cycloalkyl substituted C4-C6 diazaspiro; unsubstituted C3-C8 cycloalkyl and any one of C3-C8 cycloalkyl substituted with any one of C1-C10 alkyl, halogen, hydroxy, and amino; specifically, the substituent of the substituted phenyl group may be selected from any one of halogen, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted cycloalkyl; for example, substituents including substituted phenyl groups include halogen; C1-C10 alkoxy; unsubstituted amine groups; C1-C5 alkyl substituted amino; unsubstituted C3-C6 oxacycloalkyl; unsubstituted C3-C6 azacycloalkyl; C1-C10 alkyl, halogen, hydroxy and any substituted C3-C6 oxacycloalkyl of amino; C1-C10 alkyl, halogen, hydroxy and any substituted C3-C6 monoazacycloalkyl of amino; C1-C3 alkyl and C3-C5 cycloalkyl substituted C4-C6 diazacycloalkyl; C1-C3 alkyl and C3-C5 cycloalkyl substituted C4-C6 diazaspiro; unsubstituted C3-C8 cycloalkyl and any one of C3-C8 cycloalkyl substituted with any one of C1-C10 alkyl, halogen, hydroxy, and amino; the method comprises the steps of carrying out a first treatment on the surface of the
Further, R1, R2 and R3 in the isoindolinone compound are selected from alkoxy groups and alkoxy groups mentioned in Ar, and the alkoxy groups can be selected from C1-C10 alkoxy groups, preferably C1-C8 alkoxy groups, more preferably C1-C5 alkoxy groups, more preferably C1-C3 alkoxy groups, and most preferably methoxy groups and ethoxy groups. In addition to methoxy and ethoxy, alkoxy groups such as n-propoxy, isopropoxy, n-butoxy, tert-butoxy and isohexyloxy may be selected.
The halogen atom mentioned in the above group may be selected from fluorine and chlorine, the alkyl group may be selected from a C1-C10 alkyl group such as methyl, ethyl, N-propyl, isopropyl, N-butyl, etc., the cycloalkyl group may be a C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., the heterocycloalkyl group may be selected from a heterocycloalkyl group of at least one of O and N, and even if the heteroatom is only O or N, the number of heteroatoms may be a heterocycloalkyl group of a plurality of heteroatoms such as 2, 3 or 4, etc., for example, the heterocycloalkyl group may be selected from a heterocycloalkyl group such as morpholine, piperidine, piperazine, oxazepinyl, azepinyl, azacyclooctyl, nortropane, decahydroquinolinyl, thiomorpholinyl, etc.
Specifically, ar is selected from phenyl,
Any one of the following.
In a second aspect, the embodiment of the present invention provides a method for synthesizing the isoindolinone compound, wherein the synthesis is performed by referring to the following synthesis route:
further, synthesis is performed with reference to the following synthesis route:
it should be noted that the operating conditions and the material selection in the steps (a) to (e) are merely examples of the embodiments of the present invention, and are not limited to the selection and the reaction conditions of the materials, so long as the desired materials are prepared.
For example: the reagents and conditions of each reaction step are as follows: (a) KI, meI, DMF,80℃for 4h; (b) NBS, AIBN, DCM, reflux; (c) DIPEA, aniline ArNH2, meOH, reflux; (d) PdCl 2 (DPPF) 2 ,Cs 2 CO 3 BINAP, DMSO,3, 5-dimethoxyphenyl boronic acid pinacol ester, 110 ℃; (e) PdCl 2 (DPPF) 2 ,Cs 2 CO 3 BINAP, DMSO,3, 5-dimethoxyaniline, 110 ℃.
In a third aspect, the present invention provides an application of the isoindolinone compound according to the previous embodiment in preparing FGFR inhibitors.
In a fourth aspect, the invention provides an application of the isoindolinone compound in preparation of antitumor drugs.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment of the invention provides synthesis of an isoindolinone compound (marked as AF 1), which comprises the following specific synthesis steps:
s1, reaction a: 20g of 4-bromo-2-methylbenzoic acid (about 92.6mmol,1 eq.) are dissolved in 60mL of DMF (N, N-dimethylformamide), 77g of potassium iodide (5 eq.) and 5.85mL of methyl iodide (1 eq.) are added and the reaction is stirred at 80℃for 4h. After the reaction is completed, the reaction solution is cooled and poured into ice water, a large amount of white precipitate is precipitated, and the product (4-bromo-2-methyl benzoate) can be obtained by vacuum suction filtration, and the yield is about 90%.
