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CN111454218A - 2,4, 5-substituted pyrimidine compound and preparation method and application thereof - Google Patents

2,4, 5-substituted pyrimidine compound and preparation method and application thereof Download PDF

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CN111454218A
CN111454218A CN201910057786.3A CN201910057786A CN111454218A CN 111454218 A CN111454218 A CN 111454218A CN 201910057786 A CN201910057786 A CN 201910057786A CN 111454218 A CN111454218 A CN 111454218A
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pyrimidinediamine
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谢洪磊
李亚平
王琛
李艺
徐淑周
李忠
张丽
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Yantai Institute Of Materia Medica
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Abstract

The invention relates to a 2,4, 5-substituted pyrimidine compound, a preparation method and application thereof, and the compound has a molecular structure shown as a formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule thereof:

Description

2,4, 5-substituted pyrimidine compound and preparation method and application thereof
Technical Field
The invention relates to a pyrimidine compound and a preparation method and application thereof, in particular to a 2,4, 5-substituted pyrimidine compound serving as an EGFR inhibitor and a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry.
Background
Malignant tumors pose a great threat to human health and are on an increasing trend year by year. Among them, lung cancer is one of the most common cancers worldwide, and the incidence and mortality of lung cancer are high in China.
The clinical findings show that the T790M and L858R mutation of the EGFR is an important reason for the drug resistance of the first-generation reversible EGFR inhibitor, and the first-generation inhibitor has no proliferation inhibiting activity basically in a T790M and L858R mutated cell line H1975.
Currently, second-generation irreversible EGFR inhibitor afatinib is successfully marketed, but the medicine has strong wild type EGFR inhibitory activity, the inhibitory activity on the wild type EGFR is obviously higher than that of a T790M resistant mutant, and side effects such as skin rash of patients are serious.
In order to solve the problem of simultaneous inhibition of T790M mutation and L R mutation and reduce the inhibitory activity on wild-type EGFR, the FDA approves a third-generation irreversible inhibitor of oxitinib, which is successfully marketed and has remarkable curative effect.
Therefore, the development of novel inhibitors of EGFR-sensitive mutations and drug-resistant mutations is of great interest.
Disclosure of Invention
Aiming at the defects of the existing EGFR sensitive mutation and drug-resistant mutation inhibitors, the invention provides a 2,4, 5-substituted pyrimidine compound serving as an EGFR inhibitor, and a preparation method and application thereof.
The technical scheme for solving the technical problems is as follows:
a2, 4, 5-substituted pyrimidine compound has a molecular structure shown as a formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule thereof:
Figure BDA0001953107110000021
wherein R is1One selected from hydrogen, deuterium, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, cyano, methyl and hydroxyl;
R2selected from hydrogen, fluorine, chlorine, cyano or any of the following structures:
Figure BDA0001953107110000022
wherein,
Figure BDA0001953107110000031
represents a site of chemical bonding;
g is selected from any one of 2-isopropylsulfonylbenzene, 2-dimethyloxyphosphatene, 3-cyanobenzene, 3-chloro-4-fluorobenzene, 2-fluoro-4-bromobenzene, 3-chloro-4-fluorotoluene and 3-methylpyrazole.
Further, the 2,4, 5-substituted pyrimidine compound has a molecular structure shown as follows:
Figure BDA0001953107110000032
Figure BDA0001953107110000041
Figure BDA0001953107110000051
the 2,4, 5-substituted pyrimidine compound provided by the invention has low cytotoxicity and high selective inhibition on EGFR, and can inhibit EGFR drug-resistant mutase (such as T790M/L858R/C797S mutase) and proliferation of cell strains thereof under low concentration (such as nanomolar concentration), so that the compound can be used for treating diseases caused by EGFR mutation and is expected to be developed into a new generation of EGFR inhibitors.
The invention also claims a pharmaceutical composition, which comprises the 2,4, 5-substituted pyrimidine compound with effective dose and a pharmaceutically acceptable carrier.
