CN112592318A - 2- (4-methionyl) anilino-4-aminopyrimidine derivatives and application thereof - Google Patents

2- (4-methionyl) anilino-4-aminopyrimidine derivatives and application thereof Download PDF

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CN112592318A
CN112592318A CN202011453748.9A CN202011453748A CN112592318A CN 112592318 A CN112592318 A CN 112592318A CN 202011453748 A CN202011453748 A CN 202011453748A CN 112592318 A CN112592318 A CN 112592318A
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anilino
methionyl
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CN112592318B (en
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周孟
张荣红
王珊
廖尚高
何迅
徐国波
董永喜
关焕玉
李勇军
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Guizhou Medical University
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/42—One nitrogen atom
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to the technical field of chemical medicine, and particularly relates to a 2- (4-methyl aminoacyl) anilino-4-aminopyrimidine derivative and application thereof. The invention adopts nitro, carboxyl, cyano and the like to replace an electron-withdrawing substituent-trifluoromethyl on a Defectinib intermediate pyrimidine ring to obtain a 2- (4-methionyl) anilino-4-aminopyrimidine derivative. The 2- (4-methionyl) anilino-4-aminopyrimidine derivative is a novel FAK inhibitor, has very remarkable antitumor activity, and the in vitro activity of part of the derivative is remarkably higher than that of Defectinib; has good application prospect in preparing anti-cancer drugs for treating lung cancer, pancreatic cancer, liver cancer and the like.

Description

2- (4-methionyl) anilino-4-aminopyrimidine derivatives and application thereof
Technical Field
The invention belongs to the technical field of chemical medicine, and particularly relates to a 2- (4-methyl aminoacyl) anilino-4-aminopyrimidine derivative and application thereof.
Background
Focal Adhesion Kinase (FAK) is a highly conserved protein tyrosine kinase that localizes cell contact and cell adhesion sites; it was found in 1990 in the cell membrane and in other cell compartments like a nucleus, as one of the important substrates for the viral oncogene v-Src, and it is the phosphorylation of the first tyrosine protein kinase that is dependent on integrin-mediated cell adhesion to the cell wall.
FAK plays an important role in cell signal transduction, is a key enzyme in the process of mediated signal transmission of integrin of an adhesion molecule superfamily, mediates the function between cells and extracellular matrix, is the center of in-out signal of the cells and conducts a multi-clock signal path. The research shows that FAK is highly expressed in ovarian cancer, breast cancer, colon cancer, gastric cancer, melanoma, pancreatic cancer and other tumors. Blocking the expression of FAK can obviously inhibit the invasion and metastasis of tumor cells.
At present, a plurality of FAK inhibitors are used as antitumor drugs and are in preclinical research or clinical test. The Defectinib is a FAK inhibitor which is researched more, has obvious antitumor activity and enters phase II clinical research at present, but the single-use effect is not obvious and the side effect is obvious. Defectinib acts by inhibiting FAK phosphorylation at the Tyr397 site in a time and dose dependent manner; relevant researches show that an electron-withdrawing substituent-trifluoromethyl on a middle pyrimidine ring of the Defectinib is an important active functional group and has significant influence on the activity of the Defectinib. Therefore, the research on the replacement of trifluoromethyl on the middle pyrimidine ring of the Defectinib by other electron-withdrawing substituents has important significance for developing new medicaments with higher activity. At present, many researches on novel FAK inhibitors are reported, but researches on other electron-withdrawing substituents on the middle pyrimidine ring of Defectinib are rarely reported.
The patent with application number CN201910373081.2 discloses a deuterated Defectib compound, wherein one or more hydrogen in the Defectib compound is replaced by deuterium for synthesis; the metabolic stability and the pharmacokinetics of the Defectinib compound are improved in a deuteration mode, and the deuteration Defectinib compound with better pharmacokinetic property, lower dosage and lower toxic and side effects of metabolites is obtained. However, the structure of the patent is not changed substantially, and the invention discovers that other electron-withdrawing substituents (such as nitryl, carboxyl, cyano, amide and methoxyacyl) have equivalent or even better activity for replacing trifluoromethyl on a pyrimidine ring, and the structure is better and novel.
The patent application No. CN201180039922.8 discloses a class of pyrimidine derivatives as FAK inhibitors, modified with alkyl or acyl groups, sugars or oligopeptides and rapidly cleaved in organisms to form the compounds of formula
Figure BDA0002832600610000021
The compounds can be used as pharmaceutical active compounds for treating tyrosine kinase induced diseases, and can be used for preventing and treating cancers, angiogenesis diseases, eye diseases, inflammatory diseases and the like. Pyrimidine ring and R in the compound2The FAK inhibitors studied in this invention are connected through imine or ether linkage, which makes a clear difference in structure.
Disclosure of Invention
According to the invention, through researching an electron-withdrawing substituent on the Defectinib intermediate pyrimidine ring, the trifluoromethyl on the Defectinib intermediate pyrimidine ring is substituted by nitro, carboxyl, cyano, acylamino and methoxyacyl, so that the 2- (4-methyl aminoacyl) anilino-4-aminopyrimidine derivative is synthesized, and has very obvious antitumor activity; the method is realized through the following technical scheme.
A 2- (4-methionyl) anilino-4-aminopyrimidine derivative having the molecular structure of formula i:
Figure BDA0002832600610000031
wherein R is1Is proton, alkyl, phenyl, aralkyl, alkoxy, halogen, nitro, amino, carboxyl, hydroxyl,
Figure BDA0002832600610000032
X is nitro, cyano, carboxyl, amide or methoxyacyl; y is imino, oxygen atom; n is equal to 0, 1, 2, 3, 4, 5; the ring A is benzene, pyridine, pyrimidine, thiophene, indole, furan, pyran, imidazole and pyrazine.
