CN114957136A - Anti-tumor compound used as VEGFR inhibitor and application thereof - Google Patents

Anti-tumor compound used as VEGFR inhibitor and application thereof Download PDF

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CN114957136A
CN114957136A CN202110204122.2A CN202110204122A CN114957136A CN 114957136 A CN114957136 A CN 114957136A CN 202110204122 A CN202110204122 A CN 202110204122A CN 114957136 A CN114957136 A CN 114957136A
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ethyl acetate
cyclopropane
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张孝清
宋看看
周玲玉
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Nanjing Comer Biomedical Co ltd
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Abstract

The invention discloses a compound with VEGFR inhibitory activity or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound as an active substance, a preparation method and application thereof, wherein the compound has a structural general formula shown in formula (I),wherein R is 1 And R 2 As defined in the present invention. The medicine containing the compound can be used as a therapeutic agent for treating malignant tumors, nephropathy, immune system diseases or circulatory system diseases. Particularly in the field of malignant tumor treatment, preliminary drug activity research shows that the compound has equivalent or even better effect than a positive control substance, and pharmacokinetic experiments show that the compound has more remarkable drug absorption effect.

Description

Anti-tumor compound used as VEGFR inhibitor and application thereof
Technical Field
The invention relates to a compound with VEGFR (vascular endothelial growth factor receptor) inhibitory activity, a pharmaceutically acceptable salt or a pharmaceutical composition containing the compound as an active substance, and a preparation method and application of the compound, and belongs to the technical field of medicines.
Background
Protein kinases are closely related to the pathogenesis of a plurality of diseases such as tumors, inflammations, autoimmune diseases, neurological diseases and the like, and the kinases are widely researched as a potential target in nearly 30 years. VEGFR is receptor tyrosine kinase transmembrane protein of VEGF (vascular epidermal growth factor), consists of 7 extracellular immunity protein domains, a transmembrane domain and an intracellular tyrosine kinase binding domain 3 part, and has VEGFR-1 (FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4) e3 subtypes. After being combined with VEGF, VEGFR firstly undergoes dimerization and then autophosphorylation, so that a downstream signal path is activated and the generation of vascular endothelial cells is promoted. VEGFR expression will be higher because of the massive proliferation of tumor cells requiring new blood vessels to supply nutrients and metabolism. It is combined with receptor to induce tumor angiogenesis, can promote tumor growth, and participate in tumor metastasis and drug resistance mechanism formation. The occurrence and development of solid tumors depend on a large number of new blood vessels to deliver sufficient nutrients, and abnormal increase of VEGFR expression level is found in various solid tumor tissues such as gastric cancer, colon cancer, rectal cancer, ovarian cancer, breast cancer and the like. Blocking the VEGF/NEGFR signaling pathway has therefore become a viable approach in tumor therapy.
At present, the design idea of the medicine related to the VEGFR target point is based on the aim of finally treating by inhibiting angiogenesis around tumor cells, changing the microenvironment for tumor growth, and reducing the nutrition acquisition of the tumor cells. Until now, NMPA in china has approved 11 small molecule kinase inhibitor drugs on the market, wherein 4 VEGFR target drugs are apatinib (advanced gastric cancer), aniotinib (locally advanced or metastatic non-small cell lung cancer), furoquintinib (metastatic colorectal cancer), and fulvestrant (non-pancreatic neuroendocrine tumor); VEGFR targets are implicated in 11 of the currently approved marketed drugs by FDA, respectively, midastin (acute myelogenous leukemia, mast cell leukemia), lentivatinib (differentiated thyroid cancer), nintedanib (idiopathic pulmonary fibrosis), axitinib (renal cell carcinoma), regorafenib (colorectal cancer, lung cell cancer, gastrointestinal stromal tumor), cabozantinib (renal cell carcinoma, lung cell cancer, medullary thyroid cancer), ponatinib (chronic myelogenous leukemia, acute lymphocytic leukemia), vandetanib (thyroid cancer), pazopanib (renal cell carcinoma, soft tissue sarcoma), sunitinib (renal cell carcinoma, gastrointestinal stromal tumor, pancreatic neuroendocrine tumor) and sorafenib (thyroid cancer, renal cell carcinoma). The drug resistance, the toxic and side effects and the bioavailability are not high enough to be a great obstacle on the clinical application way of the medicine taking VEGFR as the target point, so that the development of a new medicine which is different from the chemical structure of the existing marketed medicine, takes VEGFR as the target point, has clinical drug resistance and substitution and has small toxic and side effects is an urgent need in the field of treatment of malignant tumors at present.
Disclosure of Invention
In view of the above problems, the present invention aims to develop a new generation of VEGFR-targeted TRK kinase inhibitor compounds with novel structural types and better drug properties, and find that the compounds having the general formula (I) have good antitumor activity and drug absorption.
In a first aspect of the present invention, there is provided a compound represented by the general formula (I):
Figure RE-207333DEST_PATH_IMAGE001
wherein R is 1 Selected from substituted aromatic groups; r is 2 Selected from unsubstituted, mono-substituted or di-substituted aryl, substituted aryl alkyl;
preferably, R 1 The aryl is selected from phenyl; the substituent is selected from halogen substituent, C1-3 alkyl substituent;
R 2 the aryl is selected from phenyl, quinoline and quinoxaline; the alkyl is selected from methylene and methine; the substituent is selected from halogen substituent, C1-3 alkoxy, C1-3 alkoxyacylSubstituents, aminosulfoyl, trihalomethyl, amino;
further preferably, the compound having the structure of formula (I) is selected from:
Figure RE-858894DEST_PATH_IMAGE002
Figure RE-435369DEST_PATH_IMAGE003
Figure RE-564999DEST_PATH_IMAGE004
Figure RE-176109DEST_PATH_IMAGE005
Figure RE-732992DEST_PATH_IMAGE006
Figure RE-796763DEST_PATH_IMAGE007
Figure RE-730084DEST_PATH_IMAGE008
Figure RE-946433DEST_PATH_IMAGE009
Figure RE-674217DEST_PATH_IMAGE010
Figure RE-225284DEST_PATH_IMAGE011
Figure RE-962296DEST_PATH_IMAGE012
Figure RE-220102DEST_PATH_IMAGE013
Figure RE-446684DEST_PATH_IMAGE014
Figure RE-422731DEST_PATH_IMAGE015
Figure RE-494592DEST_PATH_IMAGE016
Figure RE-872483DEST_PATH_IMAGE017
Figure RE-755120DEST_PATH_IMAGE018
Figure RE-218462DEST_PATH_IMAGE019
。
in a second aspect of the invention, there is provided a pharmaceutically acceptable salt of a compound of formula (I);
wherein the salt is selected from organic acid salt or inorganic acid salt;
preferably selected from hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, oxalic acid, citric acid, tartaric acid, malic acid, trifluoroacetic acid, succinic acid, salicylic acid, benzoic acid, phenylacetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, citric acid, maleic acid.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or diluent.
In a fourth aspect of the present invention, there is provided a use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as a VEGFR inhibitory drug for treating malignant tumor, renal disease, immune system disease or circulatory system disease;
preferably as a therapeutic agent for malignant tumors.
Compared with the prior art, the invention has the beneficial effects that:
1) the compound shown in the formula (I) has a brand-new structure, is simple and easy to synthesize, and can be used as an effective VEGFR inhibitor;
2) experiments show that the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof has good antitumor activity, compared with the existing positive drugs on the market, the compound has the same or better tumor inhibition activity and positive contrast effect, has more obvious drug absorption effect, and is expected to develop a new generation of kinase inhibitor drug to avoid the defects of poor drug resistance, poor bioavailability and the like of the existing domestic drugs.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following specific examples are intended to further illustrate the invention, but the invention is in no way limited to these examples (all materials are commercially available unless otherwise indicated).