Further, the composition also comprises one or more of gefitinib, erlotinib, afatinib, dacomitinib, oimotinib, oxib, trastuzumab, zalutumumab, pertuzumab, and apramycin.
The pharmaceutical composition has the advantages that the 2,4, 5-substituted pyrimidine compounds are used as active ingredients, the pharmaceutical composition has low cytotoxicity and high selective inhibition on EGFR, and can effectively inhibit EGFR drug-resistant mutase (such as T790M/L858R/C797S mutase) and proliferation of cell strains thereof, so that the pharmaceutical composition can be used for treating diseases caused by EGFR mutation.
The invention also claims application of the 2,4, 5-substituted pyrimidine compounds and the pharmaceutical compositions containing the 2,4, 5-substituted pyrimidine compounds in preparation of drugs for inhibiting EGFR tyrosine kinase activity or drugs for preventing and/or treating EGFR related diseases.
Further, the EGFR-related disease refers to cancer, diabetes, immune system diseases, neurodegenerative diseases, cardiovascular diseases, or diseases with acquired resistance during treatment with EGFR modulators.
Further, the disease with acquired resistance during treatment with the EGFR modulator refers to a disease caused by a T790 mutation encoded by EGFR exon 20, a disease caused by a T790 mutation comprising EGFR exon 20, or a disease caused by a C797S mutation.
Detailed Description
The principles and features of this invention are described below in conjunction with examples, which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
Definition of terms
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The term "substituted anilines" refers to 2-isopropylsulfonylaniline, 3-aminobenzonitrile, 3-aminonitrobenzene, 4-trifluoromethylaniline, 3-trifluoromethoxy aniline, 3-hydroxyaniline, 3-fluoro-4-chloroaniline, 3-methoxy-4, 6-dichloroaniline, 2-fluoro-4-bromoaniline, and 3-chloro-4-fluoroaniline.
Pharmaceutical composition
The term "active compound of the present invention" refers to a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, which has a significant EGFR inhibitory activity, and which has a higher inhibitory activity against EGFR, T790M and C797S drug-resistant mutations. The term "pharmaceutically acceptable salts" as used herein includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with organic or inorganic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acids include, but are not limited to, hydrochlorides, sulfates, hydrobromides, phosphates, nitric acid, and the like; organic acids include, but are not limited to, gluconate, maleate, succinate, tartrate, citrate, formate, benzoate trifluoroacetic acid, methanesulfonic acid, acetic acid, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases such as sodium, potassium, calcium, and the like. Including but not limited to salts with organic bases including ammonium, triethylamine, lysine, arginine, and the like. These salts can be prepared by methods known in the art.
The "solvate" referred to in the present invention means a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate out of a solvent or crystallize. For example, a complex with water is referred to as a "hydrate". Solvates of the compounds of formula (I) are within the scope of the invention.
The present invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups which are hydrolyzed under physiological conditions or released by enzymatic reactions to give the parent compound.
The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice specifications. The "therapeutically effective amount" of a compound to be administered will depend on, among other factors, the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
A "therapeutically effective amount" refers to an amount that produces a function or activity in a human or animal and is acceptable to the human or animal.
The therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof contained in the pharmaceutical composition or pharmaceutical composition of the present invention is preferably 0.1mg to 5g/kg (body weight).
Preparation method
The preparation of the compounds of formula (I) according to the invention is described in detail, but these embodiments do not limit the invention in any way. The compounds of the present invention may also be conveniently prepared by combining, optionally, the various synthetic procedures described in the specification or known in the art, such combinations being readily performed by those skilled in the art to which the invention pertains.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under a dry nitrogen atmosphere with continuous magnetic stirring, and the solvent is a dry solvent, unless otherwise specified.
Preparation of the example compounds:
example 1: preparation of 2, 5-dichloro-N- (2-isopropylsulfonylbenzene) -4-pyrimidinamine
Dissolving 2-amino-isopropylsulfonyl benzene (2g, 0.01mol) in 20m L DMF, cooling to 0 ℃ in ice bath, adding NaH (0.48g, 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2,4, 5-trichloropyrimidine (2.2g, 0.012mol), gradually returning to room temperature for reaction for 2h, pouring the reaction liquid into a large amount of ice water, separating out yellow solid, filtering, washing a filter cake with water for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate (5: 1), filtering, and drying to obtain 2.7g of white solid.