S2, reaction b: 5g of methyl 4-bromo-2-methylbenzoate (21.7 mmol,1 eq.) are dissolved in 5mL of dichloromethane. 3.5g N-bromosuccinimide (NBS, 0.9 eq.) was mixed with 0.36g azobisisobutyronitrile (AIBN, 0.1 eq.) and dissolved in 10mL methylene chloride and added dropwise to the reaction system in three portions. And (3) carrying out reflux reaction for about 10 hours, stopping the reaction when a large amount of sediment is generated in the reaction liquid, wherein the sediment is debrominated succinimide salt, and adding water for dissolution and removal. The product (4-bromo-2-bromomethylbenzoic acid methyl ester) obtained by extraction has close polarity with the non-brominated raw material and is difficult to separate, so that the mixture is spin-dried and used for the next reaction.
S3, reaction c: 5g of methyl 4-bromo-2-bromomethylbenzoate (16.2 mmol,1 eq.) are added to 20mL of methanol, 1.2 eq.) of 4- (4-methylpiperazine) aniline and 3.4mL of DIPEA (N-ethyldiisopropylamine, 1.2 eq.) are added and reacted under reflux for 48h. When the reaction is started, the reaction liquid is clarified, and when a large amount of precipitation occurs in the reaction liquid, the reaction can be ended, and the product can be obtained through vacuum suction filtration, wherein the yield is about 80%.
S4, reaction d: 2g of 5-bromo-2-anilino isoindolin-1-ones (1 equivalent) were dissolved in anhydrous DMSO, and 0.05 equivalent of DPPF palladium dichloride catalyst { i.e., [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride },2.4 equivalents of cesium carbonate, and 1.2 equivalents of 3, 5-dimethoxyphenyl-boronic acid pinacol ester were added, and reacted at 110℃for 4 hours under anhydrous and anaerobic conditions to separate the compound by silica gel column chromatography to obtain compound AF1. The yield was about 70%.
The compound AF1 was obtained and characterized by nuclear magnetic resonance, and the nuclear magnetic test results were as follows.
1 H NMR(400MHz,DMSO-d 6 )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),6.57(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 for C 27 H 29 N 3 O 3 :443.2209；found:443.2216. 13 C NMR(101MHz,Chloroform-d)δ161.23,148.43,145.01,142.61,140.81,132.62,131.86,127.66,124.24,121.31,121.02,116.58,105.78,99.93,55.53,55.49,55.09,51.08,49.31,46.19,46.16.
Example 2
The embodiment provides a synthetic method of an isoindolinone compound (BF 1), which comprises the following specific synthetic steps:
s1, reaction a: 20g of 5-bromo-3-methyl-2-carboxypyridine (about 92.6mmol,1 eq.) are dissolved in 60mL of DMF (N, N-dimethylformamide), 77g of potassium iodide (5 eq.) and 5.85mL of methyl iodide (1 eq.) are added and the reaction is stirred at 80℃for 4h. After the reaction is completed, the reaction solution is cooled and poured into ice water, a large amount of white precipitate is precipitated, and the product (5-bromo-3-methylpyridine-2-carboxylic acid methyl ester) can be obtained by vacuum suction filtration, and the yield is about 90%.
S2, reaction b: 5g of 5-bromo-3-methylpyridine-2-carboxylic acid methyl ester (21.7 mmol,1 eq.) are dissolved in 5mL of dichloromethane. 3.5g of N-bromosuccinimide (NBS, 0.9 eq.) was mixed with 0.36g of azobisisobutyronitrile (AIBN, 0.1 eq.) and dissolved in 10mL of methylene chloride, and added dropwise to the reaction system in three portions. And (3) carrying out reflux reaction for about 10 hours, stopping the reaction when a large amount of sediment is generated in the reaction liquid, wherein the sediment is debrominated succinimide salt, and adding water for dissolution and removal. The product (5-bromo-3-bromomethylpyridine-2-carboxylic acid methyl ester) obtained by extraction is similar to the non-brominated raw material in polarity and is difficult to separate, so that the mixture is spin-dried and used for the next reaction.
S3, reaction c: 5g of methyl 5-bromo-3-bromomethylpyridine-2-carboxylate (16.2 mmol,1 eq) are added to 20mL of methanol, 1.2 eq of aniline and 3.4mL of DIPEA (N-ethyldiisopropylamine, 1.2 eq) are added and the reaction is refluxed for 48h. When the reaction is started, the reaction liquid is clarified, and when a large amount of precipitation occurs in the reaction liquid, the reaction can be ended, and the product can be obtained through vacuum suction filtration, wherein the yield is about 80%.