Example 1: preparation of 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid
Figure RE-94014DEST_PATH_IMAGE020
Taking 26.2g (200 mmol) of 1, 1-cyclopropane dicarboxylic acid in a 1L reaction bottle, adding 300mL of isopropyl acetate, dissolving to obtain a clear solution, and cooling the system to 0 ℃. Slowly dropwise adding 25.3g (210 mmol) of thionyl chloride into the system, recovering to room temperature after dropwise addition, and stirring for 6 hours;
dissolving 24.4g (220 mmol) of para-fluoroaniline and 22.2g (220 mmol) of triethylamine in 100mL of isopropyl acetate, dropwise adding into the system for about 1 hour, and continuously stirring for 2 hours;
TLC detects that the raw material basically completely reacts, 500mL ethyl acetate is added, the mixture is washed by 1M hydrochloric acid solution and saturated brine respectively, an organic layer is dried by anhydrous sodium sulfate, the mixture is filtered, the solvent is evaporated under reduced pressure, 500mL normal hexane is added to a residue, the mixture is beaten and stirred for 30 minutes, the filter is carried out, and a filter cake is dried to obtain 36.6g of a product (the yield is 82%).
Example 2: preparation of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-326413DEST_PATH_IMAGE021
Taking 12.9g (100 mmol) of 4-amino-2-chloropyrimidine and 26.8g (120 mmol) of 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid into a 500mL reaction bottle, adding 200mL of dichloromethane, stirring at room temperature to dissolve, further taking 28.7g (150 mmol) of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride, adding the mixture into the reaction bottle, and stirring at room temperature for 2 hours;
TLC detects that the raw material is basically completely reacted, the solvent is evaporated under reduced pressure, 100mL of methanol is added to the residue to be dissolved, 800mL of purified water is added, stirring is carried out for crystallization for 8 hours, filtration is carried out, the filter cake is washed by 20mL of purified water, and drying is carried out, thus obtaining 28.4g of the product (yield 85%).
Example 3: preparation of N- (4-fluorophenyl) -N- (2- (phenylamino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-98060DEST_PATH_IMAGE022
Taking 70mg (0.75 mmol) of aniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 152mg (yield 62%) of product;
1 H NMR（400MHz，d 6 -DMSO）:δ=9.18(m,1H), 8.23(d,1H), 7.63-51(m,4H), 7.38-7.19(m,6H), 6.76(m,1H), 4.12(s,1H), 1.03-0.85(m,4H), [M+H] + :m/z=392.6。
example 4: preparation of N- (4-fluorophenyl) -N- (2- ((4-fluorophenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-845436DEST_PATH_IMAGE023
Taking 83mg (0.75 mmol) of para-fluoroaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of para-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 144mg (yield 56%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.13(m,1H), 8.20(d,1H), 7.72-7.58(m,4H), 7.33-7.14(m,6H), 4.18(s,1H), 1.06-0.89(m,4H), [M+H] + :m/z=410。
example 5: preparation of N- (2- ((3, 4-difluorophenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-462362DEST_PATH_IMAGE024
97mg (0.75 mmol) of 3.4-difluoroaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide were put in a 100mL single-neck flask, 11mg (0.063 mmol) of p-toluenesulfonic acid was added to 30mL of N-butanol, and the mixture was refluxed and stirred for 8 hours;
TLC detecting material reaction completion, adding purified water 100mL, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove solvent, and purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 139mg (yield 52%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.22(m,1H), 8.28(d,1H), 7.69-7.55(m,4H), 7.31-7.12(m,5H), 4.22(s,1H), 1.11-0.96(m,4H), [M+H] + :m/z=428.9。
example 6: preparation of N- (4-fluorophenyl) -N- (2- ((4-bromophenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-611583DEST_PATH_IMAGE025
In a 100mL single-neck flask, 129mg (0.75 mmol) of p-bromoaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide are placed, 11mg (0.063 mmol) of p-toluenesulfonic acid is added, 30mL of N-butanol is added, heating reflux is carried out, and stirring is carried out for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 195mg (yield 66%) of the product;
1 H NMR（400MHz，d 6 -DMSO）:δ=9.13(m,1H), 8.26(d,1H), 7.66-7.58(m,4H), 7.41-7.20 (m,6H), 4.11(s,1H), 1.08-0.92(m,4H), [M+H] + :m/z=471.2。
example 7: preparation of N- (4-fluorophenyl) -N- (2- ((4-methoxyphenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-288552DEST_PATH_IMAGE026
Taking 92mg (0.75 mmol) of p-anisidine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 180mg (yield 68%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.12(m,1H), 8.20(d,1H), 7.56-7.48(m,4H), 7.31-7.10(m,6H), 4.12(s,1H), 3.85(s,3H),0.95-0.81(m,4H), [M+H] + :m/z=422.5。
example 8: preparation of N- (2- ((3, 4-dimethoxyphenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-273957DEST_PATH_IMAGE027
Taking 115mg (0.75 mmol) of 3, 4-dimethoxyaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of p-toluenesulfonic acid into a 100mL single-neck bottle, adding 30mL of N-butanol, heating for reflux, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 284mg (yield 72%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.11(m,1H), 8.18(d,1H), 7.58-7.43(m,4H), 7.30-7.12(m,3H), 6.77(m,1H),6.13(m,1H), 4.18 (s,1H), 3.95(s,6H), 0.93-0.75(m,4H), [M+H] + :m/z=452.8。
example 9: preparation of N- (2- ((3-chloro-4-fluorophenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-428995DEST_PATH_IMAGE028
Taking 109mg (0.75 mmol) of 3-chloro-4-fluoroaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of p-toluenesulfonic acid into a 100mL single-neck bottle, adding 30mL of N-butanol, heating for refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 153mg (yield 55%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.19 (m,1H), 8.26(d,1H), 7.66-7.53(m,4H), 7.32-7.16(m,5H), 4.20(s,1H), 1.05-0.86(m,4H), [M+H] + :m/z=444。
example 10: preparation of N- (4-fluorophenyl) -N- (2- ((4- (trifluoromethyl) phenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-901565DEST_PATH_IMAGE029
Taking 121mg (0.75 mmol) of 4-trifluoromethylaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of p-toluenesulfonic acid into a 100mL single-neck bottle, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 152mg (yield 62%) of the product;
1 H NMR（400MHz，d 6 -DMSO）:δ=9.14(m,1H), 8.21(d,1H), 7.66-7.51(m,4H), 7.33-7.12(m,6H), 4.09(s,1H), 1.05-0.88(m,4H), [M+H] + :m/z=460.3。
example 11: preparation of methyl 4- ((4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) pyrimidin-2-yl) amino) benzoate
Figure RE-811752DEST_PATH_IMAGE030
Taking 113mg (0.75 mmol) of methyl 4-aminobenzoate, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating for reflux, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 136mg (yield 48%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.19(m,1H), 8.26(d,1H), 7.72-7.65(m,4H), 7.45-7.29(m,6H) , 4.05(s,1H), 3.86(s,3H), 1.01-0.88(m,4H), [M+H] + :m/z=450.3。
example 12: preparation of N- (2- ((2, 3-dimethoxyphenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-471403DEST_PATH_IMAGE031
Taking 115mg (0.75 mmol) of 2, 3-dimethoxyaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of p-toluenesulfonic acid into a 100mL single-neck bottle, adding 30mL of N-butanol, heating for reflux, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 199mg (yield 70%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.14(m,1H), 8.16(d,1H), 7.53-7.41(m,4H), 7.33-7.17(m,3H), 6.72(m,1H),6.17(m,1H), 4.12 (s,1H), 3.93(s,6H), 0.983-0.77(m,4H), [M+H] + :m/z=452.6。
example 13: preparation of N- (4-fluorophenyl) -N- (2- ((4-methylphenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-492449DEST_PATH_IMAGE032
Taking 80mg (0.75 mmol) of p-methylaniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 135mg (yield 53%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.17(m,1H), 8.24(d,1H), 7.61-7.53(m,4H), 7.33-7.10(m,6H), 4.17(s,1H), 2.43(s,3H), 1.00-0.89(m,4H), [M+H] + :m/z=406.6。
example 14: preparation of N- (2-chloropyrimidin-4-yl) -N- (4-chlorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-553946DEST_PATH_IMAGE033
Taking 2.62g (20 mmol) of 1, 1-cyclopropane dicarboxylic acid into a 250 reaction flask, adding 50mL of isopropyl acetate, dissolving to obtain a clear solution, and cooling the system to 0 ℃. Slowly dropwise adding 2.535g (21 mmol) of thionyl chloride into the system, recovering to room temperature after dropwise addition, and stirring for 6 hours;
2.79g (22 mmol) of p-chloroaniline and 2.22g (22 mmol) of triethylamine are dissolved in 20mL of isopropyl acetate, and the solution is dripped into the system for about 0.5 hour, and stirring is continued for 2 hours. Detecting the basic reaction of the raw materials by TLC (thin layer chromatography), adding 50mL ethyl acetate, washing with 1M hydrochloric acid solution and saturated saline respectively, drying an organic layer by using anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove the solvent, adding 50mL n-hexane into the residue, pulping, stirring and washing for 30 minutes, filtering, and drying a filter cake to obtain 3.82g (yield 80%) of 1- ((4-chlorphenyl) carbamoyl) cyclopropane carboxylic acid;
1.29g (10 mmol) of 4-amino-2-chloropyrimidine and 2.86g (120 mmol) of 1- ((4-chlorophenyl) carbamoyl) cyclopropanecarboxylic acid were put into a 100mL reaction flask, 300mL of methylene chloride was added thereto, and the mixture was stirred at room temperature to dissolve, and 2.87g (150 mmol) of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride was added thereto and stirred at room temperature for 2 hours. TLC detects that the raw material basically reacts completely, the solvent is evaporated under reduced pressure, 30mL of methanol is added to the residue to be dissolved and cleared, 300mL of purified water is added, stirring is carried out for crystallization for 6 hours, filtering is carried out, the filter cake is washed by 10mL of purified water, and drying is carried out, thus obtaining 2.744g (yield 78%) of the product.