Example 2: preparation of 2-chloro-5-fluoro-N- (2-isopropylsulfonylbenzene) -4-pyrimidinamine
Dissolving 2-amino-isopropylsulfonyl benzene (2g, 0.01mol) in 20m L DMF, cooling to 0 ℃ in ice bath, adding NaH (0.48g, 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2, 4-dichloro-5-fluoropyrimidine (2.0g, 0.012mol), gradually returning to room temperature for reaction for 2h, pouring the reaction liquid into a large amount of ice water, separating out yellow solid, filtering, washing a filter cake with water for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate (6: 1), filtering, and drying to obtain 2.5g of white solid.
Example 3: preparation of 2, 5-dichloro-N- (2-dimethylphosphorylbenzene) -4-pyrimidinamine
Dissolving 2-aminodimethylphosphorylbenzene (1.7g, 0.01mol) in 15m L DMF, cooling to 0 ℃ in ice bath, adding NaH (0.48g, 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2,4, 5-trichloropyrimidine (2.0g, 0.012mol), gradually returning to room temperature for reaction for 2h, pouring the reaction solution into a large amount of ice water, separating out yellow solid, filtering, washing the filter cake with water for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate which is 5:1, filtering, and drying to obtain 1.6g of white solid.
Example 4: preparation of 2-chloro-5-fluoro-N- (2-dimethylphosphorylbenzene) -4-pyrimidinamine
Dissolving 2-aminodimethylphosphorylbenzene (1.7g, 0.01mol) in 15m L DMF, cooling to 0 ℃ under ice bath, adding NaH (0.48g, 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2, 4-dichloro-5-fluoropyrimidine (2.0g, 0.012mol), gradually returning to room temperature for reaction for 2h, pouring the reaction liquid into a large amount of ice water, separating out yellow solid, filtering, washing filter cake with water for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate which is 6:1, performing suction filtration, and drying to obtain 1.5g of white solid.
Example 5: preparation of 2-chloro-5-methyl-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine
Dissolving 2-fluoro-4-bromoaniline (1.9g and 0.01mol) in 15m L DMF, cooling to 0 ℃ in an ice bath, adding NaH (0.48g and 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2, 4-dichloro-5-methylpyrimidine (2.0g and 0.012mol), gradually returning to room temperature for reaction for 5h, pouring the reaction liquid into a large amount of ice water, separating out yellow solid, filtering, washing a filter cake for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate at a ratio of 6:1, performing suction filtration, and drying to obtain 1.9g of white solid.
Example 6: preparation of 2-chloro-5-cyano-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine
Dissolving 2-fluoro-4-bromoaniline (1.9g and 0.01mol) in 15m L DMF, cooling to 0 ℃ in an ice bath, adding NaH (0.48g and 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2, 4-dichloro-5-cyanopyrimidine (2.0g and 0.012mol), gradually returning to room temperature for reaction for 1.5h, pouring the reaction liquid into a large amount of ice water, separating out yellow solid, filtering, washing a filter cake for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate (6: 1), filtering, and drying to obtain 2.2g of white solid.
Example 7: preparation of 2-chloro-5-hydroxy-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine
Dissolving 2-fluoro-4-bromoaniline (1.9g and 0.01mol) in 15m L DMF, cooling to 0 ℃ in an ice bath, adding NaH (0.48g and 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2, 4-dichloro-5-hydroxypyrimidine (2.0g and 0.012mol), gradually returning to room temperature for reaction for 1.5h, pouring the reaction solution into a large amount of ice water, separating out yellow solid, filtering, washing a filter cake for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate (6: 1), filtering, and drying to obtain 1.8g of white solid.