Preferably, said R is2Alkyl, alkoxy, alkylamino.
Preferably, the 2- (4-carbamyl) anilino-4-aminopyrimidine derivatives include, but are not limited to, the following compounds: 2- (4-methionyl) anilino-4- (4-methoxy) phenylamino-5-nitropyrimidine; 2- (4-methionyl) anilino-4- (3-fluoro-4-methoxy) phenylamino-5-nitropyrimidine; 2- (4-carbamyl) anilino-4- (2-chloro) benzylamino-5-nitropyrimidine; 2- (4-methionyl) anilino-4- (2-methoxy) benzylamino-5-nitropyrimidine; 2- (4-methylamino) anilino-4- (pyridin-3 ylamino) -5-nitropyrimidine; 2- (4-methionyl) anilino-4- (furan-3 ylamino) -5-nitropyrimidine; 2- (4-carbamyl) anilino-4- (4-fluoro) phenylamino-5-cyanopyrimidine; 2- (4-methionyl) anilino-4- (4-methoxy) phenylamino-5-carboxypyrimidine; 2- (4-methionyl) anilino-4- (3-fluoro) benzylamino-5-nitropyrimidine.
The invention also provides a synthetic method of the 2- (4-methyl aminoacyl) anilino-4-aminopyrimidine derivative, and the synthetic route is as follows:
Figure BDA0002832600610000041
preferably, the synthesis method of the 2- (4-methyl aminoacyl) anilino-4-aminopyrimidine derivative specifically comprises the following steps:
(1) synthesis of intermediate 2 (N-methyl-4-nitrobenzamide): taking a drying reactor, adding 4-nitrobenzoic acid (oxalyl chloride is added for dissolution, stirring and reacting on an oil bath kettle at 65-70 ℃ (anhydrous operation), when the solution becomes light yellow transparent liquid, decompressing and spin-drying the solution to obtain yellow solid, dissolving the yellow solid by dichloromethane, slowly adding triethylamine under ice bath, slowly adding 40% methylamine aqueous solution, stirring and reacting at room temperature, decompressing and spin-drying the solvent after complete reaction, dissolving the spin-dried mixture by ethyl acetate and water, extracting the solution by ethyl acetate for 5-6 times, drying an organic layer by anhydrous sodium sulfate, and spin-drying to obtain a white cotton-shaped product, namely a crude product of N-methyl-4-nitrobenzamide;
(2) synthesis of intermediate 3 (N-methyl-4-aminobenzamide): adding N-methyl-4-nitrobenzamide and stannous chloride hydrate into a dry reactor, adding ethyl acetate for dissolving, and stirring and reacting on an oil bath kettle at the temperature of 80 ℃; after the reaction is completed, adding anhydrous sodium carbonate to adjust the pH value to 8-9, extracting the solution for 8-10 times, drying an organic layer by using anhydrous sodium sulfate, then spin-drying, and purifying by column chromatography to obtain a white crystal, namely a crude product of the N-methyl-4-aminobenzamide;
(3) synthesis of intermediate 4(2- (4-methionyl) anilino-4-chloropyrimidine derivative): weighing 2, 4-dichloropyrimidine derivative, placing the 2, 4-dichloropyrimidine derivative in an eggplant-shaped bottle, adding 10mL of t-BuOH DC-M (1:1) mixed solvent, cooling to 0-5 ℃, adding zinc bromide, and stirring for 30 min; adding N-methyl-4-aminobenzamide at 0-5 ℃, then slowly dropwise adding triethylamine, heating to room temperature, and stirring for reacting for 20 hours; after the reaction is finished, the solvent is decompressed and dried, dissolved by ethyl acetate, concentrated and mixed, purified by silica gel column chromatography and eluted by ethyl acetate-petroleum ether to obtain yellow powder, namely the 2- (4-methyl aminoacyl) anilino-4-chloropyrimidine derivative;
(4)2- (4-methionyl) anilino-4-aminopyrimidine derivative synthesis: taking a dry reactor, adding a 2- (4-methyl aminoacyl) anilino-4-chloropyrimidine derivative, an A ring compound and N, N-diisopropylethylamine, dissolving the mixture by using acetonitrile, and carrying out reflux reaction on an oil bath kettle at the temperature of 85 ℃ for 4 hours; after the reaction is completed, the solution is dried by spinning, extracted by ethyl acetate and water, and separated by silica gel column chromatography after being concentrated, and the product is yellow solid.
Preferably, the 2, 4-dichloropyrimidine derivatives include, but are not limited to, 2, 4-dichloro-5-nitropyrimidine, 2, 4-dichloro-5-carboxypyrimidine, 2, 4-dichloro-5-cyanopyrimidine, 2, 4-dichloro-5-aminylpyrimidine, 2, 4-dichloro-5-methoxylpyrimidine; the A ring compound includes, but is not limited to, 4-methoxyaniline, o-methoxyaniline, 3-fluoro-4-methoxyaniline, 3-chloro-4-methoxyaniline, 3-fluorobenzylamine, 3-chlorobenzylamine, 3-bromobenzylamine, 2-fluorobenzylamine, 2-chlorobenzylamine, 2-bromobenzylamine, 2-methoxybenzylamine, 4-fluorobenzylamine, 4-chlorobenzylamine, 4-bromobenzylamine, 4-methoxybenzylamine, 3-methoxybenzylamine, 2-aminopyridine, 4-aminopyrimidine, 3-aminofuran.