Example 15: preparation of N- (4-chlorophenyl) -N- (2- ((4-fluorophenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-572717DEST_PATH_IMAGE034
Taking 83mg (0.75 mmol) of para-fluoroaniline, 221mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-chlorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of para-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 163mg (yield 61%) of product;
1 H NMR（400MHz，d 6 -DMSO）:δ=9.16(m,1H), 8.25(d,1H), 7.77-7.59(m,4H), 7.34-7.17(m,6H), 4.12(s,1H), 1.02-0.87(m,4H), [M+H] + :m/z=426.9。
example 16: preparation of N- (2-chloropyrimidin-4-yl) -N- (4-bromophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-781982DEST_PATH_IMAGE035
Referring to the synthesis of example 14, N- (2-chloropyrimidin-4-yl) -N- (4-bromophenyl) cyclopropane-1, 1-dicarboxamide was synthesized.
Example 17: preparation of N- (4-bromophenyl) -N- (2- ((4-fluorophenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-544401DEST_PATH_IMAGE036
Taking 83mg (0.75 mmol) of para-fluoroaniline, 248mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-bromophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of para-toluenesulfonic acid into a 100mL single-neck bottle, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 177mg (yield 60%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.14(m,1H), 8.21(d,1H), 7.74-7.51(m,4H), 7.32-7.15(m,6H), 4.10(s,1H), 1.00-0.92(m,4H), [M+H] + :m/z=471.5。
example 18: preparation of N- (2-chloropyrimidin-4-yl) -N- (4-methylphenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-270524DEST_PATH_IMAGE037
With reference to the synthesis procedure of example 14, N- (2-chloropyrimidin-4-yl) -N- (4-methylphenyl) cyclopropane-1, 1-dicarboxamide was synthesized.
Example 19: preparation of N- (4-methylphenyl) -N- (2- ((4-fluorophenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-194618DEST_PATH_IMAGE036
83mg (0.75 mmol) of para-fluoroaniline, 208mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-methylphenyl) cyclopropane-1, 1-dicarboxamide were put into a 100mL single-neck flask, 11mg (0.063 mmol) of para-toluenesulfonic acid was added, 30mL of N-butanol was added, and the mixture was refluxed and stirred for 8 hours.
TLC detects that the reaction of the raw material is almost completed, purified water is added to 100mL, ethyl acetate (50 mL. x.3) is added for extraction, the organic phase is dried over sodium sulfate, filtered, the solvent is evaporated under reduced pressure from the filtrate, and the residue is purified by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 130mg of the product (yield 51%).
1 H NMR（400MHz，d 6 -DMSO）:δ=9.12(m,1H), 8.19 (d,1H), 7.70-7.46(m,4H), 7.26-7.11(m,6H), 4.13(s,1H), 2.44(s,3H), 1.06-0.95(m,4H), [M+H] + :m/z=406.5.
Example 20: preparation of N- (2- (benzylamino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-891179DEST_PATH_IMAGE038
Taking 80mg (0.75 mmol) of benzylamine, 208mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of p-toluenesulfonic acid and 30mL of N-butanol into a 100mL single-neck bottle, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 207mg (yield 81%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.17(m,1H), 8.19 (d,1H), 7.75-7.49(m,5H), 7.24-7.15(m,6H), 4.38(s,2H), 4.03(s,1H), 1.02-0.96(m,4H), [M+H] + :m/z=406.3。
example 21: preparation of N- (2- ((4-fluorobenzyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-191710DEST_PATH_IMAGE039
Taking 94mg (0.75 mmol) of p-fluorobenzylamine, 208mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butyl alcohol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 208mg (yield 78%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.12(m,1H), 8.16 (d,1H), 7.71-7.42(m,4H), 7.22-7.11(m,6H), 4.34(s,2H), 4.07(s,1H), 1.06-0.98(m,4H), [M+H] + :m/z=424.3。
example 22: preparation of N- (4-fluorophenyl) -N- (2- ((1- (4-fluorophenyl) ethyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-493378DEST_PATH_IMAGE040
Taking 104mg (0.75 mmol) of 4-fluoro-alpha-methylbenzylamine, 208mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating for reflux, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 332mg (yield 76%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.17(m,1H), 8.19 (d,1H), 7.75-7.48(m,4H), 7.26-7.15(m,6H), 4.32(m,1H), 4.08(s,1H), 1.28(d,3H), 1.06-0.98(m,4H), [M+H] + :m/z=438.5。
example 23: preparation of N- (2- ((3, 4-difluorobenzyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-650690DEST_PATH_IMAGE041
Taking 107mg (0.75 mmol) of 3, 4-difluorobenzylamine, 208mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, adding 11mg (0.063 mmol) of p-toluenesulfonic acid into a 100mL single-neck bottle, adding 30mL of N-butanol, heating for refluxing, and stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent: ethyl acetate: petroleum ether =1: 8) to obtain 231mg (yield 83%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.17(m,1H), 8.19 (d,1H), 7.73-7.48(m,4H), 7.26-7.14(m,5H), 4.38(s,2H), 4.05(s,1H), 1.01-0.90(m,4H), [M+H] + :m/z=442.3。
example 24: preparation of N- (4-fluorophenyl) -N- (2- ((4-sulfamoylphenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-772230DEST_PATH_IMAGE042
Taking 129mg (0.75 mmol) of 4-aminobenzenesulfonamide, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 121mg (yield 41%);
1 H NMR（400MHz，d 6 -DMSO）:δ=9.17(m,1H), 8.23(d,1H), 7.76-7.57(m,4H), 7.36-7.19(m,6H), 4.14(s,1H), 2.05(s,2H), 1.02-0.87(m,4H), [M+H] + :m/z=471.5。
example 25: preparation of N- (2- ((4-bromo-2-fluorophenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-938769DEST_PATH_IMAGE043
Taking 142mg (0.75 mmol) of 4-bromo-2-fluoroaniline and 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating for refluxing, and stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 194mg (yield 63%) of the product;
1 H NMR（400MHz，d 6 -DMSO）: δ=9.17 (m,1H), 8.23(d,1H), 7.69-7.56(m,4H), 7.37-7.14(m,5H), 4.23(s,1H), 1.01-0.89(m,4H), [M+H] + :m/z=489.6。
example 26: preparation of N- (2- ((6, 7-dimethoxyquinolin-4-yl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-563785DEST_PATH_IMAGE044
153mg (0.75 mmol) of 6, 7-dimethoxyquinolin-4-amine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide are placed in a 100mL single-neck flask, 11mg (0.063 mmol) of p-toluenesulfonic acid is added, 30mL of N-butanol is added, heating reflux is carried out, and stirring is carried out for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 142mg (yield 45%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.14(m,1H), 8.16(d,1H), 7.53-7.41(m,4H), 7.33-7.17(m,3H), 6.72(m,1H),6.17(m,1H), 4.12 (s,1H), 3.93(s,6H), 0.983-0.77(m,4H), [M+H] + :m/z=503.6。
example 27: preparation of 6-aminoquinoxaline
Figure RE-360840DEST_PATH_IMAGE045
Taking 10g (65.3 mmol) of 4-nitrobenzene-1, 2-diamine in a 250mL reaction bottle, adding 100mL of ethanol, dissolving to obtain a clear solution, taking 4.55g (78.4 mmol) of glyoxal, adding the glyoxal into the system, refluxing at 80 ℃, and stirring for 12 hours. TLC detection is carried out on the raw materials, the reaction is basically complete, the raw materials are filtered, and a filter cake is dried to obtain 10.5g of an intermediate;
and (3) taking 10.5g of the intermediate into a 500mL single-neck bottle, adding 120mL of methanol, dissolving to obtain a clear solution, adding 1.05g of Pd/C, stirring at room temperature for 12 hours under a hydrogen atmosphere, and completely reacting. The mixture was filtered, and the solvent was distilled off from the filtrate to obtain 8g of a solid, which was used directly in the next reaction.