S4, reaction e: 2g of 5-bromo-2-anilino isoindolin-1-one (1 equivalent) was dissolved in anhydrous DMSO, 0.05 equivalent of DPPF palladium dichloride catalyst { i.e., [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride },2.4 equivalent of cesium carbonate, 0.15 equivalent of BINAP (2, 2' -bisdiphenylphosphino-1, 1' -binaphthyl) ligand and 1.2 equivalent of 3, 5-dimethoxyaniline were added, reacted at 110℃for 4 hours under anhydrous and anaerobic conditions, and the resultant mixture was separated by silica gel column chromatography to give compound BF1. The yield was about 70%.
The compound BF1 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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,2H),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 N 3 O 3 :361.1410；found:361.1417. 13 CNMR(101MHz,DMSO-d 6 )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.
Example 3
Reference is made to the synthetic route of example 1 aboveThe synthesis of the compound AF2 is carried out, the difference is that S4 is replaced by '3, 5-dimethoxy phenyl boric acid pinacol ester' and '2, 5-dimethoxy phenyl boric acid pinacol ester' in the reaction d, the synthesized compound AF2 is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows. 1 H NMR(400MHz,DMSO-d 6 )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 N 3 O 3 :443.2209；found:443.2217. 13 C NMR(101MHz,Chloroform-d)δ153.84,150.71,148.37,142.27,140.04,132.12,132.00,130.75,129.83,123.64,123.56,121.02,116.81,116.60,113.85,112.73,56.29,55.88,55.09,51.11,49.34,46.19.
Example 4
Compound AF3 synthesis was performed by reference to the synthetic route of example 1 above. The only difference is that in reaction c of S3, 4- (4-methylpiperazine) aniline is replaced by aniline. The compound position AF3 obtained by synthesis is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 2 O 3 :346..1317；found:346.1327. 13 C NMR(101MHz,DMSO-d 6 )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.
Wherein the intermediates are characterized as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.62(d,J＝2.2Hz,1H),8.15(d,J＝2.2Hz,1H),3.87(s,3H),2.46(s,3H).
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )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).
example 5
Referring to the synthetic route of example 1 above, the synthesis of compound AF4 was performed, except that in S3 reaction c, 4- (4-methylpiperazine) aniline was replaced with aniline; in reaction d, 3, 5-dimethoxyphenyl-boronic acid pinacol ester is replaced by 2, 5-dimethoxyphenyl-boronic acid pinacol ester. The compound position AF4 obtained by synthesis is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 2 O 3 :346.1317；found:346.1318. 13 C NMR(101MHz,Chloroform-d)δ165.38,153.97,152.17,150.85,149.04,139.27,136.63,133.71,131.70,129.28,126.99,125.00,119.46,116.75,114.68,112.71,56.24,55.97,55.93,55.90,48.44.
Example 6
The synthesis of compound AF5 was performed with reference to the synthetic route of example 1, except that in S3 reaction c, 4- (4-methylpiperazine) aniline was replaced with 3-amino-5-phenylpyrazole. The compound position AF5 obtained by synthesis is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows.
1 H NMR(400MHz,DMSO-d 6 )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 for C 25 H 21 N 3 O 3 :411.1583；found:411.1582. 13 C NMR(101MHz,DMSO-d 6 )δ161.44,144.54,143.30,142.77,142.10,129.68,129.57,128.87,127.59,125.66,123.94,122.66,105.73,100.66,92.81,55.88,55.83,49.74.
Example 7
With reference to the synthetic method of example 1, compound AF6 was synthesized, except that in S3 reaction c, 4- (4-methylpiperazine) aniline was replaced with 4-methoxyaniline. The compound position AF6 obtained by synthesis is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows.
1 H NMR(400MHz,DMSO-d 6 )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 NO 4 :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.
Example 8
With reference to the synthetic route of example 1, compound AF7 was synthesized, except that in S3 reaction c, 4- (4-methylpiperazine) aniline was replaced with 3, 4-methylenedioxy aniline. The compound position AF7 obtained by synthesis is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows.
1 H NMR(400MHz,DMSO-d 6 )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 NO 5 :388.1263；found:389.1265. 13 C NMR(101MHz,Chloroform-d)δ161.24,145.29,142.52,140.66,133.89,132.33,127.76,124.38,121.30,112.90,108.21,105.80,102.63,101.40,99.97,55.54,55.50,55.47,51.52.
Example 9
Referring to the synthetic route of example 1, compound AF8 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4-amino-N, N-dimethylaniline. The compound position AF8 obtained by synthesis is characterized by nuclear magnetic resonance, and the nuclear magnetic resonance test result is as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 2 O 3 :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.