Example 8: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (3-nitrophenyl) pyrimidinediamine
Dissolving 2, 5-dichloro-N- (2-isopropylsulfonylbenzene) -4-pyrimidinamine (3.5g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 3-aminonitrobenzene (1.7g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating for reflux reaction for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.6g of a product, and recrystallizing with ethanol to obtain 3.1g of the product.
Example 9: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (3-nitrophenyl) pyrimidinediamine
Dissolving 2-chloro-5-fluoro-N- (2-isopropylsulfonylbenzene) -4-pyrimidinamine (3.3g, 0.01mmol) in 1, 4-dioxane 20m L, sequentially adding 3-aminonitrobenzene (1.7g, 0.012mmol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.4g of product, and recrystallizing with ethanol to obtain 2.9g of product.
Example 10: preparation of 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2-chloro-5-fluoro-N- (2-dimethylphosphorylbenzene) -4-pyrimidinamine (3.0g, 0.01mmol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mmol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating up, refluxing for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.5g of product, and recrystallizing with ethanol to obtain 3.1g of product.
Example 11: preparation of 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2, 5-dichloro-N- (2-dimethylphosphorylbenzene) -4-pyrimidinamine (3.2g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.7g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.7g of product, and recrystallizing with ethanol to obtain 3.2g of product.
Example 12: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2, 5-dichloro-N- (2-isopropylsulfonylbenzene) -4-pyrimidinamine (3.5g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 4.2g of product, and recrystallizing with ethanol to obtain 3.7g of product.
Example 13: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-chloro-3-nitrophenyl) pyrimidinediamine
Dissolving 2, 5-dichloro-N- (2-isopropylsulfonylbenzene) -4-pyrimidinamine (3.5g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-chloro-3-aminonitrobenzene (2.1g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 4.5g of product, and recrystallizing with ethanol to obtain 3.8g of product.
Example 14: preparation of 2, 5-dichloro-N- (3-fluoro-4-chlorobenzene) -4-pyrimidinamine
Dissolving 3-fluoro-4-chloroaniline (1.7g and 0.01mol) in 15m L DMF, cooling to 0 ℃ in an ice bath, adding NaH (0.48g and 0.012mol) in batches, keeping the temperature for reaction for 30min, dropwise adding 2, 4-dichloro-5-methylpyrimidine (2.0g and 0.012mol), gradually returning to room temperature for reaction for 5h, pouring the reaction liquid into a large amount of ice water, separating out yellow solid, filtering, washing a filter cake for three times, drying, recrystallizing the obtained filter cake with petroleum ether and ethyl acetate at a ratio of 6:1, performing suction filtration, and drying to obtain 2.2g of white solid.
Example 15: preparation of 5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2, 5-dichloro-N- (3-fluoro-4-chlorobenzene) -4-pyrimidinamine (2.9g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.4g of a product, and recrystallizing with ethanol to obtain 2.8g of the product.
Example 16: preparation of 5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2, 5-dichloro-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine (3.4g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating up, refluxing and reacting for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.9g of product, and recrystallizing with ethanol to obtain 3.1g of product.
Example 17: preparation of 5-methyl-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2-chloro-5-methyl-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine (3.2g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying and desolventizing to obtain 3.6g of product, and recrystallizing with ethanol to obtain 2.7g of product.
Example 18: preparation of 5-cyano-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2-chloro-5-cyano-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine (3.3g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating and refluxing for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying and desolventizing to obtain 3.5g of product, and recrystallizing with ethanol to obtain 2.8g of product.
Example 19: preparation of 5-hydroxy-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine
Dissolving 2-chloro-5-hydroxy-N- (2-fluoro-4-bromobenzene) -4-pyrimidinamine (3.2g, 0.01mol) in 1, 4-dioxane 20m L, sequentially adding 2-fluoro-3-aminonitrobenzene (1.9g, 0.012mol) and concentrated hydrochloric acid (0.2g, 0.02mol), heating up, refluxing for 6h, cooling to room temperature, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain 3.3g of product, and recrystallizing with ethanol to obtain 2.4g of product.