Example 28: preparation of N- (4-fluorophenyl) -N- (2- (quinoxalin-6-ylamino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-517146DEST_PATH_IMAGE046
Taking 109mg (0.75 mmol) of 6-aminoquinoxaline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck flask, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating under reflux, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 136mg (yield 49%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.18(m,1H), 8.76(s,2H), 8.12(d,1H), 7.53-7.46(m,2H), 7.33-7.22(m,3H),7.05-6.89(m,2H), 6.72-6.65(m,2H), 4.19 (s,1H), 0.93-0.76(m,4H), [M+H] + :m/z=444.8.
example 29: preparation of N- (2- ((2, 3-dimethoxyquinoxalin-6-yl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-425059DEST_PATH_IMAGE047
Taking 154mg (0.75 mmol) of 2, 3-dimethoxy-6-aminoquinoxaline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating for refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 136mg (yield 43%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.16(m,1H), 8.17(d,1H), 7.56-7.47(m,2H), 7.36-7.28(m,3H),7.02-6.84(m,2H), 6.71-6.62(m,2H), 4.18(s,6H), 4.03 (s,1H), 0.96-0.77(m,4H), [M+H] + :m/z=504.8。
example 30: preparation of 6-amino-3-methylquinoline-2-carboxylic acid ethyl ester
Figure RE-232478DEST_PATH_IMAGE048
Taking 10g (65.3 mmol) of 4-nitrobenzene-1, 2-diamine and 11.8g (71.8 mmol) of ethyl 2-chloroacetoacetate into a 250mL reaction bottle, adding 50mL of 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid, and stirring at room temperature for 1 hour;
TLC detecting raw material reaction completely, adding ether (150 mL x 3) for extraction, concentrating organic phase, and purifying residue column chromatography (eluent is ethyl acetate: petroleum ether =1: 10) to obtain 15.3g nitro compound;
15.3g of the intermediate is put into a 500mL single-neck bottle, 120mL of methanol is added to dissolve the intermediate to obtain a clear solution, 1.53g of Pd/C1.53g is added, and the mixture is stirred for 12 hours at room temperature under the atmosphere of hydrogen to react completely. After filtration, the solvent was distilled off from the filtrate to obtain 12.8g of a solid, which was used in the next reaction.
Example 31: preparation of ethyl 6- ((4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) pyrimidin-2-yl) amino) -3-methylquinoline-2-carboxylate
Figure RE-934855DEST_PATH_IMAGE049
In a 100mL single vial, 173mg (0.75 mmol) of 6-amino-3-methylquinoline-2-carboxylic acid ethyl ester, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide were charged with 11mg (0.063 mmol) of p-toluenesulfonic acid, 30mL of N-butanol was added, and the mixture was refluxed and stirred for 8 hours;
TLC detecting the material reaction is complete, adding purified water 100mL, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 157mg (yield 47%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.13(m,1H), 8.15(d,1H), 7.62-7.54(m,2H), 7.39-7.31(m,3H),7.12-6.95(m,2H), 6.76-6.65(m,2H), 4.53(m,2H), 4.03 (s,1H), 2.66(s,3H), 1.32(t,3H), 0.96-0.77(m,4H), [M+H] + :m/z=530.2。
example 32: preparation of 6-amino-3- (trifluoromethyl) quinoxaline-2-carboxylic acid ethyl ester
Figure RE-827725DEST_PATH_IMAGE050
Referring to the synthesis method of example 30, 6-amino-3- (trifluoromethyl) quinoxaline-2-carboxylic acid ethyl ester was synthesized.
Example 33: preparation of ethyl 6- ((4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) pyrimidin-2-yl) amino) -3- (trifluoromethyl) quinoline-2-carboxylate
Figure RE-273750DEST_PATH_IMAGE051
Taking 214mg (0.75 mmol) of 6-amino-3- (trifluoromethyl) quinoxaline-2-carboxylic acid ethyl ester, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating for refluxing, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 154mg (yield 42%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.15(m,1H), 8.19(d,1H), 7.69-7.57(m,2H), 7.41-7.37(m,3H),7.16-6.98(m,2H), 6.72-6.63(m,2H), 4.55(m,2H), 4.09 (s,1H), 1.38(t,3H), 0.99-0.76(m,4H), [M+H] + :m/z=584.2。
example 34: preparation of 6-amino-3- (trifluoromethyl) quinoxalin-2 (1H) -one
Figure RE-935675DEST_PATH_IMAGE052
20g (0.19mol) of o-phenylenediamine, 34.8g (0.2mol) of ethyl trifluoroacetate, and 200mL of toluene were put in a 500mL single-neck flask and stirred at room temperature for 1 hour. Decompressing and rotary evaporating to remove the solvent, pulping the residue by using normal hexane, filtering, and drying the filter cake to obtain 39.1g, which is directly used for the next reaction;
in a 1L single-neck flask, 39.1g of the solid obtained in the previous step was placed, and 100mL of concentrated sulfuric acid was added thereto at room temperature, and 27.6g (0.27mol) of potassium nitrate was added thereto, followed by stirring for 15 minutes, heating to 50 ℃ and stirring for 2 hours, and then returning to room temperature and stirring for 24 hours. After the reaction, carefully pouring the mixture onto crushed ice, continuously stirring, filtering, and drying a filter cake to obtain 38.8g of solid which is directly used for the next reaction;
and (3) putting 38.8g of the solid in the last step into a 1L single-neck bottle, adding 350mL of methanol, dissolving to obtain a clear solution, adding 3.9g of Pd/C, and stirring at room temperature for 12 hours under a hydrogen atmosphere to completely react. Filtration was carried out, and the solvent was distilled off from the filtrate to obtain 31.2g of a solid, which was used in the next reaction.