Preferably, in the step (3), the molar ratio of the 2, 4-dichloropyrimidine derivative to the zinc bromide is 1 (1-4), and the volume-to-mass ratio of the mixed solvent t-BuOH to DCM to the 2, 4-dichloro-5-nitropyrimidine is 20 mL: 100 mg; the molar ratio of the 2, 4-dichloropyrimidine derivative to the N-methyl-4-aminobenzamide to the triethylamine is 1 (1-4) to 2-4.
Preferably, in the step (4), the molar ratio of the 2- (4-methionyl) anilino-4-chloropyrimidine derivative to the A-ring compound to the N, N-diisopropylethylamine is 1 (1-5) to (2-5).
Another object of the present invention is to provide the use of the above 2- (4-carbamyl) anilino-4-aminopyrimidine derivatives for the preparation of antitumor drugs.
The invention also aims to provide the application of the 2- (4-methylamino) anilino-4-aminopyrimidine derivative in preparing medicaments for resisting lung cancer, pancreatic cancer and liver cancer.
The invention has the beneficial effects that:
according to the invention, a novel FAK inhibitor is discovered by researching substituent groups on the Defectinib; different from the Defectinib, after the trifluoromethyl is replaced by other electron-withdrawing substituents such as nitro, carboxyl, cyano, amide and methoxyacyl, the compound has remarkable antitumor activity, and the in vitro activity of part of compounds is better than that of the Defectinib. The use of electron-donating substituents, such as amino, methyl, etc., results in a significant decrease or loss of activity.
The invention adopts electron-withdrawing groups such as nitryl, carboxyl, cyano, amide, methoxyacyl and the like to replace an electron-withdrawing substituent-trifluoromethyl on a middle pyrimidine ring of the Defectinib to obtain the 2- (4-methyl aminoacyl) anilino-4-aminopyrimidine derivative. The 2- (4-methionyl) anilino-4-aminopyrimidine derivative is a novel FAK inhibitor, has very remarkable antitumor activity, and the in vitro activity of part of the derivative is remarkably higher than that of Defectinib; the compound is simple to prepare, high in yield, low in price of raw materials and easy to obtain; has good application prospect in preparing anti-cancer drugs for treating lung cancer, pancreatic cancer, liver cancer and the like.
Detailed Description
The technical solution of the present invention is further defined below with reference to the specific embodiments, but the scope of the claims is not limited to the description.
Example 1
Synthesis of 2- (4-methionyl) anilino-4-aminopyrimidine derivatives
(1) Synthesis of intermediate 2 (N-methyl-4-nitrobenzamide):
the synthetic route is as follows:
Figure BDA0002832600610000071
the synthesis process comprises the following steps: adding 4-nitrobenzoic acid (1g,6mmol) into a 250mL dry reactor, adding oxalyl chloride (30 mL) for dissolving, stirring and reacting on an oil bath kettle at 65-70 ℃ (anhydrous operation), and when the solution becomes a light yellow transparent liquid, carrying out reduced pressure spin drying on the solution to obtain a yellow solid; methylene chloride dissolves the yellow solid, triethylamine (1.8g,178mmol) is slowly added under ice bath, and 40% methylamine water solution (287mg,5.2mmol) is slowly added, stirring is carried out at room temperature for about 30 minutes; after the reaction was completed, the solvent was spin-dried under reduced pressure, the spin-dried mixture was dissolved in ethyl acetate and an appropriate amount of water and the solution was extracted with ethyl acetate 5 to 6 times, and the organic layer was dried over anhydrous sodium sulfate and then spin-dried to obtain a crude N-methyl-4-nitrobenzamide as a white flocculent product (512mg, 57%).
(2) Synthesis of intermediate 3 (N-methyl-4-nitrobenzamide):
the synthetic route is as follows:
Figure BDA0002832600610000081
the synthesis process comprises the following steps: adding N-methyl-4-nitrobenzamide (1g,5.6mmol) and stannous chloride hydrate (6.3g,28mmol) into a 250mL dry reactor, adding ethyl acetate for dissolving, and stirring on an oil bath kettle at 80 ℃ for reaction for about 3 hours; after the reaction is completed, anhydrous sodium carbonate is added to adjust the pH value to 8-9, the extraction solution is extracted for 8-10 times, an organic layer is dried by anhydrous sodium sulfate and then is dried in a spinning way, and column chromatography purification is carried out to obtain a crude product of the N-methyl-4-aminobenzamide, wherein the product is a white crystal (610mg, 75%).
(3-1) Synthesis of intermediate 4(2- (4-methionyl) anilino-4-chloro-5-nitropyrimidine):
the synthetic route is as follows:
Figure BDA0002832600610000082
the synthesis process comprises the following steps: weighing 2, 4-dichloro-5-nitropyrimidine (50mg,333 mu mol), placing the mixture into an eggplant-shaped bottle, adding 10mL of t-BuOH mixed solvent of DCM (1:1), cooling to 0-5 ℃, adding zinc bromide (224mg,995 mu mol), stirring for about 30 minutes, adding N-methyl-4-aminobenzamide (74mg,383 mu mol) at 0-5 ℃, slowly dropwise adding triethylamine (74mg,727 mu mol), raising the temperature to room temperature, and reacting for about 20 hours with stirring; after the reaction is finished, the solvent is dried by spinning under reduced pressure, dissolved by ethyl acetate, concentrated and mixed with a sample, purified by silica gel column chromatography and eluted by ethyl acetate-petroleum ether (2: 1) to obtain yellow powder (yield: 62%).