Example 20: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (3-anilino) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (3-nitrobenzene) pyrimidinediamine (4.5g, 0.01mol) is dissolved in 30m L methanol, 0.4g palladium carbon is added to replace hydrogen, the reaction is carried out for 5h at 35 ℃, the filtration is carried out, and the filtrate is dried by spinning to obtain 3.6g of product.
Example 21: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-anilino) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine (4.7g, 0.01mol) was dissolved in 30m L methanol, 0.4g of palladium on carbon was added to displace hydrogen, the reaction was carried out at 35 ℃ for 5 hours, filtration was carried out, and the filtrate was spin-dried to obtain 3.7g of a product.
Example 22: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-chloro-3-aniline) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-chloro-3-nitrophenyl) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 30m L methanol, 0.4g of palladium on carbon was added to displace hydrogen, and the reaction was carried out at 35 ℃ for 5 hours, followed by filtration and spin-drying of the filtrate to obtain 3.9g of a product.
Example 23: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-anilino) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine (4.6g, 0.01mol) was dissolved in 30m L methanol, 0.4g of palladium on carbon was added to displace hydrogen, the reaction was carried out at 35 ℃ for 5 hours, filtration was carried out, and the filtrate was spin-dried to obtain 3.5g of a product.
Example 24: preparation of 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-anilino) pyrimidinediamine
5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine (4.4g, 0.01mol) was dissolved in 30m L methanol, 0.4g of palladium on carbon was added to displace hydrogen, and the reaction was carried out at 35 ℃ for 5 hours, followed by filtration and spin-drying of the filtrate to obtain 3.2g of a product.
Example 25: preparation of 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-anilino) pyrimidinediamine
5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-nitrophenyl) pyrimidinediamine (4.2g, 0.01mol) was dissolved in 30m L methanol, 0.4g of palladium on carbon was added to displace hydrogen, and the reaction was carried out at 35 ℃ for 5 hours, followed by filtration and spin-drying of the filtrate to obtain 3.2g of a product.
Example 26: preparation of 5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-phenylamine) pyrimidinediamine
5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrobenzene) pyrimidinediamine (4.5g, 0.01mol) is dissolved in 30m L methanol, 0.4g palladium carbon is added to replace hydrogen, the reaction is carried out for 5h at 35 ℃, the filtration is carried out, and the filtrate is dried by spinning to obtain 3.4g of product.
Example 27: preparation of 5-methyl-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-phenylamine) pyrimidinediamine
5-methyl-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrobenzene) pyrimidinediamine (4.3g, 0.01mol) is dissolved in 30m L methanol, 0.4g palladium carbon is added to replace hydrogen, the reaction is carried out for 5h at 35 ℃, the filtration is carried out, the filtrate is dried by spinning, and 3.4g of the product is obtained.
Example 28: preparation of 5-cyano-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-phenylamine) pyrimidinediamine
5-cyano-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-nitrobenzene) pyrimidinediamine (4.4g, 0.01mol) is dissolved in 30m L methanol, 0.4g palladium carbon is added to replace hydrogen, the reaction is carried out for 5h at 35 ℃, the filtration is carried out, and the filtrate is dried by spinning to obtain 3.2g of product.
Example 29: preparation of 5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-phenylamine) pyrimidinediamine
5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-nitrobenzene) pyrimidinediamine (4.1g, 0.01mol) is dissolved in 30m L methanol, 0.4g palladium carbon is added to replace hydrogen, the reaction is carried out for 5h at 35 ℃, the filtration is carried out, and the filtrate is dried by spinning to obtain 3.0g of product.
Example 30: preparation of 5-fluoro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-phenylamine) pyrimidinediamine
5-fluoro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-nitrobenzene) pyrimidinediamine (3.9g, 0.01mol) is dissolved in 30m L methanol, 0.4g palladium carbon is added to replace hydrogen, the reaction is carried out for 5h at 35 ℃, the filtration is carried out, and the filtrate is dried by spinning to obtain 2.8g of product.
Example 31: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine
Dissolving 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (4.4g and 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g and 0.012mol) and triethylamine (2.0g and 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 3.2 g.