Example 10
Referring to the synthetic route of example 2, compound BF2 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4-methoxyaniline. The synthesized compound BF2 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 2 O 4 :390.1580；found:390.1587. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 11
With reference to the synthetic route of example 2, compound BF3 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 3, 4-methylenedioxy aniline. The synthesized compound BF3 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 2 O 5 :404.1372；found:404.1367. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 12
Referring to the synthetic route of example 2, compound BF4 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4- (4-methylpiperazine) aniline. The synthesized compound BF4 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 4 O 3 :458.2318；found:458.2326. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 13
With reference to the synthetic route of example 2, compound BF5 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 3, 4-methylenedioxy aniline. The synthesized compound BF6 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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):calcd for C 24 H 22 N 2 O 5 :418.1529；found:418.1530. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 14
Reference to the synthetic route of example 2, the synthetic compound BF6 differs only in that in S3 reaction c aniline is replaced by 1-methyl-1H-pyrazol-4-amine (CAS: 127107-23-7). The synthesized compound BF6 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 for C 20 H 20 N 4 O 3 :364.1535；found:364.1537. 13 C NMR(101MHz,DMSO-d 6 )δ165.57,161.64,147.67,144.12,143.93,128.99,124.61,123.55,123.27,120.51,116.77,109.44,97.34,93.98,55.56,55.52,50.37,39.27.
Example 15
With reference to the synthetic route of example 2, compound BF7 was synthesized, except that in S3 reaction c, aniline was replaced with 4- (4-ethyl-1-piperazinyl) aniline. The synthesized compound BF7 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 4 O 3 :472.2474；found:472.2479. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 16
Referring to the synthetic route of example 2, compound BF8 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4-morpholinylaniline. The synthesized compound BF2 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 N 3 O 4 :445.2002；found:445.2007. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 17
With reference to the synthetic route of example 2, compound BF9 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 3, 4-methylenedioxy aniline. The synthesized compound BF9 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 for C 23 H 18 F 2 N 2 O 5 :440.1184；found:440.1192. 13 C NMR(101MHz,DMSO-d 6 )δ167.01,149.13,147.85,144.30,144.20,144.16,143.75,143.29,142.34,142.31,139.96,139.93,134.85,124.71,123.27,119.21,115.05,112.58,108.57,107.37,101.95,101.58,96.66,57.19,57.15,51.16.
Example 18
Referring to the synthetic route of example 2, compound BF10 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4- (4-methyl-1-piperazinyl) aniline; in reaction d, 3, 5-dimethoxyphenyl-boronic acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxyphenyl-boronic acid pinacol ester. The synthesized compound BF10 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 4 O 3 :494.2129；found:494.2134. 13 C NMR(101MHz,Chloroform-d)δ167.27,148.06,147.01,144.04,143.98,
Wherein, the structural formula of the intermediate forming BF10 and corresponding characterization data are as follows:
characterization data: 1 H NMR(400MHz,DMSO-d 6 )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).
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).
example 19
Reference to the synthetic route of example 2, synthetic compound BF11 differs only in that in S3 reaction c aniline is replaced by 3, 4-ethylenedioxyaniline (CAS: 22013-33-8); s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF11 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 2 O 5 :454.1340；found:454.1337. 13 C NMR(101MHz,DMSO-d 6 )δ166.97,149.18,144.28,144.19,144.15,143.60,143.29,140.14,134.12,124.64,123.27,117.37,114.98,112.71,108.78,107.35,96.72,64.71,57.23,57.18,50.81.