Example 35: preparation of N- (4-fluorophenyl) -N- (2- ((2-oxo-3- (trifluoromethyl) -1, 2-dihydroquinolin-6-yl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-808953DEST_PATH_IMAGE053
Taking 172mg (0.75 mmol) of 6-amino-3- (trifluoromethyl) quinoxalin-2 (1H) -one, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck flask, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating for reflux, and stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 152mg (yield 46%);
1 H NMR（400MHz，d 6 -DMSO）: δ=9.18(m,1H), 8.14(d,1H), 8.03(s,1H), 7.64-7.55(m,2H), 7.45-7.33(m,3H),7.13-6.95(m,2H), 6.76-6.64(m,2H), 4.05 (s,1H), 0.96-0.78(m,4H), [M+H] + :m/z=528.2。
example 36: preparation of N- (2- ((4-acrylamidophenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-392381DEST_PATH_IMAGE054
Taking 81mg (0.75 mmol) of p-phenylenediamine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting raw material reaction completely, adding purified water 100mL, adding ethyl acetate (50 mL x 3) for extraction, drying organic phase with sodium sulfate, filtering, evaporating filtrate under reduced pressure to remove solvent, and purifying residue column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 169mg of product;
dissolving the intermediate in 50mL of dichloromethane in a 100mL single-neck bottle, adding 108mg (0.83mmol) of DIEA, cooling to 0 ℃, dissolving 42mg (0.46mmol) of acryloyl chloride in 10mL of dichloromethane, slowly dropwise adding the mixture into the system, continuing stirring for 1 hour, returning to the room temperature, and stirring for 3 hours. TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 65mg (yield 34%) of the product;
1 H NMR（400MHz，d 6 -DMSO）: δ=10.25(s,1H), 9.12 (m,1H), 8.21(d,1H), 7.64-7.55(m,2H), 7.45-7.33(m,3H),7.13-6.95(m,2H), 6.76-6.64(m,3H),6.48(m,1H), 6.06(m,1H), 5.73(m,1H), 4.07 (s,1H), 0.93-0.72(m,4H)，[M+H] + :m/z=461.8。
example 37: preparation of N- (2- ((4- ((2-aminoethyl) amino) phenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-189567DEST_PATH_IMAGE055
Taking 81mg (0.75 mmol) of p-phenylenediamine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide into a 100mL single-neck bottle, adding 11mg (0.063 mmol) of p-toluenesulfonic acid, adding 30mL of N-butanol, heating and refluxing, and stirring for 8 hours;
TLC detecting raw material reaction completely, adding purified water 100mL, adding ethyl acetate (50 mL x 3) for extraction, drying organic phase with sodium sulfate, filtering, evaporating filtrate under reduced pressure to remove solvent, and purifying residue column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain product 168 mg;
the intermediate was dissolved in 20mL of DMF in a 100mL single-neck flask, and 115mg (0.83mmol) of potassium carbonate was added thereto, and 57mg (0.46mmol) of 2-bromoethylamine was added thereto, followed by stirring at 90 ℃ for 6 hours. TLC detecting the material reaction is completed, adding purified water 150mL, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 70mg (yield 37%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.16 (m,1H), 8.22(d,1H), 7.66-7.52(m,2H), 7.47-7.36(m,3H),7.15-6.97(m,2H), 6.76-6.65(m,3H), 5.13(s,1H), 4.07 (s,1H), 3.45(m,2H), 2.70(m,2H), 0.98-0.75(m,4H)，[M+H] + :m/z=450.6。
example 38: n is a radical of 1 - (2- (dimethylamino) ethyl) -3-methoxy-N 1 Preparation of (E) -toluene-1, 4-diamine
Figure RE-909261DEST_PATH_IMAGE056
Taking 10g (58mmol) of 5-fluoro-2-nitrobenzyl ether in a 250mL single-neck bottle, adding DMF100mL, adding potassium carbonate 16g (117 mmol), adding N, N, N' -trimethylethylenediamine 8.9g (87mmol) into the single-neck bottle, stirring for 6 hours at 90 ℃, detecting that the raw materials are basically completely reacted by TLC, dropwise adding the solution into 800mL of water, generating precipitates, filtering, drying a filter cake, and directly using the filter cake for the next reaction;
taking 12.9g (51mmol) of the intermediate in the previous step, adding 200mL of methanol into a 500mL single-mouth bottle, dissolving a clear solution, adding 1.3g of palladium-carbon catalyst into the bottle, stirring for 12 hours at room temperature under hydrogen atmosphere, detecting by TLC that the raw materials are basically completely reacted, filtering, concentrating and drying the filtrate, and directly using the filtrate in the next reaction.
Example 39: preparation of N- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-15758DEST_PATH_IMAGE057
167mg (0.75 mmol) of N are taken 1 - (2- (dimethylamino) ethyl) -3-methoxy-N 1 -toluene-1, 4-diamine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide in a 100mL single-neck flask, 11mg (0.063 mmol) of p-toluenesulfonic acid, 30mL of N-butanol, heating under reflux, stirring for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 184mg (yield 56%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.14 (m,1H), 8.18 (d,1H), 7.62-7.54(m,2H), 7.42-7.33(m,3H),7.14-7.02(m,2H), 6.23-6.09(m,2H), 4.07 (s,1H), 3.88(s,3H), 3.46(m,2H), 2.73(s,3H), 2.52(m,2H), 2.21(s,6H), 0.95-0.77(m,4H), [M+H] + :m/z=522.8。
example 40: n is a radical of 1 - (2- (dimethylamino) ethyl) -N 1 Preparation of (E) -toluene-1, 4-diamine
Figure RE-820903DEST_PATH_IMAGE058
Reference example 38 synthetic route to substitute 5-fluoro-2-nitrobenzyl ether for p-fluoronitrobenzene Synthesis of N 1 - (2- (dimethylamino) ethyl) -N 1 -toluene-1, 4-diamine.
Example 41: preparation of N- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-874309DEST_PATH_IMAGE059
145mg (0.75 mmol) of N are taken 1 - (2- (dimethylamino) ethyl) -N 1 -toluene-1, 4-diamine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide in a 100mL single-neck flask, 11mg (0.063 mmol) of p-toluenesulfonic acid and 30mL of N-butanol are added, the mixture is heated under reflux and stirred for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 179mg (yield 58%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.15 (m,1H), 8.15 (d,1H), 7.66-7.55(m,2H), 7.47-7.35(m,3H),7.17-7.06(m,2H), 6.26-6.04(m,3H), 4.04 (s,1H), 3.43(m,2H), 2.74(s,3H), 2.54(m,2H), 2.25(s,6H), 0.96-0.75(m,4H)， [M+H] + :m/z=492.8。
example 42: preparation of phenyl-4-dimethylpiperidin-4-aminopiperidine
Figure RE-510827DEST_PATH_IMAGE060
Referring to the synthetic route of example 38, phenyl-4-dimethylpiperidin-4-aminopiperidine was synthesized by replacing N, N, N' -trimethylethylenediamine with 4-dimethylaminopiperidine.
Example 43: preparation of N- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-725908DEST_PATH_IMAGE061
In a 100mL single-neck flask, 165mg (0.75 mmol) of phenyl-4-dimethylpiperidine-4-aminopiperidine and 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide are placed, 11mg (0.063 mmol) of p-toluenesulfonic acid are added, 30mL of N-butanol is added, and the mixture is heated under reflux and stirred for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 166mg (yield 51%) of product;
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.16 (m,1H), 8.19 (d,1H), 7.61-7.52(m,2H), 7.43-7.34(m,3H),7.14-7.01(m,2H), 6.36-6.14(m,3H), 4.08 (s,1H), 3.05(m,4H), 2.71(m,1H), 2.22(s,6H), 1.71(m,4H), 0.96-0.75(m,4H)， [M+H] + :m/z=518.8。
example 44: preparation of 4- (4-methylpiperazine) aniline
Figure RE-815086DEST_PATH_IMAGE062
Referring to the synthetic route of example 42, 4- (4-methylpiperazine) aniline was synthesized by replacing 4-dimethylaminopiperidine with N-methylpiperazine.