Example 32: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine
Dissolving 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (4.2g and 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g and 0.012mol) and triethylamine (2.0g and 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 3.0 g.
Example 33: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-chloro-3-acrylamido-benzene) pyrimidinediamine
Dissolving 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-chloro-3-aniline) pyrimidinediamine (4.5g, 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g, 0.012mol) and triethylamine (2.0g, 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 3.4 g.
Example 34: preparation of 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine
Dissolving 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (4.0g and 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g and 0.012mol) and triethylamine (2.0g and 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 2.3g of a product.
Example 35: preparation of 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido benzene) pyrimidinediamine
Dissolving 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (3.9g and 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g and 0.012mol) and triethylamine (2.0g and 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 2.1g of a product.
Example 36: preparation of 5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-acrylamido benzene) pyrimidinediamine
Dissolving 5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (4.3g, 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g, 0.012mol) and triethylamine (2.0g, 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 2.6g of a product.
Example 37: preparation of 5-fluoro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-acrylamido benzene) pyrimidinediamine
Dissolving 5-fluoro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (4.2g, 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g, 0.012mol) and triethylamine (2.0g, 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 2.4g of a product.
Example 38: preparation of 5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine
Dissolving 5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (3.8g and 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g and 0.012mol) and triethylamine (2.0g and 0.02mol) under ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.9g of a product.
Example 39: preparation of 5-fluoro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine
Dissolving 5-fluoro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-aniline) pyrimidinediamine (3.7g and 0.01mol) in 30m L dichloromethane, sequentially adding acryloyl chloride (1.0g and 0.012mol) and triethylamine (2.0g and 0.02mol) in an ice bath, reacting for 3h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.9g of a product.
Example 40: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-N-dimethylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.9g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-N-dimethylpiperidine (1.5g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spinning dry the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product of 3.7 g.
Example 41: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-piperidyl piperidine) -3-acrylamido benzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamidobenzene) pyrimidinediamine (4.9g, 0.01mol) was dissolved in 40m L tetrahydrofuran,adding K in sequence2CO3(3.5g, 0.025mol) and 4-piperidyl piperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 3.5 g.
Example 42: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4 '4' -dimethyl-1-methylethylenediamine) -3-acrylamidobenzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.9g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and N-methyl-N 'N' -dimethylethylenediamine (1.2g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.5 g.
Example 43: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-methylpiperazine) -3-acrylamidobenzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.9g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-methylpiperazine (1.2g, 0.012mol), heating to 90 ℃ for reaction for 8h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.3 g.
Example 44: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-morpholinylpiperidine) -3-acrylamido-benzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.9g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-morpholinylpiperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.2 g.
Example 45: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-acetylpiperazine) -3-acrylamido benzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.9g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-acetyl piperazine (1.5g, 0.012mol), heating to 90 ℃ for reaction for 8h, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.3 g.
Example 46: preparation of 5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-N cyclohexylamine) -3-acrylamido benzene) pyrimidinediamine
5-chloro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-chloro-3-acrylamido-benzene) pyrimidinediamine (5.0g, 0.01mol) was dissolved in a mixed solvent of 40m L1, 4-dioxane and water, and K was sequentially added thereto2CO3(3.5g, 0.025mol) and 4-boric acid cyclohexylamine (1.5g, 0.012mol), tetrakistriphenylphosphine palladium dichloride (0.5g)0.5g, displacing nitrogen, heating to 90 ℃ for reaction for 8h, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.0 g.
Example 47: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-piperidyl piperidine) -3-acrylamido benzene) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-piperidyl piperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 3.2 g.
Example 48: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-methylpiperazine) -3-acrylamido benzene) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.7g, 0.01mol) was dissolved in 40m L tetrahydrofuran and added successivelyInto K2CO3(3.5g, 0.025mol) and 4-methylpiperazine (1.2g, 0.012mol), heating to 90 ℃ for reaction for 8h, spin-drying the reaction solution, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 2.0g of a product.
Example 49: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-N-dimethylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-N-dimethylpiperidine (1.5g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spinning dry the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product of 3.2 g.