Example 20
With reference to the synthetic route of example 2, compound BF12 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4- (4-ethyl-1-piperazinyl) aniline; in reaction d, 3, 5-dimethoxyphenyl-boronic acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxyphenyl-boronic acid pinacol ester. The synthesized compound BF12 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 4 O 3 :508.2286；found:508.2295. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 21
Referring to the synthetic route of example 2, compound BF13 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4-morpholinylaniline; in reaction d, 3, 5-dimethoxyphenyl-boronic acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxyphenyl-boronic acid pinacol ester. The synthesized compound BF13 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 25 F 2 N 4 O 3 :481.1813；found:481.1820. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 22
With reference to the synthetic route of example 2, compound BF14 was synthesized, except that in S3 reaction c, aniline was replaced with 4- (4-methylpiperazine) aniline (CAS No. 16153-81-4); in reaction d, 3, 5-dimethoxy phenylboronic acid pinacol ester is replaced by 2, 6-dichloro-3, 5-dimethoxy phenylboronic acid pinacol ester. The synthesized compound BF14 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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),6.67(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 for C 27 H 28 Cl 2 N 4 O 3 :526.1538；found:526.1541. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 23
Referring to the synthetic route of example 2, compound BF15 was synthesized, except that in S3 reaction c, aniline was replaced with 4- (4-ethylpiperazine) aniline; in reaction d, 3, 5-dimethoxy phenylboronic acid pinacol ester is replaced by 2, 6-dichloro-3, 5-dimethoxy phenylboronic acid pinacol ester. The synthesized compound BF15 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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＝8.4Hz,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 Cl 2 N 4 O 3 :540.1695；found:540.1689. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 24
Referring to the synthetic route of example 2, compound BF16 was synthesized, except that in S3 reaction c, aniline was replaced with 4-morpholinylaniline; in reaction d, 3, 5-dimethoxy phenylboronic acid pinacol ester is replaced by 2, 6-dichloro-3, 5-dimethoxy phenylboronic acid pinacol ester. The synthesized compound BF16 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 Cl 2 N 4 O 3 :513.1222；found:513.1229. 13 C NMR(101MHz,DMSO-d 6 )δ166.90,155.25,149.33,147.92,143.33,136.88,132.75,124.58,123.07,120.68,116.02,114.41,112.83,106.94,96.57,66.57,57.18,57.14,50.72,49.34.
Example 25
Referring to the synthetic route of example 2, synthetic compound BF17, except that in S3 reaction c, aniline is replaced with 4-piperidinaniline (CAS No. 2359-60-6); in reaction d, 3, 5-dimethoxyphenyl-boronic acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxyphenyl-boronic acid pinacol ester. The synthesized compound BF17 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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),6.89(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 F 2 N 3 O 3 :479.2020；found:479.2027. 13 C NMR(101MHz,Chloroform-d)δ166.24,145.94,143.06,141.17,138.72,124.66,123.93,119.73,118.50,115.21,107.30,94.70,56.16,56.12,49.83,24.63,23.07.
Example 26
With reference to the synthetic route of example 2, compound BF18 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 4- (4-methylpiperazine) aniline; s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF18 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 for C 26 H 27 F 2 N 5 O 3 :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.
Example 27
With reference to the synthetic route of example 2, the synthetic compound BF19 differs only in that in S3 reaction c, aniline is replaced by 3-chloro-4- (4-methylpiperazine) aniline; s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF19 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 4 O 3 :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.
Example 28
Referring to the synthetic route of example 2, compound BF20 was synthesized, except that in S3 reaction c, aniline was replaced with 4-cyclohexylaniline; s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF20 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 2 O 3 :478.2068；found:478.2071. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 29
With reference to the synthetic route of example 2, compound BF21 was synthesized with the only difference that in S3 reaction c, aniline was replaced with 3-fluoro-4- (4-methylpiperazine) aniline; s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF21 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 27 H 27 F 3 N 4 O 3 :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.
Example 30
Referring to the synthetic route of example 2, compound BF22 was synthesized, except that in S3 reaction c, aniline was replaced with 4- (4-methylpiperazine) aniline; s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF22 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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),3.95(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 F 2 N 4 O 3 :494.2129；found:494.2123. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 31
Referring to the synthetic route of example 2, compound BF23 was synthesized, except that in S3 reaction c, aniline was replaced with 4-piperidinaniline; s4, in the reaction d, replacing 3, 5-dimethoxy phenyl boric acid pinacol ester with 2, 6-dichloro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF23 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )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),6.59(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 Cl 2 N 3 O 3 :511.1429；found:511.1437. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 32
Reference to the synthetic route of example 2, synthetic compound BF24 differs only in that in S3 reaction c aniline is replaced by 4-amino-N, N-dimethylaniline (CAS number: 99-98-9); s4, in the reaction d, 3, 5-dimethoxy phenyl boric acid pinacol ester is replaced by 2, 6-difluoro-3, 5-dimethoxy phenyl boric acid pinacol ester; the synthesized compound BF24 is characterized by nuclear magnetic resonance, and nuclear magnetic resonance test results are as follows.
1 H NMR(400MHz,DMSO-d 6 )δ8.50(s,1H),7.65–7.56(m,2H),7.53(d,J＝8.3Hz,1H),6.84(dt,J＝21.6,8.1Hz,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 F 2 N 3 O 3 :439.1707；found:439.1716. 13 C NMR(101MHz,DMSO-d 6 )δ166.68,148.77,147.80,144.30,144.26,144.16,143.31,142.30,139.96,130.19,124.42,123.79,121.19,114.95,113.21,107.55,96.54,57.19,57.15,50.91,40.92,40.89.