Example 45: preparation of N- (4-fluorophenyl) -N- (2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-406605DEST_PATH_IMAGE063
In a 100mL single-neck flask, 143mg (0.75 mmol) of 4- (4-methylpiperazine) aniline, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide were placed, 11mg (0.063 mmol) of p-toluenesulfonic acid was added, 30mL of N-butanol was added, and the mixture was refluxed and stirred for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 148mg (yield 48%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.18 (m,1H), 8.15 (d,1H), 7.64-7.55(m,2H), 7.47-7.35(m,3H),7.14-7.03(m,2H), 6.35-6.13(m,3H), 4.04 (s,1H), 3.52(m,4H), 2.38(m,4H), 2.21(s,3H), 0.93-0.74(m,4H), [M+H] + :m/z=490.8。
example 46: preparation of 1- (4- (4-aminophenyl) piperazin-1-yl) prop-2-en-1-one
Figure RE-648361DEST_PATH_IMAGE064
Taking 10g (71mmol) of p-fluoronitrobenzene into a 250mL single-neck bottle, adding DMF100mL, adding potassium carbonate 19.5g (142 mmol), adding N-Cbz piperazine 23.4g (106mmol), stirring for 6 hours at 90 ℃, detecting that the raw materials are basically completely reacted by TLC, dropwise adding the solution into 800mL of water, generating precipitate, filtering, drying filter cakes, and directly using the solution in the next reaction;
taking 23g (67mmol) of the intermediate in the previous step, adding 200mL of methanol into a 500mL single-neck flask, dissolving the clear solution, adding 1.3g of palladium carbon catalyst into the solution, stirring the solution at room temperature for 12 hours under hydrogen atmosphere, detecting that the raw materials are basically completely reacted by TLC, filtering, concentrating and drying the filtrate to obtain an intermediate product, dissolving 200mL of carbon dichloride into the 500mL single-neck flask, cooling the solution to 0 ℃, taking 14.7g (67mmol) of Boc anhydride, dissolving the Boc anhydride into 50mL of dichloromethane, dropwise adding the Boc anhydride into the system, and stirring the Boc anhydride at room temperature after dropwise adding. TLC detection shows that the raw material has basically complete reaction, the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography (eluent is ethyl acetate: petroleum ether =1: 3) to obtain 24.7g (yield 90%);
adding 24.7g (60mmol) of intermediate into a 500mL single-neck flask, adding 200mL of methanol, dissolving to obtain a clear solution, adding 2.5g of palladium-carbon catalyst into the clear solution, stirring at room temperature for 12 hours under hydrogen atmosphere, detecting that raw materials are basically completely reacted by TLC, filtering, concentrating and drying filtrate to obtain an intermediate product, dissolving 200mL of carbon dichloride into the 500mL single-neck flask, adding 11.6g (90mmol) of DIEA, cooling to 0 ℃, dissolving 5.9g (66mmol) of acryloyl chloride into 20mL of dichloromethane, slowly dropwise adding the mixture into the system, continuously stirring for 1 hour, recovering to room temperature, and stirring for 3 hours. TLC detecting the material was almost completely reacted, adding 500mL of purified water, extracting with ethyl acetate (50 mL. times.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent: ethyl acetate: petroleum ether =1: 4) to obtain 17.1g of intermediate product (yield 86%);
17.1g (52mmol) of the intermediate was put in a 500mL single-neck flask, 200mL of a methanol hydrochloride solution was added, the mixture was stirred at room temperature for 2 hours, TLC was used to detect that the starting material had substantially reacted completely, the solvent was distilled off under reduced pressure, and methylene chloride (100 mL. times.3) was added over and evaporated to give 11.9g of 1- (4- (4-aminophenyl) piperazin-1-yl) prop-2-en-1-one, which was used directly in the next reaction.
Example 47: preparation of N- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-34343DEST_PATH_IMAGE065
In a 100mL single vial was taken 173mg (0.75 mmol) of 1- (4- (4-aminophenyl) piperazin-1-yl) prop-2-en-1-one, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, 11mg (0.063 mmol) of p-toluenesulfonic acid was added, 30mL of N-butanol was added, and the mixture was refluxed and stirred for 8 hours;
TLC detecting the material was almost completely reacted, adding 100mL of purified water, extracting with ethyl acetate (50 mL. x.3), drying the organic phase with sodium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, and purifying by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 163mg (yield 49%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.15 (m,1H), 8.20(d,1H), 7.72-7.62(m,2H), 7.51-7.38(m,3H),7.21-7.02(m,2H), 6.88-6.73(m,3H),6.38(m,1H), 6.08(m,1H), 5.66(m,1H), 4.07 (s,1H), 3.34(m,8H), 0.93-0.72(m,4H)， [M+H] + :m/z=530.5。
example 48: preparation of 5- (4-methylpiperazin-1-yl) pyridin-2-amine
Figure RE-876397DEST_PATH_IMAGE066
Reference example 44 synthetic route to 5- (4-methylpiperazin-1-yl) pyridin-2-amine was synthesized substituting p-fluoronitrobenzene with 5-fluoro-2 nitropyridine.
Example 49: preparation of N- (4-fluorophenyl) -N- (2- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) pyrimidin-4-yl) cyclopropane-1, 1-dicarboxamide
Figure RE-271607DEST_PATH_IMAGE067
144mg (0.75 mmol) of 5- (4-methylpiperazin-1-yl) pyridin-2-amine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide were put in a 100mL single-neck flask, 11mg (0.063 mmol) of p-toluenesulfonic acid was added to 30mL of N-butanol, and the mixture was refluxed and stirred for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 98mg (yield 32%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.21 (m,1H), 8.22 (d,1H), 7.73-7.65(m,2H), 7.51-7.46(m,3H),7.22-7.13(m,2H), 6.33-6.25(m,2H), 4.12 (s,1H), 3.61(m,4H), 2.46(m,4H), 2.29(s,3H), 0.99-0.78(m,4H)， [M+H] + :m/z=491.3。
example 50: n is a radical of 5 - (2- (dimethylamino) ethyl) -N 5 Preparation of (E) -methylpyridine-2, 5-diamine
Figure RE-554820DEST_PATH_IMAGE068
Reference example 40 synthetic route, willSubstituting fluoronitrobenzene with 5-fluoro-2-nitropyridine to synthesize N 5 - (2- (dimethylamino) ethyl) -N 5 -picoline-2, 5-diamine.