(4-1) Synthesis of 2- (4-methionyl) anilino-4-amino-5-nitropyrimidine derivative:
synthesis of compound B1:
the synthetic route is as follows:
Figure BDA0002832600610000091
the synthesis process comprises the following steps: a50 mL dry reactor was charged with 4- ((4-chloro-5- (nitro) pyrimidin-2-imino) -N-methylbenzamide (100mg, 325. mu. mol), 4-methoxyaniline (80mg, 650. mu. mol), N-diisopropylethylamine (0.5. mu.L), dissolved in acetonitrile, and refluxed in an oil bath at 85 ℃ for 4 hours, after completion of the reaction, the solution was spun off, extracted with ethyl acetate and water, and concentrated and separated by column chromatography on silica gel under dichloromethane: methanol 100:1 to give a yellow solid (yield: 72%).
Synthesis of compound B2:
the synthetic route is as follows:
Figure BDA0002832600610000092
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B2 was obtained by replacing 4-methoxyaniline in step (r) with 2-methoxyaniline, with a yield of 35%.
Synthesis of compound B3:
the synthetic route is as follows:
Figure BDA0002832600610000093
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B3 was obtained by replacing 4-methoxyaniline in step (i) with 3-fluoro-4-methoxyaniline, with a yield of 42%.
Synthesis of compound B4:
the synthetic route is as follows:
Figure BDA0002832600610000101
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B4 was obtained in 34% yield by replacing 4-methoxyaniline in step (i) with 3-chloro-4-methoxyaniline.
Synthesis of compound B5:
the synthetic route is as follows:
Figure BDA0002832600610000102
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B5 was obtained in 60% yield by replacing 4-methoxyaniline in step (r) with 3-fluorobenzylamine.
Synthesis of compound B6:
the synthetic route is as follows:
Figure BDA0002832600610000103
the synthesis process comprises the following steps: referring to the preparation of compound B1, the 4-methoxyaniline in step (r) was replaced with 3-chlorobenzylamine to give compound B6 in 34% yield.
Synthesis of compound B7:
the synthetic route is as follows:
Figure BDA0002832600610000104
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B7 was obtained in 34% yield by replacing 4-methoxyaniline in step (r) with 3-bromobenzylamine.
Synthesis of compound B8:
the synthetic route is as follows:
Figure BDA0002832600610000111
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B8 was obtained in 49% yield by replacing 4-methoxyaniline in step (r) with 2-fluorobenzylamine.
Ninthly, synthesizing the compound B9:
the synthetic route is as follows:
Figure BDA0002832600610000112
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B9 was obtained in 35% yield by replacing 4-methoxyaniline in step (r) with 2-chlorobenzylamine.
Synthesis of r compound B10:
the synthetic route is as follows:
Figure BDA0002832600610000113
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B10 was obtained in 54% yield by replacing 4-methoxyaniline in step (r) with 2-bromobenzylamine.
Figure BDA0002832600610000114
Synthesis of compound B11:
the synthetic route is as follows:
Figure BDA0002832600610000121
the synthesis process comprises the following steps: the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B11 was obtained in 54% yield by substituting 4-methoxyaniline for 2-methoxybenzylamine in step (r).
Figure BDA0002832600610000122
Synthesis of compound B12:
the synthetic route is as follows:
Figure BDA0002832600610000123
the synthesis process comprises the following steps: referring to the preparation of compound B1, 4-methoxybenzylamine in step (r) was substituted for 4-fluorobenzylamine to give compound B12 in 39% yield.
Figure BDA0002832600610000124
Synthesis of compound B13:
the synthetic route is as follows:
Figure BDA0002832600610000125
the synthesis process comprises the following steps: referring to the preparation of compound B1, 4-methoxybenzylamine in step (r) was substituted for 4-chlorobenzylamine to give compound B13 in 59% yield.
Figure BDA0002832600610000126
Synthesis of compound B14:
the synthetic route is as follows:
Figure BDA0002832600610000131
the synthesis process comprises the following steps: referring to the preparation of compound B1, 4-methoxybenzylamine in step (r) was substituted for 4-bromobenzylamine to give compound B14 in 47% yield.
Figure BDA0002832600610000132
Synthesis of compound B15:
the synthetic route is as follows:
Figure BDA0002832600610000133
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B15 was obtained in 71% yield by substituting 4-methoxybenzylamine for 4-bromobenzylamine in step (r).
Figure BDA0002832600610000134
Synthesis of compound B16:
the synthetic route is as follows:
Figure BDA0002832600610000135
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B16 was obtained in 37% yield by substituting 4-methoxyaniline for 3-methoxybenzylamine in step (r).
Figure BDA0002832600610000136
Synthesis of compound B17:
the synthetic route is as follows:
Figure BDA0002832600610000137
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B17 was obtained by substituting 2-aminopyridine with 4-methoxyaniline in step (r), with a yield of 77%.
Figure BDA0002832600610000141
Synthesis of compound B18:
the synthetic route is as follows:
Figure BDA0002832600610000142
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B18 was obtained by substituting 4-aminopyrimidine with 4-methoxyaniline in step (r), with a yield of 55%.
Figure BDA0002832600610000143
Synthesis of compound B19:
the synthetic route is as follows:
Figure BDA0002832600610000144
the synthesis process comprises the following steps: referring to the preparation of compound B1, compound B19 was obtained by substituting 4-methoxyaniline for 3-aminofuran in step (r), with a yield of 39%.