Example 33
Referring to the synthetic route of example 2, compound BF25 was synthesized, differing only in the synthesis: the aniline used in S3 is replaced by 4-amino-N, N-diethylaniline (CAS: 93-05-0); in S4, the 3, 5-dimethoxyaniline used was replaced with 2, 6-difluoro-3, 5-dimethoxyaniline (CAS: 651734-54-2). The compound BF25 is synthesized and characterized by nuclear magnetic resonance, and the structural characterization data are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 for C 26 H 27 F 2 N 3 O 3 :467.2030；found:467.2030. 13 C NMR(101MHz,DMSO-d 6 )δ166.60,148.70,144.79,144.29,144.19,143.31,142.33,129.04,124.37,123.85,121.79,114.93,112.41,107.56,96.53,57.19,57.15,50.98,44.24,12.87.
Example 34
With reference to the synthetic route of example 2, compound BF26 was synthesized with the only difference that aniline used in S3 was replaced with 4- (4-methylpiperazine) aniline (CAS: 16153-81-4); in S4, the 3, 5-dimethoxy aniline used is replaced by 2, 6-difluoro-3, 5-dimethoxy aniline. The compound BF26 is synthesized and characterized by nuclear magnetic resonance, and the structural characterization data are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 30 F 2 N 4 O 3 :508.2286；found:508.2285. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 35
Referring to the synthetic route of example 2, compound BF27 was synthesized, differing only in the synthesis: the aniline used in S3 is replaced by 4- (4-ethylpiperazine) aniline (CAS: 115619-01-7); in S4, the 3, 5-dimethoxy aniline used is replaced by 2, 6-difluoro-3, 5-dimethoxy aniline. The compound BF27 is synthesized and characterized by nuclear magnetic resonance, and the structural characterization data are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 4 O 3 :522.2442；found:522.2444. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 36
Referring to the synthetic route of example 2, compound BF28 was synthesized, differing only in the synthesis: the aniline used in S3 is replaced with 4- (4-methylpiperazine) aniline; in S4, the 3, 5-dimethoxy aniline used is replaced by 2, 6-difluoro-3, 5-dimethoxy aniline. The compound BF28 is synthesized and characterized by nuclear magnetic resonance, and the structural characterization data are as follows.
1 H NMR(400MHz,DMSO-d 6 )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):calcd for C 26 H 27 F 2 N 5 O 3 :495.2082；
found:495.2091. 13 C NMR(101MHz,DMSO-d 6 )δ143.60,139.57,130.31,124.59,123.06,107.52,57.21,54.75,50.52,45.42.
Example 37
Referring to the synthetic route of example 2, compound BF29 was synthesized, differing only in the synthesis: the aniline used in S3 is replaced with 4- (4-hydroxypiperidin-1-yl) aniline; in S4, the 3, 5-dimethoxy aniline used is replaced by 2, 6-difluoro-3, 5-dimethoxy aniline. The compound BF29 is synthesized and characterized by nuclear magnetic resonance, and the structural characterization data are as follows.
1 H NMR(400MHz,DMSO-d 6 )δ8.51(s,1H),7.68–7.60(m,2H),7.53(d,J＝8.3Hz,1H),6.88(t,J＝8.0Hz,1H),6.97(d,J＝9.1Hz,2H),6.83(d,J＝8.4Hz,1H),6.77(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 F 2 N 3 O 4 :495.1970；found:495.1960. 13 C NMR(101MHz,DMSO-d 6 )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.
Example 38
Referring to the synthetic route of example 2, compound BF30 was synthesized, differing only in the synthesis: the aniline used in S3 is replaced with 4- (4-aminophenyl) morpholin-3-one; in S4, the 3, 5-dimethoxy aniline used is replaced by 2, 6-difluoro-3, 5-dimethoxy aniline. The compound BF30 is synthesized and characterized by nuclear magnetic resonance, and the structural characterization data are as follows.
1 H NMR(400MHz,DMSO-d 6 )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 for C 26 H 23 F 2 N 3 O 5 :495.1606；found::495.1606。 13 C NMR(101MHz,DMSO-d 6 )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.