Example 51: preparation of N- (2- ((5- ((2- (dimethylamino) ethyl) (methyl) amino) pyridin-2-yl) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-439600DEST_PATH_IMAGE069
Take 146mg (0.75 mmol) N 5 - (2- (dimethylamino) ethyl) -N 5 -picoline-2, 5-diamine, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide in a 100mL single-neck flask, 11mg (0.063 mmol) of p-toluenesulfonic acid, 30mL of N-butanol, heating under reflux, and stirring for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 108mg (yield 35%);
1 H NMR（400MHz，d 6 -DMSO）: δ= 9.19 (m,1H), 8.22 (d,1H), 7.53-7.46(m,2H), 7.35-7.26(m,3H),7.10-7.03(m,2H), 6.25-6.14(m,2H), 4.08 (s,1H), 3.52(m,2H), 2.66(s,3H), 2.34(m,2H), 2.15(s,6H), 0.93-0.72(m,4H)， [M+H] + :m/z=493.2。
example 52: preparation of N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide
Figure RE-441054DEST_PATH_IMAGE070
Taking 10g (58mmol) of 5-fluoro-2-nitrobenzyl ether in a 500mL single-neck bottle, adding 100mL of methanol, dissolving clear liquid, taking 1.0g of palladium carbon catalyst, adding the palladium carbon catalyst, stirring at room temperature for 12 hours under hydrogen atmosphere, detecting raw materials by TLC to basically completely react, filtering, concentrating and drying filtrate to obtain an intermediate product, adding 50mL of concentrated sulfuric acid in the 500mL single-neck bottle, cooling to-10 ℃, taking 20mL of concentrated nitric acid, slowly adding the concentrated nitric acid, stirring at low temperature for 2 hours, stirring at room temperature for 1 hour, pouring into crushed ice, quickly stirring at the same time, filtering, drying filter cakes to obtain 8.9g of nitro compounds;
and (3) taking 8.9g (48mmol) of the intermediate in the previous step, adding 200mL of carbon dichloride into a 500mL single-neck flask, cooling to 0 ℃, further taking 10.5g (48mmol) of Boc anhydride, dissolving in 50mL of dichloromethane, dropwise adding into the system, and stirring at room temperature after dropwise addition. TLC detection shows that the raw material has basically complete reaction, the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography (eluent is ethyl acetate: petroleum ether =1: 3) to obtain 13.1g of product (yield 95%);
taking 13.1g (46mmol) of intermediate into a 500mL single-neck bottle, adding DMF200mL, adding potassium carbonate 12.7g (92 mmol), adding N, N, N' -trimethylethylenediamine 5.2g (51mmol) into the single-neck bottle, stirring for 6 hours at 90 ℃, detecting that the raw materials are basically completely reacted by TLC, dropwise adding the solution into 800mL of water, generating precipitate, filtering, drying the filter cake, and directly using the solution for the next reaction;
taking 14.9g (38mmol) of the intermediate in the previous step, putting the intermediate in a 500mL single-neck flask, adding 150mL of methanol, dissolving to obtain a clear solution, adding 1.5g of palladium-carbon catalyst, stirring for 12 hours at room temperature under hydrogen atmosphere, detecting raw materials by TLC to basically completely react, filtering, concentrating and drying filtrate to obtain an intermediate product, dissolving 200mL of carbon dichloride in the 500mL single-neck flask, adding DIEA7.5g (58mmol), cooling to 0 ℃, dissolving 4.1g (46mmol) of acryloyl chloride in 20mL of dichloromethane, slowly dropwise adding the intermediate product into the system, continuing stirring for 1 hour, recovering to room temperature, and stirring for 3 hours. TLC detecting the material reaction is almost completed, adding purified water 500mL, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 4) to obtain 11.6g of intermediate product (yield 78%);
11.6g (52mmol) of the intermediate in the previous step was taken in a 500mL single-neck flask, 200mL of a methanol solution of hydrochloric acid was added, the mixture was stirred at room temperature for 2 hours, TLC was used to detect the completion of the reaction of the starting material, the solvent was distilled off under reduced pressure, and methylene chloride (100 mL. times.3) was used for multiple double-distilling to obtain 11.9g of N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, which was used directly in the next reaction.
Example 53: preparation of N- (2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure RE-436692DEST_PATH_IMAGE071
In a 100mL single vial with 219mg (0.75 mmol) of N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 210mg (0.63 mmol) of N- (2-chloropyrimidin-4-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, 11mg (0.063 mmol) of p-toluenesulfonic acid was added, 30mL of N-butanol was added, heating was refluxed, and stirred for 8 hours;
TLC detecting the material reaction is complete, adding 100mL purified water, adding ethyl acetate (50 mL x 3) for extraction, drying the organic phase with sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent, purifying the residue by column chromatography (eluent is ethyl acetate: petroleum ether =1: 8) to obtain 204mg (yield 55%);
1 H NMR（400MHz, d 6 -DMSO）: δ= 10.23(s,1H), 9.12 (m,1H), 8.16(d,1H), 7.81-7.74(m,2H), 7.58-7.50(m,2H),7.28-7.06(m,2H), 6.65-6.52(m,2H), 6.39-6.13(m,2H), 6.08(m,1H), 4.01 (s,1H), 3.82(s,3H), 3.51(m,2H), 2.78(s,3H), 2.52(m,2H), 2.19(s,6H), 0.96-0.74(m,4H), [M+H] + :m/z=591.5。
biological evaluation
Example 54: kinase assays for Compounds of the invention
1. Materials and reagents
SpectraMax Id5 Multi-Mode Reader (Molecular Devices)
White 384-well MicroPlate(Cat#264706,Nunc)
The HTRF kinEASE TK kit contains the main reagents (Cat #62 TKOPEC)
VEGFR (Cat# RP-75749, Invitrogen)
FGFR2(Cat# PV3368, Thermo)
ATP Solution 10 mM(Cat# AM-8110G, Invitrogen)
DTT 1mM(Cat#D5545,Sigma)
MgCl 2 1M(Cat#M1028,Sigma)
Test Compounds of the invention
Positive control: NVP-ACC 789.
2. Reagent preparation
TABLE 1 reaction System Components and concentrations of kinase
Figure RE-574412DEST_PATH_IMAGE072
1×Enzymatic Buffer:
1 Xenzyme buffer
200ul 5×Enzyme buffer、5ul 1M MgCl 2 25ul of 2500nM SEB, 1ul of DTT, 2ul of 2500nM supplementary enzyme buffer and 767ul of ddH 2 Preparation of O
5 × Substrate-TK and ATP working solution
The specific concentrations of Substrate-TK and ATP are shown in Table 1.
Dilution of Substrate-TK and ATP with 1 XKinase Buffer to 5-fold the reaction concentration;
5X enzyme working solution
The concentration optimization of the enzyme is completed in the previous work, the required concentration is shown in table 1, and 1 XKinase Buffer is used for preparing 5 Xenzyme working solution;
4 xStreptavidin-XL 665 working solution
The concentration of Sa-XL665 in the reaction is shown in Table 1, and a Detection Buffer is used for preparing a 4 × Streptavidin-XL665 working solution;
4 xTK Antibody-cryptate working solution
TK Antibody-cryptate was diluted 100-fold with Detection Buffer as working solution.
3. Experimental procedure
After all reagents are prepared according to the method, except for the enzyme, the sample is added after the temperature is balanced to the room temperature;
first, a 2.5% DMSO solution is prepared by using a prepared 1 XKinase Buffer (the DMSO concentration is too high to affect the reaction, and the final concentration of the DMSO is controlled to be 1%), then a test compound is diluted by using the 2.5% DMSO solution, and the screening concentration of the compound is diluted by 3-fold gradient from 10Um, and the concentration is 10. Except for the control wells, 4ul of diluted test compound solution was added to all reaction wells, and 4ul of 2.5% DMSO solution was added to the control wells;
2ul TK-biotin substrate solution was added to all reaction wells;
adding 2ul of the previously prepared enzyme solution to all reaction wells except the negative well, and adding 2ul of 1 XKinase Buffer to the negative well;
adding 2ul ATP solution into all reaction holes to start kinase reaction;
the preparation of the test solution was started 5 minutes after the completion of the kinase reaction. Using Detection Buffer in the kit to prepare Streptavidin-XL665 and TK Antibody-cryptate;
after the kinase reaction is finished, adding 5ul of diluted Streptavidin-XL665 into all reaction holes, uniformly mixing, and immediately adding diluted TK Antibody-cryptate detection liquid;
the plates were mixed well and reacted at room temperature for 1h, after which time the fluorescence signal was detected using a SpectraMax Id5 Multi-Mode Reader instrument (340 nm stimulation, 665nm, 620nm emission). Calculating the inhibition rate of each well through the activity of the whole well and the background signal well, averaging the multiple wells, and simultaneously performing half inhibition activity (IC) on each compound to be tested 50 ) Fitting.