Example 50: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-acetylpiperazine) -3-acrylamido benzene) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-acetyl piperazine (1.5g, 0.012mol), heating to 90 ℃ for reaction for 8h, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.4 g.
Example 51: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-morpholinylpiperidine) -3-acrylamido-benzene) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-morpholinylpiperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.3 g.
Example 52: preparation of 5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4- (4-N-dimethylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-fluoro-4-N- (2-isopropylsulfonylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-N-dimethylpiperidine (1.5g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spinning dry the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product of 3.5 g.
Example 53: preparation of 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4- (4-piperidinylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.6g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-piperidyl piperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.9g of a product.
Example 54: preparation of 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4- (4-morpholinopiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.6g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-morpholinylpiperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.8g of a product.
Example 55: preparation of 5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-dimethylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-chloro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.6g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-dimethylpiperidine (1.5g, 0.012mol), and the temperature is raisedReacting at 90 ℃ for 8h, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.7g of a product.
Example 56: preparation of 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4- (4 '4' -dimethyl-1-methylethylenediamine) -3-acrylamidobenzene) pyrimidinediamine
5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.4g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and N-methyl-N 'N' -dimethylethylenediamine (1.2g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 1.5 g.
Example 57: preparation of 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-dimethylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.4g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-dimethylpiperidine (1.5g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.6g of a product.
Example 58: preparation of 5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4- (4-piperidinylpiperidine) -3-acrylamidobenzene) pyrimidinediamine
5-fluoro-4-N- (2-dimethylphosphorylbenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.4g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-piperidyl piperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.6g of a product.
Example 59: preparation of 5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4- (4-piperidyl piperidine) -3-acrylamido benzene) pyrimidinediamine
5-chloro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.8g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-piperidyl piperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.1 g.
Example 60: preparation of 5-fluoro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4- (4 '4' -dimethyl-1-methylethylenediamine) -3-acrylamido-benzene) pyrimidinediamine
5-fluoro-4-N- (2-fluoro-4-bromobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.6g, 0.01mol) was dissolved in 40m L tetrahydrofuran and K was added successively2CO3(3.5g, 0.025mol) and N-methyl-N 'N' -dimethylethylenediamine (1.2g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 2.0 g.
Example 61: preparation of 5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4- (4-piperidylpiperidine) -3-acrylamido-benzene) pyrimidinediamine
5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.3g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-piperidyl piperidine (2.0g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.9g of a product.
Example 62: preparation of 5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4- (4-morpholinylpiperidine) -3-acrylamido-benzene) pyrimidinediamine
5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.3g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and 4-morpholinylpiperidine (2.0g, 0.012mol), heating to 90 ℃ for 8h, spinning to dry the reaction solution, dissolving the residue in dichloromethane, adding water,extracting, merging organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain 1.8g of a product.
Example 63: preparation of 5-chloro-4-N- (2-fluoro-4-chlorobenzene) -2-N- (4- (4 '4' -dimethyl-1-methylethylenediamine) -3-acrylamido-benzene) pyrimidinediamine
5-chloro-4-N- (3-fluoro-4-chlorobenzene) -2-N- (4-fluoro-3-acrylamido-benzene) pyrimidinediamine (4.3g, 0.01mol) was dissolved in 40m L tetrahydrofuran, followed by addition of K2CO3(3.5g, 0.025mol) and N-methyl-N 'N' -dimethylethylenediamine (1.2g, 0.012mol), heating to 90 ℃ for reaction for 8 hours, spin-drying the reaction liquid, dissolving the residue in dichloromethane, adding water, extracting, combining organic phases, drying, desolventizing to obtain a crude product, and performing column chromatography to obtain a product 1.6 g.