(3-2) Synthesis of intermediate 4(2- (4-carbamyl) anilino-4-chloro-5-cyanopyrimidine):
the synthetic route is as follows:
Figure BDA0002832600610000145
the synthesis process comprises the following steps: 2, 4-dichloro-5-cyanopyrimidine (50mg, 259. mu. mol) was weighed out into an eggplant-shaped flask, 10mL of t-BuOH: DCM (1:1) mixed solvent was added, cooled to 0-5 ℃, zinc bromide (224mg, 995. mu. mol) was added, stirring was carried out for about 2 hours, N-methyl-4-aminobenzamide (74mg, 383. mu. mol) was added at 0-5 ℃, triethylamine (73.58mg, 727. mu. mol) was slowly added dropwise, the temperature was raised to room temperature, and the reaction was carried out for about 12 hours with stirring. After the reaction is finished, the solvent is dried by spinning under reduced pressure, dissolved by ethyl acetate, concentrated and mixed, purified by silica gel column chromatography and eluted by ethyl acetate-petroleum ether (2: 1) to obtain yellow powder (yield: 69%);
(4-2) Synthesis of 2- (4-methionyl) anilino-4-amino-5-cyanopyrimidine derivative:
Figure BDA0002832600610000151
synthesis of compound B20:
the synthetic route is as follows:
Figure BDA0002832600610000152
the synthesis process comprises the following steps: a50 mL dry reactor was charged with 4- ((4-chloro-5- (cyano) pyrimidin-2-imino) -N-methylbenzamide (100mg, 348.00. mu. mol), 4-methoxyaniline (80mg, 650. mu. mol), N-diisopropylethylamine (0.5mL), dissolved in acetonitrile, and refluxed in an oil bath at 85 ℃ for 24 hours, whereupon a white solid precipitated, the solvent was spin-dried under reduced pressure, dissolved in ethyl acetate, stirred, and then subjected to column chromatography using silica gel column, and the eluent was petroleum ether, ethyl acetate 2:1, and the product was recrystallized from ethyl acetate to give a white powder (yield: 52%).
Figure BDA0002832600610000153
Synthesis of compound B21:
Figure BDA0002832600610000154
the synthesis process comprises the following steps: a50 mL dry reactor was charged with B20(100mg, 267. mu. mol), potassium carbonate (74mg, 534. mu. mol), dissolved in 15mL DMSO, charged with 30% hydrogen peroxide (13mL, 1.34mmol), reacted in an oil bath at 50 ℃ for 1h, extracted with ethyl acetate, and back-washed with water. Concentrating the extract, mixing, and packing. Separating by silica gel column chromatography, wherein the eluent is petroleum ether: ethyl acetate 1:1, the product was recrystallized from ethyl acetate to finally obtain the product as a white powder (yield: 51%).
Figure BDA0002832600610000161
Synthesis of compound B22:
Figure BDA0002832600610000162
the synthesis process comprises the following steps: reference Compound B20 preparation, step
Figure BDA0002832600610000163
The compound B22 was obtained by substituting 2-methoxyaniline with 4-methoxyaniline in (1), with a yield of 46%.
Figure BDA0002832600610000164
Synthesis of compound B23:
Figure BDA0002832600610000165
the synthesis process comprises the following steps: reference Compound B21 preparation, step
Figure BDA0002832600610000166
Substitution of B20 for B22 gave compound B23 in 47% yield.
Figure BDA0002832600610000167
Synthesis of compound B24:
Figure BDA0002832600610000168
the synthesis process comprises the following steps: reference Compound B20 preparation, step
Figure BDA0002832600610000171
The compound B24 was obtained by substituting m-phenylenediamine with 4-methoxyaniline in (1), and the yield was 34%.
Figure BDA0002832600610000172
Synthesis of compound B25:
Figure BDA0002832600610000173
the synthesis process comprises the following steps: preparation of reference Compound B21The step of
Figure BDA0002832600610000174
Substitution of B20 for B24 gave compound B25 in 47% yield.
Figure BDA0002832600610000175
Synthesis of compound B26:
Figure BDA0002832600610000176
the synthesis process comprises the following steps: reference Compound B20 preparation, step
Figure BDA0002832600610000177
The 4-methoxyaniline in the compound B26 is used for replacing 4-fluoroaniline, and the yield is 67%.
Figure BDA0002832600610000178
Synthesis of compound B27:
Figure BDA0002832600610000179
the synthesis process comprises the following steps: reference Compound B21 preparation, step
Figure BDA00028326006100001710
Substitution of B20 for B26 gave compound B27 in 32% yield.
Figure BDA00028326006100001711
Synthesis of compound B28:
Figure BDA0002832600610000181
synthesized byThe process: reference Compound B20 preparation, step
Figure BDA0002832600610000182
The 4-methoxyaniline in (1) replaces 4-methoxybenzylamine to obtain the compound B28 with a yield of 70%.
Figure BDA0002832600610000183
Synthesis of compound B29:
Figure BDA0002832600610000184
the synthesis process comprises the following steps: reference Compound B21 preparation, step
Figure BDA0002832600610000185
Substitution of B20 for B28 gave compound B29 in 63% yield.
Figure BDA0002832600610000186
Synthesis of compound B30:
Figure BDA0002832600610000187
the synthesis process comprises the following steps: reference Compound B20 preparation, step
Figure BDA0002832600610000188
The compound B30 was obtained in 61% yield by substituting 2-chlorobenzylamine with 4-methoxyaniline in (1%).