4. Data analysis
Figure RE-833355DEST_PATH_IMAGE073
。
5. Results of the experiment
1) VEGFR half inhibitory concentration IC of the compounds of the invention Using HTRF kinEASE-TK kit 50 The results are shown below (1000 nm < + + + +; 500nm < + + + ≦ 1000 nm; 100nm < + + ≦ 500 nm; 0.1nm < + + ≦ 100 nm):
TABLE 2 measurement of the half inhibitory concentration of VEGFR by the Compounds of the present invention Using HTRF kinEASE-TK kit
Figure RE-872505DEST_PATH_IMAGE075
2) Detection of half inhibitory concentration IC of the inventive Compounds on FGFR2 Using HTRF kinEASE-TK kit 50 The results are shown below:
TABLE 3 half inhibitory concentration of the compounds of the invention on FGFR2 using HTRF kinEASE-TK kit
Figure RE-609517DEST_PATH_IMAGE076
Example 55: in vitro cell testing of Compounds of the invention
1. Material
Cell lines:
a549 human non-small cell lung cancer cell strain is from cell bank of Chinese academy of sciences
The LNCap human prostate cancer cell comes from the cell bank of Chinese academy of sciences
22RV1 human prostate cancer cell from Chinese academy of sciences cell bank
Reagents and consumables:
cell viability detection kit by CellTiter-Lumi cell-luminescence method
384 well cell culture plate (Cat #3765 Corning)
Fetal bovine serum (Cat #10099141 gibco)
Culture medium (gibco)
Test samples: NVP-ACC789, I-22, I-34, I-47, I-49, I-51.
2. Reagent preparation
TABLE 4 preparation of the culture Medium
Figure RE-929640DEST_PATH_IMAGE077
Preparation of test samples:
the compound was dissolved in DMSO at 5mM and stored at-80 ℃ until use
3、IC 50 Cell viability assay protocol
1) Collecting cells in logarithmic growth phase, counting, suspending the cells with complete culture medium, adjusting the concentration of the cells to be proper, inoculating a 384-pore plate, adding 40 uL of phosphate buffer salt solution into peripheral pores of the 384-pore plate, and respectively adding 36 uL of cell suspension to be detected into other pores of each plate. The 384 cell plates were then placed in a carbon dioxide incubator overnight for culture. Observing the growth condition of the cells under a microscope, and taking pictures and archiving;
2) carrying out gradient dilution on the compounds to be detected, adding each compound dilution or 10 concentration gradients into a 384-pore plate according to 4 ul/pore, starting the final concentration of the compound acting from 1uM, carrying out 3-time gradient dilution, totaling 10 concentration points, and repeating each concentration three times;
3) placing the cell plate in a carbon dioxide incubator to culture for 72h at 37 ℃ and 5% CO 2 Concentration;
4) adding 40 uL/hole CellTiter-Lumi ™ cell activity detection reagent by a luminescence method into a cell plate, and oscillating for 10 minutes in a dark place at room temperature to stabilize luminescent signals;
5) chemiluminescence detection was performed using a SpectraMax Id5 Multi-Mode Reader, and the inhibition was calculated from the chemiluminescence intensity.
4. Data analysis
Inhibition rate of drug on tumor cell growth = (A) C -A S ）/A C *100%
A C Chemiluminescence intensity of negative control
A S Chemiluminescence intensity of sample
IC using software 50 Curve fitting and calculating IC 50 The value is obtained.
5. Results of the experiment
This experiment tested 6 compounds against 3 cell lines, with a final concentration of compounds from 1uM to 0.01nM, diluted in a three-fold gradient, totaling 10 points. The following table shows the IC of each compound in different cell lines 50 (nM) value:
TABLE 5 inhibition of A549, LNCap and 22RV1 tumor cell strains by the compounds of the present invention
Figure RE-93905DEST_PATH_IMAGE078
Preliminary drug activity research shows that the compound has good inhibitory activity on VEGFR, the effect of the compound is equivalent to or even better than that of a positive control, and the compound also has potential FGFR2 inhibitory activity. In conclusion, the compound has potential medicinal value and wide marketization prospect, and is expected to become a new antitumor drug.

Claims (8)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure 692196DEST_PATH_IMAGE001
wherein R is 1 Selected from substituted aromatic groups; r 2 Selected from unsubstituted, mono-substituted or di-substituted aryl, substituted aryl alkyl.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is 1 Selected from substituted phenyl; r 2 Selected from unsubstituted, mono-or di-substituted phenyl, quinolyl, quinoxalyl or substituted phenyl, quinoline, quinoxalylalkyl.
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R is R of said substituted phenyl 1 The substituent in (1) is selected from halogen substituent and C1-3 alkyl substituent; r of the unsubstituted, mono-substituted or di-substituted phenyl, quinoline and quinoxaline or the substituted phenyl, quinoline and quinoxaline alkyl 2 The substituent in (1) is selected from halogen substituent, C1-3 alkoxy, C1-3 alkoxy acyl substituent, aminosulfuryl, trihalomethyl and amino, and the alkyl is selected from methylene and methine.
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, characterized in that said compound having the structure of formula (I) is selected from:
Figure 37727DEST_PATH_IMAGE002
Figure 125769DEST_PATH_IMAGE003
Figure 658381DEST_PATH_IMAGE004
Figure 139172DEST_PATH_IMAGE005
Figure 73630DEST_PATH_IMAGE006
Figure 332573DEST_PATH_IMAGE007
Figure 352482DEST_PATH_IMAGE008
Figure 355073DEST_PATH_IMAGE009
Figure 144037DEST_PATH_IMAGE010
Figure 839461DEST_PATH_IMAGE011
Figure 346665DEST_PATH_IMAGE012
Figure 900750DEST_PATH_IMAGE013
Figure 809800DEST_PATH_IMAGE014
Figure 410546DEST_PATH_IMAGE015
Figure 405047DEST_PATH_IMAGE016
Figure 749440DEST_PATH_IMAGE017
Figure 512997DEST_PATH_IMAGE018
Figure 550223DEST_PATH_IMAGE019
。
5. the compound of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the salt of the compound is selected from an organic acid salt or an inorganic acid salt.
6. The organic or inorganic acid salt of the compound represented by the general formula (I) according to claim 5, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, oxalic acid, citric acid, tartaric acid, malic acid, trifluoroacetic acid, succinic acid, salicylic acid, benzoic acid, phenylacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and maleic acid.
7. The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is used for the treatment of malignant tumor, nephropathy, immune system diseases or circulatory system diseases in the use as VEGFR inhibitory drugs.
8. The use of the compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 7 as a VEGFR inhibitory drug, characterized in that the compound or the pharmaceutically acceptable salt thereof is used in the field of cancer treatment as a VEGFR inhibitory drug.
CN202110204122.2A 2021-02-24 2021-02-24 Anti-tumor compound used as VEGFR inhibitor and application thereof Pending CN114957136A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101321530A (en) * 2005-11-03 2008-12-10 顶点医药品公司 Aminopyrimidines useful as kinase inhibitors
CN101796055A (en) * 2005-05-20 2010-08-04 梅赛尔基因股份有限公司 Inhibitors of VEGF receptor and HGF receptor signaling
CN104045642A (en) * 2013-03-14 2014-09-17 辰欣药业股份有限公司 Fused ring compound containing pyrimidine or pyridine and its application as antitumor drug
CN108503650A (en) * 2017-02-27 2018-09-07 北京赛特明强医药科技有限公司 Dioxane and quinazoline compounds or its pharmaceutical salts or its hydrate and its application as tyrosine kinase inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101796055A (en) * 2005-05-20 2010-08-04 梅赛尔基因股份有限公司 Inhibitors of VEGF receptor and HGF receptor signaling
CN101321530A (en) * 2005-11-03 2008-12-10 顶点医药品公司 Aminopyrimidines useful as kinase inhibitors
CN104045642A (en) * 2013-03-14 2014-09-17 辰欣药业股份有限公司 Fused ring compound containing pyrimidine or pyridine and its application as antitumor drug
CN108503650A (en) * 2017-02-27 2018-09-07 北京赛特明强医药科技有限公司 Dioxane and quinazoline compounds or its pharmaceutical salts or its hydrate and its application as tyrosine kinase inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHUANSHENG LI ET AL.: "Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
FUSHENG ZHOU ET AL.: "Discovery of N-aryl-N0-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

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