In vitro inhibition of tumor cell proliferation Activity assay
Cells used in the laboratory in 5% CO2Culturing and passaging in a 37 ℃ incubator, culturing with RMPI 1640 culture solution containing 10% fetal calf serum, 100U/m L penicillin and 100 mug/m L streptomycin, digesting and passaging with 0.25% pancreatin-EDTA, passaging twice per week, digesting cells in logarithmic growth phase with pancreatin, preparing cell suspension with cell concentration of 10000/m L, inoculating the cells into a 96-well plate according to 1000 cells/well, adding fresh culture medium containing equal gradient concentration of drugs and corresponding solvent control in the next day, adding 100 mug L in each well, setting 6-8 dose groups in each drug administration group, setting at least three parallel wells in each group, continuing culturing for 72h at 37 ℃, discarding supernatant, adding fresh culture medium containing 100 mug L and containing 0.5mg/m L MTT in each well, continuing culturing for 4h, discarding supernatant, adding 200 mug L DMSO-purple MTT precipitate in each well, mixing with a shaker, measuring light with reference wavelength of 450nM in an enzyme-labeling instrument, processing with wavelength of 570nM, calculating effective ratio of tumor cell inhibition (OD) by using the contrast of the drugs and serum-free control of the tumor cells, and calculating the effective ratio of the drug for the tumor cell50。
Inhibition (%) ═ OD control-OD dosing)/OD control × 100%
The half Inhibitory Concentration (IC) of the 2,4, 5-substituted pyrimidines was calculated based on their growth inhibition on these cells50) Values, as shown in table 1.
Table 1 shows the activity of the compounds in inhibiting tumor cells
Figure BDA0001953107110000251
Figure BDA0001953107110000261
Figure BDA0001953107110000271
The result shows that (see table 2), the novel 2,4, 5-substituted pyrimidine compounds can obviously inhibit selective proliferation of BaF3-EGFR L858R/T790M/C797S tool cells, and the inhibition activity of most compounds on BaF3-EGFR L858R/T790M/C797S tool cells is better than that of positive control drugs.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (8)

1. A2, 4, 5-substituted pyrimidine compound, which is characterized by having a molecular structure shown as a formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule thereof:
Figure FDA0001953107100000011
wherein R is1One selected from hydrogen, deuterium, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, cyano, methyl and hydroxyl;
R2selected from hydrogen, fluorine, chlorine, cyano or any of the following structures:
Figure FDA0001953107100000012
Figure FDA0001953107100000013
represents a site of chemical bonding;
g is selected from any one of 2-isopropylsulfonylbenzene, 2-dimethyloxyphosphatene, 3-cyanobenzene, 3-chloro-4-fluorobenzene, 2-fluoro-4-bromobenzene, 3-chloro-4-fluorotoluene and 3-methylpyrazole.
2. A 2,4, 5-substituted pyrimidine compound according to claim 1, having the molecular structure:
Figure FDA0001953107100000021
Figure FDA0001953107100000031
Figure FDA0001953107100000041
3. the process for preparing 2,4, 5-substituted pyrimidines as claimed in claim 1 or 2, characterized by the following synthetic route:
Figure FDA0001953107100000051
4. a pharmaceutical composition comprising a pharmaceutically effective amount of a 2,4, 5-substituted pyrimidine compound according to claim 1 or 2 and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4, further comprising a mixture of one or more of gefitinib, erlotinib, afatinib, dacomitinib, imatinib, oxitinib, lapatinib, cetuximab, trastuzumab, zalutumumab, pertuzumab tanospiramycin, and apramycin.
6. Use of the 2,4, 5-substituted pyrimidine compound of claim 1 or 2 and the pharmaceutical composition of claim 4 or 5 for the preparation of a medicament for inhibiting the tyrosine kinase activity of EGFR or for the preparation of a medicament for the prevention and/or treatment of EGFR-related diseases.
7. The use of claim 6, wherein the EGFR-related disease is cancer, diabetes, immune system disease, neurodegenerative disease, cardiovascular disease, or disease that has acquired resistance during treatment with an EGFR modulator.
8. The use of claim 7, wherein the disease with acquired resistance during treatment with the EGFR modulator is a disease caused by a T790 mutation encoded by exon 20 of EGFR, or a disease caused by a C797S mutation.
CN201910057786.3A 2019-01-22 2019-01-22 2,4, 5-substituted pyrimidine compound and preparation method and application thereof Pending CN111454218A (en)

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