Figure BDA0002832600610000189
Synthesis of compound B31:
Figure BDA00028326006100001810
the synthesis process comprises the following steps: reference Compound B21 preparation, step
Figure BDA0002832600610000191
Substitution of B20 for B30 gave compound B31 in 45% yield.
Figure BDA0002832600610000192
Synthesis of compound B32:
Figure BDA0002832600610000193
the synthesis process comprises the following steps: reference Compound B20 preparation, step
Figure BDA0002832600610000194
The 4-methoxyaniline in (1) replaces 3-chlorobenzylamine to obtain the compound B32 with the yield of 78%.
Figure BDA0002832600610000195
Synthesis of compound B33:
Figure BDA0002832600610000196
the synthesis process comprises the following steps: reference Compound B21 preparation, step
Figure BDA0002832600610000197
Substitution of B20 for B33 gave compound B34 in 41% yield.
Figure BDA0002832600610000198
Synthesis of compound B34:
Figure BDA0002832600610000199
the synthesis process comprises the following steps: reference Compound B20 preparation, step
Figure BDA00028326006100001910
The 4-methoxyaniline in (1) replaces 4-methoxybenzylamine to obtain the compound B34 with a yield of 72%.
Figure BDA00028326006100001911
Synthesis of compound B35:
Figure BDA0002832600610000201
the synthesis process comprises the following steps: reference Compound B21 preparation, step
Figure BDA0002832600610000202
Substitution of B20 for B34 gave compound B35 in 52% yield.
(3-3) Synthesis of intermediate 4(2- (4-methionyl) anilino-4-chloro-5-methoxylpyrimidine):
the synthetic route is as follows:
Figure BDA0002832600610000203
the synthesis process comprises the following steps: 2, 4-dichloro-5-methoxyacyl pyrimidine (100mg, 485. mu. mol) is weighed and placed in an eggplant-shaped bottle, 15mL of t-BuOH: DCM (1:1) mixed solvent is added, the mixture is cooled to 0-5 ℃, zinc bromide (328mg, 995. mu. mol) is added, stirring is carried out for about 30 minutes, N-methyl-4-aminobenzamide (74mg, 738. mu. mol) is added at 0-5 ℃, triethylamine (99mg, 970. mu. mol) is slowly added dropwise, the temperature is raised to room temperature, and the mixture is stirred and reacted for about 23 hours. After the reaction, the solvent was spin-dried under reduced pressure, dissolved in ethyl acetate, concentrated, and sample-mixed, purified by silica gel column chromatography, and eluted with ethyl acetate-petroleum ether (4: 1) to obtain white powder (yield: 71%).
(4-3) Synthesis of 2- (4-methionyl) anilino-4-amino-5-methoxylpyrimidine derivative:
Figure BDA0002832600610000204
synthesis of compound B36:
the synthetic route is as follows:
Figure BDA0002832600610000211
the synthesis process comprises the following steps: a50 mL dry reactor was charged with 4- ((4-chloro-5- (methoxyacyl) pyrimidin-2-imino) -N-methylbenzamide (100mg, 313. mu. mol), 4-methoxyaniline (77mg, 650. mu. mol), N-diisopropylethylamine (0.5mL), dissolved in acetonitrile, and refluxed in an oil bath at 85 ℃ for 12 hours, after completion of the reaction, the solution was spun off, extracted with ethyl acetate and water, concentrated and chromatographed on a silica gel column with dichloromethane: methanol 150:1 as a white solid (yield: 62%).
Figure BDA0002832600610000212
Synthesis of compound B37:
Figure BDA0002832600610000213
the synthesis process comprises the following steps: compound B36(100mg, 246. mu. mol), potassium hydroxide (69mg,1.23mmol) were taken in a 25ml flask and dissolved in an appropriate amount of THF, and reacted for 12h under reflux. After the reaction, the reaction solution was spin-dried, purified water was added, the pH was adjusted to 5 to 6 with dilute hydrochloric acid, and the filtrate was filtered and the filter cake was washed with purified water several times to obtain Compound B37 (yield: 75%).
Figure BDA0002832600610000214
Synthesis of compound B38:
Figure BDA0002832600610000215
the synthesis process comprises the following steps: reference Compound B36 preparation, step
Figure BDA0002832600610000216
The compound B38 was obtained by substituting 2-methoxyaniline with 4-methoxyaniline in (1), with a yield of 68%.
Figure BDA0002832600610000217
Synthesis of compound B39:
Figure BDA0002832600610000221
the synthesis process comprises the following steps: reference Compound B37 preparation, step
Figure BDA0002832600610000222
Substitution of B36 for B38 gave compound B39 in 79% yield.
Figure BDA0002832600610000223
Synthesis of compound B40:
Figure BDA0002832600610000224
the synthesis process comprises the following steps: reference Compound B36 preparation, step
Figure BDA0002832600610000225
The 4-methoxyaniline in (1) replaces 4-methoxybenzylamine to obtain the compound B40 with a yield of 36%.
Figure BDA0002832600610000226
Synthesis of compound B41:
Figure BDA0002832600610000227
the synthesis process comprises the following steps: reference Compound B37 preparation, step
Figure BDA0002832600610000228
Substitution of B36 for B40 gave compound B41 in 85% yield.
Figure BDA0002832600610000229
Synthesis of compound B42:
Figure BDA00028326006100002210
the synthesis process comprises the following steps: reference Compound B36 preparation, step
Figure BDA00028326006100002211
The 4-methoxybenzylamine in (1) replaces 4-fluorobenzylamine to obtain the compound B42 with the yield of 44%.