Example 39
Referring to the synthetic route of example 2, compound BF31 was synthesized. Characterization data are as follows: 1 H NMR(400MHz,DMSO-d 6 )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 F 3 N 4 O 3 :512.2035；found:512.2035. 13 C NMR(101MHz,DMSO-d 6 )δ167.27,1148.03,147.04,143.96,142.10,142.27,139.78,132.17,125.47,124.61,120.81,116.63,116.33,108.19,95.71,57.22,57.13,57.14,55.09,50.83,49.38,46.13,46.14.
example 40
Compound BF3 was synthesized with reference to the synthetic route of example 2. Characterization data: 1 H NMR(400MHz,DMSO--d 6 )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):calcd for C 29 H 32 F 2 N 4 O 3 :522.2242；found:522.2242. 13 C NMR(101MHz,DMSO-d 6 )δ167.25,148.05,147.05,144.01,143.96,142.27,142.18,132.20,125.61,1124.92,120.83,119.51,116.65,116.19,108.37,95.71,63.41,63.44,55.05,50.83,49.30,46.17,46.12,16.71,16.73.
example 41
Compound BF33 was synthesized with reference to the synthetic route of example 2. The characterization is as follows: 1 H NMR(400MHz,DMSO-d 6 )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 F 2 N 4 O 3 :506.2129；found:506.2129. 13 C 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.
example 42
Compound BF34 was synthesized with reference to the synthetic route of example 2. The method comprises the following steps: 1 H NMR(400MHz,DMSO-d 6 )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),6.71(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 F 2 N 4 O 3 :520.2286；found:520.2286. 13 C NMR(101MHz,DMSO-d 6 )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.
the series of compounds synthesized in examples 1-42 above are summarized in tables 1 and 2.
Table 1 AF series Structure of Compounds
TABLE 2BF series Compound Structure
By implementing the synthetic route, 38 isoindolinone compounds which are not reported are synthesized, and the isoindolinone compounds are synthesized by High Resolution Mass Spectrum (HRMS) and nucleiMagnetic resonance hydrogen spectrum 1 H NMR) confirms the structure of the compound. The resulting compounds can be divided into two series according to whether the markush structure parent nucleus is linked by-NH-, the specific structures are shown in tables 1 and 2 above.
Experimental example 1
The isoindolinone compounds synthesized in examples 1 to 38 were analyzed for FGFR inhibition by radioisotope labeled ATP method, and the results are shown in tables 3 to 5.
Table 3 inhibition of FGFR by AF series of Compounds at 1. Mu.M (%)
Table 4 inhibition of FGFR by BF series compounds at 1 μm
TABLE 5 partial isoindolinone IC for FGFR1 50 Value of
Experimental example 2
The isoindolinone compound is subjected to an in vitro anti-tumor proliferation activity experiment, and the method is as follows:
u87, U251 and HepG2 cells are taken out from a-80 low-temperature preservation box or a liquid nitrogen tank and resuscitated, and the temperature is 37 ℃ and the concentration of CO is 5 percent 2 Culturing under the condition, inoculating the culture medium into a 96-well plate after passage twice, wherein the density depends on the cell type, and the HepG2 number is 3000 per well, and the U87 number is 1500 per well. U251 is 2000/hole. Preferably, the compound is formulated as a 10mM stock solution and diluted to 10. Mu.M using complete medium,Five concentrations of 5. Mu.M, 2.5. Mu.M, 1.25. Mu.M and 0.625. Mu.M were added to 96-well plates inoculated with cells, incubated for 72 hours, and the cell viability was measured by the cck8 method
Cell viability was calculated by the following formula:
wherein OD experiment For absorbance values of the experimental group, OD control Absorbance value, OD, for control group blank Absorbance values for the blank are shown in table 6.
Table 6 in vitro antitumor cell proliferation Activity of isoindolinone compounds
From the in vitro anti-tumor cell proliferation experimental results, the isoindolinone compound has better anti-tumor cell proliferation activity on glioma cells U251 and U87 and liver cancer cell HepG 2. Among them, isoindolinone BF21 has the best activity against IC of U251, U87 and HepG2 50 585nM, 1.21. Mu.M, 3.48. Mu.M, 2.217. Mu.M, 1.27. Mu.M, 5.38. Mu.M, respectively, stronger than AZD4547.
Experimental example 3
In order to better study the practical application effect of the isoindolinone compound, the in vitro model is used for evaluating the blood brain barrier permeability of the isoindolinone compound. Parallel artificial membrane-blood Brain Barrier permeability experiments (Parallel Artificial Membrane Assay for Blood-Brain Barrier, PAMPA-BBB) are an in vitro model that allows high throughput assessment of compound blood Brain Barrier permeability. PAMPA was originally established by Kansy in 1998 to mimic the passive absorption state of drugs in the gastrointestinal tract in oral administration. The model is a "sandwich" structure consisting of a lipophilic 96-well filter plate coated with the relevant phospholipids and a tetrafluoroethylene PTFE receiving plate. The drug molecules to be tested diffuse in the filter plate and pass through the phospholipid-coated filter membrane to enter the receiving plate, so that the effective permeation coefficients (Effective Permeability Coefficient, pe) of the drug molecules to be tested can be calculated according to a formula by measuring the concentration of the supply liquid and the receiving liquid. PAMPA constructed by using brain-specific lipids is also widely used for evaluating blood brain barrier permeability due to the characteristics of high throughput, low cost, convenient detection, high flexibility and the like of the PAMPA model, and the results are shown in Table 7.