Figure BDA00028326006100002212
Synthesis of compound B43:
Figure BDA0002832600610000231
the synthesis process comprises the following steps: reference Compound B37 preparation, step
Figure BDA0002832600610000232
Substitution of B36 for B42 gave compound B43 in 72% yield.
Figure BDA0002832600610000233
Synthesis of compound B44:
Figure BDA0002832600610000234
the synthesis process comprises the following steps: reference Compound B36 preparation, step
Figure BDA0002832600610000235
The 4-methoxyaniline in (B) replaced 3-fluorobenzylamine to give compound B44 in 68% yield.
Figure BDA0002832600610000236
Synthesis of compound B45:
Figure BDA0002832600610000237
the synthesis process comprises the following steps: reference Compound B37 preparation, step
Figure BDA0002832600610000238
Substitution of B36 for B44 gave compound B45 in 77% yield.
Experimental study 2: antitumor activity of 2- (4-methionyl) anilino-4-aminopyridine derivatives
The MTT method was used to detect the inhibitory activities of the compounds B1-B45 obtained in the examples on human lung cancer cells (A549), human pancreatic cancer cells (PANC-1) and human liver cancer cells (HEPG2), respectively, as follows: taking each tumor cell with good growth state and in logarithmic growth phase according to 5 × 103Cells were seeded in 96-well plates at a cell density of 100. mu.L/well in 5% CO2And after culturing in a 37 ℃ cell culture box for 24 hours, dividing the cells into: blank control group, different concentration group of the compound to be tested, and positive drug (Defectinib) group, each group is provided with 3 multiple wells. Adding 100 μ L of complete culture medium into blank control group, adding 100 μ L of complete culture medium containing corresponding drug concentration into different concentration groups of the compound to be tested, adding complete culture medium containing corresponding solvent concentration into different concentration DMSO groups, and culturing for 24 hrAdding 10 mu L MTT for staining for 4h, measuring the absorbance value under an enzyme-labeling instrument with the wavelength of 570nm, calculating the cell survival rate according to the absorbance value, and calculating according to the following formula:
Figure BDA0002832600610000241
the results are shown in Table 1.
TABLE 12 IC inhibition of different tumor cells by (u mol/L) anilino-4-aminopyrimidine derivatives (4-methylamino-L)50The value is obtained.
Figure BDA0002832600610000242
Figure BDA0002832600610000251
As can be seen from Table 1, most of the compounds have good anti-lung cancer tumor activity; IC of Compounds B1-B19, B26, B28, B30, B34, B37, B43, B45 on PANC-1 cells50The value is in the range of 0.18-5.83 mu mol/L, which shows that the derivative has stronger anti-pancreatic cancer tumor activity; IC of compounds B1, B3-B7, B9-B10, B12-B14, B17-B22, B25-B28, B30, B32-B35, B37, B3-B41, B43, B45 on HEPG29 cells50The value is within the range of 10 mu mol/L, which shows that the derivative has stronger anti-liver cancer tumor activity.
The in vitro anti-tumor activity results show that the compounds in the embodiments have very significant anti-tumor activity and very significant inhibitory activity on human lung cancer cells, pancreatic cancer cells and liver cancer cells. Among them, the activities of compounds B1, B3, B9, B11, B17, B19, B26, B37, and B45 were all more significant than that of Defactinib.
It should be noted that the above examples and test examples are only for further illustration and understanding of the technical solutions of the present invention, and are not to be construed as further limitations of the technical solutions of the present invention, and the invention which does not highlight essential features and significant advances made by those skilled in the art still belongs to the protection scope of the present invention.

Claims (10)

  1. A2- (4-methionyl) anilino-4-aminopyrimidine derivative having the molecular structure of formula I:
    Figure FDA0002832600600000011
    wherein R is1Is proton, alkyl, phenyl, aralkyl, alkoxy, halogen, nitro, amino, carboxyl, hydroxyl,
    Figure FDA0002832600600000012
    X is nitro, cyano, carboxyl, amide or methoxyacyl; y is imino, oxygen atom; n is equal to 0, 1, 2, 3, 4, 5; the ring A is benzene, pyridine, pyrimidine, thiophene, indole, furan, pyran, imidazole and pyrazine.
  2. 2. The 2- (4-methionyl) anilino-4-aminopyrimidine derivative of claim 1 wherein R is2Alkyl, alkoxy, alkylamino.
  3. 3. 2- (4-carbamyl) anilino-4-aminopyrimidine derivatives according to claim 1, characterized in that they include but are not limited to the following compounds: 2- (4-methionyl) anilino-4- (4-methoxy) phenylamino-5-nitropyrimidine; 2- (4-methionyl) anilino-4- (3-fluoro-4-methoxy) phenylamino-5-nitropyrimidine; 2- (4-carbamyl) anilino-4- (2-chloro) benzylamino-5-nitropyrimidine; 2- (4-methionyl) anilino-4- (2-methoxy) benzylamino-5-nitropyrimidine; 2- (4-methylamino) anilino-4- (pyridin-3 ylamino) -5-nitropyrimidine; 2- (4-methionyl) anilino-4- (furan-3 ylamino) -5-nitropyrimidine; 2- (4-carbamyl) anilino-4- (4-fluoro) phenylamino-5-cyanopyrimidine; 2- (4-methionyl) anilino-4- (4-methoxy) phenylamino-5-carboxypyrimidine; 2- (4-methionyl) anilino-4- (3-fluoro) benzylamino-5-nitropyrimidine.
  4. 4. A method for synthesizing a 2- (4-carbamyl) anilino-4-aminopyrimidine derivative according to any one of claims 1-3, wherein the synthetic route is as follows:
    Figure FDA0002832600600000021
  5. 5. a process for the synthesis of 2- (4-carbamyl) anilino-4-aminopyrimidine derivatives according to claim 4, characterized by comprising the following steps:
    (1) synthesis of intermediate 2: adding 4-nitrobenzoic acid into a drying reactor, adding oxalyl chloride for dissolving, stirring and reacting on an oil bath kettle at 65-70 ℃, and performing rotary drying on the solution under reduced pressure to obtain a yellow solid when the solution becomes a light yellow transparent liquid; dissolving a yellow solid by dichloromethane, slowly adding triethylamine in ice bath, slowly adding 40% methylamine water solution, and stirring at room temperature for reaction; after the reaction is completed, carrying out decompression spin-drying on the solvent, dissolving the spin-dried mixture with ethyl acetate and water, extracting the solution with ethyl acetate for 5-6 times, drying the organic layer with anhydrous sodium sulfate, and then carrying out spin-drying to obtain a white flocculent product, namely a crude product of the N-methyl-4-nitrobenzamide;
    (2) synthesis of intermediate 3: adding N-methyl-4-nitrobenzamide and stannous chloride hydrate into a dry reactor, adding ethyl acetate for dissolving, and stirring and reacting on an oil bath kettle at the temperature of 80 ℃; after the reaction is completed, adding anhydrous sodium carbonate to adjust the pH value to 8-9, extracting the solution for 8-10 times, drying an organic layer by using anhydrous sodium sulfate, then spin-drying, and purifying by column chromatography to obtain a white crystal, namely a crude product of the N-methyl-4-aminobenzamide;
    (3) synthesis of intermediate 4: weighing 2, 4-dichloropyrimidine derivative, placing in an eggplant-shaped bottle, adding a t-BuOH-DCM mixed solvent, cooling to 0-5 ℃, adding zinc bromide, and stirring for 30 min; adding N-methyl-4-aminobenzamide at 0-5 ℃, then slowly dropwise adding triethylamine, heating to room temperature, and stirring for reacting for 2 hours; after the reaction is finished, the solvent is decompressed and dried, dissolved by ethyl acetate, concentrated and mixed, purified by silica gel column chromatography and eluted by ethyl acetate-petroleum ether to obtain yellow powder, namely the 2- (4-methyl aminoacyl) anilino-4-chloropyrimidine derivative;
    (4)2- (4-methionyl) anilino-4-aminopyrimidine derivative synthesis: taking a dry reactor, adding a 2- (4-methyl aminoacyl) anilino-4-chloropyrimidine derivative, an A ring compound and N, N-diisopropylethylamine, dissolving the mixture by using acetonitrile, and carrying out reflux reaction on an oil bath kettle at the temperature of 85 ℃ for 4 hours; after the reaction is completed, the solution is dried by spinning, extracted by ethyl acetate and water, and separated by silica gel column chromatography after being concentrated, and the product is yellow solid.
  6. 6. The method of synthesizing 2- (4-methionyl) anilino-4-aminopyrimidine derivatives according to claim 5 wherein the 2, 4-dichloropyrimidine derivatives include but are not limited to 2, 4-dichloro-5-nitropyrimidine, 2, 4-dichloro-5-carboxypyrimidine, 2, 4-dichloro-5-cyanopyrimidine, 2, 4-dichloro-5-aminylpyrimidine, 2, 4-dichloro-5-methoxylpyrimidine; the A ring compound includes, but is not limited to, 4-methoxyaniline, o-methoxyaniline, 3-fluoro-4-methoxyaniline, 3-chloro-4-methoxyaniline, 3-fluorobenzylamine, 3-chlorobenzylamine, 3-bromobenzylamine, 2-fluorobenzylamine, 2-chlorobenzylamine, 2-bromobenzylamine, 2-methoxybenzylamine, 4-fluorobenzylamine, 4-chlorobenzylamine, 4-bromobenzylamine, 4-methoxybenzylamine, 3-methoxybenzylamine, 2-aminopyridine, 4-aminopyrimidine, 3-aminofuran.
  7. 7. The method for synthesizing a 2- (4-methionyl) anilino-4-aminopyrimidine derivative according to claim 5, wherein in the step (3), the molar ratio of the 2, 4-dichloropyrimidine derivative to the zinc bromide is 1 (1-4), and the volume-to-mass ratio of the mixed solvent t-BuOH to DCM to the 2, 4-dichloropyrimidine derivative is 20 mL: 100 mg; the molar ratio of the 2, 4-dichloropyrimidine derivative to the N-methyl-4-aminobenzamide to the triethylamine is 1 (1-4) to 2-4.
  8. 8. The method for synthesizing a 2- (4-methionyl) anilino-4-aminopyrimidine derivative according to claim 5, wherein the molar ratio of the 2- (4-methionyl) anilino-4-chloropyrimidine derivative, N-diisopropylethylamine, and the A-ring compound in the step (4) is 1 (1-5) to (2-5).
  9. 9. Use of a 2- (4-carbamyl) anilino-4-aminopyrimidine derivative according to any one of claims 1-3 for the preparation of an antitumor medicament.
  10. 10. Use of a 2- (4-carbamyl) anilino-4-aminopyrimidine derivative according to any one of claims 1-3 for the manufacture of a medicament for the treatment of lung, pancreatic and liver cancer.
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