TABLE 7PAMPA test results
The effective permeabilities of the isoindolinone compounds BF10, BF21 and BF29 are respectively-4.41, -3.99 and-4.53 which are higher than-4.77 of AZD4547, and the isoindolinone compounds have better blood brain barrier permeabilities. The isoindolinone compound provided by the embodiment of the invention takes isoindolinone as a mother nucleus, a series of novel FGFR inhibitors are designed, and the isoindolinone compound has the advantage of blood brain barrier permeability. The in vitro kinase inhibition activity, the anti-tumor cell proliferation activity and the blood brain barrier penetration capability test show that the compound has great drug development potential.
In summary, 15 isoindolinone compounds synthesized by the embodiment of the invention have good FGFR inhibition effect, the inhibition effect on FGFR1 is more than 90% at the concentration of 1 mu M, and the IC50 values of BF10, BF12 and BF28 with optimal activity on FGFR1 are respectively 4nM, 4nM and 5nM, which are close to 1nM of positive compound AZD4547. The compounds show good anti-tumor cell proliferation activity in vitro, and the anti-proliferation activity of the compounds on glioma cells U251 and U87 and liver cancer cells HepG2 is close to or higher than that of AZD4547. Of these, the best active compound BF21 has an IC50 for U251 of 581nM, which is far better than 2.217. Mu.M of AZD4547. In addition, the IC50 of BF10, BF12, BF22, BF27, BF28, BF29 are all lower than 1. Mu.M.
According to parallel artificial membrane permeability experiments, the permeability coefficients LogPe of BF10, BF21 and BF29 are respectively-4.41, -3.99 and-4.53, which are higher than-4.77 of AZD4547. The FGFR inhibitor has higher permeability than AZD4547, and theoretically has better blood brain barrier permeability.
Therefore, the isoindolinone compound is an excellent FGFR inhibitor and can be used as a lead compound for developing glioma therapeutic drugs.
Experimental example 4
Hepatic fibrosis is a common consequence of chronic liver injury and is primarily characterized by hepatocyte injury, recruitment and activation of inflammatory cells, and excessive deposition of extracellular matrix proteins (including type I, type III and type IV collagens, fibronectin, laminin, etc.), hepatic Stellate Cells (HSCs) are the major cellular source of myofibroblasts in liver fibrotic tissue in normal liver, HSCs are quiescent, but in chronic liver disease, liver is chronically in chronic injury and inflammatory states such as HBV-induced chronic hepatitis and nonalcoholic steatohepatitis (NASH), etc., TGF- β, etc., factors activate HSCs, activated HSCs secrete fibrous extracellular collagen such as college I and college III, with concomitant imbalance of matrix metalloproteinase/tissue metalloproteinase inhibitors (MMPs/TIMPs), which in turn lead to fibrosis of liver, which in turn triggers various liver diseases.
Therefore, the experimental example explores the therapeutic effect of the compound provided by the embodiment of the invention on TGF-beta induced LX-2 cell fibrosis, and the specific experimental operation is as follows:
(1) Cell starvation treatment
LX-2 was placed in DMEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100mg/ml streptotoxin, and incubated in an incubator at 37℃with 5% CO. After stable passage, cells were seeded in six well plates, after cell attachment, dead cells and serum-containing medium were washed out with PBS, and then the complete medium was replaced with serum-free medium and starved for 24 hours.
(2) In vitro fibrosis model establishment
After overnight starvation, cells were induced with TGF- β at a final concentration of 5ng/ml for 24 hours, respectively.
(3) Detecting the effect of a compound on a model of fibrotic cells
After induction with TGF-beta, the experimental group was given a final concentration of 5. Mu.M drug treatment, the control group was given an equivalent amount of DMSO, after 24 hours of reaction, cells were collected, cellular RNA was extracted, and qPCR was performed to detect the expression of COL1A1, MMP2, TGF-beta, a-SMA.
As shown in FIG. 1, the TGF-beta 1 protein can induce MMP2 gene expression in LX-2, and the tested compound can reduce MMP2 expression, which shows that the compound can inhibit TGF-beta induced liver fibrosis related gene elevation and has effects of preventing and treating organ fibrosis.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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